ACC.14: Learning curve, test limits may have derailed SYMPLICITY

WASHINGTON, D.C.—Renal denervation in treatment-resistant hypertensive patients lowered systolic blood pressure by only 2.39 mm Hg, falling short of the SYMPLICITY HTN-3 clinical trial’s superiority margin. Some experts at the American College of Cardiology (ACC) scientific session in Washington, D.C., suggested on March 29 that operator experience and no way to ascertain denervation occurred were factors.  

The disappointing results were expected. Medtronic, SYMPLICITY HTN-3’s sponsor, announced in early January that the trial had failed to meet its efficacy endpoint. SYMPLICITY HTN-3 differed from previous trials in study design. It was a prospective, single-blind, randomized sham-controlled trial, with patients receiving either renal denervation treatment with the Symplicity catheter or renal angiography as the sham control.

“There was a significant reduction in both arms at six months vs. baseline,” said Deepak L. Bhatt, MD, MPH, of Brigham and Women’s Hospital Heart and Vascular Center in Boston.

The primary efficacy endpoint was mean change in office systolic blood pressure from baseline to six months. The FDA had set a margin of 5 mm Hg to establish superiority. The secondary efficacy endpoint was the mean change in office systolic blood pressure at six months. The primary safety endpoint was a composite of adverse events.

The trial enrolled 535 patients at 88 sites in the U.S. between October 2011 and May 2013. Patients in the two groups had similar baseline characteristics. At six months, the decrease in blood pressure in the denervation group was -14.13 mm Hg vs. -11.74 in the sham group. The difference in ambulatory systolic blood pressure was even narrower, and -1.96 mm Hg.   

Some previous renal denervation studies have had strikingly different results, showing clinically meaningful benefits that extended over time with treatment. But some studies compared later results to baseline readings rather than a control. Some were not blinded, possibly allowing bias. The sham procedure also may have had a placebo effect. And while patients in the trial were instructed to continue taking antihypertensive medications, adherence was not confirmed.

Bhatt and other researchers said the lack of a method to ascertain that denervation was actually achieved posed challenges in SYMPLICITY-HTN 3.

Discussant Anthony N. DeMaria, MD, a cardiologist at the University of California, San Diego, and editor of the Journal of the American College of Cardiology commented that the negative findings announced in January surprised cardiologists. The journal had published 10 prior articles on renal denervation that were cautionary but positive.

“If one goes back there is the placebo effect and all the other potential explanations … but we have no way of knowing that denervation actually denervated,” De Maria said. He questioned whether a methodology needed to be found to ascertain procedure success.

Bhatt agreed that the negative findings should make researchers pause but “I don’t think this study invalidates all that prior pretrial work and smaller human studies. We studied a different patient population.”

He added that operators used a specific catheter. “It might be the way we used the catheter was not optimal.” Other factors may have been incorrect dose.

He proposed the field needed a “reboot” but shouldn’t be shuttered. “There has been too much provocative data to date and future investigations should occur but in a careful way. The first step must be to make sure are we actually denervating on a biological level.”

Murray Essler, MD, senior director of the Baker IDI Heart and Diabetes Institute in Melbourne, Australia, and principal investigator of the SYMPLICITY HTN-2 trial, suggested operator experience may have been a factor in the U.S. trial. As the keynote in the Louis F. Bishop Lecture, he described the preclinical data that informed the human trials that showed success in a variety of animal studies. He emphasized that renal denervation in humans is not easy and success is operator dependent.

“I think it is more likely that (they) didn’t achieve denervation,” he proposed. Other trials in Europe and Australia selected operators with demonstrated expertise in renal denervation. “That couldn’t be done in the U.S. because there was no experience with the technology,” which points to a learning curve problem.

“We have to somehow test denervation in patients,” Essler agreed. “Otherwise we tend to be in the dark.”