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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
Literature review current through: Jan 2024.
This topic last updated: Jul 27, 2023.

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 and contraindications' 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 and under investigation:

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".)

Investigational – (See "Investigational anticoagulants".)

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). Each direct inhibitor only blocks one enzyme (direct thrombin inhibitors only block thrombin; direct factor Xa inhibitors only block factor Xa).

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 "Investigational anticoagulants".)

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]. The term DOAC is commonly used.

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. A general approach is as follows:

In hospitalized patients with chronic kidney disease (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.

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 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].

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.

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'.)

The lower risk of bleeding with DOACs is especially relevant for older adults. A 2023 update of the American Geriatric Society (AGS) Beers criteria advises avoidance of warfarin and use of a DOAC for VTE or nonvalvular AF unless there are substantial barriers or contraindications to using a DOAC [28].

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) [29]. 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 [30]. An earlier study observed a lower risk of fractures with dabigatran compared with warfarin [31-33].

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 [34,35]. 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 is 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 pharmacokinetics – Warfarin 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 (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 and contraindications' 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. (See 'High BMI and post-bariatric surgery' below.)

Dosing convenience – Dabigatran and apixaban are taken twice daily, 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 AND CONTRAINDICATIONS — 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 adults undergoing hip fracture repair or hip or knee replacement".)

VTE treatment (individuals without cancer, initial anticoagulation) – (See "Venous thromboembolism: Initiation of anticoagulation", 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 "Acute ST-elevation myocardial infarction: Management of anticoagulation" 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' and "Management of heparin-induced thrombocytopenia (HIT) during cardiac or vascular surgery".)

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.)

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 [36]. 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 "Acute ST-elevation myocardial infarction: Management of anticoagulation".)

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) [36]. 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 [37]. 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); it acts rapidly, 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 [38]. It has a short in vivo plasma half-life (terminal elimination half-life approximately 40 to 50 minutes) [39]. (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 [39]. 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 [39]. 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 [39,40].

Argatroban prolongs the prothrombin time/international normalized ratio (PT/INR). When patients receiving argatroban are transitioned to warfarin, an adjusted INR target must be used during the overlap, and the INR must be repeated after 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) [41].

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 [42]. 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 [43]. The capsules should not be crushed or opened before administration, as removal of the capsule shell results in dramatic increases in oral bioavailability [44].

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 proximal and distal lower extremity deep vein thrombosis (DVT)".)

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

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 [45]. 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 [46,47]. The dosing differs according to the clinical indication and the patient's kidney function [44]:

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). Adequate treatment for VTE is full-dose anticoagulation for three to six months.

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) [27,48]. 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 disease – Dabigatran 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 [46]. 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 [49]. 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 [50-52] (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 inducers – Dabigatran 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) [44]. 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 safety 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 [53]. They recommend use of dabigatran (and other DOACs) 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 [54]. 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 drug levels have been suggested, and monitoring recommendations may change [55-60].

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) [61]. 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 [62]. 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 PT/international normalized ratio (PT/INR) should not be used [63]. (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 [64].

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) [27,65-68]. A discussion of bleeding risks and comparison with other oral anticoagulants, including vitamin K antagonists, 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 to individuals with increased thromboembolic risk. Dabigatran has a Boxed Warning regarding the risk of thrombotic events following premature discontinuation [64].

Dyspepsia is a common side effect of dabigatran, with an incidence from 12 to 33 percent in some studies [69-71]. In the RE-LY trial, which randomly assigned 18,113 individuals with AF to dabigatran or warfarin, non-bleeding gastrointestinal events (dyspepsia, dysmotility, gastrointestinal reflux) were nearly 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) [72]. 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) [73].

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 [74,75].

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) [76]. 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 effects – Rivaroxaban appears to have 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) [77]. 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 [78]. 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) [76].

Factor Xa inhibitors dosing — Direct factor Xa inhibitors are administered at a fixed dose without monitoring. It is important to use the appropriate dose (do not under-dose). Anti-factor Xa activity can be measured in unusual circumstances (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 [61,79]. 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 [80]. Examples of typical expected drug levels are listed in the individual sections below.

Dose reduction is recommended for patients who are also receiving strong dual inhibitors of CYP-3A4 and P-glycoprotein; increased bleeding has been reported with apixaban in combination with fluconazole. (See 'Dosing, monitoring, risks (apixaban)' below.)

It may be reasonable to use a lower dose of rivaroxaban in some individuals with ancestry from countries in Asia, especially Japan. (See 'Dosing, monitoring, risks (rivaroxaban)' below.)

In a study of people from Korea, use of a lower dose of apixaban for atrial fibrillation resulted in inferior efficacy compared with standard dosing [81]. (See 'Dosing, monitoring, risks (apixaban)' below.)

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) [73]. 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 [53]. 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 2021 Guideline from the International Society on Thrombosis and Haemostasis (ISTH), 2017 review, and subsequent studies of rivaroxaban and apixaban concluded that they could be administered to individuals with a BMI >40 kg/m2 (or weight >120 kg) and even ≥50 kg/m2 without dose adjustment, although data were limited [53,82-84]. (See 'Dosing, monitoring, risks (rivaroxaban)' below.)

Post-bariatric surgery – Immediate postoperative VTE prophylaxis is discussed separately. (See "Bariatric surgery: Postoperative and long-term management", 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, as summarized in the table (table 8). Apixaban absorption appears to be the least affected [53].

Apixaban is likely to be reasonable post-bariatric surgery, especially if it is not in the immediate postoperative period. The 2021 ISTH Guideline suggests using a parenteral anticoagulant for immediate post-bariatric surgery VTE treatment (first few weeks) before switching to a DOAC and then checking a trough level to ensure absorption [53].

A 2023 retrospective study evaluated VTE risk in 102 adults who required anticoagulation for VTE following bariatric surgery and were treated with a DOAC [85]. Among individuals treated with apixaban, there were no VTE recurrences during a median of 137 days of observation. Among 60 individuals treated with rivaroxaban, there was one VTE recurrence during a median of 240 days of observation. The individual had other risk factors for recurrence including chronic venous stasis, foot ulcers requiring a boot, and a BMI of 54 kg/m2 at the time of the event. (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 proximal and distal lower extremity deep vein thrombosis (DVT)".)

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

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 [86,87]. The dosing differs according to the clinical indication and the patient's kidney function. For patients from Japan, a lower dose (15 rather than 20 mg) has been validated for venous thromboembolism (VTE), secondary prevention, and atrial fibrillation (AF), and is supported by pharmacokinetic studies [88-90]. Studies from other regions in Asia (Taiwan, Thailand) appear to show similar findings, although sample sizes are smaller and more study is needed [91,92].

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 adults undergoing hip fracture repair or hip or knee replacement" and "Prevention of venous thromboembolic disease in adult nonorthopedic surgical patients".)

Use for VTE treatment in children is discussed separately. (See "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). Adequate treatment for VTE is full-dose anticoagulation for three to six months. If secondary prevention is considered after full-dose treatment, 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 [93]. (See "Selecting adult patients with lower extremity deep venous thrombosis and pulmonary embolism for indefinite anticoagulation".)

Stroke prevention in 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) [94]. CrCl can be estimated from the patient's sex, age, weight, and serum creatinine (calculator 1 and calculator 2). A 2023 update of the American Geriatric Society Beers criteria advises avoiding rivaroxaban in adults ≥65 years and using a safer alternative [28]. 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, posaconazole, or ritonavir), and concurrent use is contraindicated by Canadian product information (table 6 and table 9 and table 7) [50]. Drugs that inhibit CYP-3A4 but do not also inhibit P-glycoprotein (eg, diltiazem, fluconazole, and voriconazole) may also increase rivaroxaban effect, but to a lesser extent than dual inhibitors. Potent inducers of CYP-3A4 (eg, rifamycins, carbamazepine, St. John's wort) may reduce rivaroxaban's effects (table 9) [95-97].

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 [59,60].

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) [61]. 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 [98].

Cases of liver injury following rivaroxaban administration have been reported, although this was not seen in larger trials [99,100]. 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 [101]. (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 [102]) 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 proximal and distal lower extremity deep vein thrombosis (DVT)".)

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

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 [103]. We do not reduce the dose for individuals from countries in Asia.

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 adults undergoing hip fracture repair or hip or knee replacement" 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. Adequate treatment for VTE is full-dose anticoagulation for three to six months. If secondary prevention is considered after full-dose treatment, the dose is reduced to 2.5 mg twice daily, based on data from a randomized trial showing equivalent efficacy and reduced bleeding at the 2.5 mg twice-daily dose [104].

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 9 and table 7) [103].

In a large registry series involving nearly 100,000 patients with atrial fibrillation who were taking a DOAC, use of apixaban and concurrent systemic fluconazole, a moderate inhibitor of CYP-3A4, was associated with an increased bleeding rate (case-crossover odds ratio [OR] for different 30-day exposure periods, 3.5, 95% CI 1.4-10.6) [105]. The main increase was in gastrointestinal bleeding requiring hospitalization (65 percent of bleeding with the drug combination versus 50 percent of bleeding with apixaban alone). Topical fluconazole was not associated with increased bleeding, and other DOACs did not have the same association when combined with systemic fluconazole. While moderate CYP-3A4 inhibitors such as fluconazole are not contraindicated and do not require routine dose reduction in patients taking apixaban, this study highlights the importance of possible drug interactions and of considering alternatives that might be equally effective, such as topical therapy.

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 [106,107]. 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 [59,60].

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) [61]. 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, anti-factor Xa activity can be measured [108].

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 [103].

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 proximal and distal lower extremity deep vein thrombosis (DVT)".)

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

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 [109-112]. 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 [113]. 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 has a Boxed Warning regarding reduced efficacy in nonvalvular atrial fibrillation in patients with a high CrCl (>95 mL/minute) [114]. 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) [115]. 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 [59].

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) [61]. 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 [114].

Betrixaban — Betrixaban (Bevyxxa) was an oral direct factor Xa inhibitor with a half-life in the range of 19 to 27 hours [116]. 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.

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) [117,118] (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.

Approaches to switching between oral anticoagulants, summarized in the table (table 10) and discussed in the following sections, are derived from the drug package inserts and a 2018 clinical practice guideline from the American Society of Hematology (ASH) [119]. These are reasonable approaches when switching between anticoagulants but do not substitute for clinical judgment regarding individual patient factors.

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 "Anticoagulation for prosthetic heart valves: Management of bleeding and invasive procedures", section on 'Planning for invasive procedures'.)

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

From a DOAC to warfarin or another DOAC — 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) [117,118]. (See "Warfarin and other VKAs: Dosing and adverse effects", section on 'Initial dosing'.)

Dabigatran to warfarin – The two agents are overlapped [120]. 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 [86]. 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 [121].

Edoxaban to warfarin – For patients taking 60 mg of edoxaban, reduce the dose to 30 mg and begin the VKA concomitantly [122]. 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 for at least two days) is reached.

DOAC to another DOAC – 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.

Alternative approaches for transitioning from a direct factor Xa inhibitor to warfarin based on the pharmacodynamics of warfarin and the other anticoagulant might be reasonable. The ASH guideline suggests overlapping the two anticoagulants until the INR is therapeutic on warfarin [119]; 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 (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 [119].

From a VKA to a DOAC or argatroban — When switching from a VKA to a DOAC, the resolution of warfarin effect may take several days. 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:

Warfarin to argatroban – Start argatroban when the INR is <2. (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 [120].

Warfarin to rivaroxaban – Discontinue the VKA, monitor the PT/INR, and start rivaroxaban when the PT/INR is <3 [123].

Warfarin to apixaban – Discontinue the VKA, monitor the PT/INR, and start apixaban when the PT/INR is <2 [124].

Warfarin to edoxaban – Discontinue the VKA, monitor the PT/INR, and start edoxaban when the PT/INR is ≤2.5 [122].

Switching from a parenteral direct thrombin inhibitor to warfarin 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 "Acute ST-elevation myocardial infarction: Management of anticoagulation" and "Anticoagulant therapy in non-ST elevation acute coronary syndromes", section on 'Unfractionated heparin compared with bivalirudin'.)

Between DOACs and heparins — (See "Heparin and LMW heparin: Dosing and adverse effects", section on 'Transitioning between anticoagulants'.)

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 topics (see "Patient education: Choosing an oral medicine for blood clots (The Basics)" and "Patient education: Taking oral 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, their dosages cannot be titrated to modify anticoagulation intensity, 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 and contraindications' 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 9 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), 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, keep in mind that the resolution of VKA effect may take several days. Specific recommendations are summarized in the table (table 10) and discussed above. (See 'Transitioning between anticoagulants' above.)

Investigational approaches – (See "Investigational anticoagulants".)

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".)

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Topic 1370 Version 164.0

References

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