SYMPLICITY ABPM Data Confirm Negative Result With Renal Denervation in Hypertension

May 22, 2014

NEW YORK CITY, NY — New data from the SYMPLICITY HTN-3 trial show that catheter-based denervation of the renal artery in resistant-hypertension patients had no impact on 24-hour ambulatory blood pressure compared with a sham control[1]. In addition, there was no effect of renal denervation in day or nighttime measurements of blood pressure.

The ambulatory blood-pressure monitoring (ABPM) data from SYMPLICITY were presented this week at the American Society of Hypertension (ASH) 2014 Annual Scientific Meeting by Dr George Bakris (University of Chicago, IL) and published concurrently May 20, 2014 in the Journal of the American College of Cardiology.

The negative results of the pioneering SYMPLICITY study—the first randomized trial testing renal denervation against a sham control procedure—were initially announced by Medtronic, the trial's sponsor, in January 2014. The study was later presented at the American College of Cardiology 2014 Scientific Sessions in March, reported by heartwire , and published in the New England Journal of Medicine.

These newest data on 24-hour ABPM among the 535 randomized patients provide yet more evidence that the procedure was ineffective and failed to show a reduction in systolic or diastolic blood pressure. Among the 364 patients randomized to renal denervation, the baseline 24-hour blood pressure was 159.1/88.0 mm Hg while the daytime and nighttime blood pressures were 163.0/91.3 mm Hg and 152.5/82.5 mm Hg, respectively. There were no significant differences in baseline blood-pressure levels among the 171 patients randomized to control.

After six months, 24-hour ambulatory systolic blood pressure was reduced 6.8 mm Hg in the denervation arm and 4.8 mm Hg in the control arm, a 2.0 mm Hg difference that was not statistically significant. The daytime systolic blood-pressure reductions were also not significant between the treatment and control arm. For nighttime systolic blood pressure, the difference between the treatment and control arms was 3.3 mm Hg favoring denervation, although the reduction was not statistically significant (p=0.06).

Speaking at the ASH meeting, Dr Sandra Taler (Mayo Clinic, Rochester, MN) said the 24-hour ABPM data provide two important pieces of information. The first is that the patients randomized in the trial were "truly hypertensive," given their baseline 24-hour ambulatory blood pressure. Second, she suspects that given there were no changes in the 24-hour ABPM values, complete denervation of the renal artery did not occur.

To heartwire , Dr William White (University of Connecticut Health Center, Farmington) said the new data are robust and highlight the excellent methodology of the trial investigators. Given the rigor of the trial, the 24-hour ABPM data confirm the original trial results showing "no effect" with renal denervation in this trial.

What Does the Future Hold?

Several sessions, discussions, and posters at the ASH conference were dedicated to resistant hypertension and renal denervation. In one session, Dr Herbert Aronow (St Mary Mercy Hospital, Ypsilanti, MI) was scheduled to talk about "when" to consider renal denervation in these difficult-to-treat patients. The data—prior to the randomized, controlled SYMPLICITY study, including others testing different devices or energy sources—have consistently shown significant reductions in blood pressure. Yet there is no getting around the negative randomized trial result.

Aronow said that for physicians in the post-SYMPLICITY era, their reluctance might be characterized as such: "How could we possibly consider renal denervation when the only sham-controlled randomized trial evaluating this technology was negative on its primary end point?"

He noted that the science behind renal denervation proceeded along the normal course—plausible biological mechanism, preclinical and animal studies showing effectiveness, and studies assessing safety and effectiveness in humans—but hit a roadblock with the randomized, sham-controlled study. Like others during the meeting, Aronow speculated on what might have gone wrong, noting that the procedure has a learning curve, and physicians have no way of knowing whether denervation is achieved.

White told heartwire that an open-to-public "think-tank" session will be held at the end of June to discuss renal denervation and how to move forward. The session will include representatives from the device branch of the Food and Drug Administration, the National Heart, Lung, and Blood Institute, ASH, device companies, and clinical trialists.

They will discuss requirements for future clinical trials and attempt to outline a regulatory pathway. On the docket, said White, will be conversations about testing in appropriate clinical models, the issue of confounding with antihypertensive drugs, and whether or not future studies will need to include a sham control. White suspects that, at least in the US, studies will continue to have to show superior safety and efficacy over a sham procedure.

On the other side of the Atlantic, interventionalists gathering at EuroPCR 2014 are also hashing over SYMPLICITY-3, as well as a host of nonrandomized studies testing other renal-denervation devices. On Thursday at EuroPCR, the European Society of Hypertension released a formal statement in the main arena, affirming its support for the continuing study of renal denervation.

Medtronic suspended enrollment in SYMPLICITY-HTN 4 , a US study conducted for regulatory approval, and suspended enrollment in trials conducted in Japan and India. Earlier this year, St Jude Medical announced the stoppage of the EnligHTN-IV study, its large phase 3 study in 590 patients with resistant hypertension. At the time, St Jude Medical felt Medtronic's SYMPLICITY device would be approved for the US market, and as a result it would have problems enrolling patients to a sham procedure, given the commercial availability of a renal-denervation catheter.

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