New oral anticoagulants
For decades, vitamin K antagonists, such as warfarin, have been the mainstay of DVT treatment. NOACs, developed to optimize the management of DVT, have helped to overcome some of the limitations of traditional DVT management.21,22 Over the last 5 years, four NOACs have been approved to treat DVT.21,22 These include direct thrombin inhibitors as well as inhibitors of factor Xa.22 After extensive testing in clinical trials, rivaroxaban, dabigatran, apixaban, and edoxaban have been approved by the FDA for the treatment of DVT or venous thromboembolism (VTE). These medications have the advantage of more predictable effects, so that the need for continual monitoring is eliminated.22 The NOACs also have a shorter half-life than that of warfarin, which is an advantage if anticoagulation must be abruptly stopped.21 Although more costly, the new medications have provided a safe form of anticoagulation that requires less monitoring and follow-up in comparison with other anticoagulants.
Direct thrombin inhibitors. Dabigatran (Pradaxa) is a direct, reversible, potent competitive inhibitor of thrombin. Inhibition of thrombin prevents the conversion of fibrinogen to fibrin and thus prevents clot formation.22 The primary route of elimination is via the kidneys, which clear about 85% of the drug. In the treatment of DVT with dabigatran, it is recommended that initially the drug be administered parenterally for 5 to 10 days. Peak activity occurs within 1 to 6 hours, and the drug has a half-life of 12 to 17 hours.21,22 The dose should be adjusted in patients with renal failure, defined as creatinine clearance below 30 mL/min.22
The disadvantages of dabigatran include a higher cost compared with warfarin, the need for twice-daily dosing, and a slightly increased risk for gastrointestinal bleeding (6.1% with dabigatran vs 4% with warfarin).21,22 Initially, another disadvantage of dabigatran was the lack of a true reversal agent, although in October 2015, idarucizumab (Praxbind) was approved as a reversal agent for dabigatran. Despite the few disadvantages, dabigatran has proved to be a safer anticoagulant than warfarin.22 The RE-LY study evaluated dabigatran relative to warfarin in more than 18,000 patients over a 2-year span. The investigators found a significant reduction in the overall incidence of stroke (relative risk [RR] 0.64%, 95% confidence interval [CI] 0.51-0.81, P <0.001) and intracranial hemorrhage (RR 0.40, 95% CI 0.27-0.60, P < 0.001) when dabigatran was compared with warfarin, showing it to be a safe alternative to warfarin therapy.21,22 Two other large studies, ROCKET-AF (rivaroxaban) and ARISTOTLE (apixaban), compared these medications with warfarin. The studies showed rivaroxaban and apixaban to be superior to warfarin, with similar or lower rates of hemorrhage.23,24
Factor Xa inhibitors. Apixaban (Eliquis), rivaroxaban (Xerelto), and edoxaban (Savaysa) are all direct factor Xa inhibitors. They keep factor Xa from binding to its substrate, prothrombin, thus preventing clot formation. Multiple clearance mechanisms exist for this class of oral anticoagulants. Approximately 30% of the drug is excreted by the kidneys, with the remainder metabolized by the liver. The factor Xa inhibitors are currently used for stroke prevention and the treatment of nonvalvular atrial fibrillation as well as DVT and VTE.21,22
The major disadvantages of factor Xa inhibitors include the lack of a true reversal agent, the need for twice-daily dosing, and increased cost. Despite these few disadvantages, the NOACs have begun to replace warfarin in the treatment of DVT and VTE. NOAC dosing and treatment for DVT are summarized in Table 3.
DVT and thromboembolism are a significant source of morbidity and mortality. It is imperative that clinicians understand how to recognize and treat DVT. Over the years, the treatment of DVT has evolved to include a new class of medications, the NOACs. Although the use of NOACs presents some disadvantages, such as increased cost, a lack of antidotes, and a limited number of laboratory methods available to monitor their activity, there are clear advantages to prescribing NOACs to patients at risk for DVT. These medications have a wide therapeutic window and cause fewer drug-drug interactions than the older agents; in addition, because of their shorter half-life, it easier to discontinue treatment abruptly with NOACs than with warfarin. These features, along with the lack of the need for continual monitoring of the INR, make NOACs a safe and reasonable treatment option for patients with DVT.
John B. Hurt, MPAS, PA-C, is an assistant professor and director of clinical education, Department of Physician Assistant Studies, Samford University, in Birmingham, AL; Kristopher Maday, MS, PA-C, is the program director and associate professor, University of Tennessee Health Science Center, Physician Assistant Program, in Memphis; Michelle Brown, PhD, MS, MLS (ASCP), SBB, is an assistant professor and program director, Healthcare Simulation, University of Alabama Birmingham; and Paul M. Harrelson, MPAS, PA-C, is a program director at Samford University.
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