🧭 REBEL Rundown
📌 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
📈 Results
- Randomization:
- 1287 patients were randomized; 1280 (99.5%) received at least one dose of study drug.
- Median age was 74 years (IQR 69–78); 44% of participants were women.
- Median CHA₂DS₂-VASc score was 5, indicating a generally high stroke risk.
- At baseline, 92% had been on anticoagulation for ≥60 days; among these, 66% had used a DOAC.
- Trial Stopped Early for Benefit:
- The independent data monitoring committee recommended early trial termination (Sept 14, 2023) because both abelacimab doses showed a much lower hazard for the primary bleeding endpoint versus rivaroxaban and an overall favorable benefit–risk profile.
- At recommendation for termination, median follow-up was 1.8 years (IQR 1.7–1.9); at trial completion, median follow-up was 2.1 years (IQR 2.0–2.3).
- Early permanent discontinuation of study drug:
- Rivaroxaban: 45 patients (10.5%; 5.0% per year)
- Abelacimab 150 mg: 49 patients (11.4%; 5.4% per year)
- Abelacimab 90 mg: 58 patients (13.6%; 6.6% per year)
- Withdrawal of consent:
- Rivaroxaban: 6 patients (1.4%; 0.67% per year)
- Abelacimab 150 mg: 3 patients (0.7%; 0.33% per year)
- Abelacimab 90 mg: 14 patients (3.3%; 1.59% per year)
- Age & frailty-ish markers
- ≥80 yrs: slightly fewer in 150-mg abelacimab (18.8%) vs rivaroxaban (20.9%) and 90-mg abelacimab (20.4%).
- HAS-BLED: median 3 in rivaroxaban vs 2 in both abelacimab arms → numerically lower baseline bleeding risk in abelacimab groups.
- Stroke risk (CHA₂DS₂-VASc distribution)
- CHA₂DS₂-VASc ≤4: higher in 150-mg abelacimab (49.5%) vs rivaroxaban (43.3%) and 90-mg (44.7%).
- CHA₂DS₂-VASc ≥6: highest in rivaroxaban (26.5%), then 90-mg (23.7%), lowest in 150-mg (20.0%).
- So rivaroxaban patients are slightly higher risk by CHA₂DS₂-VASc mix.
- Comorbidities
- Heart failure: more common in rivaroxaban (47.9%) vs 150-mg (42.3%) and 90-mg (45.0%).
- CAD: a touch higher in the 90-mg group (51.1%) vs rivaroxaban (47.7%) and 150-mg (46.3%).
- Prior cerebrovascular events
- Prior ischemic stroke: highest in rivaroxaban (17.5%) vs 150-mg (13.7%) and 90-mg (13.3%).
- Prior TIA: slightly higher in 90-mg abelacimab (8.9%) vs rivaroxaban (7.5%) and 150-mg (5.8%).
- Prior anticoagulation
- Any anticoag ≥60 days: slightly more in rivaroxaban (94.0%) vs 150-mg (90.5%) and 90-mg (91.3%).
- Prior DOAC use: numerically highest in rivaroxaban (67.7%), similar in 90-mg (66.4%), a bit lower in 150-mg (63.0%).
- Concomitant antiplatelets (among those planned to receive them)
- Aspirin use: higher in both abelacimab arms (≈67%) vs rivaroxaban (54.7%).
- P2Y₁₂ inhibitor use: higher in rivaroxaban (39.6%) vs 150-mg (27.6%) and 90-mg (24.3%).
- Big picture:
- Groups are largely balanced.
- Slightly higher stroke/bleeding risk and more prior stroke in the rivaroxaban arm
- Slightly more aspirin / less P2Y₁₂ in the abelacimab arms.
- Whether these are clinically meaningful vs just random baseline variation is debatable.
💥 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. PMI
D: 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
Eric Acker, MD
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