1206778

review-article2023
VMJ0010.1177/1358863X231206778Vascular MedicinePrakash et al.

Review Article

Vascular Medicine

Factor XI/XIa inhibitors for the prevention 1­–8

© The Author(s) 2023

and treatment of venous and arterial

Article reuse guidelines:
sagepub.com/journals-permissions
DOI: 10.1177/1358863X231206778
https://doi.org/10.1177/1358863X231206778
thromboembolism: A narrative review journals.sagepub.com/home/vmj

Swathi Prakash1, Adriana C Mares1,2, Mateo Porres-Aguilar3 ,

Debabrata Mukherjee4 and Geoffrey D Barnes5

Abstract
During the past decade, direct oral anticoagulants (DOACs) have advanced and simplified the prevention and treatment
of venous thromboembolism (VTE). However, there remains a high incidence of bleeds, which calls for agents that
have a reduced risk of bleeding. Factor XI (FXI) deficiency is associated with lower rates of venous thrombosis and
stroke compared to the general population with a lower risk of bleeding. In conjunction with this, phase 2 studies have
demonstrated safety and the potential for reduced thrombotic events with FXI inhibitors as compared to currently
available medications. The aim of this review is to summarize key data on the clinical pharmacology of FXI, the latest
developments in clinical trials of FXI inhibitors, and to describe the efficacy and safety profiles of FXI inhibitors for the
prevention of venous and arterial thromboembolism.

Keywords
anticoagulation, bleeding events, factor XI, thromboprophylaxis, thrombosis, venous thromboembolism (VTE)

Introduction The contact pathway as a target for FXI

Since the advent of oral factor Xa and direct thrombin
inhibitors more than a decade ago, these direct oral anti-
coagulants (DOACs) have advanced significantly in
terms of ease of administration and use in venous throm-
boembolism (VTE) and atrial fibrillation (AF). DOACs
have a lower risk of bleeding, especially intracranial
bleeding, when compared to vitamin K antagonists
(VKAs) in patients with nonvalvular atrial fibrillation
(NVAF) for cardioembolic stroke prevention.1,2 Despite
this, there are still risks for bleeding in DOACs and an
unmet need for safer anticoagulants that are effective
with improved safety profiles in terms of major bleeding
events. This review briefly discusses the rationale, and
current and future roles of factor XI/XIa inhibitors for
the prevention of VTE, prevention of and treatment for
arterial thromboembolism (ATE), stroke prevention in
AF, and other potential therapeutic indications in the
complex subgroup of medically ill patients. This review
reports the existing data on factor XI (FXI) inhibitors for
various clinical conditions and its safety.
inhibitors
Hemostasis is a process involving platelets, clotting factors,
and endothelium at the site of vascular injury to form a blood
clot to prevent or decrease the extent of bleeding.3 The
1
 epartment of Internal Medicine, Texas Tech University Health
D
Sciences Center, El Paso, TX, USA
2
Yale University School of Medicine, New Haven, CT, USA
3
Department of Internal Medicine, Divisions of Hospital and Adult
Thrombosis Medicine, Texas Tech University Health Sciences Center
and Paul L Foster School of Medicine, El Paso, TX, USA
4
Division of Cardiovascular Diseases, Texas Tech University Health
Sciences Center and Paul L Foster School of Medicine, El Paso, TX,
USA
5
Department of Internal Medicine, Division of Cardiovascular Medicine,
Frankel Cardiovascular Center, University of Michigan, Ann Arbor, MI,
USA
Corresponding author:
Mateo Porres-Aguilar, Texas Tech University Health Sciences Center,
4800 Alberta Ave, El Paso, TX 79905, USA.
Email: maporres@ttuhsc.edu
2 Vascular Medicine 00(0)
Figure 1. Mechanism of action of common anticoagulants versus factor XI inhibitors.
Ca2+, calcium ion; IX, factor IX; IXa, factor IXa; mRNA, messenger ribonucleic acid; PL, platelet phospholipids; TF, tissue factor; Va, factor Va; VII,
factor VII; VIIa, factor VIIa; VIIIa, factor VIIIa; X, factor X; Xa, factor Xa; XI, factor XI; XIa, factor XIa; XII, factor XII; XIIa, factor XIIa.
coagulation cascade is stratified into the contact activation
(intrinsic) and the tissue factor (extrinsic) pathways which
subsequently converge to form the common pathway.4 The
tissue factor pathway is activated by tissue factor expressed
in subendothelial tissue which binds with factor VIIa and
calcium to convert factor X to factor Xa.3,4 In the contact
activation pathway, negatively charged molecules such as
dextran sulphate, silica, extracellular nucleic acids, neutro-
phil extracellular traps, long-chain polyphosphates from
infectious pathogens, platelet-derived polyphosphates, and
negatively charged artificial surfaces from indwelling medi-
cal devices can activate factor XII, which then activates FXI
followed by factor IX.5,6 The activated factor VIII, activated
factor IX, and calcium ions in turn activate factor X, which
leads to the common pathway.6 The common pathway con-
sists of factor Xa forming a complex with factor Va that
cleaves prothrombin (factor II) to thrombin (factor IIa).6
The contact system, also known as the plasma kal-
likrein-kinin system, consists of coagulation factors XIIa,
XIa, plasma pre-kallikrein along with nonenzymatic
cofactor high molecular weight kininogen. They are often
called the contact system as they require contact with arti-
ficial, negatively charged surfaces for activation. FXI is
activated by factor XIIa, which is involved in thrombus
initiation.7 Compared to the mechanism of factor Xa and
thrombin, FXI is more specific in its functions where it is
involved in clot formation but does not affect hemostasis.
In patients with hereditary FXI deficiency, there is a
decreased incidence of VTE and cardiovascular events
without the complication of spontaneous bleeding.8,9
Moreover, these patients confer a relatively lower risk for
bleeding, which mainly occurs in different mucosal sur-
faces, characterized by high fibrinolytic activity. These
findings suggest that FXI plays only a modest role within
the coagulation cascade, since FXI do not contribute to
initiation but rather thrombi stabilization and expansion.8,9
This led to the development of medications that specifi-
cally inhibit FXI and/or XIa, hoping to harness similar
thromboembolic benefits without the risk of bleeding. A
schematic representation of the mechanism of action of
DOACs and different classes of FXI inhibitors is dis-
played in Figure 1.10
Development of novel agents
targeting FXI
There are several novel agents that are directed against
FXI, which include monoclonal antibodies, small mole-
cules, natural inhibitors, antisense oligonucleotides (ASOs),
and aptamers.10,11 Natural inhibitors and aptamers have not
been discussed in this article as they have not been tested in
humans. Pharmacologic properties of different classes of
FXI inhibitors are displayed in Table 1. Table S1 in sup-
plementary material summarizes ongoing and completed
clinical trials studying Factor XI inhibitors.
Methods
We performed a search strategy for clinical trials from www.
clinicaltrials.gov from inception to February 1, 2023 using
the following key terms: “factor XI inhibitors, thrombosis”.
We searched for other clinical trials, observational studies,
retrospective studies, and prospective studies and reviews
using MEDLINE/PubMed, EMBASE, Cochrane Library,
and Web of Science database using the following MeSH
terms: “factor XI inhibitors AND thrombosis AND thrombo-
embolism”. The data obtained from this search were further
screened based on clinical relevance pertaining to this article,
which included medically ill patients (e.g., VTE, AF). The
titles and abstracts of the studies were analyzed to evaluate
relevance for this review. There were no strict eligibility
Prakash et al. 3

Table 1. Pharmacological properties of novel anticoagulants targeting factor XI and factor XIa.

Monoclonal antibodies Small molecules ASOs Aptamers

Mechanism Bind target protein Bind target protein Blocks protein biosynthesis Bind target protein
Administration route IV or SC IV or oral SC IV or SC
Frequency of administration Monthly Once or twice daily Weekly to monthly Daily
Onset of action Rapid (h – days) Rapid (min – h) Slow (weeks) Rapid (min – h)
Offset of action Slow (weeks) Rapid (min – h) Slow (weeks) Rapid (min – h)
Renal excretion No Minimal No No
CYP metabolism No Yes No No
Potential for drug-to-drug No Yes No No
interactions
Drugs Abelacimab Asundexian Fesomersen Not tested in humans
MK-2060 Milvexian IONIS-FXIRx
Osocimab ONO-7684
Xisomab 3G3 EP-7041
REGN9933 BMS-962212
REGN7508

ASOs, antisense oligonucleotides; CYP, cytochrome P450; FXI, factor XI; FXIa, FXIa inhibitors; h, hours; IV, intravenous; min, minutes; SC, subcuta-
neous.

criteria other than English written articles relevant to the
topic and clinical trials evaluating FXI inhibitors.
Factor XI/XIa inhibitors
Antisense oligonucleotides (ASOs)
Fesomersen. Fesomersen, also known as BAY2976217 or
FXI-LICA, is an antisense oligonucleotide inhibitor of FXI
which facilitates receptor-mediated hepatic uptake and
decreased circulating FXI.12 One of the major advantages of
fesomersen is its property of having triantennary N-acetyl
galactosamine (GalNAc) conjugation, which allows for
maximum drug delivery to hepatocytes where FXI synthesis
occurs. This conjugation also allows for once-a-month dos-
ing when compared to other ASOs having once-a-week dos-
ing.12 Given that this medication has no renal clearance, the
RE-THINc ESRD (ClinicalTrials.gov identifier: NCT04
534114) trial studied the safety and tolerability of fesom-
ersen in end-stage renal disease (ESRD) patients requiring
hemodialysis (HD). The goal of the study was to learn more
about the safety of BAY2976217, how it is tolerated and the
way the body absorbs, distributes, and eliminates the study
drug given as multiple doses in participants with renal
impairment who require HD. The primary outcome for this
study was incidence of major bleeding and clinically rele-
vant nonmajor bleeding (CRNMB) events during the main
treatment period and within the on-treatment time window
(up to 24 weeks) assessed by the blinded Central Indepen-
dent Adjudication Committee (CIAC) where fesomersen is
being compared against matching placebo.
IONIS-FXIRx. IONIS-FXIRx (BAY2306001 or ISIS 416858)
is an antisense oligonucleotide inhibitor of the synthesis of
FXI in the liver, which shows a reduction in FXI activity.12
IONIS-FXIRx is an unconjugated ASO which results in
weekly dosing when compared to fesomersen, as discussed
earlier.12 In a phase 2 study in ESRD patients on HD, a sig-
nificant, dose-dependent, sustained reduction in FXI
antigen and activity were noted. There were no CRNMB
events in the study and no major bleeding events occurred in
the group that received the 200 mg dose but there was only
one major bleeding event in the group that received the 300
mg dose.13 Another trial studying the effects of ISIS 416858
on the incidence of thromboembolism in patients undergo-
ing total knee arthroplasty where two doses were given pre-
operatively and one dose postoperatively showed noninferior
results in the 200 mg group (27% rate) and superior results
in the 300 mg group (4%) when compared to enoxaparin
(30% rate). Bleeding events were numerically higher in the
300 mg group (8%) and equivalent in the 200 mg group and
enoxaparin group (3% for both).14 Currently, the Study of
ISIS 416858 Administered Subcutaneously to Participants
with End-Stage Renal Disease (ESRD) on Hemodialysis
(EMERALD) (NCT03358030) trial is studying the pharma-
cokinetics and pharmacodynamics of ISIS 416858 in
patients with ESRD on HD. The primary outcome is number
of participants with major bleeding and CRNMB.
Monoclonal antibodies
Abelacimab/MAA868. Abelacimab is a monoclonal anti-
body that binds to the catalytic domain of FXI and prevents
its activation by factor XIIa and thrombin.15 In the ANT-
003 study, a single intravenous dose of 30, 50, and 150 mg
abelacimab in healthy subjects was safe and well tolerated
without any major bleeding or CRNMB events.16 In the
ANT-004 study, patients with AF were administered
monthly subcutaneous (SC) injections of abelacimab,
which led to a sustained reduction in free FXI concentra-
tions when compared to placebo. No major bleeding or
CRNMB events were noted in the ANT-004 study. The
trial was not designed to assess clinical endpoints (i.e., the
incidence of stroke and systemic embolism events in
patients with NVAF).16 The ANT-005 trial revealed that for
the efficacy outcome of preventing VTE, the single 30 mg
dose of abelacimab is noninferior to enoxaparin in patients
undergoing total knee arthroplasty, whereas the single 75
4 Vascular Medicine 00(0)
mg and 150 mg doses of abelacimab were shown to be
superior to enoxaparin.17 The rates of major bleeding and
CRNMB events were low in all arms of the study.17 In the
ongoing clinical trial AZALEA-TIMI 71 (NCT04755283),
major and CRNMB events will be compared to rivaroxaban
in patients with NVAF. The clinical trial ASTER
(NCT05171049) compares abelacimab to apixaban in
patients with cancer-associated VTE, and the clinical trial
MAGNOLIA (NCT05171075) compares abelacimab
against dalteparin for the prevention of VTE recurrence in
gastrointestinal or genitourinary cancers associated with
VTE. The ongoing LILAC-TIMI 76 (NCT05712200) trial
studies the time to ischemic strokes, systemic embolisms,
VTE, myocardial infarction (MI), and acute limb ischemia
in patients with diagnosed AF or atrial flutter.
MK-2060. MK-2060 is a monoclonal antibody against FXI
currently being studied in ESRD patients on HD to assess
for arteriovenous graft (AVG) thrombosis prevention and
bleeding events (NCT05027074). The primary endpoint is
time to first AVG thrombosis event.
Osocimab. Osocimab, also known as BAY1213790, is a
monoclonal antibody involved in the allosteric inhibition of
FXIa.18 The FOXTROT trial studied pre- and postoperative
thromboprophylaxis using osocimab in patients undergoing
knee arthroplasty. In that trial, osocimab was noninferior to
enoxaparin in the postoperative phase and superiority in the
preoperative phase with regards to prevention of VTE events.19
A recent meta-analysis showed a significant reduction of VTE
events and bleeding events in patients undergoing orthopedic
surgery.20 The ongoing CONVERT (NCT04523220) trial will
assess the safety and tolerability of low and high-dose oso-
cimab in patients with ESRD undergoing HD. Primary out-
come measures are the composite of major and clinically
relevant nonmajor bleeding events as assessed by blinded
CIAC (time frame: from the first dose at month 1 and up to 6
months) and the composite of moderate and severe adverse
events (AEs) and serious adverse events (SAEs) (time frame:
from the first dose at month 1 and up to 6 months).
Xisomab 3G3. Xisomab 3G3, also known as AB023 or
Gruticibart, is a monoclonal antibody that binds to FXI and
prevents its activation by factor XIIa.21 A single dose of
AB023 reduced intradialyzer clotting during heparin-free
HD in ESRD.22 There is another ongoing clinical trial
(NCT04465760) regarding the efficacy of xisomab at pre-
venting catheter-associated thrombosis in individuals with
a central venous catheter.
REGN9933. REGN9933 is a monoclonal antibody
against FXI which is currently undergoing phase 1 clinical
trials to assess the pharmacokinetics and pharmacodynam-
ics in healthy subjects (NCT05102136).23
REGN7508. REGN7508 is another monoclonal
antibody against FXI which is undergoing phase 1
clinical trials to assess the safety, tolerability, pharma-
cokinetics, and pharmacodynamics in healthy subjects
(NCT05603195).
Small molecules
Asundexian/BAY 2433334. Asundexian is a small molecule
inhibitor of FXIa activity which produces a direct, revers-
ible inhibition of FXIa activity.24 Asundexian is primarily
eliminated via liver metabolism but does not involve
the cytochrome p450 system.24 The PACIFIC-AF (NCT
04218266) trial showed that asundexian at 20 mg and 50
mg once-daily doses led to similar suppression of FXIa
with lower rates of bleeding as compared to apixaban.25
The PACIFIC-STROKE (NCT04304508) trial concluded
that there was no increase in major or CRNMB events
when asundexian was compared to placebo. Recognizing
that the PACIFIC-STROKE trial was not powered for
thrombotic outcome comparison, there was no difference
in the recurrence of stroke or covert brain infarctions seen
in the asundexian and placebo arms.26 A secondary analy-
sis of the PACIFIC-STROKE trial revealed a reduction of
ischemic stroke/TIA in the asundexian 50 mg arm when
compared to placebo.27 A third clinical trial, known as the
PACIFIC-AMI (NCT04304534), studied the secondary
prevention of MI, finding that when asundexian was
added to aspirin and a P2Y12 inhibitor, there was a dose-
dependent inhibition of FXIa activity without a signifi-
cant increase in bleeding rates and a decreased rate of
ischemic events.28 The ongoing OCEANIC-AF trial
(NCT05643573) compares the efficacy of asundexian
when compared to apixaban for stroke prevention in AF.
The ongoing OCEANIC-STROKE trial (NCT05686070)
assesses the time to occurrence of a stroke in patients who
recently had an ischemic stroke or high-risk transient
ischemic attack (TIA).
Milvexian. Milvexian, also known as BMS-986177, is a
small molecule reversible inhibitor with high affinity for
activated FXI.29,30 Milvexian is a cytochrome p450 inhibi-
tor with hepatic metabolism which may interfere with
other drugs that interact with cytochrome p450.7,29 In the
recently completed AXIOMATIC-SSP phase 2 trial, par-
ticipants were randomized to milvexian or placebo along
with aspirin and clopidogrel following an acute ischemic
stroke or high-risk TIA.31 The primary efficacy outcome,
symptomatic ischemic stroke, and the outcome of covert
brain infarction at 90 days were not different between mil-
vexian and placebo. Of note, no increase in bleeding was
noted with milvexian.32 The primary efficacy endpoint was
numerically lower at the 50 mg and 100 mg twice-daily
doses; there was no apparent dose–response (placebo,
16.6%; 25 mg once daily, 16.2%; 25 mg twice daily,
18.5%; 50 mg twice daily, 14.1%; 100 mg twice daily,
14.7%; 200 mg twice daily, 16.4%).
In the AXIOMATIC-TKR trial of patients undergoing
knee arthroplasty surgery, the 25 mg (25%) and 50 mg
(24%) oral milvexian groups were noted to have similar
incidence rates of VTE when compared to the enoxaparin
group (21%). However, the 200 mg oral milvexian group
was noted to have decreased VTE incidence rates (7%).
The bleeding rates of any severity are 4% in both milvexian
and enoxaparin groups.33
Prakash et al.
The ongoing LIBREXIA-STROKE (NCT05702034)
trial primarily studies stroke prevention after an acute
ischemic stroke or high-risk TIA. The ongoing LIBREXIA-
ACS (NCT05754957) studies major adverse cardiovascu-
lar events in patients who experienced acute coronary
syndrome in the past 7 days, with the trial comparing mil-
vexian versus placebo in addition to standard of care anti-
platelet therapy (either single or dual, per investigator
discretion).
ONO-7684. ONO-7684 is an oral small molecule FXIa
inhibitor with competitive and reversible inhibition.34 In
the first human, double-blind, clinical trial in healthy vol-
unteers, ONO-7684 was well tolerated at all doses and in
repeated doses without any evidence of bleeding risk.34
EP-7041. EP-7041 is an intravenous small molecule FXIa
inhibitor with a short half-life of 45 minutes, which may
not necessitate the need for a reversal agent.35 EP-7041,
also known as frunexian, was found to be safe and well
tolerated at all doses with minimal bleeding risk (infusion
site bleeding) and mild headaches (NCT02914353).36 A
prospective study of frunexian in the thromboprophylaxis
of COVID-19 patients is currently being conducted, which
included two different doses of EP-7041 (NCT05040776).
BMS-962212. BMS-962212 is an intravenous, selective,
reversible, active-site inhibitor of FXIa which produced sig-
nificant antithrombotic activity with minimal effects on
bleeding risk.37 The first in-human study revealed a quick
onset of action, short half-life, and was found to be well toler-
ated by all subjects with no signs of bleeding (NCT03197779).38
Clinical applications of FXI
inhibitors
Atrial fibrillation
The PACIFIC-AF trial was a randomized dose-finding trial
for asundexian in patients with AF where it was found that
asundexian dosed once a day at 20 mg and 50 mg led to
81% and 92% reduction percentages of FXIa at trough,
respectively.25 Overall, bleeding rates were lower in the
asundexian group compared to the apixaban group.25 The
rate of adverse effects was similar in all treatment arms,
whereas thrombotic endpoints such as cardiovascular
death, MI, systemic embolism, and ischemic stroke were
the least in the asundexian 20 mg arm.25 It has less than
15% renal elimination, making it relatively safe in chronic
kidney disease (CKD), although more trials regarding its
safety in CKD patients are required. Abelacimab is also
currently being studied for its use in AF, but results are cur-
rently not available.
VTE prevention and treatment
Abelacimab is currently undergoing several clinical trials
in VTE prevention/treatment for which results have not
been published yet. However, the ANT-005 trial studied the
incidence of VTE postoperatively in patients undergoing
5
total knee arthroplasty with a single intravenous dose of
abelacimab (30 mg, 75 mg, or 150 mg) versus enoxaparin
40 mg SC daily. The primary efficacy outcome being VTE
incidence was 13%, 5%, 4%, and 22% in the groups for
abelacimab 30 mg, 75 mg, 150 mg, and enoxaparin 40 mg,
respectively. Bleeding occurred in 2%, 2%, none, and none
of the patients in abelacimab 30 mg, 75 mg, and 150 mg
groups, and enoxaparin 40 mg, respectively.17 Abelacimab
also has zero renal clearance and would be a safe option in
patients with CKD.16
IONIS-FXIRx (also known as FXI-ASO) was studied in
patients undergoing total knee arthroplasty where they
received either 200 mg or 300 mg FXI-ASO or enoxaparin
40 mg SC daily. It was found that the primary efficacy out-
come which was VTE incidence was found to be 27%, 4%,
and 30% in the FXI-ASO 200 mg, 300 mg, and enoxaparin
40 mg groups, respectively. The 300 mg FXI-ASO group
was also found to be superior, with p < 0.001, but the 200
mg group was noninferior. Bleeding occurred in 3%, 3%,
and 8% in the FXI-ASO 200 mg, 300 mg, and enoxaparin
40 mg groups, respectively.14 Patients with creatinine clear-
ance < 60 mL/min should be avoided as evidenced in a
clinical trial,14 but it appears to be relatively safe in patients
undergoing HD without any accumulation.13
Milvexian was studied in patients undergoing elective
unilateral total knee arthroplasty where they received one
of the following postoperative regimens of milvexian (25
mg, 50 mg, 100 mg, or 200 mg twice daily or 25 mg, 50 mg,
or 200 mg once daily) or enoxaparin (40 mg once daily).
Patients with creatinine clearance < 30 mL/min, history of
severe hepatic impairment, prior history of VTE, and use of
long-term anticoagulation except for aspirin were excluded.
There was a VTE incidence of 25% in milvexian 25 mg
twice daily, 11% in 50 mg twice daily, 9% in 100 mg twice
daily, and 8% in 200 mg twice daily, whereas it was 25% in
25 mg once daily, 24% in 50 mg once daily, and 7% in 200
mg once daily compared to 21% in enoxaparin 40 mg once
daily. There was a similar bleeding risk of 4% in milvexian
and enoxaparin.33
The FOXTROT trial for osocimab studied patients
undergoing knee arthroplasty where single intravenous
osocimab postoperative doses of 0.3 mg/kg, 0.6 mg/kg, 1.2
mg/kg, or 1.8 mg/kg; preoperative doses of 0.3 mg/kg or
1.8 mg/kg; or 40 mg of SC enoxaparin once daily or 2.5 mg
of oral apixaban twice daily were administered. There was
a VTE incidence of 23.7% in groups who received 0.3 mg/
kg, 15.7% in 0.6 mg/kg, 16.5% in 1.2 mg/kg, and 17.9% in
1.8 mg/kg postoperative doses of osocimab. There was a
VTE incidence of 29.9% in 0.3 mg/kg and 11.3% in 1.8 mg/
kg preoperative doses of osocimab when compared to
26.3% VTE incidence in the enoxaparin groups and 14.5%
in the apixaban groups.19 Major or clinically relevant non-
major bleeding was seen in up to 4.7% in the osocimab
group, 5.9% in the enoxaparin group, and 2% in the apixa-
ban group.19
Stroke
The PACIFIC-STROKE trial studied asundexian in
patients with acute (< 48 h) noncardioembolic ischemic
6 Vascular Medicine 00(0)
stroke where the primary efficacy outcome was the com-
posite of incident magnetic resonance imaging (MRI)-
detected covert brain infarcts and recurrent symptomatic
ischemic stroke. The primary efficacy outcome was seen
in 19% in the placebo group, 19% in the asundexian 10 mg
group, 22% in the asundexian 20 mg group, and 20% in the
asundexian 50 mg group. Major bleeding or CRNMB was
noted in 2% of the placebo group, 4% of the asundexian 10
mg group, 3% of the asundexian 20 mg group, and 4% of
the asundexian 50 mg group.39 Several other trials, such as
the OCEANIC-STROKE trial, AXIOMATIC-SSP trial,
AZALEA-TIMI 71 trial, and LIBREXIA-STROKE trial
are currently in progress.
Myocardial infarction
The PACIFIC-AMI trial studied oral asundexian versus
placebo in patients with a recent MI on dual antiplatelet
therapy (aspirin and P2Y12 inhibitor). The efficacy out-
come was a composite of cardiovascular death, MI, stroke,
or stent thrombosis. The efficacy outcome occurred in
6.8%, 6.0%, 5.5%, and 5.5% of patients in groups of asun-
dexian 10 mg, 20 mg, or 50 mg, and placebo, respectively.
According to the main safety outcome, which was Bleeding
Academic Research Consortium types 2, 3, or 5, bleeding
occurred in 7.6%, 8.1%, 10.5%, and 9.0% of patients
receiving asundexian 10 mg, 20 mg, or 50 mg, and placebo,
respectively. This shows the efficacy outcomes among the
asundexian and placebo groups, whereas the bleeding out-
comes were the least in asundexian 10 mg.28 Online
Supplemental Table S1 summarizes ongoing and completed
clinical trials studying FXI inhibitors.
Future perspectives for FXI
inhibitors
Despite promising early phase studies of FXI inhibitors on
cardioembolic stroke prevention in NVAF, prevention of
VTE, and other thromboembolic conditions, asundexian is
the only molecule studied alongside dual antiplatelet thera-
pies to prevent cardiovascular death, MI, ischemic stroke,
and stent thrombosis. Additional studies on FXI inhibitors
need to be conducted to assess their role in the prevention
of stent thrombosis and cardiovascular outcomes in patients
with coronary artery disease.
Though certain thrombotic conditions are common and
have strong evidence supporting the anticoagulant thera-
pies (e.g., AF, VTE), others are less common or have less
evidence to support current antithrombotic therapies. These
include acute limb ischemia without a cardioembolic source
and ESRD. Finally, other clinical scenarios have a clear
thrombotic link, but currently available therapies have not
provided an optimal risk–benefit balance. The hope for fac-
tor XI and XIa inhibitor agents is that they can provide an
improved risk–benefit balance that can be applied both in
situations without currently available antithrombotic thera-
pies (e.g., ESRD) and in those where prior therapies have
led to excessive bleeding (e.g., acute MI, embolic stroke of
unknown source).
Other potential areas of research and exploration may
include problematic, challenging clinical scenarios in
which DOACs have been proven ineffective. These include
so called ‘artificial contact surfaces-associated thrombosis’
(ACSAT), such as mechanical valves, extracorporeal mem-
brane oxygenation (ECMO), left ventricular assisting
devices (LVADs), and central venous catheter-associated
thrombosis.40–43 Dabigatran posed an increased risk for
stroke and bleeding complications in patients with mechan-
ical heart valves.44 Current guidelines recommend against
the use of DOACs (favoring VKAs), specifically in patients
with mechanical valves.45
The American Society of Hematology (ASH) and the
International Society of Thrombosis and Haemostasis
(ISTH) guidelines recommend against using DOACs in
patients with antiphospholipid syndrome (APS), particu-
larly patients with high-risk APS who carry a triple positiv-
ity for lupus anticoagulant, anticardiolipins, and anti-beta-2
glycoprotein-1 antibodies.46–48 A recent systematic review
and meta-analysis of four randomized controlled trials
involving 472 patients with APS that compared DOACs
with VKAs, published by Khairani et al., demonstrated that
the use of DOACs compared with VKAs was associated
with increased odds of subsequent arterial thrombotic
events (odds ratio [OR]: 5.43; 95% CI: 1.87–15.75; p <
0.001), particularly ischemic stroke, and the composite of
ATE or VTE (OR: 4.46; 95% CI: 1.12–17.84; p = 0.03);
investigators concluded that patients with thrombotic APS
randomized to DOACs compared with VKAs appear to
have increased risk for ATE.49 In APS, one of the mecha-
nisms involves the reduction of inactivation of FXI by
antithrombin, which may pave the way for the use of FXI
inhibitors in APS.50
Several different agents targeting factor XI and XIa are
in various stages of development. Two of the oral agents
targeting factor XIa are currently in phase 3 clinical trials
(milvexian and asundexian). Others that use different routes
of administration (e.g., SC injection) and those that target
FXI in addition to factor XIa are currently being developed
(e.g., abelacimab).
Reversal of FXI inhibitor drugs remains another area
where research may be required. Although FXI is a com-
ponent of fresh frozen plasma (FFP), FFP also contains
other clotting factors, along with physiologic anticoagu-
lants, making it a diluted blood product to administer to
individuals who are bleeding. A large quantity of FFP may
also be required to reverse FXI inhibitors for this reason.
FXI concentrates is another option to reverse FXI inhibitor
bleeding complications.51 Management of bleeding in FXI
deficiency includes administration of FFP, FXI concen-
trate, recombinant factor VIIa (rFVIIa), tranexamic acid,
or epsilon-aminocaproic acid.52 Because FXIa inhibitors
can potentially impair thrombin activatable fibrinolysis
inhibitor (TAFI) activation, tranexamic acid represents a
cornerstone reversal agent for the prevention and treatment
to control bleeding, and it should be given in patients
undergoing urgent surgery or surgical interventions with a
high risk for major bleeding.53 The drawback of adminis-
tering these products includes the risk of thrombosis,
Prakash et al.
except in FFP.52 Despite having blood products to reverse
FXI inhibitors, this may not be enough to reverse all bleed-
ing complications induced by FXI inhibitors, especially in
the agents with long half-lives, which necessitate the
development and further research of specific reversal
agents.53 Any agent that inhibits the coagulation cascade
has the potential to increase bleeding risk. Although FXI
inhibitors are known to have fewer bleeding complications
due to the mechanism of action, there are limited data to
suggest the complete absence of bleeding complications.
Furthermore, clinician behavior is such that the use of an
anticoagulant at the time of bleeding may lead to a strong
desire to eliminate the anticoagulant as a potential source/
facilitator of bleeding.
Conclusions
FXI/XIa inhibitors have shown great promise in improving
the thrombosis/bleeding balance. Given the tremendous
impetus and enthusiasm among thrombosis clinicians/
researchers focusing on this fascinating arena, further confir-
mation of their efficacy and safety is highly anticipated in
ongoing, large, phase 3, randomized controlled clinical trials.
It is certainly not unreasonable that multiple medical special-
ties including hematologists, cardiologists, and vascular
medicine specialists will incorporate the frequent use of FXI/
XIa inhibitors into their daily clinical practice. Though many
hope that FXI/XIa inhibitors become the safer and ideal anti-
coagulant of choice in many clinical scenarios, we must wait
for the high-quality, phase 3 randomized trial data to better
understand if those hopes will be reflected.
Declaration of conflicting interests
The authors declared no potential conflicts of interest with respect
to the research, authorship, and/or publication of this article.
Funding
The authors received no financial support for the research, author-
ship, and/or publication of this article.
ORCID iDs
Mateo Porres-Aguilar https://orcid.org/0000-0002-2180-3000
Debabrata Mukherjee https://orcid.org/0000-0002-5131-3694
Geoffrey D Barnes https://orcid.org/0000-0002-6532-8440
Supplementary material
The supplementary material is available online with the article.
References
1. Jackevicius CA, Lu L, Ghaznavi Z, et al. Bleeding risk of direct
oral anticoagulants in patients with heart failure and atrial fibril-
lation. Circ Cardiovasc Qual Outcomes 2021; 14: e007230.
2. Ruff CT, Giugliano RP, Braunwald E, et al. Comparison of
the efficacy and safety of new oral anticoagulants with war-
farin in patients with atrial fibrillation: A meta-analysis of
randomised trials. Lancet 2014; 383: 955–962.
3. Kumar V, Abbas AK, Fausto N, et al. Robbins and Cotran
pathologic basis of disease, professional edition e-book. 9th
ed. Elsevier Health Sciences, 2014.
7
4. Palta S, Saroa R, Palta A. Overview of the coagulation sys-
tem. Indian J Anaesth 2014; 58: 515–523.
5. Travers RJ, Smith SA, Morrissey JH. Polyphosphate, plate-
lets, and coagulation. Int J Lab Hematol 2015; 37(suppl 1):
31–35.
6. Grover SP, Mackman N. Intrinsic pathway of coagulation
and thrombosis. Arterioscler Thromb Vasc Biol 2019; 39:
331–338.
7. Greco A, Laudani C, Spagnolo M, et al. Pharmacology and
clinical development of factor XI inhibitors. Circulation
2023; 147: 897–913.
8. Duga S, Salomon O. Factor XI deficiency. Semin Thromb
Hemost 2009; 35: 416–425.
9. Preis M, Hirsch J, Kotler A, et al. Factor XI deficiency is
associated with lower risk for cardiovascular and venous
thromboembolism events. Blood 2017; 129: 1210–1215.
10. Fredenburgh JC, Weitz JI. Factor XI as a target for new anti-
coagulants. Hamostaseologie 2021; 41: 104–110.
11. Tillman BF, Gruber A, McCarty OJT, et al. Plasma contact
factors as therapeutic targets. Blood Rev 2018; 32: 433–448.
12. Willmann S, Marostica E, Snelder N, et al. PK/PD modeling
of FXI antisense oligonucleotides to bridge the dose-FXI
activity relation from healthy volunteers to end-stage renal
disease patients. CPT Pharmacometrics Syst Pharmacol
2021; 10: 890–901.
13. Walsh M, Bethune C, Smyth A, et al. Phase 2 study of the
factor XI antisense inhibitor IONIS-FXIRx in patients with
ESRD. Kidney Int Rep 2022; 7: 200–209.
14. Büller HR, Bethune C, Bhanot S, et al. Factor XI antisense
oligonucleotide for prevention of venous thrombosis. N Engl
J Med 2015; 372: 232–240.
15. Koch AW, Schiering N, Melkko S, et al. MAA868, a novel
FXI antibody with a unique binding mode, shows durable
effects on markers of anticoagulation in humans. Blood
2019; 133: 1507–1516.
16. Yi BA, Freedholm D, Widener N, et al. Pharmacokinetics
and pharmacodynamics of abelacimab (MAA868), a novel
dual inhibitor of Factor XI and Factor XIa. J Thromb
Haemost 2022; 20: 307–315.
17. Verhamme P, Yi BA, Segers A, et al. Abelacimab for pre-
vention of venous thromboembolism. N Engl J Med 2021;
385: 609–617.
18. Schaefer M, Buchmueller A, Dittmer F, et al. Allosteric inhi-
bition as a new mode of action for BAY 1213790, a neutral-
izing antibody targeting the activated form of coagulation
factor XI. J Mol Biol 2019; 431: 4817–4833.
19. Weitz JI, Bauersachs R, Becker B, et al. Effect of osocimab
in preventing venous thromboembolism among patients
undergoing knee arthroplasty: The FOXTROT randomized
clinical trial. JAMA 2020; 323: 130–139.
20. Presume J, Ferreira J, Ribeiras R, et al. Achieving higher
efficacy without compromising safety with factor XI inhibi-
tors versus low molecular weight heparin for the prevention
of venous thromboembolism in major orthopedic surgery
– Systematic review and meta-analysis. J Thromb Haemost
2022; 20: 2930–2938.
21. Chan NC, Weitz JI. AB023, a novel antibody that binds fac-
tor XI and blocks its activation by factor XIIa. Arterioscler
Thromb Vasc Biol 2019; 39: 533–535.
22. Lorentz CU, Tucker EI, Verbout NG, et al. The contact
activation inhibitor AB023 in heparin-free hemodialysis:
Results of a randomized phase 2 clinical trial. Blood 2021;
138: 2173–2184.
23. Badimon JJ, Escolar G, Zafar MU. Factor XI/XIa inhibition:
The arsenal in development for a new therapeutic target in
8 Vascular Medicine 00(0)
cardio- and cerebrovascular disease. J Cardiovasc Dev Dis
2022; 9: 437.
24. Heitmeier S, Visser M, Tersteegen A, et al. Pharmacological
profile of asundexian, a novel, orally bioavailable inhibitor
of factor XIa. J Thromb Haemost 2022; 20: 1400–1411.
25. 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 multicen-
tre, randomised, double-blind, double-dummy, dose-finding
phase 2 study. Lancet 2022; 399: 1383–1390.
26. Shoamanesh A, Mundl H, Smith EE, et al. Factor XIa inhibi-
tion with asundexian after acute non-cardioembolic ischae-
mic stroke (PACIFIC-Stroke): An international, randomised,
double-blind, placebo-controlled, phase 2b trial. Lancet
2022; 400: 997–1007.
27. New anticoagulant may prevent recurrent ischaemic stroke.
European Society of Cardiology Press Office. https://www.
escardio.org/The-ESC/Press-Office/Press-releases/New-
anticoagulant-may-prevent-recurrent-ischaemic-stroke (Aug
28, 2022; accessed Oct 20, 2023).
28. Rao SV, Kirsch B, Bhatt DL, et al. A multicenter, phase
2, randomized, placebo-controlled, double-blind, parallel-
group, dose-finding trial of the oral factor XIa inhibitor
asundexian to prevent adverse cardiovascular outcomes
after acute myocardial infarction. Circulation 2022; 146:
1196–1206.
29. Perera V, Wang Z, Luettgen J, et al. First-in-human study of
milvexian, an oral, direct, small molecule factor XIa inhibi-
tor. Clin Transl Sci 2022; 15: 330–342.
30. Wong PC, Crain EJ, Bozarth JM, et al. Milvexian, an orally
bioavailable, small-molecule, reversible, direct inhibitor of
factor XIa: In vitro studies and in vivo evaluation in experi-
mental thrombosis in rabbits. J Thromb Haemost 2022; 20:
399–408.
31. Sharma M, Molina CA, Toyoda K, et al. Rationale and design
of the AXIOMATIC-SSP phase II trial: Antithrombotic
treatment with factor XIa inhibition to optimize management
of acute thromboembolic events for secondary stroke pre-
vention. J Stroke Cerebrovasc Dis 2022; 31: 106742.
32. Kumbhani DJ. Antithrombotic treatment with factor XIa
inhibition to optimize management of acute thromboembolic
events for secondary stroke prevention - AXIOMATIC-SSP.
Presented at European Society of Cardiology Congress,
Barcelona, Spain, Aug 28, 2022. https://www.acc.org/latest-
in-cardiology/clinical-trials/2022/08/27/04/12/axiomatic-
ssp. (Sep 7, 2022; accessed Oct 20, 2023).
33. Weitz JI, Strony J, Ageno W, et al. Milvexian for the preven-
tion of venous thromboembolism. N Engl J Med 2021; 385:
2161–2172.
34. Beale D, Dennison J, Boyce M, et al. ONO-7684 a novel
oral FXIa inhibitor: Safety, tolerability, pharmacokinetics
and pharmacodynamics in a first-in-human study. Br J Clin
Pharmacol 2021; 87: 3177–3189.
35. Pollack CV Jr, Kurz MA, Hayward NJ. EP-7041, a factor
XIa inhibitor as a potential antithrombotic strategy in extra-
corporeal membrane oxygenation: A brief report. Crit Care
Explor 2020; 2: e0196.
36. Hayward NJ, Goldberg DI, Morrel EM, et al. Abstract
13747: Phase 1a/1b study of EP-7041: A novel, potent,
selective, small molecule FXIa inhibitor. Circulation 2017;
136: A13747.
37. Wong PC, Pinto DJ, Watson C. Abstract 11051: A small-
molecule factor XIa inhibitor (BMS-962212) provides
robust antithrombotic activity in non-human primate model
of arterial thrombosis with low bleeding. Circulation 2018;
138: A11051.
38. Perera V, Luettgen JM, Wang Z, et al. First-in-human
study to assess the safety, pharmacokinetics and pharma-
codynamics of BMS-962212, a direct, reversible, small
molecule factor XIa inhibitor in non-Japanese and Japanese
healthy subjects. Br J Clin Pharmacol 2018; 84: 876–887.
39. Shoamanesh A, Mundl H, Smith EE, et al. Factor XIa inhibi-
tion with asundexian after acute non-cardioembolic ischae-
mic stroke (PACIFIC-Stroke): An international, randomised,
double-blind, placebo-controlled, phase 2b trial. Lancet
2022; 400: 997–1007.
40. den Exter PL, Beeres S, Eikenboom J, et al. Anticoagulant
treatment and bleeding complications in patients with left
ventricular assist devices. Expert Rev Cardiovasc Ther 2020;
18: 363–372.
41. Rajsic S, Breitkopf R, Jadzic D, et al. Anticoagulation strate-
gies during extracorporeal membrane oxygenation: A narra-
tive review. J Clin Med 2022; 11: 5147.
42. Massicotte MP, Maul TM, Snyder TA, et al. Mechanical cir-
culatory support and antithrombotic therapy: Looking for the
Holy Grail. ASAIO J 2017; 63: 1–4.
43. Citla Sridhar D, Abou-Ismail MY, Ahuja SP. Central venous
catheter-related thrombosis in children and adults. Thromb
Res 2020; 187: 103–112.
44. Ryu R, Tran R. DOACs in mechanical and bioprosthetic
heart valves: A narrative review of emerging data and
future directions. Clin Appl Thromb Hemost 2022; 28:
10760296221103578.
45. Heidenreich PA, Estes NAM, Fonarow GC 3rd, et al. 2020
Update to the 2016 ACC/AHA clinical performance and qual-
ity measures for adults with atrial fibrillation or atrial flutter:
A report of the American College of Cardiology/American
Heart Association Task Force on Performance Measures.
Circ Cardiovasc Qual Outcomes 2021; 14: e000100.
46. Pengo V, Denas G, Zoppellaro G, et al. Rivaroxaban vs war-
farin in high-risk patients with antiphospholipid syndrome.
Blood 2018; 132: 1365–1371.
47. Zuily S, Cohen H, Isenberg D, et al. Use of direct oral anti-
coagulants in patients with thrombotic antiphospholipid
syndrome: Guidance from the Scientific and Standardization
Committee of the International Society on Thrombosis and
Haemostasis. J Thromb Haemost 2020; 18: 2126–2137.
48. Ortel TL, Neumann I, Ageno W, et al. American Society
of Hematology 2020 guidelines for management of venous
thromboembolism: Treatment of deep vein thrombosis and
pulmonary embolism. Blood Adv 2020; 4: 4693–4738.
49. Khairani CD, Bejjani A, Piazza G, et al. Direct oral antico-
agulants vs vitamin K antagonists in patients with antiphos-
pholipid syndromes: Meta-analysis of randomized trials. J
Am Coll Cardiol 2023; 81: 16–30.
50. Arreola-Diaz R, Majluf-Cruz A, Sanchez-Torres LE, et al.
The pathophysiology of the antiphospholipid syndrome: A
perspective from the blood coagulation system. Clin Appl
Thromb Hemost 2022; 28: 10760296221088576.
51. McDonald V, Geoffrey SF, Rangarajan S, et al. The use of
factor XI concentrates (Hemoleven, LFB) in patients with
congenital factor XI deficiency and a known bleeding ten-
dency. Blood 2005; 106: 1796.
52. Lewandowska MD, Connors JM. Factor XI deficiency.
Hematol Oncol Clin North Am 2021; 35: 1157–1169.
53. van Es N, De Caterina R, Weitz JI. Reversal agents for cur-
rent and forthcoming direct oral anticoagulants. Eur Heart J
2023; 44: 1795–1806.