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The Paradise ultrasound renal denervation system got backing from the FDA's Circulatory System Devices Panel as a possible treatment for hypertension, as manufacturer ReCor continues to hope for regulatory approval.

On Tuesday, FDA advisors voted 10-2 that the benefits of the Paradise catheter-based system outweigh its risks when used to reduce blood pressure (BP) in patients with uncontrolled hypertension who do not respond to or tolerate antihypertensive medications, the proposed indication in the premarket application for the device.

"It's not a panacea but it's certainly an option, and I think it should be approved," said John Somberg, MD, of Rush Medical College in Chicago.

High BP is a risk factor for heart disease and stroke and affects . Fewer than one in four adults with hypertension have it under control with lifestyle interventions and available medications, according to the CDC. The last new drug class for hypertension, the direct renin inhibitors, was , suggesting innovation is needed.

Some panel members expressed their reluctance to vote yes on the Paradise, however, owing to the modest and short-term BP reductions observed after ultrasound renal denervation. The committee ultimately voted unanimously 12-0 that the Paradise system is safe, and 8-3 (with one abstention) that it is effective for the proposed indication.

"The risk seems very low, but the benefit seems very low so there's my ambivalence. It's hard for me to judge risk-benefit when both seem very low," said statistician Janet Wittes, PhD, of Washington, D.C. She later abstained from the effectiveness question but voted yes that the system's benefit outweighs its risk.

Pooling people with mild-to-moderate and stage II hypertension who discontinued their BP medications, the RADIANCE-HTN SOLO and RADIANCE II trials had together shown an average 6.3 mm Hg lower daytime ambulatory systolic BP (ASBP) at 2 months after the Paradise procedure compared with sham. For peers with resistant hypertension despite staying on at least three antihypertensives in RADIANCE-HTN TRIO, Paradise's BP reduction amounted to just 4.5 mm Hg -- which may not back ReCor's proposed indication for people not responding to BP medications, the panel said.

These results just hover around the 5-mm Hg threshold for a BP reduction to be of clinical significance in terms of preventing actual cardiovascular events, as agreed upon by FDA and industry during discussions in 2018.

"I think the totality of the evidence does favor a positive benefit-risk profile ... I think the average treatment benefit might be modest, but it's highly variable. But that's also true for medication," argued Robert Yeh, MD, MSc, MBA, of Beth Israel Deaconess Medical Center in Boston.

Abdulla Damluji, MD, PhD, MPH, of Inova Health in Fairfax, Virginia, said he agreed, adding that there is a "big space" in finding super-responders to Paradise therapy.

Nevertheless, FDA advisors generally said it is difficult to evaluate the durability of renal denervation given the available data.

Longer-term BP data suggest that the Paradise recipients' mean daytime ASBP reduction over sham was no longer significant at 6 months due to further BP lowering in both treatment arms later on in the three trials. Complicating the durability issue are the uptitration of medications in both groups at 6 and 12 months, and unblinding and permission of crossovers was allowed at these time points.

"What I grapple with is, Are we approving a product that could be used in lieu of medication and is that reasonable to have an invasive procedure in lieu of noninvasive [medication]?" said panel member Keith Allen, MD, of St. Luke's Hospital of Kansas City, Missouri, who ultimately voted no on the risk-benefit question.

"I personally don't think that the denervation will be durable. I can't think of a single area where denervation's been used ... where re-innervation doesn't occur," he said. "I think the benefit, if any, is acute, not durable, and is marginal."

The other no vote on risk-benefit came from Mark Lockhart, MD, MPH, of University of Alabama at Birmingham, who cited the durability issue and reiterated the committee's recommendation to change Paradise's proposed indication to reflect that it does not perform as well in resistant hypertension.

Regardless of effectiveness, FDA advisors said they did not have significant safety concerns of Paradise renal denervation other than a low risk related to vascular access. "I don't think the issue here is safety," Allen said.

The pooled primary safety endpoint of major adverse events through 30 days and new renal artery stenosis through 6 months was a low 1.1% across the Paradise trials. However, the system was also associated with mild-to-moderate diameter stenosis at 12 months on angiograms and MRI scans.

The Paradise system includes a catheter with an ultrasound transducer that is delivered percutaneously through the femoral artery to the renal artery under fluoroscopic guidance. An accompanying distal balloon contains cooling water to prevent arterial wall injury during thermal ablation.

ReCor has proposed a long-term postmarket registry that would pool RADIANCE II participants with up to 500 new people in a continued access study. The study proposes to track office and home BP measurements alone after Paradise denervation without 24-hour ambulatory monitoring.

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

The panel will reconvene on Wednesday for deliberations on another endovascular renal denervation system, the Symplicity Spyral from Medtronic.

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