REDUCE-AMI: Beta-blockers in MI & LVEF >=50%

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REDUCE-AMI: NEJM 2024 DOI: 10.1056/NEJMoa2401479

Bottom line: In patients with myocardial infarction, LVEF >=50%, and no other indication for beta-blockers (angina, arrhythmia, heart failure), beta-blockers do not meaningfully reduce death or recurrent myocardial infarction. Additional trials that should complete in 2024 will provide additional data, including in patients with LVEF 41-49%.

Patients (n=5020 randomized)

  • Setting: Sweden (95%), Estonia, NZ, 2017-2023

  • Included:

    • Adults 1-7 days from MI

    • Obstructive coronary artery disease (CAD) on coronary angiography (i.e. stenosis >=50%, FFR <=0.8 or iFR <=0.89 in any segment)

    • Echo after MI showing left ventricular ejection fraction (LVEF) >=50% (i.e. preserved)

  • Excluded: Any other indication for beta-blockers; any contraindication to beta-blockers.

  • Baseline:

    • Age 65, 22% female

    • Median 2 days from admission to randomization

    • LVEF & coronary angiography variables not reported

    • STEMI 35%, PCI 95-96%

    • Comorbidities: Prior MI ~7%, diabetes 14%, HTN 46%, smoking ~20%

    • Medications:

      • Beta-blocker prior to admission ~11-12%

      • At discharge: ASA/P2Y12 inhibitor 95-98%, ACEI/ARB 80%, statin, 98-99%

Intervention: Beta-blocker

  • Metoprolol (1st choice; target >=100 mg/d) or bisoprolol (target >=5 mg/d)

  • 96% prescribed beta-blocker on discharge (2/3 metoprolol, 1/3 bisoprolol), ~91% receiving at “month 2” visit, 82% receiving at “1-year” visit

Comparator: No beta-blocker

  • 10% prescribed beta-blocker on discharge

Outcomes @ median 3.5 years

Primary outcome (death from any cause or new MI): Beta-blocker 7.9%, no beta-blocker 8.3% (hazard ratio [HR] 0.96, 95% confidence interval [CI] 0.79-1.16)

  • Death: 3.9% vs 4.1% (HR 0.94, 95% CI 0.71-1.24)

  • MI: 4.5% vs 4.7%

  • Bayesian re-analysis (using https://benjamin-andrew.shinyapps.io/bayesian_trials/): Assuming non-informative prior (ignoring outdated post-MI beta-blocker RCTs from the pre-reperfusion era), posterior probability=19% of an absolute risk reduction of >=1% absolute risk reduction (HR<=0.88) at 3.5 years

Safety

  • Hospitalization for bradycardia, 2-30 AVB, hypotension, syncope, or PPM implantation: 3.4% vs 3.2% (HR 1.08, 95% CI 0.79-1.46)

  • Hospitalization for asthma or COPD: 0.6% in both groups (HR 0.94, 0.46-1.89)

Internal validity

  • Randomization using permuted blocks

  • Allocation via web-based system

  • Performance bias: Moderate crossover (18% from beta-blocker to no beta-blocker by 1 year in intervention group; ~10% to beta-blocker in comparator group) biases the results toward the null

  • Detection bias: No blinding of participants or treating clinicians (open-label), but objective (death from any cause) & semi-objective outcomes (e.g. MI hospitalization) minimize risk of detection bias

  • No loss to follow-up (but missing data for 8 who emigrated, 4 withdrew consent)

  • Intention-to-treat analysis

Generalizability & other considerations

  • Who does these results NOT apply to?

    • These results do NOT apply to patients with another valid cardiovascular indication for beta-blockers, including:

      • Angina (despite PCI/CABG, if indicated)

      • Arrhythmia (ventricular arrhythmia, atrial arrhythmia requiring rate control, congenital long QT syndrome, etc)

      • Ejection fraction <50% [especially those with heart failure]

      • HF with reduced/mildly-reduced/improved LVEF

  • With that said, these results broadly apply to patients not captured within the above, which is most patients with MI seen in contemporary practice

  • This is the first contemporary trial of beta-blockers post-MI (see https://nerdcat.org/studysummaries/beta-blockers-cad for our summary of this previous evidence)

    • Prior to this trial, practice was mainly driven by a 1999 meta-analysis of RCTs conducted 1966-1991; prior to widespread use of now-established treatments for ACS/MI (especially reperfusion with PCI/fibrinolytics, ASA, statins)

  • Several other ongoing trials will shed further light on the role of beta-blockers in patients post-MI with LVEF >40%, including:

    • ABYSS (n=3700, France): Beta-blocker continuation vs discontinuation 6 months post-MI (excluding patients with LVEF <40%, persistent angina/ischemia, HF in last 2 y, arrhythmia)

    • BETAMI (n=2900, Norway) & DANBLOCK (n=2760, Denmark): Beta-blocker vs no beta-blocker post-MI (excluding patients with LVEF <40%, clinical heart failure, LV akinesia in >=3 segments, arrhythmia)