Medtronic’s Renal Denervation System Fails to Sway FDA Advisory Panel

After a long day of debate, an advisory panel of the US Food and Drug Administration concluded today that it could not endorse the premarket approval (PMA) application for use of the Symplicity Spyral (Medtronic) renal denervation device in patients whose hypertension is uncontrolled despite the use of BP-lowering therapy, or in patients in whom antihypertensives are poorly tolerated.

Members of the Circulatory System Devices panel of the FDA’s Medical Devices Advisory Committee voted fully in support of the system’s safety (13-0), with a close vote in support of effectiveness (7-6) but reaching a tie regarding whether the benefits outweighed the risks (6-6). Chair Richard Lange, MD (Paul L. Foster School of Medicine, El Paso, TX), broke the tie with his vote of no, for a final vote on whether benefits trumped risks of 6 Yes to 7 No.

Lange further reiterated that if he had been part of the effectiveness voting, he also would have voted no on that question. Lange said he was in agreement with several members that the proposed indication for use were not supported by the data.

“Had those indications changed, my vote perhaps would have changed,” he added. “We’re faced with a negative trial, unfortunately, and we can try to explain it away, but in the end it’s a negative trial.”

The panel spent the day considering the PMA, hearing from the sponsor, various experts, and patient and industry representatives. Symplicity Spyral is supported by data from SPYRAL HTN-OFF MED, which met its primary effectiveness endpoint, and SPYRAL HTN-ON MED, which did not and was the subject of the most debate.

Medtronic noted that potential confounders may explain the disparate outcomes between HTN-OFF and HTN-ON and presented a number of different analyses, some of which confused even experienced statisticians on the panel.

Throughout the day, advisory board statisticians Benjamin Saville, PhD (Berry Consultants, Austin, TX), and Janet Wittes, PhD (Wittes LLC, Washington, DC), expressed frustration at attempts to account for differences between cohorts, as well as problems with missing data.

Could Not Recommend to Patients

After the vote, statistician Saville said while there were hints of benefit, the data did not support the overall effectiveness of the device or the risk versus benefit equation.

Julia Lewis, MD (Vanderbilt University School of Medicine, Nashville, TN), added that even the positive data from the HTN-OFF trial were too modest for her to feel confident recommending a procedure over medication.

As with the ReCor trial experience, the follow-up data on Symplicity Spyral are of relatively short duration, which as the panel repeatedly noted makes it difficult to understand the therapy’s durability over time. Showing anecdotal evidence from the Australian experience with Symplicity Spyral during the open comment period, Markus Schlaich, MD (University of Western Australia), said patients followed for an average of 9 years continued to have reductions of 12 and 9 mm Hg from baseline in their systolic and diastolic values, respectively, with lower medication burden averaging one fewer drug than they had been taking before the intervention.

At the end of the day, I can’t honestly look patients in the eye and tell them that the benefit outweighs the risk for the population at large. Richard Lange

Also speaking in the open comment period, Tiffany Randolph, MD (Moses H. Cone Memorial Hospital, Greensboro, NC), noted that while renal denervation will never take the place of diet and exercise, or replace all medications, it could be “another tool in the basket” to keep patients on track.

“We know that despite the fact that we all aim to be perfect patients, sometimes people forget to take their medications. They may not have the money or the means to consistently see their doctors over time or to take all the different prescriptions that we prescribe,” she said. “Having an alternative or an additional therapy that not only works every time someone actually remembers or has the ability to take their medicines on a daily basis, but is still working in the background, is critically important to helping to control this disease process.”

HTN-OFF

Symplicity Spyral has been in clinical use since 2013, when it received CE Mark approval in Europe. The device is already approved and in use in 70 countries. In the United States, it received FDA breakthrough designation in 2020. But before making a decision on approving the device, the FDA sought the input of its advisory committee to be assured that Symplicity Spyral meets safety and effectiveness standards based on the totality of data, as it did yesterday when reviewing the PMA for a similar device, Paradise Ultrasound Renal Denervation System (ReCor Medical). In the case of Paradise, the advisory panel voted in support of the PMA.

Symplicity Spyral is comprised of a single-use, disposable catheter and a reusable radiofrequency generator. At a length of 117 cm and compatible with 6-Fr guide catheters, it can be used in vessels with diameters ranging from 3 to 8 mm. Renal denervation is thought to decrease BP by reducing renal sympathetic activity through ablation of afferent and efferent nerve fibers in the retroperitoneal space.

After a pilot study in 2018, the FDA worked with Medtronic to agree on study designs for the SPYRAL trials and seek alignment on imaging protocols to support safety. SPYRAL HTN-OFF MED, conducted in the United States, Japan, Canada, Australia and Europe, consists of cohorts from the pilot study (n = 80) and expansion cohorts (n = 286). Patients had hypertension for at least 5 years and were either not taking antihypertensive medications or discontinued them before randomization. There was at least a 3- to 4-week washout period prior to randomization, with urine and blood analysis used to confirm stopping of medications.

Baseline office BP was roughly 163/101 mm Hg and 24-hour ambulatory was 151/98 mm Hg.

After renal angiography to ensure anatomic suitability, patients were randomized 1:1 to renal denervation or sham control (renal angiography only). The protocol had patients remaining free of all medications for 3 months after the procedure unless they met criteria for “escape” and could resume meds sooner than 3 months. These so-called escape patients had an office systolic BP of 180 mm Hg or higher or otherwise qualified as a safety concern off medication.

The primary effectiveness endpoint in HTN-OFF was the mean difference in baseline-adjusted ambulatory systolic BP at 3 months. This endpoint was assessed at an office visit and patients with an office systolic BP at or above 140 mm Hg resumed medication. After the 6-month visit, patients were unblinded and the sham participants could elect to crossover.

In the full cohort, the change in 24-hour systolic BP from baseline to 3 months was greater in the denervation arm (4.5 vs 0.6 mm Hg; P < 0.001). However, the P value was not adjusted with multiplicity. In Bayesian analysis, there was a 3.9 mm Hg between-group difference, meeting the primary effectiveness endpoint with a posterior probability of success of 0.9996. The secondary outcome was the change in office systolic BP, which also was greater with renal denervation (9.4 vs 2.3 mm Hg; P < 0.001).

HTN-ON

SPYRAL HTN-ON MED incorporated data from the 80 pilot patients and newly randomized patients. The full cohort included 206 patients in the renal denervation arm and 131 in the sham arm. The average 24-hour ambulatory BP at baseline was 149/96 mm Hg and average office BP was 163/101 mm Hg.

The mean difference in 24-hour ambulatory systolic BP was 0.03 mm Hg, favoring the renal denervation group but not meeting the primary endpoint compared with the sham group at 6 months, with a posterior probability of success of 0.508.

The primary safety endpoint was a composite of major adverse events at 30 days and new renal artery stenosis > 70% at 6 months. In renal denervation patients from HTN-ON and HTN-OFF, the primary safety endpoint rate was 0.4%, which met the 7.1% prespecified performance goal. The safety results were similar among both studies and the pilot, expansion, and full cohorts.

On angiography, no patients had a new renal artery stenosis > 70%. CT/MR angiography data for 206 patients at 12 months were available to assess for the impact of renal denervation on new renal artery stenosis. Of these, six patients (2.9%) had potential new diameter stenosis > 50% and ≤ 99%, with Medtronic concluding that the expected incidence is likely between 2.9% and 3.9% in real-world populations. Additionally, no clinically significant changes were seen in eGFR or serum creatinine.

Patient Preferences

Medtronic performed a patient preference study of 400 US patients on up to three antihypertensive meds who were not enrolled in the SPYRAL trials. Approximately one-third said they would choose interventional treatment to manage their hypertension, with the most important driver of that preference being a reduction in BP as low as 1 mm Hg or as high as 18 mm Hg.

During the panel discussion, Patrick Nachman, MD (University of Minnesota Minneapolis, MN), voiced concern about “opening the gates” to a procedure that might only benefit a minority of hypertensive patients, given lack of clear data on subgroups that might benefit most from this type of treatment.

Ultimately, Lange summed the issue up by saying “at the end of the day, I can’t honestly look patients in the eye and tell them that the benefit outweighs the risk for the population at large.”

While the advisory panel’s decision carries significant weight, the FDA does not need to follow its recommendations regarding approval.