Renal Denervation 2.0: Laying Out the Road to Recovery from Symplicity HTN-3

Part 1 looked at the shock waves set off in the renal denervation field by the failure of the Symplicity HTN-3 trial. In Part 2, experts offer ideas for reviving the transcatheter therapy.

As the shock over the failure of the Symplicity HTN-3 trial and its disruption of renal denervation’s anointment as a remarkable transcatheter therapy for resistant hypertension faded, some experts saw a salutary effect: exposure of critical gaps in the field’s scientific underpinnings.

“The whole experience is a call to revisit the pathophysiology of renal denervation as a procedure and the biologic translation between catheter ablation of renal artery nerves and the reduction in sympathetic drive and blood pressure,” David E. Kandzari, MD, of the Piedmont  Heart Institute (Atlanta, GA), noted in a telephone interview with TCTMD.

In a press statement outlining his EuroPCR 2014 analysis of denervation predictors from the Global Symplicity registry, Felix Mahfoud, MD, of Saarland University Hospital (Homburg, Germany), said, “Maybe we are moving away from Symplicity to complexity, in terms of how we deliver energy and where the sweet spots for renal denervation are.” Furthermore, “there may be a learning curve for renal denervation; there is a lot more to learn and a lot more to understand,” he added.

One example is the evolving insight into renal nerve distribution and its variability, which may lead to uneven denervation despite consistent energy application.

Contrary to earlier practice, research now suggests that ablations should be concentrated distal to the artery ostium, said Thomas F. Lüscher, MD, of University Hospital (Zurich, Switzerland), in a telephone interview. Another unresolved issue, Krishna J. Rocha-Singh, MD, of Prairie Vascular Institute (Springfield, IL), commented to TCTMD, is the depth of the nerves in the adventitia and thus the amount of energy needed to safely ablate them. 

The fact that more than 15,000 people have undergone the procedure without such issues having been better defined shows “how far renal denervation practice has outpaced the science,” Dr. Kandzari commented.

Efficacy Marker, Better Patient Selection Sorely Needed

The lack of an intraprocedural readout of denervation’s functional impact to guide operators in applying ablation is a widely acknowledged Achilles heel of the therapy in its current state.

In preclinical and small clinical studies, reduction in norepinephrine spillover and muscle sympathetic nerve activity were correlated with the degree of denervation. More recently, cardiac baroreflex sensitivity and serum levels of specific cell adhesion molecules, for example, have been proposed as biomarkers of efficacy. Thus far, however, none of the candidates, including various imaging modalities, have been independently validated, and most are clinically impractical, Dr. Kandzari said.

Another obstacle to demonstrating denervation’s efficacy is the inability to predict which types of resistant hypertension, aside from a very high baseline systolic pressure, are more or less likely to respond significantly to denervation. 

The variability in response suggests that in some patients sympathetic overactivity plays a subordinate role in hypertension, undercutting the chance that denervation would have an incremental effect. One such phenotype, Dr. Rocha-Singh proposed, may be patients with chronic, severe hypertension and poor vascular compliance.

A proposed strategy for tilting the odds in denervation’s favor is to restrict study enrollment to subgroups that showed signals of benefit in Symplicity HTN-3, such as non-African-American patients. Alternatively, Dr. Lüscher suggested randomizing African-Americans and Caucasians separately in a trial with greater power, to enable a predefined assessment of the differential effect of denervation.

However, in a telephone interview with TCTMD, Symplicity HTN-3 co-principal investigator Deepak L. Bhatt, MD, MPH, of Brigham and Women’s Hospital (Boston, MA), said he was skeptical of singling out subgroups, noting that ambulatory blood pressure (BP) reductions were not significant in any of them.

One way to avoid repeating Symplicity HTN-3’s failure, several analysts suggest, is to relax its strict inclusion criteria. The fact that many participants were on an unsustainable regimen of 5 or more medications led to shifting compliance, which in turn clouded the outcome, they assert. The trial may have “overreached in the type of patient it was pursuing,” Dr. Rocha-Singh said, adding that “we need to start [enrolling] patient populations that are on stable regimens, whether that means stable and inconsistent or stable and consistent.”

In a similar vein, Dr. Bhatt suggested that “a fairer test of renal denervation would be to do it against whatever [each patient’s] background therapy is.” As it happens, the Symplicity investigators considered that approach, he reported, but discarded it out of concern that if denervation proved effective, the FDA, third-party payers, and referring hypertension experts would ask why an expensive, invasive treatment should be used in patients who might have achieved similar BP reductions simply by taking their medications.

Another potential study population could be patients with moderate hypertension, who would be on fewer medications, Dr. Bhatt observed, adding that the currently suspended Symplicity HTN-4 was aimed at such patients. In a pharma-style design, antihypertensive medications could be “washed out” before the participants were started on a stable regimen, Dr. Rocha-Singh and others have proposed, and compliance could then be tracked using patient diaries, pill counts, or monitoring of drug metabolites in blood or urine.

However, Dr. Bhatt cautioned, the strategy might reduce the potential effect of denervation since a markedly elevated baseline systolic pressure is the strongest predictor of response. At minimum, the threshold of success for BP reduction might have to be lowered for those with moderate hypertension, Dr. Rocha-Singh observed. 

Other good candidates for a randomized trial might be nonadherent patients with uncontrolled hypertension who have experienced dangerous hypertensive crises, Dr. Bhatt added.

Two Strikes and You’re Out

All the experts interviewed agreed that the next US pivotal trial, if it happens, will be locked into a sham-control design—especially since Symplicity HTN-3 was negative. Moreover, the pressure on future investigators to ‘get it right’ will be considerable since failure of another well-designed, sham-controlled trial would effectively signal the death of renal denervation therapy, Dr. Bhatt predicted. Skepticism would prevail and industry funding would vanish, he noted. 

On the upside, Dr. Bhatt said, “we cleared a path with Symplicity HTN-3. That makes it a little bit easier for the next folks.” And with improvements in technique, technology, and trial design, the next contender has better odds of a successful outcome, commented Dr. Rocha-Singh. 

Most of the major players in the denervation device market—Medtronic, Boston Scientific, and St. Jude—remain in the game, although they are in “slow-down mode,” said Martin B. Leon, MD, of Columbia University Medical Center (New York, NY), in a telephone interview with TCTMD. 

“They’re not rushing into pivotal clinical trials. They’re going to be doing additional studies to understand if their technology has been optimized and rethinking what the trial design metrics need to be,” he added, noting that discussions with the FDA to work out future clinical research needs in the field are scheduled for June 26, 2014. 

Meanwhile, Symplicity HTN-3 has caused “collateral damage,” as many planned trials have been suspended and start-ups and smaller companies without deep pockets have begun to disappear, Dr. Rocha-Singh observed.

In Europe, Skepticism but Also ‘Insecurity’   

In the wake of Symplicity HTN-3, the European Society of Hypertension issued a statement saying that the response to its negative findings “should not be to abandon the renal denervation approach, but to perform further studies of high scientific caliber that could provide further evidence on its overall position in the treatment of resistant hypertension.”   

Nonetheless, Dr. Lüscher said that the trial has had a baleful impact in Europe, describing a prevailing sense of ‘insecurity.’

“It is not so negative that we would say to stop everything, and it’s not positive enough to let us run with it,” he noted. Both patients and physicians have become insecure in their attitudes toward the procedure, and hypertension specialists are now more reluctant to refer patients, he reported. In addition, industry funding of trials and device innovation has slowed markedly.

Dr. Lüscher, who coauthored a detailed critique of Symplicity HTN-3 in the European Heart Journal in May 2014, contended that while its design was rigorous, its performance was “a mess,” mainly because of the operators’ marked inexperience with the procedure.

“I tell patients that our experience is completely different,” he said. Moreover, “if denervation doesn’t work [as suggested by Symplicity HTN-3], it goes against all other experience,” he added, noting that sympathectomy serves as a proof of principle. In the 1950s, the surgical procedure was shown to dramatically reduce blood pressure, although it was abandoned due to severe side effects.

Today, a decision to perform renal denervation in an individual patient, especially one whose BP is dangerously out of control, seems reasonable, given that the procedure has repeatedly been shown to be safe and has at least signals of efficacy, Dr. Bhatt offered. He cautioned, however, that aggressive ablation might come with a safety trade-off.

“I’m somewhat satisfied knowing that patients are being followed appropriately for safety and efficacy,” he said. “My own bias is always to randomize if possible because that provides the greatest level of certainty that something is actually working, but following patients in registries is a good second best.” 

Similarly, Dr. Leon called the safety data from both the Global Symplicity registry and the randomized trials “very powerful,” adding, “It gives you confidence that the likelihood that you’re hurting somebody is very, very low…. With very good technique and follow-up, I think it’s acceptable to continue to allow [use in] patients.” 


The Impact on Technology  

For his part, Dr. Kandzari predicted that Symplicity HTN-3 will “slow the evolution of the technology, as the main burden for industry and the clinical community will be to demonstrate clinical efficacy and reassure safety with the existing technologies. Iterative design changes will be fairly minimal.” 

Newer-generation technologies are unlikely to make more than an incremental difference, Dr. Leon agreed, although he noted that some newer devices are making the technique less operator dependent.

Dr. Lüscher observed that while questionable application of the Symplicity catheter failed, it is hardly proof that renal denervation per se does not work. Optimal technique with other radiofrequency devices including bipolar designs may well be more effective, and it is important to keep an open mind about other denervation methods under investigation such as ex vivo ultrasound, catheter-based chemical ablation, and cryoablation. “We’ll have to wait and see if any [of these technologies] differentiates itself in important ways from the others,” Dr. Leon commented.

The Way Forward

“I think the starting point… has to be that we have a negative trial,” Dr. Bhatt said. “We have to go back to square one and see if renal denervation works rather than simply assuming that there was something funny about Symplicity HTN-3—something funny about the operators or the patients.” The argument that renal denervation is effective “in the right hands” is irrefutable but scientifically shaky, he said.

“We’ve learned more from Symplicity HTN-3 than perhaps the entire field did prior to the trial simply because of its sample size,” Dr. Kandzari concluded. “But it reminds us that our fundamental knowledge is still quite limited.”

It is difficult to predict how the trial will ultimately affect the field. “The net effect, so far as I can tell, is that there has never been as much interest in renal denervation as there is now,” Dr. Bhatt said, adding, “There are certainly a lot more questions.” 

Similarly, Dr. Rocha-Singh suggested that when a potential transformative technology such as renal denervation collides with a negative trial, it is worth reflecting on how physicians worked through the checkered history of other innovative medical devices including some early stents. “We don’t stop just because there is a single failed trial,” he commented. “We dial it back and look at [the situation]. The problem of resistant hypertension is too big to ignore.” 


Note: Dr. Leon is a faculty member of the Cardiovascular Research Foundation, which owns and operates TCTMD.  


  • Symplicity HTN-3 was sponsored by Medtronic.
  • Dr. Bhatt reports serving as co-principal investigator for Symplicity HTN-3 and on the Data and Safety Monitoring Board for the EnligHTN trial funded by St. Jude.
  • Dr. Kandzari reports receiving grant support from Abbott Vascular, Boston Scientific, and Medtronic and consulting fees from Boston Scientific and Medtronic.
  • Dr. Lüscher reports serving as a consultant for Boston Scientific, Medtronic, and St. Jude Medical.
  • Dr. Leon reports serving on the executive committee for Symplicity HTN-3 and as co-principal investigator for a forthcoming Vessix trial, sponsored by Boston Scientific.
  • Dr. Rocha-Singh reports serving as a consultant to Boston Scientific and Medtronic.