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Incidence and Predictors of Extracranial Bleeding on Oral Anticoagulants for Stroke Prevention in Patients With
Deborah M Siegal1,2, Marc Carrier1,2, M Cecilia Bahit3
1Department of Medicine (D.M.S., M.C.), University of Ottawa, Ottawa, ON, Canada.
Insights
Extracranial bleeding is common in atrial fibrillation patients on oral anticoagulants (OACs). Standardized definitions and risk factor analysis show these events are frequent and may be underrecognized, impacting patient care.
Area of Science:
- Cardiology
- Pharmacology
- Clinical Research
Background:
- Extracranial bleeding is a frequent complication of oral anticoagulant (OAC) therapy in atrial fibrillation (AF) patients.
- The clinical significance of these bleeding events may be underestimated.
- This study aimed to characterize extracranial bleeding, identify risk factors, and quantify population attributable risk in AF patients on OACs.
Purpose of the Study:
- To characterize extracranial bleeding events using standardized severity definitions in patients with atrial fibrillation (AF) receiving oral anticoagulants (OACs).
- To identify baseline risk factors associated with these bleeding events.
- To quantify the population attributable fraction for extracranial bleeding in this patient cohort.
Main Methods:
- Analysis of data from 5 pivotal randomized trials involving patients with AF receiving OACs (direct OACs or warfarin).
- Primary outcome: first episode of extracranial major or clinically relevant nonmajor bleeding, defined by International Society on Thrombosis and Haemostasis criteria.
- Statistical methods included Kaplan-Meier for cumulative incidence and multivariable Cox and logistic regression for hazard ratios and population attributable fraction.
Main Results:
- Over 73,000 patients on OACs experienced clinically relevant extracranial bleeding, with a cumulative incidence of 26% over ~2 years.
- Major bleeds occurred in 7% and clinically relevant nonmajor bleeds in 19% of patients.
- Baseline risk factors accounted for 66%-69% of the population attributable bleeding risk, with gastrointestinal bleeds being common.
Conclusions:
- Extracranial clinically relevant bleeding is a common occurrence in AF patients treated with OACs.
- This broader definition of bleeding may better represent the overall bleeding burden compared to major bleeding alone.
- While identified risk factors explain a significant portion of bleeding risk, unmeasured factors likely contribute.
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.
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