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Haley M. Phillippe, PharmD, BCPS, BCGP
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The Role of Direct Oral Anticoagulants in the Management of Venous Thromboembolism
Taylor Steuber, PharmD, BCPS
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The Role of Direct Oral Anticoagulants in the Management of Venous Thromboembolism

Taylor Steuber, PharmD, BCPS
Appropriate treatment of venous thromboembolism (VTE) is critical to minimizing long-term morbidity and mortality. The emergence of direct oral anticoagulants (DOACs) has provided clinicians with expanded therapeutic options for patients with VTE, and as a result, updated practice guidelines released by the American College of Chest Physicians favor DOACs over traditional anticoagulants, such as warfarin. The newest DOAC, betrixaban, received FDA approval in 2017, with an indication for VTE prophylaxis in hospitalized adults. Additionally, results from the XALIA study on the real-world outcomes of rivaroxaban are now available. A reversal agent for dabigatran, idarucizumab, also received FDA approval in 2017, and other reversal agents are in development. This article will provide an overview of current VTE treatment strategies, with an emphasis on the place in therapy of the DOACs.
Am J Manag Care. 2017;23:-S0
Venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE), occurs in as many as 900,00 people in the United States each year, with up to 100,000 Americans dying as a result.1 A common complication, VTE is the most preventable cause of death in hospitalized patients.2 Once VTE occurs, long-term mortality is poor, with 25% of patients not surviving 7 days and nearly 40% not surviving the first year.3 Furthermore, PE with or without DVT has been found to be an independent predictor of reduced survival compared with DVT alone.3 Among those who do survive, 30% will experience a recurrence of VTE within 10 years.4

Historically, the pathogenesis of VTE has been explained with the 3 components of Virchow’s triad: hypercoagulability, hemodynamic changes or hemostasis, and endothelial injury or damage.5 To address these underlying causes, treatment for VTE relies heavily on the use of anticoagulation therapy and VTE prophylaxis relies on a combination of anticoagulants and nonpharmacologic options. Traditional anticoagulation therapy for VTE involves the use of unfractionated heparin (UFH), low-molecular weight heparin (LMWH), or fondaparinux.6-8 While effective anticoagulants, these agents must be administered subcutaneously or intravenously, and they present significant risks during use, including development of heparin-induced thrombocytopenia and thrombotic thrombocytopenia syndrome.6-8

In 1954, the FDA approved warfarin, a vitamin K antagonist (VKA), for its use in the management of various clotting disorders.9 For almost 6 decades, warfarin remained the sole anticoagulant available for outpatient treatment of VTE. Since October 2010, the FDA has approved 5 direct oral anticoagulants (DOACs) for the treatment or prevention of VTE: dabigatran, rivaroxaban, apixaban, edoxaban, and betrixaban.10-14 Compared with warfarin, which inhibits several clotting factors, DOACs inhibit only 1 clotting factor (ie, thrombin or factor Xa) in the coagulation cascade.15 These agents collectively offer fixed, predictable dosing; reduced need for laboratory monitoring; and minimal drug-food interactions compared with VKA therapy.9-14 However, similar to warfarin, bleeding remains a concern with DOACs.9-14 In contrast to warfarin, most DOACs lack a reversal antidote; if serious bleeding occurs, only dabigatran has an approved antidote (ie, idarucizumab).9-14 The DOACs provide new opportunities for the management of VTE, but also present challenges not seen with traditional therapy. Therefore, it is imperative that healthcare practitioners understand the differences among the DOACs, as well as how they compare with warfarin. This article will provide an overview of VTE management, with a focus on the emergence of DOACs in clinical practice.

Nonpharmacologic Management

For patients with prolonged immobility following long-distance travel and surgical procedures, early and frequent mobilization is recommended.16 The use of graduated elastic compression stockings (GECSs) apply pressure to the leg to promote blood flow.17 This, coupled with appropriate leg movement, pushes blood in the lower veins back to the heart, reducing the risk for clotting.17 Intermittent pneumatic compression (IPC) devices work similarly to compression stockings. These devices use an inflatable sleeve to squeeze blood from the veins to reduce hemostasis in a more active manner than GECSs.17 Compression stockings and pneumatic compression devices are frequently used in hospital settings, particularly in patients undergoing surgical procedures. The 2012 American College of Chest Physicians (ACCP) guidelines for VTE prophylaxis recommend the use of these devices as an alternative to or in conjunction with anticoagulation therapy in 3 distinct populations: 1) nonsurgical patients, such as hospitalized medical patients; 2) nonorthopedic surgical patients; and 3) orthopedic surgery patients.18-20 In the presence of contraindications to anticoagulants, including a high bleeding risk, GECSs and IPC may be the only prophylactic methods.

Inferior vena cava (IVC) filters are an option for patients at significant risk for PE. These filters work by preventing a DVT from traveling to the pulmonary arteries and causing a PE or stroke.21 While published guidelines agree that these devices are necessary in the presence of acute VTE in patients with contraindications to or who failed anticoagulation therapy, recommendations on the use of IVC filters in patients without a contraindication are controversial.21,22 Clinicians should be aware that treatment guidelines by the ACCP recommend against the use of IVC filters in patients with VTE treated with anticoagulation.23 Seeking to resolve uncertainty in the medical community regarding the safety of IVC filters, a recent meta-analysis retrieved 1986 studies, of which 11 met inclusion criteria.24 Researchers found that although IVC filters reduce the risk of subsequent PE (odds ratio [OR], 0.50; 95% CI, 0.33-0.75), they increase the risk for DVT (OR, 1.70; 95% CI, 1.17-2.48), and have no impact on PE-related or all-cause mortality (PE-related mortality: OR, 0.51; 95% CI, 0.25-1.05; all-cause mortality: OR, 0.91; 95% CI, 0.70-1.19).24

Additional procedural options include mechanical thrombectomy or pharmacologic thrombolysis to try to dissolve the clot, indicated mainly in the most severe forms or iliofemoral location of DVT.25 Surgical thrombectomy is rarely indicated today in limb-threatening DVT. Thrombolytic therapy may be delivered through systemic therapy (mainly in PE) or by use of catheter-directed thrombolysis in DVT.26 These procedures carry significant risk for the patient, but may improve mortality and/or quality of life in patients with PE or DVT.26 Additionally, these procedures can help to prevent occurrence of postthrombotic syndrome and chronic thromboembolic pulmonary hypertension, both of which have been associated with poor quality of life.27,28 The ACCP guidelines recommend thrombolytic therapy for patients with PE associated with hypotension (grade 2B).23

Despite the potential benefits, health practitioners should be aware of the risks associated with thrombolytic therapy. A meta-analysis evaluating outcomes with the use of thrombolytic therapy compared with traditional anticoagulants (LMWH, VKA, fondaparinux, or UFH) found the use of thrombolytics to be associated with lower all-cause mortality (OR, 0.53; 95% CI, 0.32-0.88) and lower risk of recurrent PE (OR, 0.40; 95% CI, 0.22-0.74). However, thrombolytics were also associated with a greater risk of major bleeding (OR, 2.73; 95% CI, 1.91-3.91) and greater risk of intracranial hemorrhage (OR, 4.63; 95% CI, 1.78-12.04).25

Pharmacologic Management

Outcome goals in patients with PE treated with thrombolytic therapy include reducing thromboembolic burden, pulmonary vascular resistance, and right ventricular dysfunction while more rapidly restoring pulmonary capillary blood flow and effective gas exchange compared with anticoagulation alone.26 In patients with DVT, goals include saving the life, limb, or organ when urgently needed,  preventing PE in an acute setting.26 The primary goals of anticoagulant pharmacotherapy in patients with VTE are effective anticoagulation to prevent thrombus extension or embolization to prevent new thrombi from forming and reducing the risk of long-term complications.29 The 2016 ACCP guidelines for antithrombotic therapy in patients with VTE recommend the following:
  • In patients with DVT or PE, the panel recommends long-term (3 months) anticoagulant therapy over no such therapy (grade 1B)
  • In patients with DVT or PE and no cancer, the panel suggests use of dabigatran, rivaroxaban, apixaban, or edoxaban over VKA therapy (all grade 2B). If the patient cannot be treated with one of these agents, the panel recommends VKA therapy over LMWH (grade 2C)
  • In patients with DVT or PE and cancer, the panel suggests LMWH over VKA therapy, dabigatran, rivaroxaban, apixaban, or edoxaban (all grade 2C)
  • Extended-duration anticoagulant therapy is decided on a case-by-case basis dependending on the underlying cause of the VTE and patient history23
The newest agent, betrixaban, was approved by the FDA on June 23, 2017, for hospital and extended-duration prophylaxis of VTE in adult patients hospitalized for an acute medical illness who are at risk for thromboembolic complications due to moderate or severe restricted mobility and other VTE risk factors.14 Because of its recent approval, betrixaban is not included in the most recent ACCP guidelines. However, it is the only oral anticoagulant indicated for prophylaxis of VTE in adult patients hospitalized for an acute medical illness.30

The mechanisms of action, indications, dosing, important drug-drug interactions, reversal agents, drug-food considerations, and warnings and precautions for the 5 DOACs and warfarin are summarized in Table 1.9-14,29

In treatment of VTE, DOACs offer several advantages over VKA therapy. The anticoagulation effect of a VKA, such as warfarin, is indirect inhibition of vitamin K oxide reductase, resulting in decreased levels of pro-coagulant clotting factors in the direct, indirect, and common pathways. By contrast, DOACs act on the final common pathway of the coagulation cascade.15 Therefore, DOACs have a more predictable anticoagulant response, fewer drug interactions, and significantly less risk of hemorrhagic stroke compared with warfarin.9-14

Except for betrixaban and 15-mg or 20-mg doses of rivaroxaban, which must be taken with food, 10-mg doses of rivaroxaban and the 3 other DOACs may be taken without regard to timing of meals.10-14 Warfarin has a narrow therapeutic index, which may be affected by other drugs and dietary changes, and must be regularly monitored through use of the international normalized ratio (INR), which is taken daily in early therapy and advances to every 1 to 4 weeks once stable INR is achieved.9 The use of INR provides clinicians with a biomarker for current coagulation status9; in contrast, DOACs have no monitoring requirements and limited options for drug-specific testing of anticoagulation.29 A single dose of warfarin has a half-life time of approximately 1 week, although the effective half-life time ranges from 20 to 60 hours.9 All DOACs boast half-lives of less than 24 hours, although rivaroxaban has the shortest at 5 to 9 hours.10-14 These shorter half-life times help to compensate for the lack of reversal agent (for all but dabigatran) when bleeding occurs or when surgery is necessary in an acute setting, although the difficulty in determining current coagulation status can be challenging for clinicians. Conversely, the shorter half-life times necessitate stricter adherence compared with warfarin due to more rapid clearance of the drug. Despite these benefits, in patients with severe renal impairment (creatinine clearance less than 15 mL/minute), warfarin remains the drug of choice.29

Copyright AJMC 2006-2018 Clinical Care Targeted Communications Group, LLC. All Rights Reserved.
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