Catheter-Based Renal Denervation for Resistant Hypertension: Rationale and Design of the SYMPLICITY HTN-3 Trial

Hypertension represents a significant global public health concern, contributing to vascular and renal morbidity, cardiovascular mortality, and economic burden. The opportunity to influence clinical outcomes through hypertension management is therefore paramount. Despite adherence to multiple available medical therapies, a significant proportion of patients have persistent blood pressure elevation, a condition termed resistant hypertension. Recent recognition of the importance of the renal sympathetic and somatic nerves in modulating blood pressure and the development of a novel procedure that selectively removes these contributors to resistant hypertension represents an opportunity to provide clinically meaningful benefit across wide and varied patient populations. Early clinical evaluation with catheter-based, selective renal sympathetic denervation in patients with resistant hypertension has mechanistically correlated sympathetic efferent denervation with decreased renal norepinephrine spillover and renin activity, increased renal plasma flow, and has demonstrated clinically significant, sustained reductions in blood pressure. The SYMPLICITY HTN-3 Trial is a pivotal study designed as a prospective, randomized, masked procedure, single-blind trial evaluating the safety and effectiveness of catheter-based bilateral renal denervation for the treatment of uncontrolled hypertension despite compliance with at least 3 antihypertensive medications of different classes (at least one of which is a diuretic) at maximal tolerable doses. The primary effectiveness endpoint is measured as the change in office-based systolic blood pressure from baseline to 6 months. This manuscript describes the design and methodology of a regulatory trial of selective renal denervation for the treatment of hypertension among patients who have failed pharmacologic therapy. Clin. Cardiol. 2012. doi: 10.1002/clc.22008 Dr. Kandzari receives research/grant support and consulting honoraria from Medtronic CardioVascular, Abbott Vascular and Boston Scientific; Dr. Bhatt receives honoraria from WebMD and research grants from Amarin, AstraZeneca, Bristol-Myers Squibb, Eisai, Ethicon, Medtronic, Sanofi Aventis, and The Medicines Company. Dr. Oparil receives research/grant support from Merck and Co., NHLBI, Novartis, and Takeda, honoraria from Daiichi Sankyo and Pfizer, and is a consultant for Bayer, Medtronic, Novartis, Pfizer, and Daiichi Sankyo. Dr. Rocha-Singh is a consultant for Medtronic, Covidien, and Cardiosonic. Dr. Flack receives grant/research support from NIH, Daiichi Sankyo, sanofi aventis, and Novartis. He is on the Speaker Bureau for Novartis, Daiichi Sankyo, and Boehringer Ingleheim, and is a consultant for Glaxo-Smith-Kline, Novartis, NIH, Daiichi Sankyo, and Boehringer Ingleheim, Medtronic, and Back Beat Hypertension. Dr. Katzen is a consultant for Abbott, CRBard, Boston Scientific, WL Gore, and Medtronic. Dr. Massaro is a member of the Data Safety Monitoring Board and will no longer participate as a member of the SYMPLICITY HTN-3 Steering Committee. Dr. Leon, Dr. O'Neill, and Dr. Esler have nothing to disclose. Dr. Negoita, Dr. Sobotka, and Craig Straley are employees of Medtronic, Inc. Dr. Bakris receives grant/clinical trial support (paid directly to University of Chicago) from Forest Laboratories, Medtronic, and Relapysa, and is a consultant to Takeda, Abbott, CVRx, Johnson & Johnson, Eli Lilly, and the Food and Drug Administration. Dr. Bakris is on the Speaker Bureau for Takeda, and the Boards of the National Kidney Foundation and the American Society of Hypertension. He is Editor for the American Journal of Nephrology and Associate Editor for Diabetes Care and Nephrology Dialysis and Transplantation.