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Resistant Hypertension Still on the Horizon?
The sobering results of SYMPLICITY HTN-3 call into question the future of renal denervation.
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In a turn of events few had anticipated, catheter-based renal denervation, once poised to revolutionize the care of treatment-resistant hypertension, failed to reduce the primary efficacy endpoint in SYMPLICITY HTN-3.
The pivotal trial, which was presented at the American College of Cardiology Scientific Sessions in March, did not show a significant reduction in change of office systolic BP at 6 months with the Symplicity renal denervation catheter (Medtronic) in patients with severe resistant hypertension compared with a sham procedure, as the trial only met the safety endpoint.
SYMPLICITY HTN-3 (subsequently referred to as HTN-3) provided the first look at renal denervation in the setting of a sham-controlled randomized trial and, as a result, caused a rippling effect in cardiology that may be felt for years to come.
“This trial underscores the importance of doing rigorous clinical trials in interventional cardiology and any area of procedural medicine or surgery. It is important to do trials that are randomized, at a minimum, preferably blinded if possible, and sham-controlled if ethical and feasible,” said Deepak L. Bhatt, MD, MPH, executive director of interventional cardiovascular programs, Brigham and Women’s Hospital Heart and Vascular Center, Boston, and co-principal investigator of HTN-3. “In general, in the 80-plus countries outside the United States where renal denervation is being used, physicians probably ought to think twice and see whether their patients need to receive an invasive procedure where there is a large, well-done randomized controlled trial that showed no benefit.”
Delving into the Data
Bhatt, who is also Chief Medical Editor for Cardiology Today’s Intervention, presented HTN-3 data at the ACC Scientific Sessions, which indicated that the primary endpoint did not significantly differ between groups (renal denervation, –14.13 ± 23.93 mm Hg vs. sham procedure, –11.74 ± 25.94 mm Hg; P<.001 for both comparisons; P for difference=.26). Similarly, the secondary efficacy endpoint — change in mean 24-hour ambulatory systolic BP — was comparable between groups, with a reduction of –6.75 ± 15.11 mm Hg reported in the renal denervation arm and –4.79 ± 17.25 mm Hg in the sham-procedure arm (P for superiority=.98).
Deepak L. Bhatt
“The anticipation was that despite the January press release saying the primary endpoint wasn’t met, there would be some benefit. But as it turned out, it wasn’t that we missed the primary endpoint by a little, we missed it by a lot,” Bhatt said. “Furthermore, we assessed ambulatory BP — which many hypertension experts say is the gold standard in hypertension drug or device trials — and there, too, we saw no evidence of significant benefit. So, it was a consistently negative trial.”
As a result of the unexpected and significant drop of BP observed in the sham-procedure arm, there was no way renal denervation could be superior, according to Thomas F. Lüscher, MD, professor and chairman of cardiology at the University Heart Center in Zurich.
“If the placebo group shows a BP change of close to 12 mm Hg, how can you win? No drug would win against this,” said Lüscher, who is also editor-in-chief of the European Heart Journal. “In general, it is very difficult to prove superiority with a novel intervention if the control group is taking an average of 5.2 drugs. What we really need is to compare this method to normal medical therapy in patients with a stabilized BP with current antihypertensive drugs before randomization.”
According to Lüscher, achieving stable BP necessitates treating patients with the same drug and dosage for at least 8 weeks. “The first 4 weeks the BP goes down and the next 4 weeks it gets flat,” he said. “So the fact that investigators only did this for 2 weeks in HTN-3 made the interpretation of the trial difficult in my mind. Ideally, there would have been a 5 mm Hg or 8 mm Hg decrease in the sham arm, under such circumstances you could see whether renal denervation provides a significant BP reduction.”
Important Questions Remain
According to experts interviewed, HTN-3 raised several key questions that must be elucidated in future research.
“One of our observations from HTN-3 was that [renal denervation] is a safe procedure; part of the reason it may have been safe is that we underdosed the radiofrequency energy,” said Raymond R. Townsend, MD, investigator in HTN-3, and professor of medicine and director of the hypertension program at the University of Pennsylvania, Philadelphia. “So we might have seen a greater effect and perhaps a greater distance between denervation and sham if we had been a bit more aggressive. That may have caused more side effects, but it may have been more telling about the true difference between the groups.”
Similarly, Bhatt said investigators of HTN-3 may have essentially finished a dose-ranging study. “So, perhaps by increasing the dose, we’ll be able to still maintain safety, but actually get efficacy,” he said.
In addition to concerns with proper dosing, there is the hurdle of assessing whether the dosage was effective during the procedure. Currently, the only method to determine this is measuring norepinephrine spillover; however, this is too difficult and tedious to be performed on a routine basis, according to experts.
Murray D. Esler
“My Melbourne group is the only one to actually validly
test for efferent renal nerve ablation with renal
norepinephrine spillover measurements pre- and post-procedure,” said Murray D. Esler, MBBS, PhD, associate director, cardiovascular neurosciences division, Baker IDI Heart and Diabetes Institute in Melbourne. “Our experience is that on average, only 40% denervation is achieved with unipolar electrodes (range 0-85%), like the Symplicity catheter. The extreme between-patient difference in achieved denervation is disconcerting.”
“With the Symplicity catheter, the operator has to manipulate around the inside of the artery and deliver a series of lesions in a spiral-like fashion,” added Stuart Connolly, MD, professor of medicine, head of the division of cardiology at McMaster University, Hamilton, Ontario. “There are other catheters that are easier to use and deliver energy in a different manner that might have worked better.”
One such catheter, Lüscher said, is the EnligHTN renal denervation system (St. Jude Medical).
“The EnligHTN catheter features a basket design, so that if you place it well, you have much more consistent lesions [than the Symplicity catheter], which we confirmed via optical coherence tomography,” he said. “Another promising device is the Vessix balloon [Boston Scientific], which aligns very well to the wall and might be the better system to effectively destroy the nerves.”
Differences in the patient population, too, may have influenced the outcomes in HTN-3. Unlike the previous studies and registries, which included mainly white patients from Australia and Europe, 25% of the patients in HTN-3 were black.
“African Americans had a BP drop of 18 mm Hg in the sham group. How can you beat that? It’s very difficult,” Lüscher said. “So we need more trials to define the right patients for the procedure and to enroll the patients where there is still room for BP lowering with a new treatment option.”
Another aspect of the trial that has received some criticism is the lack of experienced operators performing the procedure.
“I find it problematic when people learn a procedure in a trial. The average number of renal denervation procedures performed by an operator in HTN-3 was one to five, which is ridiculous and a major drawback of this trial,” Lüscher said. “In the United States, regulations don’t allow operators to learn a technique before they go into a trial. We saw the same thing when carotid artery stenting (CAS) was being investigated in the United States: Physicians had to do five CAS procedures before they entered the trial, and of course the results were bad. In our own registry with 150 patients, we had completely different results.”
These limitations, taken as a whole, suggest that the wheels are starting to fall off HTN-3, Esler said.
“When the dust settles, HTN-3 will be seen ‘to be on the wrong side of history,’” he said.
Fallout from HTN-3
In January, when it was announced that the sham-controlled trial missed the efficacy mark, Medtronic said that it would halt the SYMPLICITY HTN-4 trial, and shortly later Covidien stated it would be ending its OneShot renal denervation program altogether. This immediately led to grim predictions about the future for renal denervation. However, the outlook improved in subsequent weeks when Medtronic announced in a press release coinciding with the presentation of HTN-3 at the ACC Scientific Sessions that after further review and consultation, they would be continuing research in the field. The company stated: “We believe further clinical investigation is warranted; Medtronic will determine the optimal path forward, along with the FDA, for the next US [investigational device exemption].”
In addition, Medtronic said it will continue to provide access to the Symplicity catheter in countries where it is approved and will continue to support a global hypertension clinical program and enroll patients in the Global SYMPLICITY Registry. Medtronic will also continue to pursue its studies of renal denervation in other disease states.
In separate email responses to Cardiology Today’s Intervention, representatives of Boston Scientific and St. Jude Medical acknowledged the potential that still exists for renal denervation and their respective catheters, but stated that the companies would be carefully reviewing HTN-3 data and consulting with scientific advisers to determine the next approaches for their renal denervation programs.
According to Connolly, it will be vitally important that industry continues its commitment to the field if renal denervation is to one day make a meaningful clinical impact.
“The field is very much dependent upon corporate decision-making,” Connolly said. “The direction the field goes will be largely decided by those companies.”
Stuart Connolly
Although it seems likely that our understanding of renal denervation as a treatment strategy will improve in the coming years with more research, a more imminent concern is what the impact of HTN-3 will be in countries where renal denervation is currently being used clinically and/or reimbursed.
“Providers will avoid paying for renal denervation, which providers tend in general to do,” said Esler, who practices in Australia. “Within the constraints this imposes, renal denervation will continue to be used clinically for resistant hypertension in countries where approvals exist, because outside the United States, HTN-3 is thought to be untrustworthy.”
Michael Böhm, MD, chairman in the department of internal medicine, University of Saarland, Homburg/Saar, remains confident that in Germany, where renal denervation is widely used, the paradigm for clinical use and reimbursement of the procedure will not be changed as a result of the trial.
“There are too many unresolved issues in HTN-3,” Böhm said. “This is recognized by physicians.”
Felix Mahfoud
Felix Mahfoud, MD, director of the interventional hypertension program at the University of Saarland, added that he does not expect HTN-3 to change the practice of physicians who are involved and engaged in the field. “For patients with true resistant hypertension, there are very few other evidence-based approaches available,” he said. “So we can wait and see whether these patients have a stroke or develop HF or end stage renal disease, or we can offer them a safe renal denervation procedure,” he said. “Right now, we are offering the procedure and discussing with them the current data on its efficacy, including HTN-3.”
Lüscher, who practices in Switzerland where renal denervation is not reimbursed, said that the procedure is currently performed out of interest. “We can get money for the angiography but not the intervention,” he said. “[HTN-3] will bring a lot of controversy, uncertainty and confusion into the field.”
SYMPLICITY Silver Linings
Although most of the attention surrounding HTN-3 has revolved around the missed efficacy endpoints and trial design limitations, experts also highlighted some of the positives that came out of the study.
“HTN-3 and the Global SYMPLICITY Registry have shown safety. This is important,” Böhm said.
Michael Böhm
Specifically, HTN-3 met the primary safety endpoint of a composite of major adverse events within 30 days or new renal artery stenosis of more than 70% within 6 months compared with an objective performance criterion of 9.8% (renal denervation, 1.4%; P<.001; sham procedure, 0.6%). Additionally, data from the Global SYMPLICITY Registry, which were presented at the ACC Scientific Sessions by Böhm, found a low rate of adverse events in real-world patients and concluded that the device met the study’s primary endpoint of safety.
Another positive, according to Bhatt, was that HTN-3 showed the value of collaboration between proceduralists and noninvasive hypertension experts.
“This is great for patient care, even if patients don’t end up getting the procedure or if renal denervation in its current form doesn’t pan out,” he said. “The collaborative approach we employed was very similar to the collaboration between cardiac surgeons and interventional and noninvasive cardiologists with transcatheter aortic valve replacement. One lasting benefit of HTN-3 is that we’ve established several such partnerships at leading medical centers throughout the United States.”
In addition, Townsend said the research has been a boon to the field of hypertension.
“In many ways, renal denervation has done for hypertension research what HIV has done for infectious diseases: It put us back in the game in terms of having a respectable organ with cool and interesting physiology that no one appreciated until recently,” he said.
The Future of Renal Denervation: BP and Beyond
Most of the experts interviewed for this article agreed that HTN-3 is the best trial to date to examine the efficacy of renal denervation; despite this, they remain hopeful, if not cautiously optimistic, that the future of renal denervation will yield a benefit for the strategy.
“What we found was that one device used in one particular way in a specific patient population provided no evident benefit. That is a very different message than to say renal denervation is dead,” Bhatt said. “I don’t think it’s dead, but I do think the field needs a bit of a reboot. In other words, we need to go back to the drawing board and engage in more preclinical and animal work.”
Böhm agreed that renal denervation is not dead, but added, “The hype is over,” he said. “Therefore, the field of renal denervation in sympathetic overactivity, including hypertension, needs to become more academic. However, I am still enthusiastic on the scientific possibilities, not only in hypertension, but also in HF.”
Although still in its early stages, research into renal denervation’s potential effect on HF has already shown safety, and some believe has great promise to one day show efficacy as well.
“In HF, we know that the sympathetic nervous system activity is increased, so it seems logical that toning down that sympathetic activity could be helpful,” Bhatt said. “But, of course, proper studies need to be done.”
Preliminary research conducted by Mahfoud, Böhm, Esler and colleagues and published in the European Heart Journal in March showed that in patients with resistant hypertension, renal denervation reduced BP and left ventricular mass index and improved ejection fraction and circumferential strain. “Taking into account this study and other research, I do think that HF with preserved ejection fraction (HFpEF) is a promising avenue for renal denervation, as is HF with reduced ejection fraction, which we are investigating now in the RE-ADAPT-HF trial in Europe,” Mahfoud said.
“HF is an interesting area because HFpEF has a mortality rate that has been unaffected by anything we do,” Townsend added. “In patients who have HF with reduced ejection fraction, you can prolong life with a beta-blocker, angiotensin receptor blocker, ACE inhibitor, mineralocorticoid receptor antagonist — you name it; patients tend to be better with it. But patients with HFpEF, no matter what you do, the survival rate is no different than it was 12 years ago.”
Townsend said that there is a variety of other comorbidities renal denervation is being tested in, including insulin resistance, sleep apnea, metabolic syndrome, atrial fibrillation and chronic kidney disease. “To date, the science is still in the trial phase,” he said.
According to Böhm, renal denervation in AF is of great interest, particularly relapse after pulmonary vein isolation and new-onset AF in hypertensive patients with dilated atria, but also in sinus rhythm as well. “Furthermore, there are interesting data on ventricular storm and ventricular arrhythmias.
“Overall, I am optimistic that we will learn a lot from future trials in other conditions like heart failure, arrhythmias and metabolic disease,” Böhm continued.
Yet, even in hypertension, Böhm remains optimistic about the future prospects of renal denervation.
“Prior to HTN-3, my impression was that renal denervation is working 80% of the time in hypertension. This view has not changed,” Böhm said. “First on the agenda now is to establish the effect on hypertension with the resistance to drugs and its related comorbidities.”
Townsend agreed. “[HTN-3] is a speed bump, not a roadblock,” he said. “I’m cautiously optimistic at this point, and I am waiting for the next round of studies to get underway to pursue this further and to establish definitively whether we have something useful here or whether this has been a many billion dollar fruitless effort.” – By Brian Ellis
Sidebar: Franz H. Messerli, MD and Vasilios Papademetriou, MD weigh in on Renal Denervation for Resistant Hypertension: Dead or Alive?