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Effect of Sacubitril/Valsartan on Reducing the Risk of Arrhythmia: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Background and Objective Relevant data of PARADIGM-HF reveals sacubitril/valsartan (SV) therapy led to a greater reduction in the risks of arrhythmia, and sudden cardiac death than angiotensin converting enzyme inhibitor (ACEI)/angiotensin receptor inhibitor (ARB) therapy in HFrEF, however, inconsistent results were reported in subsequent studies. Here, we conduct a meta-analysis of related randomized controlled trials (RCTs) to evaluate the protective effect of SV on reducing the risk of arrhythmias. Methods and Results RCTs focused on the difference in therapeutic outcomes between SV and ACEI/ARB were searched from PUBMED, EMBASE, ClinicalTrials.gov, and Cochrane Library. The results were extracted from each individual study, expressed as binary risk, 95% confidence interval (CI) and relative risk (RR). Sixteen RCTs including 22, 563 patients met the study criteria. Compared with ACEI/ARB therapy, SV therapy did significantly reduce in the risks of severe arrhythmias among patients with heart failure with reduced ejection fraction (HFrEF) (RR 0.83, 95% CI 0.73–0.95, p = 0.006), ventricular tachycardia (VT) among patients with HFrEF (RR 0.69, 95% CI 0.51–0.92, p = 0.01), cardiac arrest among patients with heart failure (HF) (RR 0.52, 95% CI 0.37–0.73, p = 0.0002), cardiac arrest among patients with HFrEF (RR 0.49, 95% CI 0.32–0.76, p = 0.001), cardiac arrest or ventricular fibrillation (VF) among patients with HF (RR 0.63, 95% CI 0.48–0.83, p = 0.001), and cardiac arrest or VF among patients with HFrEF (RR 0.65, 95% CI 0.47–0.89, p = 0.008), but reduced the risks of arrhythmias (RR 0.87, 95% CI 0.74–1.01, p = 0.07), atrial arrhythmias (RR 0.98, 95% CI 0.83–1.16, p = 0.85), and atrial fibrillation (RR 0.98, 95% CI 0.82–1.17, p = 0.82) among all patients with no significant between-group difference. The merged result was robust after sensitivity analysis, and there was no publication bias. Conclusion Our meta-analysis provides evidence that, compared with ACEI/ARB, SV can additionally reduce the risks of most arrhythmias, just the significant differences are revealed in reducing the risks of VT, severe arrhythmias, and cardiac arrest in patients with HFrEF. Besides, the positive effect of SV on VF according to statistical result of combining VF with cardiac arrest in patients with HFrEF is credibility.

Background and Objective: Relevant data of PARADIGM-HF reveals sacubitril/valsartan (SV) therapy led to a greater reduction in the risks of arrhythmia, and sudden cardiac death than angiotensin converting enzyme inhibitor (ACEI)/angiotensin receptor inhibitor (ARB) therapy in HFrEF, however, inconsistent results were reported in subsequent studies. Here, we conduct a meta-analysis of related randomized controlled trials (RCTs) to evaluate the protective effect of SV on reducing the risk of arrhythmias.

INTRODUCTION
Arrhythmia is one of the most common diseases in cardiovascular field, which has complex relationships with multiple diseases (1), especially heart failure (HF). Destruction of normal periodicity and regularity of the electrical activity in heart has been recognized as the mechanism of arrhythmia. Atrial fibrillation (AF) and ventricular arrhythmia (VA) are common and serious in patients with HF, which can cause various complications and ultimately lead to disability or death, such as thrombus caused by AF, sudden cardiac death (SCD) caused by sustained ventricular tachycardia (VT) or ventricular fibrillation (VF), etc. (2). The risk of AF has increased 3-fold in the world over the past 50 years based on the results of Framingham Heart Study (3), and the global prevalence of AF was about 46.3 million in 2016 according to the estimate of WHO (4). AF is the most common persistent arrhythmia with an average prevalence of 25% in HF (5), which can increase the risks of stroke and death (6). Sustained VA is a serious complication of HF, as it accounts for 75-80% of SCD, while about 30-50% of cardiovascular death in patients with HF was attributed to SCD (7). Arrhythmia is a challenging problem especially under the circumstance of HF, as their mutual interaction could further aggravating the state of an illness. Therefore, received widespread attention in terms of prevention, diagnosis, and treatment of arrhythmia. At present, a part of arrhythmias can be cured by new technologies with the wider application of interventional and surgical therapy (8), nevertheless, drug therapy is still currently the most important mean of the prevention and treatment of arrhythmias due to economic, scope of application of new technologies, etc.
The data of PARADIGM-HF prompted that sacubitril/valsartan (SV) therapy led to a greater reduction in the risk of SCD and significant survival benefit of SCD observed from the Kaplan-Meier curves than enalapril therapy among patients with heart failure with reduced ejection fraction (HFrEF), indicating SV may directly reduce the risk of SCD (9). Since then, the effect of SV on arrhythmia has attracted widespread concern. The effect of SV in arrhythmia is uncertain although it has been fully affirmed in HF and hypertension (10,11). The researches of Russo et al. (12), Tsai et al. (13), and Curtain et al. (14) revealed that SV could improve ventricular remodeling while reducing the risk of VA compared with angiotensin converting enzyme inhibitor (ACEI)/angiotensin receptor inhibitor (ARB), meanwhile, it could improve atrial remodeling and atrial arrhythmia by the researches of Suo et al. (15) and Li et al. (16). Nevertheless, different results on arrhythmias were reported by El-Battrawy et al. Thus far, few specifically studies about the effect of SV on arrhythmia have been investigated. The purpose of this metaanalysis is to provide some new approaches for the treatment of arrhythmia by analyzing the risks of arrhythmias in randomized controlled trials (RCTs) for SV.

Search Strategy
We searched the Cochrane Library, Embase, PubMed and ClinicalTrials.gov, the current four major medical databases, which contain the vast majority of medical research literatures, as of February 21, 2022, and it was re-run twice on March 3, 2022. The search conditions include: sacubitril valsartan, sacubitril/valsartan, sacubitril, entresto, LCZ696, AHU377, angiotensin receptor neprilysin inhibitor, neprilysin inhibitor, sacubitril valsartan sodium hydrate, sacubitril valsartan drug combination. There was no protocol for expected registration, but the search terms, inclusion criteria, and data collection forms were pre-specified in the analysis plan and remain unchanged during data collection and analysis. The publication date and language restrictions were not applied, and reference lists of related articles were also used to supplement search terms. The study included only RCT.

Study Selection
The trials included in this study need to meet the following conditions: (1) The trial is an RCT. (2) The control group is intervened with ACEI/ARB, the experimental group is intervened with SV. (3) All studies must have data on adverse events endpoint or adverse reaction of arrhythmias.

Data Extraction
The two researchers independently extracted data from RCTs that met the criteria and Cochrane reviewer's handbook. In the event of discrepancies, all authors discussed the results. The research data was retrieved from the original published manuscript or the results in ClinicalTrials.gov. Extracted the following data from each trial: 1. Name of the trial, author, registration number; 2. year of publication; 3. number of people enrolled; 4. characteristics of participants at baseline, including arrhythmia, age, gender, etc.; 5. drug in control group; 6. study duration; 7. main outcome.

Quality Assessment
Two researchers separately assessed the risk of bias for each qualified trial by the Cochrane Collaboration's tool and compiled a bias risk table as described in Cochrane Handbook (21). The quality items used to evaluate each study were as follows: sequence generation of allocation, allocation concealment, blinding of participants, blinding of outcome assessment, incomplete outcome data, selective outcome reporting, and other biases.

Outcome Measures
The number of arrhythmias listed in results of trials, including atrial arrhythmia, AF, VA, etc.

Statistical Analyses
Data of arrhythmias was analyzed by Review Manager 5.4, sensitivity analysis and publication bias detection by Stata 17.0, and I 2 was used to assess heterogeneity. I 2 ≥ 50% or the corresponding P-value (p < 0.05) was considered to have obvious heterogeneity results and then we used a random model. I 2 < 50% and the corresponding P-value (p > 0.05) was considered to have no obvious heterogeneity results and then we used a fixed model (22). The results were extracted from each trial, expressed as binary risk, 95% confidence interval (CI), and relative risk (RR). The Mantel-Haenszel method and Z test were used to determine the overall results to determine the significance of RR. The heterogeneity was assessed with the

Publication Bias and Sensitivity Analysis
Publication bias was judged using funnel plot, Begg and Berlin (24), and Egger's test (25), P < 0.05 was considered statistically significant.

Description of Selected Studies
A total of 1, 564 possible articles or studies were initially identified, and 446 possible articles were left after filtered repeated research by endnote. The remaining articles were judged by the two researchers according to criteria, final 16 RCTs were included for analysis. The flow chart is shown in Figure 1.

Quality Assessment
The quality assessment for the included studies is presented in Figures 2, 3. Randomization assignment was conducted using computer-generated random numbers in a majority of the trials and prespecified outcomes were reported by all trials. Individual studies did not specifically describe the methods used to hide and allocate sequences. Overall, the included studies are of high quality.

Sensitivity Analysis and Publication Bias
Any single study excluded would not affected the significance of our combined effect size for either outcome by sensitivity analysis (Figure 9). No obvious publication bias was found in the visual inspection of funnel plots (Figure 10), Egger's test (Figure 11) for OS with a p-value of 0.225 and Begg's Test (Figure 12) for OS with a p-value of 0.822 also proved it. Therefore, we could conclude that all the included studies have no obvious publication bias and the result is stable.

Major Findings
Compared with ACEI/ARB therapy, SV therapy did significantly reduce in the risks of severe arrhythmias, VT and cardiac arrest among patients with HFrEF, and cardiac arrest among patients with HF by 17, 31, 51, and 48%, respectively, and the reductions in the risks of arrhythmias, severe arrhythmias, atrial arrhythmias, AF and VAs among patients with HF were 13, 19, 22, and 13%, respectively with no significant betweengroup difference. Although the specific relationship between the data of cardiac arrest and VF in this meta-analysis cannot be determined, considering that the main cause of cardiac arrest is VF, we combined the data for statistical analysis, and the results revealed that SV therapy did significantly reduce in reducing the risks of cardiac arrest or VF among patients with HF, HFrEF by 37 and 35%, respectively compared with ACEI/ARB therapy. Therefore, we consider that SV therapy did significantly reduce in the risks of cardiac arrest in patients with HF, mainly HFrEF, compared with ACEI/ARB therapy. Similarly, we can speculate about the superior role of SV therapy in reducing the use of implantable cardioverter-defibrillator from SV therapy led to a reduction in the risks of VT, VF, and cardiac arrest or VF compared with ACEI/ARB therapy in HFrEF. Further research is needed to confirm these speculations. Overall, the results of our meta-analysis revealed that SV therapy in specific groups are effective and provided superior arrhythmias reduction than ACEI/ARB therapy.

Mechanisms
Cardiovascular disease mainly leads to the activation of the neuroendocrine system, including sympathetic nervous system (SNS), renin-angiotensin-aldosterone system (RAAS), and vasoactive peptides (mainly natriuretic peptides) (40). Despite the initial functional response, chronic SNS and RAAS activation increases cardiac afterload, which increasing myocardial oxygen consumption and leading to deleterious proliferative remodeling effects (41). Natriuretic peptide system (NPs) mediates the activation of cyclic guanosine monophosphatedependent signaling pathways through corresponding receptors, resulting in vasodilation, natriuretic diuresis, and lowering of blood pressure (40). In addition, cardiac filling, preload, and ventricular remodeling are reduced by NPs and corresponding receptors through inhibiting endothelin secretion, and activation of RAAS and SNS. The effect of SV is mainly considered to enhance NPs and inhibit RAAS by inhibiting neprilysin, moreover, it has more effective dual inhibitory effect on the neuroendocrine system by combining with ARB. Furthermore, enhancing the NPs has favorable cardiovascular effects in HF and is an ideal complementary therapeutic target for RAAS and SNS blockade. Enkephalinase inhibitor (NEPI) in SV exerts natriuretic diuresis, dilates blood vessels, and reduces blood pressure by upregulating the levels of NPs, bradykinin, and adrenomedullin. Also, inhibition of sympathetic tone and RAAS can reduce aldosterone, myocardial fibrosis and hypertrophy, and ventricular remodeling. In addition to counteracting the  The mechanism of SV improving arrhythmia is not clear, which may be related to the treatment with SV provided superior cardiac remodeling (including structure and electrophysiology) and fibrosis (44) reduction than angiotensin inhibition, as cardiac remodeling can lead to increased susceptibility to arrhythmia and fibrosis, a well-recognized factor for malignant VA, is an important basis of cardiac remodelling (45,46). Besides, NPs regulation has affect on myocardial electrophysiological properties and anatomical substrate, which are major factors for the development of sustained VA. The inhibition of SV on SNS and RAAS may exert a direct effect on reducing the risk of arrhythmia in HF. SNS and RAAS are activated and the secretion of neurohormone is increased in HF, lead to arrhythmia by increasing myocardial automaticity, altering conductivity and refractory periods, constricting of blood vessels to alter cardiac load, and promoting ventricular remodeling together (47,48). In pre-clinical studies, SV improved the risk of persistent VA by reducing wall stress (49) and the activity of membrane ion channels, such as sodium channel NaV1.5 protein and potassium channel proteins, associated with VT/VF, which decrease trigger factors and perpetuating/maintaining the event of Vas (50). Moreover, demonstrated superiority of SV vs. ACEI/ARB in reducing VAs though improving potential systolic and diastolic function, calcium homeostasis and conduction delay, increased pacing threshold to induce arrhythmia, a decrease of action potential duration (APD) and the maximum slope of APD restitution by inhibiting the CaMK II pathway, and down-regulation of small-conductance Ca 2+activated potassium channel type 2 (44,51,52).

Findings Relevant to Other Studies
The post hoc study of PARADIGM-HF revealed that, compared with enalapril therapy, SV therapy did significantly reduce in reducing the risk of ventricular arrhythmia and the composite arrhythmia outcome in HFrEF (14). A retrospective analysis of 1-year telemonitoring in 151 SV-treated HFrEF patients with implantable cardioverter-defibrillator/cardiacresynchronization-therapy (18) revealed that SV treatment resulted in a reduction in mean VT/VF burden, non-sustained VT and treatments, which were associated with improved biventricular pacing and a higher degree of reverse remodeling. These results are consistent with our findings that SV therapy led to a greater reduction in the risks of VT/VF compared with ACEI/ARB therapy in HFrEF. The results of the PARADIGM-HF (9) revealed that SV had a direct effect on reducing the risk of SCD compared with enalapril, which is consistent with the findings of our study that SV therapy reduced the risk of cardiac arrest in HFrEF by 51% compared with ACEI/ARB therapy. SV therapy did not affect AF burden in the study of Martens (18), and the same is true of our study. Other than these, SV therapy could reduce the risk of severe arrhythmias by 17% in HFrEF compared with ACEI/ARB therapy. Above results are consistent with consistent with our findings, confirming the reliability of our results.

Thoughts on Difference of Therapy Effect
Our study finds that SV therapy is superior in reducing the risk of certain arrhythmias merely in HFrEF compared with ACEI/ARB therapy, which may be related to the different therapeutic effects of SV in different EF spectra (53,54). Although has been recommended for the treatment of HFpEF by guidelines, SV merely has a significant therapeutic advantage in morbidity among patients with HFrEF, which could be found in other large clinical trials, due to multi-factors. The pathophysiological heterogeneity within the broader clinical spectrum of HFpEF, which may represent a different progression or disease, lead to the effect of neurohormone antagonists on HFpEF is relatively weak compared with HFrEF (55). Moreover,   there is a significant correlation between the degree of systolic dysfunction and frequency of arrhythmias, mainly VAs, in HFrEF, and improvement in LVEF was associated with a significant reduction in VAs and mortality (56)(57)(58). However, as normal EF of HF, HFpEF may not have a similar phenomenon. Interestingly, arrhythmias mainly existed among patients with HF in trials included, of which atrial arrhythmias are more common than VAs, and VAs mainly came from patients with HFrEF, while atrial arrhythmias mainly came from patients with HFpEF.
From the phenomena, we could speculate that HFrEF is mainly related to ventricular remodeling, while HFpEF related to atrial remodeling, and SV therapy is more advantageous in improving ventricular remodeling. Besides, differences in atrial fibrillation prevalence at baseline may have contributed to this result. Above may be the major reasons of inconsistent results in our study. Besides, the different levels of indexes of echocardiography at baseline also lead to different results of arrhythmias, such as left atrial strain and atrial volume  are associated with AF (59), global longitudinal strain and mechanical dispersion are associated with VAs, etc. It is difficult to analyze the relation between indexes of echocardiography at baseline and results of arrhythmias in our study, because only EVALUATE-HF, PRIME, and Wang H provide the data of echocardiography, while few participants and inconsistent indexes are included in the trials.

Strength and Limitations
We conducted a reasonable search of the literature and carefully screened it using strict standards, and the study included a large sample size. This is a more comprehensive analysis of the effect of SV in reducing the risk of arrhythmia, which only includes RCTs. Most of the studies in this analysis are large multicenter clinical trials, so the quality of our meta-analysis is very high. Our study confirms the advantage of SV in reducing VT, VF and cardiac arrest. However, several possible deficiencies should be noted: arrhythmias were not the main objective of these trials, the observation period of individual studies were short, most studies did not mention the occurrence of arrhythmias at baseline, only 4 trials on patients with non-HF, and the types of diseases targeted are limited. In addition, another large clinical study PARADISE-MI (ClinicalTrials.gov ID: NCT02924727) cannot be included for its data on arrhythmia has not published.

CONCLUSION
This meta-analysis reveals that compared with ACEI/ARB therapy, SV therapy can reduce the risks of most arrhythmias, just the significant differences were revealed in reducing the risks of VT, severe arrhythmias, and cardiac arrest among patients with HFrEF. Besides, the positive effect of SV on VF according to statistical result of combining VF with cardiac arrest in patients with HFrEF is credibility. The result of our study provides more useful information for strengthening the clinical application of SV, especially among patients with high-risk factors for VT, VF, cardiac arrest, etc. By comparing with ACEI/ARB, we can infer that the additional antiarrhythmic effect of SV may originate from the increase of endogenous vasoactive peptides through inhibiting neprilysin. Of course, the exact mechanism and beneficiary population of SV therapy on arrhythmia need to be further clarified by further studies.

DATA AVAILABILITY STATEMENT
The original contributions presented in this study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding author/s.

ETHICS STATEMENT
All procedures strictly followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). All included studies were published without ethical and informed consent dispute.

AUTHOR CONTRIBUTIONS
RW, HY, JW, and LM contributed to the literature database search, data collection, data extraction, data analysis, and writing of the manuscript. RW, HY, JW, and YW performed data analysis of the results. XZ and LW were conceptualized the topic. XZ and LW reviewed and revised this article. All authors contributed to the article and approved the submitted version.

FUNDING
This study was supported by the Talent introduction funding project of the First Affiliated Hospital of Jinan University (no. 808026).