FDA Advisors’ Recommendation on Renal Denervation Hinges on Effectiveness Question

An FDA advisory committee will meet this week to discuss the durability and clinical effectiveness of renal denervation systems for the treatment of patients with uncontrolled hypertension.

No renal denervation system is approved in the U.S for clinical use. But on Tuesday, agency advisors will make recommendations regarding the premarket application (PMA) for ReCor’s Paradise ultrasound renal denervation system based on data from trial participants staying on or off their hypertension medications. On Wednesday, the panel reconvenes for a similar discussion on the Symplicity Spyral radiofrequency-based system by Medtronic, another percutaneous interventional approach to high blood pressure (BP).

In briefing documents released ahead of the 2-day meeting, FDA staff indicated their appetite for bringing device-based hypertension treatment to market, citing “the importance of this clinical condition” and the agency’s “desire to bring novel treatments to patients.”

High BP — with a threshold of 130/80 mm Hg — is a risk factor for heart disease and stroke and affects nearly half of adults in the U.S. Fewer than one in four adults with hypertension have it under control with lifestyle interventions and medications, according to estimates from the CDC.

With device-based therapies in the picture, industry and regulators are both eager to avoid the same mistakes that felled first-generation renal denervation systems — including the lack of sham controls and a reliance on office-based BP measurements in early studies — culminating in the failed SYMPLICITY HTN-4 trial nearly a decade ago.

To get stakeholders on the same page, an FDA advisory committee in 2018 set expectations for the potential indications, effectiveness endpoints, and safety data in subsequent device development. Monitoring of ambulatory systolic BP (ASBP) in trials was recommended, as was a minimum demonstrated 5-mm Hg reduction in systolic BP to say that a device has a clinically significant benefit. Additionally, any benefit should last out to 12 months, advisors said.

Tuesday’s discussion of the Paradise ultrasound system will center on the off-medication studies RADIANCE-HTN SOLO and RADIANCE II and the on-medication trial RADIANCE-HTN TRIO. The clinical effectiveness of the device is under contention, as all three trials reported modest BP reductions — just around the 5-mm Hg cutoff — at 2 months following the Paradise procedure.

The durability of BP reduction is questionable, as the device’s mean daytime ASBP reduction over sham was no longer significant at 6 months and beyond. FDA reviewers said this can be explained by medication differences and crossovers between groups.

Also facing challenges to its effectiveness is the Symplicity Spyral, the redesigned, multi-electrode version of the device that had failed in SYMPLICITY HTN-4. Backing this device now are the SPYRAL HTN-OFF MED and SPYRAL HTN-ON randomized trials that used an adaptive Bayesian approach to heavily discount their pilot cohorts due to their incongruity with the rest of the larger expansion cohorts.

On Wednesday, FDA staff will draw attention to the fact that renal denervation met its primary effectiveness endpoint in HTN-OFF MED but not HTN-ON, which had patients with uncontrolled hypertension continue their regular BP-lowering medications throughout the trial. The treatment arm showed a nonsignificant 0.03-mm Hg ASBP reduction over sham at 6 months in HTN-ON. In a prespecified frequentist analysis of the full cohort without discounting pilot cohort data, the difference in systolic BP reached 1.9 mm Hg — still not statistically significant.

FDA reviewers acknowledged that HTN-ON may have been affected by unbalanced medication changes between the two treatment groups and unbalanced missing ASBP data.

As for safety of the two renal denervation devices, the FDA advisory committee is being asked to look beyond the pooled rates of major adverse events through 30 days and new renal artery stenosis through 6 months, which reached 1.1% across the Paradise trials and 0.4% between the two Symplicity studies.

Despite the finding of no hemodynamically significant renal artery stenosis, the advisors will be asked what they make of the Paradise system being associated with mild-to-moderate diameter stenosis at 12 months on angiograms and MRI scans.

In addition, the safety discussion around Symplicity Spyral will have to take into account Medtronic’s reliance 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.

Makers of the two renal denervation systems are proposing long-term postmarket registry studies if they are ultimately FDA approved.

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