Beta-agonists and Heart Failure
Paradoxically, as evidence accumulates of beta-blocker efficacy in COPD, observational studies point to adverse associations between beta-agonists and HF. Beta-agonists are associated with incident HF in patients with pulmonary disease, and with increased mortality and HF hospitalization in those with existing HF or LVSD (Table 4). These observations have sound physiological rationale. Down-regulation of beta1-receptors with the preservation of the beta2 subpopulation increases the sensitivity of the failing myocardium to beta2-agonists. The adverse effects of beta-agonists are numerous: ischaemia, arrhythmias, tachycardia, hypokalaemia, QT prolongation, disturbed autonomic modulation. However, association is not causation. The poor outcomes attributed to beta-agonists may reflect the underlying pulmonary disease, smoking burden, and associated pathologies, clustering of cardiovascular risk factors and disease in patients with COPD, or residual confounding by unmeasured covariates. The most recent cohort study supports this standpoint. In 1294 outpatients with HF, beta2-agonist users were older, more often male, with more frequent smoking history, coronary artery disease, pulmonary disease, and higher heart rates. Although unadjusted mortality rates for beta2-agonist users were significantly higher than non-users, adjusted mortality rates were similar after comprehensive multivariable adjustment (HR 1.04 [0.77–1.41]). Nevertheless, doubts regarding the cardiovascular safety of beta-agonists have prompted calls for randomized controlled trials. The largest such trial is examining all-cause mortality in 16 000 patients with moderate COPD and established or high risk of cardiovascular disease randomized to four treatment groups: fluticasone/vilanterol combination, fluticasone alone, vilanterol alone, or placebo.