Effect of Beta Blockers on Mortality and Morbidity in Persons Treated for Congestive Heart Failure

PURPOSE: To determine the effect of metoprolol controlled release/extended release (CR/XL) administered once daily on mortality in patients with congestive heart failure (CHF) associated with abnormal left ventricular (LV) ejection fraction. BACKGROUND: CHF with abnormal LV ejection fraction despite treatment with diuretics plus angiotensin‐converting enzyme (ACE) inhibitors plus digoxin has a very high mortality. Previous data suggested that long‐term treatment with beta‐blockers, including metoprolol, could improve survival and improve hemodynamics in patients with CHF and abnormal LV ejection fraction. METHODS: Three thousand nine hundred and ninety‐one patients aged 40 to 80 years from 313 investigational sites in 13 European countries and in the United States with chronic CHF New York Heart Association (NYHA) functional class II, III, or IV and a LV ejection fraction of 40% or less were stabilized with optimum standard therapy. Of the 3,991 patients, 77% were men, 23% were women; 33% were younger than 60 years of age, 35% were 60 to 69 years of age, 32% were 70 to 80 years of age; 66% had ischemic heart disease; 91% were receiving diuretics, 96% were receiving ACE inhibitors or angiotesin II type 1 receptor antagonists, and 64% were receiving digitalis. Randomization was preceded by a 2‐week single‐blind placebo run‐in period. Following this, 1,990 patients were randomized to metoprolol CR/XL 12.5 mg daily if NYHA functional class III or IV CHF was present (59%) or to 25 mg daily if NYHA functional class II CHF was present (41%), and 2,001 patients were randomized to double‐blind placebo. The target dose was 200 mg once daily of metroprolol CR/XL and doses were up‐titrated over 8 weeks. The primary endpoint was all‐cause mortality analyzed by intention to treat. MAIN RESULTS: The study was stopped early on the recommendation of the independent safety committee. Mean follow‐up was 1 year. All‐cause mortality occurred in 145 of 1,990 patients (7.2%) treated with metoprolol versus 217 of 2,001 patients (11.0%) treated with double‐blind placebo ( P = .0062; relative risk = 0.66, 95% confidence interval = 0.53–0.81). Compared with double‐blind placebo, metoprolol caused a significant reduction in total mortality by 34% ( P = .0052), a significant decrease in cardiovascular mortality by 38% ( P = .00003), a significant reduction in sudden cardiac death by 41% ( P = .0002), and a significant decrease in death from worsening CHF by 49% ( P = .0023). Mortality was significantly reduced by metoprolol in patients who were in the upper tertile of age as well as in the middle and lower tertiles of age. CONCLUSIONS: In patients with chronic CHF NYHA functional class II, III, or IV treated with optimum standard therapy, these data demonstrated that, compared with double‐blind placebo, metoprolol CR/XL 200 mg administered once daily caused significant reductions in all‐cause mortality by 34%, in cardiovascular mortality by 38%, in sudden cardiac death by 41%, and in death from worsening CHF by 49%.