The primary results of the OCEANIC-AF trial were unveiled at the European Society of Cardiology Congress on 1 September 2024.1 Data presentation was eagerly awaited since 19 November 2023, when the trial was stopped prematurely based on the recommendation of the Independent Data Monitoring Committee due to the inferior efficacy of asundexian compared to apixaban.2
OCEANIC-AF1 is a phase 3 multicentre, international, randomized, double-blind trial designed to evaluate the efficacy and safety of the activated factor XI (FXI) inhibitor asundexian compared to apixaban in patients with atrial fibrillation (AF) at risk for stroke. This trial is part of the larger OCEANIC program, which also includes the OCEANIC-STROKE trial (investigating asundexian in patients with recent noncardioembolic ischaemic stroke or temporary stroke-like symptoms on top of standard antiplatelet therapy) and the OCEANIC-AFINA trial (investigating asundexian in patients with AF deemed ineligible for current oral anticoagulants).
Anticoagulation with FXI inhibitors in patients with AF
AF is the most common sustained arrhythmia in current practice and is associated with an increased risk of stroke and systemic thromboembolism, which in most cases requires long-term treatment with oral anticoagulation.3–6 Despite the advent of direct-acting oral anticoagulants (DOACs), which have become a mainstay of modern practice, anticoagulation therapy in patients with AF remains burdened by the occurrence of bleeding. The search for novel agents with a lower risk of bleeding is a topic of considerable interest.7–11 Currently available DOACs are able to inhibit both pathologic thrombosis and physiologic haemostasis due to their ability to inhibit either factor X or factor II. Given that FXI is primarily involved in thrombus formation but less involved in haemostasis,12–14 selective inhibition of FXI may allow for the antagonization of thrombus formation without increasing the risk of bleeding. This concept is supported by previous observations indicating that patients with congenital FXI deficiency exhibit a reduced rate of cardiovascular events without an increased rate of spontaneous bleeding.12 Asundexian is an oral small molecule that selectively inhibits the activated form of FXI.12 In the PACIFIC-AF trial, asundexian at doses of 20 mg and 50 mg once daily demonstrated a lower rate of bleeding compared to apixaban in patients with AF, with 92% in vivo inhibition of activated FXI at the 50 mg daily dose.15 Overall, the results of randomized phase 2 trials with asundexian and other FXI inhibitors were promising,16 but insufficient to conclusively assess their comparative efficacy and safety to DOACs, requiring evaluation in large randomized trials powered for clinical outcomes.
OCEANIC-AF: design, results, and perspectives
The OCEANIC-AF trial1 originally planned to enrol approximately 18 000 patients with AF at risk for stroke to be randomly assigned to receive asundexian 50 mg once daily or standard-dose apixaban. The primary efficacy objective was to ascertain if asundexian was at least non-inferior to apixaban for the prevention of stroke or systemic embolism. The primary safety objective was to ascertain if asundexian was superior to apixaban in reducing major bleeding. A total of 14 810 patients were included in the intention-to-treat population; the mean age was 73.9 ± 7.7 years, 5214 (35.2%) were women, and the mean CHA2DS2-VASc score was 4.3 ± 1.3. The median follow-up was 155 days. Stroke or systemic embolism occurred in 98 (1.3%) patients in the asundexian group and in 26 (0.4%) patients in the apixaban group [hazard ratio (HR), 3.79; 95% CI, 2.46–5.83].1 Major bleeding occurred in 17 (0.2%) patients assigned to asundexian and in 53 (0.7%) patients assigned to apixaban (HR, 0.32; 95% CI, 0.18–0.55).1 The incidence of any adverse event was similar between groups. In a subgroup analysis that stratified participants by oral anticoagulation use for ≥6 weeks prior to randomization, the lower efficacy of asundexian for the prevention of stroke or systemic embolism was less pronounced in oral anticoagulation naïve patients (HR, 1.42; 95% CI, 0.54–3.73) than in patients on continued oral anticoagulation (HR, 4.66; 95% CI, 2.84–7.65) with significant heterogeneity (P-interaction <0.05). This observation is merely hypothesis-generating but potentially interesting for the design of future studies.1
The inferior antithrombotic efficacy of asundexian in the OCEANIC-AF trial may be attributed to several factors, including the use of an inadequate drug dose or the clinical ineffectiveness of selective inhibition of the contact pathway with FXI inhibitors. In light of these findings, more research is needed to determine whether FXI inhibition may serve as a potential therapeutic avenue for patients with AF and, if so, what is the correct level of FXI inhibition to prevent stroke (e.g. near-total suppression of FXIa activity may be necessary). Multiple studies are underway to investigate the role of FXI inhibitors in AF (Table 1) and other settings, and their results will provide valuable insights for the potential applications of FXI targeting in patient care.
Table 1.
Clinical trials investigating factor XI/XIa inhibitors in patients with AF
| Mechanism | Number | Current | ||||||
|---|---|---|---|---|---|---|---|---|
| Drug | Type | Administration | of action | Trials | Phase | Control | of patients | status |
| Asundexian | Small molecule | Oral, once daily | Selective inhibition of FXIa | PACIFIC-AF (NCT04218266) | 2 | Apixaban | 755 | Competed |
| OCEANIC-AF (NCT05643573) | 3 | Apixaban | 14 810 | Competed | ||||
| OCEANIC-AFINA (2023-505421-13) | 3 | Placebo | 2000 | Ongoing | ||||
| Abelacimab | Human monoclonal antibody | Subcutaneous, once a month | Binds to FXI and prevents its activation by FXIIa or thrombin | ANT-004, (NCT04213807) | 2 | Placebo | 28 | Competed |
| AZALEA-TIMI 71 (NCT04755283) | 2 | Rivaroxaban | 1287 | Ongoing | ||||
| LILAC-TIMI 76 (NCT05712200) | 3 | Placebo | 1900 | Ongoing | ||||
| Milvexian | Small molecule | Oral, twice daily | Selective inhibition of FXIa | LIBREXIA-AF (NCT05757869) | 3 | Apixaban | 15 500 | Ongoing |
AF, atrial fibrillation; FXIa, activated factor XI; FXIIa, activated factor XII.
Contributor Information
Felice Gragnano, Department of Translational Medical Sciences, University of Campania “Luigi Vanvitelli”, Caserta 81100, Italy; Division of Clinical Cardiology, A.O.R.N. “Sant'Anna e San Sebastiano”, Caserta 81100, Italy.
Antonio Capolongo, Department of Translational Medical Sciences, University of Campania “Luigi Vanvitelli”, Caserta 81100, Italy; Division of Clinical Cardiology, A.O.R.N. “Sant'Anna e San Sebastiano”, Caserta 81100, Italy.
Mattia Galli, GVM Care & Research, Maria Cecilia Hospital, Cotignola 48033, Italy; Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina 04100, Italy.
Paolo Calabrò, Department of Translational Medical Sciences, University of Campania “Luigi Vanvitelli”, Caserta 81100, Italy; Division of Clinical Cardiology, A.O.R.N. “Sant'Anna e San Sebastiano”, Caserta 81100, Italy.
Conflicts of interest: F.G., A.C., M.G., and P.C. declare no conflicts of interest related to the content of this article.
Data availability
The data underlying this article were taken from the quoted references.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The data underlying this article were taken from the quoted references.