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Aims: Carotid baroreflex activation therapy (BAT) restores baroreflex sensitivity and modulates the imbalance in cardiac autonomic function in patients with heart failure with reduced ejection fraction (HFrEF). We tested the hypothesis that treatment with BAT significantly reduces cardiovascular mortality and heart failure morbidity and provides long-term safety and sustainable symptomatic improvement., Methods and Results: BeAT-HF was a prospective, multicentre, randomized, two-arm, parallel-group, open-label, non-implanted control trial. New York Heart Association (NYHA) class III subjects, ejection fraction ≤35%, previous heart failure hospitalization or N-terminal pro-B-type natriuretic peptide (NT-proBNP) >400 pg/ml, no class I indication for cardiac resynchronization therapy and NT-proBNP <1600 pg/ml were randomized to BAT plus optimal medical management (BAT group) or optimal medical management alone (control). The primary endpoint was cardiovascular mortality and HF morbidity; additional pre-specified endpoints included durability of safety, quality of life (QOL), exercise capacity (6-min hall walk distance [6MHWD]), functional status (NYHA class), hierarchical composite win ratio, freedom from all-cause death, left ventricular assists device (LVAD) implantation, heart transplant. Overall, 323 patients had 332 primary events, median follow-up was 3.6 years/patient. Both 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. The system- and procedure-related major adverse neurological and cardiovascular event-free rate remained 97% throughout the trial. Symptom improvement (QOL, 6MHWD, NYHA class, all nominal p < 0.001) in the BAT group was durable in time, sustainable in extent. Win ratio (1.26, 95% CI 1.02-1.58) and freedom from all-cause death, LVAD implantation, heart transplant (hazard ratio 0.66, 95% CI 0.43-1.01) favoured the BAT group but did not reach statistical significance., Conclusion: The BeAT-HF primary endpoint was neutral; however, BAT provided safe, effective, and sustainable improvements in HFrEF patient's functional status, 6MHWD and QOL., (© 2024 CVRx and The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: The statistical significance of clinical trial outcomes is generally interpreted quantitatively according to the same threshold of 2.5% (in one-sided tests) to control the false-positive rate or type I error, regardless of the burden of disease or patient preferences. The clinical significance of trial outcomes-including patient preferences-are also considered, but through qualitative means that may be challenging to reconcile with the statistical evidence., Objective: We aimed to apply Bayesian decision analysis to heart failure device studies to choose an optimal significance threshold that maximizes the expected utility to patients across both the null and alternative hypotheses, thereby allowing clinical significance to be incorporated into statistical decisions either in the trial design stage or in the post-trial interpretation stage. In this context, utility is a measure of how much well-being the approval decision for the treatment provides to the patient., Methods: We use the results from a discrete-choice experiment study focusing on heart failure patients' preferences, questioning respondents about their willingness to accept therapeutic risks in exchange for quantifiable benefits with alternative hypothetical medical device performance characteristics. These benefit-risk trade-off data allow us to estimate the loss in utility-from the patient perspective-of a false-positive or false-negative pivotal trial result. We compute the Bayesian decision analysis-optimal statistical significance threshold that maximizes the expected utility to heart failure patients for a hypothetical two-arm, fixed-sample, randomized controlled trial. An interactive Excel-based tool is provided that illustrates how the optimal statistical significance threshold changes as a function of patients' preferences for varying rates of false positives and false negatives, and as a function of assumed key parameters., Results: In our baseline analysis, the Bayesian decision analysis-optimal significance threshold for a hypothetical two-arm randomized controlled trial with a fixed sample size of 600 patients per arm was 3.2%, with a statistical power of 83.2%. This result reflects the willingness of heart failure patients to bear additional risks of the investigational device in exchange for its probable benefits. However, for increased device-associated risks and for risk-averse subclasses of heart failure patients, Bayesian decision analysis-optimal significance thresholds may be smaller than 2.5%., Conclusions: A Bayesian decision analysis is a systematic, transparent, and repeatable process for combining clinical and statistical significance, explicitly incorporating burden of disease and patient preferences into the regulatory decision-making process., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Use of robust, quantitative tools to measure patient perspectives within product development and regulatory review processes offers the opportunity for medical device researchers, regulators, and other stakeholders to evaluate what matters most to patients and support the development of products that can best meet patient needs. The medical device innovation consortium (MDIC) undertook a series of projects, including multiple case studies and expert consultations, to identify approaches for utilizing patient preference information (PPI) to inform clinical trial design in the US regulatory context. Based on these activities, this paper offers a cogent review of considerations and opportunities for researchers seeking to leverage PPI within their clinical trial development programs and highlights future directions to enhance this field. This paper also discusses various approaches for maximizing stakeholder engagement in the process of incorporating PPI into the study design, including identifying novel endpoints and statistical considerations, crosswalking between attributes and endpoints, and applying findings to the population under study. These strategies can help researchers ensure that clinical trials are designed to generate evidence that is useful to decision makers and captures what matters most to patients., (© 2022. The Author(s).)

Aims: Heart failure with reduced ejection fraction (HFrEF) remains associated with high morbidity and mortality, poor quality of life (QoL) and significant exercise limitation. Sympatho-vagal imbalance has been shown to predict adverse prognosis and symptoms in HFrEF, yet it has not been specifically targeted by any guideline-recommended device therapy to date. Barostim™, which directly addresses this imbalance, is the first Food and Drug Administration approved neuromodulation technology for HFrEF. We aimed to analyse all randomized trial evidence to evaluate the effect of baroreflex activation therapy (BAT) on heart failure symptoms, QoL and N-terminal pro-brain natriuretic peptide (NT-proBNP) in HFrEF., Methods and Results: An individual patient data (IPD) meta-analysis was performed on all eligible trials that randomized HFrEF patients to BAT + guideline-directed medical therapy (GDMT) or GDMT alone (open label). Endpoints included 6-month changes in 6-min hall walk (6MHW) distance, Minnesota Living With Heart Failure (MLWHF) QoL score, NT-proBNP, and New York Heart Association (NYHA) class in all patients and three subgroups. A total of 554 randomized patients were included. In all patients, BAT provided significant improvement in 6MHW distance of 49 m (95% confidence interval [CI] 33, 64), MLWHF QoL of -13 points (95% CI -17, -10), and 3.4 higher odds of improving at least one NYHA class (95% CI 2.3, 4.9) when comparing from baseline to 6 months. These improvements were similar, or better, in patients who had baseline NT-proBNP &lt;1600 pg/ml, regardless of the cardiac resynchronization therapy indication status., Conclusion: An IPD meta-analysis suggests that BAT improves exercise capacity, NYHA class, and QoL in HFrEF patients receiving GDMT. These clinically meaningful improvements were consistent across the range of patients studies. BAT was also associated with an improvement in NT-proBNP in subjects with a lower baseline NT-proBNP., (© 2022 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: Regulatory and clinical decisions involving health technologies require judgements about relative importance of their expected benefits and risks. We sought to quantify heart-failure patients' acceptance of therapeutic risks in exchange for improved effectiveness with implantable devices., Methods: Individuals with heart failure recruited from a national web panel or academic medical center completed a web-based discrete-choice experiment survey in which they were randomized to one of 40 blocks of 8 experimentally controlled choice questions comprised of 2 device scenarios and a no-device scenario. Device scenarios offered an additional year of physical functioning equivalent to New York Heart Association class III or a year with improved (ie, class II) symptoms, or both, with 30-day mortality risks ranging from 0% to 15%, in-hospital complication risks ranging from 0% to 40%, and a remote adjustment device feature. Logit-based regression models fit participants' choices as a function of health outcomes, risks and remote adjustment., Results: Latent-class analysis of 613 participants (mean age, 65; 49% female) revealed that two-thirds were best represented by a pro-device, more risk-tolerant class, accepting up to 9% (95% CI, 7%-11%) absolute risk of device-associated mortality for a one-year gain in improved functioning (New York Heart Association class II). Approximately 20% were best represented by a less risk-tolerant class, accepting a maximum device-associated mortality risk of 3% (95% CI, 1%-4%) for the same benefit. The remaining class had strong antidevice preferences, thus maximum-acceptable risk was not calculated., Conclusions: Quantitative evidence on benefit-risk tradeoffs for implantable heart-failure device profiles may facilitate incorporating patients' views during product development, regulatory decision-making, and clinical practice.

Background: The study evaluated the cost of baroreflex activation therapy plus guideline directed therapy (BAT + GDT) compared to GDT alone for HF patients with reduced ejection fraction and New York Heart Association Class III or II (with a recent history of III). Baroreflex activation therapy (BAT) is delivered by an implantable device that stimulates the baroreceptors through an electrode attached to the outside of the carotid artery, which rebalances the autonomic nervous system to regain cardiovascular (CV) homeostasis. The BeAT-HF trial evaluated the safety and effectiveness of BAT., Methods: A cost impact model was developed from a U.S. health care payer or integrated delivery network perspective over a 3-year period for BAT + GDT versus GDT alone. Expected costs were calculated by utilizing 6-month data from the BeAT-HF trial and existing literature. HF hospitalization rates were extrapolated based on improvement in NT-proBNP., Results: At baseline the expected cost of BAT + GDT were $29,526 per patient more than GDT alone due to BAT device and implantation costs. After 3 years, the predicted cost per patient was $9521 less expensive for BAT + GDT versus GDT alone due to lower rates of significant HF hospitalizations, CV non-HF hospitalizations, and resource intensive late-stage procedures (LVADs and heart transplants) among the BAT + GDT group., Conclusions: BAT + GDT treatment becomes less costly than GDT alone beginning between years 1 and 2 and becomes less costly cumulatively between years 2 and 3, potentially providing significant savings over time. As additional BeAT-HF trial data become available, the model can be updated to show longer term effects.

Background: This study demonstrated the safety and effectiveness of baroreflex activation therapy (BAT) in patients with heart failure with reduced ejection fraction (HFrEF)., Objectives: The BeAT-HF (Baroreflex Activation Therapy for Heart Failure) trial was a multicenter, prospective, randomized, controlled trial; subjects were randomized 1:1 to receive either BAT plus optimal medical management (BAT group) or optimal medical management alone (control group)., Methods: Four patient cohorts were created from 408 randomized patients with HFrEF using the following enrollment criteria: current New York Heart Association (NYHA) functional class III or functional class II (patients who had a recent history of NYHA functional class III); ejection fraction ≤35%; stable medical management for ≥4 weeks; and no Class I indication for cardiac resynchronization therapy. Effectiveness endpoints were the change from baseline to 6 months in 6-min hall walk distance (6MHW), Minnesota Living with HF Questionnaire quality-of-life (QOL) score, and N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels. The safety endpoint included the major adverse neurological or cardiovascular system or procedure-related event rate (MANCE)., Results: Results from, timeline and rationale for, cohorts A, B, and C are presented in detail in the text. Cohort D, which represented the intended use population that reflected the U.S. Food and Drug Administration-approved instructions for use (enrollment criteria plus NT-proBNP <1,600 pg/ml), consisted of 245 patients followed-up for 6 months (120 in the BAT group and 125 in the control group). 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), and the MANCE free rate was 97% (95% CI: 93% to 100%; p < 0.001)., Conclusions: BAT was safe and significantly improved QOL, exercise capacity, and NT-proBNP. (Baroreflex Activation Therapy for Heart Failure [BeAT-HF]; NCT02627196)., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The Food and Drug Administration (FDA) initiated the Expedited Access Pathway (EAP) to accelerate approval of novel therapies targeting unmet needs for life-threatening conditions. EAP allows for the possibility of initial FDA approval using intermediate end points with postapproval demonstration of improved outcomes., Objective: Describe the EAP process using the BeAT-HF trial as a case study., Methods: BeAT-HF will examine the safety and effectiveness of baroreflex activation therapy (BAT) in heart failure patients with reduced ejection fraction using an Expedited and Extended Phase design. In the Expedited Phase, BAT plus guideline-directed medical therapy (GDMT) will be compared at 6 months postimplant to GDMT alone using 3 intermediate end points: 6-minute hall walk distance, Minnesota Living with Heart Failure Questionnaire, and N-terminal pro-B-type natriuretic peptide. The rate of heart failure morbidity and cardiovascular mortality will be compared between the arms to evaluate early trending using predictive probability modeling. Sample size of 264 patients randomized 1:1 to BAT + GDMT versus GDMT alone provides 81% power for the Expedited Phase intermediate end points. For the Extended Phase, the heart failure morbidity and cardiovascular mortality end point is based on an expected event rate of 0.4 events/patient/year in the GDMT arm. With an adaptive sample size selection design for robustness to inaccurate assumptions, a sample size of 480-960 randomized patients followed ≥2 years allows detecting a 30% reduction in the primary end point with a power of 97.5%., Conclusion: Through a unique collaboration with FDA under the EAP, the BeAT-HF trial design allows for the possibility of approval of BAT, initially for symptom relief and subsequently for outcomes improvement., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: In a randomized trial, baroreflex activation therapy (BAT) improved exercise capacity, quality of life and NT-proBNP in patients with heart failure with reduced ejection fraction (HFrEF). In view of different mechanisms underlying HFrEF, we performed a post-hoc subgroup analysis of efficacy and safety of BAT in patients with and without coronary artery disease (CAD)., Methods and Results: Patients with left ventricular ejection fraction <35% and NYHA Class III were randomized 1:1 to guideline-directed medical and device therapy alone or plus BAT. Patients with a history of CAD, prior myocardial infarction or coronary artery bypass graft were assigned to the CAD group with all others assigned to the no-CAD group. Of 71 BAT treated patients, 52 had CAD and 19 had no CAD. In the control group, 49 of 69 patients had CAD and 20 had no CAD. The system- or procedure-related major adverse neurological or cardiovascular event rate was 3.8% in the CAD group vs. 0% in the no-CAD group (p = 1.0). In the whole cohort, NYHA Class, Minnesota Living with Heart Failure score, 6-minute hall walk distance and NTproBNP were improved in BAT treated patients compared with controls. Statistical analyses revealed no interaction between the presence of CAD and effect of BAT (all p > 0.05)., Conclusion: No major differences were found in BAT efficacy or safety between patients with and without CAD, indicating that BAT improves exercise capacity, quality of life and NTproBNP in patients with ischemic and non-ischemic cardiomyopathy. CLINICALTRIALS., Gov Identifier: NCT01471860 and NCT01720160., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Baroreflex activation therapy (BAT) is a device-based therapy for patients with treatment-resistant hypertension. In a randomized, controlled trial, the first-generation system significantly reduced blood pressure (BP) versus sham. Although an open-label validation study of the second-generation system demonstrated similar BP reductions, controlled data are not presently available. Therefore, this investigation compares results of first- and second-generation BAT systems. Two cohorts of first-generation BAT system patients were generated with propensity matching to compare against the validation group of 30 second-generation subjects. The first cohort was drawn from the first-generation randomized trial sham group and the second cohort from the active therapy group. Safety and efficacy were compared for the second-generation group relative to the first generation. At 6 months, second-generation BAT outperformed first-generation sham systolic BP reduction by 20 ± 28 mm Hg (mean ± standard deviation, P = .008), while BP reduction in first- and second-generation active groups was similar. At 12 months, efficacy was comparable between all three groups after the sham group had received 6 months of therapy; 47% of second-generation patients achieved goal systolic BP of 140 mm Hg or less after 12 months, comparable to 50% of patients at goal in the first-generation group (P > .999). Implant procedure time, system/procedural safety, and pulse generator longevity improved with the second-generation system. Propensity-matched cohort analysis of the first- and second-generation BAT systems suggests similar therapeutic benefit and superior BP reduction of the second-generation system relative to sham control. Implantation procedure duration and perioperative safety were improved with the second-generation device. These findings should be validated in a prospective randomized trial., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Heart failure with reduced ejection fraction (HFrEF) is characterized by activation of the sympathetic nervous system and increased arterial stiffness, leading to an impaired ventricular-vascular coupling. Baroreflex activation therapy (BAT) has been shown to reduce muscle sympathetic nerve activity (MSNA) and improve clinical status of patients with HFrEF. The purpose of this investigation was to determine the effects of BAT on arterial stiffness in HFrEF., Methods and Results: MSNA, clinical variables, and parameters of central blood pressure (BP) and arterial stiffness were collected in 18 NYHA Class III HFrEF patients, nine receiving BAT and nine continuing with optimal medical management alone. Patients were followed for 3 months, with measurements at that time compared to baseline evaluation. Baseline characteristics of the groups were well matched. At 3 months, BAT did not improve central BP and arterial stiffness despite a significant amelioration of MSNA, NYHA class, Minnesota living with heart failure questionnaire score, number of heart failure medications and six-minute walking distance. The control group exhibited no significant changes in all the measured variables., Conclusions: Despite significant reductions in MSNA and clinical improvement, BAT does not appear to chronically modify arterial stiffness within this HFrEF cohort. Additional study is required to determine if this result applies to the HFrEF population as a whole.

Carotid bodies play a critical role in protecting against hypoxemia, and their activation increases sympathetic activity, arterial pressure, and ventilation, responses opposed by acute stimulation of the baroreflex. Although chemoreceptor hypersensitivity is associated with sympathetically mediated hypertension, the mechanisms involved and their significance in the pathogenesis of hypertension remain unclear. We investigated the chronic interactions of these reflexes in dogs with sympathetically mediated, obesity-induced hypertension based on the hypothesis that hypoxemia and tonic activation of carotid chemoreceptors may be associated with obesity. After 5 weeks on a high-fat diet, the animals experienced a 35% to 40% weight gain and increases in arterial pressure from 106±3 to 123±3 mm Hg and respiratory rate from 8±1 to 12±1 breaths/min along with hypoxemia (arterial partial pressure of oxygen=81±3 mm Hg) but eucapnia. During 7 days of carotid baroreflex activation by electric stimulation of the carotid sinus, tachypnea was attenuated, and hypertension was abolished before these variables returned to prestimulation values during a recovery period. After subsequent denervation of the carotid sinus region, respiratory rate decreased transiently in association with further sustained reductions in arterial partial pressure of oxygen (to 65±2 mm Hg) and substantial hypercapnia. Moreover, the severity of hypertension was attenuated from 125±2 to 116±3 mm Hg (45%-50% reduction). These findings suggest that hypoxemia may account for sustained stimulation of peripheral chemoreceptors in obesity and that this activation leads to compensatory increases in ventilation and central sympathetic outflow that contributes to neurogenically mediated hypertension. Furthermore, the excitatory effects of chemoreceptor hyperactivity are abolished by chronic activation of the carotid baroreflex., (© 2016 American Heart Association, Inc.)

Hypertension (HTN) and heart failure (HF) have a significant global impact on health, and lead to increased morbidity and mortality. Despite recent advances in pharmacologic and device therapy for these conditions, there is a need for additional treatment modalities. Patients with sub-optimally treated HTN have increased risk for stroke, renal failure and heart failure. The outcome of HF patients remains poor despite modern pharmacological therapy and with established device therapies such as CRT and ICDs. Therefore, the potential role of neuromodulation via renal denervation, baro-reflex modulation and vagal stimulation for the treatment of resistant HTN and HF is being explored. In this manuscript, we review current evidence for neuromodulation in relation to established drug and device therapies and how these therapies may be synergistic in achieving therapy goals in patients with treatment resistant HTN and heart failure. We describe lessons learned from recent neuromodulation trials and outline strategies to improve the potential for success in future trials. This review is based on discussions between scientists, clinical trialists, and regulatory representatives at the 11th annual CardioVascular Clinical Trialist Forum in Washington, DC on December 5-7, 2014., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

The purpose of this publication is to describe the intraoperative experience along with long-term safety and efficacy of the second-generation baroreflex activation therapy (BAT) system in patients with heart failure (HF) and reduced ejection fraction HF (HFrEF). In a randomized trial of New York Heart Association Class III HFrEF, 140 patients were assigned 1:1 to receive BAT plus medical therapy or medical therapy alone. Procedural information along with safety and efficacy data were collected and analyzed over 12 months. Within the cohort of 71 patients randomized to BAT, implant procedure time decreased with experience, from 106 ± 37 minutes on the first case to 83 ± 32 minutes on the third case. The rate of freedom from system- and procedure-related complications was 86% through 12 months, with the percentage of days alive without a complication related to system, procedure, or underlying cardiovascular condition identical to the control group. The complications that did occur were generally mild and short-lived. Overall, 12 months therapeutic benefit from BAT was consistent with previously reported efficacy through 6 months: there was a significant and sustained beneficial treatment effect on New York Heart Association functional Class, quality of life, 6-minute hall walk distance, plasma N-terminal pro-brain natriuretic peptide, and systolic blood pressure. This was true for the full trial cohort and a predefined subset not receiving cardiac resynchronization therapy. There is a rapid learning curve for the specialized procedures entailed in a BAT system implant. BAT system implantation is safe with the therapeutic benefits of BAT in patients with HFrEF being substantial and maintained for at least 1 year., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Aims: Increased sympathetic and decreased parasympathetic activity contribute to heart failure (HF) symptoms and disease progression. Carotid baroreceptor stimulation (baroreflex activation therapy, BAT) results in centrally mediated reduction of sympathetic and increase in parasympathetic activity. Because patients treated with cardiac resynchronization therapy (CRT) may have less sympathetic/parasympathetic imbalance, we hypothesized that there would be differences in the response to BAT in patients with CRT vs. those without CRT., Methods and Results: New York Heart Association (NYHA) Class III patients with an ejection fraction (EF) ≤35% were randomized (1 : 1) to ongoing guideline-directed medical and device therapy (GDMT, control) or ongoing GDMT plus BAT. Safety endpoint was system-/procedure-related major adverse neurological and cardiovascular events (MANCE). Efficacy endpoints were Minnesota Living with Heart Failure Quality of Life (QoL), 6-min hall walk distance (6MHWD), N-terminal pro-brain natriuretic peptide (NT-proBNP), left ventricular ejection fraction (LVEF), and HF hospitalization rate. In this sample, 146 patients were randomized (70 control; 76 BAT) and were 140 activated (45 with CRT and 95 without CRT). MANCE-free rate at 6 months was 100% in CRT and 96% in no-CRT group. At 6 months, in the no-CRT group, QoL score, 6MHWD, LVEF, NT-proBNP and HF hospitalizations were significantly improved in BAT patients compared with controls. Changes in efficacy endpoints in the CRT group favoured BAT; however, the improvements were less than in the no-CRT group and were not statistically different from control., Conclusions: BAT is safe and significantly improved QoL, exercise capacity, NTpro-BNP, EF, and rate of HF hospitalizations in GDMT-treated NYHA Class III HF patients. These effects were most pronounced in patients not treated with CRT., (© 2015 The Authors European Journal of Heart Failure © 2015 European Society of Cardiology.)

Recent technology for chronic electric activation of the carotid baroreflex and renal nerve ablation provide global and renal-specific suppression of sympathetic activity, respectively, but the conditions for favorable antihypertensive responses in resistant hypertension are unclear. Because inappropriately high plasma levels of aldosterone are prevalent in these patients, we investigated the effects of baroreflex activation and surgical renal denervation in dogs with hypertension induced by chronic infusion of aldosterone (12 μg/kg per day). Under control conditions, basal values for mean arterial pressure and plasma norepinephrine concentration were 100±3 mm Hg and 134±26 pg/mL, respectively. By day 7 of baroreflex activation, plasma norepinephrine was reduced by ≈40% and arterial pressure by 16±2 mm Hg. All values returned to control levels during the recovery period. Arterial pressure increased to 122±5 mm Hg concomitant with a rise in plasma aldosterone concentration from 4.3±0.4 to 70.0±6.4 ng/dL after 14 days of aldosterone infusion, with no significant effect on plasma norepinephrine. After 7 days of baroreflex activation at control stimulation parameters, the reduction in plasma norepinephrine was similar but the fall in arterial pressure (7±1 mm Hg) was diminished (≈55%) during aldosterone hypertension when compared with control conditions. Despite sustained suppression of sympathetic activity, baroreflex activation did not have central actions to inhibit either the stimulation of vasopressin secretion or drinking induced by increased plasma osmolality during chronic aldosterone infusion. Finally, renal denervation did not attenuate aldosterone hypertension. These findings suggest that aldosterone excess may portend diminished blood pressure lowering to global and especially renal-specific sympathoinhibition during device-based therapy., (© 2015 American Heart Association, Inc.)

Objectives: The objective of this clinical trial was to assess the safety and efficacy of carotid BAT in advanced HF., Background: Increased sympathetic and decreased parasympathetic activity contribute to heart failure (HF) symptoms and disease progression. Baroreflex activation therapy (BAT) results in centrally mediated reduction of sympathetic outflow and increased parasympathetic activity., Methods: Patients with New York Heart Association (NYHA) functional class III HF and ejection fractions ≤35% on chronic stable guideline-directed medical therapy (GDMT) were enrolled at 45 centers in the United States, Canada, and Europe. They were randomly assigned to receive ongoing GDMT alone (control group) or ongoing GDMT plus BAT (treatment group) for 6 months. The primary safety end point was system- and procedure-related major adverse neurological and cardiovascular events. The primary efficacy end points were changes in NYHA functional class, quality-of-life score, and 6-minute hall walk distance., Results: One hundred forty-six patients were randomized, 70 to control and 76 to treatment. The major adverse neurological and cardiovascular event-free rate was 97.2% (lower 95% confidence bound 91.4%). Patients assigned to BAT, compared with control group patients, experienced improvements in the distance walked in 6 min (59.6 ± 14 m vs. 1.5 ± 13.2 m; p = 0.004), quality-of-life score (-17.4 ± 2.8 points vs. 2.1 ± 3.1 points; p < 0.001), and NYHA functional class ranking (p = 0.002 for change in distribution). BAT significantly reduced N-terminal pro-brain natriuretic peptide (p = 0.02) and was associated with a trend toward fewer days hospitalized for HF (p = 0.08)., Conclusions: BAT is safe and improves functional status, quality of life, exercise capacity, N-terminal pro-brain natriuretic peptide, and possibly the burden of heart failure hospitalizations in patients with GDMT-treated NYHA functional class III HF. (Barostim Neo System in the Treatment of Heart Failure; NCT01471860; Barostim HOPE4HF [Hope for Heart Failure] Study; NCT01720160)., (Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Unlabelled: Previous trials have shown that in patients with resistant hypertension device-based baroreflex activation therapy (BAT) can substantially reduce blood pressure. However, the fact that electrodes had to be implanted bilaterally may be a drawback for further development of the technique. In this study, we explored whether unilateral stimulation would produce comparable results as bilateral stimulation. In the Pivotal trial, treatment-resistant hypertensive patients were randomized to receive either immediate BAT or deferred BAT, that is, 6 months after implantation. We adjusted stimulation parameters individually so as to provide optimal baroreflex activation. Unilateral stimulation was applied unless bilateral stimulation resulted in a greater blood pressure reduction. When we pooled the 6-month data for the group with immediate BAT and the 12-month data for the group with deferred BAT, a total of 215 patients had been stimulated on one side only (127 at the right side and 88 at the left side), whereas 80 patients had been stimulated bilaterally. Although blood pressure and heart rate did not differ between the 2 groups at baseline, all these variables were significantly lower in the unilateral than in the bilateral group after the 6-month period. When we compared the effect of right-sided stimulation with those of either left-sided or bilateral stimulation, we found right-sided stimulation to be the most effective. We conclude that unilateral and in particular right-sided BAT has a more profound effect on blood pressure than bilateral or left-sided BAT., Clinical Trial Registration Url: http://www.clinicaltrials.gov. Unique identifier: NCT00442286., (© 2014 American Heart Association, Inc.)

Chronic electric activation of the carotid baroreflex produces sustained reductions in sympathetic activity and arterial pressure and is currently being evaluated as antihypertensive therapy for patients with resistant hypertension. However, the influence of variations in salt intake on blood pressure lowering during baroreflex activation (BA) has not yet been determined. As the sensitivity of arterial pressure to salt intake is linked to the responsiveness of renin secretion, we determined steady-state levels of arterial pressure and neurohormonal responses in 6 dogs on low, normal, and high salt intakes (5, 40, 450 mmol/d, respectively) under control conditions and during a 7-day constant level of BA. Under control conditions, there was no difference in mean arterial pressure at low (92±1) and normal (92±2 mm Hg) sodium intakes, but pressure increased 9±2 mm Hg during high salt. Plasma renin activity (2.01±0.23, 0.93±0.20, 0.01±0.01 ng angiotensin I/mL/h) and plasma aldosterone (10.3±1.9, 3.5±0.5, 1.7±0.1 ng/dL) were inversely related to salt intake, whereas there were no changes in plasma norepinephrine. Although mean arterial pressure (19-22 mm Hg) and norepinephrine (20%-40%) were lower at all salt intakes during BA, neither the changes in pressure nor the absolute values for plasma renin activity or aldosterone in response to salt were different from control conditions. These findings demonstrate that suppression of sympathetic activity by BA lowers arterial pressure without increasing renin release and indicate that changes in sympathetic activity are not primary mediators of the effect of salt on renin secretion. Consequently, blood pressure lowering during BA is independent of salt intake., (© 2014 American Heart Association, Inc.)

Several features of cardiovascular devices raise considerations for clinical trial conduct. Prospective, randomized, controlled trials remain the highest quality evidence for safety and effectiveness assessments, but, for instance, blinding may be challenging. In order to avoid bias and not confound data interpretation, the use of objective endpoints and blinding patients, study staff, core labs, and clinical endpoint committees to treatment assignment are helpful approaches. Anticipation of potential bias should be considered and planned for prospectively in a cardiovascular device trial. Prospective, single-arm studies (often referred to as registry studies) can provide additional data in some cases. They are subject to selection bias even when carefully designed; thus, they are generally not acceptable as the sole basis for pre-market approval of high risk cardiovascular devices. However, they complement the evidence base and fill the gaps unanswered by randomized trials. Registry studies present device safety and effectiveness in day-to-day clinical practice settings and detect rare adverse events in the post-market period. No single research design will be appropriate for every cardiovascular device or target patient population. The type of trial, appropriate control group, and optimal length of follow-up will depend on the specific device, its potential clinical benefits, the target patient population and the existence (or lack) of effective therapies, and its anticipated risks. Continued efforts on the part of investigators, the device industry, and government regulators are needed to reach the optimal approach for evaluating the safety and performance of innovative devices for the treatment of cardiovascular disease., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

We intended to determine if acute baroreflex activation therapy (BAT) increases venous capacitance and aortic conductance. BAT is effective in resistant hypertension, but its effect on the systemic vasculature is poorly understood. Left ventricular (LV) and aortic pressures and subdiaphragmatic aortic and caval flows (ultrasonic) were measured in six anesthetized dogs. Changes in abdominal blood volume (Vabdominal) were estimated as the integrated difference in abdominal aortic inflow and caval outflow. An electrode was implanted on the right carotid sinus. Data were measured during control and BAT. Next, sodium nitroprusside (SNP) was infused and BAT was subsequently added. Finally, angiotensin II (ANG II) was infused, and three increased BAT currents were added. We found that BAT decreased mean aortic pressure (PAo) by 22.5 ± 1.3 mmHg (P < 0.001) and increased aortic conductance by 16.2 ± 4.9% (P < 0.01) and Vabdominal at a rate of 2.2 ± 0.6 ml·kg(-1)·min(-1) (P < 0.01). SNP decreased PAo by 17.4 ± 0.7 mmHg (P < 0.001) and increased Vabdominal at a rate of 2.2 ± 0.7 ml·kg(-1)·min(-1) (P < 0.05). During the SNP infusion, BAT decreased PAo further, by 26.0 ± 2.1 mmHg (P < 0.001). ANG II increased PAo by 40.4 ± 3.5 mmHg (P = 0.001). When an increased BAT current was added, PAo decreased to baseline (P < 0.01) while aortic conductance increased from 62.3 ± 5.2% to 80.2 ± 3.3% (P < 0.05) of control. Vabdominal increased at a rate of 1.8 ± 0.9 ml·kg(-1)·min(-1) (P < 0.01), reversing the ANG II effects. In conclusion, BAT increases arterial conductance, decreases PAo, and increases venous capacitance even in the presence of powerful vasoactive drugs. Increasing venous capacitance may be an important effect of BAT in hypertension., (Copyright © 2014 the American Physiological Society.)

Aims: The Neo™ System (CVRx) is an implantable device, CE certified for the treatment of resistant hypertension and investigationally used to treat systolic heart failure by electrical stimulation of the carotid baroreceptors. It is unknown whether interaction might exist between the Neo System and implantable cardioverter-defibrillators (ICDs)., Methods and Results: Compatibility of the Neo device was tested in seven consecutive patients with pre-existing ICDs. Intra- and post-operative testing was completed with ICD and Neo settings programmed to provoke interaction. Intracardiac electrograms were printed to determine interaction with the ICD. Interaction testing during implantation and follow-up showed that there was no device-device interaction. No interaction was observed at maximum atrial and ventricular sensitivity settings and maximum Neo output settings., Conclusion: Combined therapy with the Neo device and at least in this study reported that transvenous ICD systems can be performed safely., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2014. For permissions please email: journals.permissions@oup.com.)

Heart failure with preserved ejection fraction (HFpEF) is a substantial public health issue, equal in magnitude to heart failure with reduced ejection fraction. Clinical outcomes of HFpEF patients are generally poor, related annual accrual of health care expenses amount to billions of dollars, and no therapy has been shown to be effective in randomized clinical trials. Baroreflex activation therapy (BAT) produced by stimulating the carotid sinuses using an implanted device (Rheos) is being studied for the treatment of hypertension, the primary comorbidity of HFpEF. Other potential benefits include regression of left ventricular hypertrophy, normalization of the sympathovagal balance, inhibition of the renin-angiotensin-aldosterone system, arterio- and venodilation, and preservation of renal function. This paper reviews the evidence suggesting that BAT may be a promising therapy for HFpEF and introduces the HOPE4HF trial (ClinicalTrials.gov Identifier: NCT00957073), a randomized outcomes trial designed to evaluate the clinical safety and efficacy of BAT in the HFpEF population., (Copyright © 2011 Elsevier Inc. All rights reserved.)

We investigated the effects of the carotid sinus baroreflex on coupling of the left ventricle (LV) and the arterial system in twelve anesthetized dogs, with all nerves and carotid sinus circulation intact and instrumented to measure LV pressure and volume. The Rheos(R) device was used to directly electrically stimulate the carotid sinus baroreceptors. Stimulation resulted in a significant reduction in systolic blood pressure (SBP), 95.6+/-8.1 to 77.3+/-5.3 mmHg (p<0.0001) and heart rate (HR), 85+/-13.2 to 67.2+/-18.8 (p<.001). Cardiac output was unchanged. Ventricular-vascular coupling was determined by the ratio of arterial and ventricular elastance (Ea/Ees). At baseline, Ea/Ees was 1.26+/-0.27 and after stimulation decreased to 0.51+/-0.16 (p<0.001), favoring optimization of metabolic efficiency. This decrease was entirely due to a reduction in Ea while Ees was unchanged. The maintenance of end-diastolic volume (EDV) during stimulation allowed stroke work (SW) to remain unchanged as arterial pressure decreased. Thus mechanical efficiency, described as the ratio of stroke work to pressure-volume area (SW/PVA) increased from baseline of 0.51+/-0.05 to 0.69+/-0.04 (p<0.0001) during baroreceptor stimulation. We conclude that electrical activation of the carotid sinus baroreceptors results in optimization of both energetic and mechanical efficiency and has no acute effect on LV Ees. These novel findings await confirmation in chronically instrumented animals.

The baroreflex, whose role is well-known in short-term blood pressure regulation, has until recently been unexploited as a practical therapy for hypertension. Recent advancements in approach and technology embodied in the Rheos System have enabled chronic electrical activation of the baroreflex. Chronic results from feasibility studies indicate that Rheos Therapy has an acceptable safety profile and may lead to long-term control of pressure in drug-resistant hypertension patients. Other effects include significant reductions in left ventricular mass and left atrial size. The spectrum of therapeutic impact suggests that Rheos Therapy may improve long-term outcomes in drug-resistant hypertension and possibly benefit related populations. Larger-scale study in randomized, controlled trials are ongoing to verify chronic benefits.