Barostim Baroreflex Activation Therapy

Husam M. Salah, MD; Marat Fudim, MD, FACC


Baroreceptors are embedded in the walls of the major arteries, veins, and the heart and are activated in response to a rise in blood pressure (BP) and/or volume.[1] Arterial baroreceptors in the carotid sinus and aortic arch are activated mainly by an increase in BP, whereas cardiopulmonary baroreceptors in the thoracic veins and the heart are activated mainly by an increase in blood volume.[1] While activation of both arterial and cardiopulmonary baroreceptors inhibits efferent sympathetic signals to the renal, splanchnic, and skeletal-muscle vessels, resulting in vasodilation, only arterial baroreceptors activation results in activation of the parasympathetic pathway to the sino-atrial (SA) node, thus decreasing the heart rate.[1]

Due to its key role in modulating the autonomic nervous system, baroreflex dysregulation can lead to autonomic dysfunction. An autonomic dysfunction characterized by sympathetic overactivation and parasympathetic withdrawal (due to the loss of the ability to exert sympathoinhibition) is a central pathomechanism in the development and progression of several cardiovascular (CV) diseases, such as resistant hypertension and heart failure (HF).[2,3,4] Therefore, device-based targeting of the baroreflex system was suggested as a novel pathway to address autonomic dysfunction and restore the physiological autonomic balance in certain CV disease.

Baroreflex activation therapy (BAT) is a device-based approach that consists of an implanted pulse generator (implanted in the pectoral region), external programming system, and leads placed adjacent to the carotid sinus to deliver electrical pulses to the carotid baroreceptors.[5] Electrical stimulation of the carotid baroreceptors results in activation of the baroreflex system with subsequent increase in the parasympathetic outflow and inhibition of the sympathetic activity.[5]

Applications of BAT

Resistant Hypertension

The first application of BAT was in patients with resistant hypertension. The prospective, nonrandomized, feasibility DEBuT-HT (Device Based Therapy in Hypertension trial) study showed that, in patients with resistant hypertension (systolic BP [SBP] ≥160 mmHg or diastolic ≥90 mmHg despite ≥3 antihypertensive medications), BAT therapy using the Rheos® Baroreflex Hypertension Therapy™ (CVRx, Inc.) reduced mean BP by 21/12 mmHg after 3 months of therapy with a favorable safety profile.[6] In the subsequent Rheos® Pivotal trial, patients with resistant hypertension were randomized to either immediate (1 month after implantation) or deferred (after 6 months of implantation) activation of BAT therapy, and five co-primary endpoints (acute SBP response at 6 months, sustained efficacy at 12 months, procedure safety, BAT safety, and device safety).[7] While the endpoints of sustained efficacy, BAT safety, and device safety were met, the endpoints of acute response and procedural safety were not met.[7]

To address the shortcomings of the Rheos® System, a second generation, less invasive system for delivering BAT, the Barostim neo™ system (CVRx, Inc.), was developed and tested in a single-arm, open-label study of 30 patients with resistant hypertension.[8] In this study, BAT with the Barostim neo™ system resulted in a decrease in BP by 26/12 mm Hg at 6 months (p<0.001 for both) with three minor procedure-related complications within 30 days of implant, all of which resolved.[8] These results provided a reassuring safety profile for this generation. Several subsequent observational studies showed consistent results;[9] however, given the paucity of large-scale-trial-driven evidence to support the use of BAT in resistant hypertension, the contemporary European and American guidelines do not recommend the routine use of BAT in managing resistant hypertension.[10,11]

Heart Failure

In a proof-of-concept study, 11 patients with HF, New York Heart Association (NYHA) class III, and left ventricular ejection fraction (LVEF) of <40% who were ineligible for cardiac resynchronization therapy (CRT) received BAT with Barostim™ neo.[12] At 6 months, BAT resulted in a significant improvement in baroreflex sensitivity, LVEF, NYHA class, Minnesota Living with HF (MLHFQ) score, and 6-minute walk distance (P <0.05 for all) with only one complication during the study period (perioperative anemia).[12] This study was followed by the phase II HOPE4HF (Barostim® Hope of HF Study) trial, which randomized 146 patients with LVEF ≥35% and NYHA functional class III to either medical therapy alone or BAT and medical therapy. Compared to medical therapy alone, BAT with medical therapy resulted in a greater improvement in NYHA functional class, MLHFQ score, and 6-minute walk distance (P <0.05 for all). This study also demonstrated a great safety profile with a freedom from major adverse neurological and CV events of 97.2%.[13] Subsequently, the randomized, parallel-group pivotal BeAT-HF (Baroreflex Activation Therapy for HF) trial included 408 patients with LVEF ≤35% and NYHA functional class II-III in its expedited initial phase (phase I). At 6 months, BAT resulted in a significant improvement in MLHFQ score and 6-minute walk distance and reduction in the levels of NT-proB-type natriuretic peptide (P <0.05 for all) with a major adverse neurological or CV system or procedure-related event rate of 97%.5 Based on these results, the Food and Drug Administration approved the Barostim™ neo system in 2019 in patients with HF and LVEF ≤35%, current NYHA functional class III or recent NYHA functional class III, and NT-proBNP <1,600 pg/mL who are ineligible for CRT. The extended phase (phase II) of BeAT-HF aims to assess the rate of CV mortality and HF morbidity as an endpoint and is still ongoing.

Given that the currently available evidence is insufficient to derive conclusion regarding reduction in mortality of hospitalization for HF with BAT, the contemporary European and American HF guidelines do not provide specific recommendations regarding the use of BAT in patients with HF.[14,15]

Future Directions

BAT is an emerging device-based therapy for HF and resistant hypertension; more data from large-scale trials are still needed to establish the efficacy of this therapy on hard CV outcomes. In addition, development of tools and markers to identify patients with a more pronounced baroreflex dysfunction may help identify those who would benefit the most from this therapy.


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