The Rheos Pivotol Trial Evaluating Baroreflex Activation Therapy Fails to Meet Efficacy and Safety End Points in Resistant Hypertension: Back to the Drawing Board

Abstract

Despite recent advances in antihypertensive pharmacotherapy, hypertension continues to remain uncontrolled in a large percentage of the hypertensive population. Adding to this concern are recent projections suggesting that up to 50% of adults in developed countries will meet the standard definition of hypertension by 2025. Some of the most challenging patients are those with resistant hypertension, defined as a blood pressure (BP) above target despite use of at least 3 antihypertensive drugs, one of which is a diuretic, all taken at maximal (or highest-tolerated) doses. The exact prevalence of treatment-resistant hypertension (TRH) continues to be debated, but recent studies using clinic-measured BP suggest that 20% to 30% of patients with hypertension are affected. With its associated comorbidities of obesity, diabetes, and chronic kidney disease, the prevalence of TRH is expected to increase in the coming decades. Observational studies have shown that adding specific antihypertensive drugs (such as chlorthalidone) or classes of drugs (such as mineralocorticoid receptor– blocking agents) helps to control BP in patients with TRH. More recently, device-based therapy has been studied. One such investigational strategy has been designed to inhibit the neurogenic component of hypertension, which is often abnormal in these individuals. The Rheos Pivotal Trial (Rheos System, CvRx, Inc, Minneapolis, MN) was the first large-scale, manufacturer-sponsored, randomized, double-blind, paralleldesign clinical trial performed in the United States to assess the safety and efficacy of baroreflex activation therapy (BAT) delivered through a surgically implanted device in patients with TRH. The device consists of a pulse stimulation generator placed subcutaneously on the anterior chest wall with bilateral electrodes that are tunneled to each carotid sinus. It works by delivering an exogenous source of energy to the carotid baroreceptors, interpreted in the central medulla as a rise in BP. The brain then sends sympatho-inhibitory signals to the blood vessels, heart, and kidneys resulting in a reduction of BP. To be eligible for the study, patients had to have resistant hypertension ( 3 antihypertensive medications, including a diuretic) for at least 1 month with at least 1 outpatient, in-office systolic BP 160 mm Hg and a diastolic BP 80 mm Hg. In addition, patients had to be a surgical candidate for device implantation without significant carotid stenosis and have an average 24hour ambulatory systolic BP 135 mm Hg without significant orthostatic hypotension. Forty-nine centers consented and screened 590 patients between March 2007 and November 2009. Each center was allowed to implant up to 2 nonrandomized patients prior to initiating the randomized portion of the trial to become familiar with the procedure. A total of 265 patients were randomized and followed for 12 months (2 patients in group A for every 1 patient in group B) with the device implanted by either a vascular, cardiothoracic, or neurosurgeon. It was turned off in all patients for the first month. The 181 patients in group A had the device activated at 1 month (time zero) (immediate BAT activation) while the 84 in group B continued to have the device turned off until 6 months into the trial (BAT deferred), with blinding maintained for a total follow-up of 12 months. Once the device was activated, stimulation was adjusted according to a protocol-defined algorithm with best practices shared across centers. Patients and investigators remained blinded to treatment until after the 12-month visit. Outpatient BP was measured in the office using the BpTRU automated device (VSM Medtech Ltd, Vancouver, Canada) taken within 4 to 6 hours of the most recent dose of antihypertensive medication with the investigator out of the room. Programmed to take 6 measurements at 1-minute intervals, the first measurement was discarded with the device reporting the average of the last 5 measurements. This was done to minimize any white-coat effect. Investigators were allowed to change antihypertensive medications in both arms of the study during the course of the trial. There were 5 prespecified co-primary end points, 2 for efficacy (acute efficacy, sustained efficacy) and 3 for safety (procedural safety, BAT safety, and device safety). All five end points had to be met in order to meet the primary end point. Secondary end points were prespecified and included mean change in office systolic BP and a comparison of immediate vs deferred BAT. Sample size was calculated to appropriately power all co-primary end points. A pre-established statistical analysis plan was developed instructing the data monitoring committee (DMC) to perform an From the Department of Internal Medicine, University of Nevada School of Medicine, Medical Director, Risk Reduction Center, Saint Mary’s Regional Medical Center, Reno, NV; 1 and the Seinsheimer Cardiovascular Health Program, Division of General Internal Medicine ⁄Geriatrics, Medical University of South Carolina, SC Address for correspondence: Michael J. Bloch, MD, Risk Reduction Center, Saint Mary’s Regional Medical Center, 645 North Arlington Street, Suite 460, Reno, NV 89503 E-mail: mbloch@aol.com