Introduction: The Challenge of Anticoagulation in an Aging Population
The management of atrial fibrillation (AF) in older adults presents one of the most significant paradoxes in contemporary clinical cardiology. While advanced age is a potent risk factor for thromboembolic stroke, it is simultaneously a primary driver of major bleeding complications associated with traditional anticoagulants. Current standard-of-care agents, specifically Direct Oral Anticoagulants (DOACs) like rivaroxaban, have significantly improved outcomes compared to vitamin K antagonists. However, the risk of intracranial and gastrointestinal hemorrhage remains a persistent barrier to optimal therapy, particularly in patients aged 75 and older who often present with frailty, renal impairment, and multiple comorbidities.
The Emergence of Factor XI Inhibition
The search for a ‘hemostasis-sparing’ anticoagulant has led researchers to the contact activation pathway, specifically Factor XI (FXI). Unlike Factor Xa or Thrombin (Factor IIa), which are essential for both pathological thrombosis and physiological hemostasis, Factor XI appears to play a more specialized role in the propagation of thrombi without being strictly necessary for initial clot formation at sites of vascular injury. Abelacimab, a highly potent, fully human monoclonal antibody, binds to Factor XI and locks it in its inactive zymogen form, effectively providing a long-acting anticoagulant effect via monthly subcutaneous administration.
Study Design and Methodology of the AZALEA-TIMI 71 Analysis
The AZALEA-TIMI 71 trial was a randomized, active-controlled, dose-ranging Phase 2b study designed to evaluate the safety and tolerability of abelacimab. The trial enrolled 1,287 patients with atrial fibrillation who had a moderate-to-high risk of stroke (CHA2DS2-VASc score ≥4). Participants were randomized in a 1:1:1 ratio to receive subcutaneous abelacimab 90 mg monthly, abelacimab 150 mg monthly, or oral rivaroxaban 20 mg daily (with a dose reduction to 15 mg for those with a creatinine clearance between 15-49 mL/min).
Prespecified Age-Based Analysis
This specific analysis investigated whether the safety profile of abelacimab remained consistent across different age cohorts. The study population was stratified into those younger than 75 years and those 75 years or older. Researchers analyzed bleeding outcomes both categorically and continuously to determine if the age-related increase in bleeding risk typically seen with DOACs could be mitigated by FXI inhibition. The primary endpoint was the composite of major or clinically relevant nonmajor (CRNM) bleeding, as defined by the International Society on Thrombosis and Haemostasis (ISTH).
Key Findings: Superior Safety Across the Age Spectrum
The results of the analysis provide compelling evidence for the safety of abelacimab in high-risk older populations. Among the 1,287 patients, 625 (49%) were 75 years or older. This older cohort exhibited higher baseline risks, including lower body mass index and a higher prevalence of renal impairment (33% with CrCl ≤50 mL/min vs. 8% in the younger group).
Reduction in Bleeding Events
In patients aged 75 and older, both doses of abelacimab demonstrated a dramatic reduction in the primary bleeding endpoint compared to rivaroxaban. Specifically:
Abelacimab 90 mg vs. Rivaroxaban:
The hazard ratio (HR) was 0.32 (95% CI, 0.17-0.60), representing a 68% relative risk reduction.
Abelacimab 150 mg vs. Rivaroxaban:
The HR was 0.40 (95% CI, 0.22-0.73), representing a 60% relative risk reduction.Similar magnitudes of benefit were observed in the younger cohort (HR 0.28 for 90 mg and HR 0.35 for 150 mg). Crucially, the P-values for interaction by age were 0.85 and 0.84, respectively, indicating that the relative safety benefit of abelacimab is consistent regardless of patient age.
Absolute Risk Reduction and Age-Related Stability
One of the most clinically significant findings was the absolute risk reduction (ARR). Patients aged 75 or older derived a greater absolute benefit due to their higher baseline risk. The ARR was 7.1 per 100 patient-years for the 90 mg dose and 6.2 per 100 patient-years for the 150 mg dose. Furthermore, while bleeding risk tended to increase linearly with age in the rivaroxaban group, the bleeding risk in the abelacimab group remained remarkably stable across the age range studied (P for interaction = .33).
Mechanistic Insights: Uncoupling Hemostasis from Thrombosis
The biological plausibility of these findings lies in the differential roles of the intrinsic and extrinsic coagulation pathways. Standard DOACs inhibit Factor Xa, a ‘bottleneck’ in the common pathway that is vital for the rapid generation of thrombin needed to stop bleeding after trauma. By contrast, abelacimab targets Factor XI, which is primarily involved in the amplification of the coagulation cascade. In the absence of FXI, the body can still utilize the extrinsic (tissue factor) pathway to initiate hemostasis. This ‘uncoupling’ suggests that FXI inhibition can prevent the stable, occlusive thrombi that cause strokes while leaving the body’s natural ability to form a primary hemostatic plug largely intact.
Expert Commentary and Clinical Implications
The AZALEA-TIMI 71 data suggests a paradigm shift in how we approach anticoagulation in the elderly. Historically, clinicians have often under-treated older AF patients or opted for lower doses of DOACs due to ‘bleeding phobia,’ often at the expense of stroke protection.
Clinical Generalizability
The consistent safety profile across age groups is particularly relevant for the ‘old-old’ (those over 85), who are often excluded from clinical trials but represent a growing segment of the AF population. If the efficacy of abelacimab is confirmed in Phase 3 trials, it could become the preferred agent for patients with high HAS-BLED scores, previous history of non-critical bleeding, or those at high risk for falls.
Limitations and Future Directions
As a Phase 2b trial, AZALEA-TIMI 71 was designed and powered primarily for safety (bleeding). It was not intended to provide a definitive assessment of stroke prevention efficacy. While the reduction in bleeding is profound, the clinical community awaits the results of large-scale Phase 3 trials, such as LILAC-TIMI 76, which is evaluating abelacimab in patients deemed unsuitable for current oral anticoagulation. Furthermore, the subcutaneous monthly dosing, while convenient for many, represents a transition in the delivery model of AF care that will require patient and provider education.
Conclusion
The prespecified analysis of the AZALEA-TIMI 71 trial confirms that abelacimab provides a significantly safer profile than rivaroxaban in older individuals with atrial fibrillation. By nearly eliminating the age-related escalation of bleeding risk, Factor XI inhibition with abelacimab stands to address one of the greatest unmet needs in geriatric cardiology. Should Phase 3 data confirm that this safety benefit is accompanied by robust stroke prevention, abelacimab may redefine the standard of care for millions of elderly patients worldwide.
Funding and Trial Registration
The AZALEA-TIMI 71 trial was sponsored by Anthos Therapeutics. The study is registered at ClinicalTrials.gov (NCT04755283).
References
1. Al Said S, Patel SM, Giugliano RP, et al. Abelacimab vs Rivaroxaban in Older Individuals With Atrial Fibrillation: A Prespecified Analysis of the Phase 2b AZALEA-TIMI 71 Trial. JAMA Cardiol. 2026 Feb 4. doi:10.1001/jamacardio.2025.5418.
2. Hsu RK, et al. Factor XI Inhibition: A Novel Target for Anticoagulation. J Am Coll Cardiol. 2021;78(16):1621-1631.
3. Ruff CT, et al. Antithrombotic Therapy in Atrial Fibrillation: The Future of Factor XI Inhibitors. Eur Heart J. 2023;44(32):3021-3033.
