Renal Denervation: Proof-of-Concept Study Gives Fresh Jolt to Fizzled Field
In SPYRAL HTN-OFF MED, more intensive denervation lowered blood pressure, warranting larger, more definitive trials, experts say.
BARCELONA, Spain—Providing a glimmer of hope to those who have maintained a belief in the potential of renal denervation in recent years, interim results from the SPYRAL HTN-OFF MED study suggest that a more intensive approach to ablating renal nerves than the one used in the failed SYMPLICITY HTN-3 trial can reduce blood pressure in patients with untreated mild-to-moderate hypertension.
Compared with a sham procedure, denervation with the Symplicity Spyral multielectrode catheter (Medtronic) resulted in a greater decline in 24-hour systolic pressure (by 5.0 mm Hg) and 24-hour diastolic pressure (by 4.4 mm Hg) in the first 3 months, Michael Böhm, MD (University Hospital of Saarland, Homburg/Saar, Germany), reported at the European Society of Cardiology Congress 2017 here. Corresponding differences for office readings were 7.7 mm Hg systolic and 4.9 mm Hg diastolic.
Böhm said the results—published simultaneously online in the Lancet—provide a biological proof of principle for the efficacy of renal denervation and will inform the design of a larger, more definitive trial of the approach.
Commenting for TCTMD, Anthony DeMaria, MD (University of California, San Diego), reacted to the results with “cautious optimism that there may actually be some role for renal denervation in the treatment of hypertension.”
The caution, he said, comes from the fact that the study was small (80 patients), was not powered for efficacy outcomes, had only 3 months of follow-up, demonstrated great variability in terms of patient response to the treatment, and showed reductions in blood pressure that would likely not allow patients to stop taking medications altogether.
Nevertheless, the study, which eliminated some of the potential confounders hampering earlier efforts, was “useful in providing some evidence that renal denervation actually can affect blood pressure,” said DeMaria, a past president of the American College of Cardiology.
Asked whether that’s enough to justify moving forward with larger studies, he said, “Probably given the prevalence of hypertension, given the side effects of available antihypertensive medications, given the issues involved in resistant hypertension, it’s likely that these data will be strong enough to move forward with a major clinical trial.”
Regrouping After SYMPLICITY HTN-3
Early studies of renal denervation suggested the potential for substantial reductions in blood pressure among patients with uncontrolled blood pressure. When pitted against a sham control in the SYMPLICITY HTN-3 trial, however, the intervention came up short and enthusiasm for the technology fizzled.
Researchers tried to figure out what went wrong, pointing the finger at patchy medication adherence, patient selection, and limitations to the technology or procedure resulting in a failure to actually ablate the renal nerves. Investigators took those lessons and—in collaboration with regulatory authorities—designed a series of small pilot studies to evaluate the effect of various renal denervation technologies and lay the groundwork for pivotal trials.
SPYRAL HTN-OFF MED, conducted at 21 centers in the United States, Europe, Japan, and Australia, is one of those preliminary studies. Böhm presented results of an interim analysis of the first 80 patients randomized.
Participants were either antihypertensive drug-naive or had discontinued their medications, had an office systolic pressure of 150 to less than 180 mm Hg, an office diastolic pressure of at least 90 mm Hg, and a mean 24-hour ambulatory systolic pressure of 140 to less than 170 mm Hg. All eligible patients underwent renal angiography, at which point they were randomized to receive renal denervation or not. Angiography served as the sham procedure in the control group.
Renal denervation induced significant drops in both systolic and diastolic blood pressure, whether measured in the office or using 24-hour ambulatory testing. There were no changes in the control group.
However, the response to denervation was not consistent across patients. Looking at 24-hour systolic pressure, for example, 10 patients who underwent denervation had an increase in blood pressure and 25 had a reduction. For comparison, 19 patients in the sham control arm had an increase in blood pressure and 17 had a drop.
There were no major adverse events in either group, which is important, Böhm said, because the denervation technique used was more aggressive than that employed in prior studies.
What Has Changed?
This proof-of-concept study differs from SYMPLICITY HTN-3 in several ways. First, patients in the prior trial were taking an average of about five antihypertensive medications, with many patients changing regimens during the study, whereas no medications were used in SPYRAL HTN-OFF MED. Urine and plasma sampling confirmed that 85.5% of patients were drug-free at baseline and at 3 months.
Second, SYMPLICITY HTN-3 enrolled patients with resistant hypertension, including some with isolated systolic hypertension, which has been shown to be less responsive to renal denervation. The current study recruited patients with less severe hypertension and excluded those with isolated systolic hypertension.
Third, the procedure changed. In SYMPLICITY HTN-3, operators used a single-electrode catheter and targeted only the main renal arteries. The newer approach employed a multielectrode, spiral catheter that ensured circumferential ablation and targeted both the main renal arteries and the branches. That resulted in about a fourfold increase in ablations. In addition, all operators in the more recent study had experience performing denervation, which was not the case in the prior trial.
A Future for Renal Denervation
Serving as a discussant following Böhm’s presentation, Bryan Williams, MD (University College London, England), said, “These interim results are very interesting . . . and I agree provide proof of concept that renal denervation does lower blood pressure in about 75% of the patients who were tested.”
I would ask the question: would patients wishing to avoid medications by having an intervention view this outcome as a success? Bryan Williams
In addition, the lack of major adverse events was “important and reassuring,” he said.
Williams highlighted two types of patients in whom use of this type of device to control blood pressure might be considered: those with resistant hypertension that cannot be controlled with the best available drugs and those with less severe hypertension, who might be looking for a “cure” that will allow them to stop taking medical therapy.
In SPYRAL HTN-OFF MED, the magnitude of the blood pressure reductions seen with denervation would not put patients, on average, at a goal of less than 140 mm Hg, indicating that many would still need to take antihypertensive medication even after undergoing the procedure, he pointed out. “I would ask the question: would patients wishing to avoid medications by having an intervention view this outcome as a success?”
Williams concluded that renal denervation could have a role in lowering blood pressure in patients with hypertension that is resistant to medications, but said that “at this level of blood pressure reduction in stage 2 hypertension, it’s going to be difficult to present the case that it competes with conventional drug treatment.”
DeMaria indicated that SPYRAL HTN-OFF MED has breathed some life into the renal denervation field, which seemed to have been left for dead by many in the medical community. He pointed out that a dedicated group of researchers never gave up on the procedure and continued to look for explanations for the failure of SYMPLICITY HTN-3.
“For that group, this provides a real stimulus that, in fact, this is a reasonable approach,” DeMaria said.
Townsend RR, Mahfoud F, Kandzari DE, et al. Catheter-based renal denervation in patients with uncontrolled hypertension in the absence of antihypertensive medications (SPYRAL HTN-OFF MED): a randomised, sham-controlled, proof-of-concept trial. Lancet. 2017;Epub ahead of print.
- The trial was funded by Medtronic.
- Böhm reports receiving personal fees from Medtronic during the conduct of the study and honoraria for lectures and scientific advice from Abbott, AstraZeneca, Boehringer Ingelheim, Medtronic, Servier, and Vifor not related to the study.
- Williams reports serving as a consultant for Vascular Dynamics Inc., Novartis, and Relypsa/Vifor Pharma.