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August 4, 2026Circulation
Incidence and Predictors of Extracranial Bleeding on Oral Anticoagulants for Stroke Prevention in Patients With Atrial Fibrillation: A COMBINE-AF Analysis
Key result
OACs in AF are linked to a ~26% incidence of clinically relevant extracranial bleeding.
- 95% CI 18%-35%
- n=73,737
Why the study?
Extracranial bleeding is the most common complication of OAC therapy in AF, but its clinical importance may be underrecognized.
Key Points
- To characterize extracranial bleeding events and identify baseline risk factors in patients with atrial fibrillation on oral anticoagulants.
- Analyzed data from 73,737 patients in 5 pivotal randomized trials testing direct oral anticoagulants or warfarin.
- Calculated cumulative incidence of clinically relevant extracranial bleeding using the Kaplan-Meier method.
- Utilized multivariable Cox regression and logistic regression for hazard ratios and population attributable fraction.
- 10,634 patients experienced clinically relevant extracranial bleeding (cumulative incidence, 26%; 7.6 per 100 person-years).
- 3188 major bleeds occurred (cumulative incidence, 7%; 2.1 per 100 person-years).
- 66% to 69% of population attributable bleeding risk was explained by identified baseline factors.
Study Design
Type
Cohort (n=73,737)
Multicenter
Yes
Structured PICO
P
Population
73,737 patients with atrial fibrillation receiving oral anticoagulants from 5 pivotal randomized trials, followed for a mean of 705 days.
E
Exposure
Oral anticoagulants (direct oral anticoagulant or warfarin)
O
Outcome
Extracranial clinically relevant bleeding, defined as a first episode of extracranial major or clinically relevant nonmajor bleeding according to International Society on Thrombosis and Haemostasis criteriasafety
Extracranial clinically relevant bleeding is common among AF patients on oral anticoagulants, with baseline risk factors accounting for about two-thirds of the population attributable risk.
Limitations
- Additional unmeasured or unknown factors contribute to bleeding risk
Key expert perspectives
Captured external expert commentary on this paper, strongest first. Original sources are linked where available.
MEMedXY Editorial TeamMedical News Publication
“This large-scale pooled analysis robustly confirms that extracranial bleeding is a common and clinically meaningful complication in AF patients receiving OAC therapy. The differentiation between major and nonmajor bleeding using standardized ISTH criteria lends uniformity and reproducibility to event adjudication. The predominance of gastrointestinal bleeding among major extracranial bleeds aligns with prior clinical observations, underscoring the importance of GI risk assessment and management (e.g., Helicobacter pylori screening, proton pump inhibitors) in anticoagulated patients.”
Implication
Clinicians should integrate extracranial bleeding risk into OAC decisions for AF; this meta-analysis extends trial data by quantifying baseline factors' contribution to most attributable risk.
Abstract
BACKGROUND: Extracranial bleeding is the most common complication of oral anticoagulant (OAC) therapy for atrial fibrillation (AF), but its clinical importance for patients may be underrecognized. We sought to characterize extracranial bleeding events according to standardized severity definitions, identify baseline risk factors for bleeding, and quantify their population attributable fraction in patients with AF receiving OACs. METHODS: We analyzed patients receiving OACs from 5 pivotal randomized trials testing a direct OAC or warfarin in patients with AF (COMBINE-AF [A Collaboration Between Multiple Institutions to Better Investigate Non-Vitamin K Antagonist Oral Anticoagulant Use in Atrial Fibrillation]). The primary outcome was extracranial clinically relevant bleeding, defined as a first episode of extracranial major or clinically relevant nonmajor bleeding according to International Society on Thrombosis and Haemostasis criteria. The Kaplan-Meier method was used to calculate the cumulative incidence of bleeding by category. Multivariable Cox regression models were used to estimate adjusted hazard ratios (HRs) with 95% CI. Logistic regression models were used to calculate average population attributable fraction with 95% CI. RESULTS: Of 73 737 patients treated with OACs, 10 634 experienced clinically relevant extracranial bleeding over a mean follow-up of 705 days (cumulative incidence, 26% [95% CI, 18%-35%]; 7.6 per 100 person-years). This included 3188 major bleeds (cumulative incidence, 7% [95% CI, 6%-7%]; 2.1 per 100 person-years) and 7446 clinically relevant nonmajor bleeds (cumulative incidence, 19% [95% CI, 12%-28%]; 5.2 per 100 person-years). The distribution of bleeding sites differed by severity, with gastrointestinal bleeds comprising 26% of clinically relevant bleeds, 49% of major bleeds, and 15% of clinically relevant nonmajor bleeds. Risk factors for extracranial bleeding were consistent across severity bleeding categories, and baseline covariates in our multivariable models accounted for 66% to 69% of the population attributable bleeding risk. CONCLUSIONS: Extracranial clinically relevant bleeding is common among patients with AF treated with OACs and may more accurately reflect the overall burden of bleeding than major bleeding alone. Our models explained about two-thirds of the average population attributable risk, suggesting that additional unmeasured or unknown factors contribute to bleeding risk.
Circulation · meta-analysis. Factor extracranial bleeding into AF anticoagulation decisions: 26% cumulative incidence. Incidence and Predictors of Extracranial Bleeding on Oral Anticoagulants for Stroke Prevention in Patients With Atrial Fibrillation: A COMBINE-AF Analysis 73,737 AF patients: On oral anticoagulants across 5 pivotal trials. How COMBINE-AF pooled the data: 5 randomized trials → DOAC or warfarin → Mean 705 days → ISTH extracranial bleeding. 10,634 patients bled: 7.6 per 100 person-years, clinically relevant. 7% Major bleed cumulative incidence. 3188 major bleeds, 2.1 per 100 person-years. Bottom line: Weigh extracranial bleeding in AF anticoagulation; baseline factors explain most risk.
Coverage & sources
Journal, society, and media accounts. Useful signal, not independent expert judgment.
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Cite This Study
Siegal et al. (2026) conducted a cohort in Atrial Fibrillation (n=73,737). Oral anticoagulants was evaluated on Extracranial clinically relevant bleeding (first episode of extracranial major or clinically relevant nonmajor bleeding) (95% CI 18%-35%). Oral anticoagulant therapy in patients with atrial fibrillation was associated with a 26% cumulative incidence of clinically relevant extracranial bleeding over a mean follow-up of 705 days.