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The merit of beta(1)-blockade in heart failure.

Twenty-five years ago, it was known that heart failure was associated with an increase in sympathetic nervous activity, but the prevailing opinion was that this was a compensatory increase, in order to counteract depressed myocardial function, and that beta-blocker treatment might cause worsening heart failure. Consequently, beta-blockade was regarded as contraindicated in the treatment of patients with heart failure. In 1975, Finn Waagstein, Ar ke Hjalmarson and their colleagues at Sahlgrenska Hospital in Göteborg, Sweden, published an article reporting surprising effects of beta-blocker treatment in patients with congestive cardiomyopathy and severe heart failure. There was a clear alleviation of symptoms, and the working capacity and a number of non-invasive measures of cardiac function improved. This observation was the first pioneering step in a long process that has been no less than a paradigm shift as beta-blockade has become established treatment in chronic heart failure. The circle closed when the Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF) was published in June 1999, with Hjalmarson and Waagstein as co-authors. The study was designed and powered to examine whether the beta1-selective antagonist metoprolol CR/XL, in comparison with placebo treatment, was associated with a reduction in all-cause mortality. Three thousand nine hundred and ninety-one patients with chronic heart failure in NYHA functional classes II–IV and an ejection fraction of 0·40 stabilized with optimal standard therapy were enrolled in a double-blind randomized study. Ninety-five percent of the patients were treated with an ACE inhibitor or an angiotensin-II blocker. The study medication was up-titrated for 6–8 weeks, starting with 12·5 mg (NYHA functional classes III-IV) or 25 mg once daily (NYHA II) and the target dose was 200 mg once daily. The study, performed in 13 European countries and in the U.S.A., was stopped early on the recommendation of the independent safety committee, because the second, pre-planned, interim analysis showed that the pre-defined criterion for termination of the study, because of benefit, had been met and exceeded.