Background

Baroreceptors are pressure sensors contained within the walls of the carotid arteries. They are part of the autonomic nervous system that regulates basic physiologic functions such as heart rate and blood pressure. When these receptors are stretched, as occurs with increases in blood pressure, 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 blood pressure, thereby helping to maintain homeostasis of the circulatory system.

The use of baroreflex stimulation devices (also known as baroreflex activation therapy) is a potential alternative treatment for resistant hypertension and heart failure. Both hypertension and heart failure are relatively common conditions, and are initially treated with medications and lifestyle changes. A substantial portion of patients are unresponsive to conventional therapy and treating these patients is often challenging, expensive, and can lead to adverse events. As a result, there is a large unmet need for additional treatments.

Regulatory Status

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.^1,

In 2019, Barostim Neo™ was granted premarket approval (PMA P180050) and is indicated for the improvement of symptoms of heart failure – quality of life, six-minute hall walk and functional status, for patients who remain symptomatic despite treatment with guideline-directed medical therapy, are NYHA Class III or Class II (who had a recent history of Class III), have a left ventricular ejection fraction ≤ 35%, a NT-proBNP < 1600 pg/ml and excluding patients indicated for Cardiac Resynchronization Therapy (CRT) according to AHA/ACC/ESC guidelines.

It was the first device to be granted approval via the Expedited Access Pathway (EAP).^2,3, EAP will hasten the approval of novel therapies that target life-threatening conditions.

Related Policies

• Radiofrequency Ablation of the Renal Sympathetic Nerves as a Treatment for Resistant Hypertension (Policy #136 in the Surgery Section)

For members enrolled in a Fully Integrated Dual Eligible Special Needs Plan (FIDE-SNP): (1) to the extent the service is covered under the Medicare portion of the member’s benefit package, the above Medicare Coverage statement applies; and (2) to the extent the service is not covered under the Medicare portion of the member’s benefit package, the above Medicaid Coverage statement applies.

[RATIONALE: This policy was created in 2011 and has been updated regularly with searches of the PubMed database. The most recent literature update was performed through March 9, 2020.

Evidence reviews assess the clinical evidence to determine whether the use of a technology improves the net health outcome. Broadly defined, health outcomes are length of life, quality of life, and ability to function-including benefits and harms. Every clinical condition has specific outcomes that are important to patients and to managing the course of that condition. Validated outcome measures are necessary to ascertain whether a condition improves or worsens; and whether the magnitude of that change is clinically significant. The net health outcome is a balance of benefits and harms.

To assess whether the evidence is sufficient to draw conclusions about the net health outcome of a technology, 2 domains are examined: the relevance and the quality and credibility. To be relevant, studies must represent one or more intended clinical use of the technology in the intended population and compare an effective and appropriate alternative at a comparable intensity. For some conditions, the alternative will be supportive care or surveillance. The quality and credibility of the evidence depend on study design and conduct, minimizing bias and confounding that can generate incorrect findings. The randomized controlled trial (RCT) is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. RCTs are rarely large enough or long enough to capture less common adverse events and long-term effects. Other types of studies can be used for these purposes and to assess generalizability to broader clinical populations and settings of clinical practice.

Treatment Resistant Hypertension
Clinical Context and Therapy Purpose

The purpose of baroreflex stimulation devices is to provide a treatment option that is an alternative to or an improvement on existing therapies, such as medical therapy or other anti-hypertensive treatments (eg, radiofrequency ablation of renal sympathetic nerves), in patients with treatment-resistant hypertension.

The question addressed in this policy is: Does the use of baroreflex stimulation devices improve the net health outcome in individuals with treatment-resistant hypertension?

The following PICO was used to select literature to inform this policy.

Patients

The relevant population of interest is individuals with treatment-resistant hypertension.

Interventions

The therapy being considered is baroreflex stimulation (also known as baroreflex activation therapy [BAT]). Implanted devices provide electrical stimulation of the baroreceptors in the carotid arteries. Activating the baroreflex inhibits the sympathetic nervous system, causing various physiologic changes, including lowering blood pressure.

Patients with treatment-resistant hypertension are actively managed by cardiologists in an outpatient clinical setting; baroreflex stimulation devices would be implanted in an inpatient hospital setting.

Comparators

Comparators of interest include optimal medical therapy and other hypertension treatments (eg, radiofrequency ablation of renal sympathetic nerves).

Patients with treatment-resistant hypertension are actively managed by cardiologists in an outpatient clinical setting.

Outcomes

The general outcomes of interest are overall survival (OS), functional outcomes, quality of life, hospitalizations, medication use, and treatment-related morbidity.

Available literature has followed patients for up to 28 months, but in practice, patients with treatment-resistant hypertension would require long-term follow-up by cardiologists.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs.
• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
• Studies with duplicative or overlapping populations were excluded.

RCTs are important in determining the efficacy of baroreflex stimulation devices due to the natural variability in blood pressure (BP), the heterogeneity of the patient populations with high BP, and the presence of many potential outcome confounders. Case series have limited utility for determining efficacy. They can be useful for demonstrating potential of the technique, to determine the rate of short- and long-term adverse events of treatment, and to evaluate the durability of treatment response.

The Rheos^® pivotal RCT evaluated the efficacy of baroreflex stimulation for lowering BP.^4, Bisognano et al (2011) reported on this double-blind trial, which included patients with treatment-resistant hypertension defined as at least 1 systolic blood pressure (SBP) measurement of 160 mm Hg or more with diastolic blood pressure (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) showed a significant between-group difference. 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 events at 6 months (91.7% vs. 89.3%; P < 0.001 for noninferiority). The primary safety endpoint for device safety was also met, with 87.2% of patients free of device-related adverse events at 12 months, exceeding the predefined threshold of 72%.

Bakris et al (2012) reported on additional data in an extension of the Rheos trial.^5, 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. The extension study lacked a comparison group.

Several uncontrolled observational studies have also been published.^6,7,8,9, Scheffers et al (2010) reported on the largest of these, the Device Based Therapy in Hypertension Extension Trial (DEBuT-HT), which was a multicenter, single-arm feasibility study of the Rheos baroreflex activation therapy system.^8, This trial 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 (P< 0.001) and DBP was reduced by 12 mm Hg (P< 0.001). There was a smaller reduction in 24-hour ambulatory BP (n = 26), with a decrease of 6 mm Hg in SBP (P = 0.10) and a decrease of 4 mm Hg in DBP (P =.04). In 26 patients followed for 1 year, the declines in office BP were 30 mm Hg for systolic (P< 0.001) and 20 mm Hg for diastolic (P < 0.001). For ambulatory BP (n = 15), the 1-year declines were 13 mm Hg for systolic (P < 0.001) and 8 mm Hg 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 experienced perioperative stroke, 1 experienced tongue paresis due to hypoglossal nerve injury, 1 had postoperative pulmonary edema, and 1 required reintervention for device explantation.

Wallbach et al (2016) published a single-arm study using the second-generation Neo device to treat uncontrolled hypertension.^9, The study reported on 44 patients with resistant hypertension, defined as an office BP ≥ 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, mean office BP decreased to 151 mm Hg over 82 mm Hg (pre to post, P < 0.001). At 6 months, the mean number of BP medications used per patient decreased from 6.5 at baseline to 6.0 (P < 0.03). One procedure-related major adverse event occurred, a contralateral stroke. Ten (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.

Section Summary: Hypertension

One RCT has evaluated baroreflex stimulation devices. This trial, which compared the first-generation Rheos device plus medical management with medical management alone, met some but not all of its efficacy endpoints. 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). In addition, several uncontrolled studies have reported short-term reductions in blood pressure, together with adverse events such as infection, hypoglossal nerve injury, and wound complications. Additional RCTs, particularly those using the second-generation device, are needed to draw conclusions about safety and efficacy.

Treatment Resistant Heart Failure
Clinical Context and Therapy Purpose

The purpose of baroreflex stimulation devices is to provide a treatment option that is an alternative to or an improvement on existing therapies, such as medical therapy in patients with treatment-resistant heart failure.

The question addressed in this policy is: Does the use of baroreflex stimulation devices improve the net health outcome in individuals with treatment-resistant heart failure?

The following PICO was used to select literature to inform this policy.

Patients

The relevant population of interest is individuals with treatment-resistant heart failure.

Interventions

The therapy being considered is baroreflex stimulation. (also known as baroreflex activation therapy [BAT]). Implanted devices provide electrical stimulation of the baroreceptors in the carotid arteries. Activating the baroreflex inhibits the sympathetic nervous system, causing various physiologic changes, including lowering blood pressure.

Patients with treatment-resistant heart failure are actively managed by cardiologists in an outpatient clinical setting; baroreflex stimulation devices would be implanted in an inpatient hospital setting.

Comparators

Comparators of interest include optimal medical therapy, implantable devices, and transplantation.

Patients with treatment-resistant heart failure are actively managed by cardiologists in an outpatient clinical setting.

Outcomes

The general outcomes of interest are OS, functional outcomes, quality of life, hospitalizations, medication use, and treatment-related morbidity.

Available literature has followed patients for up to 12 months, but in practice, patients with treatment-resistant heart failure would be followed by cardiologists for the rest of their lives.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs.
• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
• Studies with duplicative or overlapping populations were excluded.

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 (see Regulatory section).^2, The safety and effectiveness data reviewed by the FDA was reported in the Barostim Neo-Baroreflex Activation Therapy for Heart Failure (BeAT-HF) trial.^3,

BeAT-HF examined 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) was compared at 6 months post-implant to GDMT alone using 3 intermediate end points: 6-minute hall walk distance (6MHW), Minnesota Living with Heart Failure Questionnaire, and N-terminal pro-B-type natriuretic peptide (NT-proBNP). 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, investigators randomized 264 intended use patients and the primary safety endpoint was major adverse neurological and cardiovascular event (MANCE) free rate (BAT + GDMT group only); the lower bound of the one-sided 95% CI of the MANCE-free rate had to be > 85%. Results analysts were blinded to arm assignment. At 6 months, the MANCE-free rate was 96.8% (121 of 125 patients), and the one-sided 95% lower bound was 92.8% (P <.001). Effective endpoint results are summarized in Table 1. 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 to BAT + GDMT over GDMT alone.

Table 1. 6-Month Change from Baseline for Effectiveness Endpoints in the BeAT-HF Expedited Phase Trial

	6MHWD		QOLa		NT-proBNP
	BAT + GDMT	GDMT	BAT + GDMT	GDMT	BAT + GDMT	GDMT
n	118	120	120	125	120	123
Mean (SD)	48.6 (66.3)	-7.9 (88.4)	-20.7 (25.4)	-6.2 (20.1)	-21.1% (0.4)	3.3% (0.3)
95% CI	36.5 to 60.7	-23.9 to 8.1	-25.3 to -16.1	-9.8 to -2.7	-32.3% to -8.2%	-8.9% to 17.2%
Difference	60.1		-14.1		-24.6%
95% CI	40.3 to 79.9		-19.2 to -8.9		-37.6% to -8.7%
P-value	<.001		<.001		.004

6MHWD: 6-minute hall walk distance; BAT: Barostim therapy; BeAT-HF: Barostim Neo-Baroreflex Activation Therapy for Heart Failure; CI: confidence interval; GDMT: guideline based medical treatment; NA: not applicable; QOL: quality of life; SD: standard deviation.
^a Measured by the Minnesota Living With Heart Failure Quality of Life questionnaire.

BeAT-HF includes an Extended Phase in which 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. This trial is ongoing.

Halbach et al (2018) published a post hoc subgroup analysis from a randomized trial evaluating BAT as a treatment for heart failure in comparing patients with and without coronary artery disease (CAD).^10, Patients (N = 146) from 45 centers with left ventricular ejection fraction (LVEF) < 35% and New York Heart Association (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 was 3.8% for the CAD group and 0% for CAD group (P >.99), while the system- or procedure-related complication rate was 11.5% for patients with CAD and 21.1% for those without CAD (P =.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 Class decreased by 0.6 ± 0.1 for CAD patients and by 0.4 ± 0.2 for no-CAD patients. 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 BAT (P >.05). The study was limited by its small sample size and by the subgroup analysis not being prespecified.

Abraham et al (2015) reported on one RCT 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 ≤ 35% despite guideline-directed medical therapy.^11, Patients were randomized to baroreflex stimulation (Barostim Neo System) plus medical therapy (n = 76) or to continued medical therapy alone (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 major adverse neurologic and cardiovascular events-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 <.002). Mean quality of life scores, as assessed by the Minnesota Living with Heart Failure Questionnaire, improved significantly more in the treatment group (–17.4 points) than in the control group (2.1 points; P <.001). Similarly, mean 6MWD improved significantly more in the treatment group (59.6 meters) than in the control group (1.5 meters; P =.004.).

Weaver et al (2016) reported 12-month results for 101 (69%) of 146 patients from this RCT.^12, 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 had a substantial amount of missing data.

Overall, the limitations of this RCT included a relatively small sample size for a common condition, relatively short intervention period, and 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. Additional RCTs with larger sample sizes and longer follow-up are needed to confirm these positive findings.

Section Summary: Heart Failure

The available evidence for BAT for heart failure includes two RCTs and a post hoc subgroup analysis of an RCT. All trials as compared baroreflex stimulation plus medical therapy with medical therapy alone in patients with heart failure. The 2019 RCT, the expedited trial that was used by the FDA to approve the Barostim Neo System, demonstrated that the system is safe and effective for its intended use population; however, the extended trial is still underway, and longer-term outcomes have not yet been determined. A 2018 RCT found a low rate of major adverse events and met all 3 efficacy endpoints (improvements in NYHA functional class, quality of life, and 6MWD). However, the study had methodologic limitations, including lack of blinding, a relatively small sample size for a common condition, and relatively short intervention period.

Summary of Evidence

For individuals who have treatment-resistant hypertension who receive baroreflex stimulation therapy, the evidence includes a randomized controlled trial (RCT) and several small uncontrolled studies. Relevant outcomes are overall survival (OS), functional outcomes, quality of life, hospitalizations, medication use, and treatment-resistant morbidity. The uncontrolled studies have reported short-term reductions in blood pressure in patients treated with baroreflex stimulation devices, as well as adverse events such as infection, hypoglossal nerve injury, and wound complications. The RCT comparing baroreflex stimulation with continued medical management met some efficacy endpoints but not others, as well as 2 of its 3 predefined safety endpoints. Additional RCTs are needed to permit conclusions on the efficacy and safety. Baroreflex stimulation for treatment-resistant hypertension is accessible only through a Humanitarian Device Exemption (HDE) for patients who previously participated in a pivotal trial). The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have treatment-resistant heart failure who receive baroreflex stimulation therapy, the evidence includes 2 RCTs and a post hoc subgroup analysis of an RCT. Relevant outcomes are overall survival, (OS) functional outcomes, quality of life, hospitalizations, medication use, and treatment-resistant morbidity. The expedited phase of the 2019 RCT was used by the U.S. Food and Drug Administration to approve the Barostim Neo System. The trial demonstrated that the system is safe and effective for its intended use population in the short term; however the extended trial is still underway, and longer-term outcomes have not been determined. A 2018 RCT met all 3 efficacy endpoints but had methodologic limitations, incomplete blinding, a relatively small sample size for a common condition, and a short intervention period. A second, larger, RCT designed to assess the effects of the intervention on mortality, safety, functional, and quality of life outcomes is underway. The evidence is insufficient to determine the effect of the technology on health outcomes.

SUPPLEMENTAL INFORMATION
Practice Guidelines and Position Statements
National Institute for Health and Care Excellence

In 2015, the National Institute for Health and Care Excellence (NICE) issued guidance that stated: "Current evidence on the safety and efficacy of implanting a baroreceptor stimulation device for resistant hypertension is inadequate. Therefore, this procedure should only be used in the context of research."^13,

U.S. Preventive Services Task Force Recommendations

Not applicable.

Ongoing and Unpublished Clinical Trials

Some currently unpublished trials that might influence this policy are listed in Table 2.

Table 2. Summary of Key Trials

NCT No.	Trial Name	Planned Enrollment	Completion Date
Ongoing
NCT01720160a	Barostim HOPE4HF Study	98	Mar 2021
NCT02627196a	Barostim Neo®-Baroreflex Activation Therapy® for Heart Failure (BeAT-HF)	800	Dec 2021
NCT03730519	Investigation of the Efficacy and Safety of Baroreflex Activation Therapy in Patients With Refractory Hypertension and Those With Highly Variable Blood Pressure Due to Peripheral Baroreflex Failure	25	June 2022
NCT01679132a	CVRx Barostim NEO Hypertension Pivotal Trial	310	Mar 2026

NCT: national clinical trial.
^a Denotes industry-sponsored or cosponsored trial.]
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Horizon BCBSNJ Medical Policy Development Process:

This Horizon BCBSNJ Medical Policy (the “Medical Policy”) has been developed by Horizon BCBSNJ’s Medical Policy Committee (the “Committee”) consistent with generally accepted standards of medical practice, and reflects Horizon BCBSNJ’s view of the subject health care services, supplies or procedures, and in what circumstances they are deemed to be medically necessary or experimental/ investigational in nature. This Medical Policy also considers whether and to what degree the subject health care services, supplies or procedures are clinically appropriate, in terms of type, frequency, extent, site and duration and if they are considered effective for the illnesses, injuries or diseases discussed. Where relevant, this Medical Policy considers whether the subject health care services, supplies or procedures are being requested primarily for the convenience of the covered person or the health care provider. It may also consider whether the services, supplies or procedures are more costly than an alternative service or sequence of services, supplies or procedures that are at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of the relevant illness, injury or disease. In reaching its conclusion regarding what it considers to be the generally accepted standards of medical practice, the Committee reviews and considers the following: all credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, physician and health care provider specialty society recommendations, the views of physicians and health care providers practicing in relevant clinical areas (including, but not limited to, the prevailing opinion within the appropriate specialty) and any other relevant factor as determined by applicable State and Federal laws and regulations.

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Index:
Baroreflex Stimulation Devices
Rheos Hypertension System
Carotid Baroreflex Stimulation
CVRx
Rheos System
Barostim neo

References:
1. Food and Drug Administration. Humanitarian Device Exemption (HDE): Barostim Neo Legacy System. 2014; https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfhde/hde.cfm?id=h130007. Accessed April 2, 2020.

2. Food and Drug Administration. Premarket Approval (PMA): Barostim Neo System. 16 Aug 2019; https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpma/pma.cfm?id=P180050. Accessed April 13, 2020.

3. Zile MR, Abraham WT, Lindenfeld J, et al. First granted example of novel FDA trial design under Expedited Access Pathway for premarket approval: BeAT-HF. Am Heart J. Oct 2018; 204: 139-150. PMID 30118942

4. Bisognano JD, Bakris G, Nadim MK, et al. Baroreflex activation therapy lowers blood pressure in patients with resistant hypertension: results from the double-blind, randomized, placebo-controlled rheos pivotal trial. J Am Coll Cardiol. Aug 09 2011; 58(7): 765-73. PMID 21816315

5. Bakris GL, Nadim MK, Haller H, et al. Baroreflex activation therapy provides durable benefit in patients with resistant hypertension: results of long-term follow-up in the Rheos Pivotal Trial. J Am Soc Hypertens. Mar-Apr 2012; 6(2): 152-8. PMID 22341199

6. Heusser K, Tank J, Engeli S, et al. Carotid baroreceptor stimulation, sympathetic activity, baroreflex function, and blood pressure in hypertensive patients. Hypertension. Mar 2010; 55(3): 619-26. PMID 20101001

7. Hoppe UC, Brandt MC, Wachter R, et al. Minimally invasive system for baroreflex activation therapy chronically lowers blood pressure with pacemaker-like safety profile: results from the Barostim neo trial. J Am Soc Hypertens. Jul-Aug 2012; 6(4): 270-6. PMID 22694986

8. Scheffers IJ, Kroon AA, Schmidli J, et al. Novel baroreflex activation therapy in resistant hypertension: results of a European multi-center feasibility study. J Am Coll Cardiol. Oct 05 2010; 56(15): 1254-8. PMID 20883933

9. Wallbach M, Lehnig LY, Schroer C, et al. Effects of Baroreflex Activation Therapy on Ambulatory Blood Pressure in Patients With Resistant Hypertension. Hypertension. Apr 2016; 67(4): 701-9. PMID 26902491

10. Halbach M, Abraham WT, Butter C, et al. Baroreflex activation therapy for the treatment of heart failure with reduced ejection fraction in patients with and without coronary artery disease. Int J Cardiol. Sep 01 2018; 266: 187-192. PMID 29705650

11. Abraham WT, Zile MR, Weaver FA, et al. Baroreflex Activation Therapy for the Treatment of Heart Failure With a Reduced Ejection Fraction. JACC Heart Fail. Jun 2015; 3(6): 487-496. PMID 25982108

12. Weaver FA, Abraham WT, Little WC, et al. Surgical Experience and Long-term Results of Baroreflex Activation Therapy for Heart Failure With Reduced Ejection Fraction. Semin Thorac Cardiovasc Surg. Summer 2016; 28(2): 320-328. PMID 28043438

13. National Institute for Clinical and Care Excellence (NICE). Implanting a baroreceptor stimulation device for resistant hypertension [IPG533]. 2015; https://www.nice.org.uk/guidance/ipg533. Accessed April 2, 2020.

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