Reevaluating Female Sex as a Risk Factor for Ischemic Stroke

April 15th, 2025

The CHA₂DS₂-VASc score is widely used to estimate the risk of ischemic stroke (IS) in patients with atrial fibrillation (AF) and guide oral anticoagulant (OAC) therapy decisions. Female sex has traditionally been included as an independent risk factor, based on early trials and observational data. However, it has long been debated whether this association reflects biological sex differences or confounding factors such as age, comorbidities, or sociocultural disparities in care.

The current study — a sub-analysis of the Finish Anti Coagulation in Atrial Fibrillation (FinACAF) cohort — aimed to examine whether the risk associated with female sex has changed over time and to reassess its role in stroke risk stratification in AF patients.

Study Design and Population

• Study type: Retrospective cohort study (sub-study of FinACAF)

• Data source: Nationwide Finnish healthcare registries (2007–2018)

• Sample size: 229,565 patients with newly diagnosed AF or atrial flutter

  • 50% women

  • Mean age: 73 years

  • Mean follow-up: four years

Women in the cohort generally were older, had more comorbidities, lower socioeconomic status, and higher CHA₂DS₂-VASc scores compared to men. Over the 12-year period, the average age at AF diagnosis increased (especially among men), as did the prevalence of comorbidities in both sexes.

Key Outcomes and Findings

Ischemic Stroke Incidence

• Crude IS rates: Women had consistently higher IS rates than men throughout the study (21 vs. 15 per 1,000 person-years; P < 0.001)

• However, IS rates declined over time in both sexes

• One-year mortality also decreased (from 13% to 9%) but remained higher in women

Adjusted Analyses

• After adjusting for the confounders, female sex was no longer independently associated with higher IS risk

• This finding held true across various analytical models, including:

  • Patients stratified by OAC use

  • Patients censored at OAC initiation

  • One-year follow-up data analyses

Temporal Trends

• Initially, female sex was associated with a 20% to 30% higher risk of IS.

• By the end of the study period, this association attenuated and became statistically non-significant.

• In high-risk subgroups (CHA₂DS₂-VASc >3 in women and >2 in men), the sex-related difference also declined over time.

• Among lower-risk patients, there was no sex difference in IS risk at any point during the study.

Study Strengths and Limitations

Strengths:

• Large national cohort of AF patients diagnosed across all levels of care

• Real-world population representative of everyday clinical practice

• Adjustment for OAC use and extensive confounding variables

Limitations:

• Retrospective design prone to coding and diagnostic inaccuracies

• Lack of detailed lifestyle data

• No data on OAC adherence

• Findings may not generalize beyond the Finnish (largely homogeneous) population

• Ischemic stroke events only counted if hospitalized (although nearly all Finnish stroke patients are hospitalized)

Conclusion

This sub-study from the FinACAF cohort suggests that female sex is no longer independently associated with increased ischemic stroke risk in patients with AF, particularly in the era of improved anticoagulation and comorbidity management. The results support reconsideration of sex-based scoring in CHA₂DS₂-VASc, potentially improving risk stratification and therapeutic decision-making by focusing more precisely on clinically relevant predictors.

For more information on this study and its implications, click here.