Medtronic announced that the SYMPLICITY HTN-3 clinical trial, the first and only blinded, randomised, sham controlled study of renal denervation for treatment-resistant hypertension, met its primary safety endpoint but did not meet its primary or secondary efficacy endpoints. The results were presented in a late-breaking session at the 63rd Scientific Sessions of the American College of Cardiology (ACC) and published simultaneously in The New England Journal of Medicine.
The primary efficacy endpoint was the comparison of in office systolic blood pressure (SBP) change (from baseline to six month follow-up) between the renal denervation arm (n=353) and the control arm (n=171). The result was a statistically non-significant difference of 2.39mm Hg [95% confidence interval (CI): -2.12 to 6.89, p=0.26], with a systolic blood pressure reduction of 14.1mm Hg in the renal denervation arm vs 11.7mm Hg reduction in the control arm.
The secondary endpoint was the comparison of systolic blood pressure change (from baseline to six month follow-up) in mean 24-hour ambulatory blood pressure monitor (ABPM) between the renal denervation arm and the control arm. The result was a statistically non-significant difference of 1.96mm Hg, [95% CI, -1.06 to 4.97, p=0.98], with a systolic blood pressure reduction of 6.8mm Hg in the renal denervation arm vs 4.8mm Hg reduction in the control arm.
SYMPLICITY HTN-3 met the primary safety endpoint, with a rate of major adverse events of 1.4% (upper 95% confidence bound 2.9%) in the renal denervation arm, which was significantly (p<0.001) less than the pre-specified objective performance criterion of 9.8%. The rate of major adverse events at six months, was 4% in the renal denervation arm and 5.8% in the control arm (p = 0.37). These results are consistent with the safety profile shown in all other Symplicity system trials. The Symplicity renal denervation system is the only renal denervation technology to show a safety profile demonstrated through three years.
“Based on our analysis of the SYMPLICITY HTN-3 data, we are considering many factors that may have contributed to the observed efficacy results beyond the employment of a more rigorous trial design,” says Rick Kuntz, chief scientific officer, Medtronic. “There are several differences between the SYMPLICITY studies, including the populations studied, required medication dosing, patient behaviours in terms of lifestyle and drug adherence, and potential for procedural variability. We are evaluating the contributions of these potential factors, which are hypothesis-generating and will guide us in determining the path forward with FDA.”
“While the primary efficacy endpoint was not met with this study design in these patients, SYMPLICITY HTN-3 did affirm the safety of the Symplicity renal denervation system seen in previous clinical studies,” says Deepak L Bhatt, executive director of interventional cardiovascular programmes, Brigham and Women’s Hospital Heart and Vascular Center, professor of Medicine at Harvard Medical School, and co-principal investigator. “This was a rigorously conducted trial that importantly featured a sham control and blinding of the study subjects and study team members. Unfortunately, it is not possible to determine definitively whether this trial demonstrated the failure of renal denervation to significantly reduce blood pressure or if there was a failure to achieve adequate renal denervation in these patients. Further investigation of renal denervation seems warranted.”
“SYMPLICITY HTN-3 is a rigorously conducted and well-designed renal denervation clinical trial. Moving forward, it will be important to reconcile the results of SYMPLICITY HTN-3, a tightly controlled trial, with findings from the real-world Global SYMPLICITY Registry, due to differences between the two trials, including requirement for maximum tolerated medications, population differences, close supervision of patients, and multiple touch points of patients in a tertiary care setting,” says Michael Böhm, chairman, Department of Internal Medicine, University of Saarland, Homburg/Saar, Germany and Global SYMPLICITY Registry co-chair. Six-month analysis from the first 1,000 patients enrolled in the Global SYMPLICITY Registry will be presented in a late-breaking clinical trial session during ACC.14 on Sunday, March 30, 2014.
While SYMPLICITY HTN-3 patient follow-up will continue as planned out to five years, Medtronic recently asked an independent panel of expert physicians and researchers to review the findings and make a recommendation about the future of the company’s global renal denervation hypertension programme.
In the short-term, Medtronic has made the following decisions, which have been affirmed by the independent panel of experts:
•Medtronic will continue to provide access to the Symplicity system in countries where it has regulatory approval and will continue to support a global hypertension clinical programme
•Based on the company’s detailed analysis of SYMPLICITY HTN-3, they believe further clinical investigation is warranted; Medtronic will determine the optimal path forward, along with FDA, for the next US IDE
•Medtronic will continue to enrol patients in the Global SYMPLICITY Registry
•In light of the results of the SYMPLICITY HTN-3 trial, Medtronic will discontinue the already suspended SYMPLICITY HTN-4 trial
•Medtronic will consult with local regulatory bodies to determine the future of the HTN-Japan and HTN-India clinical studies
•Medtronic will continue to pursue its studies in other disease states, including atrial fibrillation, chronic kidney disease, heart failure, etc.
In the United States, the Symplicity renal denervation system is available for investigational use only.