Revisiting sex differences in outcomes in non-valvular atrial fibrillation: a population-based cohort study

Aims In patients with non-valvular atrial fibrillation (NVAF), it is uncertain whether the higher risk of ischaemic stroke in women reported in some studies is due to residual confounding. We assessed this association using standard time-fixed and more accurate time-dependent adjustment for confounders. Methods and results Using the computerized databases of the Regie de l'assurance maladie du Quebec (RAMQ), we identified a cohort of patients with NVAF during 2000-2009 and RAMQ medication coverage. Cox proportional hazards models were used to estimate the hazard ratio (HR) of ischaemic stroke, death, and bleeding, associated with sex, adjusting for time-fixed covariates at cohort entry. This was compared with adjustment for time-dependent covariates using an age and time-matched nested case-control analysis. The cohort included 147 622 patients. During a mean follow-up of 2.9 years 11 326 patients had a stroke (incidence rate 2.6 per 100 per year). Using time-fixed adjustment for confounders, women had a moderately higher risk of ischaemic stroke than men (HR 1.16 (Confidence interval (CI) 95% 1.11-1.21). Matching on age and using time-dependent adjustment for confounders, women were not at higher risk of stroke than men (Rate Ratio 1.01; 95% CI 0.97-1.05). Mortality and bleeding rates were lower in women compared with men in both analyses. Conclusion In NVAF, women were not at higher risk of thromboembolic events than men in our study. The small increased risk reported in previous studies may be related to residual confounding, in particular from insufficient control for age.