WASHINGTON, DC (updated) — The negative result from SYMPLICITY HTN-3 "brings the renal-denervation train to a grinding halt."
Those words, written by Dr Franz Messerli (Icahn School of Medicine, New York City) and Dr Sripal Bangalore (New York University School of Medicine, New York City) in an editorial appearing alongside the SYMPLICITY HTN-3 study, which is published March 29, 2014 in the New England Journal of Medicine, highlight the disappointment of many who hoped the procedure might be a useful treatment option for patients with resistant hypertension.
That the study is negative is not news—Medtronic, the study sponsor, announced the trial missed its primary efficacy end point in early January—but the full study results are being presented for the first time here today at the American College of Cardiology 2014 Scientific Sessions .
Led by Dr Deepak Bhatt (Brigham and Women's Hospital, Boston, MA) and Dr George Bakris (University of Chicago, IL), SYMPLICITY HTN-3 is a randomized, sham-controlled renal-denervation study in 535 patients with severe resistant hypertension. After six months, the mean change in systolic blood pressure was a reduction of 14.13 mm Hg in the renal-denervation arm and 11.74 mm Hg in the sham-controlled arm, a difference of 2.39 mm Hg that was not statistically significant.
Regarding the change in the 24-hour ambulatory systolic blood pressure, the reduction at six months was 6.75 mm Hg in the renal-denervation arm and 4.79 mm Hg in the control arm, a difference of 1.96 mm Hg that was also not statistically significant.
"This blinded trial did not show a significant reduction of systolic blood pressure in patients with resistant hypertension six months after renal-artery denervation as compared with a sham control," the SYMPLICITY HTN-3 investigators conclude. Simply put, the findings "contradict the published clinical data regarding renal denervation" and highlight the "importance of conducting blinded trials with sham controls in the evaluation of new medical devices before their clinical adoption."
Overall, the procedure was safe, with no difference in the primary safety end point, a composite that included death from any cause, end-stage renal disease, embolic events, or other renal-artery or vascular complications.
More Than 10 000 Procedures Performed Worldwide
Speaking with heartwire , Bhatt said he would be very cautious about recommending this procedure, which is investigational in the US but approved in more than 80 countries worldwide, given the negative results from a large randomized controlled trial. However, he would not be so prescriptive to tell other physicians what to do when it comes to clinical practice. He said investigators studied one specific type of patient—those with severe resistant hypertension undergoing aggressive medical care and taking five antihypertensive medications—but there might be others not so well managed who continue to report to the emergency department with chest pain or hypertensive encephalopathy.
"I can understand a doctor who might feel compelled to try something he or she believes in," said Bhatt. "I wouldn't be so prescriptive or so arrogant as to dictate the care of patients throughout the world. As far as my own personal opinion, I wouldn't recommend the patient have the procedure without further data to support actual clinical outcomes."
Dr Anthony DeMaria (University of California, San Diego), who was not involved in the trial, said the negative results from SYMPLICITY surprised a lot of physicians, given previous studies touting the benefits of renal denervation. If he were a patient he would do everything possible before subjecting himself to renal denervation, he said. DeMaria, who has served as the editor in chief of the Journal of the American College of Cardiology (JACC) since 2002 (he passes the torch to Dr Valentin Fuster [Mount Sinai Medical School, New York, NY] this year), noted that 10 studies have been published in JACC showing extensive blood-pressure reductions with renal denervation, with drops in the range of 30 to 40 mm Hg, as well as improvements in other objective markers like left ventricular hypertrophy.
"Earlier studies, which were not blinded and not necessarily controlled, demonstrated that renal sympathetic denervation could be very effective in patients in whom there weren't very many therapeutic alternatives," he told the media during a press conference today. "There was an initial rush of enthusiasm and in one of the papers we published in JACC it was estimated that 10 000 of these procedures have been done worldwide."
Bhatt said that he does not believe renal denervation is "dead" but rather needs a "reboot," one that would include getting back to basics in terms of better understanding the anatomy, neurology, and physiology of the procedure. During the late-breaking clinical-trials session, others agreed with that assessment, including DeMaria and Dr David Kandzari (Piedmont Heart Institute, Atlanta, GA). Panelist Dr Sanjay Kaul (Cedars Sinai Medical Center, Los Angeles, CA) praised the SYMPLICITY investigators for directly taking the issue on.
"I think the results are clear and convincing and underscore a cautionary principle that implausibly large treatment effects seen in uncontrolled clinical trials are not reliable and seldom relevant," he said. "As you know, the regulatory standard for approval is substantial evidence or reasonable assurance of efficacy and safety using well-designed and adequately controlled trials. Your trial is an exemplar of what a well-designed and adequately trial should be."
Sean Salmon, president of coronary/renal denervation at Medtronic, said that SYMPLICITY HTN-3 is the best trial in the field, and despite the negative results, the company plans to move forward with the technology. It is currently investigating whether there was adequate ablation of the renal nerves by the operators as well as a possible interaction with direct-acting vasodilators. In the trial, 45% of patients in the sham-control arm were taking a direct-acting vasodilator compared with 37% in the renal-denervation arm. Salmon noted that of the African Americans in sham-control arm, 56% received a direct-acting vasodilator, and these patients experienced large reductions in blood pressure (-17.8 mm Hg). For nonblack patients in the control arm, 41% received direct vasodilators, and they had small reductions in blood pressure (-8.6 mm Hg). Given that vasodilators are dosed up to four times per day, there might have been a significant Hawthorne effect responsible for the large reduction in blood pressure in the control arm, which could explain the lack of benefit observed in the trial.
Based on their animal data, the company is convinced the procedure works and does not want to abandon a technology that has the potential to benefit patients. Salmon agreed with the assessment that they need to go back to the drawing board in terms of understanding how the procedure works and who might benefit in the future.
The FDA, not Europe, Gets It Right
In their editorial, Messerli and Bangalore point out the "exuberance" of renal denervation has been widespread. They note others have cited the "enormous potential" of the procedure, not just in resistant hypertension but also other diseases that are characterized by high sympathetic activity such as diabetes, heart failure, arrhythmias, and chronic kidney disease.
Speaking with heartwire , Bangalore said the negative findings are indeed surprising. He pointed out that the Food and Drug Administration (FDA) takes a lot of criticism for its slower approval pathway when compared with its European regulatory counterparts, but this is one example where such fastidiousness benefits patients and clinicians.
"In Europe, renal denervation has been available since 2010, and it's used in clinical practice," said Bangalore. "There is some controversy about the use of sham-controlled trials, but this is an excellent example of where it's better to carry out a sham procedure in the clinical-trial setting rather than approve it and carry out a procedure in clinical practice that has no benefit on patients. The FDA has been criticized for a long time, with critics saying that it stifles innovation, but this is one area where they got it right."
| The European Take on Renal Denervation
In April 2013, the European Society of Cardiology (ESC) issued a consensus statement on the use of catheter-based renal denervation for the treatment of high blood pressure. It said that the treatment can be considered a therapeutic option in patients with drug-resistant hypertension who cannot get to goal with a combination of lifestyle and pharmacologic therapy.
In Europe, Medtronic's Symplicity system has received CE Mark approval. Other approved renal-denervation systems include EnligHTN (St Jude Medical) used in the EnligHTN-1 study; Vessix V2 (Boston Scientific) used in REDUCE-HTN ; OneShot (Covidien) used in RHAS; and Paradise (ReCor Medical) used in the REALISE study.
As reported by heartwire , the 2013 EuroPCR meeting had numerous abstracts and sessions devoted to "tools and techniques" and others that focused on new and up-and-coming renal-denervation systems. Many companies seemed to be moving forward with conventional radiofrequency ablation systems, while others were exploring ultrasound, microwave, ethanol, and even Botox approaches.
To heartwire , Bangalore said the earlier trials of renal denervation showed very large reductions in systolic blood pressure, with drops frequently of 30 mm Hg or more. Nobody expected to see such a large reduction in SYMPLICITY HTN-3, and most would have been content with a 15-mm-Hg reduction, he said. While patients undergoing renal denervation had a 14.13-mm-Hg reduction in systolic blood pressure, the comparison against the sham-control arm was not statistically significant, because those patients had a near-equivalent reduction. In earlier trials, those without a sham procedure in the control arm, blood pressure in the controls was not improved, he noted.
Possible Hawthorne Effect
Speaking with heartwire , co–principal investigator Bakris said that "true" resistant hypertension occurs in about 2% to 3% of the hypertensive population. At his center, patients with hypertension refractory to treatment have blood pressures in the range of 170 mm Hg to 180 mm Hg, despite taking their medications daily (often with their spouse validating that they are in fact taking the drugs).
That patients were monitored so well, with up to eight clinical visits over the course of the trial, might be one of the reasons why SYMPLICITY failed, suggested the researchers. For example, the Hawthorne effect, where patients modify their behavior because they are being monitored extensively in a clinical trial, might have led some patients to take their medications more diligently than when on their own.
"This is my speculation why the placebo arm did as well as it did," said Bakris. "When people get into a clinical trial, they think, 'Uh-oh, now something is going to happen so I better take my meds, I don't want to screw it up.' They might have been on five or six meds but they were only taking two. Now all of sudden they're taking everything. I'm convinced that's what happened. I can't prove it, but I think that's what happened."
In their editorial, Messerli and Bangalore appear to leave the door open for renal denervation, even if it is just a crack. They point out that there appears to be wide variability in how well patients respond to therapy. For DeMaria, he believes there are solid data supporting renal denervation and that SYMPLICITY HTN-3 doesn't negate these other trials. Instead, the trial points to how little is known about the procedure. For example, there are still no markers of treatment success—physicians ablate with almost zero feedback of ablation success—and only a minimal understanding of the biology.
"We think there is some really tantalizing data out there that this can be a benefit, but we need to go all the way back to anatomy, to physiology, and even pathophysiology, to be sure we're effectively denervating so we can assess the results of the procedure."
For Kaul, the results "cut through the fog of hype" around the procedure, and he hopes that the real science behind understanding the procedure begins in earnest today.
Bhatt has received a grant from Medtronic through his institution; has received grants from Amarin, AstraZeneca, Bristol-Myers Squibb, Eisai, Ethicon, Medtronic, Sanofi, and the Medicines Company; has done unfunded research for FlowCo, PLx Pharma, and Takeda; has received fees from Duke Clinical Research Institute, the Mayo Clinic, Population Health Research Institute, the American College of Cardiology, Belvoir Publications, Slack Publications, WebMD, and Elsevier Practice Update Cardiology; has served on advisory boards for Medscape Cardiology and Regado Sciences and on the board of directors for Boston VA Research Institute and the Society of Cardiovascular Patient Care; has been chair, Get with the Guidelines, for the American Heart Association and editor in chief of the Journal of Invasive Cardiology; has received research grants from Roche; has served on data safety and monitoring and clinical-trial steering committees for Harvard Clinical Research Institute; and has served as associate editor for Clinical Cardiology, and for the American College of Cardiology as section editor, pharmacology. Bakris has received fees from Takeda, AbbVie, Novartis, Janssen, Medtronic, Relypsa, and Bristol-Myers Squibb. Disclosures for the authors are listed in the article. Messerli has consulted for Daiichi Sankyo, Pfizer, Takeda, Abbott, Servier, Medtronic, Ipca Laboratories, AbbVie, and Centrix Healthcare. Bangalore has received grants from the National, Heart, Lung, and Blood Institute and Abbott Vascular and fees from Boehringer Ingelheim, Daiichi Sankyo, Pfizer, and Abbott.
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Cite this: SYMPLICITY HTN-3: Renal Denervation Fails to Reduce BP in Resistant-Hypertension Patients - Medscape - Mar 29, 2014.