Table 3

Cornerstone hypertension, HF and AMI trials with atenolol, metoprolol and carvedilol

TrialInterventionsNImportant outcomes
Hypertension trials
 HAPPHY trial10Diuretic (bendrofluazide or hydrochlorothiazide) versus BB (atenolol or metoprolol)6569No difference between groups in terms of:
Fatal/non-fatal CAD (10.62/1000 patient years vs 9.48/1000 patient years, respectively, OR=0.88, 95% CI 0.68 to 1.14)
Fatal/non-fatal stroke (2.58/1000 patient years vs 3.35/1000 patient years, respectively, OR=1.29, 95% CI 0.82 to 2.04)
All deaths (7.73/1000 patient years vs 8.25/1000 patient years, respectively, OR=1.06, 95% CI 0.80 to 1.41)
 LIFE trial14Atenolol versus losartan9193Primary composite end point (CV death and stroke) was significantly less (11% vs 13%, HR=0.87, 95% CI 0.77 to 0.98, p=0.021) in the losartan group
Stroke (5% vs 7%, HR=0.75, 95% CI 0.63 to 0.89, p=0.001) and new-onset diabetes (6% vs 8%, HR=0.75, 95% CI 0.63 to 0.88, p=0.001) was lower in the losartan group
CV mortality (4% vs 5%, HR=0.89, 95% CI 0.73 to 1.07, p=0.206), MI (4% vs 4%, HR=1.07, 95% CI 0.88 to 1.31, p=0.491) and total mortality (8% vs 9%, HR=0.90, 95% CI 0.78 to 1.03, p=0.128) did not show any significant differences between the two groups
 CAPP trial20Captopril versus conventional treatment (diuretic or BB or both)10 985CV mortality (0.77, p=0.092) and the incidence of type 2 diabetes was found to be lower in the captopril group (RR=0.79; p=0.007) as compared with conventional treatment group
Fatal and non-fatal strokes showed a higher incidence with captopril treatment (1.25, p=0.044)
Fatal and non-fatal MI had similar incidences between the two groups (0.96, p=0.68)
 INVEST trial21Verapamil versus atenolol23 000Verapamil-treated patients had a significantly lower incidence of new-onset diabetes versus atenolol (15% lower risk; RR=0.85, 95% CI 0.77 to 0.95)
 ASCOT-BPLA trial22Atenolol versus amlodipine19 257Atenolol increased CV mortality (P=0.001), all-cause mortality (p=0.025), and the development of diabetes (p<0.0001) compared with amlodipine
AMI trials
 ISIS-166Atenolol versus control16 027Vascular mortality was significantly reduced with atenolol versus placebo at 1 year (10.7% vs 12.0%), but this did not reach significance at trial end (12.5% vs 13.4%, p=0.07). The combined end point (death, cardiac arrest or reinfarction) was significantly reduced with atenolol (p=0.0002)
 Goteborg67Metoprolol versus placebo1395Significant 36% reduction in mortality with metoprolol (p<0.03)
 MIAMI68Metoprolol versus placebo5778No significant reduction in all-cause mortality with metoprolol versus placebo (4.3% vs 4.9%, p=0.29)
 LIT69Metoprolol versus placebo2395Compared with placebo there was no significant reduction in all-cause mortality with metoprolol at 1 year (65 vs 62, p=non-significant)
 COMMIT trial63Metoprolol versus placebo45 852No statistically significant reduction in the primary composite end point of death, reinfarction or cardiac arrest (OR=0.96, 95% CI 0.90 to 1.01, p=0.10) or death alone (OR=0.99, 95% CI 0.92 to 1.05, p=0.69)
Cardiogenic shock occurred in 5.0% of the patients randomised to metoprolol and 3.9% in the placebo group (OR=1.30, 1.19 to 1.41; p<0.00001)
Reinfarction (2.0% vs 2.5%, OR=0.82, 95% CI 0.72 to 0.92, p=0.001) and ventricular fibrillation (2.5% vs 3.0%, OR=0.83, 95% CI 0.75 to 0.93, p=0.001) were less frequently seen in the metoprolol-treated group
 Basu et al70Carvedilol versus placebo151Compared with placebo, carvedilol significantly reduced cardiac events (fatal and non-fatal, 45% reduction p=0.02), ‘hard’ cardiac events (42% reduction, p<0.03) and serious cardiac events (death, reinfarction, unstable angina, CHF and ventricular tachycardia) in patients with a LVEF <45% at baseline (5 vs 13, p=0.04)
 CAPRICORN trial64Carvedilol or placebo1959All-cause mortality was lower in the carvedilol group compared with placebo (116 (12%) vs 151 (15%), 0.77 (0.60 to 0.98), p=0.03).
Carvedilol caused a 76% reduction in arrhythmias (ventricular tachycardia and fibrillation/flutter, p<0.0001), a 52% reduction in supraventricular arrhythmias (p=0.0015) and a 26% reduction in sudden cardiac death (p=0.098) compared with placebo
 CAMIS65Carvedilol versus atenolol232No difference in the LVEF between the two groups and no significant reduction in the occurrence of a first serious CV event with carvedilol versus atenolol (RR=0.88, 95% CI 0.59 to 1.30, p=0.524)
HF trials
 MERIT-HF trial40Metoprolol, placebo3991Metoprolol significantly reduced all-cause mortality by 34% (RR=0.66, 95% CI 0.53 to 0.81, p=0.00009)
Increase in mortality with metoprolol versus placebo in the US geographical region (HR=1.05, 95% CI 0.71 to 1.56)
 COMET71Carvedilol versus metoprolol3029Compared with metoprolol, carvedilol significantly reduced all-cause mortality (17% reduction, p=0.0017), CV mortality (20% reduction, p=0.0009), sudden death (23% reduction, p=0.0073), fatal stroke (63% reduction, p=0.0027), fatal or non-fatal MI (29% reduction, p=0.03), stroke or MI (25% reduction, p=0.015), fatal MI or fatal stroke (54% reduction, p=0.0002) and death after non-fatal MI or stroke (44% reduction, p=0.0086)
 COPERNICUS trial49 50Carvedilol or placebo2289The annual mortality rate in the carvedilol group was reduced by 35% (12.8% vs 19.7%, p=0.00013) and risk of death or hospitalisation was reduced by 24% (p=0.00004) as compared with the placebo group
Lower incidence of hospitalisations due to HF (17.1% vs 23.7%, p=0.0001), for a CV reason (21.3% vs 27.7%, p=0.0003) or for any reason (32.2% vs 38.1%, p=0.003) in the carvedilol group
Reduced incidence of all adverse effects (39.0% vs 45.5%, p=0.002), HF (p<0.0001), sudden death (p=0.016), ventricular tachycardia (p=0.019) and cardiogenic shock (p=0.003) with carvedilol
US Carvedilol HF study51Carvedilol, placebo1094The mortality rate in the carvedilol group was reduced by 65% (3.2% vs 7.8%, 95% CI 39% to 80%, p<0.001)
The risk of hospitalisation for CV causes was reduced by 27% (14.1% vs 19.6%, p=0.036) in the carvedilol group
The combined risk of hospitalisation and death was reduced by 38% (24.6% vs 15.8%, p<0.001) in the carvedilol group
Greater decrease in the mean heart rate with the carvedilol group as compared with placebo (12.6±12.8 vs 1.4±12.2 bpm, p<0.001)
 Australia-New Zealand HF trial52Carvedilol, placebo4155.3% increase in the LVEF (p<0.0001) and decrease in the end-diastolic and end-systolic heart dimensions by 1.7 mm (p=0.06) and 3.2 mm (p=0.001) in the carvedilol
The incidence of death or hospitalisation was also lower in the carvedilol group as compared with the placebo group (104 vs 131, RR=0.74, 95% CI 0.57 to 0.95)
 CIBIS I42Bisoprolol versus placebo641Compared with placebo, bisoprolol significantly reduced hospitalisations for cardiac decompensation (61 vs 90, p<0.01) with significantly more patients improving by at least one NYHA functional class (68 vs 48, p=0.04). No significant reduction in mortality with bisoprolol (53 vs 67, RRR=0.80, 95% CI 0.56 to 1.15, p=0.22)
 CIBIS II43Bisoprolol versus placebo2647Compared with placebo, bisoprolol significantly reduced all-cause mortality (11.8% vs 17.3%, HR=0.66, 95% CI 0.54 to 0.81, p<0.0001) and sudden death (3.6% vs 6.3%, HR=0.50, 95% CI 0.39 to 0.80, p=0.0011)
 SENIORS57Nebivolol versus Placebo2128Compared with placebo, nebivolol significantly reduced the composite end point (all-cause mortality or CV hospital admission) (14% reduction, p=0.039)
  • AMI, acute myocardial infarction; ASCOT-BPLA, Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm; BB, β-blocker; CAD, coronary artery disease; CAMIS, Carvedilol Acute Myocardial Infarction Study; CAPP, Captopril Prevention Project; CAPRICORN, Carvedilol Post Infarction Survival Control in Left Ventricular Dysfunction; CIBIS, Cardiac Insufficiency Bisoprolol Study; COMET, Carvedilol Or Metoprolol European Trial; COMMIT, Clopidogrel and Metoprolol in Myocardial Infarction Trial; COPERNICUS, Carvedilol Prospective Randomized Cumulative Survival; CV, cardiovascular; HF, heart failure; HAPPHY, Heart Attack Primary Prevention in Hypertension; INVEST, International Verapamil-Trandolapril Study; ISIS-1, First International Study of Infarct Survival; LIFE, Losartan Intervention For Endpoint Reduction; LIT, Lopressor Intervention Trial; LVEF, left ventricular ejection fraction; MERIT-HF, Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure; MIAMI, Metoprolol in Acute Myocardial Infarction; NYHA, New York Heart Association; RRR, relative risk reduction; SENIORS, Study of Effects of Nebivolol Intervention on Outcomes and Rehospitalization in Seniors With Heart Failure.