Reversal of the Anticoagulant Effect of Milvexian by 4-Factor PCC and rFVIIa in Healthy Participants: a Two-Part, Randomized, Crossover Study

Q: What are the key findings of this study?

Administration of rFVIIa and 4F-PCC partially and rapidly reversed the anticoagulant effects of milvexian, significantly reducing milvexian-induced aPTT prolongation compared to placebo.

Q: What is the clinical evidence from this study?

Study design: RCT. Population: Healthy participants (n=46). Intervention: rFVIIa and 4F-PCC vs. Placebo. Primary outcome: Absolute change in aPTT from prereversal baseline at 15 minutes after infusion of 4F-PCC (Part B) (MD -13.7 seconds, 95% CI -15.1 to -12.3, p=<0.05).

Q: What does this research mean for the field?

The anticoagulant effects of the oral factor XIa inhibitor milvexian can be rapidly and partially reversed by recombinant human factor VIIa (rFVIIa) and 4-factor prothrombin complex concentrate (4F-PCC) in healthy participants. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.NEUTRAL.

Q: What question did this study set out to answer?

To assess the reversal of the anticoagulant effects of the selective factor XIa inhibitor milvexian using recombinant human factor VIIa (rFVIIa) and 4-factor prothrombin complex concentrate (4F-PCC) in healthy participants.

Victor Dishy; Sue Sha; Anastasiya Koshkina; Fisseha Tesfaye; Alexei N. Plotnikov; Hideo Makimura; Madhu Chintala

doi:10.1097/fjc.0000000000001859

July 6, 2026Journal of Cardiovascular PharmacologyOpen Access

Reversal of the Anticoagulant Effect of Milvexian by 4-Factor PCC and rFVIIa in Healthy Participants: a Two-Part, Randomized, Crossover Study

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Key result

4F-PCC and rFVIIa rapidly reverse milvexian-induced anticoagulation, cutting aPTT prolongation by ~14 seconds vs placebo.

MD -13.7 seconds
95% CI -15.1 to -12.3
P<0.05
n=46

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Why the study?

Individuals receiving anticoagulation with milvexian, an oral factor XIa inhibitor, may require prompt reversal of anticoagulative effects.

Do rFVIIa and 4F-PCC reverse the anticoagulant effect of the factor XIa inhibitor milvexian in healthy adults?

Key Points

To assess the reversal of the anticoagulant effects of the selective factor XIa inhibitor milvexian using recombinant human factor VIIa (rFVIIa) and 4-factor prothrombin complex concentrate (4F-PCC) in healthy participants.
Two-part, randomized, crossover study in 46 healthy participants (Part A, n = 30; Part B, n = 16), with 45 completing the study.
Part A tested single doses of milvexian (100 mg or 500 mg) followed 4 hours later by IV rFVIIa (30 μg/kg) or placebo; Part B tested milvexian 200 mg q12h for 3 days followed on Day 4 by IV 4F-PCC (50 IU/kg) or placebo.
Primary endpoints were absolute changes from prereversal baseline in activated partial thromboplastin time (aPTT) and thrombin generation assay (TGA) parameters measured 15 minutes after completion of reversal agent or placebo infusions.
At 15 minutes post-infusion, rFVIIa significantly reduced milvexian-induced aPTT prolongation versus placebo in both the 100 mg (difference: −7.6 seconds, 95% CI −9.6 to −5.5; P < 0.05) and 500 mg groups (difference: −24.9 seconds, 95% CI −27.7 to −22.2; P < 0.05).
rFVIIa significantly reversed intrinsic pathway–induced endogenous thrombin potential (ETP) reductions versus placebo for milvexian 100 mg (difference: 256.6 min⋅nmol/L, 95% CI 95.3 to 417.9; P < 0.05) and milvexian 500 mg (difference: 427.3 min⋅nmol/L, 95% CI 263.7 to 590.9; P < 0.05).
In Part B, 4F-PCC significantly reversed milvexian-mediated aPTT prolongation versus placebo (difference: −13.7 seconds, 95% CI −15.1 to −12.3; P < 0.05) and increased intrinsic pathway–induced ETP (difference: 234.7 min⋅nmol/L, 95% CI 88.4 to 381; P < 0.05).

Study Design

Type

RCT (n=46)

Blinding

Open-label

Randomization

Computer-generated randomization schedule

Multicenter

No

Structured PICO

Do rFVIIa and 4F-PCC reverse the anticoagulant effect of the factor XIa inhibitor milvexian in healthy adults?

P

Population

46 healthy adults aged 18 to 54 years received milvexian followed by rFVIIa or 4F-PCC in a randomized crossover study to assess anticoagulant reversal.

I

Intervention

Part A: rFVIIa (30 μg/kg) IV infusion over 5 minutes administered 4 hours after a single dose of milvexian (100 mg or 500 mg). Part B: 4F-PCC (50 IU/kg) IV infusion over 30 minutes administered 4 hours after the last dose of milvexian (200 mg q12h for 3 consecutive days).

C

Comparator

Placebo (saline) IV infusion administered 4 hours after milvexian dosing, matching the timing and duration of the active reversal agents in Part A and Part B.

O

Outcome

Absolute changes from prereversal baseline in aPTT and TGA parameters at 15 minutes after the end of administration of reversal agents/placebo infusion.surrogate

Main Result

Mean Difference: -13.7 (95% CI -15.1–-12.3)

Absolute Event Rate: -14.2% vs -0.5%

p-value: p=<0.05

In healthy participants, the anticoagulant effects of the factor XIa inhibitor milvexian were rapidly and partially reversed by rFVIIa and 4F-PCC, providing potential reversal strategies for clinical practice.

Limitations

Conducted in healthy participants who were not on concomitant medications and had lower risk of bleeding
No provocation of bleeding
Small sample size consistent with phase 1 studies

Implication

Supports prompt reversal of milvexian in clinical bleeding; extends reversal evidence to factor XIa inhibitors.

Abstract

Milvexian is a selective, oral factor XIa inhibitor. Individuals receiving anticoagulation may require prompt reversal of anticoagulative effects. This study assessed reversal of milvexian’s anticoagulant effects by recombinant human factor VIIa (rFVIIa) and 4-factor prothrombin complex concentrate (4F-PCC) in healthy participants. This was a 2-part, randomized, crossover study. In Part A, milvexian (100 or 500mg single doses) was followed by rFVIIa (30μg/kg) or placebo 4 hours later. In Part B, milvexian 200mg was administered q12h for 3 consecutive days, with 4F-PCC (50IU/kg) or placebo given 4 hours after last dose in the morning of Day 4. Anticoagulation was assessed through activated partial thromboplastin time (aPTT) and thrombin generation (endogenous thrombin potential [ETP], peak thrombin) utilizing 2 activators: kaolin (intrinsic pathway [IP] effects) and tissue factor (TF; extrinsic pathway [EP] effects). rFVIIa partially reversed milvexian’s effects on aPTT (milvexian 100mg: ∼18%; 500mg: ∼15%), IP–induced ETP (milvexian-induced ETP reversal; 100mg: ∼50%; 500mg: ∼80%) and peak thrombin, and EP–induced peak thrombin but not ETP. Milvexian 200mg prolonged aPTT, strongly inhibited IP-induced ETP/peak thrombin, and mildly inhibited EP-induced ETP. 4F-PCC partially reversed milvexian’s effect on aPTT (∼17%) and IP–induced ETP/peak thrombin; it reversed milvexian’s effect on EP–initiated ETP (∼68% increase). Reversal was rapid (15 minutes) and long-lasting (≥8 hours). Milvexian pharmacokinetics were unchanged by reversal agents. Regimens were generally safe and well-tolerated. In conclusion, milvexian’s anticoagulant effect was partially reversed by rFVIIa and 4F-PCC. These results may offer clinicians options in situations where reversal of milvexian might be considered.

Discussion

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Cite This Study

Dishy et al. (2026) conducted an RCT in Healthy participants (n=46). rFVIIa and 4F-PCC vs. Placebo was evaluated on Absolute change in aPTT from prereversal baseline at 15 minutes after infusion of 4F-PCC (Part B) (MD -13.7 seconds, 95% CI -15.1 to -12.3, p=<0.05). Administration of rFVIIa and 4F-PCC partially and rapidly reversed the anticoagulant effects of milvexian, significantly reducing milvexian-induced aPTT prolongation compared to placebo.

synapsesocial.com/papers/6a4deabbd2ea289ef628444f https://doi.org/10.1097/fjc.0000000000001859

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Reversal of the Anticoagulant Effect of Milvexian by 4-Factor PCC and rFVIIa in Healthy Participants: a Two-Part, Randomized, Crossover Study

Figures

Key Points

Study Design

Structured PICO

Main Result

Limitations

Implication

Abstract

Discussion

Cite This Study

Reversal of the Anticoagulant Effect of Milvexian by 4-Factor PCC and rFVIIa in Healthy Participants: a Two-Part, Randomized, Crossover Study

Figures

Key Points

Study Design

Structured PICO

Main Result

Limitations

Implication

Abstract

Discussion

Cite This Study

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