Prematurely Halted Pilot Study Snaps Recent Winning Streak for Renal Denervation

SAN DIEGO, CA—A sham-controlled, pilot study of the Vessix renal denervation system (Boston Scientific) failed to replicate the positive results seen over the past year from similarly designed studies of other technologies.

REDUCE HTN: REINFORCE suffered from slow enrollment and was stopped for futility after only 51 patients were enrolled. Results reported here at TCT 2018 by Michael Weber, MD (SUNY Downstate College of Medicine, Brooklyn, NY), confirmed that the trial failed to meet its primary endpoint by showing no significant differences in ambulatory blood pressure reduction at 8 weeks between the renal denervation and sham-control groups. Patients were not receiving antihypertensive medications.

Hints of benefit emerged by 6-month follow-up, however, with a greater proportion of patients in the denervation arm achieving an office systolic pressure below 140 mm Hg (52% vs 12%; P = 0.0061) despite the fact that a similar number of patients—roughly 50%—were using medication in each arm of the trial.

“So something happened between 8 weeks and 6 months to turn the whole story around and show a benefit,” Weber said during his presentation. “I can tell you this took us by surprise.”

He proposed that the late appearance of an effect could be related to slow onset of an effect of denervation on sympathetic nervous system afferent signals, or could be an indication that renal denervation is more effective in patients taking antihypertensive medication.

“Although the study cohort was small, these preliminary data from a randomized, sham-controlled trial suggest that the Vessix catheter is likely to be of clinical value in treating hypertension,” according to a conclusion from Weber’s presentation slides.

When asked whether the findings justify moving forward with further studies of the Vessix technology, David Kandzari, MD (Piedmont Heart Institute, Atlanta, GA), said they do not, adding that this experience should not have an impact on the direction of the field of renal denervation overall.

“I don’t think this will have any influence on the forward momentum that exists with contemporary renal denervation trials,” he told TCTMD “I think people will look at this as highlighting not only the limitations of trial design in the earlier phases of when we were performing renal denervation trials, but they will also, in part, perhaps attribute it to a catheter technology that . . . was not expected perhaps to have a benefit.”

Responding to a request for comment, a Boston Scientific spokesperson said, “While we concluded enrollment for the . . . trial, we will continue to follow the enrolled patients for 3 years. We will also continue to monitor development in the renal denervation space and consider future options should we see both an opportunity to enhance patient outcomes and a viable path to commercialization.”

REDUCE HTN: REINFORCE

The evaluation of the Vessix system was one of several sham-controlled pilot studies of various renal denervation systems that resulted from a renewed research effort following the failure of the SYMPLICITY HTN-3 trial, which sent the field reeling.

Over the past year or so, results from some of those pilot studies—including SPYRAL HTN-OFF MED, SPYRAL HTN-ON MED, and RADIANCE-HTN SOLO—have started coming out, showing that denervation can lower blood pressure in patients with hypertension who are either untreated or are taking antihypertensive medications.

REDUCE HTN: REINFORCE could not duplicate those wins. The trial aimed to enroll up to 100 patients, who would be randomized after an antihypertensive washout period of 4 weeks to renal denervation with the Vessix system or a sham procedure. Enrollment was slow, prompting an interim analysis that led the data monitoring committee to determine that the trial could not reach its primary endpoint. The trial was stopped for futility in October 2017 after 51 patients had been enrolled.

In the trial, renal denervation was safe, with almost no major safety events identified through 6 months. The lone exception was a single hospitalization for hypertensive crisis.

There were no differences in either ambulatory or office blood pressure between trial arms at 8 weeks, but patients in the denervation arm seemed to achieve greater drops by 6 months. Ambulatory systolic and diastolic pressures did not differ between groups by 6 months, but denervation was associated with larger reductions in office systolic (-26.2 vs -14.8 mm Hg; P = 0.0059) and diastolic (-12.9 vs -7.5 mm Hg; P = 0.0370) pressures.

Cautious Optimism About Renal Denervation

Commenting for TCTMD, Deepak Bhatt, MD (Brigham and Women’s Hospital, Boston, MA), who was a member of the SYMPLICITY HTN-3 steering committee, said it was unfortunate that this trial was stopped. Any hints of benefit are thus encouraging but need to be viewed with caution and replicated in a repeat trial, he said.

Speaking to the field of renal denervation as a whole, Bhatt said he hopes companies will continue to pursue the approach, the technology will continue to be refined, and researchers will get a better understanding of which patients might benefit from treatment.

“All that needs to be done before any consideration of approving this,” he said. “I think approving these devices prematurely would just totally kill the field, because it would take out any financial incentive for the companies to invest in really understanding what patients might benefit or even be harmed. My hope is that the investigation continues, but continues in a scientifically rigorous way.”

Though results from other sham-controlled pilot studies have been successful in showing reductions in blood pressure, the effect sizes have been modest, Bhatt pointed out.

“There is reason for continued cautious optimism in the field of renal denervation, but I still don’t back off from my prior thoughts from the time of SYMPLICTY HTN-3 that we just need to do well-done, well-powered, sham-controlled trials and nail down whether this thing really works and it’s worth doing an invasive procedure,” he said.