The efficacy of baroreflex activation therapy for heart failure: A meta-analysis of randomized controlled trials.

INTRODUCTION: The efficacy of baroreflex activation therapy for heart failure is elusive. This meta-analysis aims to evaluate the impact of baroreflex activation therapy on treatment efficacy of heart failure.
METHODS: Several databases including PubMed, EMbase, Web of science, EBSCO, and Cochrane library databases have been searched, and we include randomized controlled trials (RCTs) regarding the efficacy of baroreflex activation therapy for patients with heart failure.
RESULTS: This meta-analysis includes 4 RCTs. Baroreflex activation therapy shows significantly positive impact on the quality of life score (standard mean difference SMD = -4.61; 95% confidence interval CI = -6.24 to -2.98; P < .00001), 6-minute hall walk (6MHW) distance (SMD = 2.83; 95% CI = 1.44- 4.22; P < .0001), New York Heart Association (NYHA) Class (SMD = -3.23; 95% CI = -4.76 to -1.69; P < .0001), N-terminal pro-brain natriuretic peptide (NT-proBNP) (SMD = -1.24; 95% CI = -1.58 to -0.89; P < .00001) and the duration of hospitalization (SMD = -1.65; 95% CI = -2.90 to -0.39; P = .01) compared with control group for heart failure, but has no obvious effect on left ventricular ejection fraction (LVEF) (SMD = 1.43; 95% CI = -0.15-3.01; P = .08), or the number of hospitalization per year (SMD = -1.17; 95% CI = -2.56-0.22; P = .10).
CONCLUSIONS: Baroreflex activation therapy can improve the treatment efficacy for heart failure.

Introduction

Patients with heart failure have increased sympathetic tone, decreased parasympathetic tone and relatively low sensitivity to inhibitory baroreflex.[ These imbalances result in vasoconstriction, activation of renin-angiotensin-aldosterone system and cardiac remodeling.[ Many ischemic and non-ischemic factors can lead to heart failure with reduced ejection fraction. The classifications of ischemic or non-ischemic cardiomyopathy are associated with prognostic implications, the selection of device-based therapies and therapeutic response.[

Baroreflex activation therapy is defined as an electrical stimulation technology delivered by an implanted device, and results in centrally mediated reduction of sympathetic outflow and increased parasympathetic activity via stimulating the carotid baroreceptor. Subsequently, arterial and venous compliance is increased and peripheral resistance is reduced.[ Baroreflex activation therapy can lead to the reduction of −30% in sympathetic nerve activity.[ In 1 RCT involving heart failure, the results revealed that the rate of neurological and cardiovascular event-free rate was up to 97.2% after baroreflex activation therapy.[

In addition, baroreflex activation therapy was reported to result in the decrease in New York Heart Association (NYHA) Class ranking and N-terminal pro-brain natriuretic peptide (NT-proBNP), the increase in 6-minute hall walk (6MHW) distance for heart failure patients.[ However, the efficacy of baroreflex activation therapy for heart failure is not clear, and the results of several studies are conflicting.[ This meta-analysis is performed to evaluate the efficacy of baroreflex activation therapy for heart failure.

Materials and methods

This meta-analysis did not require ethical approval and patient consent, because it was the secondary analysis of previously published studies based on the guidance of PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses).[

Search strategy and study selection

Several databases including PubMed, EMbase, Web of science, EBSCO, and Cochrane library databases were searched from inception to September 2018. The electronic search strategy was conducted using the following keywords: “baroreflex activation” and “heart failure”. The inclusive selection criteria included:

patients were diagnosed with heart failure;

intervention treatments were medical and device therapy plus baroreflex activation therapy versus medical and device therapy;

study design was RCT.

Data extraction and outcome measures

Some information (e.g., the number of patients, age, female, body mass index and detail methods) was extracted. Two investigators independently extracted these data, and discrepancies were resolved by consensus. The primary outcome was the quality of life score. Secondary outcomes included 6MHW distance, NYHA Class, NT-proBNP, left ventricular ejection fraction (LVEF), the number of hospitalization per year and the duration of hospitalization.

Quality assessment in individual studies

We assessed the methodological quality of each study by the modified Jadad scale, which consisted of 3 items: randomization (0–2 points), blinding (0–2 points), dropouts and withdrawals (0–1 points).[ The total score of Jadad Scale ranged from 0 to 5 points. The study had high quality if the Jadad score≥3, while the study with Jadad score <2 was thought to have low quality.[

Statistical analysis

The standard mean difference (SMD) with 95% confidence interval (CI) was calculated for all continuous outcomes. We used the random-effects model regardless of heterogeneity. I2 value more than 50% indicated significant heterogeneity.[ The heterogeneity was detected through omitting 1 study in turn or performing subgroup analysis. All statistical analyses were conducted by Review Manager Version 5.3 (The Cochrane Collaboration, Software Update, Oxford, UK).

Results

Literature search, study characteristics and quality assessment

Figure 1 demonstrated the search and selection results. We initially searched for 444 potentially articles and 4 RCTs were finally included in this meta-analysis.[

Figure 1

Flow diagram of study searching and selection process.

Table 1 showed the baseline characteristics of 4 eligible RCTs. The 4 studies were published between 2015 and 2018, and total 566 patients were involved. These studies included heart failure patients with coronary artery disease[ or cardiac resynchronization therapy (CRT).[ When performing the meta-analysis, Halfbach 2018

Table 1

Characteristics of included studies.

No.	Author	Group	Number	Age (years)	Female (n)	Body mass index (kg/m2)	NYHA: class III	Group	Number	Age (years)	Female (n)	Body mass index (kg/m2)	NYHA: class III	Jada scores
1	Halbach 2018	CAD	101	67 ± 10	11	29 ± 5	101	No-CAD	39	60 ± 13	9	28 ± 6	38	5
2	Weaver 2016	baroreflex activation	76	–	–	–	–	control	70	–	–	–	–	4
3	Zile 2015	CRT	45	68 ± 9	4	29 ± 4	45	No-CRT	95	63 ± 12	16	29 ± 5	94	5
4	Abraham 2015	baroreflex activation	71	64 ± 11	9	–	–	control	69	66 ± 12	11	–	–	4

represented patients with coronary artery disease, while Halfbach 2018

represented patients without coronary artery disease.

Zile 2015

represented patients with CRT, while Zile 2015

represented patients without CRT.

These may result in some heterogeneity.

Among the 4 studies included here, 4 studies reported the quality of life score and 6MHW distance,[ 2 studies reported NYHA Class,[ 3 studies reported NT-proBNP,[ and 2 studies reported LVEF, the number of hospitalization per year and the duration of hospitalization.[ Jadad scores of the included RCTs ranged from 3 to 5, and thus they were all considered to have high-quality.

Primary outcome: the quality of life score

Compared to control group for heart failure, baroreflex activation therapy resulted in significantly reduced quality of life score (SMD = −4.61; 95% CI = −6.24 to −2.98; P < .00001) with significant heterogeneity among the studies (I2 = 95%, heterogeneity P < .00001) (Fig. 2).

Figure 2

Forest plot for the meta-analysis of the quality of life score.

Sensitivity analysis

Significant heterogeneity was observed for the quality of life score. However, significant heterogeneity still remained when conducting sensitivity analysis via omitting 1 study in turn.

Secondary outcomes

In comparison with control group for heart failure, baroreflex activation therapy was associated with remarkably improved 6MHW distance (SMD = 2.83; 95% CI = 1.44–4.22; P < .0001; Fig. 3), decreased NYHA Class (SMD = −3.23; 95% CI = −4.76 to −1.69; P < .0001; Fig. 4) and NT-proBNP (SMD = −1.24; 95% CI = −1.58 to −0.89; P < .00001; Fig. 5), but showed no obvious impact on LVEF (SMD = 1.43; 95% CI = −0.15–3.01; P = .08; Fig. 6) or the number of hospitalization per year (SMD = −1.17; 95% CI = −2.56–0.22; P = .10; Fig. 7). In addition, the duration of hospitalization in baroreflex activation therapy was obviously shorter than that in control intervention (SMD = −1.65; 95% CI = −2.90 to −0.39; P = .01; Fig. 8).

Figure 3

Forest plot for the meta-analysis of 6MHW distance.

Figure 4

Forest plot for the meta-analysis of NYHA Class.

Figure 5

Forest plot for the meta-analysis of NT-proBNP.

Figure 6

Forest plot for the meta-analysis of LVEF.

Figure 7

Forest plot for the meta-analysis of the number of hospitalization per year.

Figure 8

Forest plot for the meta-analysis of the duration of hospitalization.

Discussion

Patients with cardiovascular diseases commonly suffer from the dysregulation of autonomic function.[ Pharmacologic therapies have been described to improve the outcomes and quality of life in patients with cardiovascular disease via addressing autonomic dysfunction. Furthermore, implantable defibrillators and resynchronization devices have been developed to treat heart failure patients with reduced ejection fraction. Several implantable devices such as baroreflex activation therapy were documented to significantly improve ejection fraction, functional capacity and quality of life for heart failure patients.[

Our meta-analysis suggests that compared to control intervention for heart failure, baroreflex activation therapy has a significantly favorable influence on the quality of life score, 6MHW distance, NYHA Class, NT-proBNP and the duration of hospitalization, but shows no obvious influence on LVEF or the number of hospitalization per year. These indicate that baroreflex activation therapy substantially benefits to improve exercise capacity and the quality of life for these patients, and should be recommended in clinical work. Patients with heart failure symptoms and disease progression have increased sympathetic and decreased parasympathetic activity. Baroreflex activation therapy is capable to induce centrally mediated reduction of sympathetic outflow and increase parasympathetic activity. The baroreflex pathway has been used for various medical and device therapies.[

Patients with ischemic cardiomyopathy are characterized by reduced contractility because of the scar formation and hibernation of myocardium.[ Furthermore, the impairment of reperfused myocardium may result in adverse remodeling and the reduction in global systolic function.[ Non-ischemic dilated cardiomyopathy can be caused by many factors.[ Different responses to treatments are observed between ischemic cardiomyopathy and non-ischemic cardiomyopathy.[ For instance, device-based therapies such as CRT have better ability to reverse left ventricular remodeling in non-ischemic patients than that in ischemic patients.[

Regarding the sensitivity analysis, there is significant heterogeneity. Different patient populations may account for this significant heterogeneity. Firstly, 1 included RCT revealed that the improved outcomes were more pronounced in patients without CRT than those patients with CRT.[ Secondly, etiology-dependent responses to therapies was crucial for the outcomes, and baroreflex sensitivity was reported to be lower in patients with coronary artery diseases than those patients without coronary lesions.[ In addition, baroreflex activation therapy showed similar efficacy in heart failure patients with and without coronary artery disease.[

The overall rate of major adverse neurological and cardiovascular events is 2.8% after baroreflex activation therapy.[ The complication rate of baroreflex activation therapy is 10% in hypertensive patients.[ In non-CRT patients, baroreflex activation therapy results in significant increase in pulse pressure possibly due to reduced vascular resistance and improved stroke volume. In contrast, this baroreflex activation therapy-induced effect on pulse pressure and systolic pressure is not observed in CRT patients.[ Interaction testing has found that baroreflex activation therapy is compatible with pacemakers and implantable cardioverter defibrillator.[ There is no statistical difference of safety profile between the CRT and no-CRT patients.[ This meta-analysis has several limitations. Firstly, only 4 RCTs are included in this meta-analysis, and more RCTs with large sample size should be conducted to explore this issue. Next, there is significant heterogeneity, which may be caused by different causes and severity of heart function. Finally, some unpublished data may lead to some bias for the pooled results.

Conclusions

Baroreflex activation therapy is effective to alleviate heart failure.

Author contributions

Conceptualization: Guoqiang Cai, Dongyin Zhang.

Formal analysis: Guoqiang Cai, Dongyin Zhang.

Investigation: Kai Guo.

Methodology: Kai Guo.

Supervision: Kai Guo, Shu Qin.

Writing – original draft: Shu Qin.

Writing – review & editing: Shu Qin.