Beta‐blockers for suspected or diagnosed acute myocardial infarction

Sanam Safi; Naqash J Sethi; Emil Eik Nielsen; Joshua Feinberg; Christian Gluud; Janus C Jakobsen

doi:10.1002/14651858.CD012484.pub2

. 2019 Dec 17;2019(12):CD012484. doi: 10.1002/14651858.CD012484.pub2

Beta‐blockers for suspected or diagnosed acute myocardial infarction

Sanam Safi ^1,^✉, Naqash J Sethi ¹, Emil Eik Nielsen ^1,², Joshua Feinberg ¹, Christian Gluud ^1,³, Janus C Jakobsen ^3,^4,⁵

Editor: Cochrane Heart Group

PMCID: PMC6915833 PMID: 31845756

Abstract

Background

Cardiovascular disease is the number one cause of death globally. According to the World Health Organization, 7.4 million people died from ischaemic heart diseases in 2012, constituting 15% of all deaths. Acute myocardial infarction is caused by blockage of the blood supplied to the heart muscle. Beta‐blockers are often used in patients with acute myocardial infarction. Previous meta‐analyses on the topic have shown conflicting results ranging from harms, neutral effects, to benefits. No previous systematic review using Cochrane methodology has assessed the effects of beta‐blockers for acute myocardial infarction.

Objectives

To assess the benefits and harms of beta‐blockers compared with placebo or no intervention in people with suspected or diagnosed acute myocardial infarction.

Search methods

We searched CENTRAL, MEDLINE, Embase, LILACS, Science Citation Index Expanded and BIOSIS Citation Index in June 2019. We also searched the WHO International Clinical Trials Registry Platform, ClinicalTrials.gov, Turning Research into Practice, Google Scholar, SciSearch, and the reference lists of included trials and previous reviews in August 2019.

Selection criteria

We included all randomised clinical trials assessing the effects of beta‐blockers versus placebo or no intervention in people with suspected or diagnosed acute myocardial infarction. Trials were included irrespective of trial design, setting, blinding, publication status, publication year, language, and reporting of our outcomes.

Data collection and analysis

We followed the Cochrane methodological recommendations. Four review authors independently extracted data. Our primary outcomes were all‐cause mortality, serious adverse events according to the International Conference on Harmonization ‐ Good Clinical Practice (ICH‐GCP), and major adverse cardiovascular events (composite of cardiovascular mortality and non‐fatal myocardial infarction during follow‐up). Our secondary outcomes were quality of life, angina, cardiovascular mortality, and myocardial infarction during follow‐up. Our primary time point of interest was less than three months after randomisation. We also assessed the outcomes at maximum follow‐up beyond three months. Due to risk of multiplicity, we calculated a 97.5% confidence interval (CI) for the primary outcomes and a 98% CI for the secondary outcomes. We assessed the risks of systematic errors through seven bias domains in accordance to the instructions given in the Cochrane Handbook. The quality of the body of evidence was assessed by GRADE.

Main results

We included 63 trials randomising a total of 85,550 participants (mean age 57.4 years). Only one trial was at low risk of bias. The remaining trials were at high risk of bias. The quality of the evidence according to GRADE ranged from very low to high. Fifty‐six trials commenced beta‐blockers during the acute phase of acute myocardial infarction and seven trials during the subacute phase.

At our primary time point 'less than three months follow‐up', meta‐analysis showed that beta‐blockers versus placebo or no intervention probably reduce the risk of a reinfarction during follow‐up (risk ratio (RR) 0.82, 98% confidence interval (CI) 0.73 to 0.91; 67,562 participants; 18 trials; moderate‐quality evidence) with an absolute risk reduction of 0.5% and a number needed to treat for an additional beneficial outcome (NNTB) of 196 participants. However, we found little or no effect of beta‐blockers when assessing all‐cause mortality (RR 0.94, 97.5% CI 0.90 to 1.00; 80,452 participants; 46 trials/47 comparisons; high‐quality evidence) with an absolute risk reduction of 0.4% and cardiovascular mortality (RR 0.99, 95% CI 0.91 to 1.08; 45,852 participants; 1 trial; moderate‐quality evidence) with an absolute risk reduction of 0.4%. Regarding angina, it is uncertain whether beta‐blockers have a beneficial or harmful effect (RR 0.70, 98% CI 0.25 to 1.84; 98 participants; 3 trials; very low‐quality evidence) with an absolute risk reduction of 7.1%. None of the trials specifically assessed nor reported serious adverse events according to ICH‐GCP. Only two trials specifically assessed major adverse cardiovascular events, however, no major adverse cardiovascular events occurred in either trial.

At maximum follow‐up beyond three months, meta‐analyses showed that beta‐blockers versus placebo or no intervention probably reduce the risk of all‐cause mortality (RR 0.93, 97.5% CI 0.86 to 0.99; 25,210 participants; 21 trials/22 comparisons; moderate‐quality evidence) with an absolute risk reduction of 1.1% and a NNTB of 91 participants, and cardiovascular mortality (RR 0.90, 98% CI 0.83 to 0.98; 22,457 participants; 14 trials/15 comparisons; moderate‐quality evidence) with an absolute risk reduction of 1.2% and a NNTB of 83 participants. However, it is uncertain whether beta‐blockers have a beneficial or harmful effect when assessing major adverse cardiovascular events (RR 0.81, 97.5% CI 0.40 to 1.66; 475 participants; 4 trials; very low‐quality evidence) with an absolute risk reduction of 1.7%; reinfarction (RR 0.89, 98% CI 0.75 to 1.08; 6825 participants; 14 trials; low‐quality evidence) with an absolute risk reduction of 0.9%; and angina (RR 0.64, 98% CI 0.18 to 2.0; 844 participants; 2 trials; very low‐quality evidence). None of the trials specifically assessed nor reported serious adverse events according to ICH‐GCP.

None of the trials assessed quality of life.

We identified two ongoing randomised clinical trials investigating the effect of early administration of beta‐blockers after percutaneous coronary intervention or thrombolysis to patients with an acute myocardial infarction and one ongoing trial investigating the effect of long‐term beta‐blocker therapy.

Authors' conclusions

Our present review indicates that beta‐blockers for suspected or diagnosed acute myocardial infarction probably reduce the short‐term risk of a reinfarction and the long‐term risk of all‐cause mortality and cardiovascular mortality. Nevertheless, it is most likely that beta‐blockers have little or no effect on the short‐term risk of all‐cause mortality and cardiovascular mortality. Regarding all remaining outcomes (serious adverse events according to ICH‐GCP, major adverse cardiovascular events (composite of cardiovascular mortality and non‐fatal myocardial infarction during follow‐up), the long‐term risk of a reinfarction during follow‐up, quality of life, and angina), further information is needed to confirm or reject the clinical effects of beta‐blockers on these outcomes for people with or suspected of acute myocardial infarction.

Plain language summary

Beta‐blockers versus placebo or no intervention for patients with suspected or diagnosed myocardial infarction

Background

According to the World Health Organization, 7.4 million people died from ischaemic heart disease in 2012, representing 15% of all global deaths. The role of acute or subacute treatment with beta‐blockers in people suspected of or diagnosed with a heart attack, rests on their inhibition of so‐called beta‐receptors. This may result in a reduction in the oxygen demand of the heart. Hence, the inhibition of the beta‐receptor may or may not decrease the complications associated with heart attack.

Review question

The aim of this Cochrane Systematic Review was to assess the benefits and harms of beta‐blockers in people with suspected or diagnosed acute myocardial infarction (heart attack).

Search date

We searched scientific databases from their inception to June 2019.

Study characteristics

We found 63 randomised clinical trials where people with or suspected of a heart attack were randomly allocated to receiving beta‐blockers compared with placebo or no intervention. The 63 trials included 85,550 adults with a mean age of 57.4 years. Only one trial was at low risk of bias. The remaining trials were at high risk of bias. The quality of the evidence according to GRADE ranged from very low to high. Fifty‐six trials commenced beta‐blockers versus control during the acute phase of acute myocardial infarction and seven trials during the subacute phase.

Study funding sources

We found 33 trials that were fully or partly funded by the industry, 20 trials that did not report their funding source, and 10 trials that were funded by other sources than the industry.

Key results and conclusion

Our present review shows that people receiving beta‐blockers compared with people receiving placebo or no intervention seem at lower risk of a new heart attack in the acute phase after a heart attack. People receiving beta‐blockers also seem at lower risk of dying from any cause and from any cardiac cause at long‐term follow‐up after a heart attack. Nevertheless, people receiving beta‐blockers do not seem to have a lower or a higher risk of dying from any cause or from any cardiac cause in the acute phase after a heart attack. The effects of beta‐blockers on all remaining outcomes (serious adverse events according to International Conference on Harmonization ‐ Good Clinical Practice, major adverse cardiovascular events (composite of dying from a cardiac cause and a new non‐fatal heart attack), new heart attack at long‐term follow‐up, quality of life, and angina) are uncertain due to none or sparse data.

Summary of findings

Background

Description of the condition

Cardiovascular disease is the number one cause of death globally (Cooper 2000; Lloyd‐Jones 2010; Nichols 2014; Rosamond 2008; Schmidt 2012). Ischaemic heart disease accounts for almost 50% of the disease burden of the cardiovascular diseases (Nichols 2014). According to the World Health Organization (WHO), 7.4 million people died from ischaemic heart disease in 2012 (WHO 2015).

Ischaemic heart disease is caused by different underlying mechanisms: (1) atherosclerotic plaque‐related obstruction of the coronary arteries; (2) focal or diffuse spasms of normal or plaque‐diseased arteries; (3) microvascular dysfunction; and (4) left ventricular dysfunction caused by acute myocardial necrosis or ischaemic cardiomyopathy (Montalescot 2013). Ischaemic heart disease increases the risk of stable angina pectoris and acute coronary syndrome (see below).

Acute coronary syndrome is a collective term for: (1) unstable angina pectoris (chest pain during rest related to ischaemia or hypoxia of the heart muscle (Roffi 2016)); (2) acute non‐ST‐elevation myocardial infarction (NSTEMI); or (3) acute ST‐elevation myocardial infarction (STEMI) (O'Gara 2013; Steg 2012). Myocardial infarction is caused by death of cardiac myocytes (myocardial necrosis) due to ischaemia (Roffi 2016; Steg 2012). The clinical definition of myocardial infarction is elevated serum levels of cardiac biomarkers (cardiac specific troponins and CK‐MB among others) and changes of the ST‐segment on an electrocardiogram (ECG) (STEMI and NSTEMI) or symptoms of cardiac ischaemia (Roffi 2016; Steg 2012).

The diagnosis of myocardial infarction is dependent on an elevation of the serum levels of cardiac‐specific troponin I, troponin T, or the myocardial band (MB) isoenzyme of creatine kinase (CK‐MB), among others (Roffi 2016; Steg 2012). However, it will often take eight to 24 hours after the first symptoms of the myocardial infarction occur before these enzymes are detectable in serum. Beta‐blockers may accordingly be commenced as an intervention in patients suspected of myocardial infarction or may be commenced as an intervention in patients diagnosed with myocardial infarction.

The cause of myocardial infarction is generally divided in to five main classes (Thygesen 2012).

Type 1: spontaneous myocardial infarction related to atherosclerotic plaque rupture, ulceration, fissuring, erosion, or dissection with resulting intraluminal thrombus in one or more of the coronary arteries often caused by coronary artery disease.
Type 2: myocardial infarction secondary to an ischaemic imbalance such as coronary artery spasm, coronary embolism, anaemia, arrhythmias, hypertension, or hypotension.
Type 3: myocardial infarction with symptoms suggestive of myocardial ischaemia and resulting in sudden unexpected cardiac death when biomarker values are unavailable or could not be obtained before death.
Type 4a: myocardial infarction associated with percutaneous coronary intervention (PCI).
Type 4b: myocardial infarction associated with stent thrombosis as documented by angiography or at autopsy.
Type 5: myocardial infarction associated with coronary artery bypass graft (CABG).

Major complications associated with myocardial infarction

Life‐threatening ventricular arrhythmias caused by changes in the electrophysiologic characteristics of the myocyte, electrolyte imbalance, continuous ischaemia, and variations in heart rate all due to obstruction and hence, reduced flow to the myocardium and myocardial necrosis (Brieger 2009; Stevenson 1989).
Mechanical complications caused by necrosis of the myocardium such as ventricular wall rupture, septum rupture, and papillary muscle rupture (Brieger 2009; Pohjola‐Sintonen 1989; Stevenson 1989).
Cardiogenic shock caused by failure of the ventricle to pump adequate amount of blood leading to a systemic hypotension (Brieger 2009; Stevenson 1989).
Acute decompensated heart failure caused by impairment in systolic and diastolic function due to myocardial ischaemia (Brieger 2009).
Depression (Thombs 2006).

Description of the intervention

The discovery of the difference between adrenergic receptors by Raymond Ahlquist in 1948 led Sir James Black to develop the first clinically useful beta‐receptor blocker (propranolol) in 1964 (Ahlquist 1948; Black 1964). This discovery was awarded the Nobel Prize in 1988 (Quirke 2006). Beta‐blockers are classified as non‐selective beta‐blockers or selective beta‐blockers according to their selectivity for one of the three subtypes of beta‐receptors.

The beta₁‐receptor is mainly located in: (1) the heart, where it induces positive chronotropic effects (increases heart rate) and positive inotropic effects (increases contractility of the myocardium); and (2) in the kidneys where activation of the beta₁‐receptor results in an increased release of renin which in turn increases blood pressure, among other effects (Golan 2011; Marlin 1975; Singh 1975).

The beta₂‐receptor is mainly located in smooth muscle cells where it promotes relaxation, in skeletal muscle cells where it promotes tremor and increased glycogenolysis, and in the liver, where it increases glycogenolysis (Golan 2011).

The beta₃‐receptor is mainly located in adipose tissue where it primarily induces lipolysis (Golan 2011).

Beta‐blockers may be administered both intravenously and orally. Three different classes of beta‐blockers exist: (1) the first generation non‐selective beta‐blockers (e.g. propranolol, oxprenolol, sotalol, timolol) affecting all beta‐receptors; (2) the second generation selective beta₁‐blockers (e.g. metoprolol, bisoprolol, acebutolol, atenolol, esmolol) mainly affecting the heart; and (3) the third generation beta‐blockers which have combined non‐selective beta‐blocking effects and alpha‐blocking effects (e.g. carvedilol) affecting all beta‐receptors plus alpha‐receptors in the vessels lowering the blood pressure.

Several beta‐blockers have been used in the management of patients with myocardial infarction. The first beta‐blockers used were the non‐selective beta‐blockers (e.g. propranolol) (Clausen 1966b; Friedman 1986). Today, the most frequently used beta‐blockers for managing myocardial infarction are the cardiac‐specific beta₁‐blockers (Chen 2005; Roffi 2016; Steg 2012).

How the intervention might work

The beta‐receptor is an adrenergic heterodimeric G‐protein‐coupled receptor (G protein‐coupled receptors are transmembrane proteins that act as key gatekeepers between external signals and cellular responses), located throughout the body. Beta‐receptors are stimulated by the sympathetic nervous system with catecholamines epinephrine (adrenaline) and norepinephrine (noradrenaline) as their primary endogenous agonists. The role of acute treatment or subacute treatment with beta‐blockers in patients suspected of or diagnosed with myocardial infarction, rests on their inhibition of the chronotropic and inotropic effects of the beta‐receptor. This may result in a reduction in heart rate, heart contractility, and blood pressure, thereby decreasing the oxygen demand of the heart (Lopez‐Sendon 2004). Hence, the inhibition of the beta‐receptor is thought to decrease ischaemia and might decrease the risk of life‐threatening ventricular arrhythmias and other complications associated with myocardial infarction (Roffi 2016; Steg 2012).

Why it is important to do this review

The prevalence of ischaemic heart disease is considerable. According to the WHO, 7.4 million people died from ischaemic heart disease in 2012 (Lloyd‐Jones 2010; Nichols 2014; Rosamond 2008; WHO 2015). A considerable reduction in disease burden and healthcare cost may therefore be alleviated by effective treatment. However, as demonstrated below, previous meta‐analyses and guidelines show contrasting findings and recommendations.

Evidence on the effects of beta‐blockers for suspected or diagnosed acute myocardial infarction

Outcomes assessed at hospital discharge

Five studies have compared the effects of beta‐blockers versus placebo, standard medical therapy, or late administration of beta‐blockers in participants with suspected or diagnosed myocardial infarction on outcomes reported at hospital discharge (Al‐Reesi 2008; Brandler 2010; Chatterjee 2013; Freemantle 1999; Yusuf 1985). While Chatterjee 2013 only assessed intravenously assessed beta‐blockers and showed a beneficial effect of early beta‐blockers on mortality, Al‐Reesi 2008, Brandler 2010, and Freemantle 1999 assessed any type of beta‐blockers and could not demonstrate a beneficial effect of beta‐blockers on mortality. Yusuf 1985 assessed the effects of beta‐blockers on the size of myocardial infarction and showed a beneficial effect when compared with no beta‐blockers. One of the meta‐analyses showed a beneficial effect of beta‐blockers on the risk of myocardial reinfarction and ventricular arrhythmia, while no beneficial or harmful effects were found on cardiogenic shock (Chatterjee 2013). Al‐Reesi 2008, Brandler 2010, and Freemantle 1999 did not assess the effects of beta‐blockers on the risk of myocardial reinfarction, ventricular arrhythmias, or cardiogenic shock.

Long‐term outcomes

Three studies compared the effects of beta‐blockers versus no beta‐blockers in participants with suspected or diagnosed myocardial infarction on long‐term outcomes (Bangalore 2014; Freemantle 1999; Yusuf 1985). While Freemantle 1999 and Yusuf 1985 showed a beneficial effect of beta‐blockers on mortality, Bangalore 2014 only found a beneficial effect on mortality in trials where the participants did not receive reperfusion in the form of revascularisation (percutaneous coronary intervention or coronary artery bypass graft) or thrombolytics (e.g. streptokinase). Bangalore 2014 found a beneficial effect of beta‐blockers on symptoms of angina and risk of recurrent myocardial infarction regardless of whether the participants received intervention for reperfusion (revascularisation or thrombolytics) or not. However, Bangalore 2014 also showed that beta‐blockers seem to increase the severity of heart failure in participants receiving intervention for reperfusion (revascularisation or thrombolytics). It must be noted that Bangalore 2014 included a larger number of trials than Freemantle 1999 and Yusuf 1985, and only Bangalore 2014 included trials after the introduction of reperfusion strategies around 1990s.

No newer studies assessing beta‐blocker treatment for patients with suspected or diagnosed myocardial infarction consisting of randomised clinical trials including different types of beta‐blocker interventions and types of myocardial infarctions have been conducted since 2014. Hoedemaker 2019 and Elgendy 2016 each included four randomised clinical trials assessing only intravenously‐assessed beta‐blocker treatment in STEMI patients. Two other studies, Dahl 2019 and Misumida 2016, only included cohort studies and observational studies, respectively.

Despite these studies, the question of whether or not beta‐blockers should be administered in the acute phase of an acute myocardial infarction has not yet been sufficiently answered. The above‐mentioned studies show conflicting results and suggest that more randomised clinical trials are needed to determine the effects of beta‐blockers. Hence, this review is of uttermost importance and is the first to take fully account of all existing randomised clinical trials assessing the effects and harms of beta‐blockers for acute myocardial infarction.

Beta‐blockers for other conditions

The role of beta‐blockers for other conditions than myocardial infarction is still debated. Beta‐blockers used to be contraindicated in patients with congestive heart failure. Beta‐blockers and non‐selective combined alpha‐ and beta‐blockers are now a part of standard treatment of congestive heart failure (Chatterjee 2013a; Yancy 2013).

Beta‐blockers are also considered an option in the treatment of hypertension, but are rarely used as first‐line treatment (Mancia 2013). A recent Cochrane Review found that beta‐blockers were inferior when compared with other antihypertensive drugs (Wiysonge 2012). Non‐selective beta‐blockers are used in the treatment of anxiety due to their effect on decreasing tremor and tachycardia (Turner 1994).

The adverse effects of beta‐blockers include both cardiac adverse effects and non‐cardiac adverse effects. Among the most serious cardiac adverse effects is exacerbation of heart failure in patients with acute decompensated heart failure, due to the need of sympathetic activity to maintain the cardiac output (Taylor 1982). In addition, beta‐blocker withdrawal has also been shown to cause exacerbation of ischaemic symptoms and precipitate acute myocardial infarction in patients with ischaemic heart disease (Houston 1981).

Perioperative beta‐blockade for major non‐cardiac surgery in patients with risk factors for ischaemic heart disease has been tested in several trials (Bangalore 2008; Devereaux 2008; Juul 2006), and seems to increase 30‐day all‐cause mortality, increase the risk of stroke, although the risk of non‐fatal myocardial infarction seems to be reduced (Bangalore 2008).

Studies of individual patients have suggested that depression, fatigue, and sexual dysfunction are among the beta‐blocker induced non‐cardiac adverse effects (Greenblatt 1974; Waal 1967; Warren 1977). However, a meta‐analysis comparing beta‐blockers versus placebo showed no difference on depressive symptoms and only a minor increase in sexual dysfunction and fatigue in patients randomised to beta‐blockers compared with placebo (Ko 2002).

Current guidelines for using beta‐blockers in patients with suspected or diagnosed myocardial infarction

The American College of Cardiology Foundation/American Heart Association (ACCF/AHA) guideline recommends acute intravenous beta‐blockers in patients suspected of STEMI who are hypertensive or have ongoing ischaemia, unless there are contraindications to beta‐blockers (allergy towards beta‐blockers, signs of acute decompensated heart failure, increased risk of cardiogenic shock, atrio‐ventricular block, asthma, or chronic obstructive lung disease) (O'Gara 2013). The guideline recommends oral beta‐blockers within the first 24 hours in patients with a STEMI and no contraindications (see above) (O'Gara 2013).

The ACCF/AHA guideline does not recommend acute intravenous beta‐blockers in patients suspected of acute NSTEMI and advise against intravenous beta‐blockers in acute patients with risk factors for cardiogenic shock (Amsterdam 2014). However, the guideline recommends oral beta‐blockers commenced within the first 24 hours in patients with a NSTEMI or unstable angina pectoris and no contraindications (see above) (Amsterdam 2014).

Former meta‐analyses have shown conflicting results and no former reviews have used Cochrane methodology to assess the effects of beta‐blockers as an acute intervention in patients suspected or diagnosed with myocardial infarction. The present systematic review has been the first to use the GRADE approach to assess the quality of a body of evidence associated with each of the outcomes, to assess the risk of systematic errors ('bias'), design errors, and risks of random errors ('play of chance'), and to include trials irrespective of outcome, follow‐up duration, number of participants, language, and publication status (Guyatt 2008; Higgins 2011; Schünemann 2013).

Objectives

We assessed the benefits and harms of beta‐blockers compared with placebo or no intervention in people with suspected or diagnosed acute myocardial infarction.

The present review is based on our peer‐reviewed, published protocol (Nielsen 2016) with amendments during the review process (see Differences between protocol and review).

Methods

Criteria for considering studies for this review

Types of studies

We included all randomised clinical trials (RCTs) irrespective of trial design, setting, blinding, publication status, publication year, language, and reported outcomes.

Types of participants

We included any participant (irrespective of age and sex) with suspected or diagnosed acute myocardial infarction (as defined by trialists).

Types of interventions

We included three types of comparisons:

beta‐blockers compared with placebo;
beta‐blockers compared with no intervention (including no placebo tablet); and
beta‐blockers added to a co‐intervention compared with a similar co‐intervention.

We accepted any type of beta‐blocker (intravenous therapy or oral administration) commenced in the acute or subacute phase of acute myocardial infarction (non‐selective beta‐blockers (propranolol, oxprenolol, sotalol, timolol); selective beta₁‐blockers (metoprolol, bisoprolol, acebutolol, atenolol, esmolol); and beta‐blockers which are combined alpha‐ and non‐selective beta‐blockers (carvedilol)) as the experimental intervention, irrespective of dose, route of administration, and duration.

We accepted any type of co‐intervention (medical therapy as well as revascularisation strategies) provided they were intended to be delivered similarly to the experimental and the control groups.

Types of outcome measures

We assessed all outcomes at two time points:

less than three months after randomisation (this was the time point of primary interest). If multiple time points were reported at less than three months, we chose the one closest to one‐month follow‐up.
maximum follow‐up beyond three months.

We chose 'less than three months follow‐up' as our primary follow‐up time point because the possible effects of beta‐blockers need some time to show, and the follow‐up period is not too long so other factors unrelated to the given trial affecting the outcomes might decrease the statistical power, i.e. the results are 'diluted' by events (e.g. traffic accidents) unrelated to the trial.

Primary outcomes

All‐cause mortality.
Serious adverse events. We defined a serious adverse event as any untoward medical occurrence that: resulted in death; was life‐threatening; required hospitalisation or prolongation of existing hospitalisation; resulted in persistent or significant disability; or jeopardised the participant according to the International Conference on Harmonization ‐ Good Clinical Practice (ICH‐GCP Guidelines) (ICH‐GCP 1997). None of the trials specifically assessed serious adverse events according to the definition by ICH‐GCP. Instead, the trials either reported composites of several specific serious adverse events or one specific serious adverse event.
Major adverse cardiovascular events (MACE), defined as a composite outcome consisting of cardiovascular mortality (defined by trialists) and non‐fatal myocardial infarction during follow‐up (defined by trialists). Additionally, we assessed cardiovascular mortality and myocardial infarction during follow‐up separately as secondary outcomes (see below).

Secondary outcomes

Quality of life measured on any valid continuous scale, such as the Short‐Form (36) Health Survey (SF‐36) (Ware 1992). None of the trials adequately assessed quality of life.
Angina measured on any valid scale, such as the Canadian Cardiovascular Angina Score (CCS) (Campeau 1976).
Cardiovascular mortality.
Myocardial infarction during follow‐up (i.e. reinfarction in the participants who were diagnosed with myocardial infarction at, or shortly after, randomisation, and first myocardial infarction in the participants who were suspected of myocardial infarction at randomisation, but where the suspicion was later rejected).

Search methods for identification of studies

Electronic searches

We searched the following databases on 18 June 2019 to identify reports of relevant randomised clinical trials (Royle 2003).

Cochrane Central Register of Controlled Trials (CENTRAL; 2019, Issue 6) in the Cochrane Library
Epub Ahead of Print, In‐Process & Other Non‐Indexed Citations, MEDLINE Daily and MEDLINE (Ovid, 1946 to 14 June 2019)
Embase (Ovid, 1974 to 17 June 2019)
LILACS (Latin American and Caribbean Health Science Information Database) (Bireme, 1982 to 18 June 2019)
Science Citation Index Expanded on the Web of Science (Clarivate Analytics, 1900 to 18 June 2019)
BIOSIS Citation Index on the Web of Science (Clarivate Analytics, 1926 to 18 June 2019)

We adapted the preliminary search strategy for MEDLINE (Ovid) for use in these databases. We applied the Cochrane sensitivity‐maximising filter for randomised clinical trials (Lefebvre 2011) to MEDLINE Ovid and adaptations of it to the other databases, except CENTRAL. The search strategy can be found in Appendix 1.

We searched all databases from their inception to the present and we imposed no restriction on language of publication or publication status. We assessed non‐English language papers by asking individuals that speak the language fluently for help. This is acknowledged in the Acknowledgements section.

Searching other resources

We searched the reference lists of included randomised clinical trials, previous systematic reviews, and other kinds of reviews for any unidentified randomised clinical trials.

Furthermore, we searched for ongoing and unidentified randomised clinical trials on 14 August 2019:

the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) search portal (apps.who.int/trialsearch);
ClinicalTrials.gov (www.clinicaltrials.gov);
Turning Research Into Practice (TRIP) (http://www.tripdatabase.com/);
Google Scholar (http://scholar.google.dk/); and
Scisearch (http://ipscience.thomsonreuters.com/).

We also examined relevant retraction statements and errata for included trials.

Data collection and analysis

We performed this systematic review following the recommendations of Cochrane (Higgins 2011). The analyses were performed using Review Manager 5.3 (RevMan 2014).

Selection of studies

Two review authors (Sanam Safi (SS) and Naqash J Sethi (NJS)) independently screened titles and abstracts for inclusion of all the potentially eligible trials. We coded all these studies as 'retrieve' (eligible or potentially eligible/unclear) or 'do not retrieve'. If there was any disagreements, a third author were asked to arbitrate (Janus C Jakobsen (JCJ)). We retrieved the full‐text study reports/publications and four review authors (SS, NJS, Emil Eik Nielsen (EEN), and Joshua Feinberg (JF)) independently screened the full‐text reports and identified trials for inclusion. Reasons for exclusion of the ineligible studies were reported (Excluded studies). We resolved any disagreement through discussion or, if required, we consulted a third author (JCJ). We identified and excluded duplicated and collated multiple reports of the same trial so that each trial rather than each report is the unit of interest in the review. We recorded the selection process in sufficient detail to complete a PRISMA flow diagram (Moher 2009) Figure 1 and 'Characteristics of excluded studies' table.

Data extraction and management

Four review authors (SS, NJS, EEN, JF) extracted and validated data independently from included trials. Any disagreement concerning the extracted data were discussed between the two authors. If no agreement could be reached, a third author (JCJ) resolved the issue. In case of relevant data not being available, we contacted the trial authors.

We used a data collection form for trial data and outcome data which was piloted on at least one trial in the review.

We extracted the following data mentioned below.

Trial characteristics: trial design (parallel, factorial, or cross‐over); number of intervention arms; duration of the trial; details of any 'run‐in' period; date of publication; inclusion and exclusion criteria; and 'Risk of bias' components (as defined below).
Participants characteristics: number of participants randomised; number of participants analysed; number of participants lost to follow‐up; mean age, and sex ratio.
Intervention characteristics: type of beta‐blocker; dose of beta‐blocker; duration of beta‐blocker therapy; and mode of administration.
Control characteristics: placebo or no intervention.
Co‐intervention characteristics: type of co‐intervention; dose of co‐intervention; duration of co‐intervention; and mode of administration.
Outcomes: primary, secondary, and exploratory outcomes specified and collected, and time points reported.
Notes: funding for trial, and notable conflicts of interest of trial authors.

Assessment of risk of bias in included studies

We used the instructions given in the Cochrane Handbook for Systematic Reviews of Interventions in our evaluation of the methodology and the risk of bias of the included trials (Higgins 2017). Four review authors (SS, NJS, EEN, and JF) assessed the included trials independently. We evaluated the risk of bias in the following 'Risk of bias' domains:

random sequence generation;
allocation concealment;
blinding of participants and personnel;
blinding of outcome assessment;
incomplete outcome data;
selective outcome reporting; and
other risks of bias.

This was done because these domains enable classification of randomised clinical trials at low risk of bias and at high risk of bias. The latter trials overestimate positive intervention effects (benefits) and underestimate negative effects (harms) (Gluud 2006; Kjaergard 2001; Lundh 2017; Moher 1998; Savovic 2012; Savovic 2012a; Schulz 1995; Wood 2008). For additional details on how the risk of bias was assessed, please see Appendix 2.

We graded each potential source of bias as high, low, or unclear and provided evidence from the study report together with a justification for our judgement in the 'Risk of bias' table. We have summarised the 'Risk of bias' judgments across different trials for each of the domains listed (see below).

Overall risk of bias

Low risk of bias: the outcome result was classified as at overall low risk of bias only if all of the bias domains described in the above paragraphs were classified as at low risk of bias.
High risk of bias: the outcome result was classified as at overall high risk of bias if any of the bias risk domains described above were classified as at unclear or high risk of bias.

Measures of treatment effect

We calculated risk ratios (RR) with 95% confidence intervals (CI) for dichotomous outcomes. We planned to calculate mean differences (MD) with 95% CI for continuous outcomes. However, none of the included trials adequately reported quality of life (our only continuous outcome).

Unit of analysis issues

We only included randomised clinical trials. For trials using cross‐over design, we planned to only include data from the first period (Elbourne 2002; Deeks 2017). For trials where multiple trial intervention groups were reported, we included only the relevant groups. If two comparisons were combined in the same meta‐analysis, we halved the control group to avoid double‐counting (Deeks 2017).

Dealing with missing data

We contacted trial authors to obtain missing data (i.e. for data extraction and for assessment of risk of bias, as specified above). However, not all trial authors responded (see Characteristics of included studies).

Dichotomous outcomes

If included trials used rigorous methodology (i.e. reporting on outcomes for all participants or multiple imputation to deal with missing data), we used these data in our primary analysis (Sterne 2009). We did not impute missing values for any outcomes in our primary analysis. In two of our sensitivity analyses ('best‐worst' and 'worst‐best'), we imputed data; see below.

Continuous outcomes

If included trials used rigorous methodology (i.e. reporting on outcomes for all participants or multiple imputation to deal with missing data), we planned to use these data in our primary analysis (Sterne 2009). We did not impute missing values for any outcomes in our primary analysis. If standard deviations (SDs) were not reported, we planned to calculate the SDs using data from the trial if possible. In two of our sensitivity analyses outcomes ('best‐worst' and 'worst‐best'), we planned to impute data, see below. However, none of the included trials adequately reported quality of life (our only continuous outcome).

Best‐worst and worst‐best case scenarios

To assess the potential impact of the missing data for dichotomous outcomes, we performed the following two sensitivity analyses when assessing each dichotomous outcome (all‐cause mortality, cardiovascular mortality, and myocardial infarction during follow‐up). We were not able to perform the following sensitivity analyses on 'MACE' as limited data were available and on serious adverse events as no data were available.

'Best‐worst' case scenario: we assumed that all participants lost to follow‐up in the experimental group survived and had no cardiovascular event; and all those participants with missing outcomes in the control group did not survive and had a cardiovascular event.
'Worst‐best' case scenario: we assumed that all participants lost to follow‐up in the experimental group did not survive and had a cardiovascular event; and all those participants with missing outcomes in the control group survived and had no cardiovascular event.

Results from both scenarios are presented in our review.

We planned that when analysing quality of life (our only continuous outcome), a ‘beneficial outcome’ would have been the group mean plus two SDs (we would then have used one SD in another sensitivity analysis) of the group mean, and a ‘harmful outcome’ would have been the group mean minus two SDs (we would then have used one SD in another sensitivity analysis) of the group mean (Jakobsen 2014).

To assess the potential impact of missing SDs for continuous outcomes, we performed the following sensitivity analysis.

Where SDs were missing and not possible to calculate, we planned to impute SDs from trials with similar populations and low risk of bias. If no such trials could be found, we planned to impute SDs from trials with a similar population. As the final option, we planned to impute SDs from all trials.

We planned to present results of this scenario in our review. However, none of the included trials adequately reported quality of life (our only continuous outcome).

Assessment of heterogeneity

Initially, we investigated forest plots to visually assess any sign of heterogeneity. We secondly assessed the presence of statistical heterogeneity by Chi² test (threshold P < 0.10) and measured the quantities of heterogeneity by the I² statistic (Higgins 2002; Higgins 2003).

We followed the recommendations for threshold by the Cochrane Handbook for Systematic Reviews of Interventions (Deeks 2017):

0% to 40%: might not be important;
30% to 60%: may represent moderate heterogeneity;
50% to 90%: may represent substantial heterogeneity;
75% to 100%: may represent considerable heterogeneity.

We investigated possible heterogeneity through subgroup analyses. We had to decide whether or not a meta‐analysis might have to be avoided (Higgins 2011). Ultimately however, none of the planned meta‐analyses were avoided.

Assessment of reporting biases

We used a funnel plot to assess reporting bias in the meta‐analyses including 10 or more trials. We visually inspected the funnel plots to assess the risk of bias. For dichotomous outcomes, we tested asymmetry with the Harbord test (Harbord 2006) if tau² < 0.1 and with the Rücker test (Rücker 2008) if tau² > 0.1. For continuous outcomes, we planned to use the regression asymmetry test (Egger 1997). However, none of the included trials adequately reported quality of life (our only continuous outcome).

Data synthesis

Meta‐analysis

We undertook this systematic review according to the recommendations stated in the Cochrane Handbook for Systematic Reviews of Interventions (Deeks 2017; Higgins 2011) for better validation of meta‐analytic results in systematic reviews. We used the statistical software Review Manager 5.3 (RevMan 2014) provided by Cochrane to meta‐analyse data.

Assessment of significance

We assessed our intervention effects with both random‐effects model meta‐analyses (DerSimonian 1986) and fixed‐effect model meta‐analyses (DeMets 1987). We used the more conservative result of the two as out primary result (Jakobsen 2014). The more conservative result was the result with the highest P value and the widest confidence interval (CI). If there was a substantial discrepancy between the results of the two models, we reported both and discussed the results (Amrhein 2019; Jakobsen 2014). We used three primary outcomes and due to the risk of multiplicity we calculated a P value less than P ≤ 0.025 and a 97.5% CI for the primary outcomes (Jakobsen 2014). We used four secondary outcomes and we, therefore, calculated a P value less than P ≤ 0.020 and a 98% CI for the secondary outcomes (Jakobsen 2014). We used an online calculator for the 97.5% and 98% CI (/www.omnicalculator.com/statistics/relative‐risk).

Subgroup analysis and investigation of heterogeneity

We performed the following subgroup analyses when assessing each outcome (all‐cause mortality, cardiovascular mortality, and myocardial infarction during follow‐up) at both our time points. We were not able to perform subgroup analyses on 'MACE' and angina as limited data were available and on serious adverse events according to ICH‐GCP and quality of life as no data were available.

A: Comparison of the effects between trials where the participants commenced beta‐blockers at different time points.

Acute phase ‐ suspected of myocardial infarction.

Subacute phase ‐ diagnosed with myocardial infarction.

B: Comparison of the effects between trials where the participants received intervention for reperfusion (coronary artery bypass graft, percutaneous coronary intervention or thrombolytics) to that in trials where the participants did not receive intervention for reperfusion.

C: Comparison of the effects between trials where the experimental group received different types of beta‐blockers.

D: Comparison of the effects between trials with different age of participants.

Age 0 to 18 years.
Age 19 to 75 years.
Age 76 years or above.

E: Comparision of the effects between trials with different clinical trial registration status.

Pre‐registration.
Post‐registration.
No registration.

F: Comparison of the effects between trials including different types of acute myocardial infarction.

NSTEMI.
STEMI.
Unstable angina pectoris.
Mixed.

Post hoc subgroup analysis

After the publication of the protocol, we added two subgroups.

G: Comparison of the effects between trials with different lengths of intervention period. This subgroup analysis was only performed at maximum follow‐up.

0 to 7 days length of intervention,
7 to 30 days length of intervention,
1 month or more length of intervention.

H: Comparison of the effects between trials with different funding.

Industry funded trials or unknown funding,
Non‐industry funded trials.

We used the formal test for subgroup differences in RevMan 5.3 (RevMan 2014).

Sensitivity analysis

To assess the potential impact of bias, we performed a sensitivity analysis in which we excluded trials at overall high risk of bias.

To assess the potential impact of the missing data for dichotomous outcomes, we performed best‐worst and worst‐best case scenarios (see Dealing with missing data).

'Summary of findings' tables

We used the GRADE system (Guyatt 2008; https://gdt.gradepro.org/app/handbook/handbook.html) to assess the quality of the body of evidence associated with each of the primary outcomes (all‐cause mortality, serious adverse events according to ICH‐GCP, and major adverse cardiovascular events); and secondary outcomes (quality of life, angina, cardiovascular mortality, and myocardial infarction during follow‐up) at both our time points constructing 'Summary of Findings' tables using the GRADEpro GDT software (ims.cochrane.org/revman/other‐resources/gradepro). The GRADE approach appraises the quality of a body of evidence based on the extent to which one can be confident that an estimate of effect or association reflects the item being assessed (Schünemann 2003; Guyatt 2008; Guyatt 2011). We assessed the GRADE levels of evidence as high, moderate, low, and very low and downgraded the evidence by one or two levels depending on the following quality measures: within‐study risk of bias, the directness of the evidence, heterogeneity of the data, precision of effect estimates, and risk of publication bias (Schünemann 2003; Guyatt 2008; Guyatt 2011). We used the methods and recommendations described in Chapter 8 (section 8.5) (Higgins 2017) and chapter 12 (Schünemann 2017) of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011) and the GRADE handbook (https://gdt.gradepro.org/app/handbook/handbook.html). We justified all decisions to downgrade the quality of trials using footnotes and we made comments to aid the reader's understanding of the review where necessary.

We included all trials in our analyses, and conducted a sensitivity analysis excluding trials at high risk of bias. If the results were similar, we based our 'Summary of findings' tables and conclusions on the overall analysis. If they differed, we based our 'Summary of findings' tables and conclusions on trials at low risk of bias.

We found one low risk of bias trial and reported its findings. For cardiovascular mortality, the results on all trials and on trials at low risk of bias differed significantly. For all other outcomes, the results did not differ significantly. Consequently, we based our 'Summary of findings' tables and conclusions on the results of trials at low risk of bias when assessing cardiovascular mortality and on the results of all trials when assessing all other outcomes (Table 1 (less than three months follow‐up) and Table 2 (maximum follow‐up beyond three months)).

Summary of findings for the main comparison. Beta‐blockers versus placebo or no intervention for suspected or diagnosed acute myocardial infarction at the time point less than three months follow‐up.

Beta‐blockers versus placebo or no intervention for patients with suspected or diagnosed myocardial infarction at the time point less than three months follow‐up
Patient or population: patients with suspected or diagnosed myocardial infarction Settings: any setting Intervention: any beta‐blocker Comparison: placebo or no intervention
Outcomes	Illustrative comparative risks*		Relative effect (adjusted CI)	No of Participants  (studies)	Quality of the evidence  (GRADE)	Comments
Outcomes	Assumed risk with placebo or no intervention	Corresponding risk with beta‐blockers	Relative effect (adjusted CI)	No of Participants  (studies)	Quality of the evidence  (GRADE)	Comments
All‐cause mortality at 'less than 3 months' follow‐up. Follow‐up: mean 21.8 days (range 1 hour to 90 days).	70 per 1000	67 per 1000  (63 to 70)	RR 0.94, 97.5% CI (0.90 to 1.0)	80,452 (46 RCTs with 47 comparisons)	⊕⊕⊕⊕¹  High	Since the sensitivity analysis excluding trials at high risk of bias and the overall meta‐analysis showed similar results, we based our summary of findings and conclusion on the overall meta‐analysis. No events occurred in either group in three trials (Hanada 2012; Norris 1978; Shirotani 2010).
Serious adverse events at 'less than 3 months' follow‐up. No data was reported in the included trials.	‐	‐	‐	‐	‐	None of the trials specifically assessed nor reported serious adverse events according to ICH‐GCP.
MACE (major adverse cardiovascular event) at 'less than 3 months' follow‐up. No data were reported in the included trials.	‐	‐	‐	‐	‐	Only two trials specifically assessed major adverse cardiovascular events (defined as a composite of cardiovascular mortality and myocardial infarction during follow‐up). However, no major adverse cardiovascular events occurred in either trial.
Quality of life at 'less than 3 months' follow‐up. No data were reported in the included trials.	‐	‐	‐	‐	‐	No data reported.
Angina at 'less than 3 months' follow‐up. Follow‐up: mean 21 days (range 12 to 30 days).	222 per 1000	155 per 1000 (69 to 351)	RR 0.70, 98% CI (0.25 to 1.84)	98 (3 RCTs)	⊕⊝⊝⊝^2,3 VERY LOW
Cardiovascular mortality at 'less than 3 months' follow‐up. Follow‐up: mean 28 days.	43 per 1000	42 per 1000  (39 to 46)	RR 0.99, 95% CI (0.91 to 1.08)	45,852 (1 RCT)	⊕⊕⊕⊝⁴   Moderate	Since the sensitivity analysis excluding trials at high risk of bias differed from the overall meta‐analysis, we based our summary of findings and conclusion on the sensitivity analysis.
Myocardial infarction at 'less than 3 months' follow‐up. Follow‐up: mean 23.3 days (range 3 to 90 days).	28 per 1000	23 per 1000  (21 to 25)	RR 0.82, 98% CI (0.74 to 0.90)	67,562 (18 RCTs)	⊕⊕⊕⊝⁵  MODERATE	Since the sensitivity analysis excluding trials at high risk of bias and the overall meta‐analysis showed similar results, we based our summary of findings and conclusion on the overall meta‐analysis. No events occurred in either group in two trials (Hanada 2012; Shirotani 2010).
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its adjusted confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its adjusted CI).  CI: Confidence interval; RR: Risk Ratio.
GRADE Working Group grades of evidence  High quality: further research is very unlikely to change our confidence in the estimate of effect.  Moderate quality: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.  Low quality: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.  Very low quality: we are very uncertain about the estimate.

Beta‐blockers compared with placebo or no intervention for patients with suspected or diagnosed myocardial infarction
Patient or population: patients with suspected or diagnosed myocardial infarction Settings: any setting Intervention: beta‐blockers Comparison: placebo or no intervention
Outcomes	Illustrative comparative risks*		Relative effect  (adjusted CI)	No of Participants  (studies)	Quality of the evidence  (GRADE)	Comments
Outcomes	Assumed risk with placebo or no intervention	Corresponding risk with beta‐blockers	Relative effect  (adjusted CI)	No of Participants  (studies)	Quality of the evidence  (GRADE)	Comments
All‐cause mortality at maximum follow‐up beyond 3 months. Follow‐up: mean 16.4 months (range 6 to 60 months).	148 per 1000	138 per 1000  (127 to 147)	RR 0.93, 97.5% CI (0.86 to 0.99)	25,210 (21 RCTs with 22 comparisons)	⊕⊕⊕⊝³  Moderate	No events occurred in either group in one trial (Hanada 2012).
Serious adverse events at maximum follow‐up beyond 3 months. No data were reported in the included trials.	‐	‐	‐	‐	‐	None of the trials specifically assessed nor reported serious adverse events according to ICH‐GCP.
MACE (major adverse cardiovascular event) at maximum follow‐up beyond 3 months. Follow‐up: mean7.5 months (range 6 to 12 months).	84 per 1000	68 per 1000  (36 to 128)	RR 0.81, 97.5% CI (0.43 to 1.52)	475 (4 RCTs)	⊕⊝⊝⊝^{1, 2}  VERY LOW
Quality of life at maximum follow‐up beyond 3 months. No data were reported in the included trials.	‐	‐	‐	‐	‐	No data reported.
Angina at maximum follow‐up beyond 3 months (mean = 6 months).	24 per 1000	15 per 1000 (5 to 48)	RR 0.64, 98% CI 0.18 to 2.0	844 ( 2 RTCs)	⊕⊝⊝⊝^1,5  VERY LOW
Cardiovascular mortality at maximum follow‐up beyond 3 months. Follow‐up: mean 12.9 months (range 6 to 24 months).	124 per 1000	112 per 1000  (103 to 122)	RR 0.90, 98% CI (0.83 to 0.98)	22,457 (14 RCTs with 15 comparisons)	⊕⊕⊕⊝¹  MODERATE	No events occurred in either group in one trial (Hanada 2012).
Myocardial infarction at maximum follow‐up beyond 3 months. Follow‐up: mean 15.5 months (range 6 to 60 months).	92 per 1000	83 per 1000  (69 to 99)	RR 0.89, 98% CI (0.75 to 1.08)	6825 (14 RCTs)	⊕⊕⊝⊝^{1, 6} Low
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its CI).  CI: Confidence interval; RR: Risk Ratio.
GRADE Working Group grades of evidence  High quality: further research is very unlikely to change our confidence in the estimate of effect.  Moderate quality: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.  Low quality: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.  Very low quality: we are very uncertain about the estimate.

Trial	Year	All‐cause mortality	Major adverse cardiovascular events	Cardiovascular mortality	Myocardial infarction during follow‐up
Andersen	1979	28 days	NR	NR	NR
Åström	1986	NR	NR	NR	NR
Australian	1984	28 days	NR	NR	NR
Australia & Swedish	1983	28 days	NR	NR	NR
Balcon	1967	28 days	NR	NR	NR
Barbar	1967	28 days	NR	NR	NR
Barber	1976	90 days	NR	NR	NR
BEAT‐AMI trial	2016	During hospitalisation (no mean time)	NR	During hospitalisation (no mean time)	During hospitalisation (no mean time)
Briant	1970	3 days	NR	NR	NR
Campbell	1984	7 days	NR	NR	NR
CAPRICORN	2001	30 days	NR	NR	NR
Clausen	1966	28 days	NR	NR	NR
COMMIT	2005	28 days	NR	28 days	28 days
CPRG	1980	60 days	NR	56 days	56 days
EARLY‐BAMI	2016	30 days	NR	30 days	30 days
EMIT	2002	42 days	NR	NR	42 days
Evemy	1977	30 days	NR	NR	NR
Gardtman	1999	30 days	NR	NR	NR
Göteborg Metoprolol Trial	1981	90 days	NR	90 days	90 days
Hanada	2012	During hospitalisation (no mean time) (no events)	During hospitalisation (no mean time) (no events)	During hospitalisation (no mean time) (no events)	During hospitalisation (no mean time) (no events)
Heber	1986	5 days	NR	NR	NR
ICSG	1984	During hospitalisation (no mean time)	NR	During hospitalisation (no mean time)	During hospitalisation (no mean time)
ISIS‐1	1986	14 days	NR	7 days	7 days
Johannessen	1987	10 days	NR	NR	NR
Ledwich	1968	7 days	NR	NR	NR
McMurray	1991	NR	NR	NR	10 days
METOCARD‐CNIC	2013	7 days	NR	NR	7 days
MIAMI	1985	15 days	NR	15 days	15 days
MILIS	1984	30 days	NR	NR	NR
Mueller	1980	3 days	NR	10 days	NR
Multicenter trial	1966	30 days	NR	30 days	NR
Nielsen	1967	28 days	NR	NR	28 days
Norris	1968	21 days	NR	NR	NR
Norris	1978	8.5 days (no events)	NR	8.5 days (no events)	NR
Norris	1980	During hospitalisation (no mean time)	NR	During hospitalisation (no mean time)	NR
Norris	1984	21 days	NR	21 days	NR
Owensby	1985	3 days	NR	NR	3 days
Peter	1978	3 days	NR	NR	3 days
Raeder	1967	21 days	NR	21 days	NR
Ranganathan	1988	2 days	NR	NR	NR
Rolli	1980	NR	NR	NR	NR
Salathia	1985	During hospitalisation (no mean time)	NR	90 days	NR
Shirotani	2010	30 days (no events)	30 days (no events)	30 days (no events)	30 days (no events)
Tereschenko	2005	30 days	NR	30 days	NR
Thompson	1979	5 days	NR	NR	NR
TIARA	1987	30 days	NR	30 days	30 days
Tonkin	1981	7 days	NR	NR	7 days
Van De Werf	1993	14 days	NR	14 days	14 days
Von Essen	1982	14 days	NR	14 days	NR
Wilcox	1980	42 days	NR	NR	NR
Yang	1984	NR	NR	NR	NR
Yusuf	1980	10 days	NR	NR	During hospitalisation (no mean time)

Trial	Year	Type and number of serious adverse events (beta‐blocker group)	Type and number of serious adverse events (control group)
Andersen	1979	41 deaths from all causes	37 deaths from all causes
Åstrøm	1986	None	1 atrial fibrillation
Australian trial	1984	1 death from all causes 6 heart failure	2 death from all causes 3 heart failure
Australia & Swedish	1983	13 deaths from all causes	13 deaths from all causes
Balcon	1967	13 deaths from all causes 11 heart failure 7 shock	14 deaths from all causes 5 heart failure 7 shock
Barbar	1967	10 deaths from all causes 20 heart failure	12 deaths from all causes 18 heart failure
Barber	1976	23 deaths from all causes 49 heart failure	25 deaths from all causes 29 heart failure
BEAT‐AMI	2016	4 ventricular tachycardia 1 atrial fibrillation	1 deaths from all causes 11 ventricular tachycardia 3 cardiogenic shock 2 myocardial infarction during follow‐up 3 atrial fibrillation
Briant	1970	5 deaths from all causes 8 ventricular tachycardia 3 ventricular fibrillation	4 deaths from all causes 2 ventricular tachycardia 2 ventricular fibrillation
Campbell	1984	1 death from all causes	2 deaths from all causes
CAPRICORN	2001	10 deaths from all causes	20 deaths from all causes
Clausen	1966	18 deaths from all causes 9 thromboembolic complications	19 deaths from all causes 6 thromboembolic complications
COMMIT	2005	1774 deaths from all causes 464 myocardial infarction during follow‐up 3224 heart failure 247 stroke 200 presumed cardiac rupture 30 pulmonary embolus 370 atrioventricular block 1141 cardiogenic shock 581 ventricular fibrillation 685 other cardiac arrest (including asystole, but excluding ventricular fibrillation and arrhythmia)	1797 deaths from all causes 568 myocardial infarction during follow‐up 2902 heart failure 220 stroke 233 presumed cardiac rupture 35 pulmonary embolus 357 atrioventricular block 885 cardiogenic shock 698 ventricular fibrillation 632 other cardiac arrest (including asystole, but excluding ventricular fibrillation and arrhythmia)
CPRG	1980	9 deaths from all causes 3 myocardial infarction during follow‐up	5 deaths from all causes 7 myocardial infarction during follow‐up
EARLY‐BAMI	2016	7 deaths from cardiac causes 3 myocardial infarction during follow‐up 2 cardiogenic shock	7 deaths from cardiac causes 2 myocardial infarction during follow‐up 1 cardiogenic shock
EMIT	2002	2 deaths from all causes 4 myocardial infarction during follow‐up 7 heart failure 2 AV‐block 1 VT/VF 8 silent myocardial ischaemic episode	1 death from all causes 2 myocardial infarction during follow‐up 8 heart failure 2 AV‐block 2 VT/VF
Evemy	1977	7 deaths from all causes 12 heart failure 3 cardiogenic shock 3 ventricular fibrillation 2 ventricular tachycardia 4 second degree AV‐block 3 complete AV‐block	4 deaths from all causes 14 heart failure 3 ventricular fibrillation 4 ventricular tachycardia 9 atrial fibrillation 1 complete AV‐block
Gardtman	1999	5 deaths from all causes 1 ventricular tachycardia 17 heart failure	4 deaths from all causes 4 ventricular tachycardia 1 AV block III 19 heart failure
Göteborg	1981	40 deaths from all causes 35 myocardial infarction during follow‐up 70 hospitalisation for any cause 12 heart failure 16 AV‐block II‐III 6 ventricular fibrillation 15 sudden circulatory collapse 10 rupture of ventricular wall	62 deaths from all causes 54 myocardial infarction during follow‐up 91 hospitalisation for any cause 25 heart failure 11 AV‐block II‐III 17 ventricular fibrillation 25 sudden circulatory collapse 15 rupture of ventricular wall
Heber	1986	5 deaths from all causes 11 heart failure	1 death from all causes 6 heart failure
ICSG	1984	3 deaths from all causes 2 myocardial infarction during follow‐up 11 heart failure 2 ventricular fibrillation 3 cerebrovascular accident 3 II/III AV‐block	4 deaths from all causes 2 myocardial infarction during follow‐up 12 heart failure 4 ventricular fibrillation 1 cerebrovascular accident 3 II/III AV‐block
ISIS‐1	1986	423 deaths from all causes 148 myocardial infarctions during follow‐up 189 cardiac arrest 180 complete heart block	493 deaths from all causes 161 myocardial infarction during follow‐up 198 cardiac arrest 152 complete heart block
Johannessen	1987	2 deaths from all causes 1 peripheral abdominal embolus	3 atrial fibrillation
Ledwich	1968	2 deaths from all causes	3 deaths from all causes
Lloyd	1988	3 ventricular tachycardia	14 ventricular tachycardia 2 ventricular fibrillation
Mcmurray	1991	1 ventricular fibrillation 2 2nd degree AV‐block 1 atrial fibrillation	1 ventricular tachycardia 1 heart failure 1 AV‐block II
METOCARD‐CNIC	2013	3 deaths from all causes 1 myocardial infarction during follow‐up 5 malignant ventricular arrhythmia 1 advanced AV‐block 6 cardiogenic shock 11 heart failure	3 deaths from all causes 10 malignant ventricular arrhythmia 2 advanced AV‐block 7 cardiogenic shock 9 heart failure
Miami	1985	123 deaths from all causes 85 myocardial infarction during follow‐up 37 ventricular tachycardia 74 asystole 160 AV block II‐III 699 heart failure 86 cardiogenic shock	142 deaths from all causes 111 myocardial infarction during follow‐up 40 ventricular tachycardia 64 asystole 153 AV block II‐III 660 heart failure 93 cardiogenic shock
MILIS	1984	4 deaths from all causes 25 heart failure 17 ventricular tachycardia 8 heart block	8 deaths from all causes 31 heart failure 28 ventricular tachycardia 9 heart block
Mueller	1980	2 deaths from all causes	1 death from all causes
Multicenter trial	1966	15 deaths from all causes 17 heart failure 9 cardiac arrest	12 deaths from all causes 7 heart failure 7 cardiac arrest
Nielsen	1967	18 deaths from all causes 2 myocardial infarction during follow‐up 7 thrombo‐embolic complications 2 heart failure	19 deaths from all causes 6 thrombo‐embolic complications 6 heart failure 2 cardiogenic shock
Norris	1968	20 deaths from all causes	17 deaths
Norris	1978	1 heart failure	1 heart failure
Norris	1980	1 death from all causes 1 ventricular fibrillation 1 cardiogenic shock 3 heart failure	1 ventricular fibrillation 1 cardiogenic shock 2 AV‐block II‐III 8 heart failure
Norris	1984	15 deaths from all causes, 7 ventricular fibrillation 22 atrial fibrillation 13 AV block II‐III 14 bundle‐branch block	14 deaths from all causes, 18 ventricular fibrillation 23 atrial fibrillation 8 AV block II‐III 14 bundle‐branch block
Owensby	1985	1 death from all causes 2 myocardial infarction during follow‐up 23 heart failure 6 AV‐block II‐III 13 ventricular tachycardia 4 ventricular fibrillation	1 death from all causes 2 myocardial infarction during follow‐up 23 heart failure 5 AV‐block II‐III 12 ventricular tachycardia 3 ventricular fibrillation
Peter	1978	1 death from all causes 1 myocardial infarction during follow‐up 5 heart failure	2 deaths from all causes 3 myocardial infarction during follow‐up 5 heart failure
Raeder	1967	2 deaths from all causes 1 AV‐block II‐III 2 atrial fibrillation	2 deaths from all causes 1 AV‐block II‐III 1 atrial fibrillation
Ramsdale	1982	None	1 heart failure 1 complete heart block
Ranganathan	1988	1 death from all causes	3 deaths from all causes
Rolli	1980	1 bundle block or hemiblock	2 ventricular fibrillation 3 heart failure 2 bundle branch block or hemiblock
Salathia	1985	25 deaths from all causes 11 ventricular fibrillation 9 with AV‐block II‐III 47 heart failure	20 deaths from all causes 14 ventricular fibrillation 18 with AV‐block II‐III 35 heart failure
Tereschenko	2005	3 deaths from all causes 4 heart failure 6 post‐infarction angina pectoris	2 deaths from all causes 7 heart failure 5 post‐infarction angina pectoris
Thompson	1979	3 deaths from all causes 6 heart failure	3 deaths from all causes 6 heart failure
TIARA	1987	3 deaths from all causes 3 myocardial infarction during follow‐up 7 ventricular tachycardia 10 heart failure	7 deaths from all causes 6 myocardial infarction during follow‐up 16 ventricular tachycardia 3 ventricular fibrillation 18 heart failure
Tonkin	1981	1 death from all causes 1 reinfarction 14 heart failure	1 death from all causes 16 heart failure 1 AV‐block
Van De Werf	1993	1 death from all causes 9 myocardial infarction during follow‐up 6 pulmonary edema 4 pericarditis 3 cardiogenic shock 9 AV block II‐III 21 ventricular tachycardia 2 ventricular fibrillation 1 stroke 2 bleeding requiring transfusion	4 death from all causes 10 myocardial infarction during follow‐up 3 pericarditis 1 cardiac rupture 7 AV block II‐III 18 ventricular tachycardia 3 ventricular fibrillation 2 stroke 1 bleeding requiring transfusion
Von Essen	1982	1 death from all causes	1 death from all causes
Wilcox (atenolol)	1980	11 deaths from all causes	8 deaths from all causes
Wilcox (propranolol)	1980	10 death from all causes	7 deaths from all causes
Yang	1984	2 AV‐block II 1 ventricular fibrillation	1 AV‐block II 2 atrial fibrillation
Yusuf	1980	7 death form all causes 46 heart failure 13 AV block II‐III 4 cardiac arrest 3 pulmonary embolus 1 renal failure 1 cardiogenic shock	16 death form all causes 6 myocardial infarction during follow‐up 56 heart failure 18 AV block II‐III 15 cardiac arrest 2 ventricular septal defect 4 cardiogenic shock

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 All‐cause mortality	46	80452	Risk Ratio (M‐H, Fixed, 95% CI)	0.94 [0.90, 0.99]
2 All‐cause mortality ‐ Acute/subacute phase	46	80452	Risk Ratio (M‐H, Fixed, 95% CI)	0.94 [0.90, 0.99]
2.1 Acute phase	42	76857	Risk Ratio (M‐H, Fixed, 95% CI)	0.95 [0.90, 1.00]
2.2 Subacute phase	4	3595	Risk Ratio (M‐H, Fixed, 95% CI)	0.79 [0.50, 1.25]
3 All‐cause mortality ‐ Reperfusion/no reperfusion	46	80452	Risk Ratio (M‐H, Fixed, 95% CI)	0.94 [0.90, 0.99]
3.1 No reperfusion	40	78206	Risk Ratio (M‐H, Fixed, 95% CI)	0.94 [0.90, 0.99]
3.2 Reperfusion (PCI , CABG, thrombolytics)	6	2246	Risk Ratio (M‐H, Fixed, 95% CI)	0.80 [0.43, 1.50]
4 All‐cause mortality ‐ Type of beta‐blocker	46	80452	Risk Ratio (M‐H, Fixed, 95% CI)	0.94 [0.90, 0.99]
4.1 Alprenolol	2	599	Risk Ratio (M‐H, Fixed, 95% CI)	1.13 [0.77, 1.66]
4.2 Atenolol	4	16890	Risk Ratio (M‐H, Fixed, 95% CI)	0.83 [0.74, 0.94]
4.3 Esmolol	2	140	Risk Ratio (M‐H, Fixed, 95% CI)	0.86 [0.21, 3.62]
4.4 Labetolol	1	166	Risk Ratio (M‐H, Fixed, 95% CI)	5.0 [0.60, 41.88]
4.5 Metoprolol	8	55034	Risk Ratio (M‐H, Fixed, 95% CI)	0.97 [0.91, 1.03]
4.6 Oxprenolol	1	313	Risk Ratio (M‐H, Fixed, 95% CI)	1.38 [0.47, 4.03]
4.7 Pindolol	2	629	Risk Ratio (M‐H, Fixed, 95% CI)	1.01 [0.49, 2.08]
4.8 Practolol	3	486	Risk Ratio (M‐H, Fixed, 95% CI)	1.02 [0.65, 1.60]
4.9 Propranolol	14	2630	Risk Ratio (M‐H, Fixed, 95% CI)	0.95 [0.76, 1.18]
4.10 Timolol	7	704	Risk Ratio (M‐H, Fixed, 95% CI)	0.65 [0.33, 1.31]
4.11 Carvedilol	2	2753	Risk Ratio (M‐H, Fixed, 95% CI)	0.50 [0.25, 1.04]
4.12 Mixed	1	108	Risk Ratio (M‐H, Fixed, 95% CI)	1.93 [0.18, 20.63]
5 All‐cause mortality ‐ Intravenously/orally commenced	46	80452	Risk Ratio (M‐H, Fixed, 95% CI)	0.94 [0.90, 0.99]
5.1 Intravenously commenced	4	1036	Risk Ratio (M‐H, Fixed, 95% CI)	0.97 [0.46, 2.04]
5.2 Orally commenced	16	5658	Risk Ratio (M‐H, Fixed, 95% CI)	0.90 [0.74, 1.10]
5.3 Mixed	26	73758	Risk Ratio (M‐H, Fixed, 95% CI)	0.95 [0.90, 1.00]
6 All‐cause mortality ‐ Above/below 75 years of age	39	79161	Risk Ratio (M‐H, Fixed, 95% CI)	0.94 [0.90, 0.99]
6.1 Below 75 years	24	12602	Risk Ratio (M‐H, Fixed, 95% CI)	0.86 [0.74, 0.99]
6.2 Mixed	15	66559	Risk Ratio (M‐H, Fixed, 95% CI)	0.96 [0.90, 1.01]
7 All‐cause mortality ‐ NSTEMI/STEMI/UAP	24	53337	Risk Ratio (M‐H, Fixed, 95% CI)	0.97 [0.92, 1.03]
7.1 STEMI	5	1828	Risk Ratio (M‐H, Fixed, 95% CI)	1.01 [0.48, 2.10]
7.2 Mixed	19	51509	Risk Ratio (M‐H, Fixed, 95% CI)	0.97 [0.92, 1.03]
8 All‐cause mortality ‐ Registration status	46	80452	Risk Ratio (M‐H, Fixed, 95% CI)	0.94 [0.90, 0.99]
8.1 Pre‐registration	5	47642	Risk Ratio (M‐H, Fixed, 95% CI)	0.99 [0.93, 1.05]
8.2 Post‐registration	1	269	Risk Ratio (M‐H, Fixed, 95% CI)	0.50 [0.16, 1.63]
8.3 No registration	40	32541	Risk Ratio (M‐H, Fixed, 95% CI)	0.87 [0.80, 0.95]
9 All‐cause mortality ‐ Funding	46	80452	Risk Ratio (M‐H, Fixed, 95% CI)	0.94 [0.90, 0.99]
9.1 Industry funded or unknown funded trials	39	78702	Risk Ratio (M‐H, Fixed, 95% CI)	0.95 [0.90, 1.00]
9.2 Non‐industry funded trials	7	1750	Risk Ratio (M‐H, Fixed, 95% CI)	0.85 [0.60, 1.20]
10 All‐cause mortality ‐ Trials at low risk of bias	2	46122	Risk Ratio (M‐H, Fixed, 95% CI)	0.99 [0.93, 1.05]
11 All‐cause mortality ‐ 'Best‐worst case scenario'	46	80522	Risk Ratio (M‐H, Fixed, 95% CI)	0.93 [0.89, 0.98]
12 All‐cause mortality ‐ 'Worst‐best case scenario'	46	80522	Risk Ratio (M‐H, Random, 95% CI)	0.93 [0.86, 1.02]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 All‐cause mortality	21	25210	Risk Ratio (M‐H, Fixed, 95% CI)	0.93 [0.87, 0.98]
2 All‐cause mortality ‐ Acute/subacute phase	21	25210	Risk Ratio (M‐H, Random, 95% CI)	0.93 [0.87, 0.99]
2.1 Acute phase	17	21368	Risk Ratio (M‐H, Random, 95% CI)	0.95 [0.89, 1.01]
2.2 Subacute phase	4	3842	Risk Ratio (M‐H, Random, 95% CI)	0.81 [0.68, 0.96]
3 All‐cause mortality ‐ Reperfusion/no reperfusion	21	25210	Risk Ratio (M‐H, Random, 95% CI)	0.93 [0.87, 0.99]
3.1 No reperfusion	16	23768	Risk Ratio (M‐H, Random, 95% CI)	0.93 [0.87, 0.99]
3.2 Reperfusion (PCI , CABG, thrombolytics)	5	1442	Risk Ratio (M‐H, Random, 95% CI)	0.83 [0.52, 1.34]
4 All‐cause mortality ‐ Type of beta‐blocker	21	25098	Risk Ratio (M‐H, Fixed, 95% CI)	0.93 [0.87, 0.99]
4.1 Alprenolol	2	566	Risk Ratio (M‐H, Fixed, 95% CI)	0.99 [0.74, 1.31]
4.2 Atenolol	3	16696	Risk Ratio (M‐H, Fixed, 95% CI)	0.94 [0.88, 1.02]
4.3 Carvedilol	3	2899	Risk Ratio (M‐H, Fixed, 95% CI)	0.78 [0.64, 0.96]
4.4 Labetolol	1	166	Risk Ratio (M‐H, Fixed, 95% CI)	1.71 [0.71, 4.14]
4.5 Metoprolol	4	2593	Risk Ratio (M‐H, Fixed, 95% CI)	0.93 [0.79, 1.09]
4.6 Pindolol	1	529	Risk Ratio (M‐H, Fixed, 95% CI)	0.97 [0.67, 1.40]
4.7 Practolol	2	386	Risk Ratio (M‐H, Fixed, 95% CI)	0.95 [0.68, 1.33]
4.8 Propranolol	4	1075	Risk Ratio (M‐H, Fixed, 95% CI)	0.88 [0.64, 1.21]
4.9 Timolol	1	88	Risk Ratio (M‐H, Fixed, 95% CI)	1.10 [0.07, 16.96]
4.10 Esmolol	1	100	Risk Ratio (M‐H, Fixed, 95% CI)	0.33 [0.01, 7.99]
5 All‐cause mortality ‐ Above/below 75 years of age	21	25210	Risk Ratio (M‐H, Fixed, 95% CI)	0.93 [0.87, 0.98]
5.1 Below 75 years	16	5862	Risk Ratio (M‐H, Fixed, 95% CI)	0.93 [0.83, 1.04]
5.2 Mixed	5	19348	Risk Ratio (M‐H, Fixed, 95% CI)	0.93 [0.86, 0.99]
6 All‐cause mortality ‐ Intravenously/orally commenced	21	25210	Risk Ratio (M‐H, Random, 95% CI)	0.93 [0.87, 0.99]
6.1 Intravenously commenced	2	370	Risk Ratio (M‐H, Random, 95% CI)	0.84 [0.30, 2.39]
6.2 Orally commenced	7	4614	Risk Ratio (M‐H, Random, 95% CI)	0.83 [0.72, 0.96]
6.3 Mixed	12	20226	Risk Ratio (M‐H, Random, 95% CI)	0.95 [0.89, 1.01]
7 All‐cause mortality ‐ Registration status	21	25210	Risk Ratio (M‐H, Random, 95% CI)	0.93 [0.87, 0.99]
7.1 Pre‐registration	3	1164	Risk Ratio (M‐H, Random, 95% CI)	0.85 [0.51, 1.40]
7.2 Post‐registration	1	269	Risk Ratio (M‐H, Random, 95% CI)	1.21 [0.70, 2.08]
7.3 No registration	17	23777	Risk Ratio (M‐H, Random, 95% CI)	0.93 [0.87, 0.98]
8 All‐cause mortality ‐ NSTEMI/STEMI/UAP	7	2128	Risk Ratio (M‐H, Fixed, 95% CI)	0.91 [0.70, 1.18]
8.1 STEMI	3	1164	Risk Ratio (M‐H, Fixed, 95% CI)	0.84 [0.51, 1.39]
8.2 Mixed	4	964	Risk Ratio (M‐H, Fixed, 95% CI)	0.94 [0.69, 1.27]
9 All‐cause mortality ‐ Length of intervention period	21	25210	Risk Ratio (M‐H, Random, 95% CI)	0.93 [0.87, 0.99]
9.1 0 to 7 days length of intervention	5	16651	Risk Ratio (M‐H, Random, 95% CI)	0.96 [0.89, 1.03]
9.2 7 to 30 days length of intervention	3	946	Risk Ratio (M‐H, Random, 95% CI)	0.86 [0.60, 1.24]
9.3 1 month and more length of intervention	13	7613	Risk Ratio (M‐H, Random, 95% CI)	0.88 [0.80, 0.98]
10 All‐cause mortality ‐ Funding	21	25210	Risk Ratio (M‐H, Fixed, 95% CI)	0.93 [0.87, 0.98]
10.1 Industry funded or unknown funded trials	18	23877	Risk Ratio (M‐H, Fixed, 95% CI)	0.92 [0.87, 0.98]
10.2 Non‐industry funded trials	3	1333	Risk Ratio (M‐H, Fixed, 95% CI)	1.00 [0.69, 1.45]
11 All‐cause mortality ‐ Trials at low risk of bias	1	270	Risk Ratio (M‐H, Fixed, 95% CI)	0.94 [0.31, 2.85]
12 All‐cause mortality ‐ 'Best‐worst case scenario'	21	25283	Risk Ratio (M‐H, Random, 95% CI)	0.89 [0.81, 0.97]
13 All‐cause mortality ‐ 'Worst‐best case scenario'	21	25283	Risk Ratio (M‐H, Random, 95% CI)	0.95 [0.85, 1.06]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Cardiovascular mortality	18	72622	Risk Ratio (M‐H, Fixed, 95% CI)	0.93 [0.87, 0.99]
2 Cardiovascular mortality ‐ Acute/subacute phase	18	72622	Risk Ratio (M‐H, Fixed, 95% CI)	0.93 [0.87, 0.99]
2.1 Acute phase	17	72309	Risk Ratio (M‐H, Fixed, 95% CI)	0.92 [0.87, 0.99]
2.2 Subacute phase	1	313	Risk Ratio (M‐H, Fixed, 95% CI)	1.23 [0.41, 3.67]
3 Cardiovascular mortality ‐ Reperfusion/no reperfusion	18	72622	Risk Ratio (M‐H, Fixed, 95% CI)	0.93 [0.87, 0.99]
3.1 No reperfusion	15	71702	Risk Ratio (M‐H, Fixed, 95% CI)	0.93 [0.87, 0.99]
3.2 Reperfusion (PCI , CABG, thrombolytics)	3	920	Risk Ratio (M‐H, Fixed, 95% CI)	0.69 [0.29, 1.62]
4 Cardiovascular mortality ‐ Type of beta‐blocker	18	72622	Risk Ratio (M‐H, Fixed, 95% CI)	0.93 [0.87, 0.99]
4.1 Esmolol	2	140	Risk Ratio (M‐H, Fixed, 95% CI)	0.86 [0.21, 3.62]
4.2 Atenolol	2	16221	Risk Ratio (M‐H, Fixed, 95% CI)	0.85 [0.75, 0.96]
4.3 Metoprolol	6	54501	Risk Ratio (M‐H, Fixed, 95% CI)	0.96 [0.88, 1.03]
4.4 Oxprenolol	1	313	Risk Ratio (M‐H, Fixed, 95% CI)	1.23 [0.41, 3.67]
4.5 Propranolol	5	1103	Risk Ratio (M‐H, Fixed, 95% CI)	1.06 [0.65, 1.73]
4.6 Timolol	2	344	Risk Ratio (M‐H, Fixed, 95% CI)	0.53 [0.20, 1.39]
5 Cardiovascular mortality ‐ Above/below 75 years of age	18	72622	Risk Ratio (M‐H, Fixed, 95% CI)	0.93 [0.87, 0.99]
5.1 Below 75 years	14	56308	Risk Ratio (M‐H, Fixed, 95% CI)	0.95 [0.88, 1.03]
5.2 Mixed	4	16314	Risk Ratio (M‐H, Fixed, 95% CI)	0.85 [0.75, 0.97]
6 Cardiovascular mortality ‐ Intravenously/orally commenced	18	72622	Risk Ratio (M‐H, Fixed, 95% CI)	0.93 [0.87, 0.99]
6.1 Intravenously commenced	3	766	Risk Ratio (M‐H, Fixed, 95% CI)	0.98 [0.42, 2.26]
6.2 Orally commenced	3	549	Risk Ratio (M‐H, Fixed, 95% CI)	0.99 [0.54, 1.82]
6.3 Mixed	12	71307	Risk Ratio (M‐H, Fixed, 95% CI)	0.92 [0.87, 0.99]
7 Cardiovascular mortality ‐ NSTEMI/STEMI/UAP	9	49303	Risk Ratio (M‐H, Fixed, 95% CI)	0.97 [0.89, 1.05]
7.1 STEMI	2	726	Risk Ratio (M‐H, Fixed, 95% CI)	0.91 [0.35, 2.41]
7.2 NSTEMI	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
7.3 Unstable angina pectoris	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
7.4 Mixed	7	48577	Risk Ratio (M‐H, Fixed, 95% CI)	0.97 [0.89, 1.05]
8 Cardiovascular mortality ‐ Registration status	18	72622	Risk Ratio (M‐H, Fixed, 95% CI)	0.93 [0.87, 0.99]
8.1 Pre‐registration	3	46578	Risk Ratio (M‐H, Fixed, 95% CI)	0.99 [0.91, 1.08]
8.2 Post‐registration	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
8.3 No registration	15	26044	Risk Ratio (M‐H, Fixed, 95% CI)	0.84 [0.76, 0.93]
9 Cardiovascular mortality ‐ Funding	18	72622	Risk Ratio (M‐H, Fixed, 95% CI)	0.93 [0.87, 0.99]
9.1 Industry funded or unknown funded trials	17	72560	Risk Ratio (M‐H, Fixed, 95% CI)	0.92 [0.87, 0.99]
9.2 Non‐industry funded trials	1	62	Risk Ratio (M‐H, Fixed, 95% CI)	2.65 [0.11, 62.56]
10 Cardiovascular mortality ‐ Trials with low risk of bias	1	45852	Risk Ratio (M‐H, Fixed, 95% CI)	0.99 [0.91, 1.08]
11 Cardiovascular mortality ‐ 'Best‐worst case scenario'	18	72681	Risk Ratio (M‐H, Random, 95% CI)	0.84 [0.72, 0.97]
12 Cardiovascular mortality ‐ 'Worst‐best case scenario'	18	72681	Risk Ratio (M‐H, Random, 95% CI)	0.93 [0.79, 1.10]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Cardiovascular mortality	14	22457	Risk Ratio (M‐H, Fixed, 95% CI)	0.90 [0.84, 0.97]
2 Cardiovascular mortality ‐ Acute/subacute phase	14	22457	Risk Ratio (M‐H, Random, 95% CI)	0.90 [0.84, 0.97]
2.1 Acute phase	10	18615	Risk Ratio (M‐H, Random, 95% CI)	0.93 [0.86, 1.00]
2.2 Subacute phase	4	3842	Risk Ratio (M‐H, Random, 95% CI)	0.78 [0.65, 0.95]
3 Cardiovascular mortality ‐ Reperfusion/no reperfusion	14	22457	Risk Ratio (M‐H, Random, 95% CI)	0.90 [0.84, 0.97]
3.1 No reperfusion	8	20386	Risk Ratio (M‐H, Random, 95% CI)	0.91 [0.84, 0.97]
3.2 Reperfusion (PCI , CABG, thrombolytics)	6	2071	Risk Ratio (M‐H, Random, 95% CI)	0.83 [0.46, 1.51]
4 Cardiovascular mortality ‐ Type of beta‐blocker	14	22457	Risk Ratio (M‐H, Random, 95% CI)	0.90 [0.84, 0.97]
4.1 Esmolol	1	100	Risk Ratio (M‐H, Random, 95% CI)	0.33 [0.01, 7.99]
4.2 Alprenolol	1	77	Risk Ratio (M‐H, Random, 95% CI)	1.03 [0.22, 4.77]
4.3 Atenolol	2	16219	Risk Ratio (M‐H, Random, 95% CI)	0.93 [0.86, 1.01]
4.4 Carvedilol	3	2899	Risk Ratio (M‐H, Random, 95% CI)	0.77 [0.61, 0.97]
4.5 Metoprolol	4	1827	Risk Ratio (M‐H, Random, 95% CI)	0.83 [0.59, 1.18]
4.6 Pindolol	1	529	Risk Ratio (M‐H, Random, 95% CI)	0.94 [0.63, 1.40]
4.7 Propranolol	3	806	Risk Ratio (M‐H, Random, 95% CI)	0.70 [0.47, 1.06]
5 Cardiovascular mortality ‐ Above/below 75 years of age	14	22457	Risk Ratio (M‐H, Random, 95% CI)	0.90 [0.84, 0.97]
5.1 Below 75 years	11	5366	Risk Ratio (M‐H, Random, 95% CI)	0.80 [0.68, 0.94]
5.2 Mixed	3	17091	Risk Ratio (M‐H, Random, 95% CI)	0.93 [0.86, 1.01]
6 Cardiovascular mortality ‐ Intravenously/orally commenced	14	22457	Risk Ratio (M‐H, Random, 95% CI)	0.90 [0.84, 0.97]
6.1 Intravenously commenced	3	999	Risk Ratio (M‐H, Random, 95% CI)	0.73 [0.33, 1.60]
6.2 Orally commenced	6	4307	Risk Ratio (M‐H, Random, 95% CI)	0.79 [0.67, 0.95]
6.3 Mixed	5	17151	Risk Ratio (M‐H, Random, 95% CI)	0.93 [0.86, 1.01]
7 Cardiovascular mortality ‐ NSTEMI/STEMI/UAP	6	2002	Risk Ratio (M‐H, Random, 95% CI)	0.88 [0.49, 1.59]
7.1 STEMI	4	1793	Risk Ratio (M‐H, Random, 95% CI)	0.85 [0.44, 1.64]
7.2 Mixed	2	209	Risk Ratio (M‐H, Random, 95% CI)	1.03 [0.27, 3.93]
8 Cardiovascular mortality ‐ Registration status	14	22457	Risk Ratio (M‐H, Random, 95% CI)	0.90 [0.84, 0.97]
8.1 Pre‐registration	4	1793	Risk Ratio (M‐H, Random, 95% CI)	0.85 [0.44, 1.64]
8.2 No registration	10	20664	Risk Ratio (M‐H, Random, 95% CI)	0.91 [0.84, 0.97]
9 Cardiovascular mortality ‐ Length of intervention period	14	22457	Risk Ratio (M‐H, Random, 95% CI)	0.90 [0.84, 0.97]
9.1 0 to 7 days length of intervention	4	17026	Risk Ratio (M‐H, Random, 95% CI)	0.93 [0.86, 1.01]
9.2 1 month and more length of intervention	10	5431	Risk Ratio (M‐H, Random, 95% CI)	0.80 [0.69, 0.94]
10 Cardiovascular mortality ‐ Funding	14	22457	Risk Ratio (M‐H, Random, 95% CI)	0.90 [0.84, 0.97]
10.1 Industry funded or unknown funded trials	12	21393	Risk Ratio (M‐H, Random, 95% CI)	0.90 [0.84, 0.97]
10.2 Non‐industry funded trials	2	1064	Risk Ratio (M‐H, Random, 95% CI)	0.89 [0.36, 2.20]
11 Cardiovascular mortality ‐ 'Best‐worst case scenario'	14	22587	Risk Ratio (M‐H, Random, 95% CI)	0.67 [0.53, 0.86]
12 Cardiovascular mortality ‐ 'Worst‐best case scenario'	14	22587	Risk Ratio (M‐H, Random, 95% CI)	1.06 [0.83, 1.36]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Myocardial infarction	18	67562	Risk Ratio (M‐H, Fixed, 95% CI)	0.82 [0.74, 0.90]
2 Myocardial infarction ‐ Acute/subacute phase	18	67562	Risk Ratio (M‐H, Fixed, 95% CI)	0.82 [0.74, 0.90]
2.1 Acute phase	17	67249	Risk Ratio (M‐H, Fixed, 95% CI)	0.82 [0.75, 0.90]
2.2 Subacute phase	1	313	Risk Ratio (M‐H, Fixed, 95% CI)	0.33 [0.09, 1.25]
3 Myocardial infarction ‐ Reperfusion/no reperfusion	18	67562	Risk Ratio (M‐H, Fixed, 95% CI)	0.82 [0.74, 0.90]
3.1 No reperfusion	14	66372	Risk Ratio (M‐H, Fixed, 95% CI)	0.81 [0.74, 0.90]
3.2 Reperfusion (PCI , CABG, thrombolytics)	4	1190	Risk Ratio (M‐H, Fixed, 95% CI)	0.90 [0.44, 1.82]
4 Myocardial infarction ‐ Type of beta‐blocker	18	67562	Risk Ratio (M‐H, Random, 95% CI)	0.82 [0.74, 0.90]
4.1 Esmolol	1	100	Risk Ratio (M‐H, Random, 95% CI)	0.20 [0.01, 4.06]
4.2 Atenolol	3	12312	Risk Ratio (M‐H, Random, 95% CI)	0.83 [0.48, 1.42]
4.3 Metoprolol	5	53921	Risk Ratio (M‐H, Random, 95% CI)	0.80 [0.72, 0.89]
4.4 Oxprenolol	1	313	Risk Ratio (M‐H, Random, 95% CI)	0.33 [0.09, 1.25]
4.5 Pindolol	1	100	Risk Ratio (M‐H, Random, 95% CI)	1.0 [0.15, 6.82]
4.6 Propranolol	2	225	Risk Ratio (M‐H, Random, 95% CI)	1.05 [0.08, 14.01]
4.7 Timolol	3	432	Risk Ratio (M‐H, Random, 95% CI)	0.73 [0.26, 2.08]
4.8 Xamoterol	1	51	Risk Ratio (M‐H, Random, 95% CI)	3.12 [0.13, 73.06]
4.9 Mixed	1	108	Risk Ratio (M‐H, Random, 95% CI)	1.93 [0.37, 10.08]
5 Myocardial infarction ‐ Above/below 75 years of age	17	67432	Risk Ratio (M‐H, Random, 95% CI)	0.82 [0.74, 0.90]
5.1 Below 75 years	13	9561	Risk Ratio (M‐H, Random, 95% CI)	0.72 [0.58, 0.89]
5.2 Mixed	4	57871	Risk Ratio (M‐H, Random, 95% CI)	0.84 [0.76, 0.94]
6 Myocardial infarction ‐ Intravenously/orally commenced	18	67562	Risk Ratio (M‐H, Random, 95% CI)	0.82 [0.74, 0.90]
6.1 Intravenously commenced	3	996	Risk Ratio (M‐H, Random, 95% CI)	1.13 [0.28, 4.51]
6.2 Orally commenced	3	452	Risk Ratio (M‐H, Random, 95% CI)	0.86 [0.16, 4.47]
6.3 Mixed	12	66114	Risk Ratio (M‐H, Random, 95% CI)	0.82 [0.74, 0.90]
7 Myocardial infarction ‐ NSTEMI/STEMI/UAP	11	49361	Risk Ratio (M‐H, Fixed, 95% CI)	0.80 [0.71, 0.90]
7.1 STEMI	3	996	Risk Ratio (M‐H, Fixed, 95% CI)	1.01 [0.29, 3.46]
7.2 NSTEMI	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
7.3 Unstable angina pectoris	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
7.4 Mixed	8	48365	Risk Ratio (M‐H, Fixed, 95% CI)	0.80 [0.71, 0.89]
8 Myocardial infarction ‐ Registration status	18	67562	Risk Ratio (M‐H, Random, 95% CI)	0.82 [0.74, 0.90]
8.1 Pre‐registration	4	46848	Risk Ratio (M‐H, Random, 95% CI)	0.82 [0.73, 0.92]
8.2 Post‐registration	0	0	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
8.3 No registration	14	20714	Risk Ratio (M‐H, Random, 95% CI)	0.82 [0.70, 0.95]
9 Myocardial infarction ‐ Funding	18	67562	Risk Ratio (M‐H, Random, 95% CI)	0.82 [0.74, 0.90]
9.1 Industry funded or unknown funded trials	15	67067	Risk Ratio (M‐H, Random, 95% CI)	0.82 [0.74, 0.90]
9.2 Non‐industry funded trials	3	495	Risk Ratio (M‐H, Random, 95% CI)	1.23 [0.22, 6.77]
10 Myocardial infarction ‐ Trials with low risk of bias	1	45852	Risk Ratio (M‐H, Fixed, 95% CI)	0.82 [0.72, 0.92]
11 Myocardial infarction ‐ 'Best‐worst case scenario'	18	67620	Risk Ratio (M‐H, Random, 95% CI)	0.75 [0.61, 0.92]
12 Myocardial infarction ‐ 'Worst‐best case scenario'	18	67620	Risk Ratio (M‐H, Random, 95% CI)	0.85 [0.67, 1.07]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Myocardial infarction	14	6825	Risk Ratio (M‐H, Random, 95% CI)	0.89 [0.74, 1.08]
2 Myocardial infarction ‐ Acute/subacute phase	14	6825	Risk Ratio (M‐H, Random, 95% CI)	0.89 [0.74, 1.08]
2.1 Acute phase	10	2983	Risk Ratio (M‐H, Random, 95% CI)	0.98 [0.72, 1.33]
2.2 Subacute phase	4	3842	Risk Ratio (M‐H, Random, 95% CI)	0.79 [0.62, 1.01]
3 Myocardial infarction ‐ Reperfusion/no reperfusion	14	6825	Risk Ratio (M‐H, Random, 95% CI)	0.89 [0.74, 1.08]
3.1 No reperfusion	7	4658	Risk Ratio (M‐H, Random, 95% CI)	0.88 [0.67, 1.15]
3.2 Reperfusion (PCI , CABG, thrombolytics)	7	2167	Risk Ratio (M‐H, Random, 95% CI)	0.87 [0.46, 1.66]
4 Myocardial infarction ‐ Type of beta‐blocker	14	6825	Risk Ratio (M‐H, Random, 95% CI)	0.89 [0.74, 1.08]
4.1 Esmolol	1	100	Risk Ratio (M‐H, Random, 95% CI)	0.20 [0.01, 4.06]
4.2 Alprenolol	1	77	Risk Ratio (M‐H, Random, 95% CI)	1.03 [0.28, 3.81]
4.3 Landiolol	1	96	Risk Ratio (M‐H, Random, 95% CI)	0.35 [0.01, 8.32]
4.4 Carvedilol	3	2899	Risk Ratio (M‐H, Random, 95% CI)	0.63 [0.43, 0.91]
4.5 Metoprolol	4	2426	Risk Ratio (M‐H, Random, 95% CI)	1.02 [0.84, 1.24]
4.6 Pindolol	1	529	Risk Ratio (M‐H, Random, 95% CI)	0.91 [0.61, 1.38]
4.7 Propranolol	2	610	Risk Ratio (M‐H, Random, 95% CI)	0.51 [0.08, 3.15]
4.8 Timolol	1	88	Risk Ratio (M‐H, Random, 95% CI)	6.57 [0.82, 52.35]
5 Myocardial infarction ‐ Above/below 75 years of age	13	6729	Risk Ratio (M‐H, Random, 95% CI)	0.89 [0.72, 1.09]
5.1 Below 75 years	11	5665	Risk Ratio (M‐H, Random, 95% CI)	0.87 [0.69, 1.10]
5.2 Mixed	2	1064	Risk Ratio (M‐H, Random, 95% CI)	1.35 [0.45, 4.07]
6 Myocardial infarction ‐ Intravenously/orally commenced	14	6825	Risk Ratio (M‐H, Random, 95% CI)	0.89 [0.74, 1.08]
6.1 Intravenously commenced	4	1095	Risk Ratio (M‐H, Random, 95% CI)	0.93 [0.26, 3.29]
6.2 Orally commenced	6	4007	Risk Ratio (M‐H, Random, 95% CI)	0.85 [0.62, 1.17]
6.3 Mixed	4	1723	Risk Ratio (M‐H, Random, 95% CI)	0.83 [0.46, 1.50]
7 Myocardial infarction ‐ NSTEMI/STEMI/UAP	7	2098	Risk Ratio (M‐H, Random, 95% CI)	1.12 [0.57, 2.18]
7.1 STEMI	5	1889	Risk Ratio (M‐H, Random, 95% CI)	1.07 [0.45, 2.54]
7.2 Mixed	2	209	Risk Ratio (M‐H, Random, 95% CI)	1.19 [0.42, 3.40]
8 Myocardial infarction ‐ Registration status	14	6825	Risk Ratio (M‐H, Random, 95% CI)	0.89 [0.74, 1.08]
8.1 Pre‐registration	4	1793	Risk Ratio (M‐H, Random, 95% CI)	1.17 [0.48, 2.88]
8.2 No registration	10	5032	Risk Ratio (M‐H, Random, 95% CI)	0.86 [0.68, 1.09]
9 Myocardial infarction ‐ Length of intervention period	14	6913	Risk Ratio (M‐H, Random, 95% CI)	0.90 [0.71, 1.13]
9.1 0 to 7 days length of intervention	5	1183	Risk Ratio (M‐H, Random, 95% CI)	1.51 [0.46, 4.96]
9.2 7 to 30 days length of intervention	1	88	Risk Ratio (M‐H, Random, 95% CI)	6.57 [0.82, 52.35]
9.3 1 month and more length of intervention	9	5642	Risk Ratio (M‐H, Random, 95% CI)	0.88 [0.74, 1.06]
10 Myocardial infarction ‐ Funding	14	6825	Risk Ratio (M‐H, Fixed, 95% CI)	0.89 [0.77, 1.04]
10.1 Industry funded or unknown funded trials	11	5665	Risk Ratio (M‐H, Fixed, 95% CI)	0.90 [0.77, 1.04]
10.2 Non‐industry funded trials	3	1160	Risk Ratio (M‐H, Fixed, 95% CI)	0.79 [0.31, 2.04]
11 Myocardial infarction ‐ 'Best‐worst case scenario'	14	6951	Risk Ratio (M‐H, Random, 95% CI)	0.56 [0.37, 0.85]
12 Myocardial infarction ‐ 'Worst‐best case scenario'	14	6951	Risk Ratio (M‐H, Fixed, 95% CI)	1.10 [0.95, 1.26]

Methods	Randomised clinical trial, parallel design, at a single site in Denmark between March 1976 and December 1978.
Participants	480 participants with definite or suspected MI were included. Male:female = 325:155. Mean age = 62.8 years. Exclusion criteria: 1) cardiogenic shock, 2) pulmonary oedema persisting after 2 hours treatment, 3) AV‐block (Morbitz type 2 and 3rd degree AV‐block), 4) bradycardia < 40 beats/minute, 5) COPD after admission, 6) non‐resident in area, 7) treatment with a beta‐blocker at admission, 8) refusal to participate, 9) terminal or other disease, 10) contraindicated to beta‐blockade.
Interventions	Experimental group: alprenolol (5 mg to 10 mg of alprenolol intravenously, followed by 200 mg orally twice daily for a year). Control group: placebo. Co‐intervention: not described. Excluded medication: other beta‐blockers and verapamil were not permitted during the study.
Outcomes	Primary: mortality. Time points reported: 28 days and 12 months.
Notes	No email was found on the author. The study did not inform about how it was funded.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Described as being double‐blinded, however, no further description was given.
Allocation concealment (selection bias)	Unclear risk	Not described.
Blinding of participants and personnel (performance bias)   All outcomes	Unclear risk	Not described.
Blinding of outcome assessment (detection bias)   All outcomes	Low risk	All deaths, side‐effects, and dropouts were recorded and classified by an independent safety monitoring board consisting of one statistician and two cardiologists not otherwise involved in the study.
Incomplete outcome data (attrition bias)   All outcomes	Low risk	A total of 108 participants (37.5%) participants dropped out from the study: 61 from the alprenolol group and 52 from the placebo group were withdrawn. However, these were followed up on when reporting mortality. Hence, there was no risk of incomplete outcome data.
Selective reporting (reporting bias)	Unclear risk	A protocol could be obtained, but was published five years after their initial trial publication. They reported the outcomes in their trial publication stated in the protocol. The trial did not report SAEs.
Other bias	Low risk	No other biases were found.

Methods	Randomised clinical trial at an unknown place.
Participants	101 patients less than 75 years of age with a suspected AMI within 6 hours were included. Male:female = not reported. Mean age = not reported. Exclusion criteria: age > 75, previous MI, SBP < 100, HR < 50, block, COPD, LVF, high risk, beta‐blocker use.
Interventions	Experimental group: timolol (5.5 mg IV + 10 mg orally twice daily for 28 days). Control group: placebo. Co‐intervention: not reported. Excluded medication: not reported.
Outcomes	Primary: infarct size, chest pain, haemodynamic function, arrhythmias. Timepoints reported: 28 days.
Notes	No email was found on the author. The study could not be found, so we used the data reported in the meta‐analysis ''Yusuf 1985'', who were able to get unpublished data by personal communication with the author. No information about the funding of the study was available.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not described.
Allocation concealment (selection bias)	Unclear risk	Not described.
Blinding of participants and personnel (performance bias)   All outcomes	Unclear risk	Not described.
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	Not described.
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	It was not mentioned if any participant was lost to follow‐up
Selective reporting (reporting bias)	Unclear risk	No protocol could be obtained, and the trial did not report on all SAEs.
Other bias	Unclear risk	Not able to assess if any other bias exist, as the main manuscript could not be obtained.

Methods	Multi‐centre randomised controlled trial in 67 centres in Japan between August 2010 and May 2014.
Participants	Patients > 18 years old were eligible for the trial if they underwent successful primary PCI within 24 hours after the onset of STEMI and had preserved left ventricular ejection fraction (LVEF> 40%) as assessed by echocardiography. Male:female = 639:155. Mean age = 64 years old. Exclusion criteria: reduced LVEF (LVEF< 40%), prior cardioverter defibrillator implantation, or contraindications to beta‐blocker therapy such as unstable haemodynamic status, bradyarrhythmias, symptomatic HF, and severe bronchial asthma and/or chronic obstructive lung diseases.
Interventions	Experimental group: carvedilol (oral, maximal dose of 20 mg). Control group: no intervention. Co‐intervention: the administration of other standard medications for STEMI patients such as aspirin, thienopyridines, statins, and inhibitors of the renin angiotensin system were also left to the physicians decision. Excluded medication: not reported.
Outcomes	Primary: composite of all‐cause death, MI, hospitalisation for acute coronary syndrome (ACS), and hospitalisation for HF. Secondary outcomes: individual components of the primary endpoint as well as cardiac death, non‐cardiac death, stroke, vasospastic angina, major bleeding, definite stent thrombosis (ST), target‐lesion revascularisation (TLR), and any coronary revascularisation. 3 composite endpoints including cardiac death/MI/ACS/HF, cardiovascular death/MI/stroke, and death/MI/stroke/ACS/HF/any coronary revascularisation. Time points reported: at 3‐month, 1‐year, and final follow‐up.
Notes	taketaka@kuhp.kyoto‐u.ac.jp The study was supported by an educational grant from the Research Institute for Production Development (Kyoto, Japan). ClinicalTrials.gov Identifier: NCT01155635.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Randomisation was performed centrally through the electronic data capture system with a stochastic minimization algorithm to balance treatment assignment.
Allocation concealment (selection bias)	Unclear risk	Not described.
Blinding of participants and personnel (performance bias)   All outcomes	High risk	Open‐label.
Blinding of outcome assessment (detection bias)   All outcomes	Low risk	an independent clinical event committee being adjudicated both the primary and secondary endpoints in a fashion blinded to the assigned treatment group.
Incomplete outcome data (attrition bias)   All outcomes	Low risk	29 participants in total were lost to follow‐up without further description. However, this was less than 5% of the total number of included participants in the analysis.
Selective reporting (reporting bias)	Low risk	Registrated to clinicaltrials.gov before randomisation (https://clinicaltrials.gov/ct2/show/NCT01155635). All outcomes in the protocol are mentioned in the paper.
Other bias	Unclear risk	The trial was prematurely terminated due to slow enrolment which can lead to bias.

Methods	Randomised clinical trial, 2 x 2 factorial design, at 1250 sites in China between August 1999 and February 2005.
Participants	45,852 participants who presented with ST elevation, left‐bundle branch block, or ST depression within 24 hours of the onset of the symptoms of suspected AMI were potentially eligible for the study.  Male:female = 33,093:12,759. Mean age = 61 years. Exclusion criteria: patients scheduled for primary percutaneous coronary intervention (PCI), a high risk of adverse effects (1) previous allergy to aspirin, (2) active bleeding or a history of haemostatic disorder, (3) very low BP (e.g. SBP persistently < 100 mmHg), (4) very low HR (e.g. persistently < 50 bpm), (5) third degree heart block or (6) cardiogenic shock) with one or other of the trial treatments or only a small likelihood of worthwhile benefit such as a negligibly low risk of MI death (e.g. unconvincing history and/or normal ECG).
Interventions	Note: there was another comparison, aspirin plus clopidogrel vs. aspirin, as per a 2 x 2 factorial design. This comparison is not discussed in this review. Experimental group: metoprolol (initial dose of up to 15 mg given intravenously, 50 mg tablet every 6 hours during days 0‐1, after two days a 200 mg tablet was given daily for up to 4 weeks). Control group: matching placebo (same regimen as the experimental group). Co‐intervention: not described. Excluded medication: non‐study beta‐blocker (and non‐study antiplatelet) therapy was to be avoided during the scheduled treatment period unless it was believed that some strong indication had developed.
Outcomes	Primary: the composite of death, reinfarction, or cardiac arrest (including ventricular fibrillation); and death from any cause during the scheduled treatment period (i.e., until first discharge or day 28). Secondary: reinfarction, ventricular fibrillation, other cardiac arrest, cardiogenic shock, and related conditions. Time points reported: first hospital discharge or 28 days, whichever came first (mean 15 days).
Notes	The authors were contacted on 25 January 2017 on zhengming.chen@ctsu.ox.ac.uk and ccstwo@public3.bta.net.cn but no answers were received. The study was funded jointly by Sanofi‐Aventis and Bristol‐Myers Squibb (manufacturers of clopidogrel) and by AstraZeneca (manufacturers of metoprolol). However, it is said that quote: "the sponsor of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. The writing committee had final responsibility for the decision to submit for publication."
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Random allocation of the study treatments involved sequentially‐numbered sealed treatment packs prepared centrally.
Allocation concealment (selection bias)	Low risk	Random allocation of the study treatments involved sequentially‐numbered sealed treatment packs prepared centrally.
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	The participants and personnel were blinded due to the use of matching placebo. It is moreover mentioned that the clinical staff who took care of the participants had no knowledge of the study treatment allocation.
Blinding of outcome assessment (detection bias)   All outcomes	Low risk	All outcomes were reviewed and, if necessary, additional information was sought to allow adjudication (without knowledge of the study treatment allocation) by clinical staff in the co‐ordinating centres.
Incomplete outcome data (attrition bias)   All outcomes	Low risk	One from each group was lost to follow‐up. Mortality data were provided according to all randomised patients.
Selective reporting (reporting bias)	Low risk	Protocol found + reported on the predefined outcomes.
Other bias	Low risk	No other biases were found.

Methods	Randomised clinical trial in Japan between January 2009 and March 2010.
Participants	96 patients with STEMI undergoing PCI within 12 hours after the onset of AMI were included. Male:female = 80:16 Mean age = 62 years. Exclusion criteria: those with Killip class 3 or 4, bradycardia < 50 bpm, hypotension with SBP < 90 mmHg, bronchospasm, or second‐ or third‐degree atrioventricular block.
Interventions	Experimental intervention: landiolol (24 hours of IV 3μg/kg/minute landiolol without loading begun after successful PCI) Control intervention: no intervention other than the co‐intervention. Co‐intervention: ACE inhibitor or angiotensin‐receptor blocker, oral β‐blocker, statin, calcium‐channel blocker, diuretics, and nitrates. PCI.
Outcomes	Primary: incidences of cardiovascular events such as cardiac arrhythmias and cardiac death. Secondary: effects of landiolol on HR and BP, and the development of any adverse effects. Time points reported: 14 days and 6 months.
Notes	The author was contacted on 29 March 2017 on okumura@cc.hirosaki‐u.ac.jp. No response received. No funding was received.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	The study was described as being randomised by an envelope method, however, no further information was given.
Allocation concealment (selection bias)	Unclear risk	Quote: "Just after PCI, the patients were randomly divided into 2 groups by an envelope method." However, it was not mentioned if this envelope was sealed and opaque.
Blinding of participants and personnel (performance bias)   All outcomes	Unclear risk	Not described.
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	Quote: "Two cardiologists who were unaware of the treatment assignment (landiolol or control) analysed the LVG results." However, it does describe whether or not the outcome assessors assessing the primary outcome 'cardiovascular events' were blinded.
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	Not described.
Selective reporting (reporting bias)	Unclear risk	No protocol could be found, and the trial did not report SAEs.
Other bias	Low risk	No other biases found.

Methods	Randomised clinical trial in France, Norway, Sweden, and the UK. Duration not mentioned.
Participants	144 participants of either sex, between 21‐70 years of age, and with suspected AMI (within 4 hours from onset) were included. Male:female = 123:21. Mean age = 55.5 years. Exclusion criteria: bradycardia (< 50 bpm), hypotension (SBP < 100 mmHg), clinical evidence of severe left ventricular failure, any degree of heart block, or a history of previous MI and a QRS duration longer than 0.11 seconds. Contraindication to beta‐blockade (rates >10 cm above the diaphragm), atrioventricular block I through III, bronchial obstruction, hypotension or bradycardia, or current treatment with a beta‐blocker, calcium antagonist, digitalis, or another antiarrhythmic agent.
Interventions	Experimental intervention: timolol (1 mg IV for the first 24 hours followed by 10 mg orally twice a day for the duration of hospitalisation). Control intervention: matching placebo (the patients receivedIV normal saline instead of IV timolol). Co‐intervention: normal supportive measures were freely allowed, but treatment with other cardioactive drugs (digitalis, nitrates, calcium antagonists, or antiarrhythmic agents) was discouraged. If such therapy was administered, the patient was not withdrawn from the study but was considered a protocol violator for the purposes of data analysis. Intramuscular injections were not allowed.
Outcomes	Outcomes: BP, pulse rate, clinical adverse events.
Notes	Email not found. The trial was supported in part by a grant from Merck, Sharp and Dohme Research Laboratories, Rahway, N.J.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: "Randomization was performed within each center and was balanced in blocks of four patients." No further description was given.
Allocation concealment (selection bias)	Unclear risk	Not described.
Blinding of participants and personnel (performance bias)   All outcomes	Unclear risk	All the tablets were identical and the trial is described as being double‐blinded. This indicates that the participants have been blinded, however there is no indication of whether the personnel have been blinded.
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	Not described.
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	Not described.
Selective reporting (reporting bias)	Unclear risk	No protocol could be obtained, and the trial did not report SAEs.
Other bias	Low risk	No other biases were found.

Methods	Randomised clinical trial at a single site in Russia.
Participants	41 participants with verified diagnosis of AMI were included. Male:female = 23:18. Mean age = 57 years. Exclusion criteria: chronic infectious diseases.
Interventions	Experimental group: propranolol (80 mg per day until discharge). Control group: no intervention other than co‐intervention. Co‐intervention: traditional therapy (anticoagulants, hypotensive drugs (not including beta‐blockers and calcium antagonists), antiarrhythmic drugs, diuretics and nitrates). Excluded medication: not described.
Outcomes	Primary: level of blood ceruloplasmin. Time points reported: 28 days.
Notes	Email not found. The funding/support was not described.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not described, other than that quote: "the patients were randomised into two groups.."
Allocation concealment (selection bias)	Unclear risk	Not described.
Blinding of participants and personnel (performance bias)   All outcomes	Unclear risk	Not described.
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	Not described.
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	It was not mentioned if any participant was lost to follow‐up
Selective reporting (reporting bias)	Unclear risk	No protocol could be obtained, and the trial did not report on all SAEs.
Other bias	Low risk	No other biases were found.

Methods	Randomised clinical trial in Denmark.
Participants	130 participants with definite or suspected MI were included. Male:female = 90:40. Mean age = not reported. Exclusion criteria: patients with complicated asthma.
Interventions	Experimental group: propranolol (10 mg orally 4 times daily, or 5 mg IV. instead of 10 mg orally for 14 days). Control group: no intervention other than co‐intervention. Co‐intervention: digitalis, diuretics, metaradrine, and procainamide. Excluded medication: not described.
Outcomes	Primary: rhythm complications and death. Time points reported: 28 days.
Notes	Email not found. Supported by 'Foreningen til hjertesygdommenes bekæmpelse'.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not described.
Allocation concealment (selection bias)	Low risk	Quote: "Each of the 8 groups were consecutively numbered and corresponding to each number a sealed envelope, which stated whether the patient should be treated with pro‐propranolol or not."
Blinding of participants and personnel (performance bias)   All outcomes	Unclear risk	Quote: "This system, which was developed by one of the department secretaries in the start of the study, ruled that the investigating personnel had no bearing on whether treatment should be given or not." However, the control group did not receive any matching placebo, which indicates that the study was not double‐blinded.
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	Not described.
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	Not described.
Selective reporting (reporting bias)	Unclear risk	No protocol could be found, and the trial did not adequately report SAEs.
Other bias	Low risk	No other biases were found.

Methods	Randomised clinical trial in Italy.
Participants	250 participants, 75 years or less, admitted to the coronary care units less than 24 hours from the onset of symptoms, typical chest pain lasting more than 30 minutes not relieved by sublingual nitrates, plasma CK rise to at least twice the upper limit of local normal values, ST‐segment elevation > 0.2 mV in V1‐V4 and 0.1 mV or more in V5‐V6, I, II, III, aVL, aVF in at least two contiguous leads. The presence of at least two of the three criteria was considered necessary. Male:female = 203:47. Mean age = 58 years. Exclusion criteria: previous MI, Killip class III or more, severe hypertension (>180 mmHg in systole, >120 mmHg in diastole, irrespective of pharmacological therapy), hypotension (<100 mmHg in systole) lasting more than 3 hours during the observation period, hypovolaemia, cardiomyopathics and severe valvular heart disease, diabetes uncontrolled by therapy, preexisting or new left bundle branch block, all contraindications to ACE‐inhibition or to beta‐blocker treatment, based on physician's decision, presence of a concomitant life‐threatening disease, and inadequate thoracic acoustic window.
Interventions	The patients were randomly divided into three study groups 1) captopril, 2) metoprolol and 3) captopril + metoprolol. We only used data from study group 1 and 3, where we classified captopril as being a co‐intervention given to both groups so that the experimental group only received metoprolol. Experimental group: metoprolol (orally, titrated up to 200 mg for at least 3 months). Control group: no intervention other than the co‐intervention. Co‐intervention: captopril up titrated to 75 mg. Excluded medication: all cardioactive drugs were allowed in the study period, with the exclusion of beta blockers.
Outcomes	Outcomes: cardiac death and non‐fatal MI; cardiac death, non‐fatal MI, unstable angina requiring hospitalisation, and congestive heart failure (transitory increase of at least two NYHA classes, or stable increase of at least one NYHA class). Time points: 15 days, 3, and 6 months.
Notes	Dr. Claudia Coletta. No email found. The study initially included 250 patients but did not report how many patients there were in each group. Later, there were only data on 236 patients. It is, therefore, unclear how many patients has been lost in each group. The funding/support of the trial was not described.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not described other than quote: "250 consecutive patients were randomly allocated to receive an open‐labelled treatment..."
Allocation concealment (selection bias)	Unclear risk	Not described other than quote: "250 consecutive patients were randomly allocated to receive an open‐labelled treatment..."
Blinding of participants and personnel (performance bias)   All outcomes	High risk	Open‐label.
Blinding of outcome assessment (detection bias)   All outcomes	High risk	Open‐label.
Incomplete outcome data (attrition bias)   All outcomes	High risk	24 participants were lost to follow‐up (9.6%). It is, however, not described to which group they belonged.
Selective reporting (reporting bias)	Unclear risk	No protocol could be obtained. The trial did not report all SAEs.
Other bias	Low risk	No other biases were found.

Methods	Randomised trial in Italy.
Participants	42 patients with AMI within 6 hours were included. Male:female = 39:3. Mean age = 52 years. Exclusion criteria: other cardiac diseases (hypertensive heart disease, valvular heart disease, cardiopathy). No patient had suffered from previous MI.
Interventions	Experimental intervention: propranolol (2 mg IV bolus followed by 0.1 mg/kg/day for the next 48 hours). Control intervention: no intervention. Co‐intervention: not described.
Outcomes	Outcomes: cumulated activity, peak plasma value, rate of release and total duration of release of MB‐CK. Time points reported: 72 hours.
Notes	Email not found. Prof, GIUSEPPE BOTTI Divisione di Cardiologia Ospedale Maggiore Via Gramsci, 14. Funding was not described.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not described sufficiently, other than that they were quote: "randomly assigned...
Allocation concealment (selection bias)	Unclear risk	Not described sufficiently, other than that they were quote: "randomly assigned..."
Blinding of participants and personnel (performance bias)   All outcomes	High risk	Not described. However, the control group did not receive any intervention, hence it could not be blinded.
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	Not described.
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	No dropout described.
Selective reporting (reporting bias)	Unclear risk	No protocol could be found. The trial did not report all‐cause mortality and all SAEs.
Other bias	Low risk	No other biases were found.

Methods	Controlled clinical trial, parallel design, at a single site in Japan. Duration not mentioned.
Participants	69 participants with AMI who underwent emergency primary percutaneous coronary intervention (PCI) for an infarct‐related artery (IRA) were recruited within 12 hours of pain onset were included. Male:female = 55:14. Mean age = 62 years. Exclusion criteria: atenolol allergy, bradycardia (HR 50 bpm), advanced heart block, Forrester subset ≥2 by right heart catheterisation including cardiogenic shock, chronic obstructive lung disease, or arteriosclerosis obliterans.
Interventions	Experimental group: atenolol (50 mg tablet once daily after successful PCI). Control group: no intervention other than the co‐intervention. Co‐intervention: PCI. Excluded medication: calcium antagonists were not allowed in either group.
Outcomes	Primary: incidence of coronary vasospasm by ergonovine provocation test, defined as N90% constriction. Secondary: death, any AMI, target vessel revascularisation, HF, anginal attack, stroke, and ventricular arrhythmia. Time points reported: 1 month.
Notes	Email not found. D. R. Ramsdale, M.R.C.P., Regional Cardiac Centre, Wythenshawe Hospital, Southmoor Rd., Manchester M23 9LT, England. The funding or support of the trial was not described.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	The patients were randomised alternatively (simple randomisation). It was not mentioned if this was done by a independent adjudicator.
Allocation concealment (selection bias)	Unclear risk	Quote: "Eligible patients were assigned alternatively.." No further information was provided.
Blinding of participants and personnel (performance bias)   All outcomes	High risk	Not described, however, since the control group did not receive any matching placebo other than the co‐intervention (PCI), we assume that the trial has not been blinded.
Blinding of outcome assessment (detection bias)   All outcomes	Low risk	Qualitative and quantitative assessments were performed by two independent cardiologists unaware of treatment assignment.
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	It was not described if any participants were lost to follow‐up.
Selective reporting (reporting bias)	Unclear risk	No protocol could be obtained, and the trial did not report all SAEs.
Other bias	Unclear risk	It is mentioned that the trial might not haven been strictly randomised which can therefore affect the validity of the trial results.

PERMALINK

Beta‐blockers for suspected or diagnosed acute myocardial infarction

Sanam Safi

Naqash J Sethi

Emil Eik Nielsen

Joshua Feinberg

Christian Gluud

Janus C Jakobsen

Abstract

Background

Objectives

Search methods

Selection criteria

Data collection and analysis

Main results

Authors' conclusions

Plain language summary

Summary of findings

Background

Description of the condition

Major complications associated with myocardial infarction

Description of the intervention

How the intervention might work

Why it is important to do this review

Evidence on the effects of beta‐blockers for suspected or diagnosed acute myocardial infarction

Outcomes assessed at hospital discharge

Long‐term outcomes

Beta‐blockers for other conditions

Current guidelines for using beta‐blockers in patients with suspected or diagnosed myocardial infarction

Objectives

Methods

Criteria for considering studies for this review

Types of studies

Types of participants

Types of interventions

Types of outcome measures

Primary outcomes

Secondary outcomes

Search methods for identification of studies

Electronic searches

Searching other resources

Data collection and analysis

Selection of studies

1.

Data extraction and management

Assessment of risk of bias in included studies

Overall risk of bias

Measures of treatment effect

Unit of analysis issues

Dealing with missing data

Dichotomous outcomes

Continuous outcomes

Best‐worst and worst‐best case scenarios

Assessment of heterogeneity

Assessment of reporting biases

Data synthesis

Meta‐analysis

Assessment of significance

Subgroup analysis and investigation of heterogeneity

Sensitivity analysis

'Summary of findings' tables

Summary of findings for the main comparison. Beta‐blockers versus placebo or no intervention for suspected or diagnosed acute myocardial infarction at the time point less than three months follow‐up.

Summary of findings 2. Beta‐blockers versus placebo or no intervention for suspected or diagnosed acute myocardial infarction at maximum follow‐up beyond three months.

Results

Description of studies

Results of the search

Included studies

Excluded studies

Risk of bias in included studies

2.

3.

Allocation

Blinding

Incomplete outcome data

Selective reporting

Other potential sources of bias

Effects of interventions

Primary outcomes

All‐cause mortality

Time point at less than three months follow‐up

Methods	Randomised clinical trial, multi‐arm, parallel design, at 20 sites in Belgium between June 1988 and December 1990.
Participants	292 patients with AMI of less or equal to 5 hours of duration were included if they met the following inclusion criteria: 1) less than 71 years of age; 2) chest pain suggestive of AMI lasting more than or equal to 30 minutes; 3) ST segment elevation of 0.2 mV in two or more limb leads or leads Vs and V6 or 0.3 mV in two or more precordial leads (V1 to V4 ) or ST elevation of 0.1 mV in two leads (II, III, aVF or Vs and V6) associated with ST depression of 0.2 mV in two precordial leads, suggesting posterior wall infarction; 4) onset of chest pain < 5 hours before initiation of therapy; 5) no previous history of angioplasty or bypass surgery; 6) no contraindications to thrombolytic therapy; 7) no intake of a beta‐blocker or calcium antagonist in the week preceding the onset of infarction; and 8) no contraindications for acute intravenous administration of beta‐blockers. Male:female = 246:46. Mean age = 58 years. Exclusion criteria: HR persistently <50 bpm, SBP persistently < 90 mmHg, clinical signs of overt heart failure or cardiogenic shock, second‐ or third‐degree AV block and history of bronchospasm or sick sinus syndrome.
Interventions	Three‐armed intervention with two experimental interventions. Experimental intervention: atenolol (5 mg to 10 mg intravenously followed by oral treatment of 25 mg to 50 mg every 12 hours for 10‐14 days). Control intervention: placebo (one or two IV injections) Co‐intervention: all patients received 100 mg alteplase over 3 hours and full IV heparinisation (5000 IU bolus injection followed by continuous infusion of 1000 IU/hour until angiography). Excluded medication: aspirin.
Outcomes	Primary: global and regional LVF and infarct size. Secondary: exercise capacity; incidence of arrhythmias, and coronary artery patency. Time point reported: 14th day.
Notes	The author was contacted on 26 January 2017 on frans.vandewerf@kuleuven.be. No response received. The study was supported by the Belgium National Fund for Scientific Research, ICI Pharma, Belgium and Boehringer Ingelherim.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not described sufficiently, however, it is said that quote: "with the use of a double‐dummy technique, eligible patients were randomised..".
Allocation concealment (selection bias)	Unclear risk	Not described.
Blinding of participants and personnel (performance bias)   All outcomes	Unclear risk	Not described sufficiently, other than the study is described as being double‐blinded.
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	Not described.
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	It was not mentioned if any participant was lost to follow‐up.
Selective reporting (reporting bias)	Unclear risk	No protocol could be obtained, and the trial did not report SAEs.
Other bias	Low risk	No other biases were found.

Study	Reason for exclusion
Antman 1989	Not a randomised controlled trial.
Assmann 1981	The trial was not randomised.
Barvik 1992	Did not include patients in the acute/subacute phase of a myocardial infarction.
Boyle 1980	The trial had no placebo/control group.
Di Pasquale 1994	It is unclear whether or not they were randomised to metoprolol in addition to captopril and how this intervention was given.
Dluzniewski 1985	Not a randomised controlled trial.
Dotremont 1968	The trial was not randomised.
Evrengul 2004	The patients were not randomised.
Galcerá‐Tomás 2001	The trial has no placebo/control group.
HINT 1987	The trial did not include participants with suspected of or diagnosed with an acute myocardial infarction.
Jardine 1986	No indication of the trial being randomised.
JBCMI 2004	The trial had no placebo/control group.
Johansson 1980	The trial is quasi‐randomised.
MEMO 1999	The trial had no placebo/control group.
Nakagomi 2011	The trial had no placebo/control group.
Park 2013	Did not include patients with acute or recent myocardial infarction.
Pouleur 1988	Included patients with ischaemic heart diseases and not only patients with acute myocardial infarction.
Puymirat 2016	A multicentre prospective cohort study and not a randomised clinical trial.
Schwartz 1992	Did not include patients with acute or recent myocardial infarction.
Sloman 1967	The control group did not receive either placebo or no intervention.
Snow 1966	The trial was not randomised.
Tekten 2002	The trial was not randomised.

Trial name or title	BEtablocker Treatment after Acute Myocardial Infarction in patients without reduced left ventricular systolic function (BETAMI)
Methods	Randomised open‐label clinical trial.
Participants	Patients older than 18 diagnosed with an acute myocardial infarction and treated with PCI or thrombolysis during current hospitalisation within the past 1‐8 days.
Interventions	Control group: no betablocker will be administered. Any other treatment or management is to be given as per usual care. Experimental group: metoprolol succinate up to a total dose of 200 mg daily. Bisoprolol up to a total dose of 10 mg daily. Carvedilol up to a total dose of 50 mg daily. Any other treatment or management is to be given as per usual care.
Outcomes	Primary outcome: the composite of death of any cause and non‐fatal MI. Secondary outcomes: non‐fatal MI; all‐cause death; ventricular arrhythmia; hospitalisation for heart failure; cardiovascular death.
Starting date	23 August, 2018
Contact information	John Munkhaugen, MD PhD, johmin@vestreviken.no Vidar Ruddox, MD PhD, vidar.ruddox@siv.no
Notes	Estimated Study Completion: 1 October, 2023. ClinicalTrials.gov Identifier: NCT03646357.

Trial name or title	Effect of intravenous metoprolol combining RIPC on myocardial protection in anterior ST‐segment elevation myocardial infarction patients undergoing primary PCI.
Methods	A prospective, multicentre, randomised, open‐label trial.
Participants	Patients ages 18 to 80 years, presenting within 6 hours of symptoms onset, with anterior STEMI, de novo occlusion of LAD (TIMI flow grade 0 to 1), and planned pPCI were eligible. Anterior STEMI was defined as the occurrence of > 20 minutes of chest pain and ST‐segment elevation (> 2 mm) in at least 2 contiguous precordial leads.
Interventions	Drug: intravenous placebo. Drug: metoprolol injectable product. Device: remote ischaemic post‐conditioning (RIPC).
Outcomes	Primary outcome: MI size. Secondary outcomes: incidence of heart failure; MI size measured by MRI; incidence of in‐hospital heart failure; MACCE; incidence of bradycardia and low blood pressure.
Starting date	17 May, 2018.
Contact information	Yu Bo, Harbin Medical University. No email found.
Notes	Estimated Study Completion: 31 December, 2020. ClinicalTrials.gov Identifier: NCT03579914

Trial name or title	Evaluation of decreased usage of betablockers after myocardial infarction in the SWEDEHEART Registry (REDUCE‐SWEDEHEART)
Methods	A registry‐based, randomised, parallel, open‐label, multicentre trial.
Participants	Patients > 18 years with MI within 1‐7 days and preserved left ventricular systolic ejection fraction who have undergone coronary angiography during hospitalisation.
Interventions	Experimental: oral beta‐blocker treatment (metoprolol succinate, bisoprolol). No Intervention: no beta‐blocker treatment.
Outcomes	Primary outcome: composite of death of any cause or MI Secondary outcomes: all‐cause death; MI; cardiovascular death; heart failure; atrial fibrillation; bradycardia, advanced AV‐block, hypotension, syncope or need for pacemaker; asthma or COPD; stroke; health‐related quality of life (HRQOL); healthcare costs.
Starting date	11 September, 2017
Contact information	Eva Jacobsson, PhD, eva.jacobsson@ucr.uu.se Troels Yndigegn, MD,
Notes	Estimated Primary Completion Date 31 August, 2020. NCT number: NCT03278509