New anti-factor XI anticoagulants are currently in development and show promise for preventing ischemic risk. However, will they become widely used, or remain limited to niche treatments? Cardiologists have raised this question after the disappointing results of the phase 3 OCEANIC-AF trial, in which the anti-XI peptide asundexian (Bayer) failed to demonstrate efficacy, leading to the trial’s termination.
At the recent European Days of the French Society of Cardiology 2025 held in Paris, France, a session focused on the anticipated indications for factor XI inhibitors. These inhibitors, administered orally, subcutaneously, or intravenously, are being tested for thromboembolic risk prevention in various conditions.
The first results of the OCEANIC-AF trial revealed a nearly fourfold higher ischemic risk with asundexian than with the direct oral anticoagulant (DOAC) apixaban in the prevention of atrial fibrillation (AF). This outcome, described as a "cold shower," marked a major setback, as OCEANIC-AF was the first phase 3 trial to evaluate this class of anticoagulants.
Unexpected Findings
Nicolas Meneveau, MD, PhD, from the Department of Cardiology at the University Hospital Jean Minjoz in Besançon, France, provided updates to Medscape’s French edition, on these anticoagulants.
"These results were really unexpected. The dose was certainly insufficient. But how can we explain that the results are so discordant about the prevention of venous thrombosis [after orthopedic surgery]?" he said.
Research has already proven unsuccessful in this area, "but rarely at this stage of development," Meneveau continued. For example, otamixaban, a once-promising injectable anti-factor Xa, was rejected because of unsatisfactory results in post-acute coronary syndrome. "Generally, when we get to the AF stage, we consider that it's won," he added.
The OCEANIC-STROKE trial, which evaluates the efficacy of 50 mg/d of asundexian poststroke in the prevention of thromboembolic risk poststroke, is ongoing and is considered an alternative to DOACs, Meneveau noted. "There was no sufficiently negative signal to stop the study."
The results of this trial and other phase 3 studies should be revealed soon. "There are now doubts about the effectiveness of these inhibitors in preventing thrombotic complications in high-risk patients. We need these results to really know their effectiveness," he emphasized.
Clinical Doubts
Doubts about these inhibitors have emerged because they are promoted as ideal anticoagulants, supposedly preventing strokes, cardiovascular events, and venous thrombosis (VT) without increasing the risk of bleeding risks. Various molecules have been developed over the past decade.
The role of factor XI in thromboembolism is not fully understood, but it may primarily affect thrombus formation. Anti-factor XI drugs may prevent thrombosis without compromising physiological hemostasis.
"These anticoagulants aim to address gaps not covered by DOACs," noted Isabelle Gouin-Thibault, PhD, head of the Hemostasis Laboratory, University Hospital of Rennes, Rennes, France, during her presentation. She specifically highlighted their potential use in high-risk patients, such as those with end-stage renal disease or cancer, as well as for thrombosis prevention in cases involving artificial surfaces.
"We can consider their use, for example, in patients with a mechanical valve, during extracorporeal membrane oxygenation, and possibly even during angioplasty," said Meneveau.
One of the first anti-factor XI drugs tested was an antisense RNA called FXI-ASO (Isis Pharmaceuticals), which was administered subcutaneously to patients.
In a phase 2 trial, on the prevention of VT after knee replacement surgery, FXI-ASO showed superior efficacy compared with enoxaparin. Another antisense RNA drug, fesomersen (Ionis), reduced deep-vein thrombosis by 86% compared with enoxaparin. In this study, the anticoagulant was injected once a month compared with once a week with FXI-ASO in the previous study.
Higher Risk
Shorter-acting small peptide inhibitors of factor XIa have gained interest due to their potential for oral administration. These inhibitors have a duration of action of 2-4 hours, similar to DOACs, and can be taken orally once or twice daily.
Asundexian was evaluated in the phase 2 PACIFIC-AF trial, where it was compared with the DOAC apixaban in patients with AF at high bleeding risk. The anti-XI peptide was associated with a 60%-70% reduction in risk for major bleeding.
However, no thromboembolic events occurred, and "no signal of benefit appeared," according to Meneveau.
The OCEANIC-AF phase 3 trial was then conducted to confirm asundexian’s non-inferiority to apixaban. The double-blind, international, multicenter trial included 14,810 patients with AF who were at risk for stroke. Participants were randomized to receive either asundexian (50 mg once daily) or apixaban (5 mg twice daily).
Interim findings showed that asundexian led to fewer bleeding events; however, stroke and embolic events were nearly four times more frequent than those in the apixaban group (hazard ratio, 3.79 [2.46-5.83]), with 98 events on asundexian (1.3%) vs 26 on apixaban (0.4%). This led to the termination of the trial.
Dosing
Meneveau noted that the increased thrombotic risk may be due to asundexian’s short half-life and once-daily dosing. In contrast, milvexian (developed by BMS and Janssen Pharmaceuticals) is administered once or twice daily at a higher dose. “A single dose of asundexian per day induces low anticoagulant levels, increasing the risk of thrombotic events,” he said.
Apart from the OCEANIC-STROKE trial for asundexian, several phase 3 trials are currently evaluating milvexian for the prevention of ischemic events in AF, poststroke, or postinfarction. The Librexia STROKE, Librexia ACS, and Librexia AF trials have enrolled more than 50,000 patients.
"Milvexian exhibits factor XI inhibition rates that are 10 times higher than asundexian," said Meneveau. However, phase 2 trials of both peptides have yielded inconclusive results. In these trials, they "do not appear to prevent stroke recurrences."
Prevention of VT
In the phase 2 AXIOMATIC-TKR trial, milvexian showed promising results in preventing VT after total knee arthroplasty, with outcomes similar to those of antisense RNA therapy.
The lowest incidence of VT was 7% with milvexian (200 mg once daily) compared with 21% with enoxaparin (40 mg/d subcutaneously), representing a risk reduction of more than 60%. Bleeding rates were similar in both groups (4%).
The third category of factor XI inhibitors under investigation is antibody-based inhibitors. These have a long half-life (20-40 days) and require only 1 monthly injection (intravenously or subcutaneously). Among the three anti-XI antibodies being studied — abelacimab, ococimab, and xisobab — abelacimab (Anthos Therapeutics) has attracted the most interest because of its inhibitory effect on factor XI.
In the ANT-005 trial, a single intravenous injection of abelacimab after total knee arthroplasty was more effective than daily subcutaneous enoxaparin injections in preventing VT.
Abelacimab in AF
In the phase 2b AZALEA-TIMI trial, a monthly subcutaneous injection of abelacimab was compared with rivaroxaban (a DOAC). The results showed an 81% reduction in major bleeding events with abelacimab, nearly eliminating gastrointestinal bleeding.
To evaluate the effect of abelacimab on ischemic risk, the LILAC-TIMI phase 3 study was launched in 2023 for patients with AF.
The phase 2 trial data showed a stroke rate of approximately 1% in both groups, with no concerning safety signals. However, further data are needed to confirm the non-inferiority of abelacimab for this indication.
Abelacimab is also being studied in two other phase 3 trials (ASTER and MAGNOLIA) — to prevent VT in patients with cancer, including those at high risk of bleeding.
Meneveau declared competing interests with Abbott, Inara, Terumo, AstraZeneca, Edwards Lifesciences, and Boston Scientific. Gouin-Thibault declared conflicts of interest with BMS/Pfizer, Bayer, Sanofi, and Leo Pharma.
This story was translated from Medscape’s French edition using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.