SYMPLICITY HTN-3 Complicates Renal-Denervation Field, Say Experts

January 10, 2014

MINNEAPOLIS, MN — Catheter-based renal denervation for the treatment of resistant hypertension has featured prominently at recent hypertension and cardiology congresses in the past few years, with numerous experts believing the procedure was one of the hottest fields in medicine.

The American Heart Association highlighted renal denervation as one of the top advances in cardiology in 2012, and the American College of Cardiology rightly predicted that the results of the SYMPLICITY HTN-3 trial would be one of the top news stories in 2014.

Well, the top-line results of SYMPLICITY HTN-3 trial were released yesterday, and while 2014 is only 10 days old, they are definitely a big deal. As reported by heartwire , the phase 3 study testing catheter-based renal denervation for the treatment of resistant hypertension failed to achieve its primary efficacy end point, which was a sustained reduction in systolic blood pressure at six months[1].

So, what exactly went wrong for the study, when other trials, including SYMPLICITY HTN-1 and 2 , showed significant reductions in systolic blood pressure?

The methodology in this study was far, far, far more rigorous than in previous studies.

"If you put it into context, I think what you have is a trial that was actually done, and this is not meant in a pejorative way, properly," Dr George Bakris (University of Chicago, IL), one of the principal investigators of SYMPLICITY HTN-3, told heartwire . "It had a sham control, and it prospectively looked at blood pressures not only in the office but also at ambulatory blood pressures. There were mandates for the use of spironolactone, the inclusion criteria were generally more difficult than previous studies, and there were anatomic criteria that were not present in other studies. I guess what I'm saying is the methodology in this study was far, far, far more rigorous than in previous studies."

As a result of this rigorous methodology, there was no significant reduction in office blood pressure in the renal-denervation arm compared with controls. While Bakris did not reveal the actual reduction in blood pressure that was observed with renal denervation, the reduction did not achieve statistical significance and was not as large as predicted.

Interestingly, St Jude Medical last month 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 beat them to 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. At the time, even the investigators were caught off guard by the company's decision, telling heartwire they would have preferred to see the trial carried out.

ESC Will Reevaluate When Data Are Published

Despite the lack of effect on blood pressure in SYMPLICITY HTN-3, there were no safety concerns raised during the trial. This is reassuring, given that the procedure is performed extensively in Europe, where it has CE Mark approval. In 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.

To heartwire , Dr Marco Valgimigli (Thoraxcenter, Rotterdam, the Netherlands), who spoke on behalf of the ESC, said that renal denervation is restricted to patients who have tried at least three medications and still can't get to goal. It should not be offered to patients unless other available and proven therapies have systematically failed. He said the ESC position has always been that the technology needs to be further studied and that it will reevaluate renal denervation's role when SYMPLICITY HTN-3 is presented and published.

Needless to say, the negative SYMPLICITY HTN-3 results "are a matter of concern," added Valgimigli, but stressed patience before jumping to conclusions.

"Under these circumstances, the failure of this study to reach its prespecified primary end point may not necessarily change the ESC position on the technology," he added. "First of all, and most important, there was no signal for a safety issue regarding the procedure. Second, when the data will be made public entirely, the ESC will take a formal position on this new finding. Not rarely, studies fail to meet their primary end points not necessarily for a lack of efficacy of a given tested treatment, so I would really be careful before drawing conclusions without being fully aware of the data."

For Bakris, the most he would say is that the trial will be presented at a major medical meeting within the next three to six months.

Do you do a second study to get absolute resolution on this? What do you do?

Dr Darrel Francis (Imperial College London, UK) on the other hand, who was not affiliated with the study or any of the other renal-denervation technologies, was extremely critical of researchers and clinicians who hyped the procedure based on results from inferior trials. He agreed with Bakris about the rigor of SYMPLICITY HTN-3 and praised the investigators for the well-conducted trial.

"I hope we learn to stop dissipating resources on buying up prominent 'key opinion leaders' who merely parrot back corporate wishful thinking and instead focus resources on top-quality trials designed to resist bias through strict blinding," Francis told heartwire . "SYMPLICITY HTN-3 was a rare example of wise commercial guardianship of the world's resources, in the true best interest of patients."

In a paper published last year in Heart[2], Francis, along with first author Dr James Howard (Imperial College London), examined discrepancies between reductions in office blood pressure and reductions in 24-hour ambulatory blood-pressure monitoring. The group predicted that the dramatic reductions observed in the early trials of renal denervation would not hold up once a true randomized, double-blind, placebo-controlled trial was conducted.

So, What Happens Now?

To heartwire , Bakris said he believes renal denervation will now enter a "moratorium." At this stage, there is no ethical reason to withdraw the technology because of safety issues, but Bakris said the Europeans will revisit their guidelines, and US payers, even if the technology were available (and it is not) are unlikely to pay for the procedure given the negative results. "So, you're left with a conundrum—do you do a second study to get absolute resolution on this? What do you do? At this point, it's really up for discussion," he said.

Bakris was clear, however, that he wouldn't be advising people to have the procedure done, even for the type of patient included in SYMPLICITY HTN-3, who were "truly resistant to medication."

There is still a lot to learn and understand about the role of renal denervation in hypertension.

Also commenting on the negative SYMPLICITY HTN-3 results, Dr Stephen Worthley (University of Adelaide, Australia) called the top-line announcement significant, saying the negative results, on initial hearing, do raise questions about the role of renal denervation. However, like others, he is awaiting the presentation and publication of the data in order to fully understand the findings.

"It is no surprise to many that the magnitude of blood-pressure reduction is not what it has been seen in the initial observational trials," Worthley told heartwire . "Although an obvious explanation is that the placebo effect is the main reason for this, we have other factors, including technical and procedural performance in centers previously without renal-denervation experience."

The Symplicity technology is approved in Australia, but Worthley wants to see the data before making changes to clinical practice or before the guidelines are changed. He said the data will be important for informing treatment decisions and in designing future trials.

"There is still a lot to learn and understand about the role of renal denervation in hypertension and other disease states. Studies such as SYMPLICITY HTN-3 are central to that knowledge base," he said in an email. "As such, it will help us to better understand which patients may be best selected for this treatment in the future. However, this is far from the end for renal denervation as a technology. This is, however, a signal that we are yet to select patients ideally suited to benefit maximally, and I look forward to reviewing in detail these data when available."

To heartwire , Francis urged physicians, researchers, and potential patients to "focus on the rebooted science of denervation, freshly reborn with SYMPLICITY HTN-3. Set aside short-term personal pecuniary rewards and focus on designing and implementing bias-resistant protocols that provide reliable knowledge."

Medtronic sponsored the SYMPLICITY-3 trial.


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