In the RECORD1, 2, and 3 studies, rivaroxaban significantly reduced the composite of DVT, nonfatal PE, and all-cause mortality, as well as major VTE compared with enoxaparin. Major bleeding events as well as clinically relevant nonmajor bleeding and hemorrhagic wound complications were similar across both groups.25-27
In the RECORD4 study, rivaroxaban significantly reduced the composite of DVT, nonfatal PE, and all-cause mortality, but not major VTE, in patients undergoing TKR. Major bleeding events as well as clinically relevant nonmajor bleeding were numerically higher in the rivaroxaban group, but this was not statistically significant. Hemorrhagic wound complications were similar across both groups.28 This study was not required for approval and was not included in the final FDA-approved package insert.29
In a pooled analysis of the 4 RECORD trials presented at the FDA advisory committee, the incidence of major bleeding was significantly higher in the rivaroxaban group (24 events [0.39%]) compared with enoxaparin (13 events [0.21%]), with a nominal P value of .08 (significant at 10% nominal level) in the total treatment duration pool.30 In a pooled analysis by Turpie and colleagues who used the same data, this difference was not determined to be statistically different.31 In addition, this pooled analysis showed that the incidence of treatment-emergent hemorrhagic wound complications was similar in patients receiving rivaroxaban and enoxaparin and that fewer treatment-emergent serious AEs occurred in patients receiving rivaroxaban compared with patients receiving enoxaparin.31
In the FDA advisory committee, an “isolated signal” for a potentially increased risk of ischemic stroke was identified: In the safety population, ischemic stroke occurred in 5 patients who had received rivaroxaban and 1 patient who received enoxaparin.30 Furthermore, cardiovascular events in the safety population were concentrated around discontinuation of rivaroxaban, which was not the case for enoxaparin. The concern of stroke following rivaroxaban discontinuation was much more robust in Rivaroxaban vs Warfarin in Nonvalvular Atrial Fibrillation (ROCKET-AF), the phase 3 trial that compared rivaroxaban and warfarin for stroke prophylaxis in AFib.32 In the study ROCKET-AF, higher rates of stroke and systemic embolism were observed at the end of the trial among patients discontinuing rivaroxaban and switching to open-label warfarin compared with patients who had been taking warfarin and were transitioned to open-label warfarin. This observation led to a black box warning in the label of rivaroxaban regarding discontinuation of this agent.33
rivaroxaban management
The approved dose of rivaroxaban for the prophylaxis of VTE is 10 mg orally once daily with or without food.29 The first dose should be taken 6 to 10 hours after surgery, once hemostasis has been established. Rivaroxaban should be administered for 35 days to patients undergoing THR and for 12 days to patients undergoing TKR. Tablets may be crushed and administered in a gastric feeding tube, but they must not be administered via feeding tubes that deliver the contents into the proximal small intestine, because reduced drug absorption may result.29
The prescribing information for rivaroxaban includes a black box warning stating that epidural or spinal hematomas have occurred in patients treated with rivaroxaban who are receiving neuraxial (ie, spinal or epidural) anesthesia or undergoing spinal puncture. For such patients, the epidural catheter should not be removed earlier than 18 hours after the last administration of rivaroxaban.29 The next rivaroxaban dose should not be administered earlier than 6 hours after the catheter is removed.29 If a traumatic puncture occurs, rivaroxaban administration should be delayed for 24 hours.29 Factors that can increase the risk of developing epidural or spinal hematomas include the use of indwelling epidural catheters, concomitant use of drugs that affect hemostasis (eg, nonsteroidal anti-inflammatory drugs [NSAIDs], platelet inhibitors, and other anticoagulants), a history of traumatic or repeated epidural or spinal punctures, and a history of spinal deformity or spinal surgery.
Rivaroxaban has not been studied in severe hepatic impairment (Child-Pugh C), and in subjects with moderate hepatic impairment (Child-Pugh B), rivaroxaban has led to increased drug exposure, with increased PD effects. Therefore, rivaroxaban should be avoided in patients with moderate to severe hepatic impairment or any hepatic disease associated with coagulopathy.29
Rivaroxaban should also be avoided in patients with severe renal impairment (a creatinine clearance [CrCl] of < 30 mL/min), because increased exposure with increased PD effects is expected. A combined analysis of the RECORD1, 2, and 3 trials did not show an increased bleeding risk for patients with moderate renal impairment (CrCl 30-50 mL/min) taking rivaroxaban. However, such patients should be observed for signs or symptoms of bleeding. Discontinuation should be considered in any patient who develops acute renal failure while taking rivaroxaban.