Prior Oral Anticoagulant Use May Influence Stroke, Bleeding Risk in AF

Oral anti-coagulant (OAC)-naive individuals with atrial fibrillation (AF) showed a significantly smaller increase in stroke or systemic embolism with the use of asundexian versus apixaban than individuals with prior OAC exposure, according to new findings.1

This secondary analysis of the Oral Factor 11a Inhibitor Asundexian as Novel Antithrombotic–Atrial Fibrillation (OCEANIC-AF) randomized clinical trial involved nearly 2500 OAC-naive patients and more than 12,000 OAC-experienced patients.

“These results suggest that patients with limited prior exposure to OACs may provide an important population for the evaluation of factor XI/XIa inhibitors as a new class of anticoagulants,” wrote the investigative team, led by John H. Alexander, MD, MHS, Duke Clinical Research Institute, division of cardiology, Duke University School of Medicine.

Although OACs are known to reduce the risk of stroke or systemic embolism in patients with atrhythmia, little or no prior exposure to OACs may put patients at a greater risk for adverse outcomes, including thromboembolic events and/or bleeding.2 OCEANIC-AF was halted early due to daily asundexian 50 mg, a novel factor XIa inhibitor, providing less efficacy than apixaban, a factor Xa inhibitor, at preventing stroke or systemic embolism.3

Enrollment criteria in the Phase 3 trial included ≤6 consecutive weeks of prior treatment with OAC at randomization, as patients already on an OAC could respond differently to asundexian compared with apixaban. Based on these criteria, this prespecified exploratory subgroup analysis evaluated the effect of asundexian versus apixaban stratified by treatment-naive or experienced OAC cohorts.

Similar to the primary trial analysis, the outcomes for the subgroup analysis were stroke or systemic embolism, with a safety outcome of International Society on Thrombosis and Haemostasis (ISTH) major bleeding. For the overall OCEANIC-AF population, 2493 (17%) were OAC naive (mean age, 72.6 years; 59% male) and 12,317 (83%) were OAC experienced (mean age, 74.2 years; 66% male).1

Upon analysis, OAC-naive patients treated with asundexian experienced a stroke or systemic embolism rate of 0.8% (n = 10), compared with 1.4% (n = 88) in the OAC-experienced arm. For the apixaban arm, those who were OAC naive had a stroke or systemic embolism rate of 0.6% (n = 7), compared with 0.3% (n = 19) in those OAC-experienced.

Further analysis revealed that patients who were OAC-naive had a smaller increase in stroke or systemic embolism with asundexian relative to apixaban (hazard ratio [HR], 1.42; 95% CI, 0.54–3.73) than those OAC experienced (HR, 4.66; 95% CI, 2.84–7.65; P for interaction =.03).

Bleeding outcomes in the safety analysis showed lower rates among both OAC-naive patients (0.2% [2 of 1228]) and OAC-experienced patients (0.2% [15 of 6145]) assigned asundexian than OAC-naive patients (1.0% [13 of 1249]) and OAC-experienced patients (0.7% [40 of 6115]) receiving apixaban.

Alexander and colleagues noted the OAC status used in the OCEANIC-AF trial could be a marker of individual characteristics impacting the risk of stroke or systemic embolism, and the benefit of OACs. In addition, they pointed to the complex interaction between the use of OACs and the patient, practitioner, and health system.

“OAC use may not be a static characteristic and has likely changed from years ago when vitamin K antagonists (VKAs) were the dominant OAC to today when direct OACs are widely available,” they wrote. “Additional research is needed into the characteristics of OAC-naive and OAC-experienced patients that drive stroke risk and, perhaps, the lack of benefit from asundexian.”

References

1. Alexander JH, Lydon EJ, Piccini JP, et al. Asundexian or Apixaban in Patients With Atrial Fibrillation According to Prior Oral Anticoagulant Use: A Subgroup Analysis of the OCEANIC-AF Randomized Clinical Trial. JAMA Cardiol. Published online March 26, 2025. doi:10.1001/jamacardio.2025.0277

2. Garcia DA, Lopes RD, Hylek EM. New-onset atrial fibrillation and warfarin initiation: high risk periods and implications for new antithrombotic drugs. Thromb Haemost. 2010;104(6):1099-1105. doi:10.1160/TH10-07-0491

3. Piccini JP, Patel MR, Steffel J, et al. Asundexian versus Apixaban in Patients with Atrial Fibrillation. N Engl J Med. 2025;392(1):23-32. doi:10.1056/NEJMoa2407105