(AO) A Real-World Assessment of Sex Differences in The Comparative Safety and Effectiveness of Direct-Acting Oral Anticoagulants Versus Warfarin

Publication Number: 331

Background: Systematic reviews and meta-analysis of trial data have reported ambivalent data regarding sex differences in the comparative effectiveness and safety of direct-acting oral anticoagulants (DOACs), vs. warfarin, among atrial fibrillation (AF) patients. Thus, additional data from real-world settings is warranted.

Objectives: To evaluate the comparative effectiveness and safety of DOACs, vs. warfarin, between female and male AF patients.

Methods: A cohort of new initiators (i.e. 180 days naïve) of warfarin and DOACs (dabigatran, rivaroxaban, apixaban and edoxaban) were identified from The Ohio State University Medical Center EMR data (2012-2020). We included only patients who had a diagnosis of AF within the 180 days prior to the index date (first fill date) of warfarin or DOAC initiation. Patients who used other anticoagulants to or on the index date were excluded. Follow-up for safety (adverse events: hemorrhagic events including intracranial hemorrhage or gastrointestinal bleeding) and effectiveness (AF sequelae: stroke, venous thromboembolism (VTE), myocardial infarction and death) outcomes were measured between the index date and end of data availability. Inverse-probability of weighting (IPTW) techniques were used to control for potential confounding from several demographic, clinical factors and dosage of the index medication. Cox proportional-hazard (CPH) regression models, weighted by IPTW, were used to compute hazard ratios (HR) and 95% confidence intervals (CI) for the average treatment effects (safety and effectiveness) of DOACs compared to warfarin. Sex differences were tested through interaction tests and sex-specific HRs were extracted. The following sensitivity analysis were conducted: 1) sex difference by individual DOACs; 3) subgroup analysis among valvular AF patients.

Results: Among 6962 (3051 females; 3911 males) DOAC and 4998 (2232 females; 2766 males) warfarin users, there were no sex differences in the comparative effectiveness of DOACs, vs warfarin (P-interaction=0.20) – DOACs were effective among females (HR=0.57, 95% CI: 0.46, 0.71) and males (HR=0.67, 95% CI: 0.57, 0.79). Similarly, there were no sex differences in the risks of adverse events between DOACs and warfarin (P-interaction = 0.52); DOACs were not associated with adverse events among either sex. Some sex differences were observed when individual DOACs were compared with warfarin for both safety and effectiveness outcomes. Most of the observed results were replicated among valvular AF patients.

Conclusions: This real-world data suggests that, overall, DOACs may be safe and effective at preventing AF sequelae among both females and males.