Characteristics and key outcomes of included studies comparing FXI inhibitors and direct oral anticoagulants (DOACs) in patients with AF.
| Author (Year) | Study type/design | Population (n, characteristics) | Intervention | Comparator | Primary outcomes | Secondary outcomes | Follow-up duration |
|---|---|---|---|---|---|---|---|
| Rao et al. (2022)[37] | Multicenter, randomized, placebo-controlled phase 2 RCT | Post-MI patients, some with AF (n = 1,601; mean age 64) | Oral asundexian | Placebo | Safety: BARC 2/3/5 HR 0.98 | Efficacy: CV death, MI, stroke/stent thrombosis HR 1.05 | 1 year |
| Sharma et al. (2024)[38] | Phase 2 dose-finding RCT | 2,368 [patients with acute mild IS or high-risk transient ischemic attack (TIA); median age 70–72 years, 33–39% aged ≥ 75 years, 33–37% female, 75–79% HTN, 27–32% diabetes] | Milvexian [oral FXIa inhibitor; doses: 25 mg once daily (QD), 25 mg twice daily (BID), 50 mg BID, 100 mg BID, 200 mg BID] + dual antiplatelet therapy (APT; aspirin + clopidogrel) | Placebo + dual APT (aspirin + clopidogrel) | Composite of symptomatic IS + covert brain infarction on MRI at Day 90 (no significant dose-response; RR range 0.91–0.99 vs. placebo) | Major bleeding (BARC Type 3/5; low rates, no increase with milvexian); symptomatic IS alone (numerical reduction in most doses, RR 0.65–0.83 except 200 mg BID RR 1.40) | 90 days |
| Piccini et al. (2022)[23] | Phase 2 dose-finding RCT | AF n = 753, mean age 73.7 | Asundexian | Apixaban | Major/CRNM bleeding: asundexian 20 mg 0.50, 50 mg 0.16; pooled 0.33 | Any AE: 47% vs. 49% | ~1 year |
| Shoamanesh et al. (2022)[28] | Phase 2b RCT | Acute non-cardioembolic stroke ≥ 45 years, n = 1,808 | Asundexian | Placebo + antiplatelet | Covert brain infarcts/recurrent stroke at 26 weeks: 19–22% | Major/CRNM bleeding 4% vs. 2% | 26 weeks |
| Perera et al. (2022)[39] | Two-part, double-blind, placebo-controlled, sequential single ascending dose (SAD) and multiple ascending dose (MAD) study | 104 healthy adults (SAD panels: 48 participants in 6 panels of 8; MAD panels: 56 participants in 7 panels of 8; randomized 3:1) | Milvexian (BMS-986177/JNJ-70033093; SAD doses: 4, 20, 60, 200, 300, or 500 mg oral; MAD: once- or twice-daily for 14 days; high-fat meal effect in 200- and 500-mg panels) | Placebo | Safety/PK/PD: Favorable safety (no clinical bleeding); dose-proportional absorption (up to 200 mg); terminal t½ 8.3–13.8 h; PD correlated with aPTT | Food effect (increased bioavailability dose-dependently); renal excretion (< 20% in all panels) | SAD: up to 72 h postdose; MAD: 14 days dosing |
| Galli et al. (2023)[22] | Meta-analysis 8 RCTs | n = 9,216 | ISIS 416858, osocimab, abelacimab, milvexian, asundexian | Enoxaparin, DOACs, placebo | Vs. enoxaparin: ↓ any bleeding RR 0.49; vs. DOACs: trend ↓; vs. Placebo ↑ any bleeding RR 1.25 | Major bleeding: non-significant vs. enoxaparin/DOACs; trend ↑ vs. placebo | Short-term perioperative/6–12 months |
| de Alcântara et al. (2026)[40] | Systematic review and meta-analysis | Patients with AF pooled from 4 RCTs (n = 16,852) | FXI inhibitors (asundexian, milvexian) | DOACs (apixaban, rivaroxaban) | Major bleeding significantly lower in FXI inhibitors (OR 0.30, 0.40% vs. 1.32%; 95% CI 0.20–0.43; p < 0.001) | Stroke/systemic embolism more common in FXI inhibitors (OR 3.20; 95% CI 1.85–5.55; p = 0.004) | Median 3–48 months across trials |
| Franco-Moreno et al. (2024)[41] | Systematic review | 18 trials; AF, stroke, MI, VTE | FXI inhibitors (phase 2) | Enoxaparin, DOACs, placebo | ↓ Thrombotic complications ~50% (TKA), modest in AF/MI/stroke | ↓ Bleeding ~60% vs. enoxaparin; safety acceptable | Short-term 12 months |
| Parsa et al. (2024)[42] | Review | Synthesis of preclinical, phase I, and phase II trials focusing on patients with AF, ACS, IS, and VTE | Milvexian (oral FXIa inhibitor; doses up to 500 mg in phase I, varying in phase II; high affinity and selectivity for FXIa) | DOACs (e.g., apixaban, rivaroxaban) or vitamin K antagonists | Anticoagulant efficacy without increased bleeding risk (phase II: no dose-dependent bleeding increase; reduced thrombotic events while preserving hemostasis) | Safety/Tolerability: Mild AEs (phase I), promising risk-benefit (phase II); PK: dose-proportional (up to 200 mg), terminal t½ 8.3–13.8 h | Not applicable (review) |
| Jain et al. 2024[43] | RCT (study design paper) | Patients with AF at risk of stroke; planned n = 15,500, mean age ~70, CHA2DS2-VASc ≥ 2 | Milvexian (FXI inhibitor) | Apixaban (DOAC) | Composite of IS/systemic embolism; major bleeding | Intracranial hemorrhage, fatal bleeding, cardiovascular mortality | Planned 3 years (ongoing trial, no outcome data reported) |
| Shahid et al. (2026)[44] | Systematic review and meta-analysis | Patients with AF pooled from 3 RCTs (n = 16,845) | FXI inhibitor (asundexian, abelacimab) | DOACs (rivaroxaban, pixaban) | Stroke/systemic embolism more common in FXI inhibitors (RR 3.32; 95% CI 2.24–4.90, p < 0.00001) | Major and minor bleeding were significantly lower in FXI inhibitors (RR 0.41; 95% CI 0.33–-0.49, p < 0.00001) and (RR 0.68; 95% CI 0.49–0.93, p = 0.02), respectively | Mean 18 months in real-world cohorts |
| Markides et al. (2025)[29] | Systematic review & meta-analysis | AF; 3 RCTs (PACIFIC-AF, OCEANIC-AF, AZALEA-TIMI 71) | Asundexian, abelacimab | DOACs (apixaban, rivaroxaban) | ↓ ISTH major or CRNM bleeding OR pooled 0.39 | ↑ IS OR 3.37; ↓ all-cause mortality OR 0.82 | Short-mid-term |
| Xue et al. (2025)[33] | Systematic review 3 RCTs | Patients AF n = 16,852 | Abelacimab, asundexian | Rivaroxaban, apixaban | ↓ Major/CRNM bleeding: abelacimab 62–69%; asundexian 50–84% | OCEANIC-AF: ↑ stroke risk with asundexian 3.8×; abelacimab trend ↑ | Short-mid-term |
| Ruff et al. (2025)[25] | Phase 2 RCT (AZALEA-TIMI 71) | AF n = 1,287, median age 74 | Abelacimab 150 mg SC, 90 mg SC | Rivaroxaban 20 mg daily | Major/CRNM bleeding: 150 mg HR 0.38, 90 mg HR 0.31 vs. rivaroxaban | AE similar | Median follow-up 3 months (stopped early) |
| Raffo et al. (2025)[21] | Narrative review | AF patients from RCTs like AZALEA-TIMI 71, PACIFIC-AF, OCEANIC-AF | FXI inhibitors (abelacimab 90/150 mg monthly SC, asundexian 20/50 mg daily oral) | DOACs (rivaroxaban 20 mg daily, apixaban 5/2.5 mg BID) | Major/CRNM bleeding (1.9–2.7/100 PY abelacimab vs. 8.1/100 PY rivaroxaban; 0.4–1.2% asundexian vs. 2.4% apixaban) | IS: higher (non-significant) with abelacimab; all-cause mortality: lower (non-significant); GI bleeding: 0.1/100 PY (abelacimab) vs. 2.1/100 PY (rivaroxaban) | Median 21 months (AZALEA-TIMI 71), 12 weeks (PACIFIC-AF) |
| Piccini et al. (2025)[27] | Phase 3 RCT (OCEANIC-AF) | AF n = 14,810, mean age 73.9 | Asundexian 50 mg daily | Apixaban standard | Stroke/systemic embolism 1.3% vs. 0.4%; HR 3.79 | Major bleeding ↓ 0.2% vs. 0.7%; AE similar | Short, trial terminated early |
| Patel et al. (2025)[45] | Phase II RCT secondary analysis | 1,284 AF patients; median age 74; 44.5% women; stratified by creatinine clearance (≤ 50 vs. > 50 mL/min) | Abelacimab 150/90 mg SC | Rivaroxaban | Major/CRNM bleeding ↓ across kidney function strata | Consistent benefit | Median ~3 months |
| Zhou et al. (2026)[46] | Quantitative modeling study | Simulated AF patient population for phase III trial dose selection; based on prior trial data (n not specified, high-risk AF patients) | Milvexian (FXI inhibitor) | Apixaban | Predicted stroke/systemic embolism risk; bleeding risk (modeled outcomes) | Pharmacokinetic/pharmacodynamic profiles, dose optimization | Not applicable (modeling study, no clinical follow-up) |
| Al Said et al. (2025)[47] | Prespecified sub-analysis of phase 2 RCT (AZALEA-TIMI 71) | AF patients with concomitant APT (subset stratified at baseline; higher bleeding risk due to dual therapy) | Abelacimab 90 mg or 150 mg SC monthly | Rivaroxaban 20 mg daily (dose-adjusted for CrCl) | Major/CRNM bleeding markedly lower with abelacimab vs. rivaroxaban in patients on APT (greater absolute risk reduction in APT group: 7.1–8.1% vs. 4.6–5.0% without APT); consistent safety benefit | IS/systemic embolism (low events, numerically similar); all-cause mortality (neutral); adverse events similar | Median ~21 months (1.8 years) |
ACS: acute coronary syndrome; AF: atrial fibrillation; AF-QoL: atrial fibrillation quality of life; aPTT: activated partial thromboplastin time; AZALEA-TIMI 71: Assessment of Factor XI Antagonism for the Long-Term Evaluation of Atrial Fibrillation-Thrombolysis in Myocardial Infarction 71; BARC: bleeding academic research consortium; BMS-986177/JNJ-70033093: Bristol Myers Squibb compound number/Johnson & Johnson compound number; CHA2DS2-VASc: congestive heart failure, hypertension, age ≥ 75 years, diabetes mellitus, stroke/TIA/thromboembolism, vascular disease, age 65–74 years, sex category; CI: confidence interval; CRNM: clinically relevant non-major; FXI: factor XI; FXIa: factor XIa; GI: gastrointestinal; HR: hazard ratio; HTN: hypertension; IS: ischemic stroke; MI: myocardial infarction; MRI: magnetic resonance imaging; OCEANIC-AF: Oral Factor XI Inhibitor Evaluation in Atrial Fibrillation; OR: odds ratio; PACIFIC-AF: Phase 2 Study of Asundexian for Stroke Prevention in Patients with Atrial Fibrillation; PD: pharmacodynamics; PK: pharmacokinetics; PY: patient-years; RCT: randomized controlled trials; RR: relative risk; SC: subcutaneous; VTE: venous thromboembolism.