Rivaroxaban
Rivaroxaban is an oral direct factor Xa inhibitor that was initially approved in November 2011 for the prevention of stroke and systemic embolism in patients with nonvalvular AF. Since then, clinical use of rivaroxaban has been expanded to include prevention of VTE after elective hip or knee arthroplasty as well as treatment of DVT and prevention of recurrent VTE after acute DVT. In the phase 3 ROCKET AF (Rivaroxaban Once-Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation) study, rivaroxaban 20 mg daily (CrCl, ≥50 mL/min) and rivaroxaban 15 mg daily (CrCl, 15-49 mL/min) were equally effective as warfarin. Compared with warfarin, rivaroxaban had a similar safety rate for bleeding and adverse events but fewer intracranial hemorrhage and fatal bleeding events.8 On the basis of the outcomes of the RECORD (Regulation of Coagulation in Orthopedic Surgery to Prevent Deep Venous Thrombosis and Pulmonary Embolism) studies comparing rivaroxaban and enoxaparin sodium, rivaroxaban 10 mg daily was approved for the prevention of VTE and pulmonary embolism after elective hip or knee arthroplasty.8
The half-life of rivaroxaban is 5 to 9 hours in the young and 11 to 13 hours in the elderly.8 As rivaroxaban takes 2 to 4 hours after ingestion to reach peak plasma concentration, it is important to know the timing and the dose taken. Because of the short half-life and rapid onset of action of this medication, bridging with another anticoagulant is not required when rivaroxaban is discontinued before surgery or initiated after surgery.8 The recommendation is to withhold rivaroxaban for 24 to 48 hours before surgery and then to administer the first postoperative dose 6 to 10 hours after surgery, or when hemostasis is achieved (Table 1).
PT is recommended for rivaroxaban detection. Conventional assays are not sensitive at low concentrations, and degree of prolongation does not reliably predict amount of medication present.3,9 However, normal PT corresponds to a drug concentration of about 30 ng/mL and is considered safe for patients undergoing surgical intervention without increased risk for bleeding.6 This recommendation was extrapolated from data in the ROCKET AF study of patients who underwent elective surgeries while on rivaroxaban.6 Commercially available chromogenic anti–factor Xa assays, used with a rivaroxaban calibration curve, are sensitive and specific for rivaroxaban plasma concentrations.3,8 However, these assays are not widely available.
If a bleeding complication occurs in a patient who is being treated with rivaroxaban, the next rivaroxaban dose should be delayed, or treatment should be discontinued, as appropriate.8 Urgency of surgery should be weighed against risk for bleeding complications on a case-by-case basis. This decision is deferred to the clinical judgment of the surgeon. In the case of a patient with severe, life-threatening bleeding or a patient who requires emergent surgery, PCC 25-50 IU/kg is the recommended reversal agent.9 Recombinant factor VIIa and aPCC have been used in experimental settings, but there is concern about the greater prothrombotic potential of these agents compared with PCC8 (Table 2).
Apixaban
Apixaban is the second factor Xa inhibitor introduced in the United States and the first to show—in the ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) study—efficacy superior to that of warfarin for the prevention of stroke and systemic embolism, all-cause mortality, and major bleeding. Furthermore, in the AVERROES (Apixaban Versus Acetylsalicylic Acid to Prevent Stroke in Atrial Fibrillation Patients Who Have Failed or Are Unsuitable for Vitamin K Antagonist Treatment) study, apixaban used in AF patients who were deemed not suitable for warfarin proved to be more effective than aspirin for stroke prevention, and had a similar rate of major bleeding.10 Apixaban is administered in a 5-mg dose 2 times daily. It has a half-life of 10 to 14 hours, is highly protein-bound, and has predominantly fecal excretion (27% is renal). Apixaban can prolong PT, but the correlation is nonlinear. Barrett and colleagues11 found that chromogenic anti–factor Xa assays provided the most accurate readings of apixaban plasma concentrations. Normal anti–factor Xa activity in patients being treated with apixaban suggests low drug levels and an intact hemostatic function, which are indicators of low bleeding risk with surgical intervention3 (Table 1).
Similar to other NOACs, apixaban has no antidote. In vitro testing showed that PCC improved thrombin generation when added to the blood of healthy donors who had received apixaban. Despite the lack of clinical experience, use of PCC 50 IU/kg may be reasonable for apixaban patients with severe or life-threatening bleeding3 (Table 2). Unlike dabigatran, apixaban cannot be eliminated with dialysis because of its high degree of protein binding. In nonemergent circumstances, delaying surgery 24 to 48 hours is considered effective in reducing the concentration of apixaban to a range that does not cause additional risk for bleeding.