For many years, vitamin K antagonists (VKAs), such as warfarin, acenocoumarol, phenprocoumon, and fluindione, have been the mainstay of thromboembolic disease management, including the management of venous thromboembolism (VTE) and atrial fibrillation (AF)-related stroke. Warfarin is the most widely used VKA in clinical practice.1 The VKAs are highly effective in preventing recurrent VTE (with a relative risk [RR] reduction of ~85% compared with placebo) and AF-related stroke (with a RR reduction of 64% compared with placebo, and a 37% RR reduction compared with antiplatelet therapy).2,3
The VKAs, however, have substantial limitations that can outweigh these advantages—including certain drug–drug and drug–food interactions, a narrow therapeutic window, and unpredictable anticoagulant effects, all of which necessitate regular laboratory monitoring to evaluate their efficacy and safety.3 In order to overcome these limitations, target-specific oral anticoagulants (TSOACs), which directly inhibit the activity of coagulation factor Xa (rivaroxaban, apixaban, and edoxaban) or thrombin (dabigatran), have been developed to replace VKAs.
Effectiveness and Safety of Target-Specific Oral Anticoagulants
In comparison with VKAs, TSOACs have predictable anticoagulant responses (enabling fixed dosing without the need for routine anticoagulation monitoring), fewer food and drug interactions, shorter half-lives, and more rapid onset of action4 (Table I4,5 ).
On the basis of large human clinical trial evidence and real-world post-marketing surveillance studies, TSOACs have at least the same efficacy and safety as VKAs or low-molecular-weight heparin for approved indications (Table II 6 ).
Drug Interactions. The TSOACs have fewer drug interactions than does warfarin, but they are subject to drug–drug interactions via the cytochrome P450 and P-glycoprotein systems: inducers or inhibitors of these factors can change the plasma levels of TSOACs.
P-glycoprotein transporter plays a major role in absorption and renal clearance. Cytochrome P450 (CYP3A4) is necessary for hepatic clearance, which itself has a substantial role in the elimination of rivaroxaban but a minor role in the elimination of apixaban and edoxaban, and no role in the elimination of dabigatran. Amiodarone, dronedarone, ketoconazole, verapamil, quinidine, clarithromycin/rifampicin, St. John's wort, carbamazepine, phenytoin, and phenobarbital are among the agents that exhibit possible drug–drug interaction with TSOACs.7
Target-Specific Oral Anticoagulants in Renal Dysfunction. All the TSOACs have some degree of renal excretion (dabigatran, 80%; rivaroxaban, 35%; and apixaban, 25%). Patients with impaired renal function are at risk of TSOAC accumulation and at higher risk of bleeding, so TSOAC doses should be modified on the basis of renal function8 (Table III5,8–10 ). Among patients with chronic kidney disease (defined as a creatinine clearance [CrCl] ≤50 mL/min), TSOACs showed no significant difference from VKAs, in efficacy or in risk of bleeding.8 The TSOACs are not recommended for use in patients who are on dialysis or who have AF and end-stage chronic kidney disease.
Management of Bleeding Events. Currently, there is no specific antidote for TSOACs, so recommendations on bleeding management usually arise from experts' opinions or laboratory endpoints. Considering TSOACs' relatively short elimination half-lives, stopping the drug and providing supportive care (such as the transfusion of blood products) might be sufficient treatment in cases of mild bleeding. In severe bleeding, prothrombin complex concentrates (PCCs), activated PCCs, or recombinant factor VIIa should be used11 (Fig. 1).
Measurement of Anticoagulant Effects. Although TSOACs do not require routine coagulation monitoring, laboratory testing can be beneficial in some situations like severe bleeding, severe renal impairment, emergency or urgent surgery, and overdose. The effects of TSOACs on coagulation assays are summarized in Table IV.12
Switching to or from a Target-Specific Oral Anticoagulant. In switching between anticoagulation regimens, the pharmacokinetics and pharmacodynamics of each anticoagulant should be considered, and the patient's coagulation status and renal function should be appropriately evaluated. Table V summarizes current recommendations as applied to various switches.7
Use of Target-Specific Oral Anticoagulants in Patients with Atrial Fibrillation. Those patients with nonvalvular AF who should be treated with anticoagulants have a choice among warfarin and the TSOACs, but the level of evidence that supports the use of warfarin (level A) is still higher than that in support of TSOACs (level B). Direct thrombin inhibitor (dabigatran) should not be used in patients with a mechanical heart valve.13 Switching from warfarin to TSOAC should be considered in cases of drug intolerance, therapeutic failure, and patient preference.14 Dabigatran and rivaroxaban are U.S. Food and Drug Administration (FDA) pregnancy category C (that is, animal reproduction studies showed adverse effects on the fetus, and there are no adequate and well-controlled studies in human beings); apixaban is FDA pregnancy category B (animal reproduction studies showed no harm to the fetus, but there are no adequate and well-controlled studies in pregnant women).14
We conclude that TSOACs are a safe and effective alternative to VKAs in suitable candidates.
Presented at the 5th Annual Symposium on Risk, Diagnosis and Treatment of Cardiovascular Disease in Women; Houston, 12 December 2014.
Section Editor: Stephanie A. Coulter, MD
From: Department of Cardiology (Drs. Saeed and Safavi-Naeini), Texas Heart Institute; and Department of Cardiology (Dr. Saeed), CHI St. Luke's Health–Baylor St. Luke's Medical Center, Houston, Texas 77030