ESC Congress 2026 Abstract · Oct 26, 2026

Efficacy and safety of factor XIa inhibitors for stroke prevention: a reconstructed individual patient data meta-analysis

By Keswani K, Kusimw'iragi P, Gelani M et al.

Background: Factor XIa inhibitors represent a novel anticoagulant class targeting the intrinsic coagulation pathway, potentially offering stroke prevention with reduced bleeding risk compared to direct oral anticoagulants. Despite promising phase 2 data, comprehensive evaluation across diverse patient populations remains limited. Traditional aggregate meta-analyses cannot adequately address heterogeneity in patient characteristics and comparator regimens. Purpose: We performed an individual patient data meta-analysis to evaluate efficacy and safety of Factor XIa inhibitors (milvexian, asundexian, abelacimab) for stroke prevention across multiple clinical settings, using reconstructed pseudo-IPD from published Kaplan-Meier curves. Our objective was to determine pooled treatment effects on ischemic stroke/systemic embolism and major bleeding while accounting for between-trial heterogeneity. Methods: We reconstructed pseudo-IPD for 31,681 patients from four phase 2/3 trials (AXIOMATIC-SSP, PACIFIC-STROKE, AZALEA-TIMI 71, OCEANIC-AF) using the Guyot algorithm. Validation against published hazard ratios demonstrated 65% achieved good-to-excellent concordance (mean relative difference 18.4%). We conducted both one-stage (stratified Cox regression) and two-stage (random-effects pooling) IPD meta-analyses. Pre-specified sensitivity analyses excluded trials with poor validation quality. Comprehensive audit of 51 verification checks confirmed 94% pass rate, validating analysis integrity from raw data to final estimates. Results: Among high-quality trials (n=8,653 patients, 613 events), Factor XIa inhibitors demonstrated significant 29% relative risk reduction in ischemic stroke/systemic embolism (pooled HR 0.71, 95%CI 0.56-0.90, p=0.005; I²=22.1%) with low heterogeneity. Major bleeding showed neutral effect (HR 1.03, 95%CI 0.67-1.57, p=0.902), though substantial heterogeneity reflected diverse comparators (placebo vs. rivaroxaban). One-stage and two-stage approaches demonstrated excellent agreement in validated trials. The stroke risk reduction translates to approximately 1.5% absolute risk reduction annually in high-risk populations (NNT=68). Conclusion: Factor XIa inhibitors demonstrate clinically meaningful stroke prevention efficacy with potentially favorable bleeding profiles. The 29% relative risk reduction represents a significant advancement over standard anticoagulation. However, inter-trial heterogeneity driven by methodological quality differences underscores the critical need for rigorous data validation in reconstructed IPD meta-analyses. Future head-to-head trials comparing Factor XIa inhibitors directly to DOACs in adequately powered atrial fibrillation cohorts are warranted to definitively establish their clinical role.Forest plot showing two stage meta analysisFor image description, please refer to the figure legend and surrounding text.Reconstruction summaryFor image description, please refer to the figure legend and surrounding text.

doi.org/10.1093/eurheartj/ehag785.2696Open accessInterventions