The FDA approved Xarelto (rivaroxaban) for the prevention of venous thromboembolism following hip or knee replacements and for the prevention of stroke in patients with nonvalvular atrial fibrillation.
Janssen Pharmaceuticals’ Xarelto
Xarelto (rivaroxaban) is the first oral factor Xa inhibitor approved for the prevention of venous thromboembolism (VTE), which includes deep vein thrombosis (DVT) and pulmonary embolism (PE), following knee or hip replacement surgery. According to the American Academy of Orthopedic Surgeons, more than 800,000 Americans undergo knee or hip replacement surgery each year, and these procedures are associated with an increased risk for blood clots that form in a deep vein, usually in the leg.1
If all or part of a DVT detaches, it can travel to the lungs and become a PE, where it may impact the flow of oxygenated blood and lead to potentially life-threatening consequences. The American College of Chest Physicians recommends the use of anticoagulants immediately following major orthopedic replacement surgery and extends its use post-discharge, as DVT and PE are the leading causes of rehospitalizations following joint replacement surgery.1
In November 2011, Xarelto also gained FDA approval to reduce the risk of stroke in patients with nonvalvular atrial fibrillation (AF). AF increases the risk of stroke approximately 4 to 5 times across all age groups and is the cause of 15% of all strokes. The American College of Chest Physicians recommends long-term anticoagulation in most patients with AF.2
Mechanism of Action3,4
Xarelto is an oral, highly selective direct factor Xa inhibitor that blocks the active site of factor Xa without the need of a cofactor for activity. Inhibition of factor Xa interrupts both the intrinsic and extrinsic pathways of the blood coagulation cascade, thus inhibiting both thrombin formation and the development of thrombi.
Pivotal data from the RECORD (Regulation of Coagulation in Orthopedic Surgery to Prevent Deep Venous Thrombosis and Pulmonary Embolism) Phase III trials compared the efficacy and safety of Xarelto 10 mg/day with subcutaneous enoxaparin 40 mg/day for prevention of VTE after total hip or knee arthroplasty. RECORD1 and RECORD2 involved hip replacement and RECORD3 and RECORD4 involved knee replacement surgeries. These studies, which enrolled more than 12,000 patients, showed that Xarelto had noninferior and possibly superior efficacy compared with enoxaparin. In RECORD1, 1.1% of patients who received Xarelto had a VTE compared with 3.9% of those who received enoxaparin.
In RECORD2, 2.0% of those treated with Xarelto had VTE compared with 8.4% of those who received enoxaparin. RECORD3 proved noninferiority, whereas RECORD4 demonstrated that Xarelto was significantly more effective in reducing the occurrence of VTE than enoxaparin. In regard to safety, the risk of bleeding was greater in patients receiving Xarelto than enoxaparin.
ROCKET AF (The Rivaboxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation) provided pivotal data to support FDA approval for the stroke prevention in nonvalvular AF indication. The study enrolled 14,264 patients with nonvalvular AF who were at a moderate-to-high risk for stroke. It compared Xarelto 20 mg/day for patients with normal kidney function and Xarelto 15 mg/day for patients with a creatinine clearance (CrCl) less than 50 mL/min to adjusted-dose warfarin.
Xarelto was shown to be noninferior to warfarin; stroke or systemic embolism occurred in 1.7% of those who received Xarelto compared with 2.2% of those who received warfarin. Overall rates of major and clinically relevant nonmajor bleeding were similar between groups.
The dosing of Xarelto for postoperative thromboprophylaxis is 10 mg orally once daily for 12 to 14 days for knee replacement and 35 days for hip replacement. The initial dose should be taken at least 6 to 10 hours after surgery once hemostasis has been established. For prevention of stroke in patients with nonvalvular AF, the dosing is 20 mg orally once daily with the evening meal. If CrCl is less than 50 mL/min, the dose must be reduced to 15 mg orally once daily.
Contraindications, Warnings, And Precautions3,4
Common side effects of Xarelto include bleeding (5%), wound secretion (2.8%), extremity pain (1.7%), muscle spasms (1.2%), pruritis (2.1%) and blister formation (1.4%). Caution should be used when spinal/epidural anesthesia or puncture is being employed, in conditions with increased risk of hemorrhage or with concomitant use of drugs affecting hemostasis, and in pregnant women.
Discontinuing Xarelto in patients with nonvalvular AF increases the risk for thrombotic events; administration of another anticoagulant is recommended if Xarelto must be discontinued. In patients with renal impairment, Xarelto should be avoided in treating thromboprophylaxis or nonvalvular AF stroke prophylaxis if CrCl is less than 30 mL/min or 15 mL/min, respectively. PT
Dr. Agbahiwe is a clinical pharmacist specialist in primary care at the Settegast Health Center in Houston, Texas, and an adjunct faculty member at Texas Southern University College of Pharmacy & Health Sciences. Mr. Okeke is a PharmD candidate at Texas Southern University College of Pharmacy & Health Sciences. Ms. Okonkwo is a PharmD candidate at the University of Houston College of Pharmacy.
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