Excessive anticoagulant effect and bleeding from warfarin can be reversed by stopping the drug and administering oral or parenteral vitamin K1 (phytonadione), fresh-frozen plasma, prothrombin complex concentrates, and recombinant factor VIIa (rFVIIa). A four-factor concentrate containing factors II, VII, IX, and X (Prothrombin Complex Concentrate, [Human]; Kcentra) (4F PCC) is available. The disappearance of excessive effect is not correlated with plasma warfarin concentrations but rather with reestablishment of normal activity of the clotting factors. A modest excess of anticoagulant effect without bleeding may require no more than cessation of the drug. The warfarin effect can be rapidly reversed in the setting of severe bleeding with the administration of prothrombin complex or rFVIIa coupled with intravenous vitamin K. It is important to note that due to the long half-life of warfarin, a single dose of vitamin K or rFVIIa may not be sufficient.
Oral Xa inhibitors, including rivaroxaban, apixaban, and edoxaban represent a new class of oral anticoagulant drugs that require no monitoring. Along with oral direct thrombin inhibitors (discussed below) this new class of direct oral anticoagulant (DOAC) drugs is having a major impact on antithrombotic pharmacotherapy.
Rivaroxaban, apixaban, and edoxaban inhibit factor Xa, in the final common pathway of clotting (see Figure 34–2). These drugs are given as fixed doses and do not require monitoring. They have a rapid onset of action and shorter half-lives than warfarin.
Rivaroxaban has high oral bioavailability when taken with food. Following an oral dose, the peak plasma level is achieved within 2–4 hours; the drug is extensively protein-bound. It is a substrate for the cytochrome P450 system and the P-glycoprotein transporter. Drugs inhibiting both CYP3A4 and P-glycoprotein (eg, ketoconazole) result in increased rivaroxaban effect. One third of the drug is excreted unchanged in the urine and the remainder is metabolized and excreted in the urine and feces. The drug half-life is 5–9 hours in patients age 20–45 years and is increased in the elderly and in those with impaired renal or hepatic function.
Apixaban has an oral bioavailability of 50% and prolonged absorption, resulting in a half-life of 12 hours with repeat dosing. The drug is a substrate of the cytochrome P450 system and P-glycoprotein and is excreted in the urine and feces. As with rivaroxaban, drugs inhibiting both CYP3A4 and P-glycoprotein, as well as impairment of renal or hepatic function, result in increased drug effect.
Edoxaban is a once-daily Xa inhibitor with a 62% oral bioavailability. Peak drug concentrations occur 1–2 hours after dosage and are not affected by food. The drug half-life is 10–14 hours. Edoxaban does not induce CYP450 enzymes. No dose reduction is required with concurrent use of P-glycoprotein inhibitors. Edoxaban is primarily excreted unchanged in the urine.