BACKGROUND: Triple antithrombotic therapy (TAT), combining dual antiplatelet therapy (DAPT) with oral anticoagulants, is commonly used in patients requiring long-term anticoagulation following acute coronary syndrome or percutaneous coronary intervention. However, TAT may increase the risk of hemorrhage. There is a dearth of data regarding the risks of bleeding with various oral anticoagulants in TAT in comparison with DAPT and individual anticoagulants and antiplatelets due to which we carried out the present study examining the real-world pharmacovigilance data. METHODS: Data were extracted from the USFDA Adverse Event Reporting System (AERS) from March 2004 to June 2024 using the Standardized MedDRA Query (SMQ) code for "haemorrhages." We employed the "case-non-case" approach in disproportionality analysis to detect safety signals for hemorrhage among anticoagulant, antiplatelet, dual antiplatelet and triple antithrombotic combinations. Reports including combinations of DAPT (acetylsalicylic acid and clopidogrel) with oral anticoagulants (acenocoumarol, apixaban, dabigatran, edoxaban, rivaroxaban, and warfarin) were analyzed. Signal detection used both frequentist (reporting odds ratio [ROR], proportional reporting ratio and Bayesian (Bayesian Confidence Propagation Neural Network, Multi-Item Gamma Poisson Shrinker algorithms. The lower limit of 95% confidence interval of ROR above 1 indicates higher reporting risk of bleeding. Following outcomes were evaluated for each TAT: death, disability and hospitalization. RESULTS: Of 20,626 unique reports, 812 involved TAT, 3,820 DAPT, and 15,995 individual antiplatelets. Most cases occurred in elderly patients (age ≥ 65 years) with a predominance of male patients. Rivaroxaban combined with DAPT presented the highest hemorrhage signal (ROR: 82.84
95% CI, 60.77-112.92), while apixaban showed the lowest (ROR: 13.11
95% CI, 9.39-18.3) and the other anticoagulants are as follows: warfarin (ROR: 15.96
95% CI: 18.36), dabigatran (ROR: 27.32
95% CI: 20.03-37.26) and acenocoumarol (ROR: 43.98
95% CI: 17.21-112.4). Mortality and hospitalization rates varied significantly among treatments, with rivaroxaban linked to the highest mortality. CONCLUSION: This study highlights the elevated hemorrhage risk associated with TAT, particularly with rivaroxaban, while apixaban appears safer in terms of bleeding and mortality. These findings underscore the need for cautious monitoring of bleeding outcomes with anticoagulant regimens, particularly rivaroxaban combinations for optimizing patient outcomes. However, the signals obtained in this study need to be validated in future trials.