Summary of Evidence

Baroreflex stimulation devices are an alternative treatment option for treatment-resistant hypertension and heart failure. Overall, there is a lack of strong published clinical evidence to demonstrate an impact on improved health outcomes. Available studies lack long-term outcomes and include significant limitations. Large well-designed randomized controlled trials are needed in the future to determine the long-term safety and efficacy of this technology.

Rationale

Baroreceptors are pressure sensors contained within the walls of carotid arteries. They are part of the autonomic nervous system that regulates basic physiologic functions such as heart rate and blood pressure (BP). When these receptors are stretched, as occurs with increases in BP, the baroreflex is activated. Activation of the baroreflex signals the brain, which responds by inhibiting sympathetic nervous system output and increasing parasympathetic nervous system output. The effect of this activation is to reduce heart rate and BP, thereby helping to maintain homeostasis of the circulatory system. The use of baroreflex stimulation devices (also known as baroreflex activation therapy) is being investigated as a potential alternative treatment for resistant hypertension and heart failure (HF). In treatment of HF, the therapy is intended to correct the imbalance between the sympathetic and parasympathetic nervous systems that underlies the condition. Baroreflex stimulation devices provide electrical stimulation of the baroreceptors in the carotid arteries using an implanted device.

In 2014, the Barostim Neo™ Legacy System received a humanitarian device exemption from the U.S. Food and Drug Administration (FDA) for use in patients with treatment-resistant hypertension who received Rheos® Carotid Sinus leads as part of the Rheos pivotal trial and were considered responders in that trial.

In 2019, Barostim Neo was granted premarket approval (PMA), indicated for the improvement of symptoms of heart failure (i.e., quality of life, six-minute hall walk, and functional status) for patients who remain symptomatic despite treatment with guideline-directed medical therapy, are New York Heart Association (NYHA) Class III or Class II (with a recent history of Class III), and have a left ventricular ejection fraction (LVEF) ≤ 35% and a N-terminal pro-B-type natriuretic peptide (NT-proBNP) < 1600 pg/ml, excluding patients indicated for Cardiac Resynchronization Therapy according to the American Heart Association/ American College of Cardiology/ European Society of Cardiology guidelines.

In 2023, Barostim Neo's indication was expanded for patients who are NYHA Class III or Class II (who had a recent history of Class III) despite treatment with guideline-directed medical therapies (medications and devices), have a left ventricular ejection fraction (LVEF) of ≤ 35%, and a NT-proBNP < 1600 pg/ml.

Hypertension

In 2011, Bisognano et al published results for the pivotal Rheos trial, a randomized, controlled, double-blind study that evaluated the efficacy of baroreflex stimulation for lowering blood pressure (BP) using the first-generation Rheos device plus medical management compared to medical management alone. This trial included patients with treatment-resistant hypertension defined as at least 1 systolic BP (SBP) measurement of 160 mm Hg or more with diastolic BP (DBP) measurement of 80 mm Hg or more after at least 1 month of maximally tolerated medical therapy. A total of 322 patients had the Rheos system implanted, and 265 patients underwent randomization. Participants were randomized in a 2:1 fashion to the device turned on or off for a 6-month period. After 6 months, all patients had the device turned on. The primary efficacy endpoints were the percentage of patients achieving at least a 10 mm Hg decrease in SBP at 6 months (acute efficacy) and the percentage of patients who maintained their BP response over the 6- to 12-month study period (sustained efficacy). Primary safety outcomes were defined thresholds for procedural safety (at least 82% of patients free from procedural adverse events at 30 days), therapy safety (not more than 15% excess treatment-related adverse events in the experimental group), and device safety (at least 72% of patients free from procedural or therapy-related adverse events at 12 months). At 6 months, 54% of patients in the stimulation group had an SBP decrease of 10 mm Hg or more compared with 46% of patients in the control group (p=0.97), indicating that the primary acute efficacy outcome was not met. The primary sustained efficacy outcome was met, with 88% of patients who responded at 6 months maintaining a response at 12 months. A secondary efficacy outcome, the percentage of patients reaching target SBP, was also reported. A total of 42% of the patients in the active treatment group reached a target SBP of 140 mm Hg compared with 24% in the control group (p=0.005). For the primary procedural safety endpoint, the predefined threshold of 82% was not met. At 30 days, the percentage of patients free of procedural adverse events was 74.8%. The primary safety endpoint for therapy safety was met, with a similar percentage of patients free of treatment-related adverse effects at 6 months (91.7% vs 89.3%, p<0.001 for noninferiority). The primary safety endpoint for the device was also met, with 87.2% of patients free of device-related adverse events at 12 months, exceeding the predefined threshold of 72%. Baroreflex stimulation-treated patients were no more likely to achieve at least a 10 mm Hg decrease in SBP at 6 months, but were more likely to reach the target SBP of 140 mm Hg or less at 6 months. The trial met 2 of its 3 predefined safety endpoints, therapy safety and device safety, but not procedural safety. The researchers concluded that the weight of the overall evidence suggests that over the long-term, baroreflex stimulation can safely reduce SBP in patients with resistant hypertension, however future clinical trials are needed to address the limitations of this study and further define the therapeutic benefit of this treatment.

Bakris et al (2012) reported on additional data in an extension of the Rheos trial. A total of 276 (86%) of the 322 implanted patients consented to long-term, open-label follow-up. After a mean follow-up of 28 months, 244 (88%) of 276 were considered to be clinically significant responders. Response was defined as sustained achievement of the target SBP (≤140 mm Hg, or ≤130 mm Hg for patients with diabetes or renal disease), or a reduction in SBP of 20 mm Hg or more from device activation. Alternatively, patients could qualify as responders if their implanted device was deactivated and if they had an increase in SBP of at least 20 mm Hg in the 30 days after device deactivation. Limitations of this extension study include the lack of a comparison group and the open label design.

Several uncontrolled observational studies have also been published. The largest of these, the DEBut-HT trial, was a multicenter, single-arm feasibility study of the Rheos baroreflex activation therapy system published in 2010 by Scheffers et al. This study enrolled 45 patients with treatment-resistant hypertension defined as a BP greater than 160/90 mm Hg, despite treatment with at least 3 antihypertensive drugs, including a diuretic. The planned follow-up was 3 months, with a smaller number of patients followed up to 2 years. In 37 patients completing the 3-month protocol, office SBP was reduced by 21 mm Hg (SD=4; p<0.001) and DBP was reduced by 12 mm Hg (SD=2; p<0.001) SBP (p=0.10) and a decrease of 4 mm Hg (SD=2) in DBP (p=0.04). In 26 patients followed for 1 year, the declines in office BP were 30 mm Hg (SD=6) for systolic p<0.001) and 20 mm Hg (SD=4) for diastolic (p<0.001). For ambulatory BP (n=15), the 1-year declines were 13 mm Hg (SD=3) for systolic (p<0.001) and 8mm Hg (SD=2) for diastolic (p=0.001). A total of 7 (16.7%) of 42 patients experienced adverse events. Three patients required device removal due to infection, 1 patient experienced perioperative stroke, 1 patient experienced tongue paresis due to hypoglossal nerve injury, 1 patient had postoperative pulmonary edema, and 1 patient required reintervention for device explantation. While this novel approach with the Rheos device holds promise for patients with resistant hypertension, large well designed randomized placebo-controlled trials are needed to demonstrate long-term safety and efficacy, as well as effects on net health outcomes.

A small single-arm study using the second-generation Neo device to treat uncontrolled hypertension was published in 2016 by Wallbach et al. The study reported on 44 patients with resistant hypertension, defined as an office BP at least 140 mm Hg or 130 mm Hg for patients with chronic kidney disease and proteinuria, despite treatment with at least 3 antihypertensive medications including a diuretic. Mean baseline office BP was 171/91 mm Hg. After 6 months of baroreflex activation therapy (BAT), mean office BP decreased to 151±26 mm Hg over 82±17 mm Hg (pre-to-post, p<0.001). At 6 months, the mean number of BP medications used per patient decreased from 6.5±1.5 at baseline to 6.0±1.8 (< 0.03). One procedure-related major adverse event occurred, a contralateral stroke. 10 (23%) of the 44 patients experienced a minor procedure-related complication. The most common minor adverse events were disturbance of wound healing (n=5 [11%]) and postoperative hematoma (n=4 [9%]). One patient had revision surgery but explantation was not needed. The researchers stated that BAT might be considered as a new therapeutic option to reduce cardiovascular risk in patients with resistant hypertension, however randomized controlled trials are needed to evaluate BAT effects on ambulatory BP measurements in patients with resistant hypertension accurately.

In 2017, de Leeuw et al published results of 6-year follow-up of 383 patients enrolled in 3 trials of BAT for treatment-resistant hypertension. Patients included those enrolled in the U.S. Rheos Feasibility Trial (n=16), the DEBut-HT (n=45), and the pivotal Rheos trial (n=322). The US Rheos Feasibility Trial was an initial phase 2 nonrandomized, feasibility, and safety study, as was the DEBUT-HT. Of the total patients available for follow-up, 143 of had completed 5 years of follow-up and 48 patients had completed 6 years of follow-up. In the entire cohort, office systolic blood pressure fell from 179±24 mmHg to 144±28 mmHg (p<0.0001); office diastolic pressure dropped from 103±16 mmHg to 85±18 mmHg (p<0.0001). Heart rate fell from 74±15 beats per minute to 71±13 beats per minute (p<0.02). Subgroup analysis determined that the effect of BAT is greater than average in patients with signs of heart failure and less than average in patients with isolated systolic hypertension. In ~25% of patients, the number of medications was reduced from a median of 6 to a median of 3. Limitations of the analysis included lack of randomization in 2 of the 3 studies and all lacked a control group during prolonged follow-up. Follow-up periods were not uniform across studies, potentially leading to biased results. Efficacy data were based on office pressures only, and as a result, effect of treatment on 24-hour ambulatory BP monitoring is unknown. The researchers noted that adherence to drug treatment prior to diagnosis of treatment resistance should be considered, but acknowledged that techniques for accurate and cost-effective measures of adherence are not available. The researchers concluded that results of the included studies provide a prompt for further research into how baroreceptors precisely work in hypertension, particularly over long periods of time, and how to optimize selection of patients who would be most likely to benefit from the therapy.

Heart Failure

In 2015, Abraham et al published results for the HOPE4HF randomized controlled trial that evaluated baroreflex stimulation for the treatment of heart failure. This trial was nonblinded and included 146 patients with NYHA Class III heart failure and an ejection fraction of less ≤ 35% despite guideline-directed medical therapy. Patients were randomized to baroreflex stimulation (Barostim Neo System) plus medical therapy (n=76) or to continued medical therapy alone (control; n=70) for 6 months. The primary safety outcome was the proportion of patients free from major adverse neurologic and cardiovascular events. The trialists specified 3 primary efficacy endpoints: changes in NYHA functional class, quality of life score, and 6-minute walk distance (6MWD). The overall MANCE-free rate was 97.2%; rates were not reported separately for the baroreflex stimulation and control groups. In terms of the efficacy outcomes, there was significant improvement in the baroreflex stimulation group versus the control group on each of the 3 outcomes. Significantly more patients in the treatment group (55%) improved by at least 1 level in NYHA functional class than in the control group (24%; p<0.002). Mean quality of life scores, as assessed by the MLHFQ, improved significantly more in the treatment group (-17.4 points) than in the control group (2.1 points; p<0.001). Similarly, mean 6MWD improved significantly more in the treatment group (59.6 meters) than in the control group (1.5 meters; p=0.004). The limitations of this RCT included a relatively small sample size for a common condition, relatively short intervention period, and a lack of blinding; some of the positive findings on the subjective patient-reported outcomes might have been due at least in part to a placebo effect.

Weaver et al (2016) reported 12-month results for 101 (69%) of 146 patients from the HOPE4HF RCT. No additional system- or procedure-related major adverse neurologic and cardiovascular events occurred between 6 and 12 months. Moreover, outcomes for NYHA functional class improvement, quality of life score, and 6MWD were all significantly better in the treatment group than in the control group at 12 months. This analysis, however, had a substantial amount of missing data. The researchers stated that although results showed long-term benefits of BAT in heart failure with reduced ejection fraction, the present knowledge base needs to be expanded. Additional RCTs with larger sample sizes and longer follow-up are needed to confirm these positive findings.

Halbach et al (2018) published a post hoc subgroup analysis from the HOPE4HF RCT evaluating BAT for heart failure in patients with and without coronary artery disease (CAD). 146 patients from 45 centers with LVEF < 35% and NYHA Class III were randomized to the BAT group (n=76) or control group (n=70). The rate of system- or procedure-related major adverse neurological or cardiovascular events (MANCE) was 3.8% for the CAD group and 0% for the no-CAD group (p>0.99), while the system- or procedure-related complication rate was 11.5% for patients with CAD and 21.1% for those without CAD (p=0.44). In the BAT group, from baseline to 6 months, quality of life scores decreased by 16.8 ± 3.4 points for CAD patients and by 18.9 ± 5.3 for no-CAD patients; NYHA classification decreased by 0.6 ± 0.1 for CAD patients and by 0.4 ± 0.2 for no-CAD patients. Left ventricular ejection fraction (LVEF) increased by 1.2 ± 1.4 for the CAD group and 5.2 ± 1.9 for the no-CAD group. No interaction was found between the presence of CAD and effect of baroreflex activation therapy (p>0.05). This study was limited by its small sample size and by the subgroup analysis not being prespecified.

In 2019, the Barostim Neo System was the first device to receive premarket approval through the U.S. Food and Drug Administration's (FDA's) Expedited Access Pathway. The safety and effectiveness data reviewed by the FDA was reported in the BeAT-HF trial (NCT02627196). BeAT-HF was a multicenter, randomized, controlled trial and evaluated the safety and effectiveness of baroreflex activation therapy (BAT) in patients with heart failure with reduced ejection fraction using an Expedited and Extended Phase design. Results for the Expedited Phase were published in 2020 by Zile et al. In the Expedited Phase, BAT plus guideline-directed medical therapy (GDMT) was compared at 6 months post-implant to GDMT alone using 3 intermediate primary endpoints: 6-minute hall walk distance (6MHW), Minnesota Living with HF Questionnaire (MLHFQ) quality-of-life score, and N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels. The rate of heart failure morbidity and cardiovascular mortality was compared between the arms to evaluate early trending using predictive probability modeling. In the Expedited Phase, 264 intended use patients were randomized. The primary safety endpoint was major adverse neurological and cardiovascular event-free rate (MANCE), which was only measured in the baroreflex group. Results analysts were blinded to arm assignment. At 6 months, BAT was safe and significantly improved QOL, 6MHW, and NT-proBNP. In the BAT group versus the control group, QOL score decreased (Δ = -14.1; 95% confidence interval [CI]: -19 to -9; p<0.001), 6MHW distance increased (Δ = 60 m; 95% CI: 40 to 80 m; p<0.001), NT-proBNP decreased (Δ = -25%; 95% CI: -38% to -9%; p = 0.004). Also, the MANCE-free rate was 96.8% (121/125 patients) at 6 months, and the one-sided 95% CI lower bound was 92.8% (p<0.001). The FDA concluded from these results that the system was safe for the intended use population, and all effectiveness endpoints showed a statistically significant benefit for BAT plus GDMT compared to GDMT alone.

In 2024, Zile et al published results for the Extended Phase of the BeAT-HF study. 323 patients were enrolled with New York Heart Association (NYHA) class III heart failure with reduced ejection fraction (264 patients in the Expedited phase and an additional 59 patients who were randomized from May 2019 to June 2020). The study population had an ejection fraction ≤ 35%, a recent heart failure hospitalization or elevated NT-proBNP levels, and no indication for cardiac resynchronization therapy. Patients were randomized to receive either BAT plus optimal medical management (n=163) or optimal medical management alone (GDMT [control]; n=163) and were followed for a median of 3.6 years post-intervention. The primary outcome was a composite of cardiovascular mortality (i.e., sudden death, heart failure, myocardial infarction, cerebrovascular accident, cardiovascular procedure, other cardiac death, other vascular death, or death of an unknown cause) and heart failure morbidity (i.e., worsening HF events that led to a hospitalization or ER visit for worsening HF, implantation of a cardiac assist device or heart transplantation). Secondary outcomes assessed the durability of safety, patient-centered symptomatic improvement (quality of life, exercise capacity, and functional status), a hierarchical composite win ratio, freedom from all-cause death left ventricular assist device (LVAD) implantation, and heart transplantation. Results showed that both the primary endpoint (rate ratio 0.94, 95% confidence interval [CI] 0.57-1.57; p=0.82) and components of the primary endpoints were not significantly different between BAT and control. For exploratory secondary outcomes, BAT was favored over the control group on the 6MHWD, MLHFQ, and improvements of 1 or more NYHA classes, but not NT-proBNP or for freedom from all-cause death. Hierarchical composite win ratio (combining cardiovascular mortality, LVAD/heart transplantation, HF event, unscheduled clinic visits with IV diuretic, change in MLWHF at 12 months ≥ 5 points) favored BAT + GDMT over control for 53.1% of comparisons (win ratio, 1.26; 95% CI, 1.02 to 1.58; p=0.04). The primary safety endpoint, MANCE-free survival, met its pre-specified performance goal of ≥ 85% (154 [97%], p<0.001) in the BAT group. The researchers stated that the interpretation of the individual levels of the Win Ratio is challenging as 2 outcome components had less than 60% of heart failure events and unscheduled clinic visits evaluated. Major limitations of the study included a lack of blinding, the absence of a control group with an implanted device, and changes in care patterns caused by the COVID-19 pandemic, and missing data for some outcomes. The researchers concluded that BAT provided safe, effective, and sustainable improvements in heart failure with reduced ejection fraction patient's functional status, 6MHWD, and QOL, however the trial failed to meet its primary efficacy composite outcome, as well as the component parts.

In 2023, Guckel et al published results for a small nonrandomized, single center, prospective study evaluating BAT in 40 patients with heart failure with reduced ejection fraction and an indication for BAT. The study aimed to analyze patients' acceptance of BAT and outcomes compared to patients treated with GDMT, as well as the effects of angiotensin-receptor neprilysin inhibitors (ARNIs) on BAT response. Ten patients (25%) opted for BAT implantation, and the remaining 30 patients served as the control group. At 12 months follow-up, BAT patients showed significant improvements in LVEF (+10% vs +3%; p=0.005), NYHA class ≥ 3 (88% improvement vs -9%; p=0.014), QoL on the EQ-5D-5L (+21% vs 0%; p=0.020), NT-proBNP levels (-24% vs 35%; p=0.044) and lower heart failure hospitalization rates compared to the control group (50% vs 83%, p=0.020).  A sub-group analysis of these outcomes showed that patients who were treated with ARNIs in addition to BAT had greater effects than ARNIs alone. Major limitations of the trial include an absence of power calculations, a small sample size, lack of blinding, use of a single center, and imbalances in patient characteristics. The researchers concluded that although BAT has generated considerable interest, acceptance appears to be ambivalent.

In 2022, Coats et al conducted a patient-level meta-analysis (n=554) comparing patients who received baroreceptor activation therapy (BAT) in addition to guideline-directed medical therapy (GDMT) or GDMT alone. Patients included in the analysis were enrolled in 1 of 2 RCTs (HOPE4HF and BeAT-HF). The studies enrolled patients with a left ventricular ejection fraction (LVEF) ≤ 35% and NYHA Class III heart failure (or Class II with a recent history of Class III). Similar to the results of the individual trials (described above), at 6 months, patients treated with BAT had improved 6-minute hall walk distance (48.5 meters; 95% CI, 32.7 to 64.2). More patients had improvements in NYHA in the BAT group with a 3.4 higher odds of improving at least 1 NYHA class compared to medical therapy alone. Quality of life as measured by the Minnesota Living with Heart Failure Questionnaire (MLHFQ) was also improved with the addition of BAT (-13.4 points; 95% CI, -17.1 to -9.6). This analysis is limited by the small number of RCTs and the open-label design of these trials.

In 2023, Molina-Linde et al published a systematic review and meta-analysis evaluating the efficacy and safety of BAT in patients with heart failure with reduced ejection fraction (HFrEF). Similar to Coats et al (above), two studies were included in the meta-analysis (HOPE4HF and BeAT-HF). The results showed that BAT led to statistically significant improvements in NYHA functional class (relative risk 2.13; 95% confidence interval [CI, 1.65 to 2.76]), quality of life (difference in means -16.97; 95% CI [-21.87 to -12.07]), 6 min walk test (difference in means 56.54; 95% CI [55.67 to 57.41]) and N-terminal probrain natriuretic peptide (difference in means -120.02; 95% CI [-193.58 to -46.45]). The system- and procedure-related complication event-free rate varied from 85.9% to 97%. The researchers stated that further studies and long-term follow-up are needed to assess efficacy in reducing cardiovascular events and mortality.

Technology Assessments

Hayes evaluates a wide range of medical technologies and provides evidence-based assessments to determine impacts on patient safety and health outcomes. In 2023, Hayes published an Evolving Evidence Review on the Barostim Neo System for treatment of heart failure. The exploration of clinical studies and systematic reviews uncovered minimal support for using Barostim Neo System for heart failure to improve quality of life and functional outcomes. After reviewing clinical practice guidelines and position statements, the review concluded that guidance appears to confer no/unclear support for the Barostim Neo System for heart failure.

Practice Guidelines & Position Statements

In 2017, the American Heart Association (AHA) issued a joint guideline for the management of high blood pressure in adults with the American College of Cardiology (ACC) and multiple other organizations. The guideline addresses studies on the use of devices that interrupt sympathetic nervous system activity including carotid baroreceptor pacing. The guideline states that several studies have investigated devices that interrupt sympathetic nerve activity (carotid baroreceptor pacing and catheter ablation of renal sympathetic nerves); however, these studies have not provided sufficient evidence to recommend the use of these device in managing resistant hypertension.

In 2022, the American Heart Association (AHA), American College of Cardiology (ACC), and Heart Failure Society of America (HFSA) published a joint guideline on management of heart failure. According to the guideline, baroreceptor stimulation has produced mixed results. Data regarding mortality and hospitalization are lacking, and more recent data have not confirmed benefit.

Reference List

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