Identifying risk factors for major bleeding in patients with atrial fibrillation using direct oral anticoagulants: a systematic review and meta-analysis.

BACKGROUND

Major bleeding (MB) remains a serious complication in atrial fibrillation (AF) patients treated with direct oral anticoagulants (DOACs), but effect estimates for individual factors vary across studies and have not been synthesized in a DOAC-specific framework.

OBJECTIVES

To provide a comprehensive DOAC-specific synthesis of risk factors associated with MB in AF patients.

METHODS

We systematically searched PubMed, Embase, and the Cochrane Library from their inception to December 2024. We included studies of DOAC-treated AF patients that reported associations between patient characteristics and MB. Random-effects meta-analyses were conducted when at least 2 studies evaluated the same risk factors using comparable definitions. Prespecified subgroup analyses were performed for the MB outcome and for individual DOAC agents.

RESULTS

Eighty-three studies involving 970 248 patients were included. Twenty-one variables were associated with MB. We confirmed several well-known risk factors for MB, including a history of bleeding, alcohol use, age ≥65 years, frailty, and high HAS-BLED (Hypertension, Abnormal renal/liver function, Stroke, Bleeding history or predisposition, Labile international normalized ratio, Elderly (>65 years), and Drugs/alcohol concomitantly) score. Importantly, this DOAC-focused synthesis also highlighted additional and previously underemphasized risk factors, including cancer, myocardial infarction or peripheral artery disease, heart failure, coronary artery disease, and the use of psychotropic or antiarrhythmic drugs. Overweight status and statin use were associated with a lower MB risk, although these findings should be interpreted with caution.

CONCLUSION

This meta-analysis provides an integrated, DOAC-specific, quantitative overview of MB risk factors across multiple clinical and treatment domains. The pooled estimates provide a contemporary evidence base to prioritize variables for refinement, recalibration, and validation of MB risk assessment strategies in DOAC-treated AF populations.