# Dose‐Response Efficacy and Safety of Factor XI/XIa Inhibitors in Atrial Fibrillation; a Systematic Review and Meta‐Analysis With Subgroup Exploration and Trial Sequential Validation

## TL;DR

Factor XI/XIa inhibitors reduce bleeding in atrial fibrillation patients but increase stroke and embolism risks compared to other anticoagulants.

## Contribution

This study provides a meta-analysis and trial sequential validation of Factor XI/XIa inhibitors in AF, highlighting their bleeding benefits and increased stroke risk.

## Key findings

- Factor XI/XIa inhibitors significantly reduced major bleeding compared to DOACs.
- Stroke and systemic embolism risks were increased with Factor XI/XIa inhibitors.
- No significant differences in mortality or serious adverse events were observed.

## Abstract

Factor XI/XIa inhibitors are emerging anticoagulants with potential to reduce bleeding complications in atrial fibrillation (AF) patients. This meta‐analysis evaluated their efficacy and safety compared to direct oral anticoagulants (DOACs) and explored dose optimization.

A systematic search of PubMed, Cochrane, and Embase was conducted through March 2025 following PRISMA guidelines. Randomized controlled trials (RCTs) comparing Factor XI/XIa inhibitors with DOACs in AF patients were included. Outcomes assessed were major bleeding, stroke, systemic embolism, all‐cause and cardiovascular mortality and serious adverse events. Risk ratios (RR) with 95% confidence intervals (CI) were pooled using a Mantel‐Haenszel random‐effects model. Heterogeneity was evaluated with the I² statistic, and evidence certainty assessed by the GRADE approach. Trial Sequential Analysis (TSA) was performed.

Three RCTs including 16,772 patients (mean age 73 years, CHA₂DS₂‐VASc 3.9–5) were analyzed. Factor XI/XIa inhibitors significantly reduced major bleeding (RR: 0.41, 95% CI: 0.36–0.46, I² = 0%) compared to DOACs. However, stroke risk was increased (RR: 3.42, 95% CI: 2.62–4.46), particularly with asundexian 50 mg (RR: 4.02). No significant differences were observed in all‐cause mortality (RR: 0.82) or cardiovascular death (RR: 1.05). Systemic embolism risk was higher (RR: 4.26), while serious adverse events were comparable (RR: 0.95). TSA indicated encouraging safety outcomes but highlighted the need for further large‐scale studies.

Factor XI/XIa inhibitors lower major bleeding risk in AF patients but increase stroke and systemic embolism rates without impacting mortality.

Efficacy and Safety of Factor XI/XIa Inhibitors vs DOAC in Atrial Fibrillation.