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

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. ### Competing Interest Statement Jeanne Moor (JM) reported no COI. Angelo Auricchio (AA) Dr Auricchio is a consultant to Boston Scientific, Backbeat, Biosense Webster, Cairdac, Corvia, Daiichi-Sankyo, Medtronic, Merit, Microport CRM, Philips, and V-Wave. He received speaker fees from Daiichi-Sankyo, Boston Scientific, Biosense Webster, Medtronic, Microport CRM, and Philips. Dr. Auricchio also participates in clinical trials for Boston Scientific, Medtronic, Microport CRM, and Zoll Medical. He also holds intellectual properties with the following: Boston Scientific, Biosense Webster, and Microport CRM. Juerg H. Beer (JHB) reports grant support from the Swiss National Foundation of Science, The Swiss Heart Foundation and the Stiftung Kardio; grant support, speakers- and consultation fees to the institution from Bayer, Sanofi and Daichii Sankyo. Leo H. Bonati (LHB) reports personal fees and nonfinancial support from Amgen, grants from AstraZeneca, personal fees and nonfinancial support from Bayer, personal fees from Bristol-Myers Squibb, personal fees from Claret Medical, grants from Swiss National Science Foundation, grants from University of Basel, grants from Swiss Heart Foundation, outside the submitted work. David Conen (DC) received consulting fees from Roche Diagnostics, and speaker fees from Servier and BMS/Pfizer, all outside of the current work. Richard Kobza (RK) receives institutional grants from Abbott, Biosense-Webster, Boston-Scientific, Biotronik, Medtronic and Sis-Medical. Michael Kuehne (MK) reports personal fees from Bayer, personal fees from Boehringer Ingelheim, personal fees from Pfizer BMS, personal fees from Daiichi Sankyo, personal fees from Medtronic, personal fees from Biotronik, personal fees from Boston Scientific, personal fees from Johnson&Johnson, personal fees from Roche, grants from Bayer, grants from Pfizer, grants from Boston Scientific, grants from BMS, grants from Biotronik, grants from Daiichi Sankyo. Giorgio Moschovitis (GM) has received advisory board or speaker's fees from Astra Zeneca, Bayer, Boehringer Ingelheim, Daiichi Sankyo, Gebro Pharma, Novartis and Vifor, all outside of the submitted work. Stefan Osswald (SO) Research grant from Swiss National Science Foundation (SNSF) for Swiss AF Cohort study (33CS30\_18474/1&2). Research grant from Swiss National Science Foundation (SNSF) for Swiss AF Control study (324730\_192394/1). Research grants from Swiss Heart Foundation (SHS). Research grants from Foundation for CardioVascular Research Basel (SKFB). Research grants from Roche. Educational and Speaker Office grants from Roche, Bayer, Novartis, Sanofi AstraZeneca, Daiichi-Sankyo, Pfizer. Tobias Reichlin (TR) has received research grants from the Swiss National Science Foundation, the Swiss Heart Foundatio, the sitem insel support fund, Biotronik, Boston Scientific and Medtronic, all for work outside the submitted study. He has received speaker/consulting honoraria or travel support from Abbott/SJM, Biosense-Webster, Biotronik, Boston Scientific and Medtronic. He has received support for his institution's fellowship program from Abbott/SJM, Biosense-Webster, Biotronik, Boston-Scientific and Medtronic. Nicolas Rodondi (NR) reported no COI. Carole Elodie Aubert (CEA) was supported by the Swiss National Science Foundation (grant number grant number PZ00P3_201672). ### Funding Statement BEAT-AF This was funded by the Swiss National Science Foundation,the Swiss Heart Foundation, the University ofBasel, Boehringer Ingelheim, Sanofi-Aventis, Merck Sharp & Dome, Bayer, Daiichi-Sankyoand Pfizer/Bristol-Myers Squibb. Swiss-AF was funded by the Swiss National Science Foundation (SNSF). This study was funded by the Young Talents in Clinical Research by Bangerter-Foundation. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethics committees of both Basel and northwestern and central Switzerland gave ethical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Due to restrictions by the Ethical Committee, data is not publicly available. Requests to access the datasets should be directed to the corresponding author.