AZALEA-TIMI 71 - Abelacimab for Stroke Prevention
Tanmaya Phanda, PharmD
3-min
The Breakthrough of Abelacimab for Stroke Prevntion: Analyzing the AZALEA-TIMI 71 Trial
This blog will review in stroke prevention in patients with atrial fibrillation, evaluate key insights of the AZALEA-TIMI 71 trial and assess abelacimab’s clinical impact and future direction.
By: Tanmaya Phanda, PharmD, InpharmD Team
Background
Atrial Fibrillation (AF) is the most common type of arrhythmia, affecting 10.5 million people in the United States. This life-long condition is due to abnormal electrical activity within the atria, resulting in irregular and rapid contractions. In addition, AF raises the likelihood of blood clot formation because blood cannot be efficiently pumped from the atria to the ventricle. As a result, AF increases the risk of cardioembolic stroke five-fold, underlining the significance of stroke prevention for these patients.
Direct oral anticoagulants (DOACs), “blood-thinners”, are FDA-approved for primary and secondary stroke prevention in patients with AF:
|
DOAC Name (Brand)
|
Mechanism of Action
|
|
Dabigatran (Pradaxa®)
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Direct Thrombin Inhibitor
|
|
Apixaban (Eliquis®)
|
Factor Xa Inhibitor
|
|
Edoxaban (Lixiana®)
|
Factor Xa Inhibitor
|
|
Rivaroxaban (Xarelto®)
|
Factor Xa Inhibitor
|
However, DOAC treatment risks bleeding, with major bleeding occurring in 2-4% and clinically relevant non-major bleeding in 10-12% of patients annually. Therefore, additional anticoagulants must be developed to provide patients with safer stroke prevention treatment options. Clinical studies have shown that targeting Factor XI is key for thrombosis but nonessential for hemostasis. Abelacimab is a fully human monoclonal antibody that inhibits Factor XI activation, reducing clot formation. Its safety profile, in particular bleeding events, needs to be further assessed in comparison to other DOACs in patients with AF for stroke prevention.
Trial Introduction
AZALEA–TIMI 71 (NCT04755283), a multinational, phase 2b, parallel-group, partially blind, randomized, active-controlled trial, assessed the safety and tolerability of abelacimab compared to rivaroxaban in adults with atrial fibrillation at moderate-high risk for stroke.
Methods
Patients were eligible if they were at least 55 years of age and had a history of atrial fibrillation or atrial flutter, a plan for anticoagulation treatment, and a CHA2DS2 -VASc score of 4 or higher or a CHA2DS2 -VASc score of 3 with either planned concomitant use of antiplatelet medications or an estimated creatinine clearance of ≤ 50 ml/min.
A total of 1287 patients were randomized 1:1:1 to one of three treatment groups: abelacimab 150 mg (subcutaneous injection, once monthly), abelacimab 90 mg (subcutaneous injection, once monthly), and rivaroxaban 20 mg (oral, once daily). Rivaroxaban was reduced to 15 mg once daily if the estimated creatinine clearance was ≤ 50 ml/min. While the trial was open-label, between abelacimab and rivaroxaban, the two abelacimab treatment arms were double-blinded. Throughout the treatment period, in-person monthly follow-up visits with safety assessments and laboratory testing every three months.
The demographics and baseline characteristics were similar in all treatment groups —Table 1.
Table 1. Patient Baseline Characteristics
|
Characteristic
|
Rivoraxaban 20 mg (N = 430)
|
Abelacimab 150 mg (N=430)
|
Abelacimab 90 mg (N = 427)
|
|
Median age (IQR) — years
|
74 (69-79)
|
74 (69-78)
|
75 (69-79)
|
|
Female — no. (%)
|
184 (42.8)
|
193 (44.9)
|
195 (45.9)
|
|
Median CHA2DS2 -VASc score (IQR)
|
5.0 (4.0-6.0)
|
5.0 (4.0-5.0)
|
5.0 (4.0-5.0)
|
|
Median HAS-BLED score (IQR)
|
3.0 (2.0 -3.0)
|
2.0 (2.0 -3.0)
|
2.0 (2.0 -3.0)
|
|
History of bleeding — no. (%)
|
36 (8.4)
|
34 (8.0)
|
29 (6.8)
|
|
Previous ischemic stroke — no. (%)
|
75 (17.5)
|
59 (13.7)
|
57 (13.3)
|
|
Anticoagulation ≥60 days — no. (%)*
|
404 (94)
|
389 (90.5)
|
389 (91.3)
|
*63-67.7% of patients on anticoagulants for at least 60 days were specifically on DOACs.
Outcomes
The primary outcome was a composite of major or clinically relevant nonmajor bleeding. Secondary outcomes included major bleeding and any bleeding event (a composite of major, clinically relevant nonmajor, or minor bleeding). Both primary and secondary outcomes were assessed in a time-to-event analysis. Before the start of the study, it was calculated that 160 events would provide 80% power to detect a 40% reduction in risk (hazard ratio = 0.6.) with abelacimab at each dose level compared with rivaroxaban. Safety was assessed with adverse events and laboratory testing data in all patients who underwent randomization and received at least one dose of their treatment arm.
Results
During a median follow-up of 2.1 years, abelacimab at 90 (2.64 events/100 person-yr) and 150 mg (3.22 events/100 person-yr) doses resulted in a lower incidence rate of major or clinically relevant nonmajor bleeding events than rivaroxaban (8.36 events/100 person-yr) —Figure 1. Both doses showed statistical significance as abelacimab 90 mg demonstrated a hazard ratio of 0.38 (95% CI: 0.24 to 0.60) while abelacimab 150 mg presented a hazard ratio of 0.31 (95% CI: 0.19 to 0.51) in comparison to rivaroxaban. (P < 0.001 for both comparisons).
Safety
The incidence of adverse events was similar throughout the treatment arms:
|
Adverse Event
|
Rivaroxaban (N = 428)
|
Abelacimab 150 mg (N =427)
|
Abelacimab 90 mg (N = 425)
|
|
Any
|
348
|
358
|
351
|
|
Serious
|
167
|
157
|
158
|
|
Led to discontinuation of the trial drug
|
29
|
29
|
32
|
Study Conclusions
Abelacimab at both subcutaneous once-monthly doses (90 mg and 150 mg) was well-tolerated and led to significantly fewer bleeding events compared to oral once-daily rivaroxaban in adults with atrial fibrillation at moderate-to-high risk for stroke.
Despite its favorable results for abelacimab, the trial presents key limitations. The open-label randomization to abelacimab or rivaroxaban increases the chance of bias, but the doses of abelacimab were blinded to help mitigate the risk. The incidence of bleeding events with abelacimab cannot be generalized to other FDA-approved DOACs other than rivaroxaban and other races, as White was the majority of the study population (94-95.3%). In addition, the small study sample prevents assessing the clinical efficacy of abelacimab, suggesting the need for larger trials.
Clinical Impact
Along with its promising safety profiles, abelacimab’s once-monthly dosing offers a convenient option for patients with AF to improve adherence. In addition, a cost-effective analysis demonstrated that abelacimab could offer a potential cost-savings of $50,000 and improvements of 1.5 quality-adjusted life years (QALY’s) per person as compared to rivaroxaban, which like all DOACs are only available under their brand names.
However, efficacy data for abelacimab remains unclear. The ongoing phase 3 LILAC–TIMI 76 trial (NCT05712200) will evaluate the efficacy of abelacimab as compared with placebo for preventing ischemic stroke and systemic embolization in high-risk patients with AF.
References:
- Ruff CT, Patel SM, Giugliano RP, et al. Abelacimab versus Rivaroxaban in Patients with Atrial Fibrillation. N Engl J Med. 2025;392(4):361-71.
- Nesheiwat Z, Goyal A, Jagtap M. Atrial Fibrillation. In: StatPearls. Treasure Island (FL): StatPearls Publishing; April 26, 2023.
- Ko D, Chung MK, Evans PT, Benjamin EJ, Helm RH. Atrial Fibrillation: A Review. JAMA. 2025;333(4):329-42.
- About Atrial Fibrillation. CDC. Published May 15, 2024. https://www.cdc.gov/heart-disease/about/atrial-fibrillation.html
- What is Atrial Fibrillation?. Heart. Published 2024. https://www.heart.org/en/health-topics/atrial-fibrillation
- Cormier S and Siegal DM. A framework for managing severe DOAC-related bleeding: Recognize, Reverse, Resume, Reduce. Thrombosis Update. 2024;15.
- Dobesh PP, Fanikos J. Direct Oral Anticoagulants for the Prevention of Stroke in Patients with Nonvalvular Atrial Fibrillation: Understanding Differences and Similarities. Drugs. 2015;75(14):1627-44.
- First-Ever Cost-Effectiveness Analysis of a Factor XI Inhibitor Demonstrates that Abelacimab, if Approved, Could Offer Significant Cost Savings as Compared to a Current Standard of Care Anticoagulant. Anthos Therapeutics. May 6, 2024. https://anthostherapeutics.com/press-release/anthos_2024-08-15_release-16/
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