Medtronic Presents SYMPLICITY HTN-3 Data and Commits to Further Clinical Investigations

March 29, 2014—Medtronic, Inc. (Minneapolis, MN) announced that the full results of the SYMPLICITY HTN-3 clinical trial were presented in a late-breaking session at the ACC.14: 63rd annual scientific sessions of the American College of Cardiology and published simultaneously online ahead of print in The New England Journal of Medicine. SYMPLICITY HTN-3 is a blinded, randomized, sham-controlled study of renal denervation for treatment-resistant hypertension. ACC.14 is being held on March 29–31, in Washington, DC.

Medtronic advised that the trial met its primary safety endpoint but did not meet its primary or secondary efficacy endpoints. In the United States, the Symplicity renal denervation system is available for investigational use only.

As summarized by Medtronic, the primary efficacy endpoint was the comparison of in-office systolic blood pressure (SBP) change (from baseline to 6-month follow-up) between the renal denervation arm (n = 353) and the control arm (n = 171). The result was a statistically nonsignificant difference of 2.39 mm Hg [95% confidence interval, -2.12–6.89; P = .26], with a SBP reduction of 14.1 mm Hg in the renal denervation arm versus 11.7 mm Hg in the control arm.

The secondary endpoint was the comparison of SBP change (from baseline to 6-month follow-up) in mean 24-hour ambulatory blood pressure monitor between the renal denervation arm and the control arm. The result was a statistically nonsignificant difference of 1.96 mm Hg [95% confidence interval, -1.06–4.97; P = .98], with a SBP reduction of 6.8 mm Hg in the renal denervation arm versus 4.8 mm Hg in the control arm.

SYMPLICITY HTN-3 met the primary safety endpoint, with a 1.4% rate of major adverse events (upper 95% confidence bound, 2.9%) in the renal denervation arm, which was significantly (P < .001) less than the prespecified objective performance criterion of 9.8%. The rate of major adverse events at 6 months was 4% in the renal denervation arm and 5.8% in the control arm (P = .37). These results are consistent with the safety profile shown in all other Symplicity system trials. The Symplicity renal denervation system has shown a safety profile demonstrated through 3 years, noted Medtronic.

According to Medtronic, SYMPLICITY HTN-3 screened 1,441 patients and randomized 535 (37%) treatment-resistant hypertension patients with office SBP ≥ 160 mm Hg at 88 medical centers in the United States. On initial screening, patients were required to be on at least three antihypertensive medications at maximally tolerated doses, one of which had to be a diuretic. There could have been no medication changes in the 2 weeks before enrollment and then randomization and no plan for any changes in the next 6 months. 

Patients recorded their home SBP and kept a diary recording their adherence to medical therapy both before randomization and at their 6-month follow-up. Changes to antihypertensive medication were not allowed during the 6-month follow-up period unless clinically necessary. Patients with 24-hour mean ambulatory blood pressure monitor < 135 mm Hg were excluded to screen for potential “white coat” hypertension. Of the 535 patients, approximately 70% had been treated for an average of 10 years for uncontrolled hypertension according to the standard of care.

Patients were blinded as to whether they actually received the full denervation procedure (treatment arm) or only renal angiography (sham control arm). Clinicians assessing blood pressure were also blinded to the treatment received by patients. A blinding index was calculated at discharge and at 6 months and proved the effectiveness of blinding. 

In Medtronic’s press release, the trial’s Coprincipal Investigator Deepak L. Bhatt, MD, commented, “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. 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.” Dr. Bhatt is Executive Director of Interventional Cardiovascular Programs at Brigham and Women's Hospital Heart and Vascular Center and Professor of Medicine at Harvard Medical School in Boston, Massachusetts.

Medtronic advised that 6-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. 

The Cochair of Global SYMPLICITY registry, Michael Böhm, MD, stated in Medtronic’s announcement, “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.” Dr. Böhm is Chairman of the Department of Internal Medicine at the University of Saarland in Homburg/Saar, Germany.

Medtronic stated that SYMPLICITY HTN-3 patient follow-up will continue as planned out to 5 years. The company has 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 program.

In the short-term, Medtronic stated it 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 program. 
• Determine the optimal path forward in consultation with the US Food and Drug Administration for the next investigational device exemption in the United States, as the company believes that its detailed analysis of SYMPLICITY HTN-3 indicates that further clinical investigation is warranted.
• Continue to enroll patients in the Global SYMPLICITY registry.
• Discontinue the already suspended SYMPLICITY HTN-4 trial.
• Consult with local regulatory bodies to determine the future of the HTN-Japan and HTN-India clinical studies.
• Continue to pursue its studies in other disease states, including atrial fibrillation, chronic kidney disease, heart failure, etc.

In the company’s press release, Medtronic’s Chief Scientific Officer Rick Kuntz, MD, stated, “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. There are several differences between the SYMPLICITY studies, including the populations studied, required medication dosing, patient behaviors 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 the FDA.”

Nina Goodheart, Vice President and General Manager of the Renal Denervation Division of Medtronic, added, “Based on the unique nature of these findings and support from the independent panel that additional research be considered to better understand the effects of the Symplicity technology for renal denervation, we remain convinced that resistant hypertension is a large unmet medical need and renal denervation remains a promising opportunity.”