Rivaroxaban is approved for prevention of embolic stroke in patients with atrial fibrillation without valvular heart disease, prevention of venous thromboembolism following hip or knee surgery, and treatment of venous thromboembolic disease (VTE). The prophylactic dosage is 10 mg orally per day for 35 days for hip replacement or 12 days for knee replacement. For treatment of DVT/PE the dosage is 15 mg twice daily for 3 weeks followed by 20 mg/d. Depending on clinical presentation and risk factors, patients with VTE are treated for 3–6 months; rivaroxaban is also approved for prolonged therapy in selected patients to reduce recurrence risk at the treatment dose. Apixaban is approved for prevention of stroke in nonvalvular atrial fibrillation, for prevention of VTE following hip or knee surgery, and for treatment and long-term prevention of VTE. The dosage for atrial fibrillation is 5 mg twice daily; the dose for VTE is 10 mg twice a day for the first week, followed by 5 mg twice a day. The prophylactic dose for prevention of VTE following hip or knee surgery or long-term prevention of VTE following initial therapy is 2.5 mg twice a day. The recommended duration of therapy in hip and knee replacement is the same as for rivaroxaban. Edoxaban is approved for prevention of stroke in nonvalvular atrial fibrillation, and to treat VTE following treatment with heparin or LMWH for 5–10 days. The dose for atrial fibrillation and VTE treatment is 60 mg once daily. For patients with creatinine clearance of 15–50 mL/min or those taking concomitant P-glycoprotein inhibitors, the dose is
CHAPTER 34 Drugs Used in Disorders of Coagulation 617 30 mg once daily. Edoxaban is contraindicated in patients with atrial fibrillation and creatinine clearance >95 mL/min, due to the increased rate of ischemic stroke in this group compared with patients taking warfarin.
Assessment of and Reversal of Anti-Xa Drug Effect
Measurement of anti-Xa drug effect is not needed in most situations but can be accomplished by anti-Xa assays calibrated for the drug in question. Andexanet alfa is a factor Xa “decoy” molecule without procoagulant activity that competes for binding to anti-Xa drugs. In clinical trials involving apixaban and rivaroxaban, andexanet given by IV infusion resulted in rapid decrease in anti-Xa effect. Non-neutralizing antibodies occurred in 17% of those treated; the effect of these antibodies with drug re-exposure is not known. Based on the available data, andexanet is likely to be the first antidote approved for use in patients treated with anti-Xa agents who require rapid reversal for surgery or uncontrolled bleeding.
The direct thrombin inhibitors (DTIs) exert their anticoagulant effect by directly binding to the active site of thrombin, thereby inhibiting thrombin’s downstream effects. This is in contrast to indirect thrombin inhibitors such as heparin and LMW heparin (see above), which act through antithrombin. Hirudin and bivalirudin are large, bivalent DTIs that bind at the catalytic or active site of thrombin as well as at a substrate recognition site. Argatroban and melagatran are small molecules that bind only at the thrombin active site.