Future of Renal Denervation May Hinge on a Handful of Small Studies
The failure of SYMPLICITY HTN-3 sapped much of the enthusiasm for renal denervation: now the field seems to be mostly on hold as investigators await the results of a few small trials incorporating lessons learned from renewed research efforts. Despite the waiting game, however, some experts remain confident that the right adjustments have been made to ensure success in treating hypertension and potentially other diseases involving sympathetic hyperactivity.
Stepping back from the “irrational exuberance” that characterized earlier renal denervation work, researchers have focused on issues of trial design, medication compliance, technology, anatomy, and procedural technique in the roughly 2 years since the initial results of SYMPLICITY HTN-3 became known and resulted in the stoppage of many other ongoing trials, according to Jay Giri, MD, MPH, of the Hospital of the University of Pennsylvania (Philadelphia, PA).
Because these issues are being addressed and there are now several devices using different modalities to accomplish denervation, “I do have a little more confidence . . . that we’re going to see the ability to denervate nerves from within the vasculature,” Giri told TCTMD, albeit without the “completely crazy 40-mm Hg drops in blood pressure” observed in earlier studies that used office instead of ambulatory readings and did not include a sham control.
SYMPLICITY HTN-3: A Wake-up Call
Reported in full in March 2014, SYMPLICITY HTN-3 showed that renal denervation with the Symplicity catheter (Medtronic) was not superior to a sham procedure for lowering ambulatory systolic blood pressure through 6 months of follow-up in patients with severe resistant hypertension, at least in part because of a larger-than-expected reduction in the sham-control group.
In the aftermath, many ongoing renal denervation trials were halted and studies in the planning stages stagnated. In Europe, where the technology is already approved for use, renal denervation dropped off in practice, with regular reimbursement withdrawn in certain countries.
According to David Kandzari, MD, of the Piedmont Heart Institute (Atlanta, GA), the clinical enthusiasm for renal denervation clearly exceeded the science, but the failure of SYMPLICITY HTN-3 presented an opportunity to revisit the basics and learn more about anatomy and the procedure.
That interest has been fed by recent studies highlighting the importance of lowering blood pressure, including SPRINT, and others showing that the control of hypertension at the population level may be worsening.
In the search for answers, many areas have been explored, including appropriate trial design, renal artery anatomy, procedural performance, and the device itself. In addition, researchers have looked at how patients in the control group of SYMPLICITY HTN-3 were treated and at the potential impact of improved adherence once the patients entered the trial.
One study, for example, showed that fewer than 25% of patients in SYMPLICITY HTN-3 had effective circumferential renal nerve ablation in both renal arteries, Kandzari said. Patients with more complete denervation tended to have greater reductions in blood pressure. Medtronic’s second-generation Symplicity Spyral multi-electrode catheter has been designed to enhance the completeness of denervation, Kandzari said.
Also, anatomical studies have changed how the procedure is performed. Initially, it was thought that there was a cluster of nerves near the ostium of the renal artery that would be an ideal target for denervation, Kandzari explained, but subsequent studies have shown that ablation may be more effective if performed in the distal segments and in the branch arteries.
Felix Mahfoud, MD, of Saarland University Hospital (Homburg, Germany), told TCTMD that denervating these more distal segments seems to reduce variability in performance across procedures and operators.
Two Steps Back
Giri said that despite new insights into anatomy and device performance, however, it still remains uncertain whether renal denervation devices are actually doing anything at all.
To settle that question, lessons learned since SYMPLICITY HTN-3 have been incorporated into the design of smaller, pilot studies that are ongoing or will be starting soon. All have been designed with FDA guidance.
Medtronic has launched 2 parallel studies—SPYRAL HTN-ON MED and SPYRAL HTN-OFF MED—to evaluate the effectiveness of the Symplicity Spyral catheter compared with a sham procedure. One will include about 100 patients taking a stable regimen of 3 antihypertensives, and the other will include about 120 patients with uncontrolled hypertension who are not taking any antihypertensives. Both started in June and will track the change in ambulatory systolic blood pressure as the primary outcome.
The Spyral catheter, noted Kandzari, who is a principal investigator for the Medtronic studies, is a 4-point electrode catheter that better achieves circumferential ablation compared with the earlier-generation device.
Boston Scientific is evaluating its Vessix system in the REDUCE HTN: REINFORCE, which started in April and will include about 100 patients with uncontrolled hypertension who are not taking any medications. It is also sham-controlled and will track ambulatory systolic blood pressure as the primary outcome.
ReCor is expected to start enrolling patients into the RADIANCE-HTN trial next month. That study will include about 292 patients divided into untreated and treated cohorts who are randomized to renal denervation with the Paradise system, which uses ultrasound instead of radiofrequency energy, or a sham procedure. And Ablative Solutions is planning a study of its Peregrine system, which involves injection of a neurolytic agent into the arterial wall via a catheter with 3 microneedles to achieve denervation.
Michael Weber, MD, of SUNY Downstate Medical Center (New York, NY), co-principal investigator of the Vessix trial, told TCTMD that the studies in patients who are not taking any antihypertensive medications will help isolate the effect of renal denervation without the confounding effects from drug treatment.
Even in the studies of patients who are treated, however, efforts have been made to standardize the regimens to allow for a better assessment of the effects of renal denervation, he said.
Citing improvements in technology, targeting of the renal nerves, and study design, Weber said these studies—which should start reporting results toward the end of this year or in early 2017—have advantages over the earlier studies, including SYMPLICITY HTN-3. For that reason, even though these ongoing studies were designed to pave the way for future pivotal trials, Weber said they might also be used when the FDA ultimately makes a decision about approving the technology.
The so-called feasibility trials, he said, ask the right questions about safety, efficacy, and whether those factors differ based on whether renal denervation is performed alone or as an adjunct to medical therapy. “It’s very hard to imagine what else you need to know about the procedures,” Weber said.
Optimism About the Future
The future of renal denervation will depend on the outcomes of these pilot trials, according to Giri, who said that widespread failure could be a fatal blow. “There’s already a big cloud over the field, but that’s going to be a potential death knell for it,” he said.
But none of the experts interviewed by TCTMD, including Giri, thought that would be the case.
“I believe in the technology, and I believe in the concept of renal denervation,” said Mahfoud, who added that he has seen many patients who clearly improve following the procedure. “We were hopefully smart enough to design good clinical studies that can document the benefit of renal denervation.”
Pilot studies will help clarify the effect of renal denervation on blood pressure, after which further studies will be needed to identify the most appropriate patients and to establish that the procedure is reducing cardiovascular morbidity and mortality, Mahfoud noted. “And once we have done that, it will become a guideline-recommended therapy, I’m pretty sure.”
Kandzari also believes that renal denervation will be able to demonstrate success in treating hypertension, assuming the right trial design is used. “Thereafter, I do believe that renal denervation would find a common role in the treatment of treatment-resistant hypertension, . . . but we’re still years from that being a reality,” he said.
For Weber, where renal denervation will be in several years depends on the results of the pilot studies and whether they are “compelling” and not just statistically significant. If only a 5- or 6-mm Hg reduction in blood pressure on average is achieved with denervation, one would have to ask whether it is worth it, he said. In that case, it would be important to find a way to identify patients with above-average responses of at least 10 to 20 mm Hg, in whom denervation would be worth the effort.
Indications Beyond Hypertension?
But hypertension is not the only disease that could be targeted by renal denervation, experts say. Before the results of SYMPLICITY HTN-3 were known, there were dozens of trials being conducted or planned involving patients with other diseases characterized by sympathetic hyperactivity, including heart failure, arrhythmia, renal insufficiency, insulin resistance, and obstructive sleep apnea.
The bulk of those studies seem to have been put in “suspended animation” over the past few years, and the potential usefulness of renal denervation in those areas remains very much uncertain, Giri said. However, he added, the 2 diseases most likely to be amenable to treatment with denervation are heart failure and arrhythmia, in which the neurohormonal axis plays a major role. “Those are the 2 places that should be really sought after almost concurrently with hypertension treatment, I would argue, because they do represent some really big potential areas of need,” he said.
There is one ongoing trial in patients with A-fib. The SYMPLICITY AF trial started last year and is evaluating whether adding renal denervation with the Symplicity Spyral catheter to pulmonary vein isolation has any benefits.
Despite the potential in other areas, however, hypertension is still the key to renal denervation’s future simply because of patient numbers, Weber said. Even if only 1% of the hypertensive population in the United States would benefit from the treatment, that is still about 1 million patients, he noted.
From Mahfoud’s perspective, because of all of the work that has been done in the wake of SYMPLICITY HTN-3, “the basis is there now to state that we really are targeting sympathetic nerves, that we can ablate them in the way we are doing it currently. . . . Now we have to understand in which clinical or cardiovascular disease renal denervation is a valid treatment option. It starts with hypertension, but for me—I mean, I’m a cardiologist—I also look at heart failure and atrial fibrillation or ventricular tachycardia as potential treatment options.”
McArdle MJ, deGoma EM, Cohen DL, et al. Beyond blood pressure: percutaneous renal denervation for the management of sympathetic hyperactivity and associated disease states. J Am Heart Assoc. 2016;4:e001415.
- Giri reports being an investigator for SYMPLICITY HTN-3.
- Kandzari reports receiving research grants through his institution and personal consulting honoraria from Boston Scientific and Medtronic Vascular.
- Mahfoud reports receiving research grants from Medtronic, ReCor, and St. Jude Medical.
- Weber reports serving as a consultant to Ablative Solutions, Boston Scientific, Medtronic, and ReCor.