XARELTO Rx

Stroke Prevention in Nonvalvular Atrial Fibrillation 

• The efficacy and safety of Xarelto was compared to warfarin in the ROCKET AF trial (NCT00403767) to reduce the risk of stroke and non-CNS systemic embolism in 14,264 patients with nonvalvular atrial fibrillation (AF). Eligible patients had 1 or more of the following additional risk factors for stroke:

• A prior stroke, transient ischemic attack, or non-CNS systemic embolism, or 2 or more of the following risk factors: age ≥75 years, hypertension, HF or LVEF ≤35%, or diabetes mellitus.

• Patients were randomly assigned to receive either:

• 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 30–50 mL/min) or warfarin (titrated to INR 2.0 to 3.0).

• Xarelto achieved noninferiority to warfarin for the primary composite endpoint of time to first occurrence of stroke (any type) or non-CNS systemic embolism (HR, 0.88 [95% CI, 0.74-1.03]). Xarelto did not demonstrate superiority to warfarin.

• The utility of Xarelto for preventing post-cardioversion stroke and systemic embolism is unknown.

Treatment of Deep Vein Thrombosis (DVT) and/or Pulmonary Embolism (PE)

• The efficacy of Xarelto was evaluated in 8281 patients for the treatment of DVT and/or PE in the EINSTEIN DVT (NCT00440193) and EINSTEIN PE (NCT00439777) studies. Patients were excluded from the studies if they required thrombectomy, insertion of a caval filter, or use of a fibrinolytic agent and patients with CrCl <30 mL/min, significant liver disease, or active bleeding.

• Patients were randomly assigned to receive either:

• Xarelto (at an initial dose of 15 mg twice daily with food for the first 3 weeks, followed by Xarelto 20 mg once daily with food) or enoxaparin 1 mg/kg twice daily for at least 5 days with vitamin K antagonist (VKA) and then continued with VKA only after the target INR (2.0–3.0) was reached.

• In both studies, Xarelto achieved noninferiority to enoxaparin/VKA for the primary composite of time to first occurrence of recurrent DVT or non-fatal or fatal PE (EINSTEIN DVT: HR, 0.68 [95% CI, 0.44-1.04]; EINSTEIN PE: HR, 1.12 [95% CI, 0.75-1.68]).

Reduction in the Risk of Recurrence of DVT and/or PE

• The efficacy of Xarelto was evaluated in 2275 patients to reduce the risk of recurrence of DVT and of PE in the EINSTEIN CHOICE study (NCT02064439).

• Patients were randomly assigned to receive either:

• Xarelto (10 or 20 mg once daily with food) or 100 mg acetylsalicyclic 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.

• Xarelto achieved superiority to aspirin 100mg for the primary composite endpoint of time to first occurrence of recurrent DVT or nonfatal or fatal PE (HR, 0.26 [95% CI, 0.14-0.47]; P <.0001).

Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement Surgery

• The efficacy of Xarelto was evaluated in a total of 9011 patients in the RECORD 1, 2, and 3 studies (NCT00329628, NCT00332020, NCT00361894).

• RECORD 1 and 2:

• These randomized, double-blind, clinical studies included 6727 patients undergoing elective total hip replacement surgery. Patients were randomly assigned to receive either Xarelto 10 mg once daily starting at least 6 to 8 hours after wound closure or enoxaparin 40 mg once daily started 12 hours preoperatively.

• In RECORD 1, Xarelto met the primary composite endpoint with a relative risk reduction of 71% in total VTE vs enoxaparin (95% CI, 50-83; P <.001). Xarelto also had a relative risk reduction of 91% in major VTE vs enoxaparin (95% CI, 71-97; P <.001).

• In RECORD 2, Xarelto met the primary composite endpoint with a relative risk reduction of 76% in total VTE vs enoxaparin (95% CI, 59-86; P <.001). Xarelto also had a relative risk reduction of 87% in major VTE vs enoxaparin (95% CI, 69-94; P <.001).

• RECORD 3:

• This clinical studiy included 6727 patients undergoing elective total knee replacement surgery. Patients were randomly assigned to receive either Xarelto 10 mg once daily starting at least 6 to 8 hours after wound closure or enoxaparin 40 mg once daily starting 12 hours preoperatively.

• In RECORD 3, Xarelto met the primary composite endpoint with a relative risk reduction of 48% in total VTE vs enoxaparin (95% CI, 34-60; P <.001). Xarelto also had a relative risk reduction of 60% in major VTE vs enoxaparin (95% CI, 14-81; P <.024).

Prophylaxis of Venous Thromboembolism in Acutely Ill Medical Patients at Risk for Thromboembolic Complications Not at High Risk of Bleeding

• 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 (NCT00571649).

• Eligible patients included adults aged ≥40 years who were hospitalized for an acute medical illness, at risk for VTE due to moderate or severe immobility, and had additional risk factors for VTE. The causes for hospitalization included HF, active cancer, acute ischemic stroke, acute infectious and inflammatory disease and acutre respiratory insufficiency.

• Patients were randomly assigned to receive either: 

• Xarelto 10mg 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 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).

• Xarelto was found to be noninferior to enoxaparin in short-term use (10±4 days) and superior in long-term use (35±4 days) vs short-term use of enoxaparin followed by placebo. However, major clinically relevant bleeding was found to be higher in the Xarelto group. 

Reduction of Risk of Major Cardiovascular Events in Patients with CAD 

• The efficacy and safety of Xarelto was evaluated in the phase 3 COMPASS trial (N=27,395) for the reduction in the risk of stroke, MI, or CV death in patients with coronary artery disease (CAD) or peripheral artery disease (PAD).

• Patients were randomly assigned to receive rivaroxaban 2.5 mg orally twice daily plus aspirin 100 mg once daily, rivaroxaban 5 mg orally twice daily alone, or aspirin 100 mg once daily alone.

• Xarelto 2.5mg twice daily + aspirin 100mg once daily showed a 24% reduction in the risk of major CV events in patients with chronic CAD and/or PAD compared with aspirin alone (HR, 0.76 [95% CI, 0.66-0.86]; P =.00004). Specifically, the data showed a 44% reduction in stroke, 25% reduction in CV death, and 14% reduction in MI. 

Reduction of Risk of Major Thrombotic Vascular Events in Patients with PAD, Including Patients after Lower Extremity Revascularization due to Symptomatic PAD

• The approval was based on data from the double-blind, placebo-controlled phase 3 VOYAGER PAD study (NCT02504216) and the COMPASS PAD study.

• VOYAGER PAD:

• The efficacy and safety of rivaroxaban in 6564 patients aged 50 years and older with symptomatic PAD after lower extremity revascularization procedures. Patients were randomly assigned 1:1 to receive Xarelto 2.5 mg twice daily plus aspirin or placebo plus aspirin.

• The primary efficacy endpoint of the study was the time to first occurrence of major thrombotic vascular events: myocardial infarction, ischemic stroke, acute limb ischemia, major amputation, or death from cardiovascular (CV) causes; the primary safety endpoint was the time to first occurrence of major bleeding events according to the Thrombolysis in Myocardial Infarction (TIMI) classification.

• Xarelto plus aspirin significantly reduced the risk of major thrombotic vascular events with an event rate per year of 6.8% vs 8.0% for placebo plus aspirin(hazard ratio 0.85; 95% CI, 0.76-0.96; P =.0085). The incidence of TIMI major bleeding did not differ significantly between Xarelto and placebo.

• COMPASS PAD:

• The efficacy and safety of Xarelto 2.5 mg twice daily vs placebo on a background of aspirin 100 mg once daily in patients with PAD.

• Xarelto plus aspirin significantly reduced the risk of major thrombotic vascular events with an event rate per year of 3.4% vs 4.8% for placebo (hazard ratio 0.71; 95% CI, 0.57-0.87). 

Treatment of Venous Thromboembolism and Reduction in Risk of Recurrent Venous Thromboembolism in Pediatric Patients

• The efficacy and safety of Xarelto was evaluated in the phase 3 EINSTEIN-Jr trial (NCT02234843) in 500 children from birth to 17 years with acute VTE who had received initial parenteral anticoagulant therapy. 

• Patients were randomly assigned 2:1 to receive either a body weight-adjusted dose of Xarelto (tablets or oral suspension) or standard of care (eg, unfractionated heparin, low molecular weight heparin, subcutaneous fondaparinux, and/or oral vitamin K antagonist). 

• There was a similar low risk of symptomatic recurrent VTE with Xarelto vs standard of care (1.2% vs 3.0%, respectively; hazard ratio [HR] 0.40; 95% CI, 0.11-1.41). Symptomatic recurrent VTE or major bleeding events occurred in 1.2% (n=4/335) of the Xarelto arm vs 4.2% (n=7/165) of the comparator arm. Complete resolution of thrombus on repeat imaging without recurrent VTE occurred in 128 of 335 children in the Xarelto group and 43 of 165 children in the comparator group.

Thromboprophylaxis in Pediatric Patients with Congenital Heart Disease after the Fontan Procedure

• The UNIVERSE study compared the efficacy and safety of Xarelto with aspirin for thromboprophylaxis in children 2 to 8 years of age with congenital heart disease who had the Fontan procedure. In Part A of the study, patients received Xarelto for 1 year, while in Part B, patients were randomly assigned to receive Xarelto or aspirin for 1 year.

• Results showed that 8.3% of patients (n=1/12) in Part A experienced a thrombotic event. In Part B of the study, 1.6% of patients (n=1/64) treated with Xarelto experienced a thrombotic event vs 8.8% of patients (n=3/34) treated with aspirin.