Your activity: 133 p.v.
your limit has been reached. plz Donate us to allow your ip full access, Email: sshnevis@outlook.com

Direct oral anticoagulants (DOACs) and parenteral direct-acting anticoagulants: Dosing and adverse effects

Direct oral anticoagulants (DOACs) and parenteral direct-acting anticoagulants: Dosing and adverse effects
Author:
Lawrence LK Leung, MD
Section Editor:
Pier Mannuccio Mannucci, MD
Deputy Editor:
Jennifer S Tirnauer, MD
Literature review current through: Feb 2022. | This topic last updated: Mar 03, 2022.

INTRODUCTION — Options for anticoagulation have been expanding steadily over the past few decades, providing a greater number of agents for prevention and management of thromboembolic disease. In addition to heparins and vitamin K antagonists, anticoagulants that directly target the enzymatic activity of thrombin and factor Xa have been developed. Appropriate use of these agents requires knowledge of their individual characteristics, risks, and benefits.

This topic review discusses practical aspects of the use of direct thrombin inhibitors (oral and parenteral) and oral direct factor Xa inhibitors, along with a brief mention of other anticoagulants in development. Indications and efficacy of these agents in specific clinical settings are presented in separate topic reviews on the relevant conditions. (See 'Indications' below.)

Management of bleeding and perioperative management of patients receiving direct thrombin inhibitors or direct factor Xa inhibitors is also discussed in detail separately. (See "Management of bleeding in patients receiving direct oral anticoagulants" and "Perioperative management of patients receiving anticoagulants".)

The following topic reviews discuss other anticoagulants in clinical use:

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

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

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

MECHANISMS OF ACTION AND TERMINOLOGY

Sites of action — Hemostasis involves several processes. These include platelet activation, generation of fibrin by activated coagulation factors, inhibition of procoagulant factors to prevent excessive clot propagation, and fibrinolysis to dissolve the fibrin clot as the endothelial surface is repaired (figure 1 and figure 2).

Although these processes are often described separately, there are multiple points of overlap and crosstalk between platelets, procoagulant factors, endogenous anticoagulant and fibrinolytic factors, and the endothelium, to promote an appropriate level of hemostasis and limit clot formation to sites of vessel injury. (See "Overview of hemostasis".)

The direct thrombin inhibitors and direct factor Xa inhibitors block major procoagulant activities involved in the generation of a fibrin clot (figure 3).

Thrombin – Thrombin (factor IIa) is the final enzyme of the clotting cascade that produces fibrin; it is formed by the proteolytic cleavage of prothrombin by factor Xa. Thrombin has a central role in coagulation: it cleaves fibrinogen to fibrin; activates other procoagulant factors including factors V, VIII, XI, and XIII; and activates platelets [1]. The active site of the thrombin enzyme is buried deep in a groove on one side of the molecule (figure 4); this deep groove and surrounding amino acids enhance the specificity of the enzyme [2,3]. (See "Overview of hemostasis", section on 'Thrombin generation'.)

Direct thrombin inhibitors (DTIs) can bind to the active site of the thrombin enzyme (univalent DTIs) or to two sites: the active site and "exosite I," a positively charged region of the thrombin molecule that is physically separated from the active site (divalent DTIs) [1,4]. Exosite I is also the site of interaction ("docking") with many physiologic thrombin substrates, including fibrinogen, factor V, protein C, thrombomodulin (a thrombin receptor on endothelial cells), and thrombin receptors (PAR1 and PAR4) on platelets [2-6].

Thrombin is active in both circulating and clot-bound forms. Direct thrombin inhibitors are able to block the action of both forms of thrombin because their site of binding to thrombin is not masked by fibrin (or binding is not obstructed). In contrast, heparins are only able to inactivate thrombin in the fluid phase, via antithrombin (previously called antithrombin III) [7-10].

Factor Xa – Factor Xa acts immediately upstream of thrombin in the clotting cascade, at the convergence point of the intrinsic and extrinsic coagulation pathways (figure 1); it is formed by the proteolytic cleavage of factor X by one of two X-ase (ten-ase) complexes, which are made up of other procoagulant factors. Inhibition of factor Xa can prevent amplified thrombin generation because one molecule of factor Xa can cleave over 1000 molecules of prothrombin to thrombin [11]. Direct factor Xa inhibitors bind to the active site of factor Xa and inhibit factor Xa activity without a requirement for cofactors [12,13]. (See "Overview of hemostasis", section on 'Multicomponent complexes'.)

Similarly to thrombin, factor Xa is active in circulating and clot-bound forms. Direct factor Xa inhibitors are able to block the action of both forms of factor Xa, whereas indirect factor Xa inhibitors such as heparin and fondaparinux (the antithrombin-binding pentasaccharide) are only able to inactivate factor Xa in the fluid phase, via antithrombin.

Terminology — Terminology for anticoagulants continues to evolve as new agents become available. The following terminology describes agents in clinical use:

Antithrombotic agent – Antithrombotic agents include both antiplatelet agents (eg, aspirin, clopidogrel) as well as anticoagulants.

Anticoagulant – Anticoagulants include a variety of agents that inhibit one or more steps in the coagulation cascade. Their mechanisms vary, including direct enzymatic inhibition, indirect inhibition by binding to antithrombin, and antagonism of vitamin K-dependent factors by preventing their synthesis in the liver and/or modification of their calcium-binding properties. Available agents include unfractionated heparin, low molecular weight heparins, fondaparinux, vitamin K antagonists, direct thrombin inhibitors, direct factor Xa inhibitors, and other agents at various stages of development. (See 'Anticoagulants in development' below.)

Direct thrombin inhibitor – Direct thrombin inhibitors (DTIs) prevent thrombin from cleaving fibrinogen to fibrin. They bind to thrombin directly, rather than by enhancing the activity of antithrombin, as is done by heparin.

Parenteral DTIs include bivalirudin (Angiomax) and argatroban (Argatra, Novastan, Arganova, Exembol).

The only oral DTI available for clinical use is dabigatran etexilate (Pradaxa).

Direct factor Xa inhibitor – Direct factor Xa inhibitors prevent factor Xa from cleaving prothrombin to thrombin. They bind directly to factor Xa, rather than enhancing the activity of antithrombin, as is done by heparin.

There are no parenteral direct factor Xa inhibitors in clinical use.

Several oral agents are available, including rivaroxaban (Xarelto), apixaban (Eliquis), and edoxaban (Lixiana, Savaysa). The generic names for these agents all end in "Xa-ban" (eg, rivaroxaban, apixaban, edoxaban).

Acronyms that have been created to refer to the orally acting direct thrombin inhibitors and direct factor Xa inhibitors together include direct oral anticoagulants (DOACs), target-specific oral anticoagulants (TSOACs), oral direct inhibitors (ODIs), and NOACs, which stands for "novel oral anticoagulants," "new(er) oral anticoagulants," and "non-vitamin K antagonist oral anticoagulants" [14-17].

COMPARISON WITH HEPARIN AND WARFARIN — Anticoagulants differ in efficacy depending on the clinical setting; there are also differences in dosing, monitoring, cost, and risks. Thus, advantages and disadvantages of each agent must be individualized to the patient and clinical setting (table 1). Recommendations for each agent are based largely on the efficacy and safety in the specific patient population and clinical indications.

However, there are settings in which efficacy and safety of long-term oral administration are similar for vitamin K antagonists and DOACs. In such cases it may be worth considering some additional advantages and disadvantages of each class of drugs in decision making [18].

Clinician familiarity with dosing — Dabigatran was the first of the DOACs to become clinically available (approved in 2010 in the United States). The direct factor Xa inhibitors became available in subsequent years. However, many clinicians remain unfamiliar with the appropriate dosing of these drugs.

The lack of clinician familiarity with recommended dosing was illustrated in a 2017 report involving over 1500 patients with venous thromboembolism (VTE) who were treated with a DOAC [19]. For initial therapy, use of a dose or dosing frequency that differed from the product labeling was common (rivaroxaban: 287 of 1591 patients [18 percent]; apixaban: 22 of 44 patients [50 percent]). There were similar degrees of deviation from the recommended doses in patients receiving long-term DOAC therapy (rivaroxaban: 14 percent; apixaban: 36 percent; dabigatran: 46 percent). Deviations from recommended dosing typically involved a dose or dosing frequency that was lower than recommended (eg, once-daily dosing instead of twice-daily dosing), and these deviations from recommended dosing correlated with higher rates of VTE recurrence (adjusted hazard ratio [HR] 10.5). Rates of bleeding and death were not different from patients who received the correct dose. In another study in patients with atrial fibrillation, under-dosing of DOACs was associated with inferior outcomes [20].

It is often stated that clinicians should become familiar with one of the DOACs and use that drug when a DOAC is indicated. However, differences among these drugs, as described below, as well as institutional or pharmacy preferences, may make a different drug a better choice for a given patient. Thus, it is important to develop familiarity with key aspects of prescribing different agents.

Chronic kidney disease — All of the DOACs are excreted by the kidney to some degree, which has led to some concern about use and dose adjustments in individuals with chronic kidney disease. The approximate degrees of excretion by the kidney are as follows:

Dabigatran – 80 to 85 percent

Edoxaban – 35 percent

Rivaroxaban – 35 percent

Apixaban – 25 percent

Despite these concerns, use of DOACs in individuals with chronic kidney disease (CKD) appears to be safe and effective, especially in individuals with mild-to-moderate CKD. A 2019 meta-analysis that included 45 trials (34,000 patients, most with atrial fibrillation) reported a statistically significant benefit over warfarin in reducing the risk of stroke in those with atrial fibrillation who had mild-to-moderately impaired kidney function (risk ratio [RR], 0.79; 95% CI 0.66-0.93), without an obvious increase in bleeding (RR for major bleeding, 0.80; 95% CI 0.61-1.04; RR for intracranial hemorrhage [ICH], 0.49; 95% CI 0.30-0.80) and a trend toward improved survival (RR, 0.88; 95% CI 0.78-0.99) [21]. Individuals with end-stage kidney disease (estimated glomerular filtration rate [GFR] <15 mL/minute/1.73 m2 or creatinine clearance [CrCl] <20 mL/minute) were mostly excluded. A 2020 systematic review that included nine studies (two of which were randomized trials) of individuals with atrial fibrillation or VTE who had CKD or were receiving dialysis found similar efficacy with DOACs versus warfarin and similar bleeding risks with apixaban versus warfarin [22].

A general approach is as follows:

In hospitalized patients with CKD, heparin is generally used.

For outpatients with mild-to-moderate CKD (CrCl 30 to 50 mL/minute or higher), the evidence discussed above suggests that DOACs are equally effective as warfarin and at least as safe, probably safer. Dose adjustments may be appropriate, as discussed below under the specific agents. (See 'Dosing (dabigatran)' below and 'Dosing, monitoring, risks (rivaroxaban)' below and 'Dosing, monitoring, risks (apixaban)' below and 'Edoxaban' below.)

For outpatients with severely impaired kidney function (CrCl <30 mL/minute), there is limited evidence to predict how DOACs may compare with warfarin, although evidence for superior efficacy and safety over warfarin continues to accumulate. Warfarin or dose-adjusted low molecular weight (LMW) heparin (table 2) is generally preferred over a DOAC in those with a CrCl <30 mL/minute who require long-term anticoagulation.

Drug adherence — Drug adherence appears to be relatively similar in large populations, although these may differ in some individuals or clinical settings. A set of strategies to maximize drug adherence and minimize bleeding have been published [23]. These emphasize useful ways to ask about compliance, reminders about medication storage, counseling about missed doses, planning for surgical procedures, avoidance of prescribed and nonprescription medications that interfere with platelet function (unless medically indicated), monitoring of kidney function, aggressive management of hypertension, and approaches to minimizing the risk of falls.

The similar adherence to DOACs versus warfarin was demonstrated in a meta-analysis of randomized trials (18 trials, 101,801 patients) that evaluated drug discontinuation rates in patients with VTE or atrial fibrillation (AF), who were treated for more than 12 weeks with a DOAC or a pharmacologically active comparator [24]. Individuals receiving a DOAC had similar rates of drug discontinuation to those receiving a vitamin K antagonist, both for VTE (13 versus 14 percent; relative risk [RR] 0.91; 95% CI 0.74-1.13) and for AF (22 percent for both types of agent; RR 1.01; 95% CI 0.87-1.17).

A review of 4863 patients who were prescribed dabigatran for atrial fibrillation found a median adherence rate of 74 percent (interquartile range, 66 to 80 percent) [25]. Adherence was higher at institutions that preselected patients for the ability to adhere to twice-daily medication and at those that provided pharmacist-based patient education and greater communication regarding medication use. Lower adherence rates could be improved by instituting these measures.

Importantly, patients prescribed a DOAC who do not or cannot take the medication as prescribed may have a greater amount of time during which they are not therapeutically anticoagulated compared with patients who miss occasional doses of warfarin. The ability to monitor the degree of nonadherence is lost when a DOAC is substituted for warfarin. As noted below, a single missed dose of a DOAC has greater potential to result in inadequate anticoagulation than a single missed dose of warfarin. (See 'Settings in which a heparin or vitamin K antagonist may be preferable' below.)

Advantages over heparin and warfarin — The DOACs differ significantly from vitamin K antagonists in their onset of action, half-life, drug-drug interactions, need for monitoring, ability to monitor should this be called into question, as well as availability of antidotes in the case of excessive bleeding (table 1). In some cases, these differences may translate into similar efficacy with greater ease of administration and lower bleeding risk. However, as noted above, the efficacy and bleeding risk depend on patient variables such as compliance and interacting medications, and all decisions must be individualized to take these factors into account.

Lower bleeding risk – Overall, all-cause mortality from DOACs appears to be lower than that from warfarin, driven primarily by a decrease in fatal intracranial bleeding risks [26]. However, direct comparison of bleeding risk with different agents is challenging because risks appear to vary in different patient populations and clinical settings, and meta-analysis often combines different doses of the same anticoagulant [27]. This issue is discussed in detail separately. (See "Risks and prevention of bleeding with oral anticoagulants", section on 'Risk factors related to the anticoagulant'.)

Possible lower risk of fractures – The risk of fractures has not been evaluated in a randomized trial, but a series of observational studies suggest that DOACs are associated with lower risk of fractures than warfarin. One retrospective series of nearly 170,000 individuals with atrial fibrillation who were started on a new anticoagulant found a lower fracture risk of the ensuing 13 months with DOACs over warfarin (hazard ratio [HR], 0.78; 95% CI 0.79-0.96) [28]. The finding was most impressive for people with preexisting osteoporosis and with apixaban versus warfarin. A second retrospective series of nearly 20,000 individuals followed for 2.4 years reported remarkably similar findings supporting a lower risk with DOACs (HR 0.84; 95% CI 0.77-0.93) with the greatest decrease seen with apixaban [29]. An earlier study observed a lower risk of fractures with dabigatran compared with warfarin [30-32].

The reason for this difference in fracture risk, if real, is unknown. Nor is it clear whether it represents an increase over baseline risk with warfarin or a decrease from baseline risk with DOACs. Suggested mechanisms range from a difference in risk of falls to alterations in bone biology. (See "Pathogenesis of osteoporosis".)

Less laboratory monitoring – Heparin and warfarin both have a relatively narrow therapeutic window and more variable dose-response relationship that depends on a variety of factors; these features lead to a requirement for frequent monitoring of clotting times to optimize the therapeutic dose range and prevent bleeding [33,34]. Dose may be affected by differing bioavailability, diet, and acute medical illnesses. In contrast, the DOACs are generally used without a requirement for monitoring of drug levels or coagulation (clotting) times. This may be an advantage for patients for whom frequent monitoring is a greater burden. It remains to be determined whether laboratory monitoring of any of the DOACs can further improve their efficacy or safety. (See 'Laboratory testing and monitoring (dabigatran)' below.)

Preferable pharmacokineticsWarfarin pharmacokinetics is affected by the level of vitamin K intake and production in the gastrointestinal tract, as well as induction of hepatic cytochromes. Thus, warfarin effect can be altered by changes in diet, administration of other medications, gastrointestinal disorders, and reduced oral intake. Patients with difficulty controlling the prothrombin time/international normalized ratio (PT/INR) may benefit from a DOAC because these agents have less variability in drug effect for a given dose than vitamin K antagonists. Affected patients may include those with unavoidable drug-drug interactions (such as frequent need for antibiotics or a large number of concomitant and variable medications) or unexplained poor warfarin control. However, it is important to determine that the INR instability with a vitamin K antagonist is not due to poor compliance, which may be easier to monitor for vitamin K antagonists than for the target-specific agents.

Favorable biology – The biology of the parenteral direct thrombin inhibitors (eg, bivalirudin, argatroban) may give them advantages over heparins in certain clinical settings such as percutaneous cardiac interventions, where inhibition of clot-bound thrombin might be important; and heparin-induced thrombocytopenia (HIT), where induction of an aggressive hypercoagulable state (due to anti-heparin-PF4 antibodies) must be avoided (see 'Indications' below).

Settings in which a heparin or vitamin K antagonist may be preferable — There are several settings in which warfarin may be preferable to one of the DOACs, or in which a DOAC is contraindicated (eg, mechanical prosthetic heart valve, pregnancy) (table 1). In addition, patients who are receiving warfarin with excellent stable INR control and minimal bleeding side effects may have little to gain by switching to a different agent. In many inpatient settings, heparins are preferable because of similar efficacy to parenteral direct thrombin inhibitors, availability of an antidote, and substantially lower costs.

Mechanical prosthetic heart valves – The direct thrombin inhibitors and direct factor Xa inhibitors are not used in patients with mechanical prosthetic heart valves, due to greater risk of valve thrombosis, which may be fatal. (See "Antithrombotic therapy for mechanical heart valves", section on 'Long-term anticoagulation'.)

Pregnancy – Direct thrombin inhibitors and direct factor Xa inhibitors are not used during pregnancy, due to lack of clinical experience in this setting; LMW heparin is preferred in most pregnant women who require an anticoagulant. If a patient taking one of these agents becomes pregnant, she should be switched to LMW heparin immediately. This issue is discussed in detail separately. (See "Use of anticoagulants during pregnancy and postpartum".)

Chronic kidney disease – DOACs are metabolized mostly in the kidney, with apixaban least dependent on clearance by the kidney (approximately 25 percent). Creatinine clearance (CrCl) can be estimated from the patient's sex, age, weight, and serum creatinine (calculator 1 and calculator 2). Concerns have existed with the use of DOACs in individuals with CrCl less than 30 mL/minute. However, data continue to accumulate, especially in individuals with atrial fibrillation, suggesting that DOACs, especially apixaban, have better to equal efficacy and safety, similar to effects in individuals with normal CrCl. (See 'Chronic kidney disease' above and "Atrial fibrillation in adults: Selection of candidates for anticoagulation".)

Severe liver disease – DOACs are hepatically metabolized to varying degrees, and most clinicians do not use DOACs in individuals with severe hepatic impairment, as shown in the table (table 3).

Antiphospholipid syndrome – In patients with the antiphospholipid syndrome (APS) who require anticoagulation, heparin followed by warfarin is the preferred therapy, especially for those with a history of arterial thrombosis or other high-risk features. (See "Management of antiphospholipid syndrome", section on 'Long-term anticoagulation'.)

Adherence – Use of DOACs may be challenging in patients who are unable to take their medication as prescribed. The lack of routine monitoring and short half-lives of these agents make it more difficult to determine if a patient is taking them appropriately. In addition, missing one or two doses can leave the patient inadequately anticoagulated; in contrast, missing a couple of doses of warfarin is unlikely to substantially increase the time outside the therapeutic range.

Gastrointestinal disease – Patients with gastrointestinal diseases, especially those with a history of bleeding, may prefer to avoid the direct factor Xa inhibitors because of an increased bleeding risk. Individuals with severe dyspepsia may not tolerate dabigatran. (See 'Risks (dabigatran)' below.)

Altered gastrointestinal anatomy – Individuals who have undergone gastrectomy or weight reduction surgeries such as gastric bypass may have altered absorption of the DOACs. Some experts consider this a reason to avoid DOAC and would use a different anticoagulant such as heparin or warfarin, for which therapeutic drug monitoring is available. Another alternative if a DOAC is used is to measure drug levels to confirm absorption.

Dosing convenienceDabigatran and apixaban require twice daily dosing, which may cause an increased burden for patients who place a higher value on taking a single daily dose of an anticoagulant. European labeling for dabigatran includes once daily dosing. Rivaroxaban and edoxaban have a once daily dosing schedule, as does warfarin.

Cost – Vitamin K antagonists are typically much less expensive than DOACs.

Inability to titrate the dose – Individuals with an aggressive hypercoagulable state may have recurrent thrombosis despite adequate anticoagulation. For individuals with warfarin, one approach is to target a higher INR. This type of dose titration is not validated for DOACs.

INDICATIONS — Clinical indications for direct thrombin inhibitors and direct factor Xa inhibitors in various settings are discussed in separate topic reviews:

Venous thromboembolism (VTE) prophylaxis (non-orthopedic) – (See "Prevention of venous thromboembolic disease in adult nonorthopedic surgical patients".)

VTE prophylaxis (orthopedic) – (See "Prevention of venous thromboembolism in adult orthopedic surgical patients".)

VTE treatment (individuals without cancer, initial anticoagulation) – (See "Venous thromboembolism: Initiation of anticoagulation (first 10 days)", section on 'Direct factor Xa and thrombin inhibitors'.)

VTE treatment (individuals without cancer, long-term anticoagulation) – (See "Venous thromboembolism: Anticoagulation after initial management", section on 'Direct thrombin and factor Xa inhibitors'.)

VTE treatment (individuals with cancer) – (See "Anticoagulation therapy for venous thromboembolism (lower extremity venous thrombosis and pulmonary embolism) in adult patients with malignancy".)

Atrial fibrillation (AF) – (See "Atrial fibrillation in adults: Selection of candidates for anticoagulation" and "Atrial fibrillation in adults: Use of oral anticoagulants".)

Acute coronary syndromes (ACS) – (See "Anticoagulant therapy in non-ST elevation acute coronary syndromes" and "Anticoagulant therapy in acute ST-elevation myocardial infarction" and "Antithrombotic therapy for elective percutaneous coronary intervention: Clinical studies", section on 'Bivalirudin' and "Acute coronary syndrome: Oral anticoagulation in medically treated patients".)

Heparin-induced thrombocytopenia (HIT) – (See "Management of heparin-induced thrombocytopenia", section on 'Direct oral anticoagulants'.)

These agents are not used in individuals with mechanical prosthetic heart valves, severe kidney disease, pregnancy, or antiphospholipid syndrome (APS). (See "Antithrombotic therapy for mechanical heart valves" and "Management of antiphospholipid syndrome".)

Possible contraindications to anticoagulation are listed in the table (table 4); however, this list is not intended to substitute for the judgment of the treating clinician who is able to weigh the risks and benefits for the individual patient.

BLEEDING

Risks of bleeding and prevention strategies — The risk of bleeding with DOACs is discussed separately. (See "Risks and prevention of bleeding with oral anticoagulants".)

Management of bleeding — Separate topic reviews discuss the management of bleeding and perioperative management in individuals receiving DOACs:

Antidotes

Dabigatran – (See "Management of bleeding in patients receiving direct oral anticoagulants", section on 'Dabigatran reversal'.)

Factor Xa inhibitors – (See "Management of bleeding in patients receiving direct oral anticoagulants", section on 'Factor Xa inhibitors'.)

Other aspects of bleeding management – (See "Management of bleeding in patients receiving direct oral anticoagulants", section on 'Major bleeding'.)

Management of invasive procedure/surgery – (See "Perioperative management of patients receiving anticoagulants".)

DIRECT THROMBIN INHIBITORS — Direct thrombin inhibitors inactivate circulating and clot-bound thrombin (factor IIa) (figure 3). This may be especially important in individuals with coronary thrombosis. (See "Anticoagulant therapy in non-ST elevation acute coronary syndromes", section on 'Unfractionated heparin compared with bivalirudin'.)

Unlike heparin, the direct thrombin inhibitors do not bind to platelet factor 4 (PF4) and thus are not able to induce or react with the anti-heparin/PF4 antibodies that cause heparin-induced thrombocytopenia (HIT). Thus, the parenteral direct thrombin inhibitors are options for anticoagulation in patients with HIT. (See "Management of heparin-induced thrombocytopenia", section on 'Anticoagulation'.)

Parenteral direct thrombin inhibitors — Parenteral direct thrombin inhibitors include bivalirudin and argatroban. These agents directly block the actions of thrombin (figure 3). (See 'Bivalirudin' below and 'Argatroban' below.)

Lepirudin is a recombinant hirudin that has been unavailable since May 2012, when the manufacturer discontinued marketing (unrelated to safety concerns) [35-37]. Desirudin (Iprivask, Revasc) was discontinued a few years later.

Bivalirudin — Bivalirudin (Angiomax, previously called Hirulog) is a synthetic 20 amino acid peptide that binds to the thrombin catalytic site and exosite I, reversibly inhibiting thrombin enzymatic activity [38]. The peptide sequence is an analog of hirudin, a protein extracted from the salivary gland of the medicinal leech. (See 'Sites of action' above.)

The indications and use of bivalirudin in patients undergoing percutaneous coronary interventions (PCI) and heparin induced thrombocytopenia (HIT) are discussed separately:

PCI – (See "Antithrombotic therapy for elective percutaneous coronary intervention: Clinical studies", section on 'Bivalirudin' and "Anticoagulant therapy in non-ST elevation acute coronary syndromes" and "Anticoagulant therapy in acute ST-elevation myocardial infarction".)

HIT – (See "Management of heparin-induced thrombocytopenia".)

Bivalirudin is administered at a dose of 0.75 mg/kg intravenously as a bolus followed by 1.75 mg/kg per hour during a procedure. Patients with kidney failure do not require a change in the bolus dose; those with creatinine clearance (CrCl) <30 mL/minute may use a lower infusion rate (eg, 1 mg/kg per hour) [38]. Intravenous administration produces an immediate anticoagulant effect. The half-life of bivalirudin is approximately 25 minutes; prolonged coagulation times return to normal approximately one hour after discontinuation [39]. The drug is metabolized in kidney, liver, and other sites [1]. Bivalirudin can be hemodialyzed.

Bivalirudin can be monitored by the activated clotting time (ACT); action is rapid and the effect can be tested within minutes of administration. Monitoring can also be performed using the activated partial thromboplastin time (aPTT), with a target of 1.5 to 2.5 times the normal range. Patients with impaired kidney function should be monitored with an activated clotting time; the therapeutic range varies with the device used.

Argatroban — Argatroban (Arganova, Argaron, Argatra, Da Bei, Exembol, Gartban, Novastan, Slonon) is a synthetic peptide-based direct thrombin inhibitor that interacts with the active site of thrombin [40]. It has a short in vivo plasma half-life (terminal elimination half-life approximately 40 to 50 minutes) [41]. (See 'Sites of action' above.)

Dosing and monitoring of argatroban differs depending on the indication:

Heparin-induced thrombocytopenia (HIT) – For patients with HIT who have normal hepatic function, argatroban is administered at an initial dose of 2 mcg/kg per minute intravenously as a continuous infusion [41]. Monitoring is done by the aPTT; a baseline aPTT should be obtained prior to administration, and the aPTT should be repeated two hours after starting therapy, and after any dose changes. The dose is adjusted to achieve a target aPTT of 1.5 to 3 times the initial baseline value, not to exceed 100 seconds [41]. Further details of the use of argatroban in HIT are presented separately. (See "Management of heparin-induced thrombocytopenia", section on 'Argatroban'.)

Percutaneous coronary intervention (PCI) – For PCI in patients with HIT or at high risk for HIT, argatroban is given as a bolus of 350 mcg/kg over three to five minutes, with an infusion of 25 mcg/kg per minute. Monitoring is done by the activated clotting time. Parameters are discussed in detail separately. (See "Antithrombotic therapy for elective percutaneous coronary intervention: General use", section on 'Heparin-induced thrombocytopenia'.)

Argatroban is hepatically metabolized, and dosing adjustment is advised in patients with hepatic impairment [1]. Dose adjustment is not required in patients with impaired kidney function [41,42].

Argatroban prolongs the prothrombin time/international normalized ratio (PT/INR). Thus, when patients receiving argatroban are transitioned to warfarin, it is necessary to use an adjusted INR target during overlap, and repeat the INR upon discontinuation of argatroban. Institutional guidelines regarding the appropriate INR target should be followed.

Oral direct thrombin inhibitor — Dabigatran is the only oral direct thrombin inhibitor available for clinical use. Additional agents are under development (eg, AZD-0837) [43].

Dabigatran

Overview (dabigatran) — Dabigatran etexilate (Pradaxa) is an orally administered prodrug that is converted in the liver to dabigatran, an active direct thrombin inhibitor that inhibits clot-bound and circulating thrombin [44]. The half-life is approximately 12 to 17 hours in individuals with normal kidney function. Absorption is unaffected by food.

Importantly, dabigatran capsules should only be dispensed and stored in the original bottle (with desiccant) or blister package in which they came, due to the potential for product breakdown from moisture and resulting loss of potency. Patients should not store or place this agent in any other container, such as pill boxes or pill organizers. Once the bottle is opened, the pills inside must be used within four months [45]. The capsules should not be crushed or opened before administration, as removal of the capsule shell results in dramatic increases in oral bioavailability [46].

Dabigatran is used in the prevention and management of VTE disease, in stroke prevention in patients with atrial fibrillation (AF), and in ischemic heart disease. These indications are discussed in detail separately:

VTE prophylaxis – (See "Prevention of venous thromboembolic disease in adult nonorthopedic surgical patients".)

VTE overview of treatment – (See "Overview of the treatment of lower extremity deep vein thrombosis (DVT)".)

VTE initial treatment – (See "Venous thromboembolism: Initiation of anticoagulation (first 10 days)".)

VTE extended treatment – (See "Venous thromboembolism: Anticoagulation after initial management".)

AF – (See "Atrial fibrillation in adults: Use of oral anticoagulants".)

Ischemic heart disease – (See "Perioperative myocardial infarction or injury after noncardiac surgery" and "Coronary artery disease patients requiring combined anticoagulant and antiplatelet therapy".)

Dabigatran should not be used in patients with mechanical prosthetic heart valves or during pregnancy. (See "Antithrombotic therapy for mechanical heart valves" and "Use of anticoagulants during pregnancy and postpartum".)

Dosing (dabigatran) — Dabigatran is generally given at a fixed dose without monitoring (table 5). It is important to use the appropriate dose (ie, do not under-dose). Maximum anticoagulant effects are achieved within two to three hours of ingestion [47]. Excretion of unchanged drug by the kidney is the predominant elimination pathway, with approximately 80 percent of an intravenous dose being excreted unchanged in the urine [48,49]. The dosing differs according to the clinical indication and the patient's kidney function [46]:

Venous thromboembolism (VTE) primary prophylaxis in surgical patients: 110 mg one to four hours after surgery, followed by 220 mg once daily for 28 to 35 days (hip replacement) or 10 days (knee replacement).

Treatment and secondary prevention of VTE: 150 mg orally twice daily after 5 to 10 days of parenteral anticoagulation (CrCl >30 mL/minute).

Stroke prevention in atrial fibrillation (AF): 110 mg orally twice daily or 150 mg orally twice daily (CrCl >30 mL/minute). European labeling suggests dose reduction in patients older than 75 years (eg, 150 mg orally once per day or 110 mg orally twice per day) [27,50]. This is discussed in more detail separately. (See "Atrial fibrillation in adults: Use of oral anticoagulants", section on 'Dosing'.)

Clinical settings in which dose modification or drug avoidance may be indicated include the following:

Chronic kidney diseaseDabigatran is excreted by the kidney, and the half-life is extended in patients with impaired kidney function. As an example, a study in volunteers with mild, moderate, and severe chronic kidney disease and kidney failure receiving dialysis found half-lives of approximately 14, 17, 19, 28, and 34 hours, respectively [48]. Dose reduction has been recommended for those with a CrCl in the range of 15 to 30 mL/minute, since such patients otherwise have had marked increases in bleeding events when taking full doses [51]. We reduce the dose in patients with CrCl 15 to 30 mL/minute (eg, 75 mg orally twice daily instead of doses listed above). Product labeling in the United States recommends avoidance of dabigatran in individuals with CrCl <15 mL/minute or in those who are hemodialysis dependent; the Canadian, United Kingdom, and European Medicines Agency labeling recommend avoidance in patients with a CrCl <30 mL/minute [52-54] (table 6). CrCl can be estimated from the patient's sex, age, weight, and serum creatinine (calculator 1 and calculator 2).

P-glycoprotein inhibitors or inducersDabigatran is a substrate for P-glycoprotein. Concomitant use of dabigatran with P-glycoprotein inducers (eg, rifampin) reduces the anticoagulant effect of dabigatran and generally should be avoided. Concomitant use of dabigatran with P-glycoprotein inhibitors (eg, ketoconazole, verapamil) in patients with kidney failure may increase the anticoagulant effect of dabigatran (table 6 and table 7) [46]. Official prescribing information and/or a drug interactions resource should be consulted for any questions.

By contrast, dabigatran is not metabolized by the cytochrome p450 system (CYP); dose changes are not generally required with concomitant administration of CYP inducers or inhibitors.

BMI – Data are limited on the efficacy and toxicity of dabigatran in individuals with a high body mass index (BMI). Based on a 2021 review of available literature, the International Society on Thrombosis and Haemostasis (ISTH) recommended that any DOAC is appropriate for individuals with BMI up to 40 kg/m2 or weight up to 120 kg [55]. They recommend use of dabigatran (and other direct oral anticoagulants) at standard dose for patients with a BMI ≤40 kg/m2 or weight <120 kg. This reflects our general practice, although it should not replace clinical judgment regarding avoidance in individuals with a lower BMI or use in those with a higher BMI.

Support for the approach of tailoring dosage according to patient variables such as age or kidney function comes from a study of 100 patients with atrial fibrillation, which found that a lower dose of dabigatran (110 mg twice daily) in patients who were older, of lower body weight, or had lower CrCl, resulted in trough levels that were comparable to the higher dose (150 mg twice daily) in patients who lacked these characteristics [56]. We do not alter dosing for individuals with different ethnic backgrounds.

Laboratory testing and monitoring (dabigatran) — Laboratory testing prior to initiating dabigatran should include platelet count, prothrombin time (PT), and activated partial thromboplastin time (aPTT), to assess and document coagulation status before anticoagulation; and measurement of serum creatinine, as a baseline and for potential dose adjustment in the event of chronic kidney disease.

Routine laboratory monitoring of coagulation times is not required for patients taking dabigatran, because drug levels are relatively predictable for a given dose, and a therapeutic range has not been established. However, possible improvements in efficacy and/or safety with monitoring of dabigatran plasma concentrations have been suggested, and monitoring recommendations may change [57-62].

If there is a concern that dabigatran drug levels are abnormally low or abnormally high, it may be appropriate to test for the presence of the drug. A consensus document from the International Council for Standardization in Haematology (ICSH) has provided examples of dabigatran drug levels for the 150 mg twice-daily dose, with an expected mean peak of approximately 157 ng/mL (25th to 75th percentile of 117 to 275 ng/mL) and an expected trough of approximately 60 to 91 ng/mL (25th to 75th percentile, 39 to 143 ng/mL) [63]. These values are intended to be used as guides to provide evidence of drug absorption, not as therapeutic targets.

Settings in which coagulation testing for dabigatran effect may be helpful include the following:

Bleeding in a patient receiving dabigatran, or with suspected dabigatran overdose – (See "Management of bleeding in patients receiving direct oral anticoagulants", section on 'Assessment of anticoagulation status'.)

Need for emergency or urgent surgery in a patient receiving dabigatran – (See "Perioperative management of patients receiving anticoagulants", section on 'Dabigatran'.)

Concerns about absorption (eg, altered gastrointestinal anatomy) or drug adherence.

In such cases, the ecarin clotting time is the best method to assess bleeding risk, but this test is not widely available. Other coagulation tests that are prolonged in the presence of therapeutic doses of dabigatran include the dilute thrombin time (dilute TT), activated partial thromboplastin time (aPTT), and the activated clotting time (ACT). In contrast, the prothrombin time (PT) cannot be used as a reliable measure of dabigatran activity. A study that compared the PT, aPTT, and TT in plasma to which dabigatran had been added found that the TT was the most sensitive test for detecting low levels of dabigatran [64]. There was test-kit variability for all of these assays, emphasizing the need for caution when comparing tests from different studies and/or manufacturers. Some clinicians find the TT too sensitive and prefer to use the aPTT to assess the presence of dabigatran. Point-of-care devices for measuring the prothrombin time/international normalized ratio (PT/INR) should not be used [65]. (See "Clinical use of coagulation tests".)

Risks (dabigatran) — As with all anticoagulants, dabigatran increases bleeding risk. An antidote is available (see "Management of bleeding in patients receiving direct oral anticoagulants", section on 'Dabigatran reversal'). Product labeling for dabigatran has a Boxed Warning regarding the risk of spinal/epidural hematoma in patients undergoing neuraxial anesthesia or spinal puncture [66].

Bleeding risks of dabigatran compared with other oral anticoagulants have been evaluated in several meta-analyses and large observational series. In general, these have shown that overall bleeding rates are similar with dabigatran compared with warfarin. Dabigatran may be associated with a slightly lower rate of intracranial hemorrhage and death, and a slightly higher risk of gastrointestinal bleeding at the 150 mg twice daily dose (but not 110 mg twice daily) [27,67-70]. A discussion of bleeding risks and comparison with other oral anticoagulants, such as vitamin K antagonists, in various clinical settings is presented separately. (See "Risks and prevention of bleeding with oral anticoagulants".)

The management of bleeding and perioperative management in patients receiving dabigatran is also discussed in detail separately. (See "Management of bleeding in patients receiving direct oral anticoagulants" and "Perioperative management of patients receiving anticoagulants".)

As with all anticoagulants, dabigatran is administered in the setting of increased thromboembolic risk. Dabigatran has a Boxed Warning regarding the risk of thrombotic events following premature discontinuation [66].

Dyspepsia is a common side effect of dabigatran, with an incidence from 12 to 33 percent in some studies [71-73]. In the RE-LY trial, which randomized 18,113 individuals with AF to dabigatran or warfarin, non-bleeding gastrointestinal events (eg, dyspepsia, dysmotility, gastrointestinal reflux) were twice as common in those who received dabigatran (16.9 versus 9.4 percent; relative risk [RR] 1.81; 95% CI 1.66-1.97 percent) [74]. This may limit dabigatran use in some patients. (See "Approach to the adult with dyspepsia".)

There does not appear to be an increased risk of serious liver injury with dabigatran, despite concerns with an earlier direct thrombin inhibitor that was not approved (ximelagatran). In a cohort study involving 51,887 patients receiving a DOAC (3778 of whom [7 percent] had prior liver disease), the adjusted hazard ratio (HR) for serious liver injury was 0.99 (95% CI 0.68-1.45), and there was a trend towards a lower risk of serious liver injury in the individuals with prior liver injury that did not reach statistical significance (adjusted HR 0.68; 95% CI 0.33-1.37) [75].

DIRECT FACTOR Xa INHIBITORS

General considerations for direct factor Xa inhibitors — Direct factor Xa inhibitors inactivate circulating and clot-bound factor Xa (figure 3). Several orally acting direct factor Xa inhibitors are clinically available. (See 'Rivaroxaban' below and 'Apixaban' below and 'Edoxaban' below.)

There are no parenteral direct factor Xa inhibitors available for clinical use. Otamixaban was developed as an intravenous factor Xa inhibitor, but development was discontinued due to an increased risk of bleeding compared with unfractionated heparin in patients with acute coronary syndromes [76,77].

Differences between factor Xa inhibitors — The following differences may warrant consideration in decision-making:

Efficacy – All of the direct factor Xa inhibitors are effective anticoagulants. However, the twice daily dosing of apixaban may result in smaller fluctuations in drug levels over the course of the day. In a retrospective review of more than 37,000 adults with venous thromboembolism (VTE) prescribed apixaban or rivaroxaban for the first time, the risk of recurrence with propensity score mapping was lower with apixaban (hazard ratio [HR] 0.77, 95% CI 0.69-0.87) [78]. There were 11.4 fewer events per 100 person-years with apixaban and an absolute difference in VTE recurrence at six months that was 0.011 lower with apixaban. Subgroup analysis did not show any difference in the findings. Bleeding (gastrointestinal and intracranial) was also lower with apixaban.

DosingRivaroxaban and edoxaban are given once daily; apixaban is given twice daily (table 5). Rivaroxaban is given with food. For VTE, edoxaban is preceded by a parenteral agent; rivaroxaban and apixaban are preceded by a period of higher initial dosing. (See 'Factor Xa inhibitors dosing' below.)

Adverse effectsRivaroxaban appears to carry a slightly higher risk of gastrointestinal bleeding. In a retrospective registry study involving over 5000 consecutive individuals taking apixaban or rivaroxaban (including all individuals who received a prescription for a DOAC in the country of Iceland), there were 241 gastrointestinal bleeding events, approximately one-half in the lower gastrointestinal tract (overall rate of gastrointestinal bleeding, approximately 4 percent) [79]. The bleeding rate was higher with rivaroxaban than apixaban (3.2 versus 2.5 per 100 person-years; HR 1.42; 95% CI 1.04-1.93). Similar findings were reported in previous population-based registry studies [80]. The higher bleeding risk with rivaroxaban may be related to the higher peak drug levels associated with once-daily dosing. A retrospective review of more than 37,000 adults with VTE who were prescribed apixaban or rivaroxaban showed less bleeding with apixaban (absolute reduction in probability of gastrointestinal and intracranial bleeding within six months of starting apixaban versus rivaroxaban, 0.015, 95% CI 0.013-0.015) [78].

Factor Xa inhibitors dosing — Direct factor Xa inhibitors are administered at a fixed dose without monitoring. It is important to use the appropriate dose (ie, do not under-dose). Anti-factor Xa activity can be measured in unusual circumstances (eg, individual with altered gastrointestinal anatomy for whom there is concern about drug absorption, individual who must take an interacting drug along with a direct factor Xa inhibitor, individual with an extremely high body mass index [BMI]).

However, if drug levels or anti-factor Xa activity is used, the purpose should be to confirm that the drug is being absorbed and that levels are not excessive, rather than to target a therapeutic range, because there is no established therapeutic range for these drugs. For reasonable levels, the clinician must rely on guidance from their institutional laboratory, information from the manufacturer, and/or data from clinical trials [63,81]. If anti-factor Xa activity is tested, it ideally should be based on an assay calibrated for the specific anticoagulant. If an assay calibrated for the specific drug is not available, it may be possible to use an assay calibrated for heparin, although this approach has not been clinically validated [82]. Examples of typical expected drug levels are listed in the individual sections below.

We do not use a lower dose of these agents in individuals with Asian ethnicity. Under-dosing based on East Asian ancestry was evaluated in a Korean population and found to be unjustified and to result in inferior efficacy compared with standard dosing [83].

Factor Xa inhibitors toxicity — Direct factor Xa inhibitors are partially excreted by the kidney (approximately 25 to 35 percent) and metabolized in the liver; drug accumulation could occur with severe hepatic impairment.

Direct factor Xa inhibitors do not appear to cause hepatotoxicity. In a cohort study involving 51,887 patients receiving a DOAC (3778 of whom [7 percent] had prior liver disease), there was not an increased risk of serious liver injury (adjusted hazard ratio [HR] 0.99; 95% CI 0.68-1.45) [75]. In the individuals with prior liver disease, there was a trend towards a lower risk of serious liver injury with the DOACs that did not reach statistical significance (adjusted HR 0.68; 95% CI 0.33-1.37).

All factor Xa inhibitors increase the risk of bleeding, and each has a Boxed Warning regarding the risk of spinal/epidural hematoma in patients undergoing neuraxial anesthesia or spinal puncture and the risk of thrombotic events following premature discontinuation.

Treatment of bleeding is discussed separately. (See "Management of bleeding in patients receiving direct oral anticoagulants".)

High BMI and post-bariatric surgery — Data are slowly accumulating demonstrating use of direct factor Xa inhibitors in individuals with a high body mass index (BMI).

High BMI – Based on a 2021 review of available literature, the International Society on Thrombosis and Haemostasis (ISTH) recommended that any DOAC is appropriate for individuals with BMI up to 40 kg/m2 or weight 120 kg [55]. For individuals with a BMI >40 kg/m2, or weight ≥120 kg with VTE, standard doses of rivaroxaban or apixaban are appropriate anticoagulant options.

A 2017 review specific to rivaroxaban concluded that it could be administered to individuals with a BMI >40 kg/m2 (or weight >120 kg) without dose adjustment, although data were limited [84]. (See 'Dosing, monitoring, risks (rivaroxaban)' below.)

Subsequently published studies have shown reasonable safety and efficacy with rivaroxaban and apixaban in different settings (venous thromboembolism treatment, atrial fibrillation) in individuals with BMI ≥50 kg/m2 and even ≥50 kg/m2 [55,85,86].

Post-bariatric surgery – Immediate postoperative VTE prophylaxis is discussed separately. (See "Bariatric surgery: Postoperative and long-term management of the uncomplicated patient", section on 'Venous thromboembolism'.)

Anticoagulant selection in individuals who have undergone bariatric surgery and require anticoagulation for another reason (atrial fibrillation, VTE) should incorporate available information on the effects of altered gastroduodenal anatomy on DOAC absorption; absorption depends on which bariatric procedure was performed. Apixaban absorption appears to be the least affected [55].  (See "Bariatric procedures for the management of severe obesity: Descriptions".)

Rivaroxaban

Overview (rivaroxaban) — Rivaroxaban (Xarelto) is an oral direct factor Xa inhibitor with a half-life of 5 to 9 hours (may be longer in older individuals [eg, 11 to 13 hours]).

Rivaroxaban is used in the prevention and treatment of venous thromboembolic (VTE) disease, in stroke prevention in patients with atrial fibrillation (AF), and in ischemic heart disease. These indications are discussed in detail separately:

VTE prophylaxis – (See "Prevention of venous thromboembolic disease in adult nonorthopedic surgical patients".)

VTE overview of treatment – (See "Overview of the treatment of lower extremity deep vein thrombosis (DVT)".)

VTE initial treatment – (See "Venous thromboembolism: Initiation of anticoagulation (first 10 days)".)

VTE extended treatment – (See "Venous thromboembolism: Anticoagulation after initial management".)

AF – (See "Atrial fibrillation in adults: Use of oral anticoagulants".)

Ischemic heart disease – (See "Prevention of cardiovascular disease events in those with established disease (secondary prevention) or at very high risk" and "Acute coronary syndrome: Oral anticoagulation in medically treated patients".)

Rivaroxaban should not be used in individuals with mechanical prosthetic heart valves or during pregnancy. (See "Antithrombotic therapy for mechanical heart valves" and "Use of anticoagulants during pregnancy and postpartum".)

Dosing, monitoring, risks (rivaroxaban) — Rivaroxaban is generally given at a fixed dose without monitoring (table 5). The 15 and 20 mg tablets used in adults are to be taken with food [87,88]. The dosing differs according to the clinical indication and the patient's kidney function.

Venous thromboembolism (VTE) prophylaxis in surgical patients: 10 mg daily; duration (12 days versus extended to 35 days) depends on the type of surgery, as discussed separately. (See "Prevention of venous thromboembolism in adult orthopedic surgical patients" and "Prevention of venous thromboembolic disease in adult nonorthopedic surgical patients".)

Use for VTE treatment in children is discussed separately. (See "Neonatal thrombosis: Management and outcome", section on 'Direct oral anticoagulants' and "Venous thrombosis and thromboembolism (VTE) in children: Treatment, prevention, and outcome", section on 'Direct oral anticoagulants'.)

Treatment and secondary prevention of VTE: 15 mg twice daily (with food) for 21 days, followed by 20 mg once daily (with food). If therapy is continued after six months, the dose can be reduced to 10 mg once daily for selected individuals. However, for those with an increased risk for VTE beyond six months of anticoagulation (eg, two or more episodes of VTE), the 20 mg once-daily dose should be used [89]. (See "Selecting adult patients with lower extremity deep venous thrombosis and pulmonary embolism for indefinite anticoagulation".)

Stroke prevention in atrial fibrillation (AF): 20 mg once daily with the evening meal (creatinine clearance [CrCl] >50 mL/minute); or 15 mg once daily with the evening meal (CrCl ≤50 mL/minute). (See "Atrial fibrillation in adults: Use of oral anticoagulants".)

Secondary prevention in individuals with stable cardiovascular disease: 2.5 mg twice daily in combination with aspirin. (See "Prevention of cardiovascular disease events in those with established disease (secondary prevention) or at very high risk", section on 'Anticoagulant therapy'.)

Rivaroxaban is not recommended for VTE prophylaxis, treatment, or secondary prevention in individuals with a CrCl <30 mL/minute. The drug should not be used in individuals with a CrCl <15 mL/minute, as well as in those with significant hepatic impairment (Child-Pugh Class B and C with coagulopathy) [90]. CrCl can be estimated from the patient's sex, age, weight, and serum creatinine (calculator 1 and calculator 2). Recommendations for individuals with a high BMI are listed above. (See 'General considerations for direct factor Xa inhibitors' above.)

Rivaroxaban interacts with drugs that are potent dual inhibitors of CYP-3A4 and P-glycoprotein (eg, systemic ketoconazole, itraconazole, voriconazole, posaconazole or ritonavir), and concurrent use is contraindicated by Canadian product information (table 6 and table 8 and table 7) [52]. Drugs that inhibit either CYP-3A4 or P-glycoprotein, as opposed to both, do not seem to significantly alter rivaroxaban [91]. Potent inducers of CYP-3A4 (eg, rifamycins, carbamazepine, St. John's wort) may reduce rivaroxaban's effects (table 8) [91-93].

Laboratory testing prior to initiating rivaroxaban should include platelet count, prothrombin time (PT), and activated partial thromboplastin time (aPTT), to assess and document coagulation status before anticoagulation; and measurement of serum creatinine and liver function tests, as a baseline and for potential dose adjustment in the event of impaired kidney or liver function.

Routine monitoring of coagulation times is not required for patients taking rivaroxaban, because drug levels are relatively predictable for a given dose, and there is no established therapeutic range. However, possible improvements in efficacy and/or safety with monitoring have been suggested [61,62].

If there is a concern that drug levels are abnormally low or abnormally high, it may be appropriate to test for the presence of the drug. A consensus document from the International Council for Standardization in Haematology (ICSH) has provided examples of rivaroxaban drug levels for the 20 mg once-daily dose, with an expected mean peak of approximately 250 to 270 ng/mL (5th to 95th percentile of 184 to 419 ng/mL) and an expected trough of approximately 26 to 44 ng/mL (5th to 95th percentile, 6 to 137 ng/mL) [63]. These values are intended to be used as guides to provide evidence of drug absorption, not as therapeutic targets.

Examples of settings in which coagulation testing for rivaroxaban effect may be helpful include the following:

Bleeding in a patient receiving rivaroxaban, or with suspected rivaroxaban overdose – (See "Management of bleeding in patients receiving direct oral anticoagulants", section on 'Assessment of anticoagulation status'.)

Need for emergency or urgent surgery in a patient receiving rivaroxaban – (See "Perioperative management of patients receiving anticoagulants", section on 'Rivaroxaban'.)

Concerns about absorption (eg, altered gastrointestinal anatomy) or drug adherence.

In such cases, testing is best done by measuring anti-factor Xa activity using an assay specifically calibrated for rivaroxaban.

If an anti-factor Xa assay calibrated to rivaroxaban is not available, it may be possible (although not ideal) to use an anti-factor Xa assay calibrated to another anticoagulant such as low molecular weight (LMW) heparin. Other assays such as the PT and aPTT are not very reliable [94].

Cases of liver injury following rivaroxaban administration have been reported, although this was not seen in larger trials [95,96]. The incidence of this complication is unknown.

As with all anticoagulants, rivaroxaban increases bleeding risk and is administered in the setting of increased thrombotic risk. Product labeling for rivaroxaban has Boxed Warnings regarding the risk of spinal/epidural hematoma in patients undergoing neuraxial anesthesia or spinal puncture and the risk of thrombotic events following premature discontinuation [97]. (See "Neuraxial anesthesia/analgesia techniques in the patient receiving anticoagulant or antiplatelet medication".)

Apixaban

Overview (apixaban) — Apixaban (Eliquis; generic formulations were approved in late 2019 [98]) is an oral direct factor Xa inhibitor with a half-life of approximately 12 hours. Among the direct factor Xa inhibitors, apixaban appears to have greater efficacy and safety in individuals with VTE, although the absolute differences were small. (See 'Differences between factor Xa inhibitors' above.)

Apixaban is used in the prevention and treatment of VTE and in stroke prevention in patients with AF. These indications are discussed in detail separately:

VTE prophylaxis – (See "Prevention of venous thromboembolic disease in adult nonorthopedic surgical patients".)

VTE overview of treatment – (See "Overview of the treatment of lower extremity deep vein thrombosis (DVT)".)

VTE initial treatment – (See "Venous thromboembolism: Initiation of anticoagulation (first 10 days)".)

VTE extended treatment – (See "Venous thromboembolism: Anticoagulation after initial management".)

AF – (See "Atrial fibrillation in adults: Use of oral anticoagulants".)

Apixaban should not be used in patients with mechanical prosthetic heart valves or during pregnancy. (See "Antithrombotic therapy for mechanical heart valves" and "Use of anticoagulants during pregnancy and postpartum".)

Dosing, monitoring, risks (apixaban) — Apixaban is generally given at a fixed dose without monitoring (table 5).

The dosing of apixaban differs according to the clinical indication and the patient's age, weight, and kidney function [99].

Venous thromboembolism (VTE) prophylaxis in surgical patients: 2.5 mg twice daily; duration (12 days versus extended to 35 days) depends on the type of surgery, as discussed separately. (See "Prevention of venous thromboembolism in adult orthopedic surgical patients" and "Prevention of venous thromboembolic disease in adult nonorthopedic surgical patients".)

Treatment and secondary prevention of VTE: 10 mg twice daily for seven days, followed by 5 mg twice daily. If therapy continues beyond six months, the dose is reduced to 2.5 mg twice daily [100].

Stroke prevention in atrial fibrillation (AF): 5 mg twice daily (CrCl >50 mL/minute); or 2.5 mg twice daily for those with any two of the following: age ≥80 years, body weight ≤60 kg, or serum creatinine ≥1.5 mg/dL.

Apixaban dose reduction is recommended for patients who are also receiving strong dual inhibitors of CYP-3A4 and P-glycoprotein (table 6 and table 8 and table 7) [99]. Recommendations for individuals with a high BMI are listed above. (See 'General considerations for direct factor Xa inhibitors' above.)

Other than betrixaban, apixaban has the least dependence on clearance by the kidney. Canadian product information states that apixaban is not recommended in individuals with CrCl <15 mL/minute; United States product information recommends dose adjustments based on CrCl, body weight, and age [101,102]. CrCl can be estimated from the patient's sex, age, weight, and serum creatinine (calculator 1 and calculator 2).

Laboratory testing prior to initiating apixaban should include platelet count, PT, and aPTT, to assess and document coagulation status before anticoagulation; and measurement of serum creatinine and liver function tests, as a baseline and for potential dose adjustment in the event of decreased kidney or liver function.

Routine monitoring of coagulation times is not required for patients taking apixaban, because drug levels are relatively predictable for a given dose, and there is no established therapeutic range. However, possible improvements in efficacy and/or safety with monitoring have been suggested [61,62].

If there is a concern that apixaban drug levels are abnormally low or abnormally high, it may be appropriate to test for the presence of the drug. A consensus document from the International Council for Standardization in Haematology (ICSH) has provided examples of apixaban drug levels for the 5 mg twice-daily dose, with an expected median peak of approximately 171 to 132 ng/mL (5th to 95th percentile of 59 to 321 ng/mL) and an expected trough of approximately 63 to 103 ng/mL (5th to 95th percentile, 22 to 230 ng/mL) [63]. These values are intended to be used as guides to provide evidence of drug absorption, not as therapeutic targets.

Settings in which coagulation testing for apixaban effect may be helpful include the following:

Bleeding in a patient receiving apixaban, or with suspected apixaban overdose – (See "Management of bleeding in patients receiving direct oral anticoagulants", section on 'Assessment of anticoagulation status'.)

Need for emergency or urgent surgery in a patient receiving apixaban – (See "Perioperative management of patients receiving anticoagulants", section on 'Apixaban'.)

Concerns about absorption (eg, altered gastrointestinal anatomy) or drug adherence.

In such cases, testing can be accomplished through the measurement of anti-factor Xa activity [103].

As with all anticoagulants, apixaban increases bleeding risk and is administered in the setting of increased thromboembolic risk. Product labeling for apixaban has Boxed Warnings regarding the risk of spinal/epidural hematoma in patients undergoing neuraxial anesthesia or spinal puncture and the risk of thrombotic events following premature discontinuation [99].

Edoxaban

Overview (edoxaban) — Edoxaban (Lixiana, Savaysa) is an oral direct factor Xa inhibitor with a half-life in the range of 10 to 14 hours.

Edoxaban is used in the prevention and treatment of VTE and in stroke prevention in patients with AF. These indications are discussed in detail separately:

VTE prophylaxis – (See "Prevention of venous thromboembolic disease in adult nonorthopedic surgical patients".)

VTE overview of treatment – (See "Overview of the treatment of lower extremity deep vein thrombosis (DVT)".)

VTE initial treatment – (See "Venous thromboembolism: Initiation of anticoagulation (first 10 days)".)

VTE extended treatment – (See "Venous thromboembolism: Anticoagulation after initial management".)

AF – (See "Atrial fibrillation in adults: Use of oral anticoagulants".)

Edoxaban should not be used in patients with mechanical prosthetic heart valves or during pregnancy. (See "Antithrombotic therapy for mechanical heart valves" and "Use of anticoagulants during pregnancy and postpartum".)

Dosing, monitoring, risks (edoxaban) — Edoxaban is generally given at a fixed dose without monitoring (table 5). Absorption is unaffected by food. For patients being treated for VTE, edoxaban is given after 5 to 10 days of parenteral anticoagulation. Typical dosing is 30 or 60 mg orally once daily [104-107]. A reduced dose of 15 mg once daily has been proposed for Japanese individuals with atrial fibrillation who are ≥80 years of age and are not considered to be candidates for standard-dose therapy [108]. Recommendations for individuals with a high BMI are listed above. (See 'General considerations for direct factor Xa inhibitors' above.)

Edoxaban is excreted by the kidney and is a substrate for P-glycoprotein. Product labeling for edoxaban has a Boxed Warning regarding reduced efficacy in nonvalvular atrial fibrillation in patients with a high CrCl (>95 mL/minute) [109]. Product information advises dose reduction for people with CrCl of 15 to 50 mL/minute, and edoxaban is not to be used in those with CrCl >95 mL/minute or <15 mL/minute (table 6) [110]. CrCl can be estimated from the patient's sex, age, weight, and serum creatinine (calculator 1 and calculator 2).

Laboratory testing prior to initiating edoxaban should include platelet count, PT, and aPTT, to assess and document coagulation status before anticoagulation; and measurement of serum creatinine and liver function tests, as a baseline and for potential dose adjustment in the event of decreased kidney or liver function.

Routine monitoring of coagulation times is not required for patients taking edoxaban, because drug levels are relatively predictable for a given dose, and there is no established therapeutic range. Possible improvements in efficacy and/or safety with monitoring have been suggested [61].

If there is a concern that edoxaban drug levels are abnormally low or abnormally high, it may be appropriate to test for the presence of the drug. A consensus document from the International Council for Standardization in Haematology (ICSH) has provided examples of edoxaban drug levels for the 60 mg once-daily dose, with an expected median peak of approximately 170 to 234 ng/mL (interquartile range [IQR], 125 to 317 ng/mL) and an expected trough of approximately 19 to 36 ng/mL (IQR, 10 to 62 ng/mL) [63]. These values are intended to be used as guides to provide evidence of drug absorption, not as therapeutic targets.

Settings in which coagulation testing for edoxaban effect may be helpful include the following:

Bleeding in a patient receiving edoxaban, or with suspected edoxaban overdose – (See "Management of bleeding in patients receiving direct oral anticoagulants", section on 'Assessment of anticoagulation status'.)

Need for emergency or urgent surgery in a patient receiving edoxaban – (See "Perioperative management of patients receiving anticoagulants", section on 'Edoxaban'.)

Concerns about absorption (eg, altered gastrointestinal anatomy) or drug adherence.

As with all anticoagulants, edoxaban increases bleeding risk and is administered in the setting of increased thrombotic risk. Product labeling for edoxaban has Boxed Warnings regarding the risk of spinal/epidural hematoma in patients undergoing neuraxial anesthesia or spinal puncture, the risk of thrombotic events following premature discontinuation [109].

Betrixaban — Betrixaban (Bevyxxa) was an oral direct factor Xa inhibitor with a half-life in the range of 19 to 27 hours [111]. It was discontinued in the United States in 2020 (for business reasons) and was not marketed in other countries.

TRANSITIONING BETWEEN ANTICOAGULANTS — The goal when transitioning between anticoagulants is to maintain stable anticoagulation. Thus, when transitioning from a DOAC to a vitamin K antagonist (VKA), it is important to keep in mind that the full effect of the VKA does not occur for the first few days, despite prolongation of the prothrombin time/international normalized ratio (PT/INR) [112,113] (see "Warfarin and other VKAs: Dosing and adverse effects", section on 'Initial dosing'). Likewise, when transitioning from warfarin to a DOAC, the resolution of warfarin effect may take several days.

The following approaches to switching between oral anticoagulants, which are summarized in the table (table 9), are derived from the drug package inserts and a 2018 clinical practice guideline from the American Society of Hematology (ASH) [114]. These are reasonable approaches when switching between anticoagulants but do not substitute for clinical judgment regarding individual patient factors.

Dabigatran to warfarin – The two agents are overlapped [115]. The number of days of overlap depends on the patient's kidney function:

Creatinine clearance (CrCl) ≥50 mL/minute – Start VKA three days before discontinuing dabigatran.

CrCl 30 to 50 mL/minute – Start VKA two days before discontinuing dabigatran.

CrCl 15 to 30 mL/minute – Start VKA one day before discontinuing dabigatran.

Rivaroxaban to warfarin – Prescribing information suggests stopping rivaroxaban and providing a parenteral agent during warfarin initiation because the INR cannot be monitored adequately during administration of a direct factor Xa inhibitor [87]. The warfarin can be started at the same time as the parenteral agent or afterwards, whichever is more appropriate for the patient's final warfarin schedule.

Apixaban to warfarin – Prescribing information suggests stopping apixaban and providing a parenteral agent during warfarin initiation because the INR cannot be monitored adequately during administration of a direct factor Xa inhibitor [116].

Edoxaban to warfarin – For patients taking 60 mg of edoxaban, reduce the dose to 30 mg and begin the VKA concomitantly [117]. For patients receiving 30 mg of edoxaban, reduce the dose to 15 mg and begin the VKA concomitantly. The INR must be measured at least weekly and just prior to the daily dose of edoxaban to minimize the effect of edoxaban on INR measurements. Discontinue edoxaban once a stable increased INR (ie, INR ≥2.0 for at least two days) is reached.

Alternative approaches for transitioning from a direct factor Xa inhibitor to warfarin based on the pharmacodynamics of warfarin and the anticoagulant might be reasonable. The ASH guideline suggests overlapping the two anticoagulants until the INR is therapeutic on warfarin [114]; two to three days of overlap with a therapeutic INR may be appropriate because the PT/INR will enter the therapeutic range before full anticoagulation occurs.

The direct factor Xa inhibitors (eg, rivaroxaban, apixaban, edoxaban) also prolong the PT/INR, which may make monitoring during the transition more challenging. Thus, when possible, the ASH guideline specifies that testing be done right before the next dose of the factor Xa inhibitor to minimize this interference [114].

When switching from a VKA to a DOAC, the product-specific package inserts differ slightly, but in general, we think it is reasonable to discontinue the VKA and initiate the DOAC when the INR is ≤2.0:

Warfarin to argatroban – Start argatroban when the INR is <2.0. (See "Perioperative management of patients receiving anticoagulants", section on 'Bridging anticoagulation'.)

Warfarin to dabigatran – Discontinue the VKA, monitor the PT/INR, and start dabigatran when the PT/INR is <2.0 [115].

Warfarin to rivaroxaban – Discontinue the VKA, monitor the PT/INR, and start rivaroxaban when the PT/INR is <3.0 [118].

Warfarin to apixaban – Discontinue the VKA, monitor the PT/INR, and start apixaban when the PT/INR is <2.0 [119].

Warfarin to edoxaban – Discontinue the VKA, monitor the PT/INR, and start edoxaban when the PT/INR is ≤2.5 [117].

When switching from one DOAC to another DOAC, no overlap is needed. The second DOAC is started when the next dose of the first DOAC would have been due.

Switching from a parenteral direct thrombin inhibitor to an oral anticoagulant is discussed separately:

Argatroban to warfarin – (See "Management of heparin-induced thrombocytopenia", section on 'Transition to warfarin or other outpatient anticoagulant'.)

Bivalirudin to warfarin – (See "Anticoagulant therapy in acute ST-elevation myocardial infarction" and "Anticoagulant therapy in non-ST elevation acute coronary syndromes", section on 'Unfractionated heparin compared with bivalirudin'.)

Aspects of anticoagulant transitioning specific to individuals with prosthetic heart valves and in the perioperative setting are discussed in detail separately:

Prosthetic heart valve – (See "Antithrombotic therapy for prosthetic heart valves: Management of bleeding and invasive procedures", section on 'Management of antithrombotic therapy for invasive procedures'.)

Perioperative management – (See "Perioperative management of patients receiving anticoagulants".)

ANTICOAGULANTS IN DEVELOPMENT — A variety of anticoagulant strategies targeting other steps in coagulation are in development for prophylaxis or treatment of venous thromboembolism (VTE):

Inhibitors of factor XI or factor XIa — Factor XIa is part of the intrinsic pathway of the clotting cascade and participates in tertiary amplification of thrombin generation (figure 2). Individuals with hereditary factor XI deficiency have a low risk of VTE but rarely have spontaneous bleeding. It has been hypothesized the inhibition of factor XI/XIa, by blocking the tertiary amplification of thrombin generation, might uncouple thrombosis prevention from normal hemostasis, allowing maximal anticoagulation without incurring more bleeding risk. (See "Factor XI (eleven) deficiency".)

Factor XI or XIa inhibition may be especially useful in the surgical setting, where tissue factor-based clotting is a major contributor to postoperative VTE, particularly orthopedic surgery, where VTE rates are high. For long-acting agents such as monoclonal antibodies and antisense therapies, often only a single dose is needed. Several approaches are under investigation:

Milvexian – Milvexian is a DOAC specific for factor XIa. In a trial that randomly assigned 1242 individuals ≥50 years who were undergoing knee arthroplasty to receive one of several doses/schedules of milvexian versus LMW heparin (enoxaparin 40 mg once daily) for 10 to 14 days postoperatively, participants assigned to milvexian had lower rates of VTE, with a dose-dependent pattern [120]. All participants underwent mandatory unilateral venography on the operated leg 10 to 14 days after surgery.

Efficacy – Postoperative VTE rates were as follows:

-Milvexian, 25 mg twice daily – 21 percent

-Milvexian, 50 mg twice daily – 11 percent

-Milvexian, 100 mg twice daily – 9 percent

-Milvexian, 200 mg twice daily – 8 percent

-Milvexian, 25 mg once daily – 25 percent

-Milvexian, 200 mg once daily – 7 percent

-Enoxaparin, 40 mg once daily – 21 percent

Safety – Bleeding rates were similar (4 percent with milvexian and 4 percent with enoxaparin). Major bleeding occurred in one individual in the enoxaparin arm and none in the milvexian arm.

Abelacimab – Abelacimab (MAA868) is a monoclonal antibody that binds to factor XI (the inactive precursor) and locks it in the inactive state, preventing it from being activated by factor XIIa or thrombin. A trial involving 412 individuals undergoing knee arthroplasty evaluated three doses of abelacimab (30, 75, or 150 mg) administered postoperatively versus enoxaparin, 40 mg once daily starting the evening before or after surgery, found a lower rate of VTE with all doses of abelacimab [121]. All participants underwent postoperative venography for VTE evaluation.

Efficacy – Postoperative VTE rates were as follows:

-Abelacimab, 30 mg – 13 percent

-Abelacimab, 75 mg – 5 percent

-Abelacimab, 150 mg – 4 percent

-Enoxaparin, 40 mg – 22 percent

Safety – The risk of bleeding was low (2, 2, and 0 percent of patients in the 30, 75, and 150 mg abelacimab cohorts).

Osocimab – Osocimab (BAY 1213790) is a monoclonal antibody that binds adjacent to the active site of factor XIa and prevents it from activating factor IX (allosteric inhibition) [122]. A trial evaluated dose-finding, timing of administration, and comparison with other anticoagulants (enoxaparin and apixaban) in 813 adults undergoing elective knee arthroplasty [123]. Individuals were randomly assigned to receive one of several weight-based doses of osocimab, some preoperatively and some postoperatively, or to receive enoxaparin (40 mg subcutaneously twice daily started the evening before surgery or six to eight hours postoperatively) or apixaban (2.5 mg orally twice per day starting 12 to 24 hours postoperatively).

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

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

The half-life of osocimab is 30 to 44 days, allowing single-dose administration for surgical prophylaxis. It is administered as an intravenous infusion over one hour.

ABO23 – ABO23 is a monoclonal antibody that blocks the activation of factor XI by factor XIIa, thus acting as a pure contact phase inhibitor [124]. By leaving intact the activation of factor XI by thrombin, this agent may allow better separation of thrombosis from hemostasis.

Antisense – A factor XI antisense oligonucleotide (FXI-ASO) has been developed that reduces factor XI to undetectable levels [125]. In an open-label trial, 300 patients undergoing elective knee replacement were randomly assigned to receive FXI-ASO at one of two doses (200 or 300 mg) or enoxaparin (40 mg) once daily [126]. The rate of VTE, assessed by venography in all patients, was dramatically reduced in those receiving the higher dose of FXI-ASO (3 of 71 patients; 3 percent), compared with the lower dose of FXI-ASO or enoxaparin (27 and 30 percent, respectively). Bleeding was not increased with the higher FXI-ASO dose (3 percent, versus 3 and 8 percent for FXI-ASO 200 mg and enoxaparin, respectively) (figure 2). Many caveats for this strategy remain, however, including a long duration of anticoagulation due to the extended half-life of the antisense therapy (up to three months), injection site reactions, and potential cost [127].

Synthetic heparin-like small molecule – Sulfated chiro-inositol (SCI) is a synthetic molecule similar to heparin that binds to and alters the conformation of factor XIa, reducing its enzymatic activity (allosteric inhibition) [128]. Preclinical testing suggests that this molecule could be effective as an anticoagulant and could be reversed by protamine sulfate.

Inhibitors of other clotting proteins

Tissue factor pathway inhibitors – The recombinant form of tissue factor pathway inhibitor (TFPI), the physiologic inhibitor of the TF/FVIIa complex, is being tested; specific TF/FVIIa and factor VIIa inhibitors (eg, nematode anticoagulant protein) are also in development [129-132].

Factor VIII inhibitor – TB-402 is a human IgG4 monoclonal antibody that is partially inhibits factor VIII. As a result of its long half-life (approximately three weeks), this agent may provide a prolonged antithrombotic effect after a single dose. This was demonstrated in a randomized phase II trial in patients following total knee replacement, in which a single postoperative intravenous injection of TB-402 was found to be as effective and safe as 10 days of the LMW heparin enoxaparin (40 mg/day for at least 10 days) in preventing postoperative VTE [133].

Thrombomodulin – When thrombin binds to thrombomodulin on the endothelial cell surface, it is converted from a procoagulant enzyme into an anticoagulant enzyme by its ability to activate protein C [134]. The recombinant form of the extracellular domain of thrombomodulin was developed as a novel anticoagulant (ART-123), and has been approved in Japan for treatment of DIC. It has a long plasma half-life of two to three days after a subcutaneous injection, such that it can be given once every five to six days with maintenance of anticoagulant activity [135]. In a phase II trial, ART-123 was shown to be efficacious for VTE prophylaxis following total hip replacement surgery [136].

Factor IXa inhibitor – REG1 consists of pegnivacogin (RB006), an injectable RNA aptamer that specifically binds and inhibits factor IXa, and anivamersen (RB007), the complementary oligonucleotide that neutralizes its anti-IXa activity if and when needed (ie, as an antidote). Initial tests of this agent combined with antiplatelet therapy in patients with coronary artery disease appeared promising [137,138]. However, a randomized trial comparing REG1 with bivalirudin in patients undergoing percutaneous coronary intervention (PCI) was terminated early, after enrollment of 3232 patients, due to severe allergic reactions with REG1 in 10 of 1616 patients (1 percent), compared with 1 of 1616 patients (0.1 percent) given bivalirudin [139]. REG1 was associated with reduced stent thrombosis and increased bleeding relative to bivalirudin, but a primary composite endpoint of death, myocardial infarction, stroke, and unplanned revascularization was similar between the two groups.

Factor XIIa inhibitor – The selective factor XIIa inhibitor rHA-Infestin-4 (recombinant human albumin fused to the factor XIIa inhibitor Infestin-4) is highly active in human plasma and profoundly protects mice and rats from pathologic thrombus formation while not affecting hemostasis [140]. This agent is being considered for the prevention and treatment of acute ischemic cardiovascular and cerebrovascular events in humans.

Protein disulfide isomerase inhibitors – Protein disulfide isomerase (PDI) is an oxidoreductase enzyme that catalyzes redox protein folding in newly synthesized proteins in the endoplasmic reticulum, including coagulation factor XI and tissue factor. PDI is also found on the surface of several types of cells, including platelets, where it promotes platelet aggregation via integrin activation [141]. Inhibition of PDI is emerging as a possible target for antithrombotic therapy that blocks the contributions of both fibrin generation and platelet activation. A number of molecules inhibit PDI, including quercetins, which are found in certain plant-based foods. Preclinical studies using a peptide inhibitor of PDI have demonstrated antiplatelet activity in vitro [142]. Clinical trials with PDI inhibitors are planned.

Polyphosphate inhibitors – Polyphosphate (released from platelets upon their activation or from a microbial source) may initiate and/or accelerate coagulation via intrinsic pathway clotting factors. A variety of compounds that inhibit polyphosphate and reduce thrombosis in preclinical models are under investigation [143].

Additional details of the hemostatic processes targeted by these anticoagulant strategies are discussed separately. (See "Overview of hemostasis".)

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

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topic (see "Patient education: Choosing a medicine for blood clots (The Basics)" and "Patient education: Taking medicines for blood clots (The Basics)")

SUMMARY AND RECOMMENDATIONS

Biology – The direct thrombin inhibitors and direct factor Xa inhibitors act at points in the coagulation cascade that appear to be rate-limiting in clot formation (figure 3). They inactivate both circulating and clot-bound activated coagulation factors, and they do not induce antiplatelet antibodies. A major advantage is the lack of requirement for monitoring, due to less variability in drug effect for a given dose. There may be a lower risk of osteoporosis with direct oral anticoagulants (DOACs). However, DOACs are expensive, their half-lives are short, they are not appropriate for all indications, and adherence is more difficult to monitor than vitamin K antagonists. (See 'Mechanisms of action and terminology' above and 'Comparison with heparin and warfarin' above.)

Indications – Indications for these agents are discussed in detail separately. Their use is not appropriate in patients with severely reduced kidney function, severe liver disease (table 3), pregnancy, antiphospholipid syndrome (APS), or mechanical prosthetic heart valves. (See 'Indications' above.)

Parenteral agents – Parenteral direct thrombin inhibitors (DTIs) include bivalirudin (Angiomax) and argatroban (Argatra, Novastan, Arganova, Exembol). These have very short half-lives and specific clinical indications such as percutaneous coronary intervention (PCI) and heparin-induced thrombocytopenia (HIT). There are no parenteral direct factor Xa inhibitors. (See 'Parenteral direct thrombin inhibitors' above.)

Oral agents – These are generally administered at fixed doses without laboratory monitoring (table 5). Dose adjustments for liver disease are presented in the table (table 3).

Laboratory testing prior to administration should include prothrombin time (PT) and activated partial thromboplastin time (aPTT), to assess and document coagulation status before anticoagulation; and measurement of serum creatinine, as a baseline and for potential dose adjustment in the event of reduced kidney function. Patients with impaired kidney function should have appropriate dose reduction or drug avoidance depending on the creatinine clearance. (See 'Dabigatran' above and 'Direct factor Xa inhibitors' above.)

Dabigatran (Pradaxa) is the only orally active DTI. It must be stored in the original blister pack with desiccant and not crushed. Dosing differs in the United States versus Europe. Dose reductions are used in impaired kidney function and with concomitant P-glycoprotein inducers or inhibitors (table 6 and table 7). Risks include bleeding, thrombosis upon discontinuation, and dyspepsia. (See 'Dabigatran' above.)

Orally active direct factor Xa inhibitors include rivaroxaban (Xarelto), apixaban (Eliquis), and edoxaban (Lixiana, Savaysa). Rivaroxaban is administered once daily and apixaban twice daily; they interact with drugs that are potent inhibitors of both CYP-3A4 and P-glycoprotein (table 6 and table 8 and table 7). Edoxaban is administered once daily; it is excreted by the kidney and is a substrate for P-glycoprotein. Risks include bleeding, and thrombosis upon discontinuation. (See 'Direct factor Xa inhibitors' above.)

Transitioning between anticoagulants – The goal is to maintain stable anticoagulation. When transitioning between a DOAC and a vitamin K antagonist (VKA; eg, warfarin), it is important to keep in mind that the full effect of the VKA does not occur for the first few days. When transitioning from a VKA to a DOAC, it is important to keep in mind that the resolution of VKA effect may take several days. Specific recommendations and options are summarized in the table (table 9) and discussed above. (See 'Transitioning between anticoagulants' above.)

Investigational approaches – Anticoagulants that inhibit other coagulation factors are in development. Factor XI (inactive or active form) appears to be a promising target. (See 'Anticoagulants in development' above.)

Bleeding – All anticoagulants increase bleeding risk. Management and prevention are discussed separately. (See "Risks and prevention of bleeding with oral anticoagulants" and "Management of bleeding in patients receiving direct oral anticoagulants" and "Perioperative management of patients receiving anticoagulants".)

REFERENCES

  1. Di Nisio M, Middeldorp S, Büller HR. Direct thrombin inhibitors. N Engl J Med 2005; 353:1028.
  2. Rydel TJ, Ravichandran KG, Tulinsky A, et al. The structure of a complex of recombinant hirudin and human alpha-thrombin. Science 1990; 249:277.
  3. Grütter MG, Priestle JP, Rahuel J, et al. Crystal structure of the thrombin-hirudin complex: a novel mode of serine protease inhibition. EMBO J 1990; 9:2361.
  4. Hirsh J, Weitz JI. New antithrombotic agents. Lancet 1999; 353:1431.
  5. Hall SW, Nagashima M, Zhao L, et al. Thrombin interacts with thrombomodulin, protein C, and thrombin-activatable fibrinolysis inhibitor via specific and distinct domains. J Biol Chem 1999; 274:25510.
  6. Sheehan JP, Sadler JE. Molecular mapping of the heparin-binding exosite of thrombin. Proc Natl Acad Sci U S A 1994; 91:5518.
  7. Weitz JI, Hudoba M, Massel D, et al. Clot-bound thrombin is protected from inhibition by heparin-antithrombin III but is susceptible to inactivation by antithrombin III-independent inhibitors. J Clin Invest 1990; 86:385.
  8. Turpie AG. New oral anticoagulants in atrial fibrillation. Eur Heart J 2008; 29:155.
  9. Berry CN, Girardot C, Lecoffre C, Lunven C. Effects of the synthetic thrombin inhibitor argatroban on fibrin- or clot-incorporated thrombin: comparison with heparin and recombinant Hirudin. Thromb Haemost 1994; 72:381.
  10. Lefkovits J, Topol EJ. Direct thrombin inhibitors in cardiovascular medicine. Circulation 1994; 90:1522.
  11. Laux V, Perzborn E, Heitmeier S, et al. Direct inhibitors of coagulation proteins - the end of the heparin and low-molecular-weight heparin era for anticoagulant therapy? Thromb Haemost 2009; 102:892.
  12. Roehrig S, Straub A, Pohlmann J, et al. Discovery of the novel antithrombotic agent 5-chloro-N-({(5S)-2-oxo-3- [4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)thiophene- 2-carboxamide (BAY 59-7939): an oral, direct factor Xa inhibitor. J Med Chem 2005; 48:5900.
  13. Samama MM. The mechanism of action of rivaroxaban--an oral, direct Factor Xa inhibitor--compared with other anticoagulants. Thromb Res 2011; 127:497.
  14. Ansell J, Crowther M, Burnett A, et al. Comment on: editorial by Husted et al. "Non-vitamin K antagonist oral anticoagulants (NOACs): no longer new or novel". (Thromb Haemost 2014; 111: 781-782). Thromb Haemost 2014; 112:841.
  15. Husted S, Lip GY, ESC Working Group on Thrombosis Task Force on Anticoagulants in Heart Disease. Response to Ansell et al. "Non-vitamin K antagonist oral anticoagulants (NOACs): no longer new or novel". (Thromb Haemost 2014; 112: 841). Thromb Haemost 2014; 112:842.
  16. Husted S, de Caterina R, Andreotti F, et al. Non-vitamin K antagonist oral anticoagulants (NOACs): No longer new or novel. Thromb Haemost 2014; 111:781.
  17. Barnes GD, Ageno W, Ansell J, et al. Recommendation on the nomenclature for oral anticoagulants: communication from the SSC of the ISTH. J Thromb Haemost 2015; 13:1154.
  18. Schulman S, Crowther MA. How I treat with anticoagulants in 2012: new and old anticoagulants, and when and how to switch. Blood 2012; 119:3016.
  19. Trujillo-Santos J, Di Micco P, Dentali F, et al. Real-life treatment of venous thromboembolism with direct oral anticoagulants: The influence of recommended dosing and regimens. Thromb Haemost 2017; 117:382.
  20. Arbel R, Sergienko R, Hammerman A, et al. Effectiveness and Safety of Off-Label Dose-Reduced Direct Oral Anticoagulants in Atrial Fibrillation. Am J Med 2019; 132:847.
  21. Ha JT, Neuen BL, Cheng LP, et al. Benefits and Harms of Oral Anticoagulant Therapy in Chronic Kidney Disease: A Systematic Review and Meta-analysis. Ann Intern Med 2019; 171:181.
  22. Cheung CYS, Parikh J, Farrell A, et al. Direct Oral Anticoagulant Use in Chronic Kidney Disease and Dialysis Patients With Venous Thromboembolism: A Systematic Review of Thrombosis and Bleeding Outcomes. Ann Pharmacother 2021; 55:711.
  23. Gladstone DJ, Geerts WH, Douketis J, et al. How to Monitor Patients Receiving Direct Oral Anticoagulants for Stroke Prevention in Atrial Fibrillation: A Practice Tool Endorsed by Thrombosis Canada, the Canadian Stroke Consortium, the Canadian Cardiovascular Pharmacists Network, and the Canadian Cardiovascular Society. Ann Intern Med 2015; 163:382.
  24. Chatterjee S, Sardar P, Giri JS, et al. Treatment discontinuations with new oral agents for long-term anticoagulation: insights from a meta-analysis of 18 randomized trials including 101,801 patients. Mayo Clin Proc 2014; 89:896.
  25. Shore S, Ho PM, Lambert-Kerzner A, et al. Site-level variation in and practices associated with dabigatran adherence. JAMA 2015; 313:1443.
  26. Chai-Adisaksopha C, Hillis C, Isayama T, et al. Mortality outcomes in patients receiving direct oral anticoagulants: a systematic review and meta-analysis of randomized controlled trials. J Thromb Haemost 2015; 13:2012.
  27. Mannucci PM. Thromboprophylaxis in the oldest old with atrial fibrillation: between Scylla and Charybdis. Eur J Intern Med 2013; 24:285.
  28. Lutsey PL, Norby FL, Ensrud KE, et al. Association of Anticoagulant Therapy With Risk of Fracture Among Patients With Atrial Fibrillation. JAMA Intern Med 2020; 180:245.
  29. Huang HK, Liu PP, Hsu JY, et al. Fracture risks among patients with atrial fibrillation receiving different oral anticoagulants: a real-world nationwide cohort study. Eur Heart J 2020; 41:1100.
  30. Lau WC, Chan EW, Cheung CL, et al. Association Between Dabigatran vs Warfarin and Risk of Osteoporotic Fractures Among Patients With Nonvalvular Atrial Fibrillation. JAMA 2017; 317:1151.
  31. Lau WCY, Wong ICK, Chan EW. Osteoporotic Fractures Associated With Dabigatran vs Warfarin-Reply. JAMA 2017; 318:91.
  32. Sugiyama T. Osteoporotic Fractures Associated With Dabigatran vs Warfarin. JAMA 2017; 318:90.
  33. Hirsh J, Bauer KA, Donati MB, et al. Parenteral anticoagulants: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008; 133:141S.
  34. Eitzman DT, Chi L, Saggin L, et al. Heparin neutralization by platelet-rich thrombi. Role of platelet factor 4. Circulation 1994; 89:1523.
  35. Greinacher A, Völpel H, Janssens U, et al. Recombinant hirudin (lepirudin) provides safe and effective anticoagulation in patients with heparin-induced thrombocytopenia: a prospective study. Circulation 1999; 99:73.
  36. Schiele F, Vuillemenot A, Kramarz P, et al. Use of recombinant hirudin as antithrombotic treatment in patients with heparin-induced thrombocytopenia. Am J Hematol 1995; 50:20.
  37. http://www.hrsa.gov/opa/programrequirements/manufacturerletters/2012/refludan05312012.pdf.
  38. http://www.angiomax.com/downloads/Angiomax_US_PI_June_2013.pdf (Accessed on September 03, 2014).
  39. Warkentin TE, Greinacher A, Koster A. Bivalirudin. Thromb Haemost 2008; 99:830.
  40. Clarke RJ, Mayo G, FitzGerald GA, Fitzgerald DJ. Combined administration of aspirin and a specific thrombin inhibitor in man. Circulation 1991; 83:1510.
  41. https://www.gsksource.com/gskprm/htdocs/documents/ARGATROBAN.PDF (Accessed on September 03, 2014).
  42. Swan SK, Hursting MJ. The pharmacokinetics and pharmacodynamics of argatroban: effects of age, gender, and hepatic or renal dysfunction. Pharmacotherapy 2000; 20:318.
  43. http://www.clinicaltrials.gov/ct2/results?term=AZD-0837 (Accessed on September 04, 2014).
  44. Hauel NH, Nar H, Priepke H, et al. Structure-based design of novel potent nonpeptide thrombin inhibitors. J Med Chem 2002; 45:1757.
  45. http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/022512s028lbl.pdf (Accessed on November 30, 2015).
  46. http://bidocs.boehringer-ingelheim.com/BIWebAccess/ViewServlet.ser?docBase=renetnt&folderPath=/Prescribing%20Information/PIs/Pradaxa/Pradaxa.pdf (Accessed on September 04, 2014).
  47. van Ryn J, Stangier J, Haertter S, et al. Dabigatran etexilate--a novel, reversible, oral direct thrombin inhibitor: interpretation of coagulation assays and reversal of anticoagulant activity. Thromb Haemost 2010; 103:1116.
  48. Stangier J, Rathgen K, Stähle H, Mazur D. Influence of renal impairment on the pharmacokinetics and pharmacodynamics of oral dabigatran etexilate: an open-label, parallel-group, single-centre study. Clin Pharmacokinet 2010; 49:259.
  49. Blech S, Ebner T, Ludwig-Schwellinger E, et al. The metabolism and disposition of the oral direct thrombin inhibitor, dabigatran, in humans. Drug Metab Dispos 2008; 36:386.
  50. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000829/WC500041059.pdf (Accessed on September 04, 2014).
  51. Gulseth MP, Wittkowsky AK, Fanikos J, et al. Dabigatran etexilate in clinical practice: confronting challenges to improve safety and effectiveness. Pharmacotherapy 2011; 31:1232.
  52. http://webprod.hc-sc.gc.ca/dpd-bdpp/info.do?lang=eng&code=84384 (Accessed on March 23, 2011).
  53. http://www.medicines.org.uk/EMC/medicine/20759/SPC/Pradaxa+75+mg+hard+capsules/ (Accessed on March 23, 2011).
  54. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000829/WC500041059.pdf (Accessed on March 23, 2011).
  55. Martin KA, Beyer-Westendorf J, Davidson BL, et al. Use of direct oral anticoagulants in patients with obesity for treatment and prevention of venous thromboembolism: Updated communication from the ISTH SSC Subcommittee on Control of Anticoagulation. J Thromb Haemost 2021; 19:1874.
  56. Chan NC, Coppens M, Hirsh J, et al. Real-world variability in dabigatran levels in patients with atrial fibrillation. J Thromb Haemost 2015; 13:353.
  57. Reilly PA, Lehr T, Haertter S, et al. The effect of dabigatran plasma concentrations and patient characteristics on the frequency of ischemic stroke and major bleeding in atrial fibrillation patients: the RE-LY Trial (Randomized Evaluation of Long-Term Anticoagulation Therapy). J Am Coll Cardiol 2014; 63:321.
  58. Rao RB. Regarding the effect of dabigatran plasma concentrations. J Am Coll Cardiol 2014; 63:2885.
  59. Reilly PA, Connolly SJ, Yusuf S, et al. Reply: regarding the effect of dabigatran plasma concentrations. J Am Coll Cardiol 2014; 63:2885.
  60. Moore TJ, Cohen MR, Mattison DR. Dabigatran, bleeding, and the regulators. BMJ 2014; 349:g4517.
  61. Powell JR. Are new oral anticoagulant dosing recommendations optimal for all patients? JAMA 2015; 313:1013.
  62. Chan N, Sager PT, Lawrence J, et al. Is there a role for pharmacokinetic/pharmacodynamic-guided dosing for novel oral anticoagulants? Am Heart J 2018; 199:59.
  63. Gosselin RC, Adcock DM, Bates SM, et al. International Council for Standardization in Haematology (ICSH) Recommendations for Laboratory Measurement of Direct Oral Anticoagulants. Thromb Haemost 2018; 118:437.
  64. Dager WE, Gosselin RC, Kitchen S, Dwyre D. Dabigatran effects on the international normalized ratio, activated partial thromboplastin time, thrombin time, and fibrinogen: a multicenter, in vitro study. Ann Pharmacother 2012; 46:1627.
  65. van Ryn J, Baruch L, Clemens A. Interpretation of point-of-care INR results in patients treated with dabigatran. Am J Med 2012; 125:417.
  66. http://bidocs.boehringer-ingelheim.com/BIWebAccess/ViewServlet.ser?docBase=renetnt&folderPath=/Prescribing%20Information/PIs/Pradaxa/Pradaxa.pdf (Accessed on September 03, 2014).
  67. http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm282820.htm (Accessed on November 07, 2012).
  68. Southworth MR, Reichman ME, Unger EF. Dabigatran and postmarketing reports of bleeding. N Engl J Med 2013; 368:1272.
  69. http://www.fda.gov/Drugs/DrugSafety/ucm396470.htm (Accessed on May 14, 2014).
  70. Desai J, Kolb JM, Weitz JI, Aisenberg J. Gastrointestinal bleeding with the new oral anticoagulants--defining the issues and the management strategies. Thromb Haemost 2013; 110:205.
  71. Schulman S, Shortt B, Robinson M, Eikelboom JW. Adherence to anticoagulant treatment with dabigatran in a real-world setting. J Thromb Haemost 2013; 11:1295.
  72. Cheng JW, Vu H. Dabigatran etexilate: an oral direct thrombin inhibitor for the management of thromboembolic disorders. Clin Ther 2012; 34:766.
  73. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009; 361:1139.
  74. Bytzer P, Connolly SJ, Yang S, et al. Analysis of upper gastrointestinal adverse events among patients given dabigatran in the RE-LY trial. Clin Gastroenterol Hepatol 2013; 11:246.
  75. Douros A, Azoulay L, Yin H, et al. Non-Vitamin K Antagonist Oral Anticoagulants and Risk of Serious Liver Injury. J Am Coll Cardiol 2018; 71:1105.
  76. Guertin KR, Choi YM. The discovery of the Factor Xa inhibitor otamixaban: from lead identification to clinical development. Curr Med Chem 2007; 14:2471.
  77. Steg PG, Mehta SR, Pollack CV Jr, et al. Anticoagulation with otamixaban and ischemic events in non-ST-segment elevation acute coronary syndromes: the TAO randomized clinical trial. JAMA 2013; 310:1145.
  78. Dawwas GK, Leonard CE, Lewis JD, Cuker A. Risk for Recurrent Venous Thromboembolism and Bleeding With Apixaban Compared With Rivaroxaban: An Analysis of Real-World Data. Ann Intern Med 2022; 175:20.
  79. Ingason AB, Hreinsson JP, Ágústsson AS, et al. Rivaroxaban Is Associated With Higher Rates of Gastrointestinal Bleeding Than Other Direct Oral Anticoagulants : A Nationwide Propensity Score-Weighted Study. Ann Intern Med 2021; 174:1493.
  80. Fralick M, Colacci M, Schneeweiss S, et al. Effectiveness and Safety of Apixaban Compared With Rivaroxaban for Patients With Atrial Fibrillation in Routine Practice: A Cohort Study. Ann Intern Med 2020; 172:463.
  81. Garcia D, Barrett YC, Ramacciotti E, Weitz JI. Laboratory assessment of the anticoagulant effects of the next generation of oral anticoagulants. J Thromb Haemost 2013; 11:245.
  82. Beyer J, Trujillo T, Fisher S, et al. Evaluation of a Heparin-Calibrated Antifactor Xa Assay for Measuring the Anticoagulant Effect of Oral Direct Xa Inhibitors. Clin Appl Thromb Hemost 2016; 22:423.
  83. Cho MS, Yun JE, Park JJ, et al. Outcomes After Use of Standard- and Low-Dose Non-Vitamin K Oral Anticoagulants in Asian Patients With Atrial Fibrillation. Stroke 2018; :STROKEAHA118023093.
  84. Moore KT, Kröll D. Influences of Obesity and Bariatric Surgery on the Clinical and Pharmacologic Profile of Rivaroxaban. Am J Med 2017; 130:1024.
  85. O'Kane CP, Avalon JCO, Lacoste JL, et al. Apixaban and rivaroxaban use for atrial fibrillation in patients with obesity and BMI ≥50 kg/m2. Pharmacotherapy 2022; 42:112.
  86. Crouch A, Ng TH, Kelley D, et al. Multi-center retrospective study evaluating the efficacy and safety of apixaban versus warfarin for treatment of venous thromboembolism in patients with severe obesity. Pharmacotherapy 2022; 42:119.
  87. http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/022406s004lbl.pdf (Accessed on June 02, 2015).
  88. Beyer-Westendorf J, Siegert G. Of men and meals. J Thromb Haemost 2015; 13:943.
  89. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/022406s024lbl.pdf (Accessed on November 01, 2017).
  90. Poulsen BK, Grove EL, Husted SE. New oral anticoagulants: a review of the literature with particular emphasis on patients with impaired renal function. Drugs 2012; 72:1739.
  91. Nutescu E, Chuatrisorn I, Hellenbart E. Drug and dietary interactions of warfarin and novel oral anticoagulants: an update. J Thromb Thrombolysis 2011; 31:326.
  92. Eikelboom JW, Weitz JI. New oral anticoagulants for thromboprophylaxis in patients having hip or knee arthroplasty. BMJ 2011; 342:c7270.
  93. Altena R, van Roon E, Folkeringa R, et al. Clinical challenges related to novel oral anticoagulants: drug-drug interactions and monitoring. Haematologica 2014; 99:e26.
  94. Siegal DM, Konkle BA. What is the effect of rivaroxaban on routine coagulation tests? Hematology Am Soc Hematol Educ Program 2014; 2014:334.
  95. Liakoni E, Rätz Bravo AE, Terracciano L, et al. Symptomatic hepatocellular liver injury with hyperbilirubinemia in two patients treated with rivaroxaban. JAMA Intern Med 2014; 174:1683.
  96. Caldeira D, Barra M, Santos AT, et al. Risk of drug-induced liver injury with the new oral anticoagulants: systematic review and meta-analysis. Heart 2014; 100:550.
  97. http://www.xareltohcp.com/sites/default/files/pdf/xarelto_0.pdf (Accessed on September 04, 2014).
  98. https://www.fda.gov/news-events/press-announcements/fda-approves-first-generics-eliquis (Accessed on January 02, 2020).
  99. http://packageinserts.bms.com/pi/pi_eliquis.pdf (Accessed on September 05, 2014).
  100. Agnelli G, Buller HR, Cohen A, et al. Apixaban for extended treatment of venous thromboembolism. N Engl J Med 2013; 368:699.
  101. http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/202155s012lbl.pdf (Accessed on November 08, 2016).
  102. http://www.pfizer.ca/sites/g/files/g10028126/f/201607/ELIQUIS_PM_184464_16June2016_E_marketed.pdf (Accessed on November 08, 2016).
  103. Wong PC, Crain EJ, Xin B, et al. Apixaban, an oral, direct and highly selective factor Xa inhibitor: in vitro, antithrombotic and antihemostatic studies. J Thromb Haemost 2008; 6:820.
  104. Camm AJ, Bounameaux H. Edoxaban: a new oral direct factor xa inhibitor. Drugs 2011; 71:1503.
  105. Dentali F, Riva N, Crowther M, et al. Efficacy and safety of the novel oral anticoagulants in atrial fibrillation: a systematic review and meta-analysis of the literature. Circulation 2012; 126:2381.
  106. http://www.daiichisankyo.com/news/detail/004033.html (Accessed on November 07, 2012).
  107. Hokusai-VTE Investigators, Büller HR, Décousus H, et al. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med 2013; 369:1406.
  108. Okumura K, Akao M, Yoshida T, et al. Low-Dose Edoxaban in Very Elderly Patients with Atrial Fibrillation. N Engl J Med 2020; 383:1735.
  109. http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/206316lbl.pdf (Accessed on January 09, 2015).
  110. http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/206316s004lbl.pdf (Accessed on November 08, 2016).
  111. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/208383s000lbl.pdf (Accessed on June 23, 2017).
  112. Cairns JA, Weitz JI. Transition from apixaban to warfarin--addressing excess stroke, systemic embolism, and major bleeding. Am Heart J 2015; 169:1.
  113. Granger CB, Lopes RD, Hanna M, et al. Clinical events after transitioning from apixaban versus warfarin to warfarin at the end of the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial. Am Heart J 2015; 169:25.
  114. Witt DM, Nieuwlaat R, Clark NP, et al. American Society of Hematology 2018 guidelines for management of venous thromboembolism: optimal management of anticoagulation therapy. Blood Adv 2018; 2:3257.
  115. http://bidocs.boehringer-ingelheim.com/BIWebAccess/ViewServlet.ser?docBase=renetnt&folderPath=/Prescribing%20Information/PIs/Pradaxa/Pradaxa.pdf (Accessed on April 30, 2015).
  116. http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/202155s000lbl.pdf (Accessed on June 02, 2015).
  117. http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/206316lbl.pdf (Accessed on April 30, 2015).
  118. http://www.xareltohcp.com/sites/default/files/pdf/xarelto_0.pdf (Accessed on April 30, 2015).
  119. http://packageinserts.bms.com/pi/pi_eliquis.pdf (Accessed on April 30, 2015).
  120. Weitz JI, Strony J, Ageno W, et al. Milvexian for the Prevention of Venous Thromboembolism. N Engl J Med 2021; 385:2161.
  121. Verhamme P, Yi BA, Segers A, et al. Abelacimab for Prevention of Venous Thromboembolism. N Engl J Med 2021; 385:609.
  122. Schaefer M, Buchmueller A, Dittmer F, et al. Allosteric Inhibition as a New Mode of Action for BAY 1213790, a Neutralizing Antibody Targeting the Activated Form of Coagulation Factor XI. J Mol Biol 2019; 431:4817.
  123. Weitz JI, Bauersachs R, Becker B, et al. Effect of Osocimab in Preventing Venous Thromboembolism Among Patients Undergoing Knee Arthroplasty: The FOXTROT Randomized Clinical Trial. JAMA 2020; 323:130.
  124. Lorentz CU, Verbout NG, Wallisch M, et al. Contact Activation Inhibitor and Factor XI Antibody, AB023, Produces Safe, Dose-Dependent Anticoagulation in a Phase 1 First-In-Human Trial. Arterioscler Thromb Vasc Biol 2019; 39:799.
  125. Zhang H, Löwenberg EC, Crosby JR, et al. Inhibition of the intrinsic coagulation pathway factor XI by antisense oligonucleotides: a novel antithrombotic strategy with lowered bleeding risk. Blood 2010; 116:4684.
  126. Büller HR, Bethune C, Bhanot S, et al. Factor XI antisense oligonucleotide for prevention of venous thrombosis. N Engl J Med 2015; 372:232.
  127. Flaumenhaft R. Making (anti)sense of factor XI in thrombosis. N Engl J Med 2015; 372:277.
  128. Al-Horani RA, Abdelfadiel EI, Afosah DK, et al. A synthetic heparin mimetic that allosterically inhibits factor XIa and reduces thrombosis in vivo without enhanced risk of bleeding. J Thromb Haemost 2019; 17:2110.
  129. Stassens P, Bergum PW, Gansemans Y, et al. Anticoagulant repertoire of the hookworm Ancylostoma caninum. Proc Natl Acad Sci U S A 1996; 93:2149.
  130. Presta L, Sims P, Meng YG, et al. Generation of a humanized, high affinity anti-tissue factor antibody for use as a novel antithrombotic therapeutic. Thromb Haemost 2001; 85:379.
  131. Lee A, Agnelli G, Büller H, et al. Dose-response study of recombinant factor VIIa/tissue factor inhibitor recombinant nematode anticoagulant protein c2 in prevention of postoperative venous thromboembolism in patients undergoing total knee replacement. Circulation 2001; 104:74.
  132. Giugliano RP, Wiviott SD, Stone PH, et al. Recombinant nematode anticoagulant protein c2 in patients with non-ST-segment elevation acute coronary syndrome: the ANTHEM-TIMI-32 trial. J Am Coll Cardiol 2007; 49:2398.
  133. Verhamme P, Tangelder M, Verhaeghe R, et al. Single intravenous administration of TB-402 for the prophylaxis of venous thromboembolism after total knee replacement: a dose-escalating, randomized, controlled trial. J Thromb Haemost 2011; 9:664.
  134. Carnemolla R, Patel KR, Zaitsev S, et al. Quantitative analysis of thrombomodulin-mediated conversion of protein C to APC: translation from in vitro to in vivo. J Immunol Methods 2012; 384:21.
  135. Moll S, Lindley C, Pescatore S, et al. Phase I study of a novel recombinant human soluble thrombomodulin, ART-123. J Thromb Haemost 2004; 2:1745.
  136. Kearon C, Comp P, Douketis J, et al. Dose-response study of recombinant human soluble thrombomodulin (ART-123) in the prevention of venous thromboembolism after total hip replacement. J Thromb Haemost 2005; 3:962.
  137. Chan MY, Cohen MG, Dyke CK, et al. Phase 1b randomized study of antidote-controlled modulation of factor IXa activity in patients with stable coronary artery disease. Circulation 2008; 117:2865.
  138. Cohen MG, Purdy DA, Rossi JS, et al. First clinical application of an actively reversible direct factor IXa inhibitor as an anticoagulation strategy in patients undergoing percutaneous coronary intervention. Circulation 2010; 122:614.
  139. Lincoff AM, Mehran R, Povsic TJ, et al. Effect of the REG1 anticoagulation system versus bivalirudin on outcomes after percutaneous coronary intervention (REGULATE-PCI): a randomised clinical trial. Lancet 2016; 387:349.
  140. Hagedorn I, Schmidbauer S, Pleines I, et al. Factor XIIa inhibitor recombinant human albumin Infestin-4 abolishes occlusive arterial thrombus formation without affecting bleeding. Circulation 2010; 121:1510.
  141. Wang L, Essex DW. A new antithrombotic strategy: inhibition of the C-terminal active site of protein disulfide isomerase. J Thromb Haemost 2017; 15:770.
  142. Sousa HR, Gaspar RS, Sena EM, et al. Novel antiplatelet role for a protein disulfide isomerase-targeted peptide: evidence of covalent binding to the C-terminal CGHC redox motif. J Thromb Haemost 2017; 15:774.
  143. Travers RJ, Shenoi RA, Kalathottukaren MT, et al. Nontoxic polyphosphate inhibitors reduce thrombosis while sparing hemostasis. Blood 2014; 124:3183.
Topic 1370 Version 152.0

References

1 : Direct thrombin inhibitors.

2 : The structure of a complex of recombinant hirudin and human alpha-thrombin.

3 : Crystal structure of the thrombin-hirudin complex: a novel mode of serine protease inhibition.

4 : New antithrombotic agents.

5 : Thrombin interacts with thrombomodulin, protein C, and thrombin-activatable fibrinolysis inhibitor via specific and distinct domains.

6 : Molecular mapping of the heparin-binding exosite of thrombin.

7 : Clot-bound thrombin is protected from inhibition by heparin-antithrombin III but is susceptible to inactivation by antithrombin III-independent inhibitors.

8 : New oral anticoagulants in atrial fibrillation.

9 : Effects of the synthetic thrombin inhibitor argatroban on fibrin- or clot-incorporated thrombin: comparison with heparin and recombinant Hirudin.

10 : Direct thrombin inhibitors in cardiovascular medicine.

11 : Direct inhibitors of coagulation proteins - the end of the heparin and low-molecular-weight heparin era for anticoagulant therapy?

12 : Discovery of the novel antithrombotic agent 5-chloro-N-({(5S)-2-oxo-3- [4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)thiophene- 2-carboxamide (BAY 59-7939): an oral, direct factor Xa inhibitor.

13 : The mechanism of action of rivaroxaban--an oral, direct Factor Xa inhibitor--compared with other anticoagulants.

14 : Comment on: editorial by Husted et al. "Non-vitamin K antagonist oral anticoagulants (NOACs): no longer new or novel". (Thromb Haemost 2014; 111: 781-782).

15 : Response to Ansell et al. "Non-vitamin K antagonist oral anticoagulants (NOACs): no longer new or novel". (Thromb Haemost 2014; 112: 841).

16 : Non-vitamin K antagonist oral anticoagulants (NOACs): No longer new or novel.

17 : Recommendation on the nomenclature for oral anticoagulants: communication from the SSC of the ISTH.

18 : How I treat with anticoagulants in 2012: new and old anticoagulants, and when and how to switch.

19 : Real-life treatment of venous thromboembolism with direct oral anticoagulants: The influence of recommended dosing and regimens.

20 : Effectiveness and Safety of Off-Label Dose-Reduced Direct Oral Anticoagulants in Atrial Fibrillation.

21 : Benefits and Harms of Oral Anticoagulant Therapy in Chronic Kidney Disease: A Systematic Review and Meta-analysis.

22 : Direct Oral Anticoagulant Use in Chronic Kidney Disease and Dialysis Patients With Venous Thromboembolism: A Systematic Review of Thrombosis and Bleeding Outcomes.

23 : How to Monitor Patients Receiving Direct Oral Anticoagulants for Stroke Prevention in Atrial Fibrillation: A Practice Tool Endorsed by Thrombosis Canada, the Canadian Stroke Consortium, the Canadian Cardiovascular Pharmacists Network, and the Canadian Cardiovascular Society.

24 : Treatment discontinuations with new oral agents for long-term anticoagulation: insights from a meta-analysis of 18 randomized trials including 101,801 patients.

25 : Site-level variation in and practices associated with dabigatran adherence.

26 : Mortality outcomes in patients receiving direct oral anticoagulants: a systematic review and meta-analysis of randomized controlled trials.

27 : Thromboprophylaxis in the oldest old with atrial fibrillation: between Scylla and Charybdis.

28 : Association of Anticoagulant Therapy With Risk of Fracture Among Patients With Atrial Fibrillation.

29 : Fracture risks among patients with atrial fibrillation receiving different oral anticoagulants: a real-world nationwide cohort study.

30 : Association Between Dabigatran vs Warfarin and Risk of Osteoporotic Fractures Among Patients With Nonvalvular Atrial Fibrillation.

31 : Osteoporotic Fractures Associated With Dabigatran vs Warfarin-Reply.

32 : Osteoporotic Fractures Associated With Dabigatran vs Warfarin.

33 : Parenteral anticoagulants: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition).

34 : Heparin neutralization by platelet-rich thrombi. Role of platelet factor 4.

35 : Recombinant hirudin (lepirudin) provides safe and effective anticoagulation in patients with heparin-induced thrombocytopenia: a prospective study.

36 : Use of recombinant hirudin as antithrombotic treatment in patients with heparin-induced thrombocytopenia.

37 : Use of recombinant hirudin as antithrombotic treatment in patients with heparin-induced thrombocytopenia.

38 : Use of recombinant hirudin as antithrombotic treatment in patients with heparin-induced thrombocytopenia.

39 : Bivalirudin.

40 : Combined administration of aspirin and a specific thrombin inhibitor in man.

41 : Combined administration of aspirin and a specific thrombin inhibitor in man.

42 : The pharmacokinetics and pharmacodynamics of argatroban: effects of age, gender, and hepatic or renal dysfunction.

43 : The pharmacokinetics and pharmacodynamics of argatroban: effects of age, gender, and hepatic or renal dysfunction.

44 : Structure-based design of novel potent nonpeptide thrombin inhibitors.

45 : Structure-based design of novel potent nonpeptide thrombin inhibitors.

46 : Structure-based design of novel potent nonpeptide thrombin inhibitors.

47 : Dabigatran etexilate--a novel, reversible, oral direct thrombin inhibitor: interpretation of coagulation assays and reversal of anticoagulant activity.

48 : Influence of renal impairment on the pharmacokinetics and pharmacodynamics of oral dabigatran etexilate: an open-label, parallel-group, single-centre study.

49 : The metabolism and disposition of the oral direct thrombin inhibitor, dabigatran, in humans.

50 : The metabolism and disposition of the oral direct thrombin inhibitor, dabigatran, in humans.

51 : Dabigatran etexilate in clinical practice: confronting challenges to improve safety and effectiveness.

52 : Dabigatran etexilate in clinical practice: confronting challenges to improve safety and effectiveness.

53 : Dabigatran etexilate in clinical practice: confronting challenges to improve safety and effectiveness.

54 : Dabigatran etexilate in clinical practice: confronting challenges to improve safety and effectiveness.

55 : Use of direct oral anticoagulants in patients with obesity for treatment and prevention of venous thromboembolism: Updated communication from the ISTH SSC Subcommittee on Control of Anticoagulation.

56 : Real-world variability in dabigatran levels in patients with atrial fibrillation.

57 : The effect of dabigatran plasma concentrations and patient characteristics on the frequency of ischemic stroke and major bleeding in atrial fibrillation patients: the RE-LY Trial (Randomized Evaluation of Long-Term Anticoagulation Therapy).

58 : Regarding the effect of dabigatran plasma concentrations.

59 : Reply: regarding the effect of dabigatran plasma concentrations.

60 : Dabigatran, bleeding, and the regulators.

61 : Are new oral anticoagulant dosing recommendations optimal for all patients?

62 : Is there a role for pharmacokinetic/pharmacodynamic-guided dosing for novel oral anticoagulants?

63 : International Council for Standardization in Haematology (ICSH) Recommendations for Laboratory Measurement of Direct Oral Anticoagulants.

64 : Dabigatran effects on the international normalized ratio, activated partial thromboplastin time, thrombin time, and fibrinogen: a multicenter, in vitro study.

65 : Interpretation of point-of-care INR results in patients treated with dabigatran.

66 : Interpretation of point-of-care INR results in patients treated with dabigatran.

67 : Interpretation of point-of-care INR results in patients treated with dabigatran.

68 : Dabigatran and postmarketing reports of bleeding.

69 : Dabigatran and postmarketing reports of bleeding.

70 : Gastrointestinal bleeding with the new oral anticoagulants--defining the issues and the management strategies.

71 : Adherence to anticoagulant treatment with dabigatran in a real-world setting.

72 : Dabigatran etexilate: an oral direct thrombin inhibitor for the management of thromboembolic disorders.

73 : Dabigatran versus warfarin in patients with atrial fibrillation.

74 : Analysis of upper gastrointestinal adverse events among patients given dabigatran in the RE-LY trial.

75 : Non-Vitamin K Antagonist Oral Anticoagulants and Risk of Serious Liver Injury.

76 : The discovery of the Factor Xa inhibitor otamixaban: from lead identification to clinical development.

77 : Anticoagulation with otamixaban and ischemic events in non-ST-segment elevation acute coronary syndromes: the TAO randomized clinical trial.

78 : Risk for Recurrent Venous Thromboembolism and Bleeding With Apixaban Compared With Rivaroxaban: An Analysis of Real-World Data.

79 : Rivaroxaban Is Associated With Higher Rates of Gastrointestinal Bleeding Than Other Direct Oral Anticoagulants : A Nationwide Propensity Score-Weighted Study.

80 : Effectiveness and Safety of Apixaban Compared With Rivaroxaban for Patients With Atrial Fibrillation in Routine Practice: A Cohort Study.

81 : Laboratory assessment of the anticoagulant effects of the next generation of oral anticoagulants.

82 : Evaluation of a Heparin-Calibrated Antifactor Xa Assay for Measuring the Anticoagulant Effect of Oral Direct Xa Inhibitors.

83 : Outcomes After Use of Standard- and Low-Dose Non-Vitamin K Oral Anticoagulants in Asian Patients With Atrial Fibrillation.

84 : Influences of Obesity and Bariatric Surgery on the Clinical and Pharmacologic Profile of Rivaroxaban.

85 : Apixaban and rivaroxaban use for atrial fibrillation in patients with obesity and BMI≥50 kg/m2.

86 : Multi-center retrospective study evaluating the efficacy and safety of apixaban versus warfarin for treatment of venous thromboembolism in patients with severe obesity.

87 : Multi-center retrospective study evaluating the efficacy and safety of apixaban versus warfarin for treatment of venous thromboembolism in patients with severe obesity.

88 : Of men and meals.

89 : Of men and meals.

90 : New oral anticoagulants: a review of the literature with particular emphasis on patients with impaired renal function.

91 : Drug and dietary interactions of warfarin and novel oral anticoagulants: an update.

92 : New oral anticoagulants for thromboprophylaxis in patients having hip or knee arthroplasty.

93 : Clinical challenges related to novel oral anticoagulants: drug-drug interactions and monitoring.

94 : What is the effect of rivaroxaban on routine coagulation tests?

95 : Symptomatic hepatocellular liver injury with hyperbilirubinemia in two patients treated with rivaroxaban.

96 : Risk of drug-induced liver injury with the new oral anticoagulants: systematic review and meta-analysis.

97 : Risk of drug-induced liver injury with the new oral anticoagulants: systematic review and meta-analysis.

98 : Risk of drug-induced liver injury with the new oral anticoagulants: systematic review and meta-analysis.

99 : Risk of drug-induced liver injury with the new oral anticoagulants: systematic review and meta-analysis.

100 : Apixaban for extended treatment of venous thromboembolism.

101 : Apixaban for extended treatment of venous thromboembolism.

102 : Apixaban for extended treatment of venous thromboembolism.

103 : Apixaban, an oral, direct and highly selective factor Xa inhibitor: in vitro, antithrombotic and antihemostatic studies.

104 : Edoxaban: a new oral direct factor xa inhibitor.

105 : Efficacy and safety of the novel oral anticoagulants in atrial fibrillation: a systematic review and meta-analysis of the literature.

106 : Efficacy and safety of the novel oral anticoagulants in atrial fibrillation: a systematic review and meta-analysis of the literature.

107 : Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism.

108 : Low-Dose Edoxaban in Very Elderly Patients with Atrial Fibrillation.

109 : Low-Dose Edoxaban in Very Elderly Patients with Atrial Fibrillation.

110 : Low-Dose Edoxaban in Very Elderly Patients with Atrial Fibrillation.

111 : Low-Dose Edoxaban in Very Elderly Patients with Atrial Fibrillation.

112 : Transition from apixaban to warfarin--addressing excess stroke, systemic embolism, and major bleeding.

113 : Clinical events after transitioning from apixaban versus warfarin to warfarin at the end of the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial.

114 : American Society of Hematology 2018 guidelines for management of venous thromboembolism: optimal management of anticoagulation therapy.

115 : American Society of Hematology 2018 guidelines for management of venous thromboembolism: optimal management of anticoagulation therapy.

116 : American Society of Hematology 2018 guidelines for management of venous thromboembolism: optimal management of anticoagulation therapy.

117 : American Society of Hematology 2018 guidelines for management of venous thromboembolism: optimal management of anticoagulation therapy.

118 : American Society of Hematology 2018 guidelines for management of venous thromboembolism: optimal management of anticoagulation therapy.

119 : American Society of Hematology 2018 guidelines for management of venous thromboembolism: optimal management of anticoagulation therapy.

120 : Milvexian for the Prevention of Venous Thromboembolism.

121 : Abelacimab for Prevention of Venous Thromboembolism.

122 : Allosteric Inhibition as a New Mode of Action for BAY 1213790, a Neutralizing Antibody Targeting the Activated Form of Coagulation Factor XI.

123 : Effect of Osocimab in Preventing Venous Thromboembolism Among Patients Undergoing Knee Arthroplasty: The FOXTROT Randomized Clinical Trial.

124 : Contact Activation Inhibitor and Factor XI Antibody, AB023, Produces Safe, Dose-Dependent Anticoagulation in a Phase 1 First-In-Human Trial.

125 : Inhibition of the intrinsic coagulation pathway factor XI by antisense oligonucleotides: a novel antithrombotic strategy with lowered bleeding risk.

126 : Factor XI antisense oligonucleotide for prevention of venous thrombosis.

127 : Making (anti)sense of factor XI in thrombosis.

128 : A synthetic heparin mimetic that allosterically inhibits factor XIa and reduces thrombosis in vivo without enhanced risk of bleeding.

129 : Anticoagulant repertoire of the hookworm Ancylostoma caninum.

130 : Generation of a humanized, high affinity anti-tissue factor antibody for use as a novel antithrombotic therapeutic.

131 : Dose-response study of recombinant factor VIIa/tissue factor inhibitor recombinant nematode anticoagulant protein c2 in prevention of postoperative venous thromboembolism in patients undergoing total knee replacement.

132 : Recombinant nematode anticoagulant protein c2 in patients with non-ST-segment elevation acute coronary syndrome: the ANTHEM-TIMI-32 trial.

133 : Single intravenous administration of TB-402 for the prophylaxis of venous thromboembolism after total knee replacement: a dose-escalating, randomized, controlled trial.

134 : Quantitative analysis of thrombomodulin-mediated conversion of protein C to APC: translation from in vitro to in vivo.

135 : Phase I study of a novel recombinant human soluble thrombomodulin, ART-123.

136 : Dose-response study of recombinant human soluble thrombomodulin (ART-123) in the prevention of venous thromboembolism after total hip replacement.

137 : Phase 1b randomized study of antidote-controlled modulation of factor IXa activity in patients with stable coronary artery disease.

138 : First clinical application of an actively reversible direct factor IXa inhibitor as an anticoagulation strategy in patients undergoing percutaneous coronary intervention.

139 : Effect of the REG1 anticoagulation system versus bivalirudin on outcomes after percutaneous coronary intervention (REGULATE-PCI): a randomised clinical trial.

140 : Factor XIIa inhibitor recombinant human albumin Infestin-4 abolishes occlusive arterial thrombus formation without affecting bleeding.

141 : A new antithrombotic strategy: inhibition of the C-terminal active site of protein disulfide isomerase.

142 : Novel antiplatelet role for a protein disulfide isomerase-targeted peptide: evidence of covalent binding to the C-terminal CGHC redox motif.

143 : Nontoxic polyphosphate inhibitors reduce thrombosis while sparing hemostasis.