Investigational anticoagulants

INTRODUCTION — 

Anticoagulants in clinical use have advantages and disadvantages related to their efficacy profile, safety, route of administration, drug interactions, and cost. All available anticoagulants increase bleeding to some degree. Strategies for developing safer and more effective anticoagulants continue to be pursued.

The development of new anticoagulants often starts with dose-finding studies in patients undergoing elective knee arthroplasty; efficacy can be objectively and efficiently assessed in such patients using venography to determine the rate of deep vein thrombosis (DVT) after surgery. Such information can then be used to inform dosing for other indications.

This topic discusses anticoagulants at later stages of development for clinical use. Approved anticoagulants are discussed in separate topic reviews.

●Parenteral

•Heparins – (See "Heparin and LMW heparin: Dosing and adverse effects".)

•Fondaparinux – (See "Fondaparinux: Dosing and adverse effects".)

•Argatroban and bivalirudin – (See "Direct oral anticoagulants (DOACs) and parenteral direct-acting anticoagulants: Dosing and adverse effects", section on 'Parenteral direct thrombin inhibitors'.)

●Oral

•Vitamin K antagonists – (See "Warfarin and other VKAs: Dosing and adverse effects" and "Biology of warfarin and modulators of INR control".)

•Dabigatran – (See "Direct oral anticoagulants (DOACs) and parenteral direct-acting anticoagulants: Dosing and adverse effects", section on 'Dabigatran'.)

•Factor Xa inhibitors – (See "Direct oral anticoagulants (DOACs) and parenteral direct-acting anticoagulants: Dosing and adverse effects", section on 'Direct factor Xa inhibitors'.)

Evidence for the efficacy of these anticoagulants for specific indications is discussed in the topics for the indications.

INHIBITORS OF FACTOR XI OR FACTOR XIa — 

Factor XI is part of the intrinsic pathway of the clotting cascade; the activated form (factor XIa) participates in the amplification of thrombin generation (figure 1). (See "Overview of hemostasis", section on 'Intrinsic or contact activation pathway'.)

Individuals with hereditary factor XI deficiency have a lower risk of venous thromboembolism (VTE) and ischemic stroke than individuals with normal factor XI levels but rarely have spontaneous bleeding; these data are presented separately. (See "Factor XI (eleven) deficiency", section on 'Clinical manifestations'.)

Mendelian randomization studies suggest that people with low factor XI levels are at reduced risk for VTE and ischemic stroke than those with normal factor XI levels but are not at increased risk for bleeding, whereas those with elevated factor XI levels are at increased risk for thrombotic events [1-3].

It has been hypothesized that inhibiting factor XI/XIa might uncouple thrombosis prevention from normal hemostasis, allowing maximal anticoagulation without incurring more bleeding risk.

Milvexian — Milvexian is an orally active, specific small molecule inhibitor of factor XIa [4,5].

Dose-finding trials with milvexian have included VTE prevention and secondary stroke prevention.

●VTE prevention – In a trial that randomly assigned 1242 individuals ≥50 years old who were undergoing knee arthroplasty to receive one of several doses/schedules of milvexian versus low molecular weight (LMW) heparin (enoxaparin 40 mg once daily) for 10 to 14 days postoperatively, those assigned to the higher milvexian dose regimens had lower rates of VTE [6]. Most of the endpoints were asymptomatic distal DVTs that were ascertained by mandatory unilateral venography on the operated leg 10 to 14 days after surgery.

•Efficacy – There was a dose-dependent reduction in postoperative VTE rates with once- or twice-daily milvexian:

-Milvexian, 25 mg once daily – 25 percent

-Milvexian, 25 mg twice daily – 21 percent

-Milvexian, 50 mg twice daily – 11 percent

-Milvexian, 100 mg twice daily – 9 percent

-Milvexian, 200 mg once daily – 7 percent

-Milvexian, 200 mg twice daily – 8 percent

-Enoxaparin, 40 mg once daily – 21 percent

•Safety – Bleeding rates (a composite of major, clinically relevant nonmajor, and minor bleeding) were similar (4 percent with milvexian and 4 percent with enoxaparin). Major bleeding occurred in one individual in the enoxaparin arm and none in the milvexian arm. Clinically relevant bleeding (a composite of major and clinically relevant nonmajor bleeding) occurred in 0.8 percent with milvexian and 1.7 percent with enoxaparin. There was no dose-dependent increase in clinically relevant bleeding over a 16-fold range of milvexian doses.

●Secondary stroke prevention – The 2024 AXIOMATIC-SSP trial randomly assigned 2366 participants age ≥40 years with acute (<48 hours) ischemic stroke or high-risk transient ischemic attack (TIA) to one of several dosing schedules of milvexian or placebo for 90 days [7]. All participants received clopidogrel 75 mg daily for the first 21 days and aspirin 100 mg daily for the first 90 days. Similar outcomes were reported with milvexian or placebo.

•Efficacy – Compared with placebo, milvexian did not substantially reduce the composite outcome of recurrent symptomatic ischemic stroke or covert brain infarction on magnetic resonance imaging at 90 days.

-Milvexian, 25 mg once daily – 16.7 percent

-Milvexian, 25 mg twice daily – 16.6 percent

-Milvexian, 50 mg twice daily – 15.6 percent

-Milvexian, 100 mg twice daily – 15.4 percent

-Milvexian, 200 mg twice daily – 15.3 percent

-Placebo – 16.8 percent

•Safety – There was no apparent dose response for major bleeding at 90 days (1 to 2 percent for all doses versus 1 percent with placebo).

The LIBREXIA AF trial (NCT05757869) will compare milvexian with apixaban in patients with atrial fibrillation. Additional trials will compare milvexian with placebo in patients receiving standard antiplatelet therapy for acute ischemic noncardioembolic stroke or high-risk TIA (LIBREXIA Stroke; NCT05702034) and for acute coronary syndrome (LIBREXIA ACS; NCT05754957) [8,9].

Asundexian — Asundexian is an orally active, specific small molecule inhibitor of factor XIa [10-12]. It has been evaluated for atrial fibrillation, acute myocardial infarction, acute ischemic noncardioembolic stroke, and high-risk TIA.

●Atrial fibrillation – The PACIFIC AF trial randomly assigned 753 patients with atrial fibrillation to asundexian 20 or 50 mg once daily or apixaban at 5 mg twice daily, with dose reduction to 2.5 mg twice daily according to the usual criteria [13]. Treatment was given for three months. The trial was underpowered to determine the efficacy of these asundexian doses relative to that of apixaban; factor XIa activity was inhibited by 94 percent (peak) and 92 percent (trough) with the 50 mg asundexian dose. There were no major bleeds in either arm, and clinically relevant nonmajor bleeding was less with asundexian (incidence ratio 0.33).

The 2025 OCEANIC AF trial randomly assigned 14,810 individuals with atrial fibrillation to asundexian 50 mg once daily or apixaban 5 mg twice daily and was stopped early because asundexian had reduced efficacy relative to apixaban [14]. Stroke or systemic embolism occurred in 1.3 percent of patients in the asundexian arm versus 0.4 percent in the apixaban arm (hazard ratio [HR] 3.8, 95% CI 2.5-5.8); major bleeding occurred in 0.2 percent with asundexian and 0.7 percent with apixaban (HR 0.3, 95% CI 0.2-0.6).

●Acute myocardial infarction – The PACIFIC AMI trial randomly assigned 1601 patients with acute myocardial infarction (ST elevation MI in 52 percent and non-ST elevation MI in 48 percent) to receive asundexian 10, 20, or 50 mg once daily or placebo; significant reductions in recurrent ischemic events were not found with asundexian [15]. All patients were receiving aspirin (81 mg once daily) and a P_2Y12 inhibitor (mostly ticagrelor or prasugrel) and nearly all underwent percutaneous coronary intervention. A composite of cardiovascular death, myocardial infarction, stroke, and stent thrombosis occurred in 6.8, 6.0, and 5.5 percent in the asundexian 10, 20, and 50 mg groups, respectively, and in 5.5 percent with placebo. Bleeding rates were similar (Bleeding Academic Research Consortium 2, 3, or 5 bleeding at six months occurred in 7.6, 8.1, and 10.5 percent with asundexian 10, 20, and 50 mg, respectively, and in 9.0 percent with placebo). Two patients receiving asundexian 50 mg and one patient receiving placebo had an intracerebral hemorrhage. Asundexian inhibited factor XIa in a dose-dependent manner, with >90 percent inhibition at the 50 mg asundexian dose.

●Acute ischemic stroke – The PACIFIC Stroke trial randomly assigned 1808 individuals with acute ischemic noncardioembolic stroke to receive asundexian 10, 20, or 50 mg or placebo once daily for six months and found no major efficacy differences [16]. The rate of a composite outcome (ischemic stroke or covert stroke on repeat brain imaging at six months) occurred in 19, 22, and 20 percent of patients in the asundexian 10, 20, and 50 mg groups, respectively, and in 19 percent with placebo. Major or clinically relevant nonmajor bleeding occurred in 4, 3, and 4 percent of the asundexian groups, respectively, and in 2 percent with placebo. Rates of hemorrhagic transformation were 0.4, 1.1, and 1.4 percent with asundexian 10, 20, and 50 mg, respectively, and 0 percent with placebo.

The OCEANIC Stroke trial (NCT05686070) will compare the addition of asundexian 50 mg once daily with a placebo to dual or single antiplatelet therapy for preventing recurrent ischemic stroke in individuals with acute noncardioembolic ischemic stroke or high-risk TIA who have systemic or cerebrovascular atherosclerosis.

Abelacimab — Abelacimab (MAA868) is a monoclonal antibody that binds to factor XI (the inactive precursor) and locks it in the inactive state, preventing it from being activated by factor XIIa or thrombin. Because it binds to the catalytic domain of factor XI, abelacimab also inhibits factor XIa. For extended use, it is administered subcutaneously once per month.

●The 2025 AZALEA trial compared bleeding rates in 1287 individuals with atrial fibrillation who were randomly assigned to abelacimab (90 or 150 mg) or rivaroxaban (20 mg once daily) [17]. The trial was stopped early because of greater safety with abelacimab. The incidence of major or clinically relevant nonmajor bleeding was 3.2 events per 100 person-years with 150 mg abelacimab, 2.6 events per 100 person-years with 90 mg abelacimab, and 8.4 events per 100 person-years with rivaroxaban (hazard ratio [HR] for 150 mg abelacimab versus rivaroxaban 0.38, 95% CI 0.24-0.60; HR for 90 mg abelacimab versus rivaroxaban 0.31, 95% CI 0.19-0.51; p<0.001 for both comparisons). Gastrointestinal bleeding was reduced by 93 percent with abelacimab compared to rivaroxaban. Adverse event rates were similar between abelacimab and rivaroxaban.

●A 2021 trial involving 412 individuals undergoing knee arthroplasty evaluated three doses of abelacimab (30, 75, or 150 mg) administered postoperatively as a single intravenous infusion versus subcutaneous enoxaparin, 40 mg once daily [18]. Patients could receive a single preoperative dose of enoxaparin. All participants underwent postoperative venography for VTE evaluation. There was a lower rate of VTE with all doses of abelacimab than with enoxaparin.

•Efficacy – Postoperative VTE rates were as follows:

-Abelacimab, 30 mg – 13 percent

-Abelacimab, 75 mg – 5 percent

-Abelacimab, 150 mg – 4 percent

-Enoxaparin, 40 mg – 22 percent

•Safety – The risk of clinically relevant bleeding (the composite of major and clinically relevant nonmajor bleeding) was low (2, 2, and 0 percent of patients in the 30, 75, and 150 mg abelacimab cohorts, respectively, and in 0 percent of those treated with enoxaparin).

Abelacimab is being evaluated in additional randomized trials in atrial fibrillation (LILAC TIMI-76 [NCT05712200]) and cancer-associated VTE (ASTER [NCT05171049] and MAGNOLIA [NCT05171075]).

Osocimab — Osocimab (BAY 1213790) is a monoclonal antibody that binds adjacent to the active site of factor XIa and prevents it from activating factor IX (allosteric inhibition) [19]. Osocimab half-life is 30 to 44 days, allowing single intravenous dose administration for surgical thromboprophylaxis. For extended use, osocimab is given subcutaneously once per month.

●A 2024 trial randomly assigned 704 participants with kidney failure undergoing dialysis to receive osocimab (lower dose or higher dose) or placebo for up to 18 months (minimal treatment period of six months) [20]. Compared with placebo, osocimab did not increase the rate of clinically relevant bleeding (11 of 224 patients [5 percent] with high-dose osocimab, 16 of 232 patients [7 percent] with low-dose osocimab, and 18 of 230 patients [8 percent] treated with placebo). Adverse event rates were also similar among the groups (51 percent with low-dose osocimab, 47 percent with high-dose osocimab, and 43 percent with placebo).

●An earlier dose-finding trial evaluated dose-finding, timing of administration, and comparison with other anticoagulants (enoxaparin and apixaban) in 813 adults undergoing elective knee arthroplasty [21]. Individuals were randomly assigned to receive one of several weight-based doses of osocimab, some preoperatively and some postoperatively, or to receive enoxaparin (40 mg subcutaneously once daily starting the evening before surgery or 12 to 24 hours postoperatively) or apixaban (2.5 mg orally twice per day starting 12 to 24 hours postoperatively).

•Efficacy – The risk of VTE (symptomatic or identified by mandatory screening venography) was lowest in individuals who received the highest osocimab dose (1.8 mg/kg) given preoperatively (11.3 percent), followed by apixaban (14.5 percent). VTE rates were 26.3 percent with enoxaparin and 15.7 to 17.9 percent with various doses of osocimab given postoperatively. In all the arms, most of the VTE events were asymptomatic; symptomatic VTE occurred in 0 to 2 percent of participants.

•Safety – The risk of major bleeding was 1 to 5 percent with osocimab (depending on dose and timing), 6 percent with enoxaparin, and 2 percent with apixaban. All bleeding events were surgical site bleeding; there were no instances of intracranial or other critical sites of bleeding. Thrombocytopenia was seen in 6 percent of the osocimab- and enoxaparin-treated patients and 2 percent of the apixaban-treated patients.

Fesomersen — Fesomersen is a ligand-conjugated factor XI antisense oligonucleotide (ASO) that blocks the synthesis of factor XI in the liver, thereby reducing the circulating levels of factor XI [22].

In an open-label trial, 300 patients undergoing elective knee replacement were randomly assigned to receive the first-generation, nonligand-conjugated ASO at one of two doses (200 or 300 mg) or enoxaparin (40 mg) once daily [23]. The rate of VTE, assessed by venography in all patients, was reduced in those receiving the higher dose of ASO (3 of 71 patients; 4 percent), compared with the lower dose of ASO (27 percent) or enoxaparin (30 percent). Bleeding was not increased with the higher ASO dose (3 percent), versus 3 percent for ASO 200 mg and 8 percent for enoxaparin.

There are caveats for this strategy, including the extended half-life of the antisense therapy (up to three months) and injection site reactions [24]. Fesomersen, the second-generation ligand-conjugated antisense oligonucleotide, has increased potency, reducing the required volume and frequency of injections and the risk of injection site reactions.

In a trial that randomly assigned 307 participants with kidney failure on hemodialysis who received subcutaneous fesomersen at a dose of 40, 80, or 120 mg or a matching placebo once monthly for up to 12 months, fesomersen produced a dose-dependent reduction in factor XI levels [25]. The rate of a composite endpoint of major bleeding and clinically relevant nonmajor bleeding was not increased with escalating doses of fesomersen (6.5, 5.1, and 3.9 percent at 40, 80, and 120 mg, respectively) versus placebo (4 percent).

Gruticibart (AB023) — Gruticibart (AB023) is a monoclonal antibody that binds to factor XI and prevents its activation by factor XIIa, thus acting as a factor XIIa inhibitor [26]. Gruticibart may allow better separation of thrombosis from hemostasis by leaving intact the activation of factor XI by thrombin.

In small trials of patients with kidney failure undergoing heparin-free hemodialysis or with cancer undergoing central venous catheter placement, gruticibart reduced dialyzer clotting or catheter thrombosis [27,28].

Sulfated chiro-inositol — Sulfated chiro-inositol (SCI) is a synthetic heparin-like molecule that binds to factor XIa and alters its conformation, thereby reducing its enzymatic activity (allosteric inhibition) [29]. Preclinical testing suggests that this molecule could be effective as an anticoagulant and could be reversed by protamine sulfate.

INHIBITORS OF OTHER CLOTTING PROTEINS — 

Other coagulation proteins involved in thrombosis are amenable to inhibition. (See "Overview of hemostasis".)

Although many agents have been investigated, none have moved forward into advanced stages of development.

ART-123 (thrombomodulin inhibitor) — Thrombomodulin is a membrane protein that acts as a cofactor for thrombin in activating protein C [30].

A recombinant form of the extracellular domain of thrombomodulin was developed as an anticoagulant (ART-123) and has been approved in Japan for the treatment of disseminated intravascular coagulation (DIC). It has a half-life of two to three days after a subcutaneous injection, such that it can be given once every five to six days with maintenance of anticoagulant activity [31]. In a phase II trial, ART-123 was effective for VTE prophylaxis following total hip replacement [32]. However, ART-123 has not progressed further for prevention or treatment of VTE.

Protein disulfide isomerase inhibitors — Protein disulfide isomerase (PDI) is an oxidoreductase enzyme that catalyzes redox protein folding in newly synthesized proteins in the endoplasmic reticulum, including coagulation factor XI and tissue factor. PDI is expressed on the surface of several cell types, including platelets, where it promotes platelet aggregation via integrin activation [33]. (See "Overview of hemostasis", section on 'Platelet secretion'.)

PDI inhibitors have the potential to attenuate thrombin generation and platelet activation. Several molecules inhibit PDI, including quercetins, which are found in certain plant-based foods. Preclinical studies using a peptide inhibitor of PDI have demonstrated antiplatelet activity in vitro [34]. In a phase II trial in patients with cancer who were at risk for VTE, isoquercetin (1000 mg daily, but not 500 mg) decreased plasma D-dimer levels by 22 percent [35].

Polyphosphate inhibitors — Polyphosphate (released from platelets upon their activation or from a microbial source) may initiate and/or accelerate coagulation via the intrinsic pathway. Compounds that inhibit polyphosphate and reduce thrombosis in preclinical models are under investigation [36].

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Anticoagulation".)

SUMMARY

●Factor XI/XIa inhibitors – Factor XI is part of the intrinsic pathway of the clotting cascade; activated factor XI (factor XIa) participates in amplifying thrombin generation (figure 1). It has been hypothesized that inhibiting factor XI/XIa might uncouple thrombosis prevention from normal hemostasis, allowing effective anticoagulation without increasing bleeding risk. (See "Overview of hemostasis", section on 'Intrinsic or contact activation pathway'.)

Several factor XI or XIa inhibitors are under development, including small molecules (ending in "xian"), monoclonal antibodies (ending in "mab"), and an antisense oligonucleotide (fesomersen):

•Milvexian – (See 'Milvexian' above.)

•Asundexian – (See 'Asundexian' above.)

•Abelacimab – (See 'Abelacimab' above.)

•Osocimab – (See 'Osocimab' above.)

•Fesomersen – (See 'Fesomersen' above.)

●Earlier stages of development – Inhibitors of thrombomodulin and protein disulfide isomerase (PDI) are under development. (See 'ART-123 (thrombomodulin inhibitor)' above and 'Protein disulfide isomerase inhibitors' above.)