# Oral factor xia inhibitor milvexian after a recent acute coronary syndrome: Rationale and design of the phase 3 (Librexia ACS)

C Michael Gibson, M Cecilia Bahit, Roxana Mehran, Shamir R Mehta, Rasha

Al Lamee, Shinya Goto, Jeffrey I Weitz, Jay Morrow, Elliot S Barnathan,

Robert A Harrington, et al.

► To cite this version:

C Michael Gibson, M Cecilia Bahit, Roxana Mehran, Shamir R Mehta, Rasha Al Lamee, et al. Oral factor xia inhibitor milvexian after a recent acute coronary syndrome: Rationale and design of the phase 3 (Librexia ACS). American Heart Journal, 2025, 285, pp.21 - 28. 10.1016/j.ahj.2025.02.011. hal-05105057

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# Oral factor xia inhibitor milvexian after a recent acute coronary syndrome: Rationale and design of the phase 3 (Librexia ACS)

C. Michael Gibson, MD, MS<sup>a</sup>, M. Cecilia Bahit, MD<sup>b,c</sup>, Roxana Mehran, MD<sup>d</sup>, Shamir R. Mehta, MD<sup>e</sup>, Rasha Al Lamee, MD<sup>f</sup>, Shinya Goto, MDPhD<sup>g</sup>, Jeffrey I. Weitz, MD<sup>h</sup>, Jay Horrow, MDMS<sup>i</sup>, Elliot S. Barnathan, MD<sup>j</sup>, Robert A. Harrington, MD<sup>k</sup>, Kenneth W. Mahaffey, MD<sup>l,m</sup>, Carolyn S.P. Lam, MBBS, PhD<sup>n,b</sup>, Karen S. Pieper, MS<sup>o</sup>, S. Claiborne Johnston, MD, PhD<sup>p</sup>, Graeme J. Hankey, MBBS, MD<sup>q,r</sup>, Alexei N. Plotnikov, MD<sup>j</sup>, Danshi Li, MD, PhD<sup>s</sup>, Hsiaowei Deng, PhD<sup>j</sup>, and Philippe Gabriel Steg, MD<sup>t</sup>, on behalf of Librexia ACS Committees and Investigators.

## ABSTRACT

**Background** Despite current antiplatelet therapy, patients remain at risk of recurrent ischemic events after acute coronary syndromes (ACS), which may reflect persistently elevated thrombin generation. Factor Xla inhibition reduces thrombin generation and may improve clinical outcomes with minimal bleeding risk.

**Design** Librexia ACS (ClinicalTrials.gov NCT05754957) is a Phase 3, randomized, double-blind, placebo-controlled, event-driven trial to test the efficacy and safety of milvexian, an oral, selective factor Xla inhibitor, in addition to conventional antiplatelet therapy after a recent ACS. Eligibility criteria include symptoms of spontaneous ischemia, a diagnosis of ACS and cardiac biomarker elevation indicative of myonecrosis within 7 days before randomization, along with at least 2 risk-enhancing factors. Participants are randomly assigned to oral milvexian (25 mg twice daily) or a matched placebo. Randomization is stratified according to the planned duration and type of antiplatelet therapy. The primary efficacy endpoint is the time to first occurrence of the composite of cardiovascular death, myocardial infarction (MI), or ischemic stroke that will enroll approximately 16,000 patients with follow-up until 875 events are accrued. The first major secondary endpoint is time to the first occurrence of cardiovascular death, MI, ischemic stroke, major adverse limb events, and symptomatic venous thromboembolism. The principal safety endpoint is Bleeding Academic Research Consortium 3c or 5 bleeding.

**Summary** The Librexia-ACS trial will determine the efficacy and safety of milvexian after ACS and will be the first trial to test whether factor Xla inhibition in addition to standard-of-care antiplatelet therapy reduces major adverse cardiovascular events without an increased risk of significant bleeding. (Am Heart J 2025;285:21–28.)

From the <sup>a</sup>Division of Cardiovascular Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, <sup>b</sup>Baim Institute for Clinical Research, Boston, MA, <sup>c</sup>INECO Neurociencias, Rosario, Argentina, <sup>d</sup>Cardiovascular Institute, Mount Sinai, New York, NY, <sup>e</sup>Population Health Research Institute, McMaster University and Hamilton Health Sciences, Hamilton, Ontario, Canada, <sup>f</sup>National Heart and Lung Institute, Imperial College London, Du Cane Road, London, W120HS, UK; Imperial College Healthcare NHS Trust, Du Cane Road, London, W120HS, UK, Hammersmith Hospital, London, UK, <sup>g</sup>Department of Medicine (Cardiology), Tokai University School of Medicine, Isehara, Japan, <sup>h</sup>Thrombosis and Atherosclerosis Research Institute and Hamilton Health Sciences, Hamilton, Ontario, Canada; Department of Medicine, McMaster University, Hamilton, Ontario, Canada; Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada, <sup>i</sup>University of Pennsylvania, Philadelphia, PA, <sup>j</sup>Janssen Research & Development, LLC, a Johnson & Johnson Company, Raritan, NJ, <sup>k</sup>Weill Cornell Medicine, Cornell University, New York, NY, <sup>l</sup>Division of Cardiovascular Medicine and the Cardiovascular Institute, Stanford University, Stanford, CA, <sup>m</sup>Stanford Center for Clinical Research, Stanford, CA, <sup>n</sup>National Heart Centre Singapore in Singapore, Duke-National University of Singapore (C.S.P.L), Singapore, <sup>o</sup>Thrombosis Research Institute, London, United Kingdom, <sup>p</sup>Department of Neurology, University of California, San Francisco, CA, <sup>q</sup>Centre for Neuromuscular and Neurological Disorders, The University of Western Australia, Perth, Western Australia, Australia, <sup>r</sup>Perron Institute for Neurological and Translational Science, Perth, Western Australia, Australia, <sup>s</sup>Bristol Myers Squibb, USA, <sup>t</sup>Université Paris-Cité, French Alliance for Cardiovascular Trials, INSERM_U1198/LVTS and AP-HP, Paris, France

Abbreviations: ACS, acute coronary syndrome; BARC, Bleeding Academic Research Consortium; CI, confidence interval; DAPT, dual antiplatelet therapy; HR, hazard ratio; MACE,

## Background

Despite modern pharmacotherapy, such as antiplatelet agents, high-dose statins, and latest generation drug-eluting stents, recurrent event rates remain high after acute coronary syndrome (ACS).<sup>1,2</sup> Although pharmacotherapy often focuses on platelets, thrombin generation remains elevated in the months after an ACS event and persistently elevated thrombin generation is

major adverse cardiovascular events; MALE, major adverse limb events; MI, myocardial infarction; NSTEMI, non-ST-segment elevation myocardial infarction; PCI, percutaneous coronary intervention; SAPT, single antiplatelet therapy; STEMI, ST-elevation myocardial infarction; ULN, upper limit of normal; VTE, venous thromboembolism.

Submitted November 13, 2024; accepted February 14, 2025

Reprint requests: C. Michael Gibson, MD, MS, Harvard Medical School, Beth Israel Lahey Cardiovascular Division, 930 Commonwealth Ave, Boston, MA, 02215.

E-mail address: charlesmichaelgibson@gmail.com.

0002-8703

© 2025 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)

https://doi.org/10.1016/j.ahj.2025.02.011
associated with a higher risk of major adverse cardiovas-
cular events.<sup>3-5</sup> Low-dose rivaroxaban in addition to dual
or single antiplatelet therapy reduced major adverse car-
diovascular events in patients with coronary artery dis-
ease in both the acute and chronic setting, but was asso-
ciated with an increased risk of bleeding.<sup>6,9</sup> Factor XIa
inhibitors may provide a safer anticoagulant option in
patients taking antiplatelet agents because factor XI is es-
sential for thrombus propagation, but mostly dispensable
for hemostasis.<sup>10,11</sup> Supporting this concept, Mendelian
randomization studies reveal lower rates of arterial and
venous thrombosis in subjects with low factor XI levels
compared with those with normal levels, with little or
no attendant risk of spontaneous bleeding.<sup>12,13</sup> There-
fore, phase 3 trials are now comparing oral factor XIa
inhibitors to a placebo on top of antiplatelet therapy in
ACS and stroke, and comparing to direct oral anticoag-
ulants in patients with atrial fibrillation (NCT05754957,
NCT05702034, NCT05686070).

Milvexian (JNJ-70033093; BMS-986177) is an oral, re-
versible, selective, high-affinity inhibitor of activated fac-
tor XI (FXIa), a serine protease involved in the intrinsic
pathway of the coagulation cascade.¹⁴ This manuscript
describes the design of A Study of Milvexian in Par-
ticipants After a Recent Acute Coronary Syndrome (Li-
brexia ACS) trial (ClinicalTrials.gov NCT05754957),¹⁵ a
phase 3, multicenter, double-blind, randomized, placebo-
controlled, parallel-group trial designed to investigate
whether milvexian, added to standard-of-care, can re-
duce the risk of major adverse cardiovascular events
(MACE) without an increased risk of significant bleeding
after a recent ACS.

Study design

Study operations

The LIBREXIA ACS study is overseen by an academic
Executive Committee. The committee provided over-
sight for the design of the protocol, supervises trial ex-
ecution, and is accountable for analysis of results and
publication. A Steering Committee of National Leaders
from each country provides global support for regula-
tory filing, recruitment and retention, analyses, and dis-
semination of the results. The ACS Executive Commit-
tee, co-chaired by Drs. C. Michael Gibson and P. Gabriel
Steg, is comprised of principal investigators and other
recognized leaders in the fields of ACS, hematology, and
biostatistics, as well as representatives from the sponsor
(Janssen Research and Development, LLC and Bristol My-
ers Squibb).

An independent blinded Clinical Events Committee
will adjudicate all suspected MACE and major adverse
limb events (MALE) outcomes both within the serious
adverse events database and those identified by investiga-
tors. The Executive Committees of the 3 ongoing phase
3 milvexian trials (Librexia ACS, Librexia AF, and Librexia

Stroke) proposed members of an unblinded Independent
Data Monitoring Committee, consisting of qualified sci-
entists not affiliated with the trial or sponsors, to jointly
oversee all 3 trials. The Independent Data Monitoring
Committee reports to the Executive Council Chair and
Executive Committee of each trial and is responsible for
overseeing the safety of each trial individually, as well as
the overall program safety based on the totality of data.
We actively promoted diversity in sex, race/ethnicity, ge-
ography, and expertise across all study aspects, includ-
ing, but not limited to, the trial leadership, site investi-
gators, and planned participants. We have devised strate-
gies to optimize trial participant diversity and enhance
retention that will be implemented throughout the trial.
As an example of our commitment with diversity, there
are currently 1,000 sites in 44 countries, with 11 sites in
Africa, 288 in Asia, 380 in Europe, 196 in North America,
and 97 in South America.

Study objectives

The primary objective of the study is to evaluate the ef-
ficacy of milvexian compared with placebo when added
to standard-of-care in reducing the risk of MACE (com-
posite of cardiovascular death, MI, and ischemic stroke)
in post-ACS patients.

Study population and patient selection

Participants eligible for enrollment include adults at
least 18 years of age within 7 days of an ACS (defined
as ST-segment elevation myocardial infarction [STEMI],
type 1 non-ST-segment elevation myocardial infarction
[NSTEMI], or unstable angina with biomarker positivity),
who have undergone cardiac catheterization with percu-
taneous coronary intervention (PCI) or are being man-
aged conservatively with or without catheterization, and
are receiving standard-of-care antiplatelet therapy as de-
termined by the investigator (Figure 1 and Figure 2). Ad-
ditionally, participants must have at least 2 of the follow-
ing risk-enhancing factors associated with an increase
in the risk of recurrent ischemic events¹⁶: age 65 or
older, diabetes mellitus, prior MI, multivessel coronary
artery disease, history of coronary artery bypass grafting
surgery before the index event, peripheral artery disease
or cerebrovascular disease, conservative management, or
high-risk angiographic features.¹⁷

Key exclusion criteria include: (1) type 2 MI (supply-demand mismatch without evidence of plaque disruption); (2) nonobstructive coronary artery disease on index angiography; (3) planned coronary artery bypass grafting or staged PCI after randomization; (4) any medical condition that requires chronic anticoagulation therapy; (5) increased risk of bleeding; (6) permanent dialysis or estimated glomerular filtration rate <15 ml/min/1.73 m²; (7) active liver disease; (8) active cancer undergoing treatment; (9) history of ischemic stroke or transient ischemic attack; (10) Killip class 3 or 4 at ran-
<figure><img src="image_3.png" /><figcaption>**Figure 1.** Study design and timeline. The study design and timeline are displayed, from initial screening to study end. BARC, bleeding academic research consortium; bid, 2 times per day; CV, cardiovascular; GTED, global targeted endpoint date; MACE, major adverse cardiovascular event; MI, myocardial infarction; NSTEMI, non-ST-segment elevation myocardial infarction; STEMI, ST-segment elevation myocardial infarction; UA, urinalysis.</figcaption></figure>

Primary Efficacy Endpoint: MACE (Major Adverse Cardiovascular Events) which is the composite of CV Death, MI, and Ischemic Stroke

Principal Safety Endpoint: BARC 3c and 5

<figure><img src="image_4.png" /><figcaption>**Figure 2.** Stratification schema at randomization. The figure shows the criteria and flow of randomization. ACS, acute coronary syndrome; DAPT, dual antiplatelet therapy; SAPT, single-agent antiplatelet therapy.</figcaption></figure>

domization; (11) history of significant drug allergy or known allergies; (12) hypersensitivity to milvexian; or (13) known activated partial thromboplastin time prolongation >1.5 x upper limit of normal or known congenital factor XI deficiency. A full detailed list of the inclusion and exclusion criteria can be found in Supplementary Table 1.

Approximately 16,000 participants will be enrolled, and follow-up will continue until an estimated 875 participants experience 1 or more primary efficacy outcome events. The enrollment period is expected to last 2.5 to 3 years, with a total study duration of about 3.5 years. As an event-driven study, if the blinded, pooled event rate is lower than expected, then the number of participants
or risk factors required for eligibility may be increased, and/or the duration of follow-ups increased to achieve the required number of participants with a primary outcome event. An interim analysis will be performed when approximately 525 participants have had 1 or more primary outcome events adjudicated. The Global Targeted Endpoint Date will be announced when about 875 participants are expected to have experienced 1 or more primary outcome events.

## Milvexian dose selection

A 25 mg twice daily oral dose of milvexian was selected based on the totality of the data including data from the two Phase 2 studies: (1) a total knee replacement study that showed this dose was as efficacious as enoxaparin in preventing venous thrombo-embolism and at least as safe (AXIOMATIC-TKR)¹⁸; and (2) data from the Antithrombotic Treatment with FXIa Inhibition to Optimize Management of Acute Thromboembolic Events for Secondary Stroke Prevention (AXIOMATIC-SSP) study in which the 25 mg twice daily dose in addition to 21 days of dual antiplatelet therapy was associated with numerically lower rates of recurrent ischemic stroke and similar rates of bleeding at 90 days compared with placebo.¹⁹ Additionally, this dose has measurable pharmacologic effect for both aPTT and FXIa inhibition. Higher doses offered no improvement in efficacy and were associated with numerically more major bleeds.

## Randomization and study intervention protocol

Participants are assigned in a 1:1 ratio to receive either milvexian 25 mg twice daily or a matched placebo. Randomization is stratified by the planned strategy chosen by the investigator at the time of randomization (Figure 2) for background, guideline-directed, individualized standard-of-care antiplatelet therapy: (1) dual antiplatelet therapy (DAPT) (ie, acetylsalicylic acid [aspirin] + P2Y₁₂ inhibitor) for >90 days postrandomization (with or without de-escalation to single antiplatelet therapy [SAPT]); (2) DAPT for ≤90 days postrandomization with de-escalation to SAPT; or (3) SAPT. SAPT includes low-dose aspirin or a P2Y₁₂ inhibitor (clopidogrel, ticagrelor, or prasugrel). Using ticagrelor, prasugrel, or clopidogrel is permitted per investigator judgment and guidelines. Notably, de-escalation from a more potent P2Y₁₂ inhibitor (ie, ticagrelor or prasugrel) to a less potent P2Y₁₂ inhibitor (ie, clopidogrel) is also allowed; however, this would not affect the previously described stratum assignment. Any change in antiplatelet medication will be noted in the electronic case report form.

At randomization on day 1, participants receive double-blind milvexian 25 mg or matching placebo orally, which is continued twice daily during the double-blind treatment period until the Global Targeted Endpoint Date is announced and the End of Treatment visit has taken place (Figure 1). Prior thrombolysis and/or PCI for the

index event is allowed if randomization is at least 4 hours after PCI or angiography and at least 24 hours after thrombolysis. For participants receiving full doses of a parenteral anticoagulant (eg, unfractionated heparin, low-molecular-weight heparin, argatroban) or parenteral antiplatelet treatment (eg, glycoprotein IIb/IIIa antagonist) before administration of the study intervention, the first dose of study drug is administered after discontinuation of parenteral antithrombotic treatment (minimum of 6 hours after unfractionated heparin or argatroban and 12 hours after low-molecular-weight heparin or glycoprotein IIb/IIIa antagonist). Participants are clinically evaluated by the investigator every 13 weeks. The schematic overview of the study is shown in Figure 1.

## Efficacy and safety outcomes

The primary efficacy outcome is the time to first occurrence of the composite of cardiovascular death, MI, or ischemic stroke. Hemorrhagic deaths will not be counted as CV death to avoid double counting in benefit risk analyses. The first major secondary endpoint is the time to first occurrence of cardiovascular death, MI, ischemic stroke, MALE, or symptomatic venous thromboembolism. The primary safety endpoint is Bleeding Academic Research Consortium 3c or 5 bleeding.²⁰ All endpoints are shown in Supplementary Table 2.

## Temporary and permanent discontinuation

Study intervention will be temporarily discontinued if the participant: (1) develops any medical condition that may require the use of anticoagulant therapy, thromboprophylaxis, fibrinolysis, or poses an increased bleeding risk; (2) undergoes PCI, coronary artery bypass grafting, or any other interventional procedure that may require the use of anticoagulant therapy, thromboprophylaxis, or poses an increased bleeding risk; (3) experiences a significant major bleeding event other than intracranial bleeding; (4) requires a lumbar puncture; (5) requires temporary dialysis; (6) experiences a platelet count drop below 50,000/µL; (7) experiences a hemoglobin concentration drop below 8 g/dL; (8) has an adverse event or laboratory value alteration of concern; (9) temporarily requires a prohibited therapy; or (10) has symptoms of a severe cutaneous allergic reaction. In cases where study intervention is interrupted to allow for urgent or elective surgery or procedures, the routine measures outlined in the protocol (Supplementary Table 1) should be considered. The hold times or delays are minimum values based on study intervention; concomitant antiplatelet or other therapy may dictate longer hold times or delays. Study intervention must be discontinued permanently if the participant: (1) requests to stop taking it; (2) becomes pregnant; (3) develops an intracranial hemorrhage; (4) requires chronic dialysis; or (5) experiences drug-induced liver injury meeting criteria for discontinuation; or (6) the investigator believes that the study inter-
vention should be discontinued for safety or tolerability reasons.

## Pharmacokinetic and pharmacodynamic evaluations

Blood samples will be collected from approximately 5,000 participants for pharmacokinetic assessment. The concentration of milvexian will be measured in samples collected from participants who were treated with milvexian using a validated, specific, and sensitive analytic tool (eg, liquid chromatography with tandem mass spectrometry). Residual plasma pharmacokinetic samples may be stored for future analysis and metabolite profiling. Plasma samples for pharmacodynamic and biomarker assays will be collected from approximately 1,000 participants in the study. The pharmacodynamic assay is the activated partial thromboplastin time. Exploratory biomarkers of disease pathophysiology include proteomic analyses and D-dimer.

## Analysis populations

Efficacy analyses will be evaluated in the intent-to-treat population, which includes all randomized participants. Analyses will be conducted according to the randomized treatment group, regardless of the treatment received. All safety analyses will be completed in the safety population, which contains all randomized participants who received at least 1 dose of study drug. Safety analyses will be based on the actual intervention received.

## Statistical considerations

Summaries by treatment group using appropriate descriptive statistics will be provided for all study variables, including demographic and baseline clinical characteristics. No imputation will be applied unless specified otherwise in the statistical analysis plan. Descriptive statistics such as mean, median, standard deviation, minimum, and maximum will summarize continuous variables. Counts and percentages will be used to summarize categorical variables. The Kaplan-Meier method will be used to summarize time-to-event variables. Event rates will be displayed as per 100 person-years. Graphical data displays may also be used to summarize the data. Unless stated otherwise, all statistical tests will be interpreted at a nominal (that is, without adjustment for multiplicity) 2-sided significance level of 0.05 and all confidence intervals (CIs) at a nominal 2-sided level of 95%.

The stratified log-rank test will be used for testing the primary hypothesis. To control the family-wise type I error rate at an alpha of 0.05 (two-sided) in testing for primary and secondary efficacy outcomes, if the superiority of milvexian over placebo on the primary efficacy outcome is established, the superiority of milvexian over placebo on secondary efficacy outcomes will be tested sequentially using a closed testing gatekeeping procedure in the predefined hierarchical order. The proposed

hierarchical order of testing is prespecified in the statistical analysis plan, but this may be updated/altered in the final statistical analysis plan without the need for a protocol amendment. Each test in the closed testing procedure will be performed at a 2-sided significance level of 0.05. If an individual test during any step is not statistically significant, subsequent tests will not be declared statistically significant. The stratified Cox regression will estimate the hazard ratio (HR) and 95% CI for the treatment effect on the primary efficacy endpoint.

An interim analysis for futility is planned when approximately 60% (n = 525) of the target number of participants with the primary efficacy events are observed. Since the study will not stop for superiority and the futility stopping rule is nonbinding, the type I error rate need not be adjusted.²¹,²²

## Sample size determination

The targeted total number of participants with 1 or more primary efficacy outcomes events was estimated using software East 6.5. The following assumptions were applied. First, if a participant has multiple events, only the first event is counted toward study size determinations. Second, the sample size was calculated assuming milvexian will be associated with a 20% relative risk reduction (HR 0.80) compared with placebo in the primary efficacy analysis, with a 2-sided significance level of 0.05 and a power of 90%. Finally, we project a nonuniform enrollment over approximately 3 years and a maximum follow-up of approximately 3.5 years. One interim analysis for futility only will be performed with a nonbinding stopping rule and O'Brien-Fleming approach (with a futility boundary of HR ~0.94 or conditional power ~5%) when approximately 525 patients with 1 or more primary efficacy endpoint events have occurred.

Given the integrated results of recent ACS studies, the estimated cumulative event rates in the placebo arm are 1.6%, 3.8%, and 5.0% at the first, sixth, and twelfth months after randomization, respectively. Based upon these assumptions, the targeted number of participants with primary efficacy endpoints is 875, which considers the beta spent during the interim review.²¹,²² Therefore, we estimate that about 16,000 participants must be randomized to either milvexian or placebo in a 1:1 ratio.

## Discussion

Despite advances in revascularization strategies, drug-eluting stent technology, and antiplatelet therapy with aspirin and potent P2Y₁₂ inhibitors, acute MI survivors are at high risk of experiencing an early recurrent cardiovascular event, especially in the first 30 to 90 days postacute MI that persist at 1 year and continue to accrue thereafter. Recurrent cardiovascular events occur in approximately 12% of acute MI survivors by the end of year 1, with 60% of those events occurring in the first
90 days.¹ The pathophysiology of ACS involves arterial thrombus formation reflecting the activation of platelets and the coagulation system at sites of atherosclerotic plaque disruption. Thrombin is a key driver of both processes.³ The persistent increase in thrombin generation in both the immediate and chronic phase following ACS has been linked to recurrent events.²⁶ This phenomenon has led to the study of various strategies to attenuate thrombin generation for secondary prevention.³,⁴,²³ Warfarin administration after ACS reduces cardiovascular events, but with a significantly increased risk of bleeding.²⁴,²⁵ Similar findings, with reduced cardiovascular events and increased bleeding, were observed in 3 studies evaluating rivaroxaban, a factor Xa inhibitor that targets thrombin (ATLAS ACS-TIMI 46,⁶ ATLAS ACS-TIMI 51,⁷ and COMPASS),⁸ and 1 with vorapaxar (TRA 2P-TIMI 50 trial),⁹ a competitive selective antagonist of the type 1 protease-activated receptor (PAR-1), the major thrombin receptor on human platelets.²⁶ The above-mentioned studies showed consistent and clinically important reductions in cardiovascular events with thrombin inhibition (on top of DAPT or aspirin alone), but at the cost of increased bleeding which complicates its clinical utility.

Genetic data has demonstrated that patients with factor XI deficiency have a lower rate of venous and arterial events without a substantial increase in bleeding. Inhibition of factor XIa may block pathologic thrombosis and may only minimally increase the risks of bleeding by preserving healthy hemostasis, thereby providing an opportunity to uncouple hemostasis from thrombosis. Factor XIa inhibition may be a suitable strategy to fulfill the dual unmet needs of preventing recurrent ischemic events post-ACS without causing undue bleeding.²⁶ Importantly, Librexia ACS is the only ongoing phase 3 trial with a factor XIa inhibitor in ACS. Asundexian, another small molecule factor XIa inhibitor, was tested in a phase 2 trial called the Study to Gather Information About the Proper Dosing and Safety of the Oral FXIa Inhibitor BAY 2433334 in Patients Following an Acute Heart Attack (PACIFIC-AMI).²⁷ This study demonstrated that asundexian, when used in addition to aspirin plus a P2Y12 inhibitor, resulted in dose-dependent, near-complete inhibition of factor XIa without a significant increase in bleeding and with a low rate of ischemic events. Despite these promising findings, the decision was made not to conduct a phase 3 trial with asundexian in patients with ACS.

In Librexia ACS, at the time of patient enrollment, the investigator chooses the most appropriate background, guideline-directed, individualized standard-of-care antiplatelet therapy for each patient, as opposed to mandating a fixed DAPT strategy. The design of this trial reflects the state of science and clinical practice throughout the study and will permit outcomes to be interpreted in light of contemporary practice.

A Study to Learn How Well the Study Treatment Asundexian Works and How Safe it is Compared to Apixaban to Prevent Stroke or Systemic Embolism in People With Irregular and Often Rapid Heartbeat (Atrial Fibrillation), and at Risk for Stroke (OCEANIC-AF) trial,²⁸ a Phase 3 trial evaluating asundexian in patients with atrial fibrillation, was stopped prematurely due to a higher incidence of stroke or systemic embolism with study drug compared to the standard dose of apixaban. Asundexian was associated with fewer major bleeding events than apixaban during the study period.

There are significant differences between the OCEANIC-AF and Librexia ACS trials. First, the patient population for OCEANIC-AF included those with atrial fibrillation and high risk for stroke, whereas Librexia ACS includes patients within 1 week of an acute coronary syndrome. Second, in terms of the comparator and background therapy, OCEANIC-AF's asundexian was compared with standard of care oral anticoagulation, apixaban standard dose, whereas in the Librexia ACS trial, milvexian is being tested against placebo on top of single antiplatelet or dual antiplatelet therapy in the post-ACS setting according to investigator discretion. Third, when examining the potency of both small molecule factor XIa inhibitors, milvexian had a higher potency in the factor XIa enzyme inhibition assay in vitro compared to that reported for asundexian.²⁹ Finally, the doses tested were different across trials. OCEANIC-AF tested asundexian 50 mg once daily against apixaban, Librexia AF³⁰ is testing milvexian 100 mg bid vs apixaban, and Librexia ACS is testing milvexian at a dose of 25 mg bid vs. placebo.

## Conclusions

Despite modern pharmacotherapy and devices, event rates remain high in post-ACS patients. Epidemiologic and venous prophylaxis trials suggest factor XIa inhibition safely reduces thrombotic events with no meaningful excess in bleeding events. Elevation of thrombin generation post-ACS is associated with adverse outcomes, and the factor XIa inhibitor milvexian has the potential to block a positive feedback loop that drives thrombin generation and promotes thrombus expansion. The LIBREXIA ACS trial will examine the efficacy and safety of milvexian among post-ACS participants and will be the first outcome study to test whether inhibition of factor XIa, in addition to standard-of-care, reduces MACE without an increased risk of significant bleeding.

## Conflict of interest

C.M.G. reports receiving research grant support from Johnson and Johnson, M.C.B reports receiving modest honoraria from Johnson and Johnson, Bristol-Myers Squibb, Anthos Therapeutics, Merck; R.M. reports institutional research payments from: Abbott, Affluent
Medical, Alleviant Medical, Amgen, Boston Scientific, Bristol-Myers Squibb, CardiaWave, Chiesi, Concept Medical, Daiichi Sankyo, Duke, Faraday, Idorsia, Janssen, MedAlliance, Medscape, Mediasphere, Medintelligence, Medtronic, Novartis, OrbusNeich, Pi-Cardia, Protembis, RM Global Bioaccess Fund Management, Sanofi; and personal fees from: Affluent Medical, Boehringer Ingelheim, Chiesi USA, Cordis, IQVIA, Medscape/WebMD Global, NovoNordisk, PeerView Institute for Medical Education, Radcliffe; S.R.M. has received institutional research grants or consulting fees from Abbott, Amgen, Canadian Institutes of Health Research, Heart and Stroke Foundation of Canada, Diapin, Janssen, Merck (data monitoring committee), Novartis, NovoNordisk; R.A.-L. serves on advisory boards for Janssen Pharmaceuticals, Abbott, and Philips; and has received speaker fees from Abbott, Philips, Medtronic, Servier, Omniprex, and Menarini; S.G. report modest honoraria from Johnson and Johnson, Anthos Therapeutics, Merck; R.M. and Amgen; J.I.W reports receiving honoraria from BMS and Johnson and Johnson and grant support to his institution.; J.H. is a former employee of Bristol Myers Squibb; E.S.B. is an employee of and owns stock in Johnson and Johnson; R.A.H. has received research grants/contracts from NHLBI (ISCHEMIA), Duke/PCORI (ADAPTABLE), Janssen (Factor XIa inhibitor), CSL (HDL), Baim Institute, UColorado, Harvard (BWH), and Merck; has served as a consultant/advisor for NHLBI (COVID/CONNECTS), Atropos Health, Bitterroot Bio, Bristol Myers Squibb, Bridge Bio, Chiesi, CSL Behring, Edwards Lifesciences Corp, Element Science, Foresight, Merck, and WebMD; and serves on the Board of Directors for AHA and Cytokinetics; K.W.M.'s financial disclosure can be reviewed at http://med.stanford.edu/profiles/kenneth-mahaffey; C.S.P.L. is supported by a Clinician Scientist Award from the National Medical Research Council of Singapore; has Received research support from Novo Nordisk and Roche Diagnostics; has Served as consultant or on the Advisory Board/ Steering Committee/ Executive Committee for Alleviant Medical, Allysta Pharma, AnaCardio AB, Applied Therapeutics, AstraZeneca, Bayer, Bioethics, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, CardioRenal, CPC Clinical Research, Eli Lilly, Hanmi, Impulse Dynamics, Intellia Therapeutics, Ionis Pharmaceutical, Janssen Research & Development LLC, Medscape/WebMD Global LLC, Merck, Novartis, Novo Nordisk, Prosciento Inc, Quidel Corporation, Radcliffe Group Ltd., Recardio Inc, ReCor Medical, Roche Diagnostics, Sanofi, Siemens Healthcare Diagnostics and Us2.ai; and serves as Co-founder and nonexecutive director of Us2.ai.; K.S.P is a member of The Thrombosis Research Institute which has received institutional research grant support from Anthos Therapeutics and Bayer Pharmaceuticals. She has received honoraria from Element Science and Artivion, Inc.; S.C.J. has received research support from Jansen, BMS, and AstraZeneca; G.J.H. re-

ports personal honoraria outside the submitted work from the American Heart Association (Associate Editor, Circulation), Bristol Myers Squibb (Steering Committee, AXIOMATIC-SSP trial of milvexian [factor XIa inhibitor] for secondary stroke prevention) and Janssen (Co-chair, Executive Committee, Librexia Stroke trial of milvexian for secondary stroke prevention); A.P. is an employee of Johnson and Johnson; D.L. is an employee of BMS; P.G.S reports receiving research grants from Amarin, Sanofi; honoraria for clinical trial work from Amarin, AstraZeneca, Bayer, Bristol-Myers Squibb, Idorsia, Janssen R&D LLC, Novartis, Pfizer, Sanofi, Servier; honoraria for consulting or speaking: Amarin, Amgen, BMS/Myokardia, Novo-Nordisk, and is Senior Associate Editor at Circulation.

### CRediT authorship contribution statement

C. Michael Gibson: Writing - review & editing, Writing - original draft, Conceptualization. M. Cecilia Bahit: Writing - review & editing, Writing - original draft, Conceptualization. Roxana Mehran: Writing - review & editing, Writing - original draft, Conceptualization. Shamir R. Mehta: Writing - review & editing. Rasha Al Lamee: Writing - review & editing. Shinya Goto: Writing - review & editing. Jay Morrow: Writing - review & editing. Carolyn S.P. Lam: Writing - review & editing. S. Claiborne Johnston: Writing - review & editing. Danshi Li: Writing - review & editing. Hsiaowei Deng: Writing - review & editing. Philippe Gabriel Steg: Writing - review & editing, Writing - original draft, Conceptualization.

### Funding

This study is sponsored by Bristol Myers Squibb and Janssen Research & Development, LLC., a Johnson & Johnson Company.

### Supplementary materials

Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.ahj.2025.02.011.

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