TW202506124A - Use of milvexian for treating or preventing adverse cerebrovascular events or adverse cardiovascular events in patients having acute coronary syndrome - Google Patents

Abstract

A Factor XIa inhibitor having therapeutic properties useful in methods for of preventing adverse cerebrovascular events or adverse cardiovascular events in human patients with acute coronary syndrome.

Description

Use of MILVEXIAN for the treatment or prevention of adverse cerebrovascular events or adverse cardiovascular events in patients with acute coronary syndrome

The present disclosure relates to the use of milvxian for treating or preventing adverse cerebrovascular events or adverse cardiovascular events in human patients with acute coronary syndrome (ACS) without significantly impairing the normal blood clotting process.

Cardiovascular disease (CVD) remains the leading cause of death worldwide. Despite the availability of current treatments, stroke remains the leading cause of death and disability worldwide. In 2019 alone, it caused 143 million disability-adjusted life years and 6.55 million deaths, accounting for a large portion of health care expenditures in Western countries. In the United States, an estimated 805,000 new and recurrent myocardial infarctions (MIs) occur each year. After experiencing an acute coronary syndrome (ACS), patients remain at increased risk. Despite advances in newer thin-strut stents/polymers, antithrombotic therapy with aspirin and/or strong P2Y12 inhibitors, widespread use of surgical and percutaneous revascularization, and targeted control of modifiable CV risk factors, the risk of recurrent cardiovascular (CV) events (such as myocardial infarction, ischemic stroke, and CV death) in the first year for acute MI survivors remains unacceptably high at more than 5%. At the end of the first year, 5% of acute MI survivors experience a recurrent CV event, and 60% of these events occur within the first 90 days. Atherosclerosis-related cardiovascular complications remain the leading cause of morbidity and mortality in the Western world and in developing countries. (Katan et al., Global burden of stroke, Semin Neurol., 2018, Vol. 38, pp. 208-211).

Milvexian (BMS-986177/JNJ-70033093) is a high-affinity, direct-acting inhibitor of human coagulation FXIa (Dilger et al., Discovery of milvexian, a high-affinity, orally bioavailable inhibitor of factor XIa in clinical studies for antithrombotic therapy. J Med Chem 2022;65(3):1770-85). Milvexian is a macrocyclic compound having the structure of formula (I): Formula (I).

Milvusin is also known by its chemical name (5R,9S)-9-(4-(5-chloro-2-(4-chloro- 1H -1,2,3-triazol-1-yl)phenyl)-6-oxopyrimidin-1(6H)-yl)-2 ¹ -(difluoromethyl)-5-methyl-2 ¹ H -3-aza-1(4,2)-pyridin-2(5,4)-pyrazolo[3-nitro]naphthalen-4-one.

Miltgen and methods of preparing Miltgen are described in U.S. Patent No. 9,453,018, which is incorporated herein by reference in its entirety. Solvates, crystalline forms, and amorphous forms of Miltgen are also known in the art. See, for example, WO2021207659 and WO2022081473. Amorphous solid dispersion compositions of Miltgen in one or more polymers have been described in WO2020210629, which is incorporated herein by reference in its entirety.

A total of 4,114 participants have been included in the Milvecin clinical program and exposed to the study intervention (milvecin, placebo, or comparator). Of the 4,114 participants, 3,229 received Milvecin, with 660 participants exposed to Milvecin in the Phase 1 study and 2,569 participants exposed to Milvecin in the Phase 2 and Phase 2a studies. In the Milvecin clinical development program, four types of serious bleeding were evaluated as adverse drug reactions: gastrointestinal bleeding, surgical bleeding, bleeding in neurologic disorders (hemorrhagic transformation of ischemic stroke and subdural hematoma), and hematuria. The results of a Phase II clinical trial of Milvexian in patients undergoing TKR (total knee replacement) were published in 2021 (Weitz et al., Milvexian for the Prevention of Venous Thromboembolism, N. Engl. J. Med. 2021, Vol. 385, pp. 2161-2172). Results of a phase II clinical trial of milvexian in addition to single or dual antiplatelet therapy (SAPT/DAPT) for the prevention of non-cardioembolic, non-lacunar ischemic stroke were announced in 2023 (Sharma et al., Safety and efficacy of factor XIa inhibition with milvexian for secondary stroke prevention (AXIOMATIC-SSP): a phase 2, international, randomised, double-blind, placebo-controlled, dose-finding trial, The Lancet Neurology, 2023, Vol. 23, pp. 46-59).

As a result, vascular and thromboembolic diseases remain the leading causes of death and disability worldwide. Despite significant advances in antithrombotic therapy, anticoagulant therapy is still limited by bleeding and many patients remain at high risk of thrombosis.

The present disclosure provides a therapeutic regimen comprising an oral formulation containing: miltvicin or a pharmaceutically acceptable salt or solvent thereof; a highly selective and potent FXIa inhibitor as described below, for targeted regulation of coagulation through inhibition of activated factor XIa (FXIa); and one or more antiplatelet therapies for the treatment and prevention of thrombosis and embolism, thereby reducing the risk of adverse cerebrovascular or cardiovascular events (such as cardiovascular death, myocardial infarction or stroke) in patients with a history of acute coronary syndrome and/or atherosclerotic vascular disease, without impairing hemostasis due to reduced thrombin generation, which is a result of the close synergy between FXIa inhibition and inhibition of platelet activation. The treatment regimens described herein are given to patients at risk for developing thromboembolic disease to prevent occlusive thrombosis (primary prevention). In some embodiments, after an initial thrombotic event, the treatment regimens described herein are given to patients to achieve secondary prevention, for example, secondary prevention of cardiovascular events in patients with a history of acute myocardial infarction or acute coronary syndrome. For ACS patients, the treatment regimens described herein achieve a more favorable balance between ischemia and bleeding risk than rivaroxaban or other direct oral anticoagulants (DOAC). The treatment regimens not only block coagulation activation on intravascular stents, but also prevent FXI-mediated thrombus stabilization and growth at sites of vascular damage.

In another aspect, the disclosed method provides a novel treatment regimen comprising a novel immediate release oral tablet containing miltvicin and standard of care antiplatelet therapy for anticoagulation of patients after ACS and at increased risk of bleeding. The disclosed method introduces the opportunity for FXIa inhibitors to be used in areas or diseases where anticoagulants are underutilized or unused.

In some aspects, the present disclosure provides a method for preventing adverse cerebrovascular events or adverse cardiovascular events in a human patient suffering from an acute coronary syndrome, wherein the method comprises administering to the human patient a treatment regimen comprising: (i) a pharmaceutical composition comprising 25 mg of miltvicin (or a pharmaceutically acceptable salt or solvent thereof); and (ii) an antiplatelet therapy selected from the group consisting of aspirin, a P2Y12 inhibitor, and a combination thereof; wherein the pharmaceutical composition is administered twice daily.

In other aspects, the present disclosure provides a method for preventing adverse cardiovascular events in a human patient diagnosed with acute coronary syndrome, wherein the method comprises administering to the human patient a treatment regimen comprising: (i) a pharmaceutical composition comprising 25 mg of miltvicin (or a pharmaceutically acceptable salt or solvent thereof) and one or more pharmaceutically acceptable formulations, and (ii) an antiplatelet therapy selected from the group consisting of aspirin, a P2Y12 inhibitor, and a combination thereof; wherein the pharmaceutical composition is administered twice daily; and wherein the adverse cardiovascular event is one or more selected from the group consisting of: all-cause mortality (ACM); cardiovascular (CV) mortality; myocardial infarction (MI); unstable angina (UA); All strokes or any stroke (ischemic, hemorrhagic, or unknown etiology); ischemic stroke; acute limb ischemia (ALI); major vascular (non-traumatic) limb resection; symptomatic venous thromboembolism (VTE: (pulmonary embolism (PE), deep venous thrombosis (DVT)); ischemia-driven coronary revascularization; stent thrombosis; hospitalization for any reason categorized as (1) planned or unplanned, (2) arterial or venous thrombotic event, or neither.

In other aspects, the present disclosure provides a method for reducing the incidence of one or more adverse thrombotic events in a human patient diagnosed with acute coronary syndrome, wherein the adverse thrombotic event is selected from new ischemic stroke, MI or all-cause death, wherein the method comprises administering to the human patient a treatment regimen comprising: (i) a pharmaceutical composition comprising about 25 mg to about 100 mg of miltiorrhiza (or a pharmaceutically acceptable salt or solvent thereof) and one or more pharmaceutically acceptable formulations, and (ii) an antiplatelet therapy selected from the group consisting of aspirin, a P2Y12 inhibitor, and a combination thereof; wherein the pharmaceutical composition is administered twice daily.

In other aspects, the present disclosure provides a method for preventing ischemic stroke in a human patient diagnosed with acute coronary syndrome, wherein the method comprises administering to the human patient a treatment regimen comprising: (i) a pharmaceutical composition comprising 25 mg of miltvicin (or a pharmaceutically acceptable salt or solvent thereof) and one or more pharmaceutically acceptable formulations, and (ii) an antiplatelet therapy selected from the group consisting of aspirin, a P2Y12 inhibitor, and a combination thereof; wherein the pharmaceutical composition is administered twice daily.

In some aspects of the disclosed methods, melissin (or a pharmaceutically acceptable salt or solvent complex thereof) is orally administered as a solid pharmaceutical composition comprising melissin (or a pharmaceutically acceptable salt or solvent complex thereof) and a pharmaceutically acceptable excipient.

In other aspects of the disclosed methods, the administration does not result in a statistically significant increase in severe bleeding complications.

Cross-reference to related applications

This application claims the benefit of U.S. Provisional Application No. 63/497,111 filed on April 19, 2023, the entire contents of which are incorporated herein by reference.

In one aspect, the disclosed methods provide a novel treatment regimen comprising a novel immediate-release oral tablet containing milvicin for anticoagulation therapy in patients following ACS and at increased risk of bleeding.

In some aspects, the disclosure provides methods of preventing adverse cerebrovascular events or adverse cardiovascular events in a human patient suffering from acute coronary syndrome, wherein the method comprises administering to the human patient a treatment regimen comprising 25 mg of milvicin twice daily.

In some aspects, the present disclosure provides a method for preventing adverse cerebrovascular events or adverse cardiovascular events in a human patient suffering from acute coronary syndrome, wherein the method comprises administering to the human patient a treatment regimen comprising a pharmaceutical composition comprising 25 mg of milvithin (or a pharmaceutically acceptable salt or solvent thereof), wherein the pharmaceutical composition is administered twice daily.

In some aspects, the disclosure provides methods for preventing adverse cerebrovascular events or adverse cardiovascular events in a human patient suffering from acute coronary syndrome, wherein the method comprises administering to the human patient a treatment regimen comprising 25 mg of milvicin twice daily and (ii) antiplatelet therapy.

In some aspects, the present disclosure provides a method for preventing adverse cerebrovascular events or adverse cardiovascular events in a human patient suffering from acute coronary syndrome, wherein the method comprises administering to the human patient a treatment regimen comprising: (i) a pharmaceutical composition comprising 25 mg of miltvicin (or a pharmaceutically acceptable salt or solvent thereof); and (ii) an antiplatelet therapy, wherein the pharmaceutical composition is administered twice daily.

In other aspects, the present disclosure provides a method for preventing adverse cardiovascular events in a human patient diagnosed with acute coronary syndrome, wherein the method comprises administering to the human patient about 25 mg of milvicin; and wherein the adverse cardiovascular event is selected from one or more of the group consisting of: all-cause mortality (ACM); cardiovascular (CV) mortality; myocardial infarction (MI); unstable angina (UA); "all strokes" or "any stroke" (ischemic, hemorrhagic, or unknown etiology); ischemic stroke; acute limb ischemia (ALI); major vascular (non-invasive) limb resection; symptomatic venous thromboembolism (VTE: (pulmonary embolism (PE), deep venous embolism (DVT)); ischemia-driven coronary revascularization; intravascular stent thrombosis; hospitalization for any reason categorized as (1) planned or unplanned, (2) arterial or venous thrombotic event, or neither.

In other aspects, the present disclosure provides methods for reducing the incidence of one or more adverse thrombotic events selected from new ischemic stroke, MI, or all-cause death in a human patient diagnosed with acute coronary syndrome, wherein the method comprises administering to the human patient a treatment regimen comprising about 25 mg to about 100 mg of milvicin twice daily.

In other aspects, the present disclosure provides methods for preventing ischemic stroke in a human patient diagnosed with acute coronary syndrome, wherein the method comprises administering to the human patient a treatment regimen comprising 25 mg of milvicin twice daily.

The present disclosure provides a method for preventing adverse cerebrovascular events or adverse cardiovascular events in a human patient with acute coronary syndrome (ACS), wherein the method comprises administering to the human patient a treatment regimen comprising: (i) 25.0 mg of milvitra twice daily; and (ii) antiplatelet therapy. In some embodiments, the antiplatelet therapy comprises a single antiplatelet therapy (SAPT). In some embodiments, the antiplatelet therapy comprises a dual antiplatelet therapy (DAPT). In some embodiments, the antiplatelet therapy is selected from aspirin or a P2Y12 inhibitor. In some embodiments, the antiplatelet therapy comprises administering DAPT containing aspirin and clopidogrel for 21 days, followed by administration of aspirin monotherapy.

The use of the Milvus treatment in the methods described in Example 1 below focuses on different patient populations from those patient populations in two Phase II clinical trials (AXIOMATIC-TKR and AXIOMATIC-SSP), such as patients with acute coronary syndrome (ACS) who are administered the treatment methods described herein to prevent adverse cardiovascular events and patients with coronary atherosclerosis (e.g., atherosclerotic plaques in the heart). The AXIOMATIC-TKR trial was performed in patients after total knee replacement surgery to prevent the development of venous thromboembolism and the AXIOMATIC-SSP trial was performed in patients with ischemic stroke due to atherothrombosis associated with cerebrovascular atherosclerosis (e.g., atheromatous plaques of the intracranial or internal cerebral carotid arteries; see Sharma et al., supra) to achieve secondary stroke prevention.

Atherosclerosis is a chronic inflammatory disease of the arterial wall and is characterized by abnormal endothelial function, resulting in lipid deposition and calcium accumulation in the subendothelial space, followed by leukocyte infiltration and smooth muscle proliferation. Vascular damage (such as occurs during erosion or rupture of atherosclerotic lesions) triggers blood clotting in an attempt to maintain hemostasis (prevent bleeding). This results in thrombosis and acute coronary syndrome (ACS). Atherothrombosis occurs as a result of thrombosis in ruptured or erosive atherosclerotic plaques and clinically manifests as myocardial infarction (MI), peripheral arterial disease (PAD), or ischemic stroke (not due to embolism from the heart) (Moliterno et al., eds., The ESC Textbook of Thrombosis, Chapter 1, Arterial Thrombosis: Pathophysiological background, pp. 3-12, Oxford University Press, Oxford, 2023).

Several animal and clinical studies have demonstrated a link between coagulation and atherothrombosis (Ngo et al., Pharmacological targeting of coagulation factor XI mitigates the development of experimental atherosclerosis in low-density lipoprotein receptor-deficient mice, J Thromb Haemost. 2021;19:1001–1017). The presence of multiple coagulation components in human atherosclerotic lesions strongly suggests a role for coagulation activity during early plaque development. In addition, thrombin, tissue factor pathway inhibitors, coagulation factor (F) VIII, and activated FX (FXa) have all been shown to induce plaque development in mice. Intrinsic pathway components, such as factor XII (FXII) and more recently factor XI (FXI), have also been shown to play a role in atherogenesis in ApoE−/− mice through unclear mechanisms.

Acute coronary syndrome (ACS) is a group of disorders associated with a sudden reduction in blood flow to the heart. Blood clots are the most common cause of the reduced blood flow, which can lead to other complications (known as severe adverse cardiovascular events) such as additional heart attacks, stroke, or even death. ACS pathophysiology involves arterial thrombosis, which involves platelet activation and fibrin formation. The underlying thrombotic mechanism in acute coronary syndrome (ACS) involves platelets and thrombin. Thrombin generation is more rapid and easily increased in ACS patients compared to patients with stable coronary disease or healthy controls. Persistently increased thrombin generation has been associated with recurrent events in both the acute and chronic phases following ACS. Thrombin generation remains elevated for years after ACS, and elevated measurements of thrombin generation are associated with higher event rates. Although acute care targets both pathways, platelet inhibition is primarily administered in the chronic phase, and thrombin plays a key role in platelet activation and fibrin formation. In ACS patients, there is also a long-term, persistent increase in thrombin generation, which is associated with a higher rate of adverse events (Bahit et al., Thrombin as target for prevention of recurrent events after acute coronary syndromes, Thrombosis Research, 2024, Vol. 235, pp. 116-121).

FXI is activated primarily by FXIIa and also by thrombin, with approximately 15% of thrombin generated via a FXIa-mediated mechanism. Elevated FXIa has been associated with ischemic stroke, venous thromboembolism, and ACS. FXIa and circulating activated tissue factor (TF) have been detected in individuals with stable CAD (76% and 6%, respectively) and ACS (symptom duration <12 h (96% and 38%, respectively) and in individuals with heart failure (Zabczyk et al., Active tissue factor and activated factor XI in circulating blood of patients with systolic heart failure due to ischemic cardiomyopathy, Pol. Arch. Med. Wewn., 120 (2010), pp. 334-340). The SMILE study found a positive correlation between plasma FXIa and ACS (Doggen et al., Levels of intrinsic coagulation factors and the risk of myocardial infarction among men: opposite and synergistic effects of factors XI and XII, Blood, 108 (2006), pp. 4045-4051). Paszek et al. reported that active factor XI was associated with the risk of cardiovascular events in patients with stable coronary artery disease (Atherosclerosis, 2022, Vol. 346, pp. 124-132). Factor XIa and active TF were present in 32.6% and 14.7% of patients with acute ischemic stroke, respectively (Goldman et al., Activation of blood coagulation and thrombin generation in acute ischemic stroke treated with rtPA, J. Thromb. Thrombolysis, 44 (2017), pp. 362-370). Circulating TF and FXIa are associated with adverse long-term outcomes in patients following ischemic cerebrovascular events (Undas et al., Circulating activated factor XI and active tissue factor as predictors of worse prognosis in patients following ischemic cerebrovascular events Thromb. Res., 128 (2011), pp. e62-66).

Increased activity of plasma FXII, FXI, or kallikrein is associated with atherosclerosis and myocardial infarction, whereas severe FXI deficiency is associated with a reduced risk of stroke and deep venous embolism. Thus, FXIa continues to exacerbate atherosclerosis, which may also lead to an increased risk of MI, stroke, and CV death.

Rupture or erosion of atherosclerotic plaques in the coronary arteries triggers platelet activation and aggregation and exposes tissue factor, which initiates the coagulation cascade and causes thrombin generation and fibrin formation. The key step in the amplification of thrombin generation is the feedback activation of factor XI by thrombin (Figure 1). Fibrin and aggregated platelets form thrombi, which block blood flow in the coronary arteries, thereby triggering ischemic events.

It has recently become clear that patients with CAD often have a systemic atherosclerotic process and that more than one-third of these patients may also have peripheral arterial disease ("PAD"). It is estimated that, regardless of current standard of care, patients following ACS may have a major adverse cardiovascular event ("MACE") rate of approximately 5% in the first year and an additional approximately 0.5% to 1% of other highly significant events such as major adverse limb events (MALEs) or symptomatic venous thromboembolism (VTE). The term MAVE (major adverse vascular events) encompasses the many types of arterial and vascular events that anticoagulants can help prevent.

Thrombin is the most potent platelet activator. Aspirin and P2Y12 inhibitors remain the cornerstone of antiplatelet therapy as current antithrombotic measures for the prevention of recurrent thromboembolic events after ACS. However, neither aspirin nor P2Y12 inhibitors block platelet activation by thrombin. The mainstay of CAD therapy is dual antiplatelet therapy with aspirin and a P2Y12 receptor inhibitor (clopidogrel, ticagrelor, or prasugrel). A pooled analysis of data from all randomized trials of aspirin versus control for the secondary prevention of ACS or chronic CAD demonstrated that aspirin reduced the risk and severity of both early and late recurrent MACE (Antithrombotic Trialists' Collaboration 2002). Similarly, long-term monotherapy with clopidogrel or aspirin produced similar results in participants with atherosclerosis, including a subgroup with an MI within 35 days before randomization (CAPRIE Steering Committee 1996). Despite improvements in invasive and medical management of patients with CAD, the annual incidence of recurrent thrombotic events after ACS of 5% or greater remains unacceptably high.

In the context of post-ACS care with rivaroxaban, targeting factor Xa is associated not only with reduced thrombin generation and reduced cardiovascular events, but also with an increased risk of bleeding. Among DOACs, rivaroxaban is the only one that has been successfully evaluated in phase III in combination with dual antiplatelet therapy in patients experiencing ACS. It reduces the risk of death from cardiovascular causes, myocardial infarction, and stroke, but increases the risk of severe bleeding. The COMPASS trial in individuals with stable atherosclerotic vascular disease demonstrated a dual pathway mechanism using antiplatelet therapy and anticoagulants to improve efficacy by reducing the risk of ischemic stroke, while the propensity for severe bleeding was increased (Eikelboom et al.; COMPASS Investigators. Rivaroxaban with or without Aspirin in Stable Cardiovascular Disease. N Engl J Med 2017;377:1319-30).

The high human and financial costs of thromboembolic events emphasize the need for new and better treatment options to manage thrombotic conditions. The challenge is to develop agents that have strong antithrombotic effects but minimal bleeding risk, as they need to interrupt the thrombotic process with minimal impact on the hemostatic process. Although many therapies are available for ACS, preventing recurrent adverse vascular events in ACS patients requires new treatment options, such as oral formulations of FXIa inhibitors.

Activated coagulation factor XIa (FXIa) is a key serine protease involved in the amplification of thrombin generation. Increased thrombin levels carry the risk of thrombosis. Inhibition of FXIa reduces thrombin generation and prevents thrombosis while maintaining normal hemostasis. Although FXIa's contribution to hemostasis is relatively small, it is involved in clot growth and stability (see Figure 1 ). Fredenburgh JC, Weitz JI. Factor XI as a target for new anticoagulants. Hamostaseologie 2021;41(2):104-10. Human factor (F) XI deficiency protects against venous thrombosis, stroke, and heart attack, whereas deficiencies of other contact pathway components, including FXII, plasma prekallikrein, or kininogen, do not protect against thrombosis. FXI deficiency, inhibitors of FXI production and activation (FXIa), and FXI antibodies that interfere with the FXI/FXII interaction reduce experimental thrombosis and inflammation. FXI inhibitors are antithrombotic in patients, and FXI and FXII deficiency protect against atherosclerosis in apolipoprotein E-deficient mice. Gill D et al., Genetically determined FXI (factor XI) levels and risk of stroke. Stroke 2018;49(11):2761-3; Salomon et al., Reduced incidence of ischemic stroke in patients with severe factor ischemic stroke. J Thromb Haemost 2020;18(12):3316-24.

Analysis of genetically measured FXI has been demonstrated, with the highest FXI levels being associated with an increased risk of ischemic stroke (Gill et al., Genetically Determined FXI (Factor XI) Levels and Risk of Stroke. Stroke. 2018;49(11):2761-2763). Patients with congenital FXI deficiency (hemophilia C) have been shown to have a reduced risk of stroke and venous thromboembolism (Gailani et al., Factor XI as a therapeutic target. Arterioscler Thromb Vasc Biol. 2016;36(7):1316-1322; Peyvandi et al.; European Network of Rare Bleeding Disorders Group. Coagulation factor activity and clinical bleeding severity in rare bleeding disorders: results from the European Network of Rare Bleeding Disorders. J Thromb Haemost. 2012 Apr;10(4):615-621). Studies in the prevention and treatment of deep venous embolism have demonstrated a reduction in venous thrombosis and a favorable bleeding profile with reduced FXI levels or FXIa inhibition. (Buller et al., Factor XI antisense oligonucleotide for prevention of venous thrombosis. N Engl J Med 2015;372(3):232-40; Weitz et al., Effect of osocimab in preventing venous thromboembolism among patients undergoing knee arthroplasty: the FOXTROT randomized clinical trial. JAMA 2020;323(2):130-9; Weitz et al., Milvexian for the prevention of venous thromboembolism. N Engl J Med 2021;385(23):2161-72.).

While factor Xa inhibitors block tissue factor-activated coagulation processes that are essential for hemostasis as well as the intrinsic pathway, factor XIa inhibition blocks thrombosis that occurs through the intrinsic pathway (or "touched" system) that may not be necessary for normal hemostasis and through the thrombin generation-enhanced pathway that appears to lead to pathological thrombosis. Therefore, in patients with atherosclerotic CAD, including those following an ACS event, FXIa inhibition has the potential to improve the benefit-risk profile compared to factor Xa or thrombin inhibitors that reduce thrombin generation, thereby preventing vascular occlusion and embolism with minimal impairment of hemostasis. The risk of recurrent ACS events is highest shortly after the index event and other events continue to accrue over time due to the progressive nature of the underlying atherosclerotic disease process. Given the high rate of recurrent events following ACS, new targets are needed that can prevent pathological thrombosis while maintaining normal hemostasis.

There are several factors that distinguish melvexan from other oral factor Xla inhibitors such as asundexian. For example, a population pharmacokinetic model was developed using pooled data on melvexan plasma concentrations in healthy adult volunteers from six Phase 1 clinical studies to characterize melvexan pharmacokinetics.

Analyzing PK data from the AXIOMATIC-SSP trial using a proprietary population PK model revealed that, based on the exposure-response relationship of milvicin in patients, administering a pharmaceutical composition comprising 25 mg of milvicin twice daily to human patients results in milvicin plasma concentrations reaching a steady state within about 3 days. In some embodiments of any of the above aspects, 25 mg of milvicin orally administered twice daily to human patients results in a plasma concentration profile that reaches a steady state within about 3 days. In some embodiments of any of the above aspects, the steady-state plasma concentration profile has the following characteristics: (i) a steady-state C _max in the range of about 217 ng/mL to about 475 ng/mL; (ii) a steady-state mean (std) C _max of 346 (129) ng/mL; (iii) a steady-state AUC _0-24 in the range of about 4350 ng*h/mL to about 10230 ng*h/mL, and (iv) a steady-state mean (std) AUC _0-24 of 7290 (2940) ng*h/mL. Additionally, based on data from Phase 1 and Phase 2 studies and the results of analyzing the exposure-response relationship of milvicin in patients using this proprietary population pharmacokinetic model, a 25 mg milvicin BID dosing regimen was selected for use in the Phase 3 trial for ACS as described in Example 1.

As used herein, the term "acute coronary syndrome" (ACS) refers to a spectrum of coronary diseases caused by atherothrombosis within the pericardial coronary arteries, usually triggered by plaque rupture or erosion. Atherothrombosis is the central pathological process driving most ACS. For example, rupture of a coronary plaque leading to thrombosis, obstructing a coronary artery, is the basis of the pathophysiology of STEMI. ACS can be divided into the following subgroups: ST-segment elevation myocardial infarction (STEMI), non-ST-segment elevation myocardial infarction (NSTEMI), and unstable angina. In cases associated with myocardial damage, this indicates a type 1 myocardial infarction (MI). If myocardial injury is not present, but clinical and electrocardiographic (ECG) findings indicate an unpredictable chest pain pattern, this is called unstable angina (UA). ACS can be further defined by the presence or absence of ST segment elevation on the ECG. In the appropriate clinical setting, the presence of significant regional ST elevations usually indicates ST-elevation myocardial infarction (STEMI) secondary to acute complete occlusion of the main pericardial coronary arteries, which, if untreated, results in transmural infarction. ACS without ST elevation (called non-ST elevation acute coronary syndrome (NSTE-ACS)) is usually associated with transient or partial coronary occlusion and more often results in a subendocardial MI, a non-ST elevation MI with minimal myocardial damage, or unstable angina with undetectable myocardial damage.

As used herein, the term "ST segment" on an electrocardiogram (ECG) encompasses the electrically neutral region of the complex between ventricular depolarization (QRS complex) and repolarization (T wave). In clinical terminology, the ST segment represents the period of time when the myocardium maintains contraction to expel blood from the ventricles. The ST segment represents an important feature of the ECG complex. It can show characteristic features that can help distinguish normal conditions from ischemic conditions (Kashou et al., ST Segment. [Updated 2023 Aug 14]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; January 2024, available from: www.ncbi.nlm.nih.gov/books/NBK459364/).

As used herein, the term "ST segment elevation" refers to a shift of the ST segment above baseline (ST elevation) when the J point is shifted above baseline. In the acute setting, ST elevation is recognized as a sign of occlusive thrombus. Early repolarization, LVH, ventricular aneurysm, left bundle branch block, and other conduction defects have been shown to be more common causes of ST elevation (compared to acute MI). It is also important to evaluate the waveform of the ST segment. The displacement of the J point can be further characterized as horizontal, upward sloping, or downward sloping; the latter two can be rapid or slow. For example, ST elevation in leads V1 and V2 can be described as a rapid downward slope, and in such cases, it is usually benign. These other characteristics of the ST segment can help distinguish between normal and ischemic conditions. For example, ST elevation with an upward tilt of the ST segment is generally considered normal, whereas ST elevation at the level of the ST segment is more characteristic of myocardial ischemia (see Kashou et al., supra).

As used herein, the term "cerebrovascular disorder" refers to a neurological problem caused by a disruption in blood flow to the brain, which causes brain cells to be damaged or die due to lack of oxygen. In some embodiments, a cerebrovascular disorder includes a transient ischemic attack. In some embodiments, a cerebrovascular disorder includes a stroke. How a stroke affects the body depends specifically on where in the brain the blood supply is cut off. In some embodiments, the cerebrovascular disorder is a vascular event that is usually categorized in a composite of various combinations, including ACM; CV death; MI; UA; "all strokes" or "any stroke" (ischemic, hemorrhagic, or unknown etiology); ischemic stroke; ALI; major vascular (non-invasive) limb resection; symptomatic VTE (PE, DVT); ischemia-driven coronary revascularization; intravascular stent thrombosis; hospitalization for any reason, for an arterial or venous thrombotic event, or neither.

In some embodiments, the term "stroke" refers to an acute onset of abnormal neurological function that results in the death of brain tissue (cerebral infarction) due to a lack of blood flow and oxygen to the brain. A stroke can be an ischemic or hemorrhagic stroke. In an ischemic stroke, the blood supply to a portion of the brain is cut off because a blood clot has blocked a blood vessel (due to a thrombus that has formed locally in an abnormal artery (e.g., atherosclerosis) or a thrombus that has formed upstream and traveled through the bloodstream). In a hemorrhagic stroke, a blood vessel ruptures, blocking normal blood flow and allowing blood to infiltrate an area of the brain, damaging the area. Most strokes start suddenly, develop rapidly, and cause brain damage within minutes (complete stroke). Less commonly, a stroke may continue to worsen over hours to days as the area of brain tissue death continues to expand (evolving stroke). Ischemic stroke can be lacunar or non-lacunar in nature. An ischemic stroke may be a cardioembolic ischemic stroke if the ischemic stroke is attributable to an artery occlusion caused by a thrombus that may have formed in the heart or on one of its valves. In some embodiments, the ischemic stroke is a non-cardioembolic ischemic stroke. Ischemic stroke is defined based on the 2013 guidelines (Sacco et al., An updated definition of stroke for the 21st century Stroke, 44 (2013), pp. 2064-2089).

In clinical trials, stroke severity was measured using the National Institutes of Health Stroke Scale (NIHSS) score (Kamel et al., Validation of the International Classification of Diseases, Tenth Revision Code for the National Institutes of Health Stroke Scale Score. Circ Cardiovasc Qual Outcomes, 2023, Vol. 16, e009215). Stroke severity was categorized as follows: 1 to 4 for mild stroke, 5 to 15 for moderate stroke, 16 to 20 for moderate to severe stroke, and 21 to 42 for severe stroke.

In some embodiments, ischemic stroke refers to neurological deficits attributable to non-lacunar acute cerebral infarction, which are detected by neuroimaging (CT or MRI) and are associated with clinical symptoms.

In some embodiments, "stroke" refers to any type of stroke (ischemic, hemorrhagic, or unknown etiology).

In some embodiments, ischemic stroke is further characterized by a National Institute of Health Stroke Score (NIHSS) ≤ 7.

In other embodiments, the ischemic stroke is further characterized by a National Institute of Health Stroke Score (NIHSS) of 8-15.

In other embodiments, the ischemic stroke is further characterized by a National Institute of Health Stroke Score (NIHSS) ≤15.

In other embodiments, another characteristic of ischemic stroke is the presence of atherosclerotic plaques, ulcers or thrombi in the supplying arteries of the relevant intracranial or carotid arteries as recorded by imaging (Doppler ultrasound or CTA or MRA or catheter angiography).

In yet other embodiments, ischemic stroke is further characterized by a modified Rankin Score. For example, in some embodiments, another feature of ischemic stroke is a modified Rankin Score (mRS) ≤3, ≤4, ≤5, or ≤6.

In some embodiments, MI is defined according to the 4th universal definition of MI (excluding type 2 MI) (Thygesen et al., Fourth universal definition of myocardial infarction (2018) Eur. Heart J., 40 (2019), pp. 237-269).

In some embodiments, cardiovascular death is coded when the primary cause of death is MI, stroke, thromboembolism in any other vascular bed, heart failure, primary arrhythmia, or a cardiovascular surgical procedure.

As used herein, the term "activated partial thromboplastin time (aPTT)" refers to a measure of the intrinsic and final common pathway of the coagulation cascade. It represents the time (in seconds) for plasma to clot after the addition of phospholipids (an intrinsic pathway activator) and calcium. The name "activated partial thromboplastin time) comes from the original form of the test, in which only the phospholipid concentration of the test was controlled (as opposed to the phospholipid and surfactant concentrations), and when the phospholipid preparation accelerates coagulation, but does not correct the long clotting time of hemophilic plasma, the name "partial thromboplastin" should be used. The term "partial" means that phospholipids are present, but tissue factors are not present. Normal and reference ranges vary depending on the reagent and instrument combination, especially the phospholipid composition.

In some embodiments, aPTT is measured as follows: plasma samples are incubated with an actin FS aPTT assay reagent containing a standard amount of phospholipids and a contact activator (ellagic acid) that activates the intrinsic coagulation pathway. After 3 minutes of incubation, calcium chloride is added to initiate coagulation and the formation of fibrin clots is measured optically. The time for clot formation (measured in seconds) is reported as the activated partial thromboplastin time (aPTT). In other embodiments, fibrin clot formation is measured by mechanical methods (viscosity).

Administration of various oral doses of milvithrin to healthy human subjects resulted in a dose-dependent and concentration-dependent prolongation of aPTT. After 2 weeks of dosing at 5 to 500 mg QD, the maximum mean change in aPTT relative to baseline was approximately 1.1 to 4.1-fold increase, and after 2 weeks of dosing at 200 mg BID, the maximum mean change in aPTT relative to baseline was 3.4-fold increase.

As used herein, the prothrombin time (PT) test is a measure of the length of time it takes for a clot to form in a blood sample and the test result of a PT analysis is referred to as the prothrombin time (in seconds). Single or multiple doses of Milvecine administered to human subjects did not affect the prothrombin time, with a maximum mean percent change from baseline of about 5%.

As used herein, "factor XI clotting activity" is determined using an aPTT-based 1-stage clotting time assay. Serial dilutions of normal pooled plasma are mixed with FXI-depleted plasma, and clotting times are measured according to the standard aPTT protocol to determine a reference range. Individual test plasma is processed in the same manner and compared to reference plasma.

In some embodiments, factor XI coagulation activity is measured as follows: Factor XI (FXI) activity is measured using actin FS (Siemens Healthcare) on a Siemens BCS® XP analyzer using a correction for the activated partial thromboplastin time (aPTT). A 6-point calibration curve (about 5% to 150%) is prepared using a secondary calibrator (standard human plasma, Siemens Healthcare Diagnostics Inc.) and known concentrations of human FXI specified by the manufacturer. A pre-selected FXI calibration level is generated by diluting about 100% of the reference standard in saline by the ^BCS® XP analyzer. A calibration curve is plotted with FXI activity (percentage (%) on the x-axis and clotting time (seconds) on the y-axis. A logarithmic/linear regression curve fit is used. The sample to be tested is mixed with plasma lacking FXI (containing less than 1% FXI and at least 75% of all other factors) to standardize all other factors. APTT reagent (actin FS) is added and the mixture is incubated. After incubation, calcium chloride is added to the mixture and the time of clot formation (measured optically) is compared to the time on the calibration curve. The samples are prepared and tested in basic dilution (1:10) by BCS ^® XP in physiological saline. In other embodiments, the formation of fibrin clots is measured by mechanical methods (viscosity).

As used herein, "thrombin generation assay (TGA)" is a global coagulation assay that assesses the thrombogenicity of a plasma sample and has been proposed to better reflect prothrombotic or hemorrhagic states than conventional coagulation assays. In traditional TGA, clotting of citrated plasma is initiated via the extrinsic pathway by the addition of tissue factor, phospholipids, and calcium. For this study, clotting was initiated via the contact activation pathway, using kaolin slurry instead, in an in vitro thrombin generation assay (TGA) using human platelet-rich plasma. Thrombin generation was continuously monitored by the products released by cleavage of a thrombin-specific fluorescent substrate. The resulting thrombinogram is used to determine a number of relevant parameters, including endogenous thrombin potential, which is defined as the area under the thrombin concentration versus time curve. In some embodiments, administration of a single dose or multiple oral doses of milvicin to a human subject is capable of inhibiting thrombin generation occurring via the intrinsic pathway, but only minimally inhibiting thrombin generation initiated by the extrinsic pathway.

As used herein, "prevention" refers to reducing the risk of occurrence. In some embodiments, prevention covers eliminating the risk of occurrence (i.e., reducing the risk of occurrence to zero). Therefore, "prevention" covers preventive treatments that are intended to reduce the probability of occurrence of a clinical disease state. In some embodiments, the treatment regimens described herein are administered to patients at risk for developing thromboembolic disease to prevent occlusive thrombosis (primary prevention). In some embodiments, after an initial thrombotic event, the treatment regimens described herein are administered to patients to achieve secondary prevention, for example, secondary prevention of cardiovascular events in patients with a history of acute myocardial infarction or acute coronary syndrome. In a clinical setting, aspirin can be used in combination with clopidogrel (or other thienopyridines) to prevent a second thrombotic event.

In some embodiments, "prevention" is synonymous with "reduced risk" or "reduced incidence" of an adverse atherosclerotic event (e.g., MACE). Reducing the risk or reducing the incidence means that the occurrence of an adverse atherosclerotic event is numerically and/or statistically significantly reduced or decreased by at least 1% or greater. Preferably, the reduction is 2% or greater, 3% or greater, 4% or greater, 5% or greater, 6% or greater, 7% or greater, 10% or greater, 20% or greater, 26% or greater, 34% or greater, 50% or greater, 64% or greater, and 74% or greater. Such reductions include confidence intervals of equal to or greater than 50%, equal to or greater than 75%, equal to or greater than 80%, equal to or greater than 90%, equal to or greater than 95%, equal to or greater than 98%, and equal to or greater than 99%. A confidence interval equal to or greater than 95% is preferred.

Within the scope of this disclosure, "prevention" is protective treatment of a disease state by administering to a patient a therapeutically effective amount of miltvicin or a pharmaceutically acceptable salt or solvent thereof to reduce and/or minimize the risk of the disease state and/or reduce the risk of recurrence of the disease state. Patients may be selected for preventive treatment based on factors known to increase the risk of developing a clinical disease state (compared to the general population). For preventive treatment, symptoms of the clinical disease state may or may not have yet been presented. "Preventive" treatment can be divided into (a) primary prevention and (b) secondary prevention. Primary prevention is defined as treatment that reduces or minimizes the risk of developing a disease state in a patient who does not yet have the disease state, while secondary prevention is defined as treatment that minimizes or reduces the risk of recurrence or secondary occurrence of the same or similar disease state.

As used herein, the term "treating" refers to relieving the signs or symptoms of a disease or condition in a patient and/or preventing a disease or condition in a patient. Unless otherwise indicated, as used herein, the terms "treating," "treatment," and similar terms shall include the management and care of a patient for the purpose of combating a disease, condition, or disorder, and include the administration of Milvecin to prevent the onset of symptoms or complications, to alleviate symptoms or complications, or to eliminate a disease, condition, or disorder. Thus, "treating" or "treatment" encompasses the treatment of a disease state in a human and includes: (a) inhibiting the disease state, i.e., arresting its development; and/or (b) relieving the disease state, i.e., causing regression of the disease state.

As used herein, a "risk factor" is a demographic factor that, independent of any medication, influences the potential risk for an event.

As used herein, the term "thrombotic event" refers to adverse cerebrovascular and/or cardiovascular events occurring in patients with acute coronary syndrome. In some embodiments, thrombotic events include severe adverse cardiovascular events (MACE), atherothrombosis, ischemic stroke, myocardial infarction, cardiovascular death, arrhythmogenic cardiomyopathy, severe adverse vascular events (MAVE), severe adverse limb events (MALE), all-cause death (ACM), symptomatic VTE or a combination thereof. In some embodiments, thrombotic events include severe adverse cardiovascular events. In some embodiments, thrombotic events include ischemic stroke. In some embodiments, thrombotic events include severe adverse vascular events. In some embodiments, thrombotic events include arrhythmogenic cardiomyopathy. In some embodiments, thrombotic events include severe adverse limb events (MALE).

As used herein, the term "atherosclerotic event" refers to major adverse cardiovascular events (MACE), major adverse vascular events (MAVE), arrhythmogenic cardiomyopathy, major adverse limb events (MALE), or a combination thereof.

As used herein, the term "major adverse cardiovascular event" or "MACE" refers to cardiovascular death, non-fatal myocardial infarction, ischemic stroke, or a combination thereof.

As used herein, the term "major adverse vascular event" or "MAVE" refers to cardiovascular death, non-fatal myocardial infarction, ischemic stroke, MALE, symptomatic VTE, or a combination thereof.

As used herein, the term "major adverse limb event" or "MALE" refers to acute limb ischemia (ALI), major noninvasive vascular resection, or a combination thereof.

As used herein, the term "symptomatic VTE" refers to pulmonary embolism, deep venous embolism, or a combination thereof.

As used herein, "pharmaceutically acceptable salts" refer to derivatives in which a compound is modified by preparing its acidic or basic salt. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic groups such as amines; and alkali metal or organic salts of acidic groups such as carboxylic acids. Pharmaceutically acceptable salts include known non-toxic salts or quaternary ammonium salts of the parent compound with, for example, non-toxic inorganic or organic acids. For example, such conventionally known non-toxic salts include salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid and nitric acid, and salts prepared from organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamine, benzoic acid, salicylic acid, p-aminobenzenesulfonic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid and hydroxyethylsulfonic acid. Pharmaceutically acceptable salts of miltiochloride can be synthesized using conventional chemical methods. Generally, such salts can be prepared by reacting miltiorrhiza with a stoichiometric amount of an appropriate base or acid in water or in an organic solvent or in a mixture of the two; generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences 18th edition, Mack Publishing Company, Easton, Pa. (1990), the disclosure of which is incorporated herein by reference.

As used herein, the term "standard of care" refers to a treatment method that is generally recognized by medical experts and widely used by health care professionals as an appropriate treatment for a certain type of disease (e.g., acute coronary syndrome). In some embodiments, standard of care includes antiplatelet therapy for patients diagnosed with acute coronary syndrome. In some embodiments, the antiplatelet therapy is selected from single antiplatelet therapy (SAPT), dual antiplatelet therapy (DAPT) or a combination thereof. In some embodiments, SAPT is selected from aspirin and a P2Y12 inhibitor. In some embodiments, SAPT includes low-dose aspirin (≤100 mg per day) or a P2Y12 inhibitor. In some embodiments, SAPT comprises aspirin. In some embodiments, SAPT comprises a P2Y12 inhibitor. In some embodiments, the P2Y12 inhibitor (alone or in combination with aspirin) is clopidogrel, ticagrelor, or prasugrel. In some embodiments, the P2Y12 inhibitor may be replaced or discontinued. In some embodiments, the step-down of antiplatelet therapy from DAPT to SAPT may reduce aspirin or P2Y12 inhibitor.

As used herein, "safe" means that the treatment regimen achieves a net clinical benefit such that the reduced risk of atherosclerotic events in humans outweighs the increased risk of adverse events (e.g., major bleeding) compared to antiplatelet therapy alone, as determined by regulatory agencies.

As used herein, "effective" means that the treatment regimen achieves a reduction in the risk and treatment of atherosclerotic events compared to antiplatelet therapy alone.

The absolute risk reduction (ARR) is the percentage of patients with an adverse outcome in the control group (i.e., the group that did not receive the treatment regimen) minus the percentage of patients with an adverse outcome in the treatment group (i.e., the group that received the treatment regimen). For example, if the incidence rate in the control group is 20% (i.e., if 20% of the patients in the control group experienced an adverse outcome) and the incidence rate in the treatment group is 12% (i.e., 12% of the patients experienced an adverse outcome), the absolute risk reduction (ARR) is 8% (i.e., 20% - 12%).

In some embodiments, the Bleeding Academic Research Consortium (BARC) criteria are described in Roxana Mehran et al., Standardized Bleeding Definitions for Cardiovascular Clinical Trials, Circulation . 2011;123:2736-2747, which is incorporated herein by reference.

In other embodiments, the Bleeding Academic Research Consortium (BARC) criteria are described in Pascal Vranckx et al., Validation of BARC Bleeding Criteria in Patients With Acute Coronary Syndromes J Am Coll Cardiol 2016;67:2135-44, which is incorporated herein by reference.

In some embodiments, the GUSTO criteria are described in "An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction." The GUSTO investigators. N Engl J Med 1993;329:673-82, which is incorporated herein by reference.

In some embodiments, the GUSTO criteria are described in Pascal Vranckx et al., Validation of BARC Bleeding Criteria in Patients With Acute Coronary Syndromes J Am Coll Cardiol 2016;67:2135-44, which is incorporated herein by reference.

In some embodiments, the TIMI criteria are described in Rao AK, Pratt C, Berke A, et al., Thrombolysis in Myocardial Infarction (TIMI) Trial—phase I: hemorrhagic manifestations and changes in plasma fibrinogen and the fibrinolytic system in patients treated with recombinant tissue plasminogen activator and streptokinase. J Am Coll Cardiol 1988;11: 1-11, which is incorporated herein by reference.

In some embodiments, the TIMI criteria are described in Pascal Vranckx et al., Validation of BARC Bleeding Criteria in Patients With Acute Coronary Syndromes J Am Coll Cardiol 2016;67:2135-44, which is incorporated herein by reference.

In some embodiments, the "Bleeding Academic Research Consortium (BARC) Type 3 criteria" are: a. Overt bleeding plus a decrease in hemoglobin of 3 to <5 g/dL (with the limitation that the decrease in hemoglobin is associated with bleeding); blood transfusion with overt bleeding; b. Overt bleeding plus a decrease in hemoglobin of ≥ 5 g/dL (with the limitation that the decrease in hemoglobin is associated with bleeding); cardiac tamponade; bleeding requiring surgical intervention to control; bleeding requiring IV vasopressors; or c. Intracranial hemorrhage confirmed by autopsy, imaging, or lumbar puncture; intraocular hemorrhage that impairs vision. See, e.g., Roxana Mehran et al., Standardized Bleeding Definitions for Cardiovascular Clinical Trials, Circulation . 2011;123:2736-2747.

In some embodiments, the "Bleeding Academic Research Consortium (BARC) Type 5 criteria" are: a. Potentially fatal bleeding; or b. Certainly fatal bleeding (obvious or confirmed by autopsy or imaging). See, e.g., Roxana Mehran et al., Standardized Bleeding Definitions for Cardiovascular Clinical Trials, Circulation . 2011; 123: 2736-2747.

In some embodiments, the "Bleeding Academic Research Consortium (BARC) Type 2 criteria" are: any clinically significant sign of bleeding is "actionable" and requires diagnostic investigation, hospitalization, or treatment by a healthcare professional. See, e.g., Roxana Mehran et al., Standardized Bleeding Definitions for Cardiovascular Clinical Trials, Circulation . 2011;123:2736-2747.

In some embodiments, the "ISTH criteria (severe bleeding or clinically relevant non-severe bleeding (CRNM)) criteria" are as follows: ISTH severe bleeding in non-surgical patients is defined as symptomatic presentation and: i. life-threatening bleeding, and/or ii. bleeding into critical areas or organs, such as intracranial, intraspinal, intraocular, retroperitoneal, intra-articular, or pericardial or intramuscular bleeding with compartment syndrome, and/or iii. bleeding resulting in a drop in hemoglobin of 20 g L ^-1 (1.24 mmol L ^-1 ) or more, or bleeding resulting from the transfusion of two or more units of whole blood or red blood cells ISTH CRNM bleeding is any sign or symptom of bleeding (e.g., bleeding in excess of that expected in the clinical setting, including bleeding detected by imaging alone) that does not meet the ISTH definition of severe bleeding but meets at least one of the following criteria: i. Requires medical intervention by a health care professional ii. Resulted in hospitalization or escalation of care iii. Prompts a face-to-face (i.e., not just telephone or electronic communication) assessment

It should be understood that when referring to, for example, amount, duration, extent of action and the like, approximate terms such as "substantially" or "about" may mean that a value is within 0% greater than or less than a specific value (that is, the value may be a specific value), a value is within 5% greater than or less than a specific value, or within 7.5% greater than or less than a specific value, or within 10% greater than or less than a specific value, or within 12.5% greater than or less than a specific value, or within 15% greater than or less than a specific value, or within 17.5% greater than or less than a specific value, or within 20% greater than or less than a specific value.

In some aspects, the disclosure relates to a method for preventing adverse cerebrovascular events or adverse cardiovascular events in a human patient suffering from acute coronary syndrome (ACS), wherein the method comprises: measuring the patient's baseline FXI coagulation activity, and then administering to the human patient a treatment regimen comprising: (i) a pharmaceutical composition comprising 25 mg of miltiorrhiza (or a pharmaceutically acceptable salt or solvent thereof); and (ii) an antiplatelet therapy selected from the group consisting of aspirin, a P2Y12 inhibitor, and a combination thereof; wherein the pharmaceutical composition is administered twice daily.

In some embodiments, the methods of the present disclosure relate to the primary prevention of adverse cerebrovascular events or adverse cardiovascular events.

In some embodiments, the methods of the present disclosure relate to secondary prevention of adverse cerebrovascular events or adverse cardiovascular events.

In some embodiments of the disclosed methods, the adverse cerebrovascular event or adverse cardiovascular event comprises one or more of stroke, heart attack, or death.

In some embodiments of the disclosed methods, the adverse cerebrovascular event or adverse cardiovascular event occurs in an organ selected from the group consisting of the heart, brain, limbs, blood supply system, or blood vessels.

In some embodiments of the disclosed methods, the adverse cerebrovascular event or adverse cardiovascular event comprises one or more major adverse cardiovascular events (MACE) selected from the group consisting of cardiovascular death, non-fatal myocardial infarction, ischemic stroke, and combinations thereof.

In other embodiments of the disclosed methods, the adverse cerebrovascular event or adverse cardiovascular event comprises one or more major adverse vascular events (MAVE) selected from the group consisting of: MACE, major adverse limb events (MALE), including one or more selected from acute limb ischemia, chronic limb ischemia, or major resection; symptomatic venous thromboembolic events, and combinations thereof.

In some embodiments of the disclosed methods, the adverse cerebrovascular event or adverse cardiovascular event is selected from the group consisting of arrhythmogenic cardiomyopathy (ACM), non-fatal myocardial infarction, ischemic stroke, and combinations thereof.

In some embodiments of the disclosed methods, the adverse cerebrovascular event or adverse cardiovascular event comprises cardiovascular death.

In some embodiments of the disclosed methods, the adverse cerebrovascular event or adverse cardiovascular event comprises arrhythmogenic cardiomyopathy (ACM).

In some aspects, the disclosure relates to methods for treating or preventing adverse cerebrovascular events or adverse cardiovascular events in a human patient suffering from acute coronary syndrome.

In some embodiments, the acute coronary syndrome is ST-segment elevation myocardial infarction (STEMI), non-ST-segment elevation acute coronary syndrome (NSTEM-ACS), non-ST-segment elevation myocardial infarction (NSTEMI), or unstable angina. In some embodiments, the acute coronary syndrome comprises ST-segment elevation myocardial infarction. In some embodiments, the acute coronary syndrome comprises non-ST-segment elevation acute coronary syndrome. In some embodiments, the acute coronary syndrome comprises non-ST-segment elevation myocardial infarction. In some embodiments, the acute coronary syndrome comprises unstable angina.

In some embodiments, the human patient suffers from NSTEM-ACS without atrial flutter. In some embodiments, the antiplatelet therapy comprises 150 mg to 300 mg of aspirin as an initial dose, followed by 75 mg to 100 mg of aspirin monotherapy once daily as a maintenance dose. In some embodiments, the maintenance dose of aspirin may be administered for a period ranging from 3 months to 3 years. In some embodiments, the maintenance dose of aspirin may be administered for a period ranging from 3 months to 1 year. In some embodiments, the maintenance dose of aspirin may be administered for a period of 1 year. In some embodiments, the antiplatelet therapy comprises aspirin and a P2Y12 inhibitor.

In some embodiments, the human patient suffers from NSTEM-ACS and atrial fibrillation.

In some embodiments, the human patient is female. In other embodiments, the human patient is male.

In some embodiments, the human patient is at least 40 years old.

In other embodiments, the human patient is at least 50 years old.

In other embodiments, the human patient is at least 60 years old.

In other embodiments, the human patient is at least 70 years old.

In some embodiments, the methods of the present disclosure comprise administering to a human patient a treatment regimen comprising: (i) a pharmaceutical composition comprising 25 mg of melvian (or a pharmaceutically acceptable salt or solvent thereof) or comprising 12.5 mg to 200 mg of melvian (or a pharmaceutically acceptable salt or solvent thereof); and (ii) an antiplatelet therapy selected from the group consisting of aspirin, a P2Y12 inhibitor, and a combination thereof.

In some embodiments, the methods of the present disclosure comprise administering to a human patient a treatment regimen comprising: (i) a pharmaceutical composition comprising 25 mg of miltiorrhiza (or a pharmaceutically acceptable salt or solvent thereof) twice daily; and (ii) an antiplatelet therapy selected from the group consisting of aspirin, a P2Y12 inhibitor, and combinations thereof.

In some embodiments, the pharmaceutical composition comprises milvicin.

In some embodiments, the pharmaceutical composition comprises a solvent complex of miltvicin.

In other embodiments, the pharmaceutical composition comprises a pharmaceutically acceptable salt of miltvicin.

In embodiments of the disclosed methods in which the pharmaceutical composition comprises a solvent or a pharmaceutically acceptable salt of melvian, the amount is then described based on melvian. That is, the amount of solvent or pharmaceutically acceptable salt in the pharmaceutical composition contains a specified amount of melvian. For example, a pharmaceutical composition comprising 25 mg of melvian (or a pharmaceutically acceptable salt or solvent thereof) refers to a pharmaceutical composition comprising 25 mg of melvian or an amount of a pharmaceutically acceptable salt or solvent of melvian equivalent to 25 mg of melvian.

In some embodiments of the disclosed methods, the treatment regimen comprises administering a pharmaceutical composition comprising 12.5 mg of milvithin (or a pharmaceutically acceptable salt or solvent thereof) twice daily.

In some embodiments of the disclosed methods, the treatment regimen comprises administering a pharmaceutical composition comprising 25 mg of milvithin (or a pharmaceutically acceptable salt or solvent thereof) twice daily.

In some embodiments of the disclosed methods, the treatment regimen comprises administering a pharmaceutical composition comprising 50 mg of milvithin (or a pharmaceutically acceptable salt or solvent thereof) twice daily.

In some embodiments of the disclosed methods, the treatment regimen comprises administering a pharmaceutical composition comprising 100 mg of milvithin (or a pharmaceutically acceptable salt or solvent thereof) twice daily.

In some embodiments of the disclosed methods, the treatment regimen comprises administering a pharmaceutical composition comprising 12.5 mg to 200 mg of milvicin (or a pharmaceutically acceptable salt or solvent thereof) twice daily.

In some embodiments of the disclosed methods wherein a composition comprising melvian (or a pharmaceutically acceptable salt or solvent thereof, based on melvian) is administered to a human patient, one of the two administrations is performed in the morning and the other of the two administrations is performed in the evening, and the administrations are performed at approximately the same time each day.

In some aspects of the disclosed methods, the pharmaceutical composition comprising melvian (or a pharmaceutically acceptable salt or solvent thereof, based on melvian) is administered twice daily for at least 12 weeks.

In some aspects of the disclosed methods, the pharmaceutical composition comprising melvian (or a pharmaceutically acceptable salt or solvent thereof, based on melvian) is administered twice daily for at least 13 weeks.

In some embodiments, the pharmaceutical composition comprising melvian (or a pharmaceutically acceptable salt or solvent thereof, based on melvian) is administered twice daily for 13 weeks.

In other embodiments, the pharmaceutical composition comprising melvian (or a pharmaceutically acceptable salt or solvent thereof, based on melvian) is administered twice daily for more than 13 weeks.

In other embodiments, the pharmaceutical composition comprising melvian (or a pharmaceutically acceptable salt or solvent thereof, based on melvian) is administered twice daily for at least 26 weeks, at least 52 weeks, at least 78 weeks, at least 104 weeks, at least 130 weeks, at least 156 weeks, at least 182 weeks, or at least 208 weeks.

In some embodiments, a pharmaceutical composition comprising melvian (or a pharmaceutically acceptable salt or solvent thereof, based on melvian) is administered twice daily for a long term (ie, indefinitely).

In some aspects, the treatment regimen used in the disclosed methods comprises administering an antiplatelet therapy selected from the group consisting of aspirin, a P2Y12 inhibitor, and combinations thereof.

In some embodiments of the disclosed methods, the antiplatelet therapy comprises single antiplatelet therapy (SAPT).

In some embodiments of the disclosed methods, the antiplatelet therapy comprises dual antiplatelet therapy (DAPT).

In some embodiments, the antiplatelet therapy comprises dual antiplatelet therapy (DAPT) for 21 days followed by single antiplatelet therapy (SAPT).

In some embodiments of the disclosed methods, the treatment regimen comprises aspirin and clopidogrel combination therapy from day 1 to day 21, followed by at least 90 days of aspirin monotherapy.

In some embodiments of the disclosed methods, the treatment regimen comprises aspirin and clopidogrel combination therapy from day 1 to day 21, followed by aspirin monotherapy from day 22 to day 90.

In some embodiments of the disclosed methods, the treatment regimen comprises DAPT for >90 days (with or without downgrading to SAPT).

In some embodiments of the disclosed methods, the treatment regimen comprises DAPT for >90 days (stepped down to SAPT).

In other embodiments of the disclosed methods, the treatment regimen comprises DAPT for >90 days (without downgrading to SAPT).

In some embodiments of the disclosed methods, the treatment regimen comprises DAPT for ≤ 90 days and step-down to SAPT.

In some embodiments of the disclosed methods, the treatment regimen comprises SAPT.

In some embodiments of the disclosed methods, the treatment regimen comprises administering aspirin and/or clopidogrel without adjusting the dosage of miltavidin.

In some embodiments, the single antiplatelet therapy is aspirin.

In some embodiments of single antiplatelet therapy, aspirin is administered in an amount of 50 to 150 mg per day, such as one of 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 81 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, or 150 mg per day.

In some embodiments of single antiplatelet therapy, aspirin is administered in an amount of 75 to 100 mg per day, such as one of the following: 75 mg, 80 mg, 81 mg, 85 mg, 90 mg, 95 mg, or 100 mg per day.

In some embodiments of single antiplatelet therapy, aspirin is administered in an amount of 75 mg per day.

In some embodiments of single antiplatelet therapy, aspirin is administered in an amount of 81 mg per day.

In some embodiments of single antiplatelet therapy, aspirin is administered in an amount of 100 mg per day.

In other embodiments, the single antiplatelet therapy is a P2Y12 inhibitor.

In some embodiments of single antiplatelet therapy, the P2Y12 inhibitor is clopidogrel, ticagrelor, or prasugrel.

In some embodiments of single antiplatelet therapy, the P2Y12 inhibitor is clopidogrel.

In some embodiments of single antiplatelet therapy, clopidogrel is administered in an amount of 75 mg to 600 mg per day, such as one of the following: 75 mg, 150 mg, 225 mg, 300 mg, 375 mg, 450 mg, 525 mg, or 600 mg per day.

In some embodiments of single antiplatelet therapy, the P2Y12 inhibitor is ticagrelor.

In some embodiments of single antiplatelet therapy, the P2Y12 inhibitor is prasugrel.

In some embodiments, the single antiplatelet therapy is ticlopidine.

In some embodiments, ticlopidine is administered in an amount of 250 to 500 mg per day, such as 150 mg or 500 mg per day.

In other embodiments of the disclosed methods, the antiplatelet therapy comprises dual antiplatelet therapy.

In some embodiments, the dual antiplatelet therapy is aspirin and ticlopidine.

In some embodiments, the dual antiplatelet therapy is aspirin and a P2Y12 inhibitor.

In some embodiments of dual antiplatelet therapy, aspirin is administered in an amount of 50 to 150 mg per day, such as one of 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 81 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, or 150 mg per day.

In some embodiments of dual antiplatelet therapy, aspirin is administered in an amount of 75 to 100 mg per day, such as one of the following: 75 mg, 80 mg, 81 mg, 85 mg, 90 mg, 95 mg, or 100 mg per day.

In some embodiments of dual antiplatelet therapy, aspirin is administered in an amount of 75 mg per day.

In some embodiments of dual antiplatelet therapy, aspirin is administered in an amount of 81 mg per day.

In some embodiments of dual antiplatelet therapy, aspirin is administered in an amount of 100 mg per day.

In some embodiments of dual antiplatelet therapy, the P2Y12 inhibitor is clopidogrel, ticagrelor, or prasugrel.

In some embodiments of dual antiplatelet therapy, the P2Y12 inhibitor is clopidogrel.

In some embodiments of dual antiplatelet therapy, clopidogrel is administered in an amount of 75 mg to 600 mg per day, such as one of the following: 75 mg, 150 mg, 225 mg, 300 mg, 375 mg, 450 mg, 525 mg, or 600 mg per day.

In some embodiments of dual antiplatelet therapy, clopidogrel is administered as a starting dose. The starting dose is administered once at the beginning of treatment.

In some embodiments, the starting dose is between 300 and 600 mg per day. In some embodiments, the starting dose is 300 mg. In other embodiments, the starting dose is 600 mg.

In some embodiments of dual antiplatelet therapy, clopidogrel is administered in an amount of 75 mg per day.

In some embodiments of dual antiplatelet therapy, clopidogrel is administered in an amount of 150 mg per day.

In some embodiments of dual antiplatelet therapy, clopidogrel is administered in an amount of 225 mg per day.

In some embodiments of dual antiplatelet therapy, clopidogrel is administered in an amount of 300 mg per day.

In some embodiments of dual antiplatelet therapy, clopidogrel is administered in an amount of 375 mg per day.

In some embodiments of dual antiplatelet therapy, clopidogrel is administered in an amount of 450 mg per day.

In some embodiments of dual antiplatelet therapy, clopidogrel is administered in an amount of 525 mg per day.

In some embodiments of dual antiplatelet therapy, clopidogrel is administered in an amount of 600 mg per day.

In some embodiments, the antiplatelet therapy is a dual antiplatelet therapy (DAPT) comprising aspirin 75 to 100 mg QD and a P2Y12 inhibitor. In some embodiments, the antiplatelet therapy is a single antiplatelet therapy (SAPT). In some embodiments, the method comprises administering an antiplatelet therapy consisting mainly of a dual antiplatelet therapy and a single antiplatelet therapy. In some embodiments, the antiplatelet therapy comprises DAPT.

In some embodiments, DAPT comprises aspirin and prasugrel. In some embodiments, DAPT comprises aspirin and prasugrel administered for 12 months.

In some embodiments, DAPT comprises aspirin and clopidogrel. In some embodiments, aspirin and clopidogrel are administered for 21 days to 12 months. In some embodiments, DAPT comprises aspirin and clopidogrel. In some embodiments, aspirin and clopidogrel are administered for 21 days. In some embodiments, aspirin and clopidogrel are administered for 6 months. In some embodiments, aspirin and clopidogrel are administered for 12 months.

In some embodiments, DAPT comprises aspirin and ticagrelor. In some embodiments, DAPT comprises aspirin and ticagrelor administered for 12 months. In some embodiments, DAPT comprises first administering aspirin 75 to 100 mg QD and a P2Y12 inhibitor for 12 months, followed by aspirin monotherapy for 6 to 12 months.

In some embodiments, DAPT comprises first administering aspirin 75 to 100 mg QD and a P2Y12 inhibitor for 21 days, followed by administration of aspirin monotherapy for 6 months.

In some embodiments, DAPT comprises first administering aspirin 75 to 100 mg QD and a P2Y12 inhibitor for 21 days, followed by administration of aspirin monotherapy for 12 months.

In some embodiments, DAPT comprises first administering aspirin 75 to 100 mg QD and clopidogrel 75 mg QD for 21 days, followed by administration of aspirin monotherapy for 6 months.

In some embodiments, DAPT comprises administering aspirin 75-100 mg QD and ticagrelor 90 mg BID for 12 months first, followed by administering aspirin 75-100 mg QD for 12 months.

In some embodiments, DAPT comprises administering aspirin 75-100 mg QD and ticagrelor 90 mg BID for 12 months first, followed by administering ticagrelor 90 mg BID for 23 months.

In some embodiments, DAPT comprises aspirin 75-100 mg QD and 75 mg ticagrelor BID. In some embodiments, aspirin 75-100 mg QD and 75 mg ticagrelor BID are administered for 12 months.

In some embodiments, DAPT comprises aspirin 81-100 mg QD and 90 mg ticagrelor BID. In some embodiments, aspirin 81-100 mg QD and 90 mg ticagrelor BID are administered for 3 years.

In some embodiments, the antiplatelet therapy comprises administration of aspirin for 30 to 90 days followed by administration of clopidogrel monotherapy. In some embodiments, the antiplatelet therapy comprises administration of aspirin for 60 days followed by administration of clopidogrel monotherapy. In some embodiments, the antiplatelet therapy comprises administration of aspirin for 90 days followed by administration of clopidogrel monotherapy.

In some embodiments, the antiplatelet therapy comprises SAPT.

In some embodiments, SAPT comprises aspirin. In some embodiments, aspirin monotherapy is administered once daily. In some embodiments, aspirin monotherapy is administered once daily for 3 months to 3 years. In some embodiments, aspirin monotherapy is administered once daily for 3 months. In some embodiments, aspirin monotherapy is administered once daily for 6 months. In some embodiments, aspirin monotherapy is administered once daily for 12 months. In some embodiments, aspirin monotherapy is administered once daily for 24 months. In some embodiments, aspirin monotherapy is administered once daily for 36 months. In some embodiments, aspirin monotherapy is administered twice daily.

In some embodiments, SAPT comprises a P2Y12 inhibitor. In some embodiments, the P2Y12 inhibitor is selected from prasugrel, clopidogrel, selatogrel, or ticagrelor. In some embodiments, the P2Y12 inhibitor is administered as a monotherapy for 3 to 6 months.

In some embodiments, SAPT comprises clopidogrel. In some embodiments, SAPT comprises ticagrelor. In some embodiments, SAPT comprises ticagrelor monotherapy followed by aspirin 20 mg twice daily.

In some embodiments, SAPT comprises aspirin 75 to 100 mg QD. In some embodiments, aspirin 75 to 100 mg QD is administered for 12 months.

In some embodiments, SAPT comprises ticagrelor 90 mg BID. In some embodiments, ticagrelor 90 mg BID is administered for 3 years.

In some embodiments, SAPT comprises clopidogrel. In some embodiments, aspirin monotherapy is administered first, followed by clopidogrel monotherapy for at least another 2 months.

In some aspects, the present disclosure relates to a method for preventing adverse cardiovascular events in a human patient diagnosed with acute coronary syndrome, wherein the method comprises administering to the human patient a treatment regimen comprising: (i) a pharmaceutical composition comprising 25 mg of milvithin (or a pharmaceutically acceptable salt or solvent thereof) and one or more pharmaceutically acceptable formulations, and (ii) an antiplatelet therapy selected from the group consisting of aspirin, a P2Y12 inhibitor, and combinations thereof; wherein the pharmaceutical composition is administered twice daily; and wherein the adverse cardiovascular event is selected from one or more of the group consisting of: all-cause death (all-cause mortality; ACM); cardiovascular (CV) death; myocardial infarction (MI); unstable angina (UA); "all strokes" or "any stroke" (ischemic, hemorrhagic, or of unknown etiology); ischemic stroke; acute limb ischemia (ALI); major vascular (non-invasive) limb resection; symptomatic venous thromboembolism (VTE: (pulmonary embolism (PE), deep venous embolism (DVT))); ischemia-driven coronary revascularization; intravascular stent thrombosis; hospitalization for any reason, categorized as (1) planned or unplanned, (2) due to arterial or venous thrombotic events or neither; and transient ischemic attack (TIA).

In other embodiments of such methods, the adverse cardiovascular event is one or more of CV death, MI, or ischemic stroke.

In some aspects, the disclosure relates to a method for reducing the incidence of one or more adverse thrombotic events selected from new ischemic stroke, MI, or all-cause death in a human patient diagnosed with acute coronary syndrome, wherein the method comprises administering to the human patient a treatment regimen comprising: (i) a pharmaceutical composition comprising about 25 mg to about 100 mg of miltiorrhiza (or a pharmaceutically acceptable salt or solvent thereof) and one or more pharmaceutically acceptable formulations, and (ii) an antiplatelet therapy selected from the group consisting of aspirin, a P2Y12 inhibitor, and combinations thereof; wherein the treatment regimen is administered twice daily.

In some embodiments of such methods, administration of the treatment regimen produces a relative risk of 0.85 or less relative to the placebo group, such as a relative risk of 0.85, 0.84, 0.83, 0.82, 0.81, 0.8, 0.79, 0.78, 0.77, 0.76, 0.75, 0.74, 0.73, 0.72, 0.71, or 0.7 relative to the placebo group.

In other aspects, the disclosure relates to a method for preventing ischemic stroke in a human patient diagnosed with acute coronary syndrome, wherein the method comprises administering to the human patient a treatment regimen comprising: (i) a pharmaceutical composition comprising 25 mg of miltvicin (or a pharmaceutically acceptable salt or solvent thereof) and one or more pharmaceutically acceptable formulations, and (ii) an antiplatelet therapy selected from the group consisting of aspirin, a P2Y12 inhibitor, and combinations thereof; wherein the pharmaceutical composition is administered twice daily.

In some embodiments of such methods, the clinical benefit of the treatment regimen in reducing the incidence of clinical ischemic stroke is maintained throughout the 90-day treatment period.

In some embodiments of the disclosed methods, the patient's baseline FXI coagulation activity is measured. As used herein, the term "baseline FXI coagulation activity" refers to the patient's FXI coagulation activity prior to administration of a treatment regimen comprising a pharmaceutical composition containing miltvicin (or a pharmaceutically acceptable salt or solvent thereof).

In some embodiments, factor XI (FXI) activity is measured using actin FS (Siemens Healthcare) on a Siemens ^BCS® XP analyzer using a correction for the activated partial thromboplastin time (aPTT). A 6-point calibration curve (about 5% to 150%) is prepared using a secondary calibrator (standard human plasma, Siemens Healthcare Diagnostics Inc.) and known concentrations of human FXI specified by the manufacturer. A pre-selected FXI calibration level is generated by diluting about 100% of the reference standard in saline using the ^BCS® XP analyzer. A calibration curve is plotted with FXI activity (percentage (%) on the x-axis and clotting time (seconds) on the y-axis. A logarithmic/linear regression curve fit is used. The sample to be tested is mixed with plasma lacking FXI (containing less than 1% FXI and at least 75% of all other factors) to standardize all other factors. APTT reagent (actin FS) is added and the mixture is incubated. After incubation, calcium chloride is added to the mixture and the time of clot formation (measured optically) is compared to the time on the calibration curve. The samples are prepared and tested in basic dilution (1:10) by BCS ^® XP in physiological saline. In other embodiments, the formation of fibrin clots is measured by mechanical methods (viscosity).

In some embodiments of the methods of the disclosure, administration of the treatment regimen results in a decrease in the patient's FXI coagulation activity by about 7% to about 70% relative to baseline.

In other aspects, in the methods of the present disclosure, administration of the treatment regimen results in a decrease in the patient's FXI coagulation activity by about 7% to about 20% relative to baseline.

In some embodiments, in the methods of the present disclosure, administration of a treatment regimen results in a decrease in the patient's FXI coagulation activity relative to baseline by about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67% or about 68%, about 69% or about 70%.

In other embodiments, in the methods of the present disclosure, administration of the treatment regimen results in a decrease in the patient's FXI coagulation activity by about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, or about 20% relative to baseline.

In other embodiments, in the methods of the present disclosure, administration of the treatment regimen reduces the patient's FXI coagulation activity by the amount shown in Table 5 of Example 2.

In some aspects of the disclosed methods, administration of the treatment regimen prolongs activated partial thromboplastin time (aPTT) in a range of about 27% to about 64% relative to baseline.

In some embodiments of the disclosed methods, administration of a treatment regimen increases activated partial thromboplastin time (aPTT) by about 27% to about 64% relative to baseline, such as about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61%, about 62%, about 63%, or about 64%. As used herein, "baseline" refers to a patient's aPTT prior to any administration of a treatment regimen.

In some embodiments of the disclosed methods, administration of the regimen prolongs activated partial thromboplastin time (aPTT) by the amount shown in Table 4 of Example 2.

In some embodiments, aPTT is determined as follows: plasma samples are incubated with an actin FS aPTT assay reagent containing a standard amount of phospholipids and a contact activator (Turkish tannic acid) that activates the intrinsic coagulation pathway. After 3 minutes of incubation, calcium chloride is added to initiate coagulation and the formation of fibrin clots is measured optically. The time for clot formation (measured in seconds) is reported as the activated partial thromboplastin time (aPTT). In other embodiments, fibrin clot formation is measured by mechanical methods (viscosity).

In some aspects of the disclosed methods, the pharmaceutical composition comprising melvian (or a pharmaceutically acceptable salt or solvent thereof) is an oral solid pharmaceutical composition.

In some embodiments of the methods of the present disclosure, the oral solid pharmaceutical composition comprises a spray-dried amorphous solid dispersion (SDP) consisting essentially of free form of miltiorrhiza and a pH-dependent enteric-soluble polymer.

In some embodiments of the methods of the present disclosure, the SDP comprises free form of miltiorrhiza and a pH-dependent enteric soluble polymer in a weight ratio of 3:1 (miltiorrhiza:polymer).

In some embodiments of the methods of the present disclosure, the pH-dependent enteric polymer is cellulose acetate trimellitate (CAT), cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose phthalate (HPMCP), ES grade hydroxypropyl methylcellulose (HPMC ES); LF, LG, MF, MG or HF grade hydroxypropyl methylcellulose acetate succinate (HPMC-AS), such as Aqoat®; polyvinyl acetate phthalate (PVAP), such as Sureteric® and Opadry®; and insect resins, such as SSB® Aquagold, or polyvinylpyrrolidone (PVP).

In some embodiments of the methods of the present disclosure, the pH-dependent enteric soluble polymer is hydroxypropylmethylcellulose-AS MG.

In some embodiments of the methods of the present disclosure, the oral solid pharmaceutical composition further comprises a binder, such as microcrystalline cellulose (MCC), silicified microcrystalline cellulose (SMCC), or a combination thereof.

In some embodiments of the methods of the present disclosure, the oral solid pharmaceutical composition further comprises a filler, such as lactose monohydrate.

In some embodiments of the methods of the present disclosure, the oral solid pharmaceutical composition further comprises a disintegrant.

In some embodiments of the methods of the present disclosure, the oral solid pharmaceutical composition further comprises a lubricant.

In some embodiments of the disclosed methods, the oral solid pharmaceutical composition is a tablet.

In some embodiments of the disclosed methods, the oral solid pharmaceutical composition is an immediate release tablet.

In some embodiments of the disclosed methods, the oral solid pharmaceutical composition is a direct compression tablet.

In some embodiments of the disclosed methods, the oral solid pharmaceutical composition is a compressed tablet.

In some embodiments of the methods of the present disclosure, the oral solid pharmaceutical composition is a film-coated tablet.

In some embodiments of the methods of the present disclosure, the film coating comprises polyvinyl alcohol, titanium dioxide, polyethylene glycol-polyvinyl alcohol graft copolymer, and talc.

In some embodiments of the methods of the present disclosure, the film coating comprises a polyethylene glycol-polyvinyl alcohol graft copolymer.

In some embodiments, the film coating comprises polyvinyl alcohol, iron oxide, polyethylene glycol (PEG) polyvinyl alcohol graft copolymer, and talc.

In some embodiments, the film coating comprises Opadry QX 321A220063 Yellow, a film coating material comprising polyvinyl alcohol, iron oxide, polyethylene glycol (PEG) polyvinyl alcohol graft copolymer and talc.

In some embodiments, the oral solid pharmaceutical composition is a tablet having the composition and/or properties shown in Table A: Table A. Film-coated tablets of Milvecine in 100 mg or 25 mg strengths Components quantity wt.% Amount per dose (25 mg) Amount per dose (100 mg) ^SDP 22.22 33.33 133.3 Silicified Microcrystalline Cellulose 43.07 64.6 258.4 Lactose Monohydrate 28.71 43.067 172.267 Cross-linked sodium carboxymethyl cellulose 5.0 7.5 30 Magnesium stearate 1.0 1.5 6 Total weight of core tablets 100 150 600 OpadryQX 321A220063 Yellow ^c 3.0 4.5 18.0 154.5 618 Tablet hardness Average 60 N to 120 N (Ph. Eur. 2.9.8), preferably 90 N Average 140 N to 220 N (Ph. Eur. 2.9.8), preferably 180 N Tablet brittleness ＜ 0.5 % ＜ 0.5 % Disintegration time in water (seconds) 13 18 ^b SDP: a spray-dried amorphous solid dispersion prepared according to the composition and method described in WO 2020210629. SDP consists essentially of free form of melvian and hydroxypropylmethylcellulose acetate succinate (HPMCAS-MG) in a weight ratio of 3:1 (melvian:HPMCAS-MG). ^c OpadryQX 321A220063 Yellow: a film coating material comprising polyvinyl alcohol, iron oxide, polyethylene glycol (PEG) polyvinyl alcohol graft copolymer and talc.

As used herein, the term "disintegration time" refers to the time required for a tablet to break down into granules under a set of specified conditions. In some embodiments, the disintegration time is measured in distilled water at 37° C. using a disc using the apparatus described in the European Pharmacopoeia (PTZ-E Pharma Test, Hainburg, Germany).

In some embodiments where the solid pharmaceutical composition is a tablet, the tablet has a disintegration time in water at 37°C of less than 60 seconds.

In some embodiments where the solid pharmaceutical composition is a tablet, the tablet has a disintegration time of less than 20 seconds in water at 37°C.

In other embodiments wherein the solid pharmaceutical composition is a tablet, the tablet has a disintegration time of less than 15 seconds in water at 37°C.

In other embodiments wherein the solid pharmaceutical composition is a tablet, the tablet has a disintegration time of less than 10 seconds in water at 37°C.

In some embodiments of the disclosed methods, the solid pharmaceutical composition is a capsule.

In some aspects of the disclosed methods, the human patient to whom the pharmaceutical composition comprising miltvicin (or a pharmaceutically acceptable salt or solvent thereof) is administered is unable to swallow a tablet dosage form.

In some embodiments of the disclosed methods, an oral solid pharmaceutical composition is dispersed in an aqueous medium to form an aqueous dispersion to be administered.

In some embodiments of the disclosed methods, the oral solid pharmaceutical composition is a tablet, which is dispersed in an aqueous medium to form an aqueous dispersion to be administered.

In some embodiments of the disclosed methods, the oral solid pharmaceutical composition is a tablet that is orally administered as an aqueous dispersion by dispersing the tablet in an aqueous medium in less than 1 minute.

In those embodiments where the oral solid pharmaceutical composition is dispersed in an aqueous medium to form an aqueous dispersion, the aqueous medium is water, saline, phosphate buffer, vegetable juice or fruit juice, including, for example, applesauce.

In those embodiments where the oral solid pharmaceutical composition is a tablet dispersed in an aqueous medium to form an aqueous dispersion, the aqueous medium is water, saline, phosphate buffer, vegetable juice or fruit juice, including, for example, applesauce.

In some embodiments of the disclosed methods wherein an oral solid pharmaceutical composition is dispersed in an aqueous medium to form an aqueous dispersion to be administered, the aqueous dispersion is administered to a human patient via a nasogastric tube or a spoon.

In some embodiments of the disclosed methods wherein an oral solid pharmaceutical composition is dispersed in an aqueous medium to form an aqueous dispersion to be administered, the aqueous dispersion is administered to a human patient via a nasogastric tube or a spoon.

In some embodiments of the disclosed methods, oral administration of a pharmaceutical composition comprising miltvicin (or a pharmaceutically acceptable salt or solvent thereof) results in a miltvicin plasma half-life ranging from about 13 hours to about 16 hours. Methods for determining plasma half-life in human patients are known to those skilled in the art (and include, for example, those described in the protocols in the Examples below).

In some embodiments of the disclosed methods, a pharmaceutical composition comprising miltiorrhiza (or a pharmaceutically acceptable salt or solvent thereof) is administered to a human patient such that the miltiorrhiza plasma concentration reaches a steady state in about 3 to 6 days. As used herein, the term "steady state" refers to a steady state plasma concentration as defined by regulatory agencies such as the U.S. Food & Drug Administration (FDA) and the European Medicines Agency (EMA).

There are several factors that distinguish melvexan from other oral factor Xla inhibitors such as asundexian. For example, a population pharmacokinetic model was developed using pooled data on melvexan plasma concentrations in healthy adult volunteers from six Phase 1 clinical studies to characterize melvexan pharmacokinetics.

Analyzing PK data from the AXIOMATIC-SSP trial using a proprietary population PK model revealed that, based on the exposure-response relationship of milvicin in patients, administering a pharmaceutical composition comprising 25 mg of milvicin twice daily to human patients results in milvicin plasma concentrations reaching a steady state within about 3 days. In some embodiments of any of the above aspects, 25 mg of milvicin orally administered twice daily to human patients results in a plasma concentration profile that reaches a steady state within about 3 days. In some embodiments of any of the above aspects, the steady-state plasma concentration profile has the following characteristics: (i) a steady-state Cmax ranging from about 217 ng/mL to about 475 ng/mL; (ii) a steady-state mean (std) Cmax of 346 (129) ng/mL; (iii) a steady-state AUC0-24 ranging from about 4350 ng*h/mL to about 10230 ng*h/mL, and (iv) a steady-state mean (std) AUC0-24 of 7290 (2940) ng*h/mL. Additionally, based on data from Phase 1 and Phase 2 studies and the results of analyzing the exposure-response relationship of milvicin in patients using this proprietary population pharmacokinetic model, a 25 mg milvicin BID dosing regimen was selected for use in the Phase 3 trial for ACS as described in Example 1.

In some embodiments of the disclosed methods, the pharmaceutical composition comprising melvian (or a pharmaceutically acceptable salt or solvent thereof) is administered without regard to the timing of food intake.

In some aspects of the disclosed methods, the administration does not cause a statistically significant increase in severe bleeding complications. In these aspects, "statistically significant increase" refers to an increase relative to the patient's severe bleeding baseline (i.e., the patient's severe bleeding before administration of the pharmaceutical composition comprising milvicin (or a pharmaceutically acceptable salt or solvent thereof)).

In some embodiments of the methods of the present disclosure, administration does not result in a statistically significant increase in severe bleeding complications as assessed by ISTH criteria.

In some embodiments of the methods of the disclosure, administration does not result in a statistically significant increase in severe bleeding complications as assessed by CRNM bleeding criteria.

In some embodiments of the methods of the present disclosure, administration does not result in a statistically significant increase in severe bleeding complications as assessed by ISTH CRNM bleeding criteria.

In some embodiments of the methods of the disclosure, administration does not result in a statistically significant increase in severe bleeding complications as assessed by ISTH severe or CRNM bleeding criteria.

In some embodiments of the methods of the disclosure, administration does not result in a statistically significant increase in severe bleeding complications as assessed by GUSTO, BARC or TIMI criteria.

In some embodiments of the methods of the disclosure, administration does not result in a statistically significant increase in severe bleeding complications as assessed by BARC 3c and 5 categories.

In some embodiments of the methods of the disclosure, administration does not result in a statistically significant increase in severe bleeding complications as assessed by BARC 3b, 3c, and 5 categories.

In some embodiments of the methods of the disclosure, administration does not result in a statistically significant increase in severe bleeding complications as assessed by BARC 3b category.

In some embodiments of the methods of the disclosure, administration does not result in a statistically significant increase in severe bleeding complications as assessed by BARC 3c category.

In some embodiments of the methods of the disclosure, administration does not result in a statistically significant increase in severe bleeding complications as assessed by BARC 5 category.

In some embodiments of the disclosed methods, administration does not cause a statistically significant increase in GUSTO severe or life-threatening bleeding.

In some embodiments of the methods of the disclosure, administration does not result in a statistically significant increase in non-CABG TIMI major bleeding.

In some embodiments of the methods of the disclosure, administration does not result in a statistically significant increase in the occurrence of clinically relevant non-severe bleeding.

In some embodiments of the methods of the disclosure, administration does not result in a statistically significant increase in clinically relevant non-severe bleeding as assessed by BARC 2, BARC 3a, or BARC 4.

In some embodiments of the methods of the disclosure, administration does not result in a statistically significant increase in clinically relevant non-severe bleeding as assessed by ISTH non-severe clinically relevant bleeding.

In some embodiments of the methods of the disclosure, administration does not cause a statistically significant increase in clinically relevant non-severe bleeding as assessed by GUSTO moderate bleeding.

In some embodiments of the methods of the disclosure, administration does not result in a statistically significant increase in clinically relevant non-severe bleeding as assessed by TIMI CABG-related severe bleeding.

In some embodiments of the methods of the disclosure, administration does not result in a statistically significant increase in clinically relevant non-severe bleeding as assessed by TIMI mild bleeding.

In some embodiments of the methods of the disclosure, administration does not result in a statistically significant increase in clinically relevant non-severe bleeding as assessed by TIMI bleeding requiring medical assistance.

In some embodiments of the methods of the disclosure, the relative risk of bleeding according to the Bleeding Academic Research Consortium (BARC) type 3 or type 5 criteria caused by the treatment regimen compared to placebo in combination with antiplatelet therapy is no greater than 3, such as no greater than one of the following: 3.0, 2.9, 2.8, 2.7, 2.6, 2.5, 2.4, 2.3, 2.2, 2.1, 2.0, 1.9, 1.8, 1.7, 1.6, 1.5, 1.4, 1.3, 1.2, 1.1, 1.0, 0.9, 0.8, 0.7, 0.6, or 0.5.

In some embodiments of the methods of the disclosure, the relative risk of bleeding according to the Bleeding Academic Research Consortium (BARC) type 3 or type 5 criteria caused by the treatment regimen compared to placebo in combination with antiplatelet therapy is no greater than 3, such as no greater than one of the following: 3.0, 2.9, 2.8, 2.7, 2.6, 2.5, 2.4, 2.3, 2.2, 2.1, 2.0, 1.9, 1.8, 1.7, 1.6, 1.5, 1.4, 1.3, 1.2, 1.1, 1.0, 0.9, 0.8, 0.7, 0.6, or 0.5.

In some embodiments of the disclosed methods, the relative risk of severe bleeding according to the Bleeding Academic Research Consortium (BARC) type 3 or type 5 criteria is independent of the amount of milvicin administered.

In other embodiments of the disclosed methods, the human patient does not suffer from severe bleeding according to the Bleeding Academic Research Consortium (BARC) type 3 and 5 criteria.

In some embodiments of the methods of the disclosure, the relative risk of bleeding according to the Bleeding Academic Research Consortium (BARC) type 2 criteria caused by the treatment regimen compared to placebo plus standard of care is no greater than 2.6, such as no greater than one of the following: 2.6, 2.5, 2.4, 2.3, 2.2, 2.1, 2.0, 1.9, 1.8, 1.7, 1.6, 1.5, 1.4, 1.3, 1.2, 1.1, 1.0, 0.9, 0.8, 0.7, 0.6, or 0.5.

In some embodiments of the methods of the disclosure, the treatment regimen causes a relative risk of bleeding according to the Bleeding Academic Research Consortium (BARC) type 2 criteria of no greater than 2.6, such as no greater than one of the following: 2.6, 2.5, 2.4, 2.3, 2.2, 2.1, 2.0, 1.9, 1.8, 1.7, 1.6, 1.5, 1.4, 1.3, 1.2, 1.1, 1.0, 0.9, 0.8, 0.7, 0.6, or 0.5, compared to placebo combined with antiplatelet therapy.

In some embodiments of the disclosed methods, the relative risk of bleeding according to the Bleeding Academic Research Consortium (BARC) type 2 criteria is independent of the amount of milvicin administered.

In other embodiments of the disclosed methods, the human patient does not suffer from bleeding according to Bleeding Academic Research Consortium (BARC) type 2.

In some embodiments of the methods of the disclosure, the relative risk of bleeding according to ISTH criteria (major bleeding or clinically relevant non-major bleeding (CRNM)) caused by the treatment regimen compared to placebo combined with standard of care is no greater than 3, such as no greater than one of the following: 3.0, 2.9, 2.8, 2.7, 2.6, 2.5, 2.4, 2.3, 2.2, 2.1, 2.0, 1.9, 1.8, 1.7, 1.6, 1.5, 1.4, 1.3, 1.2, 1.1, 1.0, 0.9, 0.8, 0.7, 0.6, or 0.5.

In some embodiments of the methods of the disclosure, the relative risk of bleeding according to ISTH criteria (major bleeding or clinically relevant non-major bleeding (CRNM)) caused by the treatment regimen compared to placebo combined with antiplatelet therapy is no more than 3, such as no more than one of the following: 3.0, 2.9, 2.8, 2.7, 2.6, 2.5, 2.4, 2.3, 2.2, 2.1, 2.0, 1.9, 1.8, 1.7, 1.6, 1.5, 1.4, 1.3, 1.2, 1.1, 1.0, 0.9, 0.8, 0.7, 0.6 or 0.5.

According to the present disclosure, administration of milvithin is generally safe and well tolerated. For example, administration of milvithin at a dosage of 25 mg, 50 mg, or 100 mg does not cause clinically significant QTc interval prolongation. For example, administration of milvithin at a dosage of 25 mg, 50 mg, or 100 mg does not produce a ΔΔQTc of 10 msec or longer. In some aspects, administration of milvithin at a dosage of 25 mg, 50 mg, or 100 mg produces a ΔΔQTc of less than 10 msec. In some aspects, administration of milvithin at a dosage of 25 mg, 50 mg, or 100 mg produces a ΔΔQTc of less than 9 msec. In some aspects, administration of milvithin at a dosage of 25 mg, 50 mg, or 100 mg produces a ΔΔQTc of less than 8 msec. In some embodiments, administration of milvithin at a dose of 25 mg, 50 mg, or 100 mg results in a QTc of less than 7 msec of ΔΔQTc. In some embodiments, administration of milvithin at a dose of 25 mg, 50 mg, or 100 mg results in a ΔΔQTc of less than 6 msec of ΔΔQTc. In some embodiments, administration of milvithin at a dose of 25 mg, 50 mg, or 100 mg results in a ΔΔQTc of less than 5 msec of ΔΔQTc. In some embodiments, administration of milvithin at a dose of 25 mg, 50 mg, or 100 mg results in a ΔΔQTc of less than 4 msec of ΔΔQTc.

Administration of milvithin at a dose of 25 mg does not cause clinically significant QTc interval prolongation. In some embodiments, administration of milvithin at a dose of 25 mg produces a ΔΔQTc of less than 10 msec. In some embodiments, administration of milvithin at a dose of 25 mg produces a ΔΔQTc of less than 9 msec. In some embodiments, administration of milvithin at a dose of 25 mg produces a ΔΔQTc of less than 8 msec. In some embodiments, administration of milvithin at a dose of 25 mg produces a ΔΔQTc of less than 7 msec. In some embodiments, administration of milvithin at a dose of 25 mg produces a ΔΔQTc of less than 6 msec. In some embodiments, administration of milvithin at a dose of 25 mg produces a ΔΔQTc of less than 5 msec. In some aspects, administration of Milvicin at a dose of 25 mg produces a ΔΔQTc of less than 4 msec.

Administration of milvithin at a dose of 50 mg does not cause clinically significant QTc interval prolongation. In some embodiments, administration of milvithin at a dose of 50 mg produces a ΔΔQTc of less than 10 msec. In some embodiments, administration of milvithin at a dose of 50 mg produces a ΔΔQTc of less than 9 msec. In some embodiments, administration of milvithin at a dose of 50 mg produces a ΔΔQTc of less than 8 msec. In some embodiments, administration of milvithin at a dose of 50 mg produces a ΔΔQTc of less than 7 msec. In some embodiments, administration of milvithin at a dose of 50 mg produces a ΔΔQTc of less than 6 msec. In some embodiments, administration of milvithin at a dose of 50 mg produces a ΔΔQTc of less than 5 msec. In some aspects, administration of Milvicin at a dose of 50 mg produces a ΔΔQTc of less than 4 msec.

Administration of milvithin at a dose of 100 mg does not cause clinically significant QTc interval prolongation. In some aspects, administration of milvithin at a dose of 100 mg produces a ΔΔQTc of less than 10 msec. In some aspects, administration of milvithin at a dose of 100 mg produces a ΔΔQTc of less than 9 msec. In some aspects, administration of milvithin at a dose of 100 mg produces a ΔΔQTc of less than 8 msec. In some aspects, administration of milvithin at a dose of 100 mg produces a ΔΔQTc of less than 7 msec. In some aspects, administration of milvithin at a dose of 100 mg produces a ΔΔQTc of less than 6 msec. In some aspects, administration of milvicin at a dose of 100 mg produces a ΔΔQTc of less than 5 msec. In some aspects, administration of milvicin at a dose of 100 mg produces a ΔΔQTc of less than 4 msec.

The present disclosure relates to a method for preventing thrombotic events in adult patients following acute coronary syndrome (ACS), comprising administering 25 mg BID of Milvecine in combination with antiplatelet therapy. The present disclosure relates to a method for preventing thrombotic events in adult patients following acute coronary syndrome (ACS), comprising administering 25 mg BID of Milvecine in combination with antiplatelet therapy.

It should be understood that references herein to methods of using miltiorrhiza or compositions comprising miltiorrhiza to treat or prevent the conditions disclosed herein should also be construed as references to: (i) miltiorrhiza or compositions comprising miltiorrhiza used in methods of treating or preventing the conditions disclosed herein; and/or (ii) the use of miltiorrhiza or compositions comprising miltiorrhiza for the manufacture of a medicament for treating or preventing the conditions disclosed herein. Method of Use Aspects Aspect 1. A method for preventing adverse cerebrovascular events or adverse cardiovascular events in a human patient with acute coronary syndrome, wherein the method comprises administering to the human patient a treatment regimen comprising: (i) a pharmaceutical composition comprising 25 mg of milvithin (or a pharmaceutically acceptable salt or solvent thereof); and (ii) an antiplatelet therapy selected from the group consisting of aspirin, a P2Y12 inhibitor, and a combination thereof; wherein the pharmaceutical composition is administered twice daily. Aspect 2. The method of aspect 1, wherein the antiplatelet therapy is a P2Y12 inhibitor. Aspect 3. The method of aspect 2, wherein the P2Y12 inhibitor is clopidogrel, ticagrelor, or prasugrel. Aspect 4. The method of any one of aspects 1 to 3, wherein the antiplatelet therapy is aspirin. Aspect 5. The method of any one of Aspects 1 to 4, wherein the human patient is treated with aspirin and clopidogrel combination therapy from day 1 to day 21, followed by aspirin monotherapy for at least 90 days. Aspect 6. The method of Aspect 5, wherein the patient is treated with aspirin and/or clopidogrel without adjusting the dose of milvitra. Aspect 7. The method of any of the preceding aspects, wherein the method is used for primary prevention of adverse cerebrovascular events or adverse cardiovascular events. Aspect 8. The method of any of the preceding aspects, wherein the method is used for secondary prevention of adverse cerebrovascular events or adverse cardiovascular events. Aspect 9. The method of any of Aspects 1 to 8, wherein the adverse cerebrovascular events or adverse cardiovascular events include one or more of stroke, heart attack, or death. Aspect 10. The method of any one of aspects 1 to 9, wherein the adverse cerebrovascular events or adverse cardiovascular events occur in an organ selected from the heart, brain, limbs, blood supply system or blood vessels. Aspect 11. The method of any one of aspects 1 to 10, wherein the adverse cerebrovascular events or adverse cardiovascular events include one or more major adverse cardiovascular events (MACE) selected from the group consisting of cardiovascular death, non-fatal myocardial infarction, ischemic stroke and combinations thereof. Aspect 12. The method of any one of aspects 1 to 11, wherein the adverse cerebrovascular events or adverse cardiovascular events include one or more major adverse vascular events (MAVE) selected from the group consisting of MACE; major adverse limb events (MALE), including one or more selected from acute limb ischemia, chronic limb ischemia or major resection; symptomatic venous thromboembolic events, and combinations thereof. Aspect 13. The method of any one of Aspects 1 to 12, wherein the adverse cerebrovascular event or adverse cardiovascular event is selected from the group consisting of arrhythmogenic cardiomyopathy (ACM), non-fatal myocardial infarction, ischemic stroke, and combinations thereof. Aspect 14. The method of any one of Aspects 1 to 11, wherein the adverse cerebrovascular event or adverse cardiovascular event comprises cardiovascular death. Aspect 15. The method of any one of Aspects 1 to 10, wherein the adverse cerebrovascular event or adverse cardiovascular event comprises arrhythmogenic cardiomyopathy (ACM). Aspect 16. A method for preventing adverse cardiovascular events in a human patient diagnosed with acute coronary syndrome, wherein the method comprises administering to the human patient a treatment regimen comprising: (i) a pharmaceutical composition comprising 25 mg of milvithin (or a pharmaceutically acceptable salt or solvent thereof) and one or more pharmaceutically acceptable formulations, and (ii) an antiplatelet therapy selected from the group consisting of aspirin, a P2Y12 inhibitor, and a combination thereof; i. wherein the pharmaceutical composition is administered twice daily; and ii. wherein the adverse cardiovascular event is selected from one or more of the group consisting of: all-cause death (all-cause =Cardiovascular mortality; ACM); cardiovascular (CV) death; myocardial infarction (MI); unstable angina (UA); "all strokes" or "any stroke" (ischemic, hemorrhagic, or of unknown etiology); ischemic stroke; acute limb ischemia (ALI); major vascular (non-invasive) limb resection; symptomatic venous thromboembolism (VTE: (pulmonary embolism (PE), deep venous embolism (DVT))); ischemia-driven coronary revascularization; intravascular stent thrombosis; hospitalization for any reason, categorized as (1) planned or unplanned, (2) due to an arterial or venous thrombotic event, or neither; and transient ischemic attack (TIA). Model 17. A method as in aspect 16, wherein the adverse cardiovascular event is one or more of CV death, MI, or ischemic stroke. Aspect 18. A method for reducing the incidence of one or more adverse thrombotic events selected from new ischemic stroke, MI, or all-cause death in a human patient diagnosed with acute coronary syndrome, wherein the method comprises administering to the human patient a treatment regimen comprising: (i) a pharmaceutical composition comprising about 25 mg to about 100 mg of milvithin (or a pharmaceutically acceptable salt or solvent thereof) and one or more pharmaceutically acceptable formulations, and (ii) an antiplatelet therapy selected from the group consisting of aspirin, a P2Y12 inhibitor, and combinations thereof; wherein the pharmaceutical composition is administered twice daily. Aspect 19. A method for preventing ischemic stroke in a human patient diagnosed with acute coronary syndrome, wherein the method comprises administering to the human patient a treatment regimen comprising: (i) a pharmaceutical composition comprising 25 mg of milvithin (or a pharmaceutically acceptable salt or solvent thereof) and one or more pharmaceutically acceptable formulations, and (ii) an antiplatelet therapy selected from the group consisting of aspirin, a P2Y12 inhibitor, and a combination thereof; wherein the pharmaceutical composition is administered twice daily. Aspect 20. The method of aspect 19, wherein the clinical benefit of the treatment regimen in reducing the incidence of ischemic stroke is maintained throughout the 90-day treatment period. Aspect 21. A method as in any of the foregoing aspects, wherein administration of the treatment regimen results in a decrease in the patient's FXI coagulation activity by about 7% to about 20% relative to baseline. Aspect 22. A method as in any of the foregoing aspects, wherein administration of the treatment regimen results in an increase in activated partial thromboplastin time (aPTT) by about 27% to about 64% relative to baseline. Aspect 23. A method as in any of the foregoing aspects, wherein the administration does not result in a statistically significant increase in severe bleeding complications. Aspect 24. A method as in any of the foregoing aspects, wherein the pharmaceutical composition comprising milvicin (or a pharmaceutically acceptable salt or solvent thereof) is an oral solid pharmaceutical composition. Aspect 25. A method as in aspect 24, wherein the oral solid pharmaceutical composition is a tablet. Aspect 26. The method of aspect 25, wherein the tablet is an immediate release tablet. Aspect 27. The method of aspect 25 or aspect 26, wherein the disintegration time of the tablet in water is less than 20 seconds. Aspect 28. The method of any of the foregoing aspects, wherein the administration produces a plasma half-life of miltvicin in the range of about 13 hours to about 16 hours. Aspect 29. The method of any of the foregoing aspects, wherein the administration causes the plasma concentration of miltvicin to reach a steady state on about the 3rd day to the 6th day. Aspect 30. The method of any of the foregoing aspects, wherein the pharmaceutical composition comprising miltvicin (or a pharmaceutically acceptable salt or solvent thereof) is administered without regard to the timing of food intake. Aspect 31. The method of any of the preceding aspects, wherein the human patient is unable to swallow a tablet dosage form. Aspect 32. The method of any of aspects 25 to 31, wherein the tablet is dispersed in an aqueous medium to form an aqueous dispersion. Aspect 33. The method of aspect 32, wherein the aqueous medium is water, saline, phosphate buffer, vegetable juice or fruit juice, including, for example, applesauce. Aspect 34. The method of aspect 32 or aspect 33, wherein the aqueous dispersion is administered to the human patient via a nasogastric tube or spoon. Aspect 35. The method of any of aspects 25 to 34, wherein the pharmaceutical composition is orally administered in the form of an aqueous dispersion by dispersing an oral tablet in an aqueous medium in less than 1 minute. Aspect 36. A method for preventing adverse cerebrovascular events or adverse cardiovascular events in a human patient with acute coronary syndrome, wherein the method comprises orally administering to the human patient a treatment regimen comprising: (i) a pharmaceutical composition comprising 25 mg of milvithin (or a pharmaceutically acceptable salt or solvent thereof); and (ii) an antiplatelet therapy; wherein the pharmaceutical composition is administered twice daily. Aspect 37. The method of aspect 36, wherein the antiplatelet therapy is a P2Y12 inhibitor. Aspect 38. The method of aspect 37, wherein the P2Y12 inhibitor is clopidogrel, ticagrelor, or prasugrel. Aspect 39. The method of any of aspects 36 to 38, wherein the antiplatelet therapy is aspirin. Aspect 40. The method of any one of Aspects 39 to 42, wherein the human patient is treated with aspirin and clopidogrel combination therapy from day 1 to day 21, followed by aspirin monotherapy for at least 90 days. Aspect 41. The method of Aspect 43, wherein the patient is treated with aspirin and/or clopidogrel without adjusting the dose of milvitra. Aspect 42. The method of any one of Aspects 39 to 44, wherein the method is used for primary prevention of adverse cerebrovascular events or adverse cardiovascular events. Aspect 43. The method of any one of Aspects 39 to 45, wherein the method is used for secondary prevention of adverse cerebrovascular events or adverse cardiovascular events. Aspect 44. The method of any one of aspects 39 to 46, wherein the adverse cerebrovascular events or adverse cardiovascular events comprise one or more of stroke, heart attack or death. Aspect 45. The method of any one of aspects 39 to 47, wherein the adverse cerebrovascular events or adverse cardiovascular events occur in an organ selected from the heart, brain, limbs, blood supply system or blood vessels. Aspect 46. The method of any one of aspects 39 to 48, wherein the adverse cerebrovascular events or adverse cardiovascular events comprise one or more major adverse cardiovascular events (MACE) selected from the group consisting of cardiovascular death, non-fatal myocardial infarction, ischemic stroke and combinations thereof. Aspect 47. The method of any one of Aspects 39 to 49, wherein the adverse cerebrovascular event or adverse cardiovascular event comprises one or more major adverse vascular events (MAVE) selected from the group consisting of: MACE; major adverse limb events (MALEs) including one or more selected from acute limb ischemia, chronic limb ischemia, or major resection; symptomatic venous thromboembolic events, and combinations thereof. Aspect 48. The method of any one of Aspects 39 to 50, wherein the adverse cerebrovascular event or adverse cardiovascular event is selected from the group consisting of: arrhythmogenic cardiomyopathy (ACM), non-fatal myocardial infarction, ischemic stroke, and combinations thereof. Aspect 49. The method of any one of Aspects 39 to 50, wherein the adverse cerebrovascular event or adverse cardiovascular event comprises cardiovascular death. Aspect 50. The method of any of Aspects 39 to 51, wherein the adverse cerebrovascular event or adverse cardiovascular event comprises arrhythmogenic cardiomyopathy (ACM). Aspect 51. A method for preventing adverse cardiovascular events in a human patient diagnosed with acute coronary syndrome, wherein the method comprises administering to the human patient a treatment regimen comprising: (i) 25.0 mg of milvitra twice daily and (ii) antiplatelet therapy; Adverse cardiovascular events were defined as one or more of the following: all-cause mortality (ACM); cardiovascular (CV) mortality; myocardial infarction (MI); unstable angina (UA); "all strokes" or "any stroke" (ischemic, hemorrhagic, or unknown etiology); ischemic stroke; acute limb ischemia (ALI); major vascular (non-traumatic) limb resection; symptomatic venous thromboembolism (VTE: (pulmonary embolism (PE), deep venous embolism (DVT)); blood-driven coronary revascularization; intravascular stent thrombosis; hospitalization for any reason, classified as (1) planned or unplanned, (2) due to an arterial or venous thrombotic event, or neither; or a transient ischemic attack (TIA); and wherein the method achieves at least one of the following clinical outcomes: (1) achieving a steady-state plasma concentration profile of Milvecine within about 6 days; (2) achieving a steady-state plasma concentration profile of Milvecine characterized by: (i) about 217 ng/mL to about 475 ng/mL, (ii) a steady-state mean (std) C _max of 346 (129) ng/mL, (iii) a steady-state _AUC 0-24 of about 4350 ng*h/mL to about 10230 ng*h/mL, or (iv) a steady-state mean (std) AUC _0-24 of 7290 (2940) ng*h/mL; (3) a change in QTc from baseline of less than 10 milliseconds; (4) a steady-state AUC or C max of ₃₄₆ (129) ng/mL; _max , there is no clinically relevant effect on any bleeding caused by milvicin exposure in the human patient; (5) minimizes hemostatic impairment in the human patient; (6) there is no clinically significant change in prothrombin time, wherein the maximum mean percentage change from baseline is about 5%; or (7) any combination of the foregoing clinical results. Aspect 52. A method for preventing adverse cardiovascular events in a human patient diagnosed with acute coronary syndrome, wherein the method comprises administering to the human patient a treatment regimen comprising: (i) 25.0 mg milvicin twice daily and (ii) antiplatelet therapy; Adverse cardiovascular events were defined as one or more of the following: all-cause death (ACM); cardiovascular (CV) death; myocardial infarction (MI); unstable angina (UA); "all strokes" or "any stroke" (ischemic, hemorrhagic, or of unknown etiology); ischemic stroke; acute limb ischemia (ALI); major vascular (non-invasive) limb resection; symptomatic venous thromboembolism (VTE: pulmonary embolism (PE), deep venous thrombosis (DVT)); ischemia-driven coronary revascularization; intravascular stent thrombosis; hospitalization for any reason, categorized as (1) planned or unplanned, (2) due to an arterial or venous thrombotic event, or neither; or transient ischemic attack (TIA). Aspect 53. A method for preventing all-cause mortality in a human patient diagnosed with acute coronary syndrome, wherein the method comprises administering to the human patient a treatment regimen comprising: (i) 25.0 mg of milvicin twice daily and (ii) antiplatelet therapy. Aspect 54. A method for preventing adverse cardiovascular events in a human patient diagnosed with acute coronary syndrome, wherein the method comprises administering to the human patient a treatment regimen comprising: (i) 25.0 mg of milvicin twice daily and (ii) antiplatelet therapy. Aspect 55. A method for preventing myocardial infarction in a human patient diagnosed with acute coronary syndrome, wherein the method comprises administering to the human patient a treatment regimen comprising: (i) 25.0 mg of milvicin twice daily and (ii) antiplatelet therapy. Aspect 56. A method for preventing stroke in a human patient diagnosed with acute coronary syndrome, wherein the method comprises administering to the human patient a treatment regimen comprising: (i) 25.0 mg of milvicin twice daily and (ii) antiplatelet therapy. Aspect 57. A method for preventing ischemic stroke in a human patient diagnosed with acute coronary syndrome, wherein the method comprises administering to the human patient a treatment regimen comprising: (i) 25.0 mg of milvicin twice daily and (ii) antiplatelet therapy. Aspect 58. A method for preventing ischemic stroke in a human patient diagnosed with acute coronary syndrome, wherein the method comprises administering to the human patient a treatment regimen comprising: (i) 25.0 mg of milvicin twice daily and (ii) antiplatelet therapy. Aspect 59. A method for preventing unstable angina in a human patient diagnosed with acute coronary syndrome, wherein the method comprises administering to the human patient a treatment regimen comprising: (i) 25.0 mg of milvicin twice daily and (ii) antiplatelet therapy. Aspect 60. A method for preventing acute limb ischemia in a human patient diagnosed with acute coronary syndrome, wherein the method comprises administering to the human patient a treatment regimen comprising: (i) 25.0 mg of milvicin twice daily and (ii) antiplatelet therapy. Aspect 61. A method for preventing major vascular (non-invasive) limb resection in a human patient diagnosed with acute coronary syndrome, wherein the method comprises administering to the human patient a treatment regimen comprising: (i) 25.0 mg of milvicin twice daily and (ii) antiplatelet therapy. Aspect 62. A method for preventing symptomatic venous thromboembolism in a human patient diagnosed with acute coronary syndrome, wherein the method comprises administering to the human patient a treatment regimen comprising: (i) 25.0 mg of milvicin twice daily and (ii) antiplatelet therapy. Aspect 63. A method for preventing pulmonary embolism in a human patient diagnosed with acute coronary syndrome, wherein the method comprises administering to the human patient a treatment regimen comprising: (i) 25.0 mg of milvicin twice daily and (ii) antiplatelet therapy. Aspect 64. A method for preventing deep venous embolism in a human patient diagnosed with acute coronary syndrome, wherein the method comprises administering to the human patient a treatment regimen comprising: (i) 25.0 mg of milvicin twice daily and (ii) antiplatelet therapy. Aspect 65. A method for preventing deep venous embolism in a human patient diagnosed with acute coronary syndrome, wherein the method comprises administering to the human patient a treatment regimen comprising: (i) 25.0 mg of milvicin twice daily and (ii) antiplatelet therapy. Aspect 66. A method for preventing ischemia-driven coronary revascularization in a human patient diagnosed with acute coronary syndrome, wherein the method comprises administering to the human patient a treatment regimen comprising: (i) 25.0 mg of milvicin twice daily and (ii) antiplatelet therapy. Aspect 67. A method for preventing stent thrombosis in a human patient diagnosed with acute coronary syndrome, wherein the method comprises administering to the human patient a treatment regimen comprising: (i) 25.0 mg of milvicin twice daily and (ii) antiplatelet therapy. Aspect 68. A method for preventing hospitalization for any reason in a human patient diagnosed with acute coronary syndrome, wherein the hospitalization is classified as (a) planned or unplanned, (b) due to an arterial or venous thrombotic event, or neither, wherein the method comprises administering to the human patient a treatment regimen comprising: (i) 25.0 mg of milvicin twice daily and (ii) antiplatelet therapy. Aspect 69. A method for preventing a transient ischemic episode in a human patient diagnosed with an acute coronary syndrome, wherein the method comprises administering to the human patient a treatment regimen comprising: (i) 25.0 mg of milvicin twice daily and (ii) an antiplatelet therapy. Aspect 70. A method for preventing an adverse cerebrovascular event in a human patient diagnosed with an acute coronary syndrome, wherein the method comprises orally administering to the human patient a treatment regimen comprising: (i) 25 mg of milvicin; and (ii) an antiplatelet therapy twice daily. Aspect 71. A method for preventing adverse cardiovascular events in a human patient diagnosed with acute coronary syndrome, wherein the method comprises orally administering to the human patient twice daily a treatment regimen comprising: (i) 25 mg of milvithin; and (ii) antiplatelet therapy. Aspect 72. A method for preventing adverse cerebrovascular events in a human patient with acute coronary syndrome, wherein the method comprises orally administering to the human patient a treatment regimen comprising: (i) a pharmaceutical composition comprising 25 mg of milvithin and a pharmaceutically acceptable formulation; and (ii) antiplatelet therapy; wherein the pharmaceutical composition is administered twice daily. Aspect 73. A method for preventing adverse cardiovascular events in a human patient with acute coronary syndrome, wherein the method comprises administering to the human patient a treatment regimen comprising: (i) a pharmaceutical composition comprising 25 mg of milvitra and a pharmaceutically acceptable formulation; and (ii) an antiplatelet therapy; wherein the pharmaceutical composition is administered twice daily. Aspect 74. The method of any of Aspects 70 to 73, wherein the adverse cerebrovascular events or cardiovascular events comprise ischemic stroke. Aspect 75. The method of any of Aspects 70 to 74, wherein the adverse cerebrovascular events or cardiovascular events comprise one or more of stroke, heart attack, or death. Aspect 76. The method of any one of aspects 70 to 75, wherein the adverse cerebrovascular events or adverse cardiovascular events occur in an organ selected from the heart, brain, limbs, blood supply system or blood vessels. Aspect 77. The method of any one of aspects 70 to 76, wherein the adverse cerebrovascular events or adverse cardiovascular events include one or more major adverse cardiovascular events (MACE) selected from the group consisting of cardiovascular death, non-fatal myocardial infarction, ischemic stroke and combinations thereof. Aspect 78. The method of any one of aspects 70 to 77, wherein the adverse cerebrovascular events or adverse cardiovascular events include one or more major adverse vascular events (MAVE) selected from the group consisting of MACE; major adverse limb events (MALE), including one or more selected from acute limb ischemia, chronic limb ischemia or major resection; symptomatic venous thromboembolic events, and combinations thereof. Aspect 79. The method of any of Aspects 70 to 78, wherein the adverse cerebrovascular events or adverse cardiovascular events are selected from the group consisting of arrhythmogenic cardiomyopathy (ACM), non-fatal myocardial infarction, ischemic stroke, and combinations thereof. Aspect 80. The method of any of Aspects 70 to 79, wherein the adverse cerebrovascular events or adverse cardiovascular events comprise cardiovascular death. Aspect 81. The method of any of Aspects 70 to 80, wherein the adverse cerebrovascular events or adverse cardiovascular events comprise arrhythmogenic cardiomyopathy (ACM). Aspect 82. A method for preventing ischemic stroke in a human patient diagnosed with acute coronary syndrome, wherein the method comprises orally administering to the human patient twice daily a treatment regimen comprising: (i) 25 mg of milvicin; and (ii) an antiplatelet therapy. Aspect 83. The method of any of the preceding aspects, wherein the administration produces a steady-state plasma concentration profile of milvicin within about 3 days. Aspect 84. The method of any of the preceding aspects, wherein the administration produces a steady-state plasma concentration profile of milvicin having the following characteristics: (i) a steady-state Cmax in the range of about 217 ng/mL to about 475 ng/mL, (ii) a steady-state _mean (std) _Cmax of 346 (129) ng/mL, (iii) a steady-state _AUC0-24 in the range of about 4350 ng*h/mL to about 10230 ng*h/mL, and (iv) a steady-state mean (std) _AUC0-24 of 7290 (2940) ng*h/mL. Aspect 85. The method of any of the preceding aspects, wherein the administration does not cause clinically significant prolongation of the QTc interval. Aspect 86. The method of any of the preceding aspects, wherein the administration does not produce a clinically relevant effect on any bleeding caused by exposure to milvicin as measured by steady-state AUC or _Cmax . Aspect 87. The method of any of the preceding aspects, wherein the administration minimizes hemostatic impairment in the human patient. Aspect 88. The method of any of the preceding aspects, wherein the treatment regimen comprises an immediate release tablet. Aspect 89. The method of aspect 91, wherein the disintegration time of the immediate release tablet in water at 37°C is less than 20 seconds. Aspect 90. The method of any of the preceding aspects, wherein the administration results in a terminal half-life of miltvicin in plasma in the range of about 13 hours to about 16 hours. Aspect 91. The method of any of the preceding aspects, wherein the treatment regimen is administered without regard to the timing of food intake. Aspect 92. The method of any of aspects 88 to 91, wherein the immediate release tablet is dispersed in an aqueous medium to form an aqueous dispersion. Aspect 93. The method of aspect 92, wherein the aqueous medium comprises water or applesauce. Aspect 94. The method of any of the preceding aspects, wherein the antiplatelet therapy comprises administering a single antiplatelet therapy (SAPT) over a period of time in the range of about 1 month to about 36 months. Aspect 95. The method of aspect 94, wherein the antiplatelet therapy comprises administering SAPT during a period ranging from about 3 months to about 12 months. Aspect 96. The method of aspect 94, wherein the antiplatelet therapy comprises administering SAPT during a period ranging from about 6 months to about 12 months. Aspect 97. The method of aspect 94, wherein the antiplatelet therapy comprises administering SAPT for 3 months. Aspect 98. The method of aspect 94, wherein the antiplatelet therapy comprises administering SAPT for 6 months. Aspect 99. The method of aspect 94, wherein the antiplatelet therapy comprises administering SAPT for 12 months. Aspect 100. The method of aspect 94, wherein the antiplatelet therapy comprises administering SAPT for 24 months. Aspect 101. The method of any of aspects 94 to 100, wherein the SAPT is selected from aspirin and a P2Y12 inhibitor. Aspect 102. The method of any of aspects 94 to 101, wherein the SAPT comprises aspirin. Aspect 103. The method of aspect 102, wherein the aspirin is administered once daily. Aspect 104. The method of aspect 102, wherein the aspirin is administered once daily during a period ranging from about 3 months to about 3 years. Aspect 105. The method of aspect 102, wherein the aspirin is administered once daily for 3 months. Aspect 106. The method of aspect 102, wherein the aspirin is administered once daily for 6 months. Aspect 107. The method of aspect 102, wherein aspirin is administered once daily for 12 months. Aspect 108. The method of aspect 102, wherein aspirin is administered once daily for 24 months. Aspect 109. The method of aspect 102, wherein aspirin is administered once daily for 36 months. Aspect 110. The method of aspect 102, wherein aspirin is administered twice daily. Aspect 111. The method of aspect 102, wherein aspirin is administered once daily in an amount of 75 mg to 100 mg. Aspect 112. The method of aspect 102, wherein aspirin is administered once daily in an amount of 75 mg to 100 mg for a period of 12 months. Aspect 113. The method of any of aspects 94 to 101, wherein the SAPT comprises a P2Y12 inhibitor. Aspect 114. The method of any of aspects 94 to 101, wherein the SAPT comprises a P2Y12 inhibitor selected from prasugrel, clopidogrel, celatropin or ticagrelor. Aspect 115. The method of aspects 113 or 114, wherein the P2Y12 inhibitor is administered during a period ranging from about 3 months to about 6 months. Aspect 116. The method of aspects 113 or 114, wherein the P2Y12 inhibitor comprises clopidogrel. Aspect 117. The method of aspects 113 or 114, wherein the P2Y12 inhibitor comprises ticagrelor. Aspect 118. The method of Aspect 113 or 114, wherein the P2Y12 inhibitor comprises ticagrelor administered at 90 mg twice daily. Aspect 119. The method of Aspect 113 or 114, wherein the P2Y12 inhibitor comprises ticagrelor administered at 90 mg twice daily over a period of 3 years. Aspect 120. The method of Aspect 113 or 114, wherein the P2Y12 inhibitor comprises first administering ticagrelor, followed by aspirin monotherapy at 20 mg twice daily. Aspect 121. The method of any of Aspects 113 or 114, wherein the SAPT comprises first administering aspirin monotherapy for a period ranging from 30 days to 90 days, followed by clopidogrel monotherapy. Aspect 122. The method of any of Aspects 113 or 114, wherein the SAPT comprises administering aspirin monotherapy first for a period of 60 days, followed by administering clopidogrel monotherapy. Aspect 123. The method of any of Aspects 34 to 122, wherein the SAPT comprises administering aspirin monotherapy first for a period of 90 days, followed by administering clopidogrel monotherapy. Aspect 124. The method of any of Aspects 94 to 123, wherein the SAPT comprises administering aspirin monotherapy first, followed by administering clopidogrel monotherapy for a period of at least 2 months. Aspect 125. The method of any of Aspects 94 to 123, wherein the SAPT comprises first administering aspirin monotherapy for a period ranging from 30 days to 90 days, followed by administering clopidogrel monotherapy for a period of at least 2 months. Aspect 126. The method of any of Aspects 1 to 93, wherein the antiplatelet therapy comprises dual antiplatelet therapy (DAPT). Aspect 127. The method of Aspect 126, wherein the DAPT comprises aspirin and prasugrel. Aspect 128. The method of Aspect 126, wherein the DAPT comprises aspirin and prasugrel administered for 12 months. Aspect 129. The method of Aspect 126, wherein the DAPT comprises aspirin and clopidogrel. Aspect 130. The method of aspect 126, wherein the DAPT comprises aspirin and clopidogrel administered for a period of 21 days to 12 months. Aspect 131. The method of aspect 126, wherein the DAPT comprises aspirin and clopidogrel administered for a period of 21 days. Aspect 132. The method of aspect 126, wherein the DAPT comprises aspirin and clopidogrel administered for a period of 6 months. Aspect 133. The method of aspect 126, wherein the DAPT comprises aspirin and clopidogrel administered for a period of 12 months. Aspect 134. The method of aspect 126, wherein the DAPT comprises aspirin and ticagrelor. Aspect 135. The method of aspect 126, wherein the DAPT comprises aspirin and ticagrelor administered for 12 months. Aspect 136. The method of aspect 126, wherein the antiplatelet therapy comprises DAPT consisting of: aspirin administered once daily at 75 mg to 100 mg, and a P2Y12 inhibitor. Aspect 137. The method of aspect 126, wherein the antiplatelet therapy comprises first administering DAPT, followed by SAPT. Aspect 138. The method of aspect 126, wherein the antiplatelet therapy comprises first administering DAPT, followed by aspirin monotherapy. Aspect 139. The method of aspect 126, wherein the antiplatelet therapy comprises DAPT consisting of 75 to 100 mg aspirin and a P2Y12 inhibitor administered once daily for a first period of 12 months, followed by aspirin monotherapy for a second period of 6 months. Aspect 140. The method of aspect 126, wherein the antiplatelet therapy comprises DAPT consisting of 75 to 100 mg aspirin and a P2Y12 inhibitor administered once daily for a first period of 21 days, followed by aspirin monotherapy for a second period of 6 months. Aspect 141. The method of aspect 126, wherein the antiplatelet therapy comprises DAPT consisting of 75 to 100 mg aspirin once daily and 75 mg clopidogrel once daily for a first period of 21 days, followed by aspirin monotherapy for a second period of 6 months. Aspect 142. The method of aspect 126, wherein the antiplatelet therapy comprises DAPT consisting of 75 to 100 mg aspirin once daily and a P2Y12 inhibitor for a first period of 21 days, followed by aspirin monotherapy for a second period of 12 months. Aspect 143. The method of aspect 126, wherein the antiplatelet therapy comprises DAPT consisting of 75 to 100 mg aspirin once daily and 90 mg ticagrelor twice daily. Aspect 144. The method of Aspect 126, wherein the antiplatelet therapy comprises DAPT consisting of 75 to 100 mg aspirin once daily and 90 mg ticagrelor twice daily for a period of 12 months. Aspect 145. The method of Aspect 126, wherein the antiplatelet therapy comprises DAPT consisting of 81 to 100 mg aspirin once daily and 90 mg ticagrelor twice daily. Aspect 146. The method of Aspect 126, wherein the antiplatelet therapy comprises DAPT consisting of 81 to 100 mg aspirin once daily and 90 mg ticagrelor twice daily for 3 years. Aspect 147. The method of aspect 126, wherein the antiplatelet therapy comprises DAPT consisting of 75 to 100 mg aspirin once daily and 90 mg ticagrelor twice daily for a first period of 12 months, followed by 75 to 100 mg aspirin monotherapy once daily for a second period of 12 months. Aspect 148. The method of aspect 126, wherein the antiplatelet therapy comprises DAPT consisting of 75 to 100 mg aspirin once daily and 90 mg ticagrelor twice daily for a first period of 12 months, followed by 90 mg ticagrelor twice daily for a second period of 23 months. Aspect 149. The method of any of the preceding aspects, wherein the clinical benefit of the treatment regimen in reducing the incidence of ischemic stroke is maintained throughout the 90-day treatment period. Aspect 150. The method of any of the preceding aspects, wherein the clinical benefit of reducing the incidence of ischemic stroke is maintained throughout the 180-day treatment period. Aspect 151. The method of any of the preceding aspects, wherein the clinical benefit of reducing the incidence of ischemic stroke is maintained throughout the 12-month treatment period. Aspect 152. The method of any of the preceding aspects, wherein administration of the treatment regimen results in a reduction in the patient's FXI coagulation activity of about 7% to about 20% relative to baseline. Aspect 153. The method of any of the preceding aspects, wherein administration of the treatment regimen causes an increase in activated partial thromboplastin time (aPTT) in the range of about 27% to about 64% relative to baseline. Aspect 154. The method of any of the preceding aspects, wherein the administration does not cause a statistically significant increase in severe bleeding complications. Aspect 155. The method of any of the preceding aspects, wherein the pharmaceutical composition comprising milvicin (or a pharmaceutically acceptable salt or solvent thereof) is an oral solid pharmaceutical composition. Aspect 156. The method of aspect 155, wherein the oral solid pharmaceutical composition is a tablet. Aspect 157. The method of aspect 156, wherein the tablet is an immediate release tablet. Aspect 158. The method of any of the preceding aspects, wherein the human patient is unable to swallow a tablet dosage form. Aspect 159. The method of any of aspects 156 to 158, wherein the tablet is dispersed in an aqueous medium to form an aqueous dispersion. Aspect 160. The method of aspect 159, wherein the aqueous medium is water, saline, phosphate buffer, vegetable juice or fruit juice, including, for example, applesauce. Aspect 161. The method of aspect 159 or aspect 160, wherein the aqueous dispersion is administered to the human patient via a nasogastric tube or spoon. Aspect 162. The method of any of the preceding aspects, wherein the pharmaceutical composition is orally administered as an aqueous dispersion by dispersing an oral tablet in an aqueous medium in less than 1 minute. Aspect 163. The method of any of the preceding aspects, wherein the pharmaceutical composition comprises an amorphous form of milvicin mixed with a polymer. Aspect 164. The method of any of the preceding aspects, wherein the pharmaceutical composition comprises a spray-dried amorphous solid dispersion consisting of 75 w/w% milvicin and 25 w/w% HPMC-AS. Aspect 165. The method of any of the preceding aspects, wherein the method does not cause clinically significant QTc interval prolongation. Use of Milvecin Aspects Aspect 1. Milvecin for use in a method for preventing adverse cerebrovascular events or adverse cardiovascular events in a human patient with acute coronary syndrome, wherein the method comprises administering to the human patient a treatment regimen comprising: (i) a pharmaceutical composition comprising 25 mg of Milvecin (or a pharmaceutically acceptable salt or solvent thereof); and (ii) an antiplatelet therapy selected from the group consisting of aspirin, a P2Y12 inhibitor, and a combination thereof; wherein the pharmaceutical composition is administered twice daily. Aspect 2. Milvecin as used in aspect 1, wherein the antiplatelet therapy is a P2Y12 inhibitor. Aspect 3. Milvecin as used in aspect 2, wherein the P2Y12 inhibitor is clopidogrel, ticagrelor, or prasugrel. Aspect 4. Milvecin as used in any of Aspects 1 to 3, wherein the antiplatelet therapy is aspirin. Aspect 5. Milvecin as used in any of Aspects 1 to 4, wherein the human patient is treated with aspirin and clopidogrel combination therapy from day 1 to day 21, followed by aspirin monotherapy for at least 90 days. Aspect 6. Milvecin as used in Aspect 5, wherein the patient is treated with aspirin and/or clopidogrel without adjusting the Milvecin dosage. Aspect 7. Milvecin as used in any of the preceding Aspects, wherein the Milvecin used is for primary prevention of adverse cerebrovascular events or adverse cardiovascular events. Aspect 8. Milvecin as used in any of the above aspects, wherein the Milvecin used is used for secondary prevention of adverse cerebrovascular events or adverse cardiovascular events. Aspect 9. Milvecin as used in any of aspects 1 to 8, wherein the adverse cerebrovascular events or adverse cardiovascular events include one or more of stroke, heart attack or death. Aspect 10. Milvecin as used in any of aspects 1 to 9, wherein the adverse cerebrovascular events or adverse cardiovascular events occur in an organ selected from the heart, brain, limbs, blood supply system or blood vessels. Aspect 11. Milvecin as used in any of aspects 1 to 10, wherein the adverse cerebrovascular events or adverse cardiovascular events include one or more major adverse cardiovascular events (MACE) selected from the group consisting of: cardiovascular death, non-fatal myocardial infarction, ischemic stroke and combinations thereof. Aspect 12. Milvecin for use in any of Aspects 1 to 11, wherein the adverse cerebrovascular event or adverse cardiovascular event comprises one or more severe adverse vascular events (MAVE) selected from the group consisting of: MACE; severe adverse limb events (MALE), including one or more selected from acute limb ischemia, chronic limb ischemia, or severe resection; symptomatic venous thromboembolic events, and combinations thereof. Aspect 13. Milvecin for use in any of Aspects 1 to 12, wherein the adverse cerebrovascular event or adverse cardiovascular event is selected from the group consisting of: arrhythmogenic cardiomyopathy (ACM), non-fatal myocardial infarction, ischemic stroke, and combinations thereof. Aspect 14. Milvecin for use in any of Aspects 1 to 11, wherein the adverse cerebrovascular event or adverse cardiovascular event comprises cardiovascular death. Aspect 15. Milvecine for use in any of Aspects 1 to 10, wherein the adverse cerebrovascular event or adverse cardiovascular event comprises arrhythmogenic cardiomyopathy (ACM). Aspect 16. Milvecine for use in a method for preventing adverse cardiovascular events in a human patient diagnosed with acute coronary syndrome, wherein the method comprises administering to the human patient a treatment regimen comprising: (i) a pharmaceutical composition comprising 25 mg of Milvecine (or a pharmaceutically acceptable salt or solvent thereof) and one or more pharmaceutically acceptable formulations, and (ii) an antiplatelet therapy selected from the group consisting of aspirin, a P2Y12 inhibitor, and a combination thereof; i. wherein the pharmaceutical composition is administered twice daily; and ii. The adverse cardiovascular event is one or more of the following: all-cause death (ACM); cardiovascular (CV) death; myocardial infarction (MI); unstable angina (UA); "all strokes" or "any stroke" (ischemic, hemorrhagic, or unknown etiology); ischemic stroke; acute limb ischemia (ALI); major vascular (non-invasive) limb resection; symptomatic venous thromboembolism (VTE: (pulmonary embolism (PE), deep venous embolism (DVT))); ischemia-driven coronary revascularization; intravascular stent thrombosis; hospitalization for any reason, categorized as (1) planned or unplanned, (2) due to arterial or venous thrombotic events or neither; and transient ischemic attack (TIA). Aspect 17. Milvecine as used in Aspect 16, wherein the adverse cardiovascular event is one or more of CV death, MI, or ischemic stroke. Aspect 18. Milvecine for use in a method for reducing the incidence of one or more adverse thrombotic events selected from new ischemic stroke, MI, or all-cause death in a human patient diagnosed with acute coronary syndrome, wherein the method comprises administering to the human patient a treatment regimen comprising: (i) a pharmaceutical composition comprising about 25 mg to about 100 mg of Milvecine (or a pharmaceutically acceptable salt or solvent thereof) and one or more pharmaceutically acceptable formulations, and (ii) an antiplatelet therapy selected from the group consisting of aspirin, a P2Y12 inhibitor, and a combination thereof; wherein the pharmaceutical composition is administered twice daily. Aspect 19. Milvecine for use in a method for preventing ischemic stroke in a human patient diagnosed with acute coronary syndrome, wherein the method comprises administering to the human patient a treatment regimen comprising: (i) a pharmaceutical composition comprising 25 mg of Milvecine (or a pharmaceutically acceptable salt or solvent thereof) and one or more pharmaceutically acceptable formulations, and (ii) an antiplatelet therapy selected from the group consisting of aspirin, a P2Y12 inhibitor, and a combination thereof; wherein the pharmaceutical composition is administered twice daily. Aspect 20. Milvecine as used in Aspect 18 or Aspect 19, wherein the clinical benefit of the treatment regimen in reducing the incidence of ischemic stroke is maintained throughout the 90-day treatment period. Aspect 21. Milvecin as used in any of the foregoing aspects, wherein administration of the treatment regimen reduces the patient's FXI coagulation activity by about 7% to about 20% relative to baseline. Aspect 22. Milvecin as used in any of the foregoing aspects, wherein administration of the treatment regimen causes an activation partial thromboplastin time (aPTT) to be prolonged by about 27% to about 64% relative to baseline. Aspect 23. Milvecin as used in any of the foregoing aspects, wherein the administration does not cause a statistically significant increase in severe bleeding complications. Aspect 24. Milvecin as used in any of the foregoing aspects, wherein the pharmaceutical composition comprising Milvecin (or a pharmaceutically acceptable salt or solvent thereof) is an oral solid pharmaceutical composition. Aspect 25. Milvecin as used in Aspect 24, wherein the oral solid pharmaceutical composition is a tablet. Aspect 26. Milvecin as used in Aspect 25, wherein the tablet is an immediate release tablet. Aspect 27. Milvecin as used in Aspect 25 or Aspect 26, wherein the disintegration time of the tablet in water is less than 20 seconds. Aspect 28. Milvecin as used in any of the foregoing aspects, wherein the administration produces a Milvecin plasma half-life in the range of about 13 hours to about 16 hours. Aspect 29. Milvecin as used in any of the foregoing aspects, wherein the administration allows the Milvecin plasma concentration to reach a steady state on about the 3rd to 6th day. Aspect 30. Milvecin as used in any of the above aspects, wherein the pharmaceutical composition comprising Milvecin (or a pharmaceutically acceptable salt or solvent thereof) is administered without regard to the timing of food intake. Aspect 31. Milvecin as used in any of the above aspects, wherein the human patient is unable to swallow a tablet dosage form. Aspect 32. Milvecin as used in any of aspects 25 to 31, wherein the tablet is dispersed in an aqueous medium to form an aqueous dispersion. Aspect 33. Milvecin as used in aspect 32, wherein the aqueous medium is water, saline, phosphate buffer, vegetable juice or fruit juice, including, for example, applesauce. Aspect 34. Milvecine as used in Aspect 32 or Aspect 33, wherein the aqueous dispersion is administered to the human patient via a nasogastric tube or a spoon. Aspect 35. Milvecine as used in any of Aspects 25 to 34, wherein the pharmaceutical composition is orally administered in the form of an aqueous dispersion by dispersing an oral tablet in an aqueous medium in less than 1 minute. Aspect 36. Milvecine for use in a method for preventing adverse cerebrovascular events or adverse cardiovascular events in a human patient with acute coronary syndrome, wherein the method comprises orally administering to the human patient a treatment regimen comprising: (i) a pharmaceutical composition comprising 25 mg of Milvecine (or a pharmaceutically acceptable salt or solvent thereof); and (ii) an antiplatelet therapy; wherein the pharmaceutical composition is administered twice daily. Aspect 37. Milvecin as used in Aspect 36, wherein the antiplatelet therapy is a P2Y12 inhibitor. Aspect 38. Milvecin as used in Aspect 37, wherein the P2Y12 inhibitor is clopidogrel, ticagrelor or prasugrel. Aspect 39. Milvecin as used in any of Aspects 36 to 38, wherein the antiplatelet therapy is aspirin. Aspect 40. Milvecin as used in any of Aspects 36 to 39, wherein the human patient is treated with aspirin and clopidogrel combination therapy from day 1 to day 21, followed by aspirin monotherapy for at least 90 days. Aspect 41. Milvecin as used in Aspect 40, wherein the patient is treated with aspirin and/or clopidogrel without adjusting the Milvecin dosage. Aspect 42. Milvecin as used in any of Aspects 36 to 41, wherein the Milvecin used is used for primary prevention of adverse cerebrovascular events or adverse cardiovascular events. Aspect 43. Milvecin as used in any of Aspects 36 to 42, wherein the Milvecin used is used for secondary prevention of adverse cerebrovascular events or adverse cardiovascular events. Aspect 44. Milvecin as used in any of Aspects 36 to 43, wherein the adverse cerebrovascular events or adverse cardiovascular events include one or more of stroke, heart attack or death. Aspect 45. Milvecin for use as in any one of Aspects 36 to 44, wherein the adverse cerebrovascular events or adverse cardiovascular events occur in an organ selected from the heart, brain, limbs, blood supply system or blood vessels. Aspect 46. Milvecin for use as in any one of Aspects 36 to 45, wherein the adverse cerebrovascular events or adverse cardiovascular events include one or more major adverse cardiovascular events (MACE) selected from the group consisting of cardiovascular death, non-fatal myocardial infarction, ischemic stroke and combinations thereof. Aspect 47. Milvecin for use in any of Aspects 36 to 46, wherein the adverse cerebrovascular event or adverse cardiovascular event comprises one or more major adverse vascular events (MAVE) selected from the group consisting of: MACE; major adverse limb events (MALEs) including one or more selected from acute limb ischemia, chronic limb ischemia, or major resection; symptomatic venous thromboembolic events, and combinations thereof. Aspect 48. Milvecin for use in any of Aspects 36 to 47, wherein the adverse cerebrovascular event or adverse cardiovascular event is selected from the group consisting of: arrhythmogenic cardiomyopathy (ACM), non-fatal myocardial infarction, ischemic stroke, and combinations thereof. Aspect 49. Milvecin for use in any of Aspects 36 to 47, wherein the adverse cerebrovascular event or adverse cardiovascular event comprises cardiovascular death. Aspect 50. Milvecine for use in any of Aspects 36 to 48, wherein the adverse cerebrovascular event or adverse cardiovascular event comprises arrhythmogenic cardiomyopathy (ACM). Aspect 51. Milvecine for use in a method for preventing adverse cardiovascular events in a human patient diagnosed with acute coronary syndrome, wherein the method comprises administering to the human patient a treatment regimen comprising: (i) 25.0 mg Milvecine twice daily and (ii) antiplatelet therapy; Adverse cardiovascular events were defined as one or more of the following: all-cause mortality (ACM); cardiovascular (CV) mortality; myocardial infarction (MI); unstable angina (UA); "all strokes" or "any stroke" (ischemic, hemorrhagic, or unknown etiology); ischemic stroke; acute limb ischemia (ALI); major vascular (non-traumatic) limb resection; symptomatic venous thromboembolism (VTE: (pulmonary embolism (PE), deep venous embolism (DVT)); blood-driven coronary revascularization; intravascular stent thrombosis; hospitalization for any reason, classified as (1) planned or unplanned, (2) due to an arterial or venous thrombotic event, or neither; or a transient ischemic attack (TIA); and wherein the method achieves at least one of the following clinical outcomes: (1) achieving a steady-state plasma concentration profile of Milvecine within about 6 days; (2) achieving a steady-state plasma concentration profile of Milvecine characterized by: (i) about 217 ng/mL to about 475 ng/mL, (ii) a steady-state mean (std) C _max of 346 (129) ng/mL, (iii) a steady-state _AUC 0-24 of about 4350 ng*h/mL to about 10230 ng*h/mL, or (iv) a steady-state mean (std) AUC _0-24 of 7290 (2940) ng*h/mL; (3) a change in QTc from baseline of less than 10 milliseconds; (4) a steady-state AUC or C max of ₃₄₆ (129) ng/mL; _max , there is no clinically relevant effect on any bleeding caused by milvicin exposure in the human patient; (5) minimizes hemostatic impairment in the human patient; (6) there is no clinically significant change in prothrombin time, wherein the maximum mean percentage change from baseline is about 5%; or (7) any combination of the foregoing clinical results. Aspect 52. Milvicin for use in a method of preventing adverse cardiovascular events in a human patient diagnosed with acute coronary syndrome, wherein the method comprises administering to the human patient a treatment regimen comprising: (i) 25.0 mg of milvicin twice daily and (ii) antiplatelet therapy; Adverse cardiovascular events were defined as one or more of the following: all-cause death (ACM); cardiovascular (CV) death; myocardial infarction (MI); unstable angina (UA); "all strokes" or "any stroke" (ischemic, hemorrhagic, or of unknown etiology); ischemic stroke; acute limb ischemia (ALI); major vascular (non-invasive) limb resection; symptomatic venous thromboembolism (VTE: pulmonary embolism (PE), deep venous thrombosis (DVT)); ischemia-driven coronary revascularization; intravascular stent thrombosis; hospitalization for any reason, categorized as (1) planned or unplanned, (2) due to an arterial or venous thrombotic event, or neither; or transient ischemic attack (TIA). Aspect 53. Milvecine for use in a method of preventing all-cause mortality in a human patient diagnosed with acute coronary syndrome, wherein the method comprises administering to the human patient a treatment regimen comprising: (i) 25.0 mg of Milvecine twice daily and (ii) antiplatelet therapy. Aspect 54. Milvecine for use in a method of preventing cardiovascular mortality in a human patient diagnosed with acute coronary syndrome, wherein the method comprises administering to the human patient a treatment regimen comprising: (i) 25.0 mg of Milvecine twice daily and (ii) antiplatelet therapy. Aspect 55. Milvecine for use in a method of preventing myocardial infarction in a human patient diagnosed with acute coronary syndrome, wherein the method comprises administering to the human patient a treatment regimen comprising: (i) 25.0 mg of Milvecine twice daily and (ii) antiplatelet therapy. Aspect 56. Milvecine for use in a method of preventing stroke in a human patient diagnosed with acute coronary syndrome, wherein the method comprises administering to the human patient a treatment regimen comprising: (i) 25.0 mg of Milvecine twice daily and (ii) antiplatelet therapy. Aspect 57. Milvecine for use in a method of preventing ischemic stroke in a human patient diagnosed with acute coronary syndrome, wherein the method comprises administering to the human patient a treatment regimen comprising: (i) 25.0 mg of Milvecine twice daily and (ii) antiplatelet therapy. Aspect 58. Milvecine for use in a method of preventing ischemic stroke in a human patient diagnosed with acute coronary syndrome, wherein the method comprises administering to the human patient a treatment regimen comprising: (i) 25.0 mg of Milvecine twice daily and (ii) antiplatelet therapy. Aspect 59. Milvecine for use in a method for preventing unstable angina in a human patient diagnosed with acute coronary syndrome, wherein the method comprises administering to the human patient a treatment regimen comprising: (i) 25.0 mg of Milvecine twice daily and (ii) antiplatelet therapy. Aspect 60. Milvecine for use in a method for preventing acute limb ischemia in a human patient diagnosed with acute coronary syndrome, wherein the method comprises administering to the human patient a treatment regimen comprising: (i) 25.0 mg of Milvecine twice daily and (ii) antiplatelet therapy. Aspect 61. Milvecine for use in a method of preventing major vascular (non-invasive) limb resection in a human patient diagnosed with acute coronary syndrome, wherein the method comprises administering to the human patient a treatment regimen comprising: (i) 25.0 mg of Milvecine twice daily and (ii) antiplatelet therapy. Aspect 62. Milvecine for use in a method of preventing symptomatic venous thromboembolism in a human patient diagnosed with acute coronary syndrome, wherein the method comprises administering to the human patient a treatment regimen comprising: (i) 25.0 mg of Milvecine twice daily and (ii) antiplatelet therapy. Aspect 63. Milvecine for use in a method of preventing pulmonary embolism in a human patient diagnosed with acute coronary syndrome, wherein the method comprises administering to the human patient a treatment regimen comprising: (i) 25.0 mg of Milvecine twice daily and (ii) antiplatelet therapy. Aspect 64. Milvecine for use in a method of preventing deep venous embolism in a human patient diagnosed with acute coronary syndrome, wherein the method comprises administering to the human patient a treatment regimen comprising: (i) 25.0 mg of Milvecine twice daily and (ii) antiplatelet therapy. Aspect 65. Milvecine for use in a method of preventing deep venous embolism in a human patient diagnosed with acute coronary syndrome, wherein the method comprises administering to the human patient a treatment regimen comprising: (i) 25.0 mg of Milvecine twice daily and (ii) antiplatelet therapy. Aspect 66. Milvecine for use in a method of preventing ischemia-driven coronary revascularization in a human patient diagnosed with acute coronary syndrome, wherein the method comprises administering to the human patient a treatment regimen comprising: (i) 25.0 mg of Milvecine twice daily and (ii) antiplatelet therapy. Aspect 67. Milvecine for use in a method of preventing stent thrombosis in a human patient diagnosed with acute coronary syndrome, wherein the method comprises administering to the human patient a treatment regimen comprising: (i) 25.0 mg of Milvecine twice daily and (ii) antiplatelet therapy. Aspect 68. Milvecine for use in a method of preventing hospitalization for any reason in a human patient diagnosed with acute coronary syndrome, wherein the hospitalization is classified as (a) planned or unplanned, (b) due to an arterial or venous thrombotic event, or neither, wherein the method comprises administering to the human patient a regimen comprising: (i) 25.0 mg of Milvecine twice daily and (ii) antiplatelet therapy. Aspect 69. Milvecine for use in a method of preventing a transient ischemic episode in a human patient diagnosed with acute coronary syndrome, wherein the method comprises administering to the human patient a treatment regimen comprising: (i) 25.0 mg of Milvecine twice daily and (ii) antiplatelet therapy. Aspect 70. Milvecine for use in a method of preventing an adverse cerebrovascular event in a human patient with acute coronary syndrome, wherein the method comprises orally administering to the human patient a treatment regimen comprising: (i) 25 mg of Milvecine; and (ii) antiplatelet therapy twice daily. Aspect 71. Milvecine for use in a method of preventing adverse cardiovascular events in a human patient with acute coronary syndrome, wherein the method comprises orally administering to the human patient twice daily a treatment regimen comprising: (i) 25 mg of Milvecine; and (ii) antiplatelet therapy. Aspect 72. Milvecine for use in a method of preventing adverse cerebrovascular events in a human patient with acute coronary syndrome, wherein the method comprises orally administering to the human patient a treatment regimen comprising: (i) a pharmaceutical composition comprising 25 mg of Milvecine and a pharmaceutically acceptable formulation; and (ii) antiplatelet therapy; wherein the pharmaceutical composition is administered twice daily. Aspect 73. Milvecine for use in a method of preventing adverse cardiovascular events in a human patient with acute coronary syndrome, wherein the method comprises administering to the human patient a treatment regimen comprising: (i) a pharmaceutical composition comprising 25 mg of Milvecine and a pharmaceutically acceptable formulation; and (ii) an antiplatelet therapy; wherein the pharmaceutical composition is administered twice daily. Aspect 74. Milvecine as used in any of Aspects 70 to 73, wherein the adverse cerebrovascular events or cardiovascular events comprise ischemic stroke. Aspect 75. Milvecine as used in any of Aspects 70 to 74, wherein the adverse cerebrovascular events or cardiovascular events comprise one or more of stroke, heart attack, or death. Aspect 76. Milvecin for use as in any of Aspects 70 to 75, wherein the adverse cerebrovascular events or adverse cardiovascular events occur in an organ selected from the heart, brain, limbs, blood supply system or blood vessels. Aspect 77. Milvecin for use as in any of Aspects 70 to 76, wherein the adverse cerebrovascular events or adverse cardiovascular events include one or more major adverse cardiovascular events (MACE) selected from the group consisting of cardiovascular death, non-fatal myocardial infarction, ischemic stroke and combinations thereof. Aspect 78. Milvecin for use in any of Aspects 70 to 77, wherein the adverse cerebrovascular events or adverse cardiovascular events include one or more major adverse vascular events (MAVE) selected from the group consisting of: MACE; major adverse limb events (MALE), including one or more selected from acute limb ischemia, chronic limb ischemia, or major resection; symptomatic venous thromboembolic events, and combinations thereof. Aspect 79. Milvecin for use in any of Aspects 70 to 78, wherein the adverse cerebrovascular events or adverse cardiovascular events are selected from the group consisting of: arrhythmogenic cardiomyopathy (ACM), non-fatal myocardial infarction, ischemic stroke, and combinations thereof. Aspect 80. Milvecin for use in any of Aspects 70 to 79, wherein the adverse cerebrovascular events or adverse cardiovascular events include cardiovascular death. Aspect 81. Milvecin for use in any of Aspects 70 to 80, wherein the adverse cerebrovascular events or adverse cardiovascular events comprise arrhythmogenic cardiomyopathy (ACM). Aspect 82. Milvecin for use in a method for preventing ischemic stroke in a human patient with acute coronary syndrome, wherein the method comprises orally administering to the human patient twice daily a regimen comprising: (i) 25 mg of Milvecin; and (ii) antiplatelet therapy. Aspect 83. Milvecin for use in any of the preceding Aspects, wherein the administration produces a steady plasma concentration profile of Milvecin within about 3 days. Aspect 84. Milvecin for use as in any of the preceding aspects, wherein the administration produces a steady-state plasma concentration profile of Milvecin having the following characteristics: (i) a steady-state _Cmax in the range of about 217 ng/mL to about 475 ng/mL, (ii) a steady-state mean (std) _Cmax of 346 (129) ng/mL, (iii) a steady-state _AUC0-24 in the range of about 4350 ng*h/mL to about 10230 ng*h/mL, and (iv) a steady-state mean (std) _AUC0-24 of 7290 (2940) ng*h/mL. Aspect 85. Milvecin for use as in any of the preceding aspects, wherein the administration does not result in clinically significant QTc interval prolongation. Aspect 86. Milvecin for use as in any of the preceding aspects, wherein the administration has no clinically relevant effect on any bleeding resulting from Milvecin exposure as measured by steady-state AUC or _Cmax . Aspect 87. Milvecin for use as in any of the preceding aspects, wherein the administration minimizes hemostatic impairment in the human patient. Aspect 88. Milvecin for use as in any of the preceding aspects, wherein the treatment regimen comprises an immediate-release tablet. Aspect 89. Milvecin for use as in Aspect 88, wherein the immediate-release tablet has a disintegration time of less than 20 seconds in water at 37°C. Aspect 90. Milvecin for use as in any of the preceding aspects, wherein the administration results in a Milvecin plasma terminal half-life in the range of about 13 hours to about 16 hours. Aspect 91. Milvecin for use as in any of the preceding aspects, wherein the treatment regimen is administered without regard to the timing of food intake. Aspect 92. Milvecin for use as in any of aspects 88 to 91, wherein the immediate release tablet is dispersed in an aqueous medium to form an aqueous dispersion. Aspect 93. Milvecin for use as in aspect 92, wherein the aqueous medium comprises water or applesauce. Aspect 94. Milvecin as used in any of the foregoing aspects, wherein the antiplatelet therapy comprises administering a single antiplatelet therapy (SAPT) during a period ranging from about 1 month to about 36 months. Aspect 95. Milvecin as used in aspect 94, wherein the antiplatelet therapy comprises administering SAPT during a period ranging from about 3 months to about 12 months. Aspect 96. Milvecin as used in aspect 94, wherein the antiplatelet therapy comprises administering SAPT during a period ranging from about 6 months to about 12 months. Aspect 97. Milvecin as used in aspect 94, wherein the antiplatelet therapy comprises administering SAPT for 3 months. Aspect 98. Milvecin as used in aspect 94, wherein the antiplatelet therapy comprises SAPT administered for 6 months. Aspect 99. Milvecin as used in aspect 94, wherein the antiplatelet therapy comprises SAPT administered for 12 months. Aspect 100. Milvecin as used in aspect 94, wherein the antiplatelet therapy comprises SAPT administered for 24 months. Aspect 101. Milvecin as used in any of aspects 94 to 100, wherein the SAPT is selected from aspirin and a P2Y12 inhibitor. Aspect 102. Milvecin as used in any of aspects 94 to 101, wherein the SAPT comprises aspirin. Aspect 103. Milvecin as used in aspect 102, wherein aspirin is administered once daily. Aspect 104. Milvecin as used in Aspect 102, wherein aspirin is administered once daily during a period ranging from about 3 months to about 3 years. Aspect 105. Milvecin as used in Aspect 102, wherein aspirin is administered once daily for 3 months. Aspect 106. Milvecin as used in Aspect 102, wherein aspirin is administered once daily for 6 months. Aspect 107. Milvecin as used in Aspect 102, wherein aspirin is administered once daily for 12 months. Aspect 108. Milvecin as used in Aspect 102, wherein aspirin is administered once daily for 24 months. Aspect 109. Milvecin as used in Aspect 102, wherein aspirin is administered once daily for 36 months. Aspect 110. Milvecin as used in Aspect 102, wherein aspirin is administered twice daily. Aspect 111. Milvecin as used in Aspect 102, wherein aspirin is administered once daily in an amount of 75 mg to 100 mg. Aspect 112. Milvecin as used in Aspect 102, wherein aspirin is administered once daily in an amount of 75 mg to 100 mg for a period of 12 months. Aspect 113. Milvecin as used in any of Aspects 94 to 101, wherein the SAPT comprises a P2Y12 inhibitor. Aspect 114. Milvecin for use in any of Aspects 94 to 101, wherein the SAPT comprises a P2Y12 inhibitor selected from prasugrel, clopidogrel, celatropin or ticagrelor. Aspect 115. Milvecin for use in Aspects 113 or 114, wherein the P2Y12 inhibitor is administered during a period ranging from about 3 months to about 6 months. Aspect 116. Milvecin for use in Aspects 113 or 114, wherein the P2Y12 inhibitor comprises clopidogrel. Aspect 117. Milvecin for use in Aspects 113 or 114, wherein the P2Y12 inhibitor comprises ticagrelor. Aspect 118. Milvecin for use as in Aspect 113 or 114, wherein the P2Y12 inhibitor comprises ticagrelor administered at 90 mg twice daily. Aspect 119. Milvecin for use as in Aspect 113 or 114, wherein the P2Y12 inhibitor comprises ticagrelor administered at 90 mg twice daily over a period of 3 years. Aspect 120. Milvecin for use as in Aspect 113 or 114, wherein the P2Y12 inhibitor comprises ticagrelor administered first, followed by aspirin monotherapy administered at 20 mg twice daily. Aspect 121. Milvecin for use in any of Aspects 113 or 114, wherein the SAPT comprises first administering aspirin monotherapy for a period ranging from 30 days to 90 days, followed by administration of clopidogrel monotherapy. Aspect 122. Milvecin for use in any of Aspects 113 or 114, wherein the SAPT comprises first administering aspirin monotherapy for a period ranging from 60 days, followed by administration of clopidogrel monotherapy. Aspect 123. Milvecin for use in any of Aspects 94 to 122, wherein the SAPT comprises first administering aspirin monotherapy for a period ranging from 90 days, followed by administration of clopidogrel monotherapy. Aspect 124. Milvecin for use as in any of Aspects 94 to 122, wherein the SAPT comprises first administering aspirin monotherapy, followed by administration of clopidogrel monotherapy for a period of at least 2 months. Aspect 125. Milvecin for use as in any of Aspects 94 to 122, wherein the SAPT comprises first administering aspirin monotherapy for a period ranging from 30 days to 90 days, followed by administration of clopidogrel monotherapy for a period of at least 2 months. Aspect 126. Milvecin for use as in any of Aspects 1 to 93, wherein the antiplatelet therapy comprises dual antiplatelet therapy (DAPT). Aspect 127. Milvecin as used in Aspect 126, wherein the DAPT comprises aspirin and prasugrel. Aspect 128. Milvecin as used in Aspect 126, wherein the DAPT comprises aspirin and prasugrel administered for 12 months. Aspect 129. Milvecin as used in Aspect 126, wherein the DAPT comprises aspirin and clopidogrel administered for a period of 21 days to 12 months. Aspect 131. Milvecin as used in Aspect 126, wherein the DAPT comprises aspirin and clopidogrel administered for a period of 21 days. Aspect 132. Milvecin as used in Aspect 126, wherein the DAPT comprises aspirin and clopidogrel administered for a period of 6 months. Aspect 133. Milvecin as used in Aspect 126, wherein the DAPT comprises aspirin and clopidogrel administered for a period of 12 months. Aspect 134. Milvecin as used in Aspect 126, wherein the DAPT comprises aspirin and ticagrelor. Aspect 135. Milvecin as used in Aspect 126, wherein the DAPT comprises aspirin and ticagrelor administered for 12 months. Aspect 136. Milvecin as used in Aspect 126, wherein the antiplatelet therapy comprises DAPT consisting of: aspirin administered once daily at 75 mg to 100 mg, and a P2Y12 inhibitor. Aspect 137. Milvecin as used in Aspect 126, wherein the antiplatelet therapy comprises administering DAPT first, followed by administering SAPT. Aspect 138. Milvecin as used in Aspect 126, wherein the antiplatelet therapy comprises first administering DAPT, followed by aspirin monotherapy. Aspect 139. Milvecin as used in Aspect 126, wherein the antiplatelet therapy comprises DAPT consisting of: 75 to 100 mg of aspirin and a P2Y12 inhibitor once daily for a first period of 12 months, followed by aspirin monotherapy for a second period of 6 months. Aspect 140. Milvecin as used in Aspect 126, wherein the antiplatelet therapy comprises DAPT consisting of: 75 to 100 mg aspirin and a P2Y12 inhibitor administered once daily for a first period of 21 days, followed by aspirin monotherapy for a second period of 6 months. Aspect 141. Milvecin as used in Aspect 126, wherein the antiplatelet therapy comprises DAPT consisting of: 75 to 100 mg aspirin and 75 mg clopidogrel administered once daily for a first period of 21 days, followed by aspirin monotherapy for a second period of 6 months. Aspect 142. Milvecin as used in Aspect 126, wherein the antiplatelet therapy comprises DAPT consisting of 75 to 100 mg aspirin and a P2Y12 inhibitor administered once daily for a first period of 21 days, followed by aspirin monotherapy for a second period of 12 months. Aspect 143. Milvecin as used in Aspect 126, wherein the antiplatelet therapy comprises DAPT consisting of 75 to 100 mg aspirin once daily and 90 mg ticagrelor twice daily. Aspect 144. Milvecin as used in Aspect 126, wherein the antiplatelet therapy comprises DAPT consisting of 75 to 100 mg aspirin once daily and 90 mg ticagrelor twice daily for a period of 12 months. Aspect 145. Milvecin as used in Aspect 126, wherein the antiplatelet therapy comprises DAPT consisting of 81 to 100 mg aspirin once daily and 90 mg ticagrelor twice daily. Aspect 146. Milvecin as used in Aspect 126, wherein the antiplatelet therapy comprises DAPT consisting of 81 to 100 mg aspirin once daily and 90 mg ticagrelor twice daily for 3 years. Aspect 147. Milvecin as used in Aspect 126, wherein the antiplatelet therapy comprises DAPT consisting of 75 to 100 mg aspirin once daily and 90 mg ticagrelor twice daily for a first period of 12 months, followed by 75 to 100 mg aspirin monotherapy once daily for a second period of 12 months. Aspect 148. Milvecin as used in Aspect 126, wherein the antiplatelet therapy comprises DAPT consisting of 75 to 100 mg aspirin once daily and 90 mg ticagrelor twice daily for a first period of 12 months, followed by 90 mg ticagrelor twice daily for a second period of 23 months. Aspect 149. Milvecin as used in any of the preceding Aspects, wherein the clinical benefit of the treatment regimen in reducing the incidence of ischemic stroke is maintained throughout the 90-day treatment period. Aspect 150. Milvecin as used in any of the preceding Aspects, wherein the clinical benefit of reducing the incidence of ischemic stroke is maintained throughout the 180-day treatment period. Aspect 151. Milvecin for use as in any of the preceding aspects, wherein the clinical benefit of reducing the incidence of ischemic stroke is maintained throughout the 12-month treatment period. Aspect 152. Milvecin for use as in any of the preceding aspects, wherein administration of the treatment regimen reduces the patient's FXI coagulation activity by about 7% to about 20% relative to baseline. Aspect 153. Milvecin for use as in any of the preceding aspects, wherein administration of the treatment regimen causes an increase in activated partial thromboplastin time (aPTT) by about 27% to about 64% relative to baseline. Aspect 154. Milvecin for use as in any of the preceding aspects, wherein the administration does not cause a statistically significant increase in severe bleeding complications. Aspect 155. Milvecin as used in any of the preceding aspects, wherein the pharmaceutical composition comprising Milvecin (or a pharmaceutically acceptable salt or solvent thereof) is an oral solid pharmaceutical composition. Aspect 156. Milvecin as used in Aspect 155, wherein the oral solid pharmaceutical composition is a tablet. Aspect 157. Milvecin as used in Aspect 156, wherein the tablet is an immediate release tablet. Aspect 158. Milvecin as used in any of the preceding aspects, wherein the human patient is unable to swallow a tablet dosage form. Aspect 159. Milvecin as used in any of Aspects 156 to 158, wherein the tablet is dispersed in an aqueous medium to form an aqueous dispersion. Aspect 160. Milvecin as used in Aspect 159, wherein the aqueous medium is water, saline, phosphate buffer, vegetable juice or fruit juice, including, for example, applesauce. Aspect 161. Milvecin as used in Aspect 159 or Aspect 160, wherein the aqueous dispersion is administered to the human patient via a nasogastric tube or a spoon. Aspect 162. Milvecin as used in any of the foregoing aspects, wherein the pharmaceutical composition is orally administered in the form of an aqueous dispersion by dispersing an oral tablet in an aqueous medium in less than 1 minute. Aspect 163. Milvecin as used in any of the foregoing aspects, wherein the pharmaceutical composition comprises an amorphous form of Milvecin mixed with a polymer. Aspect 164. Milvecin for use as in any of the above aspects, wherein the pharmaceutical composition comprises a spray-dried amorphous solid dispersion consisting of 75 w/w% Milvecin and 25 w/w% HPMC-AS. Aspect 165. Milvecin for use as in any of the above aspects, wherein the Milvecin used does not cause clinically significant QTc interval prolongation. Other aspects Aspect 1. A method for preventing adverse cerebrovascular events or adverse cardiovascular events in a human patient with acute coronary syndrome, wherein the method comprises administering to the human patient a treatment regimen comprising: (i) a pharmaceutical composition comprising 25 mg of milvithin (or a pharmaceutically acceptable salt or solvent thereof); and (ii) an antiplatelet therapy selected from the group consisting of aspirin, a P2Y12 inhibitor, and a combination thereof; wherein the pharmaceutical composition is administered twice daily. Aspect 2. The method of aspect 1, wherein the antiplatelet therapy is a P2Y12 inhibitor. Aspect 3. The method of aspect 2, wherein the P2Y12 inhibitor is clopidogrel, ticagrelor, or prasugrel. Aspect 4. The method of any one of aspects 1 to 3, wherein the antiplatelet therapy is aspirin. Aspect 5. The method of any one of Aspects 1 to 4, wherein the human patient is treated with aspirin and clopidogrel combination therapy from day 1 to day 21, followed by aspirin monotherapy for at least 90 days. Aspect 6. The method of Aspect 5, wherein the patient is treated with aspirin and/or clopidogrel without adjusting the dose of milvitra. Aspect 7. The method of any of the preceding aspects, wherein the method is used for primary prevention of adverse cerebrovascular events or adverse cardiovascular events. Aspect 8. The method of any of the preceding aspects, wherein the method is used for secondary prevention of adverse cerebrovascular events or adverse cardiovascular events. Aspect 9. The method of any of Aspects 1 to 8, wherein the adverse cerebrovascular events or adverse cardiovascular events include one or more of stroke, heart attack, or death. Aspect 10. The method of any one of aspects 1 to 9, wherein the adverse cerebrovascular events or adverse cardiovascular events occur in an organ selected from the heart, brain, limbs, blood supply system or blood vessels. Aspect 11. The method of any one of aspects 1 to 10, wherein the adverse cerebrovascular events or adverse cardiovascular events include one or more major adverse cardiovascular events (MACE) selected from the group consisting of cardiovascular death, non-fatal myocardial infarction, ischemic stroke and combinations thereof. Aspect 12. The method of any one of aspects 1 to 11, wherein the adverse cerebrovascular events or adverse cardiovascular events include one or more major adverse vascular events (MAVE) selected from the group consisting of MACE; major adverse limb events (MALE), including one or more selected from acute limb ischemia, chronic limb ischemia or major resection; symptomatic venous thromboembolic events, and combinations thereof. Aspect 13. The method of any one of Aspects 1 to 12, wherein the adverse cerebrovascular event or adverse cardiovascular event is selected from the group consisting of arrhythmogenic cardiomyopathy (ACM), non-fatal myocardial infarction, ischemic stroke, and combinations thereof. Aspect 14. The method of any one of Aspects 1 to 11, wherein the adverse cerebrovascular event or adverse cardiovascular event comprises cardiovascular death. Aspect 15. The method of any one of Aspects 1 to 10, wherein the adverse cerebrovascular event or adverse cardiovascular event comprises arrhythmogenic cardiomyopathy (ACM). Aspect 16. A method for preventing adverse cardiovascular events in a human patient diagnosed with acute coronary syndrome, wherein the method comprises administering to the human patient a treatment regimen comprising: (i) a pharmaceutical composition comprising 25 mg of milvithin (or a pharmaceutically acceptable salt or solvent thereof) and one or more pharmaceutically acceptable formulations, and (ii) an antiplatelet therapy selected from the group consisting of aspirin, a P2Y12 inhibitor, and combinations thereof; wherein the pharmaceutical composition is administered twice daily; and wherein the adverse cardiovascular event is selected from one or more of the following groups: all-cause mortality (ACM); cardiovascular (CV) death; myocardial infarction (MI); unstable angina (UA); "all stroke" or "any stroke" (ischemic, hemorrhagic or unknown etiology); ischemic stroke; acute limb ischemia (ALI); severe hemorrhage non-invasive) limb resection; symptomatic venous thromboembolism (VTE: (pulmonary embolism (PE), deep venous thrombosis (DVT)); ischemia-driven coronary artery revascularization; stent thrombosis; hospitalization for any reason, categorized as (1) planned or unplanned, (2) due to arterial or venous thrombotic event or neither; and transient ischemic attack (TIA). Aspect 17. A method as in aspect 16, wherein administration of the treatment regimen results in a relative risk reduction (RRR) of at least 25% for symptomatic venous thromboembolism (VTE: (pulmonary embolism (PE), deep venous embolism (DVT)) in the patient without increased bleeding, relative to a placebo group. Aspect 18. A method as in aspect 16, wherein the adverse cardiovascular event is one or more of CV death, MI, or ischemic stroke. Aspect 19. A method for reducing the incidence of one or more adverse thrombotic events selected from new ischemic stroke, MI, or all-cause mortality in a human patient diagnosed with acute coronary syndrome, wherein the method comprises administering to the human patient a treatment regimen comprising: (i) from about 25 mg to about 100 mg of mg of milvithin (or a pharmaceutically acceptable salt or solvent thereof) and one or more pharmaceutically acceptable formulations, and (ii) an antiplatelet therapy selected from the group consisting of aspirin, a P2Y12 inhibitor, and a combination thereof; wherein the pharmaceutical composition is administered twice daily. Aspect 20. A method as in aspect 19, wherein administration of the treatment regimen produces a relative risk of 0.85 or less relative to a placebo. Aspect 21. A method for preventing ischemic stroke in a human patient diagnosed with acute coronary syndrome, wherein the method comprises administering to the human patient a treatment regimen comprising: (i) comprising 25 mg of milvithin (or a pharmaceutically acceptable salt or solvent thereof) and one or more pharmaceutically acceptable formulations, and (ii) an antiplatelet therapy selected from the group consisting of aspirin, a P2Y12 inhibitor, and a combination thereof; wherein the pharmaceutical composition is administered twice daily. Aspect 22. The method of aspect 21, wherein the administration of the treatment regimen results in a relative risk reduction (RRR) of at least 25% in the occurrence of a clinical ischemic stroke event in the patient without an increase in bleeding compared to the placebo group. Aspect 23. The method of aspect 21 or aspect 22, wherein the clinical benefit of the treatment regimen in reducing the incidence of clinical ischemic stroke is maintained throughout the 90-day treatment period. Aspect 24. The method of any of the preceding aspects, wherein the administration of the treatment regimen results in a decrease in the patient's FXI coagulation activity by about 7% to about 20% relative to baseline. Aspect 25. The method of any of the preceding aspects, wherein the administration of the treatment regimen results in an increase in activated partial thromboplastin time (aPTT) by about 27% to about 64% relative to baseline. Aspect 26. The method of any of the preceding aspects, wherein the administration does not result in a statistically significant increase in severe bleeding complications. Aspect 27. The method of any of the preceding aspects, wherein the pharmaceutical composition comprising milvithrin (or a pharmaceutically acceptable salt or solvent thereof) is an oral solid pharmaceutical composition. Aspect 28. The method of aspect 27, wherein the oral solid pharmaceutical composition is a tablet. Aspect 29. The method of aspect 28, wherein the tablet is an immediate release tablet. Aspect 30. The method of aspect 28 or aspect 29, wherein the disintegration time of the tablet in water is less than 20 seconds. Aspect 31. The method of any of the foregoing aspects, wherein the administration produces a plasma half-life of miltvicin in the range of about 13 hours to about 16 hours. Aspect 32. The method of any of the foregoing aspects, wherein the administration causes the plasma concentration of miltvicin to reach a steady state on about the 3rd to 6th day. Aspect 33. The method of any of the foregoing aspects, wherein the pharmaceutical composition comprising miltvicin (or a pharmaceutically acceptable salt or solvent thereof) is administered without regard to the timing of food intake. Aspect 34. The method of any of the preceding aspects, wherein the human patient is unable to swallow a tablet dosage form. Aspect 35. The method of any of aspects 28 to 34, wherein the tablet is dispersed in an aqueous medium to form an aqueous dispersion. Aspect 36. The method of aspect 35, wherein the aqueous medium is water, saline, phosphate buffer, vegetable juice or fruit juice, including, for example, applesauce. Aspect 37. The method of aspect 35 or aspect 36, wherein the aqueous dispersion is administered to the human patient via a nasogastric tube or spoon. Aspect 38. The method of any of aspects 28 to 37, wherein the pharmaceutical composition is orally administered in the form of an aqueous dispersion by dispersing an oral tablet in an aqueous medium in less than 1 minute.

Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the embodiments described herein.

All publications, patents, and patent applications mentioned in this specification are incorporated herein by reference as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated herein by reference. Examples Example 1. A Phase 3 , Randomized, Double-Blind, Placebo-Controlled, Event-Driven Study to Demonstrate the Efficacy and Safety of the Oral Factor XIa Inhibitor Milvecin Following Recent Acute Coronary Syndrome

This is a Phase 3, multicenter, randomized, double-blind, placebo-controlled, parallel-group, event-driven, superiority, group sequential study to evaluate the efficacy and safety of milvicin in participants recruited within 7 days of ACS (defined as biomarker-positive STEMI or NSTEMI or UA) who have undergone cardiac catheterization for PCI or are being conservatively managed with or without catheterization and are receiving standard of care antiplatelet therapy at the discretion of the investigator .

Approximately 16,000 participants were randomized within 7 days of an ACS event to achieve a prespecified number of 875 participants with one or more primary efficacy outcome events.

Inclusion Criteria : Each potential participant must meet all of the following criteria to be recruited into the study: Age 1. ≥18 years old. Participant Type and Disease Characteristics 2. Participants must have had index events that met all 3 of the following criteria within 7 days prior to randomization: a) Clinical syndrome consistent with spontaneous cardiac ischemia b) Diagnosis of ACS (i.e., STEMI, non-STEMI, or UA) c) Elevated cardiac biomarkers (e.g., sarcoma I, sarcoma T, CK-MB) above the upper limit of normal as measured by local laboratories. 3. Participants must have at least 2 of the following risk factors: a) Age 65 years or older b) Diabetes mellitus c) History of prior MI (in addition to the index ACS event) d) Multivessel CAD (Note: this can be a history of multivessel CAD or a history of univessel CAD where the index ACS event occurred in a different coronary artery, thereby defining multivessel CAD) e) History of CABG surgery prior to the index ACS event f) History of PAD or cerebrovascular disease (e.g., atherosclerosis of the carotid arteries, intracranial artery stenosis. Please note that enrollment excludes participants with a history of TIA or stroke.) g) Conservative management (i.e., no PCI or CABG after the index ACS event) h) Any one or more of the following angiographic high-risk features a. Total stent length >30 mm b. Thrombotic target lesionsc. Bifurcation lesions treated with more than one endovascular stentd. Calcified target lesions treated with atherectomye. Treatment of an obstructed left main artery or proximal left anterior descending artery for index ACS (or clinical diagnosis of anterior STEMI) Weight is not applicable. Sex and contraception / pregnancy prevention requirements4 . All female participants of childbearing potential must undergo a high-sensitivity negative serum β-hCG or urine test at screening. 5. Female participants must not be pregnant, breastfeeding, or planning pregnancy until day 4 (5 half-lives) after the last dose of study intervention. 6. Female participants must be a. of no childbearing potential b. of childbearing potential and using a highly effective method of contraception (failure rate <1% per year when used consistently and correctly) and agree to maintain a highly effective method until Day 4 (5 half-lives) after the last dose of the study intervention - the end of relevant exposure. 7. Female participants using hormonal contraceptives should use an additional non-hormonal method of contraception (higher than required in inclusion guideline 6b) until Day 4 (5 half-lives) after the last dose of the study intervention - the end of relevant exposure.

Exclusion Criteria : Any potential participant who meets any of the following criteria will be excluded from participation in the study: Medical Conditions 1. MI secondary to ischemia due to increased oxygen demand or decreased oxygen delivery (Type 2 MI) or perioperative MI as the index ACS event. 2. Minimal or non-obstructive CAD (i.e., visual stenosis <50% as determined by the investigator) based on angiography performed prior to any PCI for the index ACS event. 3. Planned CABG or staged PCI subsequent to randomization (Note: Participants may be evaluated for recruitment after completion of planned staged PCI). 4. Any condition requiring long-term anticoagulation therapy as determined by the investigator and/or based on local guidelines. Note: Participants who have an indication for long-term antiplatelet therapy following implantation of a bioprosthetic non-mechanical valve (e.g., transcatheter aortic valve replacement) do not meet this exclusion criterion and are eligible for study participation. 5. Conditions that significantly increase the risk of bleeding (e.g., clinically significant bleeding within the first 3 months, known bleeding predisposition, etc.) 6. Requirement for permanent dialysis or eGFR <15 mL/min/1.73 ^m2 at screening. 7. Current active liver disease (e.g., acute hepatitis and known cirrhosis), including participants receiving antiviral therapy for hepatitis 8. Active cancer undergoing chemotherapy or radiation or immunotherapy 9. CABG performed during the index event 10. History of ischemic stroke or TIA 11. Killip grade 3 or 4 at the time of randomization 12. History of any severe drug allergy (e.g., systemic anaphylaxis, Stevens-Johnson Syndrome, toxic epidermal necrolysis, DRESS) 13. Known allergy, hypersensitivity, or intolerance to Milvecin or its formulations (referring to Milvecin IB) 14. Known aPTT prolongation >1.5×ULN or known congenital FXI deficiency Prior / concomitant therapy 15. Planned use of any contraindicated therapy, concomitant therapy, including isoniazid (INH) Prior / concurrent clinical study experience 16. Receipt of an investigational study intervention or use of an invasive investigational medical device within 4 weeks prior to the planned first dose of study intervention, or current enrollment in an investigational study diagnostic assessment 17. Any of the following laboratory results based on local laboratories, confirmed by repeat verification prior to randomization, meeting the criteria described below: - Platelet count <75,000/μL - ALT >3x ULN - Total bilirubin ≥1.5×ULN unless an alternative causative factor is identified, such as Gilbert's Syndrome - hemoglobin <8.0 g/dL Other Exclusion Criteria 18. Employees of the Investigator or the Research Site who are directly participating in the proposed study or participating in other studies at the direction of the Investigator or the Research Site, and family members of such employees or Investigators 19. Any condition that, in the Investigator's opinion, participation is not of primary concern to the participant (e.g., impairing health), or that may prevent, limit, or confound protocol-specified assessments or that is expected to result in a life expectancy of <12 months 20. At screening, any participant will not be considered to follow the study contact schedule, or to allow contact with the participant or designated family members or healthcare practitioners, until the end of the study, in order to determine any endpoint events and/or vital status, or the participant should be discontinued from the study medication or discontinued from the study early. 21. Psychiatric condition or cognitive impairment/dementia that prevents the participant from understanding the nature, potential risks, and benefits of the study. 22. Incarcerated participants, including prisoners or participants held against their will for treatment of a mental illness. 23. Known current drug abuse. Study Treatment and Interviewing

Participants received milvicin (25 mg orally twice daily) or matching placebo on a background of standard-of-care antiplatelet therapy. Randomized participants were stratified according to the intended antiplatelet strategy determined by the investigator as: 1) DAPT duration >90 days (with or without downgrading to SAPT); 2) DAPT duration ≤90 days with downgrading to SAPT; or 3) SAPT. Based on existing protocol assumptions, the total study duration was approximately 3.5 years. Background antiplatelet therapy:

The planned use of SAPT or DAPT and the duration of DAPT will be adjudicated by the investigator based on standard of care criteria and recorded at the time of randomization.

SAPT can be low-dose aspirin (≤100 mg per day) or a P2Y12 inhibitor.

P2Y12 inhibitors (alone or in combination with aspirin) can be clopidogrel, ticagrelor, or prasugrel.

P2Y12 inhibitors may be changed or discontinued. Such changes must be recorded on the eCRF.

De-escalation of DAPT to SAPT may require discontinuation of aspirin or P2Y12 inhibitors and must be documented in the eCRF.

For example, the background antiplatelet therapy regimen and duration may consist of: SAPT consisting of ≤100 mg ASA daily until the end of the study; SAPT consisting of 75 mg clopidogrel daily until the end of the study; DAPT consisting of ≤100 mg ASA daily + 75 mg clopidogrel daily for 90 days, followed by 75 mg clopidogrel daily until the end of the study; or a combination of the foregoing.

The study will consist of 3 periods: a screening period up to 7 days after the index ACS event and prior to randomization, a double-blind treatment period, and a 30-day run-on period. Treatment will begin on the day of randomization and continue until the target number of participants has experienced one or more primary efficacy outcome events (followed by an EOT visit [within 30 days after GTED]). Therefore, the duration of treatment containing the study intervention will vary depending on when the participant is randomized. The minimum time that the last randomized participant is expected to be treated with the study intervention is approximately 3 months as of GTED.

Study interventions may be taken without regard to the timing of food intake. For participants who cannot swallow medications, study interventions may be dissolved in water and given via NG tube or applesauce.

Milvithin is a direct compression film-coated tablet, and its formula is described in Table 1 below: Table 1. 100 mg strength of Milvithin film-coated tablets Components quantity wt.% Amount of medication per dose (25 mg, Example 17 ) Amount of medication per dose (100 mg, Example 18 ) SDP ^b 22.22 33.33 133.3 Silicified Microcrystalline Cellulose 43.07 64.6 258.4 Lactose Monohydrate 28.71 43.067 172.267 Cross-linked sodium carboxymethyl cellulose 5.0 7.5 30 Magnesium stearate 1.0 1.5 6 Total weight of core tablets 100 150 600 OpadryQX 321A220063 Yellow ^c 3.0 4.5 18.0 154.5 618 Tablet hardness Average 60 N to 120 N (Ph. Eur. 2.9.8), preferably 90 N Average 140 N to 220 N (Ph. Eur. 2.9.8), preferably 180 N Tablet brittleness ＜ 0.5 % ＜ 0.5 % Disintegration time in water ( seconds) 13 18 a. The direct compression immediate release film-coated tablets of Milvecine are prepared according to the provisional application US 63/483,486, which is incorporated herein in its entirety. b. SDP means spray dry powder, which comprises a spray dry amorphous solid dispersion of Milvecine in HPMC-AS-MG grade polymer at a weight ratio of 3:1 (Milvecine:HPMC-AS-MG). c. Opadry QX 321A220063 Yellow is composed of Macrogol (PEG) polyvinyl alcohol graft copolymer, talc, titanium dioxide, glyceryl monocaprylate type I, polyvinyl alcohol and iron oxide yellow.

As used herein, the term "disintegration time" refers to the time required for a tablet to break down into granules under a set of specified conditions. In some embodiments, the disintegration time is measured in distilled water at 37° C. using a disc using the apparatus described in the European Pharmacopoeia (PTZ-E Pharma Test, Hainburg, Germany).

Tablets containing SDP (spray dried powder) were prepared as follows (Example 17, Example 18). A solution containing about 12.3 wt.% melvian P1.acetone (equivalent to about 11.25 wt.% melvian free form) and about 3.75 wt.% HPMC-AS MG (AQOAT® AS-MG, Shin-Etsu Chemical Co., Ltd. (Niigata, Japan)) in a solvent mixture containing 80/20 w/w% DCM/MeOH was prepared. The clear solution was spray dried at 21°C using a Buchi B-290 spray dryer with a 35 Kg/hr drying gas flow rate capacity and the following parameters: 25 mm (301 L/hr) atomizing gas flow rate; 7.7 g/min feed rate; 67/44°C inlet/outlet temperature, -19°C condenser temperature, 0.7 mm nozzle orifice diameter, and 1.4 mm nozzle cap diameter. The spray drying process was carried out for 11 minutes to obtain 11.5 g (89% yield) of wet SDP. The wet SDP was dried in a vacuum oven (Heraeus, model VT6130 M) at about 200 mbar vacuum at 40 °C under nitrogen flow for 24 hours to obtain 10.7 g (83% yield) of the desired dry SDP.

The SDP product was a white powder with 98.8% and 99.9% purity by HPLC analysis. The PXRD diffraction pattern showed a halogen pattern without crystalline peaks, indicating that the product was amorphous .

Primary, secondary, and exploratory efficacy endpoints covered the following individual events, often categorized in various combinations of composites, including ACM; CV death; MI; UA; “all strokes” or “any stroke” (ischemic, hemorrhagic, or unknown etiology); ischemic stroke; ALI; major vascular (non-invasive) limb resection; symptomatic VTE (PE, DVT); ischemia-driven coronary revascularization; stent thrombosis; hospitalization for any reason; categorized as (1) planned or unplanned, (2) arterial or venous thrombotic events, or neither; and TIA. An independent CEC will adjudicate efficacy outcome events as defined in the CEC charter ( Table 2 ). Table 2. Primary and secondary endpoints Target End main Milvecine was shown to be superior to placebo in reducing the risk of MACE (a composite of CV death, MI, and ischemic stroke) in addition to standard care When did MACE first occur? secondary Milvecine was shown to be superior to placebo in reducing the risk of MAVE (composite of CV death, MI, ischemic stroke, MALE, and symptomatic VTE) in addition to standard care When MAVE first occurred To determine whether milvicin reduces the risk of the composite of ACM, MI, and ischemic stroke compared with placebo Time of first occurrence of ACM, MI, and ischemic stroke To determine whether milvicin reduces the risk of CV death compared with placebo Time of CV death To determine whether milvicin reduces the risk of ACM compared with placebo ACM Time Pharmacokinetic evaluation

Plasma samples were collected from approximately 5,000 participants. Miltgen concentrations were measured in samples collected from Miltgen-treated participants using a validated, specific and sensitive (e.g., LC-MS/MS) method by the trial sponsor or under the supervision of the trial sponsor.

Residual plasma PK samples can be stored for future analysis and metabolite profile analysis. Based on individual plasma concentration-time data and using actual doses and sampling times, a population PK model was used to derive PK parameters (e.g., apparent clearance, etc.) for exposure-response analysis of milvicin and related variables. Pharmacodynamic and biomarker assessment

Plasma samples from approximately 1,000 participants were collected for PD and biomarker analysis. The PD analysis was aPTT. The exploratory biomarkers of disease pathophysiology were proteomics and D-dimer. Safety Assessment

Bleeding endpoints covered the following individual events, often categorized in various combinations of composites, including BARC categories 2, 3a, 3b, 3c, 4, and 5; ISTH in severe and CRNM categories; GUSTO in (1) severe or life-threatening and (2) moderate categories; and TIMI in non-CABG-related severe category, CABG-related severe category, mild category, and medical assistance required category. These bleeding outcome events were adjudicated by an independent CEC as defined in the CEC charter. Overall safety and tolerability were assessed by evaluation of AEs, clinical laboratory tests, and vital signs. Statistical Methods

For all study variables, treatment group summaries were provided using appropriate descriptive statistics, including demographic and baseline characteristics. Unless otherwise specified, no imputation was used in SAP. Continuous variables were summarized using descriptive statistics (e.g., mean, median, standard deviation, minimum, and maximum). Categorical variables were summarized using counts and percentages. Time-to-event variables were summarized using the Kaplan-Meier method. Graphical data displays were also available to summarize data.

Unless otherwise stated, all statistical tests were interpreted at a nominal (i.e., not adjusted for multiplicity) two-sided significance level of 0.05 and all CIs were interpreted at a nominal two-sided level of 95%.

The primary hypothesis was tested using a stratified log-rank test. In order to control the family-wise type I error rate at α 0.05 (two-sided) when testing the primary and secondary efficacy results, if the primary efficacy result of milvicin was determined to be superior to placebo, a closed testing procedure was used to test the superiority of milvicin to placebo in the secondary efficacy results in a predefined hierarchical order.

Stratified Cox regression was used to estimate HRs and 95% CIs for treatment efficacy based on the primary efficacy endpoints.

An interim analysis for futility was planned when approximately 60% of the target number of participants had a primary efficacy event. Since the study was not stopped for superiority, the type I error rate did not need to be adjusted. Example 2. Prevention of new ischemic stroke or new latent cerebral infarction after acute ischemic stroke or transient ischemic attack

The AXIOMATIC-SSP (Antithrombotic Therapy Using Factor XIa Inhibition to Optimize Management of Acute Thromboembolic Events in Secondary Stroke Prevention) study was a multicenter, phase 2, randomized, double-blind, placebo-controlled, dose-ranging study of milvecitin for the prevention of new ischemic stroke or new occult cerebral infarction after acute ischemic stroke or TIA in participants receiving ASA and clopidogrel. The primary objective was to estimate the dose-response relationship of milvecitin in participants with ischemic stroke or TIA treated with ASA and clopidogrel by assessing the composite of new ischemic stroke during treatment and new occult cerebral infarction detected by magnetic resonance imaging (MRI) at day 90 (assessed by central review). The target randomization ratio by the end of the study was 2:1:1:1:1:1 (placebo, milvicin 25 mg QD, 25 mg BID, 50 mg BID, 100 mg BID, and 200 mg BID). The original design included two additional dose groups: milvicin 50 mg QD and 100 mg QD, but the protocol was amended (Revised Protocol 05) to make these groups closer to random assignment, thereby simplifying the study design while maintaining scientific rigor to achieve the trial objectives, minimize the number of study participants exposed to the new investigational drug, reduce the burden on participants and sites, and streamline study procedures. Due to early termination of enrollment in the 50 mg QD and 100 mg QD treatment groups and limited numbers of participants in both groups, these groups were not included in the efficacy analyses presented, but were included in baseline characteristics (milvicin combined), individual disposition, and safety.

The study enrolled participants aged ≥40 years with an ischemic stroke or TIA. Ischemic stroke was defined as a neurologic deficit attributable to a non-lacunar acute cerebral infarction detected by neuroimaging and associated with clinical symptoms and a National Institutes of Health Stroke Score (NIHSS) ≤7 at randomization. TIA was defined as an acute onset neurologic deficit attributable to focal cerebral ischemia based on history or examination, with complete resolution of the deficit and absence of cerebral infarction based on neuroimaging and an ABCD score ≥6; or the presence of motor symptoms. Regardless of whether the index event was an ischemic stroke or TIA, evidence of atherosclerotic plaques, ulcers, or thrombi in the relevant intracranial or carotid arteries documented by imaging was required, and all participants were required to have a modified Rankin score of ≤3 before the index event. After presentation, eligible participants were screened for potential inclusion in the study as quickly as possible and randomized within 48 hours of the index event. After signing the informed consent, participants received ASA 100 mg QD and a single starting dose of clopidogrel 300 mg if they were not already receiving standard care. Participants were then randomized to receive either milvicin or placebo + open-label uncoated ASA 100 mg and 75 mg QD for the next 21 days. Participants continued treatment with milvicin or placebo + open-label uncoated ASA 100 mg alone from Day 22 until Day 90. Baseline MRI was performed within 48 hours of the index event and prior to randomization. Second MRI was performed on Day 90 ± 6 days. All participants were required to remain on study treatment until the Day 90 to Day 96 MRI was performed.

From January 27, 2019, to December 24, 2021, 2,799 participants were enrolled and 2,366 participants were randomized to 8 treatment groups. The 200 mg BID group was opened on June 05, 2021, after approximately 1,387 participants were enrolled and after the DMC reviewed the unblinded data to assess the safety of the open-dose group. As previously described, participants were randomized to the 50 mg QD (N=22) and 100 mg QD (N=18) treatment groups at the end of the implementation of the revised protocol amendment 05. Overall, the mean (standard deviation [SD]) age of the participants was 69.6 (±10.81) years. The majority of participants were male and white. Overall, the majority of index events (75.7%) were ischemic strokes, with approximately 96% of randomized participants having an NIHSS ≤5. TIAs accounted for 24.1% of index events; 53.4% of participants with TIAs had an ABCD2 score ≥6. Baseline disease characteristics were balanced between treatment groups, but NIHSS scores of 6 to 7 were higher in the 200 mg BID group (4.7%) than in the other groups (range: 2.1% to 4.0%). Because of the crossover opening of the treatment groups and the broadening of the NIHSS inclusion from ≤5 to ≤7 (occurring as a result of the same protocol amendment), more participants with NIHSS scores of 6 or 7 were assigned to the highest dose group. The most common comorbidities/risk factors were hypertension, diabetes, smoking history, and hypercholesterolemia. All baseline conditions were well balanced among treatment groups.

The dose-response relationship between miltiorrhiza treatment (including placebo) and the primary composite endpoint of symptomatic ischemic stroke during the study period and new occult cerebral infarctions on MRI at day 90 was analyzed based on the Common Multiple Comparison Procedure-Modeling (MCP-Mod) analysis, and the results are presented by treatment group.

In the AXIOMATIC-TKR study, milvitra at a dose of 25 mg twice daily showed similar efficacy to enoxaparin and a favorable safety profile. In the AXIOMATIC-SSP study, milvitra at a dose of 25 mg twice daily was numerically superior to placebo in preventing clinical ischemic stroke (HR 0.69, 95% CI 0.36 to 1.30), but no further improvement in efficacy was observed at the higher dose.

At the 50 mg and 100 mg BD doses, the values of the primary endpoint were lower, but there was no dose-response tendency. At all doses of Milvecine except 200 mg twice daily, Milvecine reduced the numerical values of the incidence of clinical ischemic stroke events (acute IS and excluding cryptic cerebral infarction) in the ITT population (see Table 3 below ). At doses of 25 mg BID to 100 mg BID, Milvecine effectively reduced clinical ischemic stroke in patients after ischemic stroke or TIA, and these doses showed a relative risk reduction (RRR) of approximately 30% for ischemic stroke in the treatment group compared to the placebo group (see Figure 3 ). Table 3. Summary of clinical ischemic stroke and undetermined stroke - all randomized participants Placebo N=691 25 QD N=328 25 BID N=318 50 BID N=328 100 BID N=310 200 BID N=351 Symptomatic stroke events Number of individuals who experienced the event n Occurrence rate (n/N %) 38 (5.5) 15 (4.6) 12 (3.8) 13 (4.0) 11 (3.5) 27 (7.7) Number of individuals with ischemic stroke n Incidence rate (n/N %) 38 (5.5) 15 (4.6) 12 (3.8) 13 (4.0) 11 (3.5) 27 (7.7) Number of individuals with undetermined stroke n Incidence rate (n/N %) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) Number of individuals with hemorrhagic stroke n Incidence rate (n/N %) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) (95% CI) (1) (3.8, 7.2) (2.3, 6.8) (1.7, 5.9) (1.9, 6.1) (1.5, 5.6) (4.9, 10.5) Relative Risk (RR) 0.83 0.69 0.72 0.65 1.40 95% CI of RR (2) (0.46, 1.49) (0.36, 1.30) (0.39, 1.33) (0.33, 1.25) (0.87, 2.25) Including clinical events up to day 21 (1) Wald 95% CI within group (2) 95% CI of RR constructed using Wald confidence limits Program source: BMS_GBS\CV010\OZA75318\Biostatistics\Production\Tables\CSR\rt-ef-clinstk.sas

Subgroup analyses of symptomatic ischemic stroke according to stroke subtype confirmed that the majority of new ischemic stroke events in all milvitamins-treated and placebo groups were attributable to large vessel atherosclerosis.

The rate of the secondary efficacy endpoint composite of new ischemic stroke, MI, and all-cause death was lower in the milvecin group than in the placebo group at dose levels of 25 mg QD to 100 mg BID (Table 4). The relative risk of this composite event in the milvecin group compared with the placebo group ranged from 0.78 to 0.85 in the 25 mg QD to 100 mg BID range, but there was no obvious dose-response tendency. Table 4. Summary of the composite rate of new ischemic stroke, MI , and all-cause death - all randomized subjects Placebo N=691 25 QD N=328 25 BID N=318 50 BID N=328 100 BID N=310 200 BID N=351 Number of new ischemic stroke, MI and all-cause death (n/N %) Number of individuals who experienced the event n (n/N%) 42 (6.1) 17 (5.2) 15 (4.7) 16 (4.9) 16 (5.2) 33 (9.4) Ischemic stroke number n (n/N%) 38 (5.5) 15 (4.6) 12 (3.8) 13 (4.0) 11 (3.5) 27 (7.7) Undetermined stroke number n (n/N%) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) Number of myocardial infarctions n (n/N%) 2 (0.3) 1 (0.3) 2 (0.6) 1 (0.3) 2 (0.6) 3 (0.9) All-cause mortality n (n/N%) 5 (0.7) 3 (0.9) 3 (0.9) 2 (0.6) 5 (1.6) 4 (1.1) (95% CI) (1) (4.3, 7.9) (2.8, 7.6) (2,4, 7.0) (2.5, 7.2) (2.7, 7.6) (6.3, 12.5) Relative risk (RR) compared to the placebo group (2) 0.85 0.78 0.80 0.85 1.55 95% CI of RR relative to placebo group (2) (0.49, 1.47) (0.44, 1.38) (0.46, 1.41) (0.49, 1.49) (1.0, 2.4) Clinical events and deaths were included until day 90. Individuals were randomly divided into 50 mg QD (N=22) and 100 mg QD (N=18) treatment groups until the implementation of the revised protocol was terminated. (1) Wald 95% CI within the group (2) 95% CI of RR constructed using Wald confidence limits

The rates of participants who completed the treatment period were similar between the placebo and treatment groups across the 25 mg QD to 100 mg BID dose range. Across the 25 mg QD to 100 mg BID dose range of Milvithron, 20.7% to 25.8% of participants discontinued treatment prematurely compared to 23.4% of participants in the placebo group. The rate of premature discontinuation was higher in the 200 mg BID group (31.6%), primarily due to AEs. Similarly, the overall most common reason for participants not completing the study treatment period in the other dose groups was AEs.

SAS® version 9 or higher was used for statistical analysis, tabulation, and graphical presentation. The DoseFinding package of R (version 3.1.3 or higher) was also used to perform multiple comparison modeling analyses.

A subset of the ITT population (1995 subjects total) including subjects with at least one PD endpoint was evaluated after the first dose of milvecin. The percentage change (%) from baseline in aPTT and factor XI coagulation activity was summarized by treatment group and nominal time point. In addition, exposure-response relationship (E-R) analysis was performed using data collected from all treated subjects (2334 subjects total) to explore the relationship between milvecin exposure and the percentage change (%) from baseline in aPTT and factor XI coagulation activity. A dose-dependent increase in aPTT and a dose-dependent decrease in factor XI coagulation activity were observed in the milvecin-treated group.

Summary statistics of the activated partial thromboplastin time (aPTT) and the percentage change from baseline for the pharmacodynamic groups are shown in Table 5 below: Table 5. Summary Statistics of Activated Partial Thromboplastin Time (aPTT) and Percent Change from Baseline for Pharmacodynamic Groups Consultation Laboratory test : aPTT ( seconds) Time point value Percent change from baseline Treatment group N average value SE Min Median Max average value SE Min Median Max Baseline before medication Placebo 645 26.46 0.14 14.7 25.90 55.9 25 mg BID 284 27.19 0.36 19.1 26.25 105.7 Day 1 4h Placebo 575 27.56 0.37 18.7 25.90 121.4 5.18 1.35 -55.3 0.4 383.7 25 mg BID 260 35.06 0.5 19.9 34.65 92.1 31.05 1.79 -34.4 27.06 121.4 Day 1 12h Placebo 570 27.20 0.56 14.6 25.90 319.5 3.21 1.67 -55.8 -0.17 839.7 25 mg BID 246 35.27 0.40 23.8 34.30 64.7 32.67 1.57 -37.2 30.41 141.2 Day 1 24 hours Placebo 582 26.95 0.48 14.7 25.75 251.9 3.35 1.91 -55.5 -1.22 847.0 25 mg BID 259 39.68 0.59 25.7 38.60 121.3 49.41 2.40 -67.5 44.40 354.3 Any time on day 21 Placebo 559 25.98 0.14 14.7 25.50 46.9 -0.78 0.59 -56.1 -1.27 97.4 25 mg BID 237 45.20 0.79 25.9 43.80 138.1 69.60 3.28 -66.7 64.26 425.1 Any time on day 90 Placebo 503 26.77 0.19 15.2 26.00 74.0 2.47 0.77 -54.0 0.83 184.6 25 mg BID 226 42.15 0.73 23.2 41.85 125.3 58.30 3.20 -55.5 54.37 452.0

The coagulation activity of FXI observed in this study was as follows: Table 6. Summary Statistics of Factor XI Coagulation Activity Measurements and Percent Changes from Baseline - Pharmacodynamic Group Consultation Laboratory test : FXI coagulation activity (%) Time point value Percent change Treatment group N average value SE Min Median Max average value SE Min Median Max Baseline before medication Placebo 645 113.0 0.93 10.0 113.0 150.0 25 mg BID 281 112.9 1.27 37.0 112.0 150.0 Day 1 4h Placebo 569 111.6 1.00 10.0 113.0 150.0 2.19 2.78 -89.5 -0.93 1150 25 mg BID 254 103.3 1.43 10.0 100.0 150.0 -7.21 1.24 -89.5 -8.48 186.5 Day 1 12h Placebo 570 111.2 0.95 30.0 111.0 150.0 4.62 3.39 -80.0 -0.86 1170 25 mg BID 241 103.1 1.41 36.0 101.0 150.0 -6.89 1.34 -63.3 -7.63 202.7 Day 1 24 hours Placebo 581 114.2 0.92 33.0 115.0 150.0 5.01 2.55 -71.1 0.88 1190 25 mg BID 253 100.9 1.27 58.0 98.0 150.0 -9.69 1.13 -38.3 -11.30 159.5 Any time on day 21 Placebo 554 117.5 1.43 10.0 117.0 711 8.73 3.21 -92.3 2.27 1340 25 mg BID 233 90.52 1.38 44.0 88.0 148.0 -18.1 1.24 -67.2 -19.10 121.6 Any time on day 90 Placebo 503 112.0 0.98 10.0 111.0 150.0 4.48 3.46 -91.6 -1.04 1320 25 mg BID 223 91.05 1.54 29.0 89.0 150.0 -17.7 1.90 -72.1 -20.16 305.4 Nominal time points were used in the analysis of PD biomarker data. For post-baseline time points, N represents the number of individuals with baseline and post-baseline values for that time point. Values greater than the upper limit of quantitation were set as the upper limit of summary statistics. Baseline = non-missing results at the time point "Baseline - Pre-dose", where the collection day for each treatment group was less than or equal to the day of the first active administration of study drug. Individuals were randomly divided into 50 mg QD (N=22) and 100 mg QD (N=18) treatment groups at the end of the implementation of Revision 05. Example 3. Bioavailability study and results of 25 mg and 100 mg DC film-coated tablets versus 25 mg and 100 mg SDP oral capsules in healthy participants

The first Phase 1 trial is an open-label, randomized, crossover study evaluating relative oral bioavailability, pharmacokinetics, and food effects following a single dose (for Parts 1, 3, and 4) or multiple doses (for Part 2). Part 1 of this first Phase 1 study will evaluate the relative bioavailability and food effects of a single dose of 200 mg milvicin administered as a film-coated DC tablet compared to a 100 mg comparator SDP oral capsule under fasted and fed conditions. Part 2 of this first Phase 1 study will evaluate the pharmacokinetics (PK) of 200 mg milvithin as film-coated DC tablets, administered in multiple doses (milvithin administered twice daily for 5 days) and comparative SDP oral capsules administered at 25 mg or 200 mg. The 100 mg and 25 mg capsule formulations ( see Table 7 below) are described in WO 2020210629, wherein the capsules comprise MCC and anhydrous lactose DC, wherein the weight ratio of binder (MCC) to filler (anhydrous lactose) is 1:1. The composition and physical properties of 25 mg and 100 mg film-coated DC tablets are provided in Table 1 above.

Blood samples were drawn at predetermined time points after drug administration as described in the clinical study protocol. Sample concentrations were measured using a validated analytical method (liquid chromatography coupled to tandem mass spectrometry). Individual subject pharmacokinetic parameters (e.g., Cmax, AUC _last , and AUC _∞ ) were derived from the time-concentration profiles by a non-compartmental approach using Phoenix ^™ WinNonlin® (version 8.1, Pharsight, A Certara ^™ Company, LP, Princeton, NJ, USA) software. Table 7. Composition of 100 mg and 25 mg SDP capsule formulations Components 100 mg SDP capsule 25 mg SDP capsule In particles SDP of 75% Compound(I):HPMCAS* 133.3 33.33 Microcrystalline Cellulose (MCC) 167.7 41.925 Anhydrous lactose DC 167.7 41.925 Weight ratio of MCC to anhydrous lactose 1:1 1:1 Cross-linked sodium carboxymethyl cellulose 12.5 3.125 Colloidal Silica 2.50 0.625 Magnesium stearate 1.25 0.3125 Total amount in particles 485 121 Outside the particles Cross-linked sodium carboxymethyl cellulose 12.5 3.125 Magnesium stearate 2.5 0.625 Total 500 125 *Preparing SDP according to the composition and method described in WO 2020210629

The treatment regimens for Part 1 and Part 2 are summarized in Table 8 below. Table 8. Treatment regimens used in Part 1 and Part 2 treatment Preparation Dosage food A ( Part 1A ) 100 mg DC* oral film-coated tablet 200 mg (2 x 100 mg) Fasting C ( Part 1A ) 100 mg SDP oral capsule 200 mg (2 x 100 mg) Fasting D ( Part 1B ) 100 mg DC* oral film-coated tablet 200 mg (2 x 100 mg) Eating F ( Part 1B ) 100 mg SDP oral capsule 200 mg (2 x 100 mg) Eating G ( Part 2A ) 100 mg DC* oral film-coated tablet 200 mg (2 x 100 mg) BID lasts for 5 days H ( Part 2A ) 100 mg SDP oral capsule 200 mg (2 x 100 mg) BID lasts for 5 days I ( Part 2B ) 25 mg DC* oral film-coated tablet 25 mg (1×25 mg) BID lasts for 5 days J ( Part 2B ) 25 mg SDP oral capsule 25 mg (1×25 mg) BID lasts for 5 days *DC : Direct Compression **RC : Roller Compaction

For the 200 mg dose, the absolute bioavailability of the 100 mg SDP capsule comparator formulation was 52% under fasting conditions and 72% under fed conditions.

In part 1 of the single-dose administration regimen, at a dose of 200 mg, 100 mg DC film-coated tablets showed about 9.0% to about 11% improvement compared to oral SDP capsules. 100 mg DC* oral film-coated tablets are less affected by food. To achieve better patient compliance, preferably, Milvith is administered with or without food. Drug formulations that are less affected by food provide better patient compliance.

In part 2 of the multiple-dose BID regimen, 2×100 mg DC film-coated tablets showed a bioavailability that was approximately 5% to 7% lower than that of 2×100 mg SDP oral capsules. 25 mg DC film-coated tablets (DC tablets) showed a bioavailability that was approximately 11% to 13% lower than that of 25 mg SDP oral capsules (see Figures 5A to 5D for the curves of the change in the amount of milvitra over time after BID administration).

In the second Phase 1 trial, Part 1 was an open-label, randomized, 3-way crossover study conducted in healthy participants to evaluate the relative oral bioavailability, pharmacokinetics, and food effects of a single oral dose of 200 mg milvicin as 2 × 100 mg SDP DC tablets compared to 200 mg as 2 × 100 mg SDP granule capsules under fasting conditions, and to evaluate the effect of food on the bioavailability of milvicin after a single dose of 200 mg milvicin as 2 × 100 mg SDP DC tablets. Part 2 was an open-label, randomized, two-way crossover study in healthy participants that evaluated the PK and relative bioavailability of a single oral dose of 50 mg milvicin as 2 × 25 mg SDP tablets versus 50 mg milvicin as 2 × 25 mg SDP granule capsules in healthy participants under fasting conditions.

In a pooled analysis of PK (AUC _inf and C _max ) data generated under fed and fasted conditions for 2×100 mg and 1×25 mg SDP DC tablets and 25 mg and 100 mg SDP granule capsule formulations from two Phase 1 trials, the results demonstrated that tablets exhibited less inter-participant PK variability than capsules in healthy participants.

Clinical study results show that for tablets with similar dissolution rates, the AUC _∞ (also known as AUC _inf ) of 2×100 mg DC* oral film-coated tablets (coated tablets) relative to 2×100 mg granule capsule formulations meets the bioequivalence criterion. Example 4.

Delayed cardiac repolarization is an adverse side effect of some non-antiarrhythmic drugs. Because of the potential clinical consequences of delayed cardiac repolarization, it is recommended that new pharmaceutical agents be carefully evaluated for their ability to prolong the QT/QTc interval.

In vitro study results indicate that milvicin inhibits cardiac potassium (hERG/IKr) channel currents with weak to moderate potency at concentrations that greatly exceed unbound concentrations in plasma of individuals treated with milvicin at clinically relevant doses. The present study, conducted after the in vitro study results became available, evaluated the effects of milvicin on cardiac repolarization in healthy individuals, an important aspect of cardiovascular safety.

This placebo-controlled and positive-controlled TQT study was conducted to evaluate the effects of multiple doses of milvicin at therapeutic and supratherapeutic doses on QT/QTc interval duration and ECG morphology at steady state in healthy adults. Target End main • To evaluate the effect of milvicin on the QT/QTcF interval in healthy participants when administered at therapeutic doses (100 mg twice daily as capsules) and supratherapeutic doses (200 mg twice daily as solution) for 4 days. • QTcF, change in QTcF from baseline (ΔQTcF), and placebo-corrected change in QTcF from baseline (ΔΔQTcF). secondary • To evaluate the effects of milvicin on other ECG parameters and ECG intervals in healthy participants when administered at therapeutic doses (100 mg twice daily as capsules) and supratherapeutic doses (200 mg twice daily as solution) for 4 days. • HR, ΔHR, ΔΔHR, PR, ΔPR, ΔΔPR, QRS duration, ΔQRS duration, and ΔΔQRS duration. • Assay sensitivity was assessed by evaluating the mean ΔQTc (ΔΔQTc) between moxifloxacin and placebo on Day 4. • QTc, baseline QTc, change in QTc from baseline (ΔQTc), placebo-corrected change in QTc (for QTcB and QTcP) from baseline (ΔΔQTc). • To assess the relationship between systemic plasma concentrations of milvicin and QT/QTc changes. • Characterize Milbemax concentration-ΔΔQTcF relationship.

The upper limit of the two-sided 90% CI for the maximum difference in the mean change from baseline in the QTc interval (ΔQTc; based on the initial calibration method - QTcF) between milvicin and placebo (ΔΔQTc) was less than 10 milliseconds at both the therapeutic dose (100 mg twice daily as a capsule) and the supratherapeutic dose (200 mg twice daily as a solution) was less than 10 milliseconds.

A total of 66 participants were enrolled in the study and randomly assigned to 1 of 4 possible treatment sequences. All 66 (100.0%) participants enrolled in the study were included in the safety and PD analyses: 55 participants each in the milvicin 100 mg and 200 mg groups, 58 participants in the moxifloxacin group, and 57 participants in the placebo group.

Pharmacokinetic analysis was performed on plasma concentrations of each participant. Sixty-one participants were included in the PK analysis set, i.e., all randomized participants who received at least one dose of active study intervention and whose PK profile allowed accurate calculation of at least one PK parameter. PK/PD analyses were based on participants included in the PD analysis set who had at least one milvecin concentration measurement.

All 66 (100.0%) participants enrolled in the study received at least one full dose of the study intervention.

Forty-five (68.2%) participants completed all 4 planned cycles of study intervention. According to the study intervention, 52 participants received milvicin 100 mg capsules twice daily for 4 days, 54 participants received milvicin 200 mg solution twice daily for 4 days, 58 participants received a single dose of 400 mg moxifloxacin, and 56 participants received placebo for 4 days.

There were no consistent or clinically relevant changes in mean vital signs over time.

No treatment-emergent QTcF or QTcB actual values >480 ms or changes from baseline >60 ms were observed during the study. ECG abnormalities were not reported as TEAEs during the study.

When 100 mg was administered twice daily as a capsule (therapy A) and 200 mg was administered twice daily as a solution (therapy B), the exposure to milvicin (i.e., C _max and AUC during the dosing interval) on day 4 was approximately 2- to 3-fold higher than that on day 1. Pharmacodynamic Results:

Following administration of 100 and 200 mg milvicin, the upper limits of the two-sided 90% CI for ΔΔQTcF during the post-dose measurement intervals on Days 1 and 4 were below the protocol-specified limit of 10 ms at all time points (i.e., the highest upper limits for 100 mg and 200 mg milvicin were 5.16 ms and 4.57 ms, respectively), indicating that there were no clinical or regulatory issues affecting the QT interval according to the ICH E14 guidelines. These results were confirmed based on the ΔΔQTcF of milvicin _Tmax , i.e., the upper limits of the 90% CI for milvicin _Tmax were below 10 ms following twice-daily administration of 100 mg or 200 mg, based on analyses using milvicin _Tmax on Days 1 and 4 (combined) or milvicin Tmax on Days 1 and 4, respectively.

Study-specific and Bazett's corrections also showed no clinical or regulatory effects on the QT interval according to ICH E14 guidelines. Analytical sensitivity for moxifloxacin was also demonstrated when Bazett's or study-specific power corrections were used for HR.

No treatment-emergent QTc Actual values >480 ms were observed during the study. No treatment-emergent changes from baseline in QTcF or QTcP >60 ms were observed during the study. One participant (1.7%) had a treatment-emergent QTcB change from baseline >60 ms during the study (i.e., after taking moxifloxacin).

No consistent or clinically relevant changes in HR, RR interval, PR interval, or QRS width were observed over time. No clinically significant differences were observed between treatment groups. Pharmacokinetic / pharmacodynamic Results :

Based on the results of linear mixed-effects modeling, no statistically significant relationships were observed between milvicin concentration and ΔΔQTcF (p=0.8454), ΔΔQTcP (p=0.7102), or ΔΔQTcB (p=0.8670). At _Cmax , no statistically significant effect of treatment (100 or 200 mg milvicin) on ΔΔQTc was observed (p＞0.5). Conclusions:

No notable study limitations were identified by the trial sponsor.

Milvecin 100 and 200 mg was generally safe and well tolerated in healthy adult participants when administered in multiple doses.

All upper limits of the two-sided 90% CIs for the time-matched differences in the change from baseline in QTcF between 100 mg milvicin and placebo and between 200 mg milvicin and placebo were less than 10 ms. Therefore, milvicin at therapeutic doses (100 mg) and supratherapeutic doses (200 mg) showed no evidence of clinical or regulatory issues causing QT/QTc interval prolongation according to the ICH E14 guidelines.

Moxifloxacin was used as a positive control to demonstrate analytical sensitivity.

Based on the results of linear mixed-effects modeling, no statistically significant relationship was observed between Milvus concentration and ΔΔQTcF (p=0.8454).

Figure 1 shows the coagulation pathway. Legend: FXII, factor XII; FXIIa, activated factor XII; FXI, factor XI; FXIa, activated factor XI; FIX, factor IX; FIXa, activated factor IX; FVIIa, activated factor VII; FVII, factor VII; FX, factor X; FXa, activated factor X. See Kakkar et al., FXI inhibition: The Holy Grail of Haemostasis-Sparing Anticoaulation, EMJ , 2021, Vol. 6, pp. 12-20; and Fredenburgh et al., FXIa as a Target for New Anticoagulants, Hamostaseologie , 2021, Vol. 41, pp. 104-110.

Figure 2 depicts the activated partial thromboplastin time as described in Example 2. The mean (±SD) percent change in aPTT from baseline due to treatment versus time is presented in Figure 2. A dose-dependent increase in the percent change in aPTT from baseline was observed with milvicin over the dose range of 25 mg QD to 200 mg BID. Summary statistics for aPTT measurements and percent change from baseline for the PD population are provided in Table 5. Nominal time points relative to the previous dose of milvicin were used in the PD biomarker data analysis. The 4-hour time point included all tests collected from 0.5 to 6 hours, the 12-hour time point included all tests collected from 6 to 12 hours, and the 24-hour time point included all tests collected from 12 to 72 hours.

FIG3 shows the Kaplan-Meier plot of ischemic stroke and undetermined stroke time for all randomized individuals.

FIG4 shows the Kaplan-Meier curves of ischemic stroke and undetermined stroke time for all randomized individuals.

FIG5A shows the comparison of the change of plasma concentration of miltiorrhiza on the first day after BID administration of the direct compression film-coated tablet of the present disclosure (2×100 mg) and the change of plasma concentration of miltiorrhiza on the first day after BID administration of miltiorrhiza capsule (2×100 mg). See Example 3.

FIG5B shows the comparison of the change of plasma concentration of miltiorrhiza on the 5th day after BID administration of the direct compression film-coated tablet of the present disclosure (2×100 mg) and the change of plasma concentration of miltiorrhiza on the 5th day after BID administration of miltiorrhiza capsule (2×100 mg). See Example 3.

FIG5C shows the comparison of the change of plasma concentration of miltiorrhiza over time on the first day after BID administration of the direct compression film-coated tablet (1×25 mg) of the present disclosure and the change of plasma concentration of miltiorrhiza over time on the first day after BID administration of miltiorrhiza capsule (1×25 mg). See Example 3.

FIG5D shows the comparison of the change of plasma concentration of miltiorrhiza on the 5th day after BID administration of the direct compression film-coated tablet (1×25 mg) of the present disclosure and the change of plasma concentration of miltiorrhiza on the 5th day after BID administration of miltiorrhiza capsule (1×25 mg). See Example 3.

Claims (18)

A method for preventing adverse cerebrovascular events or adverse cardiovascular events in a human patient suffering from acute coronary syndrome, wherein the method comprises administering to the human patient a regimen comprising: (i) a pharmaceutical composition comprising 25 mg of milvexian (or a pharmaceutically acceptable salt or solvent thereof); and (ii) an antiplatelet therapy selected from the group consisting of aspirin, a P2Y12 inhibitor, and a combination thereof; wherein the pharmaceutical composition is administered twice daily. The method of claim 1, wherein the antiplatelet therapy is a P2Y12 inhibitor. The method of claim 2, wherein the P2Y12 inhibitor is clopidogrel, ticagrelor or prasugrel. The method of claim 1, wherein the antiplatelet therapy is aspirin. The method of claim 1, wherein the human patient is treated with aspirin and clopidogrel combination therapy from day 1 to day 21, followed by treatment with aspirin monotherapy for at least 90 days. A method for preventing adverse cardiovascular events in a human patient diagnosed with acute coronary syndrome, wherein the method comprises administering to the human patient a regimen comprising: (i) a pharmaceutical composition comprising 25 mg of milvithin (or a pharmaceutically acceptable salt or solvent thereof) and one or more pharmaceutically acceptable formulations, and (ii) an antiplatelet therapy selected from the group consisting of aspirin, a P2Y12 inhibitor, and combinations thereof; wherein the pharmaceutical composition is administered twice daily; and wherein the adverse cardiovascular event is one or more selected from the group consisting of: all-cause mortality (ACM); cardiovascular (CV) death; myocardial infarction (MI); unstable angina (UA); "all strokes" or "any stroke" (ischemic, hemorrhagic, or unknown etiology); ischemic stroke; acute limb ischemia (ALI); major vascular (non-invasive) limb resection; symptomatic venous thromboembolism (VTE: (pulmonary embolism (PE), deep venous thrombosis (DVT))); ischemia-driven coronary revascularization; intravascular stent thrombosis; hospitalization for any reason, categorized as (1) planned or unplanned, (2) due to an arterial or venous thrombotic event, or neither; and transient ischemic attack (TIA). The method of claim 6, wherein the adverse cardiovascular event is one or more of CV death, MI, or ischemic stroke. A method for reducing the incidence of one or more adverse thrombotic events selected from new ischemic stroke, MI, or all-cause death in a human patient diagnosed with acute coronary syndrome, wherein the method comprises administering to the human patient a regimen comprising: (i) a pharmaceutical composition comprising about 25 mg to about 100 mg of miltvicin (or a pharmaceutically acceptable salt or solvent thereof) and one or more pharmaceutically acceptable formulations, and (ii) an antiplatelet therapy selected from the group consisting of aspirin, a P2Y12 inhibitor, and combinations thereof; wherein the pharmaceutical composition is administered twice daily. A method for preventing ischemic stroke in a human patient diagnosed with acute coronary syndrome, wherein the method comprises administering to the human patient a regimen comprising: (i) a pharmaceutical composition comprising 25 mg of milvithin (or a pharmaceutically acceptable salt or solvent thereof) and one or more pharmaceutically acceptable formulations, and (ii) an antiplatelet therapy selected from the group consisting of aspirin, a P2Y12 inhibitor, and combinations thereof; wherein the pharmaceutical composition is administered twice daily. The method of claim 9, wherein the clinical benefit of the regimen in reducing the incidence of clinical ischemic stroke is maintained throughout the 90-day treatment period. The method of claim 1, wherein the administration of the regimen results in a decrease in the patient's FXI coagulation activity by about 7% to about 20% relative to baseline. The method of claim 1, wherein the administration of the regimen results in an increase in activated partial thromboplastin time (aPTT) in the range of about 27% to about 64% relative to baseline. The method of claim 1, wherein the administration does not result in a statistically significant increase in severe bleeding complications. The method of claim 1, wherein the pharmaceutical composition comprising milvicin (or a pharmaceutically acceptable salt or solvent thereof) is an oral solid pharmaceutical composition. The method of claim 1, wherein the administration results in a plasma half-life of miltvicin in the range of about 13 hours to about 16 hours. The method of claim 1, wherein the administration allows the plasma concentration of Milvus to reach a steady state in about 3 to 6 days. The method of claim 1, wherein the pharmaceutical composition comprising milvicin (or a pharmaceutically acceptable salt or solvent thereof) is administered without regard to the timing of food intake. The method of claim 1, wherein the method does not result in clinically significant prolongation of the QTc interval.