Medical Policies - Therapy


Baroreflex Stimulation Devices

Number:THE801.034

Effective Date:10-15-2018

Coverage:

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Use of baroreflex stimulation implanted devices is considered experimental, investigational and/or unproven in all situations, including but not limited to, treatment of hypertension and heart failure.

Description:

Baroreflex stimulation devices provide electrical stimulation of the baroreceptors in the carotid arteries using an implanted device. Activation of the baroreflex inhibits the sympathetic nervous system, resulting in various physiologic changes, including slowed heart rate and lower blood pressure. A device for baroreflex stimulation has been developed, but has not received U.S. Food and Drug Administration (FDA) approval other than a humanitarian device exemption (HDE) for patients who had previously participated in a clinical trial.

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 (BP). 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 and can lead to high costs and adverse effects. As a result, there is a large unmet need for additional treatments.

One device is approved for sale in Europe for hypertension and heart failure patients. This second-generation system consists of a unilateral electrode and lead attached to the carotid sinus and a pulse generator implanted subcutaneously in the chest wall. Programming is performed using radiofrequency telemetry with an external laptop computer and software. The first-generation system had bilateral leads attached to each carotid sinus and a larger pulse generator.

Regulatory Status

In 2014, the Barostim neo® Legacy System (CVRx) received a HDE from the 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) and heart failure patients.

In 2015, CVRx received expedited access pathway designation from the FDA for Barostim Therapy® to treat heart failure. (2) This pathway designation does not guarantee that an application to the FDA will ultimately be approved.

Rationale:

This medical policy was created in July 2011 and has been updated periodically with searches of the MEDLINE database. The most recent literature update was performed through March 6, 2018.

Medical policies 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.

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.

Hypertension

The Rheos pivotal RCT evaluated the efficacy of baroreflex stimulation for lowering BP. (3) This double-blind trial reported by Bisognano et al. (2011), 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) 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 end points were the percentage of patients achieving at least 10 mm Hg decrease in SBP at the 6-month time point (acute efficacy) and the percentage of patients who maintained their BP response over the 6- to 12-month time 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 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 end point, 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 end point of 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 end point 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%.

Patients who actively participated in the Rheos pivotal trial were followed after 12 months, and additional data were reported in a 2012 extension trial by Bakris et al. (2012). (4) 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 a responder 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. (5-8) The largest of these, the DEBut-HT trial, was a multicenter, single-arm feasibility study of the Rheos baroreflex activation therapy system reported by Scheffers et al. (2010). (7) This study enrolled 45 subjects, with treatment-resistant hypertension defined as a BP of greater than 160/90 mm Hg, despite treatment with at least 3 antihypertensive drugs, including a diuretic. The planned follow-up period 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=0.04). In 26 patients followed for 1 year, the declines in office BP were 30 mm Hg systolic (p<0.001) and 20 mm Hg diastolic (p<0.001). For ambulatory BP (n=15), the 1-year declines were 13 mm Hg systolic (p<0.001) and 8 mm Hg diastolic (p=0.001). A total of 7 (16.7%) of 42 patients experienced adverse events. Three patients required device removal due to infection; one experienced perioperative stroke; one experienced tongue paresis due to hypoglossal nerve injury; one had postoperative pulmonary edema; and another required reintervention for device explantation.

A single-arm study using the second-generation Neo device to treat uncontrolled hypertension was published by Wallbach et al. (2016). (8) 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, 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 end points. 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 end points (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.

Heart Failure

One RCT has evaluated baroreflex stimulation for the treatment of heart failure. This trial, reported by Abraham et al. (2015), was nonblinded and included 146 patients with New York Heart Association (NYHA) class III heart failure and an ejection fraction of 35% or less despite guideline-directed medical therapy. (9) Patients were randomized to receive 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 neurological and cardiovascular events. The trialists specified 3 primary efficacy end points: changes in NYHA functional class, quality of life (QOL) 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 a 1 level in NYHA functional class than in the control group (24%; p<0.002). Mean QOL 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<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.).

Twelve-month results for 101 (69%) of 146 patients were reported by Weaver et al. (2016). (10) 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, QOL 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.

Another RCT evaluating baroreflex stimulation for heart failure is underway (see Table 1). The Baroreflex Activation Therapy for Heart Failure Clinical Trial (BeAT-HF), which has a stated completion date of 2021, will have a much larger sample size (estimated enrollment, 800) than the Abraham trial and will assess cardiovascular mortality and heart failure morbidity as well as safety, functional, and QOL outcomes. This trial is being conducted as part of the data plan for Food and Drug Administration approval under an expedited access pathway designation.

Section Summary: Heart Failure

One RCT has compared baroreflex stimulation plus medical therapy with medical therapy alone in patients with heart failure. This RCT found a low rate of major adverse events and met all 3 efficacy end points (improvements in NYHA functional class, QOL, 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. A second RCT, with a much larger sample size that will assess mortality rates, is underway.

Summary of Evidence

For individuals with treatment-resistant hypertension who receive baroreflex stimulation therapy, the evidence includes 1 randomized controlled trial (RCT) and several small uncontrolled trials. Relevant outcomes are overall survival, 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 end points but not others as well as 2 of its 3 predefined safety end points. Additional RCTs are needed to permit conclusions on the efficacy and safety. In addition, baroreflex stimulation currently has a very narrow U.S. Food and Drug Administration (FDA) approval (i.e., for patients who previously participated in a pivotal trial) and broader approval or clearance is needed for wider application. 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 an RCT. Relevant outcomes are overall survival, functional outcomes, quality of life, hospitalizations, medication use, and treatment-resistant morbidity. The RCT met all 3 efficacy end points but had methodologic limitations, including lack of blinding, a relatively small sample size for a common condition, and a relatively 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. In addition, the only baroreflex stimulation device with humanitarian device exemption approval currently has only a very narrow FDA approval (i.e., for patients who previously participated in a pivotal trial) and broader approval or clearance is needed for wider application. The evidence is insufficient to determine the effects of the technology on health outcomes.

Practice Guidelines and Position Statements

National Institute for Health and Care Excellence

In 2015, National Institute for Health and Care Excellence 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.” (11)

Ongoing and Unpublished Clinical Trials

Some currently unpublished trials that might influence this review are listed in Table 1.

Table 1. Summary of Key Trials

NCT Number

Trial Name

Planned Enrollment

Completion Date

Ongoing

NCT01679132a

CVRx Barostim Hypertension Pivotal Trial

310

Sept 2020 (suspended)

NCT01720160a

Barostim HOPE4HF Study

98

Jan 2021

NCT02627196a

Barostim Therapy for Heart Failure (BeAT-HF)

800

Apr 2021

Unpublished

NCT01471860a

Neo Randomized Heart Failure Study

94

May 2015 (completed)

NCT: national clinical trial.

a Denotes industry-sponsored or cosponsored trial.

Contract:

Each benefit plan, summary plan description or contract defines which services are covered, which services are excluded, and which services are subject to dollar caps or other limitations, conditions or exclusions. Members and their providers have the responsibility for consulting the member's benefit plan, summary plan description or contract to determine if there are any exclusions or other benefit limitations applicable to this service or supply. If there is a discrepancy between a Medical Policy and a member's benefit plan, summary plan description or contract, the benefit plan, summary plan description or contract will govern.

Coding:

CODING:

Disclaimer for coding information on Medical Policies

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.

The presence or absence of procedure, service, supply, device or diagnosis codes in a Medical Policy document has no relevance for determination of benefit coverage for members or reimbursement for providers. Only the written coverage position in a medical policy should be used for such determinations.

Benefit coverage determinations based on written Medical Policy coverage positions must include review of the member’s benefit contract or Summary Plan Description (SPD) for defined coverage vs. non-coverage, benefit exclusions, and benefit limitations such as dollar or duration caps.

CPT/HCPCS/ICD-9/ICD-10 Codes

The following codes may be applicable to this Medical policy and may not be all inclusive.

CPT Codes

0266T, 0267T, 0268T, 0269T, 0270T, 0271T, 0272T, 0273T

HCPCS Codes

None

ICD-9 Diagnosis Codes

Refer to the ICD-9-CM manual

ICD-9 Procedure Codes

Refer to the ICD-9-CM manual

ICD-10 Diagnosis Codes

Refer to the ICD-10-CM manual

ICD-10 Procedure Codes

Refer to the ICD-10-CM manual


Medicare Coverage:

The information contained in this section is for informational purposes only. HCSC makes no representation as to the accuracy of this information. It is not to be used for claims adjudication for HCSC Plans.

The Centers for Medicare and Medicaid Services (CMS) does not have a national Medicare coverage position. Coverage may be subject to local carrier discretion.

A national coverage position for Medicare may have been developed since this medical policy document was written. See Medicare's National Coverage at <http://www.cms.hhs.gov>.

References:

1. Food and Drug Administration. Humanitarian Device Exemption (HDE): Barostim Neo Legacy System. 2014. Available at: <https://www.accessdata.fda.gov> (accessed April 11, 2018).

2. CVRx. CVRx® Announces Expedited Access Pathway Designation by FDA for Barostim Therapy® for the Treatment of Heart Failure in Order to Accelerate Access for US Patients. 2015. Available at: <http://www.cvrx.com> (accessed April 11, 2018).

3. 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 9 2011; 58(7):765-773. PMID 21816315

4. 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):152-158. PMID 22341199

5. 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):619-626. PMID 20101001

6. 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. Jun 11 2012; 6(4):270-276. PMID 22694986

7. 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 5 2010; 56(15):1254-1258. PMID 20883933

8. 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):701-709. PMID 26902491

9. 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

10. 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

11. National Institute for Clinical and Care Excellence (NICE). Implanting a baroreceptor stimulation device for resistant hypertension [IPG533]. 2015. Available at: <https://www.nice.org.uk> (accessed April 11, 2018).

12. Baroreflex Stimulation Devices. Chicago, Illinois: Blue Cross Blue Shield Association Medical Policy Reference Manual (2018 May) Therapy 8.01.57.

Policy History:

Date Reason
10/15/2018 Document updated with literature review. The following change was made to Coverage: 1) modified examples of experimental, investigational and/or unproven indications to include heart failure. Added references: 1-2, 8, 10-11.
8/15/2017 Reviewed. No changes.
8/15/2016 Document updated with literature review. Coverage unchanged.
10/1/2015 Reviewed. No changes.
6/15/2014 Document updated with literature review. Coverage revised to note that the use of baroreflex stimulation devices is considered experimental, investigational and/or unproven for all indications including but not limited to: related conditions associated with high sympathetic tone. Title changed from: Baroreflex Activation Therapy (BAT) for the Treatment of Drug-Resistant Hypertension.
7/1/2011 New medical document. Baroreflex Activation Therapy (BAT) ® for the treatment of drug-resistant hypertension, using any carotid sinus stimulation device (e.g. Rheos Baroreflex Hypertension Therapy System®), is considered experimental, investigational and unproven.

Archived Document(s):

Title:Effective Date:End Date:
Baroreflex Stimulation Devices08-15-201710-14-2018
Baroreflex Stimulation Devices08-15-201608-14-2017
Baroreflex Stimulation Devices10-01-201508-14-2016
Baroreflex Stimulation Devices06-15-201409-30-2015
Baroreflex Activation Therapy (BAT) for the Treatment of Drug-Resistant Hypertension07-01-201106-14-2014
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