Linking To And Excerpting From CoreIM’s “Beta-Blockers & REDUCE-AMI Trial: Beyond Journal Club Segment with NEJM Group”

Posted on June 27, 2025 by Tom Wade MD

Today, I review, link to, and excerpt from CoreIM‘s Beta-Blockers & REDUCE-AMI Trial: Beyond Journal Club Segment with NEJM Group.

All that follows is from the above resource.

Posted: June 25, 2025
By: Dr. Chris Kotanidis, Dr. Clem Lee, Dr. Shreya P. Trivedi and Dr. Greg Katz
Graphic: Dr. Jimin Hwang
Peer Review: Dr. Jane Leopold

Podcast: Play in new window | Download

Time Stamps

  • 00:48 Background on Beta Blockers and Their Mechanism
  • 02:41 Historical Context of Beta Blockers in Heart Disease
  • 04:56 Capricorn Trial and Its Impact
  • 07:17 Emergence of Doubts About Beta Blockers
  • 10:09 Introduction to the REDUCED-AMI Trial
  • 15:52 Discussion on Trial Interpretation and Clinical Implications
  • 16:18 Comparison with Other Trials and Future Directions

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Show Notes

Background

  • Beta blockers decrease myocardial oxygen demand by reducing:
    • Heart rate
    • Blood pressure
    • Myocardial contractility
  • Trials that established the clinical benefit of beta blockers in patients with left ventricular ejection fraction (LVEF) <40% and stabilized HF:
    • NOTE: These trials were conducted in the pre-reperfusion, pre-P2Y12 inhibitor* era

*Antiplatelet medicines – P2Y12 inhibitors from Medline Plus

Guidelines

  • 2025 ACC/AHA Guideline: early initiation of oral beta-blocker therapy post-MI to reduce the risk of arrhythmias and reinfarction for the management of patients with acute coronary (Class IA indication).
    • NOTE: Long-term benefit from continued use after hospital discharge remains unclear in patients with preserved LVEF!
  • 2023 ESC Guideline:prescribing beta-blockers after uncomplicated ACS in patients with LVEF >40% is less well established.

Evolution and mechanism of action of beta-blockers

  • Types of beta‐blockers:
    • Non‐selective beta‐blockers
    • Selective beta‐blockers
  • Beta₁‐receptor
    • Location:
      • Heart
        • Positive chronotropic effects (increases heart rate)
        • Positive inotropic effects (increases contractility of the myocardium)
      • Kidney
        • Increased release of renin, which in turn increases blood pressure
  • Beta₂‐receptor
    • Location:
      • Smooth muscle cells
        • Promotes relaxation
      • Skeletal muscle cells
        • Promotes tremor and increased glycogenolysis
      • Liver
        • Increases glycogenolysis
  • Beta₃‐receptor
    • Location:
      • Adipose tissue
        • Induces lipolysis
  • Administration: intravenous and oral
  • First‐generation non‐selective beta‐blockers
    • Affect all beta‐receptors.
    • (e.g. propranolol, oxprenolol, sotalol, timolol)
  • Second‐generation selective beta‐blockers
    • Mainly affect the heart
    • e.g. metoprolol, bisoprolol, acebutolol, atenolol, esmolol
  • Third‐generation beta‐blockers,  combined non‐selective beta‐blocking effects and alpha‐blocking effects (e.g. carvedilol)
    • Affect all beta‐receptors plus alpha‐receptors in the vessels, lowering blood pressure
    • e.g. carvedilol

Beta blockers following an MI by decade

  • 1980s
    • Beta-Blocker Heart Attack Trial or BHAT (1982)
      • Multicenter, randomized, double-blind, placebo-controlled trial
      • Evaluated the effect of propranolol on mortality in patients who had survived an acute myocardial infarction
        • Population: 3,837 patients within 5–21 days after myocardial infarction
        • Randomization:  propranolol (180–240 mg/day in divided doses) or placebo
          • Maintenance dose was determined based on serum drug levels
        • Primary endpoint: total mortality during an average follow-up of 27 months
        • Outcome: Propranolol significantly reduced total mortality compared to placebo
          • Greatest benefit observed in patients at higher risk, such as those with persistent ST-segment depression on ECG after infarction
        • Clinical impact: Established long-term beta-blocker therapy as a standard of care for secondary prevention after myocardial infarction, especially in high-risk subgroups
  • 1990s
    • CAPRICORN (Carvedilol Post-Infarct Survival Control in Left Ventricular Dysfunction) trial (2001)
      • Multicenter, randomized, double-blind, placebo-controlled study
      • Evaluated carvedilol in patients with left ventricular ejection fraction (LVEF) ≤40% after acute myocardial infarction (MI)
        • Population: 1,959 patients were enrolled 3–21 days post-MI, all clinically stable and already receiving standard post-MI therapy, including ACE inhibitors, aspirin, and statins
          • Approximately half had clinical heart failure at baseline.
        • Randomization: carvedilol (starting at 6.25 mg twice daily, titrated as tolerated to a maximum of 25 mg twice daily) or placebo, with a mean follow-up of 1.3 years.
        • Outcome (Primary): All-cause mortality was significantly reduced in the carvedilol group (11.9%) compared to placebo (15.3%)
          • Hazard ratio 0.77 (95% CI 0.60–0.98, p=0.03)
          • Relative risk reduction: 23%
        • Outcome (Secondary): Carvedilol also reduced cardiovascular mortality, recurrent nonfatal MI, and the composite of all-cause mortality or nonfatal MI
        • Clinical Impact: carvedilol provides additional mortality and morbidity benefit in post-MI patients with LV dysfunction, on top of contemporary standard-of-care therapies
  • 2000s
    •  Advent of modern therapies!
      • Anti-platelet agents
      • Statins
      • Percutaneous coronary interventions
    • This led to a re-evaluation of the role of beta blockers!
      • Questions arose regarding their efficacy in stable ischemic heart disease (IHD) without recent MI or heart failure. 
  • 2010s
    • Meta-analysis (2015)
    • Population: 10 observational studies with a total of 40,873 patients who had acute myocardial infarction (AMI) and underwent percutaneous coronary intervention (PCI)
    • Results:
      • Oral beta-blocker use after PCI for AMI was associated with a significant reduction in all-cause mortality
        • Adjusted hazard ratio 0.76, 95% CI 0.62–0.94
      • The survival benefit of beta-blockers was significant within the first year of follow-up, but not consistently observed beyond one year.
      • The mortality benefit was most pronounced in patients with
        • Reduced ejection fraction
        • Lower use of other secondary prevention drugs
        • Non-ST-segment elevation myocardial infarction (NSTEMI)
      • There was no significant mortality benefit or reduction in cardiac death, recurrent myocardial infarction, or heart failure readmission with oral beta-blocker therapy for patients with preserved LVEF after acute myocardial infarction treated with percutaneous coronary intervention.
  • 2021 Cochrane systematic review
    • in patients who have had a myocardial infarction but do not have heart failure (and with LVEF >40%):
      • Beta-blockers probably reduce the risks of all-cause mortality and myocardial reinfarction compared with placebo or no intervention
        • However, the evidence base is limited by high risk of bias from trials from the pre-reperfusion era and lack of modern-era trials. 

REDUCE-AMI, NEJM, 2024

REDUCE-AMI

  • Study Design: Registry-based, prospective, open-label, parallel-group, randomized clinical trial
    • Three countries: Sweden (38 centers), Estonia (1 center), and New Zealand (6 centers)
  • Population: Sept 2017-May 2023
    • 5020 patients were enrolled;
      • 2508 were assigned to beta blockade
      • 2512 to non beta blockade.
  • The median age of the patients was 65 years, 22.5% of the patients were women, and 35.2% had an ST-segment elevation myocardial infarction.
  • Methods:
    • Inclusion criteria:
      • Men or women age ≥18 at the time of signing the informed consent
      • Day 1-7 after type 1 MI(either ST elevation MI or non-ST-elevation MI)
        • According to the fourth universal definition of MI
      • Coronary angiography performed during hospitalization.
      • Obstructive coronary artery disease documented by coronary angiography,
        • Stenosis ≥50 %
        • FFR ≤0.80 or
        • iFR ≤0.89 in any segment at any time point before randomization.
      • Echocardiography performed after the MI showing a preserved  ejection fraction defined as EF≥50%.
    • Exclusion criteria:
      • Any condition that may influence the patient’s ability to comply with study protocol
      • Contraindications for beta-blockade
      • Indication for beta-blockade other than as secondary prevention according to the treating physician
    • Randomization: 1:1 according to trial center
      • Assigned by a Web-based system
      • Beta-blocker group:
        • Metoprolol (first choice) or bisoprolol (alternative) during the remaining hospital stay and received a prescription for continued use after discharge.
          • Encouraged to aim for metoprolol dose of at least 100mg or bisoprolol dose of at least 5mg

Primary endpoint:

    • Composite of death from any cause or new myocardial infarction
  • Secondary endpoints:
    • death from any cause
    • death from cardiovascular causes
    • myocardial infarction
    • hospitalization for atrial fibrillation
    • hospitalization for heart failure
  • Results:
    • Population:
        • Median age: 65 years
        • 22.5% of the patients were women
        • 35.2% had an ST-segment elevation myocardial infarction
      • Beta-blocker group: 2508 patients w
        • 1560 (62.2%) treated with metoprolol
        • 948 (37.8%) treated with bisoprolol
      • Median follow-up: 3.5 years (interquartile range, 2.2 to 4.7) in each trial group.
    • Primary:
    • Secondary:
      • Beta-blocker treatment did not appear to lead to a lower cumulative incidence of the secondary end points of:
        •  death from any cause
        • death from cardiovascular causes
        • myocardial infarction
        • hospitalization for atrial fibrillation
        • hospitalization for heart failure

ABYSS, NEJM, 2024

  • Study Design: multicenter, open label, randomized, noninferiority trial
    • Conducted at 49 sites in France
  • Randomization: patients with a history of myocardial infarction, in a 1:1 ratio
    •  Interruption or continuation of beta-blocker treatment
  • Follow up: Median of 3 years
  • Outcomes:
    • Interruption of long-term beta-blocker therapy was NOT noninferior to continuation for the composite outcome of:
      • death
      • nonfatal MI
      • nonfatal stroke
      • cardiovascular hospitalization The risk difference for the primary outcome was 2.8 percentage points (95% CI, <0.1 to 5.5), failing to meet the pre specified noninferiority margin of 3%
    • No improvement in quality of life with beta-blocker interruption  Nnumerical increase in recurrent angina and coronary-related hospitalizations was observed in the interruption group,
      • Though these were not formally tested for significance.

Conclusions/Takeaways

  • Beta blockers remain a mainstay of management for patients with reduced ejection fraction following myocardial infarction and in patients with chronic systolic heart failure and no prior myocardial infarction.
  • In patients with preserved left ventricular function after an uncomplicated myocardial infarction, the benefit of beta blockers is uncertain and should not be assumed based on older trials.
  • Longstanding clinical practices  should be periodically re-evaluated in light of changes in the standard of care.
    • Most evidence should have an expiration date.
      • Just because something has been standard for decades does not mean it remains the best approach today.
  • Historical studies supporting beta blockers after myocardial infarction were conducted in the pre-reperfusion era and may not apply to all patients treated with contemporary revascularization, lipid lowering , and antithrombotic therapies.
  • REDUCE-AMI found no benefit from routine beta blocker initiation in post-MI patients with preserved ejection fraction, challenging a longstanding default approach in cardiology.

Other resources:

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