Is Abelacimab the Next Step in AF Anticoagulation? Early Signals and Remaining Questions

Written by Dr. Eric Acker, Dr. Rana Humza, and Dr. Frank Lodeserto
REBEL Crit, REBEL EM
Medical Category: Cardiovascular
abelacimab, Anticoagulation, Atrial Fibrillation, AZALEA–TIMI 71, bleeding risk, DOACs, factor XI inhibitor, Rivaroxaban, stroke prevention

December 15, 2025

📌 Key Points

🧬 Abelacimab is a novel Factor XI inhibitor showing promise for patients with moderate–high risk atrial fibrillation.
🩸 Significantly less bleeding compared with rivaroxaban in this phase 2 trial.
⚠️ Efficacy remains uncertain—the study was not powered to assess stroke prevention.
🔄 Needs phase 3 confirmation, especially in head-to-head comparison with apixaban.
🧭 Potential future alternative for patients unable to tolerate current DOACs.

📝 Introduction

Antithrombotic therapy is a cornerstone in the treatment of atrial fibrillation (AFib), though it carries a significant risk of bleeding. While Vitamin K antagonists (VKAs), the oldest anticoagulants, were largely supplanted by direct oral anticoagulants (DOACs) following trials like ARISTOTLE¹ and ROCKET AF², the risk of bleeding with these newer agents still exists.

Enter Abelacimab, a novel drug designed to provide thrombosis protection while minimizing the impact on hemostasis. Abelacimab is a fully human monoclonal antibody that specifically targets and inhibits both Factor XI (FXI) and its activated form, Factor XIa (FXIa). Its pharmacokinetics suggest complete suppression of FXIa, requiring a single intravenous dose administered once a month.

🧾 Paper

Ruff CT, Patel SM, Giugliano RP, et al. Abelacimab versus Rivaroxaban in Patients with Atrial Fibrillation. N Engl J Med. 2025;392(4):361-371. PMID: 39842011

⚙️ What They Did

CLINICAL QUESTION

In adults ≥55 years with atrial fibrillation at moderate-to-high risk of stroke, does monthly subcutaneous abelacimab (90 mg or 150 mg) compared with daily rivaroxaban reduce the incidence of major or clinically relevant non-major bleeding?

STUDY DESIGN

Type of Study: Multinational, phase 2b, randomized, active-controlled, parallel-group trial
Blinding:
- Partially blinded — abelacimab dose levels (90 mg vs 150 mg) blinded
- Open-label — rivaroxaban arm not blinded
Randomization:
- 1:1:1 allocation
- Central computerized system
- Stratified by:
- Concomitant antiplatelet use
- Creatinine clearance (≤50 vs >50 mL/min)
Sites: 95 centers across 7 countries
Follow-up:
- Monthly in-person visits
- Median follow-up at termination: 1.8 years
- Median total trial follow-up: 2.1 years
Safety Monitoring:
- Independent Data Monitoring Committee (DMC)
- Central adjudication of events, blinded to treatment assignment
Trial Stopped Early:
- Due to unexpectedly large reduction in bleeding events with abelacimab compared with rivaroxaban
Analysis Approach:
- Cox proportional hazards model
- Competing risk sensitivity analyses
- On-treatment analysis population used for primary endpoint

POPULATION

Inclusion Criteria:

Age ≥55 years
History of atrial fibrillation or atrial flutter
Moderate-to-high stroke risk, defined as:
- CHA₂DS₂-VASc ≥4, or
- CHA₂DS₂-VASc = 3 with:
  - Planned concomitant antiplatelet therapy, or
  - Estimated creatinine clearance ≤50 mL/min
Plan to receive anticoagulation therapy
Able to provide informed consent

Exclusion Criteria:

Hypersensitivity to study drugs or contraindication to rivaroxaban
Intracranial or intraocular bleeding within the past 3 months
Clinically significant mitral stenosis (valve area <1.5 cm²)
Mechanical heart valve or other indication for anticoagulation besides AF
Known left atrial myxoma or left ventricular thrombus
Prior left atrial appendage closure or removal
Active endocarditis
Any other condition that, in investigators’ judgment, would compromise safety or protocol adherence (protocol-based clinical judgment exclusion)

INTERVENTION & CONTROL

Intervention:

Abelacimab (Factor XI inhibitor), administered subcutaneously once monthly:
- 150 mg dose
- 90 mg dose
Doses were blinded between abelacimab groups.

Control:

Rivaroxaban, administered orally once daily:
- 20 mg daily
- 15 mg daily if CrCl ≤50 mL/min
Rivaroxaban arm was open-label.

OUTCOMES

Primary Outcome:

Major or clinically relevant non-major (CRNM) bleeding
- Defined by ISTH criteria
- Time-to-first event analysis

Key Exploratory Outcomes:

Gastrointestinal (GI) bleeding
Ischemic stroke or systemic embolism
Net clinical outcome, defined as:
- Ischemic stroke
- Systemic embolism
- Major or CRNM bleeding
- Death from any cause
Death from any cause or any stroke (post hoc)

Secondary Outcomes:

Major bleeding
Any bleeding event (composite of:
- Major bleeding
- Clinically relevant non-major bleeding
- Minor bleeding)

Safety Measures:

Adverse events
- Overall adverse event rates
- Serious adverse events
- Adverse events leading to discontinuation
Injection-site reactions: Assessed only in abelacimab groups (SQ administration)
Laboratory safety monitoring: Central lab testing at baseline and every 3 months
Free Factor XI level monitoring:
- Measured before and after abelacimab administration
- Used to confirm pharmacodynamic effect
Antidrug antibody testing (ADA)
- Evaluated for immunogenicity
- No antidrug antibodies detected
Independent Clinical Events Committee (blinded)
- Bleeding events
- Stroke
- Systemic embolism
- Cause of death
Data Monitoring Committee (independent): Recommended early trial termination due to marked reduction in bleeding with abelacimab

📈 Results

OUTCOMES

DEMOGRAPHICS

OUTCOMES

DEMOGRAPHICS

💥 Critical Results

Primary Outcome: Major or Clinically Relevant Non-Major Bleeding:

Abelacimab 150 mg: 3.22 events per 100 PY
HR 0.38 (95% CI 0.24–0.60) vs rivaroxaban
Abelacimab 90 mg: 2.64 events per 100 PY
HR 0.31 (95% CI 0.19–0.51) vs rivaroxaban
Rivaroxaban: 8.38 events per 100 PY
- ~62–69% relative reduction in the primary bleeding outcome

Stroke or Systemic Embolism (Not powered for efficacy):

Abelacimab 150 mg: 1.21 events per 100 PY
HR 1.47 (0.56–3.85)
Abelacimab 90 mg: 1.36 events per 100 PY
HR 1.65 (0.64–4.25)
Rivaroxaban: 0.83 events per 100 PY
- Numerically more ischemic strokes in both abelacimab arms
- CIs wide → imprecise, cannot draw efficacy conclusions

Death from Any Cause:

Abelacimab 150 mg: 2.65 per 100 PY
Abelacimab 90 mg: 3.20 per 100 PY
Rivaroxaban: 3.52 per 100 PY
- No significant mortality difference

💪 Strengths

Randomized trial with 1:1:1 allocation—minimizes selection bias.
Central computerized randomization with stratification (antiplatelet use, CrCl) improving balance of prognostic factors.
Central blinded adjudication of major outcomes (bleeding, stroke, systemic embolism, death), reducing measurement bias.
Dose-blinding within abelacimab groups prevents differential co-intervention or monitoring based on dose.
Excellent follow-up completeness (99.7% of potential patient-years).
Long duration (median 2.1 years) provides more stable bleeding safety data compared with short phase 2 trials.
Predefined, validated ISTH bleeding criteria—standardized and objective.
Outcomes clinically meaningful (major and CRNM bleeding).
Groups were well balanced on key prognostic variables (age, sex, CHA₂DS₂-VASc, renal function, prior anticoagulation).
Trial monitored by an independent Data Monitoring Committee (DMC) with prespecified stopping rules.
Demonstrated dose-dependent FXI suppression, supporting biological plausibility.

⚠️ Limitations

Open-label comparator arm (rivaroxaban) increases risk of performance and detection bias (systematic differences in care, reporting, or monitoring).
Although events were centrally adjudicated blind, patients and clinicians knew the assigned drug class.
Only compared with rivaroxaban, which may have a higher bleeding risk than other DOACs (e.g., apixaban).
Limits external validity and may exaggerate the magnitude of safety benefit.
Phase 2 study focused on safety, not stroke prevention.
Stroke outcomes imprecise, with wide confidence intervals, making efficacy conclusions unreliable.
Stopped early for benefit → inflates treatment effect estimates and reduces long-term certainty.
>94% White population, limiting applicability to diverse racial/ethnic groups.
Trial population older, with high CHA₂DS₂-VASc—may not generalize to lower-risk AF patients.
Monthly SQ injection vs daily oral pill introduces potential differences in adherence and behavior that may influence outcomes.
Although large for phase 2, still modest for outcomes like stroke and mortality—risk of type II error for efficacy endpoints.
Funded by Anthos Therapeutics; although analyses were independent, funding source is considered a potential bias per Users’ Guide.

🗣️ Discussion

The Use of Rivaroxaban

The choice of Rivaroxaban as a comparator is a notable point. Observational trials suggest that Rivaroxaban may have a higher incidence of major bleeding compared to Apixaban. While the ROCKET AF² trial showed Rivaroxaban to be non-inferior to warfarin with decreased intracranial bleeding, and the ARISTOTLE trial¹ demonstrated Apixaban had a lower bleeding risk compared to warfarin (with similar GI bleeding risks), there are no head-to-head randomized controlled trials directly comparing these two DOACs. If observational data from a 2020 retrospective study published in the AHA⁴ showing a decreased bleeding risk in patients receiving Apixaban is accepted, then the use of Rivaroxaban in this study could be considered a design limitation.

The OCEANIC-AF trial⁵, which utilized Apixaban, was stopped early due to Asundexian’s lack of efficacy. The authors of the AZALEA-TIMI 71 study argue this was due to Asundexian targeting the active FXIa factor, as opposed to Abelacimab’s mechanism of targeting the non-activated FXI. We can only speculate why the study designers did not choose Apixaban as the comparator drug given these considerations.

Efficacy Comparison

This Phase 2 trial exhibited an atypical primary focus on safety outcomes, specifically bleeding risks. While Phase 2 trials commonly assess a drug’s efficacy in treating the targeted condition (e.g., stroke prevention), this study did not align with that norm (however, did in part examine dose-dependent differences). Ultimately, clinicians will require an understanding of this drug’s efficacy in preventing stroke in patients with Afib. The LILAC-TIMI 76 trial⁶ may help to illuminate Abelacimab’s efficacy, but subsequent data will be necessary to determine its superiority to existing DOACs and Vitamin K antagonists

Overall, Abelacimab shows promise in its endeavor to affect thrombosis formation while having less impact on hemostasis. This trial provides a good safety profile, but Abelacimab will require further testing against Apixaban to more fully assess its comparative bleeding risk and to establish superiority or non-inferiority.

Future Direction

Future research, such as the LILAC-TIMI 76 trial⁶, is currently underway. This randomized controlled trial is comparing Abelacimab to placebo for VTE prevention in a population deemed unsuitable for oral anticoagulation. The results of this upcoming study have significant implications for a novel agent for patients with contraindications to DOACs and may even pose an alternative to the increasingly popular left atrial appendage closure devices in this patient population. ClinicalTrials.gov currently lists an Apixaban vs. Abelacimab trial in recruitment for VTE prophylaxis in patients with malignancy, suggesting a potential future comparison⁷, though it’s not explicitly clear if the makers of Abelacimab intend to pursue this comparison for AFib.

📘 Author's Conclusion

“Among patients with atrial fibrillation who were at moderate-to-high risk for stroke, treatment with abelacimab resulted in markedly lower levels of free factor XI and fewer bleeding events than treatment with rivaroxaban.”

💬 Our Conclusion

This Phase 2 study successfully showed Abelacimab to be superior to rivaroxaban in terms of bleeding risk. Despite this, a direct comparison with apixaban is necessary because observational data indicates that apixaban has a more favorable bleeding risk profile than rivaroxaban. Further studies focused on patients unable to take oral anticoagulation could have significant implications for both patient care and the left atrial appendage closure device industry.

🚨 Clinical Bottom Line

Abelacimab markedly reduces bleeding compared with rivaroxaban, but larger trials—particularly against apixaban—are needed to confirm its safety and determine its efficacy for stroke prevention in atrial fibrillation.

📚 References

Granger CB, Alexander JH, McMurray JJ, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011;365(11):981-992. PMID: 21870978
Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365(10):883-891. PMID: 21830957
Ruff CT, Patel SM, Giugliano RP, et al. Abelacimab versus Rivaroxaban in Patients with Atrial Fibrillation. N Engl J Med. 2025;392(4):361-371. PMID: 39842011
Bonde AN, Martinussen T, Lee CJ, et al. Rivaroxaban Versus Apixaban for Stroke Prevention in Atrial Fibrillation: An Instrumental Variable Analysis of a Nationwide Cohort. Circ Cardiovasc Qual Outcomes. 2020;13(4):e006058. PMID: 32283966
Piccini JP, Patel MR, Steffel J, et al. Asundexian versus Apixaban in Patients with Atrial Fibrillation. N Engl J Med. 2025;392(1):23-32. PMID: 39225267
Anthos Therapeutics, Inc. Study to evaLuate the effIcacy and Safety of abeLacimab in High-rIsk atrial fIbriLLAtion pAtients Unsuitable for oral antiCoagulants (LILAC-TIMI 80). ClinicalTrials.gov identifier: NCT05712200. Updated January 11, 2023. Accessed November 16, 2025. https://clinicaltrials.gov/study/NCT05712200
A Study Comparing Abelacimab to Apixaban in the Treatment of Cancer-associated VTE. ClinicalTrials.gov identifier: NCT05171049. Posted December 20, 2024. Updated June 22, 2024. Accessed November 16, 2025. https://clinicaltrials.gov/study/NCT05171049.
Piccini JP, Caso V, Connolly SJ, et al. Safety of the oral factor XIa inhibitor asundexian compared with apixaban in patients with atrial fibrillation (PACIFIC-AF): a multicentre, randomised, double-blind, double-dummy, dose-finding phase 2 study. Lancet. 2022;399(10333):1383-1390. PMID: 35385695
Verhamme P, Yi BA, Segers A, et al. Abelacimab for Prevention of Venous Thromboembolism. N Engl J Med. 2021;385(7):609-617. PMID: 34297496
Schulman S, Kearon C; Subcommittee on Control of Anticoagulation of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. J Thromb Haemost. 2005;3(4):692-694. PMID: 15842354

Post Peer Reviewed By: Mark Ramzy, DO (X: @MRamzyDO), and Marco Propersi, DO (X: @Marco_Propersi)

👤 Guest Author

Humza Rana, MD

PGY-3 Internal Medicine Resident

Aspiring Cardiology Fellow Cape Fear Valley Medical Center Fayetteville NC

Eric Acker, MD

PGY-3 Internal Medicine Resident

Chief Resident Aspiring Cardiology Fellow Cape Fear Valley Medical Center Fayetteville NC

🔎 Your Deep-Dive Starts Here

Cite this article as: Dr. Eric Acker, Dr. Rana Humza, and Dr. Frank Lodeserto, "Is Abelacimab the Next Step in AF Anticoagulation? Early Signals and Remaining Questions", REBEL EM blog, December 15, 2025. Available at: https://rebelem.com/is-abelacimab-the-next-step-in-af-anticoagulation-early-signals-and-remaining-questions/.