Sacubitril/valsartan improves the prognosis of acute myocardial infarction: a meta-analysis

Abstract

Objective

To systematically evaluate the effect of sacubitril/valsartan (SV) on the prognosis of patients with acute myocardial infarction (AMI), and to provide evidence for expanding the clinical application of SV.

Methods

PubMed, EMbase, Web of Science, and Cochrane Library were searched from inception to October 2023 for randomized controlled trials (RCTs) of SV in patients with AMI. The article was screened and evaluated by the Cochrane 5.1.0 bias risk assessment tool. RevMan5.3 was used for meta-analysis of the outcome indicators.

Results

Ten RCTs involving 7230 patients were included. The results showed that SV increased left ventricular eject fraction (MD = 2.86, 95% CI [1.81–3.90], P < 0.00001) and reduced readmission rate (RR = 0.46, 95% CI [0.32–0.68], P < 0.0001), decreased N-terminal pro-brain natriuretic peptide (MD = −477.46, 95% CI [−914.96 to −39.96], P = 0.03), and reduced major adverse cardiovascular and cerebrovascular event (MACCE) (RR = 0.48, 95% CI [0.27–0.85], P = 0.01). There was no significant difference in the rate of adverse reaction (AR) between the trial group and the control group (RR = 0.88, 95% CI [0.60–1.30], P = 0.52).

Conclusion

SV can effectively improve the prognosis of AMI, prevent complications, and there is no significant difference in safety compared with angiotensin-converting enzyme inhibitor/angiotensin receptor blocker.

Introduction

Acute myocardial infarction (AMI) is the most serious cardiovascular disease, and ST-segment elevation myocardial infarction (STEMI) is the most dangerous type of myocardial infarction, with high incidence of complications and mortality, and poor prognosis [1]. Previous studies have confirmed that left ventricular remodeling caused by STEMI is clearly associated with an increased risk of cardiovascular adverse events [2,3]. Sacubitril/valsartan (SV) is an angiotensin receptor neuropeptide inhibitor (ARNI), which consists of the angiotensin receptor blocker (ARB) valsartan and the neuropeptide inhibitor precursor sacubitril in a 1:1 ratio. In PARADIGM-HF, compared with enalapril, SV reduced the risk of composite primary outcomes of cardiovascular death or hospitalization due to heart failure (HF) by 20%. Therefore, SV has become a new cornerstone for the treatment of HF with reduced ejection fraction [4]. Several studies have shown that early application of SV can effectively and safely inhibit ventricular remodeling in animal models of myocardial infarction [5,6]. However, there is still controversy over the long-term benefits of SV in patients with AMI. Therefore, a large number of clinical trials are currently being conducted, and some research results have been achieved.This study summarizes the latest research evidence for systematic evaluation, providing evidence-based evidence for the clinical application of SV.

Proposed methods

Search strategy

The computer searched PubMed, EMbase, Web of Science, and Cochrane Library, using the following English search terms: AMI, ST Elevation Myocardial Infarction, Non-ST Elevation Myocardial Infarction, LCZ696, Entresto, SV, randomized controlled trial (RCT), randomized, etc. The search time was from the establishment of the database to October 2023.

Inclusion criteria

The inclusion criteria were as follows: (1) patients diagnosed with AMI; (2) RCTs; (3) at least one of the following outcomes was compared between the experimental group and the control group: left ventricular eject fraction (LVEF), N-terminal pro-brain natriuretic peptide (NT-proBNP), readmission rate, major adverse cardiovascular and cerebrovascular event (MACCE), and adverse reaction (AR); (4) English-language literature with complete data.

Exclusion criteria

The exclusion criteria were as follows: (1) Incompatibility between research objectives and themes; (2) inability to obtain full text or duplicate reports; (3) animal experiments, duplicate reports, reviews, experience summaries, and literature research.

Data extraction

The following information was extracted from the included studies: first author name, sample size, gender, age, and intervention measures. The primary endpoints were efficacy (including LVEF, NT-proBNP, and readmission rate), and the secondary endpoints were safety (including MACCE and AR).

Quality assessment

We used the Cochrane 5.1.0 risk of bias tool to assess the quality of included studies [7], and the risk of bias for each study was classified as high, low, or unclear. We resolved any disagreements through consensus.

Statistical analyses

RevMan 5.3 software was used for meta-analysis. The odds ratio (RR) was used as the summary statistic for count data meta-analysis, and the mean difference (MD) was used as the summary statistic for measurement data meta-analysis. The heterogeneity size was tested using P and I². When I² < 50% and P > 0.1, it was considered that there was little statistical heterogeneity between studies, and the fixed-effect model was used for analysis; otherwise, the random-effect model was selected. Sensitivity analysis was performed by removing each literature one by one in RevMan 5.3 software for analysis, and the publication bias was judged by drawing a funnel plot.

Results

Literature search and selection

A total of 129 articles were initially retrieved. The information on the articles was imported into the EndNote X9.1 software, and after duplicate checking and screening, 10 articles were finally included [8–17]. The screening process and results of the articles are shown in Fig. 1.

Fig. 1.

Flowchart of study selection process.

Basic characteristics of included studies

A total of 7230 patients were included in the study, including 3636 in the experimental group and 3594 in the control group. The basic characteristics of the included literature are shown in Table 1.

Table 1.

Basic characteristics of the included articles

Author (year)	Disease	Sample size		Sample size		Age		Intervention		Outcomes
		E	C	E(M/F)	E(M/F)	E	C	E	C
M.A.PfefferB 2021 [8]	STEMI/NSTEMI	2830	2831	2167/663	2131/700	64.0 ± 11.6	63.5 ± 11.4	SV	ACEI	④
Amil M. Shah 2022 [9]	STEMI	279	265	201/78	201/64	65.0 ± 11.9	62.3 ± 11.2	SV	ACEI	①
Yi Zhang 2020 [10]	STEMI	79	77	59/20	55/22	60.3 ± 11.7	60.0 ± 10.9	SV	ACEI	①②③⑤
Pei Yang 2023 [11]	STEMI	85	63	75/10	57/6	59.07 ± 11.532	59.92 ± 12.019	SV	ACEI	①④
Hai Fan 2023 [12]	STEMI/NSTEMI	39	39	28/11	31/8	71.33 ± 10.52	68.00 ± 11.45	PCI+SV	PCI+ARB	①③
Guiping Wang 2023 [13]	AMI	60	60	36/24	33/27	≥64(31) <64(29)	≥64(34) <64(26)	SV	ACEI	②④
Guoli Lin 2022 [14]	Acute anterior wall STEMI	55	54	49/6	47/7	61.38 ± 12.31	59.74 ± 11.53	SV	ARB	①②③
Mahmoud Abdelnabi 2023 [15]	STEMI	96	96	64/32	63/33	58 ± 11.7	58 ± 11.3	SV	ARB	①⑤
Mahmoud Abdelnabi 2021 [16]	STEMI	45	40	30/15	29/11	58 ± 11.6	59.6 ± 11.6	SV	ARB	①⑤
Haiyan Wang 2020 [17]	AAMI	68	69	52/16	54/15	59.13 ± 7.15	60.56 ± 7.62	SV	ACEI	①③④

① LVEF: left ventricular ejection fraction; ② readmission rate; ③ NT-proBNP, N-terminal pro-brain natriuretic peptide; ④ AR, adverse reaction; ⑤ MACCE, major adverse cardiovascular and cerebrovascular event.

AAMI, acute anterior wall myocardial infarction; ACEI, angiotensin-converting enzyme inhibitor; AMI, acute myocardial infarction; ARB, angiotensin receptor blocker; C, control; E, experimental; NSTEMI, non-ST-segment elevation myocardial infarction; PCI, percutaneous coronary intervention; STEMI, ST-segment elevation myocardial infarction; SV, sacubitril/valsartan.

Risk of bias

The methodological quality of the studies included in this analysis was assessed using RevMan 5.3. Among the 10 studies analyzed, 8 studies [9–16] were described as randomized, 1 study [8] was randomized double-blind, and 1 study [17] was randomized using envelope method. The risk assessment of bias included in the study is shown in Figs. 2 and 3.

Fig. 2.

Summary of risk bias in articles.

Fig. 3.

Proportion of articles with risk bias.

Efficacy of SV in improving the prognosis of AMI

The LVEF, NT-proBNP, and readmission rate after treatment were combined between the experimental group and the control group to evaluate the efficacy of SV in improving the prognosis of AMI. The comprehensive results showed that patients in the SV group showed significantly better efficacy, as evidenced by increased LVEF (MD: 2.86, 95% CI: 1.81–3.90, P < 0.00001; I²: 54%, P = 0.03) (Fig. 4) and reduced readmission rate (RR: 0.46, 95% CI: 0.32–0.68, P < 0.0001; I²: 0%, P = 0.73) (Fig. 5) and decreased NT-proBNP (MD: −477.46, 95% CI: −914.96 to −39.96, P = 0.03; I²: 99%, P < 0.00001) (Fig. 6). Subgroup analysis of LVEF showed that the use of SV in STEMI patients had a statistically significant effect on the increase of LVEF(MD: 2.12, 95% CI: 0.53–3.72, P = 0.009; I²: 60%, P = 0.03) (Fig. 7)

Fig. 4.

Meta-analysis results of LVEF.

Fig. 5.

Results of meta-analysis of readmission rate.

Fig. 6.

Results of meta-analysis of NT-proBNP.

Fig. 7.

Subgroup analysis results of LVEF.

Safety of SV for AMI

The comparison of the incidence of MACCE and AR between the two groups evaluated the safety of SV treatment for AMI. The summary results showed that the incidence of MACCE in the SV group was significantly lower (RR: 0.48, 95% CI: 0.27–0.85, P = 0.01; I²: 0%, P = 0.84) (Fig. 8). At the same time, there was no significant difference in the incidence of AR between the two groups (RR: 0.88, 95% CI: 0.60–1.30, P = 0.52; I²: 57%, P = 0.07) (Fig. 9).

Fig. 8.

Results of meta-analysis of MACCE.

Fig. 9.

Results of meta-analysis of incidence of AR.

Sensitivity analysis and publication bias

Sensitivity analysis was conducted on LVEF, readmission rate, and NT-proBNP. The results of LVEF and readmission rate were stable, and the included studies did not significantly affect the overall results. The results of NT-proBNP were unstable, which may be due to the presence of comorbidities in the included patients.

A funnel plot was drawn for the LVEF outcome indicator to test for publication bias. The results showed that the left and right sides of the funnel plot were not completely symmetrical, indicating a possible publication bias, as shown in Fig. 10.

Fig. 10.

Risk of bias assessment.

Discussion

Since the clinical application of PCI, the incidence of complications in AMI has dropped to less than 1%, resulting in a decrease in mortality, but the burden remains high [18].For STEMI patients, PCI can quickly achieve revascularization of occluded coronary arteries, reduce the infarct size, and save the patient's life, but HF is prone to occur after PCI, which significantly increases the risk of death [19,20]. Research indicates that in patients with STEMI, the overactivation of the renin-angiotensin-aldosterone system (RAAS) causes myocardial hypertrophy, fibroblast proliferation and differentiation, leading to ventricular remodeling, which in turn induces HF [8].HF is not only the most common complication of STEMI but also one of the most important indicators of poor prognosis [21]. According to the guidelines and consensus, all patients with AMI should be treated with beta-blockers or ACEI/ARB as soon as possible without contraindications [22,23], ACEI/ARB have significant benefits in reducing cardiovascular mortality, preventing HF, and improving the prognosis of myocardial infarction. In recent years, SV have gradually shown their superiority over ACEI drugs in anti-ventricular remodeling [24].In 2019, the European Society of Cardiology Heart Failure Association expert consensus recommended that SV be used as an alternative to ACEI/ARB to reduce the risk of hospitalization and mortality in patients with HF with reduced ejection fraction. For patients hospitalized with new-onset HF or decompensated chronic HF, it is considered appropriate to start using SV instead of ACEI/ARB to reduce the short-term risk of adverse events [25].SV is a newly developed anti-HF drug in the cardiovascular field. After oral administration, it quickly decomposes into enkephalase inhibitor and valsartan, which not only inhibits RAAS, but also inhibits enkephalase, enhances the activity of natriuretic peptide, and fights against adverse effects caused by RAAS system (such as sodium retention and vasoconstriction). At the same time, Sacubitril can reduce myocardial cell death Based on the mechanism of hypertrophy and impaired myocardial cell contractility, SV have significant benefits in improving cardiac contractile and diastolic function [26]. Research has found that LVEF is an independent predictor of all-cause mortality in patients with AMI, suggesting that LVEF is closely related to the prognosis of patients [27]. A meta-analysis study has shown that elevated NT-proBNP levels are independently associated with increased all-cause mortality and MACE risk, and can be used as a promising biomarker for risk classification in patients with AMI [28].The results of this study showed that the SV group had statistical significance (P < 0.05) compared to the ACEI/ARB group in increasing LVEF, reducing NT -proBNP, reducing readmission rate, and reducing MACCE, Subgroup analysis showed that the use of SV in patients with STEMI had a statistically significant effect on increasing LVEF (P < 0.05). This indicates that SV can effectively improve ventricular remodeling, reduce the incidence of conscientious cerebrovascular events, lower readmission rates, and improve patient prognosis and quality of life. A total of four studies observed AR, mainly including hypotension, cough, hyperkalemia, and allergic reactions. There was no significant difference in the AR rate between the two groups (P > 0.05), suggesting that SV is safe for use in AMI.

This study has the following limitations: (1) only one study was randomized double-blind trial, and nine studies had unclear allocation concealment, and the overall quality of the literature was not high; (2) some outcome indicators were highly heterogeneous, and the heterogeneity may be due to the inclusion of comorbidities, which requires further research; (3) the sample size included was small, and its efficacy may be overestimated.

Conclusion

In summary, SV can effectively improve the prognosis of AMI, prevent complications, and has good safety. In the future, more high-quality RCT studies on the application of SV in AMI should be conducted to provide evidence-based evidence for expanding clinical indications.

Acknowledgements

Conflicts of interest

There are no conflicts of interest.