Renal Denervation Shown Safe and Effective in Pivotal Trial

Bruce Jancin

March 30, 2020

Catheter-based renal denervation took a step closer to attaining legitimacy as a nonpharmacologic treatment for hypertension with presentation of the primary results of the SPYRAL HTN-OFF MED pivotal trial at the joint scientific sessions of the American College of Cardiology and the World Heart Federation. The meeting was conducted online after its cancellation because of the COVID-19 pandemic.

"We saw clinically meaningful blood pressure reductions at 3 months," reported Michael Boehm, MD, chief of cardiology at Saarland University Hospital in Homburg, Germany.

That's encouraging news, as renal denervation (RDN) was nearly abandoned as a potential treatment for hypertension in the wake of the unexpectedly negative results of the SYMPLICITY HTN-3 trial (N Engl J Med. 2014;370:1393-401). However, post hoc analysis of the trial revealed significant shortcomings in design and execution, and a more rigorous development program for the percutaneous device-based therapy is well underway.

The SPYRAL HTN-OFF MED pivotal trial was designed under Food and Drug Administration guidance to show whether RDN reduces blood pressure in patients with untreated hypertension. The prospective study included 331 off-medication patients in nine countries who were randomized to RDN or a sham procedure, then followed in double-blind fashion for 3 months.

The primary outcome was change in 24-hour ambulatory systolic blood pressure from baseline to 3 months. From a mean baseline 24-hour ambulatory blood pressure of 151.4/98 mm Hg, patients in the RDN group averaged a 4.7 mm Hg decrease in 24-hour SBP, which was 4 mm Hg more than in sham-treated controls.

Statistically, this translated to a greater than 99.9% probability that RDN was superior to sham therapy. The RDN group also experienced a mean 3.7 mm Hg reduction in 24-hour DBP, compared with a 0.8 mm Hg decrease in controls.

Office SBP — the secondary endpoint — decreased by a mean of 9.2 mm Hg with RDN, compared with 2.5 mm Hg in controls.

These results probably understate the true antihypertensive effect of RDN for two reasons, Dr. Boehm noted. For one, previous studies have shown that the magnitude of blood pressure lowering continues to increase for up to 1–2 years following the procedure, whereas the off-medication assessment in SPYRAL HTN-OFF MED ended at 3 months for ethical and safety reasons.

Also, 17% of patients in the control arm were withdrawn from the study and placed on antihypertensive medication because their office SBP reached 180 mm Hg or more, as compared to 9.6% of the RDN group.

A key finding was that RDN lowered blood pressure around the clock, including nighttime and early morning, the hours of greatest cardiovascular risk and a time when some antihypertensive medications are less effective at blood pressure control, the cardiologist observed.

The RDN safety picture was reassuring, with no strokes, myocardial infarctions, major bleeding, or acute deterioration in kidney function.

A surprising finding was that, even though participants underwent blood and urine testing for the presence of antihypertensive drugs at baseline to ensure they were off medication, and were told they would be retested at 3 months, 5%–9% nonetheless tested positive at the second test.

That elicited a comment from session chair Richard A. Chazal, MD, of Fort Myers, Fla.: "I must say, as a clinician who sometimes has trouble getting his patients to take antihypertensives, it's fascinating that some of the people that you asked not to take the medications were taking them."

While the primary outcome in SPYRAL HTN-OFF MED was the 3-month reduction in blood pressure while off of antihypertensive medication, the ongoing second phase of the trial may have greater clinical relevance.

At 3 months, participants are being placed on antihypertensive medication and uptitrated to target, with unblinding at 6 months. The purpose is to see how many RDN recipients don't need antihypertensive drugs, as well as whether those that do require less medication than the patients who didn't undergo RDN.

Dr. Boehm characterized RDN as a work in progress. Two major limitations that are the focus of intense research are the lack of a predictor as to which patients are most likely to respond to what is after all an invasive procedure, and the current inability intraprocedurally to tell if sufficient RDN has been achieved.

"Frankly speaking, there is no technology during the procedure to see how efficacious the procedure was," he explained.

Discussant Dhanunaja Lakkireddy, MD, deemed the mean 4.7 mm Hg reduction in 24-hour SBP "reasonably impressive — that's actually a pretty good number for an antihypertensive clinical trial." He was also favorably impressed by RDN's safety in a 44-site study.

"The drops in blood pressure are not enough to really make a case for renal denervation to be a standalone therapy. But adding it as an adjunct to standard medications may be a very reasonable strategy to adopt. This is a fantastic signal for something that can be brought along as a long-term add-on to antihypertensive medications," commented Dr. Lakkireddy, chair of the ACC Electrophysiology Council and medical director of the Kansas City Heart Rhythm Institute.

Simultaneous with Dr. Boehm's presentation, the SPYRAL HTN-OFF MED Pivotal Trial details were published online (Lancet 2020 Mar 29. doi: 10.1016/S0140-6736(20)30554-7).

The study was sponsored by Medtronic. Dr. Boehm reported serving as a consultant to that company and Abbott, Amgen, Astra, Boehringer-Ingelheim, Cytokinetics, Novartis, ReCor, Servier, and Vifor.

Lancet. Published online March 29, 2020. Abstract

American College of Cardiology 2020 Scientific Session (ACC.20)/World Congress of Cardiology. Abstract 406-15. Presented March 29, 2020.

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