Risk factors of major bleeding associated with direct oral anticoagulant treatment in patients with venous thromboembolism: a systematic review and meta-analysis

Q: What is the clinical evidence from this study?

Study design: Systematic Review and Meta-Analysis. Population: Venous thromboembolism (VTE) (n=258726). Intervention: Age (and other prognostic risk factors) vs. Younger age / absence of risk factors. Primary outcome: Major bleeding (OR 1.19, 95% CI 0.89-1.59).

Q: What does this research mean for the field?

In patients with venous thromboembolism treated with direct oral anticoagulants, age is not statistically significantly associated with the risk of major bleeding, while evidence for other prognostic factors remains limited and of low certainty. Novelty: ClaimNovelty.SYNTHESIS. Consensus alignment: ConsensusAlignment.NEUTRAL.

Hairong Zhan; Fuxin Ma; Jintuo Zhou; Jinhua Zhang

doi:10.3389/fmed.2026.1869818

October 15, 2026Frontiers in MedicineOpen Access

Risk factors of major bleeding associated with direct oral anticoagulant treatment in patients with venous thromboembolism: a systematic review and meta-analysis

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Key result

Age is not associated with major bleeding risk in DOAC-treated venous thromboembolism.

OR 1.19
95% CI 0.89-1.59
n=258,726

Why the study?

Systematic evaluations of prognostic factors associated with major bleeding during DOAC treatment in patients with VTE remain scarce.

Do prognostic risk factors, such as non-recommended dosing or age, increase the risk of major bleeding in adult patients with venous thromboembolism treated with direct oral anticoagulants?

Key Points

To identify and evaluate prognostic factors associated with major bleeding in patients receiving direct oral anticoagulants for venous thromboembolism.
Conducted a systematic review and meta-analysis adhering to PRISMA guidelines by searching PubMed and Web of Science databases for studies published before September 18, 2026.
Identified studies examining prognostic and risk factors for major bleeding associated with DOAC therapy in patients diagnosed with venous thromboembolism.
Quantitative pooling was feasible only for age across 2 studies, which demonstrated no statistically significant association with major bleeding based on very low-certainty evidence.
Evidence for other prognostic factors—including declining adherence, composite risk scores (ATRIA, ORBIT, VTE-BLEED), and prior warfarin therapy—derived from single studies with low or very low certainty.

Study Design

Type

Systematic Review and Meta-Analysis (n=258,726)

Structured PICO

Do prognostic risk factors, such as non-recommended dosing or age, increase the risk of major bleeding in adult patients with venous thromboembolism treated with direct oral anticoagulants?

P

Population

258,726 adult patients with venous thromboembolism treated with direct oral anticoagulants across 7 observational studies.

E

Exposure

Direct oral anticoagulants (DOACs) as a class (including apixaban, rivaroxaban, and edoxaban) for the treatment of VTE, specifically evaluating the impact of clinical prognostic factors (such as age, non-recommended subtherapeutic dosing, and medication adherence) on bleeding risk.

C

Comparator

Patients without the specific evaluated prognostic risk factors (e.g., standard label-recommended DOAC dosing versus non-recommended dosing, or varying age groups) or patients who did not experience major bleeding.

O

Outcome

Major bleeding, defined according to the International Society on Thrombosis and Haemostasis (ISTH) criteria (symptomatic bleeding in a critical area or organ; bleeding causing a decrease in hemoglobin level of at least 2 g/dL or requiring transfusion of at least two units of whole blood or red blood cells; or fatal bleeding).safety

Main Result

Odds Ratio: 1.19 (95% CI 0.89–1.59)

Current evidence on prognostic risk factors for major bleeding in DOAC-treated VTE patients is largely derived from limited, low-certainty observational data, emphasizing the need for robust prospective studies to refine bleeding risk assessment.

Limitations

Literature search restricted to PubMed and Web of Science, potentially missing relevant studies in other databases.
Most prognostic factors were evaluated in only a single study, preventing quantitative meta-analysis for factors other than age.
Included studies were predominantly retrospective observational studies with high risk of bias.
Pooling different DOAC agents may have obscured drug-specific differences in bleeding risk.
Heterogeneity across studies in patient populations, prognostic factor definitions, and covariate adjustment.
Data were sourced only from PubMed and Web of Science, which may not capture all relevant studies.
Only seven observational studies, four of which were retrospective, were included.
Most prognostic factors were evaluated in only one study, and the certainty of evidence was predominantly low or very low.
The included studies differed in patient populations, definitions of prognostic factors, statistical models, and covariate adjustment, which may have introduced heterogeneity and residual confounding.
Pooling different DOAC agents may have obscured agent-specific differences in bleeding risk due to unavailable drug-specific effect estimates.

Implication

Does not support age-based bleeding risk stratification in VTE patients on DOACs; leaves open identification of reliable prognostic factors.

Abstract

Background Direct oral anticoagulants (DOACs) are commonly prescribed for venous thromboembolism (VTE), but major bleeding (MB) remains an important complication of treatment. Despite their widespread use, systematic evaluations of prognostic factors associated with major bleeding during DOAC treatment remain scarce. To address this gap, we conducted a systematic review to identify prognostic factors associated with major bleeding during DOAC treatment in patients with VTE. This study seeks to enhance the safety and efficacy of anticoagulation therapy for VTE patients. Method and results A systematic review and meta-analysis were conducted to search the PubMed and Web of Science databases for studies published before September 18, 2026. The review adhered to predefined inclusion and exclusion criteria to identify studies that investigated risk factors for major bleeding associated with DOAC treatment in patients diagnosed with VTE. Among the evaluated prognostic factors, quantitative pooling was possible only for age, which was reported in two studies; the remaining factors were summarized individually. Low-certainty evidence from a single study suggested a possible association between non-recommended dosing regimens and major bleeding. Evidence regarding declining adherence was also limited and of very low certainty. For age, very low-certainty evidence from the pooled analysis of two studies did not demonstrate a statistically significant association with major bleeding. Conclusion The available evidence suggests possible associations between several prognostic factors and major bleeding in patients with VTE treated with DOACs; however, most findings are supported by low- or very low-certainty evidence and frequently by single studies. These findings should therefore be interpreted cautiously and require validation in larger, high-quality prospective studies.

Discussion

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Cite This Study

Zhan et al. (2026) conducted a systematic review and meta-analysis in Venous thromboembolism (VTE) (n=258,726). Age (and other prognostic risk factors) vs. Younger age / absence of risk factors was evaluated on Major bleeding (OR 1.19, 95% CI 0.89-1.59). A pooled analysis of two studies found no statistically significant association between age and the risk of major bleeding in patients with venous thromboembolism treated with direct oral anticoagulants (OR 1.19).

synapsesocial.com/papers/6ad49f5fcc23993462cc5310 https://doi.org/10.3389/fmed.2026.1869818

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Risk factors of major bleeding associated with direct oral anticoagulant treatment in patients with venous thromboembolism: a systematic review and meta-analysis

Key Points

Study Design

Structured PICO

Main Result

Limitations

Implication

Abstract

Discussion

Cite This Study

Risk factors of major bleeding associated with direct oral anticoagulant treatment in patients with venous thromboembolism: a systematic review and meta-analysis

Key Points

Study Design

Structured PICO

Main Result

Limitations

Implication

Abstract

Discussion

Cite This Study

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