When Medtronic announced in January that SYMPLICITY HTN-3 failed to meet its efficacy endpoint, it sounded like the beginning of the end for renal denervation as a treatment for uncontrolled hypertension. The trial revealed limitations with this catheter-based approach, but it and other research also provide glimmers of hope.

Renal denervation in treatment-resistant hypertensive patients lowered office systolic blood pressure by only 2.39 mm Hg at six-month follow-up in  SYMPLICITY HTN-3, falling short of the clinical trial’s superiority margin. The negative finding, presented March 29 at the American College of Cardiology (ACC) scientific session in Washington, D.C., came as no surprise after the trial’s sponsor made its public announcement and added that it would evaluate next steps. HTN-3 was the largest and most rigorous trial to date in the hot field of renal denervation: a prospective, single-blind, randomized sham-controlled trial, with 364 patients receiving renal denervation treatment with the Symplicity catheter and 171 patients undergoing renal angiography as the sham control.

But beyond the headline, the negative trial’s results also offered insights that could guide future directions. “There are two major lessons from the trial,” says Deepak L. Bhatt, MD, MPH, HTN-3’s lead investigator and an interventional cardiologist at Brigham and Women’s Hospital Heart and Vascular Center in Boston. “One is cautious optimism and hope for the field to move forward.”

Second, the device industry should recognize the value of conducting rigorous randomized trials. “I don’t think every procedure out there needs a blinded, sham-controlled clinical trial, but if there isn’t going to be a blinded, sham-controlled clinical trial then there at least needs to be a good intellectual and scientific justification of why not,” Bhatt argues. “The default strategy, in general, for evaluation of new technologies should, at a minimum, be randomized trials, preferably blinded.”

Denervation doubts

A major stumbling block in renal denervation is the lack any reliable method to ascertain that denervation took place. Reductions in blood pressure after denervation may be gradual, so there is no immediate feedback. This has handicapped all renal denervation research, which includes a variety of approaches beyond catheter-based radiofrequency ablation. As a result, investigators may have to go through a time-consuming iterative process by tweaking dose or techniques, Bhatt says.

Procedural differences between HTN-3 and other trials also might explain discrepancies. Experience and a learning curve gap between operators in the U.S.-based HTN-3, where the device is investigational only, and other sites, where the device has been approved, may be another.

“One of the limitations of this therapy, unfortunately, is that in many ways the performance of the procedure has exceeded the clinical evidence,” says David Kandzari, an HTN-3 investigator and director of interventional cardiology and chief scientific officer at Piedmont Heart Institute in Atlanta. “Pathologists and physicians debate the distribution of the renal nerve anatomy, the depth of the nerves and the efficacy of the ablation, and procedurally we have no metric that tells us that we effectively performed renal interruption.”

Murray Essler, MD, senior director of the Baker IDI Heart and Diabetes Institute in Melbourne, Australia, and lead investigator of the SYMPLICITY HTN-2 trial, listed the strong preclinical data that demonstrated efficacy in animals during a lecture at ACC.14. HTN-2, which was smaller with no blinding or sham control, found a mean decrease in office systolic blood pressure of 32 mm Hg and 28 mm Hg at six-month and one-year follow-up, respectively. Essler suggested operators in the U.S. were less familiar with the technology and may have failed to achieve denervation. He agreed that without a validated test to verify denervation “we tend to be in the dark.”

While operators in HTN-3 lacked familiarity with renal denervation, they were proficient in catheter-based interventions, Bhatt counters. If the algorithm was flawed or operators were instructed to use insufficient energy, then that could affect results. Alternatively, it is possible that renal denervation is not as simple as it has been billed to be and requires many procedures to become proficient. 

“If that is true then that is a lesson in itself—that this procedure really isn’t ready for widespread use and it is something that should be used by only specialized, high-volume operators and centers,” Bhatt says.

Devilish details

Six-month results from the Global SYMPLICITY Registry, also presented at ACC.14, showed a decrease of 12 mm Hg in 751 patients. Michael Böhm, MD, PhD, of University of Saarland in Homburg, Germany, and Global SYMPLICITY Registry lead investigator, pointed out that the registry enrolled only white patients while 25 percent of patients in the denervation group and 29 percent in the sham-procedure group in HTN-3 were black.

An analysis of between-group differences in HTN-3 favored renal denervation for patients whose race was other than black. In addition, a greater percentage of patients in the denervation group than in the sham group achieved reductions of 5 mm Hg or more and of 10 mm Hg or more in both office systolic blood pressure and office diastolic blood pressure at six months.

“Although that wasn’t the primary endpoint in the trial, that tells me it (denervation) did something,” says Michael R. Jaff, DO, medical director of the Massachusetts General Hospital Vascular Center, who was not involved with the trials. “These were hard-to-control blood pressure patients.”

Despite some positive signals, Bhatt cautions against reading too much into top-line results in a trial that overall was negative until more in-depth analyses are performed. “I am cautiously optimistic that we might find some signals of efficacy that are believable, but when I say believable I mean believable enough to do another trial and not believable enough to say this is a group where we should go ahead and start doing a procedure,” he says.

Bhatt hopes to gain procedural insights by evaluating data from HTN-3 and the registry study to compare the relationship between factors such as dose or technique and blood pressure reductions. “There are a number of procedural details that potentially do explain the positive results in prior trials but not our trial,” he says.

The negative findings stunned and disappointed many physicians and patients who are wrestling with treatment-resistant hypertension. But HTN-3 and other renal denervation initiatives also have served the community by raising awareness about hypertension.

“Hypertension is a disease that is often silent until it results in irreversible damage like renal failure or a stroke or blindness,” Kandzari says. In a busy clinic, high blood pressure previously may have been a blip on a patient or physician’s radar screen that was canceled out by more seemingly urgent problems. “Renal denervation reminded clinicians of the impact of hypertension and that we need to redirect our attention to it.”