Clinical Outcomes with Beta-Blockers for Myocardial Infarction:A Meta-Analysis of Randomized Trials

In Review

Bangalore S, et al. "Clinical outcomes with β-blockers for myocardial infarction: a meta-analysis of randomized trials". The American Journal of Medicine. 2014. 127(10):939-953.
PubMed • Full text

Clinical Question

In patients who have suffered a myocardial infarction (MI), what are the roles of early beta-blocker therapy and post-MI beta-blocker therapy in reducing morbidity and mortality?

Bottom Line

Beta-blockers post-MI, as well as the use of early IV beta-blockers in management of acute MI may not provide mortality reductions, may only provide decreased reinfarction rates and angina up to the first 30 days following the MI, and increase heart failure and cardiogenic shock.

Major Points

Multiple guidelines recommend the initiation of oral beta-blockers after myocardial infarction based on data that they reduce mortality. Unfortunately, the majority of these studies are from the “pre-reperfusion era”, or when there was a different standard of care for the management of acute MI. Recently, a large, prospective cohort from the REACH registry identified that there was no difference in all-cause mortality, cardiovascular mortality, nonfatal stroke, and nonfatal MI between those treated with a beta-blocker post-MI and those who were not.

This 2014 meta-analysis of randomized trials looked at randomized trials that compared beta-blockers with controls in patients with myocardial infarction. The trials were stratified based on whether or not they were conducted in the pre-reperfusion era or the reperfusion era. It was found that while there were significant effects on reducing all-cause mortality, cardiovascular mortality, myocardial infarction, sudden death, and cardiogenic shock in the pre-reperfusion era, there was only a significant effect on recurrent MI (NNT=209) and angina (NNT=26). Even though the short term outcomes of MI and angina were reduced, heart failure (NNH=79) and cardiogenic shock (NNH=90) were increased.

Guidelines

AHA/ACCF Secondary Prevention and Risk Reduction Therapy for Patients with Coronary and Other Atherosclerotic Disease (2011, adapted)

• Beta-blocker therapy should be used in all patients with left ventricular dysfunction with heart failure or prior MI (Level of Evidence: A)
• Beta-blocker therapy should be started and continued for three years in all patients with normal left ventricular function who have had and MI or ACS (Level of Evidence: B)

NICE Guidance-MI--secondary prevention: Secondary prevention in primary and secondary care for patients following a myocardial infarction (2013, adapted)

• Offer people a beta-blocker as soon as possible after an MI, when the person is hemodynamically stable
• Continue a beta-blocker for at least 12 months after an MI in people without left heart ventricular systolic dysfunction or heart failure
• Continue a beta-blocker indefinitely in people with left ventricular systolic dysfunction
• Offer all people who have had an MI more than 12 months ago, who have left ventricular systolic dysfunction, a beta-blocker whether or not they have symptoms
• Do not offer people without left ventricular dysfunction or heart failure, who have had an MI more than 12 months ago, treatment with a beta-blocker unless there is an additional clinical indication for a beta-blocker

Design

• Intention-to-treat meta-analysis of randomized trials
• 60 RCTs included in final analysis (102,003 patients)
  • Pre-reperfusion era vs. reperfusion era
    • Pre-reperfusion era (n=48 trials)
    • Reperfusion era (n=12)
      • Defined as >50% of patients receiving thrombolytics or with revascularization or with aspirin/statin
  • Acute MI vs. prior MI (all outcomes were pooled for acute MI, then for prior MI and stratified as pre-reperfusion and reperfusion)
    • Acute MI (n=40 trials)
    • Post-MI (n=20 trials)
• Systematic search occurred until February 2013
• Mean follow up of trials: 10 months (range: in hospital to 4 years)
  • 640,891 patient-months of follow-up
• Primary Outcome: All-cause mortality

Population

Inclusion Criteria

• Trials comparing beta-blockers with controls in patients with myocardial infarction
• RCTs enrolling at least 100 patients

Exclusion Criteria

• Trials comparing two different beta-blockers
• Post-MI heart failure/ left ventricular dysfunction trials

Outcomes

P values stated are interaction values for the pre-reperfusion era vs. the reperfusion era trials; p<0.10 is significant.

Primary Outcomes

All cause mortality

Acute myocardial infarction trials (p=0.02; I2=0.0%)

Pre-reperfusion: IRR 0.86; 95% CI 0.79-0.94

Reperfusion: IRR 0.98; 95% CI 0.92-1.05

IV beta-blockers

Pre-reperfusion: IRR 0.83; 95% CI 0.75-0.92

Reperfusion: IRR 0.98; 95% CI 0.92-1.05

Secondary Outcomes

Cardiovascular mortality

Acute myocardial infarction

Pre-reperfusion: IRR 0.87; 95% CI 0.78-0.98

Reperfusion: IRR 1.00; 95% CI 0.91-1.09

IV beta-blockers

Pre-reperfusion: IRR 0.88; 95% CI 0.78-0.99

Reperfusion: No impact

Sudden death

Acute myocardial infarction

Pre-reperfusion: IRR 0.77; 95% CI 0.56-1.05

Reperfusion: IRR 0.94; 95% CI 0.86-1.01

IV beta-blockers

Pre-reperfusion: IRR 0.59; 95% CI 0.38-0.91

Reperfusion: No impact

Recurrent myocardial infarction

Acute myocardial infarction (p=0.56, I2=0.0%)

Pre-reperfusion: IRR 0.78; 95% CI 0.62-0.97

Reperfusion: IRR 0.72; 95% CI 0.62-0.83 (NNT=209)

IV beta-blockers

Pre-reperfusion: IRR 0.78; 95% CI 0.62-0.98

Reperfusion: IRR 0.72; 95% CI 0.0.62-0.84

Angina pectoris

Acute myocardial infarction (p=0.39; I2=0.0%)

Pre-reperfusion: IRR 0.88; 95% CI 0.82-0.95

Reperfusion: IRR 0.80; 95% CI 0.65-0.98 (NNT=26)

IV beta-blockers

Pre-reperfusion: IRR 0.88; 95% CI 0.82-0.95

Reperfusion: IRR 0.80; 95% CI 0.65-0.99

Heart failure

Acute myocardial infarction (p=0.46; I2=0.0%)

Pre-reperfusion: IRR 1.06; 95% CI 0.98-1.16

Reperfusion: IRR 1.10; 95% CI 1.05-1.16 (NNH=79)

IV beta-blockers

Pre-reperfusion: IRR 1.07; 95% CI 0.97-1.08

Reperfusion: IRR 1.10; 95% CI 1.05-1.16

Cardiogenic shock

Acute myocardial infarction (p=0.03; I2=0.0%)

Pre-reperfusion: IRR 1.05; 95% CI 0.89-1.23

Reperfusion: IRR 1.29; 95% CI 1.18-1.41 (NNH=90)

Stroke

Acute myocardial infarction

Pre-reperfusion: IRR 2.96; 95% CI 0.47-18.81

Reperfusion: IRR 1.09; 95% CI 0.91-1.30

IV beta-blockers

Pre-reperfusion: IRR 1.06; 95% CI 0.89-1.27

Reperfusion: IRR 1.29; 95% CI 1.18-1.41

Drug discontinuation

Acute myocardial infarction (p<0.0001; I2=74.8%)

Pre-reperfusion: IRR 1.13; 95% CI 1.02-1.24

Reperfusion: IRR 1.64; 95% CI 1.55-1.73

Results for post-MI trials were similar for all outcomes.

Sensitivity Analysis

Because the results of the reperfusion trials are largely influenced by one trial (COMMIT), a sensitivity analysis looked at the results excluding COMMIT which still yielded no mortality benefit for beta-blockers (IRR 0.76; 95% CI 0.48-1.21). The analysis was also done to solely look at the trials with low risk for bias since many of the results for the beneficial effect on mortality in the acute MI trials was influenced by high risk for bias trials. No benefit was found here either (IRR 0.96; 95% CI 0.91-1.02).

Criticisms

• 36/48 pre-reperfusion trials were determined to be at high risk for bias, while 6/12 of the reperfusion trials were
• The results from the reperfusion trials are driven by the results from the COMMIT trial
• The the effect of reperfusion vs. modern medical therapy was unable to be distinguished in the reperfusion trials

Funding

There was no funding for this meta-analysis. One author, PJD, has received grants from various drug companies.