Evidence Table 7

Randomized controlled trials of beta blockers for post myocardial infarction

Author,
Year
Country
Study designEligibility criteriaExclusion criteriaInterventions (drug, regimen, duration)Allowed other medications/interventionsMethod of outcome assessment and timing of assessmentAge
Gender
Ethnicity
Other population characteristics (diagnosis, etc)Number screened/eligible/enrolledNumber withdrawn/lost to fu/analyzedOutcomesMethod of adverse effects assessment?Adverse effects reportedWithdrawals due to adverse events (%, adverse n/enrolled n)Comments
Head-to-head controlled trials
Wilcox 1980
UK

Fair quality
RCTClinical diagnosis of suspected MI within the previous 24 hoursAlready taking a beta blocker; severe heart failure; sinus bradycardia of under 40 beats per minute; in second or third degree heart block; systolic BP of >90 mm Hg; history of asthma or diabetes; residence too far away.Propranolol (pro) 120–160 mg daily
Atenolol (ate) 100 mg daily
Placebo x one year

Treatment initiated within 24 hours post-MI
NRClinic visits at 3-month intervals
Cause of death was established from hospital and general practitioners' records and from postmortem reports
Mean age(% patients)
<35 yrs: pro=3.8; ate=3.9; pla=2.3
−45 yrs: pro=12.9; ate=10.2; pla=16.3
−55 yrs: pro=33.3; ate=35.4; pla=31.0
−65 yrs: pro=32.6; ate=27.6; pla=31.0
> 65 yrs: pro=17.4; ate=22.8; pla=19.4
% male: Pro=84%; Ate=89%; Pla=81%
Race: NR
Hypertension: Pro=11%; Ate=10%; Pla=15%
Angina: Pro=27%; Ate=31%; Pla=24%
Infarction: Pro=21%; Ate=16%; Pla=19%
Drugs being taken for cardiovascular system: Pro=14%;
Ate=14%; Pla=20%
Drugs taken for other purposes: Pro=14%; Ate=14%; Pla=11%
662 screened/388 eligible/388 randomizedWithdrawn=171(44. 1%)
/lost to fu NR
/analyzed=388
Mortality
At 6 weeks: pro=10(7.5%); ate=11(8,6%); pla=15(11.6%)
At 1 year: pro=17(12.9%); ate=19(14.9%); pla=19(14.7%)
Side effects separately recorded as either volunteered or elicitedNRWithdrawals due to(# pts/%):
Hypotension: pro=14(10.6%); ate=18(14.2%);
pla=2(1.6%)
Bradycardia: pro=8(6.1%); ate=9(7.1%); pla=3(2.3%)
2nd degree heart block: pro=3(2.3%); ate=1(0.8%);
pla=2(1.6%)
3rd degree heart block: pro=1(0.7%); ate=4(3.1%);
pla=2(1.6%)
Heart failure: pro=7(5.3%); ate=3(2.4%); pla=8(6.2%)
Asthma: pro=1(0.7%); ate=0; pla=0
Other: pro=10(7.5%); ate=16(12.6%); pla=23(17.8%)
Jonsson 2005
Norway
Open RCTAge 18–80 w/chest pain for more than 30 mins consistent with acute MI if admitted to hospital w/in 24hrs after onset with diagnosis confimred by significant increase in cardiac enzymes with or without EKG changes.Use of beta blockers during 3 mos preceding trial, history of cardiomyopathy, myopericarditis, cardiac surgery (w/in 1 mo of trial), bradycardia, hypotension, AV block grade 2–3, severe COPD, hemodynamically significant valvular defects including aortic stenosis, SBP <100 or >220 mmHg or DBP >120 mmgHg, Killip class 4 shock or heart failure, renal failure w/serum creatinine >160 mmol/L, hepatic impairment or platelet count <100,000 or white cell count <2000. Patients <18 or >80 yrs also excluded as were patients with any routine regulatory reason (participating in another study, drug contraindication, risk of teratogen effect, alcohol or drug abuse, psychatric disorder, serious concomitant disease , cancer or inability to give consent.)atenolol 12.5mg bid titrated to 50mg
bid by 6 wks
carvedilol 6.25mg bid titrated to 25mg bid by 6 wks
Statins
Aspirin
Warfarin
Diuretics
ACE inhibitor/ARB
Hospital and clinic assessments weekly weeks 1–6; clinic assessment month 3 and 12

CV endpoints evaluated by investigators and controlled by blinded endpoint committee
Carvedilol
59.5 (SD 11.2) yrs
85% male
93% white

Atenolol
61.7 (SD 11.4) yrs
71% male
93% white
Previous MI: Car=6%; Ate=6%
Angina: Car=55%; Ate=54%
Hypertension: Car=20%; Ate=19%
Hyperlipidemia: Car=9%; Ate=11%

Additional medications:
aspirin: Car 89%; Ate 95% (P=0.044)
warfarin + aspirin: Car 7%; Ate 1% (P=0.022)
diuretics: Car 8%; Ate 21% (P=0.004)
NSD between groups for use of warfarin (4% both groups), ACE
inhibitors/ARBs (27;33%) or statins (97%; 98%)
nr/nr/23211/nr/232 (safety analysis; unclear if this is the same for efficacy analysis)CV events
Time to first serious CV event - unadjusted analysis
Car vs Ate RR 0.88 (95% CI -.59 to 1.30; P=0.524)
Adujsted for diuretic use
Car vs Ate RR 1.0 (95% CI 0.6 to 1.5; P=0.990)

LVEF at 12 mos
Car 57.1%; Ate 56.0% (P=NS)
Clinical exams and information on all AEs registered at every visitNo serious AEs reported


Cold hands/feet: Car 20%; Ate 33.3% (P=0.025)
Other AEs: NSD between groups for the following: dizziness, dyspnea, fatigue, muscle pain, flatulence, insomnia, atrial fibrillation, depression, nausea, coughing, ancle edema, anxity, impotence, nightmare occurrence, hyperhydrosis, constipation, diarrhea, skin reaction, dyspepsia
NR
Mrdovic 2007RCTConsecutive patients who presented with clinical and electrocardiographic signs of acute anterior wall ST elevation myocardial infarction (STEMI) and LV EF of ≤45% on the echocardiogram performed within the first 72 hrs from the onset of symptoms.Contradictions for beta blocker therapy including Killip class 3 or 4 heart failure, systolic arterial hypotension of <90 mm Hg, bradycardia of <50 beats per minute, second- or third-degree atrioventricular block, chronic obstructive pulmonary disease requiring bronchodilation therapy, and peripheral arterial disease with symptoms at rest. Also excluded were those already treated with adrenergic blockers or agonists or calcium-channel blockers.Inhospital:
metoprolol tartrate 50 mg bid
carvedilol 12.5 mg bid
Postdischarge:
metopolol tartrate 100 mg bid
carvedilol 25 mg bid
Carvedilol vs. Metoprolol
Concomitant therapy:
streptokinase 65.8% vs. 60.0%
asprin 89.7% vs. 89.9%
intravenous metropolol 23.2% vs.
25.9%
digitalis 18.1% vs. 25.3%
diuretics 40% vs. 44.3%
inotropes 5.2% vs. 10.1%
statins 51.6% vs. 48.1%
ace inhibitors 98.7% vs. 99.3%
Patients were reviewed at 6-month intervals for the assessment of tolerability and adverse cardiac events. Follow-up period continued until 233 primary endpoints were reached.
Primary end point: fime to first composite cardiac adverse event (t-CAE) including all-cause mortality; rehospitalization for cardiovascular event; revascularization with percutaneous coronary intervention or bypass surgery; postinfarction angina pectoris with documented electorcardiopraphic signs of ischemia; and heart failure requiring additional treatment with digitalis, diuretics, or inotropic agents.
Secondary end point: time to composite hard events (t-CHE) including cardiovascular death and nonfatal reinfarction.
Health related quality of life:
Short Form-36 (SF-36) questionnaire with 36 items and 8 domains. Each group of domains was reduced to a summary measure.
Carvedilol
60.5 (SD 10.4) yrs
70% male
Ethnicity NR

Metoprolol
62.9 (SD 10.5) yrs
69% male
Ethnicity NR
Diabetes Car= 26.5%; Met=27.1% (P=0.97)
Hypertension Car=63.9%; Met=67.1% (P=0.34)
Hyperlipidemia Car=55.5%; Met=44.3% (P=0.037)
493/318/313Withdrawn:
Inhospital - car.=8;
met.=22 (P=0.011)
During follow up -
car.=10; met.=16
(P=0.22)
Lost to fu: car.=7;
met.=0
Analysed: car.=155;
met.=158
Carvedilol vs. metoprolol
Primary end point:
time to first composite cardiac adverse event (t-CAE)
all-cause death 8 (5.4%) vs. 14 (9.8%) P=0.21
postinfarction angina 29 (19.6%) vs. 39 (27.3%) P=0.16
HF 20 (13.5%) vs. 28 (19.6%) P=.21
rehospitalizatoin 11 (7.4%) vs. 17 (11.9%) P=0.23
revascularization 30 (20.3) vs. 37 (25.9%) P=0.33

Secondary end point:
time to composite hard events (t-CHE)
cardiovascular death 7 (4.7%) vs. 12 (8.4%) P=0.26
nonfatal reinfarction 9 (6.1%) vs. 12 (8.4%) P=0.47

Health-related quality of life (HRQL) (adjusted for age and baseline differences)
general health 54 (SD 9) vs 50 (SD 14) P=0.037
physical functioning 70 (SD 22) vs. 62 (SD 23) P=0.011
role physical 68 (SD 30) vs. 60 (SD 28) P=0.058
vitality 58 (SD 23) vs. 50 (SD 23) P=0.008
social functioning 77 (SD 27) vs. 70 (SD 26) P=0.036
role emotional 85 (SD 24) vs. 80 (SD 28) P=0.13
mental health 56 (SD 18) vs. 51 P=0.035
bodily pain 91 (SD 19) vs. 88 (SD 21) P=0.32
PCS 52 (SE 4) vs. 51 (SE 4) P=0.086
MCS 53 (SE 4) vs. 52 (SE 5) P=0.16
Patients were reviewed at 6-month intervals for tolerability and adverse cardiac events.Only patients who were withdrawn from the study due to an AE are included.

carvedilol vs. metoprolol

In hospital:
8 vs. 22
total sample: progression of HF (n=19)
hypotension (n=5)
second or third degree atrioventricular block (n=5)
bronchial obstruction (n=1) (OR car. 0.98, CI 0.14–0.63, P=0.011)

During follow-up:
10 vs. 16 were withdrawn because of adverse effects or clinical deterioration (OR 0.59, CI 0.26–1.36, P=0.22).
Inhospital: car=8 (5%) vs. met.=22 (14%)
total sample: HF n=19
hypotension n=5
second- or thrid-degree atrioventricular block n=5
bronchial obstruction n=5
Follow up:
car=10 (6%) vs. met.=16 (10%)
Total number of withdrawls
car=18 (12%) vs. met=36 (23%) (OR for carvedilol .39, CI 0.21–0.73, P=0.003)
Acebutolol vs placebo
Boissel
1990
France

Fair quality
RCTAt least 2 of the following risk factors:
(1) Typical chest pain of ≥ 1 hour in duration, typical Q waves and significant release of cardiac enzyme(s)
(2) admitted for this acute event > 2 and < 22 days before
(3) presented ≥ 7 of the secondary risk factors of the selection algorithm, including ≥ 1 "major" secondary risk factor (history of dyspnea when walking on flat ground, documented atrial fibrillation, ventricular fibrillation, ventricular tachycardia, overt heart failure or sinusal tachycardia during the reference event, recurrent AMI or angina pectoris before the eighth day)
Heart rate <45 beats/min; complete auriculoventricular block and acute heart failure that required treatment with ≥ 2 drugs of different classes (e.g., diuretics and vasodilators); contraindication to beta blocking treatment; age > 75 years; death; malignancy; valvular disease; coma; asthma; chronic bronchopneumopathy; Raynaud syndrome; participation in another study; patients enrolled in APSI beforeAcebutolol 400 mg daily
Placebo x 1 year

Treatment initiated within 2–22 days
post-MI
NRPrimary outcome: Total deathMean age=62.9 years
73% male
Ethnicity nr
Angina pectoris=41.5%
Unstable angina=28.9%
Congestive heart failure=27.1%
Renal failure=3.6%
Diabetes mellitus=14.6%
Cigarette smoker (actual or past)=65.5%
Systemic hypertension=32.9%
Atrial flutter or fibrillation=13.5%
Ventricular flutter or fibrillation=5%
Number of secondary risk factors (median)=8
nr/nr/607Withdrawn=211 (34.8%)
/0 lost to fu
/analyzed=607
Acebutolol (n=298) vs placebo (n=309)
Total mortality: 17 (5.7%) vs 34 (11%); P=0.019
Vascular death: 12 (4%) vs 30 (9.7%); P=0.006
Reinfarction: 6 (2%) vs 4 (1.3%); P=NS
Fatal or nonfatal reinfarction: 9 (3%) vs 11 (3.6%); P=NS
Acute pulmonary edema: 20 (6.7%) vs 15 (4.9%); P=NS
Fatal or non-fatal cardiac failure: 22 (7.4%) vs 22 (7.1%); P=NS
Ventricular flutter or ventricular fibrillation: 1 (0.3%) vs 0; P=NS
Ventricular flutter, ventricular fibrillation, or fatal arrhythmia: 0 vs 3 (1%); P=NS
Other vascular events: 35 (11.7%) vs 28 (9.1%); P=NS
Other nonvascular events: 51 (17.1%) vs 70 (22.7%); P=NS
nrAcebutolol (n=298) vs placebo (n=309)


Angina pectoris: 98 (32.9%) vs 92 (29.8%); P=NS
Heart failure: 137 (46%) vs 105 (34%); P=0.003
Conduction or rhythm disturbance: 102 (34.2%) vs 101 (32.7%); P=NS
Sinus bradycardia: 48 (16.1%) vs 16 (5.2%); P<0.001
Sinus tachycardia: 8 (2.7%) vs 26 (8.4%); P=0.002
Atrioventricular block: 17 (5.7%) vs 15 (4.9%); P=NS
Right bundle branch: 11 (3.7%) vs 16 (5.2%); P=NS
Left bundle branch: 4 (1.3%) vs 7 (2.3%); P=NS
Flutter or atrial fibrillation: 16 (5.4%) vs 12 (3.9%); P=NS
Extrasystola or ventricular tachycardia: 16 (5.4%) vs 26 (8.4%); P=NS
Other arrhythmia: 24 (8.1%) vs 29 (9.4%); P=NS
Acebutolol (n=298) vs placebo (n=309)

Withdrawals due to adverse events: 12 (4%) vs 11 (3.5%); P=NS
Carvedilol vs placebo
Basu
1997
UK

Fair quality
RCTChest pain; ECG changes; serum concentration of creatine kinase; MB isoform consistent with diagnosisAlready on ACE or beta blockers; contraindications to ACE or beta blockers; Killip class IV heart failure; cardiogenic shock; severe bradycardia; hypotension; second to third degree heart block; left bundle branch block; severe valvular disease; insulin-dependent DM; renal failure; known malignancy; other severe disease; pregnancyCarvedilol (car) 2.5–50 mg daily
Placebo (pla) x 6 months

Initial dose loaded intravenously
Aspirin - 100%
Heparin - 97%
Oral/iv nitrates - 97%
Patients were reviewed at 3-month intervals

Exercise test (Bruce protocol)

Endpoints: cardiac death, reinfarction, unstable angina, heart failure, emergency coronary revascularization, ventricular arrhythmias requiring intervention, cerebra vascular accident and initiation of additional cardiovascular drug therapy other than sublingual nitrates for angina
Mean age: car=60; pla=60
% male: car=84; pal=84.5
Race: NR
Site of MI:
Anterior - Car=51%; Pla=49%
Inferior - Car=49%; Pla=51%
Type of MI:
Q-wave - Car=80%; Pla=80%
Non-Q-wave - Car=20%; Pla=20%
Heart failure at entry (Killip II/III): Car=45%; Pla=28%
Thrombolysed: Car=99%; Pla=96%
Median time to thrombolysis: Car=3.8 hours; Pla=3.9 hours
Smoker: Car=67%; Pla=53.5%
Non-smoker: Car=33%; Pla=46%
Previous IHD: Car=20%; Pla=25%
NIDDM: Car=12%; Pla=18%
Median time to infusion: Car=16.8 hours; Pla=16.7 hours
416
screened/NR/151
enrolled
146 analyzed(car=75; pla=71)Serious cardiac events: car=18(24%); pla=31(43.7%)
Deaths/reinfarctions: car=11(14.7%); pla=6(8.4%)
NRDizziness(% patients): car=6.5%; pla=1.4%Withdrawals due to non-cardiac adverse events(#pts): car=4(5.3%); pla=3(4.2%)
Anonymous, 2001;
McMurray 2005
International
RCT

Carvedilol Post-
Infarct Survival
Control in LV
Dysfunction (CAPRICORN)

Fair quality
RCT>18 years; stable, definite MI occurring3–21 days prior to randomization; left-ventricular ejection fraction of 40% or less; receipt of concurrent treatment with ACE inhibitors for at least 48 hours and stable dose for 24+ hours unless proven intolerance to ACE inhibitors; heart failure appropriately treated with diuretics and ACE inhibitors during acute phaseRequired continued diuretics or inotropes; uncontrollable heart failure; unstable angina; uncontrolled hypertension; bradycardia; unstable insulin-dependent DM; continuing indication for beta blockers for any condition other than heart failure; requiring ongoing therapy with inhaled beta agonists or steroidsCarvedilol (car) up to 50 mg daily Placebo (pla) x 1.3 years (mean) of follow-upACE inhibitors(% patients)=98
Reperfusion therapy(% patients)=46
Patients were reviewed every 3 months during the first year, and every 4 months thereafterCarvedilol:
Mean age 63
73% male
Placebo:
Mean age 63
74% male
Smoking history:
Current - Car=33%; Pla=32%
Previous - Car=27%; Pla=25%
Never - Car=39%; Pla=43%
Medical history:
Previous MI - Car=31%; Pla=29%
Previous angina - Car=57%; Pla=54%
Previous hypertension - Car=55%; Pla=52%
Previous DM - Car=21%; Pla=23%
Other vascular disease - Car=17%; Pla=16%
Previous revascularization - Car=12%; Pla=11%
Hyperlipidemia - Car=32%; Pla=33%
SIte of MI:
Anterior - Car=59%; Pla=54%
Inferior - Car=21%; Pla=21%
Other - Car=20%; Pla=25%
Medications at time of randomization:
ACE inhibitor - Car=98%; Pla=97%
Aspirin - Car=86%; Pla=86%
NR/NR/1959 randomizedPermanent withdrawals(excluding death):
car=192(20%);
pla=175(18%)/lost to fu nr/1959 analyzed
Co-primary endpoints(# patients/%)
All-cause mortality: car=116(12%); pla=151(15%) (P=0.031)
All-cause mortality or cardiovascular-cause hospital admission:
car=340(35%); pla=367(37%) (NS)

Secondary endpoints(# patients/%)
Sudden death: car=51(5%); pla=69(7%) (NS)
Hospital admission for heart failure: car=118(12%); pla=138(14%) (NS)

Other endpoints(# patients/%)
Cardiovascular-cause mortality: car=104(11%); pla=139(14%) (P=0.024)
Death due to heart failure: car=18(2%); pla=30(3%) (NS)
Non-fatal MI: car=34(3%); pla=57(6%) (NS)
All-cause mortality or non-fatal MI: car=139(14%); pla=192(20%) (P=0.002)
Atrial fibrillation/flutter: car=2.3%; plac=5.4%; HR 0.41 (95% CI 0.25–0.68; P=0.0003)
Ventricular fibrillation/flutter/tachycardia: car=0.9%; pla=3.9%; HR 0.24 (95% CI 0.11–0.49; P<0.0001)
Cardiac arrest in first 30 days of the trial: car=0.5%; pla=0.7%; HR 0.72 (95% CI 0.23–2.25; P=0.56)
Composite endpoint in first 30 days (all cause mortality, nonfatal MI, or cardiac arrest)
Car=31, 3.2%; pla 53, 5.4%; HR 0.58, 95% CI 0.38–0.91, P=0.02)
NRNRNR
First 30 days of the trial:
car=2.4%; pla=2.6% (NS)
Original primary endpoint (all- cause mortality) amended during the trial to co-primary endpoints of all-cause mortality (alpha=0.005) and all-cause mortality+cardiovascular hospitalization(alpha=0.045) apparently due to advice by Data Safety Monitoring Board (DSMB) that a blinded interim analysis had shown that power to detect pre-specified total mortality effect size was under threat
Metoprolol vs placebo
Anonymous
1987
USA

Lopressor Intervention Trial

Fair quality
RCTAges 45–74; hospitalized for acute MIHistory of CABG; permanent pacemaker; contraindication to beta blocker therapy; conditions likely to require beta blocker therapy; administration of any beta blocker within 3 days before the start of pre-entry evaluation; planned therapy with aspirin, sulfinpyrazone clofibrate;=, or dipyridamole; life threatening conditions other than CHF; conditions likely to affect protocol compliance; history of adverse reaction to metoprolol or its analogues.Metoprolol (met) 200 mg daily
Placebo (pla) x 1 year

Treatment interval: 5–15 days post-MI
Interim visits conducted at 1, 3, 7 and 12 monthsMean age = 58
% Male = 83%
% White = 90.5%
Previous medical history:
MI = 14.5%
Angina = 25%
CHF = 2%
Hypertension = 36%
Diabetes = 7.5%
Location of infarct:
Anterior = 50.3%
Inferior = 56%
Anterior & inferior = 2%
High lateral = 2.5%
True subendocardial = 2.5%
NR/NR/2395 enrolledWithdrawn:
met=381(31.9%);
pla=355(29.6%)/los
t to fu
NR/analyzed=2395
Total mortality (# patients/%)
</= 90 days: met=23(1.9%); pla=37(3.1%)
</= 210 days: met=42(3.5%); pla=54(4.5%)
</= 365 days: met=65(5.4%); pla=62(5.2%)
</= 540 days: met=86(7.2%); pla=93(9.8%)
NROverall incidence: met=34.6%; pla=23.8%

Incidence of (%):
Body as a whole: met=9.1; pla=6.2
Cardiovascular: met=17.2; pla=9.6
Digestive: met=4.3; pla=3.3
Endocrine: met=0; pla=0
Haemic/lymphatic: met=0.2; pla=0.2
Metabolic/nutritional: met=1.2; pla=0.5
Musculoskeletal: met=0.3; pla=0.4
Nervous system: met=8.7; pla=7.7
Respiratory: met=4.1; pla=2.7
Skin/appendages: met=1.3; pla=1.5
Special senses: met=2.8; pla=1.3
Urogenital system: met=1.6; pla=1.0
Overall withdrawal due to adverse events(%):
met=13.1; pla=5.8
Hjalmarson, 1981
Herlitz, 1984
Herlitz, 1997
Sweden

Goteborg Metoprolol Trial

Good quality
RCTGeographic location; chest pain of acute onset and 30 minutes’ duration or ECG signs of acute MI with estimated onset of infarction within previous 48 hours; age 40–74;Contraindications to beta blockade; need for beta blockade; administrative considerationsMetoprolol (met) 15 mg intravenously; 200 mg orally
Placebo (pla)

Treatment interval(mean): 11.3 hours
Initial dose loaded intravenously (3 injections); then administered orally x 3 months
Arrhythmias: iv lidocaine or procainamide
CHF: furosemide 40–80 mg iv, then oral
Chest pain: iv morphine; sl ntg; oral anticoagulants
Physician examination at 1-week and 3 months after inclusionEntire sample:
Mean age: met=60; pla=60
% male: met=75.6; pla=76.2
Race nr

Subgroup of patients with indirect signs of mild-to-moderate CHF (met n=131; pla n=131)
Mean age: met=63; pla=63
% male: met=75; pla=76
Race nr
Clinical history:
Previous infarction - Met=21.2%; Pla=22.7%
Angina pectoris - Met=35.7%; Pla=34.7%
Hypertension - Met=29.1%; Pla=29.7%
Smoking - Met=49.7%; Pla=50.3%
Clinical status at entry:
Pulmonary rales (24) - Met=11.6%; Pla=9%
ECG signs of infarction (1) - Met=49.9%; Pla=47.8%
Heart rate >100 beats/minute (1) - Met=4.7%; Pla=6.2%
Systolic BP <100 mm Hg (2) - Met=3.3%; Pla=4.4%
Dyspnea at onset of pain (29) - Met=28.8%; Pla=30.8%
2802
screened/2619
eligible/1395
randomized (met n=698; pla n=697)
Withdrawn:
met=131(19.1%);
pla=131(19.1%)/los
t to fu NR
/1395 analyzed
Entire sample:
Mortality: met=40/698(5.7%); pla=62/697(8.9%); Odds ratio=0.62(95% CI 0.40–0.96)
Reinfarction: met=35/698(5%); pla=54/697(7.7%); Odds ratio=0.63(95% CI 0.39–0.99)

Subgroup with mild-to-moderate CHF:
Mortality: met=13/131(10%); pla=25/131(19%); Odds ratio=0.47(95% CI 0.21–1.0); P=0.036
Reinfarction: met=9/131(7%); pla=10/131(8%); NS
NRNRWithdrawals due to overall adverse events:
met=22(3.2%); pla=22(3.2%)

Withdrawals due to(# pts/%):
Hypotension: met=29(4.2%); pla=13(1.9%) (P=0.018)
Bradycardia: met=18(2.6%); pla=5(0.7%) (P=0.011)
Heart failure: met=4(0.6%); pla=7(1.0%) (NS)
Olsson, 1985

Stockholm Metoprolol Trial

Fair quality
RCTResidence within catchment area; admission to coronary care unit within 48 hours from onset of symptoms and development of acute MI; sinus rhythm without complete bundle branch block.Systolic BP <100 mm Hg; sever cardiac failure not responding to digitalis or diuretics; severe intermittent claudication; obstructive pulmonary disease; need for beta-adrenoceptor blockade; other major disease; unwillingness to participate.Metoprolol (met) 200 mg daily
Placebo (pla) x 36 months

Treatment interval: 48 hours post-MI
Angina: non-beta-andrenergic blocking antianginal agentsInterim visits conducted every 3 monthsMean age: met=60; pla=59
% male: met=78; pla=83
Race = NR
Smokers: Met=53%; pla=60%
Ex-smokers: Met=19%; Pla= 18%
Previous MI: Met=24.5%; Pla=26.5%
DM before MI: Met=10%; Pla=6%
Cerebrovascular incidence before MI: Met=5%; Pla=3%
Site of infarction:
Anterior: Met=44%; Pla=51%
Inferior: Met=38%; Pla=31%
Unknown: Met=18%; Pla=18%
Previous MI = 26.75%
Hypertension = 11.5 %
Smoking habit = 47%
Previous history of angina = 46.25%
Previous history of dyspnoea = 28.38%
Initial ventricular ectopic activity = 22.88%
Initial supraventricular ectopic activity = 5%
nr/nr/30173(24.2%)
withdrawn/lost to fu nr/301 analyzed
Sample size: met n=154; pla n=147
Total mortality (# patients/%): pla=31(21.1%); met=25(16.2%) (NS)
Cardiac mortality (# patients/%): pla=29(19.7%); met=20(13.0%) (NS)
Sudden death (# patients/%): pla=21(14.3%0; met=9(5.9%) (P<0.05)
Reinfarction (# patients/%): pla=31(21.1%); met=18(11.7%) (P<0.05)
NRNRWithdrawals due to (# patients/%):
Uncontrolled angina: pla=16(10.9%); met=6(3.9%) (P<0.05)
Heart failure: pla=1(0.7%); met=7(4.5%) (P<0.05)
Symptomatic bradycardia: pla=1(0.7%); met=1(0.6%) (NS)
Hypotension: pla=0; met=2(1.3%)
Salathia
1985
Northern Ireland

Belfast Metoprolol Trial

Fair quality
RCTAdmission to CCU at Ulster HospitalDelay from onset of pain exceeded 6 hours; initial rhythm VF; initial rhythm agonal; systolic BP >90 mm Hg associated with heart rate <100 beats min- 1; clinical pulmonary edema or CHF; sinus or junctional bradycardia (<60 min-1), with systolic BP >90 mmHg and not responding to patient’s legs elevated; received a beta-adrenergic blocking drug or a type I antiarrhythmic drug during previous 48 hours; atrio-ventricular block greater than first degree; previous admission to the study.Metoprolol (met) 15 mg iv, followed by 200 mg oral daily dosage
Placebo (pla) x 1 year

Treatment interval: 48 hours post-MI
NRNRAge ≤65 = 548
>65 = 252
% Male 71.5%
Race: NR
1556
screened/800
eligible/800
enrolled
Withdrawn nr/lost to fu nr/800 analyzedTotal mortality (# patients/%)
At 3 months: met=37/416(8.9%); pla=35/384(9.1%)(NS)
At one year: met=52/416(12.5%); pla=53/384(13.8%)(NS)

Sudden death (# patients/%)
At 3 months: met=4/416(1.0%); pla=3/384(2.1%)(NS)
At one year: met=8/416(1.9%); pla=18/384(4.7%) (P<0.05)
NR# patients (%)
Hypotension: met=20/416(4.8%); pla=14/384(3.6%) (NS)
Heart failure: met=47/414(11.4%); 35/378(9.3%) (NS)
NR
Pindolol vs placebo
Australian & Swedish Study
1983
Australia, Sweden

Fair quality
RCTClinical diagnosis of acute MI within previous 21 days; had to meet 2 of the following criteria: retrosternal severe chest pain of 20+ minutes duration, resistant to nitroglycerine and startinh in previous 48 hours; pulmonary edema without previously known valvular disease; shock without suspicion of acute hypovolaemia or intoxication; transient elevation of glutamine oxaloaecetic acid transminase or asptarate amino transferase in serum to values exceeding the normal limits for the laboratory on at least 2 readings with a maximum approximately 24 hours after the estimated onset of infarction, coupled with absent or less pronounced elevation of glutamine pyruvic acid transaminase or alinine amino transferase in serum; ECG series with presence of Q waves and/or presence of the disappearance of localized ST-elevation combined with development of T-inversion in at least 2 of the routine 12 leads; clinical course complicated by electrical and/or mechanical complications.Uncontrolled heart failure; unrelated heart disease; persistent heart block of second or third degree; persistent bradycardia <50 beats/minute; obstructive airways disease; uncontrollable insulin dependent diabetes; known hypersensitivity to beta blocking drugs; other diseases serious enough to worsen the short-term prognosis irrespectively of the MI; pregnancy; necessity to use beta blocking drug or calcium antagonists; unable to return for regular control.Pindolol (pin) 15–20 mg daily
Placebo (pla) x 24 months

Treatment interval: up to 21 days post-MI
NRFollow-up visits: months 1, 3, 6, 12, 18 and 24

Primary endpoint: death
Mean Age:Pin=58; Pla=58
% male: Pin=83; Pla=83
Australian: Pin=48%; Pla=48%
Swedish: Pin=52%; Pla=51.5%
History:
Smoking: Pin=48%; Pla=43%
Hypertension: Pin=24%; Pla=28% (values indicated are those with a 10% or greater variation between patients randomized to pin. or pla.)
Angina pectoris: Pin=36%; Pla=32%
Functional limitation: Pin=30%; Pla=30%
Prior MI: Pin=18%; Pla=16%
Diabetes: Pin=5%; Pla=8% (values indicated are those with a 10% or greater variation between patients randomized to pin. or pla.)
Anterior or lateral infarction: Pin=47%; Pla=46%
Other site of infarction: Pin=53%; Pla=54%
Medication used at time of randomization:
Digitalis: Pin=31%; Pla=34%
Diuretics: 74%; Pla=75%
Vasodilators (nitrates): Pin=23%; Pla=22%
Antiarrhythmics: Pin=54%; Pla=51%
Anticoagulants: Pin=72%; Pla=71%
Medication used at time of discharge:
Digitalis: Pin=31%; Pla=32%
Diuretics: Pi46%; Pla=42%
Nitrates: Pin=39%; Pla=35%
2500
screened/529
eligible/529
enrolled
126(23.8%) withdrawn/lost to fu nr/529 analyzed (pin n=263; pla n=266)(# patients/%)
Total mortality: pla=47(17.7%); pin=45(17.1%) (NS)
Cardiac death: pla=43(16.2%); pin=40(15.2%) (NS)
Cardiac sudden death: pla=31(11.7%); pin=28(10.6%) (NS)
Non-cardiac death: pla=4(1.5%); pin=5(1.9%)
NROverall incidence: pin=89(33.8%); pla=45(16.8%)
(P=0.0001)
Withdrawals due to adverse events (# patients/%):
pin=50(19%); pin=22(8.3%) (P=0.0003)

Withdrawals due to:
Cardiac failure: pin=20(7.6%); pla=11(4.1%)
Hypotension: pin=3(1.1%); pla=1(0.4%)
Reinfarction: pin=1(0.4%); pla=3(1.1%)
Propranolol vs placebo
Roberts, 1984
Rude, 1986
Roberts, 1988
United States

Multicenter
Investigation of the
Limitation of Infarct
Size (MILIS)

Fair-poor quality
RCT
Single- blind
Age <76; history of at least 30 minutes of ischemic pain within 18 hours of potential therapy; new or presumably new ECG changesCardiogenic shock; advanced cardiac or other disease that would interfere with prognosis; participation in conflicting protocol; inability to participate because of geographical or psychological reasons; recent major surgery or MI; permanent cardiac pacemaker; previous participation in the protocol; failure or inability to give informed consentPropranolol (pro): initial dose infused intravenously (0.1 mg per kg of body weight); subsequent oral dosing initiated at 20 mg and increased with an HR target of 45–60
BPM
Placebo (pla) x 7 days
NRFollow-up visits: months 3 and 6
Telephone vital status interview: 6-month intervals thereafter
Mean age: pro=54.9; pla=54.6
% male: pro=72.4; pla=74.1
% white: pro=82.1; pla=83.7
Mean age = 54.7
Male = 73.2%
White = 83%
Current smokers = 50%
White collar workers = 39%
High school or higher education = 61.3%
Regular drinkers = 22%
Medical history before recent infarction:
Hypertension requiring medication = 44%
Documented previous infarction = 14.5%
Angina >3 weeks before recent infarction = 39%
CHF in previous 3 weeks = 5%
Diabetes = 19%
Previous cardiac arrest = 0.7%
Previous cardiac surgery = 5%
Previous cardiac arrythmias = 7%
Screened=7597/Eligible=2408/Eligible after application of exclusion criteria=1589/Eligible for Group A (no contraindications to beta blocker therapy)=879 (pron=134; pla n=135; hyaluronidase=131)Overall patient withdrawals nr/lost to fu=1(treatment group nr)/analyzed=269Mortality(after 36-months of follow-up): pro=24/134(17.9%); pla=20/135(14.8%)

Treatment period=10 days

Beta blockade at 3 months(% pts): pla=37%; pro=53%
Beta blockade at 6 months(% pts): pla=40; pro=54
NRCardiac failure (%): pla=23; pro=19NR
Anonymous, 1982
Goldstein, 1983
Anonymous, 1983
Lichstein, 1983
Furberg, 1984
Jafri, 1987
United States

Beta-blocker Heart Attack Trial (BHAT)

Fair quality
RCTMen and women aged 30–69; hospitalized with symptoms and ECG and enzymatic changes compatible with acute MIChronic obstructive lung disease; severe CHF; bradycardia; life-threatening illness other than CHF; need for beta blocking drugsPropranolol (pro) 180 mg (82% of patients) or 240 mg (18% of patients) (n=1916) Placebo (pla) (n=1921)

Treatment initiated 5–21 days post-MI
% patients
Vasodilator: pro=47.8; pla=47.1
Diuretic: pro=40.8; pla=42.3
Tranquilizer: pro=28.0; pla=30.4
Digitalis: pro=26.9; pla=26.3
Aspirin: pro=21.5; pla=21.6
Antiarrhythmic: pro=20.7; pla=25.6
Potassium: pro=16.3; pla=17.7
Antihypertensive, excluding diuretic:
pro=11.8; pla=13.4
Anticoagulant: pro=9.8; pla=8.5
Dipyridamole: pro=6.2; pla=5.5
Insulin: pro=4.8; pla=4.2
Hormonal: pro=4.5; pla=4.4
Oral hypoglycemic: pro=5.5; pla=3.2
Sulfinpyrazone: pro=4.3; pla=5.0
Clinic visits at 3-month intervals

Deaths classified by blinded mortality classification subcommittee (relative/witness report; death certificates; attending physician; hospital records; autopsy)
Propranolol:
Mean age: 54.7
84% male
Placebo:
Mean age: 54.9
85.1% male
Mean systolic BP mm Hg: Pro=112.3; Pla=111.7
Mean diastolic BP mm Hg: Pro=72.5; Pla=72.3
Mean heart rate, beats per minute: Pro=76.2; Pla=75.7
Mean cholesterol, mg/dL: Pro=212.7; Pla=213.6
Mean weight, kg:
Men - Pro=80.2; Pla=79.8
Women - Pro=67.4; Pla=66.5
Current smoker: Pro=57.4%; Pla=56.9%
Medical history:
Prior MI - Pro=13.9%; Pla=13.2%
Hypertension - Pro=41.1%; Pla=40.1%
Angina pectoris - Pro=35.8%; Pla=36.5%
CHF - Pro=9%; Pla=9.4%
DM - Pro=11.7%; Pla=11.3%
Taking propranolol or other beta blocker: Pro=7.2%; Pla=6.8%
In-hospital events occurring before randomization:
Atrial fibrillation - Pro=6.8%; Pla=5.7%
CHF - Pro=14.3%; Pla=14.9%
Vetricular tachycardia - Pro=23%; Pla=23.2%
Use of antiarrhythmic drug - Pro=45.8%; Pla=46%
Medications being used at time of randomization:
Antiarrythmic - Pro=16.6%; Pla=17.9%
Anticoagulant - Pro=13.9%; Pla=15.1%
Antiplatlet - Pro=7.1%; Pla=6.8%
Diuretic - Pro=16.1%; Pla=18%
Vasodilator - Pro=36%; Pla=36.3%
Digitalis - Pro=12.5%; Pla=13%
Oral hypoglycemic - Pro=2.2%; Pla=1.8%
Screened: 16,400
Eligible/enrolled (total=3,837):
pro=1916;
pla=1921
Overall number withdrawn nr/12(0.3%) lost to fu/3837 analyzed (pro n=1916; pla n=1921)NNT; RR (95% CI)

Total mortality: NNT=39; RR=0.73(0.59–0.91)

Deaths due to:
Cardiovascular disease: NNT=44; RR=0.74(0.59–0.93)
Sudden arteriosclerotic heart disease: NNT=78; RR=0.72(0.53–0.99)
Non-sudden arteriosclerotic heart disease: NNT=97; RR=0.73(0.52–1.03)
Other cardiovascular disease:
NNT=1882(harm); RR=1.14(0.43–3.03)
Noncardiovascular disease: NNT=322; RR=0.65(0.31–1.36)
NR% patients with complaints:
Shortness of breath: pro=66.8; pla=65.5
Bronchospasm: pro=31.3; pla=27.0 (P<0.005)
Rapid heartbeat: pro=10.8; pla=15.1 (P<0.001)
Cold hands, feet: pro=10.0; pla=7.7 (P<0.025)
Tiredness: pro=66.8; pla=62.1 (P<0.005)
Reduced sexual activity: pro=43.2; pla=42
Depression: pro=40.7; pla=39.8
Nightmares: pro=39.7; pla=36.9
Faintness: pro=28.7; pla=26.6
Insomnia: pro=21.1; pla=18.8
Blacking out: pro=9.1; pla=10.3
Hallucinations: pro=5.9; pla=4.5
Diarrhea: pro=5.5; pla=3.6 (P<0.01)
% patient withdrawals due to:
CHF: pro=4; pla=3.5 (NS)
Hypotension: pro=1.2; pla=0.3 (P<0.005)
Pulmonary problems: pro=0.9; pla=0.7 (NS)
Sinus bradycardia: pro=0.7; pla=0.3 (NS)
New or extended MI: pro=0.4; pla=0.4 (NS)
Serious ventricular arrhythmia: pro=0.3; pla=1.0 (P<0.025)
Heart block: pro=0.1; pla=0.1 (NS)
Syncope: pro=0.1; pla=0.1 (NS)
Tiredness: pro=1.5; pla=1.0 (NS)
Disorientation: pro=0.6; pla=0.6(NS)
Depression: pro=0.4; pla=0.4 (NS)
Faintness: pro=0.5; pla=0.2 (NS)
Nightmares: pro=0.1; pla=0.2 (NS)
Insomnia: pro=0.2; pla=0.0 (NS)
Reduced sexual activity: pro=0.2; pla=0.0 (P<0.05)
GI problems: pro=1.0; pla=0.3 (P<0.01)
Dermatologic problems: pro=0.3; pla=0.1 (NS)
Cancer: pro=0.2; pla=0.1 (NS)
Hansteen 1982
Norway

Fair quality
RCTMI according to WHO criteria, screened on fourth day after MI, only those with increased risk of death were included.Contraindications to beta blockade; uncontrolled heart failurePropranolol (pro) 160 mg daily
Placebo (pla) x 12 months

Treatment interval: 4–6 days post-MI
NRFollow-up visits: months 2, 6 and 12Mean age: Pro= 58; Pla=58.8
% male: Pro=84.5%; Pla=85.5%
No previous CHD: Pro=51.4%; Pla=48.6%
Angina pectoris: Pro=30.6%; Pla=31.9%
Previous MI: Pro=18%; Pla=19.5%
Hypertension (treated): Pro=22.3%; Pla=18.15
Intermittent claudication: Pro=8.6%; Pla=5.7%
CVD: Pro=3.2%; Pla=2.5%
Drug treatment before admission:
Digitalis: Pro=6.1%; Pla=5.7%
Diuretics: Pro=19.1%; Pla=16%
Other antihypertensives: Pro=7.9%; Pla=6.4%
Daily smoker: Pro=58.3%; Pla=64.9%
Ex-smoker: Pro=28.1%; Pla=24.2%
4929
screened/eligible nr/560 enrolled
Withdrawals:
pro=70(25.2%);
pla=72(25.5%)/lost to fu nr/560 analyzed
pro n=278; pla n=282
# patients/%

Sudden death: pro=11(3.9%); pla=23(8.1%) (P=0.038)
Type 1: pro=9(3.2%); pla=17(6.0%) (NS)
Type 2: pro=1(0.3%); pla=3(1.1%)(NS)
Type 3: pro=1(0.3%); pla=3(1.1%)(NS)
Fatal reinfarction: pro=11(3.9%); pla=10(3.5%) (NS)
Other cardiac deaths: pro=0; pla=2(0.7%)(NS)
Other deaths: pro=3(1.1%); pla=2(0.7%)(NS)
Total deaths: pro=25(8.9%); pla=37(13.1%) (NS)
Total cardiac deaths: pro=22(7.9%); pla=35(12.4%) (NS)
Non-fatal reinfarctions: pro=16(5.7%); pla=21(7.4%) (NS)
Total no of cardiac events: pro=38(13.7%); pla=56(19.8%) (NS)
NROverall incidence(% pts): pro=57; pla=51

Most common adverse events(# pts/%):
Bradycardia: pro=88(31.6%); pla=13(4.6%) (P<0.05)
Heart failure: pro=18(6.5%); pla=25(8.9%)
Hypotension: pla=23(8.2%); pla=9(3.2%) (P<0.05)
Bronchospasm: pro=10(3.6%); pla=10(3.5%)
Cold hands/feet: pro=31(11.1%); pla=30(10.6%)
Dizziness/asthenia: pro=38(13.7%); pla=19(6.7%)
# patients/%
Withdrawals due to:
Atrioventricular or sinoatrial block: pro=3(1.1%); pla=3(1.1%)
Sinus bradycardia: pro=7(2.5%); pla=1(0.3%)
Heart failure: pro=22(7.9%); pla=16(5.7%)
Hypotension: pro=1(0.3%); pla=1(0.3%)
Bronchospasm: pro=1(0.3%); pla=1(0.3%)
Intermittent claudication: pro=2(0.7%); pla=0
Cold hands/feet: pro=1(0.3%); pla=0
Nightmares: pro=3(1.1%); pla=3(1.1%)
Dizziness/asthenia: pro=2(0.7%); pla=1(0.3%)
Other symptoms: pro=3(1.1%); pla=2(0.7%)
Reinfarction: pro=6(2.2%); pla=4(1.4%)
Baber 1980
Multinational

Fair quality
RCTDiagnosis of anterior MI based on ECG abnormalities od an anterior infarction described as “very probable” on WHO ECG criteria; either a typical history or serum enzyme levels (AST and LDH) at least twice the accepted upper limit of normal or three times if CK was used.Bronchospasm; atrioventricular block greater than first degree; sinus bradycardia; persistent heart failure; beta blockade at the time of infarction.Propranolol (pro) 120 mg daily
Placebo (pla) x 9 months

Treatment interval:
2–14 days post-MI
NRFollow-up visits: months 1, 3, 6 and 9Mean age: Pro=55; Pla=54.8
% male: Pro=86%; Pla=83%
Previous angina:
Positive: Pro=35%; Pla=40%
Concurrent disease:
Hypertension: Pro=13%; Pla=15%
Peripheral artery disease: Pro=1%;
Pla=2%
Diabetes: Pro=3%; Pla=4%
Smokers: Pro=64%; Pla=65%
Previous angina:
Positive: Pro=35%; Pla=40%
Angina more than 3 months: Pro=15%; Pla=19%
Previous infarct:
History of cardiac failure:
Concurrent disease:
Hypertension: Pro=13%; Pla=15%
Peripheral artery disease: Pro=1%; Pla=2%
Diabetes: Pro=3%; Pla=4%
Smokers: Pro=64%; Pla=65%
nr/nr/720Total withdrawals:
pla=88(24%); pro=82(23%)/lost to fu nr/720 analyzed
pla n=365; pro n=355

# pts/%
Cardiac deaths: pla=18(4.9%); pro=19(5.4%)
Non-cardiac deaths: pla=2(0.5%); pro=3(0.8%)
Cardiac deaths after withdrawal: pla=7(1.9%); pro=6(1.7%)
Total deaths: pla=27(7.4%); pro=28(7.9%)
Non-fatal reinfarctions: pla=14(3.8%); pro=15(4.2%)
NRNRReinfarction: pla=9(2.5%); pro=10(2.8%)
Cardiac failure: pla=22(6.0%); pro=22(6.2%)
Cardiac failure alone: pla=17(4.6%); pla=10(2.8%)
Angina: pla=13(3.6%); pro=7(1.9%)
Arrhythmias: pla=11(3.0%); pro=7(1.9%)
Adverse reaction: pla=5(1.4%); pro=12(3.4%)
Other: pla=38(10.4%); pro=42(11.8%)

From: Evidence Tables

Cover of Drug Class Review: Beta Adrenergic Blockers
Drug Class Review: Beta Adrenergic Blockers: Final Report Update 4 [Internet].
Helfand M, Peterson K, Christensen V, et al.
Portland (OR): Oregon Health & Science University; 2009 Jul.
Copyright © 2009, Oregon Health & Science University, Portland, Oregon.

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