What is the clinical evidence from this study?

Study design: Systematic Review. Population: Atrial fibrillation. Intervention: Factor XI inhibitors vs. Direct oral anticoagulants (DOACs). Primary outcome: Major bleeding (RR 0.31, 95% CI 0.21-0.46).

April 22, 2026Open Access

Factor XI inhibitors versus direct oral anticoagulants for stroke prevention in atrial fibrillation: a systematic review of efficacy and safety

Key Result

Factor XI inhibitors significantly reduced major bleeding (RR 0.31) but increased the risk of stroke or systemic embolism (RR 3.17) compared with DOACs in patients with atrial fibrillation.

Key Points

This review evaluates the efficacy and safety of factor XI inhibitors versus direct oral anticoagulants for stroke prevention in atrial fibrillation.
Included 20 studies: 11 randomized controlled trials and 9 other reviews or cohort studies.
Compared efficacy and safety outcomes of FXI inhibitors with direct oral anticoagulants in atrial fibrillation patients.
Primary outcomes were stroke or systemic embolism, major bleeding, and all-cause mortality.
FXI inhibitors showed a reduced risk of major bleeding (RR 0.31; 95% CI 0.21–0.46) compared to DOACs.
Increased risk of stroke or systemic embolism with FXI inhibitors (RR 3.17; 95% CI 2.18–4.62).
No significant difference in all-cause mortality (RR 0.85; 95% CI 0.67–1.08).

Study Design

Type

Systematic Review

Structured PICO

Do Factor XI inhibitors reduce stroke or systemic embolism and major bleeding in patients with atrial fibrillation compared to DOACs?

Population

Patients diagnosed with atrial fibrillation (AF) from 20 studies (11 RCTs, 5 systematic reviews or meta-analyses, and 4 narrative, cohort, or modeling studies).

Intervention

Factor XI (FXI) inhibitors (e.g., asundexian, abelacimab, milvexian)

Comparator

Direct oral anticoagulants (DOACs) (e.g., apixaban, rivaroxaban)

Outcome

Stroke or systemic embolism, major bleeding, and all-cause mortalityhard clinical

Factor XI inhibitors significantly reduce major bleeding compared to DOACs but are less effective for stroke prevention in patients with atrial fibrillation.

Main Result

Effect estimate: RR 0.31 (95% CI 0.21-0.46)

Limitations

Heterogeneity of study populations, including differences in AF severity, comorbidities, and follow-up durations
Reliance on phase 2 trials and interim data from phase 3 studies
Absence of standardized assessments for patient-reported outcomes
Sparse real-world evidence for FXI inhibitors compared with DOACs

Abstract

Background: Atrial fibrillation (AF) substantially increases the risk of ischemic stroke (IS), underscoring the need for effective anticoagulation strategies. Direct oral anticoagulants (DOACs) have largely supplanted vitamin K antagonists (VKAs) due to their favorable safety profile and ease of use. Factor XI (FXI) inhibitors, which target the intrinsic coagulation pathway, are emerging as potential alternatives that may offer reduced bleeding risk. This systematic review evaluates the efficacy and safety of FXI inhibitors compared with DOACs for stroke prevention in AF. Methods: A total of 20 studies fulfilled the inclusion criteria, comprising 11 randomized controlled trials (RCTs), five systematic reviews or meta-analyses, and four narrative, cohort, or modeling studies. Eligible investigations compared FXI inhibitors with DOACs in patients diagnosed with AF. The primary outcomes assessed were stroke or systemic embolism, major bleeding, and all-cause mortality. Methodological quality was evaluated according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) framework, the revised Cochrane Risk of Bias 2 (RoB 2) tool for RCTs, and the Newcastle-Ottawa Scale (NOS). Results: FXI inhibitors were associated with a significant reduction in major bleeding relative risk (RR) 0.31; 95% confidence interval (CI) 0.21–0.46 and clinically relevant non-major bleeding (RR 0.66; 95% CI 0.47–0.93) compared with DOACs. Conversely, FXI inhibitors demonstrated an increased risk of stroke or systemic embolism (RR 3.17; 95% CI 2.18–4.62), as observed in the OCEANIC-AF trial hazard ratio (HR) 3.79; 95% CI 2.46–5.83. No significant difference was noted in all-cause mortality (RR 0.85; 95% CI 0.67–1.08). Limited evidence suggests that FXI inhibitors may also reduce bleeding-related hospitalizations. Discussion: FXI inhibitors provide a favorable bleeding profile but are less effective than DOACs for stroke prevention in patients with AF. Further long-term RCTs are warranted to delineate their role, particularly in populations at high risk of bleeding.

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