FDA panel says risks of radiofrequency renal denervation device outweigh benefits
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Key takeaways:
- An FDA panel voted that for adults with uncontrolled hypertension, the benefits of a radiofrequency renal denervation device do not outweigh its risks.
- Panelists said any reduction in BP was modest.
A slim majority of FDA advisory panelists rejected that the benefits of a radiofrequency renal denervation system outweigh the risks for use in adults with uncontrolled hypertension despite use of antihypertensive medications.
Responding to the question during a meeting of the FDA’s Circulatory System Devices Panel of the Medical Devices Advisory Committee, panelists initially voted 6-6, with one abstention, that the benefits of the Symplicity Spyral radiofrequency renal denervation system (Medtronic) outweigh the risks for adults with uncontrolled hypertension, leading the panel chair, Richard Lange, MD, MBA, to break the tie and also cast a “no” vote.
Panelists also voted 7-6 that the radiofrequency renal denervation system is effective for use in patients with uncontrolled hypertension, and unanimously (13-0) supported the device’s safety.
If approved, the system would have an indication for the reduction of BP “in patients with uncontrolled hypertension despite the use of antihypertensive medications or in patients in whom BP lowering therapy is poorly tolerated,” according to briefing documents from the FDA and Medtronic. The device received an FDA breakthrough device designation in March 2020.
During the meeting, some panelists expressed concerns about a modest reduction in BP with the device, as well as the potential for device overuse among clinicians.
BP reduction ‘mild at best’
“While this is a very safe procedure, the efficacy was mild at best and only was at 3 months,” Keith Allen, MD, director of surgical research at St. Luke’s Hospital of Kansas City, Missouri, said after the vote. “Once medicines were re-introduced, that [benefit] went away at 6 months and the SPYRAL HTN-ON MED trial was negative. We sometimes think the threshold for efficacy should be lower when the device is very safe, we still have to think of the overall health care burden particularly of devices that are going to be used in patients, and whether that is appropriate.”
However, some panelists stated they were comfortable that data presented during the meeting did show a BP benefit, with some members noting that there was heterogeneity of effect with some participants experiencing a significant BP reduction.
“My voting was influenced by two things: I was comfortable with the bulk of the data presented, and the unmet need and the fact that hypertension has not been effectively treated with current tools,” Randall Starling, MD, MPH, professor of medicine at the Heart, Vascular and Thoracic Institute at the Cleveland Clinic, said after the vote. “More tools are needed to treat BP.”
Robert Yeh, MD, MSc, MBA, director of the Center for Outcomes Research in Cardiology at Beth Israel Deaconess Medical Center in Boston, agreed the device could fill an unmet need.
“We can quibble about the magnitude ... there was variation in the effectiveness,” Yeh said after voting in support of the device. “There will be patients who would benefit. It will behoove the committee to identify who those patients are. Making the device available will help the community identify who those patients are and accelerate treatment of patients in need.”
Study results debated
The premarket application approval request is based primarily upon SPYRAL HTN-OFF MED and SPYRAL HTN-ON MED, both prospective, sham-controlled, single-blind randomized studies conducted in the U.S., Canada, Japan, Europe and Australia.
SPYRAL HTN-OFF MED enrolled adults with hypertension whose medications could be discontinued at the start of the trial. The primary effectiveness endpoint was the mean difference in baseline-adjusted 24-hour ambulatory systolic BP (ASBP) from baseline to 3 months after renal denervation or the sham procedure. That study showed a statistically significant reduction of 3.9 mm Hg ASBP among participants in the radiofrequency renal denervation arm vs. sham controls.
SPYRAL HTN-ON MED enrolled adults with uncontrolled hypertension with BP medications continued during the trial. The primary endpoint was the mean difference in the baseline-adjusted 24-hour ASBP at 6 months after renal denervation or the sham procedure. That study showed a nonsignificant 0.03 mm Hg ASBP reduction among participants in the renal denervation arm vs. sham controls, not meeting its primary endpoint. Medtronic attributed the results to changes that occurred among patients in the sham group. Researchers identified a 10-fold difference in changes in medications that would favor BP lowering in the sham control group, which researchers said was an unexpected reduction not observed in previous studies.
In 2018, the Circulatory System Devices Panel recommended a 5-7 mm Hg relative BP reduction in renal denervation-treated patients vs. controls as a clinically meaningful threshold for effectiveness, according to the FDA.
“We have one study that is negative and one study that is minimally positive, and I have no reason be biased or believe one [study] is more valid than the other,” Julia Lewis, MD, professor of medicine in the division of nephrology at Vanderbilt University School of Medicine in Nashville, Tennessee, said after voting. “We still do not know the efficacy of this. If it gets on the market, the anecdotal small samples size of each physician using this intervention will not allow them to select out the patients that will benefit from those who will not. To not have a definitive study that better defines if it is efficacious and in whom is a disservice to the public.”
The primary safety endpoint was the rate of major adverse events at 30 days after the procedure and renal artery stenosis at 6 months among participants who received renal denervation pooled from SPYRAL HTN-OFF MED and SPYRAL HTN-ON MED. The safety event rate was 0.04%, which met the predefined safety endpoint performance goal of 7.1%
Additionally, researchers also found that renal denervation therapy contributed to sustained BP reductions out to 3 years without increasing medication burden. The Global SYMPLICITY Registry is the largest and longest study of real-world patients with uncontrolled hypertension treated with renal denervation, documenting long-term safety and effectiveness of the Symplicity renal denervation system.
More data needed
Speaking on behalf of Medtronic, Raymond R. Townsend, MD, FAHA, professor of medicine and director of the Hypertension Program at the Hospital of the University of Pennsylvania, said that BP control with drugs alone often worsens over time.
“Renal denervation represents a complementary option that we can provide patients that have tried antihypertensive lifestyle changes and medications and yet remain uncontrolled with a reasonable clinical option for BP improvement,” Townsend said. “The trials presented along with the patient preference study indicate hypertensive patients are willing to consider denervation and this is supported by many thousands of people worldwide already treated with renal denervation and more than 10 years of clinical data. This is also supported by what we saw in the OFF-MED and ON-MED studies.”
Speaking after breaking the tie vote, Lange said that he also would have voted “no” on the device’s efficacy, saying that stronger data are needed.
“We are facing a negative trial, unfortunately,” Lange said. “We can try to explain it away, but in the end, it is a negative trial. I cannot honestly look patients in the eye and tell them the benefit outweighs the risk in the patient population at large.”
In briefing documents, Medtronic stated it plans to continue follow-up of subjects in SPYRAL HTN-OFF MED and SPYRAL HTN-ON MED trials for an additional 24 months to assess long-term safety, effectiveness and BP reduction durability at 5 years after renal denervation.
The FDA is not required to follow the recommendations of its advisory panels, but it usually does.
References:
- FDA briefing documents. Available at: https://www.fda.gov/media/171411/download. Accessed Aug. 23, 2023.
- Medtronic briefing documents. Available at https://www.fda.gov/media/171412/download. Accessed Aug. 23, 2023.
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FDA. Circulatory System Devices Panel of the Medical Devices Advisory Committee (MDAC) Live Video. Presented Aug. 23, 2023. Accessed Aug. 23, 2023.
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