Research ArticleBaroreflex Activation Therapy provides durable benefit in patients with resistant hypertension: results of long-term follow-up in the Rheos Pivotal Trial
Introduction
Despite the availability of a wide variety of pharmacotherapies, resistant hypertension (HTN) persists as a significant public health challenge, comprising approximately 20% to 30% of all hypertensive patients.1, 2, 3 The cost of HTN to the US health care system in 2010 alone has been estimated at $76.6 billion.4 Prevalence of resistant HTN in the industrialized world is expected to continue to rise as the population ages. The burden of HTN on the health care system, as well as increased cardiovascular mortality related to resistant HTN, requires intervention beyond standard pharmacological therapy.5
Baroreflex Activation Therapy (BAT) is a unique approach to HTN therapy wherein electrical stimulation of carotid sinus baroreceptors evokes coordinated reductions in sympathetic traffic to the heart, vasculature, and kidneys, as well as augmented parasympathetic activity. The net effect of BAT is to preserve homeostasis at a lower-energy state by restoring sympatho-vagal balance while promoting natriuresis and redistribution of blood volume away from the central compartment.6 BAT is applied by implanting a stimulator similar to a pacemaker, along with one or more leads attached to the carotid sinus.
To test if BAT is effective at lowering blood pressure (BP) in resistant patients, the Rheos Pivotal Trial (NCT00442286) was conducted. The study was a randomized, double-blind, controlled trial that evaluated the effects of BAT over 12 months in 322 patients (Figure 1).7 Of the 322 patients implanted with the first-generation Rheos System, 265 were randomized 1 month after implantation in a 2:1 ratio to receive BAT immediately (active therapy, Group A) or after a 6-month deferral (control, Group B), respectively. The remaining patients received therapy immediately in an open-label fashion (roll-in). The trial had 5 coprimary end points. Three of the end points were met (all P < .001): sustained pressure reduction through 12 months, noninferiority of safety for comparing control to active therapy through 6 months, and device safety through 12 months. At 6 months, change in systolic BP (SBP) and percentage of patients achieving SBP lower than 140 mm Hg demonstrated statistically and clinically significant treatment benefits in the active therapy group relative to control.
As previously described,7 the trial data monitoring committee notified the sponsor during follow-up that they believed one of the trial end points would not be met. In response, the US Food and Drug Administration (FDA) determined that the study should continue following all patients until at least 12 months of therapy, and that all consenting patients continue to receive active therapy after 12 months until battery depletion.
Until a permanent mechanism could be established, the FDA instituted a process for approval of routine battery replacement through individual compassionate use applications. This approach rapidly became untenable, as the agency was inundated with petitions detailing physician opinion that BAT provided clinical benefit. To resolve the situation, FDA established rigorous criteria to identify clinically significant responders to BAT so that they could continue to receive therapy long term. The purpose of the present publication is to describe the results of the responder qualification process and the long-term follow-up that it has enabled.
Section snippets
Study Design and Patient Population
The long-term follow-up (post-month 12) portion of the Rheos Pivotal Trial is a single-arm, open-label continuation of the randomized protocol previously described. The trial was approved by FDA as part of an investigational device exemption. Institutional review boards of participating US institutions and ethics committees of participating European institutions approved the protocol. Participating patients provided their written, informed consent. All patients actively participating in the
Patient Cohort
The status of the 322 patients implanted in the original Rheos Pivotal Trial is shown in Figure 2. Twenty-one patients were withdrawn before approval of the long-term protocol. Of the 301 patients active when the protocol was approved, 25 patients did not consent (2 deaths, 5 explants, and 18 withdrawals), and 276 either consented or remained eligible to consent to the long-term phase of the protocol. The vast majority of these patients (244, 88%) are clinically significant responders. The
Discussion
With more than 9000 patient-months of aggregate follow-up covering up to 4.4 years, continuing observations of efficacy strongly support BAT as a therapy with great potential in resistant HTN. Of the 322 patients implanted in the Rheos Pivotal Trial, three-fourths experienced therapeutic benefit, thereby qualifying as therapy responders per FDA criteria. The response rate may increase, as the status of 32 patients (10% of the original cohort) is as yet undetermined. Of the remaining 46 patients
Acknowledgments
The authors recognize the contributions of the patients, investigators, and clinical research coordinators at the institutions that continue to participate in the Rheos Pivotal Trial.
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Funding/support: None listed.
Conflict of interest: Drs Bakris, Nadim, and Bisognano have received research grant support from CVRx and are presently paid consultants or advisors of CVRx, Inc. Dr Bakris is an investigator for Relapysa and Medtronic; a consultant for Abbott, Takeda, Lilly, and Servier; a board member of the National Kidney Foundation; and the president of the American Society of Hypertension. Dr Lovett is an employee of CVRx, Inc. Ms. Schafer is a former employee and currently a paid consultant of CVRx, Inc.