Thrombotic and Hemorrhagic Adverse Events of Direct Oral Anticoagulants: An Analysis of Sex-Related Differences Using Food and Drug Administration Adverse Event Reporting System

Q: What is the clinical evidence from this study?

Study design: Observational. Population: Adverse events associated with direct oral anticoagulants (n=148490). Intervention: Apixaban vs. Dabigatran. Primary outcome: Gastrointestinal hemorrhage reporting odds ratio (ROR 2.32, 95% CI 2.20-2.45, p=<.001).

Q: What does this research mean for the field?

Apixaban and edoxaban are associated with significantly higher reporting risks for gastrointestinal hemorrhage compared to dabigatran, with RORs of 2.32 and 2.95, respectively. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.NEUTRAL.

Mehmet Şahinbaş; Burcu ŞAHİNBAŞ; Ezgi Ağadayı

doi:10.14744/anatoljcardiol.2025.5827

January 1, 2026The Anatolian Journal of CardiologyOpen Access

Thrombotic and Hemorrhagic Adverse Events of Direct Oral Anticoagulants: An Analysis of Sex-Related Differences Using Food and Drug Administration Adverse Event Reporting System

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Key result

Apixaban was associated with a significantly higher risk of reported gastrointestinal hemorrhage compared with dabigatran (ROR 2.32), with hemorrhagic events generally more common in females and thrombotic events in males across DOACs.

Why the study?

Do Factor Xa inhibitors alter the reporting risk of hemorrhagic and thrombotic adverse events compared to dabigatran, and do sex-specific differences exist in these safety profiles?

Key Points

To evaluate sex-specific differences in the most frequently reported hemorrhagic and thrombotic adverse events associated with direct oral anticoagulant therapy using postmarketing surveillance data.
Conducted a retrospective pharmacovigilance disproportionality analysis of FAERS reports from each drug's approval date through 2024, restricting cases to those reported by healthcare professionals with a single direct oral anticoagulant as primary suspect.
Analyzed reports for dabigatran (n = 37,537), rivaroxaban (n = 61,983), apixaban (n = 43,930), and edoxaban (n = 5040) across six adverse events, using dabigatran as the reference comparator to compute reporting odds ratios (RORs) with 95% CIs.
Gastrointestinal hemorrhage reporting risk was significantly higher with apixaban (ROR = 2.32, P < .001, 95% CI: 2.20-2.45) and edoxaban (ROR = 2.95, P < .001, 95% CI: 2.54-3.42) versus dabigatran, with events reported significantly more often in females taking dabigatran (P < .001).
Intracranial hemorrhage was reported more frequently in males receiving dabigatran (P = .003) and rivaroxaban (P = .004), while overall disproportionality was increased for edoxaban (ROR = 1.76, P < .001, 95% CI: 1.49-2.09) and rivaroxaban (ROR = 1.09, P = .007, 95% CI: 1.02-1.15).
All agents showed higher reporting risk for myocardial infarction (apixaban ROR = 2.37, P < .001, 95% CI: 2.08-2.71), especially in males, whereas pulmonary embolism and ischemic stroke were more frequently reported in female rivaroxaban users (P < .001 and P = .018).

Study Design

Type

Observational (n=148,490)

Structured PICO

Do Factor Xa inhibitors alter the reporting risk of hemorrhagic and thrombotic adverse events compared to dabigatran, and do sex-specific differences exist in these safety profiles?

P

Population

148,490 adverse event reports from the FDA Adverse Event Reporting System involving patients treated with direct oral anticoagulants, analyzed to identify sex-specific differences in hemorrhagic and thrombotic complications.

E

Exposure

Factor Xa inhibitors (rivaroxaban, apixaban, edoxaban)

C

Comparator

Dabigatran (Factor IIa inhibitor) serving as the reference comparator

O

Outcome

Reporting odds ratios (RORs) for six major adverse events: gastrointestinal hemorrhage, intracerebral hemorrhage, pulmonary embolism (PE), deep vein thrombosis (DVT), ischemic stroke, and myocardial infarction (MI)safety

Main Result

Odds Ratio: 2.32 (95% CI 2.2–2.45)

p-value: p=<.001

Limitations

Reporting biases inherent to spontaneous reporting systems
Incomplete or missing data, including missing sex information in many reports
Lack of denominator information (prescription data) to normalize adverse event reports to actual drug users
Inability to establish causal interference or direct comparison of absolute risk between drugs
Subject to reporting biases inherent to disproportionality analyses
Incomplete or missing data (e.g., sex not specified in >50% of edoxaban reports)
Exclusion of healthy populations and lack of denominator information (prescription data)
Potential confounding factors and missing indication-specific information
ROR provides only an approximate estimate of disproportionality and does not allow for causal inference

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Answers are grounded in this paper and cite their sources.

Implication

Significant sex-specific differences exist in the safety profiles of direct oral anticoagulants, highlighting the need for individualized anticoagulant selection based on sex and system-specific adverse event risks.

Abstract

BACKGROUND: Sex-related differences in the safety profiles of direct oral anticoagulants (DOACs) remain insufficiently understood. This study aimed to evaluate sex-specific differences in the most frequently reported hemorrhagic and thrombotic adverse events (AEs) associated with DOAC therapy using data from the Food and Drug Administration Adverse Event Reporting System (FAERS). METHODS: A retrospective pharmacovigilance analysis was conducted using FAERS reports from each DOAC's approval date through 2024. Only cases in which a single DOAC was designated as the primary suspect and the report was submitted by a healthcare professional were included. Six major AEs were evaluated: gastrointestinal hemorrhage, intracerebral hemorrhage, pulmonary embolism (PE), deep vein thrombosis, ischemic stroke, and myocardial infarction (MI). Dabigatran served as the reference comparator. Reporting odds ratios (RORs) with 95% CIs were calculated to identify disproportionate reporting signals. RESULTS: Hemorrhagic and thrombotic AE patterns demonstrated notable sex differences. Gastrointestinal hemorrhage risk was higher with apixaban (ROR = 2.32, P < .001, 95% CI: 2.20-2.45) and edoxaban (ROR = 2.95, P < .001, 95% CI: 2.54-3.42) compared with dabigatran, while female dabigatran users reported these events more frequently (P < .001). Intracranial hemorrhage was reported more often among males using dabigatran and rivaroxaban (P = .003 and P = .004). All DOACs were associated with increased MI reports (e.g., apixaban ROR = 2.37, P < .001, 95% CI: 2.08-2.71), particularly among males. Conversely, PE and ischemic stroke were more frequently reported in female rivaroxaban users (P < .001 and P = .018). CONCLUSIONS: Significant sex-specific differences exist in DOAC safety profiles. Recognizing these patterns may inform individualized anticoagulant selection and enhance pharmacovigilance-driven personalized medicine.

Discussion

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Cite This Study

Şahinbaş et al. (2026) conducted an observational in Adverse events associated with direct oral anticoagulants (n=148,490). Apixaban vs. Dabigatran was evaluated on Gastrointestinal hemorrhage reporting odds ratio (ROR 2.32, 95% CI 2.20-2.45, p=<.001). Apixaban was associated with a significantly higher risk of reported gastrointestinal hemorrhage compared with dabigatran (ROR 2.32), with hemorrhagic events generally more common in females and thrombotic events in males across DOACs.

synapsesocial.com/papers/698d6dc15be6419ac0d52f07 https://doi.org/10.14744/anatoljcardiol.2025.5827

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Thrombotic and Hemorrhagic Adverse Events of Direct Oral Anticoagulants: An Analysis of Sex-Related Differences Using Food and Drug Administration Adverse Event Reporting System

Key Points

Study Design

Structured PICO

Main Result

Limitations

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

Thrombotic and Hemorrhagic Adverse Events of Direct Oral Anticoagulants: An Analysis of Sex-Related Differences Using Food and Drug Administration Adverse Event Reporting System

Key Points

Study Design

Structured PICO

Main Result

Limitations

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

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