CLINICAL RESEARCH STUDY Clinical Outcomes with b-Blockers for Myocardial Infarction: A Meta-analysis of Randomized Trials Sripal Bangalore, MD, MHA,a Harikrishna Makani, MD,b Martha Radford, MD,a Kamia Thakur, MD,a Bora Toklu, MD,c Stuart D. Katz, MD,a James J. DiNicolantonio, PharmD,d,e P.J. Devereaux, MD, PhD,f Karen P. Alexander, MD,g Jorn Wetterslev, MD, PhD,h Franz H. Messerli, MDb a New York University School of Medicine, New York, NY; bSt. Luke’s Roosevelt Hospital, Mt. Sinai School of Medicine, New York, NY; Virginia Commonwealth University, Richmond; dMid America Heart Institute, St. Luke’s Hospital, Kansas City, Mo; eWegmans Pharmacy, Ithaca, NY; fPopulation Health Research Institute, Hamilton, Ont., Canada; gDuke Clinical Research Institute, Durham, NC; hThe Copenhagen Trial Unit, Copenhagen University Hospital, Copenhagen, Denmark. c ABSTRACT BACKGROUND: Debate exists about the efficacy of b-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 b-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 ¼ .02) was noted such that b-blockers reduced mortality in the prereperfusion (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, b-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, b-blockers reduced myocardial infarction (IRR 0.72; 95% CI, 0.62-0.83) (number needed to treat to benefit [NNTB] ¼ 209) and angina (IRR 0.80; 95% CI, 0.65-0.98) (NNTB ¼ 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] ¼ 79), cardiogenic shock (IRR 1.29; 95% CI, 1.18-1.41) (NNTH ¼ 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, b-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 b-blockers post myocardial infarction. ! 2014 Elsevier Inc. All rights reserved. " The American Journal of Medicine (2014) 127, 939-953 KEYWORDS: b-blockers; Myocardial infarction; Outcomes; Reperfusion Funding: None. 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 0002-9343/$ -see front matter ! 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjmed.2014.05.032 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. 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. E-mail address: sripalbangalore@gmail.com 940 The American Journal of Medicine, Vol 127, No 10, October 2014 For more than a quarter of a century, b-blockers have been a (CAPRICORN) trial,11 as b-blockers have been proven to cornerstone in the treatment of patients with myocardial be efficacious in such cohorts.12 infarction. The American College of Cardiology Foundation/ American Heart Association (ACCF/AHA) ST-elevation Trial Selection and Assessment of Risk of Bias myocardial infarction guideline gives a class I recommenTwo authors (KT, SB) independently reviewed trial eligidation for oral b-blockers within the first 24 hours in patients bility and assessed risk of bias using the Cochrane Collabwith myocardial infarction, and a oration criteria based on the class IIa indication for intravenous following components: sequence CLINICAL SIGNIFICANCE b-blockers for patients who are generation of allocation; allocation hypertensive or having ongoing " In the treatment of patients with concealment; blinding of particiischemia.1 Not surprisingly, the pants, staff, and outcome assessors; myocardial infarction, b-blockers reCenters for Medicare and Medicaid incomplete outcome data; selective duced mortality in the pre-reperfusion Services, the National Committee outcome reporting; and other sourbut not in the reperfusion era, where for Quality Assurance, the National ces of bias.13 Trials with high or there was reduction (short-term) in Quality Forum, and the Joint Comunclear risk of bias for the first 3 myocardial infarction and angina, but mission on Accreditation of Healthcriteria were considered as high increase in heart failure, cardiogenic care Organizations have adopted risk of bias trials and the rest as shock, and drug discontinuation. b-blocker use at discharge post trials with lower risk of bias. myocardial infarction as a quality " The benefit for recurrent myocardial indicator. infarction and angina reduction by bOutcomes However, many of the data to blockade in the reperfusion era appeared The primary outcome was all-cause support the use of b-blockers in to be short term (30 days). mortality. Secondary outcomes myocardial infarction predate reperwere cardiovascular mortality, sudfusion and contemporary medical den death, recurrent myocardial therapy with statins and antiplatelet infarction, angina pectoris, heart failure, cardiogenic shock, agents.2-4 Recent data have called into question the role of bstroke, and drug discontinuation. In trials that reported longblockers in myocardial infarction.5-8 Moreover, there has term outcomes beyond the randomized treatment phase, been longstanding controversy over the required duration of only the outcomes associated with randomized treatment treatment post myocardial infarction, with the ACCF/AHA 9 phase were extracted. guidelines recommending a minimum of 3 years, while the European Society of Cardiology guidelines recommend long-term therapy only in patients with left ventricular Data Extraction and Synthesis systolic dysfunction.10 Studies have shown that the mortality rate after a myocardial Our objectives were to evaluate: 1) the impact of coninfarction falls steeply and progressively from the onset of temporary treatment (reperfusion/aspirin/statin) status on pain to the end of the first 48 hours.14 Therefore, trials were the association of b-blocker use and outcomes in paclassified as acute myocardial infarction trials (randomized tients with myocardial infarction; 2) the role of early within 48 hours of symptom onset) or postmyocardial infarcintravenous b-blocker; and 3) the required duration of tion trials (randomized > 48 hours of symptoms). In addition, b-blocker use. trials were classified as reperfusion-era trials if > 50% of 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 “b-blockers” and the names of individual b-blockers, and “myocardial infarction,” until February 2013 (Week 1). Inclusion criteria were trials comparing b-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 b-blockers; and 2) postmyocardial infarction heart failure/ left ventricular systolic dysfunction trials such as the Carvedilol Post-Infarct Survival Control in LV Dysfunction 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) Statement15,16 using standard software (STATA 9.0, StataCorp, College Station, Tex). The analysis used the incident rate of outcomes per 100 personmonths 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 Bangalore et al b-Blockers for Myocardial Infarction 941 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 b-blocker dose to test for the effect of intravenous b-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 b-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. Figure 1 Study selection. (pre-reperfusion vs reperfusion) was tested by a test for interaction,17 with Pinteraction < .10 considered significant and indicated a treatment effect that differed considerably 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 previously19,20 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) combining acute myocardial infarction and Figure 2 b-blockers vs controls for the outcome of all-cause mortality in acute myocardial infarction trials. Analysis stratified by reperfusion status. CI ¼ confidence interval; COMMIT ¼ Clopidogrel and Metoprolol in Myocardial Infarction Trial; EMIT ¼ Esmolol Myocardial Ischemia Trial; ICSG ¼ The International Collaborative Study Group; IRR ¼ incident rate ratio; ISIS-1 ¼ First International Study of Infarct Survival Collaborative Group; MEMO ¼ Metoprolol-Morphine Study Group; METOCARD-CNIC ¼ Effect of Metroprolol in Cardioprotection During an Acute Myocardial Infarction trial; MIAMI ¼ Metoprolol in Acute Myocardial Infarction; MILIS ¼ Multicenter Investigation for the Limitation of Infarct Size; RIMA ¼ Rimodellamento Infarcto Miocardico Acuto Study; TIMI ¼ Thrombolysis in Myocardial Infarction; UKCSG ¼ UK Collaborative Study Group. 942 Table 1 The American Journal of Medicine, Vol 127, No 10, October 2014 Baseline Characteristics of Included Trials Year Sample Size Cohort b-Blocker Control Treatment Duration Revascularized (%) Quality Ahlmark et al Amsterdam Metoprolol Trial22 Andersen et al23 APSI24 Australian and Swedish Pindolol Study25 Baber et al26 Balcon et al27 Barber et al28 Barber et al29 Basu et al30 1974 1983 1979 1997 1983 162 584 480 607 529 Post Post AMI Post Post Alprenolol Metoprolol Alprenolol Acebutolol Pindolol Placebo Placebo Placebo Placebo Placebo 2 1 1 6 2 NR NR NR NR NR 1 1 1 2 1 1980 1966 1967 1976 1997 720 114 107 298 151 Post MI AMI AMI AMI AMI Propranolol Propranolol Propranolol Practolol Carvedilol Placebo Placebo Placebo Placebo Placebo 9 months 28 days 1 month 2 years 6 months 1 1 1 1 1 BHAT31 Briant & Norris32 Clausen et al33 COMMIT5 CPRG34 EIS35 EMIT36 1982 1970 1967 2005 1981 1984 2002 3837 119 130 45,852 313 1741 108 Post MI AMI AMI AMI Post MI Post MI AMI Propranolol Alprenolol Propranolol Metoprolol Oxprenolol Oxprenolol Esmolol Placebo Placebo Placebo Placebo Placebo Placebo Placebo 2 years Hospital 14 days 1 month 56 days 1 year 6 weeks Federman et al37 Fuccella et al38 Gardtman et al39 1984 1968 1999 101 220 262 AMI AMI AMI Timolol Oxprenolol Metoprolol Placebo Placebo Placebo 28 days 3 weeks 1 month Hjalmarson et al40 Heber et al41 Herlitz et al3 ICSG42 ISIS-12 JBCMI43 1981 1987 1988 1984 1986 2004 1395 166 1395 144 16027 1090 AMI AMI AMI AMI AMI Post MI Metoprolol Labetalol Metoprolol Timolol Atenolol b-blockers Placebo Control Placebo Placebo Control CCB 3 months 5 days 5 months Hospital stay 7 days 1.2 years Julian et al44 LIT45 Lombardo et al46 Mazur et al47 METOCARD-CNIC48 MEMO49 MIAMI50 MILIS51 Multicenter Trial52 Multicenter International53 Nakagomi et al54 Norris et al55 Norris et al56 Norwegian57 Norwegian Multicenter Propranolol trial58 Owensby & O’Rourke59 RIMA60 Roque et al61 Rossi et al62 Salathia et al4 Schwartz et al63 Snow et al64 Snow et al22 1982 1987 1979 1984 2013 1999 1985 1984 1966 1975 2011 1984 1968 1983 1982 1456 2395 260 204 270 265 5778 269 195 3038 120 735 454 1884 560 Post Post AMI Post AMI AMI AMI AMI AMI Post Post AMI AMI Post Post MI MI Sotalol Metoprolol Oxprenolol Propranolol Metoprolol Metoprolol Metoprolol Propranolol Propranolol Practolol Atenolol Propranolol Propranolol Timolol Propranolol Placebo Placebo Placebo Placebo Controls Morphine Placebo Placebo Placebo Placebo Benidipine Control Placebo Placebo Placebo 1 year 1 year 21 days 1.5 years 1 day 6 months 15 days 9 days 28 days 3 years 3 years Hospital stay 3 weeks 33 months 1 year NR NR NR NR 95 % Streptokinase, 7% tPA 9% CABG NR NR 54.5% lytics NR NR 64.5%lytics 42.5% PCI NR NR 22.5%Lytics 7% PTCA (52% of patients with MI) NR NR NR NR NR 82.8% (6.3% lytics; 76.5% PCI) NR 0% NR NR 95% PCI 54% lytics NR NR NR NR 92.5% NR NR NR NR 1985 1999 1987 1983 1985 1992 1966 1980 100 149 200 182 800 973 107 143 AMI AMI AMI AMI AMI Post MI AMI AMI Pindolol Metoprolol Timolol Atenolol Metoprolol Oxprenolol Propranolol Practolol Placebo Captopril Placebo Control Placebo Placebo Control Control Hospital stay 6 months 2 years Hospital stay 1 year 4 years 14 days Hospital stay NR NR NR NR NR NR NR NR Trial 21 MI MI MI MI MI MI MI MI MI years year year years years 2 2 1 2 1 1 2 1 1 1 1 1 1 1 2 2 2 1 1 1 2 1 2 1 1 2 2 2 2 1 2 2 1 1 1 1 2 1 1 Bangalore et al Table 1 b-Blockers for Myocardial Infarction 943 Continued Year Sample Size Stockholm Metoprolol Trial Taylor et al66 TIMI IIB 1988 1982 1991 Thompson et al67 Galcerá-Tomás et al68 UKCSG22 Van de Werf et al69 Wilcox et al70 Wilcox et al71 Wilcox et al71 Wilhelmsson et al72 Yusuf et al73 1979 2001 1984 1993 1980 1980 1980 1974 1983 Trial 65 Cohort b-Blocker Control 301 1103 1434 Post MI Post MI AMI 143 121 108 194 315 261 256 230 477 AMI AMI AMI AMI AMI AMI AMI Post MI AMI Metoprolol Oxprenolol Immediate metoprolol Practolol Atenolol Timolol Atenolol Oxprenolol Propranolol Atenolol Atenolol Atenolol Placebo Placebo Deferred Metoprolol Placebo Captopril Placebo Placebo Placebo Placebo Placebo Placebo Control Treatment Duration Revascularized (%) Quality 3 years 4 years 6 days NR NR 100% lytics 1 2 1 5 days Hospital stay Hospital stay Hospital stay 6 weeks 1 year 1 year 2 years 10 days NR 91.5% NR 100% lytics NR NR NR NR NR 1 2 1 1 2 2 2 1 2 AMI ¼ acute myocardial infarction; APSI ¼ Acebutolol et Prévention Secondaire de l’Infarctus; BHAT ¼ Beta Blocker Heart Attack Trial; COMMIT ¼ Clopidogrel and Metoprolol in Myocardial Infarction Trial; CPRG ¼ Coronary Prevention Research Group; EIS ¼ European Infarction Study; EMIT ¼ Esmolol Myocardial Ischemia Trial; ICSG ¼ The International Collaborative Study Group; ISIS -1 ¼ First International Study of Infarct Survival Collaborative Group; JCBMI ¼ The Japanese beta Blockers and Calcium Antagonists Myocardial Infarction; LIT ¼ Lopressor Intervention Trial Research Group; MEMO ¼ MetoprololMorphine Study Group; METOCARD-CNIC ¼ Effect of Metroprolol in Cardioprotection During an Acute Myocardial Infarction trial; MIAMI ¼ Metoprolol in Acute Myocardial Infarction; MILIS ¼ Multicenter Investigation for the Limitation of Infarct Size; PCI ¼ percutaneous coronary intervention; Post MI ¼ post myocardial infarction; RIMA ¼ Rimodellamento Infarcto Miocardico Acuto Study; TIMI ¼ Thrombolysis in Myocardial Infarction; tPA ¼ tissue plasminogen activator; UKCSG ¼ UK Collaborative Study Group. Figure 3 b-blockers vs controls for the outcome of myocardial infarction in acute myocardial infarction trials. Analysis stratified by reperfusion status. CI ¼ confidence interval; COMMIT ¼ Clopidogrel and Metoprolol in Myocardial Infarction Trial; EMIT ¼ Esmolol Myocardial Ischemia Trial; ICSG ¼ The International Collaborative Study Group; IRR ¼ incident rate ratio; ISIS-1 ¼ First International Study of Infarct Survival Collaborative Group; MEMO ¼ Metoprolol-Morphine Study Group; METOCARD-CNIC ¼ Effect of Metroprolol in Cardioprotection During an Acute Myocardial Infarction trial; MIAMI ¼ Metoprolol in Acute Myocardial Infarction; MILIS ¼ Multicenter Investigation for the Limitation of Infarct Size; RIMA ¼ Rimodellamento Infarcto Miocardico Acuto Study; TIMI ¼ Thrombolysis in Myocardial Infarction; UKCSG ¼ UK Collaborative Study Group. 944 The American Journal of Medicine, Vol 127, No 10, October 2014 Figure 4 b-blockers vs controls for the outcome of angina pectoris in acute myocardial infarction trials. Analysis stratified by reperfusion status. CI ¼ confidence interval; COMMIT ¼ Clopidogrel and Metoprolol in Myocardial Infarction Trial; EMIT ¼ Esmolol Myocardial Ischemia Trial; ICSG ¼ The International Collaborative Study Group; IRR ¼ incident rate ratio; ISIS-1 ¼ First International Study of Infarct Survival Collaborative Group; MEMO ¼ Metoprolol-Morphine Study Group; METOCARDCNIC ¼ Effect of Metroprolol in Cardioprotection During an Acute Myocardial Infarction trial; MIAMI ¼ Metoprolol in Acute Myocardial Infarction; MILIS ¼ Multicenter Investigation for the Limitation of Infarct Size; RIMA ¼ Rimodellamento Infarcto Miocardico Acuto Study; TIMI ¼ Thrombolysis in Myocardial Infarction; UKCSG ¼ UK Collaborative Study Group. postmyocardial infarction trials; 2) excluding trials that compared b-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 bblockers 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 ¼ 20) were postmyocardial infarction trials (Table 1).21-73 Reperfusion-Era Status and Outcomes A majority of the trials (n ¼ 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 ¼ .02) was noted with reperfusion status such that b-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). In the pre-reperfusion era, b-blockers were associated with reductions in cardiovascular mortality (IRR 0.87; 95% CI, 0.78-0.98), myocardial infarction (IRR 0.78; 95% CI, 0.620.97) (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, b-blockers were associated with reductions in myocardial infarction (IRR 0.72; 95% CI, 0.62-0.83) (number needed to treat to benefit [NNTB] ¼ 209) (Figure 3) and angina (IRR 0.80; 95% CI, 0.65-0.98) (NNTB ¼ 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] ¼ 79) (Figure 5), cardiogenic shock (IRR 1.29; 95% CI, 1.18-1.41) (NNTH ¼ 90) (Figure 6), and drug discontinuation (IRR 1.64; 95% CI, 1.55-1.73) (Figure 7), with no impact on cardiovascular mortality Bangalore et al b-Blockers for Myocardial Infarction 945 Figure 5 b-blockers vs controls for the outcome of heart failure in acute myocardial infarction trials. Analysis stratified by reperfusion status. CI ¼ confidence interval; COMMIT ¼ Clopidogrel and Metoprolol in Myocardial Infarction Trial; EMIT ¼ Esmolol Myocardial Ischemia Trial; ICSG ¼ The International Collaborative Study Group; IRR ¼ incident rate ratio; ISIS-1 ¼ First International Study of Infarct Survival Collaborative Group; MEMO ¼ Metoprolol-Morphine Study Group; METOCARDCNIC ¼ Effect of Metroprolol in Cardioprotection During an Acute Myocardial Infarction trial; MIAMI ¼ Metoprolol in Acute Myocardial Infarction; MILIS ¼ Multicenter Investigation for the Limitation of Infarct Size; RIMA ¼ Rimodellamento Infarcto Miocardico Acuto Study; TIMI ¼ Thrombolysis in Myocardial Infarction; UKCSG ¼ UK Collaborative Study Group. (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 postmyocardial infarction trials were largely similar (Figures 8-11). Intravenous b-Blocker and Outcomes In the pre-reperfusion-era trials, a significant interaction was observed (Pinteraction ¼ .09) such that the benefit for all-cause mortality was driven by trials where early intravenous b-blocker (IRR 0.83; 95% CI, 0.75-0.92) was administered, but not in trials where b-blockers were administered orally (IRR 0.99; 95% CI, 0.83-1.19). Similarly, early intravenous b-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 b-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 b-Blockers Usage In the pre-reperfusion era, b-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, b-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). 946 The American Journal of Medicine, Vol 127, No 10, October 2014 Figure 6 b-blockers vs controls for the outcome of cardiogenic shock in acute myocardial infarction trials. Analysis stratified by reperfusion status. CI ¼ confidence interval; COMMIT ¼ Clopidogrel and Metoprolol in Myocardial Infarction Trial; EMIT ¼ Esmolol Myocardial Ischemia Trial; ICSG ¼ The International Collaborative Study Group; IRR ¼ incident rate ratio; ISIS-1 ¼ First International Study of Infarct Survival Collaborative Group; MEMO ¼ Metoprolol-Morphine Study Group; METOCARD-CNIC ¼ Effect of Metroprolol in Cardioprotection During an Acute Myocardial Infarction trial; MIAMI ¼ Metoprolol in Acute Myocardial Infarction; MILIS ¼ Multicenter Investigation for the Limitation of Infarct Size; RIMA ¼ Rimodellamento Infarcto Miocardico Acuto Study; TIMI ¼ Thrombolysis in Myocardial Infarction; UKCSG ¼ UK Collaborative Study Group. Trial Sequential Analysis DISCUSSION The cumulative Z-curve crosses the futility boundary, showing with confidence the lack of even a 10% reduction in the risk of mortality with b-blocker when compared with controls in the reperfusion era (Figure 12). In patients with a myocardial infarction, a significant interaction of reperfusion-era status on the association of b-blocker and outcomes was seen such that while b-blockers were associated with reduction in events, including mortality in the pre-reperfusion era (driven by trials where early intravenous b-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. Sensitivity Analysis Various sensitivity analyses outlined in the methods yielded largely similar results (data available on request). In addition, there was no benefit of b-blockers for mortality in the reperfusion era even after exclusion of the COMMIT trial (IRR 0.76; 95% CI, 0.48-1.21; P ¼ .25). Furthermore, the beneficial effect of b-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 ¼ .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 ¼ .18). In the meta-regression analysis, the beneficial effect of bblockers on mortality diminished with increasing percentage of patients with reperfusion therapy (P ¼ .056) (Figure 13). Efficacy of b-Blockers in the Reperfusion Era Why is there a lack of efficacy of b-blockers in the reper- fusion 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 prereperfusion strata with a sample size of 31,479 patients Bangalore et al b-Blockers for Myocardial Infarction 947 Figure 7 b-blockers vs controls and drug discontinuation in acute myocardial infarction trials. Analysis stratified by reperfusion status. CI ¼ confidence interval; COMMIT ¼ Clopidogrel and Metoprolol in Myocardial Infarction Trial; EMIT ¼ Esmolol Myocardial Ischemia Trial; ICSG ¼ The International Collaborative Study Group; IRR ¼ incident rate ratio; ISIS-1 ¼ First International Study of Infarct Survival Collaborative Group; MEMO ¼ Metoprolol-Morphine Study Group; METOCARD-CNIC ¼ Effect of Metroprolol in Cardioprotection During an Acute Myocardial Infarction trial; MIAMI ¼ Metoprolol in Acute Myocardial Infarction; MILIS ¼ Multicenter Investigation for the Limitation of Infarct Size; RIMA ¼ Rimodellamento Infarcto Miocardico Acuto Study; TIMI ¼ Thrombolysis in Myocardial Infarction; UKCSG ¼ UK Collaborative Study Group. 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 reperfusionera trials, there is firm evidence to rule out even a 10% reduction in mortality with b-blockers. In the First International Study of Infarct Survival (ISIS1) 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.2 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.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. bblockers are beneficial in this setting by preventing sudden death, which was the major cause of mortality in the prereperfusion 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 b-blockers.74 Conceivably, b-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 prereperfusion 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 riskebenefit ratio no longer seems to be favorable. A number of trials have shown that reperfusion therapy, aspirin, or statin reduces infarct size.75-78 In addition, both streptokinase and aspirin prevent cardiac arrest, including death, due to ventricular fibrillation in the ISIS-2 trial.79 948 The American Journal of Medicine, Vol 127, No 10, October 2014 Figure 8 b-blockers vs controls for the outcome of all-cause mortality in postmyocardial infarction trials. Analysis stratified by reperfusion status. APSI ¼ Acebutolol et Prévention Secondaire de l’Infarctus; BHAT ¼ Beta-Blocker Heart Attack Trial; CI ¼ confidence interval; CPRG ¼ Coronary Prevention Research Group; EIS ¼ European Infarction Study; IRR ¼ incident rate ratio; JCBMI ¼ The Japanese beta Blockers and Calcium Antagonists Myocardial Infarction; LIT ¼ Lopressor Intervention Trial Research Group. Figure 9 b-blockers vs controls for the outcome of myocardial infarction in post myocardial infarction trials. Analysis stratified by reperfusion status. APSI ¼ Acebutolol et Prévention Secondaire de l’Infarctus; BHAT ¼ Beta-Blocker Heart Attack Trial; CI ¼ confidence interval; CPRG ¼ Coronary Prevention Research Group; EIS ¼ European Infarction Study; IRR ¼ incident rate ratio; JCBMI ¼ The Japanese beta Blockers and Calcium Antagonists Myocardial Infarction; LIT ¼ Lopressor Intervention Trial Research Group. Bangalore et al b-Blockers for Myocardial Infarction Figure 10 b-blockers vs controls for the outcome of heart failure in post myocardial infarction trials. Analysis stratified by reperfusion status. APSI ¼ Acebutolol et Prévention Secondaire de l’Infarctus; BHAT ¼ Beta-Blocker Heart Attack Trial; CI ¼ confidence interval; CPRG ¼ Coronary Prevention Research Group; EIS ¼ European Infarction Study; IRR ¼ incident rate ratio; JCBMI ¼ The Japanese beta Blockers and Calcium Antagonists Myocardial Infarction; LIT ¼ Lopressor Intervention Trial Research Group. Figure 11 b-blockers vs controls and drug discontinuation in postmyocardial infarction trials. Analysis stratified by reperfusion status. APSI ¼ Acebutolol et Prévention Secondaire de l’Infarctus; BHAT ¼ Beta-Blocker Heart Attack Trial; CI ¼ confidence interval; CPRG ¼ Coronary Prevention Research Group; EIS ¼ European Infarction Study; IRR ¼ incident rate ratio; JCBMI ¼ The Japanese beta Blockers and Calcium Antagonists Myocardial Infarction; LIT ¼ Lopressor Intervention Trial Research Group. 949 1.00 (0.65, 1.54) NA NA NA NA 0.25 (0.03, 2.25) NA 0.81 (0.62, 1.06) NA 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, b-blockers will remain highly efficacious in preventing events, as has been shown in numerous heart failure trials,12,80,81 and in preventing ventricular arrhythmias and sudden death. One may be tempted to conclude 0.73 (0.48, 1.11) NA 0.64 (0.43, 0.97) NA Figure 12 Trial Sequential Analysis using fixed-effect metaanalysis 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 ¼ 0%), and a ¼ 0.05 and b ¼ 0.10. Reperfusion era 0.81 (0.66, 0.98) NA Events > 1 year Pre-reperfusion Reperfusion era NA 0.20 (0.01, 4.20) NA 1.16 (1.03, 1.30) 1.49 (1.01, 2.19) 1.88 (0.51, 6.96) NA 1.07 (0.91, 1.27) 3.83 (1.56, 9.41) 1.54 (0.60, 3.95) 4.00 (0.45, 35.79) 0.61 (0.49, 0.76) NA 0.84 (0.71, 1.00) 1.50 (0.53, 4.21) 0.79 (0.71, 0.88) 1.50 (0.53, 4.21) Events between 30 days and 1 year Pre-reperfusion Reperfusion era 0.77 (0.64, 0.91) 0.71 (0.23, 2.25) 0.94 (0.75, 1.18) 1.03 (0.72, 1.48) 1.03 (0.87, 1.21) 1.29 (1.18, 1.41) 1.06 (0.97, 1.16) 1.10 (1.05, 1.16) 2.96 (0.47, 18.81) 1.09 (0.91, 1.30) Events at 30 days Pre-reperfusion 0.87 (0.79, 0.96) 0.98 (0.92, 1.05) 0.86 (0.77, 0.96) 1.00 (0.91,1.10) 0.82 (0.59, 1.13) 0.94 (0.86, 1.01) 0.81 (0.63,1.04) 0.72 (0.62, 0.84) 0.89 (0.83, 0.95) 0.81 (0.66, 1.00) Cardiogenic Shock Heart Failure Stroke Angina MI Sudden Death CV Death Death Landmark Analyses: b-Blockers vs Controls (From Fixed-effect Model) Table 2 1.11 (1.00, 1.23) 1.64 (1.55, 1.73) The American Journal of Medicine, Vol 127, No 10, October 2014 Withdrawal 950 Figure 13 Meta-regression analysis of the relationship of percentage of patients with reperfusion therapy on the risk ratio of mortality with b-blockers. Bangalore et al b-Blockers for Myocardial Infarction from the pre-reperfusion-era trials that b-blockers will also be efficacious in patients with myocardial infarction treated conservatively (that is, no reperfusion). However, in the COMMIT trial,5 there was no benefit of b-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 b-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 b-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 b-blockers in the pre-reperfusion era, most of the trials were high risk for bias. CONCLUSIONS In this analysis of b-blockers in myocardial infarction, a significant interaction of reperfusion-era status on the association of b-blocker and outcomes was seen, in that b-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 b-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 b-blockers for myocardial infarction, especially in patients undergoing contemporary treatment. References 1. 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