Hemostasis and Thrombosis Issues

Rivaroxaban (Xarelto) Has Arrived
In July 2011, FDA approved a second novel oral anticoagulant drug, rivaroxaban (Xarelto, Janssen Pharmaceuticals Inc). Rivaroxaban is the first oral, rapid acting, highly selective direct inhibitor of factor Xa dosed once daily for the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation (AF) and prevention of deep vein thrombosis in the setting of knee or hip replacement surgery. Inhibition of factor Xa interrupts the intrinsic and extrinsic coagulation pathways, inhibiting both thrombin formation and development of thrombi, but it does not inhibit thrombin (activated factor II), and has no effects on platelets.

For the stroke indication, FDA advisors focused primarily on data from ROCKET AF (NEJM 2010) trial conducted in AF patients at high risk for stroke. The trial met its primary end point of demonstrating noninferiority to warfarin for the composite primary end point of stroke or non-central nervous system embolism (P <.001). Rivaroxaban proved superior to warfarin in an analysis that compared “as-treated” patients (P = .015), but not in the intention-to-treat analysis (P = .117). In a subgroup analysis looking specifically at secondary stroke prevention, rivaroxaban was associated with a 13% lower risk of recurrent stroke or systemic embolism compared with warfarin.

Selected Rivaroxaban Drug Facts

• Rivaroxaban is an oxazolidinone derivative and structurally similar to the antibiotic linezolid, but has no antibiotic activity
• Dosed at 10 mg once daily orally, with or without food
• No routine blood monitoring of international normalized ratio values or other coagulation parameters is required
• Has a comparable rate of any bleeding, including major bleeding, versus enoxaparin Pharmacokinetic Parameters
• Bioavailability: 80% to 100% • Cmax: 2 to 4 hours (10 mg oral). It is well absorbed from the gut and maximum inhibition (both free factor Xa and factor Xa bound in the prothrombinase complex) occurs 4 hours after a dose.
• Metabolism/Elimination: Metabolic degradation (about 2/3 of administered dose) is metabolized by cytochrome P450 (CYP)3A4 , CYP2J2, and CYP-independent mechanisms.
• Elimination: about 1/3 unchanged in as by direct renal excretion • Half-life: 7 to 11 hours for 10-mg tablet Selected Drug Interactions
• Drugs that Inhibit CYP3A4 Enzymes and Drug Transport Systems. Avoid concomitant administration with combined P-glycoprotein (P-gp) and strong CYP3A4 inhibitors, which causes significant increases in rivaroxaban exposure.
• Drug-Disease Interactions with Drugs that Inhibit CYP3A4 Enzymes and Drug Transport Systems. Due to potentially significant increase in rivaroxaban exposure, use only if benefit justifies risk in patients with renal impairment with concomitant use of P-gp and weak or moderate CYP3A4 inhibitors.
• Drugs that Induce CYP3A4 Enzymes and Drug Transport Systems. Avoid P-gp and strong CYP3A4 inducers due to decreases in rivaroxaban exposure. Due to increased bleeding risk, avoid concurrent use with other anticoagulants. Nonsteroidal anti-inflammatory drugs, aspirin, and clopidogrel increase the risk of bleeding when used concomitantly.

Use In Specific Populations

• Geriatric Patients. In clinical trials, patients 65 years of age and older experienced an increase in exposure, so assessment of renal function prior to starting therapy with rivaroxaban is advised.
• Renal Impairment. Observe renally impaired patients closely, and promptly evaluate any signs or symptoms of blood loss in patients with moderate renal impairment (creatinine clearance [CrCl] 30 to <50 mL/min). Avoid use in patients with severe renal impairment (CrCl <30 mL/min).
• Hepatic Impairment. Avoid use in patients with moderate (Child-Pugh, grades B and C) hepatic impairment or with any hepatic disease associated with coagulopathy.
• Pregnancy. Rixaroxaban is Pregnancy Category C.

Apixaban (Eliquis) Coming Soon
A third new, novel, orally-dosed anticoagulant drug, apixaban (Eliquis, Bristol-Myers Squibb/Pfizer), is approved in Europe, but not the United States, for the prevention of venous thromboembolic events in patients who have undergone elective hip or knee replacement surgery. Recently released preliminary details from the ARISTOTLE trial suggest that apixaban was noninferior to warfarin in the AF/stroke setting for prevention of stroke and systemic embolism. The trial enrolled over 18,000 AF patients to either a twice daily dose of apixaban 5 mg twice daily or doseadjusted warfarin. Approval of apixaban in the United States is expected during Fall 2011. When approved, apixaban would compete with dabigatran and rivaroxaban.

Mr. Brown is professor emeritus of clinical pharmacy and a clinical pharmacist at Purdue University College of Pharmacy, Nursing, and Health Sciences, Department of Pharmacy Practice, West Lafayette, Indiana. This column’s information is based on current studies and references, but it may be changed without notice with newer studies or with different patient populations.