New class of anticoagulant found to ‘overwhelmingly’ reduce bleeding events in patients with atrial fibrillation

Researchers have reported that a drug representing a new class of anticoagulants showed an “overwhelming” reduction in bleeding events compared with standard-of-care treatment in patients with atrial fibrillation (AF).

Results of the phase II ‘AZALEA-TIMI 71’ study, published in the New England Journal of Medicine on 22 January 2025, showed that the monoclonal antibody abelacimab — a factor XI inhibitor — significantly reduced bleeding compared with the anticoagulant rivaroxaban.

The researchers enrolled 1,287 participants with AF and a moderate-to-high risk of stroke from across 95 study sites globally. Participants were assigned in a 1:1:1 ratio to receive either a 150mg or 90mg subcutaneous injection of abelacimab once monthly or 20mg oral rivaroxaban once daily.

At three months, the median reduction in free factor XI levels was 99% with abelacimab 150mg and 97% with abelacimab 90mg.

As a result, the trial was stopped early on the recommendation of the independent data monitoring committee, owing to a “greater-than-anticipated reduction in bleeding events with abelacimab”.

The incidence rate of major or clinically relevant non-major bleeding was 3.2 events per 100 person-years with abelacimab 150mg and 2.6 events per 100 person-years with abelacimab 90mg, compared with 8.4 events per 100 person-years with rivaroxaban.

When compared with rivaroxaban, abelacimab 90mg and 150mg reduced major or clinically relevant non-major bleeding by 69% and 62%, respectively.

“These results, together with the efficacy of abelacimab in preventing thromboembolic events, warrant larger-scale testing,” the researchers said.

“The primary end point of the ‘AZALEA-TIMI 71’ trial focused on bleeding outcomes and future studies must now clarify the efficacy of abelacimab in preventing cardioembolic events, such as ischemic stroke and systemic embolism.”

Abelacimab, which is not currently approved for any indication in any country, works by binding to both inactive and active forms of factor XI, which “plays a critical role in pathologic thrombosis but is less involved in normal hemostasis”, the authors explained.

“This distinction suggests that inhibiting factor XI could reduce pathologic thrombosis without substantially impairing hemostasis,” they added.

Commenting on the study, Frances Akor, consultant pharmacist, anticoagulation, at Imperial College NHS Healthcare Trust, said: “The results of this two-year phase II study in AF patients add to the growing evidence that inhibition of factor XI may preferentially impact thrombosis over haemostasis; therapeutic factor XI inhibition appears to be associated with a reduced risk of bleeding compared to currently licensed direct oral anticoagulants (DOACs).  

She added that while the early termination of the trial owing to its greater-than-expected benefit is encouraging, “the results of phase III studies are needed, not only to further establish the safety of abelacimab but also to explore its efficacy with respect to stroke and systemic embolism prevention in non-valvular AF and venous thromboembolism (VTE) recurrence rates for VTE patients”.

“Considering that best value DOACs are now well established as first-line anticoagulation, and given the current phase III programme for abelacimab and its high cost relative to currently available anticoagulation options, the potential use of abelacimab would need to be very well-defined before it could be successfully introduced into the health system,” Akor said.

Paul Wright, consultant cardiovascular pharmacist at Barts Health NHS Trust, described the study as “exciting”.

“The results of the paper echo other studies demonstrating the safety of factor XI inhibition compared to current gold standard therapy with DOACs,” he added. 

However, he warned: “A caution to note is the suggestion that these agents may not be as effective in reducing ischaemic events and we see in this trial numerically more ischaemic strokes in the abelacimab arms. 

“The results of larger phase III trials are now eagerly awaited to see if the trade off with reduced bleeding can be done without the expense of increased ischaemic events as this will offer a useful option, particularly in those individuals who may not be offered DOACs due to increased bleeding risk.” 

In November 2024, NHS England reported that nearly 92% of patients with AF had been anticoagulated, meeting its target of treating 90% of AF patients with DOACs by 2029 five years early.

In January 2024, NHS England advised prescribers to supply generic apixaban over edoxaban as a preferred DOAC for the treatment of AF in new patients.