Background: Direct oral anticoagulants (DOACs) – apixaban, rivaroxaban, dabigatran, and edoxaban– are increasingly preferred over warfarin for stroke prevention in atrial fibrillation and treatment of venous thromboembolism. Despite guideline support, many clinicians remain cautions due to variable bleeding profiles across agents. While randomized trials demonstrate safety advantages for DOACs, their stringent inclusion criteria limit real-world generalizability. Observational studies, which reflect routine practice, are essential to assess bleeding and thromboembolic risks in broader populations. Comparative evaluation of major bleeding, gastrointestinal (GI) bleeding, intracranial hemorrhage (ICH), and stroke can inform optimal anticoagulant selection.

Objectives: To evaluate observational data comparing bleeding outcomes between DOACs and warfarin in general adult populations, focusing on four clinical outcomes: Major bleeding, GI bleeding, ICH, and stroke.

Methods: Recent high-powered observational studies, indexed in PubMed and Embase, comparing DOACs with warfarin in adults (≥ 18 years) population were reviewed to assess at least one of the following outcomes: Major bleeding, GI bleeding, ICH, and stroke. Studies restricted to specific subgroups (e.g., cancer, dialysis, cirrhosis) were excluded to maintain generalizability. Priority was given to large cohort studies employing adjusted analyses such as propensity score matching or multivariable modeling.

Results: Across diverse adult populations, DOACs were associated with either similar or lower risk of major bleeding compared to warfarin (HR 0.70-1.00). GI bleeding risk varied by DOAC agents: Apixaban showed consistently lower rates (HR 0.60-0.80), while rivaroxaban and high dose dabigatran were associated with slightly elevated risk (HR 1.10-1.30). All DOACs showed significant reduced risk of ICH relative to warfarin, with HR ranging from 0.40 to 0.60 – a 40-60% relative risk reduction. Stroke outcomes were generally equivalent or improved with DOACs, with most HRs ranging from 0.70 to 0.90, reinforcing their efficacy in preventing thromboembolic events. These results were consistent across diverse healthcare systems and large real-world datasets.

Conclusions: This review provides robust real-world evidence that DOACs offer a superior safety and effectiveness profile compared to warfarin in adult patients requiring anticoagulation. DOACs significantly reduce the incidence of ICH and stroke– two of the most clinically devasting complications– while maintaining comparable or lower rates of major and GI bleeding. These findings validate guideline recommendations and strongly support the preferential use of DOACs as the standard of care for anticoagulation in everyday clinical practice.

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2025
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