Evaluating the effects of sacubitril/valsartan with ST-elevated myocardial infarction: a systematic review and meta-analysis

Abstract

Background:

ST-segment elevation myocardial infarction (STEMI) continues to be a leading cause of cardiovascular (CV) morbidity and mortality worldwide, posing an ongoing clinical and public health burden. Although angiotensin-converting enzyme inhibitors (ACEIs) remain integral to guideline-recommended therapy following STEMI, recent evidence indicates that sacubitril/valsartan may offer superior cardioprotective benefits. This meta-analysis aims to systematically evaluate and compare the efficacy and safety of sacubitril/valsartan versus ACEIs in the management of patients with STEMI.

Methods:

PubMed and Cochrane databases were systematically searched from inception to July 2024 to identify randomized controlled trials (RCTs) comparing sacubitril/valsartan and ACEIs in patients with STEMI. Data were synthesized using a random-effects model to calculate risk ratios (RRs) and weighted mean differences (WMDs), each with 95% confidence intervals (CIs). A P-value < 0.05 was considered statistically significant.

Results:

A total of five RCTs comprising 4915 participants were included in the final analysis. Sacubitril/valsartan therapy was associated with a significant reduction in major adverse cardiovascular events (MACE) [RR: 0.66 (0.50, 0.86); P = 0.002] and hospitalizations for heart failure (HHF) [RR: 0.67 (0.49, 0.92); P = 0.01]. Treatment with sacubitril/valsartan also significantly improved left ventricular ejection fraction (LVEF) [WMD: 2.60 (1.53, 3.68); P < 0.00001] and reduced NT-proB-type natriuretic peptide (NT-proBNP) levels (WMD: −268.89 [−422.35, −115.42]; P = 0.0006). No significant differences were observed in the risk of recurrent myocardial infarction [RR: 1.02 (0.39, 2.71); P = 0.96), CV death [RR: 0.78 (0.61, 1.01); P = 0.06], or all-cause mortality [RR: 0.85 (0.68, 1.06); P = 0.15]. Safety analyses revealed no significant differences in the risk of cough [RR: 0.63 (0.15, 2.72); P = 0.54], hypotension [RR: 1.68 (0.97, 2.91); P = 0.06], worsening renal function [RR: 0.51 (0.22, 1.21); P = 0.13], or hyperkalemia [RR: 0.59 (0.17, 2.01); P = 0.40].

Conclusion:

Sacubitril/valsartan therapy significantly reduces MACE and HHF and improves LVEF in patients with STEMI, without increasing the risk of adverse safety outcomes. Future well-powered randomized trials are needed to confirm these results and support clinical guideline recommendations.

Introduction

Despite advances in therapeutic strategies and a decline in incidence and hospitalization rates, ST-segment elevation myocardial infarction (STEMI) remains a significant global health burden, with approximately 750 000 cases reported annually in the United States and substantial associated morbidity and mortality[1]. Approximately 38% of patients hospitalized with acute coronary syndrome present with STEMI[2]. Inhibition of the renin–angiotensin system is a key component of guideline-directed medical therapy for acute myocardial infarction (AMI). Both the European Society of Cardiology (ESC) and the American Heart Association (AHA)/American College of Cardiology guidelines provide a Class I recommendation for the use of angiotensin-converting enzyme inhibitors (ACEIs) in the management of STEMI[3]. ACEIs have long been established as standard of care after AMI, supported by landmark trials such as the SAVE, CONSENSUS, and VALIANT studies^[4–6^]. More recently, sacubitril/valsartan, an angiotensin receptor–neprilysin inhibitor, has emerged as a promising therapeutic option. Sacubitril/valsartan combines neprilysin inhibition, which augments beneficial vasoactive peptides, with angiotensin II type 1 receptor blockade, thereby counteracting neurohormonal activation and promoting vasodilation, natriuresis, and anti-remodeling effects. It prevents degradation of natriuretic peptides, bradykinin, and adrenomedullin, thereby promoting vasodilation, natriuresis, and anti-remodeling effects. Valsartan selectively blocks angiotensin II type-1 receptors, attenuating vasoconstriction, sodium retention, and maladaptive remodeling^[6,7^].

Recent evidence suggests that sacubitril/valsartan may offer superior therapeutic benefits compared to ACEIs in the treatment of STEMI. Although current guidelines recommend sacubitril/valsartan as a cornerstone in heart failure management, their role in STEMI remains uncertain[6]. Prior meta-analyses have evaluated sacubitril/valsartan in post–AMI populations that included both patients with STEMI and non-STEMI (NSTEMI)^[8,9^]. However, STEMI represents a distinct subgroup characterized by complete coronary occlusion, higher thrombotic burden, and greater risk of adverse ventricular remodeling. Whether sacubitril/valsartan offers incremental benefit over ACEIs, specifically in patients with STEMI remains uncertain. Optimal timing of initiation has not been clearly defined. While prior AMI-focused meta-analyses pooled patients with STEMI and NSTEMI, important differences in pathophysiology and prognosis raise concerns about confounding, highlighting the need for subgroup-specific evidence. Comparative safety data in acutely infarcted patients remain limited, particularly with respect to hypotension, renal dysfunction, and hyperkalemia in a hemodynamically vulnerable population. This systematic review and meta-analysis therefore focuses exclusively on randomized controlled trials (RCTs) of sacubitril/valsartan versus ACEIs in patients with STEMI, aiming to synthesize available evidence on efficacy and safety. In preparation of this manuscript, we have adhered to the TITAN Guidelines 2025 on the declaration and responsible use of artificial intelligence in academic publishing[10]. These standards ensure transparency, reproducibility, and integrity in the reporting process

Methods

This systematic review and meta-analysis was designed and reported in accordance with the Cochrane Handbook and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines^[11,12^].

Objectives, eligibility criteria, and outcomes

We included RCTs enrolling adult patients diagnosed with STEMI according to ESC/AHA criteria, comparing sacubitril/valsartan against ACEIs, and reporting at least one clinical or echocardiographic outcome of interest. We excluded observational studies, case reports, reviews, trials without a comparator group, or those in which patients with STEMI could not be analyzed separately from NSTEMI. The outcomes of interest included major adverse cardiovascular (CV) events [MACE, defined as a composite of CV death, recurrent myocardial infarction (MI), hospitalization for heart failure [HHF], stroke, and arrhythmias], HHF, recurrent MI, CV death, LVEF, left ventricular end-systolic volume (LVESV), left ventricular end-diastolic volume (LVEDV), cough, hypotension, worsening renal function, hyperkalemia, and NT-proB-type natriuretic peptide (NT-proBNP) levels.

HIGHLIGHTS

• Sacubitril/valsartan significantly reduces major cardiovascular events compared to ACE inhibitors in patients with ST-segment elevation myocardial infarction (STEMI).

• It improves left ventricular ejection fraction and lowers NT-proBNP levels, suggesting enhanced cardiac recovery.

• Despite superior efficacy, sacubitril/valsartan does not increase adverse events, supporting its safety in STEMI.

Data sources and search strategy

We systematically searched PubMed (1946–July 2025), Cochrane CENTRAL (1991–July 2025). The search strategy combined keywords and Medical Subject Headings (MeSH) terms, including: (“sacubitril/valsartan” OR “ARNI” OR “angiotensin receptor–neprilysin inhibitor”) AND (“ST-elevation myocardial infarction” OR “STEMI” OR “acute myocardial infarction” OR “myocardial infarction [MeSH]”) AND (“angiotensin-converting enzyme inhibitors” OR “ACE inhibitors” OR “enalapril” OR “captopril”). Full electronic strategies for each database are provided in Supplemental Digital Content Table S1, available at: http://links.lww.com/MS9/B187. Two reviewers independently screened titles and abstracts. Full texts were reviewed to assess eligibility, and reasons for exclusion were documented. Three full-text studies were excluded due to mixed AMI populations (n = 2) or lack of comparator (n = 1).

Data extraction and risk of bias assessment

Baseline characteristics and outcome data were extracted using prespecified data collection forms, including trial identifiers. Extracted variables included total sample size, number of patients receiving sacubitril/valsartan and ACEIs, mean age, mean body mass index (BMI), proportion of male patients, type and dosage of sacubitril/valsartan and ACEI, baseline LVEF, estimated glomerular filtration rate (eGFR), and the proportion of patients with prior myocardial infarction (MI), hypertension, diabetes, and follow-up duration. The quality of included trials was assessed using the Cochrane Risk of Bias tool[13]. Two independent reviewers (R.K. and S.K.) performed data extraction and quality assessment, with any discrepancies resolved through discussion with a third reviewer (A.K.).

Statistical analysis

For continuous outcomes, we used the change in means and corresponding standard deviations (SDs) from baseline. When change scores were not directly reported, they were calculated using the following formulas: ΔMean = Mean endpoint − Mean baseline; ΔSD = √(SD² baseline + SD² endpoint − [2 × r × SD baseline × SD endpoint]). To minimize estimation bias in ΔSD, we conservatively assumed a correlation coefficient (r) of 0.71. When outcomes were reported as median (interquartile range), the Box–Cox method was applied to impute mean (SD) values. For clinical and safety outcomes, we extracted and pooled risk ratios (RRs) with 95% confidence intervals (CIs), while for continuous variables such as echocardiographic parameters and NT-proBNP levels, weighted mean differences (WMDs) with 95% CIs were calculated. All analyses were performed using a random-effects model. Statistical significance was defined as a P-value < 0.05. Heterogeneity was assessed using the I² statistic, with values of 25%, 50%, and 75% indicating low, moderate, and high heterogeneity, respectively. Statistical analyses were conducted using Review Manager (Version 5.5; Cochrane Collaboration, Oxford, UK).

Results

Literature search and selection

Following the screening of 245 titles and abstracts, eight studies were selected for full-text review. Of these, five RCTs comprising a total of 4915 participants met the eligibility criteria and were included in the final analysis.^[5–7,14,15^] Three full-text articles were excluded because of (1) mixed AMI populations without separate STEMI data (n = 2) and (2) non-randomized trial design (n = 1). A detailed summary of the study selection process is presented in the PRISMA flowchart (Fig. 1).

Figure 1.

PRISMA flowchart.

Baseline characteristics

The mean age of participants ranged from 52.0 ± 9.2 to 62.7 ± 11.4 years, with the proportion of male patients varying between 75% and 86% across studies. Reported BMI values ranged from 24.1 ± 2.8 to 28.7 ± 4.3 kg/m². Mean baseline LVEF ranged from 36.0 ± 8.8% to 54.7 ± 10.8%. Baseline eGFR values ranged from 73.2 ± 22.5 to 81.9 ± 24.2 mL/min. In all included trials, the majority of patients underwent primary percutaneous coronary intervention as standard STEMI management. Sacubitril/valsartan or ACEIs were generally initiated within 1–7 days post-MI, after hemodynamic stabilization. The prevalence of prior MI, hypertension, and diabetes ranged from 6% to 75%, 34% to 68.4%, and 22.1% to 40%, respectively. Follow-up durations ranged from 24 to 37 weeks. Patient characteristics are detailed in Table 1.

Table 1.

Baseline characteristics of included studies.

Study ID (Year)	Total number of patients (n)	Patients receiving ARNIs (n)	Patients receiving ACEIs (n)	Age, years Mean ± SD	BMI (kg/m2)	Male %	Type of ACEI	LVEF % Mean ± SD	eGFR, mL/min Mean ± SD	Previous MI %	Hypertension %	Diabetes%	ARNI dosage	Follow-up duration
Wang et al[16]	137	68	69	59.13 ± 7.15	26.54	76.5	Enalapril	41.91 ± 3.28	N/R	75	47.1	22.1	24/26 mg or49/51 mg	24 weeks
Dong et al[7]	131	64	67	60.3 ± 9.9	24.1 ± 2.8	79.4	Enalapril	45.75 ± 9.7	81.9 ± 24.2	6	47.3	25.2	50 mg or 100 mg or200 mg	24 weeks
Rezq et al[5]	200	100	100	52 ± 9.2	28.7 ± 4.3	86	Ramipril	-	-	-	34	40	50 mg twice daily orally that was increased to 100 mg twice daily orally after 2 weeks if tolerated	6 months
Zhang et al[6]	156	79	77	60.3 ± 11.7	24.77 ± 2.65	74.70	Perindopril	54.7 ± 10.8	-	-	68.4	31.6	-	6 months
Mann et al[17]	4291	2153	2138	62.7 ± 11.4	28 ± 4.9	77.6	Ramipril	36.0 ± 8.8	73.2 ± 22.5	12.5	60.8	39.5	97–103 mg	6 months

ARNI, angiotensin receptor–neprilysin inhibitor; ACEI, angiotensin-converting-enzyme inhibitor.

Meta-analysis results

Clinical outcomes

MACE: Four studies evaluated the effect of sacubitril/valsartan therapy on MACE. Meta-analysis revealed a significant reduction in MACE incidence with sacubitril/valsartan compared to ACEIs [RR: 0.66 (0.50, 0.86); P = 0.002; I² = 0%; Fig. 2].

Figure 2.

Forest plot assessing the effect of sacubitril/valsartan versus ACEI on major adverse cardiovascular events (MACE), hospitalization for heart failure (HHF), recurrent myocardial infarction (MI), cardiovascular (CV) death, all-cause death, and outpatient heart failure (HF).

HHF: Three studies assessed the impact of sacubitril/valsartan on HHF. Pooled results demonstrated a significant reduction in HHF with sacubitril/valsartan therapy [RR: 0.67 (0.49, 0.92); P = 0.01; I² = 32%; Fig. 2].

Recurrent MI: Three studies reported on recurrent MI. Meta-analysis showed no significant difference in MI incidence between sacubitril/valsartan and ACEIs [RR: 1.02 (0.39, 2.71); P = 0.96; I² = 0%; Fig. 2].

CV death: Three studies assessed the effect of sacubitril/valsartan therapy on CV death. Meta-analysis showed no significant difference in the incidence of CV death between sacubitril/valsartan and ACEIs [RR: 0.78 (0.61, 1.01); p = 0.06; I² = 0%; Fig. 2).

All-cause death: Three studies evaluated the impact of sacubitril/valsartan on all-cause mortality. Pooled analysis revealed no significant difference in all-cause death rates [RR: 0.85 (0.68, 1.06); P = 0.15; I² = 0%; Fig. 2].

Outpatient HF: Three studies investigated the effect of sacubitril/valsartan on outpatient HF. Meta-analysis demonstrated no significant difference in outpatient HF incidence [RR: 0.54 (0.25, 1.16); P = 0.11; I² = 29%; Fig. 2].

Echocardiographic measures

LVEF: Three studies assessed the impact of sacubitril/valsartan therapy on LVEF. Meta-analysis demonstrated a significant increase in LVEF with sacubitril/valsartan [WMD: 2.60 (1.53, 3.68); P < 0.00001; I² = 0%; Fig. 3A).

Figure 3.

Forest plot assessing the effect of sacubitril/valsartan versus ACEI on (a) left ventricular ejection fraction (LVEF), (b) left ventricular end-diastolic volume (LVEDV), and (c) left ventricular end-systolic volume (LVESV).

LVEDV: Two studies evaluated LVEDV changes. Pooled analysis indicated no significant difference with sacubitril/valsartan therapy [WMD: −8.13 (−22.53, 6.28); P = 0.27; I² = 98%; Fig. 3B].

LVESV: Two studies examined LVESV. Meta-analysis showed no significant reduction with sacubitril/valsartan [WMD: −6.77 (−15.61, 2.07); P = 0.13; I² = 92%; Fig. 3C].

Safety outcomes

Cough: Two studies assessed the effect of sacubitril/valsartan therapy on cough. Meta-analysis indicated no significant difference in cough incidence [RR: 0.63 (0.15, 2.72); P = 0.54; I² = 0%; Fig. 4].

Figure 4.

Forest plot assessing the effect of sacubitril/valsartan versus ACEI on the incidence of cough, hypotension, worsening renal function, and hyperkalemia.

Hypotension: Two studies evaluated hypotension risk. Meta-analysis showed no significant increase with sacubitril/valsartan [RR: 1.68 (0.97, 2.91); P = 0.06; I² = 0%; Fig. 4].

Worsening renal function: Three studies examined the impact of sacubitril/valsartan on renal function. No significant difference in worsening renal function was observed [RR: 0.51 (0.22, 1.21);P = 0.13; I² = 0%; Fig. 4].

Hyperkalemia: Two studies reported on hyperkalemia risk. Meta-analysis demonstrated no significant difference between sacubitril/valsartan and ACEIs [RR: 0.59 (0.17, 2.01); P = 0.40; I² = 0%; Fig. 4].

Laboratory parameters

NT-proB-type natriuretic peptide

Two studies evaluated NT-proBNP levels. Pooled analysis showed that sacubitril/valsartan therapy significantly reduced NT-proBNP levels [MD: −268.89 (−422.35, −115.42); P = 0.0006; I² = 18%; Fig. 5].

Figure 5.

Forest plot assessing the effect of ARNI versus control on NT-proB-type natriuretic peptide (NT-proBNP) levels. ARNI, angiotensin receptor–neprilysin inhibitor

Risk of bias evaluations of included studies

Most included studies demonstrated a low risk of bias in random sequence generation, allocation concealment, blinding of outcome assessment, incomplete outcome data, selective reporting, and other potential biases. However, one study[6]exhibited a high risk of bias concerning the blinding of participants and personnel, indicating possible performance bias. Despite this, the overall low risk across the majority of bias domains reflects strong methodological quality among the included trials. These findings support the credibility of the pooled results. A detailed summary of the risk of bias across individual studies is provided in Supplemental Digital Content Figure S1, available at: http://links.lww.com/MS9/B186.

Discussion

In this meta-analysis involving 4915 patients comparing the effects of sacubitril/valsartan versus ACEIs in patients with STEMI, we report several important findings. First, sacubitril/valsartan therapy significantly reduced the incidence of MACE, HHF, and NT-proBNP levels. However, no significant differences were observed in recurrent MI, CV death, or all-cause mortality between sacubitril/valsartan and ACEI groups. Second, sacubitril/valsartan therapy was associated with a significant improvement in LVEF, although no significant changes were observed in LVEDV or LVESV. Finally, sacubitril/valsartan demonstrated a safety profile comparable to ACEIs.

Previous meta-analyses comparing sacubitril/valsartan and ACEIs have included mixed AMI populations comprising both patients with STEMI and NSTEMI^[8,9,18^]. Although often grouped under AMI, STEMI and NSTEMI differ markedly in pathophysiology, clinical presentation, and patient characteristics^[19,20^]. For example, NSTEMI patients tend to be older and have a higher burden of comorbidities, which may introduce confounding bias. By restricting our analysis to patients with STEMI, our study offers a more precise evaluation of the comparative effectiveness of sacubitril/valsartan versus ACEIs in this high-risk subgroup.

The observed reduction in MACE, HHF, and NT-proBNP levels with sacubitril/valsartan therapy is clinically meaningful. NT-proBNP is a well-established prognostic biomarker in CV disease, and reductions in its levels have been associated with improved outcomes[16]. Moreover, reduced HHF rates imply a decreased burden on healthcare systems and improved patient quality of life. These benefits may be attributed to the dual mechanism of sacubitril/valsartan – simultaneously inhibiting the renin–angiotensin system and enhancing the natriuretic peptide system – resulting in broader CV protection than ACEIs alone[17]. Consequently, sacubitril/valsartan may offer a more effective therapeutic strategy for patients with STEMI, particularly those at increased risk of heart failure.

Sacubitril/valsartan also led to a significant improvement in LVEF, a key determinant of long-term prognosis in STEMI survivors^[21–24^]. This suggests potential for sacubitril/valsartan to enhance myocardial recovery and overall cardiac function. However, their effect on other echocardiographic parameters, including LVEDV and LVESV, was non-significant, and the magnitude of LVEF improvement was modest (WMD 2.6%). These findings suggest that while sacubitril/valsartan may enhance systolic function, their impact on broader aspects of ventricular remodeling remains limited. Further studies are warranted to evaluate the effects of sacubitril/valsartan on comprehensive measures of cardiac remodeling and to explore combination therapies that may yield additional benefits.

In terms of safety, our analysis found no significant difference between sacubitril/valsartan and ACEIs across key adverse events, including cough, hypotension, hyperkalemia, and renal dysfunction. However, the PARADIGM-HF trial, which focused on patients with heart failure, did report a significantly higher incidence of hypotension with sacubitril/valsartan[25]. While these findings may not directly translate to the STEMI population, hypotension remains a potential concern, particularly in elderly patients, those with impaired renal function or advanced left ventricular dysfunction, and individuals on concomitant vasodilators or with comorbid aortic stenosis. The vasodilatory properties of sacubitril/valsartan, particularly at higher doses, may contribute to this risk. Future trials are needed to define optimal dosing strategies that maximize efficacy while minimizing adverse effects in this population.

The clinical implications of our findings are considerable. The demonstrated benefits of sacubitril/valsartan therapy in reducing MACE, lowering NT-proBNP, and improving LVEF support its potential role in STEMI management. Given its favorable safety profile and mechanistic advantages, sacubitril/valsartan therapy could be integrated into treatment protocols for high-risk STEMI patients. However, larger, well-powered, long-term RCTs are essential to confirm these findings, determine optimal initiation timing and dosing, and better characterize sacubitril/valsartan use in various subpopulations, such as those with diabetes or severe systolic dysfunction.

This study has several limitations. Most included trials were small and underpowered, with short follow-up durations. Echocardiographic outcomes such as LVEDV and LVESV were incompletely reported, limiting conclusions about remodeling. Only selected ACEIs (ramipril, enalapril, and perindopril) were studied, restricting generalizability. Potential confounding from concomitant medications (e.g., beta-blockers and mineralocorticoid receptor antagonistss) could not be evaluated. Finally, dose–response effects of sacubitril/valsartan remain undefined

Conclusion

This meta-analysis is the first to compare sacubitril/valsartan therapy with conventional ACEIs specifically in patients with STEMI, revealing that sacubitril/valsartan treatment significantly reduces MACE and HHF, enhances LVEF, and lowers NT-proBNP levels. Nonetheless, additional large-scale, long-duration RCTs are warranted to confirm these effects and to inform evidence-based clinical guidelines for the optimal application of sacubitril/valsartan in this setting.

Ethical approval

Ethical approval for this was not necessary because all the data used in this study is publicly available in the trials referenced within the manuscript.

Consent

This study type is systematic review and meta-analysis of previously published publicly available studies. We included studies that took written informed consent from the participants of the study.

Sources of funding

Not applicable.

Author contributions

A.K.: and R.K.: conceived the idea and designed the study. S.K. extracted the data and analyzed it. K. created the illustrations. A.K. critically revised the manuscript. All authors drafted the manuscript.

Conflicts of interest disclosure

Not applicable.

Research registration unique identifying number (UIN)

1. Name of the registry: National Institute for Health Research (NIHR) International prospective register of systematic reviews (PROSPERO). 2. Unique Identifying number or registration ID: CRD42025055616. 3. Hyperlink to your specific registration (must be publicly accessible and will be checked): crd.york.ac.uk/PROSPERO/display_record.php?RecordID=055616.

Guarantor

Sayed Jawad.

Provenance and peer review

It was not invited but rather not commissioned and externally peer-reviewed.

Data availability statement

All the data used in this study is publicly available in the trials, which are referenced in the bibliography.

Disclosures

None.