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The pivotal trial evaluating the use of Medtronic's renal denervation system in patients with treatment-resistant hypertension failed to meet its primary efficacy endpoint, the company announced Thursday.
No specific numbers were provided, but the announcement confirms rumors that renal denervation was no better than a sham intervention for lowering office systolic blood pressure through 6 months among patients who continued taking their anti-hypertensives.
The trial's data safety monitoring board, however, determined that the trial did meet its primary safety endpoint, the rate of major adverse events a month after randomization and renal artery stenosis through 6 months.
"We felt it was important that we share the top-line results with the medical community and with patients as soon as we could," one of the co-principal investigators of the trial, , of Brigham and Women's Hospital in Boston, said in an email to ľֱ. "We are still analyzing the large amount of data from the trial, and once we have a full understanding of the results and implications to the field, we will submit for peer review, presentation, and publication."
Bhatt said the American College of Cardiology meeting coming up at the end of March would likely be the earliest that the full results could be available.
“On the heels of very promising data from SYMPLICITY HTN-2 most of us expected positive results out of HTN-3, so it should come as no surprise that these findings today left most of us a bit dumbfounded,” , of Saint Joseph Mercy Health System in Michigan, told ľֱ. Aronow was an investigator in the trial.
In recent years, concerns have been raised that the magnitude of the blood pressure reductions seen in renal denervation studies without control groups would not hold up in controlled trials, and those concerns now appear to be well founded.
SYMPLICITY HTN-3, which randomized 535 patients with treatment-resistant hypertension and a starting systolic blood pressure over 160 mm Hg, had a sham-control group in which patients underwent angiography alone.
The use of a sham control makes the trial unique and suggests that some of the benefit seen in earlier studies could have been due to a placebo effect, said Aronow, who spoke on behalf of the Society for Cardiovascular Angiography and Interventions.
But, “I think it’s a little bit too early to jump to definitive conclusions,” he said, pointing to lack of full results or verification from other similar trials.
“We typically prefer to see results from multiple trials before making decisions about moving forward with new therapies, especially paradigm-shifting therapies,” he said.
Medtronic said in a press release that it "intends to formulate a panel of independent advisers made up of physicians and researchers who will be asked to make recommendations about the future of the global hypertension clinical trial program, as well as provide advice on continued physician and patient access to the SYMPLICITY technology in countries with regulatory approvals."
Pending that review, Medtronic will halt three trials currently being conducted to support regulatory approval: SYMPLICITY HTN-4 in the U.S., which enrolled its first patient in November, HTN-Japan, and HTN-India. Other studies -- including the Global SYMPLICITY post-market surveillance registry and studies looking at renal denervation for other conditions -- will continue.
“I do not think this is the end of renal denervation,” commented another study investigator , of Detroit Medical Center. “This may just be the wrong approach and/or learning curve issues with rolling out the study to multiple operators. There is ample data that renal denervation reduces blood pressure in animal models and in smaller human trials, and there are at least 30 different methods being tested to denervate the renal arteries.”
She suggested that the failure of the trial could have been related to this particular denervation system.
“It was technically difficult to assure that the radiofrequency probe was oriented correctly and that it was touching the wall of the renal artery,” she said in an email. “This may have resulted in the energy being dissipated into the bloodstream instead of into the vessel. Also, the nerves are very deep and the energy level may not have been high enough to penetrate.”
Aronow, however, said that it is premature to conclude whether any other renal denervation systems would have fared better in the trial, which “set the bar high.”
“We have to be careful not to conclude that there’s something about Medtronic’s device that’s off,” he said.
The disappointing results of SYMPLICITY HTN-3 follow the announcement last month that the pivotal trial for St. Jude Medical's renal denervation system -- EnligHTN-IV -- was stopped after enrolling fewer than 10 patients because of anticipated recruitment difficulties.
UPDATE: This article, originally published Jan. 9, 2014, at 11:16 a.m., was updated with new material (Jan. 9, 2014, at 3:50 p.m.).
From the American Heart Association: