AF-Related Stroke in Women Versus Men

This section discusses sex differences in the risk and prevention of stroke between women and men with AF

In this section:

Risk of stroke in female versus male patients with AF

The principal burden of AF is that it increases the risk of stroke almost fivefold versus patients without AF. AF-related strokes appear to be more severe in women than men.

Female patients with AF and additional stroke risk factors are at a greater risk of stroke than male patients with AF. Female sex is included as a stroke risk factor in the CHA2DS2-VASc scoring system, which is recommended as a model for predicting stroke risk in patients with AF and as a guide for the use of anticoagulant therapy by European Society of Cardiology (ESC) and American College of Cardiology/American Heart Association (ACC/AHA) guidelines.

CHA2DS2-VASc risk factors for atrial fibrillation-related stroke
The CHA2DS2-VASc scoring system for the assessment of stroke risk in patients with AF.

Female patients with AF tend to be older and more likely to have hypertension or thyroid disease than male patients with AF. However, they are less likely to have atherosclerotic cardiovascular disease (e.g. CAD). Large cohort studies of patients with AF not receiving anticoagulants show that, after adjustments for differences in baseline stroke risk factors, female sex increases the risk of ischaemic stroke by 1.2–1.5-fold. These findings are supported by prospective registry data from GARFIELD-AF and ORBIT AF, which showed a 1.3–1.4-fold increase in stroke/systemic embolism in women versus men. Further analysis of stroke risk by sex and age shows that the risk of stroke is specifically increased in elderly female patients (≥75 years old) but not in female patients aged <75 years old.

Age-adjusted risk of thromboembolism between men and women
Rate of thromboembolism (ischaemic stroke, systemic embolism or TIA) at 1-year follow-up in 87,202 Danish patients with AF not receiving anticoagulants, according to sex and age.

These observations form the basis for sex-specific recommendations for anticoagulant therapy in patients with AF.

2016 ESC atrial fibrillation guideline recommendations to prevent thromboembolism with oral anticoagulants in women and men with atrial fibrillation
2016 ESC AF guideline recommendations for oral anticoagulant therapy to prevent thromboembolism in female and male patients with AF.

Stroke prevention in women versus men with AF

ESC guidelines recommend oral anticoagulation for stroke prevention in all male and female patients with two or more additional stroke risk factors – treatment options include NOACs and VKAs. Prospective registry data from GARFIELD-AF, ORBIT AF and PREFER AF indicate that a similar proportion of men and women receive oral anticoagulants for stroke prevention. However, other data sources indicate that men are more likely to be prescribed an oral anticoagulant than women – this includes data from the large US PINNACLE registry (that included over 200,000 patients with AF) and data from UK general practice.

Proportion of men and women with newly diagnosed atrial fibrillation receiving antithrombotic treatment

Antithrombotic treatment in 28,864 newly diagnosed male and female patients with AF in the GARFIELD-AF registry.

Differences between oral anticoagulant treatments

Women comprised 35–40% of the enrolled populations in phase III trials of NOACs versus warfarin for stroke prevention in patients with AF. Subgroup analyses by sex indicate that the relative efficacy and safety of the NOACs versus warfarin in each trial was similar between men and women. These observations are reinforced by a meta-analysis of pooled data from all four trials.

Efficacy and safety outcomes of NOACs and warfarin in women and men with atrial fibrillation

Meta-analysis of efficacy and safety outcomes in male and female patients enrolled in the major phase III stroke prevention in AF trials (ROCKET AF, RE-LY, ARISTOTLE and ENGAGE AF–TIMI 48), comparing NOACs with warfarin (no data available for major bleeding outcomes in RE-LY). For ROCKET AF, the major and non-major clinically relevant bleeding outcome was used.

Another meta-analysis of NOAC stroke prevention trials in patients with AF (including the ARISTOTLE, RE-LY, ROCKET AF, SPORTIF III/V and BAFTA trials) suggested that the residual risk of stroke and systemic embolism is almost 30% higher in women treated with warfarin than in men. This higher residual risk of stroke and systemic embolism seen in women taking warfarin may reflect the fact that achieving optimal warfarin control is more difficult in women than men. Female sex is included as a predictor of low time in therapeutic range in the SAME-TT2R2 score, which can help to identify patients who may struggle to achieve adequate anticoagulation control with VKAs. Although no sex differences in risk of thromboembolic events were found in those taking NOACs, major bleeding was reduced in women versus men, suggesting a higher net clinical benefit of NOACs versus warfarin in women with AF.

Where women versus men with AF stand

The risk of developing AF is similar between women and men. However, women with AF are more likely to experience AF symptoms, which can reduce their quality of life. Patients with AF have a fivefold increased risk of stroke versus patients without AF. Women with AF, specifically women aged ≥75 years, have a greater risk of stroke compared with men.

Meta-analyses of phase III AF studies have shown women with AF treated with warfarin have an increased risk of thromboembolic events compared with men, whereas those receiving a NOAC experienced a greater reduction in major bleeding. These findings suggest NOACs provide a greater clinical benefit over VKAs for women with AF, although this has yet to be fully established.

Next section: VTE Treatment with NOACs in Women

Approval No.: G.COM.GM.XA.11.2017.1950

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