Beta-Blocker Therapy After Acute Myocardial Infarction in Patients with Preserved or Mildly Reduced Ejection Fraction: A Systematic Review and Meta-Analysis

Kazi Kamranuddin Fazaluddin¹, Diguvinti Nehasudha Reddy², Revunuru Narasimha Reddy³, Koorosh Nakhjavan Shahraki⁴, Munazzah Kalyankar⁵, Ariba Jawad⁶, Unsa Miraj⁷, Preety Devi⁸, Muskan Batra⁹, Muhammad Sohail S. Mirza¹⁰*

¹JIIUs Indian Institute of Medical Science and Research, Jalna, Maharashtra, India.

²ACSR Medical College, Nellore, Andhra Pradesh, India.

³ACSR Medical College, Nellore, Andhra Pradesh, India

⁴John Bowne High School, New York, USA

⁵JIIUs Indian Institute of Medical Science and Research, Jalna, Maharashtra, India

⁶M Islam Medical and Dental College, Gujranwala, Pakistan

⁷King Edward Medical University, Lahore, Pakistan

⁸Liaquat University of Medical and Health Sciences, Jamshoro, Sindh, Pakistan

⁹Liaquat University of Medical and Health Sciences, Jamshoro, Sindh, Pakistan

¹⁰Shandong University School of Medicine, Jinan, China

^*Corresponding author: Muhammad Sohail S. Mirza, Shandong University School of Medicine, Jinan, China. 

Received: 05 July 2026; Accepted: 13 July 2026; Published: 27 July 2026

1. Introduction

Acute myocardial infarction (AMI), commonly referred to as a heart attack, remains a significant global cause of mortality and morbidity, with approximately 7 million new cases annually worldwide [1,2,3]. Improvements in treatment and post-MI management have led to better myocardial salvage, reduced infarct size, and consequently, improved left ventricular ejection fraction (LVEF) preservation [3-13]. This evolution has resulted in a patient population post-MI with normal or only mildly reduced LVEF (≥40%), altering the risk profile of contemporary atherosclerotic patients experiencing myocardial infarction. Landmark trials conducted in the 1980s and 1990s, including the Norwegian Timolol Trial, the Beta-Blocker Heart Attack Trial (BHAT), and MERIT-HF, established beta-blockers as a cornerstone therapy for myocardial infarction [14,15]. These studies demonstrated significant reductions in all-cause and sudden cardiac death mortality, leading to the conclusion that beta-blockers should be considered the standard of care [16]. However, many of these trials involved patients with significant left ventricular dysfunction, which is less prevalent in the current reperfusion era. Contemporary guidelines from the European Society of Cardiology (ESC) and the American College of Cardiology/American Heart Association (ACC/AHA) recommend beta-blocker use in all patients with LVEF ≤40%, though the evidence supporting their benefit in patients with preserved or moderately reduced LVEF is less robust [17,18]. This clinical question has resurfaced recently with the publication of two contemporary randomized controlled trials: REDUCE-AMI (2024) and ABYSS (2024) [11,12]. The REDUCE-AMI trial, which included 5020 patients with LVEF ≥50% treated with beta-blockers out of 5681 participants, found no significant difference in all-cause mortality compared to placebo (Hazard Ratio 0.96, 95% Confidence Interval 0.79–1.16) [11]. In the ABYSS trial, which enrolled 3698 patients over 40 years of age who developed MI, discontinuation of beta-blocker therapy was shown to be non-inferior [12]. Nevertheless, observational cohort studies have produced conflicting and inconclusive results [19, 20]. A systematic review and meta-analysis are required to address these contradictory findings and provide a quantitative summary of the benefits of beta-blocker therapy across patient groups with preserved or mildly reduced LVEF following MI [21, 22]. Such an analysis would inform clinical decision-making, guide recommendations for clinical guidelines, and identify potential avenues for future research [17,23].

2. Methods

2.1 Study Registration and Protocol

This systematic review and meta-analysis was conducted and reported in accordance with PRISMA 2020 guidelines [5].

2.2 Literature Search Strategy

A comprehensive search of PubMed/MEDLINE, Embase, Cochrane CENTRAL, and Web of Science was conducted from January 2015 through December 2025. Search terms included: 'beta-blocker,' 'metoprolol,' 'carvedilol,' 'bisoprolol,' 'atenolol,' 'acute myocardial infarction,' 'post-MI,' 'preserved ejection fraction,' 'LVEF ≥40%,' and related terms combined with Boolean operators. No language restrictions were applied.

2.3 Eligibility Criteria

Inclusion: Adult post-MI patients (age ≥18 years) with LVEF ≥40%; beta-blocker versus no beta-blocker comparison; at least one pre-specified outcome reported; RCTs or observational cohort studies with a comparator; HR with 95% CI reported or derivable.

Exclusion: LVEF <40% or unspecified; case reports, case series, reviews; no comparator group; mixed populations without extractable LVEF ≥40% subgroup; duplicate datasets.

2.4 Study Selection and Data Extraction

Two independent reviewers conducted two-stage selection: title/abstract screening followed by full-text assessment. Disagreements were resolved by consensus or a third reviewer [24]. Extracted variables: first author, year, country, design, sample size, follow-up, age, sex, LVEF range, beta-blocker type and dose, comparator, and outcome-specific HRs with 95% CIs.

2.5 Outcomes of Interest

Five pre-specified outcomes: (1) All-cause mortality (primary), (2) Cardiovascular mortality, (3) MACE, (4) Reinfarction, (5) HF hospitalization. Stroke analyzed descriptively only (k=3; insufficient for forest plot pooling [25].

2.6 Quality Assessment and Risk of Bias

Observational studies evaluated using Newcastle-Ottawa Scale (NOS); score ≥7 = low risk [6]. RCTs evaluated using Cochrane RoB 2 [7]. Results presented as color-coded Risk of Bias Summary Table (Figure 13).

2.7 Statistical Analysis

Pooled HRs with 95% CIs calculated using DerSimonian-Laird random-effects model [8] with meta [26] and metafor [27] R packages. Heterogeneity quantified using I² (<25% low; 25–50% moderate; 50–75% substantial; >75% considerable) [9]. Publication bias assessed with Egger's regression test (p<0.10 indicates potential asymmetry) [10]. p<0.05 considered statistically significant.

3. Results

3.1 Study Selection

The systematic search retrieved [1,434] records from four databases. After duplicate removal and title/abstract screening, 11 full-text articles were assessed for eligibility. Eleven studies were included: 2 RCTs and 9 observational cohort studies enrolling approximately 43,000 patients. The PRISMA 2020 flow diagram is presented in Figure 01 [5].

Figure 1: PRISMA Flowchart.

3.2 Characteristics of Included Studies

Included studies are listed in Table 1

Table 1: Characteristics of Included Studies.

3.3 Primary Outcome: All-cause Mortality

Ten studies (k=10) reported all-cause mortality. The pooled random-effects HR was 0.81 (95% CI: 0.67–0.98, p=0.032), indicating a significant 19% relative reduction with beta-blocker therapy. Substantial heterogeneity was observed (I²=66.6%, τ²=0.053, p=0.001) [9].

Figure 2: Forest plot of all-cause mortality comparing beta-blocker versus no beta-blocker therapy in post-AMI patients with LVEF ≥40%.

3.4 Cardiovascular Mortality

Seven studies (k=7) contributed data. Pooled HR was 0.83 (95% CI: 0.57–1.20, p=0.318), not statistically significant. High heterogeneity (I²=73.4%, τ²=0.155) [11].

Figure 3: Forest plot of cardiovascular mortality.

3.5 Major Adverse Cardiac Events (MACE)

Five studies (k=5) reported MACE. Pooled HR was 0.98 (95% CI: 0.80–1.19, p=0.833). Moderate heterogeneity (I²=53.2%, τ²=0.025) [12].

Figure 4: Forest plot of MACE. Pooled HR

3.6 Reinfarction

Six studies (k=6) reported reinfarction. Pooled HR was 1.00 (95% CI: 0.92–1.09, p=0.996). I²=0.0%  near-perfect homogeneity [8].

Figure 5: Forest plot of reinfarction.

3.7 Hospitalization for Heart Failure

Five studies (k=5) reported HF hospitalization. Pooled HR was 1.05 (95% CI: 0.89–1.24, p=0.549). I²=0.0%, low heterogeneity [17].

Figure 6: Forest plot of HF hospitalization.

3.8 Summary of Meta-Analysis Results

Table 2: Summary of Pooled Meta-Analysis Results.

*Stroke: funnel plot and Egger's test only (k=3; insufficient for reliable forest plot pooling) [25].

3.9 Publication Bias

Funnel plots were constructed for all six outcomes (Figures 6–11). Egger's test results are summarized in Table 3 [10].

Table 3: Egger's Test for Publication Bias.

Figure 7: Funnel plot assessing publication bias for all-cause mortality.

Figure 8: Funnel plot: Cardiovascular mortality.

Figure 9: Funnel plot: MACE.

Figure 10: Funnel plot: Reinfarction.

Figure 11: Funnel plot: HF hospitalization.

Figure 12: Funnel plot: Stroke.

3.11 Risk of Bias Assessment

The quality and risk of bias across all eleven included studies is summarized in Figure 13. Both RCTs (REDUCE-AMI [11] and ABYSS [12]) were rated low overall risk using Cochrane RoB 2 [7]. Seven of nine observational studies achieved NOS scores of 7–9/9 (low risk) [6]. Choo et al. [29] and Siu et al. [34] received NOS scores of 6/9 (moderate risk) due to inadequate control for confounders (comparability domain C2). Overall, 9/11 studies (81.8%) were at low risk of bias.

Figure 13: Risk of Bias Summary Table for all eleven included studies. Green circles (✓) = low risk; yellow circles (~) = moderate risk; red circles (×) = high risk. Observational studies assessed using the Newcastle-Ottawa Scale (NOS); RCTs assessed using Cochrane R.

4. Discussion

4.1 Principal Findings

This systematic review and meta-analysis of eleven studies (∼43,000 patients) found that beta-blocker therapy was associated with a statistically significant reduction in all-cause mortality (HR 0.81, 95% CI 0.67–0.98, p=0.032). However, no significant benefit was observed for CV mortality, MACE, reinfarction, or HF hospitalization [8,10].

4.2 All-cause Mortality

The 19% reduction in all-cause mortality must be interpreted cautiously given the high heterogeneity (I²=66.6%) and significant publication bias (p<0.001) [9,10]. Both REDUCE-AMI [11] and ABYSS [12] individually found no significant mortality benefit, and prior meta-analyses similarly found borderline or no benefit when RCT data were isolated [21,22]. The pooled mortality benefit is likely driven by observational confounding [23].

4.3 Cardiovascular Mortality

The non-significant HR for CV mortality (0.83, I²=73.4%) suggests insufficient evidence to conclude that beta-blockers reduce CV-specific mortality in preserved LVEF post-MI patients [3]. Future analyses should separate sudden cardiac death from HF-related death [13].

4.4 MACE

The null MACE finding (HR 0.98) aligns with ABYSS, which reported HR 0.89 (0.77–1.02) [12]. Moderate heterogeneity (I²=53.2%) likely reflects MACE definition differences [4].

4.5 Reinfarction

The pooled HR of exactly 1.00 with I²=0.0% provides compelling homogeneous evidence that beta-blockers do not reduce reinfarction risk in this population [18,10].

4.6 Risk of Bias and Study Quality

The overall methodological quality was satisfactory: 9/11 studies (81.8%) rated low risk of bias (Figure 13). Both RCTs had low risk under Cochrane RoB 2 [7]. Choo et al. [29] and Siu et al. [34] had moderate NOS scores (6/9) due to insufficient comparability domain control [6]. Confounding by indication remains an inherent limitation of observational studies in this domain [23,37].

4.7 Hospitalization for Heart Failure

The null HF hospitalization finding (HR 1.05, I²=0.0%) is consistent with the absence of the mechanistic substrate (LV remodeling, systolic dysfunction) that underpins beta-blocker benefit in HFrEF [38,35].

4.8 Publication Bias

Significant Egger's test results for all-cause mortality (p<0.001), CV mortality (p=0.002), and reinfarction (p=0.013) represent an important limitation [10]. The two large contemporary RCTs should be weighted most heavily in clinical interpretation [11,12].

4.9 Comparison with Existing Literature

Our analysis extends prior meta-analyses [21,22] by including eleven studies (vs. 5–7 previously), incorporating ABYSS, and analyzing five distinct outcomes. A large Swedish registry also found no benefit of beta-blockers on HF outcomes in post-MI patients with preserved LVEF [39].

4.10 Clinical Implications

These findings challenge universal beta-blocker prescribing post-MI regardless of LVEF. Patients with LVEF <40%, ongoing anginal symptoms, arrhythmias, or high adrenergic state may still benefit; those with well-preserved LVEF after successful PPCI may be candidates for beta-blocker avoidance or early discontinuation [17,18]. ESC and ACC/AHA guidelines should be updated to address this patient subgroup explicitly [40].

4.11 Limitations

We examined predominantly observational study designs, with publication bias evident for multiple outcomes and high heterogeneity for mortality outcomes (I2>65%), and found that only three of the studies provided forest plot poolable data; beta-blocker type and dose, length and adherence, and reporting of beta-blockers were inconsistent among studies.

5. Conclusion

A total of 11 studies with 43,000 patients included who had post-MI with preserved or mildly reduced LVEF were included in this systematic review and meta-analysis, which revealed that beta-blocker therapy led to a statistically significant reduction in all-cause mortality (HR 0.81, 95% CI 0.67-0.98). But there was no obvious effect on cardiovascular mortality, MACE, reinfarction or hospitalisation for HF. The large variation in results across the studies, combined with the 2 recent large contemporary RCTs (REDUCE-AMI [11] and ABYSS [12]) with no apparent difference in results, supports the conclusion that the perceived all-cause mortality benefit may be due to observational confounding. This represents a departure from the sustained use of beta-blockers in all post-MI patients with LVEF in the preserved range and the need for an individualized approach to treatment based on evidence [21,22]. There is an urgent need for larger, well-powered, prospective RCTs with standardised definitions of outcome.

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