Overview of the Direct Oral Anticoagulants

Abstract

Over the past 6 decades, warfarin has proven efficacious in reducing stroke risk in patients with atrial fibrillation and reducing the risk of recurrent venous thromboembolism in patients with acute deep vein thrombosis or pulmonary embolism. However, there have been multiple challenges with using warfarin including delayed onset of action, need for bridging and monitoring as well as many drug-drug and drug-food interactions. Hence, long years of research have led to the development of direct oral anticoagulants. Of the 4 direct oral anticoagulants currently approved by the Food and Drug Administration, 1 is a direct thrombin inhibitor (dabigatran) and the other 3 are direct factor Xa inhibitors (apixaban, rivaroxaban and edoxaban). Direct oral anticoagulants have been found to be at least as effective as warfarin with fewer bleeding complications. This paper provides an overview of the evolution of anticoagulation therapies and an extensive literature review of the new direct oral anticoagulants. KEY WORDSanticoagulation, direct oral anticoagulant, bleeding n INTRODUCTIONIn the 1920s, cattle in Canada and the northern United States suffered from severe internal bleeding that was associated with diet. It was discovered that spoiled sweet clover hay (Melilotus alba and Melilotus officinalis) contained a hemorrhagic factor, a coumarin compound that was isolated and named dicoumarol, that reduced the activity of prothrombin.1,2 A related derivative, warfarin, was initially used as a rodenticide and eventually moved to clinical application. Warfarin acts as an inhibitor of vitamin K epoxidase reductase, which catalyzes the reduction of oxidized vitamin K.3 The latter is essential for the carboxylation of coagulation proteins for factors II, VII, IX, and X. 4,5 Based on multiple clinical trials, warfarin was proven to reduce stroke risk in patients with atrial fibrillation (AF) and to reduce recurrent venous thromboembolism (VTE) after the initial event.6 However, warfarin has multiple pitfalls including delayed therapeutic onset, interindividual variability in anticoagulant effect, significant drug-drug and drug-food interactions, dietary restrictions, and an increased need for monitoring. 4,7 Research to develop more convenient new anticoagulation therapies with better efficacy and fewer side effects has been ongoing for decades. Based on their mechanism of action, the direct oral anticoagulants (DOACs) can be divided into 2 groups: direct thrombin (factor IIa) and direct FXa inhibitors. 4 The effects of DOAC are seen within a few hours of ingestion, generally require no monitoring, and have fewer drug-drug interactions when compared with warfarin. Furthermore, they have been proven to be at least as effective as warfarin with fewer bleeding complications. 8,9 The Food and Drug Administration (FDA) has approved idarucizumab as a specific antidote to dabigatran and is currently considering andexanet alfa as a reversal agent for the available anti-Xa agents. This paper will review the novel anticoagulant ther...

Current status of oral anticoagulant reversal strategies: a review

“…Of the four oral factor Xa inhibitors on the market: rivaroxaban, apixaban, edoxaban and betrixaban, none are dialyzable and there is little utility for the use of activated charcoal to reduce systemic absorption outside of a two hour window from ingestion (5,27,28). Unlike the direct reversal provided by idarucizumab for dabigatran, factor Xa reversal remains a slightly more complex dilemma.…”

“…Apart from dabigatran, which acts as a direct thrombin inhibitor, the remaining DOACs are factor Xa inhibitors. As a class, DOACs have begun to be utilized with increased frequency (4), presumptively due to the fact that they do not require international normalized ratio (INR) monitoring (5), and offer similar efficacy while at the same time offering an improved safety profile (6)(7)(8)(9). As of 2016, DOAC prescriptions exceeded those for warfarin in outpatient office visits for atrial fibrillation (4).…”

Andexanet Alfa Versus Prothrombin Complex Concentrates/Blood Products as Apixaban/Rivaroxaban Reversal Agents: A Survey Among Pediatric Hematologists

“… 1 Direct oral anticoagulants (DOACs) were introduced to the market in 2010 with the approval of dabigatran, an oral direct thrombin inhibitor. 2 , 3 Four other DOACs have been released and approved by the FDA for adult stroke prevention in atrial fibrillation, the treatment and secondary prevention of deep vein thrombosis (DVT) and pulmonary embolism: rivaroxaban (2011), apixaban (2012), edoxaban (2015) and betrixaban (2017). 2 , 3 These agents are classified as direct oral factor X a inhibitors (DXIs).…”

“… 2 , 3 Four other DOACs have been released and approved by the FDA for adult stroke prevention in atrial fibrillation, the treatment and secondary prevention of deep vein thrombosis (DVT) and pulmonary embolism: rivaroxaban (2011), apixaban (2012), edoxaban (2015) and betrixaban (2017). 2 , 3 These agents are classified as direct oral factor X a inhibitors (DXIs). The stable pharmacokinetic profile of these agents eliminates the need for frequent pharmacodynamic monitoring that was a necessity for pediatric patients taking warfarin (International Normalized Ratio-INR) or low molecular weight heparin (LMWH; anti-Xa levels).…”

“…The stable pharmacokinetic profile of these agents eliminates the need for frequent pharmacodynamic monitoring that was a necessity for pediatric patients taking warfarin (International Normalized Ratio-INR) or low molecular weight heparin (LMWH; anti-Xa levels). [2][3][4][5][6][7][8] The most recently published rivaroxaban trial in pediatric patients showed no increased bleeding when compared to standard anticoagulation [3% non-major bleeding in the rivaroxaban arm and 2% (major and non-major in the standard arm [HR 1.58, 95% CI 0.51-6.27]]. 9 The use of DOACs in pediatrics will obviate the need for anticoagulation monitoring and provide an alternative route of administration [oral], preferable for patients and families.…”