Highlight
- Long-term beta-blocker therapy after acute myocardial infarction (MI) with preserved left ventricular ejection fraction (LVEF ≥50%) shows no significant reduction in risk of death or recurrent MI compared to no beta-blocker use.
- Discontinuation of beta-blockers within 12 months after acute coronary syndrome (ACS) in patients with LVEF ≥40% did not increase major adverse cardiovascular events (MACE), with a potential differential risk in STEMI versus NSTEMI subgroups.
- Meta-analysis indicates declining mortality benefits of beta-blockers post-MI over time, particularly beyond the first year and in patients with preserved EF, suggesting possible detrimental effects with prolonged use in this population.
Study Background and Disease Burden
Beta-blockers have been a cornerstone of secondary prevention following myocardial infarction for decades, primarily based on trials conducted in patient populations with large infarcts treated before the modern era of reperfusion therapies and intensive risk factor management. Contemporary management of MI includes early percutaneous coronary intervention (PCI), potent antithrombotic agents, high-intensity statins, and renin-angiotensin-aldosterone system inhibitors, dramatically improving prognosis and altering baseline risk profiles. These advances particularly affect patients with preserved left ventricular ejection fraction (LVEF), who represent a growing subset of MI survivors due to timely revascularization and management.
The burden of ischemic heart disease remains significant worldwide, with recurrent MI and mortality risks necessitating evidence-based secondary prevention strategies. However, the role and benefit magnitude of long-term beta-blocker therapy in patients without reduced LVEF or heart failure (HF) is increasingly questioned, especially given potential side effects and patient tolerability concerns. This has spurred new clinical trials and real-world analyses to clarify beta-blocker utility in this population.
Study Design
Three pivotal recent studies provide complementary evidence:
1. The REDUCE-AMI Trial was a large, randomized, open-label, parallel-group study conducted at 45 centers across Sweden, Estonia, and New Zealand enrolling 5020 patients with acute MI and preserved LVEF (≥50%) who underwent early coronary angiography. Participants were randomized to long-term beta-blocker treatment (metoprolol or bisoprolol) versus no beta-blocker therapy. The primary endpoint was a composite of death from any cause or new MI, with a median follow-up of 3.5 years.
2. A multicenter prospective real-world cohort study emulated a target trial assessing the safety of beta-blocker discontinuation within 12 months after ACS in patients with LVEF ≥40%. Among 2077 eligible patients discharged on beta-blockers, 1758 continued therapy at one year, and 319 discontinued. Using inverse probability weighting, outcomes over the subsequent 4 years were compared between continuation and discontinuation groups, with the primary endpoint being major adverse cardiovascular events (MACE), a composite of cardiovascular death, MI, stroke, transient ischemic attack, unplanned revascularizations, or unstable angina hospitalization.
3. A comprehensive updated meta-analysis incorporated 24 contemporary studies enrolling 290,349 MI patients without reduced EF (≤40%) or HF, comparing outcomes between beta-blocker users and non-users. Primary outcome was all-cause mortality; secondary outcomes included major adverse cardiac and cerebrovascular events (MACCE) and cardiovascular mortality. Subgroup analyses and meta-regression explored event-free periods and temporal trends.
Key Findings
REDUCE-AMI Trial
Beta-blocker treatment did not significantly reduce the risk of the primary composite endpoint of death from any cause or recurrent MI compared to no beta-blocker therapy (7.9% vs. 8.3%, hazard ratio [HR] 0.96; 95% confidence interval [CI], 0.79 to 1.16; P=0.64). Secondary endpoints, including all-cause mortality, cardiovascular death, recurrent MI, hospitalization for atrial fibrillation or heart failure, were similarly comparable across groups. Safety outcomes such as hospitalization for bradycardia, AV block, hypotension, syncope, asthma or COPD exacerbations, and stroke did not significantly differ. These findings suggest no incremental benefit of long-term beta-blockers in patients with preserved LVEF post-MI in this well-treated modern cohort.
Beta-blocker Discontinuation Cohort Study
Discontinuing beta-blockers within 12 months after ACS with LVEF ≥40% was not associated with an increased risk of MACE compared to continuation (14.1% vs. 14.3%; adjusted HR 0.98; 95% CI, 0.72-1.34; P=0.91) over a 4-year follow-up. Notably, subgroup analysis indicated a potential increased risk with discontinuation after ST-elevation MI (STEMI) (adjusted HR 1.46, 95% CI 0.99-2.16) relative to non-ST elevation MI (NSTEMI) patients (adjusted HR 0.70, 95% CI 0.40-1.22; Pinteraction=0.033). Left ventricular ejection fraction did not significantly modify outcomes. These results support the safety of stopping beta-blockers after one year in patients with preserved or mildly reduced EF, especially post-NSTEMI, while cautioning in STEMI cases.
Updated Meta-Analysis
Overall, beta-blocker therapy was associated with an 11% reduction in all-cause mortality (HR 0.89; 95% CI, 0.81-0.97), though with considerable heterogeneity. In patients with a 1-year event-free period, outcomes including all-cause mortality, cardiovascular mortality, and MACCE were statistically equivalent between users and non-users. Meta-regression revealed a declining mortality benefit of beta-blockers over time with a temporal trend towards null effect in post-2010 studies. Specifically, in patients with preserved EF enrolled after 2010, beta-blockers yielded no reduction in all-cause mortality (HR 0.97; 95% CI, 0.90-1.04), a non-significant trend toward increased cardiovascular mortality (HR 1.29; 95% CI, 0.96-1.72), and a significant increase in MACCE (HR 1.24; 95% CI, 1.01-1.52). These findings raise concerns about potential adverse cardiovascular events linked to beta-blocker use in this population on long-term follow-up.
Expert Commentary
These contemporary data challenge traditional dogma favoring universal long-term beta-blocker therapy following MI irrespective of cardiac function. The REDUCE-AMI trial’s robust randomized design in a modern reperfusion era supports de-escalation of beta-blocker use in stable MI patients with preserved EF, reflecting evolving risk profiles due to improved acute and secondary management.
The observational cohort on beta-blocker discontinuation provides complementary real-world evidence that stopping beta-blockers safely might be considered after the first post-MI year in patients with preserved or mildly reduced EF, aligning with clinical intuition and efforts to minimize polypharmacy and side effects. However, clinicians should individualize decisions, particularly in STEMI patients, where residual ischemic risk may justify continued therapy.
The meta-analysis substantiates that beta-blocker benefits may be confined to early post-MI periods or patients with reduced EF, while suggesting potential harm or neutral effects in prolonged use among patients with preserved EF. Mechanistically, beta-blockers reduce myocardial oxygen demand and arrhythmias but may negatively impact peripheral hemodynamics or metabolic parameters in some patients.
Notable limitations include variation in beta-blocker types, dosages, adherence, and patient phenotypes across studies. The REDUCE-AMI trial was predominantly conducted in Sweden, which may limit generalizability. Moreover, subgroup analyses in discontinuation and meta-analysis studies suggest heterogeneity based on MI type and timing.
Current international guidelines from the European Society of Cardiology (ESC) recognize the uncertainty of beta-blocker benefits post-MI with preserved EF and advise individualized treatment duration and consideration of patient risk factors and tolerance.
Conclusion
The evolving evidence landscape indicates that long-term beta-blocker therapy after myocardial infarction in patients with preserved left ventricular function may not confer significant mortality or recurrent MI benefits beyond the initial post-event period. Discontinuation of beta-blockers within one year appears safe in real-world cohorts without increased cardiovascular risk, particularly after NSTEMI. Meta-analytic data reflect diminished efficacy in contemporary reperfusion-era patients and suggest possible adverse outcomes associated with prolonged beta-blocker use in those with preserved EF.
Clinicians should tailor beta-blocker therapy decisions post-MI with consideration of individual patient characteristics, MI subtype, and emerging data, with a growing paradigm toward personalized medicine. Further research is warranted to delineate patient subgroups who might derive the most benefit or harm from beta-blocker therapy and to refine duration and dosing strategies.
References
1. Yndigegn T, et al; REDUCE-AMI Investigators. Beta-Blockers after Myocardial Infarction and Preserved Ejection Fraction. N Engl J Med. 2024 Apr 18;390(15):1372-1381. doi: 10.1056/NEJMoa2401479. PMID: 38587241.
2. Johner N, et al. Safety of beta-blocker discontinuation after acute coronary syndromes with preserved or mildly reduced left ventricular ejection fraction: a target trial emulation from a real-world cohort. Eur J Prev Cardiol. 2025 Jun 3;32(8):622-632. doi: 10.1093/eurjpc/zwae346. PMID: 39454630.
3. Chi KY, et al. Beta-blockers for secondary prevention following myocardial infarction in patients without reduced ejection fraction or heart failure: an updated meta-analysis. Eur J Prev Cardiol. 2025 Jun 3;32(8):633-646. doi: 10.1093/eurjpc/zwae298. PMID: 39298680; PMCID: PMC11922798.
