General Information

Xarelto (rivaroxaban) is a factor Xa inhibitor that selectively blocks the active site of factor Xa and does not require a cofactor (such as Anti-thrombin III) for activity. Activation of factor X to factor Xa (FXa) via the intrinsic and extrinsic pathways plays a central role in the cascade of blood coagulation.

Xarelto is specifically indicated for the following:

• to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation
• for the treatment of deep vein thrombosis (DVT)
• for the treatment of pulmonary embolism (PE)
• for the reduction in the risk of recurrence of DVT and/or PE in patients at continued risk for recurrent DVT and/or PE after completion of initial treatment lasting at least 6 months.
• for the prophylaxis of DVT, which may lead to PE in patients undergoing knee or hip replacement surgery
• for the prophylaxis of venous thromboembolism (VTE) and VTE related death during hospitalization and post hospital discharge in adult patients admitted for an acute medical illness who are at risk for thromboembolic complications due to moderate or severe restricted mobility and other risk factors for VTE and not at high risk of bleeding
• for use in combination with aspirin to reduce the risk of major cardiovascular events (cardiovascular death, myocardial infarction, and stroke) in patients with coronary artery disease
• for use in combination with aspirin to reduce the risk of major thrombotic vascular events (myocardial infarction, ischemic stroke, acute limb ischemia, and major amputation of a vascular etiology) in patients with PAD, including patients who have recently undergone a lower extremity revascularization procedure due to symptomatic PAD
• for the treatment of VTE and reduction in the risk of recurrent VTE in patients from birth to less than 18 years after at least five days of initial parenteral (injected or intravenous) anticoagulant treatment; and thromboprophylaxis (prevention of blood clots and blood-clot related events) in children aged two years and older with congenital heart disease who have undergone the Fontan procedure

Xarelto is supplied as tablets for oral administration. The recommended dosage/administration is as follows:

• Nonvalvular Atrial Fibrillation: 15 or 20 mg, once daily with food
• Treatment of DVT and/or PE: 15 mg orally twice daily with food for the first 21 days followed by 20 mg orally once daily with food for the remaining treatment
• Reduction in the Risk of Recurrence of DVT and/or PE in patients at continued risk for DVT and/or PE: 10 mg once daily with or without food, after at least 6 months of standard anticoagulant treatment
• Prophylaxis of DVT Following Hip or Knee Replacement Surgery: 10 mg orally once daily with or without food
• Prophylaxis of VTE in Acutely Ill Medical Patients at Risk for Thromboembolic Complications Not at High Risk of Bleeding: 10 mg once daily, with or without food, in hospital and after hospital discharge for a total recommended duration of 31 to 39 days
• CAD or PAD: 2.5 mg orally twice daily with or without food, in combination with aspirin (75-100 mg) once daily
• Dosing in pediatrics is based on body weight. See dosing recommendations in the Full Prescribing Information drug label.

Mechanism of Action

Xarelto (rivaroxaban) is a factor Xa inhibitor that selectively blocks the active site of factor Xa and does not require a cofactor (such as Anti-thrombin III) for activity. Activation of factor X to factor Xa (FXa) via the intrinsic and extrinsic pathways plays a central role in the cascade of blood coagulation.

Side Effects

Adverse events associated with the use of Xarelto for DVT may include, but are not limited to, the following:

• major bleeding events
• wound secretion
• pruritus

The most common adverse event associated with the use of Xarelto for the reducuction in the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation is bleeding.

The most common adverse effect associated with the use of Xarelto is bleeding.

The Xarelto drug label comes with the following Black Box Warning:

(A) Premature discontinuation of Xarelto increases the risk of thrombotic events Premature discontinuation of any oral anticoagulant, including Xarelto, increases the risk of thrombotic events. To reduce this risk, consider coverage with another anticoagulant if Xarelto is discontinued for a reason other than pathological bleeding or completion of a course of therapy. (B) Spinal/epidural hematoma Epidural or spinal hematomas have occurred in patients treated with Xarelto who are receiving neuraxial anesthesia or undergoing spinal puncture. These hematomas may result in long-term or permanent paralysis.  Monitor patients frequently for signs and symptoms of neurological impairment and if observed, treat urgently. Consider the benefits and risks before neuraxial intervention in patients who are or who need to be anticoagulated.

Clinical Trial Results

The FDA approval of Xarelto for prophylaxis of deep vein thrombosis was based on three trials, RECORD 1, 2, and 3, conducted in 9,011 subjects.
RECORD 1 and 2
These randomized, double-blind studies enrolled 6,727 subjects undergoing elective total hip replacement surgery. The trials compared Xarelto 10 mg once daily starting at least 6 to 8 hours after wound closure versus enoxaparin 40 mg once daily started 12 hours preoperatively. In RECORD 1, the mean exposure duration to active Xarelto and enoxaparin was 33.3 and 33.6, respectively. In RECORD 2, the mean exposure duration to active Xarelto and enoxaparin was 33.5 and 12.4, respectively. After Day 13, oral placebo was continued in the enoxaparin group for the remainder of the double-blind study duration.
RECORD 1 Results
The study met its primary endpoint, demonstrating a 71% relative risk reduction (RRR) (p<0.001) in total VTE (composite of deep vein thrombosis, non-fatal pulmonary embolism and all-cause mortality) for the rivaroxaban arm compared to the enoxaparin arm (1.1% and 3.9%, respectively). The secondary endpoint was also achieved, with a 91% RRR (p<0.001) in major VTE (composite of proximal deep vein thrombosis, non-fatal pulmonary embolism and VTE-related death) observed in the rivaroxaban arm versus the enoxaparin arm (0.2% and 2.1%, respectively). Rivaroxaban also demonstrated a similar rate of major bleeding to enoxaparin (0.3% and 0.1%, respectively, p=0.178).
RECORD 2 Results
Data showed a 76% RRR (p<0.001) in total VTE and an 87% RRR (p<0.001) in major VTE for subjects treated with rivaroxaban compared with those treated with enoxaparin. Rivaroxaban demonstrated a similar rate of major bleeding compared to enoxaparin (0.1% and 0.1%, respectively, p=0.980).
RECORD 3
This randomized, double-blind study enrolled 1,684 subjects undergoing elective total knee replacement surgery. The trial compared Xarelto 10 mg once daily started at least 6 to 8 hours after wound closure versus enoxaparin 40 mg once daily started 12 hours preoperatively. The mean exposure duration to active Xarelto and enoxaparin was 11.9 and 12.5 days, respectively. Subjects treated with Xarelto demonstrated a 48% relative risk reduction in total DVT, pulmonary embolism (PE) and all-cause mortality when compared to enoxaparin (p<0.001). Major VTE occurred in 1.0% of the Xarelto-treated group and in 2.6% of the enoxaparin-treated group (p=0.01) with a relative risk reduction of 62%. Symptomatic VTE occurred in 1.0% of subjects who received Xarelto, compared to 2.5% of those in the enoxaparin group, a relative risk reduction of 60%. Major bleeding rates were 0.6% and 0.5%, and any bleeding rates were 4.9% and 4.8% for the Xarelto and enoxaparin groups, respectively.

The FDA approval of Xarelto for the reduction in the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation was based on a multi-national, double-blind, non-inferiority study. This study, ROCKET AF, enrolled 14,264 subjects with nonvalvular atrial fibrillation. The subjects received Xarelto (at a dose of 20 mg once daily with the evening meal in patients with CrCl >50 mL/min and 15 mg once daily with the evening meal in patients with CrCl 30 to <50 mL/min) or warfarin (titrated to INR 2.0 to 3.0), the standard of care. The median treatment duration was 590 days.The trial was designed to demonstrate that Xarelto preserved more than 50% of warfarin’s effect on stroke and non-CNS systemic embolism. Xarelto demonstrated non-inferiority to warfarin for the primary composite endpoint of time to first occurrence of stroke (any type) or non-CNS systemic embolism, but superiority to warfarin was not demonstrated.

The FDA approval of Xarelto for risk reduction of major cardiovascular (CV) events in people with chronic coronary or peripheral artery disease was based on COMPASS, a Phase 3 clinical study of 27,395 patients with chronic CAD or PAD from 33 countries. The trial examined the use of Xarelto, alone or in combination with aspirin, for the long-term prevention of major adverse CV events, including heart attack, stroke and CV death. Results showed a significant 24% reduction of the risk of major CV events in patients with chronic CAD and/or PAD with the Xarelto 2.5-mg vascular dose twice daily plus aspirin 100 mg once daily, compared to aspirin alone. Specifically data showed a 42% reduction in stroke, 22% reduction in CV death and 14% reduction in heart attack. The risk of major bleeding was significantly higher in patients taking the Xarelto/aspirin regimen compared to aspirin alone, with no significant increase in fatal or intracranial bleeds.

EINSTEIN Deep Vein Thrombosis and EINSTEIN Pulmonary Embolism Studies

Xarelto for the treatment of DVT and/or PE was studied in EINSTEIN DVT and EINSTEIN PE, multi-national, open-label, noninferiority studies comparing Xarelto (at an initial dose of 15  mg twice daily with food for the first three weeks, followed by Xarelto 20 mg once daily with food) to enoxaparin 1 mg/kg twice daily for at least five days with VKA and then continued with VKA only after the target INR (2.0-3.0) was reached. Patients who required thrombectomy, insertion of a caval filter, or use of a fibrinolytic agent and patients with creatinine clearance <30  mL/min, significant liver disease, or active bleeding were excluded from the studies. The intended treatment duration was 3, 6, or 12 months based on investigator’s assessment prior to randomization. A total of 8281 (3449 in EINSTEIN DVT and 4832 in EINSTEIN PE) patients were randomized and followed on study treatment for a mean of 208  days in the Xarelto group and 204 days in the enoxaparin/VKA group. In the EINSTEIN DVT and EINSTEIN PE studies, Xarelto was demonstrated to be non-inferior to enoxaparin/VKA for the primary composite endpoint of time to first occurrence of recurrent DVT or non-fatal or fatal PE. In each study the conclusion of non-inferiority was based on the upper limit of the 95% confidence interval for the hazard ratio being less than 2.0.

XARELTO for reduction in the risk of recurrence of DVT and of PE was evaluated in the EINSTEIN CHOICE study, a multi-national, double-blind, superiority study comparing XARELTO (10 or 20 mg once daily with food) to 100 mg acetylsalicylic acid (aspirin) once daily in patients who had completed 6 to 12 months of anticoagulant treatment for DVT and/or PE following the acute event. The intended treatment duration in the study was up to 12 months. Patients with an indication for continued therapeutic-dose anticoagulation were excluded. Because the benefit-risk assessment favored the 10 mg dose versus aspirin compared to the 20 mg dose versus aspirin, only the data concerning the 10 mg dose is discussed below. A total of 2275 patients were randomized and followed on study treatment for a mean of 290 days for the XARELTO and aspirin treatment groups. In the EINSTEIN CHOICE study, XARELTO 10 mg was demonstrated to be superior to aspirin 100 mg for the primary composite endpoint of time to first occurrence of recurrent DVT or non-fatal or fatal PE.

The efficacy and safety of XARELTO for prophylaxis of venous thromboembolism in acutely ill medical patients at risk for thromboembolic complications not at high risk of bleeding was evaluated in the MAGELLAN study (Multicenter, rAndomized, parallel Group Efficacy and safety study for the prevention of venous thromboembolism in hospitalized medically iLL patients comparing rivaroxabaN with enoxaparin. MAGELLAN was a multicenter, randomized, double-blind, parallel-group efficacy and safety study comparing XARELTO to enoxaparin, in the prevention of VTE in hospitalized acutely ill medical patients during the in-hospital and post-hospital discharge period. Patients were randomized to receive either XARELTO 10 mg once daily for 35 ±4 days starting in hospital and continuing post hospital discharge (n=4050) or enoxaparin 40 mg once daily for 10 ±4 days starting in hospital followed by placebo post-discharge (n=4051). The major efficacy outcome in the MAGELLAN trial was a composite endpoint that included asymptomatic proximal deep venous thrombosis (DVT) in lower extremity, symptomatic proximal or distal DVT in the lower extremity, symptomatic non-fatal pulmonary embolism (PE), and death related to venous thromboembolism (VTE). A total of 6024 patients were evaluable for the major efficacy outcome analysis. 

A primary efficacy outcome event occurred in 78 of 2938 patients (2.7%) receiving rivaroxaban and 82 of 2993 patients (2.7%) receiving enoxaparin at day 10 and in 131 of 2967 patients (4.4%) who received rivaroxaban and 175 of 3057 patients (5.7%) who received enoxaparin followed by placebo at day 35. A principal safety outcome event occurred in 111 of 3997 patients (2.8%) in the rivaroxaban group and 49 of 4001 patients (1.2%) in the enoxaparin group at day 10 and in 164 patients (4.1%) and 67 patients (1.7%) in the respective groups at day 35.