AN Old Debate Still in the β-Phase?

This article refers to 'Relationship between heart failure, concurrent chronic obstructive pulmonary disease and beta-blocker use: a Danish nationwide cohort study', by M. Sessa et al., published in this issue on pages 548-556.The introduction of 𝛽-blockers into heart failure with reduced ejection fraction (HFrEF) treatment represented a revolution.Almost 40 years later, they are long accepted as standard therapy in HFrEF. 1 They changed the belief that sympathetic activation contributes to stabilizing HFrEF, and rather proved the opposite.With the change of the century, several trials demonstrated the positive effects of several 𝛽-blockers to reduce both morbidity and mortality in HFrEF. 1 𝛽-Blockers can be classified, depending on their affinity levels for 𝛽1-(predominantly present in the heart) and 𝛽2-adrenergic receptors (present in vascular and pulmonary smooth muscle), into (i) non-selective 𝛽-blockers, which block competitively both receptors, and (ii) selective 𝛽-blockers with higher affinity for 𝛽1than 𝛽2-receptors.This cardio-selectivity is dose-dependent.Additionally, 𝛽-blockers have other actions such as 𝛼1-adrenoreceptor blockade (carvedilol, labetalol) producing peripheral vasodilatation, 𝛽2-adrenergic receptor agonism (celiprolol), or mechanisms other than blocking adrenoreceptors (bucindolol, nebivolol).These differences between agents may result in non-uniform effects, questioning a single class effect of 𝛽-blockers.The disappointing results of bucindolol in the BEST trial indeed suggested that differences between 𝛽-blockers might matter.In 2003, the large randomized COMET trial compared the effects of the two 𝛽-blockers carvedilol and metoprolol.The carvedilol group showed a significant 17% reduction in mortality as compared to metoprolol. 2 Unfortunately, the short working formulation of metoprolol (tartrate) in relatively low dose was used in the COMET trial 2 as compared to metoprolol succinate in the MERIT-HF trial, 1 resulting in a debate about the relevance of the COMET trial that is still not completely resolved.This debate may be fuelled anew by the publication of a large Danish heart failure cohort, presented in this issue of the Journal.3 The opinions expressed in this article are not necessarily those of the Editors of the