RENAL DENERVATION FAILED

MINNEAPOLIS, MN — The SYMPLICITY HTN-3 trial, a phase 3 study testing catheter-based renal denervation for the treatment of resistant hypertension, failed to achieve its primary efficacy end point, according to a statement released by Medtronic^[1].

Despite no safety concerns, the study, which randomized 535 treatment-resistant hypertension patients, failed to show that treatment with the investigational procedure resulted in a sustained reduction in systolic blood pressure.

The results are surprising, given the positive findings from theSYMPLICITY 2 study, a study that did not include a sham-control arm. In contrast, the SYMPLICITY HTN-3 study was more rigorously designed to assess the efficacy of the procedure, as all patients randomized to the control arm underwent a sham procedure. The primary end point of the study was the change in office systolic blood pressure at six months, while the six-month change in the average 24-hour systolic blood pressure assessed by ambulatory blood pressure monitoring was a secondary end point.

The primary safety end point was the incidence of major adverse events that occurred one month after treatment until six months. According to Medtronic, no safety issues arose during the trial.

In the statement, Dr George Bakris (University of Chicago, IL), a coinvestigator of the study along withDr Deepak Bhatt (Brigham and Women's Hospital, Boston, MA), said they were disappointed in the result. He added that the study was "the most rigorous renal-denervation clinical trial conducted to date" and that they plan to submit the findings for presentation at an upcoming scientific congress.

To heartwire , Bhatt said they are still analyzing the large amount of data from the trial, but once they have a "full understanding of the results and implications to the field, we will submit for peer review, presentation, and publication." He added that they felt it was important to share the medical community and with patients as soon as they could.

Medtronic said it plans to meet with advisors, including researchers and clinicians, to determine what to do next with the SYMPLICITY program. Currently it plans to suspend enrolment in SYMPLICITY 4, a US study conducted for regulatory approval, and suspend enrollment in trials conducted in Japan and India. It said it will "continue to ensure patient access to the Symplicity technology at the discretion of their physicians in markets where it is approved" and will continue its postmarket surveillance registry.

The news is a blow to the hopes of renal denervation, an experimental procedure that has seen its share of hype and excitement in recent years. It appears to throw a wrench into the plans of other companies. Just last month, St Jude Medical announced the stoppage of the EnligHTN-IV study, its large phase 3 study in 590 patients with resistant hypertension. That device used a multielectrode renal-denervation system in patients with resistant hypertension but was stopped because of concerns about slow enrollment. At the time, St Jude Medical felt Medtronic's SYMPLICITY device would be approved for the US market and as a result it would have problems enrolling patients to a sham procedure, given the commercial availability of a renal-denervation catheter.

Dr William White (University of Connecticut Medical Center, Farmington), the lead investigator of EnligHTN-IV, foresaw some problems that might arise given St Jude's approach. In December, White toldheartwire that St Jude was making a lot of assumptions about SYMPLICITY HTN-3—that it would be positive, that the device would be the first to market—and should have proceeded with its trial regardless of the Medtronic outcome. "The clinical scientist in me would have preferred that we go ahead as planned," he told heartwire at the time. "I think we would have gained a great deal of knowledge."

In April 2013, the European Society of Cardiology (ESC) issued a consensus statement on the use of catheter-based renal denervation for the treatment of high blood pressure. It said that the treatment can be considered a therapeutic option in patients with drug-resistant hypertension who cannot get to goal with a combination of lifestyle and pharmacologic therapy.

In Europe, Medtronic's Symplicity system has received CE Mark approval. Others include EnligHTN (St Jude Medical), used in the EnligHTN-1 study; Vessix V2 (Boston Scientific), used in REDUCE-HTN ;OneShot (Covidien), used in RHAS; and Paradise (ReCor Medical) used in the REALISE study.

Medtronic sponsored the SYMPLICITY HTN-3 trial.