Background: Patients with atrial fibrillation (AF) are at a higher risk of stroke. For non-valvular AF (NVAF), direct oral anticoagulants (DOACs) are the preferred initial treatment for stroke prevention due to their lower risk of stroke, mortality, and intracranial hemorrhage compared to warfarin. The global prevalence of atrial fibrillation is increasing due to the aging population. However, many patients, especially elderly individuals with frailty and multiple comorbidities, find it challenging to adhere to DOAC therapy. Factors such as frailty, dementia, anemia, and chronic kidney disease play a significant role in the decision-making process for prescribing anticoagulants in older patients. Despite the benefits of DOACs, there are concerns about bleeding risk in specific patient subgroups, such as those with mechanical heart valves, thrombotic antiphospholipid syndrome, and advanced renal and liver disease.

Methods: We conducted a meta-analysis by searching PubMed, Scopus, and Cochrane Central for studies comparing factor XI/XIa inhibitors with DOACs in patients with NVAF. Our primary outcome was the occurrence of major or clinically relevant non-major bleeding (CRNM) according to the ISTH criteria. Statistical analysis was done using Review Manager. Heterogeneity was examined using I2 statistics.

Results: We evaluated data from two RCTs with 2042 NVAF patients. In AZALEA-TIMI 71, 1287 patients received abelacimab 150 mg (n = 427), abelacimab 90 mg (n = 425), or rivaroxaban 20 mg (n = 430). In PACIFIC-AF, 755 patients were assigned to asundexian 20 mg (n=249), asundexian 50 mg (n=254), or apixaban (n=250). The patients had an average CHA2DS2-VASc score of 4.45 (±1.15) and a mean age of 73.6 years (±8.5). Of the participants, 42.45% were female, 25% had preexisting chronic kidney disease, 13.85% had a history of prior ischemic stroke, and 8.6% had a history of prior bleeding. The primary endpoint, major or CRNM (HR 0.31; 95% CI 0.22-0.44; p < 0.00001; I2=0%), was significantly lower in patients treated with Factor XI therapeutics compared with Factor Xa inhibitors.

Conclusion: Patients assigned to either dose of Factor XI inhibitors asundexian or abelacimab exhibited significantly lower rates of bleeding compared to the DOACs. The inhibition of Factor XI appears to be a promising strategy for preventing abnormal blood clots and reducing the risk of bleeding in patients with atrial fibrillation. Further evaluation in a Phase 3 trial is needed.