Scientific Advisory Committee on Medical Devices used in the Cardiovascular System Summary of Proceedings June 17, 2021

June 17, 2021

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.