Cluster and Registry Trial of the Working Group of Heart Failure in Denmark. Are Carvedilol and Metoprolol Succinate Comparable Treatments in Heart Failure Patients With Reduced Ejection Fraction

Background:

Heart failure with reduced ejection fraction:

The overall prevalence of heart failure with reduced ejection fraction (HFrEF) is 1-2% in the adult population and increasing with age to more than 10% in the population over 70 years. Patients with HFrEF have markedly reduced life expectancy, physical capacity and quality of life. Activation of the sympathetic nervous system is one of the cardinal pathophysiologic abnormalities in patients with HFrEF. Levels of circulating catecholamines increase in patients with HFrEF in proportion to the severity of the disease and those with the highest plasma levels of norepinephrine have the most unfavorable prognosis.

Beta-blocker in heart failure with reduced ejection fraction:

Prospective randomized clinical trials of sympathetic antagonists with several different beta-blockers have shown that these medications can reduce symptoms, improve left ventricular function, increase functional capacity, decrease the number of hospitalization for worsening heart failure and mortality in patients with HFrEF. Current heart failure guidelines therefore recommend treatment with a beta-blocker in HFrEF patients as a class 1A indication. However, small differences exist between beta-blockers. Metoprolol is a second generation beta-blocker that selectively inhibit β1-adrenoceptors, whereas carvedilol is a third generation beta-blocker, that nonselectively inhibit β1-adrenoceptors with additional inhibition of α1-adrenoceptors. Therefore, controversy exists whether beta-blockers exert a class effect or whether one beta-blocker is superior to another. In the largest prospective randomized clinical trial that directly compared the efficacy of beta-blockers, the Carvedilol or Metoprolol European Trial (COMET), carvedilol increased survival in patients with HFrEF compared with metoprolol tartrate. However, the results of the COMET trial was debated for two reasons. First, it compared carvedilol with the short-acting metoprolol tartrate formulation. Metoprolol tartrate, however, is not the formulation used in key HFrEF metoprolol trials and is not recommended in current heart failure guidelines. Second, the metoprolol tartrate target dose in the COMET trial was 50 mg twice daily, whereas the long-acting metoprolol succinate dose in the Metoprolol CR/XL Randomized Intervention Trial (MERIT) trial was 200 mg once daily,10 as recommended by the heart failure guidelines. Further, Carvedilol was dosed at full guideline target dose in COMET.