OCEANIC-AF Stopped Early for Inferior Efficacy After 14,830 Patients: What the Failure of This FXIa Inhibitor Means for Anticoagulation Research

The OCEANIC-AF trial — one of the largest atrial fibrillation anticoagulation studies in recent years — was terminated early after an independent data monitoring committee (IDMC) determined that asundexian (BAY 2433334), Bayer’s investigational factor XIa (FXIa) inhibitor, was inferior to apixaban (Eliquis®) in preventing stroke and systemic embolism.

The termination decision

On November 19, 2023, Bayer announced that the IDMC had recommended stopping the Phase 3 trial based on interim surveillance showing inferior efficacy of asundexian versus the apixaban control arm. At the time of termination, 14,830 of a planned 18,000 patients had been randomised across 1,069 sites.

Trial design

OCEANIC-AF (NCT05643573) was a double-blind, double-dummy, Phase 3 trial enrolling patients with atrial fibrillation at elevated stroke risk. It launched December 5, 2022, and carried three co-primary endpoints: (1) the composite of stroke or systemic embolism (efficacy), (2) ISTH major bleeding (safety), and (3) the composite of stroke, systemic embolism, or ISTH major bleeding. ISTH major bleeding was defined as fatal bleeding, bleeding into a critical organ, a haemoglobin drop of ≥2 g/dL, or transfusion of ≥2 units of packed red blood cells.

Results

Full results were presented at the European Society of Cardiology (ESC) Annual Congress on September 1, 2024, and simultaneously published in the New England Journal of Medicine (DOI: 10.1056/NEJMoa2407105). Patients on asundexian experienced significantly more strokes and systemic embolic events than those on apixaban (1.3% vs. 0.4%; hazard ratio 3.79). Asundexian did, however, produce fewer major bleeding events than apixaban during the observation period.

What this means for FXIa inhibition

The genetic rationale for FXIa inhibition — derived from observations that individuals with congenital factor XI deficiency have lower rates of stroke without a commensurate increase in bleeding — had generated substantial excitement. OCEANIC-AF demonstrated that pharmacological FXIa inhibition at the dose tested is insufficient to prevent cardioembolic stroke in atrial fibrillation, even as it reduces bleeding. Whether higher degrees of FXIa inhibition, different patient populations, or alternative FXIa inhibitors can thread that needle remains an open research question. Thirteen pre-specified secondary endpoints — including ischemic stroke, all-cause mortality, cardiovascular death, and intracranial haemorrhage — should be interpreted in the context of the early termination.