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A radiofrequency-based renal denervation system for uncontrolled hypertension got a cool reception from FDA advisors who nevertheless left the door open for regulatory approval.

On Wednesday, the FDA's Circulatory System Devices Panel voted 6-7 (with one abstention) that the benefits of the Symplicity Spyral multi-electrode catheter system do not outweigh its risks when used to lower blood pressure (BP) in patients with uncontrolled hypertension despite the use of antihypertensive medications, or in patients in whom BP-lowering therapy is poorly tolerated, the indication proposed by manufacturer Medtronic.

With myriad questions surrounding both benefit and risk of the device, "I think we're left with a lot of uncertainty," said Mark Lockhart, MD, MPH, of University of Alabama at Birmingham, who provided one of the no votes.

The FDA is not required to follow the advice of its advisory committees, but it often does.

Hypertension is a global public health problem that is on the rise around the world despite available lifestyle and medical treatments. There may be room for more innovative therapies, as no device-based system is currently approved in the U.S. for hypertension, and the last new drug class for hypertension, the direct renin inhibitors, was approved in 2007.

"I think we have to be cautious not to confound the desperateness of the unmet need with a willingness to throw anything at that unmet need," said panelist Julia Lewis, MD, of Vanderbilt University School of Medicine in Nashville, Tennessee. "It's not going to help people's blood pressure or their cardiovascular outcomes to have a procedure that is potentially either not effective or minimally effective."

She and other committee members expressed more uncertainty regarding Symplicity Spyral renal denervation compared with the Paradise ultrasound system, which got a 10-2 vote for risk-benefit the day before.

Like the Paradise, the Symplicity Spyral is designed to reduce BP by reducing the renal sympathetic activity that contributes to hypertension. Unlike the Paradise, however, Symplicity Spyral sends radiofrequency energy through the renal arterial wall to ablate the adjacent sympathetic nerves, and has enough electrodes to deliver up to four simultaneous radiofrequency ablations in a helical pattern.

Symplicity Spyral has a special place in the field of renal denervation since it is a redesigned version of the first-generation device that failed nearly a decade ago in SYMPLICITY HTN-3. Since that pivotal trial, industry has learned not to rely on studies lacking sham controls and has been given a 5-mm Hg ambulatory systolic BP reduction (ASBP) target as a surrogate for demonstrating clinical benefit.

Wednesday's FDA panel struggled with Symplicity Spyral's muddy track record of BP lowering before ultimately voting 7-6 in support of the device's effectiveness for its proposed indication.

Renal denervation with the Spyral resulted in a significant but modest 3.9-mm Hg ASBP reduction in the SPYRAL HTN-OFF MED trial of people who had their medications withdrawn in the first 3 months post-procedure. Most denervation patients had antihypertensive dosage reduced somewhat but were unable to get off their medications completely. Durability data were also not convincing -- drops in BP from baseline appeared to grow larger beyond 3 months post-denervation, though the same could be said for the sham group.

Then there is Spyral's failure in the subsequent study SPYRAL HTN-ON MED.

In this trial of patients with uncontrolled hypertension who continued their regular BP-lowering medications, renal denervation did not meet its primary effectiveness endpoint at 6 months according to Bayesian analysis. FDA reviewers acknowledged that HTN-ON may have been confounded by unbalanced medication changes between the two treatment groups and substantial missing BP data.

Curiously, Black Americans in this trial had contrasting results depending on whether office or ambulatory BP measurements were used. Reductions in 24-hour systolic BP were larger for the sham group, whereas office systolic BP drops were more impressive with Spyral denervation.

Robert Yeh, MD, of Beth Israel Deaconess Medical Center in Boston, and John Somberg, MD, of Rush Medical College in Chicago, were among the panelists who advocated for better identification of people who will respond to Spyral's radiofrequency renal denervation, rather than getting hung up on its low mean treatment effect. Both ultimately voted yes for Spyral's risk-benefit balance.

In any case, the committee voted unanimously 13-0 that the Symplicity Spyral system is at least safe for the hypertension population.

Between the two Symplicity studies, the pooled rates of major adverse events through 30 days and new renal artery stenosis through 6 months reached 0.4%. Notably, to assess renal artery stenosis, Medtronic did not have adequate CT and MRI scans and relied instead on renal ultrasounds that are known to be operator-dependent in quality and to lack sensitivity to milder stenosis. Renal imaging was also not performed after 12 months.

In the event the Spyral is approved, Medtronic is proposing a 5-year postmarket registry study that will include the original HTN-OFF and HTN-ON participants and a new AFFIRM continued access cohort of up to 1,200 people. Prespecified subgroup analysis is planned for those with isolated systolic hypertension, chronic kidney disease, and type 2 diabetes.

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