Renal Denervation Fails to Meet Efficacy Endpoints Compared with Placebo Procedure

WASHINGTON, DC—In a turn of events for renal denervation, 6-month results of the SYMPLICITY HTN-3 trial show no benefit of the procedure in terms of systolic blood pressure reduction compared with a sham procedure, according to results presented March 29, 2013, at the American College of Cardiology/i2 Scientific Session and simultaneously published in the New England Journal of Medicine. The results had been anticipated since January of this year, when the main company behind the novel procedure, Medtronic, announced that the trial failed to meet its primary endpoint.

A team led by Deepak L. Bhatt, MD, MPH, of Brigham and Women’s Hospital (Boston, MA), randomized 535 patients with severe resistant hypertension to renal denervation with the Symplicity Catheter System (n = 364; Medtronic, Mountain View, CA) or a sham procedure (n = 171) at 88 US centers from October 2011 to May 2013. All patients were prescribed a minimum of 3 antihypertensive medications, including 1 diuretic.

Not That Simple

At 6 months, there was no difference in the change in office blood pressure (primary endpoint) between the treatment and placebo groups (-14.13 ± 23.93 mm Hg vs -11.74 ± 25.94 mm Hg; P = 0.26 for superiority). There was also no difference in the change in ambulatory blood pressure at 6 months (-6.75 ± 15.11 mm Hg vs -4.79 ± 17.25 mm Hg; P = 0.98 for superiority).

Additionally, there was no difference in the change in heart rate from baseline to 6 months between the renal denervation and placebo groups (-3.8 ± 11.2 vs -2.7 ± 10.9 beats per minute; P = 0.30).

With regard to the primary safety endpoint (composite of death, end-stage renal disease, embolic events resulting in end-organ damage, renovascular complications, or hypertensive crisis at 1 month or new renal-artery stenosis of more than 70% at 6 months), similar rates were observed in the denervation and placebo groups (1.4% vs 0.6%; P = 0.67).

Results were maintained in prespecified subgroup analysis, although non-African Americans tended to benefit from renal denervation more so than African Americans (P = 0.09).

“These results underscore the importance of blinding and sham controls in evaluations of new devices, and have ramifications that go beyond interventional cardiology,” Dr. Bhatt said. “Further study in rigorously designed clinical trials will be necessary, and indeed such studies are warranted, to confirm previously reported benefits of renal denervation in patients with resistant hypertension or to validate alternate methods of renal artery denervation.”

No Need to ‘Close the Book’ On Renal Denervation Yet

In an accompanying editorial, Franz H. Messerli, MD, of Mount Sinai Roosevelt Hospital (New York, NY), and Sripal Bangalore, MD, of New York University School of Medicine (New York, NY), write that SYMPLICITY HTN-3 “brings the renal-denervation train to a grinding halt.”

Because of the perceived success of the SYMPLICITY HTN-1 and HTN-2 trials, all of the reasons for the negative results presented in the current study are unclear. “At first blush, the most likely explanation for the findings. . .is the inclusion of a sham-control group,” they say. “Lack of efficacy could also be caused by incomplete or ineffective denervation. No reliable markers of renal denervation are available, and questions remain as to what exactly the procedure accomplishes.”

Since “exuberance about renal denervation has been widespread,” Drs. Messerli and Bangalore observe, “we will have to come to grips with two facts: the SYMPLICITY studies merely document the natural history of resistant hypertension in clinical trials, and the time has come to turn the page on renal denervation for hypertension but by all means, let’s not close the book.”

Field Needs a ‘Reboot’

Anthony N. DeMaria, MD, of the University of California San Diego (La Jolla, CA), said he was “totally surprised that JACC had published 10 prior studies, all of which were cautionary but nonetheless positive, . . . So if one goes back and looks at the placebo effect and all the other explanations [for why SYMPLICITY HTN-3 was negative], we have no way of knowing if denervation actually denervated.”

Dr. Bhatt responded that while all prior research on the topic should still stand, “we do need to take pause and reconsider.

“I don’t think that this negative study invalidates all that preclinical work, the animal work, and the smaller human studies. We studied a different patient population, we used a different catheter, and it might be that the way we used the catheter wasn’t optimal,” he continued. “While I believe this trial in this population with this catheter was quite definitively negative, I would really hate to think that this trial killed the field of renal denervation, much as I think there may have been a little bit of excessive exuberance about renal denervation by interventional cardiologists going in.”

The field may need a “reboot,” according to Dr. Bhatt, because “there has been too much provocative data to date. Future investigation should occur but in a careful way. The first step is to make sure we are actually denervating at a biologic level. Once that is certain in preclinical data, then I think rigorous clinical trials are still necessary.”

Was the Protocol Too Rigorous?

Playing devil’s advocate, Valentin Fuster, MD, PhD, of Mount Sinai School of Medicine (New York, NY), said that even if all of the prior studies on real denervation were wrong, the protocol of SYMPLICITY HTN-3 was such that “this is not the way we see patients in the office. We have to be very very careful in interpreting this study.”

Dr. Bhatt replied, “I don’t think that this trial despite its rigor is absolutely definitive for the field of renal artery denervation. Our trial might have been so rigorous that it eliminated the ability to see a real benefit that in real world clinical practice might exist.”

David E. Kandzari, MD, of the Piedmont Heart Institute (Atlanta, GA), observed that the data provide an “opportunity to revisit the translation of technology to the basic science of pathophysiology,” adding that the patient population of the study is “very esoteric [and] artificial.

“Aside from not having a procedural biomarker of efficacy, it’s equally important to recognize we do not have any predictor at a patient demographic level of a treatment effect other than having very high blood pressure,” he continued.

Given the “pretty good” reduction in blood pressure seen in the control arm over the study, Dr. Bhatt acknowledged the possibility of a bit of artificiality in the protocol. Going forward, “we’re going to see if procedural aspects impacted whether renal denervation actually [would] work if it were done correctly,” he said, adding that there was also the possibility that they did not administer the optimal dose of denervation.

 

With respect to clinical practice outside the United States, Dr. Bhatt said he remains “cautiously optimistic about the field. . . . Personally, I would be cautious about offering a procedure to patients in the face of a large, negative, randomized clinical trial. Having said that, as a practicing physician I would never be so proscriptive to say it shouldn’t be done.” For example, a noncompliant patient who presents often with hypertensive crises every few months might benefit from this procedure, he observed.

 

Study Details

 

Patients were receiving an average of 5 antihypertensive medications, and on average 4 of them were at maximally tolerated doses. Baseline office systolic BP was 180 mm Hg for both cohorts.

 

 

Sources:

1. Bhatt DL, Kandzari DE, O’Neill WW, et al. A controlled trial of renal denervation for resistant hypertension. N Engl J Med. 2014;Epub ahead of print.

2. Messerli FH, Bangalor S. Renal denervation for resistant hypertension? [editorial]. N Engl J Med. 2014;Epub ahead of print.

 

 

 

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• Long-term Outcomes with Renal Denervation Show Sustained Benefit
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• Symplicity Works: Renal Denervation Reduces Resistant Hypertension