Editor's Note: Since October 2010, the US Food and Drug Administration (FDA) has approved 3 new anticoagulants that, for the first time, offer patients with such conditions as stroke in the setting of atrial fibrillation (AF), deep vein thrombosis, and pulmonary embolism a long-awaited alternative to the vitamin K antagonist warfarin. This new class of drugs, called "target-specific oral anticoagulants" (TSOACs), includes dabigatran, rivaroxaban, and apixaban. These are the first new oral anticoagulants available since warfarin was approved for use in 1954.
Although these new drugs have demonstrated certain advantages to warfarin, they also have some clear disadvantages, including the lack of available antidotes should a major bleeding event occur.
Ann K. Wittkowsky, PharmD, Director of Anticoagulation Services at the University of Washington Medical Center in Seattle, spoke about the new anticoagulants at Hospital Medicine 2014 in Las Vegas. Her presentation included an overview of the indications for these agents, a comparison of their mechanisms vs the mechanism of warfarin, and special considerations that should be made when prescribing TSOACs. She worked with Medscape to provide an abridged version of this presentation for our readers.
What are the indications for dabigatran, rivaroxaban, and apixaban?
Dr. Wittkowsky: In the United States, options for oral anticoagulation changed significantly in October 2010, when dabigatran was first approved for stroke prevention in nonvalvular AF. Since then, rivaroxaban has been approved for venous thromboembolism (VTE) prophylaxis in orthopedic surgery, for stroke prevention in AF, and more recently for initial and extended treatment of VTE. Apixaban is a more recent addition; it is approved for stroke prevention in AF and is approved by the FDA for VTE prevention after orthopedic surgery. Apixaban has also been submitted to the FDA for the initial and extended treatment of VTE.
How do these TSOACs compare with a vitamin K antagonist, such as warfarin, and how do they compare with each other?
Dr. Wittkowsky: A very thorough meta-analysis comparing the effectiveness and safety of the new anticoagulants with that of warfarin for stroke prevention in atrial fibrillation was published in March of this year.[1] But in addition to this clinical comparison, it is important to compare the pharmacokinetic and pharmacodynamics characteristics of these agents, and how those characteristics influence their use.
Underlying pharmacokinetic properties, such as clearance and metabolism, protein binding, and volume of distribution, influence their half-lives, dialyzability, and requirements for dosing adjustment in renal impairment. Although they are all reversible with respect to their binding to the catalytic site of either factor II or factor X, that is not to be confused with reversibility of the drug effect by an antidote. At this point, there are no commercially available antidotes for any of these drugs, which means that if catastrophic bleeding occurs, there is no easy way to reverse their action.
These agents achieve rapid maximum serum concentrations compared with warfarin, which takes 5-10 days or more to reach a therapeutic effect. They also have fairly short half-lives that are sufficient for once- or twice-daily dosing, but which also allow them to clear somewhat rapidly once they are discontinued, particularly in patients with normal renal function. The dialysis characteristics are influenced by volume of distribution and molecular size. Dabigatran is dialyzable to some extent, whereas rivaroxaban and apixaban are not.