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Requests for reprints should be addressed to Sripal Bangalore, MD, MHA, Cardiac Catheterization Laboratory, Cardiovascular Outcomes Group, Cardiovascular Clinical Research Center, New York University School of Medicine, The Leon H. Charney Division of Cardiology, New York, NY 10016.
Debate exists about the efficacy of β-blockers in myocardial infarction and their required duration of usage in contemporary practice.
Methods
We conducted a MEDLINE/EMBASE/CENTRAL search for randomized trials evaluating β-blockers in myocardial infarction enrolling at least 100 patients. The primary outcome was all-cause mortality. Analysis was performed stratifying trials into reperfusion-era (> 50% undergoing reperfusion or receiving aspirin/statin) or pre-reperfusion-era trials.
Results
Sixty trials with 102,003 patients satisfied the inclusion criteria. In the acute myocardial infarction trials, a significant interaction (Pinteraction = .02) was noted such that β-blockers reduced mortality in the pre-reperfusion (incident rate ratio [IRR] 0.86; 95% confidence interval [CI], 0.79-0.94) but not in the reperfusion era (IRR 0.98; 95% CI, 0.92-1.05). In the pre-reperfusion era, β-blockers reduced cardiovascular mortality (IRR 0.87; 95% CI, 0.78-0.98), myocardial infarction (IRR 0.78; 95% CI, 0.62-0.97), and angina (IRR 0.88; 95% CI, 0.82-0.95), with no difference for other outcomes. In the reperfusion era, β-blockers reduced myocardial infarction (IRR 0.72; 95% CI, 0.62-0.83) (number needed to treat to benefit [NNTB] = 209) and angina (IRR 0.80; 95% CI, 0.65-0.98) (NNTB = 26) at the expense of increase in heart failure (IRR 1.10; 95% CI, 1.05-1.16) (number needed to treat to harm [NNTH] = 79), cardiogenic shock (IRR 1.29; 95% CI, 1.18-1.41) (NNTH = 90), and drug discontinuation (IRR 1.64; 95% CI, 1.55-1.73), with no benefit for other outcomes. Benefits for recurrent myocardial infarction and angina in the reperfusion era appeared to be short term (30 days).
Conclusions
In contemporary practice of treatment of myocardial infarction, β-blockers have no mortality benefit but reduce recurrent myocardial infarction and angina (short-term) at the expense of increase in heart failure, cardiogenic shock, and drug discontinuation. The guideline authors should reconsider the strength of recommendations for β-blockers post myocardial infarction.
In the treatment of patients with myocardial infarction, β-blockers reduced mortality in the pre-reperfusion but not in the reperfusion era, where there was reduction (short-term) in myocardial infarction and angina, but increase in heart failure, cardiogenic shock, and drug discontinuation.
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The benefit for recurrent myocardial infarction and angina reduction by β-blockade in the reperfusion era appeared to be short term (30 days).
For more than a quarter of a century, β-blockers have been a cornerstone in the treatment of patients with myocardial infarction. The American College of Cardiology Foundation/American Heart Association (ACCF/AHA) ST-elevation myocardial infarction guideline gives a class I recommendation for oral β-blockers within the first 24 hours in patients with myocardial infarction, and a class IIa indication for intravenous β-blockers for patients who are hypertensive or having ongoing ischemia.
2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: executive summary: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines.
Not surprisingly, the Centers for Medicare and Medicaid Services, the National Committee for Quality Assurance, the National Quality Forum, and the Joint Commission on Accreditation of Healthcare Organizations have adopted β-blocker use at discharge post myocardial infarction as a quality indicator.
However, many of the data to support the use of β-blockers in myocardial infarction predate reperfusion and contemporary medical therapy with statins and antiplatelet agents.
Randomised trial of intravenous atenolol among 16 027 cases of suspected acute myocardial infarction: ISIS-1. First International Study of Infarct Survival Collaborative Group.
beta-Blocker use in patients after percutaneous coronary interventions: one size fits all? Worse outcomes in patients without myocardial infarction or heart failure.
Moreover, there has been longstanding controversy over the required duration of treatment post myocardial infarction, with the ACCF/AHA guidelines recommending a minimum of 3 years,
AHA/ACCF Secondary Prevention and Risk Reduction Therapy for Patients with Coronary and other Atherosclerotic Vascular Disease: 2011 update: a guideline from the American Heart Association and American College of Cardiology Foundation.
ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: the Task Force for the management of acute coronary syndromes (ACS) in patients presenting without persistent ST-segment elevation of the European Society of Cardiology (ESC).
Our objectives were to evaluate: 1) the impact of contemporary treatment (reperfusion/aspirin/statin) status on the association of β-blocker use and outcomes in patients with myocardial infarction; 2) the role of early intravenous β-blocker; and 3) the required duration of β-blocker use.
Methods
Study Design And Eligibility Criteria
We performed a systematic search (using PUBMED, EMBASE, Cochrane Central Register of Controlled Trials [CENTRAL], and Google Scholar), without language restriction, for randomized trials using the Medical Subject Headings terms “β-blockers” and the names of individual β-blockers, and “myocardial infarction,” until February 2013 (Week 1).
Inclusion criteria were trials comparing β-blockers with controls (placebo/no treatment/other active treatment) in patients with myocardial infarction enrolling at least 100 patients.
Exclusion criteria were: 1) trials comparing 2 different β-blockers; and 2) postmyocardial infarction heart failure/left ventricular systolic dysfunction trials such as the Carvedilol Post-Infarct Survival Control in LV Dysfunction (CAPRICORN) trial,
Two authors (KT, SB) independently reviewed trial eligibility and assessed risk of bias using the Cochrane Collaboration criteria based on the following components: sequence generation of allocation; allocation concealment; blinding of participants, staff, and outcome assessors; incomplete outcome data; selective outcome reporting; and other sources of bias.
Trials with high or unclear risk of bias for the first 3 criteria were considered as high risk of bias trials and the rest as trials with lower risk of bias.
Outcomes
The primary outcome was all-cause mortality. Secondary outcomes were cardiovascular mortality, sudden death, recurrent myocardial infarction, angina pectoris, heart failure, cardiogenic shock, stroke, and drug discontinuation. In trials that reported long-term outcomes beyond the randomized treatment phase, only the outcomes associated with randomized treatment phase were extracted.
Data Extraction and Synthesis
Studies have shown that the mortality rate after a myocardial infarction falls steeply and progressively from the onset of pain to the end of the first 48 hours.
Therefore, trials were classified as acute myocardial infarction trials (randomized within 48 hours of symptom onset) or postmyocardial infarction trials (randomized > 48 hours of symptoms). In addition, trials were classified as reperfusion-era trials if > 50% of patients received reperfusion either with thrombolytics or with revascularization or aspirin/statin. Otherwise, they were considered to be pre-reperfusion-era trials.
Statistical Analysis
We performed an intention-to-treat meta-analysis in line with recommendations from the Cochrane Collaboration and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement
using standard software (STATA 9.0, StataCorp, College Station, Tex). The analysis used the incident rate of outcomes per 100 person-months to obtain the log incident rate ratios (IRR) of one treatment relative to another treatment.
Analysis was performed for the acute myocardial infarction and postmyocardial infarction cohorts separately after stratifying trials based on the reperfusion-era status. For the primary outcome, the difference between the 2 strata (pre-reperfusion vs reperfusion) was tested by a test for interaction,
with Pinteraction < .10 considered significant and indicated a treatment effect that differed considerably between the 2 strata. If the test for interaction for the primary outcome was significant, all other outcomes were interpreted separately for the 2 strata. In addition, further analysis was performed categorizing trials by early initial intravenous dose vs no initial intravenous β-blocker dose to test for the effect of intravenous β-blocker on outcomes. Finally, a series of landmark analyses (at 30 days post myocardial infarction, between 30-day and 1-year and > 1-year landmark time points) were performed to evaluate the duration of benefit of β-blocker. Patients who died were censored at the beginning of each landmark analysis, that is, for the 30-days to 1-year analysis, patients who died within 30 days were excluded.
and is similar to interim analyses in a trial, where monitoring boundaries are used to decide whether a trial could be terminated early for efficacy or for futility.
Sensitivity Analysis
Various sensitivity analyses were performed to test the robustness of the results. Analysis was performed: 1) combining acute myocardial infarction and postmyocardial infarction trials; 2) excluding trials that compared β-blockers with active comparator; 3) using traditional meta-analysis with counts rather than patient-months; 4) restricting analyses to trial enrolling ≥ 400 patients; 5) excluding ClOpidogrel and Metoprolol in Myocardial Infarction Trial (COMMIT); and 6) based on the quality assessment of the trials. In addition, a meta-regression analysis was performed to evaluate the relationship of percentage of patients with reperfusion in each trial on the risk ratio of β-blockers vs controls for mortality.
Results
Trial Selection
We identified 60 trials that enrolled 102,003 patients who were followed up for a mean of 10 months (range: in-hospital to 4 years), with 640,891 patient-months of follow-up (Figure 1). Fourteen trials (20,418 patients) provided data on > 1-year follow-up. Forty trials were considered as acute myocardial infarction trials and the rest (n = 20) were postmyocardial infarction trials (Table 1).
Persistent reduction of mortality for five years after one year of acebutolol treatment initiated during acute myocardial infarction. The APSI Investigators. Acebutolol et Prevention Secondaire de l'Infarctus.
The Lopressor Intervention Trial: multicentre study of metoprolol in survivors of acute myocardial infarction. Lopressor Intervention Trial Research Group.
Lombardo M. Selvini A. Motolese M. Beta-blocking treatment in 440 cases of acute myocardial infarction: a study with oxprenolol. Proceedings of Florence International Meeting on Myocardial Infarction. Excerpta Medica,
Amsterdam1979
Effect of early metoprolol on infarct size in ST-segment elevation myocardial infarction patients undergoing primary percutaneous coronary intervention: the Effect of Metroprolol in Cardioprotection During an Acute Myocardial Infarction (METOCARD-CNIC) Trial.
Failure of intravenous pindolol to reduce the hemodynamic determinants of myocardial oxygen demand or enzymatically determined infarct size in acute myocardial infarction.
Effects of early treatment with captopril and metoprolol singly or together on six-month mortality and morbidity after acute myocardial infarction. Results of the RIMA (Rimodellamento Infarto Miocardico Acuto) study. The RIMA researchers.
G Ital Cardiol.1999; 29 (discussion 125–129): 115-124
Effects of early use of atenolol or captopril on infarct size and ventricular volume A double-blind comparison in patients with anterior acute myocardial infarction.
Short-term effects of early intravenous treatment with a beta-adrenergic blocking agent or a specific bradycardiac agent in patients with acute mycardial infarction receiving thrombolytic therapy.
Persistent reduction of mortality for five years after one year of acebutolol treatment initiated during acute myocardial infarction. The APSI Investigators. Acebutolol et Prevention Secondaire de l'Infarctus.
Randomised trial of intravenous atenolol among 16 027 cases of suspected acute myocardial infarction: ISIS-1. First International Study of Infarct Survival Collaborative Group.
The Lopressor Intervention Trial: multicentre study of metoprolol in survivors of acute myocardial infarction. Lopressor Intervention Trial Research Group.
Lombardo M. Selvini A. Motolese M. Beta-blocking treatment in 440 cases of acute myocardial infarction: a study with oxprenolol. Proceedings of Florence International Meeting on Myocardial Infarction. Excerpta Medica,
Amsterdam1979
Effect of early metoprolol on infarct size in ST-segment elevation myocardial infarction patients undergoing primary percutaneous coronary intervention: the Effect of Metroprolol in Cardioprotection During an Acute Myocardial Infarction (METOCARD-CNIC) Trial.
Failure of intravenous pindolol to reduce the hemodynamic determinants of myocardial oxygen demand or enzymatically determined infarct size in acute myocardial infarction.
Effects of early treatment with captopril and metoprolol singly or together on six-month mortality and morbidity after acute myocardial infarction. Results of the RIMA (Rimodellamento Infarto Miocardico Acuto) study. The RIMA researchers.
G Ital Cardiol.1999; 29 (discussion 125–129): 115-124
Effects of early use of atenolol or captopril on infarct size and ventricular volume A double-blind comparison in patients with anterior acute myocardial infarction.
Short-term effects of early intravenous treatment with a beta-adrenergic blocking agent or a specific bradycardiac agent in patients with acute mycardial infarction receiving thrombolytic therapy.
AMI = acute myocardial infarction; APSI = Acebutolol et Prévention Secondaire de l'Infarctus; BHAT = Beta Blocker Heart Attack Trial; COMMIT = Clopidogrel and Metoprolol in Myocardial Infarction Trial; CPRG = Coronary Prevention Research Group; EIS = European Infarction Study; EMIT = Esmolol Myocardial Ischemia Trial; ICSG = The International Collaborative Study Group; ISIS -1 = First International Study of Infarct Survival Collaborative Group; JCBMI = The Japanese beta Blockers and Calcium Antagonists Myocardial Infarction; LIT = Lopressor Intervention Trial Research Group; MEMO = Metoprolol-Morphine Study Group; METOCARD-CNIC = Effect of Metroprolol in Cardioprotection During an Acute Myocardial Infarction trial; MIAMI = Metoprolol in Acute Myocardial Infarction; MILIS = Multicenter Investigation for the Limitation of Infarct Size; PCI = percutaneous coronary intervention; Post MI = post myocardial infarction; RIMA = Rimodellamento Infarcto Miocardico Acuto Study; TIMI = Thrombolysis in Myocardial Infarction; tPA = tissue plasminogen activator; UKCSG = UK Collaborative Study Group.
A majority of the trials (n = 48; 31,479 patients) were in the pre-reperfusion era, with only 12 trials in the reperfusion era (48,806 patients). The pre-reperfusion-era trials were mainly high risk for bias trials (36/48 trials), whereas this proportion was somewhat lower in the reperfusion-era trials (6/12 trials).
In the acute myocardial infarction trials, a significant interaction (Pinteraction = .02) was noted with reperfusion status such that β-blockers reduced mortality in the pre-reperfusion era (IRR 0.86; 95% CI, 0.79-0.94) but not in the reperfusion era (IRR 0.98; 95% CI, 0.92-1.05) (Figure 2).
Figure 2β-blockers vs controls for the outcome of all-cause mortality in acute myocardial infarction trials. Analysis stratified by reperfusion status. CI = confidence interval; COMMIT = Clopidogrel and Metoprolol in Myocardial Infarction Trial; EMIT = Esmolol Myocardial Ischemia Trial; ICSG = The International Collaborative Study Group; IRR = incident rate ratio; ISIS-1 = First International Study of Infarct Survival Collaborative Group; MEMO = Metoprolol-Morphine Study Group; METOCARD-CNIC = Effect of Metroprolol in Cardioprotection During an Acute Myocardial Infarction trial; MIAMI = Metoprolol in Acute Myocardial Infarction; MILIS = Multicenter Investigation for the Limitation of Infarct Size; RIMA = Rimodellamento Infarcto Miocardico Acuto Study; TIMI = Thrombolysis in Myocardial Infarction; UKCSG = UK Collaborative Study Group.
In the pre-reperfusion era, β-blockers were associated with reductions in cardiovascular mortality (IRR 0.87; 95% CI, 0.78-0.98), myocardial infarction (IRR 0.78; 95% CI, 0.62-0.97) (Figure 3), and angina (IRR 0.88; 95% CI, 0.82-0.95) (Figure 4), with no difference for sudden death (IRR 0.77; 95% CI, 0.56-1.05), heart failure (Figure 5), cardiogenic shock (Figure 6), or stroke (IRR 2.96; 95% CI, 0.47-18.81). In the reperfusion era, β-blockers were associated with reductions in myocardial infarction (IRR 0.72; 95% CI, 0.62-0.83) (number needed to treat to benefit [NNTB] = 209) (Figure 3) and angina (IRR 0.80; 95% CI, 0.65-0.98) (NNTB = 26) (Figure 4) at the expense of an increase in heart failure (IRR 1.10; 95% CI, 1.05-1.16) (number needed to treat to harm [NNTH] = 79) (Figure 5), cardiogenic shock (IRR 1.29; 95% CI, 1.18-1.41) (NNTH = 90) (Figure 6), and drug discontinuation (IRR 1.64; 95% CI, 1.55-1.73) (Figure 7), with no impact on cardiovascular mortality (IRR 1.00; 95% CI, 0.91-1.09), sudden death (IRR 0.94; 95% CI, 0.86-1.01), or stroke (IRR 1.09; 95% CI, 0.91-1.30).
Figure 3β-blockers vs controls for the outcome of myocardial infarction in acute myocardial infarction trials. Analysis stratified by reperfusion status. CI = confidence interval; COMMIT = Clopidogrel and Metoprolol in Myocardial Infarction Trial; EMIT = Esmolol Myocardial Ischemia Trial; ICSG = The International Collaborative Study Group; IRR = incident rate ratio; ISIS-1 = First International Study of Infarct Survival Collaborative Group; MEMO = Metoprolol-Morphine Study Group; METOCARD-CNIC = Effect of Metroprolol in Cardioprotection During an Acute Myocardial Infarction trial; MIAMI = Metoprolol in Acute Myocardial Infarction; MILIS = Multicenter Investigation for the Limitation of Infarct Size; RIMA = Rimodellamento Infarcto Miocardico Acuto Study; TIMI = Thrombolysis in Myocardial Infarction; UKCSG = UK Collaborative Study Group.
Figure 4β-blockers vs controls for the outcome of angina pectoris in acute myocardial infarction trials. Analysis stratified by reperfusion status. CI = confidence interval; COMMIT = Clopidogrel and Metoprolol in Myocardial Infarction Trial; EMIT = Esmolol Myocardial Ischemia Trial; ICSG = The International Collaborative Study Group; IRR = incident rate ratio; ISIS-1 = First International Study of Infarct Survival Collaborative Group; MEMO = Metoprolol-Morphine Study Group; METOCARD-CNIC = Effect of Metroprolol in Cardioprotection During an Acute Myocardial Infarction trial; MIAMI = Metoprolol in Acute Myocardial Infarction; MILIS = Multicenter Investigation for the Limitation of Infarct Size; RIMA = Rimodellamento Infarcto Miocardico Acuto Study; TIMI = Thrombolysis in Myocardial Infarction; UKCSG = UK Collaborative Study Group.
Figure 5β-blockers vs controls for the outcome of heart failure in acute myocardial infarction trials. Analysis stratified by reperfusion status. CI = confidence interval; COMMIT = Clopidogrel and Metoprolol in Myocardial Infarction Trial; EMIT = Esmolol Myocardial Ischemia Trial; ICSG = The International Collaborative Study Group; IRR = incident rate ratio; ISIS-1 = First International Study of Infarct Survival Collaborative Group; MEMO = Metoprolol-Morphine Study Group; METOCARD-CNIC = Effect of Metroprolol in Cardioprotection During an Acute Myocardial Infarction trial; MIAMI = Metoprolol in Acute Myocardial Infarction; MILIS = Multicenter Investigation for the Limitation of Infarct Size; RIMA = Rimodellamento Infarcto Miocardico Acuto Study; TIMI = Thrombolysis in Myocardial Infarction; UKCSG = UK Collaborative Study Group.
Figure 6β-blockers vs controls for the outcome of cardiogenic shock in acute myocardial infarction trials. Analysis stratified by reperfusion status. CI = confidence interval; COMMIT = Clopidogrel and Metoprolol in Myocardial Infarction Trial; EMIT = Esmolol Myocardial Ischemia Trial; ICSG = The International Collaborative Study Group; IRR = incident rate ratio; ISIS-1 = First International Study of Infarct Survival Collaborative Group; MEMO = Metoprolol-Morphine Study Group; METOCARD-CNIC = Effect of Metroprolol in Cardioprotection During an Acute Myocardial Infarction trial; MIAMI = Metoprolol in Acute Myocardial Infarction; MILIS = Multicenter Investigation for the Limitation of Infarct Size; RIMA = Rimodellamento Infarcto Miocardico Acuto Study; TIMI = Thrombolysis in Myocardial Infarction; UKCSG = UK Collaborative Study Group.
Figure 7β-blockers vs controls and drug discontinuation in acute myocardial infarction trials. Analysis stratified by reperfusion status. CI = confidence interval; COMMIT = Clopidogrel and Metoprolol in Myocardial Infarction Trial; EMIT = Esmolol Myocardial Ischemia Trial; ICSG = The International Collaborative Study Group; IRR = incident rate ratio; ISIS-1 = First International Study of Infarct Survival Collaborative Group; MEMO = Metoprolol-Morphine Study Group; METOCARD-CNIC = Effect of Metroprolol in Cardioprotection During an Acute Myocardial Infarction trial; MIAMI = Metoprolol in Acute Myocardial Infarction; MILIS = Multicenter Investigation for the Limitation of Infarct Size; RIMA = Rimodellamento Infarcto Miocardico Acuto Study; TIMI = Thrombolysis in Myocardial Infarction; UKCSG = UK Collaborative Study Group.
Figure 8β-blockers vs controls for the outcome of all-cause mortality in postmyocardial infarction trials. Analysis stratified by reperfusion status. APSI = Acebutolol et Prévention Secondaire de l'Infarctus; BHAT = Beta-Blocker Heart Attack Trial; CI = confidence interval; CPRG = Coronary Prevention Research Group; EIS = European Infarction Study; IRR = incident rate ratio; JCBMI = The Japanese beta Blockers and Calcium Antagonists Myocardial Infarction; LIT = Lopressor Intervention Trial Research Group.
Figure 9β-blockers vs controls for the outcome of myocardial infarction in post myocardial infarction trials. Analysis stratified by reperfusion status. APSI = Acebutolol et Prévention Secondaire de l'Infarctus; BHAT = Beta-Blocker Heart Attack Trial; CI = confidence interval; CPRG = Coronary Prevention Research Group; EIS = European Infarction Study; IRR = incident rate ratio; JCBMI = The Japanese beta Blockers and Calcium Antagonists Myocardial Infarction; LIT = Lopressor Intervention Trial Research Group.
Figure 10β-blockers vs controls for the outcome of heart failure in post myocardial infarction trials. Analysis stratified by reperfusion status. APSI = Acebutolol et Prévention Secondaire de l'Infarctus; BHAT = Beta-Blocker Heart Attack Trial; CI = confidence interval; CPRG = Coronary Prevention Research Group; EIS = European Infarction Study; IRR = incident rate ratio; JCBMI = The Japanese beta Blockers and Calcium Antagonists Myocardial Infarction; LIT = Lopressor Intervention Trial Research Group.
Figure 11β-blockers vs controls and drug discontinuation in postmyocardial infarction trials. Analysis stratified by reperfusion status. APSI = Acebutolol et Prévention Secondaire de l'Infarctus; BHAT = Beta-Blocker Heart Attack Trial; CI = confidence interval; CPRG = Coronary Prevention Research Group; EIS = European Infarction Study; IRR = incident rate ratio; JCBMI = The Japanese beta Blockers and Calcium Antagonists Myocardial Infarction; LIT = Lopressor Intervention Trial Research Group.
In the pre-reperfusion-era trials, a significant interaction was observed (Pinteraction = .09) such that the benefit for all-cause mortality was driven by trials where early intravenous β-blocker (IRR 0.83; 95% CI, 0.75-0.92) was administered, but not in trials where β-blockers were administered orally (IRR 0.99; 95% CI, 0.83-1.19). Similarly, early intravenous β-blocker was associated with benefit for cardiovascular mortality (IRR 0.88; 95% CI, 0.78-0.99), sudden death (IRR 0.59; 95% CI, 0.38-0.91), myocardial infarction (IRR 0.78; 95% CI, 0.62-0.98), and angina pectoris (IRR 0.88; 95% CI, 0.82-0.95), with no difference in heart failure (IRR 1.07; 95% CI, 0.97-1.18) and cardiogenic shock (IRR 1.06; 95% CI, 0.89-1.27). In the reperfusion era, early intravenous β-blocker was associated with reduction in myocardial infarction (IRR 0.72; 95% CI, 0.62-0.84) and angina pectoris (IRR 0.80; 95% CI, 0.65-0.99), an increase in heart failure (IRR 1.10; 95% CI, 1.05-1.16) and cardiogenic shock (IRR 1.29; 95% CI, 1.18-1.41), and no impact on mortality (IRR 0.98; 95% CI, 0.92-1.05), cardiovascular mortality, sudden death, and stroke.
Landmark Analysis: Required Duration of β-Blockers Usage
In the pre-reperfusion era, β-blockers were associated with significant benefit at 30 days (for all-cause mortality, cardiovascular mortality, and angina), between 30 days and 1 year (for all-cause mortality, cardiovascular mortality, sudden death, and myocardial infarction), and even for events > 1 year (for all-cause mortality and sudden death) (Table 2). However, in the reperfusion era, β-blockers were associated with no benefit at most time points except myocardial infarction and angina at 30 days, a significant increase in heart failure, cardiogenic shock and drug discontinuation at 30 days, and an increase in heart failure and drug discontinuation between 30 days and 1 year (Table 2).
Table 2Landmark Analyses: β-Blockers vs Controls (From Fixed-effect Model)
The cumulative Z-curve crosses the futility boundary, showing with confidence the lack of even a 10% reduction in the risk of mortality with β-blocker when compared with controls in the reperfusion era (Figure 12).
Figure 12Trial Sequential Analysis using fixed-effect meta-analysis in the reperfusion era. The required information of 49,990 patients is based on an anticipated intervention effect of 10% relative risk reduction, a control event proportion of 7.36% (estimated from the cumulated comparator event proportion), absence of heterogeneity (diversity = 0%), and α = 0.05 and β = 0.10.
Various sensitivity analyses outlined in the methods yielded largely similar results (data available on request). In addition, there was no benefit of β-blockers for mortality in the reperfusion era even after exclusion of the COMMIT trial (IRR 0.76; 95% CI, 0.48-1.21; P = .25). Furthermore, the beneficial effect of β-blockers for mortality in the acute myocardial infarction cohort was driven by trials with high risk for bias (low-quality trials) (IRR 0.82; 95% CI, 0.72-0.94; P = .005), whereas no benefit was observed in trials with low risk for bias (high-quality trials) (IRR 0.96; 95% CI, 0.91-1.02; P = .18). In the meta-regression analysis, the beneficial effect of β-blockers on mortality diminished with increasing percentage of patients with reperfusion therapy (P = .056) (Figure 13).
Figure 13Meta-regression analysis of the relationship of percentage of patients with reperfusion therapy on the risk ratio of mortality with β-blockers.
In patients with a myocardial infarction, a significant interaction of reperfusion-era status on the association of β-blocker and outcomes was seen such that while β-blockers were associated with reduction in events, including mortality in the pre-reperfusion era (driven by trials where early intravenous β-blockers were administered), the benefits were reduced in the reperfusion era with reductions in myocardial infarction and angina (short-term only) at the expense of increases in heart failure, cardiogenic shock, and drug discontinuation with no mortality benefit. The results were consistent in several sensitivity analyses performed to assess the robustness of the results.
Efficacy of β-Blockers in the Reperfusion Era
Why is there a lack of efficacy of β-blockers in the reperfusion era? Some of the considerations are the following: Are the negative results in the reperfusion-era trials due to lack of power to show a difference? Has the underlying substrate changed due to reperfusion/contemporary medical therapy?
For the acute myocardial infarction trials, the pre-reperfusion strata with a sample size of 31,479 patients had a power of 92% to detect a hazard ratio of 0.95 for benefit and 1.05 for harm. However, the reperfusion strata with a sample size of 48,806 patients had a greater power of 99% to detect the same hazard ratio. Thus, the power to detect a difference was, if anything, better for the reperfusion strata. Moreover, the TSA showed that for the reperfusion-era trials, there is firm evidence to rule out even a 10% reduction in mortality with β-blockers.
In the First International Study of Infarct Survival (ISIS-1) trial, only 5% of patients were on an antiplatelet agent at discharge, none received reperfusion, but atenolol (vs controls) resulted in a reduction in vascular death.
Randomised trial of intravenous atenolol among 16 027 cases of suspected acute myocardial infarction: ISIS-1. First International Study of Infarct Survival Collaborative Group.
On the contrary, in COMMIT, all patients received aspirin, 50% received dual antiplatelet therapy, two-thirds were on an angiotensin-converting enzyme inhibitor, and 54% received fibrinolytics. In COMMIT, metoprolol was not superior to placebo for both the co-primary endpoints of 30-day mortality and 30-day death/myocardial infarction or cardiac arrest, despite almost 3 times the sample size and greater power than that of the ISIS-1 trial.
The difference therefore appears to be both reperfusion and aggressive contemporary medical therapy. Reperfusion and contemporary medical therapy modify the underlying substrate in patients with a myocardial infarction. In the pre-reperfusion era, lack of reperfusion and contemporary medical therapy likely resulted in extensive myocardial scarring, providing a substrate for re-entrant circuits and fatal ventricular arrhythmias. β-blockers are beneficial in this setting by preventing sudden death, which was the major cause of mortality in the pre-reperfusion era. In the reperfusion era, prompt reperfusion reduces the likelihood of extensive scar formation. Moreover, contemporary medical and device therapies are also efficacious at reducing the risk of arrhythmic deaths, thereby further reducing the impact of β-blockers.
Beta-blocker use and survival in patients with ventricular fibrillation or symptomatic ventricular tachycardia: the Antiarrhythmics Versus Implantable Defibrillators (AVID) trial.
Conceivably, β-blockers, due to their negative inotropic effects, may reduce myocardial contractility, which in the setting of stunned myocardium during a myocardial infarction could lead to heart failure and cardiogenic shock. While in the pre-reperfusion era the risk of heart failure and cardiogenic shock was likely outweighed by the benefits of preventing ventricular arrhythmias and sudden death, in the reperfusion era the risk–benefit ratio no longer seems to be favorable.
A number of trials have shown that reperfusion therapy, aspirin, or statin reduces infarct size.
A prospective trial of intravenous streptokinase in acute myocardial infarction (I.S.A.M.). Mortality, morbidity, and infarct size at 21 days. The I.S.A.M. Study Group.
Acute reduction of myocardial infarct size by a hydroxymethyl glutaryl coenzyme A reductase inhibitor is mediated by endothelial nitric oxide synthase.
Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2. ISIS-2 (Second International Study of Infarct Survival) Collaborative Group.
There is, thus, ample evidence to suggest that the underlying substrate is altered by the use of these therapies in patients with myocardial infarction.
Clinical Implications
Based on the above data, it may be reasonable to conclude that in patients who develop extensive scars (patients with delayed presentation and large myocardial infarction) and therefore are prone to develop heart failure or ventricular arrhythmias, β-blockers will remain highly efficacious in preventing events, as has been shown in numerous heart failure trials,
and in preventing ventricular arrhythmias and sudden death. One may be tempted to conclude from the pre-reperfusion-era trials that β-blockers will also be efficacious in patients with myocardial infarction treated conservatively (that is, no reperfusion). However, in the COMMIT trial,
there was no benefit of β-blockers for mortality in patients who did or did not receive fibrinolytic therapy, likely underscoring the role of contemporary medical therapy in patients who are treated conservatively. In addition, one may consider β-blockers short term (30 days) after a myocardial infarction to reduce the risk of recurrent myocardial infarction and angina, but this has to be weighed against the potential harm of heart failure and cardiogenic shock.
Study Limitations
The results in the reperfusion era are driven by the COMMIT trial. However, in the sensitivity analysis excluding COMMIT, there was still no benefit of β-blockers for mortality in the reperfusion era. The categorization of pre-reperfusion vs reperfusion era was not done based on calendar years, as there was wide variability in the use of medication and reperfusion. Moreover, our results were consistent in the sensitivity analysis where percentage of reperfusion was considered for each trial as a continuous variable in the meta-regression analysis rather than artificial categorization into pre-reperfusion vs reperfusion era. We were unable to separate out the effect of reperfusion from modern medical therapy given the limitations of a trial-level meta-analysis. Moreover, although a significant benefit was noted for β-blockers in the pre-reperfusion era, most of the trials were high risk for bias.
Conclusions
In this analysis of β-blockers in myocardial infarction, a significant interaction of reperfusion-era status on the association of β-blocker and outcomes was seen, in that β-blocker reduced the risk of events, including mortality in the pre-reperfusion-era trial, but not in the reperfusion-era trials. In patients undergoing contemporary treatment, data supports use of β-blockers short term (30 days) to reduce recurrent myocardial infarction and angina, but this has to be weighed at the expense of increase in heart failure, cardiogenic shock, and drug discontinuation, with no mortality benefit. Guidelines should reconsider the current recommendations for β-blockers for myocardial infarction, especially in patients undergoing contemporary treatment.
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Conflicts of Interest: PJD is part of a group that has a policy of not accepting honorariums or other payments from industry for their own personal financial gain. They do accept honorariums or other payments from industry to support research endeavors and for reimbursement of costs to participate in meetings such as scientific or advisory committee meetings. Based on study questions he originated and grants he wrote, he has received grants from Abbott Diagnostics, Astra Zeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Covidien, Stryker, and Roche Diagnostics. He has also participated in an advisory board meeting for GlaxoSmithKline and an expert panel meeting for Astra Zeneca. The remaining authors have nothing to disclose.
Authorship: All authors had access to the data and played a role in writing this manuscript.
We would like to commend Bangalore et al1 for their well-executed meta-analysis evaluating clinical outcomes of beta-blockade in the setting of acute myocardial infarction. While the authors advocate that the current guidelines reconsider the strength of recommendations for beta-blockers post myocardial infarction, we feel that this conclusion may be premature, based on several limitations inherent to this type of analysis.
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