Scientific Advisory Committee on Medical Devices Used in the Cardiovascular System: Meetings

Core committee members: Eric Cohen (Chair), Chris Feindel, Alan Menkis, Jillianne Code, Christopher Cheung

Regrets: John Ducas, Marino Labinaz,  Joaquim Miró, John G. Webb, Raymond Yee, Anita Asgar, Shelley Zieroth, Brent Mitchell

Guest speakers: Kongteng Tan, Sudhir Nagpal, and Atul Verma

Health Canada staff: Bruce Randall, Kevin Day, Ian Aldous, Ben Elliott, Chris Schmidt, Geoffrey Green, Jianming Hao, Karen Kennedy, Lanyi Xu, Roy Masters, Mark Korchinski, Karen Fletcher, Liam Bowes, Fatiha Chellat, Joseph Chiu, Ellen Fraser, Patrizia Farina, Niraj Patel, Bisi Lawuyi, Dominique Lacombe

Opening remarks (Bruce Randall)

The Director General of the Medical Devices Directorate welcomed attendees to the SAC-MDUCS meeting. Mr. Randall identified the 2 meeting topics: Thrombectomy and atherectomy issues; and concerns regarding Pulse Field Ablation Systems and their increased stroke risks. He provided standard housekeeping remarks, and reiterated that the Summary of Proceedings will be posted on the Health Canada website.

Review of the agenda and declaration of affiliations and interests (Eric Cohen)

The Chair thanked and welcomed the meeting attendees. He requested declarations of new or potential conflicts of interest related to the topics presented. There were none that restricted SAC-MDUCS members from participating.

Summary of previous advice used (Kevin Day)

Mr. Day described the committee’s recommendations on topics from previous meetings:

• Heart Failure with preserved Ejection Fraction (Dr. S Zieroth: June 2024)
• Extracorporeal Membrane Oxygenation (ECMO) (Dr. E Fan: November 2022)
• Pulse Field Ablation Systems (Dr. A Verma November 2023)
• Drug Coated Balloons (Dr. Bertrand: December 2010; HC: January 2024)

He explained how Health Canada applied the recommendations to demonstrate the significant impact these discussions have on the regulation of medical devices in Canada. 

Presentation #1: Peripheral Arterial Disease, part 1 (Kongteng Tan, University Health Network)

Dr. Tan described the disease and clinical course of Peripheral Arterial Disease (PAD), and highlighted the range of symptomology from claudication associated with focal disease to critical limb threatening ischemia (CLTI) associated with diffuse disease. Endovascular treatment for claudication was described as controversial and generally indicated after first line treatments (i.e. exercise, medication) have failed. In Canada, most PAD interventions involve patients with CLTI.  There is a lot of variability in terms of how clinicians are treating CLTI, in part because there is a lack of good quality clinical data.

An overview of atherectomy devices and PAD treatment modalities, including surgical bypass, was presented. It was noted that treatment approaches and device choices vary across centers and operators (e.g. drug coated balloons (DCB), bare metal stents (BMS), drug eluting stents (DES), intravascular lithotripsy (IVL), stent-grafts, and atherectomy). Dr Tan emphasized that POBA remains the standard of care for simple PAD (i.e. short non-calcified focal lesions), and is needed for post-treatment dilatation regardless of other device interventions used. Calcified lesions are treated with stents or stent-graft devices, and in some cases are preceded by IVL.  Cutting balloons and scoring balloons are also used for calcified lesions.  In advanced disease, including CLTI, DCB and DES may be placed in dilatation resistant lesions. Dr. Tan highlighted that there is a move away from implants due to high incidence rates of restenosis, fractures and the impact on future interventions, with the exception of short below-the-knee lesions, where the use of a scaffold has demonstrated early clinical benefit.

During discussions, Health Canada asked about the indications for stent/BMS use. Dr. Tan indicated that stents are used when necessary, such as in cases of vessel rupture following angioplasty and he estimated that approximately 25% of cases require stenting. Dr. Nagpal added that stenting was preferable for longer lesions. Atherectomy for in-stent restenosis (ISR) was described as operator- and lesion-dependant, with device performance dependant on the operator. Regarding clinical data collection, Dr. Tan reiterated the substantial challenges with collecting clinical data, but indicated that RCT or registry data from the first 200 patients treated with a new technology could yield a great deal of information.

When asked to comment on recent evidence showing divergent outcomes between surgical and endovascular approaches (e.g. BEST-CLI vs. BASIL-2 studies), Dr. Tan noted that evolving treatment strategies and the frequent use of multiple devices within one procedure contribute to challenges in conducting high-quality clinical trials. Current intravascular trends: avoid metal unless needed for dissections or rupture; vessel preparation with specialty balloons/atherectomy is important to reduce the incidence of dissection, achieve better luminal gain and better drug delivery; the use of intra-vascular ultrasound (IVUS) for improved detection of dissection and thrombus.

Finally, Dr. Tan indicated that confidence in single-arm clinical studies for PAD/CLTI is improved when the studies are multicenter trials, with adequate sample size (>100 patients) and comprehensive reporting of procedural success and clinical endpoints such as complications (dissection/perforation/occlusion/embolization), amputation rate, Rutherford score improvement, target lesion patency and reintervention rates. While Dr. Tan believes that randomized control trials are needed to properly assess PAD technologies, their conduct is challenged by the large number of devices available and used to treat PAD; the large spectrum of clinical severity from claudication to gangrene; the substantial range of anatomical severity; and the complexity and heterogeneity of the patient populations. Dr. Tan indicated that important clinically relevant endpoints to assess PAD technology effectiveness include amputation rate, clinically driven intervention rate (bypass or endovascular), mortality rate and changes in Rutherford classification, with improvement in Rutherford score representing the minimum threshold for a clinically significant benefit.

Presentation #2: Peripheral Arterial Disease, part 2 (Sudhir Nagpal, The Ottawa Hospital)

Dr. Nagpal gave a comprehensive review of drug-eluting technology in peripheral vascular disease (PVD), focusing on the evolution of drug-coated balloons (DCBs) and drug-eluting stents (DESs), their mechanisms and supporting clinical evidence. He noted that drug-eluting technology in the PVD space primarily involves paclitaxel, an anti-proliferative medication delivered via balloons or stents.

Early landmark trials (Thunder and FEM pack, 2007–2008), demonstrated reduced reintervention rates with drug-eluting balloons compared to plain old balloon angioplasty (POBA). The Zilver PTX trial, and subsequent registry data from Japan, influenced clinical practice, leading to the adoption of DESs as first-line therapy in selected PVD conditions. Concerns raised in the 2018 Katsanos meta-analysis regarding an increased all-cause long-term mortality with paclitaxel-coated devices led to safety notices from the FDA and Health Canada in 2019.  These notices have since been updated and restrictions reduced.

Dr. Nagpal reviewed subsequent large-scale studies, including the SAFE-PAD trial and a meta-analysis by Dr. Gray (Lancet, 2023), both of which found no significant mortality difference between drug-coated and non-drug-coated devices up to nine years. The SWEDEPAD trials from Sweden provided mixed results, with SWEDEPAD 2 showing a five-year signal of increased mortality in the paclitaxel-coated device group for patients with claudication. SWEDEPAD 2 also did not show a quality of life or reintervention benefit in these same patients when treated with drug-coated devices.  In SWEDEPAD 1, although target vessel reinterventions were reduced in the drug-coated group during the first year, this difference was not sustained in further follow-up and time to ipsilateral above-ankle amputation was not different.  That said, there was no difference in all-cause mortality observed. Dr. Nagpal suggested the various results do not support use of paclitaxel devices for routine treatment of claudication, but that these devices may still have a role in select cases based on individualized decisions and complex lesions with restenosis, ISR, long lesions, or high-risk anatomy.  In these more challenging anatomies, newer techniques are being explored with approaches such as  atherectomy followed by DCB. He suggested that assessment should not be limited to mortality outcomes but should also determine whether meaningful clinical benefit is being achieved, as this appears to diminish over time. Overall, the data support selective and judicious use of paclitaxel-coated devices in patients with claudication rather than routine adoption in clinical practice.

Clinical data for Critical Limb Threatening Ischemia (CLTI) patients suggests that the benefits of DCBs are limited to the early post-procedural period, with early benefits limited to improvements in patency and reduced reinterventions, which equalize within 6-12 months and comparative benefits are rarely observed at 5 years relative to POBA. From a safety perspective in SWEDEPAD 1, there was no mortality signal in CLTI patients. Dr. Nagpal explained that early clinical benefits can be a real advantage for select patients, particularly working individuals or in situations where short-term wound healing, pain reduction, or lower procedural risk is beneficial. 

Although there is some uncertainty regarding safety and efficacy in recent PAD clinical trial results, many previous RCTs and meta-analyses have demonstrated clinical benefit without a clear mortality signal. Therefore, requiring large RCTs to support licensing of new devices may preclude patient access to a technology that could significantly improve short-term quality of life in select populations. Dr. Nagpal states that smaller randomized trials (RCT) using well-developed historical controls may be appropriate. He expressed that, although single-arm studies (<300 patients) may also provide supportive clinical evidence, they cannot replace RCTs. For smaller RCTs, the committee noted that other methods, such as propensity score matching or Bayesian borrowing, can be used for the control arm to increase numbers and to obtain statistical power. Overall, while DCB early benefits do have clinical value in some patient populations, there continues to be a need for robust long-term safety and effectiveness evidence.

In response to questions regarding Sirolimus DCBs, Dr. Nagpal compared paclitaxel (cytotoxic) and sirolimus (cytostatic) drug-coated devices, noting that sirolimus has a higher safety margin and a different mechanism of action, where uptake of sirolimus is not as rapid. Given the large experience of use of Sirolimus in coronary vessels, Sirolimus is likely as safe as paclitaxel in PVD but effectiveness is less predictable, and this would need to be investigated in long-term studies.

In discussing absorbable scaffolds, it was acknowledged that there is a lack of long-term data and that there remains a need to confirm safety and effectiveness in the PVD population.  Although early data from the Esprit trial is promising, data is limited to less complex lesions, relatively small patient populations, and study design issues such as differences in anticoagulation therapies given in different arms make the data difficult to interpret. Everolimus coated stents are frequently used in cardiac stenting, but their use in the PVD space must be confirmed. Concerns were raised about the ability to perform bypass surgery after scaffold resorption and overall uncertainty regarding the clinical benefits of these newer technologies.

The discussion after the presentation focussed on the following points:

• How recent clinical evidence is influencing medical practice for drug-eluting balloons and stents, post-procedure medication protocols, and the assessment of outcomes in a heterogeneous population.
• From a regulatory perspective, Health Canada's approach to data requirements for device licensing, including the need to balance timely access with long-term safety and effectiveness data. Health Canada highlighted that one-year follow-up data are generally required for device licensing, while requirements for longer-term data are challenging in a pre-market space.
• The increased scrutiny of clinical effectiveness, with the recognition that earlier industry-sponsored studies may have shown benefit but did not use relevant endpoints like limb salvage and wound healing, and that recent trials do not clearly show benefit at 1-year.
• Reflections on the evolution of clinical trial evidence, the potential for early trials to overestimate benefits, and the challenges in identifying causes of increased mortality in recent studies. Several hypotheses were discussed regarding observed mortality signals, however the underlying causes remain uncertain.

Presentation #3: Level of concern regarding PFA systems and increased stroke risks
(Atul Verma, McGill University Health Center)

Issue #1: Hemolysis

Hemolysis observed with Pulse Field Ablation (PFA) systems was described by Dr. Verma as a device-specific phenomenon related primarily to catheter design (e.g. shape, size, and number of exposed and active electrodes) and the exposure of blood to excess electrical field (field not focused uniquely on the target tissue). Design features that increase hemolysis include multiple simultaneously activated electrodes, and exposed electrodes on both sides of the catheter. Design strategies that help minimize hemolysis include a relatively small electrode surface area, limiting simultaneous electrode activation, and shieling non-target-facing electrodes.

Hemolysis was originally detected with PFA when an increase in serum creatinine was observed which resulted in kidney injury. Free plasma hemoglobin released during hemolysis is toxic to renal tubules, and contributes to coagulopathy (potentially producing platelet mediated clots and subsequent stroke) , nitric oxide depletion and vasoconstriction. Dr. Verma compared post-procedural free plasma hemoglobin levels across four commercially available PFA catheters to highlight that hemolysis severity differs largely between systems.  He highlighted the important role of catheter design, the number of active electrodes, and how exposed the blood is to electric fields and excess heat generated from the electrodes. Dr. Verma noted that boluses of fluid have been proposed as a mitigating treatment and although they are effective at reducing hemolysis-related damage, they cause other issues that then need to be addressed.

Issue #2: Heat

The second factor that can lead to PFA treatment-related complications, especially stroke/TIA, is the thermal profile of the catheter.  Although PFA is intended to create lesions via a non-thermal mechanism, clinically relevant heat generation may occur depending on catheter design and energy delivery burst pattern. Dr. Verma noted that tissue damage typically occurs with sustained temperature rises over 50 degrees for over 30 seconds. He indicated that avoidance of heat stacking, applying burst energy patterns, and irrigation around the electrodes can control and mitigate thermal risk.  Dr. Verma noted that a well-designed PFA catheter system should not rely on high rates of irrigation, which can cause clinical problems that will need to be addressed.

Electrode edge shape plays a significant role in the thermal profile, known as edge effect heating, with flat or sharp outer electrode edges producing localized heating. Rounding these edges can mitigate this effect. Covering sharp edges has also been attempted, but this can result in melting of the covering polyurethane. Char has been observed with PFA systems designed with sharp electrode edges and Dr. Verma suggests that this is likely a significant contributor to the higher-than-expected stroke and TIA rates observed with these catheters. For one such catheter, sharp and exposed edges produced edge effect heating in excess of 80°C .  Excessive heat can also cause microbubble formation during PFA application, further increasing procedural stroke risk.

Issue #3: Vasospasm

Coronary vasospasm has been observed with PFA application. Vasoconstriction is observed when PFA is used near the cavotricuspid and mitral isthmuses. While intravenous nitroglycerin may mitigate the risk of vasospasm, large doses are required and nitroglycerin is not always effective. Avoidance of PFA in those particular areas was suggested as a preferable mitigation strategy. 

Chronic coronary changes can occur after vasospasm and are also observed with radiofrequency and cryothermy ablation. Dr. Verma noted that he is less concerned with these changes than with vasospasm, but acknowledged that the level of concern varies amongst clinicians. Dr. Cohen echoed Dr. Verma’s concerns about vasospasm, highlighting that nitroglycerin treatment is not always effective.

Labeling warnings against PFA treatment in sensitive areas such as the cavotricuspid and mitral isthmuses were considered appropriate rather than contraindications. It was acknowledged that some physicians might disagree with labeling changes as nitroglycerin treatment is possible and might soon be optimized in combination with other therapies (e.g. calcium channel blockers or Lidocaine) to mitigate the risk of vasospasm. It was noted that epicardial ablation using PFA right on top of the coronary arteries does not appear to cause vasospasm, possibly due to the presence of electrically insulative fat.

The discussion after the presentation focussed on the following:

Regarding clinical evidence requirements to support licensing of new PFA systems, Dr. Verma expressed that randomized trials are unable to identify incidences of rare complications. Randomized trials are best used for effectiveness comparisons between PFA systems. Single-arm trials are considered acceptable as long as there is more intensive monitoring.  As an example, the USA FDA is moving toward PFA trials that are shorter (8-months (including a 2 month blanking period) for iterative technologies, 12-months for new technologies), with the duration of AF recurrence endpoints increased to 6 mins (from 30 seconds) and AF burden metrics incorporated into the definition of success. The US Heart Rhythm Society will soon publish a PFA scientific document as well. Dr. Verma suggested that pre-clinical testing should be also be considered. The USA FDA will soon publish guidance including a set of mandated pre-clinical tests demonstrating PFA safety.  These are expected to include:

• Thermal Profile testing using a thigh prep, fibre optic temperature sensing at surface, 3mm, and 7mm depth
• Hemolysis testing using plasma free hemoglobin as a marker
• Vasospasm testing for proximity to sensitive areas

When discussing the possibility of mitigating hemolysis by adjusting the pulse form, Dr. Verma responded that the pulse form and catheter design are related and that hemolysis is largely related to catheter design. He highlighted that adjustments to the pulse form would need to be validated with some form of GLP pre-clinical testing and that this testing should be repeated for 1X, 2X, 4X and 8X typical treatment, to assess the safety profile and the tissue depth given that a small adjustment to the pulse form may significantly change the therapy effectiveness. It was noted that a new clinical trial would not be required by the FDA for an iterative change to the device but that such a change will require a new set of GLP studies.

Finally, Dr. Verma highlighted that despite the issues presented above, the overall incidence of adverse events is low and that PFA is still a safe technology. He expressed support for post-market monitoring through registries to capture rare adverse events (e.g. chronic vessel damage, late vasospasm), and highlighted that the USA FDA has historically mandated these.

When asked about PFA application in the ventricle, Dr. Verma responded that ventricular application of PFA and other modalities (such as RF) is different from atrial applications, comes with its own set of complexities, and is beyond the scope of this discussion.

Next steps, closing remarks and adjournment of meeting (Eric Cohen and Kevin Day)

The Chair thanked all participants and reminded everyone about respecting the confidential information that was presented during the meeting. Kevin Day acknowledged the thoughtfulness and the great input provided during the presentations and discussions. Health Canada will contact committee members regarding the date of the next meeting. 

Core committee members: Dr. Eric Cohen (Chair), Dr. Renzo Cecere, Dr. L. Brent Mitchell, Dr. Jillianne Code, Dr. Joaquim Miró, Dr. Alan Menkis, Dr. Marino Labinaz, Dr. Christopher Cheung, Dr. Christopher Feindel, Dr. Anita Asgar, Dr. John Ducas

Regrets: Dr. John G. Webb, Dr. Raymond Yee, Dr. Shelly Zieroth

Speakers: Dr. Renzo Cecere, Associate Professor of Surgery, McGill University

Surgical Director, Heart Failure & Thoracic Transplant Program Director, Mechanical Cardiac Assistant Program McGill University Health Centre; Dr. Anita Asgar (formerly) Interventional Cardiologist working at the Institut de Cardiologie de Montreal.

Health Canada staff: Elham Aghbashi, Ian Aldous, Marianne Ariganello, Liam Bowes, Chujian Chen, Kevin Day, Ben Elliott, Ruth Ewhrudjakpor, Monica Forero, Ian Glasgow, Geoffrey Green, Jianming Hao, Janet Hendry, Karen Kennedy, Mariana Klinovski, Mark Korchinski, Marc Lamoureux, Daniel Manor, Roy Masters, Miriam Ostroscki, Rohail Qureshi, Bruce Randall, Veronique Robichaud, Chris Schmidt, Peggy Seely, Hui Shen, Lanyi Xu.

Opening remarks (Bruce Randall)

Bruce Randall, Director General of the Medical Devices Directorate welcomed attendees to the SAC-MDUCS meeting, and described some organizational updates. Rosslynn-Miller Lee who was Director of the Bureau of Evaluation has accepted the Director General role of the Business Facilitation and Modernization Directorate and is replaced on an interim basis by, Marc Lamoureux. Roxanne Lewis joined the directorate as Director of Bureau of Investigational Testing, Special Access and Post-Market Surveillance. He introduced the meeting topics and highlighted that the topic related to differential cardiovascular device outcomes for female vs male patients is also associated with broader Health Canada initiatives focussed on gender and sex-based analyses within both drug and medical device contexts, which are intended to improve the quality of disaggregated data. He also welcomed Dr. Christopher Chung and Dr. Shelly Zieroth, who are joining the SAC MDUCS committee as full members.

Review of the agenda and declaration of affiliations and interests (Dr. Eric Cohen)

The Chair thanked and welcomed the meeting attendees. He reminded committee members and asked that they ensure their declarations of actual or potential conflicts of interest are disclosed and current. There were none that restricted SAC-MDUCS members from participating.

Summary of previous advice used and general considerations for the meeting (Kevin Day)

Mr. Day described how the committee’s recommendations on topics from previous meetings have been used in regulatory work and decision making:

• Heart Failure (HF) with preserved Ejection Fraction (HFpEF), June 2024
• Left Bundle Branch Area Pacing (LBBAP), June 2024
• Pulsed Field Ablation (PFA) Systems, November 2023
• Transcatheter Tricuspid Heart Valves (TTHV), November 2023
• ECMO lessons learned in pandemic and future use, November 2022

Mr. Day highlighted the importance of the input from clinical experts as it contributes to better quality regulatory decisions and to increased confidence in Health Canada regulatory decisions.

Presentation #1: Evolving issues with circulatory support (Dr. Renzo Cecere)

Dr. Cecere is a Heart Surgeon from Montreal with extensive experience in heart transplantation and mechanical circulatory support. He presented on the topic, Mechanical Circulatory Support (MCS): Expanding Access, Equity and Technology for Canada.

Dr. Cecere explained that MCS can be used across a spectrum of durations ranging from short (acute) or long (chronic) term applications. The need for MCS stems from a significant global burden of Heart Failure (HF), as well as the limited global availability of organs that is estimated at less than 5500 annually. In Canada, the HeartMate 3 (HM3) is the only ventricular assist device (VAD) currently licensed for long term use. The MOMENTUM 3 trial (2019) demonstrated reasonable performance of the HM3 with a 77.9% freedom from disabling stroke or pump replacement rate, and low pump thrombosis rate (1.1%) at two (2) years. Devices available outside of Canada include the Carmat Total Artificial Heart (TAH) and Syncardia TAH, which is an evolution of Jarvik TAH. He explained that long-term devices may be used as either a Bridge-to-Transplant (BTT) or a permanent “Destination” Therapy (DT), although patients often move between indications as clinical conditions change. Emerging long-term applications of MCS devices include treatment of congenital heart disease (i.e. single ventricle defects) and some cases of advanced pulmonary hypertension. Key challenges with long-term MCS use include infection (20-40%) that is often associated with exit site and drive-line components, pediatrics in which anatomic space limitations preclude use (although PediMag and Berlin EXCOR (MDL 78881) are alternatives) and bleeding risks are increased even with recommended anticoagulation limits.

MCS devices designed for short-term use include the Impella microaxial flow pump, and Extra Corporeal Mechanical Oxygenation (ECMO) systems. Short-term applications include cardiogenic shock following acute myocardial infarction (AMI) and the need for temporary stabilization following high-risk cardiac surgeries. The DANGERSHOCK trial showed significantly improved all-cause mortality rates at 180 days with Impella and standard of care vs. standard of care alone for cardiogenic shock in patients with ST elevated MI (STEMI): 45.8% vs 58.5% respectively. Dr. Cecere indicated that key challenges with short-term device use include vascular complications (e.g. 6-10% with Impella).

Dr. Cecere responded to Health Canada’s specific questions about long-term MCS use. He indicated that 200 to 300 MCS devices are annually implanted in Canada for long-term applications, and that usage in Europe and the U.S. was higher. He estimated that 60 to 70 % of implants are intended to bridge to transplant (BTT), while in 30 to 40% of patients devices represent a destination therapy (DT). In contrast, 60% of global MCS device implantation for long-term use is for DT. He indicated that MCS use has expanded beyond the treatment of end stage left ventricular HF for: congenital heart disease (structural heart defects), post-MI shock, restrictive cardiomyopathy (selective use e.g. amyloidosis), RV failure, and pulmonary hypertension. He indicated the one-year survival rate with the HM3 is comparable to heart transplantation, with a median device lifetime of seven (7) years, but acknowledged the risk-benefit must consider anticoagulant dependency, stroke, bleeding and infection risks.

He identified the following under-served patient populations: pediatric patients (small sized devices are required); rural patients (limited access outside major teaching hospitals); anti-coagulant intolerant patients (currently no device options without anticoagulation); and, simultaneous RV and LV failure. He identified device alternatives available outside of Canada, including the pulsatile Carmat Total Artificial Heart (TAH) available in Europe, and marketed with reduced clot risks. He also described devices currently under development: the Leviticus device with a wireless design that eliminates transcutaneous driveline for improved patient mobility and reduced infection risks, and the miniaturized,  non-pulsatile Jarvik Heart. Dr. Cecere highlighted the criticality of the HM3 for heart failure management, as it is currently the only licensed VAD in Canada, but acknowledged Health Canada’s Special Access Program (SAP) for non-licensed devices, potential use of the Impella and ECMO systems, as well as the need to actively promote heart transplantation.

Dr. Cecere responded to specific questions about short-term MCS use posed by Health Canada. Short-term applications include: cardiogenic shock (Impella and ECMO: AIRES Trial showed improved survival); high-risk percutaneous coronary intervention (PCI) (Impella: Protect II Trial showed reduced MACE); post-operative support (Tandem heart and ECMO: ECLS Registry showed improved survival with ECMO); decompensated heart failure (Impella and ECMO: INTERMACS registry showed improved 1-year survival); and, respiratory failure (ECMO: Improved survival demonstrated in COVID patients). Standard durations for short-term MCS support devices are: 2-7 days for intra-aortic balloon pump (IABP); up to 7 days and extended to 14 days off-label for the Impella; 3-14 days (combined cardiac and pulmonary failure) for the VA ECMO; 7-28 days for the VV ECMO; and, 7-14 days for the Tandem Heart. He explained that short-term MCS allows for time to assess the patient for recovery or to transition to long-term support either as BTT or DT.

He stressed that most short-term devices are unsuitable beyond 1-3 weeks and are not designed for pediatric use. In particular, Impella device use is associated with hemolysis and vascular injury at the access site, and ECMO devices are is associated with bleeding, infection and thromboembolism.

The Q&A session with committee members included the following topics:

• Post-cardiac surgery choice to use ECMO, even in futile cases
  • Dr. Cecere recommended that all options should be vetted, discussions should be had and choices should be made before surgery; he indicated that ECMO was often viable, but acknowledged the significant resource implications.
• Wireless ventricular support devices, and challenges with their use for life-saving interventions
  • Dr. Jillianne Code expressed her enthusiasm for wireless MCS devices as she expected those devices designs to dramatically increase quality of life (QoL).
  • Dr. Cecere explained that the power needed to drive a spinning pump was significant and transcutaneous power transfer could burn the skin; he suggested that improvements in the efficacy of transcutaneous transduction are needed.
• Guideline recommendations for use of destination therapy (DT).
  • Dr. Cecere explained the advanced technology incorporated into the HeartMate 3 has rendered it a competitor to heart transplantation. He emphasized that DT decisions should be patient and family centered, with consideration of organ availability. Guideline indications for DT are similar to heart transplantation, and LVAD implantation may also be used to ‘test’ therapy.
• Incorporation of AI into MCS devices.
  • Dr. Cecere indicated that he was not aware of AI incorporation into MCS devices yet, although he thought there would be enough data for machine learning, provided that algorithms are validated.
• DT vs. re-transplantation due to limited availability of organs and patients with increased responses to Panel Reactive Antibodies (PRA).
  • Dr. Cecere indicated DT was not an option as he was concerned about infection risk and RV viability in transplanted patients.

Presentation #2: Differential Cardiovascular Device Outcomes for Female vs Male Patients (Dr. Anita Asgar)

Mr. Day gave a brief introduction about differential sex-based outcomes. He highlighted potential sensitivities with such discussions, and indicated that biological sex based outcomes are different from gender-based outcomes. He conceded that the Health Canada meeting participants are not experts in sex and gender based issues and that currently there doesn’t exist agreed upon definitions or vocabulary for sex and gender based discussions. Mr. Day indicated that the discussions surrounding these topics will be mostly sex-based. He explained that the motivation behind this topic comes from several sources and previous SAC MDUCS discussions that revealed potential sex-based differences in which some outcomes were worst for female patients. As part of the government’s sex and gender based policy for a Sex and Gender-Based Analysis Plus (SGBA Plus) initiative, the cardiovascular division is looking to identify areas where outcomes from the use of cardiovascular devices differ between sexes. He indicated that sex-based outcomes represents a single aspect of SGBA Plus, but hopes it will progress our work and contribute to making good regulatory decisions.

Dr. Asgar acknowledged the challenges associated with the topic and began her presentation on, Differential Cardiovascular Device Outcomes for Female vs. Male Patients, which focused on sex-based differences in valvular heart disease, electrophysiology, and heart failure.

Dr. Asgar explained that valvular heart disease (VHD) is common in the aging North American population (2.5%) with mitral regurgitation (MR) and aortic stenosis (AS) representing the most commonly observed disease types, and mitral valve disease being the leading cause of severe VHD in North America. Degenerative heart disease is more common in North America, while rheumatic heart disease is more common in developing countries.

VHD prevalence is equal among males and females, but degenerative mitral valve disease including mitral valve (MV) prolapse tends to be more common in females. Dr. Asgar indicated that females tend to present with less severe mitral regurgitation (MR), but with increased leaflet thickening and anterior or bi-leaflet prolapse. Females also have a higher prevalence of MV calcification and rheumatic disease. She explained that these female-specific factors complicate routine MV repair or surgery. Females with severe MR undergoing MV surgery tend to present when older and with more comorbidities including atrial fibrillation (AF), renal insufficiency, and heart failure (HF). In addition, imaging to characterize MR severity, and LV dilatation in particular, is critical for MV intervention, but parameters are often not adjusted for body size.  Since females are generally smaller, if corrections are not made, LV dilatation may be missed or under-diagnosed. Moreover, existing guidelines, which are not sex-specific, do not correct or account for body size.

In patients with acute decompensated heart failure, moderate or severe MR is more common in females regardless of ejection fraction, and has been shown to be associated with increased mortality at one (1) year. Data describing outcomes after MV surgery show higher mortality and major adverse cardiac and cerebral events (MACCE), and worse QoL scores in females. Dr. Asgar suggested the timing of intervention may influence the outcomes.

Dr. Asgar shared that females also tend to present later with aortic stenosis (AS) than males and exhibit more advanced disease with respect to: increased frailty, high blood pressure, and are more likely to have concomitant mitral valve disease, which increases risk. She explained that while the degree of AS and hemodynamics may be similar, females exhibit different pathologic features: less AV calcification, more fibrosis and dense connective tissue, concentric LV remodelling in response to AS is more frequently observed as compared to eccentric remodelling in males, which results in small LV cavities and a higher prevalence of paradoxical low-flow/low-gradient aortic stenosis, which has been associated with higher mortality. According to data from a US database (2017), females are less likely to undergo surgical aortic valve replacement than males, tend to be older, and have higher in-hospital mortality and morbidity after surgical aortic valve replacement (SAVR). Females also had more vascular complications, and more blood transfusions compared to males.

Sex-based differences have also been reported for trans-catheter aortic valve replacement (TAVR) intervention. The PARTNER trial revealed higher stroke rates and vascular complications in female patients, while data from the Sapien 3 trail (PARTNER II S3 high risk cohort) did not report stroke differences, but did show more vascular complications that were mirrored in an analysis of registry data conducted by Dr. Asgar. She highlighted that the registry data also showed higher bleeding rates but lower rates of permanent pacemaker implantation (PPI).

Dr. Asgar highlighted that very few females are included in the majority of electrophysiology clinical trials (9-20% representation). This is particularly true in major implantable cardiac defibrillator (ICD) and ventricular tachycardia (VT) ablation trials. Females are also less likely to receive an ICD than males. As reported on the IC/ES website, females that did received an ICD were more likely to develop complications; the complication rate increased by 55% at one year as compared to males. These data are derived from a collaboration of 18 major cardiac centres in Ontario. A 2017 dataset that compared survival of females and males receiving any implantable rhythm interventional device showed better survival in females. Dr. Asgar also identified a selective benefit for left bundle branch (LBB) pacing (vs. bi-ventricular pacing) in males but not females, from small registry data. No significant differences in complications were observed.

A mortality difference was seen between males and females with atrial fibrillation (AF), with higher female mortality. Registry data related to left atrial appendage occlusion (LAAO) using the Watchman device revealed that in-hospital adverse events were more frequent for females. Similarly, the AMULET IDE showed a higher incidence of in-hospital adverse events seen in females with the Amulet device (largely attributable to major bleeding and pericardial effusion requiring intervention). No difference was apparent in the antithrombotic regimen between males and females. However, a European registry, EWOLUTION showed no difference in long-term safety and efficacy, but females had more pericardial effusions.

With respect to Heart Failure (HF) Dr. Asgar emphasized differences in drug doses, which are not adapted to either body size or to sex-specific differences. She suggested that female patients who are relatively smaller may be receiving larger relative doses and thereby a greater number of side-effects. She also described a common device-based HF intervention, cardiac resynchronization therapy (CRT), for which females seem to derive greater benefit than men, and at a lower QRS duration (130 ms in females vs. 140 ms in males). With respect to LVAD use in end-stage heart failure, data from the INTERMACS showed fewer females received a Left Ventricular Assist Device (LVAD) than males (3984 vs 14884), females were less likely to receive a heart transplant, and younger females exhibited lower survival and higher risk of stroke and major bleeding, even after multivariate adjustment.

The Q&A session with committee members included the following topics:

• Whether VHD trials should correct for patient size as one might expect females (generally smaller with smaller vessels) to experience more bleeding and vascular complications with TAVR and that survival would therefore be reduced
  • Dr. Asgar indicated that the data had not been corrected, and added that similar trends appear with surgical mitral valve repair (females have poorer outcomes) but not with trans-catheter or edge-to-edge repair.
  • Dr. Cohen suggested that females and relatively smaller ventricles may cause unique problems for SAVR and that non-sex-based dosing of perioperative medications and patient age (female patients often present older than male patients) are factors that may also contribute to the observed outcomes.
• Dosing of anti-coagulation drugs based on patient size
  • Dr. Asgar clarified that drug dosing in adults is standardized without considering body size; she suggested that may contribute to bleeding risk in females.
• When female patients do worse than males treated with cardiovascular medical devices
  • Dr. Asgar indicated that females are under-treated with almost all cardiovascular devices, tend to have more complications (often involving bleeding and vascular access complications), and are understudied, which renders the impact, not well understood.
• Device types/conditions in which sex-based physiological or anatomical differences are significant enough so that separate sex-based risk/benefit analyses should be required to support pre-market licensing decisions or inform post-market surveillance
  • Dr. Asgar highlighted the following device types: haemodynamic/circulatory support, heart failure devices (i.e. electrophysiology devices), LAA occlusion devices, and valvular interventions.
• Device types associated with clinically significant differences in outcomes that warrant sex-specific labelling (e.g. warnings, different indications for use, contraindications, sizing recommendations, clinical data summaries).
  • Dr. Asgar indicated the available data are not robust, which would make labelling recommendations difficult. She suggested that LAAO devices may include warnings for higher complication rates in females. She also suggested there might be a benefit in better understanding who would benefit from CRT and when, but that might be best left to clinical guidance.
• Magnitude of a sex-based difference in therapeutic outcomes would be clinically significant enough that pooled data would be insufficient to assess safety or effectiveness (pre- or post-market).
  • Dr. Asgar indicated that sex-based differences are not adequately understood, but thought maybe these data should be obligatory. She indicated that females are not small males, and this can only be understood by requiring representation of female participants in clinical trials.
• Subsequent committee discussions centered around the types of data and analyses needed to truly understand sex-based differences, which were thought to include: stratification by size; life-stage (i.e. pre- vs. post-menopausal); the presence of genetic factors (i.e. connective tissue disease).
• The difficulty in finding a balance between requiring manufacturers to provide more data and discouraging Canadian licensure of medical devices was also discussed with committee members underlining the need for regulators to incentivise the provision of better data and suggesting that some of this might be done through requiring post-market studies.

Next steps, closing remarks and adjournment of meeting (Dr. Eric Cohen)

The Chair reminded members to review minutes from the previous meetings and thanked the speakers and members for their contributions and adjourned the meeting.

Core committee members: Dr. Eric Cohen (Chair), Alan Menkis, Christopher Feindel, Jillianne Code, L. Brent Mitchell, Raymond Yee

Regrets: Anita Asgar, Joaquim Miró, John Ducas, John G. Webb, Marino Labinaz, Renzo Cecere

Guest speakers: Dr. Shelley Zieroth, Cardiologist, Director of SBH Heart Failure and Transplant Clinics; Dr. Christopher Cheung, Cardiologist & Cardiac Electrophysiologist, Sunnybrook Research Institute 

Observers: Chris Kamel

Health Canada staff: Alexandra Rozender, Ben Elliott, Bruce Randall, Chris Schmidt, Ellen Fraser, Geoffrey Green, Ian Aldous, Jennifer Mihill, Jianming Hao, Karen Kennedy, Kevin Day, Lanyi Xu, Ladan Rabiey Motmaen, Laurène Bakouche, Lynn Primeau, Mariana Klinovski, Marianne Ariganello, Maxime Tondreau, Monica Forero, Natalia Mavrinskaya, Panyada Phandanouvong, Patti-Ann Gladden, Rosslynn Miller-Lee, Roxanne Dube-Cyr, Roy Masters, Ruth Ewhrudjakpor, Suchit Ahuja

Opening remarks (Bruce Randall)

Bruce Randall, the Director General of the Medical Devices Directorate, welcomed attendees to the SAC-MDUCS meeting. He identified the 2 meeting topics: Heart Failure with preserved Ejection Fraction, and Left Bundle Branch Area Pacing (LBBAP). He provided standard protocol remarks, such as the drafting of the Summary of Proceedings and the importance of completing the security screening process. He also welcomed a new observer, Chris Kamel, who is representing Canada’s Drug Agency and replacing Gino De Angelis.

Review of the agenda and declaration of affiliations and interests (Dr. Eric Cohen)

The Chair thanked and welcomed the meeting attendees. He requested declarations of actual or potential conflicts of interest. There were none that restricted SAC-MDUCS members from participating.

Summary of previous advice used and general considerations for the meeting (Kevin Day)

Mr. Day described the committee’s recommendations on topics from previous meetings:

• Pulsed Field Ablation Systems (November 2023)
• Transcatheter Tricuspid Heart Valves (November 2022)
• Renal Denervation (October 2021)
• Left Atrial Appendage Occlusion Devices (April 2022)
• Drug Coated Balloons (March 2019, January 2020 and November 2023)
• His Bundle pacing (March 2019)

A discussion with committee members followed on the analyses of evaluating the safety and effectiveness of long-standing devices and potential actions taken by Health Canada. Mr. Day commented that the review of these types of devices is based on feedback received from the Canadian clinical community on devices not performing as expected. He also explained that the systematic review of these devices would be challenging due to the large number of medical devices licenced in Canada.

Presentation #1: Heart Failure with preserved Ejection Fraction (Dr. Shelley Zieroth)

Dr. Zieroth disclosed her affiliations and proceeded with her presentation on device therapy considerations in patients with Heart Failure with preserved Ejection Fraction (HFpEF) and Heart Failure with reduced Ejection Fraction (HFrEF).

Dr. Zieroth provided a comparison of the terminology on the Ejection Fraction (EF) classification of Heart Failure (HF). She explained the differences between a HF with  reduced, mildly reduced, preserved as well as with improved EF. She indicated that from a pharmacologic perspective, there are limited options with only SGLT2 (sodium-glucose cotransporter-2) inhibitors having a high level evidence recommendation for HFpEF patients while others pharmacological therapies have weaker recommendations.  For HFrEF, there are significantly more pharmaceutical options with four different classes of drugs having high level evidence recommendations for use. Dr. Zieroth also spoke on sex based differences and recent recommendations from the American College of Cardiology, and indicated that there is a superior survival in women with HFpEF even though the symptom burden is worse.

Dr. Zieroth presented a breakdown of device therapies being explored in HFpEF and provided a clinician perspective on this subject.

She presented data showing that Left Atrial Pressure (LAP) is a good indicator for heart failure. Data showed elevated left atrial pressure (> 25 mmHg) often preceded acute decompensated heart failure hospitalizations (ADHF). She indicated that reducing LAP earlier before the on-set of ADHF , which can be difficult to manage with drug therapies alone, has been shown to reduce death and hospitalizations in early clinical trials.

Dr. Zieroth presented a list of six investigational interatrial shunt devices, some of which are available in other regulatory jurisdictions, which typically aim to lower left atrial pressure in patients with HF.  She explained that they mostly work by creating a communication between the left atrium and the right atrium by piercing the interatrial septum, but that some other shunts create a communication between the left atrium and the coronary sinus.

Dr. Zieroth described various trials performed with different interatrial shunt devices.

The reduce LAP-HF I trial indicated that one device (Corvia Interatrial Shunt Device) initially used for HFmrEF and HFpEF patients, showed improvements in wedge pressure (PCWP) with exertion, with no major adverse cardiac events, but no significant changes in functional status or quality of life.

However, for the more recent RELIEVE-HF trial (V-Wave Ventura Interatrial Shunt) enrolling patients with both HFrEF and HFpEF, the results demonstrated different responses between the two stratified group.  Although overall, the trial was neutral for the primary effectiveness endpoint that included Death, LVAD/Heart transplant, and all HF hospitalization, the HFrEF patients had significantly improved outcomes with the shunt, and the HFpEF (including HFmrEF) experienced increased harms and adverse events with the shunt.

Dr. Zieroth spoke briefly about cardioMEMS PAP sensors, which has a significant potential to reduce heart failure hospitalizations across a continuum of ejection fraction. The CHAMPION trial showed that there is a significant reduction in heart failure hospitalization at six months by monitoring elevated pulmonary artery (PA) pressures in patients with HFpEF.

Dr. Zieroth also spoke on Cardiac Contractility Modulation (CCM) which has been shown to be safe. She briefly described how the device is implanted and provided information of the FIX-HF-5C study that was performed with this device in subjects with  left ventricular ejection fraction ≥25% and ≤45%. The study showed that CCM improves peak oxygen consumption (pVO2) (15.04 ml O₂/kg/min vs. 14.20 ml O₂/kg/min).  There was a greater benefit observed in patients with higher LVEF within this largely HFrEF population, which has prompted interest in studying the device in a HFpEF patient population.  She also shared information on the CCM-HFpEF pilot study led by Cecila Linde that was performed on patients with HFpEF. This pilot study showed improvements over time in the quality of life score (Kansas City Cardiomyopathy Questionnaire) as well as echocardiographic improvements in patients who received this therapy. She also briefly spoke on the AIM HIGHer (Assessment of Implantable CCM in the Heart Failure Group with Higher Ejection Fraction) ongoing Clinical Trial.

She also spoke on the mechanism of Baroreceptor Activation Therapy (BAT) in HF patients and associated ongoing trials. The Baroreflex Activation Therapy for Heart Failure (BeAT-HF) trial that studied patients with HFrEF demonstrated safety and feasibility with a reduction in N-terminal pro-B-type natriuretic peptide (NT-proBNP), and an improvement in six-minute walk tests and quality of life in patients who received the baroreceptor activation therapy. She noted that there are ongoing trials in HFpEF patients with hypertension that are showing a reduction in NT-proBNP and in blood pressure.

Dr. Zieroth also spoke on splanchnic nerve modulation, and indicated that increased sympathetic tone and splanchnic volume redistribution cause pulmonary congestion, which can be prevented by blocking splanchnic volume redistribution to the chest. She explained the procedure to block splanchnic volume redistribution to the chest. She also described a recently published paper in the European Journal of Heart failure from 2021 on the surgical ablation of the splanchnic nerve for the treatment of HFpEF, and stated that this technique is evolving to surgical procedures. She also briefly spoke on the pipeline of clinical trials, but indicated that splanchnic nerve modulation is not yet ready for general clinical use.

Dr. Zieroth also provided some information on the Carillon Mitral Contour System, tricuspid valve interventions and other valve repair interventions for the treatment of HF, CRT in HFpEF patients, Left Ventricular (LV) expanders, and Mechanical Circulatory support devices.  In general, there are no substantial results available for these investigational devices and/or interventions.  In some cases, no significant investigative work is on-going due to limited perceived benefits. From a clinical standpoint, it is not currently clear that LV expanders will have a significant role due to potential pericardial concerns and thrombosis risks.  The use of Mechanical Circulatory Support (MCS) devices for HFpEF patients is limited, although there are a few approaches that are still under development for HFpEF.

A discussion with the committee members followed on these topics, including:

• systolic and diastolic heart failures terminologies and their association with HFpEF
  • Dr. Zieroth indicated that systolic and diastolic dysfunction can coexist in patients, although patients with HFpEF typically have less systolic dysfunction
• the use of a shunt in the heart as opposed to using different medical devices
  • Dr. Zieroth commented that factors such as substances, sizes, and anchoring procedures influence the differences between devices.
• The importance of the findings from the RELIEVE-HF studies was emphasized
  • RCT trials are important as findings were unexpected
  • Harm caused by the shunt in LVEF > 40% should be considered in future investigations in this patient population
  • Benefit for patients with LVEF < 40% is also meaningful and worthy of further investigation
• It was noted by a committee member that during the delivery of MitraClip devices, an iatrogenic atrial septal defect (ASD) is created
  • It was questioned whether persistent ASDs may have contributed to the positive findings of the MitraClip studies, as the shunt may provide benefits to HFrEF patients
• the possibility of HFpEF being underdiagnosed, especially for those without access to an academic center
  • Dr.Zieroth agreed that HFpEF is underdiagnosed due to medical conditions that coexist and that mask the diagnosis and that increased access to natriuretic peptide testing is crucial for accurate diagnosis and prevention of heart failure
• the microvascular dysfunction as a possible cause of cardiac diastolic dysfunction and the need for potential treatments or diagnoses
  • Dr. Zieroth confirmed that microvascular dysfunction has been recognized as an important pathophysiology in the setting of HFpEF, and particularly in women. Although there are therapies that are considered for microvascular dysfunctions, there are no outcomes available for trials specific to patients with HFpEF
• objective data as a way to differentiate different phenotypes of HFpEF
  • Dr. Zieroth commented that there has been a lot of research looking at the phenotyping which could lead to other potential therapies
• lived experience perspective including quality of life and symptom burden
• It was noted that HFpEF clinical trials should include endpoints related to symptom burden in addition to mortality and other safety outcomes
  • Endpoints of HF Hospitalization and symptom burden (KCCQ) should be used
  • It was also noted that WIN ratios are becoming more common within pre-specified endpoints in clinical trials

Presentation #2: Left Bundle Branch Area Pacing (LBBAP) (Dr. Christopher Cheung)

Dr. Cheung presented on LBBAP.

Dr. Cheung first provided an introduction to LBBAP. He highlighted pacing induced cardiomyopathy, which can occur from right ventricular (RV) pacing at the apex that can reduce left ventricular ejection fraction (LVEF) in some patients, especially with a high burden of ventricular pacing. He noted that over the years, researchers have explored ways to improve physiological pacing through Cardiac Resynchronization Therapy (CRT) and Cardiac Physiologic Pacing (CPP) treatments, such as His Bundle Pacing (HBP) and LBBAP.  Dr. Cheung noted that compared to HBP, LBBAP can produce stable pacing thresholds, adequately sense R-wave amplitudes, and has a higher likelihood to correct LBBB by pacing more distal to the site of conduction block.  He showed results indicating that LBBAP allows for improved electromechanical coupling, thus facilitating more physiologic electrical and mechanical ventricular activation and stated that the left bundle branch area may be a more suitable site for pacing therapy than the RV apex.

Dr. Cheung provided an overview of the implantation technique for LBBAP, which positions the pacing lead into the interventricular septum approximately 15-20 mm below the Tricuspid Valve annulus. He also spoke on the tools for LBBAP.  He noted specialized sheaths are required, but are available from most manufacturers.  Small calibre leads are used, often with a fixed active helix (approximately 1.8 mm long) and lumenless (no stylet) designs, although some stylet-driven leads have been used. He concluded that part of the presentation confirming that in considering the lead implant technique:

• no formalized training is currently available for LBBAP.
• additional fluoroscopy is used compared to RV apical placement when delivering the lead into the septum
• indicators of successful LBBAP placement include short left ventricular activation time (LVAT) < 74-80 msec, long V6-V1 interpeak interval time (e.g. > 33-40 msec), and a shorter QRS complex duration.
• although selective LBBAP is preferred, even with septal LV or septal RV pacing (if the LBB is not captured), the resulting pacing and ventricular synchronization is likely better than with standard RV apical pacing.

Dr. Cheung moved on to speak on the success rate and safety profiles of LBBAP. He presented findings from the multicentre European MELOS (Multicenter European Left Bundle Branch Area Pacing Outcomes Study) study (2533 participants), showing that the rate of successful LBBAP implantation was 92.4%. The rate of LBBAP lead complications was 8.3%, which included acute perforation (3.7%), lead dislodgement (1.5%), and acute chest pain (1.0%); the rate of pacing device implantation complications was 3.43%.  He also spoke on LBBAP lead fracture and indicated that some studies have shown that leads can fracture at the implantation site. He also presented findings from the TECSPAM study that looked at explantation of HBP and LBBAP leads (341 patients) with a dwell time of 22+/- 26 months.  Results showed that the rate of complete procedural success was 99%.  Helix entrapment with lead breakage can occur, as can late lead perforation into the LV.  He also spoke on the safety of these leads when undergoing Magnetic Resonance Imaging (MRI) and indicated that he is not aware of any safety issues being reported, although patients should wait 4-6 weeks after implantation prior to an MRI.

Dr. Cheung moved on to speak on the evidence and guidelines for LBBAP. He shared a timeline of important studies that have shown good outcomes with LBBAP and provided a summary of these studies.  It was highlighted that most current evidence supporting the use of LBBAP is based on observational registries and retrospectives studies, with limited long-term data.  Although there are several RCTs on-going comparing LBBAP to conventional RV apical pacing and CRT, most of this data is not currently available. The initial case report on LBBAP implantation was in 2017.  He discussed an observational registry in patients with normal LVEF that found that patients with LBBAP implantation had better outcomes (mortality, HF hospitalization or device upgrade at 3 years), and a narrower paced QRS duration compared to patients with RV apical pacing.  Benefits in this registry were magnified for patient with high pacing burden (>40%).  In addition, he indicated that the LBBP-RESYNC RCT trial studied patients that were undergoing Cardiac Resynchronization Therapy (CRT) with either LBBAP or bi-ventricular pacing (BiVp), and results showed superior LVEF improvement, and comparable QRS narrowing. He also spoke about the SYNCHRONY trial that compared LBBAP and BiVp as initial CRT strategies. Results showed relative to BiVp, LBBAP reduced HF-hospitalizations, shortened QRS duration, and improved LVEF, with no significant difference in all-cause mortality or long-term complications.

Dr. Cheung also spoke on guidelines supporting LBBAP. He mentioned that Canadian guidelines are currently being updated, whereas the joint Heart Rhythm Society (HRS), Asia Pacific Heart Rhythm Society (APHRS), and Latin American Heart Rhythm Society (LAHRS) guidelines were updated in 2023. In these updated guidelines, he noted that for patients in bradycardia with substantial ventricular pacing (≥ 20% - 40%), CPP is reasonable to reduce the risk of pacing-induced cardiomyopathy.  Even for patients with less than substantial ventricular pacing (< 20%), CPP may be considered as an alternative to RVP. Further, CPP is recommended in some cases for systolic dysfunction with LBBB if effective CRT cannot be achieved with BiVp.  Weaker recommendations are also included for CPP as an alternative to CRT with BiV pacing in some situations. 

Dr. Cheung moved on to speak on other considerations for LBBAP. He suggested that in most cases, LBBAP is likely more desirable than HBP due to the simpler implant, the stability of the lead and low thresholds for capture, and the lack of far-field right atrial sensing. He also discussed concerns regarding interoperability with other pulse generator features, such as AV delay settings or automated optimization of thresholds.  Dr. Cheung noted that short AV intervals can be programmed to overcome native conduction (e.g. for CRT), and he did acknowledge that there may be more variability in thresholds for LBBAP systems, based on whether selective LBB capture vs. non-selective LBB capture, vs. LV septal capture is achieved. He highlighted considerations regarding co-existence of LBB pacing lead with CRT leads placed in the coronary sinus, and indicated that there is an interest in LBBAP optimized CRT in cases where LBBAP is insufficient in achieving QRS narrowing. In these cases, the addition of a Coronary Sinus (CS) lead can achieve resynchronization, which is currently only possible in cardiac resynchronization therapy pacemaker (CRT-P) devices, as there are not sufficient IS-1 connections in the current CRT-D devices. Dr. Cheung also spoke on whether new pacing settings are unique to LBBAP or if LBBAP can be supported with existing programming options, and confirmed that all pacemakers have unipolar pacing options that will allow for dedicated pacing from the tip and that bipolar cardiac resynchronization therapy defibrillator (CRT-D) devices have either unipolar pacing or functional unipolar pacing.  It was noted that with lead placement for LBBAP, defibrillation coils may not be positioned as needed within the heart, and future lead design changes may be required to accommodate ICD and CRT-D systems.

Dr. Cheung concluded his presentation stating that a study is ongoing on a novel small-diameter defibrillation lead, and early preliminary results have shown high defibrillation success and a low occurrence of lead-related major complications.  It was noted that this lead is currently being implanted in standard RV locations and that there is no information about the lead performance for physiologic pacing, but that a dedicated study of the lead in the conduction system is underway.

A discussion with the committee members followed on these topics, including:

• that follow up data about long term outcomes should be monitored for LBBAP
• the expectation that physiological pacing (and preferred LBBAP) may become the standard of care in the future
• the representation of women in LBBAP studies and the analysis based on sex; currently, no such specific data is available but it is an important area for future study.
• the risks associated with septal perforation, noting that the occurrence is rare and the severity is limited even when the lead perforates into the LV, the potential increased interference with tricuspid valve function of LBBAP leads that have a more significant bend compared to RV apical pacing leads
• the CRT responder rate and concerns when addressing a CRT non responder; it was acknowledged that, currently, there is not a lot of clinical data for this.
• It was noted that there is uncertainty about the impact of a different lead configuration in LBBAP vs. RVAP for the routing and placement of defibrillation coils.

Next steps, closing remarks and adjournment of meeting (Dr. Eric Cohen)

The Chair suggested that moving forward we should consider having 2 topics to allow in depth discussions following the presentations. He thanked the members for their contributions and closed the meeting.

Core committee members: Eric Cohen (Chair), Chris Feindel, Raymond Yee, Alan Menkis, Barry Rubin, Joaquim Miró, Marino Labinaz, Renzo Cecere, John Ducas

Regrets: Anita Asgar, Brent Mitchell, Jillianne Code, John Webb

Guest speakers: Dr. Atul Verma, Director, Division of Cardiology at McGill University Health Centre and Dr. Chris Cheung, Cardiologist & Cardiac Electrophysiologist, Sunnybrook Research Institute

Observers: Gino De Angelis, Yannick Auclair

Health Canada staff: Bruce Randall, Kevin Day, Chris Schmidt, Roy Masters, Karen Kennedy, Rosslynn Miller-Lee, Firdous Hadj-Moussa, Monica Forero, Irfan Manji, Laurène Bakouche, Ben Elliott, Geoffrey Green, Ellen Fraser, Lanyi Xu, Sally Prawdzik, Simardeep Dhindsa, Ian Aldous, Sabah Khan, Melanie Adams, Mark Korchinski, Seely Peggy, Mariana Klinovski, Patti-Ann Gladden, Andrea Adamson, Jessica Babawy, Emily Tran, Marianne Ariganello, Jianming Hao, Twinkle Masilamani, Daphne Chen, Imama Zafar, Luxmani Sanmugasuntharam, Jimmy Huynh

Welcome (Dr. Eric Cohen)

Dr. Eric Cohen welcomed attendees to the Scientific Advisory Committee on Medical Devices used in the Cardiovascular System (SAC-MDUCS) meeting. He introduced himself as the new chair of the committee and thanked Dr. John Ducas for his commitment as the previous chair. He handed the meeting over to Bruce Randall for his opening remarks.

Opening remarks and updates on committee governance (Bruce Randall)

Bruce Randall, as the new acting Director General of the Medical Devices Directorate, introduced himself. He thanked Dr. Eric Cohen for accepting the position of chair of the committee. He also expressed gratitude for Dr. Rubin’s long-standing commitment to the committee, as this would be his final SAC-MDUCS meeting.

Mr. Randall identified two meeting topics: pulsed field ablation and portable and home use devices in cardiovascular medicine. He added that Health Canada will provide a brief presentation on the committee's structure, governance, and values later in the proceedings. He then provided standard protocol remarks, such as the Summary of Proceedings and the importance of completing the security screening process.

Review of the agenda and declaration of affiliations and interests (Dr. Eric Cohen)

The Chair requested declarations of actual or potential conflicts of interest. There were none that restricted SAC-MDUCS members from participating. The Chair also indicated that some members were being contacted to update their security clearances.

Summary of previous advice used (Kevin Day)

Mr. Day described the committee’s recommendations on topics from previous meetings:

• Transcatheter tricuspid heart valves (November 2022)
• Patient reported outcomes in cardiovascular trials (November 2022)
• Renal denervation (October 2021)
• Leadless pacemakers (April 2022)
• Drug Coated Balloons (March 2019, and January 2020)

A discussion with committee members followed on Paclitaxel drug coated balloons (DCBs). The Committee confirmed that the fields of vascular surgery and peripheral vascular interventions are no longer concerned about the late-mortality signal associated with paclitaxel-coated devices; they believe the benefits of the devices outweigh the risks. The Committee agreed that the safety signal previously identified for Paclitaxel coated balloons used in the peripheral arteries above the knee does not warrant limiting the use of these devices. The Committee also agreed that Health Canada should no longer require specific warnings associated with a potential increase in all-cause mortality in labelling of DCBs. In addition, the Committee agreed that there is no further need for Health Canada to publish more about this issue. Finally, the Committee recommended that Health Canada contact Dr. Thomas Forbes, who previously presented at the March 2019 SAC-MDUCS meeting, to further endorse the expert opinion of the Committee.

Presentation provided by Health Canada on committee's structure, governance, and values (Sally Prawdzik and Kevin Day)

Sally Prawdzik, acting director of the Office of Policy and International Programs, presented on Health Canada’s regulatory mandate for health products and on the activities carried out by the Medical Devices Program. She described the types of pre-market submissions reviewed within the Medical Devices Directorate, such as the Investigational Testing Authorization, Special Access Program, and Medical Device Licences and COVID-19 Authorizations. Ms. Prawdzik also provided some background information on the SAC-MDUCS committee, its role, structure, and values.

Kevin Day, manager of the Cardiovascular Division, Bureau of Evaluation (BE), spoke to the role of Health Canada’s subject matter experts and BE responsibilities towards the SAC-MDUCS. Mr. Day described the value and benefits of the SAC-MDUCS and highlighted areas that were within the scope of the committee, and areas that were outside the scope of the committee. Follow-up questions were raised by committee members regarding the following topics:

• Monitoring Systems, regulated as medical devices by assessing the sensitivity and specificity of algorithms, data, and analysis as Class III or IV devices. The integration of patient monitoring and electronic records was also discussed;
• Artificial Intelligence (AI), potentially advising medical professionals and patients on next steps in care;
• Older devices and the liability associated with device failure or when devices are at an end of life; and Health Canada’s post-market approach to addressing safety signals and concerns through annual review requirements for licence holders and the request of additional data.

Presentation #1: pulsed field ablation (Dr. Atul Verma)

Dr. Verma presented on new pulsed field (PF) technologies used in cardiac ablation. He described thermal and earlier electric cardiac ablation techniques and the associated risks for patients with atrial fibrillation (AF). He also stated that the challenge in this area continues to be the generation of durable and transmural lesions. Following this, he provided information on the percutaneous cardiac Pulsed Field Ablation (PFA) process (wherein cell destruction occurs by predominantly programmed cell death or apoptosis). He explained the complexity of pulse “recipes” and the parameters that must be taken into consideration for their optimization, such as pulse magnitude and duration. He then provided a comparison of the parameters that can be changed on the pulse field generator and the expected effects of these.

He continued his presentation on PF pulses, preferred cell and tissue selectivity (and the reasons for this, e.g. fat tissue between myocardium and esophagus) and compared pre-clinical work and data on:

• Radiofrequency (RF) energy versus PFA, on phrenic nerves
• Radiofrequency Ablation (RFA) versus PFA and their chronic effects on porcine (pig) esophagus e.g. lack of pulmonary vein stenosis

Dr. Verma explained the differences between bipolar and monopolar catheters, their relative advantages and disadvantages, and presented data on incidental heating from PFA and the effects of contact force and lesion sizes. Moreover, Dr. Verma described the advantages of PFA as a potential replacement for other energy sources for AF ablation. He showed data to support the increased safety of PFA, increased efficiency of PFA (procedural time), and equal efficacy (success rates) for PFA vs thermal ablation. He also explored issues with the use of PFA, including:

• Musculo-skeletal recruitment,
• Profound vagal responses causing asystole,
• Coughing due to stimulation of J receptors in pulmonary veins,
• The variation of esophageal heating and incidental heat,
• Potential for problems like coronary vasospasm when used in the cavo-tricuspid/mitral isthmus,
• Improved conduction of PFA energy through scar tissue compared to thermal ablation,
• Large device sizes’ potential for mechanical intra-cardiac damage, and
• The challenge of “stunning” in determining when to stop ablating (methods being researched include use of unipolar EGMs and optical techniques).

Finally, Dr. Verma ended his presentation by mentioning that hybrid PFA/thermal system are also under investigation (though results are a few years away) and explaining why PFA is unlikely to be used for ventricular based ablation procedures in the near future as thicker ventricular tissue is not well suited to PFA ablation - especially bipolar systems, which generate shallower lesions than unipolar.

Discussions with the committee members followed on several topics, including some concluding statements:

• The safety of the intervention (overall, the safety profile seems better than thermal)
• The efficiency of the intervention (typically better than thermal, 40min PFA vs. 1.5-2h thermal ablation)
• The efficacy of the intervention (equivalent to thermal ablation – both freedom from AF and durability of effect – but important to keep in mind that these are first generation PFA systems with limited long-term clinical follow-up data),
• The relative merits of endpoints for AF trials, noting that the current standard is freedom from 30 seconds of atrial arrhythmia recurrence (e.g. 30 seconds or more of a sustained episode of AF, atrial flutter, or atrial tachycardia) over the follow-up period, although AF burden as well as quality of life measures have distinctive benefits.
  • It was further noted that there can be large differences between the reported endpoint outcomes – e.g. 50% decrease in freedom from AF recurrence can be the same as 99% decrease in AF burden. Practically though, AF burden is expensive to measure since it requires implantable loop recorders and therefore it is likely that freedom from 30s recurrence of AF will continue to be used in the near future,
• The difference in lesion depth between bipolar and unipolar systems (generally bipolar 2-3mm, unipolar 3-4mm).
• Assessing transmurality and assessing effectiveness of ablation (electrical endpoints won’t work; will need other methods)
• The learning curve when deploying this technology (depends on the catheter design – some are familiar, some aren’t. Typical comfort after about 5 cases)
• Whether randomized data was required to support licensure (consensus was that single arm studies against appropriate objective performance criteria and inclusion/exclusion criteria would be acceptable e.g. 2017 HRS Consensus statement)

Presentation #2: Portable and Home Use Devices in Cardiovascular Medicine (Dr. Christopher Cheung)

Dr. Cheung presented on heart rhythm devices and current studies on arrhythmia monitoring, through portable and home use devices.

He spoke on the existing devices used for cardiac rhythm assessment of different durations (Point-in-time, intermittent, and continuous/long-term) and described emerging equivalent portable devices. For instance, Dr. Cheung explored medical device wearables that measure irregular heart rates such as smartwatches. He presented study results that were performed on smartwatch devices, as well as discussed device limitations. He also presented study results that were performed on wristbands and smartwatch devices. These included studies intended to evaluate the feasibility of using these types of devices in a primary care environment for applications such as AF screening. Further, Dr. Cheung explored handheld electrocardiogram (ECG) monitoring devices and explained the mode of data transmission. Dr. Cheung communicated the challenges of these devices, especially on the accuracy of the results.

Dr. Cheung moved on to present case examples of how these devices can be used in the general population. He focused on:

• Screening for Atrial Fibrillation (AF) with handheld ECGs
• AF detection in hospital
• QT measurement (electrocardiographic parameter) and its interpretation

He also spoke to the accuracy of automated ECG interpretation of ECG recordings obtained with smartwatches to detect AF. He presented study results comparing these results with those obtained using a traditional ECG,  In some cases, study devices were able to achieve relatively high sensitivity and specificity among interpretable results, however, the number of uninterpretable recordings was quite high. In other cases, automated results showed poor sensitivity that improved substantially when over-read by a physician. 

Additionally, Dr. Cheung highlighted developing applications for wearable devices (such as smartwatches) in the diagnosis of additional arrhythmias and AF burden.

He commented on the direction of device development for portable ECG devices and discussed the risks associated with arrythmia detection technology, such as erroneous detection and missed diagnoses. Risks for patients with cardiac implantable electronic devices were also discussed following descriptions of a recent study that showed interference with and from smartwatches.

Dr. Cheung focused on other areas where the use of wearable technology has been explored. He presented study results related to:

• The use of artificial intelligence (AI) to predict left ventricular dysfunction from smartwatch ECG recordings
• The use of wearable technology for heart failure monitoring and detection of heart failure exacerbation
• The use of wearables in a cardiac rehabilitation space, to increase healthy behaviour

Furthermore, Dr. Cheung concluded his presentation by discussing promising preliminary studies of possible future applications of AI algorithms to improve diagnostics, predict future arrhythmias, and fill in data gaps from missing data.

A discussion followed on these topics, including:

• The clinical burden of AF associated with stroke risks
• The use of devices in the primary care environment
  • The presenter suggested that these devices are primarily used for screening and that patients will undergo subsequent testing before clinical decisions are made.
  • However, there are some cases where wearable device data may provide valuable information, such as for rare and infrequent arrhythmias where a Holter doesn't capture these events but the events are captured by a wearable device.  In these cases, data from wearable devices may be accepted as valid measures of these events
  • It was agreed that more reliance on wearable technologies in primary clinical decision making may occur as more devices become available and as more data becomes available to demonstrate appropriate sensitivity and specificity
• The transition to technology-based healthcare for patient extension of virtual care
  • Committee members suggested that this is seen as a positive, allowing more people to access health care. Also, seen to reduce burden on health care system, by allowing patients to self-manage and avoid coming to the doctor/hospital each time.

Next steps, closing remarks and adjournment of meeting (Dr. Eric Cohen)

The Chair suggested that Health Canada create a survey to be sent out to committee members for their preference on the meeting format (virtual, in-person, or hybrid) and frequency for future meetings. Dr. Cohen thanked the members for their contributions and closed the meeting.

Core committee members: John Ducas (Chair), Anita Asgar, Chris Feindel, Raymond Yee, Eric Cohen, Alan Menkis, Brent Mitchell, Barry Rubin, Jillianne Code, Joaquim Miró

Regrets: John Webb, Marino Labinaz, Renzo Cecere

Guest speakers: Eddy Fan, UHN ECMO Program, Neil Fam, Interventional Cardiology and Cardiac Cath Labs at St. Michael’s Hospital, and George Wells, University of Ottawa Heart Institute

Observers: Gino De Angelis, Yannick Auclair

Health Canada staff: David Boudreau, Karen Tso, Kevin Day, Marianne Ariganello, Ben Elliott, Chris Schmidt, Ellen Fraser, Firdous Hadj-Moussa, Geoffrey Green, Jianming Hao, Karen Kennedy, Lanyi Xu, Maurice Sylvain, Monica Forero, Natalia Mavrinskaya, Renate Kandler, Roy Masters, David Hou, Marie-Rose Saade, Grant Kealey, Melanie Bradley, Panyada Phandanouvong, Alexander Spring, Chujian Chen, Lisa-Gaye Pryce, Hui Shen, Mark Korchinski, Rosslynn Miller-Lee, Rany Shamloul, Weimin Zhao

Opening remarks and updates on committee governance (David Boudreau)

The Director General of the Medical Devices Directorate welcomed attendees to the SAC-MDUCS meeting. Mr. Boudreau identified the 3 meeting topics: tricuspid valve interventions; extracorporeal membrane oxygenation; and patient-reported outcomes in cardiovascular trials and clinical practice. He then provided updates within the Medical Devices Directorate before handing the meeting over to the chair:

• Cardiovascular Device Approval
• Sex- and Gender-Based Analysis Plus
• The agile licensing for medical devices initiative
• The advanced therapeutic products framework

Review of the agenda and declaration of affiliations and interests (John Ducas)

The Chair thanked and welcomed the meeting attendees. He requested declarations of actual or potential conflicts of interest and indicated that some members were being contacted to update their security clearances. There were none that restricted SAC-MDUCS members from participating. Dr. Ducas has announced that he is stepping down as Chair, and he will stay on the committee as a committee member. He asked if the other members would consider taking on this role.

Summary of previous advice used (Kevin Day)

Mr. Day described the committee’s recommendations on topics from 3 previous meetings:

• LAA Occlusion devices (April 2022)
• Intravascular Lithotripsy atherectomy devices (November 2020)
• Use and access to transcatheter aortic valve replacement devices (November 2020)

He explained how Health Canada used the recommendations to inform decisions about medical device licensing and to help in its assessments of clinical trials and Special Access Program applications.

Presentation #1: Extracorporeal Membrane Oxygenation (ECMO): Lessons learned during the pandemic and recommendations for future clinical use (Eddy Fan)

Dr. Fan provided an overview of the use of ECMO for severe acute respiratory distress syndrome (ARDS) before and during the COVID-19 pandemic. He included the most recent clinical data to illustrate lessons learned during the pandemic due to the unprecedented demand for ECMO:

• survival rates among patients receiving ECMO for COVID-19 were higher if ECMO was deployed earlier
• early adopting centres (with experience with ECMO before the COVID-19 pandemic) reported better outcomes
• certain pre-cannulation factors increase mortality (such as longer duration of symptoms, longer mechanical ventilation)
• patient selection is important and there are numerous factors to consider to reduce mortality rates and occurrences of disabilities among patients (such as age, sex, and chronic lung disease)

Dr. Fan pointed to a lack of high-quality clinical evidence for patient selection and how to manage patients on ECMO. He discussed the best clinical practices for ECMO use in adults going forward, including how to manage critically ill patients with COVID-19; mechanical ventilation in patients with ARDS; and management of patients supported with VV ECMO. As there is little high-quality data to guide clinical recommendations, Dr. Fan noted that these guidelines are mainly suggestions. He also described situations in which ECMO is unlikely to be successful, including patients with chronic cardiac disease with no hope of recovery or transplant.

Dr. Fan looked at some studies that focused on ECMO with COVID-19 compared with other studies that required lung or cardiopulmonary support.

For example, he highlighted that COVID-19 does not spread through ECMO or dialysis membranes. Dr. Fan concluded that more research is required on ECMO use in COVID-19 patients and suggested we consider new data as the pandemic evolves. 

A discussion followed on these and related topics, including the following:

• guidelines and criteria used in patient selection for ECMO support and duration of ECMO support
  • In one study of ARDS and COVID-19, it was highlighted that 35% of patients were still on ECMO support after 28-days; some duration beyond 100-days
  • Situations where ECMO is unlikely to be successful included:
    • Chronic respiratory or cardiac disease with no hope of recovery or transplant
    • Severe aortic regurgitation or type-A aortic dissection
    • Advanced age in ARDS
    • ARDS with multiorgan failure
    • Prolonged pre-ECMO mechanical ventilation
  • cardiac support for patients who need a transplant
  • cardiac support for patients with post-cardiotomy cardiogenic shock, which may occur after an operation
  • the importance of having a multidisciplinary team meeting on a regular basis
  • post-intensive care syndrome for patients being on ECMO for an extended period
  • better outcomes for the patients being on ECMO versus “traditional” methods
  • funding received for venoarterial (VA) ECMO and VV ECMO

Presentation #2: Clinical assessment and use of emerging technologies for Transcatheter Tricuspid Valve Interventions (Neil Fam)

Dr. Fam reviewed tricuspid regurgitation (TR), how it is assessed and traditionally treated, and the challenges for successful treatment. He indicated that surgeries for isolated TR are rare and have a high mortality rate, and consequently, TR has been undertreated. Dr. Fam highlighted that there is an unmet need for something less invasive. That unmet need explains why there is such an increase in interest in the devices that tackle TR.

Dr. Fam presented two effective edge-to-edge transcatheter tricuspid valve repair (TTVr) devices: TriClip and PASCAL/Ace, which are used in randomized trials. He also discussed the Limitations of TTVr devices (such as difficulty imaging the valve). He also noted that TTVr is safe, but not always effective.  He identified different Transcatheter Tricuspid Valve Replacement (TTVR) devices, such as the EVOQUE valve, Cardiovalve, TriCares Topaz valve, and LuX valve, that show some early promising results.

Dr. Fam presented what is known about TTVR, its challenges, potential solutions, and limitations.  Challenges included conduction abnormalities, paravalvular leakage (PVL), embolism, thrombosis, and bleeding.  Limitations included difficulties treating large annuli (e.g. > 60 mm), inferior vena cava-tricuspid annulus (IVC-TA) angle/offset, some right heart anatomies, need for lifelong anticoagulation, unknown durability, and endocarditis risk – especially with jailed leads. When repair is feasible, it can outperform replacement in some cases. He also spoke about heterotopic valves and spacers that can be used for patients who cannot have a valve replacement.

Dr. Fam emphasized the importance of a functional heart team composed of many healthcare professionals for both transcatheter tricuspid valve repair and replacement, including an interventional cardiologist, cardiac surgeon, imaging specialist, heart failure specialist, and nurse coordinator.

Dr. Fam summarised that Transcatheter tricuspid valve intervention (TTVI) meets an unmet need in patients with right heart failure as a way to improve symptoms, reduce heart failure hospitalizations, and possibly improve mortality. Patients’ enrollment in trials helps to advance these studies. Current TTVI devices cannot treat all TR patients, so ongoing innovation is needed.

A discussion followed on these and related topics, including:

• clinical trial design for the TTVI devices and new devices under development; how to select a good comparator to determine device safety and effectiveness; and trial approvals in Canada
• reimbursement of the approved devices by the public healthcare system
• best measures of risks and benefits (heart failure, quality of life) based on the outcomes of the studies; surgical standard of risk;
• access to these devices for medium vs high risk surgical patients – it was noted that the paradigm used for clinical investigations for TAVR is not as applicable to TTVR ;
• determining what level of improvement in tricuspid regurgitation is clinically meaningful
  • It was noted that for older patients, improvements in quality of life (e.g. reducing TR from severe to moderate) is acceptable
  • For younger patients, more substantial improvements should be required
• Patient selection for Transcatheter Tricuspid Valve Interventions
  • TTVr: small leaflet gaps, mild tethering, RV dysfunction, contraindication for anticoagulation
  • TTVR: large leaflet gaps, tethered leaflets, lead-induced TR
  • TTVr or TTVR: Symptoms of right heart failure, Good RV function, Leaflet gap < 7 mm, Excellent imaging, No pulmonary hypertension
• coexistence with other cardiac diseases and treatment pathways as well as the strategy used for the patients with pacemakers

Presentation #3: Patient Reported Outcomes in Cardiovascular Trials and Clinical Practice (George Wells and Jillianne Code as a key discussant)

Dr. Wells defined a patient reported outcome (PRO) as an assessment of a person’s health, well-being, and treatment from the patient’s perspective; it consists of symptoms, functional status, and health related quality of life (HR-QoL) measures.

He explored:

• the types of PROs used in the clinical assessment of cardiovascular devices and clinical scenarios where PROs are bypassed
• examples of when PROs data is not used in clinical practice, such difficulty linking PROs to particular treatments since many factors influence outcomes
• how often, when, and for how long PROs should be measured (for example, he suggested collecting PROs during and outside of medical appointment times)
• the importance of general PRO instruments (such as EQ-5D), which focus on overall well being, and disease-specific instruments (such as KCCQ), which are more responsive to treatment
• PRO measures, the development of PRO instruments to measure HR-QoL, and characteristics of PRO instruments
  • It was noted that KCCQ (Kansas City Cardiomyopathy Questionnaire) and MLHFQ (Minnesota Living with Heart Failure Questionnaire) were viewed as reasonable PRO instruments that were largely viewed as appropriately validated for having a numerical value for a minimal clinically meaningful difference

Dr. Wells also spoke on data interpretation of PROs, which included:

• limitations in interpreting PRO measures (for example, concepts may vary between questionnaires)
• a strategy to address key interpretive issues of decision-makers
• examples of clinically relevant differences for cardiovascular-related PRO instruments

Dr. Wells concluded his presentation with recommendations on how to interpret data for cases where the PRO measures diverge from other objective endpoints.

Dr. Code spoke as a patient representative with lived experience with heart failure. She pointed to the subjectivity and error found in the current PRO instruments. Dr. Code expressed concern that the current quality of life measures of PRO instruments used in the literature include only physiological conditions and symptomatic quality of life measures. Instead, PRO instruments should include patient reported experience measures. She indicated that emotional, cognitive, social, psychosocial aspects are just as important but are overlooked or underplayed.

A discussion followed on these and related topics, including the following:

• Whether quality of life information needs to be included in the informed consent form (completed by the patients on the early stages of a study)
• how the data presented can be used to help patients be clear about what they want as this would help physicians understand what the patients want and provide them with the relevant information
• What to include in the questionnaires, how many questions to include, and how to ensure that questions reflect PROs and experiences while also being relevant clinically and for research literature

Next steps, closing remarks and adjournment of meeting (John Ducas)

The Chair thanked all participants, reminded all members to consider taking the role of committee chair, and closed the meeting.

Core committee members: John Ducas (Chair), Alan Menkis, Barry Rubin, Chris Feindel, Eric Cohen, Jillianne Code, Raymond Yee

Regrets: Anita Asgar, Brent Mitchell, Joaquim Miró, John Webb, Marino Labinaz, Renzo Cecere

Guest speakers: Jacqueline Saw, Interventional Cardiologist, Vancouver General Hospital and St Paul’s Hospital, and Raymond Yee, Professor of Medicine, Schulich School of Medicine & Dentistry and the University of Western Ontario

Guest discussant: Bernard Thibault, Cardiologist, Montreal Heart Institute and Associate Professor at the Université de Montréal

Observers: Gino De Angelis, Yannick Auclair

Health Canada staff: David Boudreau, Karen Tso, Kathy Soltys, Emanuela Fedele, Kevin Day, Anber Ikram, Marianne Ariganello, Ben Elliott, Bisi Lawuyi, Chris Schmidt, Elaine Wong, Elham Aghbashi, Ellen Fraser, Firdous Hadj-Moussa, Geoffrey Green, Jianming Hao, Julie Proulx, Julie Taing, Karen Kennedy, Kathleen O’Callaghan, Lanyi Xu, Mark Korchinski, Martina Buljan, Maurice Sylvain, M'omena Dawood, Monica Forero, Myriam Gauthier, Natalia Mavrinskaya, Nathalie Duval, Peggy Seely, Renate Kandler, Roy Masters

Opening remarks (David Boudreau)

The Director General of the Medical Devices Directorate welcomed attendees to the SAC-MDUCS meeting and observers from the Canadian Agency for Drugs and Technologies and the Institut national d’excellence en santé et en services sociaux. Mr. Boudreau identified the 2 meeting topics: left atrial appendage occlusion devices and leadless pacemakers. He then provided updates within the Medical Devices Directorate before handing the meeting over to the chair:

• ongoing efforts to facilitate access to COVID-19 medical devices through interim orders
• the agile licensing for medical devices initiative
• the advanced therapeutic products pathway
• recent consultations on the guidance for medical device meetings and for clinical evidence requirements

Review of the agenda and declaration of affiliations and interests (John Ducas)

The Chair thanked and welcomed the meeting attendees. He requested declarations of actual or potential conflicts of interest. There were none that restricted SAC-MDUCS members from participating.

Summary of previous advice used and general considerations for the meeting (Kevin Day)

Mr. Day described the committee’s recommendations on topics from 3 previous meetings:

• renal denervation and hypertension treatments (June 2021)
• atherectomy devices in calcified lesions, and the use and performance of transcatheter mitral valve repair (November 2020)
• use of the Special Access Program (SAP) for first human use and associated clinical ethics (March 2019)

He explained how Health Canada used the recommendations to inform decisions about medical device licensing and to help in its assessments of clinical trials and SAP.

Presentation #1: Left atrial appendage occlusion devices (Jacqueline Saw)

Dr. Saw presented clinical data on how left atrial appendage (LAA) occlusion devices are performing in Canada and worldwide, with Amulet and Watchman (including the new version, Watchman FLX) being the most commonly used. She highlighted the current indications for LAA closure in Canada. Using randomized control trial and large registry data, Dr. Saw:

• explored safety and effectiveness endpoints in populations who are contraindicated to long-term oral anticoagulation
• compared device usage with post-implant antithrombotic therapy
• discussed the use of combination therapy with ablation, oral anticoagulation and transcatheter aortic valve replacement

She also presented on the safety issues of these devices, including pericardial effusion, device migration/embolization, device-related thrombus and peri-device leakage.

Overall, Dr. Saw indicated that LAA closure can be performed safely, with good technical success and with effective long-term results. However, as is generally the case with invasive procedures, females have worse complication rates than males.

Dr. Saw also noted that a minimalist approach is being taken to LAA closure through same-day discharge and avoiding general anesthesia. Looking forward, she described some of the devices on the horizon, including new devices (such as single lobe design and lobe and disc design) and new iterations of current devices (such as improved seals).

A discussion followed on these and related topics, including the following:

• device positioning (need for pre-imaging and considering placement depth)
• device usage among patients in Canada (subject to provincial approval and funding)
• hemodynamic changes due to occlusion devices (no adverse effects reported)
• clinical evidence requirements for new devices seeking approval in Canada (need for randomized clinical trials demonstrating non-inferiority to a licensed device)
• use of other therapies after use of LAA occlusion devices (possible to ablate after implanting an LAA occlusion device)

Presentation #2: Leadless pacemakers (Raymond Yee)

Dr. Yee gave an update on leadless pacemakers with contributions from guest discussant Dr. Bernard Thibault. Dr. Yee described the primary rationale for using leadless pacemakers, which is to reduce the risk of complications associated with the lead. He also provided an overview of devices for which we have the most clinical experience (Nanostim/Aveir SJM/Abbott, Micra Medtronic, WiCS EBR).

Dr. Yee compared pre-market data with post-market data for leadless pacemakers (Micra’s investigational device exemption versus its post-market approval registry) and found that success rates were sustained in the real world, meaning that these devices implant well and safely. He also compared data on leaded and leadless pacemakers, noting that major complication rates continue to increase over time for leaded pacemakers but plateau for leadless pacemakers. Leadless pacemakers also appear to show stable electrical properties over time (for example, pacing thresholds) and lower rates of infection compared to leaded systems.

Finally, Dr. Yee described the progression of leadless pacemakers since early clinical use (Micra and Nanostim), including safety data over time indicating good short- to early mid-term results. He emphasized that more long-term data is needed to understand the long-term benefits and risks (for example, long-term extraction of chronic devices). He also emphasized that current leadless pacemakers do not offer physiologic pacing options (for example, His bundle or left bundle branch), which is becoming increasingly common in leaded systems. It was acknowledged that the use of leadless pacemakers in Canada remains fairly low (<5% at his facility).

Dr. Yee went on to address 3 blocks of questions, with discussion interspersed throughout, including comments on patient experiences of leadless pacemakers:

• implantation and retrieval of leadless pacemakers, for example:
  • type of patients chosen for leadless implantation versus traditional pacing systems
  • such patients are at high risk for infection
  • optimal implant location
• involvement of leadless pacemakers in patients needing more than single -chamber pacing, for example:
  • use of transvenous system when the patient requires other active implantable medical device therapies
• future considerations, for example:
  • comparing strengths and weaknesses of available and emerging leadless pacemaker technologies
  • discussion of clinical evidence requirements for future pivotal trials

Next steps, closing remarks and adjournment of meeting (John Ducas)

The Chair asked members for their preference for virtual, in-person or hybrid meetings in the future. During that discussion, the next meeting date was proposed and members were encouraged to submit meeting topics. The Chair advised that a high-level summary would be posted on Health Canada's website. He thanked the members for their contributions and closed the meeting.

Core committee members: John Ducas (Chair), Eric Cohen, Renzo Cecere, Jillianne Code, Barry Rubin, Alan Menkis, Brent Mitchell, Chris Feindel

Regrets: Anita Asgar, Marino Labinaz, Miro Joaquim, John Webb, Raymond Yee

Guest speakers: Ross Feldman, Cardiac Sciences Lead, Shared Health Manitoba and St. Boniface Hospital; Marcel Ruzicka, Medical Director, Renal Hypertension Program, The Ottawa Hospital; J. David Spence, Director, Stroke Prevention & Atherosclerosis Research Centre, Robarts Research Institute, Western University

Health Canada staff: David Boudreau, Kevin Day, Ben Elliott, Andrea McKenzie, Bisi Lawuyi, David Yoon, Elaine Wong, Firdous Hadj-Moussa, Geoffrey Green, Jianming Hao, Karen Kennedy, Marc Lamoureux, Mark Korchinski, Martina Buljan, Maurice Sylvain, Monica Forero, Peggy Seely, Renate Kandler, Roy Masters, Saira David, Veronique Robichaud

Opening remarks (David Boudreau)

The Director General of the Medical Devices Directorate (MDD) welcomed attendees to the SAC-MDUCS meeting. He introduced the topics that will be discussed:

• renal denervation and carotid sinus stimulation as treatments for hypertension
• clinical evidence requirements and clinical trial design for these technologies

He indicated that the Canadian Agency for Drugs and Technologies in Health would be joining Health Canada’s scientific advisory committees as permanent observers, starting with the next meeting. Before handing the meeting over to the Chair, he also provided a brief update on activities related to the Medical Devices Action Plan, including the progress report for the Medical Devices Action Plan, which was published in May 2021.

Review of the agenda and declaration of affiliations and interests (John Ducas)

The Chair outlined the meeting agenda and requested declarations of actual or perceived conflicts of interest. There were none that restricted SAC-MDUCS members from participating. He was joined by Kevin Day in welcoming the meeting participants and inviting discussions from clinical, regulatory and patient perspectives.

Presentation #1: Renal denervation in the management of hypertension: Second time around (Ross Feldman)

Dr. Feldman discussed where we are 10 years after the initial use of renal denervation technologies. Renal innervation (both afferent and efferent) regulates blood pressure and denervation lowers blood pressure in experimental models. First-generation renal denervation technologies mainly used radiofrequency ablation using a single electrode device.

Studies conducted from 2009 to 2015 on these first-generation devices included discrepant clinical results on the impact of renal denervation on lowering blood pressure. Early Symplicity studies (HTN-1, and -2 studies) demonstrated significant lowering of blood pressure. However, the subsequent Symplicity HTN-3 study failed to demonstrate this.

After 2015, second-generation renal denervation technologies were developed. These second-generation technologies are showing some promise in lowering blood pressure by approximately 5 mmHg. This is comparable to 1 standard dose of an antihypertensive drug.

Presentation #2: Renal sympathetic denervation for treatment of hypertension post Symplicity HTN-3 trial (Marcel Ruzicka)

Dr. Ruzicka presented renal denervation trial data to help explain the progression from first- to second-generation renal denervation technologies. He began by describing the results obtained in uncontrolled first-generation renal sympathetic denervation trials. Next, he moved on to explain why there was an initial uptake in the use of renal denervation for the treatment of resistant hypertension. He then described the disappointing results obtained from the first sham-controlled trial (Symplicity HTN-3).

Dr. Ruzicka went on to examine gaps in the internal validity of the Symplicity HTN-3 trial, such as those related to the following:

• patient selection (do we know that the patient has hypertension and increased central/renal sympathetic activity?)
• procedure (how do we assess that renal denervation was achieved?)
• operator issues (did all physicians performing renal denervation have similar levels of experience?)
• numerous aspects of study design

He wrapped up his presentation by discussing the current status of second-generation renal denervation technologies.

Today, radiofrequency ablation and ultrasound renal denervation catheters are being developed and tested. Both have had some early randomized clinical control trials, including sham procedures. Trials have shown systolic blood pressure decreases by 4 to 7 mmHg.

Presentation #3: Does carotid baroreceptor stimulation have a place in the management of resistant hypertension and heart failure? (David Spence)

Dr. Spence discussed the utility of carotid baroreceptor stimulation in managing hypertension. While it is useful in cases of true refractory hypertension, he suggested that few patients who are well managed are truly refractory to anti-hypertensive medications.

Instead, Dr. Spence advocated for using physiologically individualized therapy for resistant hypertension based on levels of stimulated plasma renin and aldosterone. These levels reveal the presence of a primary aldosteronism phenotype (low renin, high aldosterone), which is best treated with aldosterone antagonists, or a Liddle phenotype (low renin, low aldosterone), which is best treated with amiloride. A Liddle phenotype is far more common than most physicians suppose in 10% to 20% of patients with resistant hypertension and more common in people of African origin.

He suggested that the same considerations would apply to renal denervation. Before deploying such devices, the underlying physiological cause of the hypertension should be diagnosed and treated appropriately.

Dr. Spence outlined several challenges associated with carotid sinus therapy:

• it is invasive
• correct placement of the stimulator may be difficult
• a technologist is required to adjust the device
• the device has a limited battery life
• there are limited data from randomized controlled trials

Dr. Spence suggested that carotid baroreceptor stimulation should not be approved for general use in Canada but should be treated like an emergency drug release.

Finally, Dr. Spence suggested that the situation is very different in patients with heart failure where the device could be approved with limited indications for use. He suggested that this therapy may benefit high-risk patients despite the challenges associated with this technology.

General discussion about medical device treatments of hypertension

A brief discussion followed about medical device treatments of hypertension. The discussion included how we can reasonably weigh unknown risks against a 5 mmHg reduction with renal denervation, as we do not fully understand the impact of permanently ablating the renal nerves (for example, impact on hypotensive cardiac disease, increased risk hypotensive responses and risk of heart failure).

Also discussed were the shortcomings of randomized clinical trials. They do not necessarily indicate other clinically important cardiovascular outcomes beyond blood pressure reduction. There is also often a lack of quality-of-life measures.

Presentation #4: Clinical evidence requirements, clinical trial design and patient population: Discussion from clinical and patient perspectives (directed by Ben Elliott from Health Canada and John Ducas, Chair)

Committee members discussed the effectiveness of these technologies. They agreed that while almost all hypertension can be controlled using medication, a very small number of patients could benefit from these technologies.

While hypertension is a manageable disease, Canada has, in some areas, taken a step backwards in high-quality guideline-directed blood pressure control in recent years.

Committee members discussed whether:

• Canadians are being appropriately diagnosed and treated
• these technologies would benefit Canadians who may not have access to clinicians who are able to help them carefully manage their hypertension

The committee also discussed the complex nature of non-adherence to medications among patients, including side effects, cost of medication and the role of guideline‐directed medical therapy.

The committee discussed the complex question of whether devices should hold the same regulatory requirement and clinical trial design standard of safety and efficacy as anti-hypertensive drugs. They explored the similarities (for example, interpatient variability) as well as the differences (for example, much smaller population sizes for devices) between them.

Committee members expressed different opinions about the threshold of when to consider using these technologies, such as whether it is necessary to first exhaust all other medication options. The point was raised that caution should be exercised because we do not fully understand the long-term consequences, such as how patients would react to blood volume challenges in cases of shock following renal denervation.

The committee discussed minimum premarket requirements:

• a randomized control trial of 500 to 1,000 patients followed for at least 1 year that includes sham control. However, some strongly advocated for more than 1 year

In the post-market, a large surveillance trial should be required. This could include international registries to detect less frequent adverse events that we expect may be an issue with this technology. The committee discussed the possibility that consequences may be related to the procedure, device or operator. It was suggested that the use of a hypertension team for patient selection could be added as a recommendation to the label.

The committee agreed on the validity of blood pressure as an endpoint provided it is done well:

• with randomized control trials
• with a sham control and
• requiring the measurement of ambulatory blood pressure rather than just office blood pressure

The committee also suggested that key adverse events be included as part of study endpoints, including acute problems (bleeding, embolization) and chronic problems (renal artery stenosis). However, it was noted that there remain many long-term unknowns. The long-term follow up of stenosis requires imaging and is complex.

Differences between patient subgroups were discussed, such as sex, gender, race, ethnicity and specific comorbidities. The committee concluded that clinical trials should include Black populations. Some committee members suggested that patient representation should reflect the clinical population in Canada, assuming sham control compares well to correct for poorly managed people at baseline.

Next steps, closing remarks and adjournment of meeting (John Ducas)

The Chair advised that a high-level summary would be posted on Health Canada's website. He extended profound thanks to the members for their contributions before closing the meeting.

Core committee members: John Ducas (Chair), John Webb, Renzo Cecere, Anita Asgar, Alan Menkis, Barry Rubin, Brent Mitchell, Chris Feindel, Eric Cohen, Jillianne Code, Raymond Yee

Regrets: Marino Labinaz, Joaquim Miro

Guest speakers: Kunal Minhas, Director, Cardiac Catheterization Laboratory, St. Boniface Hospital, Winnipeg; Vincent Chan, Cardiac Surgeon, University of Ottawa Heart Institute

Health Canada staff: David Boudreau, Saira David, Gaya Jayaraman, Kevin Day, Ben Elliot, Chris Schmidt, Daniel Yoon, Geoffrey Green, Ian Aldous, Jianming Hao, Julia Bairos, Karen Kennedy, Lanyi Xu, Mark Korchinski, Maurice Sylvain, Monica Forero, Peggy Seely, Renate Kandler, Roy Masters

Opening remarks (David Boudreau)

The Director General of the Medical Devices Directorate (MDD) welcomed attendees to the first virtual meeting of SAC-MDUCS during this unprecedented time of the COVID-19 pandemic. He identified the following topics for SAC-MDUCS consideration during the meeting:

• Devices used in the treatment of heavily calcified coronary lesions;
• Transcatheter aortic valve replacement (TAVR) to treat aortic valve disease; and
• Percutaneous mitral valve repair or replacement technologies, including Mitraclip.

He also described how Health Canada has implemented innovative and agile regulatory measures to help prioritize and expedite the regulatory review of in-demand COVID-19 medical devices. He then provided a brief update on activities related to the Medical Devices Action Plan before handing the meeting over to the Chair.

Review of the Agenda and Declaration of Affiliations and Interests (John Ducas)

The Chair outlined the meeting agenda and requested declarations of actual or potential conflicts of interest. There were no declared affiliations and interests that restricted SAC-MDUCS members' participation.

Summary of Previous Advice Used and General Considerations for the Meeting

Kevin Day provided a summary of previous advice used by Health Canada:

• Health Canada believes that there are data to support the use of drug-coated balloons in some patients. Furthermore, the clinical use of drug-coated balloons can be appropriately controlled through the practice of medicine as we continue to monitor uncertainties and outcomes.
• We continue to work towards licensing TAVR replacement in low-risk patient populations.
• Interatrial shunting for heart failure and pulmonary arterial hypertension continue to be of interest within the Special Access Program (SAP) and in clinical trials.

Presentation #1: Atherectomy Devices for the Treatment of Heavily Calcified Coronary Lesions (Kunal Minhas)

Kunal Minhas's presentation focused on the characteristics of severely calcified coronary lesions; the challenges in assessing and treating these lesions; and an assessment of the risks and benefits of devices used to treat severely calcified coronary lesions. He offered a clinical perspective on the clinical performance of devices used in the assessment and treatment of heavily calcified coronary lesions, including current practices in Canada. Dr. Minhas also spoke to the limited use of existing technologies, such as rotational and orbital atherectomy devices, as well as promising features of newer atherectomy technologies. He presented on the benefits and risks associated with the range of available devices and the technologies in development. He also contextualized the most commonly used of these technologies within contemporary treatment decision algorithms. This further highlighted how unique aspects of different technologies can be used to the greatest clinical advantage.

After the presentation, the committee discussed the differences between intravascular lithotripsy and other atherectomy devices that are currently available. The discussion touched on the degree of calcification; particulate embolization; dissection and perforation; the possibility of death, heart attack, and restenosis; and the induction of cardiac ectopics with coronary intravascular lithotripsy.

The committee further considered the potential impact of these factors on Health Canada's regulation of these technologies and the potential authorization of these technologies through SAP. Patient populations that would benefit the most from these technologies include patients with severely calcified lesions and lesions that are difficult to cross or dilate. Health Canada will continue to monitor the usage of these devices and any adverse events associated with them, as these effects could become significant as use broadens.

Presentation #2: Use and access to TAVR devices (John Webb; Renzo Cecere)

John Webb spoke from an interventional cardiological perspective and Renzo Cecere from a surgical perspective. The presentations focused on the use of TAVR for the treatment of aortic valve disease with two main areas of focus. The first was the use of TAVR in low-risk patient groups and whether there are any conditions where the use of TAVR should be limited in these groups. In general, improvements in rates of death and disabling stroke were highlighted for TAVR (using transfemoral access) compared to surgery. In some areas, surgery may be associated with improved outcomes compared to TAVR, such as pacemaker implant rates, structural valve deterioration, and mild paravalvular leakage. The implications of the broader use of TAVR in low-risk patients were also presented. These included considerations for future interventions; the feasibility and risks of valve-in-valve procedures; and the risks associated with alternative access sites, thrombosis, coronary artery occlusion, and calcified left ventricular outflow tract for TAVR.

The discussions highlighted that, given that all valves will fail eventually, maintaining coronary access after a valve-in-valve procedure is a potential problem. Clinicians and Health Canada should consider how the transcatheter valve performs in the context of TAVR-in-TAVR and TAVR-in-surgical aortic valve replacement (SAVR) interventions. Consideration should be given when selecting the first TAVR device (e.g., intra-annular vs. supra-annular, sealed skirt) for implantation, especially in a low-risk patient population. As younger patients with longer life expectancies are implanted with TAVR devices, there may be a need to access the coronary arteries to treat future coronary artery disease after a valve-in-valve re-intervention. Additionally, the committee noted that patient age is not a sole determinate of the best intervention (i.e., TAVR vs. SAVR), and labelling should not restrict use based on age alone. This decision making is the role of the Heart Team.

As TAVR indications expand into lower risk and younger patient population, new transcatheter valves cannot be approved for low-risk patients until long-term durability is assessed in high- and intermediate-risk patients. The committee noted that surgical valve replacement was considered a very good option for young, low-risk patients.

The second focus was on the emergence of new technologies and a comparison to the well-established and more mature TAVR systems currently available. In general, performance of the market-leading technologies should continue to be used as the required clinical performance for market access in Canada. Low-risk patients should be treated with valves for which we have significant clinical data, including long-term follow up.

After the presentation, the committee discussed how practical access to TAVR in Canada is dependent on risk level and the age of patient populations. The evolution of prosthetic heart valve composition (mechanical or tissue) as well as the flexibility, structure, and durability of devices were considered. The committee noted that the choice of TAVR vs SAVR is well-positioned within the practice of medicine in the context of a Heart Team in Canadian health care facilities. The importance of considering patient preference in treatment options was also discussed.

Presentation #3: Emergence of New Transcatheter Mitral Valve Replacement and Transcatheter Mitral Repair Devices (Anita Asgar; Vincent Chan)

Anita Asgar spoke from an interventional cardiological perspective and Vincent Chan from a surgical perspective. The presentations focused on the use of devices to repair or replace leaking mitral valves. While Mitraclip has been on the market for several years, other percutaneous mitral valve repair or replacement technologies have been slow in developing, and many have been associated with poor clinical outcomes. The mitral valve and mitral valve disease are complex, and there are currently many devices under clinical investigation for the treatment of mitral regurgitation (MR).

The presentations provided an update on the clinically acceptable outcomes for different patient populations for a wide range of devices that address leaflet repair (edge-to-edge), annular repair (annuloplasty), chordal repair or replacement, and valve repair and replacement. The presentation proposed ideal characteristics for a percutaneous mitral valve repair system, including transeptal delivery; the ability to reposition the device for proper alignment; non-obstruction of the left ventricular outflow track; avoiding the need for long-term anticoagulation; and an allowance for future interventions.

The presentation also provided guidance on clinical trial design considerations (i.e., trial design, patient population (e.g., primary vs. secondary MR), patient exclusion criteria, control group, and study size). In most cases, trials should be randomized against surgery or the mitral clip for both degenerative and functional MR with endpoints recommended by the Mitral Valve Academic Research Consortium. Exceptions to this include mitral annular calcification, which is not currently well managed with existing therapeutic interventions and might use predefined objective performance criteria that are well matched with the patient population to be studied. It was noted that surgical outcomes for mitral valve replacement and most types of mitral valve repair are quite good and continue to improve, thereby presenting the need for contemporary comparators for clinical trials.

After the presentations, the committee discussed the role of surgeons and interventional cardiologists in the treatment of mitral valve disease and acknowledged the importance of having an interdisciplinary team looking at structural heart disease and heart failure. This is particularly important given the range of treatment options available from medical management to surgical intervention. The importance of site experience (e.g., more than 23 cases per year), long-term outcomes, and patient preference was further discussed.

What Health Canada has heard and Wrap-up (Kevin Day)

Kevin Day thanked the committee for their work and for the excellent discussions of the day. He emphasized that Health Canada strives to ensure timely access to these cardiac medical devices once there is adequate evidence of safety and effectiveness. He noted the importance of accessing clinical trials for emerging technologies and accessing SAP for unmet clinical needs.

While regulating rapidly evolving cardiovascular medical device technologies continues to be challenging, the recommendations and deliberations of the committee provide valuable insight about the safety and effectiveness of these technologies. These committee meetings facilitate an informed assessment of cardiovascular medical devices even in the early stages of clinical data collection and have also helped to contextualize those data.

Next Steps, Closing Remarks and Adjournment of Meeting (John Ducas)

The Chair advised that a high-level summary would be posted on Health Canada's website. He indicated that the next SAC-MDCUS meeting was expected in May or June of 2021. The Chair thanked the members for their contributions and closed the meeting.

Core committee members: John Ducas (Chair), Anita Asgar, Jillianne Code, Renzo Cecere, Eric Cohen, Barry Rubin, Joaquim Miro, Alan Menkis, Marino Labinaz

Regrets: Brent Mitchell, Chris Feindel, John Webb, Raymond Yee

Guest speakers: Thomas Forbes, Sudhir Nagpal, Dheeraj Rajan, Ahmed Kayssi

Health Canada staff: David Boudreau, Saira David, Kevin Day, Ana Ludke, Ben Elliott, Chris Schmidt, Christine Lefebvre, Daniel Yoon, Despina Miteva, Elaine Wong, Eva McGrath, Fatiha Chellat, Geoffrey Green, Giovanni Di Rienzo, Ian Aldous, Jianming Hao, Karen Kennedy, Lanyi Xu, Maurice Sylvain, Maxime Tondreau, Monica Forero McGrath, Patrick Fandja, Roy Masters, Timao Li, Xiaoli Ma

Opening remarks (David Boudreau)

The Director General of the Medical Devices Directorate (MDD) welcomed all committee members and guest speakers, including new committee member Jillianne Code (patient representative). He introduced the new directorate and its role in overseeing the regulation of medical devices.

He then discussed the importance of SAC-MDUCS and the Medical Devices Action Plan, which was published in December 2018. Finally, he described the overall focus of the meeting:

• understanding the use of paclitaxel drug-coated balloons/stents (PCB/PCS) for treating peripheral arterial disease (PAD) in order to strengthen pre-market evaluation, post-market surveillance and public transparency of information

Review of the agenda and affiliations and interests (John Ducas)

The Chair outlined the meeting agenda and requested declarations of actual or potential conflicts of interest. There were none that restricted SAC-MDUCS members from participating.

Summary of previous advice used and general considerations for the meeting (Kevin Day)

Mr. Day summarized advice received from the previous SAC-MDUCS meeting, including His bundle pacing, labelling considerations, and using the Special Access Program to grant early access to devices. He indicated that the feedback received in this meeting would influence regulatory decisions within Canada.

After the publication of the Katsanos meta-analysis paper, concerns arose about the use of drug-coated balloons (DCBs). Health Canada published a notice on May 9, 2019, about the risk-benefit profile of DCBs and informed patients of the risks. The notice was consistent with subsequent messaging by the Medicines and Healthcare products Regulatory Agency and the United States Food and Drug Administration (U.S. FDA). Up to the date of this meeting, no regulatory agency has withdrawn paclitaxel drug-coated balloons.

In light of this context, the goal of this meeting was to discuss objective evidence and clinical expertise on how to regulate Paclitaxel Coated Devices (PCD) in order to address the outstanding concerns. These concerns largely focused on the observed increase in all-cause mortality associated with paclitaxel DCBs.

Presentation #1: Overview of clinical outcomes associated with paclitaxel DCBs used for the treatment of PAD (Ian Aldous)

Dr. Aldous gave a detailed overview of the clinical outcomes associated with PCD for treating peripheral vascular disease. His timeline of events started with the 2018 publication of the Katsanos meta-analysis paper, and he summarized the Katsanos data.

Dr. Aldous discussed the following letters sent by Health Canada:

• Section 39 letter to current licence holders
• safety alert letter to health care professionals that recommended alternative treatment options

He also discussed the 2019 U.S. FDA panel meeting. The FDA panel had concluded that a mortality signal did exist, though it could not elaborate on whether it was a device-specific effect or a class effect.

He also provided a summary of current devices licensed in Canada and outlined the most current information received from manufacturers.

The discussion that followed mainly focused on how the U.S. FDA and Health Canada shares information, as there had been limited interactions between the 2 regulatory bodies. Also discussed were the benefits of paclitaxel, including symptomatic relief in patients with claudication, and the increased risk of death and signal of increased all-cause-mortality.

Presentation #2: Current clinical practice in the use of DCBs used for the treatment of PAD (Thomas L. Forbes)

Dr. Forbes began his presentation by providing some context around PAD. He noted that the U.S. FDA/Vascular and InterVentional Advances (VIVA) meeting participants looked at patient-specific data around paclitaxel. With additional follow-up data included in the analysis, the late mortality signal was reduced but was still statistically significant.

In the face of this continued paclitaxel uncertainty, Dr. Forbes suggested that research and development within the medical industry would quickly pivot to other drug therapies. He indicated that we should be asking, “Why is there a survival advantage with treatment with a non-coated device (mortality drops to 8.1%)?” In response, he suggested a number of possible explanations, such as additional medical visits, increased likelihood of being on the right medication or other factors like exercise and medical management.

Dr. Forbes also commented on the Katsanos below-the-knee meta-analysis (2020). Paclitaxel was associated with worse outcomes for the composite amputation free survival endpoint (but not individual outcomes (for instance, freedom from all-cause death and major amputation)) at 1 year.

The discussion that followed focused on current clinical practices in Canada for treating PAD in cases of asymptomatic PAD, intermittent claudication and chronic limb-threatening ischemia. Also discussed was how clinical practice for treating PAD has evolved in Canada over the last year and how Canadian clinicians have interpreted the data associated with paclitaxel DCBs. This includes:

• a more selective use of paclitaxel
• improved patient awareness and consent
• critiques of the Katsanos meta-analysis
• hospitals’ interpretation of the Health Canada statement as a recall

Also addressed were the ongoing debates about modifying clinical guidelines for treating PAD. A last discussion point explored relevant clinical associations and working groups that could help to inform Health Canada’s regulatory considerations in this area.

Dr. Forbes advocated for an expanded role for post-market/post-approval registries. There was some support for limiting use of paclitaxel DCBs to patients with more severe disease (critical limb ischemia) and limiting their use for patients with claudication.

Presentation #3: Patient benefit associated with the use of DCB and plain old balloon angioplasty in above-the-knee PAD (Ahmed Kayssi)

Dr. Kayssi began his presentation with the conclusion that while drug-eluting technologies above the knee do result in improved patient benefits, it depends on how we understand those benefits. While the benefits are clear when measured by anatomic criteria, we cannot measure benefits according to clinical outcome criteria because they are not detected in trials.

Dr. Kayssi gave a few explanations for why patient-reported criteria are not more widely used in clinical trials:

• more patients are needed
• we lack robust instruments to measure patient-reported outcomes
• qualitative research is less prominent in medical research

He suggested that clinical trials often do not provide meaningful contributions to patient care. This is due to poor data collection methods, selectively reported publications, inappropriately interpreted results, and poor study design and outcomes.

Dr. Kayssi explained that clinical outcomes are often not given priority in cardiovascular trials because device trials aim to obtain regulatory approval rather than answer clinically relevant questions. Death and amputation are important but insufficient on their own.

Dr. Kayssi also suggested there are no good instruments available to assess patient treatment preferences. Existing quality-of-life instruments are not sensitive enough, though qualitative research on human behaviour may offer more insight in the future. Dr. Kayssi discussed quality-of-life endpoints when assessing the clinical benefits of DCBs (for example, when and how often to measure endpoints and other means of capturing clinical benefits), as most outcomes are poorly specified.

The discussion focused on whether Health Canada appropriately communicated risks following the Katsanos meta-analysis. Also discussed was whether pre-market device trials should require a higher burden of proof, similar to drug trials. In response, some committee members emphasized the differences between drugs and devices, especially around user factors. There are also competing perspectives to consider. For example, patients want new therapies, which can motivate early approval. Specifically, patients who face worse outcomes are also willing to take more risks. This phenomenon aligns with the Health Canada communications, which recommends use for sicker and more high-risk patients (for example, critical limb ischemia populations).

Presentation #4: Clinical expert opinion on appropriate indications for use and labelling requirements for paclitaxel DCBs in treatment of above-the-knee PAD (Sudhir Nagpal)

Dr. Nagpal began his presentation by providing context around peripheral vascular disease claudication and the prevalence of PAD, with reference to the Katsanos paper. He considered circumstances in which the treatment options should be used and relative risks (for example, patients with claudication at high risk of restenosis).

Dr. Nagpal considered whether DCBs were recommended:

• in patients with short life expectancies
• in patients with various conditions (for example, with critical limb ischemia or acute limb ischemia)
• as a re-intervention in patients who failed previous procedures (for example, DCB, percutaneous transluminal angioplasty, drug eluting stents or bare metal stents for in-stent restenosis)

Dr. Napal also addressed whether DCBs should be restricted to a maximum lesion length or have a limit on multiple uses of the subject devices. He also considered whether there are specific considerations for paclitaxel-eluting stents that are significantly different compared to DCBs.

The discussion focused on whether objective evidence was available at the population level to support indications for use and to introduce greater restrictions for limiting use to high-risk populations.

The committee also discussed how labelling changes, public notifications or contraindications in information for use could affect clinical practice. For example, the committee considered whether Health Canada should require manufacturers to update their labelling with revised indications for use or whether clinicians should manage use based on evolving clinical evidence with a broader indication for use on the label. The committee members largely supported clinician management of the use of DCBs.

Presentation #5: Patient perspective, patient preference and informed consent (Jillianne Code)

Dr. Code’s presentation focused on patient communication and informed consent:

• the types and amount of information that is most helpful to patients
• how to communicate effectively with patients about emerging issues
• Health Canada’s role in communication, especially improving communications between clinicians and patients

Dr. Code also considered whether Health Canada should:

• enforce labelling changes as a risk mitigation strategy
• take action to ensure that patients have appropriate access to safe and effective medical devices for treating PAD

The discussion focused on informed consent, sources of information for patients and Health Canada’s role in disseminating information. For example, Health Canada is not responsible for patient duty of care, so the information that Health Canada disseminates cannot be patient-specific.

Also discussed were effective ways of communicating with patients about emerging device-related issues, such as through:

• social media
• letters to their health care professionals
• information sessions and webinars
• patient-led organizations
• family caregivers (who are often present at appointments)

Also discussed were the type and amount of information patients typically want, such as:

• expected level of pain
• impact on quality of life
• “significant” complications
• potential for long-term adverse effects
• whether hospitalization would be required
• whether the proposed treatment could cause harm or death

Presentation #6: Evidentiary requirements for new DCBs (Karen Kennedy and Ben Elliott)

Through this presentation and discussion, Health Canada was seeking to determine the minimum clinical data requirements for future licensing decisions for paclitaxel DCBs and paclitaxel-eluting stents used to treat PAD.

The presenters began by explaining the current expectations of Health Canada. Health Canada expects a 1-year follow-up (minimum) from randomized controlled trial data to license a Class IV DCB or paclitaxel-eluting stent. Traditionally, these trials have been conducted across PAD patients to compare target lesion revascularization (TLR) rates (or a similar metric). These studies typically randomize treatment with the study device with non-drug coated balloon angioplasty. In light of the possibility of a late mortality risk with drug-eluting devices, Health Canada is reconsidering these expectations.

The presenters provided case studies for discussion in an effort to generalize recommendations for pre- and post-market clinical requirements for DCBs and paclitaxel-eluting stents. The committee identified clinically driven target lesion revascularization as a valuable endpoint but irrelevant to patients, while amputation-free survival was considered a good endpoint. The committee primarily recommended staying with a 1-year endpoint with long-term, meta-analysis style follow-up across device classes.

Recommendations for pre-market clinical evidence focused on endpoints, study design, patient populations, control groups and sample sizes. The committee was supportive of requiring Randomized Control Trials for DCBs with primary endpoints at 1 year and follow-up for at least 5 years. Sample size should be powered for a patency endpoint. Consideration should be given to the population studied, acknowledging that critical limb ischemia and claudication are different diseases.

Presentation #7: Requirements for use other than within the superficial femoral artery of DCB/DES (Chris Schmidt and Dheeraj Rajan)

Through this presentation and discussion, Health Canada was seeking to determine the clinical need and risk-benefit profile of paclitaxel DCBs and paclitaxel-eluting stents, specifically those used:

• below the knee
• in the arm (arteriovenous fistula for dialysis patients)
• in other vascular applications in the context of the all-cause-mortality signal identified in patients with PAD who have been treated in the superficial femoral artery

The presenters explained that most of the clinical data and analysis available were generated from treating PAD in the superficial femoral artery. In Canada, DCBs that are indicated for use below the knee or in the arm are Class II devices. They are not required to have a scientific pre-market evaluation of safety and effectiveness. The presenters explained that the clinical data available for these devices is limited.

Discussions focused on the following:

• clinical differences between patients (isolated superficial femoral artery disease or distal/more diffuse disease involving popliteal and infrapopliteal arteries)
• treatment of different patients in Canada (arteriovenous fistula, below-the-knee PAD)
• risk-benefit of treatments (DCB use below the knee and also DCB use in arteriovenous fistula)
• safety and effectiveness of coronary PCBs

Closing remarks and adjournment of meeting (John Ducas)

The Chair provided closing remarks and thanked the committee for their time and insight. Health Canada thanked the committee for their participation. The Chair adjourned the meeting.

Core committee members: John Ducas (Chair), Anita Asgar, Renzo Cecere, Eric Cohen, Marino Labinaz, Alan Menkis, Barry Rubin, Raymond Yee

Regrets: Christopher Feindel, Brent Mitchell, John Webb

Invited Guests: Munir Boodhwani, Thomas Forbes, Eric Wasylenko

Health Canada Representatives:

• Bureau of Cardiology, Allergy and Neurological Sciences (BCANS, TPD): Émilie Carrier, Timao Li
• Bureau of Policy, Science and International Programs: Despina Miteva, Carl Poulin, Andrew Raven,
• Director General's Office: John Patrick Stewart
• Medical Devices Bureau: Ian Aldous, David Boudreau, Kevin Day, Ben Elliott, Monica Forero, Jianming Hao, Amanda Jones, Karen Kennedy, Mark Korchinski, Roy Masters, Catherine Milley, Chris Schmidt, Peggy Seely, Maurice Sylvain, Lanyi Xu
• Marketed Health Products Directorate (MHPD): Patrick Fandja, Dongjiang Song, Elaine Wong, Hui Zheng
• Regulatory Operations and Enforcement Branch (ROEB): Barbara Harrison

Abbreviations used in this record:

ACM:

All cause mortality

AV node:

Atrio-ventricular node

BBB:

Bundle branch block

BMS:

Bare metal stent

CHF:

Congestive Heart Failure

CLI:

Critical limb ischemia

CRT:

Cardiac resynchronization therapy

CV:

Cardiovascular

DAPT:

Dual Antiplatelet Therapy

DES:

Drug eluting stent

FET:

Frozen elephant trunk

FIH:

First-in-human

HBP:

His bundle pacing

HC:

Health Canada

HCP:

Healthcare professional

HF:

Heart failure

IFU:

Instructions for Use

LV:

Left ventricle

LBBB:

Left bundle branch block

MDB:

Medical Devices Bureau

MDSAP:

Medical Devices Single Audit Program

MPP:

Multi-point pacing

MR:

Mitral regurgitation

MRI:

Magnetic Resonance Imaging

MVR:

Mitral valve replacement

NOAEL:

No observable adverse effect level

PAD:

Peripheral artery disease

PCT:

Pacing Capture Threshold

PCI:

Percutaneous Coronary Intervention

RV:

Right ventricle

RCT:

Randomized Controlled Trial

RDS:

Regulatory Decision Summary

SAC-MDUCS:

Scientific Advisory Committee on Medical Devices Used in the Cardiovascular System

SAP:

Special Access Program

SAR:

(MRI) Specific absorption rate

SND:

Sinus node dysfunction

TAVI:

Transcatheter aortic valve implantation

TAVR:

Transcatheter aortic valve replacement

TMVI:

Transcatheter mitral valve implantation

TMVR:

Transcatheter mitral valve replacement

TPD:

Therapeutic Products Directorate

TEE:

Transesophageal echocardiogram

US FDA:

United States Food and Drug Administration

V:

Volt

Presentations are available upon request. The responses outlined below are representative of the discussions/recommendations generated by the committee.

1. Roundtable, Opening Remarks & Welcome

Dr. John Patrick Stewart, Director General, TPD

Dr. Stewart provided opening remarks, introducing TPD's role in overseeing the regulation of medical devices and drugs, and welcomed all committee members and guest speakers. He highlighted the recent media coverage on medical devices and, in particular, the rigorous premarket safety review of medical devices already in place but acknowledged room for improvement. He also commended the committee on serving as a great source of information used to guide the regulation of new medical devices.

Dr. Stewart highlighted the three pillars of the Medical Devices Action Plan and HC's plan to further explore increased patient input.

2. Review of the Agenda, Affiliations and Interests Declarations, and Confidentiality Agreement

David Boudreau, Executive Director, MDB

Dr. John Ducas, Committee Chair

Mr. Boudreau provided an overview of the projects supporting the Medical Devices Action Plan, ranging from regulatory review to international collaboration to increased disclosure and release of information.

Dr. Ducas thanked members for participating in the meeting and confirmed acceptance of the agenda. Committee members, presenters, and observers introduced themselves and provided a verbal update of declarations of affiliations and interests from those initially declared. No declarations required any restrictions on members' participation.

3. Summary of how Health Canada has used information generated from previous SAC-MDUCS meetings

Kevin Day, MDB

Mr. Day provided a summary of past committee discussions and highlighted how information from those discussions influenced medical device decision-making at HC.

• Transcatheter heart valves: The committee noted that transfemoral access is the preferred approach for standard TAVR and that additional caution is warranted with alternative approaches. Based on this, HC assesses indications for use with these approaches differently. The committee also highlighted that pacemaker implantation is not a benign intervention and considers it an important post TAVR consequence, which should be considered in the context of risk/benefit assessments. As indications have moved from extreme to high and intermediate risk patients, who are younger and healthier, HC now has stronger clinical justification to request longer term data for TAVR valves from manufacturers, despite international standards requiring only five-year data.
• DAPT following coronary stenting with DES: Following the presentation of the 2018 CCS guidelines with strong rationales supporting early termination of the DAPT, HC is now supportive and ensures that references to those guidelines appear in the IFU documents. As part of assessing clinical data for DES devices and determining appropriate clinical comparators, it was helpful for HC to learn that BMS are no longer commonly used, and that DES are considered the gold standard technology.
• CRT for heart failure – the potential for multi-point pacing (MPP) to enhance CRT response rates continues to be of interest to HC. Following a committee recommendation, HC is obtaining feedback from manufacturers about the effectiveness of algorithms, and there is a sense that these algorithms are not being widely adopted.
• Drug coated balloons/stents – as HC analyzes the potential increase in late all cause mortality (ACM) associated with paclitaxel coated balloons or stents in the periphery, it has been helpful to incorporate clinical perspectives on how these devices are used in Canada.

Mr. Day thanked the committee for helping shape how HC responds to changes in the medical device field.

4. Discussion on Patient Group Representative

Health Canada employees and Committee members

HC has committed to including patient group representatives on all scientific advisory committees. Draft criteria was discussed for MDUCS's patient group representative. The candidate should be able to share:

• patient experiences and/or important considerations from patients with the use of CV medical devices;
• the impact of CV medical devices on the quality of life of patients;
• insight on the decision-making process with respect to the use of a CV medical device; and
• considerations about patient preferences in selecting appropriate cardiovascular medical devices.

Patients should be informed and involved in decision-making but given the complexity of the discussions, representatives require a certain level of understanding of cardiovascular medical devices, physiology, and medical language.

The committee offered several thoughts for HC to consider in the selection process.

5. Ascending Aortic Dissection - Treatment

Presenter: Dr. Munir Boodhwani (Guest speaker)

Dr. Boodhwani introduced himself as a principal investigator of post-market surveillance for the Thoraflex device and an executive member with the Canadian Thoracic Aortic Collaborative. He presented a brief overview of the pathophysiology of Type A dissection and clinical outcomes.

6. SAP Authorization of Devices for First-in-human or Early Developmental Use

Presenters: Dr. Anita Asgar (Committee member), and Dr. Eric Wasylenko (Guest speaker)

Clinical Case Study

Dr. Asgar described a clinical case she was involved in that required authorization through the Special Access Program for a first/second-in-human TMVI heart valve, for which limited pre-clinical information was available. She presented a timeline of the patient's condition, her clinical experience with the FIH mitral valve, and the health outcomes from its use.

Clinical Ethics

Dr. Wasylenko introduced himself and indicated that he had no conflicts of interest to declare. He also acknowledged that the information he presents has been adapted from other organizations he has worked with; he chairs the ethics consultative group for the Public Health Agency of Canada.

Dr. Wasylenko presented the ethical considerations involved in physician decision-making, including attitudes towards health outcomes. His presentation also delved into the risk matrix approach and factors to ensure that decision-making is performed ethically, including the influence of physicians and the need to balance a patient's autonomy to make an informed decision with the duty to provide benefit.

He described the risk matrix approach and presented five considerations to help ensure that health decision- making is insightful and ethically done well:

1. Vulnerability of the patient due to multiple potential coercive forces (hope, family pressures, bravery and courageousness, physician-patient relationships), while patient autonomy should also be respected.
2. Balancing of respect for a patient's autonomous choosing vs. fulfilling the professed duty of a clinician to provide benefit. There is a place for benign paternalism to have some influence, particularly when decisions need to be made outside of normal circumstances.
3. Influence of clinicians and health care providers on the patient.
4. The patient's wants/needs and goals need to be understood and together with the knowledge and experience of the treating clinicians become the agreed-upon Goals of Care. For each patient, the clinician cannot assume that the relative importance of: life meaning; meaning of suffering; attention to quality of life and length of life; symptom abatement; and support of functional capability is the same for each individual patient.
5. Safeguards help navigate issues and may include: assurance that goals of care conversations are skillfully had; inclusion of relevant people within the patient's circle; consideration of whether the institution has a decisional collaborator role; establishment of an up-front mechanism for transparent reporting that recognizes unique patient privacy concerns; assurance of availability of clinical supports in the event of device or process failure to minimize and manage unanticipated harms; and, assurance of the availability of an informed substitute decision-maker in case the intervention results in the patient becoming incapable of making an informed decision during the remainder of an episode of care or further care..

7. Drug Coated Balloon (DCB) – The Paclitaxel Effect

Presenter: Dr. Thomas L. Forbes (Guest speaker)

Dr. Forbes prefaced his presentation by acknowledging that two manufacturers of paclitaxel-coated devices provide financial support to the University of Toronto division in the form of unrestricted education grants, and that he was the national Principal Investigator for a study involving a Cook endograft. He provided some background, described the use of paclitaxel-coated stents and balloons for PAD, and highlighted study findings, including the initial meta-analysis (Katsanos et al., 2018) that reported a dose-dependent increase in ACM following the application of paclitaxel-coated stents and balloons in the femoropopliteal artery. Dr. Forbes also summarized industry and government responses and described the paradigm shift in treating patients with less severe PAD.

8. Use of labelling (IFU & Other)

Presenter: Dr. John Ducas (Chair)

Dr. Ducas summarized the recent media attention surrounding medical device adverse events and information that is made available for public consumption. He outlined several possible rationales and discussed how clinicians use labelling, highlighting clinical data from sources such as clinical trials and real world evidence.

Furthermore, he presented a summary of the views and opinions of the Canadian Medical Protective Association concerning potential medical and legal risks associated with "off-label" use, along with recommendations for minimizing clinician liability.

9. Acceptable PCT Change in LV vs. RV

Presenter: Dr. Ben Elliott (Senior Scientific Evaluator, MDB)

Dr. Elliott presented the proposed HC approach to MR-Conditional labelling for pacing systems that are more susceptible to RF-induced lead heating than previously licensed MR-Conditional systems. As elevated lead temperature may be associated with myocardial damage (including fibrosis) and increased pacing capture thresholds (PCTs), HC seeks to mitigate MRI-related risk (i.e. reduced battery life and loss of capture) by introducing limits on MRI scan conditions for patients implanted with pacing systems where MRI scan-induced heating may lead to PCT increase.

10. His Bundle Pacing

Presenter: Dr. Raymond Yee (Committee member)

Dr. Yee presented on the usage of HBP. He explained that although RV pacing has been the standard treatment for significant bradycardia, there is renewed interest in HBP as it is thought to achieve superior hemodynamic results and patient outcomes. In addition, right sided pacing is known to negatively impact hemodynamics and LV function. He described situations where it could be used and an overview of early attempts.

11. Closing Remarks and Adjournment of Meeting

Dr. John Ducas (Chair)

The Chair provided closing remarks and thanked the committee for their time and insight. HC thanked the committee for their participation. The meeting was adjourned.

Committee Members Present: John Ducas (Chair), Eric Cohen, Marino Labinaz, Renzo Cecere, Brent Mitchell

Regrets: Alan Menkis, Christopher Feindel, Barry Rubin, John Webb, Raymond Yee

Invited Guests: Anita Asgar, Kevin R. Bainey, John Granton, Ashish Shah

Health Canada Representatives:

Office of Science: Hripsime Shahbazian

Medical Devices Bureau (MDB): Patrick Stuart, David Boudreau, Kevin Day, Ian Aldous, Marianne Ariganello, Ben Elliot, Monica Forero, Jianming Hao, Amanda Jones, Karen Kennedy, Mark Korchinski, Roy Masters, James McGarrity, Catherine Milley, Chris Schmidt, Maurice Sylvain, Lanyi Xu

Bureau of Cardiology, Allergy and Neurological Sciences (BCANS):Timao Li

Marketed Health Products Directorate (MHPD): Patrick Fandja

Regulatory Operations and Regions Branch (RORB): Barbara Harrison

Abbreviations used in this record:

ASA:

Acetylsalicylic acid

ACC:

American College of Cardiology

ACS:

Acute Coronary Syndrome

ACT:

Activated Clotting Time

AHA:

American Heart Association

AI:

Aortic Insufficiency

ASX:

Asymptomatic

BID:

Twice daily

CABG:

Coronary artery bypass grafting

CHF:

Congestive Heart Failure

CT:

Computed Tomography

CTA:

Computed Tomography Angiography

CRT:

Cardiac resynchronization therapy

DAPT:

Dual Antiplatelet Therapy+

EES:

Everolimus-Eluting Stent

EVAR:

Endovascular aortic aneurysm repair

HC:

Health Canada

IPG:

Implantable pulse generator

LA:

Left atrium

LM:

Left Main

MDB:

Medical Devices Bureau

MRA:

Magnetic Resonance Angiography

MRI:

Magnetic Resonance Imaging

NSTE-ACS:

Non-ST-segment elevation acute coronary syndrome

OD:

Once daily

PAH:

Pulmonary Arterial Hypertension

PCT:

Pacing Capture Threshold

PCI:

Percutaneous Coronary Intervention

PFO:

Patent Foramen Ovale

POBA:

Plain old balloon angioplasty

PPM:

Permanent Pacemaker

PTCA:

Percutaneous transluminal coronary angioplasty

RA:

Right atrium

RCT:

Randomized Controlled Trial

SAC-MDUCS:

Scientific Advisory Committee on Medical Devices Used in the Cardiovascular System

SAP:

Special Access Program

TAVI:

Transcatheter aortic valve implantation

TAVR:

Transcatheter aortic valve replacement

TTE:

Transthoracic echocardiogram

TPD:

Therapeutic Products Directorate

TEE:

Transesophageal echocardiogram

V:

Volt

VAD:

Ventricular Assist Device

VARC-2:

Valve Academic Research Consortium-2

VCD:

Vascular Closure Device

VIV:

Valve-in-Valve

1. Opening Remarks & Welcome

Dr. J. Patrick Stewart, Director General, Therapeutic Products Directorate

Dr. J. Patrick Stewart opened the meeting and welcomed all committee members and guest speakers. Dr. Stewart identified and described current and ongoing efforts related to Stakeholder engagement including the creation of a new digital health unit with a focus on cyber security, which touches the cardiovascular space. Dr. Stewart highlighted the value of the input provided by the SAC-MDUCS.

2. Review of the Agenda, Affiliations and Interests Declarations, and Confidentiality Agreement

David Boudreau, Executive Director, MDB

Dr. John Ducas, Committee Chair

David Boudreau reviewed the agenda items with the committee and presented the guest speakers.

3. Summary of How Health Canada has used Information Generated from Previous SAC-MDUCS Meetings

Kevin Day, MDB

Mr. Kevin Day presented a brief summary of how previous advice and recommendations provided by the committee have been considered by Health Canada (HC).

The following topics were noted:

• MRI conditional IPGs: based on feedback, it was encouraged to increase the PCT allowance to 1.0 V with proper warnings in the labelling.
• Renal Denervation: the importance in using sham controls and monitoring drug compliance was highlighted.
• Remote monitoring of IPGs: it was helpful for HC to better understand the contracting elements associated with manufacturers, given that ICD remote monitoring is available in Canada but not for pacemakers.
• Intra-atrial shunting: the SAC-MDUCS recommended proceeding with caution, and provided good guidance and understanding.
• Various techniques available to improve CRT responder rate: Multipoint Pacing algorithms have been introduced in CRT devices and SAC-MDUCS recommended they should be limited to CRT non-responders, and labelling warnings should indicate that potential for reduced battery life with Multipoint Pacing.
• Drug Coated Balloon Angioplasty: the SAC-MDUCS recommended consideration of non-inferior safety and superior effectiveness. POBA continues to be used as a comparator for BTK interventions.
• Ventricular Assist Devices: the SAC-MDUCS discussions provided good background of VAD technologies and challenges, including that of thrombosis issues. The information provided by the committee supported the licensure of the HeartMate 3 device in January 2018.

Mr. Day offered that the SAC-MDUCS discussions significantly influence how HC regulates medical devices, and on how HC understands the risks associated with these regulations. The discussions further provide HC with some very meaningful basis to challenge some of the manufacturers and also help position the technology in an appropriate space in the Canadian medical system.

4. PFO Closure Devices

Dr. Ashish Shah, Guest Speaker

In Canada, about 345 PFO closure procedures were performed in 2016. This is an estimate of the number of devices used in Canada, based on the sale numbers of Amplatzer and Gore devices.

Three major trials were published in 2017 that compared PFO closure with medical therapy. All three trials showed the rate of stroke/cryptogenic stroke was significantly lower with PFO closure as compared to medical therapy, and patients with: a substantial shunt, persistent shunting, atrial septal aneurysm, and those on antiplatelet, but not anticoagulant medical therapy, benefitted most.

5. Large Bore Femoral Artery Closure Devices

Dr. Marino Labinaz, Committee Member

Dr. Labinaz introduced himself and declared he had no disclosures and no financial interests in catheters or closure devices.

There are no consistent definitions in the literature; however, large bore vascular access sheaths are generally defined as those larger than 10 Fr. He indicated that this value refers to the internal diameter of the catheter, while the external diameter impacts the patient and is what the artery 'sees'; he also offered that the external diameter is also not generally published. E.g. the 14 Fr Edwards e-sheath has an external diameter of 23 Fr, which further expands when the valve goes through it.

First device by Abbott was a suture-based technology, the Prostar XL. Dr. Labinaz described a 2011 meta-analysis (Eur J Vasc Endovasc Surg (2011) 41, 201-213). Across 692 patients, Prostar XL had a 90% success rate (defined as adequate hemostasis without the need to convert to surgical repair), was 1 hour shorter, and has a complication rate 10% less than that of the surgical arm. The Prostar XL became the gold standard for large bore device closure.

Furthermore, the effectiveness of the Prostar XL and the Proglide devices for vascular closure following TAVI procedures were compared by Barbash et al. (Eur Heart J. 2015 Dec 14; 36(47):3370-9). Major vascular complication rate (VARC) was significantly higher in the Prostar XL vs. the Proglide group (9.5% vs. 5%) and included major bleeding, and acute injury (transfusion, and hypotension). However, mortality rate was not increased. Also, stenosis rate was higher with the Proglide due to the "pinch" that the sutures create on the artery, which is normally left alone. Based on the subgroup analysis, with sheath sizes larger than 18 Fr, it appears that the Prostar XL could be better for closing large arteriotomies.

A systematic review of the safety and efficacy of the ProstarXL vs. Proglide after TAVR and EVAR, Maniotis et al. (2017) showed all vascular complications (VARC) were numerically higher with the Prostar XL, and while mortality was not greater, acute kidney injury was higher with ProstarXL. Dr. Labinaz indicated his own experience was similar, and based on these data his center uses the Proglide for large bore device closure.

The Japanese OCEAN-TAVI study compared single versus double Proglide in 16Fr to 20Fr TAVI (Kodama A et al Catheter Cardiovasc Interv 2017: 90 E55-62), and found a single Proglide in transfemoral TAVI could achieve equivalent, acceptable rates of technical success and procedural complications compared with the double Proglide technique. Dr. Labinaz indicated he uses a single Proglide technique in 2/3 of patients, especially if they are 14 Fr eSheaths, and observes less "pinching", stenosis with a single Proglide.

The safety and efficacy of the MANTA plug-style system, as compared to the Proglide (two device technique) was demonstrated in patients undergoing TAVI (Int J Cardiol. 2018 Jul 15; 263:29-31). Device failure rates were not significant different, but were greater in the Proglide group.

6. Evolving Clinical Use of TAVR and Increasing Clinical Data Stratification

Dr. Anita Asgar, Guest Speaker

Dr. Asgar introduced herself as an Interventional Cardiologist at the Montreal Heart Institute, and declared that she is a consultant for Medtronic, Edwards LifeSciences and Abbot Vascular.

She indicated it is important to realize that TAVI technologies have undergone multiple design iterations, and despite the multiple differences in design, they are intended to do the same thing.

What's been learned is how to better evaluate and classify patients, as outlined in the ACC/AHA 2014 guideline risk assessment. In addition, clinicians have learned which patients they should not treat, such as those with important co-morbidities and those who are frail and considered to be at prohibitive risk (medically futile).

Current indications for TAVI are approved for high-risk patients and there is a pending approval for intermediate-risk patients (data is currently available). The question remains if the indications should be expanded to low-risk patients.

Intermediate-risk Patients

The PARTNER 2A RCT showed no difference in primary endpoint for all-cause mortality or disabling stroke for TAVR vs SAVR at 2 years, in intermediate-risk patients. Of note, in the transfemoral-access cohort, TAVR resulted in a lower rate of death or disabling stroke than surgery, whereas in the alternative access cohort, the outcomes were similar to or worse than those with surgery and appear to be inferior to those with transfemoral TAVR. Take home message for surgeons: intermediate-risk patients who can achieve transfemoral access, TAVI is better. If you have to use alternative access, SAVR is better. SURTAVI trial also showed no differences in the primary endpoints between TAVR and SAVR in intermediate-risk patients, which led the ACC to change the indications in 2017 and recommend TAVI as a Class II indication for patients at intermediate surgical risk. For high and prohibitive risk, TAVI is now a Class I indication. The FDA approved TAVI for intermediate-risk patients in August 2016. However, only SAVR has a Class I indication for low risk patients.

There has been a movement for a TAVI-specific risk assessment that includes imaging, and TAVI approaches are now being done under minimal sedation, in which patients are conscious. So, in terms of the next frontier: low risk, patients with asymptomatic AS, moderate AS and HF, and TAVI valve in valve.

Low-risk Patients

Two new trials are underway, have completed enrollment, and are now in the follow-up phase. The PARTNER 3 trial compares TAVR (transfemoral access only) to SAVR in low-risk patients (STS<4). An alternative access registry will be included. Recall that the results in the alternative access arm were quite poor in the PARTNER 2 trial. The primary endpoint will be all-cause mortality, all strokes or re-hospitalization at 1-year post-procedure.

Dr. Asgar suggested that special considerations related to low-risk patients were raised in the NOTION trial (Europe), 2009, which compared TAVI to SAVR in lower-risk patients over 70 years of age. The primary outcome was composite of all-cause mortality, stroke or MI, safety outcomes at one year. It took them 4 years to randomize. The trial was designed to show superiority of COREVALVE (1st gen), but their primary outcome estimates were very inaccurate: 5% event rate in the TAVI arm and 15% in the SAVR arm. These are older patients with low STS, and low rates of co-morbidities. The study was underpowered, so one should not expect to see differences. Five-year outcomes of this trial show, no sig difference in all-cause mortality or stroke, or MI. Messages from this: the low risk population was comprised of older individuals with few/low burden comorbidities. We expect their improvement in QoL would be better. TAVI access route should be an important consideration – transfemoral approach is better. In a healthier or low-risk population, their tolerance for risk is much lower. Important for this population is valve durability; because they represent a healthier population, their life expectancy is also expected to be greater and with this the need for long-term valve durability, as well as future coronary access (valve leaflets may obstruct coronary ostia) is important as they may need an intervention in the future. As the TAVI outcomes had fewer bleeding complications, more vascular complications, less acute kidney injury, but very high PPM implantation (~1/3) vs. 2% for surgery.

With respect to valve durability, there are some data that describe bioprosthetic failure out to 72 months that is not different between TAVI vs. SAVR arms.

Comparing these two options in low-risk patients, PPM implantation is a risk and cost issue, as patients are "condemned" to continual follow-up. Pts that become pacemaker dependent after TAVI, and are RV paced, are more likely to be readmitted with HF. This is becoming an issue.

It's important to recognize that all valves are not created equally, and because each one has different complications, each valve must be evaluated differently. In Quebec, Dr. Asgar indicated she has seen pacemaker rates from 10 to 50% depending on the valve that's used.

7. Treatment of Unprotected Left Main Coronary Disease

Dr. Eric Cohen, Committee Member

The motivation for the talk is that there are recent and important RCT trial results that inform LM revascularization, NOBEL and EXCEL findings are not completely concordant with existing guidelines for the treatment of Left Main Disease. In addition, Dr. Cohen acknowledged that HC may be anticipating broadened indications for DES that include LM use.

Treatments of Left Main Disease (LMD) are much broader than just the indications for use for a particular device, as there is uncertainly within the medical community about the role of stenting in left main disease and when it should be done. An interventionalist's hierarchy of decision-making considerations when treating left main disease includes: define anatomy, determine whether revascularization required (there's a big spectrum of mild to moderate LM disease), identify burden of ischemia, consider symptoms, medical therapy appropriateness or treatment in the presence of other CA disease, and the options available for LM treatment (stent vs bypass). Dr. Cohen indicated that there is often no choice, so it becomes a question of whether the LM anatomy suitable for intervention. The choice of stent and whether the stent is indicated for LM are often the last and least important considerations.

Context and background: paper from 1981 CAS study registry (CA patients). The findings showed that patients treated medically didn't do well for LM, and surgery was superior, and this was clear across all subsets. One may even extrapolate from these data that LM lesions that are not hemodynamically important, may become just as stable with aggressive medical treatment, but RCT data are needed. Today, everyone is treated with statins/ASA, so we don't know the natural history of moderate LM patients.

One of the very first angiography reports, emergency POBA for LM was attempted and shown to be the appropriate treatment. In another study of 20 patients, POBA trial (1985) concluded that bypass is best for stable elective LM patients, but emergency PTCA is better for unstable high risk patients when surgical risk is too high. Dr. Cohen stated that although this study is more than 30 years old, this approach is still used today.

What limited the development of LM PCI was the unpredictability of the acute result with POBA, and late restenosis risk, as well as the uncertainty in treating bifurcations. Generally, the thinking was the surgery was preferable to PCI and that pervaded clinical decision making.

Historically, most RCT trials suggested there was some equipoise between PCI and surgery, and surgery was largely favoured. The trials were relatively small, and occurred prior to 2011, so PCI did not include 2nd generation stents.

Contemporary studies, meta-analysis - EXCEL and NOBLE trials.

At a time when approaches to bifurcations were established, as well as the ability to support patients hemodynamically (maturity of PCI of the left main), the EXCEL trial included 2,000 randomized patients (+ 1,000 in a registry). Patients with a high burden of ischemia were included (50-70%), and those with intermediate to high complexity lesions. Primary endpoint was death, stroke or MI at 3 years, and was designed as a NI trial with a provision to test for superiority between CABG and PCI (Xience V). Average age was 66 years; however, LM stenting is generally done on much older patients. Approx. 30% were diabetic. 5-7% had a prior MI/TIA which impacts surgical risk. Based on syntax scores, lesion complexity was a bit higher than mild/moderate. No significant difference at 3 years. But, adverse events are higher with CABG. Five-year data is pending. Therefore, the non-inferiority hypothesis was met. When you add in ischemia-driven revascularization – the event rate is higher with PCI, but it's not clear whether the re-interventions were for LM or other segments.

The NOBLE trial included patients, in whom the vast majority had stable LM disease. There were similar inclusion criteria; NOBLE excluded CTO or bifurcation disease. Primary endpoint included: death, stroke, MI and primary TLR. Stent used was mostly the Biolimus. Event rates were lower than expected, and recruitment needed to be extended. The challenge is that too many eras of technology were covered. Only 15% diabetics (half of N.American level) and Syntax score was intermediate. It was structured as a non-inferiority trial, but failed. CABG was superior on the primary endpoint. Non-procedural MI is higher in the PCI group. The findings seem to indicate that bypassing the troubled coronary vasculature is associated with fewer adverse events. TLR is higher with PCI, but rate is ~10% with CABG.

The guidelines have not been revised. Surgery gets Class II (B level evidence) and PCI gets a IIa for low complexity, and IIb for moderate complexity, and III for high complexity. It's hard to imagine the data to support PCI would become more convincing over time. In Canada, there is a 2014 position statement on multi-vessel revascularization that references LM. Dr. Cohen's position is that an individualized approach is warranted, which should consider: coronary complexity, technical feasibility, co-morbidities, local expertise, and patient preference. Patients should be made aware of a historical preference for CABG, but that more recent data has demonstrated some equipoise.

He presented several "Indications for Use" documents and highlighted that the indications only mention increasing the lumen diameter, and don't reflect any barriers to doing LM. He believed that the precautions for LM are in the same category as complex acute MI.

Committee Members Present: John Ducas (Chair), Renzo Cecere, Marino Labinaz, Alan Menkis, Brent Mitchell, Joaquim Miró, Raymond Yee

Regrets: Eric Cohen, Christopher Feindel, Barry Rubin, John Webb

Invited Guests: Mathieu Bernier, Yaariv Khaykin, Ratika Parkash, Marcel Ruzicka

Health Canada Representatives:

Office of Science: Hripsime Shahbazian

Medical Devices Bureau (MDB, TPD): Kevin Day, Ian Aldous, Marianne Ariganello, Ben Elliot, Ian Glasgow, Jianming Hao, Karen Kennedy, Mark Korchinski, James McGarrity, Roy Masters, Catherine Milley, Chris Schmidt, Maurice Sylvain, Lanyi Xu, Marc Lamoureux, Amanda Jones

Bureau of Cardiology, Allergy and Neurological Sciences (BCANS, TPD): Mick Gelsema, Timao Li

Regulatory Operations and Regions Branch (RORB): Barbara Harrison

Marketed Pharmaceuticals and Medical Devices Bureau (MHPD): Patrick Fandja, Hui Zheng, Shirley Chou, Elaine Wong

Abbreviations used in this record:

6MWT:

six minute walk test

ABPM:

ambulatory blood pressure monitoring

ACS:

acute coronary syndrome

ADHF:

acute decompensated heart failure

AE:

atrio-esophageal

AF:

atrial fibrillation

AFL:

atrial flutter

AP:

accessory pathway

ASD:

atrial septal defect

BIVAD:

biventricular assist devices

BNP:

B-type natriuretic peptide

BP:

blood pressure

BTK:

below the knee

BTT:

bridge to transplant

CHF:

congestive heart failure

CIED:

cardiac implantable electrical device

CFAE/CFE:

complex fractionated (atrial) electrogram

CFS:

contact force sensing

CPVA:

circumferential pulmonary vein ablation

CRT:

cardiac resynchronization therapy

CT:

computerized tomography

CTI:

cavo-tricuspid isthmus

DCB:

drug coated balloons

DSMB:

Data and Safety Monitoring Board

EAT:

ectopic atrial rhythm

ED:

emergency department

EF:

ejection fraction

ER:

emergency room

GFR:

glomerular filtration rate

eGFR:

estimated glomerular filtration rate

GDMT:

guideline-directed medical therapy

HF:

heart failure

HFpEF:

heart failure with preserved ejection fraction

HFrEF:

heart failure with reduced ejection fraction

HTN:

hypertension

IASD:

interatrial shunt device

ICD:

implantable cardioverter defibrillator

IFU:

instructions for use

ITA:

Investigational Testing Authorization

INTERMACS:

Interagency Registry for Mechanically Assisted Circulatory Support

KCCQ:

Kansas City cardiomyopathy questionnaire

LA:

left atrium

LAP:

left atrial pressure

LVAD:

left ventricular assist device

LVEF:

left ventricular ejection fraction

LV:

left ventricle

MACCE:

major cardiovascular and cerebrovascular event

MACNE:

major adverse cardiovascular or neurological event

MDB:

medical devices bureau

MHLF:

Minnesota living with heart failure questionnaire

MR:

magnetic resonance

MRI:

magnetic resonance imaging

MSK:

musculo-skeletal

MSNA:

muscle sympathetic nervous system activity

NSR:

normal sinus rhythm

NHLBI:

National Heart, Lung, and Blood Institute

NT-pro-BNP:

N-terminal-pro-BNP

NYHA:

New York Heart Association

OMM:

optimal medical management

PCI:

percutaneous coronary intervention

PCWP:

pulmonary capillary wedge pressure

PCT:

pacing capture threshold

PTA:

percutaneous transluminal angioplasty

PTFE:

polytetrafluoroethylene

PV:

pulmonary vein

PVC:

premature ventricular contraction

PVI:

pulmonary vein isolation

QoL:

quality of life

Qp/Qs:

pulmonary-to-systemic flow ratio

RA:

right atrium

RAS:

renal artery stenosis

RBF:

renal blood flow

RCS:

remote catheter System

RCT:

randomized clinical trial

RDN:

renal denervation

RF:

radiofrequency

RHC:

right-sided heart catheterization

RM:

remote monitoring

ROC:

receiver operating characteristic (analysis)

RV:

right ventricle

RVAD:

right ventricular assist device

RVF:

right ventricular failure

RVMI:

right ventricular myocardial infarction

RVR:

ventricular rate or response

SAC-MDUCS:

Scientific Advisory Committee on Medical Devices Used in the Cardiovascular System

SAEs:

serious adverse events

SAP:

special access program

SBP:

systolic blood pressure

SD:

Standard Deviation

TAVR:

transcatheter aortic valve replacement

TAH:

total artificial heart

TEE:

transesophageal echocardiography

TIA:

transient ischemic attack

TMVR:

transcatheter mitral valve replacement

TPD:

Therapeutic Products Directorate

VT:

ventricular tachycardia

VAD:

ventricular assist devices

1. Opening Remarks & Welcome

Dr. John Ducas, Committee Chair

Dr. Ducas opened the meeting, welcomed the committee members and guest speakers. He invited Dr. Pat Stewart, the current Director General of the Therapeutic Products Directorate (TPD), to provide opening remarks. Dr. Stewart introduced himself, thanked the committee members and guest speakers for sharing their time and expertise and acknowledged the efforts all participants had made to attend the meeting. He noted that the Government is moving forward with number of initiatives to try and improve access and appropriate use of health products. In medical device area Health Canada is looking at innovative health technology, artificial intelligence, home monitoring. He provided updates regarding International Medical Device Regulators Forum (IMDRF) and discussions regarding relying more heavily on Real World Data to inform regulatory decisions. He noted the importance of the Scientific Advisory Committee on Medical Devices Used in the Cardiovascular System (SAC-MDUCS) to Health Canada's regulatory review and decision-making process and acknowledged the committee on its continued support. He concluded by wishing the committee members and participants a productive meeting.

2. Review of the Agenda, Affiliations and Interests Declarations, and Confidentiality Agreement

Dr. John Ducas, Committee Chair

The Chair reviewed the agenda items with the committee. The agenda was accepted with minor adjustments to accommodate last minute changes. Question 5: Treatment of Unprotected Left Main Coronary Artery Stenosis has been postponed to the next meeting. Instead a new topic was added to the agenda to address the use of Cardiac Implantable Electrical Devices (CIEDs) used in an MRI setting that was originally submitted for e-consultation. Members were reminded to disclose any conflicts prior discussion and as the meeting proceeds.

He invited Hripsime Shahbazian to address the next topic.

3. Review of Terms of Reference, Membership and members Affiliations and Interests

Hripsime Shahbazian, Office of Science, TPD

Hripsime Shahbazian informed the members that, as discussed at the last meeting in 2016, Health Canada conducted a membership renewal for this committee. The revised Membership List and Summary of Expertise, Experience and Affiliations and Interests for SAC-MDUCS are now posted on Health Canada Website.

She noted that further to discussion at the last meeting the Terms of Reference (ToR) for this committee was also revised to include the following statement:

"Before each committee meeting the chair will ask the members/invited experts to provide their consent to the recording of their views and opinions in the Record of Proceedings (RoP) and to the publication of the RoP on Health Canada's Website."

In addition, the revised ToR now includes a requirement to select a Vice-chair, who at the request of the Chair, or in the case of the Chair's absence, will chair the meeting(s) and take on the Chair's other tasks, as required.

The revised ToR was reviewed and officially accepted by the members on February 22, 2017 and is now posted on Health Canada Website.

In closing Hripsime Shahbazian congratulated the committee members for the Committee's 15th anniversary. She noted that some of the members have served on the committee since its inception, including Dr. Raymond Yee (past chair), Dr. John Ducas (current chair), Dr. Joaquim Miró and Dr. L. Brent Mitchell as well as two of the ad hoc members: Dr. Stephen Lownie and Dr. Chris Simpson.

She thanked all members and presenters for their active participation and contribution to the advisory process.

4. Summary of How Information from Previous Meeting Is Being Used

Kevin Day, Medical Devices Bureau, TPD

Mr. Kevin Day presented a brief summary of how previous advice and recommendations provided by the committee have been considered by Health Canada.

The following key discussion topics and their impact were noted:

CRT Response and Multi-Point Pacing have been very active:

• Working with recommendation to limit use to 'failed' CRT
• From previous SAC-MDUCS discussions, battery impact being included in IFU
• Allowing access to algorithms where there does not appear to be a safety concern
• Some on-going monitoring taking place

Drug Coated Balloons (DCBs) continue to be an active area:

• Good to assess superior effectiveness compared to PTA
• Good for reference that not all DCB are the same
• Additional attention given to Below the Knee (BTK) and Dialysis indications
• Challenge with Class II indications

Transcatheter Mitral Valve Replacement (TMVR) is an active area in terms of ITA and SAP:

• Better understanding of patient need and potential patient population to be treated
• Very good context for the emerging technologies

Transcatheter Aortic Valve Replacement (TAVR):

• Good context for upcoming trials in lower risk patient populations
• As access routes continue to evolve, this poses challenges in labelling and indications for use
  • Transfemoral continues to be best
  • Apical, direct Aortic, subclavian, axillary, vena cava, etc.?
    • Note that most valves will be fine for 5-years
• It is both helpful and unsettling
• Support for issuing licences with longer term conditions

On-going discussions:

• Insights into MR Conditional Cardiac Implantable Electronic Devices and limits on PCT and MR impact
  • What does MR conditional mean?
    • He noted that the committee will have an opportunity to discuss this topic today.

Building on previous discussions the following areas were noted as well:

• Intra-atrial Shunting
• Renal Denervation
• Ventricular Assist Devices
• Cardiac Ablation and treatment of AF

Mr. Day thanked members for their ongoing dedication to the committee.

5. Update on Remote (Robotic) Navigation for Ablation and Other Aspects of the Treatment of AF (and Other Arrhythmias)

Invited Speaker: Dr. Yaariv Khaykin

Dr. Khaykin introduced himself, disclosed his affiliations and proceeded to address the questions posed by Health Canada.

Objective: There continue to be numerous licence amendments to add new features to complex mapping and robotic navigation systems for ablation. At the same time, there is some clinical data coming out that suggests that outcomes associated with the use of these technologies, and their new features, is not providing a clear benefit to patients; certainly the data is not consistent. Health Canada would like an update to better understand the current challenges with these technologies, in the context of the current state of complex ablation (e.g. AF). This update is intended to provide us with the most current clinical viewpoint in order to best assess the safety and effectiveness of the technologies and the appropriate claims and indications for use.

1. Specific treatments associated with AF

Provide an update on the treatment of AF in Canada including the indications for use or patients that are treated with catheter ablation, the clinical outcomes achieved for these patients, and the optimization of the therapy given. Additionally, please address the following specific cases:

1. There has been some data recently suggesting that identification of rotors for the treatment of AF (Focal Impulse and Rotor Modulation (FIRM) Ablation) is less effective than anticipated. It would be useful to discuss risks and challenges of these systems including:
   1. Discuss whether cardiac mapping system guided ablation is beneficial for treating patients with persistent or long-standing persistent atrial fibrillation. Contradictory results have come out in recent clinical studies, such as Substrate and Trigger Ablation for Reduction of Atrial Fibrillation (STAR-AFII) study (N Eng J Med 2015;372: 1812-1822), and Conventional Ablation for Atrial Fibrillation with or Without Focal Impulse and Rotor Modulation (CONFIRM) study (J Am Coll Cardiol 2012;60:628-636).
   2. Discuss how the current systems allow you to identify arrhythmia areas of interest and discuss the rates of clinical success associated with terminating AF when treating these areas.
2. For patients with heart failure and Afib, are there special benefits for Afib ablation, such as observed in CASTLE-AF (Catheter Ablation vs. Standard Conventional Treatment in Patients With LV Dysfunction and AF (CASTLE-AF) ClinicalTrials.gov Identifier: NCT00643188)?
   1. What are the limitations of this study and what patients are most suited for this type of intervention?

2. Robotic Guidance and Mapping Systems

Provide an update on robotic guidance and electro-anatomic mapping systems for catheters for the diagnosis and treatment of arrhythmias. Please include any new clinical evidence related to safety and effectiveness of the technology, novel systems currently under development, and any future trends in this area. Discuss the successes and challenges associated with these systems. Please also address the following:

1. Have features introduced in the past, such as semi-automated navigation, contact pressure feedback, image registration and integration with other systems, improved workflow, accuracy, and clinical outcomes for ablation procedures. Are systems now safer and/or more effective?
2. What is the best current clinical evidence that has demonstrated the safety and effectiveness of this technology and how are outcomes impacted by the use of the robotic guidance and mapping systems.

Dr. Khaykin started by providing background information on remote (robotic) navigation for ablation and other aspects of the treatment of AF (and other arrhythmias). He explained that fluoroscopy was historically used to visualize simple ablation targets, but because of atrial anatomy complexity fluoroscopic images are inadequate to locate less obvious targets. He also highlighted the concern for radiation exposure for operators.

He identified and briefly discussed the challenges associated with ablation procedure in general:

• While reasonable outcomes are expected and tied to operational procedural volume and experience, the atria are complex anatomical structures, and there are few highly experienced centers in Canada; providing services to patients in remote areas remains difficult,
• There are conflicting theories regarding the etiology of the arrhythmia, as well as appropriate therapeutic targets, particularly in patients with persistent and longstanding persistent AF,
• There remains and inability to directly assess lesion sufficiency so that fibrillation does not return,
• There is a risk of damaging collateral structures,
• Patient and operator exposure to fluoroscopy, and
• Operator disability related to wearing lead aprons.

Dr. Khaykin identified the perceived benefits of complex mapping, such as the ability to:

• Reduce need for fluoroscopy,
• Log special sites and ablation lesions,
• Extrapolate physiological processes using activation maps, and
• Monitor catheter tissue interface to predict whether the lesion is sufficient and not damaging.

He also reviewed some benefits of robotic magnetic navigation:

• Reduction of fluoroscopy radiation exposure for the operator and patients,
• Reduction of MSK strain on the operator,
• Automation of workflow, and
• Possibility to provide access for remote patients (e.g. Stereotaxis system).

Complex mapping has evolved over time. Initially, the goal was catheter visualization in non-fluoroscopic 3D space to create 3D "primary" maps, signal propagation maps, and voltage maps (to identify scar tissue, which is important for ablation of ischemic VT). This approach was also intended to help visualize multiple electrodes with concurrent signal acquisition. Side-by-side image Sync and image reconstruction using pre-acquired CT and MRI images allowed ablation to be carried out on a previously acquired CT image. In 2007, real-time registration (alignment and reconstruction) of ultrasound images replaced the need to register pre-acquired images, and allowed for more precise localization of multiple catheters, as well as integration of tissue contact information to mitigate forces and pressures that could result in perforation or damage to collateral structures, but ensure sufficient force to create the lesion. Furthermore, merging images from multiple modalities enables the user to project ablation points into real life ultrasound images. Other types of derivative maps were created to help predict target ablation areas. These maps show fractionation, rotors, as well as other signal characteristics for morphology pace mapping (e.g. ventricular tachycardia and PVCs which are known to lead to cardiomyopathy in some patients). He acknowledged this type of mapping has been very challenging, but with the development of morphology and 3D maps, patient treatment may be helped.

He described early 3D mapping (early 2000) as slow and tedious as it required point by point system inputs for location interpolation in 3D space. Those early procedures were known to take four to six hours, and because patients were given a lot of fluid in the process, their anatomies could have changed and rendered the maps unusable. More recent is the integration of fluoroscopy, which allows the registration of those images for background mapping. This too has allowed operators to reduce patient exposure to fluoroscopy. Another very recent innovation is contact force imaging with the use of colour coded tags that represent force-time integrals. These tags are automatically generated based on predefined ablation parameters ("objectified lesions").

Next Dr. Khaykin discussed the significance of ablating tissues around the pulmonary veins (PVs), as they are known to generate extra beats. He indicated that electrically isolating PVs and preventing activity from entering the atrium can prevent atrial fibrillation in some patients. He noted that while PV isolation/ablation was once called a "curative" approach, he believes this approach modifies the statistical risk of a patient going out of rhythm.

In response to the question of whether mapping and robotic navigation systems provide clear outcome benefits to patients, Dr. Khaykin presented data demonstrating that procedure time has decreased and efficacy has improved over time.

Early data comparing non-fluoroscopic 3D imaging compared to conventional fluoroscopic guided procedures shows that acute success and complications are not significantly different (Sporton et al, 2004; Khaykin et al, 2012), however there was a significant reduction in fluoroscopy time and radiation dose/time across a number of different clinical conditions.

In Addition there has been an improvement in "case" (procedure) time, from 4 - 6 hours, to 1.5 - 2.5 hours in most centers, and attributed the improvement to ultrasound integration, the use of non-gated mapping, and catheter (tip) irrigation. In addition to shorter procedure time, delivery of targeted energy has also contributed to RF time reduction. Dr. Khaykin estimates an average reduction of 100 fold per case; therefore patient radiation exposure is now expected to be below that received during pacemaker implantation.

Dr. Khaykin noted that non-randomized data from a historical database (~400 PVIs) demonstrate that the introduction of new technologies (e.g. CARTO 3) makes a difference. Christoph et al. (2015) compared the CARTO 3 with the newer CARTO-UNIVU, and showed significant reductions in fluoroscopy time across multiple arrhythmia types with the newer system (AFL, AF, EAT, and VT; but not AP, and PVC).

Contact Force Sensing (CFS)

Dr. Khaykin introduced contact force sensing technology and described the TactiCath ablation catheter that uses light properties to measure pressure/force at the tip in contact with the tissue. The catheter has a 65 or 75 mm deflectable curve, and uses fiber optic technology for optimal stability during contact force measurement. There is risk of perforation if too much force is used.

Dr. Khaykin noted that there are considerable inter-operator differences in the amount of applied force during first time use. Some operators were using between 1 and 38 g, while others were using up to 123 g. These differences make it challenging to compare outcome data from different centers because each operator uses different levels of pressure, therefore randomized studies that compare multiple centers, are actually comparing different operator approaches that are not the same. It was also noted that insufficient force produces inadequate lesions; successful lesions were achieved using ≥ 20 g force (400 gs – force time integral).

He described comparative force data for TactiCath and SmartTouch catheters; however, he noted that it is questionable whether the forces expressed from different systems are measures of absolute pressure. Dr. Khaykin feels these forces are relative to the individual technologies and therefore cannot be used interchangeably between systems.

He presented discussed the TOUCH AF study (Conti et al, 2017) that involved the SmartTouch catheter, and compared CFS guided vs. CFS blinded ablation for persistent AF. The study showed that there were no differences in RF time, or single procedure freedom from arrhythmia at 12 months. However, an older technology was used, only very experienced operators were involved, and no CFS standard had been established. Using data from his center, his group set out to determine the impact of CFS on re-do procedures via ROC analysis to determine predictive value of recoverable lesions. They found a significant improvement in outcomes. He also presented data from a meta-analysis describing multi-center experiences (Zhou et al, 2017) and noted that collectively there is a significant trend towards positive outcomes with CFS ablation. A similar trend was observed for major, and to a lesser extent, minor complaints. In addition, fluoroscopy time and radiation dose were overall statistically lower in CFS ablation procedures.

There was a concern that if CFS was introduced with navigation systems that moves the user away from feeling the contact force of the catheter that may result in increase of perforation risk. There was a question whether there are any factors of successful contact force measurement. Dr. Khaykin indicated that at his center, ablation catheters are used manually (feeling the contact force), as they have no other way. He noted that there are a few centers in Canada that have the robotic and magnetic navigation technology. With respect to perforation risk and in the case of the Stereotaxis system, which can apply a maximum of 10 g per spot, this amount of force, is at the minimum range to create stable lesions. It was noted that 10 g is barely enough to create a stable lesion and this may be one of the reasons why there has not been broad adoption of this technology.

Health Canada asked what level of evidence would be required to support specific targeted levels of force. Dr. Khaykin recommended that manufacturers should suggest contact forces that are within the specifications of their own technology and avoid extrapolating from or referencing other systems. He noted that while it would be nice to establish force levels based on randomized studies, two levels of data collection would be required: retrospective data collection and evaluation to forecast parameters, and then conduct a randomized study. He felt that currently there is enough data to start randomized study to determine whether these systems truly offer an advantage.

There was a question whether there are any animal and human tissue specific data that correlate to the amount of (real or virtual) force used (g) with the completeness of a tissue lesion. Dr. Khaykin indicated that the objective is to link force with lesion completeness, and highlighted the problem of most data coming from bench studies of a perfused thigh muscle, which are very controlled, and not indicative of in vivo conditions.

There was a comment that some element of safety is needed, however the data can't come from humans because of AE fistula risk; if too much pressure is applied to the back wall with too much time it may damage structures. It is important for operators to have that information.

There was a concern that if contact force varies for different areas of the heart (e.g. at the cavotricuspid isthmus), it may not be useful to have recommendations that are not dependent on the anatomical region. Dr. Khaykin agreed that operators first need to collect bench type data. It was recommendation that animal and human data are needed to develop recommendations before conducting a randomized study.

There was a question regarding how large the pressure safety factor is between optimal ablation and adverse events. Dr. Khaykin noted that based on animal data, the manufacturer of the SmartTouch indicates that perforation risk is increased when the user reaches an average input of 120 g, however, it does not get close to that level. The biggest concern with AF ablation is esophageal injury, because the esophagus happens to run right in the area that we are trying to ablate: between the pulmonary veins in the back of the left atrium. Also, because the anatomy of the esophagus and thickness of the atrium vary between people, there's absolutely no way to ablate the pulmonary veins without at some point doing ablation over the esophagus. However, risk of esophageal injury is very low; it's estimated at 1 in 2000. His center hasn't seen many injuries to surrounding structures, particularly with evolving technologies, and the adverse event rates are much lower than they used to be. Nevertheless, we are still concerned about esophageal injuries. He noted that at this time we do not have the technology to predict, prevent or study AEs, as they remain a low risk complication.

It was agreed that ablation force recommendations will have to be location specific since there is a large variation of tissue thickness.

It was noted that while there is a regulatory need to better define and understand the safety of force contact technologies, there is little motivation for manufacturers to run randomized studies at this time.

Magnetic and Robotic Navigation

Dr. Khaykin described the Stereotaxis navigation system that uses a magnetic vector to direct the ablation catheter tip. He noted that this technology has existed since 2000.

Several non-randomized comparisons involving older generation systems show non-significant decrease in procedural, fluoroscopy, or ablation times for magnetic and robotic systems compared to conventional ablation, across various types of arrhythmia.

Dr. Khaykin noted that long term outcomes of navigation for atrial fibrillation in 112 patients were published this year (Yuan et al, 2017). These non-randomized data show some improvement in symptoms, without significant differences in procedure times, or complication rates. A meta-analysis (Proietti et al, 2013) of non-randomized data shows no significant freedom from arrhythmia with remote magnetic navigation, but perhaps a small reduction in complications. Dr. Khaykin highlighted that the greatest amount of force used with remote navigation is 10 g, and that the risk of perforation and esophageal damage is expected to be low.

Dr. Khaykin presented data from a comparison of robotic navigation vs. conventional ablation (Steven, 2010) that show significant reductions in fluoroscopy time, operator radiation exposure and exposure time with robotic systems; however, procedure duration trended towards a significant increase. He also described a worldwide survey of robotic AF ablation (Bai et al, 2012) involving 1728 procedures across 12 centers, which demonstrated an overall complication rate of 4.7% and 67.1% success rate after 18 (±4) months follow-up. In addition, another meta-analysis of non-randomized data by Zhang et al (2014) showed no significant improvement, a trend towards more complications, but reduced fluoroscopy time with robotic systems.

In a randomized comparison between the Hanson and manual SmartTouch (Russo et al. 2016), the use of touch feedback improved success at 1 year and reduced fluoroscopy time, however he did not believe the one year value of 90%. He noted his use of the Hansen system with animals, but found there was no contact force or manual feedback.

Next he described the findings from The Man and Machine Trial (Rillig et al. 2017). In this study a comparison between manual and robotic ablation showed no difference in procedural clinical outcomes at 15 months, but the use of robotic systems was associated with longer procedure times. He highlighted that a fistula was found in one patient treated with the robotic system. This individual had a reddened area in the esophagus without symptoms, clinicians intervened and attempted repair. During continued monitoring in hospital the lesion fistulised and the patient died. Dr. Khaykin noted that lesion is a very challenging complication, one that operators worry about, and that is extremely difficult to predict and treat.

There was a question if there is any new data that indicate an increased risk of pericardial effusion with the Hanson system. Dr. Khaykin indicated he wasn't aware of any new data, but cited The Man and Machine study in asserting there was no difference in pericardial effusions or other complications with that system, apart from the AE fistula, that was an isolated event.

The committee members were asked to comment if it would be sufficient for manufacturers of robotic systems to demonstrate non-inferiority to manual procedures to support regulatory approval. Dr. Khaykin indicated that demonstrating non-inferiority of complication rate was probably more important than non-inferiority of success rate. He added that thesetechnologies have been around for 10-12 years, and recruitment of 200 to 300 patients is achievable to answer these questions.

There was a comment that all atria are different, and these differences dictate catheter "loiter" times required to create lesions; perhaps this would be better achieved by the use of robotics. Dr. Khaykin indicated that AE fistulas are seen with every technology used in the atrium, including cryoablation, laser ablation, andRF balloons. Therefore, every type of energy has resulted in unpredictable fistula formation. He agreed that it would be great to come up with a set-it-and-forget-it-formula, but we're not quite there yet.

Next Dr. Khaykin described AMIGO Remote Catheter System (RCS), which uses modern technology and consists of two components, the Amigo RCS and the Amigo remote controller.

Other Remote Navigation Technologies were mentioned:

• MRI driven catheter manipulation
• Stereotactic arrhythmia radio ablation (STAR)-using much higher radiation dose

He showed a screenshot of the CyberKnife software in which a pre-acquired MRI image is used to target ablation. He indicated it delivers a much higher radiation dose as compared to fluoroscopy, but the radiation is used to create contiguous lesions.

Benefits of cardiac mapping system guided ablation for patients with persistent or long-standing persistent AF

Dr. Khaykin discussed mechanisms of atrial fibrillation and reiterated that ablation began with PVI, because of the firing that occurs there, and it is known that some occurs outside of the PVs. Also, chronic fibrillation is described in terms of multiple wavelets where there are rotors for entry, and parasympathetic ganglia heavily innervate all around the back of the atrium, and right around the pulmonary veins. The typical approach with PV isolation presumably works to prevent and insulate those extra beats coming from the pulmonary veins. Other techniques involve: ablating across the roof or floor of the atria to isolate the back wall, which is histologically part of the pulmonary vein antrum; and ablating the mitral isthmus line (a number of these patients develop a flutter around the mitral annulus so that the line from the left anterior pulmonary vein to the mitral annulus is considered the 'classical' mitral isthmus line).

Dr. Khaykin presented studies for ablation of long-standing persistent AF. A number of studies have reviewed combinations of lines. Earley et al. (2006) reported that 42 patients with permanent AF were treated with CPVA with roof line and CTI line, and 52% of patients required a second procedure, but up to 74% success was reported with cumulative procedures. In another study (Oral et al. 2006) 146 patients randomized to amiodarone + cardioversion with or without CPVA. The proportion of patients treated with CPVA that achieved NSR improved at each successive time point as compared to patients that did not receive CPVA.

Other ablation strategies address areas outside of the PVs. In particular, areas of "fractionation" or unusual electrical activity have been targeted, as these areas are thought to be important in maintaining atrial fibrillation. Nademanee et al. (2004) treated 64 patients with chronic AF by targeting CFAEs; patients were ablated until 95% converted to a sinus rhythm (20% had received ibutilide which likely assisted with conversion). The major complication rate was 5%, and redo rate was 30%, which he considered acceptable for this population.

Oral et al. (2009) treated 119 patients using incremental left atrial complex fractionated atrial electrograms (CFAE) ablation, and reported 79% success with AF termination during APVI, and 36% with cardioversion. In a comparison of biatrial vs. left atrial ablation, comparable to a maze procedure, patients that underwent biatrial ablation did much better, although procedural times were longer, number of complications was greater and so was fluoroscopy exposure.

Dr. Khaykin noted that this is not feasible in all patients. He indicated that incremental ablation was better than incremental biatrial ablation. He explained the hierarchical approach begins with PV isolation, and from there a roof line may be added, and if a patients is still in AF, they ablate a line to the left atrial appendage, and may add a floor line and then isthmus line. After that other sites are explored. The data demonstrate that as operators move incrementally through these targets, the cumulative incidence of AF termination increases (Haissaguerre et al. 2005). The study only involved 60 patients and 87% had their AF terminate during ablation, and overall success at 11 months was 95%. However, Dr. Khaykin noted that his early experience with AF ablation in 2004 and 2009 (Khaykin et al. 2010) involved PVI followed by CFAE ablation in patients who were still in AF, and the results were less than expected; he reported a 44% success rate at one year following the first procedure.

The STAR AF trial (substrate versus trigger ablation for reducing atrial fibrillation: a randomized multicenter trial) randomized 100 high-burden paroxysmal/persistent patients to PVI, CFE, or hybrid PVI+CFE ablation (using proprietary St. Jude algorithm) (Verma et al. 2010). The hybrid combined PVI+CFE ablation approach resulted in statistically superior freedom from AF. Similarly, several studies have demonstrated the superiority of stepwise and combination PVI and CFAE approaches (Brooks et al. 2010).

As part of the larger STAR AF II trial, 589 patients were randomized to PVI, PVI+CFE, and PVI + linear roof and mitral valve isthmus line ablation. Results were surprising: patients treated with PVI alone did marginally better than the other approaches at 18 months, and data show no apparent benefit of adding CFAE and linear ablations. However, Dr. Khaykin cautioned that these findings should be interpreted in the context of the navigation system(s) used: the addition of CFE with the proprietary algorithm was not helpful, and no contact force information was available to operators.

Arrhythmia areas of interest

Dr. Khaykin indicated that when considering specific abnormal electrograms, it is unclear whether they identify areas important for maintaining atrial fibrillation, or whether they represent wave front collisions. He noted that there are a number of mapping systems that are focussed on time and frequency domains, as well as proprietary measures that seek to identify those abnormal points such as: CARTO, EnSite, Rhythmia, Topera and Acutis and there are a number of algorithms available as part of these systems that attempt to interpret these electrograms in the time domain. Dr. Khaykin does not believe these algorithms are able to pinpoint the most important areas responsible for the arrhythmia maintenance, and cited the inability to reproduce results of identification of abnormal rhythms. He briefly described the CARTO, Rhythmia and EnSite Precision systems.

He discussed the non-randomized CONFIRM study (Narayan et al. 2012/2014) that included 107 patients and showed that patients treated with FIRM+PVI ablation vs PVI alone did better over time with 56% AF termination, and the study extension showed patient successes were durable. He indicated there are no randomized studies at present, but several registries, the largest group of which showed 59% of patients exhibited AF termination; however, patients were mixed with respect to previous procedures (PVI). Interestingly, the authors reported there was no association between AF termination and eventual actual freedom from fibrillation. He suggested that we need to wait for proper randomized studies (REAFFIRM and REDO-FIRM) to determine whether this algorithm can be relied upon.

He described the use of 'basket' technology (US MEDICAL) that incorporates ultrasound crystals and 48 electrodes, and is intended to reconstruct the 3D anatomy of the chamber from beat to beat in real time, and projects activation. Patients with persistent or long-standing persistent AF at 6 sites were treated with an algorithm intended to identify local firing and rotors. They found multiple underlying mechanisms; on average the algorithm identified 6.2 mechanisms per patient.

Atrial fibrillation and heart failure

Dr. Khaykin described the CASTLE-AF trial that enrolled 397 patients with AF, CHF and EF < 35% that were randomized to ablation or medical therapy (Marrouche et al. 2017). The primary outcome (mortality and HF related hospitalization) and each individual endpoint were significantly reduced in patients treated with ablation. Similarly, the Ablation vs. Amiodarone for Treatment of Atrial Fibrillation in Patients With Congestive Heart Failure and Implanted ICD/CRTD – (AATAC) Trial (Di Biase et al. 2016) showed that significantly more patients with AF and CRT-D achieved freedom from AF following ablation, than those that did not. Also, CHF related hospitalization was 31% vs. 58% (P>0.001), and mortality was 8% vs 18% (P=0.037) in favour of ablation. Also, as part of an older study- Pulmonary Vein Antrum Isolation versus AV Node Ablation with Bi-Ventricular Pacing for Treatment of Atrial Fibrillation in Patients with Congestive Heart Failure (PABA-CHF) (Khan et al. 2008) 81 patients with AF, NYHA II to III, and EF <40% were randomized to PVI vs. AV node ablation and biventricular pacing. Patients treated with PVI showed significant improvement in QoL questionnaire, 6MWT, and ejection fraction at 6 months. He also presented the findings of a meta-analysis (Zhu et al, 2016) that excluded the CASTLE-AF or AATAC data, but also confirmed significant improvement in EF and QoL in ablated CHF patients. He added that his experiences ablating CHF patients with defibrillators were positive, despite lower success rates, and the need for multiple ablations.

There was a question whether the presence or absence of anticoagulation was critical. Dr. Khaykin indicated he does not know whether ablation lowers the risk of stroke; however, anticoagulation increases the risk of post-procedural bleeding, and that patients do better without anticoagulation. He acknowledged that the current guidelines suggest ablation should be ignored and anticoagulated as if the patient has never had an ablation. He also stated there were no temporal associations between AF and stroke, and that lots of work needs to be done in this area.

In conclusion he noted that:

• There are multiple technologies on the market that allow for the precise reconstruction of the anatomy with secondary maps (activation, voltage, fractionation), but their usefulness hast not been validated; he believes further research is necessary.
• Contact sensing technology has already shown improved outcomes, with the caveat that individual technologies are not comparable.
• There is lack of consensus on the best approach to treat persistent and long standing persistent AF. Ablation is not curative, but simply reduces the statistical probability of an event. Clinical reductions in symptoms and event frequency should be considered wins.
• There is evidence to consider AF ablation is superior to standard treatment in patients with CHF and AF.
• Current magnetic navigation technologies are expected to produce similar results to manual catheter manipulation, but offer reduced fluoroscopy exposure.
• Current robotic navigation technologies produce similar clinical outcomes, with reduced patient and operator fluoroscopy exposure, but at the cost of longer procedures.

Dr. Khaykin concluded his presentation.

Dr. Cecere arrived to the meeting.

6. Update for the Renal Denervation Systems for the Treatment of Hypertension

Speaker: Dr. Marcel Ruzicka

Dr. Ruzicka introduced himself, disclosed his affiliations and proceeded to address the questions posed by Health Canada.

OBJECTIVES: In March 2012, based on data from HTN-1 and HTN-2, Health Canada licenced the Symplicity Renal Denervation System in Canada. Prior to licensing, applications had also been received by Health Canada under the Special Access Program. Following the results of HTN-3 and the lack of effectiveness that was observed, Renal Denervation was not actively performed and the originally licensed Symplicity system licence was cancelled. At our meeting on 2014-11-28, Dr. Raj Padwal discussed the outcomes and the limitations that were seen in the testing of the renal denervation systems, including data from HTN-3. As there is now renewed clinical activity associated with Renal Denervation, Health Canada is requesting input and recommendations on how the assessment of new systems should be considered in the context of applications for Clinical Trials and Licences.

More than three years have now past since publication of the SYMPLICITY HTN-3 trial (Renal Denervation in Patients with Resistant/Uncontrolled Hypertension) results in 2014. A number of weaknesses in the trial data, as well as in the technology and its use have been discussed. Based on the lessons learned from the clinical testing of the Symplicity Renal Denervation System, please discuss the following:

1. Provide a brief overview of the current state of development and testing or use of renal denervation systems, including the Symplicity Spyral and EnligHTN systems.
2. Based on the lesson learned from the SYMPLICITY HTN series of trials including HTN-3, if a new renal denervation system is proposed for investigational testing, what critical information should be assessed and required, such as inclusion/exclusion criteria, measures for truly resistant hypertension, trial design with a sham control group, medication adherence, specific endpoints such as ambulatory blood pressure, physicians' experience, duration of follow-up, etc. Are there key pre-clinical data requirements?
3. Discuss any new clinical evidence supporting or refuting the beneficial effects of Renal Denervation on resistant hypertension;
4. Has there been any new progress in the methodology for monitoring the effectiveness of a renal denervation procedure.
5. Are there any techniques other than Radio Frequency, such as using ultrasound or chemical denervation, used for renal denervation, and if so, what are the advantages and disadvantages of these techniques? What kind of critical information should be assessed if a clinical trial using such a technique is proposed?
6. What evidence would you require in order to introduce Renal Denervation into regular clinical practice in Canada?

Dr. Ruzicka noted that he will discuss the renal sympathetic denervation for treatment of hypertension post Symplicity HTN-3 Trial. He will look at:

• Efficacy and Safety Endpoints of Symplicity HTN-3 Trial
• Relevance of Renal Sympathetic Hyperactivity in Hypertension
• Limitations in Internal Validity of pre Symplicity HTN-3 Trial

He noted that the Symplicity HTN-3 Trial was a prospective, single blind, randomized (2:1), and sham-controlled trial, with 6 months follow-up.

Primary efficacy endpoint was:

• The mean change in office SBP from baseline to 6 months in denervation group compared to mean change in office SBP in sham control group (superiority margin 5 mmHg)

Secondary efficacy endpoint (which study was powered for) was:

• The change in mean 24-hr ambulatory SBP at 6 months

Primary safety endpoint was:

• A composite of major adverse events defined as death from any cause, ESRD, and embolic event resulting in end-organ damage, renal artery or other vascular complications, hypertensive crisis within 30 days, new renal artery stenosis ≥ 70% within 6 months

Next he discussed inclusion and exclusion criteria.

Inclusion criteria were:

• Before referral: SBP ≥ 160 mmHg (average of 3 measurements at an office visit) on ≥ 3 BP lowering drugs at maximally tolerated doses including diuretic, with no changes in BP medications within 2 weeks before referral
• Post referral: 2 weeks of home BP monitoring (AM and PM) and diary of adherence to BP medications
• Confirmatory screening visit: SBP ≥ 160 mmHg, review of adherence to medication, and average SBP from 24-hr ABPM ≥ 135 mmHg

Exclusion criteria included:

• known secondary causes of hypertension
• multiple renal arteries
• renal artery diameter < 4 mm and/or length < 20 mm

Study treatment (2:1 randomization and blinding):

Treatment group: renal artery denervation (Symplicity renal denervation catheter, Medtronics)

Sham control: renal angiography

Blood pressure medication: No changes to BP lowering drugs allowed during the 6-month follow-up.

Intention to treat principle:

• 316 patients required on the basis of the 9.8% safety performance criterion to provide 80% power, with the use of a one-sided significance level of 0.05.
• Considering expected patient attrition, authors calculated that 530 patients will need to be enrolled.
• A superiority margin of 5 mmHg for the primary efficacy end point was considered a clinically meaningful BP reduction based on the observed decreases in cardiovascular morbidity with small reductions in SBP (2-5 mmHg) with pharmacotherapy.

The trial concluded that:

"This blinded trial did not show a significant reduction of systolic blood pressure in patients with resistant hypertension 6 months after renal-artery denervation as compared with a sham control."

This trial did show that RDN is a relatively well tolerated procedure, with a low major adverse event rate (1.4%).

Why renal sympathetic denervation is a reasonable hypothesis for treatment of hypertension?

Dr. Ruzicka listed milestones in treatment of hypertension:

1930

• Sedatives

1940

• Walter Kempner – Salt Free Diet
• Lumbo-Dorsal Sypathectomy

1945

• Vasodilators

1950

• Diuretics, Sypathetic Ganglion Blockers

1960

• Central Sympatholytcs

1970

• α – Blockers, ß-Blockers

1980

• Calcium Channel Blockers

1990

• Ace-Inhibitors, ANG II Receptor blockers,

2000

• Re-discovery of Aldosterone Blockers

He described the Renal Sympathetic Nervous System:

Renal Sympathetic Afferents

• Mechanoreceptors/Chemoreceptors within kidney
• Central Projections to Hypothalamus
• Modulation of Central Sympathetic Outflow

Renal Sympathetic Efferents

• Central Sympathetic Outflow to kidneys
  • β1 - juxtaglomerular granular cells- renin release rate- stimulates increase release rate of renin
  • α1a - intrarenal vasculature- RVR and RBF- stimulates decrease in GFR and RBF
  • α1b - renal tubular epithelium - tubular sodium absorption- stimulates sodium and water retention

Role of RSNA in Experimental HTN:

• Studies have been inconsistent in determining whether renal denervation prevents/delays the development of HTN or not.

He noted limitations to internal validity of the pre Symplicity HTN -3 studies:

• Patient Selection Process
• Does this patient have sympathetically driven HTN?

Dr. Ruzicka explained that we do not know, and there is no easy way to administer a test to directly assess central sympathetic outflow and/or renal sympathetic activity. If a decrease in central and renal sympathetic activity in response to RDN is the major mechanism for BP lowering, one could consider "acute BP response to clonidine" to predict response (or a lack thereof) to RDN. MSNA might also be a predictor for elevated sympathetic activation.

Regression to the mean – in pretty much all of the studies reported decreases in BP were much larger compared to those based on day-time average from 24-hr ABPM (and this could be related to significant number of patients with white coat effect and/or true to regression to the mean).

Dr. Ruzicka explained that this issue was addressed in Symplicity HTN-3 as patients underwent 2-week period of daily ambulatory BP measurements and had then 24-hr ABPM.

He noted that the placebo effect – that is well documented in HTN trials could have played a role in earlier trials as they were either not controlled or the control arm was not blinded. He indicated that this issue was addressed in Symplicity HTN-3 with the sham control as patients were blinded to whether they received renal angiogram only or renal angiogram with RDN.

Adherence to BP lowering drugs

Dr. Ruzicka noted that one could also speculate that patients post RDN who are not blinded may increase their adherence to "lower" number of BP lowering drugs and/or in believe that they "(semi)cured". Symplicity HTN-3 trial did not include rigorous methods of assessments of compliance with BP lowering drugs.

Mechanistic explanations for lack of BP response to Renal Sympathetic Denervation

Dr. Ruzicka described the technical aspects of catheter-based renal sympathetic denervation:

• Distribution of renal sympathetic nerves
• Highly operator dependent technique
• New radio ablation catheters

To address the question whether the treatment does what it is supposed to do Dr. Ruzicka provided examples of old and new catheters for renal sympathetic denervation.

Regarding new evidence for safety and efficacy of renal sympathetic denervation for treatment of resistant hypertension he noted that at this time all we have is the Global Symplicity Registry, which is a prospective, multi-center, non-randomized international registry for RDN that provides safety and efficacy data up to 36 months post procedure. It provides excellent safety record, and similarly excellent efficacy record, however many patients are lost to follow up.

He indicated that there are three major clinical trials underway:

• SPYRAL HTN OFF/ON MED - Global Clinical Study of Renal Denervation With the Symplicity Spyral™ Multi-electrode Renal Denervation System in Patients With Uncontrolled Hypertension in the Absence of Antihypertensive Medications (SPYRAL HTN-OFF MED)
  • Design: prospective, randomized, single blind trial,
  • Participants: patients with resistant HTN
  • Procedure: sham procedure vs RDN
  • Device: Symplicity SPYRAL multi-electrode RDN system, sponsored by Medtronic Vascular Corp.
  • Primary outcomes: acute and chronic safety, change in BP by 24-hr ABPM from baseline to 36 months
  • Number of participants: 100
  • Study completion: 9/2020
  • Primary completion date: 1/2018 (final data collection)
• The RADIANCE HTN – This is a study of the ReCor Medical Paradise System in Clinical Hypertension (IRB no. 42715)
  • Design: prospective, randomized, triple blind
  • Participants: patients with resistant HTN
  • Procedure: sham procedure vs RDN
  • Device: The Paradise RDN Ultrasound System, Sponsored by ReCor Medical, Inc.
  • Number of participants: 292
  • Primary Outcome: mean reduction in daytime average ambulatory SBP from baseline to 2 months post procedure
  • Completion date: 8/2021
  • Primary Completion Date: 8/2018 (final data collection for primary outcome)
• REDUCE HTN REINFORCE - REDUCE-HTN: This study is designed to demonstrate the effect of Boston Scientific Vessix Renal Denervation System
  • Design: prospective, randomized, single blind
  • Participants: patients with resistant HTN
  • Procedure: sham procedure vs RDN
  • Device: Vessix RDN – sponsored by Boston Scientific Corp.
  • Number of participants: 51
  • Primary outcome: mean reduction in average 24-hr ambulatory systolic blood pressure (baseline to 8 weeks post procedure)
  • Study Completion: 3/2021
  • Primary Completion Date: 2/2018 (final data collection date for primary outcome)

Catheter-Based Renal Sympathetic Denervation for Resistant Hypertension: A Multicenter Safety and Proof of Principle Cohort Study was discussed next. It is a prospective observational study with:

Inclusion criteria:

• Resistant HTN (SBP>160 mmHg while on 3 BP lowering drugs including diuretics
• GFR (MDRD) > 45 ml/min/1.73m2

Exclusion criteria:

• Renovascular abnormality on angiogram
• Central Sympatholytic (Clonidine/Moxonidine)
• Warfarin

Safety:

• One renal artery dissection prior to radioablation (Treating with stent)
• No RAS (IN 1-6 mths F/U)
• Visceral interabdominal pain during radioblastation
• (Narcotics)

The study concluded that:

"Catheter-based renal denervation causes substantial and sustained BP reduction without serious events in patients with resistant hypertension. Prospective randomised controlled trials are needed to investigate the usefulness of this procedure in the management of this condition."

Dr. Ruzicka described the Symplicity HTN-2 Trial:

Study design:

• Prospective, open-label, randomized (1:1), controlled (renal sympathetic denervation + pharmacotherapy vs pharmacotherapy only) trial
• Follow-up: 6 months

Primary efficacy end point:

• The mean change in office SBP from baseline to 6 months in denervation plus pharmacotherapy group compared to mean change in office SBP in pharmacotherapy only group

Secondary efficacy end points:

• the change in mean 24-hr ambulatory SBP at 6 months
• the change in home blood pressure at 6 months
• number of patients with decrease in SBP ≥ 10 mmHg
• number of patients with achieved office SBP < 140 mmHg

Secondary safety endpoint:

• acute procedural safety
• chronic procedural safety (reduction in eGFR > 25% or new RAS > 60%)
• a composite cardiovascular end point (acute myocardial infarction, sudden cardiac death, new onset CHF, stroke, aortic or lower limb revascularization procedure, lower limb amputation, death from aortic or peripheral arterial disease, hemodialysis, death from renal failure, hospital admission for atrial fibrillation or hypertensive emergency)

Inclusion criteria:

• SBP ≥ 160 mmHg on ≥ 3 BP lowering drugs at maximally tolerated doses including diuretic, with no changes in BP medications within 2 weeks before referral
• 2 weeks of home BP monitoring and diary of adherence to BP medications

Exclusion criteria included:

• eGFR (MDRD formula) < 45 ml/min/1.73 m2
• renal artery diameter < 4 mm and/or length < 20 mm

Statistical analysis – primary end point:

• 50 patients per group required for 80% power to show benefit of renal denervation over control intervention assuming at least 12 mmHg difference between the groups with a 21 mmHg SD of the change in SBP from baseline to 6 months (a two-sided significance level of 0.05).

Safety endpoints:

Acute procedural safety

• Femoral artery pseudoaneurysm (n=1), back pain (n=1), intraprocedural bradycardia (n=7) and hypotension (n=1)

Chronic procedural safety (reduction in eGFR > 25% or new RAS > 60%)

• Decrease in eGFR > 25% (RDN n=2, controls n=3)
• One progression of RAS (43 out of 49 patients had imaging at 6 months)

A composite cardiovascular end point or serious adverse events

• Hypertensive emergency (RDN n=3, controls n=2)
• TIA (RDN n=1, controls n=2)
• ACS-PCI (RDN n=1, controls n=1)

Health Canada noted that after receiving two randomised trials, a decision was made to licence the device. However when the HTN-3 results came out, they were not in agreement with the early findings. Given some of the history of these devices and the fact that we anticipate receiving future data on this technology providing additional trial data with complex patient population with large confounding factors and discordant observations that we have seen so far how do we approach new data that would be received for assessment of this technology?

One of the members commented that making the technology available to users based on available evidence at that time was a positive decision not a failure. The evidence provided at that time indicated the safety and benefits of this technology. The efficacy would be established as the technology is used.

It was also noted that true resistant hypertension is rare and likely only present in around 5% of hypertension patients.

There was a short discussion regarding the regulatory requirements around the safety and effectiveness. It was suggested that perhaps this could be a topic for discussion at a future meeting.

This concluded Dr. Ruziicka's presentation.

Dr. Ruzicka and Yee left the meeting.

7. Home Monitoring in Canada

Invited Speaker: Dr. Ratika Parkash

Dr. Parkash introduced herself, disclosed her affiliations and proceeded to address the questions posed by Health Canada.

Objectives: As medical devices become more autonomous, automated home monitoring systems are becoming increasingly important as a means of updating physicians as to patient and device status. Recently, Health Canada has received license amendment applications to add important device safety improvements to currently licensed implantable devices which depend on the patient having an automated home monitoring system. There is some concern that in certain cases, this may not be an effective a risk mitigation mechanism. Health Canada would like to better understand the prevalence of, ease of access to, and effectiveness of automated home monitoring systems in Canada in order to better understand the risks and benefits of using these systems as a vehicle for mitigating risks associated with device hazards and failures.

Provide an update on the current state of automated home monitoring of medical devices in Canada with specific reference to life-sustaining implantable devices such as pacemakers/defibrillators.

Please address the following:

1. How prevalent is home monitoring of device-implanted patients in Canada and how significant a risk is there that a pacemaker-dependent patient does not have access to home monitoring (and thereby safety improvements)?
2. How effective are home monitoring systems at communicating device or patient issues to a physician who is able to respond? Under what circumstances an important report might be missed or overlooked?
3. What is the current process for receiving, reviewing, and responding to home monitoring reports? How easy is it to identify a serious or urgent case? How quickly can health care professionals respond in the case of an urgent report (e.g. imminent device or battery failure, or sudden change in patient condition)?
4. Does increasing the amount of transmitted data increase the risk that important reports are not identified quickly (e.g. is the amount of data transmitted appropriate or useful)?
5. What, if any, considerations should Health Canada be requiring from manufacturers to ensure that home monitoring solutions both cover the affected population and provide useful alerts to clinicians in a timely and appropriate manner?
   1. What kind of information should be being transmitted and to whom
   2. should prioritization mechanisms be incorporated into the reporting
   3. should companies be responsible for information triage

Dr. Parkash began her presentation by stating that in 2011 there were 25,000 pacemaker (PM) implants and 7000 implantable defibrillator (ICD) implants yearly in Canada, with approximately 120 000 patients living with these devices.

She explained that the recommended follow-up for these devices is based on consensus and position statements, with the majority of patients requiring at least yearly visits to a specialized device clinic during the lifetime of their device. She noted that there are many nuances for the need for follow-up. During the life of these patients, many issues may arise, such as atrial or ventricular arrhythmias that may result in syncope, stroke or sudden death, need for increased monitoring resulting from device advisories, or minor programming adjustments to improve device performance, or simply the need for enhanced surveillance as the device battery depletes and replacement is anticipated.

Dr. Parkash described the remote monitoring technology components:

• CIED is equipped with a micro-antenna that communicates with a small external device (at bedside or wearable) commonly known as the transmitter.
• The information transfer to the communicator can occur at preset time intervals with the participation of the patient (waving a wand over the device) or it can be sent automatically (wirelessly) without their participation.
• The encrypted data are then uploaded to an Internet-based database on a secure central server.
• The data processing facilities at the central database, depending on the clinical urgency, can trigger an alert for the physician(s) that can be sent via email, fax, text message, or phone. It can take several hours between the event occurring and the clinicians being notified.
• The details are also posted on the secure website for viewing by the physician (or their delegate) at their convenience.

She noted that remote monitoring technology has changed over time:

• Original design/technology did not permit real-time communication
• Data transfer can take several hours, depending on mode of data transfer ie cell-based, internet-based
• Newer technology is now using a smart phone app and data transfer is performed using cell towers
  • Disadvantage is requirement of cell towers for this to occur
  • In Canada, this is an issue in rural communities – we need to continue having support for land-line solutions.

How prevalent is home monitoring of device-implanted patients in Canada and how significant a risk is there that a pacemaker-dependent patient does not have access to home monitoring (and thereby safety improvements)?

Dr. Parkash noted that:

• Device clinics integrate RM capability into their routine functions and include this service as part of the standard of care for ICD/CRT patients (Strong Recommendation, Moderate quality evidence)
  • For one manufacturer (Medtronic) at one Canadian facility, approximately 90% of ICD patients have RM, but only 7% of pacemaker patients have RM.
  • Other manufacturers (Abbott) has less support provided
• RM is generally not supported for pacemaker patients in Canada as these are excluded from the standard contract with the device manufacturers.
• A recent position statement by Yee et al recommended that for CIED patients in whom no device issues are identified, routine follow-up assessment during the maintenance phase should blend remote monitoring (RM) with in-clinic assessments beginning after the 3-month post-implant assessment, alternating assessments between in-clinic and RM transmissions in a 1:1 ratio (Conditional Recommendation, Low-Quality Evidence).

How prevalent is home monitoring of device-implanted patients in Canada and how significant a risk is there that a pacemaker-dependent patient does not have access to home monitoring (and thereby safety improvements)?

She noted that:

• Use of remote monitoring for pacemakers is extremely low:
  • Only 37% of patients (34,259) used RM (in the United States)
  • Pacemaker-dependent patients are highly unlikely to be on remote monitoring unless they have an implantable defibrillator in place
  • The largest trial on remote monitoring excluded pacemaker dependent patients for safety reasons

She explained that one of the barriers to increased use of remote monitoring is cost:

• Device contracts don't include device remote monitoring, so it is an added cost.
• There is no billing for remote monitoring in Canada (so no budget to cover those costs).

Other barriers include:

• Clinic flow
• Ability to deal with all the remote devices.
• Privacy issues (because the information goes through the US, and information is available for use by the American government due to the patriot act.)
• Some patients decline it because they would prefer to see the doctor in the clinic.

How effective are home monitoring systems at communicating device or patient issues to a physician who is able to respond? Under what circumstances an important report might be missed or overlooked?

Dr. Parkash noted that:

• Effectiveness as outlined in the clinical trials demonstrates:
  • Reduction in time to actionable events
  • Significant benefit for advisory-related issues
• Patient-related factors are reflected in:
  • Success rates of 89-100% in the clinical trials in the literature
  • Patient satisfaction – excellent, Quality of life improved over standard of care
  • Compliance – 79% in real-world data (Rosenfeld et al PACE 2014;37:820-7), in the studies >85%
• There are some issues with patients not being around their home monitor for an alert to be transmitted, these are uncommon, and less likely to occur in the future with smart phone-based technology
• Potential for delayed in clinic response – generally next business day, however there could be delays if the transmission did not work.
• Failure of the technology to transmit is a very low, the chances of a report being missed or overlooked is generally very low (although we don't have a lot of data about this).

She provided information on current knowledge for RM – ICD (Implantable cardioverter defibrillator) and discussed results of systematic review studies.

Longest follow-up is 2 years; most are 1 – 1.5 yr. follow-up. All adverse events (syncope, death, etc.) are lower in the active, monitored group, and these studies have been powered for non-inferiority.

• Significant reduction in ICD shocks and battery longevity is longer due to lower number of capacitor charges required for those shocks
• Only one study showed reduction in mortality, most systematic reviews border on significance for mortality
• Reduction in time to clinical event (mean of 25 days)

Next Dr. Parkash presented registry data of 69 556 patients that showed 50% reduction in mortality in RM patients. She also provided results of Comparative Follow-up Schedule with Home Monitoring (COMPAS) study looking at pacemaker data for 2012 patients (the only randomized RM trial), for 18 months which confirmed non-inferiority of remote monitoring and a mean 117-day gain in the event detection.

Next Dr. Parkash discussed advantages and disadvantages for remote monitoring:

Advantages:

• A reduction in travel time and in-clinic wait-time, although this benefit would be especially great for patients living in rural and remote communities.
• The potential earlier detection of events could result in quicker physician intervention when needed and improved patient safety.
• The immediate follow-up after these events could provide reassurance or a perception of greater security for patients.
• In the longer term, earlier detection and treatment may result in improved disease management, better health, and potentially less or shorter hospital admissions.

Disadvantages include:

• Some patients may be technically challenged or live in areas with communication quality issues related to fixed telephone lines or poor coverage for mobile networks.
• Patients may also have a concern for the privacy and security of their medical and personal information on the Internet.
• They may also have a false sense of security when using RM and avoid following up with a physician when the need arises.
• Constant surveillance with RM may have uncertain effects on patients' quality of life and may result in adjustment issues involving increased anxiety or the fear of constant observation. (This is a potential disadvantage, has not been proven.)

What is the current process for receiving, reviewing, and responding to home monitoring reports? How easy is it to identify a serious or urgent case? How quickly can health care professionals respond in the case of an urgent report (e.g. imminent device or battery failure, or sudden change in patient condition)?

Dr. Parkash provided information on after hours care. During office hours, if there was a remote transmission they would generally respond to it immediately. Anecdotally (though there is no data for this), the number of calls that need to be responded to within a 24/7 timeline is low. Calgary and Ottawa may be the only two clinics that have a 24/7 response system for remotes.

Dr. Mitchell noted that one other issue is that in patients that live in other cities, the only way that the ER doctor knows what is going on with the device is by receiving the transmission report from the patient's doctor, as the report is not sent to the ER.

She noted that eight of the clinics (36%) routinely call patients after a remote transmission is received. Most only call patient when there is an issue. Currently no direct line from the patient to their device clinic if they present to the ED, it is up to the discretion of the ED physician whether the device clinic learns of the patient's visit to the ED. This is the current state of operation in Canada.

Next she provided results from the patient perspective – patient survey n=512:

• 16.7% sometimes/always feel nervous when attending clinic
• 33% felt secure not going to hospital to have device checked, 20% were unsure, 47% preferred coming to hospital
• 75.8% of patients know what to do if they experience a shock (191/252)
• 90.8% of patients feel that a phone call after the remote transmission was very important
• 52% are nervous or scared when they receive an alert

Does increasing the amount of transmitted data increase the risk that important reports are not identified quickly (e.g. is the amount of data transmitted appropriate or useful)?

Dr. Parkash explained that:

• This does not seem to be an issue
• Workload is currently increased with the current system of blended RM and in-clinic visits
• Overall, as clinical studies demonstrate, effectiveness of RM is proven, irrespective of increased amount of data
• The use of alerts is critical to ensuring that important reports are not missed and to manage information overload
  • a sensitivity of 100% and a specificity of 97% (positive predictive value 96%, negative predictive value 100% (Osca et al Rev Esp Cardiol 2009;62:886-95)

It is a huge burden, we haven't streamlined: we need to sort out which alerts need to be reviewed and which ones do not.
What, if any, considerations should Health Canada be requiring from manufacturers to ensure that home monitoring solutions both cover the affected population and provide useful alerts to clinicians in a timely and appropriate manner?

Dr. Parkash provided the following recommendations:

• Ensure that remote monitoring is available in all areas of Canada
  • The changes in technology using cellular-based transmission is an advancement but not having technology that permits patients who live in areas where cell towers don't provide coverage is an issue. Manufacturers are removing the option of non-cellular based transmission; Dr. Parkash believes this is an issue.
• Technology should advance to permit more rapid monitoring of patients i.e. in the event of an appropriate ICD shock, remote monitoring technology should permit more rapid response, rather than having delays that don't permit near real-time response. We don't need absolute real-time response but near real-time would be desired.
• Ideally information should be transmitted to patient, family physician and specialty provider in forms that are relevant and understood by each of these users, particularly so that patients understand what is going on with their device when they have an alert or a remote transmission is sent.
• Mechanisms to handle the amount of data transmitted through RM would be of significant benefit, such as machine learning to assist in interpretation of transmissions where a triage system permits more urgent issues to be dealt with
  • The responsibility of where this lies is unclear – ideally information triage should be device agnostic, or universal, rather than device company specific
  • Patient care should be performed by trained personnel, rather than device companies.

She indicated that in Canada we have not streamlined the process yet. Establishing servers in Canada has major cost implications. We need to address many aspects of this process, such as:

• Remote monitoring
• Remote programming
• Privacy issues
• Some patients are not comfortable with use of this technology.

There was a comment that now that this data has been received by the physician, there is an expectation and obligation to assess the transmissions, despite the sheer volume of information, because it has been shown that there is a benefit to the patient by analyzing the data. It was noted that physicians are getting "snowed in" by all the information.

While not shown with a superiority study, it seems likely that transmissions will provide increased safety. It is going to become very important to determine how the algorithms will work and how we will assess their safety.
There was a question regarding a change in the criteria of the action event. It was explained that there have been changes with how we deal with atrial arrhythmias, but now they have become actionable events, where previously it was not clear what to do. All other events have remained the same.

Depletion of the battery as a result of remote monitoring is now minimal, so this is not a concern.

All studies have demonstrated a reduction in "in-clinic" visits, however they don't account for the increase in workflow.

It was explained that since each province has their health information protection act, this causes major delays (years of delays) to get remote monitoring approved from a privacy standpoint.

Remote programing

In Canada, there is currently a study (~ 100 patients) to look at Remote view: reprogramming from afar (in another clinic, not at home). But device companies have backed off of this significantly due to the length and cost of privacy approval by institutions in Canada.

This concluded Dr. Parkash's presentation.

Dr. Parkash and Dr. Khaykin left the meeting.

Ventricular Assist Devices

Speaker: Dr. Renzo Cecere

Dr. Cecere introduced himself, disclosed his affiliations and proceeded to address the questions posed by Health Canada.

Objectives: Health Canada has evaluated a number of Left Ventricular Assist devices, with more limited exposure to Right Ventricular Assist Devices. At our meeting on 2015-06-26, Dr. Vivek Rao provided an overview of Mechanical Circulatory Support with a focus on the clinical impacts of left ventricular support using continuous flow or pulsing flow, and how these may promote or reduce pump thrombosis. Health Canada is requesting additional clinical insights on the therapy provided for right heart failure in the context of end stage heart failure patients. Health Canada is also requesting a general update on new developments within the area of circulatory support in the past two to three years of left, right, and bi-ventricular heart failure, especially as improved outcomes may lead to an increase in the use of this type of technology in Canada.

The left ventricular assist devices (LVADs) have become a standard of care among patients with end stage heart failure. However, right ventricular failure (RVF) after LVAD implantation or cardiac shock is frequent, with reported rates as high as 50% of LVAD recipients, and with very poor prognosis. RVF represents a major cause for postoperative multi-organ failure and death.

1. What are the risk factors for RVF? What are the hemodynamic characteristics during RVF in comparison with LVF and bi-ventricular failure?
2. What treatment options for RVF are available (with focus on treatment using medical devices)? What is appropriate timing for RVAD implantation?
3. Provide an update on current evidence and clinical trials on both left and right ventricular assist devices (e.g., MOMENTUM 3 trial) as well as experience in bi-ventricular support.
4. Provide an update on how and when devices are currently being used in Canada.
5. Discuss the risks and benefits of ventricular assist devices. Particularly, discuss the risk of pump stop and pump thrombosis using ventricular assist devices and risk mitigation strategies.

Dr. Cecere described the evolution of Ventricular Assist Devices:

• Generation 1 devices: HeartMate, Novacor (1994-2000) –pulsatile, positive displacement, large size, placement in abdominal cavity
• Generation 2 devices: Jarvik, HeartMate II, INCOR (2000-2006) –continuous, axial flow with bearings, medium size, pericardial placement
• Generation 3 devices: HeartMate III, HVAD, MVAD, HeartAssist5 (2006-2015) –continuous, Levitating rotor- centrifugal or axial, miniature, placement in pericardium

He discussed some of the current Ventricular Assist Devices (VAD) with pulsatile flow pumps versus continuous flow pumps, centrifugal pumps versus axial pumps.

He presented the results of ENDURANCE Designation Therapy Trial- HeartWare HVAD for the treatment patients with advanced heart failure ineligible for cardiac transplantation.

He described the fully magnetically levitated circulatory pump for advanced heart failure.

Next he described the Multicenter Study of MagLev Technology in Patients Undergoing Mechanical Circulatory Support Therapy with HeartMate 3 (MOMENTUM 3) trial which was:

• Non-blinded randomized trial that compared the centrifugal-flow pump (HeartMate 3) with the axial-flow pump (HeartMate II) in patients with advanced heart failure
• The HeartMate 3 (HM3) was associated with a higher rate of survival free of disabling stroke or survival free of reoperation to replace or remove the device at 6 months after implantation than was implantation of the HeartMate II (HM2) among patients with advanced heart failure, irrespective of their eligibility for transplantation.
• The incremental benefits associated with the HM3 observed in this 6-month analysis were due to the absence of suspected or confirmed pump thrombosis leading to surgical pump exchange or urgent transplantation.
• There were no significant differences between the two pumps in the associated rates of other major complications
• There was a trend toward a higher rate of disabling strokes with HM3 than with HM2
• Higher rate of right heart failure events managed with a right ventricular assist system with the axial-flow pump than with the centrifugal flow pump.

Dr. Cecere noted a number of limitations with this study:

• There was no blinding
• The surgeons at most, if not all, of the participating centers had long-term experience in the implantation of HM2, and thus the surgical and medical outcomes were potentially biased against the HM3
• The decision to remove or replace a pump for suspected or confirmed pump thrombosis was informed by the lactate dehydrogenase level or evidence of pump dysfunction but was at the discretion of the local site investigators
• The trial findings should not be extrapolated to a broader population with less severe heart failure

Trends in LVAD Use: The INTERMACS Registry Data was discussed next.

Dr. Cecere noted that experience with VADs is different from Province to Province thus it is difficult to provide Canada wide information. He provided information on the evolution in the use of long-term LVAD in Quebec: 2010-12 versus 2013-15 and comparison with the INTERMACS Registry:

He noted that use of LVADs in patients in cardiogenic shock has decreased over the last 6 years in Quebec. During the same period, LVAD has been used more frequently as destination therapy (DT) compared to bridge to transplant (BTT), with approximately 46% of patients now being DT candidates. In BC, funding is only provided for BTT patients. Changes in patient selection have been associated with improvements in clinical outcome. However, LVADs are still inferior to heart transplants. Funding is a significant issue as the devices cost approximately $120,000 and a full set of battery replacements costs $40,000.

Continued monitoring, timely feedback and participation in a large international registry likely contribute to optimizing quality of care. Quebec has recently developed a consensus document regarding standards of LVAD programs, in collaboration with clinical experts from each active institution. A companion summary of quality indicators, in line with INTERMACS, will be used to evaluate performance in the coming years.

Dr. Cecere noted that in Canada we are very fragmented in data collection and availability.

He discussed the Ontario Health Technology Assessment Series which has published on Left Ventricular Assist Devices for Destination Therapy in 2016. Ontario Health Technology Advisory Committee recommends that:

• Continuous-flow left ventricular assist devices (LVAD) are publicly funded as permanent therapy (also known as destination therapy) in patients with end-stage heart failure who are ineligible for heart transplantation.
• The Cardiac Care Network and Trillium Gift of Life Network provide guidance regarding which hospitals should offer this procedure and which patients should be eligible.
• The Cardiac Care Network and Trillium Gift of Life Network ensures data is collected on survival and quality of life for individuals receiving continuous flow LVAD as permanent therapy, and that this data be reviewed by Ontario Health Technology Advisory Committee in 2 years.

The full report is available at: Health Quality Ontario: Left Ventricular Assist Devices for Destination Therapy: OHTAC Recommendation (www.hqontario.ca)

Dr. Cecere discussed the NHLBI Randomized Evaluation of VAD InterVEntion before Inotropic Therapy (REVIVE-IT) pilot study.

• In 2008 it was believed that field of advanced HF treatment was ready for a trial to assess the use of long-term LVAD therapy in patients less ill than patients currently eligible for destination therapy VAD
• The specific objective was to compare LVAD therapy with optimal medical management in patients with less advanced HF than current LVAD indications, and
• To determine if wider application of permanent LVAD use for less ill patients would be associated with improved survival, quality of life, or functional capacity

Study hypothesis

• VAD therapy will improve functional status at 12 months and all-cause mortality will be no worse than that in the OMM arm of the study

Patient population

• Estimated mortality rate 20%– 30% at 1 year
• Patient population inclusion criteria:
  • hospitalization in past 6 months
  • NYHA class IV or advanced class III
  • maximal evidence-based therapies for 3 months
  • duration of HF of at least 1 year
  • no inotropic support for 30 days before enrollment
  • Randomized between VAD and OMM arms.
• Primary end-point: a composite of survival and functional outcome
• Secondary end-points: safety, secondary functional and physiologic markers, health-related quality of life indicators, neurocognition, and cost-effectiveness.
• Patients should be followed for at least 2 years

First patient enrolment started in December 2014, in January 2015 the FDA notified that REVIVE-IT trial was placed on clinical hold after series of consecutive pump thrombus events was observed in patients receiving the device (HM II) for current FDA-approved labeling indications outside of the context of REVIVE-IT study at a REVIVE-IT clinical site. In March 2015 the DSMB met to discuss issues leading to the clinical hold, and in April 2015 REVIVE-IT study discontinued after NHLBI acceptance of DSMB recommendations

Dr. Cecere noted that for a trial similar to REVIVE-IT to move forward in the future, several important issues need to be addressed, including:

• Identification of a study device with a safety profile that satisfies clinical equipoise for trial investigators and regulatory agencies
• An improved understanding of patient characteristics that will permit more accurate assessment of HF prognosis
• New technology will be required to advance LVAD therapy into a population with less advanced HF.

VAD for Right Heart Dysfunction

Decision to implant dual HVADs (13 pts off-label use on the right side) (reference: J Heart Lung Transplant 2016; 35:466-473) was based on a combination of:

• Hemodynamic parameters:
  • RV stroke work index,
  • Mean pulmonary arterial pressure
  • Trans pulmonary gradient
• Echocardiographic markers:
  • Degree of RV dilation
  • RV systolic impairment
  • Estimated pulmonary arterial systolic pressure
  • Severity of tricuspid regurgitation

RVF was defined in the HeartMate II Clinical Trial as either:

• The need for an RVAD in addition to the LVAD (group 1),
• Continuous inotropic support for at least 14 days after implantation (group 2), or
• Late inotropic support starting 14 days after implantation (group 3).
• Data from groups 1 and 2 were combined to form an early RVF group, whereas group 3 patients were examined separately (late RVF group)

The post-operative outcomes showed that 6 out of 13 (46%) patients died, and 4 out of 13 (31%) patients had RVAD thrombosis. It was stated that a combination of hemodynamic and clinical variables can be used to identify patients who might be at high risk for RVF.

Device options include direct and indirect RV bypass, as well as intracorporeal (Impella RP) and extracorporeal (Tandem RV assist device (RVAD), Protek Duo, venoarterial extracorporeal membrane oxygenation (VA-ECMO)) options.

Although there is some use of LVADs, including the HVAD, in Bi-ventricular support, the designs are not optimized for this application (e.g. cannula can be too long), and outcomes are poor. It isn't clear that Bi-VAD support is better than TAH.

TandemHeart in Right Ventricular Failure: nine (9) patients with MR-RVF between 2008-2010 received a TandemHeart RV support device. The etiologies included sepsis, post-cardiotomy, and acute RVMI. Results suggested that earlier support using right ventricular assist device could result in better clinical outcomes.

In general, RVF is a major problem with LVAD use. There are RV architecture changes due to septal shift with LV unloading and LVAD support. Recent efforts are to minimize septal shift that compromizes RV filling. There is less septal shift with new continuous flow devices, but this also means there is less ventricular recovery (e.g. for bridge to recovery). Variability in flow rates over the cardiac cycle is important.

Dr. Cecere discussed the RECOVER RIGHT Trial that is FDA approved prospective, multicenter, single arm study that evaluated the safety and probable benefit of a novel percutaneous VAD ( Impella RP) in patients with RVF refractory to medical treatment and deemed to require hemodynamic support.

In the RECOVERY RIGHT trial, the Impella RP, which is a size 22 Fr pump on an 11 Fr catheter and flow rate > 4 L/min was used. The results showed that hemodynamic improvement was reproducible in most patients as shown by increased Cardiac Index and decreased Central Venous Pressure.

Discussion on the risk factors, detection, and management of pump thrombosis followed.

There was a question whether the right ventricular failure is due to pulmonary hemodynamic changes or truly due to right ventricular itself. Dr. Cecere noted that it could be both: hemodynamic changes and right ventricle itself (e.g. right ventricular myocardial infarction) could contribute to development of right ventricular failure.

A question was asked whether the flow rates are clinically different (between the HM2 and HM3). It was explained that there is no difference.

Regarding the rate of driveline infection it was noted that it is relatively frequent and could be up to 20%, but of minor clinical impact.

There was a question regarding the accuracy of flow rate measurement of the right ventricular assist device considering the pressure difference between the left and right ventricles. It was explained that the flow rates are measured by algorithm (indirect measurement). Dr. Cecere noted that there are lots of ways for the flow rate measurement; however, we need to look at the patients' conditions and look at the clinical picture, not just the measurement.

This concluded Dr. Cecere's presentation.

Dr. Cecere and Dr. Mitchell left the meeting.

Dr. Yee returned to the meeting.

9. Use of Cardiac Implantable Electrical Devices (CIEDs) used in an MRI setting.

Discussion lead: Dr. Yee with contributions from Dr. Parkash and Dr. Mitchell.

This topic was originally circulated for e-consultation to Dr. Yee, Dr. Parkash and Dr. Mitchell.

Mr. Kevin Day introduced the topic to the committee member.

Acceptance Criteria for MR Conditional labeling

Until recently, applications to label Cardiac Implantable Electronic Device (CIED) system as "MR Conditional" have been supported by evidence that there is a very small likelihood of a chronic rise in pacing capture threshold (PCT) > 0.5V and an extremely remote likelihood of a rise in PCT > 1.0V due to a Magnetic Resonance (MR) scan induced RF heating of the lead electrode at the prescribed conditions. Available evidence suggests that no permanent damage is done to the underlying cardiac tissue when the rise in PCT is < 0.5 V. It is also noted that a change in PCT of < 0.5V is generally accepted as falling within expected background variation of PCT that may be observed clinically even without undergoing an MR scan.

Recently, Health Canada has received applications to amend licensed cardiac leads, including LV leads, which are currently contraindicated to MR scans and have them re-labelled as "MR conditional". For some of these leads, modelling estimates predict a significant possibility of a chronic rise in PCT > 1.0V and increases in PCT of 2.5V in worst case scenarios allowed by the labelled conditions.

Health Canada wishes to better appreciate how labelling can be used to effectively provide clinicians with the information needed to make informed decisions about the use of CIED systems in an MR environment, and to better understand what outcomes might be considered as unacceptable. For example, a device labelled as 'MR Conditional' has generally been interpreted to mean that under the conditions provided, the device will be safe to use and there is an expectation that no harm will be done to the patient. In cases where the chronic PCT increases by more than 1.0 V, this may be indicative of permanent scarring of the endocardial tissue. Although CIEDs can pace at higher voltage levels and overcome an increase in PCT, some permanent damage has been done, both in terms of endocardial damage as well as a significant reduction in battery life for the CIED.

Health Canada acknowledges that in some specific individual cases, MR scans can be a highly desirable imaging modality, without which adequate information about an underlying serious condition may not be obtained.

Health Canada requested an e-mail consultation to gather information from the clinical community so that Health Canada can gauge the level of concern associated with the use of CIED systems in an MR environment, and the potential impact to the endocardial tissue and PCT.

Specifically, Health Canada requested feedback regarding the following questions:

1. Do you believe that for a device to be labelled as MR Conditional, that the predicted rise in PCT should not be greater than 0.5 V, for at least a large percentage of the 'worst-case' scanning conditions allowed by the MR Conditions provided in the labelling? If so, what percentage of patients should this be?
2. Do you believe that devices labelled as MR Conditional should not cause permanent damage to endocardial tissue?
3. Would you be comfortable with term 'MR Conditional' meaning that after the MR Scan, it will continue to be possible to pace the patient with a PCT less than the maximum possible output of the CIED, even if this means some damage to the underlying endocardium may occur?
4. Do you believe it is appropriate to include additional data in the labelling outlining the probability of damage and rise in PCT that may occur if the proposed MR parameters are exceeded (such as a larger Specific Absorption Rate (SAR))? This information might be used in cases where moving forward with an MR scan was considered medically necessary.
5. Are there other considerations from your clinical perspective that you feel Health Canada should be aware of as we try and define appropriate limits for MR conditional parameters for active implantable devices?

Dr. Mitchell and Dr. Parkash had to leave the meeting early. Dr. Yee agreed to lead the discussion. He noted that he conferred with Dr. Mitchell earlier at the meeting and has Dr. Prakash's input and will try to respond to these questions on behalf of the group.

Dr. Yee noted that that there are various approaches from center to center between cardiologists and radiologists and these approaches may differ significantly. He proceeded to address the questions in order posed by Health Canada.

Do you believe that for a device to be labelled as MR Conditional, that the predicted rise in PCT should not be greater than 0.5 V, for at least a large percentage of the 'worst-case' scanning conditions allowed by the MR Conditions provided in the labelling? If so, what percentage of patients should this be?

Dr. Yee provided the following recommendations:

• Yes, predicted rise in PCT should not be greater than 0.5 V. Clinicians are comfortable with 0.5 V limit, however, they feel that we are setting the bar very high. In clinical setting we are not seeing a dramatic increase.
• In medicine the confidence interval surrounding any given statement is usually 95%. Accordingly, it would be reasonable that the percentage of patients not harmed by an interventional purported not to be harmful should be at least 95%. Dr. Parkash suggested 99% in her response.

Do you believe that devices labelled as MR Conditional should not cause permanent damage to endocardial tissue?

The following recommendation was provided:

• Yes and no. It may be too high a standard to meet if we phrase it as "no permanent damage". It is preferable to qualify the statement by saying no tissue damage of sufficient severity as to lead to clinical deterioration of the patient or clinically significant deterioration in device function, of which PCT is the most important parameter.
• Dr Parkash indicated that they should not cause permanent damage and that creation of scar in endocardial tissue can lead to life-threatening arrhythmia if it occurs in the ventricle. It may also compromise the ability to pace safely. However, Dr Yee also pointed out that scarring already occurs where the lead is implanted, and it is unclear whether MRI-induced damage would be different.
• This would have to be looked at in context and the clinical need for the patient to undergo the MRI.

Would you be comfortable with term 'MR Conditional' meaning that after the MR Scan, it will continue to be possible to pace the patient with a PCT less than the maximum possible output of the CIED, even if this means some damage to the underlying endocardium may occur?

Dr. Yee provided the following suggestions:

• No. It is unacceptable to label any device as "MRI Conditional" if the CIED is susceptible to experiencing sufficient damage after exposure to MRI environment that PCT rises to a degree anywhere approaching the maximum pacing output of the CIED. That degree of tissue damage effectively shortens the life of the device and results in premature generator and lead replacement which exposes the patient to added risk of harm. In other words, just being able to say that the device will continue to pacing is at maximum output is not truly safe and is antithetical to the whole concept of MRI safety.

Do you believe it is appropriate to include additional data in the labelling outlining the probability of damage and rise in PCT that may occur if the proposed MR parameters are exceeded (such as a larger Specific Absorption Rate (SAR))? This information might be used in cases where moving forward with an MR scan was considered medically necessary.

Dr. Yee recommended that:

• If we already have a requirement in the labelling that the "MRI Conditional" designation is only applicable for the same MRI conditions under which the device was tested and shown to be "safe" then inclusion of such a statement should not be included.
• There may not be a benefit in additional labelling.

Are there other considerations from your clinical perspective that you feel Health Canada should be aware of as we try and define appropriate limits for MR conditional parameters for active implantable devices?

Dr. Yee felt that:

• Use of leads and pulse generators from different manufacturers, and whether the labelling would apply in these cases, if both had MR conditional labelling. However, all systems licensed so far are specifically for leads and cans from the same manufacturer, as this is the combination that is used in the evaluation of safety.

Dr. Yee noted that while he supports loosening the MRI Conditional label to allow for unrestricted rises in PCT up to the maximum output of a device, he also thinks that applying an arbitrary limit of ≤ 0.5V rise in PCT may also be overly restrictive. It really depends upon the baseline PCT prior to MRI exposure. For example, if the baseline PCT pre-MRI is 0.5V and the PCT rises by 0.6V post-MRI, that degree of change is over 100% but is of minimal clinical consequence since that rise has minimal impact upon battery longevity. Even a rise of 1-2 V, while undesirable, is not catastrophic and might well be worth it for the patient if the need for the MRI is strong. On the other hand, a rise of 1V or less in someone with a high baseline PCT (say 3.5V) may have a much greater impact. It may not be the absolute amount of PCT rise that is critical but, rather, the percentage rise. At a low baseline PCT (say, less than 1.5V) a 30% rise in PCT with MRI might be acceptable but the same percentage rise would be unacceptable at baseline PCT above 3-4V, let's say. Having said that, he recognizes that the PCT is not the focus solely because of the clinical consequences of such a rise but that a PCT rise is also representative of permanent tissue injury and the desire is to ensure that MRI exposure does as little harm as possible. However, he considers that some degree of tissue damage is acceptable the clinical setting and the debate is really about how much and how best to quantitate it.

Dr. Yee concluded the discussion.

10. Atrial Shunt/Flow Devices for the Treatment of Heart Failure

Speaker: Dr. Mathieu Bernier

Dr. Bernier introduced himself, disclosed his affiliations and proceeded to address the questions posed by Health Canada.

Objectives: Atrial shunt devices for the treatment of heart failure are new and novel devices that Health Canada would like to have a better understanding of the technology and patient populations that may benefit from implantation with such a device. This topic was previously presented at our 2015 meeting by Dr. Sebastien Bergeron (Laval), however the technology is still considered new and is evolving. Currently, a few technologies have been authorized through SAP and ITA, but since there is little clinical experience with these devices, it is a challenge to review these applications. A better understanding would help to determine requirements for clinical trial designs and possible future licensing decisions.

Provide an update on the devices used for atrial shunting. This should focus on interatrial left to right shunting in heart failure patients with preserved left ventricular ejection fraction (HFpEF). Other applications, such as left atrial pressure decompression into the coronary sinus or right to left atrial shunting, may also be discussed. Please include an overview of clinical evidence related to safety and effectiveness of the technology, novel systems currently under development, and any future trends in this area. In your discussion, please address the following:

1. Provide a brief overview of the principle concept of interatrial shunting for the treatment of heart failure as background information. Also, discuss any safety risks associated to interatrial shunting.
2. Provide a summary of atrial shunt/flow devices, in particular those intended to treat heart failure with preserved LVEF. For example, such devices include interatrial shunting from left atrium to right atrium either directly (trans-septal) or through the coronary sinus (a novel concept for this approach: a device system recently being requested via SAP). Devices could also include applications for pediatric patients.
   1. Discuss the history of the different device designs and clinical uses.
   2. Discuss the rationale of device designs, including uni-directional flow versus bi-directional flow devices.
3. Provide an update of clinical evidence of safety and effectiveness. Discuss any lessons learned in regards to patient selection (including hemodynamic parameters), the population that will benefit the most, and best measures of safety and effectiveness.
4. Provide recommendations on clinical trial designs including which endpoints are critical to measure the safety and effectiveness of these devices. Are randomized studies possible and what is the best control group?
5. Provide recommendations for clinical data requirements that would demonstrate the safety and effectiveness of these devices for licensing purposes. Discuss which measures of effectiveness are useful and how much clinical improvement should be demonstrated.
6. Provide your opinion on the future trends of novel devices for heart failure.

Dr. Bernier started by indicating that there is not much experience with atrial shunting in heart failure. There is very limited data. He will provide an update based on their clinic's experience in this area.

He explained that heart failure can be associated with either low EF or normal EF, however both have the same symptoms: shortness of breath and low exercise capacity. Days or weeks before a patient presents with decompensated HF, the left atrial pressure (LAP) is ≥ 25 mmHg, as measured by intracardiac monitors. Increased LAP is the cause of lung congestion in acute decompensated heart failure (ADHF). The main treatment for elevated LAP is diuretics to relieve symptoms.

Shunting is considered an alternative to diuretics for lowering LAP, particularly in patients already receiving optimal medical therapy, not eligible for advanced HF treatments, and in whom symptom relief and quality of life improvement is needed.

He described the V-Wave Interatrial Shunt that is an hourglass shape device made of polytetrafluoroethylene (PTFE) and a self-expending Nitinol frame. He noted that the first generation device included a porcine pericardium one way valve that only allowed shunting from the left to the right atrium, through a 5 mm middle orifice, while right to left flow was prevented. The shunt is placed at the thinnest part of the intra-atrial septum, in the center of the fossa ovalis, which is the easiest location to access.

First-in-man Clinical Data:

Dr. Bernier explained that they have a fairly large HF clinic and follow approximately 1000 patients, out of which 60% are low EF patients. While all patients receive optimal medical therapy, some remain symptomatic without any other treatment options. These patients were identified for potential shunting. The V-Wave was implanted in a cohort of 22 patients on compassionate grounds using Health Canada's Special Access Program (SAP).

Data was collected from these patients to evaluate the feasibility and safety of the V-Wave system for HF treatment. Collected data included:

• Procedural success (successful device implantation with no peri-procedural death); and
• Safety (device/procedure-related MACNE - device related death, stroke, device embolization, pericardial effusion requiring intervention and device related re-intervention or surgery), at 3 and 12 months.

Additional data included:

• MACNE and SAEs at 12 months; and, exploratory efficacy - clinical and hemodynamic parameters (swan-ganz and TEE, 6 Min.HWT) after 12-months of follow-up.

Inclusion/Exclusion Criteria:

Main Inclusion Criteria

• Chronic HF of ischemic, or non-ischemic etiology, irrespective of LVEF (80% low EF)
• NYHA Class III, or ambulatory Class IVa
• On guideline driven maximally tolerated medical, and device therapy
• Elevated BNP/NT-proBNP

Main Exclusion Criteria

• Isolated right-sided HF
• Moderate-severe RV dysfunction
• Severe pulmonary hypertension

The gradient between LA and RA was between 5 to 15 mmHg.

Procedure:

• Procedures performed by trans femoral venous approach, under general anaesthesia and TEE guidance
• Patients received anticoagulation therapy (Coumadin) for at least 3 months following the procedure
• Follow-up (1, 3, 6, 12 months and yearly thereafter to 5 years)

Assessments:

• NYHA class
• Six-minute walk test
• Quality of life questionnaires (KCCQ; MHLF)
• Right heart catheterization (baseline, 3, and 12 months)
• NT-proBNP
• Transthoracic Echo
• Transesophageal Echo (1, 3, and 12 months)

Study Population:

• Through Canadian Special Access Program
  • 22 patients enrolled (16 HFrEF, 6 HFpEF)
• First-In-Man Multicenter Feasibility Study
  • Israel and Spain (5 centers)
  • 16 patients enrolled (15 HFrEF, 1 HFpEF)
• Total study population: 38
• All subjects completed 12 month follow-up (none lost to follow-up)

The study provided the following results:

Procedural outcomes:

• Procedural Success = 38/38 (100%)
  • No device malpositioning, dislodgement/embolization or device replacement
  • Procedure time = 72 ± 24 min
    (Includes: TEE, RHC, transseptal, shunt placement, all study measurements)
  • Median LOS: 2 days (IQR: 1-3)
• In-Hospital Adverse Events:
  • 1 Cardiac tamponade (treated by pericardiocentesis)
  • 3 Vascular access complications (all treated non-invasively), none at the Canadian center.

Safety endpoint:

• Primary safety: 97.4% freedom from Device/Procedure-Related MACNE at 3 months
  • Death: 0, Stroke: 0, MI: 0, Device Embolization: 0, Cardiac Tamponade: 1
• Secondary safety: 92.1% freedom from any MACNE at 12 months
  • Death: 2 (CV – not device or procedure related related to arrhythmia), Stroke: 0, MI: 0

Other Serious Adverse Events included acute decompensated Heart Failure (HF) (9), bleeding (4), renal impairment (3) and Ventricular Tachycardia (VT) (1).

Although small patient numbers introduces considerable variability, there was a 'clear' improvement from baseline at which all patients were Class III to IV. Between 3 and 12 months a significant proportion moved to Class I to II.

Quality of Life (QoL) Change: 70%, 59%, and 70% improvements from baseline at 3, 6 and 12 months respectively.

6MWT Change (m): Compared to baseline at three months, patients could walk on average 40 m more. At the 12 month follow-up, patients could walk on average 28 m more.

Echo follow-up: key observation is the decline in shunt patency rate after three months; colour Doppler shows flow from left to right atrium. By 12 months, almost 20% were not patent.

There was no change in hemodynamic parameters, eGFR and NT-proBNP from baseline to 12 months follow-up.

Members asked how patient improvements are explained without changes in wedge pressure (PCWP). Dr. Bernier explained that wedge pressure is dynamic and changes throughout the day in both directions, and average changes are small. Approximately 80% of patients actually exhibited at least 5 mmHg decreases from baseline. He noted that this is an imperfect measure to use as a comparator.

It was noted that this procedure is vulnerable to placebo effects. Would there be a sham control for the next study? Dr. Bernier explained that the chance of a placebo effect is high, and the next RCT will include a sham control.

There was a comment regarding the finding that NT-proBNP levels did not change from baseline. It was suggested that this finding might just indicate the device is not effective. Dr. Bernier indicated that the future RCT will shed additional light on this issue.

It was noted that the hole that is created by the device may not be large enough. It was also noted that if wedge pressure is decreased significantly you would expect the cardiac output to decrease as well. Dr. Bernier explained that this isn't always clear, based on where you are on the Starling Curve, but as stated earlier, BNP and wedge pressure are imperfect measurements.

There was a concern regarding taking the patient off anticoagulants after three months. Dr. Bernier noted that patients that are already taking those medications will continue to do so, and for the others, they are not sure what the best approach is.

Dr. Bernier presented comparison of baseline characteristics between the V-Wave patients and a historical control cohort (CHAMPION). He noted that V-Wave population was older, sicker and better treated, or had higher risk baseline characteristics than CHAMPION. It was also noted that the "unofficial" comparison of hospitalization rates of the current cohort to the CHAMPION control shows HF hospitalization rates were low relative to historical well-matched advanced Class III HF populations. Similarly, this difference was shown in HF patients with reduced EF.

He indicated that 1st, generation device contained a valve, however in the first 21 patients, device narrowing over time was observed.

Legacy V-Wave Shunt: Valve Function at 1 Year:

• Absence of L-R shunt flow was observed in 5/36 (14%) surviving patients
• Color doppler vena contracta jet in the valve region was narrowed or skewed off-axis in 13/36 (36%) pts
• The absence of shunt function was associated with worsening symptoms
• Qp:Qs 1.17 ± 0.12 at implant fell to 1.10 ± 0.13 at 1 year (P=0.04)
• Bioprosthetic leaflets developed neointimal proliferation (pannus) with thickening, as observed on 2.5 year explant specimens: commissural fusion, fixation and stenosis - not associated with acute deterioration or thromboembolic events
• The higher the wedge pressure at baseline, the less likely the shunt was to be closed at follow-up, and less likely the patients would present with symptoms. Patent shunts were associated with improved hemodynamics.
• Patent shunts were associated with reduced mortality, HF-Hospitalization and all-cause hospitalization (mean 26-month FU).

There was a question if patients receive the valved device. Dr. Bernier explained that all 38 patients received the valved device.

Generation 2: V-Wave Interatrial Shunt:

• The next device will be a shunt without a valve. The device has been re-designed to be similar, but without a valve, not unlike an ASD.
• As shown in animal testing, unlike valved shunts, Generation 2 Shunts were superior in Normal Physiology (2-3 mmHg L-R gradient) as evidenced by no late lumen loss at 6 months.

RELIEVE-HF Pivotal RCT is designed to establish the efficacy of the non-valved conduit.

Design:

• Sham-controlled, blinded (patient and HF team), adaptive design
• ~400 randomized + ~120 roll-in patients at 60 sites (40 US + 20 OUS)

Population:

• NYHA class III or ambulatory class IVa on GDMT (eligibility committee review)
• HFrEF or HFpEF – no specific LVEF criteria
• Hospitalization for worsening HF within 1 year or elevated BNP/NT-proBNP
• Outcome Measures:
• Primary Effectiveness: hierarchical comparison of mortality, transplant/LVAD, HF hospitalization, and 6MWD using Finkelstein-Schoenfeld/Win Ratio
• Primary Safety: Device-related MACNE at 30 days (performance criteria)
• Health economic metrics
  • The main issue will be blinding and internal validity.

There was a question regarding how can HF team be blinded? Dr. Bernier explained that the device is almost impossible to see on X-ray. They'll have to figure out how to blind from echo readings. It will be a challenge.

In conclusion Dr. Bernier noted that the V-Wave Interatrial Shunt:

• Is safe to implant and can be implanted with high procedural success and low morbidity
• Improves symptoms, QoL, and left-sided hemodynamics without worsening right-sided cardiac function
• Has been associated with reduced heart failure hospitalization and mortality compared to well-matched historical controls on GDMT
• Appears well-suited for class III/ambulatory class IV, HFrEF and HFpEF patients, with high-risk characteristics

Dr. Bernier noted that a pivotal RCT is needed to for the Generation 2 V-Wave support the previous findings, and will begin soon to evaluate the safety and efficacy in patients with HFrEF and HFpEF.

There was a question related to diastolic dysfunction. Dr. Bernier noted that a paper in the Lancet reported that REDUCe Elevated Left Atrial Pressure in Patients with Heart Failure (REDUCE LAP-HF) trial on a small number of patients with HFpEF implanted with the interatrial shunt device (IASD, Covia Medical) showed improvement. An improvement in wedge pressure was demonstrated with exercise. An RCT for diastolic dysfunction involving that device is expected to begin soon.

To address the question of a device implanted in the coronary sinus Dr. Bernier indicated it is unknown how a CRT device might interact with the coronary sinus shunting device and further study is required.

There was a question regarding the ideal pressure gradient for the pulmonary artery, and the ideal flow rate. Dr. Bernier explained that the shunt is a fixed size at 5 mm, and the gradient between the atria is generally very small. Patient inclusion criteria were arbitrarily chosen: > 5 mmHg and < 15 mm Hg. They don't know what the ideal gradient or flow across the device should be. There was a concern about the potential for shunting to contribute to right heart failure. Dr. Bernier indicated that patients with right heart failure were excluded.

It was noted that in the history of HF, there have been no studies in Class III patients as they have been so well managed with medical treatment (as well as ambulatory Class IV), therefore this device may only offer improvement for those that would improve anyway. Dr. Bernier noted that while not representing a definitive therapy, difference would be worthwhile.

There was a suggestion that the static difference may not be observable, but present at exercise (where wedge pressures are higher), which is typically not well studied. The patients with preserved EF are difficult to treat, as no medical therapy (diuretics) works well.

There was a concern that the V-Wave design has largely stayed the same and will protrude into the atria. Would this result into a tissue ingrowth that would close the shunt? Also, could the device be closed if need be? Dr. Bernier explained that the device could be plugged, or during LVAD implantation, could be closed with a patch. In addition there was a concern for thromboembolic events on the left side. Dr. Bernier indicated that potential for thromboembolic events is unknown. He noted that he has not closed a device, but that it could be done. There was a comment that nitinol mesh devices, like other atrial flow devices (e.g. Occlutech), are generally not associated with thrombus, but others may be.

There was a question whether the loss of the valve will cause any complications. It was noted that the presence of a valve is associated with more turbulent flow, and risks are likely fewer without a valve.

It was suggested that if this procedure works it would be a bridge to another therapy; it would buy more time for the patient.

Dr. Bernier concluded his presentation.

11. Next Steps, Closing Remarks and Adjournment of Meeting

Dr. John Ducas, Committee Chair

The Chair thanked committee members and invited speakers for their participation and valuable input. Members will be canvassed to select a date for the next meeting.

Meeting adjourned.

Committee Members: John Ducas (Chair), Renzo Cecere, Eric Cohen, John Ducas (Chair), Christopher Feindel, Marino Labinaz, Brent Mitchell, Joaquim Miró, Barry Rubin, John Webb, Raymond Yee, John Webb (via teleconference/WebEx)
Regrets: Alan Menkis
Invited Guests: Mark Peterson, Kong Teng Tan
Health Canada Representatives:
Office of Science: Hripsime Shahbazian, Larissa Lefebvre,
Medical Devices Bureau (MDB, TPD): Kimby Barton, Kevin Day, Ian Aldous, Ben Elliot, Ian Glasgow, Jianming Hao, Karen Kennedy, Mark Korchinski, James McGarrity, Bisi Lawuyi, Roy Masters, Catherine Milley, Chris Schmidt, Maurice Sylvain, Lanyi Xu
Bureau of Cardiology, Allergy and Neurological Sciences (BCANS, TPD): Mick Gelsena, Xiaobing Guo, Tiamo Li
Regulatory Operations and Regions Branch (RORB): Collin Pinto
Marketed Pharmaceuticals and Medical Devices Bureau (MHPD): Melanie Bousquet, Patrick Fandja, Chengwen Ren

Abbreviations used in this record:

AI:

aortic insufficiency

AV:

atrioventricular

BiV:

bi-ventricular

BMS:

bare metal stent

CABG:

coronary artery bypasses grafting

CRT:

cardiac resynchronization therapy

DCB:

drug coated balloons

DEB:

drug eluting balloons

DES:

drug eluting stent

EAO:

effective orifice area

ICD:

implantable cardioverter defibrillator

ISR:

in-stent restenosis

LVAD:

left ventricular assist device

LVEF:

left ventricular ejection fraction

LV:

left ventricle

MACCE:

Major Cardiovascular and Cerebrovascular Event

MDB:

medical devices bureau

NYHA:

New York Heart Association

pAVD:

paced Atrial-Ventricular Delay

pAVI:

paced Atrial-Ventricular Interval

PCI:

percutaneous coronary intervention

POBA:

plain old balloon angioplasty

RCT:

randomized clinical trial

SAC-MDUCS:

scientific advisory committee on medical devices used in the cardiovascular system

SAP:

special access program

sAVD:

sensed Atrial-Ventricular Delay

sAVI:

sensed Atrial-Ventricular Interval

SAVR:

surgical aortic valve replacement

SFA:

superficial femoral artery

STEMI:

ST-elevation myocardial infarction

STS:

The Society of Thoracic Surgeons

TAVI:

transcatheter aortic valve implantation

TAVR:

transcatheter aortic valve replacement

TMVR:

transcatheter mitral valve replacement

TLR:

target lesion revascularization

TPD:

Therapeutic Products Directorate

TVR:

target vessel revascularization

1. Opening Remarks & Welcome

Dr. John Ducas, Committee Chair

Dr. Ducas opened the meeting, welcomed the committee members and guest speakers. Kimby Barton, the current Interim Director of the MDB and Senior Executive Director of the Director General's Office of the Therapeutic Products Directorate (TPD), introduced herself, thanked the committee members and guest speakers for sharing their time and expertise and acknowledged the efforts all participants had made to attend the meeting. She summarized issues that were brought to the committee for discussion and recommendations. She noted the importance of the Scientific Advisory Committee on Medical Devices Used in the Cardiovascular System (SAC-MDUCS) to Health Canada's regulatory review and decision-making process. She acknowledged the committee on its continued support and noted that their past recommendations have been helpful in numerous license evaluations. She concluded by wishing the committee members and participants a productive meeting.

2. Review of the Agenda, Affiliations and Interests Declarations, and Confidentiality Agreement

Dr. John Ducas, Committee Chair

The Chair reviewed the agenda items with the committee. The agenda was accepted with minor adjustments to accommodate all speakers. Members were asked to disclose any conflicts that may arise as the meeting proceeds.

He invited Hripsime Shabazian to address the next topic.

3. Review of Terms of Reference, Membership and members Affiliations and Interests

Hripsime Shahbazian (Office of Science, TPD)

Hripsime Shahbazian informed the committee members regarding renewal of membership, as per the SAC-MDUCS Terms of Reference (ToR), which requires that memberships should be reviewed periodically. She noted that the Office of Science conducted membership renewal in 2014, and after 2 years it is time once more to revise and update membership for the committee. At this time HC would like to reaffirm member's continued interest in participating as a member or an ad hoc member of the SAC-MDUCS.

The Affiliations and Interests Declaration Forms need to be revisited as well. This form requests information from member's current situation as well as history regarding their affiliations and interests over the last five years. Once completed, the information provided in this declaration will be reviewed and then used by Health Canada to produce a "Summary of Expertise, Experience, and Affiliations and Interests." Every member will have an opportunity to review, amend and/or approve their own summary which will be posted to Health Canada's website as required under section 3.0 of the Health Canada Policy on External Advisory Bodies (2011) to promote our Branch's commitment to be open and transparent regarding the membership of its advisory bodies.

In addition, members will be asked to provide an updated Biography. Each member will be asked to review their biography as it appears now on Health Canada web and indicate whether it is acceptable as written or whether changes are required to this version.

Furthermore, Mrs. Shahbazian noted that before each committee meeting the chair will ask the members/invited experts to provide their consent to the recording of their views and opinions in the Record of Proceedings (RoP) and to the publication of the RoP on Health Canada's Web site. Once a draft RoP is prepared by the Secretariat it will be circulated to members for review, and final approval by the Chair and Executive Secretary. All members/invited experts that attended the meeting will be given the opportunity at the time of reviewing the draft RoP to ensure that their views are properly recorded. The final RoP will effectively summarize the proceedings to reflect the advice offered. The Secretariat is responsible for the distribution of the RoP. This process will be reflected in the revised ToR and will be circulated to the members for their review and acceptance. All members supported this requirement.

Mrs. Shahbazian thanked members for their continued support.

4. Summary of how Health Canada has used information generated from previous SAC-MDUCS meetings

Kevin Day, Medical Devices Bureau (MDB)

Mr. Kevin Day presented a brief summary of how previous advice and recommendations provided by the committee have been considered by Health Canada.

The following topics were noted:

• Bioabsorbable Vascular Scaffolds: good overview of both the strengths and weaknesses of the technology were noted. Health Canada will continue to monitor the device performance as the data becomes available.
• Chronic Heart Failure and Baroreceptor Activation Therapy: background information was valuable in determining if the technologies should be approved for the Canadian market.
• Inferior Vena Cava Filters: Health Canada has received positive feedback regarding the Notice including the focus on increased patient follow-up.
• Leadless Pacemakers: was informed of clinical trials and adverse event assessments with other leadless pacemakers, and determined appropriate indications for use and appropriate clinical endpoints.
• LAA Closure Devices: Health Canada continues to monitor and access the data as it becomes available.

Mr. Day thanked members for their ongoing dedication to the committee.

5. Various techniques to improve cardiac resynchronization therapy (CRT) responder rates

Dr. Raymond Yee, Committee Member

Dr. Yee disclosed his affiliations and proceeded to address the questions posed by Health Canada.

OBJECTIVE: Increasingly, manufacturers of CRT systems are trying to introduce new features that appear to target improving the CRT responder rates. Frequently, the clinical data is relatively weak in terms of demonstrating improved clinical outcomes that are associated with clinically relevant endpoints with these new features. Health Canada requests input and recommendations on how these new features should be reviewed and what level of evidence should be required prior to issuing a licence to these types of features for CRT systems.

1. The idea makes sense and most device manufacturers now include some functionality to try and optimize AV delay in CRT systems. However, there exists meta-analysis and other data that don't support the clinical benefit of AV delay optimization. Do the experts believe this represents an effective treatment strategy?

   Experts agree that sAVi (sensed AV interval) & pAVi (paced AV interval) programming are important for optimal cardiac function in HF patients, and VVi (Ventricle to Ventricle interval) programming may be valuable in partially overcoming problems of suboptimal LV lead placement. However, it should be remembered that the important AV intervals pertain to the left heart so that the timing of LA and LV contraction are most important. CRT non-responder rates continue to be around 35% with ranges reported in the range of 15% to 45%. Experts desire but are skeptical of finding an algorithm that improves CRT response rates, and the magnitude of benefit may be limited since CRT response is determined by multiple factors. Optimization algorithms are important in setting programming boundaries, and patients require continual follow-up as their hearts remodel. Optimization algorithms should be efficacious and safe; desire ones that are more simple, less costly to implement and less resource intensive than ECHO optimization but that may not be achievable. Continuous or auto-adjusting algorithms are preferred; continuous adjustment will be required as the patient remodels. Hemodynamic-based algorithms with closed loop feedback preferred.

2. What methods and features of existing CRT systems are being used to try and improve CRT responder rates? Is there data to support these improvements?

   Three strategies for increasing CRT response rate were presented: patient selection, procedural modifications, and post-implant care. Optimization algorithms are involved in the post-implant phase only.

   Patient characteristics associated with greater responder rates, based on RCT studies include:

   • women have a higher response rate than men (men still respond) due in part to greater proportion of patients with non-ischemic cardiomyopathy
   • extent of focal myocardial scar
   • prior history of HF hospitalization
   • left bundle branch block (patients with right bundle or non-specific interventricular induction delay showed no benefit in the subgroup analysis)
   • greater QRS duration/width (i.e. > 150 ms – greater degree of myocardial dysynchrony) (but the RAFT study showed that patients with paced QRS complexes at ≥ 200 msec tended to not respond)
   • left atria size (larger LA did worse)
   • atrial fibrillation (patients who stayed in sinus rhythm did better)

   Smaller trials have identified predictors of poor CRT response including:

   • poor RV function
   • poor renal function
   • greater myocardial scar burden

   The presence of arrhythmias has an effect on ability to pace. The devices are programmed to pace in a range of between 50-60 beats/min to as high as 120-130 beats/min depending on the patient. The age and functional capacity of a patient, at baseline, will determine the programmed pacing. Generally, the less CRT pacing being delivered (pacing burden) by the device, the less likely the patient will respond (analogous to drug dosage in pharmacologic therapy).

   Atrial fibrillation is a major clinical problem limiting response, with the two major consequences being: loss of atrial systole, and higher heart rate (which decreases the ability to pace).

   Two treatment strategies are available for AF patients (insufficient scientific evidence regarding which is the best):

   1. Maintain sinus rhythm (rhythm control) with antiarrhythmic drugs or AF ablation, and
   2. Ventricular rate controls by AV node blocking drugs or AV node ablation.

   The clinical benefit of CRT in patients with permanent AF is currently undergoing assessment by randomized clinical trial: RAFT Perm-AF.

3. What have we learned and what data is there to support the possible identification of responders or non-responders prior to implantation.

   Definition of CRT responder

   It is important to note that there are various definitions of CRT response and they do not necessarily correlate:

   • Clinical or subjective using criteria such as decreased HF symptoms, decreased QoL Score, and change in NYHA functional Class > 1
   • LV remodeling or objective using criteria such as; absolute change in LVEF >= 5% or change in LVESV >= 10-15%
   • clinically relevant endpoints including total or cardiovascular mortality, HF hospitalization; and, combined clinical composite score.

   Response/non-response to CRT is usually determined 3-6 months post-implant. Suboptimal AV timing has been identified in majority in many of non-responders, but there are other contributing factors including arrhythmias.

   The location of the pacing leads is another important factor determining likelihood of CRT response and is potentially within the control of the physician. Dr. Yee suggested that pacing the LV lead near the apex has been shown to have poorer outcomes (MADIT-CRT). However, there may be individual patients in whom this may be the best or only placement option. Pacing basally in posterolateral or anterolateral wall segments generally is better but lead placement is limited by coronary venous anatomy. Therefore, procedure-based strategy for trying to increase response rate involves optimal lead placement, particularly the LV lead. Approaches include targeting LV leads to avoid myocardial scar and to pacing at the site of latest LV wall segment activation (Q-LV).

   Myocardial scar slows conduction of electrical wavefronts to the rest of the LV so pacing within scar would not be expected to synchronize wall segments as effectively. There is much less information about the importance of RV pacing site and RV scar. The MAPIT-HF trial, which was a smaller trial, found that site of RV pacing is also a factor in determining response. Patients whose pacing leads avoided scar in either ventricle showed the greatest likelihood of responding (80% response rate) versus 54.5% responded the RV lead landed at the site of RV scar and 25% if the LV lead was located at the site of scar. The response rate was zero if both leads happened to land in scarred myocardium.

   Results from two randomized clinical trials (TARGET & ImagingCRT) indicate that imaging-directed lead placement increases CRT response. TARGET was the first trial to test the hypothesis. In half the patients, LV lead position was guided by echocardiographic radial strain tracking. Study details include:

   • 220 patients, randomized, primary endpoint was echo defined response of greater or equal to a 15% decrease in LV end systolic volume.
   • Control: LV lead was placed by the surgeon's preference
   • Targeted: LV lead was echo guided and placed away from scaring
   • Primary endpoint response: was LVESV decrease by ≥ 15% from baseline
   • Response rate in the control group was 55% and was 70% in the targeted lead placement group
   • Cost is minimal in terms of procedure time (no significant increase is procedure time)

   In addition, it's best to place the lead at the latest activated site defined either mechanically or electrically. Most people do it electrically by measuring the QLV interval (during intrinsic supraventricular rhythm) which is defined as the time from the initial deflection of the QRS on the surface ECG to local intrinsic activation at the LV stimulation site. Furthermore, the greater the degree of narrowing of the biventricular paced QRS (to the narrowest width), the greater the likelihood of response.

   Alternative pacing strategies are also being tested. For example, biventricular pacing has been compared to His bundle pacing in a crossover design in two small studies. Patients were followed for a year, and His pacing had similar effects on EF, NYHA Class, QoL, or 6MHW.

   Discussion regarding area of scar:

   There was a comment, "Dead meat don't beat", made by the committee, which raised the question, "Is scar burden responsible for the lack of response?" Dr. Yee responded that it is an important factor but it is but one of many. He indicated that the more scar [present], the less likely you'll see a response, and that this was supported by MRI data in CRT patients.

4. What are the risks and benefits of multi-site pacing compared to standard Bi-Ventricular (BiV) pacing. The discussion might include:
   1. a quantitative or qualitative comparison of the safety and effectiveness of Multi-site versus BiV pacing;

      CRT-P (CRT-Pacemaker) is a BiV pacemaker. CRT-D is the same as a CRT-P with the addition of implantable cardioverter-defibrillator (ICD) function. 95% of the CRT-D pacemakers are implanted. However, the reason a CRT-D is not implemented has to do more with patient preference – they do not want to receive a shock and die.

      Dr. Yee indicated that there are many different versions of multisite pacing and they need to be distinguished. Some versions may be more efficacious than others and it is important not to lump them all together. He suggested that multisite pacing may potentially increase CRT responders, because it would allow physicians to choose the best combinations of pacing sites. He identified the risks as:

      • increased procedure complexity and time, radiation exposure
      • lead dislodgments, and lead-lead interactions
      • potential for increased battery energy consumption

      The benefits include: improved CRT response reduced HFH (Heart Failure Hospitalization) and mortality. He indicated that at this time there is insufficient evidence to support this strategy.

      Four trials have compared these approaches (TRIP-HF, Lanerczyk, Rogers, Pappone). All have small number of patients and are unicenter or multicenter, have serious design limitation (e.g. crossover studies lack a wash out phase), different endpoints are used in each, and too many different alternatives are evaluated (2 RVs leads, 2 RV + 2 LV leads) to interpret. Also, patients with prior pacemakers were included.

   2. evidence that Multi-site pacing could provide a quantifiable clinical benefit compared with BiV including the support from available data from pivotal clinical trials;

      It is important to distinguish between multipoint pacing (MPP) using electrodes on a single LV lead in one coronary vein versus electrodes on separate LV leads in two different coronary veins.

      The Multi-Point Pacing Technology (MPP) trial (only in Abstract Form – not yet published) is an industry sponsored, multi-centered, randomized study, comparing multipoint pacing 2 sites in the LV combined with RV versus standard BiV pacing using a single quadra polar lead, longitudinally along the LV. The primary safety endpoint was freedom from system-related complications at 9 months. The primary efficacy endpoint was non inferiority of response of MPP at 9 months compared to 3 months of BiV pacing. Safety response (93.2% freedom from system-related complications) met the safety endpoints. Effectiveness endpoint showed no substantive difference between MPP and standard BiV pacing, although Dr. Yee pointed out that the study showed a trend towards multipoint pacing having a worse outcome but non-significantly; the available data did not point to a benefit, but only ensured there was no harm.

   3. the clinical implications of reducing battery life with Multi-site pacing

      Reduced battery longevity results in more generator replacements during the device lifetime and more exposure to infection, which translates to higher lead extraction risk.

      The potential impact of MPP on battery life was discussed. It was suggested that turning the MPP feature on results in a loss of one year of battery life. There was a suggestion that manufacturers should develop and provide software that includes a warning function to notify the user of the battery life that would be lost from activating multipoint pacing.

      Other alternative CRT pacing strategies were discussed:

      • His bundle pacing (at the base of the His bundle) may correct LBBB.
      • 2 separate LV leads vs. one IS-4 lead, seems to be no worse.
      • LV Endocardial pacing is more physiologic and provides homogeneous LV activation. The ALSYNC trial included a single cohort to assess the safety and performance of atrial trans-septal tools and LV endocardial BiV pacing. It included 138 non-responder patients for which CRT was indicated, as well as those who failed or were unsuitable for conventional LV lead placement. A 89.4% success rate was reported, and at 6 months NYHA improved in 59% of patients. Also, freedom from complications at 6 months f/u 82.2%
      • Q-LV interval mapping, and CRT response was evaluated as part of the SMART AV sub-study, that included 426 of the 846 patients in the main study. Q-LV intervals greater than 95 ms were associated with significantly lower LVESV and LVEDV, and significantly higher LVEF, but lower QoL scores.

      Optimizing Atrial-Ventricular timing was presented as another alternative CRT pacing strategy, as LA and LV systolic timing is critical to systolic and diastolic function.

5. Discuss when these features might be employed for patients; are these features mostly likely to be used only once someone is identified as a non-responder?

   This depends on the nature of the technology (hardware vs software solution) aimed at improving CRT response and the balance of benefit vs. risk. If hardware based, it would be best implemented in every patient at the time of implant since not easy to predict who will be a non-responder, and it might also make responders even better if applied to everyone. However, it may need to be reserved for non-responders only if risk and costs of applying the technology are high. If software based, it may be reasonable to allow these features to be turned on in cases where the patient has been identified as a non-responder.

   How and when are you confident that someone will not respond to standard CRT?

   CRT response is usually determined at 3 or 6 months post-implant. If the patient is not responding to CRT therapy by 6-months, it [response] is unusual, but not impossible to be a "late responder".

   If features are only to be used with non-responders, does this change the evidence required to demonstrate improved responder rates?

   No. The definition of response is problematic. Having said that, however non-response is defined, the need and type of evidence that a new technology converts non-responders to responders remains the same.

   Dr. Yee indicated that aftercare of patients with CRT is important by trying to optimize response in patients.

   • Watch for atrial fibrillation and try to control atrial fibrillation to maximize pacing algorithms to try and mimic optimization.
   • Timing cycles based on the right side (pacing is typically right heart based) whereas controlling LA/LV systolic timing is critical to systolic and diastolic function.
   • Use echo to optimize: echo optimization involves trying to optimize the AV delay so that the E wave (represents the ventricular filling) and the A wave (represents the atrial systole) are optimally separated instead of overlapping. This is done to ensure optimal filling of the ventricle between contractions.

   Most centers do not perform routine echo optimization on all CRT patients since it is time consuming and expensive (ECG based timing is more common practice). When in doubt the AV delay is set to a short number.

   Optimal LA-LV timing depends upon the following:

   • RA to LA conduction time
   • AV nodal and RV to LV conduction time
   • Body position / preload
   • Heart rate / activity level
   • Intra-individual and inter-individual factions

   Optimal RV-LV timing depends on the following:

   • Severity of antegrade LV conduction delay (LBBB and intra-myocardial)
   • Location and severity of myocardial scar
   • Epicardial vs. endocardial pacing site (anisotropic conduction)
   • Conduction time between RV and LV pacing electrodes

   Dr. Yee summarized the current practices and thinking.

   1. If the substrate or lead placement is poor, AV and VV adjustments will only marginally improve response rates.
   2. Hemodynamic based adjustments are preferred to auto-adjusting algorithms.
   3. Routine echo based AV, VV timing optimization is not recommended or practiced, but is reserved for non-responders.
   4. sAVD (sensed AV delay) and pAVD (paced AV delay) are set to relatively short values (E.g. 100 and 130 msec respectively)
   5. BiV pacing % is monitored and attempt are made to maximize the amount of BiV pacing.
   6. aCRT (adaptive) has advantages of automation, and reduced battery energy consumption.
   7. Some work to better measure CRT response is being done with accelerometers embedded within leads and with impedance measures in the leads.

Dr. Peterson, Dr. Tan and Dr. Webb joined the meeting.

6. Transcatheter Aortic Valve Replacement (TAVR)

Dr. Marino Labinaz, Committee Member

Dr. Labinaz disclosed his affiliations and proceeded to address the questions posed by Health Canada.

OBJECTIVE: With more clinical data becoming available for the outcomes associated with TAVR systems, the next major regulatory assessment will involve considering the use of TAVR in intermediate risk patients. To date, there is not a lot of long-term data associated with TAVR systems and Health Canada is concerned that issues such as valve durability and possibly valve thrombosis could present problems as the technology is introduced into healthier patient populations. It is also less clear as these intermediate risk patients could be reasonable surgical candidates, what role the Heart Team will play in the decision making process. Health Canada is looking for recommendations and clinical issues to consider as we anticipate having to assess licence applications for this intermediate risk patient population.

To date, only two families of TAVR systems are licensed within Canada (Sapien and CoreValve). Licensing has been limited to high risk patients for these devices. In some cases, approval for femoral access routes have allowed for a broader patient population compared to alternate access routes such as direct aortic or trans-apical.

Clinical trials are currently underway to generate clinical information required to support expanding the indications to include a healthier target population who are currently typically treated with surgical bioprosthetic valves. Recommendations and comments on the following issues are requested:

Dr. Labinaz presented the CoreValve US Pivotal Trial and the PARTNER 2A Trial as some background on use in intermediate risk patients.

The CoreValve Trial

The CoreValve Trial was designed as a high risk trial but unintentionally became an intermediate risk trial due to the patient characteristics (i.e. STS scores of 7.4 ± 3.2) of the subjects enrolled. Inclusion criteria were: New York Heart Association (NYHA) functional class II or greater; severe aortic stenosis (AVA ≤ 0.8 cm2 or AVAI ≤ 0.5 cm2/m2 AND mean gradient > 40 mm Hg or peak velocity > 4 m/sec at rest or with dobutamine stress echcocardiogram); and, risk of death at 30 days after surgery was estimated at ≥ 15% or greater, and the risk of death or irreversible complications within 30 days was < 50%.

Baseline demographics were comparable between TAVR and SAVR cohorts, but the prevalence of diabetes was significantly higher in the latter group. Surgical risk assessment included consideration of Society of Thoracic Surgeons (STS) predicted Risk of mortality estimate and allowed the heart team to identify other risk factors that were not captured in the STS risk model. A STS predicted risk greater than 10 was considered high, and the average scores in this trial were 7.3 and 7.5 in the TAVR and SAVR groups respectively, and lower than anticipated. Dr. Labinaz offered that the low risk scores reflect inclusion of lower risk patients. Non-STS assessments of co-morbidities, frailty, and disability were also generally similar between groups.

There was a question whether this is the first time for an indication-free trial. Are operators effective at determining risk, or is STS not a valid score to determine risk in this group of patients? Some general discussions were held about the accuracy of the STS score. It was generally agreed that although helpful, there can be important factors of risk for a specific patient that are not accounted for in the STS score.

Primary endpoint was all cause mortality at 1 year. The transcatheter and surgical rates were 14.2% and 19.1% respectively. After 6 months the groups behaved similarly, as "the harm had been paid upfront". A similar trend was observed at 2-years: all-cause mortality showed a TAVR and SAVR rates were approximately 27% and 37% respectively. All stroke incidences between groups were not significantly different, but tended be lower in TAVR as compared to SAVR patients (8.8% and 12.6% respectively; P=0.10). However, the composite endpoint of all-cause mortality or major stroke was significantly lower at 12 months in the TAVR group (16.3% vs. 22.5%). It is important to note that more than half the strokes happened after the first 30 days, and that identifies another area of concern.

When considering 1-year Major Cardiovascular and Cerebrovascular Events (MACCE), the transcatheter group showed an absolute difference of approximately 7% at 12 months compared to the surgical group (20.4% vs 27.3%, respectively; P=0.03). Bleeding, and new onset or worsening atrial fibrillation were roughly doubled with surgery (38.4 % vs. 16.6%; and, 32.7% vs. 15.9% respectively), and acute kidney injury was more than doubled (15.1% vs. 6.0%). Conversely, pacemaker implantation rate was almost doubled with TAVR (22.3% vs. 11.3%).

Echocardiographic Findings:

• TAVI valve gives much larger EAOs (effective orifice area) compared to the surgical valve at all-time points (no sing of early deterioration)
• Big EAO's important when we talk about TAVR and strategies for repeated procedures

Post implant there were significant differences between TAVR and SAVR at each time point for both EOA and mean gradient. TAVR valves gave a much larger effective orifice area (EOA) compared to surgical valves at all-time points to one year (no sign of early deterioration). This raised discussion regarding differenced in valve design that influence EOA. Big EAO is important when we talk about strategies for repeated procedures. The average aortic valve size is 23mm (open surgery), is rigid, and has a cuffed ring which can't be oversized due to risk of coronary obstruction, in order to put in larger surgical valves another procedure such as aortic root enlargement is required. In comparison, the TAVR valve is available in sizes of 26 to 29 mm, and the stent is a thin-walled metal. TAVR valves must be oversized to get a good seal. Also, the CoreValve is oversized much more than SAPIEN (balloon expandable) valves. Incidence of paravalvular leak and regurgitation is always higher with TAVR than with surgery, and this held true in the findings, that showed significant differences at all time-points up to one year. Pacemaker implant rates were also high for the CoreValve group. This rate may reduce over time with improvements in implantation techniques.

Subgroup analysis showed that age, gender, or BMI did not make a difference (TAVR vs SAVR) for 1 year mortality.

The PARTNER 2A Trial

The Partner 2A was a randomized trial that enrolled intermediate risk (operable) patients with STS scores ≥ 4% (Avg. 5.8%). There were 1500 patients in the transfemoral arm, 500 in the non-transfemoral (transapical/transaortic) arm, and the primary end point was all-cause mortality or disabling stroke at 2 years. The TAVR device studied was the SAPIEN XT. Inclusion criteria was severe aortic stenosis (AS) defined as echo-derived AVA ≤ 0.8 cm2 and mean AVG > 40 mm Hg or peak jet velocity > 4.0 m/s; cardiac symptoms defined as NYHA functional class ≥ II; and, intermediate risk which was (i) determined by the multi-disciplinary Heart Team (ii) using a guideline STS ≥ 4% and (iii) adjudicated by a case review committee.

Statistical Analysis Plan:

The primary hypothesis was non-inferiority (ratio of 1.20) of test (SAPIEN XT) versus control (surgery) for all-cause mortality or disabling stroke at 2 years. Assumptions for 1:1 randomization: event rate: 30% in both trial arms, and power at 80%. 2032 patients were randomized with approximately 98% follow-up in both arms.

Emphasis was brought on to the evolution in the devices. The SAPIEN XT was first implanted October 30, 2012. This valve is no longer used in Canada, as practice has moved to using the SAPIEN 3. This is the problem with providing recommendations; by the time the data is available, the end users are already using the next generation device which is generally much improved. For example, the SAPIEN 3 device has a cuff that reduces PV leak rate, and smaller sheath sizes which reduce vascular complication rates.

Patient Characteristics:

Average age of 81.6 years, average STS score of 5.8%, good LV ejection fraction, approximately 20% had moderate to severe MR, frailty was close to half, 10% had permanent pacemaker, and 1/3 had COPD.

Procedural Characteristics:

Anesthesia time, procedure time and ICU / total time in the hospital were significantly less with TAVR. Procedural deaths were equally low in both groups at ~ 1%.

The primary non-inferiority (NI) endpoint (ITT analysis of all-cause mortality or disabling stroke) at 2 years was met. The TAVR and SAVR groups were not significantly different (19.3% vs 21.1%), but TAVR was numerically better (based on combined transfemoral and non-transfemoral access routes). The SAPIEN XT valve met the non-inferiority end-point (relative risk ratio of 1.2) with a significant p-value (0.001). Also, all subgroup analysis favored TAVR expect transthoracic access route, which favored surgery. This indicates that access site plays a role in patient outcomes.

Surgery vs. transfemoral TAVR ITT analysis for all-cause mortality or disabling stroke at 2 years showed a significantly lower rate in the TAVR group (16.8% vs. 20.4%; P=0.05). Other clinical endpoints at 2 years (ITT) showed significantly more life-threatening bleeding with surgery than with TAVR. Major vascular complications were higher with TAVR (using SAPIEN XT not SAPIEN 3 in this trial). New permanent pacemaker with surgery was more than what was predicted and with TAVR was less then what was predicted. The need for a new permanent pacemaker was almost identical between the two options (11.8% TAVR vs 10.3% SAVR). Re-intervention and endocarditis were slightly higher with TAVR compared to surgery.

It was noted that moderate paravalvular regurgitation with TAVR at 2 years was 8.0% while with surgery it was only 0.6%, which is greater than a 10-fold difference; in the S3 trial (SAPIEN 3) moderate valvular leak was only 3%.

Paravalvular leak (PVL) is BAD, and is demonstrated by the following data (all-cause mortality at 2 years): none, trace or mild PVL is associated with mortality rates from 13.5% to 14.1% at 2 years, while mortality rates associated with moderate or severe PVL were significantly increased (34.0%; P<0.001). Therefore, reducing PVL is an important goal which has been demonstrated by the LOTUS and SAPIEN 3 devices that have low PVLs.

1. Consultation before Treatment: For intermediate risk patient populations, is the role of the Heart Team still important and what are the dynamics like here between the surgeons and the interventionalists? How much weight is allocated to patient preference and how is this considered by the various Heart Team members?

   All TAVR programs in Canada have a Heart Team. These teams function differently in different institutions but have an important role in intermediate and high risk patients. However, the definition of intermediate risk is arbitrary and difficult. The STS Score is only a tool and shouldn't be the only mechanism used to determine the definition. A heart team with multidisciplinary expertise is essential in determining if a patient is a good candidate for a specific procedure.

   Will there be a role for the Heart Team when low risk patients are included? Do we have the resources in Canada, to have a surgeon and cardiologist, to scrub into every case? Thought – a gradation of team for intermediate to low risk patients. Perhaps some low risk procedures would only have 1 operator.

   Patient's preference is always considered, and informed consent is essential.

   Valve leaflet immobility and thrombosis: Valve thrombosis and leaflet immobility have been identified as potential issues in up to 40% of patients receiving TAVR's detected using a variety of approaches. This has also been identified in surgical bioprosthetic valves too. The leaflet mobility and thrombus issues can be treated in most patients with antiplatelet/anticoagulant therapy. Should patients receiving TAVR's or surgical bioprosthetic valves be followed more frequently to identify patients at risk for antiplatelet/anticoagulant therapy? Does this concern increase as healthier and younger patients are treated?

   It doesn't matter if you are young or old; if the patient's valve doesn't work, then that's a problem. References were made to "Possible Subclinical leaflet thrombosis in Bioprosthetic Aortic Valves" (Makkar et al.). There are no clinical characteristics to identify who will have leaflet immobility. CT Imaging shows reduced leaflet motion. Clinical outcomes: Pooled registry data suggested that reduced leaflet motion can result in increased neurological events (TIA), but no such relationship was seen in the PORTICO IDE Study data. Subclinical Thrombosis in Bioprosthetic Valves is being studied and there continues to be interest in learning more. At this time, it is early to have specific clinical recommendations.

   Galileo sub-study is ongoing, and investigates high risk patients who were not good candidates for oral anticoagulant (OAC) preventative treatment.

2. Valve Durability: Preclinical bench testing for the durability of bioprosthetic aortic valves including TAVR's is usually stopped at the equivalent of about five years in vivo. Chronic animal studies are usually carried out with small numbers of animals for periods of about six months. It is assumed that the durability of TAVR's and conventional bioprosthetic valves are similar. Differences in design and the need for compression and folding to fit the valves into the delivery systems may result in damage leading to decreased durability. A recent report from Dvir at EuroPCR cautioned that the durability of TAVRs might not be comparable to that of SAVR's. The study followed patients who received early model TAVRs (mostly early balloon expandable Sapien valves). Using a Kaplan-Meier analysis, Dvir reported that the curve for freedom from valve degeneration drops from 94% at 4 years to 82% at 6 years and to approximately 50% at 8 years among surviving patients. Dvir estimated that approximately 40% of degenerated valves would eventually fail. Should TAVR Manufacturers be required to provide long-term premarket and post market data (five to ten years) to demonstrate equivalence to surgical biprosthetic valves?

   Full paper has not yet been published therefore the following information was extrapolated from the abstract. The Long Term TAVR Durability (Dvir) study enrolled 704 patients with a mean age of 82, and includes more than 5 years of follow-up. TAVR procedures performed between April 2002 and May 2011. 378 TAVR patients (Sapien XT 36%, Sapien 50%, Cribier-Edwards 14%) were included. Of those, 100 survived more than 5 years and were examined for moderate to severe intra-valvular AI (not present at 30 day eco) and/or stenosis (mean gradient > 20 mm Hg). 35 cases had valve degeneration (2/3 due to AI and 1/3 due to stenosis). The estimated 8 year rate of structural degeneration is 50%. While ten year data is key, the data aren't there yet as some centers are only coming up on the 10 year mark. However, after four years of experience with CoreValve transcatheter heart valves, none showed deterioration in valve function. In addition, the five year outcome, out of Vancouver, after transcatheter aortic valve implantation, failure rate is very low. The first five years are considered a "free pass", as even poor performing valves have historically performed well for the first five years, but the period from 5 to 10 years is considered critical.

3. Access type: According to many clinical guidelines, alternate access routes for TAVR are associated with worse outcomes. As considerations move to intermediate risk patient populations, is it justified to consider alternate access routes when the candidates may be reasonable surgical candidates. Please discuss data available for this (iliofemoral vs. non-iliofemoral such as subclavian, direct aortic, transapical, etc.)

   A meta-analysis of transcatheter implants was conducted approximately 1 year ago (Chandrasekhar et al. 2015) and compared access types across 17,000 patients including transfemoral, transapical, direct aortic, and subclavian (did not include the new transcaval). At 30 days, there was close to a 50% less mortality by transfemoral versus non-transfemoral routes; however, when compared to subclavian or axillary access, there we no significant difference. Comparison to transapical showed that the transfemoral route wins hands down. 30 day stroke rates were not different between transfemoral versus non-transfemoral routes, but transfemoral was superior to subclavian/axillary routes. Therefore, transfemoral should be the first choice, and the other options should be considered secondary. Transapical is a last resort, and intermediate risk patients would be sent for a surgical valve instead. In some cases, a drop of approximately 10% in LVEF has been observed for patients treated with a transapical approach.

4. Valve in valve: Similar to different access routes, valve-in-valve indications may have limitations when considering intermediate risk patient populations. Is there evidence that valve in valve indications would be acceptable in an intermediate patient population? Should patients with failed TAVR valves be considered candidates for TAVR in TAVR procedures? What evidence is there that Patient/Prosthesis Mismatch can be adequately controlled. What evidence is required to allow you as a clinician to feel comfortable doing this?

   Not a lot has been done on patient prosthetic mismatch (PPM) and TAVR. A German study was conducted on Redo TAVR, and failed TAVR looking at PPM after the second TAVR. The results indicate that PPM does not seem to be a big deal with TAVR in TAVR procedures. The reason for this is that large valves, 29-31mm in size, are being inserted, and the same size valve is put in due to TAVR oversizing, which does not create a smaller orifice in PPM. However, the durability of the valve may pose an issue. If there were a calcified valve, TAVR stent and another stent beside, the stent may cause an issue. PPM occurs more often with SAVR than with TAVR. One study showed the incidence of PPM at 12 months in a TAVR cohort was 7.0%, as compared to 20.7% in the SAVR group (p < 0.0001). If PPM is predicted in a patient, regardless of the risk, going TAVR instead of SAVR would be a better initial strategy, unless surgical root enlargement is a viable option. However, most surgeons will not perform TAVR inside a 21 mm surgical valve, as that size is too small.

   The published study by D. Dvir, "Transcatherer Aortic Valve Implantation in Failed Bioprosthetic Surgical Valves", was discussed. Time to failure is 10 years. Regurgitation alone occurs less frequently as the mechanism of valve failure than stenosis alone, and regurgitation and stenosis combined occur just as frequently as regurgitation alone. Clinical outcomes were considered good, and TAVR with failed valves larger than 21 mm showed medium term outcomes, although more data will be needed. Predictors of 1 year mortality include: valve size (smaller than 21mm is worse); failure type (regurgitation is better than stenosis); transapical access is worse; and as STS score increases, the outcomes worsen.

5. Patient selection: With the possible expansion of indications for use into intermediate risk patient populations, what clinical concerns increase in terms of the patient population that is now represent. Are there any additional concerns as the patient population becomes larger and presumably more diverse? Are there concerns with treating intermediate risk patients that were not of significant concern with high risk patients that had a reduced life expectancy?

   New concerns in treating low to intermediate risk patients include: higher incidence of bicuspid valves (TAVR in these patients may not behave as well); and, maintaining access to coronary arteries (E.g. a 60 y/o patient undergoes SAVR and lives to 85 may develop coronary artery disease that requires intervention). It is important to ensure the stent frame of the valves do not cover the coronary ostium and prevent coronary access. Other considerations include the impact of permanent pacemakers, reduced hospital length of stay/resources, impact on hospital resources/physicians (smaller team), careful screening and importance of heart team, and interaction between treatment of aortic stenosis and other cardiac disease.

   The ensuing discussing centered on findings from a Montreal Heart Institute study that identified a 20% mortality rate or re-operation at 10 years for mechanical valves not performing well. The long term performance of TAVR valves will have to be put in a realistic and appropriate contemporary context.

Dr. Yee left the meeting.

7. Transcatheter Mitral Valve Replacement (TMVR)

Dr. Mark Peterson, Invited Guest Speaker

Cardiac Surgeon in Toronto, ON

There are a host of therapies that may change the treatment of mitral insufficiency and mitral stenosis. Health Canada would be interested in an update on the potential transcatheter mitral valve replacement devices, their recent clinical results, and future directions for these technologies.

1. What are the challenges for the design of transcatheter mitral valves due to the complex anatomy and physiology of heart?
2. Several transcatheter mitral valves are currently being tested in human, such as Tiara, Caisson TMVR, CardiAQ Valve, and the Tendyne Transcatheter Mitral Valve Implantation System. What current clinical evidence is available? What clinical data is expected to be available in a few years?
3. At present, does the clinical evidence point to an appropriate indication for use or specific population?
4. What clinical evidence would be considered to be sufficient for regulatory approval for a specific population? What clinical endpoints should be assessed for the safety and effectiveness of this type of device? How much data is required to move this technology from ITA and SAP in the regulations to licensing?

Dr. Peterson disclosed his affiliations and proceeded to address the questions posed by Health Canada. He started his presentation by discussing TMVR, TAVI and TAVR:

1. TMVR: transcatheter mitral valve replacement
2. TAVI or TAVR: transcatheter aortic valve implantation or replacement

He noted that TAVR is becoming, in some places, the standard of care compared to the Surgical Aortic Valve Replacement (SAVR), which was the golden standard of care in the past. Based on the European Aortic Valve Procedures data the surgical valve implantation and TAVR rates are increasing year after year. In Ontario, TAVR represents 30% of all valve replacements, and demonstrates Canada is following the European trend.

TAVR has been shown, in global randomized trials (PARTNER Trial Cohort A), to be as good as SAVR for high risk patients at 5 years, and with similar rates of all-cause mortality or disabling stroke in intermediate-risk patients at 2 years, as presented by Dr. Labinaz earlier this morning.

TAVR has matured and it is now present in the Acute Cardiac Care Association's (ACCA) European Guidelines, and the current algorithm embraces the heart team concept. The guidelines for the decision making process are followed for intermediate to high risk patients in order to decide whether the patient is a good candidate for TAVR. First-in-man trials were headed by Dr. Cribier in 2002, and mortality reached 30%. However, there has been a large evolution of devices and are now available in a variety of sizes. Also, multiple iterations have resolved various issues including valvular access, sheath size, etc. In 2016, there is only 1 of 11 cardiovascular programs in Ontario that is not performing TAVR; therefore, TAVR has become a commonly accepted technology.

However, there are no published, randomized, Phase I trials for TMVR because they don't exist. What is the reason for this discrepancy? Mitral valve disease is more prevalent compared to aortic valve disease (based on a population based study published in Lancet, 2006), although aortic disease is much more commonly treated. As you age, the prevalence of moderate or severe mitral valve or aortic valve disease increases and there is a significantly larger increase in moderate or severe mitral than aortic valve disease in those aged 55 and older.

Dr. Peterson noted that a large portion of mitral regurgitation (MR) patients are left untreated, either being deemed ineligible for surgical treatment or being denied surgical intervention. However, if you have no mitral regurgitation, your survival rate at 5 years is very good despite having coronary disease. If you have severe regurgitation, your 4 year survival rate is dismal. This is a clear signal – if regurgitation increases, the survival rate decreases.

The structure of the mitral valve is different from that of the aortic valve, with much more complexity. Understanding the mitral valve will help with design and technical challenges with TMVR. Also important is that mitral disease represents a much more heterogeneous population of diseases. Any one component of the mitral valve may be diseased (e.g. leaflets, annulus, ventricles, etc.) which can cause mitral regurgitation, as opposed to the aortic valve disease, in which the vast majority of patients are treated for calcified aortic stenosis.

Mitral disease can be divided into two types: if the valve itself is affected, it's called a primary mitral regurgitation, and can occur from degenerate leaflets (rheumatically or due to endocarditis); and if the disease occurs in the ventricle, it is called secondary or functional mitral regurgitation. In degenerative disease, the cords may be ruptured (Barlow's disease which causes mitral regurgitation). Diseases of the ventricle include dilated cardiomyopathies (in which the mitral valve is pulled into the ventricle, resulting in mitral regurgitation), long standing coronary disease, or geometric shape change in the ventricle (causing the valve to become severely incompetent through tethering or displacing of the apparatus). In conclusion, the heterogeneity of the disease and the complexity of the valve structure are real challenges for engineers who are designing a single fit for all types of valves.

Current treatment options for primary MR include surgical repair, and there are options for the use of robotic or thoracoscopic assists which allow treatment of patients through minimally invasive incisions (the advantages of which are debated). Secondary MR as it relates to coronary disease is treated with medical therapy, or resynchronization therapy.

The question remains, what do we do with the large population of MR patients who have either fallen out of the high risk category, or are ineligible for surgical treatment and denied surgical intervention? How do we determine the proper treatment method for those patients? Of surgical candidates, up to 50% are not referred to surgery, even if a surgical indication exists.

The unmet clinical challenge is addressing those patients not treated. Surgical treatment rate of moderate to severe patients with degenerative MR (DMR) is ~ 53%, and for those with functional MR (FMR) is ~16%. Low treatment rates in FMR patients are the result of previous guideline that didn't stress surgical intervention, and low treatment rates in DMR are due to patients being asymptomatic, with stable LVEF, and substantial comorbidities contributing higher risk.

Percutaneous options for mitral valve disease were described.

1. Patients with rheumatic mitral stenosis, provided they have an anatomically suitable valve, would be candidates for balloon valvotomy.
2. For patients with congenital regurgitation, but who are too high risk for open surgery, the mitral clip is the dominant repair strategy.
3. Valve in valve therapy can be done by implanting a TAVR valve. The rigid sewing ring of the mitral valve functions as an anchor. In this case you are not treating the mitral valve anatomy but treating the bioprosthetic valve, and this approach seems to work well.
4. Percutaneous closure devices to treat peri-valvular mitral regurgitation
5. Devices with specific TAVR-like design for mitral valve diseases

Why we need alternative care rather than surgery?

A case study of transcatheter mitral valve replacement (transvenous-transseptal mitral valve-in-valve) was presented:

72 year old male patient with six months of progressive shortness of breath (SOB), who is now NYHA Class III. Patient's medical history (PMHx) includes: Hancock II bioprosthetic AVR and MVR in 1998; atrial fibrillation (AF), sick sinus system (SSS) and on warfarin; coronary artery disease (CAD) with previous non-ST elevated myocardial infarction (NSTEMI) with percutaneous coronary intervention (PCI) in the circumflex coronary artery (Cx) in 2013; and, smoker with severe chronic obstructive pulmonary disease (COPD).

Echo showed dilated left ventricle, preserved ejection fraction, severe MR due to flail leaflet, and valve gradients of 8-9 mmHg. Catheterization showed patent circumflex stent. Right heart catheterization (RHC) showed systolic, diastolic, and mean pulmonary artery pressures of 53/20/39 mmHg respectively. Pulmonary capillary wedge pressure (PCWP) was 23 mmHg, and the V waves were 45 mmHg. CT scan showed the mitral valve annular area was 5.09 cm2, and was considered low risk for left ventricular output tract obstruction (LVOTO).

In consultation with the heart team (key players: surgeons, cardiologist, fellows (surgical and interventional) etc.), all data is exhaustively vetted. The discussion of options would have included: redo open mitral valve replacement (leading to replacement of the aortic valve), or either trans-apical, or trans-septal valve-in-valve.

The actual outcome:

Cannulated the femoral vein, went up across the right atrium, and through the atrial septum (transeptal puncture). The challenge was determining how to get the prosthesis to the mitral space. Options were transapical or transeptal delivery. However the turn via the transeptal delivery does not allow for much freedom of motion – both methods provide anatomical and technical challenges. Valve-in-valve is off label but many surgeons believe there is a solid indication and niche in performing this technique in all bio prosthetic valves. The anatomical constraints of the mitral valve are negated by the bio prosthetic valve.

The problem is getting the device where it needs to be. The device doesn't go through the septum therefore you are in the atrium, and then you must proceed through the septum then into the bishop. It was stated that the valve may not need to be modified but a better delivery system.

In the early days the mitral clip had numerous complexities in trying to position the device. Currently, with experience and over time the complexities are less. However, the design idea for the TMVR was that for the valve would be easier to implant than a mitral clip although getting there is still a significant limitation. As opposed to the mitral clip, once you have the properly designed TMVR in place you eliminate, not reduce but eliminate the mitral regurgitation (MR) and then there less recurrent MR.

Design features that are different then a TAVI valve:

• Atrial flange that is designed to sit on top of left atrium, on top of the mitral valve. Note that the mitral valve is not symmetrical but rather D-shaped. This was taken into account when they designed the flexible strut to sit closer to the aortic valve.
• One size fits all valve with a 29 mm cylinder.
• Coating was designed to create seal and contribute to healing, however it may contributed to some of the thrombosis.
• Unique to the device as the paddles, which are designed to open up and as the valve is centered in the middle of the ventricle, the paddles are closed, one paddle captures the interior of the leaflet and one paddle captures the posterior leaflet.

One similarity is the leaflet inside the cylinder are bovine pericardial.

Fortis Valve was acquired under Special Access Program (SAP) and under compassionate use. The fifth case was conducted at St. Michael's hospital in Toronto. 7 of 11 patients survived.

There was a discussion among the members around tethering and the necessity of the cords of the device.

Lessons learned are similar to the TAVI story.

Factors that effected the outcomes were both technical and patient selection, in particular, the recognition that cohort c patients (those with a STS score greater than 15%) probably don't benefit don't benefit from TAVR however if you select cohort c patients for TMVR or patients with ejection fractions of 10-15%, they would also do poorly. Other lessons learnt were the anatomical issues relating to anti-coagulation.

Where is TMVR development today?

In the last two years, industrial sector saw $2 billion being spent which resulted large medical devices companies acquire nascent technology in this filed and approximately 33 different devices are various iterations of devices being developed. The USA has recognized that in the TAVI field they were behind Germany, Europe and slightly behind Canada and were only to put TAVI valves in special circumstances. Therefore they developed an early feasibility pathway that would allow them adopt and support innovation and new technology. Currently there are 6 devices approved for early feasibility in the USA, two of them are the CardiaAQ device and the Medtronic Intrepid device. All devices are various forms of purpose built transcatheter mitral valves to be deployed either transapically or transeptically.

More commonly used devices are:

1. CardiaAQ was designed for both transeptal and transapical delivery, has an expanding nitinol frame, it preserves the cords and utilizes the leaflets, open frame promotes atrial flow, intra-annular skirt to minimize paravalvular leaks and to minimize LVL obustruction.
2. Medtronic Intrepid is similar in design to the CardiAQ, it was an inner and outer stent for fixation and sealing with a 27 mm bovine pericardial valve and is effective in relieving mitral regurgitation.

Challenges for TMVR:

• Patient selection and screening (example: hard to justify applying this technique for patients who are candidates for mitral clips, anatomical criteria and screening results)

Discussion around being a candidate for other procedures that may be standard of care versus undergoing a TMVR. For example, once you have a mitral clip implanted you are no longer eligible for TMVR in the future.

In conclusion, transcatheter mitral valve replacement is complex, certainly anatomically more complex than TAVR, more patients with heterogeneous group of diseases, group of feasibility in first in man studies, also users to highlight the anatomical and related factors that have led to the successes by continued device refinement, patient selection and screening it will lead to a viable therapy to treat TMVR.

TMVR First-in-man Clinical Experience: Fortis (Edwards)

Background:

Mitral regurgitation is more common than aortic stenosis in the elderly population, who are also at higher risk, and survival is poor if left untreated. Mitral surgery risk increases with: advanced age; multiple comorbidities; prior CABG; and low ejection fraction. Less invasive mitral valve therapy has the potential to treat high risk patients. All cases of human implantation performed on "compassionate" grounds (not within trial protocol). 11 patients were implanted worldwide, survival is 7/11 (64%) to date. Causes of death were acute kidney injury (AKI) and multiple organ failure (MOF) (4 days), heart failure (76 days), valve thrombosis (15 days), and incomplete P2 capture with conversion to mitral valve replacement/sepsis (7 days).

Lessons learned from the Fortis experience: it was not dissimilar to the TAVR story. The Fortis was too thrombogenic. Outcomes were largely influenced by degree of LV dysfunction, pulmonary disease, renal disease, redo surgery, etc. The mitral patient may require longer to see benefit than the aortic. Mitral valve pathology related to annular dimensions must be considered. The anatomy of P2 and pre-operative imaging must exclude potential for LVOT obstruction. Saddle shaped valve annulus may increase challenges in reducing paravalvular leakage.

Currently 33 TMVR devices in development, 6 have been approved for early feasibility studies in US (CardiaQ, Tendyne, Neovasc, Intrepid, Caisson, and Mvalve/Lotus).

CardiAQ – Edwards TMVR

The first in human trial ran in June of 2012. The valve can be implanted via a transseptal or transapical route. Has a unique anchoring mechanism that utilizes native leaflets and preserved chords. To date 13 patients have been treated with 2 procedure-related and 7 non-valve-related deaths. The RELIEF Trial is set to start.

Intrepid – Medtronic TMVR

The outer stent is designed for fixation and sealing, and the inner stent houses a 27 mm bovine pericardial valve. It also houses a flexible brim which aids imaging during implantation. To date, 27 implantations have been performed with 4 deaths related to the procedure, none related to the device, and 3 not related to the procedure or the device. Pre-procedure MR evaluation showed 19 patients with MR of 4+ and 8 with MR of 3+. The latest follow-up saw 22 patients with MR of 0+ and 2 with MR of 1+.

In conclusion Dr. Peterson summarized that TMVR is very complex, but 'Proof of Principal' is established by first-in-man and early feasibility studies. Ongoing work will establish better patient selection, procedural steps, and post-operative management, which includes anticoagulation. As a note on patient selection, it was highlighted that TMVR may not perform well in patients with a very low LVEF.

8. Drug Coated Balloons (cardiac)

Dr. John Ducas, Committee member

Dr. Kong Teng Tan, Guest Speaker

OBJECTIVE: Assisted by recommendations given by SAC-MDUCS, Health Canada has licensed Drug Coated Balloons (DCBs) for both peripheral and coronary use based on superior effectiveness compared to POBA in terms of endpoints such as clinically driven revascularization and patency. As the technology becomes more readily available in Canada, it would be helpful to understand how it is being used in clinical practice in Canada, whether there are any emerging concerns associated with its use, and whether POBA as a comparator is still appropriate.

Currently, there are several DCBs licensed in Canada. The Pantera Lux is indicated for BMS-ISR in the coronary arteries. The Lutonix 035 DCB PTA Catheter is indicated for percutaneous transluminal angioplasty, after pre-dilatation, of obstructive de novo or non-stented restenotic lesions in native superficial femoral or popliteal arteries, with reference vessel diameters of

4 – 7 mm. The Lutonix 014 Drug Coated PTA Dilatation Catheter is intended for percutaneous transluminal angioplasty of obstructive de novo or non-stented restenotic lesions in the native popliteal, tibial, and peroneal arteries ≥2.0 and ≤4.0 mm in diameter.

1. How are DCB currently being used in Canada?
2. What level of clinical data is required to authorize a new license for a new DCB? Is POBA still the best comparator group for DCB studies for a superiority RCT? Are there differences in anatomical locations - coronary vs peripheral?
3. Are there any safety concerns associated with DCBs, especially given some recent clinical trial findings? Studies of interest might include In.Pact Admiral RCT. How long should DCBs be followed to determine their safety profile compared to other interventions?
4. What level of data is required for an expansion of indications for use?
   • De novo versus restenotic versus in-stent restenosis?
   • Above the knee versus below the knee?
   • Longer length balloons and longer length lesions.
5. Specific to the treatment of ISR, discuss the following:
   1. Should the standard of care for ISR be PTA/PTCA or DES as the comparator against which DCB should be compared?
   2. Are BMS ISR treated differently than DES ISR?
   3. Are their differences in DES in the treatment of ISR, e.g. EES vs. other DES
6. Discuss the future directions with DCB in the coronary anatomy and in the peripheral anatomy.

Dr. Ducas disclosed his affiliations and proceeded to address the questions posed by Health Canada. He focused on the use of drug-coated balloons to treat coronary artery disease

He noted that currently the use of drug eluting stent (DES) is the treatment of choice for most PCI because: the anti-proliferative coating drastically reduces neo intimal hyperplasia, devices are highly deliverable, and they have relatively low thrombogenicity, low rates of target vessel revascularization (TVR) rates, and current generation DESs are safer and more effective than first-generation devices. Their use is supported by robust data and experience in multiple clinical scenarios involving complex diseases, involvement of the left main (LM) coronary artery, bifurcations, and S-T segment elevated myocardial infarction (STEMI).

However, there are some known limitations due to the metal cage left behind:

• vasomotility may be affected
• strut malapposition that may lead to late thrombosis
• "jailing" of side braches that may affect future PCI
• full metal jacket that may preclude coronary artery bypass graft (CABG) procedures
• complex bifurcation lesions remain a problem
• applying multiple layers of stents is required in certain patients with in stent restenosis

The use of drug-coated balloons (DCBs) represents another treatment option. A matrix coating sits on the balloon surface, and contains an excipient and active drug (E.g. Paclitaxel) with a high retention rate of up to one week, or longer. Inflation of the balloon deposits the highly lipophilic drug onto the surrounding tissue surfaces. First generation balloons had problems with control of drug delivery that included loss of drug substance during delivery, non-uniformity of drug coating on the balloon, embolization of the drug, and increased serum drug levels resulting from inflation of multiple balloons.

Dr. Ducas highlighted treatment gaps that have been potentially addressed by using DCBs by referring to a past SAC-MDUCS discussion (2010-12-10):

• In-stent restenosis (ISR)
• Small vessels
• Bifurcations
• Acute myocardial infarctions (AMI)
• Chronic total occlusions (CTOs)

Next he referred to the Health Canada, Regulatory decision summary for the PANTERA LUX PACITAXEL RELEASING PTCA BALLOON CATHETER that indicates the application was filed 2012-08-07, and a regulatory decision was made on 2015-07-09. The manufacturer cited the superiority of paclitaxel eluting balloon (SeQuent Please) to POBA, and then invoked the the similarity of the Pantera LUX to the SeQuent Please to justify approval of the Pantera LUX. At that time the SAC-MDUCS committee endorsed POBA as an appropriate comparator.

Dr. Ducas noted that recently there have been number of technical improvements made in DCB technology including:

• advanced folding technologies to minimize drug loss during delivery
• altering drug concentration
• altering size drug particles
• selection of non-crystalline formulations
• drug encapsulation using nanoparticles allowing incorporation sirolimus on DCB
• Use of zotarolimus (more lipophilic)

Several sirolimus-DEB already received CE-mark approval.

However, clinical experience very limited. Dr. Ducas noted that while DCBs have proven efficacy, clinical experience very limited. The data are limited to small studies with first generation DCBs, and the class effect is unproven and there are no randomized head to head trials of DCBs.

Number of studies were presented next.

A Swedish registry –SCAAR (Per Bondesson et al. 2012) that included 1129 patients, compared two DCB. The cumulative risk of restenosis was both greater and earlier (time since PCI) with ELUTAX as compared to the SeQuent Please at one year follow up.

In a comparison of the efficacy of the Xience everolimus eluting stent and SeQuent drug eluting balloon in treating ISR, freedom from MACE (cardiac death, MI, and TVR) was significantly greater in the Xience group (91% vs 85%; P<0.04;n=498) (Alfonso et al. 2016).

Stella et al. (2012) describe a multi-center randomized comparison of DCB plus BMS versus BMS versus DES in bifurcation lesions treated with a single-stenting technique: six month angiographic and 12 month clinical results. Pretreatment of both the main branch and side branch with the DCB failed to show angiographic and clinical superiority over conventional BMS, using a provisional T-stenting technique. DES showed superior angiographic results as compared to DCB and BMS.

Dr. Ducas concluded his presentation indicating that DCB was clearly superior to POBA for ISR, but that it was less clear whether DCB is equivalent to current DES devices for any indication. Also, based on a very small, non-RCT study by Kawamoto et al. (2015), the superiority of DCB to DES was uncertain in recurrent ISR with already present multiple layers of. Also, Dr. Ducas emphasized, DCB is not approved for other PCI uses, as limited published data in small vessels and bifurcations are not compelling. He suggested that DCB use in Canada is probably limited (currently < 1% of patients receive DCB), but future innovations may expand their through the Special Access Program.

Dr. Yee returned to the meeting.

Dr. Mitchell left the meeting.

Dr. Tan declared his affiliations. His presentation focused on the use of drug-coated balloons for peripheral vascular disease. He defined some specific terminologies to aid interpretation of his presentation.

Binary restenosis: > 50% restenosis of treated segment that is measured by duplex or angiogram.

Target lesion revascularization (TLR): a clinically driven re-intervention of a previously treated segment, that is usually about half of the binary stenosis rate.

Dr. Tan explained that current endovascular techniques involving stents or balloons are immediately effective at revascularization, but within 6 months patients may suffer multi-level restenosis, and they are frequently more occluded than before the procedure. Plain Old Balloon Angioplasty (POBA) has been shown to have very poor primary patency with lesions greater than 5cm in length. A one month restenosis rate of 23% has been described (Romiti, 2008). Therefore patients with long lesions would require multiple interventions to keep the arteries open, and are associated with worse outcomes.

He indicated that intimal hyperplasia occurs in 20-50% of intervened arteries, but anti-proliferative agents can decrease intimal hyperplasia. Paclitaxel and the "limus family" of drugs have demonstrated this effect, as evidenced by coronary restenosis rates of 20% and 5% associated with bare metal stents and drug eluting stents respectively. He also indicated that wound healing depends on patent arteries. He noted that approximately 30% of patients with critical limb ischemia (CLI) will require interventions following initial endovascular therapy due to restenosis of target lesions, which will occur within 1 to 2 years (BASIL Trial, 2005: Haider, 2006; Giles, 2008; Conrad, 2009). He indicated that DES worked relatively well, but is not used much as people don't like implanting stents in the legs.

The currently approved DES for peripheral vascular disease (PVD) is the ZILVER PTX (Cook Medical). The ZILVER PTX randomized clinical trial compared the Zilver PTX (paclitaxel) with POBA. Primary patency (defined as peak systolic velocity ratio, PSVR < 2.0) rate was significantly greater in patients treated with Zilver PTX as compared to optimal PTA, and PTA at 12 months with rates of 83.1%, 65.3%, and 32.8% respectively. Also, the Zilver PTX was compared to the bare Zilver to determine if the significantly higher patency rate was due to the drug effect. 12 month patency (defined as PSVR < 2.0) was statistically higher in the Zilver PTX group as compared with the bare Zilver (89.9% vs. 73.0%). The reduction in 12 month restenosis rate was 63% (27.0% with the bare Zilver as compared to 10.1% with the Zilver PTX). At 30 months the primary patency remains statistically significant, and at 24 months there was very little target lesion revascularization (TLR) (Dake et al. 2013).

As part of the MAJESTIC trial, Boston Scientific's ELUVIA drug eluting SFA stent coated with paclitaxel provided a primary patency rate of 96.4% (Müller-Hülsbeck et al. 2016), but there were concerns with strut fracture. The ELUVIA coating is similar to that used on the TAXUS DES (coronary stent) with slower release of paclitaxel.

However, despite the positive results, stents are not widely used for fear of stent fractures.

There is lots of movement in legs, hips and knees, and this movement can cause fractures which in turn cause internal hyperplasia, and it is usually quite severe.

Dr. Tan discussed the advantages of drug coated balloons as compared to stents and included the absence of stent-related complications, more uniform drug delivery, use in all locations (as well as across joints or major arterial branches), and use in small vessels (stents aren't placed in small vessels because they thrombus right away).

He described the use of DCBs across the knee, and indicated that about 20 DCBs are available in Europe.

DCB design was described as including an angioplasty balloon, coated and bound with a carrier / excipient (urea, sorbitol, BTHC, shellac, isopropamide, citrate ester, polyethylene glycol), and a drug (in Canada all balloons are paclitaxel based). He indicated that drug dose generally ranges between 2 to 3 micrograms/mm2, but is dependent on the excipient and how much drug can be loaded. Also, he noted that coating processes are highly variable (dependent on the manufacturer), and that all design factors will affect balloon efficacy.

He noted that Paclitaxel inhibits cell division by interfering with microtubule function, and the more paclitaxel applied, the less neointimal hyperplasia is seen. Balloon drug losses occur during delivery (20%, from handling outside of patient), are delivered to the vessel wall (20%), and wash into the blood stream (40%). 20% of the loaded drug remains on the balloon.

Dr. Tan suggested drug loss may be decreased through coating/excipient formulations that include a higher drug load, ensure uniformity of coating, stability during delivery in blood vessels, uptake of drug to vessel wall (enhanced transfer efficiency), drug retention in vessel, reduced downstream loss (risk of embolization) and balloon design.

Above the Knee

Number of randomized trials exist that compare POBA with DCB for use in the superficial femoral artery (SFA):

InPact SFA (Medtronic), Levant 2 (Bard/Lutonic), and Biolux (Biotronic). All three coated balloons showed higher primary patency rates, and lower clinical TLR rates compared to POBAs. Based on this, Dr. Tan indicated that DCB use was good for SFA applications.

The randomized THUNDER trial investigated the effectiveness of a paclitaxel-coated balloon (PCB) for restenosis prevention in the femoropopliteal arteries at five years (Tepe et al. 2015). Rates of first TLR at five years in patients treated with POBA were significantly higher than in those treated with PCB (55.6% vs 20.8% respectively). Time to TLR was also significantly higher in patients treated with DCB (607 vs. 206 days). Similarly, binary restenosis at five years was significantly higher in the POBA cohort vs. PCB (54% vs. 17% respectively).

Another problem is in-stent restenosis, as it occurs in 30% to 50% of SFA stenting. Available, but ineffective treatments include angioplasty with POBA, cutting balloon, cryoplasty, atherectomy, relining with a bare stent, the use of drug-eluting stents, or angioplasty with DCBs.

Zeller et al. (2013) showed that 12 month primary patency of femoropopliteal ISR with paclitaxel eluting stents was 79%, based on data from the Zilver PTX single arm prospective study. Krankenberg et al. (2015) showed freedom from TLR at 6 and 12 months was significantly greater in DCB treated patients as compared to those treated with POBA for in-stent restenosis in the femoral artery (90.8% vs. 52.6% at 12 months respectively). Recurrent binary in-stent restenosis at six months was also significantly lower in the DCB vs. POBA cohorts (15.4% vs. 44.7% respectively).

Treatment for instant-restenosis

1. PTA
2. Cutting balloon
3. Cryoplasty
4. Atherectomy
5. Recline with bare stent
6. Recline with covered stent
7. DES

However, options 1 – 5 have all proven to be in-effective.

Below the Knee

When treating below the knee using coronary DES off-label for infrapopliteal disease, consider that DES has lower target lesion revascularization rates, the cost of DES is much higher than POBA, DES is currently used off-label for failed POBA, and multiple stents are often needed as the longest coronary stent is only 3.8 cm.

Randomized trials comparing DES (sirolimus and everolimus coated) to BMS for infrapopliteal lesions < 4cm have shown 12 month primary patency rates of 71% to 85%, and 54% to 56% respectively.

Schmidt et al. (2011) reported on the treatment of long infrapopliteal lesions (176 ± 88 mm) using a paclitaxel-coated balloon (InPact Amphirion, Medtronic); at 3 months the restenosis rate was 27%, as compared to a historical POBA control of 69%.

The DEBATE-BTK randomized, single-center trial compared DCB vs. POBA treatment for long below the knee de novo lesions in diabetics. Freedom from TLR rate was significantly higher following DCB treatment, as compared to PTA at one year. Binary restenosis rate was also significantly less in the DCB group (27% vs. 74.3% respectively) (Liistro et al. 2013).

In a multicenter, randomized comparison of 12 month efficacy endpoints for DCB vs POBA for the treatment of critical limb ischemia in infrapopliteal arteries, Zeller et al. (2014) showed that the InPact Amphirion DEB exhibited comparable efficacy to POBA with respect to late lumen loss and binary restenosis rates, but there was a trend towards increased major amputation rate through to 12 months with the DCB (Zeller et al. 2014).

Similarly, the 12 month results from the BIOLUX P-II randomized trial involving Biotronik's Passeo-18 LUX DEB showed that TLR rates, patency loss, and target extremity amputation were comparable to POBA.

Outcome differences between above and below the knee interventions are attributed to: smaller arteries, longer lesions, suboptimal drug delivery, calcifications and embolization of coating material [below the knee].

Questions:

1. How are DCB currently being used in Canada?

   Both above the knee (SFA and popliteal) and below the knee uses are largely second line of treatment after failure of conventional angioplasty or conventional balloon/stent (purely because of cost). Their use as the primary device only occurs in selected centers. Their use as a below the knee primary treatment is rare. Used in patients with failed previous angioplasty.

2. What level of clinical data is required to authorize a new license for a new DCB? Is POBA still the best comparator group for DCB studies for superiority RCT? Are there differences in anatomical locations - coronary vs peripheral?

   DCBs are designed differently hence RCT is required for all DCBs regardless of locations (above or below the knee). In addition, coronary artery disease is not similar to peripheral vascular disease, particularly because of forces acting on limb arteries (radial compression, longitudinal compression/extension, flexion and torsion) as compared to coronary arteries. In Germany, they approved all drug coated balloons for SFA and popliteal arteries.

3. Are there any safety concerns associated with DCBs, especially given some recent clinical trial findings?

   For SFA and popliteal arteries, the risks are low as shown in current clinical data (many different trials with various manufacturers all showing consistent results). However, there are concerns with below the knee interventions; two randomized trials have shown poor results in infra-popliteal segment, and there is a major concern of worse outcome with DCB as compared to POBA. DCB in renal/mesenteric arteries and leg bypass –insufficient data for any recommendation. For dialysis interventions, randomized trial shows slight improvement in patency compared to plain balloon

4. How long should DCBs be followed to determine their safety profile compared to other interventions?

   Every balloon manufacturer has to be assessed individually. For above the knee applications, 1-2 year data should be sufficient to determine if there is a positive outcome. For below the knee, 6-12 month data should be sufficient to determine if there is a positive outcome.

5. What level of data is required for an expansion of indications for use?
   1. De novo versus restenotic versus in-stent restenosis?

      This issue was not specifically addressed except as noted below.

   2. Above the knee versus below the knee?

      For above the knee, the data is conclusive that DCB is superior to POBA whether it is a de-novo or restenotic lesion. Below the knee more data are needed.

   3. Longer length balloons and longer length lesions.

      Longer lesions are associated with poorer outcomes regardless of treatment type. With longer balloons there is a limitation, in that the risk of embolization of balloon coating material increases.

6. Specific to the treatment of ISR, discuss the following:
   1. Should the standard of care for ISR be PTA or DES as the comparator against which DCB should be compared?

      ISR should be treated by DCB as primary treatment. Placing a DES is indicated if there is stent fracture or dissection proximal or distal to the pre-existing stent.

   2. Are BMS ISR treated differently than DES ISR?

      Cardiology literature shows that DCB and DES are superior to POBA alone (ISAR-DESIRE 3). BMS ISR is generally longer, diffuse and occurs earlier (less than 12 months). DES ISR is focal, often at both ends of the stent and occurs later (after 12 months). DES restenosis is generally shorter and less severe than restenosis observed following POBA. DCB and DES have both been used with good success, but generally stenting is avoided in the small peripheral vessels if possible.

7. Discuss the future directions with DCB in the coronary anatomy and in the peripheral anatomy.

   In Peripheral Vascular Disease, DCB is the first line of treatment for SFA/popliteal disease in many European countries and the USA, with exceptions in severely calcified lesions, where there may be suboptimal drug transfer. In these cases, DES is considered. For below the knee applications, POBA is still the standard of care.

This concluded Dr. Tan's presentation.

9. Pediatric Devices

Dr. Joaquim Miro, Committee Member

Dr. Miro disclosed his affiliations and proceeded to address the questions posed by Health Canada.

OBJECTIVES: Pediatric devices come with specific challenges for the Medical Devices Bureau. Based on the small number of patients that need to be treated with many of these devices, licensing and specific pediatric indications are often not pursued. Regulatory decisions are often made either through the Special Access Program or more rarely through Clinical Trials. To better understand the challenges and use of pediatric devices, we would like to have Dr. Miro discuss these issues and for him to highlight to Health Canada, issues he feels would help Health Canada better regulate these kinds of devices so that appropriate devices and data might be available to clinicians and to Canadians.

Health Canada is interested in finding out more about the use of pediatric medical devices in Canada and some of the specific challenges faced by these devices. Given their limited use and the limited information available about their use in a pediatric population, as well as the challenges associated with running clinical trials in a pediatric population, we are asking for an overview of these devices so that Health Canada can make informed and appropriate regulatory decisions for these devices. Although Health Canada welcomes information on any number of devices associated with treating pediatric patients, areas that might be considered include:

1. An overview of devices and alternatives used for patients with congenital heart disease and some of the unique requirements this may present.

   Dr. Miro noted that pediatric congenital cardiology deals with a very different substrate than adult's cardiology. The affected population is much smaller, and the incidence of congenital heart disease is between 3-5 patients per 1,000 live births. Acquired cardiac disease that includes coronary artery disease, aortic valve disease, mitral valve disease, and atrial fibrillation, is expected to occur in 50% to 100% of individuals. From this, one could predict that everyone will need some type of treatment.

   There is greater lesion variety and complexity in the pediatric population, and patients can be large as well as being much smaller and range from 100 kg to premature infants at 800 g. They have smaller vessels and their anatomy is expected to change as patients grow. This means malformations will change over time and require implantation of different devices because devices will break and not grow with patients, particularly given life expectancies greater than 80 years.

   The small number of patients with specifics needs creates numerous challenges for device development and availability:

   • High cost of research (E.g. bench test studies, animal studies).
   • Lengthy and increasingly burdensome regulatory process (2-3 times the cost and time requirement increases over the past 20 years;
   • By the time the device is approved, there may already be another iteration since technology is evolving rapidly.
   • Interest from industry to develop new pediatric devices is decreasing (must consider multiple complex shapes and sizes to treat low incidence malformations).
   • Industry is more interested in developing devices for adults, including devices for TAVR, since there is more money in the number of devices being implanted.

   Dr. Miro suggested that the complexity and heterogeneity of congenital patients creates a powerful stimulus for innovation.

   He presented an overview an overview of devices and alternatives used for patients with congenital heart disease and some of the unique requirements this may present. He noted that from a regulatory perspective, devices used in congenital heart disease can be obtained through the following processes:

   1. Regular licensing – IFU compliance
   2. Regular licensing – Off-label use
   3. Unlicensed Device: Special Access
   4. Custom made devices: Special access
   5. Regular licensing – IFU compliance
   6. Regular licensing – IFU compliance

      This is the preferred route as most patients, and their parents prefer a licensed device that is designed to treat common malformations. He listed examples of such devices:

      • Septal occlusion devices include: Amplatzer ASD, PFO, and muscular VSD, Gore ASD and PFO.
      • Vascular occlusion devices include: Amplatzer PDA (ADO I, ADO II, ADO II AS), Amplatzer vascular plugs (1, 2, 3, 4), and Coils.
      • Stents and stent grafts include: Palmaz, CP stent, Andrastent XXL for coarctation and pulmonary artery.
      • Balloons include: Tyshak and Nucleus for valve dilation, Z-Med for large vessel dilation, BiB for stent placement, and Mullins for stent re-dilation.

      He described the unique clinical requirements for pediatric devices include: immediate efficacy and safety, long term efficacy and integrity, and miniaturisation of devices (E.g. vascular access delivery systems). He noted that issues with mechanical integrity should be expected, but are acceptable if function of device is preserved.

      Dr. Miro suggested that because pediatric patient populations are small, and regulators require animal and bench testing, perhaps regulators would consider accepting studies and regulatory decisions from other countries in lieu. Furthermore, he suggested the Special Access Program could be accepted as a "path to regulation" in which Canadian investigators could pool clinical results. Creation of registries was suggested as well.

   7. Regular licensing – Off-label Use

      Congenital intervention has a long tradition of adaptation and innovation. Dr. Miro noted that off-label use is more the rule than the exception, as devices are borrowed from interventional radiology or adult cardiology (e.g. coronary, biliary and iliac stents in coarctations and pulmonary stenosis of small patients; coronary stents to keep PDA open (palliation of cyanotic malformations; Sapien valve in pulmonary position).

      Devices are borrowed from pediatric intervention (E.g. Amplatzer Duct Occluder II (ADOII) device made for Patent Duct Arteriosus (PDA's) which isn't that good for PDAs, but is frequently used for VSD); use of several CP stents, designed for the aorta, in the RV, and it's important to remember that the RV is a muscle and that any stent developed for vascular indications is an excellent example of an off-label use with possible consequences (material fatigue, leading to fractures is expected).. Therefore, two or three stents are inserted.

      Dr. Miro suggested the following regulatory considerations. He noted that the initial licensing is where we need to put the efforts, and once a device is licensed it is the duty of physicians to find new applications, discuss with patients, report all results to the medical community, and report dramatic complications to regulatory agencies. He explained that trying to regulate off-label use would be counter-productive for the patients, inefficient, costly, and could pose legal problems (E.g. any physician sued for an off-label complication would try to prove that it was actually allowed, and implicate Health Canada). Voluntary changes in IFU by the manufacturer, to include new established indications should be welcomed. Warnings for adverse events should be updated and included in the IFU.

      He stressed the importance of informing the patient and/or family, when a device is used off label and for the physician to then report on the results whether good or bad.

      A discussion regarding off-label use and concerns for the use of devices in an unintended and different environment ensued. The example used was biliary stents. Bio-compatibility of these devices is reviewed by Health Canada, however their intended use in the biliary and not vascular system, therefore hemo-compatability will not be reviewed or established. As a result, Health Canada cannot provide comments on off-label use in an environment different from the one that is indicated.

   8. Unlicensed devices -Special Access Program (SAP)

      Of developed countries in 2016, Canada is probably the least difficult country in which congenital cardiac devices can be obtained via special access. There is a fine balance between access and scrutiny. Scrutiny is necessary to protect patients against clearly unsafe devices, and to avoid the use of SAP as a permanent business plan that excludes eventual licensing. Many cardiac malformations need to be considered as "orphan diseases" with too few patients to support the effort/investment of regular licensing. Dr. Miro suggested that access to SAP devices gives a definite advantage to Canadian patients, as compared to American patients. (E.g. Amplatzer for ASD-PDA and VSD occluders; bare and covered CP stents; Amplatzer membranous VSD occluders; Gore large ASD occluder; Lifetech memb VSD device (in process); Venus pulmonary valve (in process)).

      Special access will always remain a necessity for cardiac congenital disease, as its disappearance would lead to unnecessary open heart surgeries, and even deaths. It was suggested that whenever possible, SAP should lead to licensing, and perhaps through a special licensing process for devices that treat rare conditions. Also, the relation of trust between Health Canada and physicians will always be primordial; the burden of proving the necessity of a device belongs to the physician. Avoid using special access as a permanent business plan excluding eventual licensing.

   9. Custom made devices - SAP

      In rare instances, no devices are available, including off-label use. The congenital interventionist must find a manufacturer ready to craft the device. Most custom-made devices are size modified adult devices, and fundamental changes in mechanical properties are not expected.

      Dr. Miro suggested Health Canada should be vigorous in vetting these devices for safety for immediate use with less focus on long term use. In pediatric cases, immediate safety and efficacy is considered to be 30 days, while long term safety and efficacy data is often not available; it would take too long to generate this data. When looking at intra-cardiac devices (big devices in small hearts), they are not always expected to last mechanically for life, since in many instances they will be explanted at a subsequent open heart surgery. If they last 2-3 years and break, without directly harmful consequences other than accelerating a surgery that was planned anyway, this may be an acceptable outcome. Metal fatigue should not be the basis of refusal unless the device fails within the first 3 years.

      He also suggested that Health Canada should not vigorously scrutinize a smaller version of a device or delivery systems for which safety and efficacy have been demonstrated for the larger sizes.

      He also noted that large animal testing is not possible with pediatric devices, and that the most Health Canada will see are studies involving 10-12 animals. He suggested that asking for specific studies in Canada for every single device is not realistic, and that Health Canada should accept data from good studies, and licensing and approval decisions from other jurisdictions with good regulatory agencies.

      To gain clinical data, he suggested that Health Canada apply some pressure on applicants to report their results, if the requested device is made available through the special access program (SAP).

      He also suggested that Health Canada to host a session at the Canadian Cardiology Society (CCS) and present on the Special Access Programme. This may include information on pediatric devices approved and used through the SAP in the past year. He indicated this would encourage physicians to share their experiences and information, and thereby help physicians better identify appropriate indications for use of pediatric devices.

      Dr. Miro also proposed the creation of a SAP registry, and reiterated that physicians who access devices through the SAP should be obliged [required] to provide patients' information, devices inserted into patients, and any catastrophic events. Making this information readily available would allow physicians to access vital information about the safety of specific devices/procedures and for the family to exercise an informed consent..

      The following challenges were discussed with committee members:

      1. development and testing of pediatric devices
      2. marketing of these devices in Canada.
      3. Health Canada's related policies (e.g. fee remissions), and whether Health Canada should be modelling approaches used in other jurisdictions.
2. Use of TAVI valves in the pulmonary position as opposed to the Melody valve, which has known problems (e.g. stent fracture) and is intended as a temporary device.

   Dr. Miro highlighted that any percutaneous valve and surgical bioprosthetic valves are temporary (Circulation. 2015; 131: 1960-70). He interpreted the Initial US experience as a learning curve that showed freedom from surgery was 87%, and freedom from re-intervention was 70% at 6 years. Most surgeries and re-interventions were related to fractures, and their incidence was greatly reduced by pre-stenting (HR=0.29).

   In a comparison of the Melody and Sapien valves, he indicated the initial and largest experiences were with the Melody valve, it offered easy deployment (BiB balloon), has a long landing zone, and is re-dilatable for re-valving. Drawbacks of the Melody include fracturing, endocarditis, necessity of a 22 Fr system (it is impossible to insert in patients less than 25 kg, unless hybrid approach), and the largest diameter of conduit/RVOT of 24mm.

   Possible advantages of the Sapien valve are: largest diameter conduit / RVOT of 29 mm; steerable delivery system of 16 Fr; fewer reported fractures; and lower incidences of endocarditis reported. Drawbacks of the Sapien valve include: single balloon deployment; shorter landing zone; less re-dilatable for re-valving.

   Dr. Miro noted that due to constant research investment in TAVI, it is likely that the Melody valve will be gradually replaced by devices with improved characteristics, and the current valves can only address less than half of patients that need valves. There is an on-going need for devices designed to treat patients with a dilated native RVOT.

3. Use of septal closure devices

   Dr. Miro indicated that the Amplatzer Atrial Septal Occluder (ASO) is the undisputed gold standard as it can close any size of ostium secundum defect, and almost any variation of anatomy in all sizes of patients. For this reason, Dr. Miro thought there was no significant demand for new devices. He indicated the one major drawback is erosion, which is somewhat predictable and occurs in 1/500 patients with a mortality rate of between 10-20%. Despite this, he indicated it is better than open heart surgery. The Gore GSO device does not have the same issue with erosion, but it cannot close medium or large ASDs. To be a credible contender device, it should treat the majority of patients, offer minimal or no risk of erosion, and be implantable in other types of ASD.

   Amplatzer devices can close almost any variant of Patent Ductus Arteriosus (PDA) anatomy in all sizes of patients. Currently available are the ADO I, ADO II, ADO II AS, ACP II, muscular ventricular septal defect (mVSD) devices for large PDAs and coil-based devices, Nit-Occlud and in small to medium PDAs. Therefore, there is not much need for new devices for PDA closure. Also, it's not clear what new advantage a device would offer and why you would need any PDA devices via the special access program.

   Although the Amplatzer muscular VSD devices can close most defects of this type, delivery systems are too large and stiff for smaller patients. Some special access justifications include the need for softer devices with smaller and steerable delivery systems.

   Dr. Miro indicated that there are no specific devices licensed in developed countries for membranous VSD closure. The incidence of AV block with mVSD1 is 5%, but the mVSD2 has shown excellent results in 38 patients between 2011 and 2014, but development was halted due to financial reasons. The device with characteristics adapted to the membranous septum, but with a lower incidence of AV blocks is the Lifetech CERA.

4. What evidence might be required for percutaneous interventions that simply 'buy some time' in patients who might need multiple open cardiac surgeries over their lifetime?

   Dr. Miro stressed that "buying some time" when you are a very sick before next surgery is not trivial. For some patients, buying time is not trivial, and avoiding an open heart surgery is not trivial, as the number of re-operations must be considered; The mortality rate increases with every re-operation and it is approximately 12% with the 5th surgery.

   Therefore the same evidence that is required for regular interventions; safety and efficacy in the short term (30 days) and the mid-term (1 year) is required. There are less concerns regarding long term evidence because these devices will need to be replaced, as they are not lifelong devices. They are being inserted to "buy some time".

Dr. Miro concluded his presentation.

10. Next Steps, Closing Remarks and Adjournment of Meeting

Dr. John Ducas, Committee Chair

The Chair thanked committee members and invited speakers for their participation and valuable input. Members will be canvassed to select a date for the next meeting.

Meeting adjourned.

Committee Members Present: John Ducas (Chair), Eric Cohen, Marino Labinaz, Alan Menkis, Barry Rubin, Raymond Yee, Joaquim Miró, Christopher Feindel

Invited Guests: William Geerts, John Parker, Nancy Santesso, Jacqueline Saw

Health Canada Representatives:

• Office of Science: Hripsime Shahbazian, Caroline Hunt
• Medical Devices Bureau: Kevin Day, Ian Aldous, Ian Glasgow, Jianming Hao, Karen Kennedy, Mark Korchinski, Christine Lefebvre, James McGarrity, Catherine Milley, Maurice Sylvain,  Lanyi Xu, Chris Schmidt
• Therapeutic Products Directorate Director General Office:  Marion Law, Kimby Barton
• Marketed Health Products Directorate:  Amanda Jones, Patrick Fandja
• Health Products and Food Branch Inspectorate:  Barbara Harrison

Regrets: Renzo Cecere, Brent Mitchell, John Webb, Toffy Mussivand

Abbreviations used in this record:

6-MHW:

6 Minute Hall Walk

AAA:

abdominal aortic aneurysm

ACP:

Amplatzer cardiac plug

AF:

atrial fibrillation

BAT:

Baroreceptor Activation Therapy

BMI:

body mass index

BVS:

Bioresorbable Vascular Scaffold

CHF:

Chronic Heart Failure

CRT:

cardiac resynchronization therapy

DAPT:

dual antiplatelet therapy

DES:

Drug Eluting Stent (DES)

DOAC:

direct oral anticoagulant

DVT:

Deep Vein Thrombosis

ICD:

implantable cardioverter-defibrillator

IFU:

instructions for use

IPG:

implantable pulse generator

IVC:

inferior vena cava

GRADE:

Grading of Recommendations, Assessment, Development and Evaluation

LAA:

left atrial appendage

LAAC:

Left atrial appendage closure

LVAD:

left ventricular assist device

LVEF:

left ventricular ejection fraction

LV:

left ventricle

MACCE:

Major Adverse Cardiac and Cerebral Events

MCUSA:

maximum circular unsupported surface area

MDB:

medical devices bureau

MI:

myocardial infarction

MS:

multiple sclerosis

MRI:

magnetic resonance imaging

NVAF:

non-valvular atrial fibrillation

OAC:

oral anticoagulant

OPC:

objective performance criteria

PG:

performance goal

PPM:

permanent pacemaker

RCT:

randomized clinical trial

RV:

right ventricle

SAC-MDUCS:

scientific advisory committee on medical devices used in the cardiovascular system

SAP:

special access program

SE:

systemic embolism

SVC:

superior vena cava

TAVI:

trans-catheter aortic valve implantation

TAVR:

trans-catheter aortic valve replacement

TEE:

trans-esophageal echocardiogram

TIA:

transient ischemic attack

TLF:

target lesion failure

TPD:

Therapeutic Products Directorate

VKA:

vitamin K antagonist

VTE:

venous thromboembolism

1. Opening Remarks & Welcome

Dr. John Ducas, Committee Chair

Marion Law, Director General, TPD

Dr. Ducas opened the meeting, welcomed the committee members and guest speakers. Marion Law, the current Director General of the Therapeutic Products Directorate (TPD), introduced herself, thanked the committee members and guest speakers for sharing their time and expertise and acknowledged the efforts all participants had made to attend the meeting. Ms. Law highlighted the importance of the Scientific Advisory Committee on Medical Devices Used in the Cardiovascular System (SAC-MDUCS) to Health Canada’s regulatory review and decision-making process.  She commended the committee on its continued support and noted that their past recommendations have been helpful in numerous license evaluations.  Ms. Law concluded by reviewing the topics of the day’s agenda and wished the committee members and guests fruitful deliberations.

2. Review of the Agenda, Affiliations and Interests Declarations, and Confidentiality Agreement

Dr. John Ducas, Committee Chair

The Chair reviewed the agenda items with the committee. The agenda was accepted with minor adjustments to accommodate all speakers. Members were asked to disclose any conflicts that may arise as the meeting proceeds.

Presentations are available upon request.

The responses outlined below are representative of the discussions/recommendations generated by the committee. 

3. Summary of how Health Canada has used information generated from previous SAC-MDUCS meetings

Kevin Day, Medical Devices Bureau (MDB)

Mr. Kevin Day presented a brief summary of how previous advice and recommendations provided by the committee have been considered by Health Canada.

The following topics were noted:

• Continuous Flow LVADs, thrombosis, anticoagulation, and pump speeds: committee feedback has been helpful in resolving post-market concerns.
• Thrombectomy Systems and the TOTAL trial: Recommendations from the committee have assisted the MDB in applying appropriate regulatory scrutiny in this area.
• LAA closure devices: the committee’s input and recommendations were taken into account for the licensing of the Watchman LAA Closure Device on 2016-01-19. 
• Human Factors and Cardiovascular Medical Devices: support from the committee on this topic has helped make this a basic requirement for a number of cardiovascular medical devices.
• Durability of Bioprosthetic Valves: committee feedback has been helpful in resolving post-market concerns and in assessing the need for longer term durability testing as the expected durability of bioprosthetic valves increases.
• Labelling considerations for IPG and significant risk/benefit factors:  Noted that the MDB is requiring more data to be included about the impact new features have on battery life, which is becoming a significant issue for emerging approaches for LV pacing with multiple vectors per beat.

It was noted that the Committee’s input ensures that good clinical oversight is continually being considered towards decision making processes for license, clinical trial, and special access applications.

Mr. Day thanked members for their ongoing dedication to the committee.

4. Leadless Pacemakers

Dr. Raymond Yee, Committee Member

Dr. Yee disclosed his affiliations and proceeded with his presentation.

He described a patient case study where the option of a leadless pacemaker was considered a lifesaving technology. The patient had abandoned leads, no superior venous access for new leads and had a previous epicardial system that failed. In this situation the leadless pacemaker was used as a rescue intervention providing an example of an ideal candidate for SAP.

Dr. Yee noted that there are many complications associated with traditional pacemaker leads, and leads are considered the Achilles Heel of pacing devices. The need to insert pacemaker leads for conventional systems can lead to complications. He indicated that these complications, especially in the acute phase, can be underreported, so accurate data on lead related complications are hard to obtain. Additionally, chronically implanted leads can fail structurally or fail to function effectively and need to be replaced while the non-functioning leads are usually left in the patient. These abandoned leads are always a contraindication for MRI scans and many implanted and functioning leads continue to be a contraindication for MRI scans. Lead failure is not limited to any one manufacturer and it is difficult to predict which lead models will have a higher failure rate.

Dr. Yee noted that based on published data (from the Danish registry where every lead and generator is tracked), a 9.5% complication rate at 6-months was reported. Lead-related complications were 2.8 -3% for new device implants or lead-related revision procedures.  However, even opening a pocket to replace a generator can stress and injure leads. In the Danish study, generator replacement had a lead-related complications rate of 0.9. The FOLLOWPACE Study reported a 5.5% lead-related complication rate in the first 6 months post-implant. Manufacturer-based databases are an added source of lead reliability but they often rely on physician reporting and therefore are of limited reliability. Nonetheless, the leads with the best long term reliability do become evident to physicians overtime. For instance the Sprint Quattro ICD lead is regarded as a very reliable ICD lead with an approximate survival rate of 95% at 10 years based upon data from the manufacturer.

Dr. Yee provided an overview of history of leadless pacemakers. He explained that the concept of leadless pacemaker is not new although sufficiently advanced devices ready for potential market release are only being tested.  Currently, several leadless pacemaker systems are available (although none are licensed in Canada), and are single chamber devices only. Dr. Yee described three systems that have undergone clinical testing: the LCP Nanostim by St. Jude Medical, the Micra by Medtronic and the WICS EBR.  He noted that both Nanostim and Micra devices offer single chamber RV pacing, with similar dimensions (weight of approximately 2 g and a volume of 1 cc). Both devices possess retrieval mechanisms. Dr. Yee indicated that pacing systems, either conventional leads or leadless devices, are placed wherever a stable location can be found with good electrical parameters in the patients’ myocardium. Implantation location is not limited to the apex, but should be a stable location with the best measurement of electrical parameters (sensing amplitude and pacing threshold/impedance).

On the other hand, the concept, design and purpose of the WICS leadless pacemaker system is entirely different from the Nanostim and Micra, and consists of two implanted components - an intracardiac device and subcutaneous device. WICS is designed to pace the LV in tandem with a separately implanted conventional right sided pacemaker or ICD. The intracardiac device is placed in the LV endocardium and does not have any self-contained energy source such as a battery power. Instead, the unit contains components that convert ultrasound energy to electricity. The subcutaneous portion of the WICS device system consists of a “generator” and subcutaneous pad “electrode” implanted in the chest wall that transmits ultrasound to the intracardiac hardware.  Dr. Yee described the design as ingenious, but complex, and noted that a recent study was terminated after 4 perforations and 1 death. Results of a second patient study have been reported but only involved 35 patients. There is scant other data available concerning the device at present.

Dr. Yee presented findings from the Nanostim Leadless II multi-center, prospective, non-randomized trial that involved 526 patients, with 6 months adverse events from the first 300 patients as the primary safety endpoint. He noted that most of the users had not implanted the device in humans before the trial. The study was limited to patients who did not require dual chamber pacing and were appropriate for single chamber (there is currently no ability to implant two leadless devices and communicate between the two).  The patient population in Leadless II was relatively elderly (mean age was 75).  He did note, however, that the BMIs were low, and, sadly not entirely reflective of a North American one.  He was impressed that there weren’t more perforations, given the age of the study group.

A question was asked whether there is a lower limit on patient size and if these devices could be used in a pediatric population. Dr. Yee estimated that leadless pacemakers could be implanted in patients as small as 20 kg but not less than 10 kg. This estimate was supported by members of the committee. Dr. Yee also expressed some concern about increased risks of perforations in the elderly with low BMIs, who are more fragile.

Dr. Yee stated that perforations are not uncommon, and that a major factor may be the delivery system rather than the device itself.  Stiff delivery sheaths make delivery difficult because of inferior handling and manipulability. He explained that the right ventricle is less than 2 mm thick in some locations and can therefore be easily penetrated. In future delivery system generations, performance could be improved with a decrease in size and increased handling of delivery sheaths.

The trial demonstrated a good implant success rate of 96% with 30% requiring repositioning after initial deployment. Dr. Yee commented that this statistic could be interpreted as evidence that the repositioning feature worked as intended.

Leadless II trial complication rates (526 patients) were as follows: 6.5% total, 1.5% perforation, 1.1% vascular complication, 1.5% dislodgement/migration, 0.8% retrieval/re-implant. Retrievals/re-implants were due to pacing threshold issues which occurred at 8±6.4 days.  Although the effectiveness threshold was set at 85% (85% or more patients would have acceptable pacing parameters at or below a given value) and met in this trial, a better level would likely be 90%.

The Leadless II trial primary endpoints surpassed performance goals for safety (freedom from serious adverse device effects (SADEs) at 6 months: 93.3% vs. PG of 86%), efficacy (acceptable pacing capture threshold (<= 2.0 V at 0.4 msec.) and a therapeutically acceptable sensing amplitude (R wave >= 5.0 mV, or a value equal to or greater than the value at implantation) through 6 months: 90.0% vs. PG of 85%), and procedure/implantation (successful device implantation: 93.4% vs. PG of 85%).  In addition the investigators reported decreased capture thresholds between implant and pre-discharge, and out to 12 months, which Dr. Yee interpreted as a good sign, instead of increasing over time as is often seen with conventional leads. Also, impedance significantly decreased from implantation to 12 months. While Dr. Yee considered these findings supportive of safety and effectiveness, he stated that higher impedance (R) values would provide better battery longevity.

There was a comment that a perforation rate of 1.6% seems high compared to that of single right ventricular leads and further details for cardiac perforation and clinical implications were asked. Dr. Yee explained that perforation with conventional leads is probably under-detected and under-reported. This complication is seen most often in the elderly and when it occurs, the implanter simply withdraws the lead and repositions: rarely does it result in clinically significant sequelae such as cardiac tamponade or prompt further investigations to document if the patient is hemodynamically stable and asymptomatic. Even when it is significant, these events are not reported except in the context of a clinical trial or mandatory registry.

There was a question whether there would be an interaction between these devices and previous devices already implanted in the chamber, such as previously placed leads, which may create electrical noise and impact sensing. Dr. Yee commented that contact between hardware can generate electrical noise and potentially interfere with pacemaker function. The solution is to place devices far enough apart and there is sufficient space in the RV for multiple devices; he also thought that the size is such that it would be feasible to implant 3-4 devices in an individual within their lifetime.

Dr. Yee described Micra leadless pacemaker, and indicated that while it is sized similarly to the Nanostim, it has a no magnet mode. This is a drawback as pacing cannot be forced in an emergency.

The Micra trial (Reynolds et al. 2016) enrolled 725 patients with characteristics similar to those included in the Leadless II trial, had a very good survival curve with 4% major complications at 6 months which Dr. Yee described as acceptable.  Micra trial complications included: 1.6% perforation, 1% vascular, 0 dislodgement/migration, 0 retrieval/re-implant, and one death attributed to metabolic acidosis. Dr. Yee felt that the large sheaths in elderly patients could be a major factor in the perforations. The Micra trial showed a good pacing threshold with a time course that was remarkably stable.

It was noted that battery life on leadless pacemakers is approximately 10 years based on pacing voltage of 1.5 V. Dr. Yee indicated that higher impedance spares battery life because of less current loss (Ohm’s Law). The electrical performance data of the Micra study are remarkably similar to the Nanostim study.

There was a question on need for steroid coating similar to leads. It was noted that both systems include a steroid coating. Dr. Yee commented that the value of steroids is in blurring the spike in pacing threshold that occurs usually within the first three months with non-steroid coated leads. The time profile seen so far in Nanostim and Micra may partially reflect the influence of steroid coating but, so far, no signal of an acute rise in pacing thresholds post-implant has been observed. More data will be required before the value of steroid coating can be re-evaluated in the context of leadless pacemakers.

A discussion on the fixation of leadless devices followed. There was a comment that without good fixation movement is of potential concern due to interaction with structures such as chordae. Dr. Yee commented that these were early days but did seem that both Nanostim and Micra fixation mechanisms seem to be working well with a low dislodgement rate. The Nanostim fixation is a screw similar to leads. The Micra may experience less motion due to the 4 fixation tines. It was asked whether use of imaging would be encouraged to see if there is movement or interaction with other devices. Dr. Yee noted that interaction of pacing leads with chordae and valve leaflets is rarely noted but it is also true that it is rarely looked for with conventional leads.  For Micra implants magnified fluoroscopic imaging is looked at during traction on the tether to test for fixation but interaction with any right heart structure might be minimized by the presence of the delivery sheath and would not be seen until it was removed. Moreover the leadless pacemaker implants typically target sites deep in the RV such as the junction of the septal and free walls so such interactions would be unlikely.

Retrievability/extractability of these devices was discussed next. Dr. Yee noted that extraction of a leadless pacemaker is easier than traditional leads. In the Leadless II trial, 7 retrievals were successful, although these were short term implant retrievals. Devices implanted for 5 years may be much harder to explant but are still thought to be easier and less risky than conventional leads. Conventional leads are usually fibrosed and adhered to the vein wall along their lead bodies and laser lead extraction can lacerate the central venous structures in addition to tearing the RV myocardial wall. It was also suggested that the need for extraction of the leadless devices may be less, due to less infection than experienced with leads.  Devices will not likely be removed if there is no problem. It is possible to implant multiple leadless pacemakers side by side within the same chamber.  Dr. Yee noted it is feasible to select points that will pace and that 3-4 devices would fit in the chamber.

There was a concern regarding the severity should leadless devices detach; the worst case scenario being pulmonary embolism.  Dr. Yee commented that this is a legitimate concern and there is a need to see minimum 12 month data on dislodgement to determine if fixation is secure.  He was of the opinion that if it hadn’t dislodged by 12 months than it is unlikely to ever dislodge.

A question was asked if thrombosis is observed on the leadless devices and whether there is a need for anticoagulation. Dr. Yee commented that thrombus is frequently observed on conventional pacing leads and they come and go, as thrombi are continually formed and absorbed. It is still an open question whether they are clinically important (no evidence of poorer outcomes) and whether anticoagulation is required.

He summarized his presentation noting that:

• Device technology has come a long way.
  • Leadless cardiac pacing is feasible in humans and evolving rapidly
  • Shows good short-term efficacy;
  • Has similar short term safety profile to transvenous pacing;
• May provide an alternative for those with difficult transvenous or epicardial access
• Long term data still required
  • Safety and device performance
  • Extractability

At the end of the presentation Dr. Yee addressed the questions provided by Health Canada.

Question 1: Who is the target patient population for these devices? Will these devices completely replace single-chamber pacemakers?

Dr. Yee talked in terms of near term and long-term target populations. In the near term, he considered these devices feasible for select patients now because they have demonstrated good pacing performance with reasonable procedural safety. They are reasonable as a bail-out option since such patients have little alternative. Although initially considered for those with limited venous access, high infection risk, and one device lifetime, he specifically noted that it is a reasonable option for patients being considered for epicardial or abdominal PGs since these devices are fraught with problems and often last less than 5 years. Leadless pacemakers are also an option for those who require a second RV device since there is room for multiple devices.  Nevertheless, there is a need to be cautious about patients targeted and build experience going forward. He did not think these devices would replace existing pacing systems in the short-term, until more longer term performance, safety and extractability data show equivalent safety and performance to conventional pacemakers.

There was a question about the active patient and rate response. Dr. Yee commented that there is not a lot of data on this and we need clinical data to demonstrate that leadless pacemakers are as good as conventional pacemakers with respect to rate response (i.e. physically active patients).  Dr. Yee noted that the Micra device tries to filter out the heart motion, whereas the Nanostim bases its algorithm on venous blood temperature.  Dr. Yee suggested that manufacturers of these devices will need to demonstrate their performance with a standardized test (e.g., treadmill test) in response to exercise and physical activity.

Question 2: The useful life of the device is probably in the range of ten years. Tissue growth may prevent explantation. Is this a problem?

This was answered throughout presentation.  Extractability is certainly an issue but there may be trade off in terms of less risk.  The devices will not require extraction if there is no problem like infection.

Endothelialization is expected with any intravascular hardware, leadless or leaded. The dimension of the issue will change but the risks of extraction may be the same or less because:

• No lead to fibrose to SVC wall or thrombose SVC
• Extraction sheaths will be similar to current tools but larger until device size decreases further.

Question 3: Are there specific contraindications, warnings or precautions that should appear in the labeling.

• Significant risk of cardiac perforation and highlight embolization risk.
• Restricted to use in patients who cannot receive standard PPM
• Not for use in RA or LV.
• Use with caution in patients with TV prosthesis; not for use with TV mechanical prosthesis

Question 4: Will there be a learning curve? What training is required? Who should implant them?

Yes, there is a steep learning curve related more to the maneuverability of the delivery sheath. It is much different than a lead implant and operators need experience with sheaths and catheters.  It was recommended to have initial animal or simulator training, followed by proctoring for the first 4 to 6 cases.

Question 5: Can you predict who will need dual (or more) chamber pacing or ICDs. If you could predict, which type of system would you prefer to implant?

The indications for pacemakers and ICDs are fairly clear and codified in practice guidelines. Put simply, if the LVEF < 30-35%, an ICD is indicated, not a leadless pacemaker. A CRT device (CRT-P or CRT-D) is indicated in heart failure patients with EF<40% with a wide ORS.  The use of dual chamber pacemakers is still controversial. Randomized comparative trials have failed to show clinical benefit from dual chamber pacemakers compared to single chamber pacing with the exception of lower rates of AF. Despite this, many physicians still believe there exists an important role for dual chamber pacemakers and clinical practice varies by center and implanter.

Question 6: How should regulatory requirements for safety and effectiveness be resolved for this new technology, e.g. a randomized clinical trial, registry etc. Describe potential controls and trial safety and effectiveness endpoints.

A RCT would best support safety and effectiveness in an ideal world. That being said, safety can be demonstrated without a RCT using good historical controls and conservative estimates for conventional pacing systems. If the devices are indicated for a bailout indication (e.g. patients who are ineligible for standard pacemaker), then RCT not likely required.  If leadless devices are considered for replacing standard systems, something closer to a RCT may be required.

The following endpoints were indicated:

• Safety - acute procedural complications: perforation, vascular access (pseudoaneurysms/aneurysms), major bleeding or hematoma, early dislodgments, embolization
• Efficacy - successful deployment of LLPM, acute and chronic electrical performance, need for re-operation at 12-24 months.

Question 7: Are there some OPCs that you could recommend for performance or should Health Canada require RCTs to study this new technology.

No standard OPC exist, however the following is recommended and should be an amalgam of criteria rather than focus solely on one safety or efficacy endpoint (Kirkfeldt Eur HJ 2014):

• Need for re-intervention @ 6 months <2.5%
• Dislodgment (<2.5%), cardiac perforation (<0.6%)
• High pacing threshold requiring reoperation (<1%) OR
• Battery longevity is the critical clinical endpoint
• >85%pts will have pacing threshold (_V@_ms) at 12 months that allows for battery longevity ≥7 years (100% VP, impedance of 500 ohms and programmed pacing output safety margin of ≥2)

Battery longevity should be considered as a performance criterion under real world conditions and not just the idealized labelled value with a given pacing threshold of X.  Bench testing according to ISO standard tests is not enough, the manufacturer should demonstrate that the real world longevity is reachable.

Dr. Miro joined the meeting.

5. Patient Preference

Dr. Nancy Santesso, Guest Speaker

Dr. Santesso introduced herself and disclosed her affiliations.  She noted that she is a member of the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) working group which uses the GRADE approach, a systematic method, of creating guidelines.

She was asked to address patient preference in informed health decision making:

In the past few years, there has been increased interest focused on the importance of allowing for better patient preference in informed health decision making. Health Canada is starting to explore how we might incorporate patient preference considerations during premarket review. Patient preference may be defined as: qualitative or quantitative assessments of the relative desirability or acceptability of attributes that differ among alternative diagnostic or therapeutic strategies.

She began her presentation indicating that Health Canada is already accounting for patient preferences; however, could be more formal, could use better data, could be more transparent, and could learn from others in Canada.

An example was given using a lay scenario to describe how patient preferences are accounted for. The GRADE method was described.

• The important patient outcomes need to be decided at the beginning. Only these outcomes are considered in the decision.
• Values are added to each outcome and there is a balancing act to determine which outcomes hold more weight; consideration must be given to whose values will be used.
• Outcomes are decided using input from our own values, values of other people present, and from asking others.
• If someone identifies another outcome later in the process it is not considered in the decision since it was not identified as an important outcome.

A question was asked about the reliability of data from surveys. Dr. Santesso described a hierarchy for obtaining documentation and referenced the FDA guidance document, which she described as quite well done.

A question was asked regarding how design changes over the lifecycle of a product are accounted for in the decision making if all important outcomes must be identified at the beginning. Dr. Santesso responded that feedback for new critical outcomes can be factored in if new data reveals their need.  This requires going back and making the decision over again. There needs to be transparency on the weight of each outcome.

Dr. Santesso presented on how to determine the critical and important outcomes for the decision. This was focussed on methods including scoping literature and surveys. Potentials for surveys include patient groups, professional groups, and program managers.

Patient values are used to weight the outcomes. Patient values can be obtained from:

• Asking the panel to reflect on experiences making decision with patients
• A patient representative as a panelist
• Consulting patient representatives
• Performing a value rating exercise of patients
• Original studies of rating values of patient
• A literature review of those studies

The first three on the list are similar to focus groups or unsystematic observational studies.  Patient values can also be elicited from studies and qualitative research.

Dr. Santesso noted that separate panels with patients and citizens may be necessary if having a patient at the table may change the conversation.

Dr. Santesso highlighted that it can often be difficult to weigh the patient population choice (obtained via panels and surveys) versus the individual patient choice. Patient preference is one factor of a decision.  There is a need for transparency on how it is considered.

SAC members noted that often clinicians can convince patients of just about anything.

She suggested list of key questions to consider when making recommendations:

• Is there important uncertainty about or variability in how much people value the main outcomes? This should be clear to potential users - clinicians and patients. If so, these outcomes must be addressed on an individual basis. If not, a panel can address the outcomes.
• Is the intervention acceptable to key stakeholders? This should be clear to potential users - clinicians and patients.

The overall risks and benefits become desirable and undesirable consequences. This is a balancing of benefits X value, acceptability, feasibility versus risks X value, resources, equity.

1. Should Health Canada account for patient preference? We are used to thinking of interventions and devices in terms of Risk and Benefit. How could we capture patient preference as a “benefit” and how can we assess this against a possible increased risk. Note: Health Canada would still have to be confident in the safety and effectiveness or appropriateness of a device prior to issuing a licence or authorizing special access or a clinical trial.
   • Risks and benefits can be weighed using patient values (or other key stakeholders)
   • Patient preference as an outcome of factor in decision making
2. Would it be helpful if the use of patient preference data was included in the labelling, or elsewhere (for example, Summary Basis of Decision) to identify this as a factor in the regulatory decision.
   • Make outcomes and criteria transparent to potential users of device.  This includes a clear statement on what was considered, including values and preferences.
   • Useful in individual decision making
     • Clinicians should recognize that different choices will be appropriate for each individual and that clinicians must help each individual arrive at a management decision consistent with his or her values and preferences.
3. How is patient preference accounted for in the Canadian clinical environment? Is it generally included in Canadian Clinical Practice guidelines? How would an assessment of patient preference at pre-market review fit with current practice?
   • GRADE approach to clinical practice guidelines
   • Institute of Medicine Standards

General discussion on the topic of patient preference ensued.  Patient preference and its relation to informed consent were discussed. It was noted that the main concern here is whether the values of the patient are the same as the physician.  There was a question whether it would be beneficial for Health Canada to require informed consent similar to what is done in clinical trials.  General consensus was that this is already done and physicians have a legal obligation to disclose risks to the patient. It was noted that some of this is regulated at the provincial level already.  It was further commented that there is no ability to monitor the consent process.

Discussion evolved to how physicians can be better prepared to inform patients and where this information can be found.

• There is a need to convert clinical trial data into more meaningful information for patients to understand how they may personally benefit.  For example, replace “numbers needed to treat” with “this will increase your life expectancy by x”
• Physicians could use guidance on factors to discuss with a patient that they might not think to consider.
• Anything to enhance the process of a physician having information to give to a patient is of benefit.
• This information would be “hidden” in the labelling - not a useful source.
• Medical associations are a good source of information.
• May be of value to more closely monitor these types of outcomes in clinical trials
• An unbiased patient pamphlet that does not come from the manufacturer could be helpful. Medical associations perhaps are a good place to develop such information brochures.

6. Considerations with LAA Occluders

Dr. Jacqueline Saw, Guest Speaker

Dr. Saw introduced herself and disclosed her affiliations.

Dr. Saw was asked to provide a review of the use of Left Atrial Appendage (LAA) occluders including a discussion about the appropriate anticoagulation/antiplatelet regimen prior to and following implantation.

She started by providing an outline of her presentation:

• Background rationale for LAA closure
• Landscape of LAA closure
• Devices available: endovascular and epicardial
• Scientific evidence for endovascular LAA closure: OAC eligible and ineligible patients
• Cost-effectiveness analysis of LAA closure
• Discussion on proposed questions

Background Overview of Why LAA Closure is performed

Dr. Saw explained that LAA closure is being positioned as a possible alternative to oral anticoagulant (OAC) therapy for atrial fibrillation. Functional changes, structural remodeling, blood stasis and potentially hypercoagulability can occur within the left atrial appendage (LAA), especially during atrial fibrillation (AF), and this can result in thrombus formation.  Thrombi formation in the LAA has been identified in over 90% of patients with nonvalvular atrial fibrillation (NVAF) in various studies, mostly by using trans-esophageal echocardiogram (TEE).  Particular anatomical and functional characteristics of the LAA in adults contribute to the occurrence of thrombus. LAA morphology between individuals is highly variable, but may be described as long, tubular, or multi-lobed; it is a blind-ended pouch with excessive trabeculations which can cause blood stasis. Dr. Saw indicated that different anatomies would require different devices.

She also indicated that thromboembolic events, because of AF, lead to stroke, and that 35% of patients with AF will suffer a stroke in their life time. She also suggested these events would result in relatively high rates of disabling stroke or mortality.

Clinical guidelines recommend that most patients should be treated with anticoagulation as the standard of care, unless they are at low risk or have a contraindication to anticoagulation.  Dr. Saw presented data from the Registry of the Canadian Stroke Network (2003-2007) that showed 90% of AF patients who had a stroke were not receiving Guideline-recommended treatment using Oral Anticoagulants (OACs), and in that population, 30% received suboptimal anticoagulation, 30% received antiplatelet therapy, and 30% received no treatment.

Meta-analysis studies have shown that New Direct OACs (DOACs) have demonstrated a reduction in the occurrence of stroke or systemic embolization compared to Warfarin. The real clinical benefits, however, have been limited because:

• ~30% eligible patients are not on OAC.
• OACs can be contraindicated, not tolerated and subsequently discontinued in 20% to 40% of patients,
• There are bleeding risks
• Long-term adherence is suboptimal

Landscape of LAA Closure

It is projected that there will continue to be an increase in the population affected by AF, which is the most common adult arrhythmia.  In 2000, there were 5.1 million in the United States affected by AF; by 2050 projections indicate there will be 15.9 million with AF.  This represents 1% to 2% of the total population. As such, Dr. Saw indicated the LAA closure market is expected to grow 6x.

LAA Closure Devices Available

Dr. Saw noted that currently, there are a number of endocardial (percutaneous) and epicardial LAA closure devices available on the market or in the development stage.

The first generation of endocardial closure device PLAATO has been removed from the market while the 2nd generation of closure devices are available in European market including Watchman (and Watchman FLX), Amplatzer Cardiac Plug (ACP), Amulet, and WaveCrest. Several other endocardial LAA closure devices are being tested in the preclinical trial evaluation.

Two epicardial LAA closure devices, Lariat and AtriClip, have been approved by FDA and CE marked, and two other devices are either in the clinical trial evaluation or pre-clinical trial evaluation stages.

Watchman was CE marked in 2005, approved by FDA in March 2015, licenced by Canada in January 2016, and is now available in over 55 countries with 15,000 implants. Watchman is a nitinol frame with 5 sizes ranging from 21 to 33 mm (2-4 mm oversize). It is delivered through transseptal puncture via 14 Fr sheaths, and is repositionable and retrievable. It can be expanded radially to maintain its position within the LAA. This device is covered with a 160 µm PET membrane and promotes healing (by endothelialisation) within 45 days.

Watchman FLX has been designed in order to simplify the procedure and minimize adverse events. Specifically, Watchman FLX has a shorter device length than the Watchman with decreased recapture forces and better conformability.  It received CE Mark in Nov 2015.

ACP was CE marked in 2008, is used in Canada under the Special Access Program (SAP), with approximately 10,000 implants worldwide.  ACP is constructed of a nitinol mesh and Dacron polyester sewn into both the lobe and disc, connected by a central waist.  It has 8 sizes 16-30 mm (3-5 mm oversize). The shape fits most LAA, and it is retrievable and re-deployable, until it is released.

Amulet (2nd Gen ACP) has a recessed end screw, a larger disc diameter, a longer lobe length, a longer waist length, and sizes up to 34 mm.

Other LAA closure devices including WaveCrest, Ultrasept, PFM Device, and LARIAT were described briefly.  It was noted that the LARIAT is generally not used in Canada.

Scientific evidence for endovascular LAA closure: OAC eligible & ineligible patients

Dr. Saw noted that clinical evidence for the safety and effectiveness of endovascular LAA closure devices has been collected via an RCT on the stroke prevention in patients treated with endovascular closure devices using WATCHMAN compared with warfarin.

WATCHMAN clinical trial program includes 8 completed or ongoing trials with a total of over 3700 pts with over 6000 pt-years follow-up data currently available.

• Pilot
• PROTECT-AF Study (N=707)  
• CAP Registry
• ASAP
• PREVAIL
• CAP2 Registry
• EWOLUTION
• WASP

It was noted that in the PROTECT-AF Study (Reddy et al. 2014) that results at 3.8 years were promising.  Although some acute events were higher than anticipated (e.g. 4.8% pericardial effusion), these were partially attributed to the learning curve.

There was a question about the interpretation of the PREVAIL RCT (Holmes et al. 2014) data where 2 of the 3 endpoints were not met.  Dr. Saw indicated that the data was supportive of safety and effectiveness of the Watchman when taken in the totality of the evidence.  In the PREVAIL RCT data, outcomes in the warfarin arm, which was relatively small, reflected a very low stroke rate compared to the expected outcomes seen historically in this patient population.

Real World Experience

A prospective real-world registry study EWOLUTION registry (Boersma et al. 2016) included 1021 patients in 47 centers in Europe, Russia, Middle East with follow-up for 3 months and included 61.8% ineligible for OAC (38.7% prior major bleed or predisposition to bleed). DAPT was used in 59.5% post-implant (OAC 27%). The Procedural Success was 98.5%. There were 2.7% serious procedural/device-related safety events to 7 days including perforation, tamponade, ischemic stroke, device embolization, and vascular complications. The 30-day mortality was 0.8%.

Canadian WATCHMAN Experience

A Canadian Multi-center Experience with Watchman for percutaneous LAA closure presented by Dr. Saw at AHA 2015 included 106 patients with atrial fibrillation.  At baseline, only 32% of patients were on any anticoagulant, with 13% on no antithrombotic medication and 39% on a single antiplatelet medication.  Procedural Success was 97.2% and the Composite Major Safety Events at 7-days was 0.9% (Composite of all-cause death, ischemic stroke, SE, or device-/procedural-related events requiring surgery or major endovascular intervention within 7 days). The rates of stroke rate, TIA, and systemic embolization (SE) were 0%, 1.9%, and 0%, respectively. At discharge, there were 73.4% on DAPT alone. The Canadian pooled stroke/TIA/SE rate of 3.3 %/Yr was reduced by 66% and 59% when compared to the estimated rates by CHADS-VASc and CHADS, respectively.

German Study Data

The long-term results of Watchman LAA closure with some data up to 5 years (mean follow-up period of 3.0+- 1.6 years) showed the rates on Post-procedural DAPT for 6 months and Post-procedural VKA and Aspirin were 41.8% and 58.2%, respectively. The annual rates of TIA, stroke, intracranial hemorrhage, and death were 0.7%, 0.7%, 1.1%, and 3.5%, respectively. The study concluded that LAA closure with the Watchman device is safe and feasible for stroke protection in patients with atrial fibrillation. Low ischemic events rates demonstrate its effectiveness during long-term follow-up (Wiebe et al. 2015).

ACP Registries

There have been a number of registries on ACP worldwide with a total of 1058 patients included, including a registry of 52 patients in Canada. The averaged technical success has been 97.2%. The annual stroke is 2.3%, which is reduced by 59% based on estimated CHA₂DS₂-VASc score. The annual major bleeding is 2.1%, which is reduced by 61% based on HAS-BLED score. The rates of embolization and thrombus formation were 1% and 4.4%, respectively.

A multi-nation, multi center AMPLATZER Amulet observational post-market study with proposed 1000 subjects is ongoing.  Enrollment may be completed in 3 months. 

The results from real-world LAA studies on 976 subjects treated with DAPT for various durations ranging from 1 month to 6 months were also presented.

Cost-Effectiveness of LAA Closure (LAAC)

A general overview of the cost effectiveness of LAA closure was presented.  Some of the assumptions made within the study were questioned by members of the committee.  Overall, Dr. Saw indicated that LAA closure is believed to be a good alternative to DOAC or VKA.

The current clinical guidelines on LAA closure/occlusion/excision

The ESC Guidelines (2012) recommend (Class IIb) that “the interventional, percutaneous LAA closure may be considered in patients with a high stroke risk and contraindicated for long-term oral anticoagulation” (Level of Evidence B).   

The AHA Guidelines (2014) states that “the usefulness of closure of the left atrial appendage with the WATCHMAN device in patients with ischemic stroke or TIA and AF is uncertain (Class IIb; Level of Evidence B). It is also stated that “This approach is likely to have the greatest clinical utility for AF patients at high risk of stroke who are poor candidates for oral anticoagulation.

The 2014 Focus Update of the Canadian Cardiovascular Society Guidelines for the Management of Atrial Fibrillation states that “We suggest these non-approved LAA closure devices not be used, except in research protocol or in systemically documented use protocols in patients at high risk of stroke (CHADS₂ score ≥2) for who antithrombotic therapy is precluded (Conditional Recommendation, Low-Quality Evidence).

The reason why LAA closure is not 1^st line therapy is because no RCT of DOAC vs. LAA closure has been completed and that the upfront costs with LAA closure is high. The LAA closure requires physician training/skills, has procedural risks, and has procedural requirements (anaesthesiologist and TEE, and overnight admission).

Dr. Saw proceeded to address questions posed by Health Canada:

1. Given the apparent need to treat patients in Canada that are contraindicated to Warfarin, what level of clinical evidence is required to license other LAA occlusion devices in this patient population?
   1. Given that the Watchman LAA occlusion device was effectively authorized based on the totality of evidence and Meta analyses of clinical trial data and not explicitly on RCT data, could authorization of future devices be based on single arm registry data with comparisons to historic controls.
   2. Given that there are no LAA occlusion devices licensed for use in a patient population contraindicated to Warfarin, what kind of clinical endpoints or appropriate historical controls could be used?

Dr. Saw was supportive that the evidence available for the Watchman and the ACP is sufficient for licensing purposes in Canada.  Dr. Saw indicated that single arm registry data with historic controls was appropriate to assess the safety and effectiveness of the LAA Closure devices at this time.  Dr. Saw felt that the totality of the evidence was important to consider.  Dr. Saw also indicated that given the need for LAA occlusion devices in Canada, and based on the important differences in the available devices, that there would be benefit to having both devices available to clinicians.

For future devices, similar endpoints compared to those used in the Watchman Studies could be used for a patient population contraindicated to Warfarin, although in this patient population, bleed risks are less important as neither group is on OACs.  Dr. Saw felt that the manufacturers should be able to demonstrate a 50% reduction in stroke rates compared to the rates predicted by the CHA₂DS₂-VASc scale. CV death and Systemic embolization would also be factors to consider. For the population that is contraindicated to OACs, a comparison against doing nothing, where baseline stroke risk is predicted by CHA₂DS₂-VASc score, may be a sufficient historical control. Dr. Saw did mention that a RCT against DAPT may be useful but did not state it was necessary.

SAC-MDUCS committee members were asked to indicate their general agreement to this approach.  Although there was a certain level of unease, the committee did not raise any objections to this approach.

2. If post-market studies were to be proposed for future LAA occlusion devices, does the post-market study outlined for the Watchman device provide a good design for other devices, even if the patient population is somewhat different, i.e. a patient population that is contraindicated to Warfarin?

A post-market study would need to demonstrate objective evidence of stroke and systemic embolism reduction. Dr. Saw thought that pre-defined endpoints for post-market studies could be somewhat modified compared to the pre-defined Objective Performance Criteria (OPC) used in the Watchman post-market study if the study focused strictly on patients who were contraindicated to OACs. She stated that the population studied in Canada would be those contraindicated to OACs as this is current practise (and what is funded). She believes the warfarin eligible population is different and perhaps OPCs to be used for devices other than Watchman, in patients contraindicated to OACs, should be derived from large studies of that specific device in the contraindicated to OAC population.  She noted that patients contraindicated to OACs typically have significant health complexities.

Committee members strongly supported creation of registries to gather post-market data, information on device performance. It was suggested that perhaps Health Canada could work with Provinces to establish post-market registries.

3. How are the newer OACs being introduced into the treatment of patients at high risk of stroke that might also be considered for LAA occlusion?

Although it is acknowledged that novel direct oral anticoagulants (DOACs) are becoming the standard of care, there is no good clinical data to compare the use of DOACs compared to LAA closure devices. Therefore, the novel OACs are used for first-line treatment and LAA closure devices are still reserved for second-line treatment options. Committee members added that the limited use code in Ontario prevents physicians from prescribing newer OACs unless warfarin or VKAs cannot be tolerated.

A question was asked, if a manufacturer of an LAA occlusion device came forward with registry, some argument on historical control and indication different from the WATCHMAN solely in a contraindicated population, would the committee be supportive of HC issuing a license for that device with requirements for post-market follow up with different pass/fail criteria.

It was concluded that the biggest role is in the safety signals.  First, need to identify devices which clearly don’t meet the minimal safety criteria and after that, post market surveillance is the key. 

Dr. Parker joined the meeting.

7. Evolution of DES Technology

Dr. Marino Labinaz, Committee Member

Dr. Labinaz introduced himself and disclosed his affiliations.

Dr. Labinaz outlined the objectives of his presentation and began with an overview of Drug Eluting Stent (DES) use in Canada.  He noted that although several years ago, clinical usage was not dominated by DES, now approximately 90% of coronary stents implanted in Canada are DES, and at some centres such as the Ottawa Heart Institute, 99% of coronary stents are DES.  He highlighted that there are very few cases that remain where it is justifiable to use a Bare Metal Stent in the coronary arteries.

Dr. Labinaz provided a brief history of Drug Eluting Stents (DES). He explained that the development of DES was in response to reducing restenosis that occurred with bare metal stents. In the early 2000s, studies showed that 18 months after implantation of a sirolimus eluting stent there was persistent inhibition of neointimal hyperplasia. It was concluded that the issue of restenosis had been solved with the use of DES. Data from subsequent studies supported this conclusion. However, there was growing evidence that late stent thrombosis was occurring with DES. SCAR registry data showed that compared to bare metal stents the death rate for DES was increasing, in contrast to a plateauing of death rate of BMS patients. Meta-analysis of data from 4 randomized clinical trials (RCT) revealed that the thrombosis event rate after 1 year was higher compared to bare metal stents. Clinicians quickly learned that there are issues of bleeding with prolonged Dual Antiplatelet Therapy (DAPT) (1 year).

The severity of bleeding adverse events was also highlighted.  Although this is sometimes viewed as a minor event, data supports that there is a 3 times increase in mortality one year after a bleeding event compared to the mortality for patients who do not have a bleeding event.  Dr. Labinaz stressed that bleeding and its downstream effects are under-appreciated, and can be as significant as an MI. It is based on these considerations that work has been on-going to determine appropriate duration of DAPT for DES.  Dr. Labinaz did note, however, that there is relatively little good data to determine optimum duration of DAPT.

He indicated that investigators began to question whether they could shorten the duration of DAPT. A study was designed to investigate shortened DAPT for patients implanted with DES. Follow-up for the study was designed to be for 4 years after procedure. Results from the study demonstrated that not all stents are created equally.

The Resolute analysis looked at the effects of DAPT being interrupted within the first month. A higher stent thrombosis event rate was observed if DAPT was interrupted within the month versus a zero rate if DAPT was interrupted after 3-12 months.

Xience data showed that interruption within first 3 months had a higher event rate than interruption after 3 months. In the Optimize study, 3 months versus 12 months DAPT was investigated. The study showed no difference in Major Adverse Cardiac and Cerebral Events (MACCE) (all-cause death, MI, stroke, major bleeding) at one year. Prolonged DAPT therapy may make sense. DAPT therapy not just related to device but also related to patient.

A DAPT study was conducted to assess the benefits of 12 versus 30 months of DAPT for preventing stent thrombosis and MACE (2 primary endpoints). Almost ⅔ of stents used in this study were 2^nd generation DES. MI event rate continues to rise. DAPT beyond 1 year reduced risks of stent thrombosis and MACCE but was associated with an increased risk of bleeding/hemorrhagic stroke. Moderate or severe bleeding rates in the DAPT and placebo groups were significantly different at 2.5% vs. 1.6% respectively. In addition, the mortality rates in the DAPT vs. placebo groups were 2.0% and 1.5% respectively. Although all-cause mortality was increased in the DAPT group, a large proportion of deaths were considered bleeding related.

A FDA meta-analysis concluded there was no difference in all cause death between clopidogrel and aspirin used for 12 months or longer, versus use of both medications or aspirin alone for 6 months or less. There was no increase in cancer related events.

The Pegasus study which was not a stent related study also showed that with prolonged DAPT bleeding was significantly increased.

Based on these results the goal was to try and come up with a score to determine who would benefit the most from DAPT. A DAPT score was created. Scores < 2 saw more bleeding showing no benefit from DAPT. Scores > 2 saw significant benefit from ischemic stroke.

Guidelines for recommendation for duration of DAPT after ACS were developed in 2012. These guidelines are already out of date. An update to the original exists. Three new recommendations have been added. It also recommends individualizing duration of DAPT.

A new study has presented a challenge to the whole concept of DAPT. The study looked at monotherapy for DES patients. Prolonged monotherapy with no major bleeding was observed.

Dr. Labinaz described third generation DES:

• Biodegradable Scaffolds
• Biodegradable Polymers on Metal Stents
• Polymer Free Drug Eluting Stents

He noted that the polymer coating is an issue with DES. There are a number of shortcomings often associated with polymers during stent delivery. Durable coatings have potential for:

• continued source of inflammation
• impaired healing
• thrombosis risk

The third generation DES attempt to address issues with polymer coating.

The Absorb study showed that after 12 months vessels had become pulsatile. The ABSORB III RCT was a prospective randomized, single-blind, multi-center trial was conducted to evaluate safety and effectiveness of Absorb™ Bioresorbable Vascular Scaffold (BVS).  Individual events were low. One signal observed in the study was for patients with BVS there was a significant increase in stent thrombosis in vessel < 2.5 mm. ABSORB meta-analysis showed no difference observed compared to second generation DES.

LEADERS study was discussed. It was noted that the study’s preliminary results are out but the study is not powered well.

Dr. Labinaz listed the objectives for the Next Generation BVS Stents:

• More uniform strut distribution
• More even support of arterial wall
• Lower MCUSA (maximum circular unsupported surface area)
• Lower late stent area loss
• Higher radial strength
• Improved stent retention
• Unchanged:
  • Material
  • Strut thickness

He proceeded to address the specific questions posed by Health Canada regarding duration of DAPT following stent implantation:

a) Considerations around DAPT and shortening DAPT - modification required for the CCS Guidance statement that recommends a minimum of 1-year DAPT?

“The user is advised to take under consideration the recommendations made in the joint statement by the Canadian Cardiovascular Society and the Canadian Association of Interventional Cardiology (Can J Cardiol Vol 29, 2013) whereby all patients receiving a DES should be maintained on dual antiplatelet therapy for at least 12-months. The recommendations also emphasize the need to carefully consider the benefits and risks on an individual patient basis when choosing between Drug Eluting Stents and Bare Metal Stents; the duration of dual antiplatelet therapy and the need to counsel patients regarding the risks of prematurely discontinuing dual antiplatelet therapy. This label and all recommendations referenced are intended for information purposes only and should not be relied upon to make decisions concerning a patient's health care without further medical review.”

Dr. Labinaz listed the issues with prolonged DAPT:

• Increase risk of bleeding
• Need for oral anticoagulants
• Need for procedures and surgeries
• Interaction with other medications
• Cost

Dr. Labinaz noted that as new evidence is coming out it may alter these recommendations that were drafted in 2012.  References to contemporary guidelines for DAPT may be appropriate. Dr. Labinaz suggested that new guidelines may be based on various risk factors for bleeding and ischemic complications.  In general, 1-year of DAPT will likely be recommended.  If the patient has a high bleeding risk, 1-month duration of DAPT may be advocated as sufficient.  If the patient is at a low risk for bleeding, however, at a higher risk for embolic and ischemic events extending DAPT beyond 1-year is likely appropriate.

b) How should Health Canada address new licence applications for 3rd generation DES with biodegradable coatings and excipients as well as bioabsorbable vascular scaffolds. Should a Guidance statement be included in the labelling for DAPT?

It was recommended that the above noted guidance statement not be included in the labelling based on new data and changes that are likely to be made to the clinical practice guidelines. Dr. Labinaz presented preclinical data on the Absorb that showed pulsatility recovery and restored vasomotion at 2 years (Gogas et al. 2015). He also indicated that the Absorb III trial (Ellis et al. 2015) demonstrated non-inferiority to the Xience in an ITT analysis of target lesion failure (TLF) at 1 year. Moreover, he reported on the ABSORB meta-analysis that included 3389 patient outcomes from 4 RCTs; while no significant difference in death, MI or revascularization was reported between the Absorb and Xience, definite and probably thrombosis rates approached significance at 1.3% and 0.6% respectively. Dr. Labinaz suggested that because ST rates were similar, the potential benefit with the Absorb stent is “theoretical” normal vessel function.

c) If non-inferiority is demonstrated between a third generation DES with a second generation DES, are there clinically relevant differences (either positive or negative) that should be noted in the labelling?

It was noted that there may be differences between the devices, as highlighted with the ABSORB where there may be an increased risk of stent thrombosis, especially in smaller vessels.  It will be important to assess the data at a detailed level to determine what differences may exist.

d) Are there reasons why clinicians may not want to use some of the third generation devices in their practice, in spite of clinical data demonstrating non-inferiority?

Dr. Labinaz indicated that there may be many reasons not to use third generation stents, including:

• Inadequate Non-Inferiority Trial (e.g. too small, irrelevant endpoint, highly selected patients)
• Cost
• Deliverability
• Ease of Use
• Changes in post-procedural medical therapy
• Shelf-life, sterility, storage requirements
• Technical limitations (e.g. bifurcations, sizing)
• Availability and size catalogue

e) What should be the clinical requirements for the approval of new third generation DES; RCT vs. OPC. Do we need 2000 patients; do we need 1 and 2 year follow-up; do we need to randomize to a good currently licensed DES?

Clinical requirements for approval of 3rd Generation DES should include:

• Adequately powered randomized clinical trial with clinically meaningful endpoints against a currently approved 2nd generation drug eluting stent
• Minimum of 1 year follow-up
• Number of patients dictated by sample size calculation for an adequately powered trial (unlikely 2000 pts)
• Historical control group is inadequate since field is rapidly changing and cannot ensure that historical group is comparable

8. Baroreceptor Activation Therapy

Dr. John Parker, Guest Speaker

Dr. Parker introduced himself and disclosed his affiliations. 

Dr. Parker proceeded to discuss Baroreceptor Activation Therapy (BAT) application for the treatment of hypertension and heart failure and address specific questions posed by Health Canada.

Recently, BAT has been applied for the treatment of hypertension and heart failure. There have been several clinical trials conducted on these devices.

1. What is the mechanism of action for BAT in the treatment of heart failure?

Dr. Parker began with an overview of the sympathetic activity in Chronic Heart Failure (CHF):

• Sympathetic activation is prominent in the setting of CHF
• most available information concerns chronic CHF with reduced ejection fraction
  • Little or no information about CHF with preserved ejection fraction
• Sympathetic activation plays a critical role in CHF disease progression and prognosis

He explained that Sympathetic (neurohormonal) system activation occurs as a compensatory mechanism in patients with heart failure as a means of maintaining cardiac output, blood pressure and adequate tissue perfusion; in particular, sympathetic activation is observed in patients with heart failure with reduced ejection fraction (HFrEF). In the context of Congestive Heart Failure (CHF), increased sympathetic activation drives disease progression and worsens patient prognosis. He noted that much less is known about the role of sympathetic activation in HF with preserved EF (HFpEF; those with EF > 35%) as most available information is derived from patients with HFrEF.

Sympatholytics including beta-blockers were first introduced in the 1990s and are still considered a potent HF treatment because they block sympathetic activation. Dr. Parker described data that supported the role of sympathetic activation in heart failure. Cohn et al. (1984) showed a substantial decrease in survival probability in patients with plasma norephinephrine (PNE) levels > 400 pg/mL, as well as a significantly greater cardiac norephinephrine (NE) spillover (pmol/min) in CHF patients. Al-Hesayen, A and Parker, JD (2004) showed that both CHF and “normal LV” patients exhibited reduced LV filling pressures and increased cardiac output , infusion with the vasodilator sodium nitroprusside, did not improve either renal plasma flow (RPF) or glomerular filtration rate (GFR). Kaye et al. (1995) reported cardiac NE spillover rate was the strongest prognostic marker for survival probability, with a threshold of > 310 pmol/min.

A near tripling of sympathetic activation was reported in renal failure as well.

Dr. Parker outlined mechanisms of cardiac sympathetic activation in HF:

• Afferent
• Central
• Prejunctional.

Afferent:

Dr. Parker stated that baroreceptors on the carotid artery (“arterial baroreceptors”) monitor blood pressure continuously, with decreased pressures causing increased sympathetic outflow to the heart, kidney and periphery. Cardiopulmonary baroreceptors function in the same way. Newton and Parker (1996) reported blunted baroreflex control of cardiac sympathetic activity in heart failure patients as evidenced by a non-significant increase in cardiac norepinephrine spillover (CANESP) in heart failure patients (with elevated baseline CANESP) as compared to a significant increase in CANESP in normal patients.  Although a reduction in effect was observed over time, this reduction in effect over time has not been observed to the same extent in the Baroreceptor Activation Therapy Studies to date.

Central:

By way of example of the role that centrally mediated sympathetic activation, Dr Parker introduced the example of clonidine, a drug which reduces sympathetic overactivity centrally, and reduces peripheral vascular resistance. Azevedo et al. (1999) studied the effect of clonidine (centrally acting alpha2-agonist; decreases peripheral vascular resistance) on sympathetic activity in heart failure. They reported a substantial fall in arterial pressure as well as reduced sympathetic activity in the heart (reduced CANESP). However, because of substantial side effects, centrally acting sympatholytics are not used clinically.

Prejunctional:

Dr. Parker described prejunctional sympathetic intervention as it relates to afferent sympathetic output, and used the example of renal sympathetic denervation for the treatment of resistant hypertension. Krum et al. (2009) reported that renal denervation caused significant and sustained blood pressure reductions in hypertensive patients over 12 months, while later more definitive controlled trial results of Bhatt et al. (2014) showed no treatment effect. 

The effect of baroreceptor activation has been known for many years. In particular, stimulation of the carotid baroreceptors is known to reduce heart rate, increase vasodilation and increase natriuresis (sodium excretion) by the kidneys. As a further example Dr. Parker presented a NEJM paper from 1967 which had demonstrated reduced angina when carotid sinus nerves were stimulated.  However, translating this known effect to a safe and effective device is challenging. 

He described the CVRx Barostim neo device, and made the following comments:

• the surgical procedure is “not for the faint of heart” and not without surgical risks
• as the voltage (“dose”) goes up, there is a clear and immediate reduction in heart rate and blood pressure
• 4-year data were presented from a non-randomised feasibility study (Kroon et al, 2010), and showed a sustained reduction of SBP, but only involved 18 patients.  Data will follow-up to 5 and 6 years will be available shortly.
• Although not part of the question, he addressed findings from the Rheos hypertension pivotal trial, which was designed as a double blind crossover trial, and which missed its primary endpoints: difference in 6 month reduction in SBP was < 20% goal, sustained effectiveness was not significantly different between groups at 12 months, and short term (30 day) procedure adverse events were higher than expected and missed OPC of 82% (4.4% permanent nerve injury; 4.8% transient nerve injury; 4.4% general surgical complications; and 2.6% respiratory complications.)
• For heart failure specifically, Dr. Parker presented a positive proof of concept study in dogs. Sabbah et al. (2011) reported small but significant reductions in LVEDP, increase in cardiac output, increase in LVEF%, and decreased PNE in 14 dogs compared to 6 control dogs.

2. What clinical evidence for the safety and effectiveness would be considered to be sufficient for premarket licence approval of the intended use in patients with heart failure?

Dr. Parker described the BAT for HFrEF study (also known as the XR-1 Randomized HF Study) - a randomised BAT versus medical therapy trial with 146 patients randomized 1:1.  He stated that although the study was primarily exploratory, there is a primary effectiveness objective specified, namely to determine whether the Barostim neo produces an increase in LVEF at 6 months post implant.  The study had no blinding and there was no sham or crossover included in the study.  The patient population is fairly sick, with Class III HF, but have relatively low BPs, i.e. they are “well treated”.  Dr. Parker described the inclusion/exclusion criteria as “straightforward”.  The implants were well tolerated, and it appears the clinicians were well trained in technique.  Dr. Parker found the reported complication rates acceptable, and indicated BAT therapy did not produce hypotension in patients. BAT was found to reduce NYHA HF class. QoL increased, and N-terminal pro Brain natriuretic peptide (NT-proBNP) went down.    

Key point: Dr. Parker noted that NT-proBNP is the only truly objective endpoint in this trial. He also acknowledged that most regulatory agencies focus on “hard endpoints” including mortality and HF related hospitalization and mortality.   This is notwithstanding the fact that the reduction was very small, and the treatment group had a higher baseline; however, he still felt that it indicated that there is some benefit to the treatment.

Dr. Parker noted that the effect of BAT on LV Ejection was not statistically significant. He acknowledged that the 6-minute walk test is not overly meaningful.

Dr. Parker cautioned that in the MOXCON drug trial, that acted on a similar mechanism; there was an observed increase in cardiac mortality in a large trial. A total of 71 patients were implanted with the BAT neo.  The neo received CE mark based on this trial.

3. What are the most appropriate clinical endpoints when studying the effectiveness of treating heart failure?

Dr. Parker recommended that a combined endpoint of heart failure hospitalisation and mortality “has to be the goalpost”, and that this is typically what is used for heart failure drugs.  Other endpoints like exercise tolerance are not appropriate.  A larger trial with the recommended endpoints is required.  A sham trial is not required if hard endpoints are used (e.g. death, or possibly, blood markers), although a crossover trial design might be beneficial.

4. What is the appropriate target population for this type of device?

Dr. Parker suggested that appropriate target populations include patients with both reduced and preserved ejection fraction, because the latter group are often hypertensive and may stand to benefit from this therapy.

Members commented on the small BAT-induced NT-proBNP reductions. Question was asked whether Dr. Parker believed the reduction of this biomarker was a reasonable surrogate endpoint. He thought it was, and added that he believed the 6MHW distance was not a good test.

Dr. Parker was asked about the effects of afferent neural traffic from the contralateral side; he was unsure but referred to carotid massage given only on the right side. There was a question about the potential for BAT-induced bradycardia and Dr. Parker indicated he was unaware of any such reports.

Dr. Parker reiterated that a sham study design is not required if hard endpoints (death, or possibly blood markers) are used. He was also asked about long-term remodelling and functional improvement as a result of BAT and reiterated that a small +5% increase in ejection fraction was reported without any other significant changes.

Dr. Parker was also asked if there were any metabolic studies done in relation to BAT; he was not aware of any. Dr. Parker noted that in endarterectomy, nerve damage may be observed at a rate of approximately10%.  The rate seen in this study was only 5%, although the amount of dissection would be less for implanting the BAT neo compared to endarterectomy.

Finally, Dr. Parker suggested that, based on the experience with beta blockers, we might expect to see a 5% (absolute) change in ejection fraction.  However, this has yet to be shown.

9. IVC Filters

Dr. William Geerts, Committee Member

Dr. Geerts introduced himself and disclosed his affiliations. 

Dr. Geerts was asked to discuss use of Inferior vena cava (IVC) filters and address specific questions posed by Health Canada.

Inferior vena cava (IVC) filters are medical devices designed to be inserted into the IVC to trap emboli and prevent pulmonary embolism (PE). There have been serious concerns about the safety and effectiveness of these devices and new RCT data has shown little to no benefit using the technology in certain patient populations. Health Canada has been working on these issues for years and has prepared the following recommendations:

1. Follow the appropriate clinical guidelines on the use of IVC filters. Currently, Health Canada considers that the indications for use of IVC filters recommended in the 9th ACCP guidelines and AHA/ACC are appropriate.
   1. In patients with acute proximal DVT of the leg and contraindication to anticoagulation, we recommend the use of an IVC filter
   2. In patients with acute PE and contraindication to anticoagulation, we recommend the use of an IVC filter

Note that the FDA provides the following indications:

For the prevention of recurrent pulmonary embolism via placement in the vena cava in the following situations:

1. Pulmonary thromboembolism when anticoagulants are contraindicated
2. Failure of anticoagulant therapy in thromboembolic diseases
3. Emergency treatment following massive pulmonary embolism where anticipated benefits of conventional therapy are reduced
4. Chronic, recurrent pulmonary embolism where anticoagulant therapy has failed or is contraindicated

2. Make and implement appropriate follow-up plan in cooperation with patients to ensure compliance of patients to the follow-up plan.
3. Take necessary measures to improve the retrieval rates of implanted retrievable IVC filters when not needed.
4. It is strongly recommended that the patients who receive the procedure should be automatically scheduled for retrieval consultation at time of placement of an IVC filter. This information should be presented on the labeling for the IVC filters.
   Health Canada would like to seek feedback from the SAC members regarding these recommendations.

Dr. Geerts began with the recent news of the two class action lawsuits in Canada regarding IVC filters. He believed that these were the first two in Canada, although many lawsuits have been filed in the US.

He indicated that he does not believe there is widespread IVCF overuse in Canada, but indicated that he is aware of Canadian cases in which the use of an IVC filter was not necessary or appropriate. He expressed the view that the most worrisome aspects of IVC use are filter fracture and embolization and failure to remove filters when they are no longer necessary.

Dr. Geerts provided an outline of his presentation:

• Types of filters
• Epidemiology of IVCF use
• Indications
• Evidence from clinical trials
• Complications
• Guidelines & national policies
• Summary and suggestions

He proceeded to discuss types of IVC Filters:

• Permanent
• Temporary.

Temporary filter may be tethered or retrievable. He indicated that retrievable designs are the most common, with the (Cook Medical) Celect and Gunther Tulip models being the most common in Canada.  He commented that there may be a small clinical role for the “tethered” type designs, but none are licenced in Canada at this time.

Regarding indications, there are 2 categories:

• “Therapeutic” for patients with venous thromboembolism (VTE) in which anticoagulation is contraindicated, or in addition to anticoagulation) and
• “Prophylactic” for patients without VTE, and presumed to be at high risk for pulmonary embolism from trauma, bariatric surgery, or orthopedic surgery.

Based on US data (Stein, 2004; Smouse, 2010; Stein, 2011) IVC filter placement has increased exponentially over the past 40 years, with the largest per cent increases attributed to the “prophylactic” indication group. Therapeutic IVC filter use was reported to increase 42% between 1998 and 2005, while prophylactic use increased 157% during this same period.

Dr. Geerts also discussed the large variation in IVC filter use for VTE by hospitals (White, 2013; US data) and by different countries where  the rate of IVC filter placement in US patients was 25x greater than in German, French, British, Italian and Spanish patients combined (Lee, 2015).  He suggested this kind of variation cannot be explained based on clinical factors, and presented possible reasons for the US increase: expanded indications, ease of placement, more experienced inserters, removable filters, “defensive” medicine, and possible financial incentives. He emphatically stated that the exponential increase in use is not the result of additional evidence for safety or benefit. While he was not aware of any Canadian use data, he did provide information on use of IVCFs at Sunnybrook (his institution); where they inserted an average of only 21 IVCFs per year between 2006 and 2015 for all indications (none were for a prophylactic indication). Furthermore, in trauma patients, Sunnybrook placed an average of 4 IVCFs per year between 2000-2015 (none prophylactic) and 76% were removed during the trauma admission.

Additional data from the Ottawa Hospital (Duffet, 2014) was included.

Dr. Geerts summarised his interpretation of the only 2 RCTs available which purport to support the use of IVC filters.

Decousus (1998) described the PREPIC study which included 400 patients with DVT and treated for increased PE risk, and randomized to either anticoagulation (AC), or AC+IVC filter. Pulmonary embolism (PE) at Day 12 was significantly lower in the IVC filter group. Dr. Geerts asserted that this study “has been grossly misinterpreted” because they included asymptomatic PEs and mostly unadjudicated deaths (although attributed to PE) in the endpoint, thus overstating the effect of the use of filters. Similarly, the PREPIC-2 trial (Mismetti, 2015) enrolled 399 patients in 18 French centers that were randomized into AC, or AC and retrievable IVC filter groups. No significant differences in PE at 3 months, or fatal PEs were reported. Dr. Geerts indicated there was a numerical increase in PE rate in patients implanted with IVCFs (6 vs 3), and Fatal Pes (6 vs 2). He also highlighted that access site hematoma, filter thrombosis, unsuccessful retrieval and non-retrieval of filter rates were 2.6%, 1.6%, 6.7% and 21% respectively. Finally, he noted that systematic reviews have found no Level 1 evidence to support the use of filters for prophylactic indication (i.e. without a VTE).

Dr. Geerts presented information on the FDA requirement for additional IVCF clinical data from manufacturers, who were given a choice to either participate in the PRESERVE study, or to conduct their own post-marketing surveillance (“522” studies). Starting in Nov 2015, the first patient entered into the PRESERVE study, which is a multi-device trial intended to examine current practice and to evaluate safety and effectiveness of these devices.  A total of 300 patients per device type were required, with up to 24 months of follow up. Manufacturers were also given the option to combine data from multiple devices to enhance data collection.

Dr. Geerts then provided a detailed analysis of IVC-related complications. Key points made were that PE (and occasional fatal PE) still occurs with a filter in place (i.e. filters trap larger clots, but not all clots), and that long-term fracture and embolization are big problems with these designs.

He estimated that IVC filter use is associated with a minimum major complication rate of 3-5% and commented that this was greater than the complication rate from treated PE or from major PE in high risk trauma patients. He showed the results of a study that showed the risk of IVCF fracture in patients, followed over time with imaging, was 40% at 5.5 years. He shared that fractured filter arms could migrate and perforate the right ventricle, leading to tamponade, and can penetrate other organs especially the aorta, duodenum and retroperitoneal space.

Other adverse consequences he attributed to IVCF placement included: unnecessary delays in initiating AC prophylaxis or therapy in patients who have a filter and potential risk of complications during pregnancy and exercise.

He noted that it is very likely that complication rates attributed to PE/TE are less than the complication rates due to filter use, even though the filters are intended to reduce PE.

Dr. Geerts presented information from the American College of Chest Physicians, which recommend against thromboprophylaxis of IVC filters in trauma patients or those with spinal cord injuries (Gould, 2012), and against the use of IVC filters in patients with acute DVT or PE who are being treated with anticoagulants (Kearon, 2016). He also highlighted the FDA’s concern over the retrieval of IVC filters after the risk of PE/TE has passed. Their 2014 recommendation is, “The FDA recommends that implanting physicians and clinicians responsible for the ongoing care of patients with retrievable IVC filters consider removing them as soon as protection from pulmonary embolism is no longer needed”.

The recommendations from Thrombosis Canada were presented. Dr. Geerts closed with a recommendation for a single indication for IVC filter use (recent proximal DVT plus an absolute contraindication to full anticoagulation), and also provided a summary of the guidelines in place at Sunnybrook.

With respect to the Health Canada proposal, he provided the following comments:

• He thinks that while the AHA/ACC guidelines provide some good advice, they are now 5 years old and expand the indications inappropriately, therefore he suggests deleting reference to them (identified in Section  a of preamble above).
• He agreed with Indication 1 (identified in Section  a - i of preamble above)
• Indication 2, possible, but it is not what he or his institution does (identified in Section a - ii of preamble above). He suggested the following wording: In patients with acute PE and contraindication to anticoagulation, use of an IVC filter can be considered.
• He does not think that patients should take the primary responsibility for appropriate follow-up - the institution that places the filter should assume this responsibility 
• He emphatically agrees that necessary measures should be taken to improve retrieval rates of implanted filters
• He feels that the retrieval should be scheduled at the time of placement.
• Regarding the FDA indications (identified in Section  a of preamble above) he noted that Health Canada may want to comment that there is no direct evidence to support any of these indications and that Health Canada does not endorse this list of indications.

Dr. Geerts provided some final thoughts:

• It would be important to have Canadian data on IVCF use, indications, types of filters, retrieval rates, complications, and costs in the Canadian environment.
• Retrieval is much easier at 6 days than at 6 months.  His institution performs retrievals before patient is discharged.
• Hospitals should have written policies on IVC filter use
• New filter approvals must present lots of safety data, and must be subject to post approval data provision requirements.

Discussion took place about how best to share this information, in particular with interventional radiologists who are implanting these devices. It was noted that Health Canada has difficulty with information communication as the majority of manufacturers have been unwilling to make label changes. Different means of communication were discussed (i.e. patient implant cards) or a possibility to reaching out to radiologists and suggesting their involvement in a solution. Dr. Geerts thinks while it’s too little too late to introduce patient implant cards, he feels that engaging radiologists would be the main next step. We could certainly identify leaders in radiology who would be willing to participate.

Dr. Ducas noted the differences in IVCF implantation rate between Sunnybrook and Ottawa Hospitals, and suggested if they could get together to examine use differences and compare post-market issues.  He also suggested if Health Canada would network with provincial representatives to work on a registry.

Dr. Geerts suggested that a position statement from HC may not only highlight the importance of device removal, but also drive the communication process. Dr. Geerts mentioned that he is involved with the CIHR-funded CANVECTOR group, which is involved in research, knowledge translation, patient involvement and education; he suggested this as a potential platform for collaboration.

Dr. Geerts was generally not supportive of IVCF use, with the exception of a single indication: recent proximal DVT plus an absolute contraindication to full anticoagulation. He was in agreement with indication a i), and would not refute a ii), but this was not practiced at his hospital.

Furthermore, he felt that patients should not have to take the primary responsibility for appropriate follow-up, retrieval rates are in need of improvement and retrieval should be scheduled at time of placement. He also urged that hospitals have written policies in place.

With respect to regulation, sufficient safety data should accompany IVC filter applications and post approval data should be required.

A HC position paper and/or statement were suggested as a potential vehicle for communicating the importance of patient follow up and device removal.

10. Next Steps, Closing Remarks and Adjournment of Meeting

Dr. John Ducas, Committee Chair

The Chair thanked committee members and Health Canada staff for their participation and valuable input. 

Members will be canvassed to select a date for the next meeting, likely in the late fall of 2016.

Meeting adjourned.

Committee Members Present: John Ducas (Chair), Eric Cohen, Marino Labinaz, Alan Menkis, Barry Rubin, Raymond Yee, John Webb(via teleconference/WebEx)

Invited Guests: Sébastien Bergeron, Vivek Rao, Sanjit Jolly

Health Canada Representatives:

• Office of Science: Hripsime Shahbazian
• Office of Planning, Performance, and Review Services: Caroline Hunt
• Medical Devices Bureau: Carey Agnew, Kevin Day, Ian Aldous, Patrick Fandja, Ian Glasgow, Ian Grimwood, Jianming Hao, Karen Kennedy, Mark Korchinski, Christine Lefebvre, James McGarrity, Catherine Milley, Michael Rosu-Myles, Philip Neufeld, Jason Pearman, Maurice Sylvain, KokSwang Tan, Lanyi Xu, Brian Wong

Regrets: Joaquim Miró, Renzo Cecere, Christopher Feindel, Brent Mitchell

Abbreviations used in this record:

AAA:

abdominal aortic aneurysm

AMI:

acute myocardial infarction

ATP:

anti-tachycardia pacing

AVR:

aortic valve replacement

BMC:

bone marrow cell

CABG:

coronary artery bypass grafting

CACs:

circulating angiogenic cells

CADTH:

Canadian Agency for Drugs and Technologies in Health

CPC:

cardiac progenitor cell

CSF:

cerebrospinal fluid

CT:

computed tomography

DEB:

drug eluting balloons

ECC:

extracorporeal circulation

EEC:

endovascular elephant trunk completion

EPC:

endothelial progenitor cell

EVAR:

evolution of endovascular aneurysm repair

HF:

human factors

ICD:

implantable cardioverter-defribrillator

IFU:

instructions for use

LVEF:

left ventricular ejection fraction

MDB:

medical devices bureau

MI:

myocardial infarction

MEP:

motor-evoked potentials

MRI:

magnetic resonance imaging

MSC:

mesenchymal stem cell

OEC:

open elephant trunk completion

OPC:

objective performance criteria

RCT:

randomized clinical trial

SAC-MDUCS:

scientific advisory committee on medical devices used in the cardiovascular system

SAP:

special access program

SCI:

spinal cord fluid

SEP:

somatosensory evoked potentials

SVT:

supraventricular tachycardia

TAA:

thoracic aortic aneurysm

TAVI:

transcatheter aortic valve implantation

VF:

ventricular fibrillation

VT:

ventricular tachycardia

VTA:

ventricular tacky arrhythmia

1. Opening Remarks & Welcome

Dr. John Ducas, Committee Chair

Cindy Evans, A/DG, TPD

Dr. Ducas opened the meeting, welcomed the committee members and guest speakers. Cindy Evans, the Senior Executive Director of the Therapeutic Products Directorate (TPD), thanked the committee members and guest speakers for sharing their time and expertise and acknowledged the efforts all participants had made to attend the meeting. Ms. Evans highlighted the importance of the Scientific Advisory Committee on Medical Devices Used in the Cardiovascular System (SAC-MDUCS) to Health Canada’s regulatory review and decision-making process.  She commended the committee on its continued support and noted that their past recommendations have been helpful in numerous license evaluations.  Ms. Evans concluded by reviewing the topics of the day’s agenda and wished the committee members and guests fruitful deliberations.

2. Review of the Agenda, Affiliations and Interests Declarations, and Confidentiality Agreement

Dr. John Ducas, Committee Chair

The Chair reviewed the agenda items with the committee. The agenda was accepted with minor adjustments to accommodate all speakers. Members were asked to disclose any conflicts that may arise as the meeting proceeds.

Presentations are available upon request.

The responses outlined below are representative of the discussions/recommendations generated by the committee. 

3. Summary of how Health Canada has used information generated from previous SAC-MDUCS meetings

Kevin Day, Medical Devices Bureau (MDB)

Mr. Kevin Day presented a brief summary of how previous advice and recommendations provided by the committee have been considered by Health Canada.

The following topics were noted:

• Absorb Bioresorbable Vascular Scaffold: committee feedback has been helpful in determining additional considerations for evaluating this new technology.
• LAA closure Devices: The MDB has faced challenges regarding the clinical data currently available for these devices and previous discussions and recommendations have been useful in providing some perspective.   
• Sutureless (minimally sutured) Heart Valves: these valves represent another expanding area within the field of medical devices.  The committee’s input and recommendations provided a better understanding of this technology before issuing a license for the Perceval Heart Valve (licensed in Canada on June 15, 2015).
• Drug Coated Balloons: we continue to reference recommendations of this committee in terms of minimal requirements regarding trial sizes and follow-up.  There has been a lot of activity on the drug coated balloons front, both on coronary and peripheral indications where the committee’s input has been helpful.  

He also provided updates on additional SAC-MDUCS engagements where Health Canada solicited expert opinion on two specific issues whereby select SAC-MDUCS members provided recommendations through an email consultation process.

• TAVR/TAVI sub-clinical valve immobility (February 2015):  members were consulted on an issue regarding observations brought forth to Health Canada.  Specifically, observations of ‘sub-clinical’ leaflet motion anomalies, possibly due to thrombus formation on TAVI systems, typically occurring at the base of the valve leaflet on the aortic side adjacent to the valve frame. 
• Pericardial closure patches (April 2015):  members were consulted on an issue regarding pericardial closure devices, specifically, concern associated with the effectiveness of a proposed device made from porcine derived collagen.  Health Canada requested the committee’s clinical recommendations for actions that could be taken to provide appropriate regulatory oversight on the issue and to ensure Canadians continue to have timely access to safe and effective medical devices.

It was noted that the Medical Devices Bureau (MDB) uses the recommendations and advice provided by the SAC-MDUCS when discussing clinical trials or licensing requirements with Industry.  The Committee’s input also ensures that good clinical oversight is continually being applied towards decision making processes.  Mr. Day summarized that since 2012, approximately 25 evaluations have specifically referenced the Committee’s discussions and that the MDB continues to rely on the expertise of the Committee as new technologies and challenges arise.

A question regarding how the SAC-MDUCS agendas are developed was posed by one of the Committee members.  It was explained that several factors drive the topics of the MDUCS’ agendas including, but not limited to:

• Constant surveillance of publications to check on any new developments, signals;
• Pre-submission meetings;
• Monitoring the activity of the Special Access Program;
• A change in work, philosophies, or features surrounding previously-discussed technologies.

Mr. Day thanked members for their ongoing dedication to the committee. 

Before proceeding with the agenda Dr. Ducas acknowledged the passing of Dr. Bilodeau, one of the long serving core members of this committee.

** Dr. John Webb joined the meeting by webex/teleconference.

4. TAVR Valve in Valve Procedures

Dr. John Webb, Committee Member,

Participated by Teleconference

While the three TAVR devices currently licensed in Canada are not indicated for ‘valve-in-valve’ use, this situation is often encountered clinically.  Please discuss the frequency of this clinical situation, the options available to this patient population and the risks and benefits of using a TAVR device within an existing prosthetic valve.

Dr. Webb joined the meeting via webex to address this topic.  After declaring his affiliations, he proceeded with his presentation and addressed the questions posed by Health Canada.

Dr. Webb’s presentation included the following topics in relation to TAVR valve-in-valve procedures:

• Valve durability (transcatheter valves vs. surgical valves);
• Apical access;
• Low profile systems for patients with small femoral arteries;
• Accurate positioning;
• Hemodynamic function;
• Coronary obstruction;
• Mitral and Tricuspid valve-in-valve options;
• Vancouver British Columbia’s valve-in-valve experience.

1. What clinical evidence should Health Canada require to expand the indications of currently licensed TAVR devices to include ‘valve-in-valve’ use?

Dr. Webb explained that valve-in-valve use is an evolving field and clinicians are still learning.  There is an enormous amount of information available such as the global valve-in-valve registry that includes over 1500 valve-in-valve implants (aortic, mitral, and tricuspid). The registry demonstrates a trend of improving outcomes and can also be useful in highlighting certain valves that may introduce greater concerns such as coronary obstruction. 

The valves of particular concern are freestyle, unstented valves that introduce higher levels of risk. Despite the increased risk, however, these valves are only refused based on patient screening (e.g., patients at a higher risk of coronary obstruction would be refused). Similarly, in terms of high gradients, some valves have smaller internal diameters than others and appropriate patient screening would therefore play an important role.

Dr. Webb indicated that it should not necessarily be the role of Health Canada to exclude certain surgical valves but instead be the responsibility of the surgeons and cardiologists to make appropriate decisions on which patients should be deemed good candidates. Furthermore, based on current valve-in-valve outcomes, he thought it reasonable to expect that if a valve is licensable for a TAVR device, follow-through to a valve-in-valve indication would be acceptable. Dr. Webb noted that it is unlikely that there will be a randomized controlled trial in Canada, especially given that this indication has already been approved in Europe and is on its way to being approved in the United States.

2. How does the type of TAVR (i.e., self-expanding, balloon-expandable, repositionable) impact use in ‘valve-in-valve’ procedures?

Technical advances have led to the development of newer, smaller devices that work well in patients with smaller arteries.  As a result, TAVI procedural approaches have been moving away from the transapical access routes towards less invasive transfemoral approaches (90% of TAVI patients are now treated with the transfemoral approach).

Low profile systems

Dr. Webb noted that early generations of the Edwards SAPIEN expandable valves had large sheath diameters (24F, 22F, and 16F) that made less invasive approaches difficult.  Therefore, the third generation valve, the SAPIEN 3, was designed to contain an artery sheath diameter of 14F (comparable to the diameter of a pencil) and an external fabric cuff to improve sealing.  This 40% reduction in cross-sectional area in addition to the anti-leakage fabric cuff dramatically improved outcomes as evidenced by the results of the most recent series of clinical trials run in Europe and the US.  Trial results demonstrated a mortality risk of around 2% in high-risk patients and 1% in intermediate-risk patients.  The SAPIEN 3 has received market approval in both Europe and the US. 

Other lower profile systems include the EnVeo R delivery catheter and the CENTERA delivery catheter.

He explained that if a low profile system is unavailable, alternative access points are transapical, aortic, subclavian, transcarotid, transvenous, and translumbar.

Transapical procedures

Dr. Webb noted that if a transapical procedure is to be performed, one of the following four devices should be used:

• SAPIEN
• Portico
• Jenavalve (used in valve-in-valve patients)
• Engager
  • Equipped with arms that can clip to the aortic valve.

He further explained that most surgical valves that fail in the mitral position will be treated with transapical access. The CoreValve cannot be used in these cases because it would be mounted in the opposite direction which would create disruption of flow. Recently, there has been some experience with the Lotus valve because it can be deployed transapically in the right direction. The Lotus is also removable.

Mitral valve-in-valve and Tricuspid valve-in-valve procedures

Dr. Webb noted that the valves that have been used for mitral and tricuspid valve-in-valve procedures have been the Medtronic Melody and the Edwards Sapien XT.  These valves are used because they can be mounted in the correct direction, ensuring no disruption in flow.  In some rare cases, the Lotus valve has also been used in mitral valve-in-valve procedures.

He explained that performing a mitral valve-in-valve procedure using a transvenous approach introduces potential difficulties including accurate positioning, and correct puncture through the apex.  As a result, the trend has favored transseptal transcatheter mitral valve-in-valve implantation because there is no puncture through the apex required and there is much less morbidity associated with the procedure.

The Sapien XT presents many advantages that make it a popular choice for transseptal and tricuspid surgical procedures.  Some of its most notable advantages are:

• Additional suction;
• Longer length for more accurate and easy positioning;
• Bendable catheter tip to create a stable, accurate position.

It was noted that for transfemoral procedures, the CoreValve can be used in most patients.  The CoreValve is designed for first time positioning accuracy and enhanced sealing which makes recapture extremely difficult or impossible. 

Repositionable Valves

Dr. Webb reviewed a list of repositionable valves currently being manufactured.

• The CoreValve
  • Can be used in most patients transfemoral;
  • Manufactured in multiple different sizes. 
  • Repositionable to a very limited extent;
  • Important to implant high with high gradients;
  • Positioning is important to obtain higher durability in valve-in-valve patients.
• Portico (being used in Canada)
  • Desirable for valve-in-valve procedures;
• CoreValve Evolut R
  • Similar capturability as the Portico valve;
• Lotus
  • Increased control;
  • Can be fully recoiled (can be taken out and put back in);
  • Has not been used much in valve-in-valve procedures;
• Centera;
• Direct Flow;
• Edwards Sapien 3
  • Cannot be recaptured, however, has more controlled delivery (accurate positioning controls);
  • Being used routinely in Europe for valve-in-valve implants;
  • Negligible risk of atrioventricular (AV) block because the surgical valve protects it, annular rupture, and paravalvular (PV) leak; 
  • Most Sapien 3 valve-in-valve patients are discharged the next day.

3. Some surgical AVR bioprosthetic valves may be more suited for valve-in-valve procedures.  Should this information be available in the labeling of either the surgical valves or the TAVR valves as a contraindication or warning?  Currently no valves are licensed for this indication in Canada.

Dr. Webb mentioned that Health Canada should not necessarily assume responsibility for excluding or including certain surgical valves.  This responsibility, according to Dr. Webb, should be left to the surgeons and cardiologists. 

Dr. Webb also noted that given current outcomes, a valve that is considered licensable for TAVR devices could feasibly follow-through to a valve-in-valve indication without the need for a randomized trial.  Individual programs, according to Dr. Webb, will likely continue to make decisions for individual patients rather than wait for there to be expansion of the indication to include a valve-in-valve approach.

When asked about the possibility of requiring warnings on some valves to indicate the danger of performing valve-in-valve procedures with specific devices, Dr. Webb did not feel these would be necessarily helpful.  Alternatively, he suggested that these kinds of issues be discussed at surgical meetings and training sessions.

Dr. Webb concluded his presentation and the chair opened the floor to questions. The following questions were discussed:

What are minimum data requirements to approve a valve for valve in valve procedure? Should it be valve specific? How important is the height of the valve itself in assessing the risk of coronary obstruction?

It was noted that the trials are allcomers, and at this time no one is considering to do a randomized trial. There is no feasibility to get a randomized trial in Canada. Valve in valve procedures are safer. It is a question of screening the patients appropriately. It was also noted that the centers do not refuse this procedure based on valve type. Therefore there is no reason to exclude certain valve types.

Assessing the risk of coronary obstruction is extremely complicated; it would be too simplistic to pay attention to the valve height alone.  However, if the coronaries are low, the risk is higher and if the coronary is occluded, mortality rates exceed 50%.  One way to dramatically lower risk is to use a repositionable valve or the SAPIEN 3 that can be positioned accurately.  Valves that are implanted at the appropriate height allow for a better pace maker rate.

Given that screening for valve-in-valve procedures is complex, which centers should be doing it?

Dr. Webb noted that in British Columbia, there is a regional program with a site assigned to carry out low volume procedures (transapical, aortics, etc.) and two additional sites assigned to carry out transfemoral procedures exclusively.  However, meetings are underway to expand the program.  The expanded program will include any centers that currently perform TAVI procedures. 

The access through SAP was discussed. It was noted that HC encourages the users to opt for a licensed product however it is difficult to refuse access through SAP if physician believes it is the best product for their patient.

Some members felt that changing the SAP access may impact on available choices and impact on cost of health care.

Dr. Webb concluded by noting the growing popularity of ‘valve-in-valve’ procedures.  The procedure is being performed more routinely because it is extremely teachable and relatively easy to perform.

Dr. Webb disconnected from the meeting.

4. Thrombectomy in patients with STEMI

Dr. Sanjit Jolly, Guest Speaker

Currently, there are a number of thrombectomy devices licensed for use in Canada.  The evidence for the use of these devices is weaker than in some other areas as there are not a substantial number of well-designed randomized controlled clinical trials.

Dr. Jolly thanked the Committee for inviting him to attend the meeting and speak to this topic.  He began with a brief bio and declared his affiliations before proceeding with his presentation and addressing the questions posed by Health Canada.

Dr. Jolly’s presentation addressed the following topics in relation to thrombectomy in patients with STEMI:

• Review of the rationale for thrombectomy in STEMI;
• Review of the results of the TOTAL trial.

1. What is the current evidence for the mechanical thrombectomy and manual (aspiration) thrombectomy in STEMI patients, typically performed prior to PCI?

Dr. Jolly recommended that future trials of thrombectomy devices should carefully collect stroke outcomes (safety) to determine safety in addition to efficacy.  He added that manual thrombectomy should be reserved as a bailout procedure in patients with STEMI.

Dr. Jolly reviewed and discussed the following clinical trials:

• TAPAS Trial: Thrombectomy (Export) versus PCI alone during PPCI. 
  • Trial results demonstrated a modest improvement in the surrogate outcome in routine thrombectomy. 
  • After the TAPAS trial, Guidelines were revised which marked an increase in thrombectomy use (1 in 5 of all STEMI cases in the United States received manual thrombectomy).
• TOTAL Trial: randomized trial of manual aspiration thrombectomy and PCI versus PCI alone in STEMI patients.  This was a large sample trial of nearly 11,000 patients.   
  • Trial conclusions: routine thrombectomy compared to PCI alone with only bailout thrombectomy did not reduce Cardio Vascular (CV) death, Myocardial Infarction (MI), shock or heart failure within 180 days.  Also, routine thrombectomy was associated with increased risk of stroke within 30 days. 
• TOTAL and TASTE trials emphasized the need to conduct large randomized trials of common interventions even when small trials appear positive.
• Angiographic Sub-study of the TOTAL trial: a randomized trial of manual thrombectomy during PCI for STEMI.
  • Conclusions: routine thrombectomy did not result in an improvement in final myocardial blush or TIMI Flow following PPCI for STEMI.  Also, routine thrombectomy reduced angiographic distal embolization.  Distal embolization was independently associated with mortality in multivariable analysis.
• Stroke in the TOTAL trial: randomized trial of manual aspiration thrombectomy in STEMI.
  • Conclusions: Routine thrombectomy compared to PCI alone (with only bailout thrombectomy) is associated with increased risk of stroke that is evident within 48 hours.  Also, there is an increase in primarily ischemic strokes as well as hemorrhagic strokes.

2. What key messages should be taken from recent clinical data from the TOTAL Study (NEJM, 2015, 372;15:1389-1398)?  How should Health Canada translate these results to other similar manual thrombectomy devices?  What is the impact on the results from this study on the current clinical practice guidelines for the use of thrombectomy in patients with STEMI?

Dr. Jolly presented a detailed analysis on stroke using data from the TOTAL trial.  Factors such as timing, stroke severity, stroke subtypes, and independent stroke predictors were analyzed.  In instances where the report was unclear in terms of the stroke subtype, the case was reviewed in a blind fashion to increase the rigor of the analysis.  The following list includes observations generated by the analysis:

• Slightly longer procedural times;
• Slightly higher use of 5 French catheters;
• Smaller diameter catheters were used more frequently;
• Stroke within 30 days was increased;
• Stroke and TIA at 90 days and 180 days was increased;
• There was a significant increase in stroke severity and major or fatal strokes;
• Most strokes were ischemic strokes (0.7 versus 0.4%);
• Within the first 48 hours, there was a significant increase in stroke while at all other time points, the difference was not significant;
• Mortality of stroke within 180 days was nearly 31% versus 3% if no stroke occurred;
• Independent predictors: thrombectomy, age, sex, peripheral vascular disease, previous stroke, prior diabetes, CABG, etc.

When all data from all available randomized trials were compiled in a meta-analysis, an increase in stroke was demonstrated.  Furthermore, when the meta-analysis was observed for mortality, there was a trend for reduction in mortality. Dr. Jolly noted that an important caveat for this meta-analysis, is that it was very tenuous in terms of what method was used (fixed model).  A trend did exist; however, it was not definitive; it emphasized the importance of these small reductions (powered for a 20% reduction).

3. In the design of a clinical trial for this type of device, what clinical outcomes should be measured and assessed?  What are the appropriate follow-up durations?

Routine thrombectomy is associated with an increase in stroke.  Therefore, future trials should carefully collect stroke outcomes in addition to efficacy outcomes. 

4. Should Health Canada require additional post-market studies for any of the existing licensed thrombectomy devices?  Please provide some recommendations if you feel additional studies are required.

Dr. Jolly suggested that requiring a warning about an increased risk of stroke is not necessary as it would not change how the device is being used. The strategies for this device continue to be largely physician driven.

5. In some cases, thrombectomy devices targeted CABG thrombosis as these could be very ‘dirty’.  Please comment if further investigation is needed in this area and if this indication continues to be appropriate.

Not addressed.

Questions posed by Committee Members

1. Was stenting analyzed for benefit in patients with direct stenting?  Would that negate the benefit of thrombectomy?

It was noted that any analysis done on interaction with direct stenting would be flawed.  When interaction by sight was analyzed, there was no significant interaction for stroke or for the primary outcome. Operator technique can never be ruled out as a contributor.

Dr. Jolly concluded his presentation

6. Interatrial shunting for patients with left ventricular failure

Dr. Sebastien Bergeron, Guest Speaker

As there has been more clinical activity associated with creating interatrial shunts in the treatment of patients with left ventricular failure, Health Canada is requesting clinical insights into this treatment to better understand:

1. The potential benefits and risks of the treatment,
2. The key device design considerations, and
3. The ideal patient population that may be ideally suited for this treatment.

Dr. Bergeron thanked the Committee for inviting him to attend the meeting. He introduced himself, declared his affiliations, and proceeded to address the topics and questions provided by Health Canada.

Dr. Bergeron began by describing how the pathology and CRT treatment of heart failure is well understood.  Despite this understanding coupled with good drugs, CRT treatment and surgery, many patients continue to be diagnosed with Heart Failure in both Canada and the United States.  Most of these patients have a poor quality of life and will be seen in the emergency room monthly.  Dr. Bergeron explained that a structural device within the world of Heart Failure would be beneficial and described a novel intra-atrial shunt called the V-Wave device to the Committee. 

The V-Wave device is indicated for left ventricular failure and was designed to release the elevated filling pressures of the left atrium by shunting blood from the left atrium to the right atrium.  The device is percutaneously implanted and is equipped with a tricuspid valve.

• Preliminary Study (DelRio CL, AHA 2013): The V-Wave device was implanted into sheep with chronic ischemic Heart Failure.  The sheep underwent serial/selective coronary embolizations resulting in chronic left HF.  They were randomized into either a control group or a V-Wave group.  Results demonstrated higher left ventricular ejection fractions (LVEFs) and lowered left-atrial pressures in the V-Wave group. 
• The V-Wave Shunt FIM Safety and Feasibility Study: this is a first in man (FIM) study with intra-patient comparisons expected to be completed by December 2016.  Inclusion criteria for the study was as follows:
  • Patient is ≥ 18 and < 85 year old;
  • Patient has chronic ischemic or non-ischemic cardiomyopathy NYHA Class III or ambulatory Class IV heart failure despite optimal medical therapy;
  • Patient LVEF >15% and ≤ 40%;
  • Patient has elevated Left Atrial Pressure (LAP);
  • Patient has normal Right Atrial Pressure (RAP);
  • BNP or NTproBNP levels are >300 or >1500 pg/mL, respectively.    

Six patients (mean age of 67) with profound diastolic dysfunction were followed and all six were considered too sick to qualify for heart transplant or LVAD.  The V-Wave device was implanted in all patients with no thrombosis and no embolization.  30 days after V-Wave implantation, flow remained persistent. 

3 months post implantation, the following observations were made: 

• Patients could be re-classified from Class III to Class II;
• proBNP levels decreased for all six patients;
• Patients were experiencing less shortness of breath. 
• Echocardiogram results showed no change in LVEF;
• Diastolic diameters of the patients remained the same;
• There was no change in the right ventricle function or volume.

1.  What is the rationale for creating left-to-right shunt for the treatment of left ventricular failure?

Dr. Bergeron noted that left atrial decompression through a left-to-right shunt represents a novel concept for the treatment of patients with left ventricular failure.  The V-Wave device demonstrates the feasibility of applying this new therapy with the successful and uneventful implantation (e.g., no thrombosis or embolization) of the device, which is associated with significant improvement in functional, quality of life and hemodynamic parameters.

Early studies have shown that management of left atrial pressure is associated with improvement in NYHA functional class and increased LVEF, Dr. Bergeron reported. He went on to state that decompression of the left atrium with the non-invasive V-Wave catheter can be considered safe.

2. What are the indications for this treatment?  What hemodynamic parameters are suitable for this treatment?  Under what conditions should shunting not be done?

This treatment is intended to decrease the left atrium pressure by the shunting of blood from the left atrium to the right atrium. 

Regarding suitable hemodynamic parameters, Dr. Bergeron suggested the following patient selection criteria:

• NYHA functional class III or IV;
• A pulmonary wedge pressure (PWP) of > 15mmHg and < 28mmHg;
• A pressure gradient less than 16 mmHg between the left and right ventricle.

According to Dr. Bergeron, shunting should not be done if the patient does not meet all of the above-mentioned selection criteria.

It has been firmly established that CRT results in a reduction of symptoms and a decrease in morbidity and mortality in patients diagnosed with moderate to severe chronic heart failure  (ACC/AHA C, NYHA class III/IV).  This demonstrates the importance of appropriate patient evaluation and determination of NYHA class. 

Patients with class III or IV with a pulmonary wedge of more than 15mmHg but less than 28mmHG and a gradient of less than 16 between the left and right ventricle are ideal candidates to receive the V-Wave device.   
 

7. LV only pacing and LA + LV only pacing - what are the benefits and how should this be studied?

Dr. Raymond Yee, Committee Member

Recently, studies have been proposed to investigate the possibility of having a dual chamber pacemaker work with left heart signals instead of with right heart signals.  In this situation, leads placed through the coronary sinus will both sense and pace the left atrium (LA) and the left ventricle (LV).  This approach may introduce new challenges as typically, sensing has been performed exclusively on the right side of the heart.

Dr. Yee declared his affiliations, and proceeded to address the topic and questions posed to him by Health Canada.

Trends in Pacemaker Therapy

The factors that have been driving the development of devices over the last few decades have been the relentless desire to develop more physiologic pacing.  This push towards increased development is the driving force behind the introduction of left atrial and left ventricular pacing despite the fact that pacing is predominantly a right heart function. 

Current pacing is right-heart based because it is easy to do and safe.  Right ventricular pacing, however, is no longer considered “good enough” since clinical outcomes have been less than optimal.  Inherently, right heart pacing is non-physiologic as pacing does not occur directly on the sinus node (asynchronous), causing “dyssynchronous ventricular activation”, a worsening of the temporal relationship between the right atrium and left atrium.  This suboptimal LV performance leads to an increase in mortality (DAVID Trial, 2002), heart failure (MOST), and atrial fibrillation (CTOPP, DANPACE, 2011). 

Review of Clinical Studies

Dr. Yee provided a brief review of the DAVID Trial and the BLOCK-HF Trial.

LA and LV Systolic Timing

He noted that in right heart pacing, it is assumed that what is being done for the right heart is good for the left heart and, if the only objective is to increase the patient’s heartrate, this assumption would be correct.  However, there are two factors at play: the time taken for interatrial activation, which is critical to left heart function, and AV nodal and LV conduction time, which determines the optimal timing of right ventricle and right atrial pacing.  

In current right heart pacing practice, the left side of the heart is not typically monitored or observed.  On the rare occasion that monitoring of the left heart does occur, it is predominantly because the patient has had a heart failure. 

An important question to be posed, given that the left side of the heart drives performance and outcomes, is whether there is a benefit to trying to pace the left side correctly.

Dr. Yee presented two possible processes to pace the left side of the heart:

• Two separate leads: one lead is implanted into the atrium to cause early activation in the left atrium. 
  • The left atrium lead is placed in the interatrial septum, coronary sinus or atrial branch. 
  • The LV lead would then be placed through the coronary vein, coronary sinus, or a mini thoracotomy. 
• A single lead:  one lead has two sets of electrodes; one set of ventricular electrodes and one set of right atrial electrodes.  The lead tip and ventricular electrodes are placed in the coronary vein and the atrial electrodes in the coronary sinus.  

LV-Only Pacing Benefits

There is limited data pulled from acute studies that looked at the difference between LV echocardial pacing and RV pacing, however, this novel field has still yet to accumulate significant data.

Although LV pacing attempts to be more physiological, it is done through the coronary veins and is still unphysiologic: epicardial to endocardial activation.

Is LV pacing superior to RV pacing?

One acute study focused on the questions of LV pacing’s superiority over RV pacing.  The Kass (Circulation 1999) study involved 18 patients with dilated cardiomyopathy (DCM) and no bradycardia indication.

1. What are the benefits and risks of the LA-LV pacing mode?

The benefit and risks of LA-LV pacing mode were outlined as follows:

Benefits

• Hemodynamic; optimal AV timing
• Pacing LA to reduce AF episodes

Risks

• Ventricular arrhythmias
  • In low LVEF patients only?
  • Nonetheless, low rate of occurrence

Dr. Yee noted that there is a potential for possibly reducing atrial fibrillation, however, this has yet to be studied.  Thus far, the studies looking at pacing the interatrial septum have not shown any benefit from dual-site atrial pacing.

2. What differences may be anticipated in sensing cardiac signals from the left heart compared to the right heart?

From the coronary sinus, the LA signal will vary in amplitude and frequency content:

• Location and course of the cardiac signal (CS);
• Contact of the LA electrodes with the roof of the CS;
• Will often contain a far field LV signal also.

LV amplitude will generally be good to better than RV unless there is myocardial scar.

There is a larger mass in the myocardium in the left section which creates better left ventricular signals than could be achieved in the RV unless the lead lands in scar tissue.  There is a larger population with endocardial scar pathology, which, consequently translates into better ventricular signals on the right ventricle.

The left atrium is more variable.

Atrial signals will be as good as or better than a diseased right atrium.

3. Does this represent an appealing approach for patients requiring dual chamber pacing?

This potentially does represent an appealing approach for patients requiring dual chamber pacing.  Hemodynamic advantages are significant; however, they’re influenced by the following factors:

• Ease of implant;
• Reliability of hardware is obtaining acceptable sensing;
• Reliability of electrical performance over chronic implant;
• Extraction for injection.
  • The more robust a mechanism you create to ensure a lead stays put, the harder it is to extract.  

4. Are there additional benefits that might improve a CRT system by allowing pacing and sensing of the left heart to drive resynchronization?

Yes, some additional benefits that might improve a CRT system by allowing pacing and sensing of the left heart to drive resynchronization are:

• Hemodynamics advantages accrue from knowing the time of LA activation (to optimize timing of RV/LV pacing output).
• LV sensing is less important; may be helpful to know relative RV and LV signal to calculate optimal RV/LV output timing, less important.
• Reduce atrial fibrillation by LA pacing.

In an ideal world, a lead would be inserted into the left atrium and the procedure would be followed by an epicardiogram that would be performed every 6 months thereafter to maintain optimal function.  In practice, however, only non-responders receive epicardiograms.

Left ventricular sensing is much less important.

5. In standard CRT devices, is there a likely benefit to sensing and pacing the LV instead of the RV and the primary ventricular signal?

Probably not, the LV is usually activated late so sensing a late signal is of limited value.  Though, RV sensing may still be valuable to coordinate LV output timing (as per adaptive CRT).

6. What clinical endpoints should be included in clinical trials to determine the safety and effectiveness of systems that are investigating left heart sensing and pacing?

The same clinical endpoints as for CRT studies should be included in clinical trials to determine the safety and effectiveness of systems that are investigating left heart sensing and pacing.   These endpoints are as follows:

• Composite of total mortality (or CV mortality),
• HF events,
• Ventricular tachyarrhythmias,
• New AF or progression to persistent AF.

8. LVAD: Issues associated with continuous flow with periodic pulsatility, increased numbers of patients on long-term support - what is best practice regarding anticoagulation?

Dr. Vivek Rao, Guest Speaker

Continuous flow left ventricular assist devices (LVAD) have emerged as the standard therapy option for patients with advanced heart failure.  They offer several advantages over previously used pulsatile-flow LVADs, including improved durability, less surgical trauma, higher energy efficiency and lower thrombogenicity.  These benefits translate into better survival, lower frequency of adverse events, improved quality of life and higher functional capacity of patients.  However, there is mounting evidence showing unanticipated consequences of continuous-flow support such as acquired aortic valve insufficiency and acquired Von Willebrand syndrome.  Recently, there has been an effort to introduce some pulsatility to continuous flow devices to mitigate these unanticipated consequences.

Dr. Rao thanked the Committee for inviting him to present on this topic.  He introduced himself, reviewed his disclosures, and proceeded to address the topic and questions posed to him by Health Canada.

An overview of the current evidence on the difference between continuous and pulsatile mechanical circulatory support focusing on the complications that were unanticipated with the long-term support of patients with continuous flow devices.

Dr. Rao provided a brief overview of objectives for his presentation:

• Describe the need for mechanical circulatory support;
• Briefly review indications for MCS;
• Review adverse events associated with prolonged MCS;
• Discuss the potential benefits of new technology.

Dr. Rao noted that every year, 50,000 patients are diagnosed with Heart Failure in Canada.  The ideal solution for these patients was once considered cardiac transplantation because of its success rates (5 year survival >75%), however, there are limitations to this therapy including a limited supply of donors and, consequently, a growing waiting list mortality rate.  

The number of adult and pediatric heart transplants per year has plateaued at around 1000.  Also, because the median survival (11 years) and conditional survival (13 years) associated with this therapy are so similar, transplantation is associated with constant attrition.

An increase in mechanical devices has led to an increase in cardiac transplantations being carried out on patients with mechanical circulatory support devices (ventricular assist device (VAD) patients).  In 2014, 50% of patients in North America were transplanted with a device.  Results have indicated no change in survival rates with the exception of patients on Extracorporeal Membrane Oxygenation (ECMO). 

Why use VADs to support Cardiac Transplantation?

A ventricular assist device (VAD) provides a bridge to transplant for high-risk candidates and a bridge to recovery for high-risk donors.  Also, VADs are used as backups in advanced cardiac care scenarios (e.g., high-risk surgical intervention, reversible causes of heart failure).  Finally, VADs are used to provide therapy for end-stage heart disease, or “destination therapy”.   An increasingly important indication in the United States is destination therapy for patients who are beyond the limits of transplantation.     

The current standard for ventricular assist devices (VADs)

From an engineering perspective, current devices are designed to last forever.  However, because of the adverse event profile of some devices, transplantation will continue to have a role.

The current standard of VAD, the HeartMate II, was introduced in Canada in 2006.  It is much smaller and has been estimated to have a lifespan of between 7 and 10 years.

Frequency of VAD use

Dr. Rao explained that funding from the Ministry of Health has resulted in an increase in VAD use.  In Canada in 2015, there have already been 18 VAD implants and 21 transplants.  The VAD implants are mostly being performed at transplant centers across the country.

Regarding VAD data, there are sufficiently large amounts of long-term data available.  Over 5000 patients have been supported by VADs for over a year and over 300 patients have been supported for over 5 years.  As follow-up continues, it can be expected that the curves will come down and more patients will be given extended support.

Dr. Rao explained that survival is based on the durability of the device.  The Heartmate II demonstrated significantly better survival rates in the older, sicker population than the Heartmate I.

Clinical evidence that supports the incorporation of pulsatility to continuous flow devices may mitigate some of the complications observed. 

The Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) data was published in 2012.  The analysis looked at incremental survival associated with transplantation over the last 30 years.  When survival rates of INTERMACS, Rematch (2201) and Transplants were compared, a significant improvement was observed between older generation devices (Rematch) and newer generations (INTERMACS).  Transplant survival rates remained the highest.

Provide an overview of any additional new features or products that could have significant impact on the clinical outcomes of patients who require an LVAD in the near future.

Dr. Rao provided an overview of some additional new features/products.

It has been hypothesized that a lower rpm could mean higher durability.  The HeartWare device was designed with a lower rpm that provides the same flow; it mimics pulsatility and promotes aortic valve opening.  The device also has a special levitation system that may also increase durability. 

• HeartWare HVAD
  • Designed for infinite durability, no breakable parts;
  • Intrapericardial implant, no preclotting required;
  • Full Mag-Lev technology;
  • Very flexible driveline;
  • 75 patients followed independently at 5 Canadian sites.  All Canadian implants were between May 2010 and September 2012 with 100% complete follow-up by December 2012.
  • 5 site experience across Canada.  Reflected all Canadian implants between 2010 and 2012.  Complete follow-up by end of 2012.
  • Associated with implant mortality of less than 13%.
• Device characteristics for Heartmate II compared to HeartWare
  • Heartmate II: second generation, first implant in 2000, 7800-11000 rpm, abdomen (pre-peritoneal).
  • HeartWare: third generation, first implant in 2006, 2400 - 3200 rpm, pericardial space.

A Canadian study of the HeartWare HVAD followed 75 patients independently at 5 Canadian sites.  Follow-up was completed on all patients by December 2012 (Total of 44.9 years of patient experience) and results demonstrated persistent ‘late’ tamponade thought to be due to heparin bridge.

Key points of 2006 Guidelines (HeartMate II)

• Bridge with heparin until International Normalized Raio (INR) is greater than 2;
• Maintain INR between 2 and 3;
• Maintenance therapy with warfarin, ASA, dipyridamole.

Key points of initial HeartWare HVAD IFU

• Bridge with heparin until INR is greater than 1.7;
• Maintain INR between 1.7 and 2.3;
• Maintenance therapy with warfarin, ASA (81mg).

The data show that HeartMate II patients experience relatively low rates of stroke and pump thrombosis with INRs greater than 1.5.

Dr. Rao reviewed the ADVANCE Trial.  He mentioned that the trial showed a 6% pump thrombus rate; a clinical experience that resulted in establishing revised recommended INR targets of between 1.5 and 2 by HeartWare.

Dr. Rao’s Opinion: pump thrombosis is a recognized complication of any mechanical circulatory support device:

• Axial flow;
• Centrifugal flow;
• Paracorporeal, short term.

While the recent concerns regarding increased pump thrombus rates are valid; it may be iatrogenic in nature, noted Dr. Rao.

Current TGH Protocol

All VADs:

• Complete reversal of heparin in the operating room;
• ASA 325mg PO/PR on POD#1;
• If the patient is extubated, start coumadin POD#2;
• All patients receive heparin to maintain PTT 50-80s.
  • HeartMate II: Target INR 2.5
  • HeartWare: Target INR 2.5
• There are now higher speeds (9000 or 2800 for HVAD) in all devices.

Dr. Rao went on to describe the results of a comprehensive review on the detection and management of aortic insufficiency in patients with a continuous-flow left ventricular assist device.

• Cumulative incidence of  >2+ AI at 2 years ~ 30%
• Balanced management approach:
  • Attempt aortic valve opening if possible;
  • Ensure adequate hemodynamic support;
  • Avoid excess support.

In summary, Dr. Rao noted that heart failure remains an important and growing problem in society.  Transplantation will never meet the need of heart failure patients, therefore, advancements in VAD technology will allow patients to live normal lives with survival matching or exceeding that of heart transplant.

9. Durability of Bioprosthetic Valves

Dr. Eric Cohen, Committee Member

In the past, bioprosthetic valves were recommended for aortic valve replacement (AVR) in older patients and those unable to tolerate anticoagulation therapy. Lately, mechanical valves are being displaced by prosthetic valves as preferred options for aortic valve replacement procedures. The expanding market for these devices includes patients receiving conventional surgical bioprosthetic valves such as Medtronic’s Hancock valve, Sorin’s Mitroflow valve and Edward’s C-E Perimount Magna valve and patients receiving bioprothetic valves as components of the newer sutureless valves such as Sorin’s Perceval S Heart Valve and the increasingly popular transcatheter valves including Edward’s Sapien XT Valve and Medtronic’s Corevalve. This trend is occurring against the backdrop of the proven long term durability of mechanical valves.

One major issue with bioprosthetic valves is structural valve deterioration (SVD). Cusp tears and thickening, calcification, pannus formation, and thrombus formation lead to SVD and unfavourable hemodynamic characteristics resulting in the need for valve explantation and replacement. Recently, in a single center study conducted in France involving 617 consecutive patients (aged 76.1±6.3 years) who underwent aortic valve replacement with a Mitroflow prosthesis (models 12A/LX), it was reported that the cumulative probability of SVD increased significantly from 0.8% at 2 years to 8.4% at 5 years (Sénage et al. Circulation. 2014;130: 2012-2020 and Kaneko et al. Circulation. 2014;130: 1997-1998). Among the 39 patients with SVD, 13 patients (33%) had an accelerated SVD once the mean gradient exceeded 30 mm Hg.  Small-diameter prosthesis (19 and 21 mm) was used in 64.2% of the patients and this was a significant risk factor for SVD in the analyses. In the ISTHMUS study with over 1500 patients (Eur J Cardiothorac Surg 2011;39:18-26), actuarial freedom from SVD was 65.5% at 18 years with patients < 60 years of age with actuarial freedom from SVD at 54.4% at 18 years (2.2 pt/yr).  In a similar study of the Hancock II valve with over 1100 patients in Toronto (Ann Thorac Surg 2010;90:775- 81), freedom from SVD was 63.4% at 20 years but only 29.2% in patients < 60 yoa.  Based on their results Sénage et al. recommended the following:

• Monitoring patients who received older-generation Mitroflow valves with frequent echocardiography should be mandatory to prevent undesired complications, especially in high-risk patients, e.g. patients who have a small prosthesis and gradient >30 mm Hg across the bioprosthesis. Echocardiogram surveillance should be performed at ≤6 months for early detection. SVD and its accelerated pattern is a life-threatening condition, not only in young but also in old people, an incentive to a close follow-up after implantation.
• Aggressive treatment is needed even in asymptomatic patients once the gradient becomes severe. Given the poor outcome of these patients, re-operative aortic valve surgery or a transcatheter procedure for high risk non-small-annulus patients should be offered when the diagnosis of SVD is made, even if the patient is asymptomatic.
• Users should be warned about the possibility of increasing numbers of patients implanted with Mitroflow A12 and LX presenting with early SVD over the next few years.
• Given the poor outcome of these patients, re-operative aortic valve surgery or a transcatheter procedure for high risk non-small-annulus patients should be offered when the diagnosis of SVD is made, even if the patient is asymptomatic.

It should be noted that the Mitroflow Models A12 and LX models have been largely replaced by the Model DL. The Model DL is manufactured using an anti-mineralization process (phospholipid reduction treatment) intended to decrease calcification and subsequent SVD.

Dr. Cohen introduced himself, reviewed his disclosures, and proceeded to address the topics and questions provided by Health Canada.

Dr. Cohen’s presentation began with a brief description to provide the committee with some context.  He explained that there has been a long-term trend of an increasing proportion of bioprosthetic versus mechanical valves and that novel anti-coagulants have not safely extended to mechanical valves.  Also, he noted that there has been use of bioprosthetic valves in young adults even knowing that the durability is less and they will likely face repeat procedures in their lifetime.  There have been concerns regarding durability generally; however, the soran mitroflow in particular has generated heightened concerns of durability.  

There is an attractiveness of trans-catheter valves as a subsequent intervention that perhaps shifts valves even further towards tissue valves in younger people, with caveats:

• It’s an unproven strategy for younger patients over the long-term;
• Uncertain how many times this can be done;
• Technical limitations (annulus size, coronary obstruction, etc.)

Trans-catheter valves arn’t a catch-all solution for all of these issues and do not justify the widespread use of tissue valves in young patients.

Dr. Cohen described the Mitroflow valve.  It is a bovine pericardium mounted external to the stent and it’s positioned surgically supra-annularly which is to allow it to be used in smaller annulus.  Those features together supposedly provide superior hemodynamics.  Because of these features, this valve has been used preferentially in patients with small annulus (e.g., small, elderly females).  This preferential use creates an uneven playing field when comparing the outcomes of this valve.

Dr. Cohen outlined the different iterations and history of the Sorin Mitroflow valve since it was first introduced in 1982 as the Mitroflow A11 in Europe and Canada.  Additionally, he reviewed the following studies/papers:

• Mitroflow aortic pericardial bioprosethesis—clinical performance, Jamieson Eur J Cardiothor Surg, 2009;36:818
  • Used only newer Mitroflow model (A12/LX);
  • 70% women with 19/21 mm valves;
  • Mean time to explant for SVD 7.8 years;
  • Hazard function for SVD increasing over time;
  • Cumulative incidence of SVD - 90% over 10 years.
• Early Structural Valve Deterioration of Mitroflow Aortic Bioprosthesis—Mode, Incidence, and Impact on Outcome in a Large Cohort of patients
  Thomas Sénage, MD, et. Al. Circulation. 2014; 130L2012-2020
  • Just over 600 patients;
  • Mitroflow valves used selectively in patients with small annulus;
  • Small trend over time towards increasing gradient.
• Modes of failure in explanted mitroflow pericardial valves
  Ann Thorac Surg. 2011 Nov; 92(5): 162-7. Doi: 10.1016/j.athoracsur.2011.06.092
• Accelerated Degeneration of a Bovine Pericardial Bioprosthetic Aortic Valve in Children and Young Adults
  Susan F. Saleeb, et.al.
  • Compared magna valve with the mitroflow and showed a striking difference, the mitroflow outperformed.
• Pathological Evaluation of 28 Mitroflow Pericardial Valves: A 12-Year Experience
  Ann Thorac Surg. 99(1)
  • Structural valve deterioration was seen in 18 or 19 explanted valves with implant durations of at least 30 months, and is related to valve design.  It appears that clinical should carefully consider Mitroflow valve implantation in all patients, even in patients older than 65 years old, given the early presence of structural valve deterioration.

Some concerns regarding the Mitroflow valves were outlined:

• Whether it performs similar, better or worse than other tissue valves in large sizes is not the issue because its benefits are purported to be in smaller sizes and that is where it has been selectively used.
• Evidence is reasonable clear that in small sizes (19/21) there is at least a subset of patients with accelerated SVD.
• Also concerning for very early SVD in very young patients.
• There are biologic factors that give reasonable plausibility to these concerns
  • Mechanical design features in earlier model (leaflet abrasion)
  • Absence of anti-calcification treatment.

Dr. Cohen continued his presentation by addressing each of Health Canada’s questions.

1. Are there substantial differences between the different surgical bioprosthetic  valves marketed in Canada that make one or more of these products superior to the others in general or for particular groups of patients?

Although there are observations about different performance of certain valves, the ability to conclude conclusively if one is better than the other is extremely difficult.  Effectively, there are no randomized trials randomizing one valve to another, especially not with long-term outcomes and large numbers of patients.  Consequently, it is mainly observational work, trying to compare one type of valve to observed results with a different valve.  If there are differences, explained Dr. Cohen, they are subtle. 

2. Have differences in design, valve materials (porcine versus bovine pericardium), anti-mineralization treatments or other changes in the manufacture of bioprosthetic valves substantially changed rates of SVD and long-term durability?

Yes, differences in design have changed rates of SVD and long-term durability.  First generation bioprosthetic valves were not given any anti-calcification treatment and, consequently, showed high rates of potential calcification.  As a result, second generation valves received calcification treatment and performed better accordingly. 

There are potentially important differences in design, explained Dr. Cohen.  Some of these differences could include:

• Whether valve tissue is fastened on the inside or outside of the ring;
• Whether there are lining sutures around the struts create differential tensions on the valve material;
• Variables in the actual design.

Variables in design and features can provide superior hemodynamics, especially for small annulus.  The Sorin Mirtroflow, for example, features bovine pericardium mounted external to the stent and is positioned supra-annularly, features that together are believed to provide superior hemodynamics. 

One component that has evolved is standardized reporting of what constitutes valve related mortality, valve related morbidity, and what the definition of structural valve deterioration is.  Some thought has gone into the different ways of statistically analyzing these effects, for example, whether actual or actuarial probabilities are used.  Actuarial probability is based on the declining denominator of the people still remaining at risk (e.g., once a patient dies from another cause, in a sense they are no longer at risk for valve deterioration) while the actual probability includes everybody, predicting the probability of failure that is not inevitable, but can be precluded by other events such as death.  There have been attempts to try to find better ways of expressing this, however, currently; it is not consistently reported in the same way.

One of the basic facts is that at a younger age, patients are more likely to have SVD regardless.  This is primarily because of two factors: living longer and calcification occurs more quickly than in older patients.

A general concept that cardiologists are familiar with, noted Dr. Cohen, are the competing risks and benefits of mechanical valves which have a price to pay in terms of anticoagulation versus bioprosthetic valves that have a higher risk of re-operation, especially in younger people. 

3. Are more aggressive recommendations on surveillance and prophylactic replacement of bioprosthetic valves warranted?

Dr. Cohen listed Dr. Thomas Sénage’s recommendations:

• Monitoring patients who received older-generation Mitroflow valves with frequent echocardiography should be mandatory to prevent undesired complications, especially in high-risk patients, e.g. patients who have a small prosthesis and gradient >30 mm Hg across the bioprosthesis. Echocardiogram surveillance should be performed at ≤6 months for early detection. SVD and its accelerated pattern is a life-threatening condition, not only in young but also in old people, an incentive to a close follow-up after implantation.
• Aggressive treatment is needed even in asymptomatic patients once the gradient becomes severe. Given the poor outcome of these patients, reoperative aortic valve surgery or a transcatheter procedure for high risk non-small-annulus patients should be offered when the diagnosis of SVD is made, even if the patient is asymptomatic.
• Users should be warned about the possibility of increasing numbers of patients implanted with Mitroflow A12 and LX presenting with early SVD over the next few years.
• Given the poor outcome of these patients, reoperative aortic valve surgery or a transcatheter procedure for high risk non-small-annulus patients should be offered when the diagnosis of SVD is made, even if the patient is asymptomatic.

Current follow-up recommendations:

• American (2014)
  • initial trans-t-echo (TTE) 6 weeks to 3 months post implant (I-B)
  • repeat TTE if change in signs or symptoms (I-C)
  • TEE if signs/symptoms suggest prosthetic valve dysfunction (I-C)
  • annual TTE for bioprosthetic valve only after 10 years (IIa - C)
  • no routine imaging for mechanical valves
• European
  • annual TTE after 5 years

If one were to adopt these recommendations, mentioned Dr. Cohen, it would be a dramatic change in monitoring frequency.  Increased monitoring has been widely accepted; however, the recommendation for re-operation for high gradients is less accepted.

4. Should the minimum standard for durability testing of bioprosthetic valves be extended?

Three facts have evolved out of a 15 year durability testing experience with accelerated fatigue testing of prosthetic heart valves. First, the component of a prosthetic valve that fails in vitro fails in vivo. Second, the site of fatigue in the component worn in vitro is the same site of wear found on clinical specimens.  Third, those valves with high durability in vitro appear to have similar durability in patients. 

Parameters of testing:

• Accelerated wear testing
  • 200 million cycles for tissue valves
  • 400 million for mechanical (ISO)
  • 600 million for mechanical (FDA) 
  • includes specification of closing pressure, interim inspection, etc.
  • Valve stent 600 million cycles
  • CF intravascular stent 400 million
  • NB one year = 40 million cycles

In conclusion Dr. Cohen noted that recent references about the correlation of bench testing and clinical failure are hard to find.

10. Next Steps, Closing Remarks and Adjournment of Meeting

Dr. John Ducas, Committee Chair

The Chair thanked committee members and Health Canada staff for their participation and valuable input.  He highlighted the importance of attendance to these meetings and asked that members make attending future meetings in their entirety a priority in the future. This will allow full participation to all topics discussed.

Members will be canvassed to select a date for the next meeting.

Meeting adjourned.

Committee Members Present: John Ducas (Chair), Renzo Cecere, Christopher Feindel, Alan Menkis, Brent Mitchell, Barry Rubin, Raymond Yee, John Webb

Invited Guests: Thomas Forbes, Reda Ibrahim, Prasad Jetty, Raj Padwal

Health Canada Representatives:

• Office of Science: Hripsime Shahbazian
• Office of Planning, Performance, and Review Services: Caroline Hunt
• Medical Devices Bureau: Carey Agnew,Kevin Day,Ian Aldous, Patrick Fandja, Ian Glasgow, Ian Grimwood, Jianming Hao, Karen Kennedy, Mark Korchinski, Christine Lefebvre, James McGarrity, Catherine Milley, Michael Rosu-Myles, Philip Neufeld, Jason Pearman, Maurice Sylvain, KokSwang Tan, Lanyi Xu, Brian Wong

Regrets: Luc Bilodeau, Eric Cohen, Marino Labinaz, Joaquim Miró

Abbreviations used in this record:

AAA:

abdominal aortic aneurysm

AMI:

acute myocardial infarction

ATP:

anti-tachycardia pacing

AVR:

aortic valve replacement

BMC:

bone marrow cell

CABG:

coronary artery bypass grafting

CACs:

circulating angiogenic cells

CADTH:

Canadian Agency for Drugs and Technologies in Health

CPC:

cardiac progenitor cell

CSF:

cerebrospinal fluid

CT:

computed tomography

DEB:

drug eluting balloons

ECC:

extracorporeal circulation

EEC:

endovascular elephant trunk completion

EPC:

endothelial progenitor cell

EVAR:

evolution of endovascular aneurysm repair

HF:

human factors

ICD:

implantable cardioverter-defribrillator

IFU:

instructions for use

LVEF:

left ventricular ejection fraction

MDB:

medical devices bureau

MI:

myocardial infarction

MEP:

motor-evoked potentials

MRI:

magnetic resonance imaging

MSC:

mesenchymal stem cell

OEC:

open elephant trunk completion

OPC:

objective performance criteria

RCT:

randomized clinical trial

SAC-MDUCS:

scientific advisory committee on medical devices used in the cardiovascular system

SAP:

special access program

SCI:

spinal cord fluid

SEP:

somatosensory evoked potentials

SVT:

supraventricular tachycardia

TAA:

thoracic aortic aneurysm

TAVI:

transcatheter aortic valve implantation

VF:

ventricular fibrillation

VT:

ventricular tachycardia

VTA:

ventricular tacky arrhythmia

1. Opening Remarks & Welcome

Dr. John Patrick Stewart, A/DG, TPD

The Interim Senior Executive Director of the Therapeutic Products Directorate (TPD), Dr. John Patrick Stewart opened the meeting and welcomed the committee members and guest speakers.  He thanked them for sharing their time and expertise and acknowledged the efforts all participants had made to attend the meeting. Dr. Stewart highlighted the importance of the Scientific Advisory Committee on Medical Devices Used in the Cardiovascular System (SAC-MDUCS) to Health Canada’s regulatory review and decision-making process.  He provided the Committee with a brief update on the Government’s current position as well as next steps regarding Bill C-17, a piece of legislation created to enhance the safety of Canadians by expanding Government authority over the product lifecycle of a drug. He noted that Health Canada will continue to seek committee advice to plan future approaches to address device related issues. Dr. Stewart concluded by wishing the committee members and guest speakers fruitful deliberations.

2. Review of the Agenda, Affiliations and Interests Declarations, and Confidentiality Agreement

Dr. John Ducas, Committee Chair

The Chair reviewed the agenda items with the committee.  The agenda was accepted as established. 

Verbal affiliations and interest declarations were completed. No conflicts were identified at this time. Members were also asked to disclose any conflicts that may arise as the meeting proceeds.

Presentations are available upon request.

The responses outlined below are representative of the discussions/recommendations generated by the committee.

3. Summary of How Health Canada Has Used Information Generated from Previous SAC-MDUCS Meetings

Kevin Day, Medical Devices Bureau (MDB)

Mr. Kevin Day presented a brief summary of how previous advice and recommendations provided by the SAC-MDUCS have been considered by Health Canada.

The following topics were noted:

• DF-4 Connectors: previous discussions and recommendations regarding requirements for clinical evidence and post-market follow-up for DF-4 connectors were considered in license rejection decision after manufacturers failed to provide post-market follow-up.
• Drug Eluting Balloons: drug eluting balloons (DEBs) have  been a very important area in discussions with the manufacturers and feedback received from the committee regarding enforcing superiority against angioplasty and minimum trial sizes, with one year follow-up have had implications on clinical trial designs for licensing purposes. 
• Suturless Valves: discussions on suturless valves compared to surgical valves, compared to TAVI and the importance of longer term follow-up data with evidence of morbidity and mortality associated with these devices have provided a better understanding of this technology before issuing a license.
• Stem Cells: information obtained from previous discussions on stem cells has been very helpful regarding a recent clinical trial in which stem cells were being generated by a medical device.
• AAA Devices: currently using discussions and recommendations from the committee to aid in reviews of additional branch devices.
• Implantable cardioverter-defibrillators (ICDs): recommendations received from the committee regarding ICDs have been helpful in determining appropriate patient population.

The Medical Devices Bureau (MDB) is using the recommendations and advice provided by the SAC-MDUCS when discussing clinical trials or licensing requirements with Industry.  The Committee’s input also ensures that good clinical oversight is continually being applied towards decision making processes.   

Mr. Day thanked members for their ongoing dedication to the committee. 

4. Renal Denervation - Next Steps for a Regulatory Body, Typical Use, Requirements for New Licenses

Dr. Raj Padwal, Guest Speaker

The first renal denervation system was licensed in Canada in 2012 following clinical data from three studies including one randomized unblinded study and a discussion on this topic by this Scientific Advisory Committee. 

An overview of Health Canada’s approach to licensing renal denervation technologies was presented.

In 2014, additional data from a larger single blinded study put the clinical effectiveness of renal denervation into question.  In light of recent developments, the committee has been asked to address several questions posed by Health Canada. 

Dr. Raj Padwal was invited as a guest speaker to address this topic.  He thanked the committee for the invitation and provided a short bio. After declaring his affiliations Dr. Padwal proceeded to address the questions posed by Health Canada.

Dr. Padwal provided a brief background information to help frame the topic of his presentation.  He noted that:

• Surgical sympathectomy was one of the earliest treatments for high blood pressure, predating drug therapy, and was used for malignant hypertension (1930).  This was a precursor for renal intervention.
• Renal denervation is a minimally invasive procedure that disrupts both the afferent and efferent nerves, as they are both implicated in the pathway of high blood pressure. 
  • Currently, there are no tests to verify whether denervation has been successful.
• Resistant hypertension is the failure to achieve blood pressure target (<140/90mm Hg) despite treatment with three antihypertensive drugs (including a diuretic) at optimal doses. 
  • Hypertension affects 20% of Canadian adults.
  • When adherence, lack of optimal therapy, and white coat effect are taken into account, the number of adult Canadians with true resistant hypertension would likely be around 0.2%.
• Two main factors that increase susceptibility to resistant hypertension are:
  • Age: geriatric patients have stiff vessels, which have been correlated with high blood pressure. 
  • Weight: obese patients (usually young) are at risk of resistant hypertension since the path of physiology involves central adiposity.

Dr. Padwal proceeded to address the topics presented by Health Canada.

Provide and discuss recommendations for clinical data requirements for licensing for new renal denervation systems (e.g., non-inferiority compared to a currently licensed renal denervation system, superiority compared to a sham control, etc.)

Dr. Padwal provided the following recommendations regarding clinical data requirements and trial design for these new systems:

• Trials should be double blinded;
• Comparators should be optimal medical therapy;
• Study populations should include patients with resistant hypertension and these individuals should have a 24-hour ambulatory blood pressure (to rule out white coat effect);
• Adherence should be assessed and non-adherent patients excluded;
• Blood pressure measurements should be carried out with careful attention;
• Interventionalist should be as experienced as possible.

It was noted that the SYMPLICITY-3 methodology should be considered Industry standard.  Also, non-inferiority should play no role in clinical data requirements for new renal denervation systems. 

What endpoints should be studied in clinical trials for hypertension and what represents a clinically significant improvement (e.g., office SBP, ABPM)?  What are the incremental benefits of lowering the different measures of blood pressure?  Will these incremental benefits be observed consistently across different groups of hypertensive patients?

Dr. Padwal noted that systolic blood pressure is considered the strongest indicator of outcome, therefore, with regards to endpoints in clinical trials for hypertension, systolic blood pressure ascertained through ambulatory blood pressure monitoring (ABPM) could be an acceptable primary endpoint. Automated office measurements should not be considered an acceptable primary endpoint since the white coat effect introduces subjectivity.  It could, however, be considered a secondary endpoint.

Hypertension studies should assess/provide:

• Morbidity and mortality (safety);
• Short-term data (complications);
• Long-term data (renal function, renal artery stenosis).

The use of “support of blood pressure” data is a good validated surrogate endpoint.  The absolute increased risk when blood pressure increases is much greater in the elderly than it is in the young in terms of stroke mortality events. 

Dr. Padwal noted that individuals with a high 5 or 10-year risk of cardiovascular disease will avoid the highest number of events through blood pressure reduction.  Therefore, the best patient population for hypertension studies would be high-risk patients. 

Discuss the risks and benefits of renal denervation given available clinical information.  Provide insights and interpretations of difference between HTN-1 and -2 compared to SYMPLICITY HTN-3.  What is your understanding on why the positive results from HTN-1 and HTN-2 were not seen in HTN-3?

Dr. Padwal explained that these differences in risks and benefits between renal denervation studies largely relate to methodology. He further noted that the operator experience plays a significant role (e.g., many operators in the SYMPLICITY HTN-3 had performed less than two procedures).  It was recommended that interventionalists with significant experience in the renal arteries carry out the procedure.

Dr. Padwal noted that currently there is no test available allowing assessment of proper and effective execution of the renal denervation procedure.  As a result, benefits of the procedure remain unclear.  Despite an unknown level of efficacy, however, the safety of the procedure has been assessed and the risks appear low.  The major concern has been deterioration in renal function.  The caveat is that long-term data for large patient numbers are not available.

Dr. Padwal provided a list of potential contributing factors to differences between studies:

• No assessment test available;
• Relying on non-standardized blood pressure measurements;
• White coat effect and non-adherence;
  • SYMPLICITY HTN-3 had two screening visits and implemented a 24 hour ambulatory measurement as the second screening to limit the number of patients with white coat effect and non-adherence.
  • Patients experiencing white coat effect will not present with elevated blood pressure on an ambulatory measure.
• Improper training pathways prior to implementing the procedure.
• The SYMPLICITY HTN-2 trial had follow-up assessors who were not blinded.

The following optimal regimen was recommended:

• Assess for non-adherence;
• Perform 24 hour ABPM;
• Discontinue interfering drugs;
• Rule out secondary causes;
• Optimize health behaviors;
• Use long acting synergistic combinations (ACE or ARB/DHP CCP/diuretic);
• Simplify dosing schedule;
• Nocturnal dosing;
• Minimize cost.

Are there specific shortcomings in the design of currently available renal denervation systems that might significantly impact their safety and effectiveness?  Please discuss any new designs in development that might be promising.

Dr. Padwal recommended that an assessment program/measurement must be developed to determine the effectiveness of the procedure.  The suggestion of using a urine metabolite to determine whether denervation has taken place was provided.

It was also recommended that in addition to developing an assessment program/measurement, there should be more experimental animal model data obtained.

Currently, what patient populations should be treated with renal denervation in Canada?  What qualifies a patient as having refractory hypertension in terms of blood pressure levels and medical therapy treatment?

Dr. Padwal suggested that patients who refuse other treatment (low adherence to pharmaceutical treatment) could be considered appropriate candidates for renal denervation as a last resort. 

He explained that the level of pathogenesis of a given patient with hypertension related to the sympathetic nervous system remains unknown.  A number of studies have demonstrated that the sympathetic nervous system is implicated, however, other contributing factors are not accounted for (e.g., it is unknown what percentage a patient’s hypertension is caused by the sympathetic nervous system).

It was noted that no patient population clearly stands out because the efficacy is uncertain.  [The SYMPLICITY criteria of SBP >160 (150 in DM) and refractor HTN is reasonable to study as long as truly refractory]. Thus, the procedure should be performed mostly within the confines of research studies. Because of concerns regarding efficacy, it is not recommended that all patients with refractory hypertension be considered for RDN.

It was suggested that a case could be made for allowing the procedure to be performed in patients with mod-severe elevations in BP (160/100 mm Hg or higher; especially if target organ damage is present) and who are clearly not able to tolerate or adhere to therapy.  Therefore, despite questions regarding efficacy, a case could be made that the benefits outweigh the risks even if the procedure largely produces some kind of ‘placebo’ response.  But, few patients would be in this category.

Provide and discuss recommendations for action to be taken for currently licensed renal denervation systems in light of the currently available clinical trial data.

It was suggested that since these devices are licensed, one could allow these to remain licensed to allow ‘compassionate’ or ‘last resort’ cases to be done.  These should only be done in the context of:

• A fully informed patient;
• A specialty hypertension clinic to manage the patient;
• Experienced interventionalists.

Do you feel Health Canada should require more rigorous clinical trial data from novel cardiovascular medical device technology prior to licensing them for use in Canada?

It was recommended that the SYMPLICITY-HTN-3 trial be used as the standard with the addition of the requirement for an experienced operator.

Dr. Padwal concluded by acknowledging that truly resistant hypertension is not as common as believed.  He noted that better research data for renal denervation is needed (both mechanistic and clinical) and that further research, such as developing an appropriate procedure-assessment tool, is required before routine clinical use can be implemented.  Finally, more attention should be paid to proper methodology in clinical studies.

Dr. Padwal left the meeting.

5. Use of LAA Closure Devices, Clinical Requirements and Patient Populations

Dr. Reda Ibrahim, Guest Speaker

What level of clinical evidence is required to be confident in the safety and effectiveness of implantable endocardial Left Atrial Appendage (LAA) closure devices?  The target population for these devices is typically patients with non-valvular atrial fibrillation who are at increased risk of stroke due to thrombotic emboli originating from the LAA.  The gold standard for prevention of strokes in the non-valvular AF patients at greatest risk of stroke according to their CHADS₂/CHA₂DS₂-Vasc score is medical anticoagulation or antiplatelet (e.g., aspirin, warfarin).

Dr. Ibrahim thanked the committee for inviting him as a guest speaker. Before proceeding to address the topics provided by Health Canada he provided a short bio and declared his affiliations.

Dr. Ibrahim provided a brief overview of anticoagulation in atrial fibrillation (AF) as well as the limitations of the anticoagulant treatment and he outlined the rationale for Left Atrial Appendage Occlusion (LAAO) as a response to AF being associated with poor atrial contractility. He described type of patients who are at high risk of bleeding.

As a clinician, what level of evidence would you like to see to be confident in the safety and effectiveness of the implantable LAA closure devices? Please comment on:

1. Appropriate clinical endpoints (e.g., ischemic or hemorrhagic stroke);

Dr. Ibrahim noted that regarding the effectiveness of the implantable LAA closure devices, the following clinical endpoints should be required:

• Evidence of stroke prevention (ischemic and hemorrhagic);
• Evidence of systemic embolism prevention;
• Evidence of death prevention (total and CV).

In addition, regarding safety of the implantable LAA closure devices he recommended that the following primary endpoints should be required:

• Evidence of minimal complications per procedure;
• Evidence of minimal bleeding episodes.

2. Non-inferiority or superiority trial designs;

Dr. Ibrahim suggested that a superiority trial run against a placebo or an antiplatelet agent may be considered ethical; however, if the device is compared to warfarin or novel oral anticoagulants (NOACs), a non-inferiority trial would be sufficient.

3. Appropriate comparators for clinical safety (warfarin, NOACs);

He noted that NOACs are appropriate comparators for clinical safety as they are a safer choice when decreasing intracardial bleeding.

Dr. Ibrahim recommended Apixaban as the NOAC of choice.

4. Appropriate patient population;

Dr. Ibrahim suggested that an appropriate patient population would include patients with an elevated risk of bleeding (e.g., geriatric patients).

He noted that antiplatelet agents are not sufficient on their own to protect patients against stroke.

5. Appropriate duration of follow-up (both for pre-market and post-market monitoring). It was suggested that the appropriate duration of pre-market follow-up should be at least 6 weeks (preferably 1 year).  Most complications related to LAA closure occur within 6 weeks (peri-procedural) and most of the patients have a TEE at 45 days to exclude thrombus and/or significant residual flow around the device.

It was suggested that within the field of LAA closure, post-approval studies should be a condition to pre-market approval to assess:

• Device safety;
• Effectiveness;
• Reliability in the real-world setting;
• The learning curve;
• Effectiveness of training programs;
• How well device performs in certain groups of patients.

It was noted that the appropriate duration of post-market follow-up should be at least 1 year (preferably 5 years). 

Are there patients that can be appropriately treated today with some of the devices in development that have sufficient clinical evidence to be licensed in Canada?  Discuss the available clinical evidence that provides you with sufficient confidence to use these devices.

Dr. Ibrahim commented on numerous sources of clinical evidence including:

• Prevention in patients with non-valvular atrial fibrillation (PREVAIL) trial;
• Aspirin and Plavix^® registry (ASAP registry);
• Multicenter experience with the amplatzer cardiac plug (ACP);
• Canadian registry.

He discussed the Randomized Trial of LAA Closure vs. Warfarin for Stroke/Thromboembolic Prevention in Patients with Non-valvular Atrial Fibrillation (PREVAIL). The PREVAIL trial was a prospective randomized evaluation of the WATCHMAN™ LAA Closure Device in patients with atrial fibrillation versus long term Warfarin therapy.  The trial included 407 patients from 41 US centers.  Enrolled patients experienced significantly less complications and a 95% implant success rate.

Dr. Ibrahim noted that one of the challenges with the PREVAIL trial, pertained to the efficacy endpoint. The first co-primary efficacy endpoint at 18 months follow-up was missed because of the exceptionally low number of strokes that occurred within the Warfarin group (control). The WATCHMAN™ device did achieve non-inferiority, however, for the second co-primary efficacy endpoint (stroke or systemic embolism >7 days after the randomization).

Regarding the question whether the WATCHMAN™ device is an appropriate alternative to Warfarin therapy Dr. Ibrahim noted that it is unsuitable since Warfarin is no longer the standard of care.

Next he discussed the Aspirin and Plavix^® registry (ASAP registry). The ASAP registry is a non-randomized feasibility study designed to determine if the WATCHMAN™ device is a safe and effective treatment for people unable to take Warfarin. The registry included 125 patients from 4 European centers. The average CHADS₂ score of enrolled patients was 2.7 and the post-procedure anti-platelet regimen included intake of clopidogrel over six months as well as an indefinite uptake of Aspirin.  Patients were followed-up for up to one year after 3, 6, 12, 18, and 24 months. In addition, A TEE was conducted at 3 and 12 months to check proper placement of the device and closure of the LAA. The ASAP registry showed 3 ischemic strokes (3.75% vs 7.37% expected rate) and 4 patients with device-related thrombus.

Dr. Ibrahim also discussed the Multicenter Experience with the Amplatzer Cardiac Plug (ACP). He noted that the Amplatzer Cardiac Plug (ACP) is a well-proven technology thus far. The largest registry (969 patients and 1216 patient follow-up years) has recently been published wherein the three main indications for LAAO were: previous major bleeding, high bleeding risk, and coronary (CAD) stenting.  The registry demonstrated a high success rate of 97% with a 4% rate of complications (0.6% death rate) and, in terms of efficacy, a 60% reduction of bleeding risk and a 60% reduction in stroke.

What are considered to be the best medical practices for anticoagulation or antiplatelet therapy for implantable endocardial LAA closure devices being studied, both pre-operatively and post-operatively? 

Dr. Ibrahim noted that pre-operatively: most patients are treated with antiplatelet agents following bleeding episodes. 

Post-operatively:

• Following WATCHMAN: at least 6 weeks of anticoagulation followed by 6 months of DAPT before monotherapy.
• Following Amplatz Cardiac Plug: 3 to 6 months of DAPT (based on the experience with other Amplatzers) followed by monotherapy.

Are there other available therapies (e.g. AF ablation) that are changing what an appropriate comparator group would look like for clinical studies?

Dr. Ibrahim mentioned two future randomized studies:

• LAAO versus antiplatelet agents in patients with bleeding or at high risk of bleeding;
• LAAO versus NOACs (Apixaban) in patients eligible to anticoagulation.

Dr. Ibrahim noted that AF ablation is not an alternative to anticoagulation.

Is surgical closure of the LAA still frequently done if there is a concomitant open heart procedure being done on a patient deemed to be at risk for stroke?

Dr. Ibrahim noted that LAA occlusion is still being performed during surgery for the following patients/procedures:

• In patients with thrombus in the LAA;
• During valve repair or replacement;
• In the context of research projects.
• In patients with bleeding on anticoagulation.

In conclusion Dr. Ibrahim noted that there is a clear clinical need for an alternative to oral anticoagulation in patients with AF.  Left Atrial Appendage Occlusion is a safe and effective procedure to prevent ischemic and bleeding events and it should be considered as an alternative to Warfarin and/or for patients who bleed on anticoagulant therapy.

6. TAVI - Clinically Significant Technological Features

Dr. John Webb, Committee Member

There are several new unlicensed TAVI products with new design features that may make them superior for an aspect of the surgical procedure compared to licensed devices.  Discuss the potential benefits of the new designs over licensed alternatives.  Health Canada would like to better understand how much these new features may benefit the patient and when they become reason enough to allow access to an unlicensed device through the Special Access Program (SAP).

In your discussion, consider the following patient specific concerns and whether the newer designs address them.

• Coronary ostium height;
• Sinus of Valsalva diameter;
• Degree of calcification;
• Oblong or irregular shaped annulus;
• Valve size;
• Need for embolic protection;
• Route of delivery.

Dr. Webb declared his affiliations and proceeded to provide a brief overview of transcatheter valves before addressing the discussion points outlined by Health Canada. 

He noted that currently there is a wealth of data on transcatheter valves including data from the CoreValve US pivotal trial high risk study; a randomized, controlled trial comparing CoreValve transcatheter aortic valve implantation (TAVI) to surgical valve replacement in a high risk patient population.  The trial data demonstrated a dramatically lower mortality rate in high risk (7.8% STS score) patients. 

He explained that over the last decade, the number of TAVI patients has increased, especially as vascular complications and death rates decrease.  The draw to TAVI is largely being driven by morbidity; TAVI patients have shorter hospital stays, less post-procedural pain and a quicker recovery in terms of mobility. However, as the number of patients accepted for TAVI increases, waitlists grow longer and, consequently, more patients die before they receive treatment. 

Transfemoral (TF) TAVR reduces procedure time and has fewer complications due to the smaller catheter sizes now available.  These favorable outcomes have led to increased funding.

He described some of the New Valve Features such as:

• Repositionable valves: the key to a successful implantation is control and accuracy.  Valves can be implanted too high or too low which may cause leaks and embolisms.  In order to address the concerns over implantation, repositionable valves were developed to allow for valve repositioning after deployment.
• Self-positioning valves: motorized delivery allows for stable deployment and single operator use.  Self-positioning valves are designed to facilitate multiple interventional and surgical delivery approaches.
• Valves with clip delivery:  these valves actively clip onto the native leaflets which allow implantation of calcified valves.
• Bicuspid valves have been considered an exclusion for transfemoral TAVI, however, with new features being introduced, newer valves do very well in the bicuspid.       

Different valves have different implications (e.g., a self-expanding valve may not have good hemodynamics if it has not been fully expanded) and these differences influence the decision to choose one valve over another for any particular patient. 

Stroke and TAVI

• The risk of stroke is lower with TAVI than with surgical approaches.
• The Claret Medical Sentinel™ is a popular embolic control device designed to capture and remove debris dislodged during endovascular procedures.  It utilizes a proximal embolic filter delivered to the brachiocephalic artery, and a distal embolic filter delivered to the left common carotid artery.  A large randomized trial using this device is ongoing.

Paravalvular Leaks and TAVI

• A paravalvular leak is a complication associated with the implantation of a prosthetic heart valve whether surgical or a TAVI approach.  A leak occurs when there is a lack of appropriate sealing between the structure of the implanted valve and the cardiac tissue and even mild leaks can be associated with late mortality.  Improper sealing can occur if:
  • The valve is too small;
  • The valve is deployed too high;
  • The valve is deployed too low;
  • The valve is under-expanded.
• Possible Solutions
  • Self-expanding valves: while these valves may address the issue of fit, they tend to recoil and repositioning techniques such as snare will cause a greater risk of stroke.
  • Variety in valve sizes: there is now a larger variety of valve sizes and physicians have become better at sizing.  The gaps between each valve size, however, remain significant. 

Coronary Occlusion

Coronary occlusion can be a life-threatening complication of TAVI.  A patient being considered for TAVI is considered high risk if their coronary artery is less than 12 mm from the annulus because the risk of the native leaf pushing up over the coronary artery and causing a coronary obstruction is higher.

Native Leaflets Incorporated: JenaValve, Engager, Helio Sapien

• The JenaValve™ TAVI System includes additional features to first generation valve implantation systems.  It is repositionable during implantation procedure to ensure correct and precise positioning within the native valve. 
• The Engager seals the annulus by capturing the native leaflets with the control arms and conforming to the anatomy with the self-expanding frame.  This feature helps reduce the risk of paravalvular leaks and coronary obstruction.
• The Helio dock system acts as an anchor to help stabilise the SAPIEN XT valve for patients with aortic insufficiency. The native leaflets in the heart are captured between the transcatheter heart valve and the dock.

Durability

Taking all TAVI studies into account, the mean age of TAVI patients is 83 years old.  In an 83 year old patient, the TAVI valves are expected to last for 5.5 years. Routinely, TAVI valves will last for at least 5 years, however, many will last longer.

Dr. Webb noted that more surgeons are moving towards bio-prosthetic valves.  The durability associated with valve-in-valve implants is unknown; however, they are expected to have a shorter lifespan since they are not fully inflated.  It should be noted that some surgical valves are not suitable for valve-in-valve procedures.  For example, with a small surgical valve, a valve-in-valve procedure would not be suitable simply due to the hemodynamics. 

Dr. Webb shared his own experience with the stentless valve with the Committee.  He mentioned that, in his experience, these valves did not last as long because they did not possess the structural support.  The stentless valves began to fail between 7 and 9 years after the procedure was done. 

Dr. Webb stated that the issue of durability, is only an issue for intermediate risk patients (with an average age of 60) since they will likely outlive their valve.  For these intermediate risk patients, however, the valve-in-valve procedure becomes an option. 

The “Perfect” Valve

Dr. Webb presented a list of features that would contribute to a “perfect” valve: 

• Lower profiles to minimize vascular injury;
• Femoral, apical, aortic, and subclavian access options;
• Features that facilitate accurate positioning;
• Repositionable/removable abilities;
• Zero risk of paravalvular leak (e.g., have various types of sealing)

Pacemakers

The cost associated with pacemakers is higher because of the following factors:

• Longer hospital stays;
• Long-term monitoring;
• They need to be replaced.

For the above-mentioned reasons, pacemaker and core-valve referral rates have fallen to between 12 and 30%.

Health Canada is becoming increasingly aware of some imaging abnormalities associated with some of the TAVR devices, specifically with leaflet motion.  Could you please comment on that?

Dr. Webb spoke about a US trial in which, on occasion, the CT scan would show that one of the leaflets did not open.  None of the patients in the trial experienced any clinical events.  Therefore, he noted that one can stipulate that what’s happening here is related to an imaging abnormality rather than to sub-clinical outcomes.

Dr. Webb, Dr. Ibrahim and Dr. Yee left the meeting. Dr. Yee will return for his presentation.

7. Aortic Dissection devices - Treatment approach, patient population, dissection type, appropriate control

Dr. Prasad Jetty, Guest Speaker &

Dr. Thomas Forbes, Guest Speaker

Dr. Prasad Jetty and Dr. Thomas Forbes were invited to address this topic. They introduced themselves and both indicated that they had no disclosures to declare and proceeded to address the topics identified by Health Canada.  Dr. Jetty opened the discussion. He provided a brief overview of aortic dissection.

He noted that an aortic dissection is a spontaneous tear in the innermost layer of aorta (intima) allowing blood to be driven into the media layer, creating two channels for blood flow. If the tear continues, it can interfere with the visceral vessels or could potentially lead to a stroke.  Aortic dissection is typically caused by hypertension and is often uncontrolled.  It is a rare condition that affects men and is observed more often in Caucasians and African Americans. 

He explained that there are two types of aortic dissections:

• Uncomplicated: not interfering with any of the branch vessels.
• Complicated: the false lumen can expand and rupture or compress the true lumen.  If the carotid artery is affected, a stroke can occur.  

Dr. Jetty noted that an aortic dissection is caused by a tear in the intima, whereas, an aneurysm is a gradual deterioration of the aortic wall. It is asymptomatic and risk of rupture and death are dependent on diameter of aneurysm.  

Currently, the gold standard for identifying an aortic dissection is a CT scan.  This scan will help identify the location of the tear which will allow for appropriate classification of the dissection.  Classification determines how to proceed with management of the tear.  If the tear is in the ascending aorta, for example, it can propagate and is considered a Type A dissection (surgical emergency, close to the coronary and arch vessels, risk of death is significant).  If the tear occurs in the descending thoracic aorta, it is considered a Type B dissection. Management for a Type B dissection is determined by whether the dissection is considered complicated or uncomplicated.

Type A Dissection Repair:

• Emergency cardiac surgery;
• resection of intimal tear;
• replacement of the affected aorta with graft;
• reconstitution of flow through true lumen;
• 25% operative mortality.

Type B complicated (rupture or malperfusion) Dissection Repair: There are two options for repair:

• Option one: an open surgical repair. For many years open surgery was the only option. However, due to the high mortality rates, this type of management has been abandoned for acute Type B aortic dissections.
• Option two: an endovascular repair with a stent graft. Through small, percutaneous incisions, a device is delivered through the femoral artery into the thoracic artery and a stent is deployed. The goal of the repair is to seal the proximal tear site, re-expand the true lumen and obliterate the false lumen or have it thrombus. This type of management is less invasive and has a much lower morbidity and mortality than the surgical repair.

A question was posed to Dr. Jetty regarding the possibility for a randomized control trial that looked at endovascular repair using stent grafts in Type B dissections. Dr. Jetty noted that stent grafts have a good track record in the aorta for thoracic aneurysms.  The incidence rate of type B dissection is extremely low; therefore, a randomized control trail would not be feasible or ethical.  

STABLE Trial on Aortic Dissection was described. Rather than opening the chest cavity and clamping off the aorta to surgically implant a graft to treat the damaged section of the thoracic aorta, physicians insert a catheter loaded with a self-expanding, fabric covered stent-graft through a surgical opening in the femoral artery. The catheter is guided through the patient’s blood vessels under fluoroscopy until the device is positioned across the dissected section of the aorta. The stent-graft then expands upon deployment from the catheter to reopen the original path through the aorta and should reduce blood flow into the false pathway in the damaged vessel wall, thereby restoring normal aortic blood flow. The uncovered Zenith Dissection Stent is used to expand the true lumen in the distal thoracic aorta where preservation of the side branch artery blood flow is critical.

Type B uncomplicated Dissection Repair: the visceral vessels and the carotid are not compromised in an uncomplicated dissection.  A significant proportion of uncomplicated dissections become complicated (in the range of 30%) and, after these patients’ aorta is dissected, they do not have the same life expectancy (after 5 years, approximately 60% have died).  As is the case in a complicated repair, there are two options:

• Option one: optimal medical therapy in the form of antihypertensive medication and monitoring.
• Option two: intravascular stent repair. 

Traditionally, in Type B uncomplicated dissection, patients are treated non-operatively.  Patients will be put on optimal medical therapy and will require lifelong CT surveillance to ensure the false lumen does not expand and rupture.

Dr. Jetty concluded his presentation with a case report in which the STABLE procedure was used to address a Type B uncomplicated dissection repair.

Dr. Forbes continued the discussion.  He outlined the objectives of his talk:

• Incidence, etiology, classification, progression, outcome of aortic dissection;
• Difference between Aortic Dissection (AD) and aneurysms.
• Clinical guidelines for acute and chronic AD;
• Evidence for treatment of AD with stent grafts;
• Challenges for RCT to compare open surgery vs. stent graft vs. medical management;
• Stent graft requirements for AD’s;
• Evidence of necessary for PMA of new stent graft;
• FDA approach, i.e., single arm studies etc.

Dr. Forbes reviewed the difference between the two types of dissections:

• Type A: involves the ascending aorta.
• Type B: involves the descending aorta.

Type B dissection involves the aorta from the top down to the thoracic and abdominal aorta.  It can also involve the branches (to the spinal cord, legs, kidneys, etc.). Type B Aortic Dissections
Are defined as follows:

• Acute: within 2 weeks of dissection (occasional patient with a silent dissection with no symptoms).  Can be misdiagnosed as a myocardial infarction (MI).
• Subacute: 2 weeks to 3-6 months.  Longer term complications.
• Chronic: greater than 3-6 months.

Acute uncomplicated: all patients with type B aortic dissection will undergo hypertension control.  If the pain resolves and the aorta does not expand or rupture, these patients are denoted as acute uncomplicated. 

Acute complicated: within the first 2 weeks of dissection but the patient is failing medical management.  The complications can include: aorta expansion, persistent pain, or the new channel can compress the blood supply to important organs called a malperfusion. 

Chronic: if the patient survives the first acute phase, they are left with a dissection and will have a lifelong dissected aorta which may or may not dilate depending on progression of medical management.  If the dissection becomes complicated, the patient will develop an aneurysm. 

Acute Aortic Syndrome

There are a number of pathologies that can present in the thoracic aorta; these include aortic dissection, intramural thrombus, and penetrating atherosclerotic aortic ulcer.

Dr. Forbs described available Clinical Guidelines:

The Canadian Guideline “CCS/CSCS/CSVS Position Statement on Thoracic Aortic Disease Interventions” is currently being written.

Dr. Forbes noted that the US Clinical Guidelines were published in 2010.  He highlighted that the Guidelines recommend that acute dissections be managed medically unless they are complicated.  When the dissection is complicated, the recommendation for management was endovascular repair.

He summarized recommendations of the European Guidelines:

• For Type A: surgery.
• For Uncomplicated Type B: medical therapy.
• For Complicated Type B: endovascular repair.

He noted that prior to Stent Grafts:

• Uncomplicated Type B aortic dissections: treated medically.
• Complicated acute Type B AD’s: treated with open surgery, which was associated with high mortality, morbidity and poor long term outcomes.
• Currently, Rx of complicated acute and aneurysmal chronic Type B AD’s has shifted towards stent grafts.

Dr. Forbes commented on three key aortic dissection trials:

• Acute, complicated Type B AD—STABLE Trial.
• Acute, uncomplicated Type B AD—ADSORB Trial.
• Sub-acute, uncomplicated Type B AD—INSTEAD-XL Trial.

The STABLE Trial focused on complicated dissections.  It was a small study and most of the patients were acute (earlier in presentation, the higher the complication rate).  Also, the majority of the patients had a degree of dilation and malperfusion.  An uncovered dissection stent, specifically designed for this indication was used.  The aim of the trial was to expand the stent so it could be placed across the vessels.  If a covered stent had been used, the origin of the vessels would be occluded. 

The ADSORB Trial focused on acute, uncomplicated dissections.  The trial compared optimal medical therapy (OMT) to TEVAR and OMT.  In this trial, rather than patient-specific outcomes, the main endpoint was aortic remodeling.  There were 30 patients randomized to each group (no in-hospital deaths).  Initial results for the trial showed that the TEVAR and OMT group had better results in terms of aortic remodeling.  The long term data has not yet been obtained.

The INSTEAD-XL Trial looked at endovascular repair of Type B aortic dissection.  It published longer term data of the randomized investigation of stent grafts in aortic dissection.  The two year data showed no advantage to a stent graft while the 5 year data showed improved survival, fewer deaths due to aortic problems and non-aortic problems.

Dr. Forbes outlined the main predictors of aortic dissection as follows:

• Younger age;
• Larger aortic diameter;
• A large false lumen that does not thrombose in the acute or sub-acute phase;
• Degree of false lumen thrombosis;
• The number of tears between the two channels.

He provided a summary of existing evidence:

• Acute complicated type B dissections, whether aortic expansion or malperfusion, are treated endovascularly with stent grafts.
• If possible, a period of medical management might be beneficial since results in the subacute phase are better than in the acute phase.
• Some long term benefit to patients treated with stent grafts in the subacute phase (INSTEAD-XL).
• It remains unclear whether acute, uncomplicated Type B aortic dissections should be treated early (with a stent graft) or not (ADSROB).

He noted that dissections are very complex and require lifelong management. Endovsacular repair of Type A aortic dissections has some status of approval on a compassionate level for patients that are turned down for open repair. 

Stent Grafts for Type B Aortic Dissections

Dr. Forbs noted that most stent graft systems are designed for aneurysms. There are covered and uncovered stents.  

Some of the different features include:

• Proximal configuration—retrograde dissection (bare metal upper stent to allow secure fixation).  Some stents have hooks or barbs that latch on to the aorta to hold it in place and others are covered right proximal.
• A retrograde Type A dissection usually results in death.  Some predictors are design features such as a bare stent.  Barbs have been associated with retrograde Type A dissections; therefore, many surgeons chose their grafts for dissections differently than they chose them for aneurysms.  It could be more of an oversizing issue than a proximal component of the stent graft since, when measuring the diameter of the aorta; the need to oversize is even less than in other procedures. 

Next he provided an overview of the FDA Regulatory Approach:

• TEVAR for Type B aortic dissections and BTAI had become “standard of care” in US, but no approved TEVAR device for these indications.
• Gore TAG device approved for TAA but not for other pathologies.
• Optimally RCT data would support new indications but low incidence, variability, lack of clinical equipoise between stent graft and open repairs.
• Single arm studies.
• With absence of control arm, need a prospectively defined measure of success.
• For dissections, data was collected from five IDE study, a common set of definitions was set and applied retroactively.
• Master file provides comparative group.
• Pre and Post-market studies, non-pathology specific approval.

FDA Regulatory Response

• FDA met with societies and industry to best evaluate stent grafts to support labels that would cover all the pathologies they were used for after their approval for TAA in 2005.
• Because of difficulty with studies (RCT etc.), FDA agreed to allow a broad indication for an individual endograft (rather than specific lesion type).
• Submission of safety data for treatment of TAA, BTAI, acute complicated Type B aortic dissections.

This concluded the presentation.

Dr.’s Jetty and Forbes thanked the Committee for the opportunity to present at this meeting and left the meeting.

Dr. Menkis left the meeting.

Dr. Yee returned to the meeting to deliver his presentation.

8. Intracompatibility between IS-4 Leads and Cans

Dr. Raymond Yee, Committee Member

In advance of the release of ISO 27186 - Four pole connector system for implantable cardiac rhythm management devices - Dimensional and test requirements the Scientific Advisory Committee was asked to comment on appropriate clinical study requirements. Since then, both IS4 and DF4 leads, as well as compatible pulse generators have been licensed in Canada.

Dr. Yee declared his affiliations and proceeded with a brief introduction before addressing the questions posed by Health Canada.

Dr. Yee noted that there were two basic standards that dealt with the connection between the lead and the generator.  The first standard is the IS-1 standard (introduced in early 1990s) which governs unipolar and bi-polar, low voltage pacing leads.  There was then a DF-1 standard which covered unipolar defibrillation coils.  Since there are now leads that require more than 2 electrodes, there was a need for new standards. The DF4/IS4 standards apply to leads with 3 to 4 electrodes. 

He explained that the IS4 is a low voltage pacing lead and the DF4 is a high voltage lead involving pacing and defibrillation. 

He discussed the adoption rate of DF4 Leads vs. DF1 Leads. Initially, the percentage of DF4 leads was less than 10%, however, that number has now settled in at about 20-25%.  The vast majority of leads implanted now are DF4 standard.  Other manufacturers show a similar trend.  This trend suggests that the DF4 has been adopted by the medical community.   

He summarized issues addressed by IS4/DF4:

• Interchangeability between manufacturers;
• Lead complexity;
• Operator errors - misconnects;
  • Reduced the complexity.  With only one pin, there is less risk of operator error. 
• Hardware bulk.
  • The yoke is immediately removed which was a source of physician complaint.

He explained that when comparing a DF1 and a DF4, the DF4 is much more complex.  With the DF4, all four electrodes form one connector and go into one port which streamlines the port. 

Dr. Yee described issues Created by IS4/DF4:

• Legacy IS1/DF1 systems and generator replacements;
• High implant DFT’s (Cogert, HRJ 2012);
• Isolated component failures;
• Pacing
  • If the physician’s preference is to implant the lead with the tip at the apex, another lead must be added for pacing.  This cannot be done with the DF4.
  • If the pacing sensing component of a lead fails, the DF4 lead must be abandoned and replaced with a DF1 lead.
• Sealing ring/connector variability (Bracke, HRJ 2014).

After this brief overview Dr. Yee proceeded to address the questions posed by Health Canada.

Provide an update on the available clinical data for the DF4 leads, especially as it relates to adverse events, lead fractures, inconsistent results between lead manufactures, and anything which should be given special consideration during regulatory review.

Dr. Yee noted that there is no major evidence suggesting that there is a signal of concern for reliability in DF4 leads or IS4 leads.  There has only been one IS4 issue reported where there was an insulation issue in which the conductor wires on the inside could abrade and permeate through the insulation of the lead. 

Dr. Yee mentioned that there are no concerns of integrity of the DF4 family.  It has been 2-4 years now and the medical community has not observed any signal suggesting reliability problems. 

Provide an update on the available clinical data for the IS4 leads, especially as it relates to rates of phrenic nerve stimulation, adverse events, and claims of improved CRT response, and anything which should be given special consideration during regulatory review.

IS4 LV leads (quadripolar LV leads): limited publication on some of the manufacturers. 

Dislodgment rates are not zero (the hope for the IS4 leads was that the likelihood of stability would increase so that the two best placed poles are chosen).  Also, there is no control over the caliber of the veins.

Regarding nerve stimulation, there have been four reports where the rates of femoral stimulation range from 10% to 40%, vein choose is crucial.  If a lateral vein is chosen, nerve stimulation can be avoided.  Having four electrodes grants more flexibility and can eliminate stimulation issues (though not entirely).

Clinical Response

There is no clinical response data currently available.  There is acute and short term data dealing with dual LV site pacing. A clinical trial will be starting in Canada to look at the use of quadripolar and clinical response to CRT therapy. 

Currently, two kinds of data exist:

• Data looking at dual LV site pacing where two separate leads are placed into two separate veins (different from quadripolar leads). 
• Three small sample size studies comparing routine pacing versus dual LV site pacing in two separate veins. 
  • The first study used echo and results demonstrated that better echo parameters (time for ejection of blood) were reported suggesting the dual pacing was slightly better. 
  • Similarly, the TRUST study claimed that NYHA improved by 1.4 classes versus 1 class. 
  • The third study suggested that patients could walk further (25 meters).

Dual site LV pacing has two separate leads in two separate veins.  The IS4 quadripolar LV leads do not have that, they put all four electrodes in one vein and there is very little data to support that that works. 

There is no long term data showing that response rate to CRT using the ISF improves response.

The interchangeability between implantable leads and pulse generators from different manufacturers was to be one of the benefits of ISO 27186, though there are reports of failed interoperability, is this a concern amongst the clinical community in Canada?

Dr. Yee highlighted one area, noting that it may not be the root cause of the problem.  The dimensions and properties of the leads are well specified.  The difference between the IS4 and IS1 are the sealing rings.  On the IS1, the sealing rings are reasonable for blocking fluid from ingressing into the port (causing a short out of the connection).  With the DF4 standard, there are no sealing rings on the lead; they are on the connector blocks themselves.  There is no way of taking a DF1 lead and pushing it into the DF4 block.

Dr. Yee stated that he had contacted companies to ask about what they thought was the root of the problem.  The response he received was that the standard is fairly robust and specific but that there is one aspect that is not spelled out which is robustness.  They noted that when it comes to pushing this lead into a DF4 connector head, user is  informed how much force to apply in order to get it inserted properly, however, it is not specified what happens to the lead as it is being gripped and pushed.  The segment just beyond what is covered by the DF4 standard may be more malleable than desirable which means that when the lead is pushed, it flexes.

DF4/IF4 incompatibility amongst manufacturers is an annoyance for physicians; however, it is not a major concern.  The percentage of implants that mix manufacturers is unknown; however, it is likely the minority and can be overcome using mineral oil.

9. Late Breaking Issues in Cardiovascular Devices

Prior to moving on to closing remarks, the Committee participated in a brief discussion on late breaking issues on cardiovascular devices.

1. Bioabsorbable Vascular Scaffolds and their Appropriate Patient Populations
   Ian Aldous , Medical Devices Bureau (MDB),

Round-table, Committee Members

Health Canada provided a brief presentation of the topic. It was noted that the bioabsorbable scaffolds present a unique platform for vascular stents.  Some recent studies (ABSORB II) have suggested that drug eluting bioabsorbable scaffolds perform in a similar manner to some of the other traditional drug eluting stents. 

Currently, there are two types of bioabsorbable vascular scaffolds:

• PLLA stents: the stent is covered in a bioabsorbable polymer.
• An entirely bioabsorbable scaffold.

Health Canada posed number of questions to the committee members:

Are there any clinically important differences in terms of typical clinical use or clinical outcomes between the traditional DES and drug eluting bioabsorbable scaffolds?

Is there a particular patient population for which drug eluting bioabsorbable scaffolds are better suited than traditional stenting?  Who do you predict will get bioabsorbable scaffolds in Canada if one were to be licensed?

The Committee agreed that if there is a licensed alternative on the market, the new product needs to show superiority.  Currently we have a gold standard: flexible, drug eluting, second generation stents.

Regarding a particular patient population, the Committee noted that patients in need of re-stenting could be good candidates since these stents are being sold as potentially less thrombogenic and better for “access to site” for future procedures. 

The risk profile of bioabasorbable stents is different than traditional stents in that they are not permanent.  How important is it to you as a clinician that the stent is not a permanent implant?  Based on the different risk profile of a bioabsorbable scaffold, to what should they be compared to?  (i.e., DES, BMS, angioplasty, medical therapy, non-inferior vs. superior).

The Committee noted that there is a theoretical disadvantage because the structure disappears after 12 months; the vessel may have contracture that is prevented by the presence of the scaffolding. 

The main difference is that bioabsorbable stents are bulkier, hard to introduce. Thrombosis rate is not better.  There does not seem to be any advantage in using bioabsorbable stents at this time.

The Committee recommended that the device must be equivalent to the gold standard stent, especially with regard to thrombosis and restenosis. 

2. Dual Antiplatelet Therapy- Responses to dual antiplatelet therapy duration clinical trial results from AHA

Kevin Day, Medical Devices Bureau (MDB),

Round-table, Committee Members

Late-stent thrombosis concerns erupted in 2006, have triggered a flurry of investigation on how long dual antiplatelet therapy would need to be continued. The many observational and predominantly small- to moderate-sized studies were inconsistent and inconclusive, though, leading the FDA to mandate what became the DAPT trial. It randomized people to discontinue use of clopidogrel (Plavix) or prasugrel (Effient) plus aspirin either 12 or 30 months after coronary artery stenting. The risks and benefits of long-term dual antiplatelet therapy remain unclear. Optimal duration of dual antiplatelet therapy (DAPT) after DES implantation might be shorter than currently recommended 1-year interval.

The Committee was asked to comment on optimal duration of dual-antiplatelet therapy. Members stated that there are two reasons for which a patient is put on antiplatelet therapy after a stent is implanted.  The first is due to the stent and the second is due to the other arteries. If a patient is put on dual-antiplatelet therapy for 1 month versus 12 months, there is a 20% reduction in myocardial infarction and stroke at 12 months.  It is not surprising, noted the Committee, that there may be some benefit to prolonged dual antiplatelet therapy like less stent thrombosis and less thrombosis in other arteries. 

10. Next Steps, Closing Remarks and Adjournment of Meeting

Dr. John Ducas, Committee Chair

The Chair thanked committee members and Health Canada staff for their participation and valuable input.  He highlighted the importance of attendance to these meetings and asked that members make attending future meetings in their entirety a priority in the future. This will allow full participation to all topics discussed.

Members will be canvassed to select a date for the next meeting.

Meeting adjourned.