Highlights
– An individual-patient data meta-analysis of five randomized trials (17,801 patients) found no reduction in the composite of all‑cause death, myocardial infarction, or heart failure with beta‑blocker therapy in patients with LVEF ≥50% after MI (HR 0.97; 95% CI 0.87–1.07; P=0.54).
– Secondary endpoints (all‑cause death, recurrent MI, heart failure) were similarly neutral; point estimates favored neither routine use nor harm.
– Contemporary care (primary PCI, potent antiplatelet therapy, statins, ACEi/ARBs) may have reduced the incremental value of routine long‑term beta blockade in patients without other indications.
Background and clinical context
Beta‑adrenergic blockers have been a cornerstone of post‑myocardial infarction (MI) therapy for decades. Early randomized trials and meta‑analyses in the pre‑reperfusion era demonstrated reductions in arrhythmic death and reinfarction that supported routine use. Current practice, however, evolved in a very different therapeutic landscape: rapid reperfusion, widespread statin use, effective antiplatelet therapy, and routine secondary prevention measures have lowered baseline event rates. Whether routine, long‑term beta‑blocker therapy provides additional outcome benefit in patients who sustain an MI but have preserved left ventricular ejection fraction (LVEF ≥50%) and no other indication (such as heart failure, symptomatic ischemia, or tachyarrhythmia) has therefore remained uncertain.
Study design and methods
The report under discussion is an individual‑patient data meta‑analysis pooling randomized data from five open‑label trials that randomized patients with recent MI, LVEF ≥50%, and no other indications for beta‑blockers to beta‑blocker therapy or no beta‑blocker therapy. The trials included were REBOOT (7,459 patients), REDUCE‑AMI (4,967), BETAMI (2,441), DANBLOCK (2,277), and CAPITAL‑RCT (657), for a combined population of 17,801 patients.
Patients were randomized to receive a beta‑blocker versus no beta‑blocker. The primary end point was a composite of death from any cause, myocardial infarction, or heart failure. Event rates were analyzed using a one‑stage fixed‑effects Cox proportional‑hazards model, with a median follow‑up of 3.6 years (IQR 2.3–4.6).
Key findings
Overall results: Of 17,801 patients, 8,831 (49.6%) were assigned to beta‑blocker therapy and 8,970 (50.4%) to no beta‑blocker. A primary‑endpoint event occurred in 717 patients (8.1%) in the beta‑blocker group and 748 patients (8.3%) in the no‑beta‑blocker group. The hazard ratio (HR) for the composite primary endpoint was 0.97 (95% CI, 0.87–1.07; P = 0.54), indicating no statistically significant difference between strategies.
Individual components:
- All‑cause death: 335 events in the beta‑blocker group versus 326 in the no‑beta‑blocker group (HR 1.04; 95% CI, 0.89–1.21).
- Myocardial infarction: 360 events versus 407 events (HR 0.89; 95% CI, 0.77–1.03).
- Heart failure: 75 events versus 87 events (HR 0.87; 95% CI, 0.64–1.19).
These component analyses were directionally neutral with confidence intervals crossing unity and no evidence of meaningful benefit for routine beta‑blocker therapy in the primary population (LVEF ≥50% and no other indication).
Secondary and subgroup considerations
The pooled analysis permits assessment of consistency across trials and subgroups; however, the primary pooled estimates were null. Point estimates for recurrent MI favored beta‑blocker therapy modestly (HR 0.89) but did not reach statistical significance. No clear signal of benefit emerged for death or heart failure. The trials were open‑label and patient selection varied but shared the key inclusion criterion of preserved EF without other indications.
Safety and tolerability
Large randomized trials and meta‑analyses prior to this pooled analysis have documented typical beta‑blocker adverse effects (bradycardia, hypotension, fatigue, sexual dysfunction) and rare but serious events (e.g., cardiogenic shock when initiated acutely in high‑risk patients). The present pooled analysis focused on efficacy endpoints; its neutral primary outcome implies that routine exposure to beta‑blocker adverse effects may not be justified when there is no demonstrable reduction in hard clinical outcomes for this population.
Biologic and mechanistic interpretation
Beta blockers may reduce mortality after MI through multiple mechanisms: suppression of life‑threatening ventricular arrhythmias, reduction of myocardial oxygen demand during ischemia, and attenuation of adverse remodeling. However, in the contemporary era, the incidence of fatal arrhythmia and progressive post‑MI remodeling has been markedly reduced by timely reperfusion, widespread use of high‑intensity statins, renin–angiotensin system blockade, and revascularization. When baseline risk of arrhythmic death and recurrent ischemia is low, the absolute benefit of additional therapy is more difficult to demonstrate. The neutral pooled effect suggests the magnitude of any remaining benefit is either very small or confined to specific subgroups not adequately represented or powered in these trials.
Strengths of the analysis
– Individual‑patient data meta‑analysis design increases analytic rigor and consistency across trials compared with aggregate data pooling.
– Large sample size (n=17,801) and reasonably long follow‑up (median 3.6 years) provide reliable effect estimates for the target population.
– Inclusion of multiple contemporary randomized trials enhances generalizability across geographic and practice settings contributing data to the five trials.
Limitations and caveats
– All trials were open‑label, which could influence some subjective endpoints and prescribing behavior, although the primary endpoints are hard clinical outcomes less susceptible to bias.
– Heterogeneity in beta‑blocker agent, dose, timing of initiation, and adherence across trials could dilute a treatment effect if benefit depends on a particular regimen.
– Although large overall, the analysis may still be underpowered to detect modest benefits in specific subgroups (e.g., large anterior MI, persistent tachycardia, patients with incomplete revascularization) or to identify rare harms.
– The trials excluded patients with other indications for beta blockade; therefore, findings do not apply to patients with heart failure, significant LV dysfunction, symptomatic ischemia, uncontrolled hypertension, or arrhythmias.
Clinical implications and recommended approach
This pooled randomized evidence strongly supports rethinking the routine, indefinite prescription of beta blockers after MI in patients with preserved LVEF and no other indication. Clinicians should consider the following pragmatic, evidence‑based approach:
- Do not reflexively continue or start long‑term beta‑blocker therapy solely on the basis of a recent MI when LVEF is preserved (≥50%) and no other indication exists.
- If a beta blocker is started in the acute setting for hemodynamic control, arrhythmia suppression, or symptomatic ischemia, reassess need at hospital discharge and during early outpatient follow‑up. Consider stopping if no ongoing indication and the patient experiences adverse effects.
- Continue beta blockers long term for patients with clear indications: heart failure with reduced EF, symptomatic angina, persistent tachyarrhythmias or rate control needs, or hypertrophic obstructive cardiomyopathy, as these populations were not addressed by this analysis.
- Individualize decisions for higher‑risk subgroups (large MI, incomplete revascularization, high baseline heart rate) while recognizing the absence of a demonstrable group‑level benefit in this pooled analysis.
Future research directions
Remaining questions include whether specific subgroups derive benefit (for example, very large infarcts despite preserved EF, or patients with high sympathetic tone), optimal timing and duration of therapy if benefit exists, and the comparative effectiveness of different beta‑blocker agents and doses. Mechanistic studies and randomized trials stratified to these higher‑risk phenotypes may help refine recommendations.
Conclusion
An individual‑patient data meta‑analysis of five randomized trials and 17,801 patients demonstrates that routine beta‑blocker therapy after MI does not reduce the composite of death, recurrent MI, or heart failure in patients with preserved LVEF (≥50%) and no other indication for beta blockade. These data support a paradigm shift away from universal long‑term beta‑blocker prescription in this subgroup, favoring individualized decision‑making that balances potential symptomatic benefit or other indications against the absence of demonstrated outcome benefit and the risk of adverse effects.
Funding and registration
As reported in the pooled analysis: funded by Centro Nacional de Investigaciones Cardiovasculares Carlos III and others. PROSPERO database number CRD420251119176.
References
Kristensen AMD, Rossello X, Atar D, Yndigegn T, Kimura T, Latini R, Lindahl B, Halvorsen S, Olsen MH, Fuster V, Hofmann R, Vikenes K, Maeng M, Erlinge D, Pocock S, Karlström P, Bakken A, Lange T, Barrabés JA, Benatar J, Raposeiras‑Roubin S, Held C, Piepoli M, Fagerland MW, Holmager T, Ozasa N, Prescott EIB, Munkhaugen J, Jernberg T, Ibanez B; Beta‑Blocker Trialists’ Collaboration Study Group. Beta‑Blockers after Myocardial Infarction with Normal Ejection Fraction. N Engl J Med. 2025 Nov 9. doi: 10.1056/NEJMoa2512686. Epub ahead of print. PMID: 41211954.