Sex-specific association of cardiovascular drug doses with adverse outcomes in atrial fibrillation

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Abstract Objectives Women with heart failure (HF) with reduced ejection fraction receiving submaximal doses of beta-blockers and renin-angiotensin system (RAS) inhibitors have a lower risk of mortality or hospitalizations for heart failure. However, optimal doses of beta-blockers or RAS inhibitors in women with atrial fibrillation (AF) with and without HF are unclear. We investigated sex-specific associations of beta-blocker and RAS inhibitor doses with cardiovascular outcomes in patients with AF with and without HF. Methods We used data from the prospective BEAT-AF and Swiss-AF cohorts on patients with AF. The outcome was major adverse cardiovascular events (MACE), including death, myocardial infarction, stroke, systemic embolization, and HF-related hospitalization. Predictors of interest were spline (primary analysis) or quartiles (secondary analysis) of beta-blocker or RAS inhibitor dose in percent of the maximum dose (reference), in interaction with sex. Cox models were adjusted for demographics, comorbidities and co-medication. Results Among 3,961 patients (28% women), MACE occurred in 1,113 (28%) patients over 5-year median follow-up. Distributions of RAS inhibitor and beta-blocker doses were similar in women and men. Cox models revealed no association between beta-blocker dose or RAS inhibitor dose and MACE. In a subgroup of patients with AF and HF, the lowest hazard of MACE was observed in women prescribed 100% of RAS inhibitor dose. However, there was no association between RAS dose quartiles and MACE. Conclusions In these two cohorts of patients with AF, doses of beta-blockers and RAS inhibitors did not differ by sex and were overall not associated with MACE. What is already known on the subject Sex-specific analyses of beta-blocker and renin angiotensin system (RAS) inhibitor doses in patients with heart failure with reduced ejection fraction have revealed a lower hazard of death or heart failure-related hospitalisation in women receiving low doses compared to maximum doses. The pathophysiology and pharmacotherapy of atrial fibrillation show sex differences, but the potential sex-specific associations of different drug doses with cardiovascular outcomes are unknown in this population. What this study adds This study identifies no associations between beta-blocker doses and major adverse cardiovascular events in patients with atrial fibrillation. How this study might affect research, practice or policy The findings of the present study reassure that the recommended maximum doses of beta-blockers and RAS inhibitors appeared safe among patients of both sexes with atrial fibrillation.

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