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Clinical Outcomes with β-blockers for Myocardial Infarction A Meta-Analysis ofRandomized Trials
Sripal Bangalore, MD, MHA Harikrishna Makani, MD Martha Radford, MD KamiaThakur, MD Bora Toklu, MD Stuart D. Katz, MD James J. DiNicolantonio, PharmDP.J. Devereaux, MD, Ph.D Karen P. Alexander, MD Jorn Wetterslev, MD, Ph.D FranzH. Messerli, MD
PII: S0002-9343(14)00470-7
DOI: 10.1016/j.amjmed.2014.05.032
Reference: AJM 12553
To appear in: The American Journal of Medicine
Received Date: 15 May 2014
Revised Date: 22 May 2014
Accepted Date: 22 May 2014
Please cite this article as: Bangalore S, Makani H, Radford M, Thakur K, Toklu B, Katz SD,DiNicolantonio JJ, Devereaux PJ, Alexander KP, Wetterslev J, Messerli FH, Clinical Outcomes withβ-blockers for Myocardial Infarction A Meta-Analysis of Randomized Trials, The American Journal ofMedicine (2014), doi: 10.1016/j.amjmed.2014.05.032.
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Clinical Outcomes with β-blockers for Myocardial Infarction A Meta-Analysis of Randomized Trials
Sripal Bangalore, MD, MHA, Harikrishna Makani, MD, Martha Radford, MD, Kamia Thakur, MD, Bora Toklu, MD, Stuart D. Katz, MD, James J. DiNicolantonio, PharmD, P. J. Devereaux,
MD, Ph.D, Karen P. Alexander, MD, Jorn Wetterslev, MD, Ph.D, Franz H. Messerli, MD
New York University School of Medicine, New York, NY [SB, MR, KT, SDK] St. Luke’s Roosevelt Hospital, Mt. Sinai School of Medicine, New York, NY [HM, FHM]
Virginia Commonwealth University, Richmond, VA [BT] Mid America Heart Institute, St. Luke’s Hospital, Kansas City, Missouri and Wegmans
Pharmacy, Ithaca, New York [JJD] Duke Clinical Research Institute, Durham, NC [KPA]
Population Health Research Institute, Hamilton, ON, Canada [PJD] The Copenhagen Trial Unit, Copenhagen University Hospital, Copenhagen, Denmark [JW]
Word Count: 2913 Running Title: β-blockers for Myocardial Infarction Funding Source: None Disclosures: Dr. Devereaux: 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 boarding meeting for GlaxoSmithKline and an expert panel meeting for Astra Zeneca. Rest of the authors have nothing to disclose Correspondence: Sripal Bangalore, MD, MHA, FACC, FAHA, FSCAI, Director of Research, Cardiac Catheterization Laboratory, Director, Cardiovascular Outcomes Group, Cardiovascular Clinical Research Center, Associate Professor of Medicine, New York University School of Medicine, The Leon H. Charney Division of Cardiology, New York, NY 10016. Email: [email protected] Phone: 2122633540 Fax: 2122633988
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ABSTRACT
BACKGROUND: Debate exists regarding 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 and/or receiving aspirin/statin) or pre-reperfusion era trials.
RESULTS: Sixty trials with 102003 patients satisfied the inclusion criteria. In the acute
myocardial infarction trials, a significant interaction (Pinteraction=0.02) was noted such that β-
blockers reduced mortality in the pre-reperfusion[Incident Rate Ratio (IRR)=0.86, 95% 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) (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)
(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).
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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
guidelines should reconsider the strength of recommendations for β-blockers post myocardial
infarction.
KEY WORDS: β-blockers, myocardial infarction, outcomes, reperfusion
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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.(1) 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, much of the data to support the use of β-blockers in myocardial infarction predates
reperfusion and contemporary medical therapy with statins and antiplatelet agents.(2-4) Recent
data have called into question the role of β-blockers in myocardial infarction.(5-8) 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,(9) while the
ESC guidelines recommends long-term therapy only in patients with left ventricular systolic
dysfunction.(10)
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
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We performed a systematic search (using PUBMED, EMBASE, and 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, ‘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) post myocardial
infarction heart failure/left ventricular systolic dysfunction trials such as the Carvedilol Post-
Infarct Survival Control in LV Dysfunction (CAPRICORN) trial,(11) as β-blockers have been
proven to be efficacious in such cohorts.(12)
Trial Selection and Assessment of Risk of Bias
Two authors (K.T, S.B) 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.(13) 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
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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 an myocardial infarction falls steeply and
progressively from the onset of pain to the end of the first 48-hours.(14) Therefore, trials were
classified as acute myocardial infarction trials (randomized within 48 hours of symptom onset)
or post myocardial 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 and/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(15, 16) using standard software (STATA 9.0, STATA Corp,
Texas). 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 post myocardial infarction
cohorts separately after stratifying trials based on the reperfusion era status. For the primary
outcome \, the difference between the two strata (pre-reperfusion vs. reperfusion) was tested by a
test for interaction, (17) with Pinteraction<0.10 considered significant and indicated a treatment
effect which differed considerably between the 2 strata. If the test for interaction for the primary
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outcome was significant, all other outcomes were interpreted separately for the two 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 days
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, i.e.,
for the 30 days to 1-year analysis, patients who died within 30-days were excluded.
Trial Sequential Analysis. Trial sequential analysis (TSA ver 0.9 Beta)(18) anticipating a 10%
relative risk reduction was performed on the primary outcome. The methodology has been
described previously(19, 20) 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) combing acute myocardial infarction and post myocardial
infarction trials; 2) excluding trials that compared β-blockers to 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 beta blockers vs. controls for mortality.
RESULTS
Trial Selection
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We identified 60 trials that enrolled 102003 patients who were followed up for a mean of 10
months (range: in-hospital to 4 years) with 640891 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 post myocardial infarction trials
(Table 1).
Reperfusion Era Status and Outcomes
Majority of the trials (N=48; 31479 patients) were in the pre-reperfusion era with only 12 trials
in the reperfusion era (48806 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=0.02) was noted
with reperfusion status such that β-blockers reduced mortality in the pre-reperfusion era [Incident
Rate Ratio(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 2a).
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 2b), and angina(IRR=0.88, 95% CI 0.82-0.95) (Figure 2c) with no difference for sudden
death(IRR=0.77, 95% CI 0.56-1.05), heart failure (Figure 2d), cardiogenic shock (Figure 2e) 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) (NNTB=209) (Figure 2b) and
angina(IRR=0.80, 95% CI 0.65-0.98) (NNTB=26) (Figure 2c) at the expense of an increase in
heart failure(IRR=1.10, 95% CI 1.05=1.16) (NNTH=79) (Figure 2d), cardiogenic
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shock(IRR=1.29, 95% CI 1.18=1.41) (NNTH=90) (Figure 2e) and drug
discontinuation(IRR=1.64, 95% CI 1.55-1.73) (Figure 2f) 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).
Results in the post myocardial infarction trials were largely similar (Figure 3a-d).
Intravenous Β-Blocker and Outcomes
In the pre-reperfusion era trials, a significant interaction was observed(Pinteraction = 0.09) 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),
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
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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 to 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 to 1 year (Table 2).
Trial Sequential Analysis
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 4).
Sensitivity Analysis
Various sensitivity analysis 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= 0.25). 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=0.005) whereas no benefit was observed in trials with low-risk for bias (high quality trials)
(RR=0.96, 95% CI 0.91-1.02; P=0.18). In the meta-regression analysis, the beneficial effect of β-
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blockers on mortality diminished with increasing percentage of patients with reperfusion therapy
(P=0.056) (Figure 5).
DISCUSSION
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 trialsthe pre-reperfusion strata with a sample size of
31479 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 48806 patients had a greater power of 99%
to detect the same hazard ratio. Thus, the power to detect a difference, if anything, was 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.
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In the ISIS-1 trial only 5% of patients were on an anti-platelet agent at discharge, none
received reperfusion but atenolol (vs. controls) resulted in a reduction in vascular death .(2) On
the contrary, in COMMIT, all patients received aspirin, 50% received dual antiplatelet therapy,
2/3rds were on an angiotensin converting enzyme inhibitors 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.(5) 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. (21) Conceivably, β-blockers, due to their negative
inotropic effects may reduce myocardial contractility, which in the setting of stunned
myocardium during an 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, whereas 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.(22, 23) (24) (25) In addition, both streptokinase and aspirin prevent cardiac arrest including
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death due to ventricular fibrillation in the ISIS-2 trial.(26) 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
scar (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,(12, 27, 28) 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 (i.e., no reperfusion). However, in the COMMIT trial,(5) 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 is 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
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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-perfusion era, most of the trials were high risk for bias.
CONCLUSIONS
In this analysis of beta-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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FIGURE LEGENDS
Figure 1. Study selection.
Figure 2a. β-blockers vs. controls for the outcome of all-cause mortality in acute myocardial
infarction trials. Analysis stratified by reperfusion status. IRR = incident rate ratio
Figure 2b. β-blockers vs. controls for the outcome of myocardial infarction in acute myocardial
infarction trials. Analysis stratified by reperfusion status. IRR = incident rate ratio
Figure 2c. β-blockers vs. controls for the outcome of angina pectoris in acute myocardial
infarction trials. Analysis stratified by reperfusion status. IRR = incident rate ratio
Figure 2d. β-blockers vs. controls for the outcome of heart failure in acute myocardial infarction
trials. Analysis stratified by reperfusion status. IRR = incident rate ratio
Figure 2e. β-blockers vs. controls for the outcome of cardiogenic shock in acute myocardial
infarction trials. Analysis stratified by reperfusion status. IRR = incident rate ratio
Figure 2f. β-blockers vs. controls and drug discontinuation in acute myocardial infarction trials.
Analysis stratified by reperfusion status. IRR = incident rate ratio
Figure 3a. β-blockers vs. controls for the outcome of all-cause mortality in post myocardial
infarction trials. Analysis stratified by reperfusion status. IRR = incident rate ratio
Figure 3b. β-blockers vs. controls for the outcome of myocardial infarction in post myocardial
infarction trials. Analysis stratified by reperfusion status. IRR = incident rate ratio
Figure 3c. β-blockers vs. controls for the outcome of heart failure in post myocardial infarction
trials. Analysis stratified by reperfusion status. IRR = incident rate ratio
Figure 3d. β-blockers vs. controls and drug discontinuation in post myocardial infarction trials.
Analysis stratified by reperfusion status. IRR = incident rate ratio
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Figure 4. Trial Sequential Analysis using fixed-effect meta-analysis in the reperfusion era. The
required information of 49990 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.
Figure 5. Meta regression analysis of the relationship of percentage of patients with reperfusion
therapy on the risk ratio of mortality with β-blockers.
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Table 1. Baseline Characteristics of Included Trials Trial Year Sample Size Cohort β-blocker Control Treatment
duration Revascularized (%) Quality
Ahlmark et al(29) 1974 162 Post MI
Alprenolol Placebo 2 years NR
1
Amsterdam Metoprolol Trial(30)
1983
584
Post MI
Metoprolol
Placebo
1 year
NR
1
Andersen et al(31) 1979 480 AMI Alprenolol Placebo 1 year NR
1
APSI(32) 1997
607
Post MI
Acebutolol
Placebo
6 years
NR
2
Australian and Swedish Pindolol Study(33)
1983
529
Post MI
Pindolol
Placebo
2 years
NR
1
Baber et al(34) 1980 720 Post MI
Propranolol
Placebo
9 months
NR
1
Balcon et al(35)
1966
114
AMI
Propranolol
Placebo
28 days
NR
1
Barber et al(36)
1967
107
AMI
Propranolol
Placebo 1 month
NR
1
Barber et al(37)
1976
298
AMI
Practolol
Placebo
2 years
NR
1
Basu et al(38)
1997
151
AMI
Carvedilol
Placebo
6 months
95 % Streptokinase, 7% tPA
1
BHAT(39)
1982
3837
Post MI
Propranolol
Placebo
2 years 9% CABG
2
Briant et al(40)
1970
119
AMI
Alprenolol
Placebo
Hospital
NR
2
Clausen et al(41)
1967 130
AMI
Propranolol
Placebo
14 days
NR
1
COMMIT(5) 2005 45,852 AMI Metoprolol Placebo 1 month 54.5% lytics 2
CPRG(42) 1981 313 Post Oxprenolol Placebo 56 days NR 1
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EIS(43)
1984
1741
Post MI
Oxprenolol
Placebo
1 year
NR
1
EMIT(44)
2002
108
AMI
Esmolol
Placebo
6 weeks
64.5%lytics 42.5% PCI
2
Federman et al(45)
1984 101
AMI
Timolol
Placebo
28 days
NR
1
Fuccella et al(46)
1968 220
AMI
Oxprenolol Placebo
3 weeks
NR
1
Gardtman et al(47)
1999 262
AMI Metoprolol Placebo 1 month
22.5%Lytics 7% PTCA (52% of patients with MI)
1
Goteborg(48) 1981 1395 AMI Metoprolol Placebo 3 months
NR
1
Heber et al(49)
1987 166
AMI Labetalol
Control
5 days
NR
1
Herlitz et al(3)
1988 1395
AMI
Metoprolol
Placebo
5 months
NR
1
ICSG(50)
1984 144
AMI
Timolol
Placebo
Hospital Stay
NR
1
ISIS-1(2)
1986 16027
AMI
Atenolol
Control
7 days
NR
2
JBCMI(51) 2004 1090 Post MI
Β-blockers CCB 1.2 years 82.8% (6.3% lytics; 76.5% PCI)
2
Julian et al(52)
1982 1456
Post MI
Sotalol
Placebo
1 year
NR
2
LIT(53)
1987 2395
Post MI
Metoprolol
Placebo
1 year
0%
1
Lombardo et al(54)
1979 260
AMI
Oxprenolol
Placebo
21 days
NR
1
Mazur et al(55) 1984 204 Post Propranolol Placebo 1.5 years NR 1
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METOCARD-CNIC(56)
2013 270 AMI Metoprolol Controls 1 day 95% PCI 2
MEMO(57)
1999 265
AMI
Metoprolol Morphine 6 months
54% lytics
1
MIAMI(58)
1985 5778
AMI
Metoprolol
Placebo
15 days
NR
2
MILIS(59)
1984 269 AMI Propranolol
Placebo
9 days
NR
1
Multicenter Trial(60)
1966 195 AMI Propranolol
Placebo
28 days
NR
1
Multicenter International(61)
1975 3038
Post MI
Practolol Placebo
3 years
NR
2
Nakagomi et al(62)
2011 120
Post MI
Atenolol
Benidipine
3 years
92.5%
2
Norris et al(63)
1984 735
AMI
Propranolol
Control
Hospital Stay
NR
2
Norris et al(64)
1968 454
AMI
Propranolol
Placebo
3 weeks
NR
2
Norwegian(65)
1983 1884
Post MI
Timolol
Placebo
33 months
NR
1
Norwegian Multicenter Propranolol trial(66)
1982 560
Post MI
Propranolol
Placebo
1 year
NR
2
Owensby et al(67)
1985 100
AMI
Pindolol
Placebo
Hospital Stay
NR
2
RIMA(68)
1999 149
AMI
Metoprolol
Captopril
6 months
NR
1
Roque et al(69)
1987 200
AMI
Timolol
Placebo
2 years
NR
1
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1983 182
AMI
Atenolol
Control
Hospital Stay
NR
1
Salathia et al(4)
1985 800
AMI
Metoprolol
Placebo
1 year
NR
1
Schwartz et al(71)
1992 973
Post MI
Oxprenolol
Placebo
4 years
NR
2
Snow et al(72)
1966 107
AMI
Propranolol
Control
14 days
NR
1
Snow et al(30) 1980 143 AMI Practolol Control Hospital Stay
NR 1
Stockholm Metoprolol Trial(73)
1988 301
Post MI
Metorpolol
Placebo
3 years
NR
1
Taylor et al(74)
1982 1103
Post MI
Oxprenolol
Placebo
4 years
NR
2
TIMI IIB 1991 1434 AMI Immediate Metoprolol
Deferred Metoprolol
6 days 100% lytics 1
Thompson et al(75)
1979 143
AMI
Practolol
Placebo 5 days
NR
1
Tomas et al(76)
2001 121
AMI
Atenolol
Captopril
Hospital Stay
91.5%
2
UKCSG(30)
1984 108
AMI
Timolol
Placebo
Hospital Stay
NR
1
Van de Werf et al(77)
1993 194
AMI
Atenolol
Placebo
Hospital Stay
100% lytics
1
Wilcox et al(78) 1980 315 AMI Oxprenolol Placebo 6 weeks NR 2
Wilcox et al(79)
1980 261
AMI
Propranolol
Placebo
1 year
NR 2
Wilcox et al(79)
1980 256
AMI
Atenolol
Placebo
1 year
NR 2
Wilhelmsson et 1974 230 Post Atenolol Placebo 2 years NR 1
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Yusuf et al(81)
1983 477
AMI
Atenolol
Control
10 days NR 2
AMI = acute myocardial infarction; APSI = Acebutolol et Pre´vention Secondaire de l’Infarctus; BHAT = Beta Blocker Heart Attack Trial; COMMIT = Clopidogrel and Metoprolol in Myocardial Infarction Trial; 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; MIAMI = Metoprolol in Acute Myocardial Infarction; MILIS = Multicenter Investigation for the Limitation of Infarct Size; Post MI = post myocardial infarction; RIMA = Rimodellamento Infarcto Miocardico Acuto Study; UKCSG = UK Collaborative Study Group
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Table 2. Landmark Analyses: B-blockers vs. Controls (From Fixed Effect Model)
Death CV Death Sudden Death
MI Angina Stroke Heart Failure
Cardiogenic Shock
Withdrawal
Events at 30 days Pre-reperfusion
0.87 (0.79, 0.96)
0.86 (0.77, 0.96)
0.82 (0.59,1.13)
0.81 (0.63,1.04)
0.89 (0.83, 0.95)
2.96 (0.47, 18.81)
1.06 (0.97, 1.16)
1.03 (0.87, 1.21)
1.11 (1.00, 1.23)
Reperfusion era
0.98 (0.92, 1.05)
1.00 (0.91,1.10)
0.94 (0.86,1.01)
0.72 (0.62,0.84)
0.81 (0.66, 1.00)
1.09 (0.91, 1.30)
1.10 (1.05, 1.16)
1.29 (1.18, 1.41)
1.64 (1.55, 1.73)
Events between 30-days and 1-year Pre-reperfusion
0.79 (0.71, 0.88)
084 (0.71, 1.00)
0.61 (0.49, 0.76)
0.77 (0.64, 0.91)
0.94 (0.75, 1.18)
1.54 (0.60, 3.95)
1.07 (0.91, 1.27)
1.88 (0.51, 6.96)
1.16 (1.03, 1.30)
Reperfusion era
1.50 (0.53, 4.21)
1.50 (0.53, 4.21)
NA 0.71 (0.23, 2.25)
1.03 (0.72, 1.48)
4.00 (0.45, 35.79)
3.83 (1.56, 9.41)
NA 1.49 (1.01, 2.19)
Events >1-year Pre-reperfusion
0.81 (0.66,0.98)
0.73 (0.48, 1.11)
0.64 (0.43, 0.97)
0.81 (0.62,1.06)
NA 0.20 (0.01, 4.20)
0.25 (0.03, 2.25)
NA 1.00 (0.65, 1.54)
Reperfusion era
NA NA NA NA NA NA NA NA NA
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• β-blockers reduced mortality in pre-reperfusion[IRR=0.86, 95% CI=0.79-0.94] but not in
the reperfusion era(IRR=0.98, 95% CI=0.92-1.05) where there was reduction (short-term)
in myocardial infarction(IRR=0.72, 95% CI=0.62-0.83) and angina(IRR=0.80, 95%
CI=0.65-0.98) but increase in heart failure(IRR=1.10, 95% CI=1.05-1.16), cardiogenic
shock(IRR=1.29, 95% CI=1.18-1.41) and drug discontinuation.
• In contemporary treatment of MI, β-blockers have no mortality benefit but reduce
myocardial infarction and angina (short-term) with increase in heart failure, cardiogenic
shock and drug discontinuation.
