Question: What is the effectiveness of adding a beta blocker versus placebo to improve outcome in...
10
Grading: 1++ High-quality meta-analyses, systematic reviews of RCTs, or RCTs with a very low risk of bias
Reference number 3841
Chen ZM;Jiang LX;Chen YP;Xie JX;Pan HC;Peto R;Collins R;
Addition of clopidogrel to aspirin in 45852 patients with acute myocardial infarction:randomised placebo-controlled trial
2005366pgs 1607 1621
Study Type: Randomised Controlled Trial
Patient Characteristics Inclusion criteria: Post MI recruited within 24 h of suspected acute MI onset (ST elevation (87%), left bundle block (6%), or ST depression (7%)). Mean age ± SD = 61 ± 11 years, male and female (28%). Patients with hypertension: 8%.
Intervention Immediately: 162 mg aspirin plus 75 mg clopidogrel. Subsequently: 162 mg aspirin plus 75 mg clopidogrel once daily for up to 4 weeks (or, if earlier, until hospital discharge or death): 22 961 patients.
Comparisons Immediately: 162 mg aspirin plus placebo. Subsequently: 162 mg aspirin plus placebo once daily for up to 4 weeks (or, if earlier, until hospital discharge or death): 22 891 patients.
Study Length Up to 4 weeks.
Outcomes Primary: Composite of death, reinfarction, or stroke. Death from any cause. Secondary: Re-infarction, stroke, cardiogenic shock, heart failure, presumed cardiac rupture, ventricular fibrillation, other cardiac arrest, pulmonary embolism.
Funding Sanofi-Aventis, Bristol-Myers Squibb, Astra-Zeneca, MRC UK, BHF, Cancer Research UK.
Effect Primary: Composite of death, reinfarction, or stroke: 2121/22961 (9.2%) treatment versus 2310/22891 (10.1%) placebo, OR of 0.91 (95% CI 0.86 to 0.97, P = 0.002). About 2 weeks of clopidogrel therapy associated with 9 (SE 3) fewer patients with death, reinfarction or stroke in hospital per 1000 allocated treatments. Death from any cause: 1726/22961 (7.5%) treatment versus 1845/22891 (8.1%) placebo, OR of 0.93 (95% CI 0.87 to 0.99, P = 0.03). Arrhythmia: 432/22961 (1.9%) treatment versus 454/22891 (2.0%) placebo. Asystole: 642/22961 (2.8%) treatment versus 697/22891 (2.0%) placebo. Cardiac rupture: 188/22961 (0.8%) treatment versus 210/22891 (0.9%) placebo. Cardiogenic shock: 503/22961 (2.2%) treatment versus 562/22891 (2.5%) placebo. Reinfarction: 133/22961 (0.5%) treatment versus 101/22891 (0.4%) placebo. Stroke: 72/22961 (0.3%) treatment versus 87/22891 (0.4%) placebo. Other: 92/22961 (0.4%) treatment versus 103/22891 (0.4%) placebo. Secondary: Reinfarction: Died, any cause: 209/22961 (0.9%) treatment versus 223/22891 (1.0%) placebo, OR of 0.93 (95% CI 0.77 to 1.13, P = 0.46). Survived: 270/22961 (1.2%) treatment versus 330/22891 (1.4%) placebo, OR of 0.81 (95% CI 0.69 to 0.95, P = 0.01). All: 479/22961 (2.1%) treatment versus 553/22891 (2.4%) placebo, OR of 0.86 (95% CI 0.76 to 0.97, P = 0.02). Allocation to clopidogrel produced 14% (95% CI 3–4) proportional reduction in the risk of any reinfarction. Stroke: Ischaemic (or unknown): 164/22961 (0.7%) treatment versus 194/22891 (0.8%) placebo, OR of 0.84 (95% CI 0.68 to 1.03, P = 0.10). Haemorrhagic: 53/22961 (0.2%) treatment versus 56/22891 (0.2%) placebo, OR of 0.98 (95% CI 0.67 to 1.42, P = 0.90). Died, any cause: 90/22961 (0.4%) treatment versus 108/22891 (0.5%) placebo, OR of 0.83 (95% CI 0.63 to 1.10, P = 0.19). Survived: 127/22961 (0.6%) treatment versus 142/22891 (0.6%) placebo, OR of 0.89 (95% CI 0.70 to 1.13, P = 0.33). All: 217/22961 (0.9%) treatment versus 250/22891 (1.1%) placebo, OR of 0.86 (95% CI 0.72 to 1.03, P = 0.11). Cardiogenic shock: 983/22961 (4.3%) treatment versus 1043/22891 (4.6%) placebo, OR of 0.94 (95% CI 0.86 to 1.02, P = 0.15). Heart failure: 3033/22961 (13.2%) treatment versus 3093/22891 (13.5%) placebo, OR of 0.97 (95% CI 0.92 to 1.03, P = 0.34). Presumed cardiac rupture: 209/22961 (0.9%) treatment versus 224/22891 (1.0%) placebo, OR of 0.93 (95% CI 0.77 to 1.12, P = 0.45). Ventricular fibrillation: 624/22961 (2.7%) treatment versus 655/22891 (2.9%) placebo, OR of 0.95 (95% CI 0.85 to 1.06, P = 0.35). Other cardiac arrest: 867/22961 (3.8%) treatment versus 913/22891 (8.1%) placebo, OR of 0.94 (95% CI 0.86 to 1.04, P = 0.24). Pulmonary embolism: 32/22961 (0.1%) treatment versus 33/22891 (0.1%) placebo, OR of 0.97 (95% CI 0.59 to 0.91.57, P = 0.03). Safety: Bleeding: Fatal: 73/22961 (0.32%) treatment versus 74/22891 (0.32%) placebo, excess per 1000 (SE) = −0.1 (0.5), P = 0.92. Cerebral: 39/22961 (0.17%) treatment versus 41/22891 (0.18%) placebo. Non-cerebral: 36/22961 (0.16%) treatment versus 37/22891 (0.16%) placebo. Non-fatal: 61/22961 (0.27%) treatment versus 51/22891 (0.22%) placebo, excess per 1000 (SE) = 0.4 (0.5), P = 0.35. Cerebral: 16/22961 (0.07%) treatment versus 15/22891 (0.07%) placebo. Transfused: 46/22961 (0.20%) treatment versus 36/22891 (0.16%) placebo. Any: 134/22961 (0.58%) treatment versus 125/22891 (0.55%) placebo, excess per 1000 (SE) = 0.4 (0.7), P = 0.59. Additional drug therapy during hospital stay: Non-study antiplatelet therapy: 10% patients. Anticoagulation therapy (chiefly heparin): 75%.
Reference number 368
Dargie HJ;
Effect of carvedilol on outcome after myocardial infarction in patients with left-ventricular dysfunction: the CAPRICORN randomised trial.
2001357Lancetpgs 1385 1390
Study Type: Randomised Controlled Trial
Patient Characteristics Inclusion criteria: Confirmed MI occurring within the previous 21 days, aged > 18 years, mean age 63 years (25–90), male and female (27%), LV ejection fraction ≤ 40% (mean directly by 2D electrocardiography radionuclide or contrast ventriculography) or indirectly by wall motion score index ≤ 1.3, concurrent treatment with ACE inhibitor for > 48 h with the dose being stable for > 24 h unless proven intolerance of ACE inhibitors. Exclusion criteria: Continued requirement for IV inotropic therapy or uncontrolled heart failure, ongoing or expected need for b-blockage, complicating clinical conditions including unstable angina, uncorrected significant valve disease, hypotension < 90 mmHg, bradycardia < 60 bpm., uncontrolled hypertension, unstable IDDM, significant pulmonary, hepatic or renal impairment, ongoing therapy with inhaled beta-2 agonists or steroids, rate-limiting calcium channel blockers, antiarrythmics (except amiodarone), immunosuppressive agents, pregnancy, continuing lactation or planned pregnancy, inability or unwillingness to give informed consent.
Intervention Carvediol Up-titration phase to 25 mg. Initial dose 6.25 mg, if tolerated continued on a twice daily basis. If not tolerated, same dose was re-administered 12 h later. If again not tolerated two further attempts to introduce drug were made, but at the lower dose of 3.123 mg. If that dose was not tolerated patients were followed up off study medication. Following successful initial dosing, patient returned to outpatients at 3–10 day intervals for up-titartion to target of 25 mg or maximum dose tolerated. Up-titration phase lasted approximately 4 to 6 weeks and dose of ACE inhibitor was not altered. 975 patients.
Comparisons Placebo: 984 patients.
Study Length Mean follow-up: 1.3 years. Minimum time 3 months.
Outcomes Primary: All cause mortality. Composite of all cause mortality or cardiovascular-cause hospital admission. Secondary: Sudden death. Hospitalization for heart failure.
Funding None listed.
Effect Primary: All cause mortality: Treatment 116/975 (12%) versus placebo 151/984 (15%), hazard ratio 0.77 (95%CI 0.60 to 0.98), P = 0.031. Composite of all cause mortality or cardiovascular- cause hospital admission: Treatment 340/975 (35%) versus placebo 367/984 (37%), hazard ratio 0.92 (95%CI 0.80 to 1.07), P = 0.296. Secondary: Sudden death: Treatment 51/975 (5%) versus placebo 69/984 (7%), hazard ratio 0.74 (95%CI 0.51 to 1.06), P = 0.098. Hospitalization for heart failure: Treatment 118/975 (12%) versus placebo 138/984 (14%), hazard ratio 0.86 (95%CI 0.67 to 1.09), P = 0.215. Other: Cardiovascular-cause mortality: Treatment 104/975 (11%) versus placebo 139/984 (14%), hazard ratio 0.75 (95%CI 0.58 to 0.96), P = 0.024. Death due to heart failure: Treatment 18/975 (2%) versus placebo 30/984 (3%), hazard ratio 0.60 (95%CI 0.33 to 1.07), P = 0.083. Non-fatal MI: Treatment 34/975 (3%) versus placebo 57/984 (6%), hazard ratio 0.59 (95%CI 0.39 to 0.90), P = 0.014. All cause mortality or non-fatal MI: Treatment 139/975 (14%) versus placebo 192/984 (20%). hazard ratio 0.71 (95%CI 0.57 to 0.89), P = 0.002.
Reference number 3755
Freemantle N;Cleland J;Young P;Mason J;Harrison J;
Beta-blockade after myocardial infarction: systematic review and meta regression analysis
1999318BMJpgs 1730 1737
Study Type: Systematic Review
Patient Characteristics Post MI patients. Acute phase, long term therapy.
Intervention β blockers
Comparisons placebo.
Study LengthShort term trials: up to 6 weeks after onset of pain (51 RCTs). Long term trials: 6 weeks to 48 months (31 RCTs).
Outcomes Mortality. Reinfarction.
Funding Not listed.
Effect Short term trials: Overall 3062/29260 died (10.1%). Of the 51 RCTs identified, only 45 observed deaths in either in treatment or placebo groups. The quality of group of trials may be influenced by the small numbers of patients recruited in some of the trials and also the small numbers of deaths. Pooled random effects odds ratio: 0.96 (95%CI 0.85 to 1.08), a 4% reduction in odds of death. Equates to an annual reduction of 0.4 deaths in 100 patients for treatment up to six weeks, not significant (−0.2 to 10). 50 patients would require treatment to avoid one death (100 to ∞). Long term trials: Overall 2415/24975 died (9.7%) in 31 trials. Pooled random effects odds ratio: 0.77 (0.69 to 0.85), a 23% reduction in odds of death. Equates to an annual reduction of 1.2 deaths in 100 patients (0.6 to 1.7), 84 patients would require treatment to avoid one death. For reinfarction (22 trials): annual reduction in reinfarction of 0.9 events in every 100 (0.3 to 1.6), 107 patients would need to be treated to avoid one non-fatal infarction. Predictors of benefit: initial intravenous dose of β blocker on mortality in long term trials. Applying covariate term in the analysis suggested no additional benefit among patients treated in this manner, odds ratio 0.87 (95%CI 0.61 to 1.22). Equally this analysis indicated that there is no reason to delay treatment with a β blocker. Early initiation will lead to a greater period when benefits may be accrued from treatment. Choice of drug: Individually, only four drugs achieved a reduction in the odds of death: Propranolol: OR 0.71 (95%CI 0.59 to 0.85), Timolol: OR 0.59 (95%CI 0.46 to 0.77), Metoprolol: OR 0.80 (95%CI 0.66 to 0.96), Acebutolol: OR 0.49 (95%CI 0.25 to 0.93). Acebutolol is supported by a single moderately sized study (open to considerable measurement error). RCTs including propranolol, timolol and metoprol include 63% of the available evidence on the long term effect of β blockage in post MI patients. Other β blockers that did not show a reduction in odds of death: Atenolol, Labetalol, Oxprenolol, Pindolol, Practolol.
Reference number 3783
Ko DT;Hebert PR;Coffey CS;Sedrakyan A;Curtis JP;Krumholz HM;
Beta-blocker therapy and symptoms of depression, fatigue, and sexual dysfunction
2002288JAMApgs 351 357
Study Type: Systematic Review
Patient Characteristics Post MI patients, RCTs that enrolled ≥ 100 patients and ≥ 6 months of follow-up.
Intervention β blockerrs.
Comparisons Placebo.
Study Length Follow-up range: 6 to 59 months.
Outcomes Adverse effects: Fatigue 10 trials, 17 682 patients. Sexual dysfunction 6 trials, 14 897 patients. Depressive symptoms 7 studies, 10 662 patients.
Funding Not stated.
EffectFatigue: Weighted event rates: β blockers 34% versus placebo 30%., RRI (95%CI) = 15% (2 to 26). Withdrawal because of fatigue: β blockers 1.8% versus placebo 0.5%., RRI (95%CI) = 163% (16 to 494). Sexual dysfunction: Weighted event rates: β blockers 19% versus placebo 17%. RRI (95%CI) = 10% (−4 to 25), not significant. Withdrawal because of sexual dysfunction: β blockers 1.2% versus placebo 0.3%. RRI (95%CI) = 397% (203 to 716). Depressive symptoms: Withdrawal because of depressive symptoms: β blockers 21.7% versus placebo 20.5%. RRI (95%CI) = 12% (−11 to 41), not significant.

From: Appendix C, Clinical Evidence Extractions

Cover of Post Myocardial Infarction
Post Myocardial Infarction: Secondary Prevention in Primary and Secondary Care for Patients Following a Myocardial Infarction [Internet].
NICE Clinical Guidelines, No. 48.
National Collaborating Centre for Primary Care (UK).
Copyright © 2007, National Collaborating Centre for Primary Care.

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