WASHINGTON, DC — Is renal denervation for the reduction of blood pressure in treatment-resistant hypertension "dead in the water," or is this new technology and treatment strategy just struggling through some early growing pains?
That was the question debated by two experts before a packed room this week at TCT 2014 , with Dr David Kandzari (Piedmont Heart Institute, Atlanta, GA) taking the view that recent failures have allowed researchers to learn even more about renal denervation, while Dr Sripal Bangalore (New York University School of Medicine, NY) stated the current technology, at least in this iteration, is not effective for the reduction in blood pressure.
The effectiveness of renal denervation, of course, has been questioned ever since the SYMPLICITY HTN-3 trial was halted due to lack of efficacy. The first randomized trial with a sham-controlled arm, SYMPLICITY HTN-3 included 535 patients with 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. Similarly, there was no significant reduction in the 24-hour ambulatory blood-pressure measurement.
"Perhaps our greatest fault with renal denervation itself is that the clinical enthusiasm for this patient population that otherwise had no therapeutic options led to the greater adoption of this clinically and far exceeded the science itself," said Kandzari. "The results of HTN-3 are welcome, in a sense, because they provide an opportunity to revisit the basic science of this technology."
Speaking out against renal denervation in its current form, Bangalore, a hypertension expert, noted that a predebate vote found that most of the audience still believed that renal denervation had a future. The audience, however, included interventionalists, some of who perform the procedure, researchers involved in preclinical and clinical testing, and some company executives with renal-denervation technology in their pipeline.
"The reason this is important is because many times our preconceived notions dictate how we look at data," said Bangalore.
He pointed out that within the past decade, the number of publications on the treatment of resistant hypertension has increased exponentially. Such an increase tracks with the development of renal denervation, he added. The first open-label, nonrandomized trial testing renal denervation—the SYMPLICITY HTN-1 study—showed a significant 26-mm-Hg reduction in systolic blood pressure at six months and a 32-mm-Hg reduction at three years. However, even at three years, patients were taking, on average, 5.6 antihypertensive medications, said Bangalore.
That being said, for patients with coronary artery disease, treatment-resistant hypertension is associated a significantly increased risk of cardiovascular events and all-cause mortality. Resistant hypertension is also associated with an increased risk of cerebrovascular and kidney-related clinical events. Despite this, there is no agreement on how to define resistant hypertension or its true prevalence, said Bangalore. And the enthusiasm for the procedure has been on full display, with estimates showing that more than 10 000 patients had undergone renal denervation by 2013.
Truly Understanding Renal Denervation
Speaking during the debate, Kandzari said the development path of renal denervation has been troublesome, "with not only the closure of clinical trials but the closure of programs altogether," he said. Still, he believes there is an opportunity for studying renal denervation, including its potential use in clinical practice, stating that "it is by no means dead in the water."
With SYMPLICITY HTN-3, Kandzari said there have been a number of reasons proposed for the study's failure. Such speculation has included everything from the patients studied, the procedure itself, and the confounding variables of patient and physician behavior. Exploratory analyses have suggested there might have been an interaction with antihypertensive medications, especially drugs that influence the neurohormonal cascade. Along with data from the Global SYMPLICITY Registry , there are also data to suggest that an increase in the number of renal-ablation attempts correlated with increased reductions in systolic blood pressure.
"This raised the potential concern that there might be variances in how the procedure was performed," said Kandzari.
The quality of the ablation procedure is one hypothesis that has been raised for the SYMPLICITY HTN-3 failure. As reported previously by heartwire , a criticism of renal denervation is that there is no way for interventionalists to assess ablation success. During the debate, Kandzari said that just 19 of 364 patients had complete four-quadrant circumferential ablation in both renal arteries and that more complete ablation may lead to greater treatment success. Also, researchers are still learning exactly where the renal nerves lie, with studies suggesting that in the more distal ends of the renal arteries there might be a greater concentration of renal nerves.
For Kandzari, psychological factors might have also influenced the results. Within sham-controlled studies like SYMPLICITY HTN-3, "big-day bias" or the "check-once-more bias" might overestimate or underestimate blood pressures. Physician behavior might have also played a role, he added, noting that 40% of patients in both treatment arms had a change in their medications despite study protocol requesting drug consistency until six months. This might have confounded the treatment effect of renal denervation, said Kandzari.
For Dr Eric Bates (University of Michigan, Ann Arbor), a panelist on the debate session, Kandzari did an "excellent rationalization" for the negative SYMPLICITY HTN-3 trial. While apologizing for sounding harsh, he said such a rationalization did leave him with some hope for renal denervation. However, he contrasted renal denervation's failure with the careful development of transcatheter aortic-valve replacement (TAVR) for aortic stenosis. In those TAVR studies, there was a strict protocol for enrolling a specific type of patient, a rigid treatment protocol for the comparator arm, and a definite technique for implanting the device.
Kandzari disagreed with the analogy, noting the renal denervation is a procedure in which there is still very little basic science. "It's not as intuitive as a transcatheter valve might be," he said. "We were very limited in our preclinical study of this technology, and the technology to drive this forward was largely predicated on the success of these earlier clinical trials with all of their limitations."
Not Closing the Book
Speaking during the debate, Bangalore said that some attempts have been made to identify patient subgroups who might benefit from the procedure, but even these should be viewed with caution. Also, much has been made of the reduction in systolic blood pressure in the sham arm of SYMPLICITY, with some believing this placebo effect might have worn off by one year. However, even one-year results showed no difference in blood pressure between those randomized to renal denervation and the control patients.
"Let's not forget that even leeches can reduce blood pressure," said Bangalore. "What we really need is a therapy that can reduce morbidity and mortality." The data supporting the blockade of sympathetic activation suggest no evidence of benefit, with the clinical guidelines even moving away from beta-blockers, pushing them down to at least fourth-line therapy, said Bangalore.
On the whole, Kandzari said the debate today is not so much whether there is evidence to support the routine use of renal denervation in clinical practice but rather to ask whether there is sufficient evidence to support further studies. "The answer, clearly, is yes," he said. Bangalore seemed to agree, noting that the thoughts on the procedure first shifted from the hype of earlier studies to the disappointment with SYMPLICITY HTN-3. However, there is now movement away from such disillusionment and disappointment into understanding what went wrong and how to best move forward.
"The time has come to turn the page on renal denervation in its current form, but I want to emphasize, by all means, not to close the book," said Bangalore.
Dr Usman Baber (Mount Sinai Hospital, NY), another panelist during the debate, said that SYMPLICITY HTN-3 was a difficult trial to enroll patients. Given the unknown prevalence of resistant hypertension—it has been suggested to be as low as 7% to 8%—the population-level impact of this invasive and costly procedure was unknown. He noted that sympathetic hyperactivity is prevalent in other disease states, such as diastolic heart failure, and renal denervation has been linked with reduced left ventricular mass and an improvement in diastolic indices.
"Let's not forget other areas, which are much more prevalent, where this technology might be very useful," said Baber.
Heartwire from Medscape © 2014
Cite this: Dead or Treading Water: Experts Debate Future of Renal Denervation for Resistant Hypertension - Medscape - Sep 14, 2014.