Rivaroxaban: a promising novel anticoagulant

The currently available anticoagulants are hampered by many drawbacks. These include substantial interpatient variability in effects, significant bleeding risks, need for laboratory monitoring for some or all patients, potential for drug interactions, need for patient-specific dosing, lack of oral dosage forms (for nearly all anticoagulants) and many others. Several novel investigational anticoagulants are being studied that will remedy many of these disadvantages.

Rivaroxaban is a new anticoagulant with a novel mechanism of action. This agent is marketed under the name of Xarelto and is available in Europe, but not yet in the United States. Rivaroxaban inhibits the action of Factor Xa, at the start of the common pathway in the coagulation cascade. Its action is specific to Factor Xa and it binds in a dose- dependent fashion without the need for antithrombin. It inhibits free Factor Xa, as well as that bound in the prothrombinase complex and already-formed clot.

Lisa K. Lohr

This agent does prolong common coagulation tests such as the international normalized ratio (INR) and partial thromboplastin time (PTT), and it is thought that the INR is more sensitive to the effects of rivaroxaban. However, due to its consistent anticoagulant effects, lab test monitoring was not done in clinical trials.

Rivaroxaban has good oral absorption (bioavailability 60%-80%) and the maximum concentration is reached two to four hours after administration. The time to the maximum inhibition of Factor Xa is only one to four hours, and the half-life of the inhibition is six to seven hours. Food increases the oral absorption and reduces interpatient variability; in clinical trials, it was administered with food.

It is eliminated by multiple pathways in the body. About one-third is excreted unchanged in the urine, about one-third is excreted unchanged in the feces, and about one-third as metabolites (multiple) in the urine and stool.

The serum half-life ranges from five to nine hours in young people and 11 to 13 hours in the elderly. The area under the curve (AUC) is increased by 45% to 65% in patients with mild to moderate renal dysfunction; therefore, a dose modification will probably be needed.

Patients with a creatine clearance <30 mL/minute were not included in the trials to date. Rivaroxaban does not inhibit or induce the P450 system and drug interactions are not likely.

Trial results

Clinical phase-3 trials with rivaroxaban have been completed and the results published for thromboprophylaxis in patients undergoing total hip and total knee arthroplasties. These trials, named RECORD1, RECORD2, RECORD3 and RECORD4, were multinational, randomized, double blind, controlled trials comparing oral rivaroxaban and subcutaneous enoxaparin. Table 1 shows the results of these four trials. The primary efficacy outcome measure was the proportion of patients with a composite of DVT or pulmonary embolism or any-cause mortality.

A few issues regarding these trials should be pointed out. In the RECORD1, -2 and -3 trials, the comparator group (enoxaparin 40 mg once daily) is not the standard prophylaxis dose recommended for these high-risk groups. Only the RECORD4 trial used the 30-mg twice daily comparator group. In addition, the RECORD2 trial compared a long course of rivaroxaban with a short course of enoxaparin. The longer course is usually recommended for this patient group.

In these trials of thromboprophylaxis in total hip and total knee arthroplasties, rivaroxaban seems to be similar or better than enoxaparin in efficacy, and similar in bleeding complications. Trials are ongoing in the following patient populations: deep vein thrombosis treatment, pulmonary embolism treatment, thromboprophylaxis in atrial fibrillation, acute coronary syndrome, and in hospitalized medically ill patients. Trials specifically in the treatment or prophylaxis of venous thromboembolism in cancer patients have not been done.

Adverse effects

Rivaroxaban is well tolerated. Reported incidences of major bleeding complications are less than 1% in published trials. Adverse effects other than bleeding complications have been rare. The incidence of liver dysfunction is low and not different than that seen with enoxaparin. Rivaroxaban should be safe to use in patients with heparin-induced thrombocytopenia, as it does not react with heparin-induced thrombocytopenia antibodies. The dose being studied in thromboprophylaxis is a 10-mg oral dose taken once daily. The doses being studied in treatment of VTE are 10 mg twice daily and 20 mg once daily.

In summary, rivaroxaban is a very promising new anticoagulant. It is an orally available agent with consistent anticoagulant activity with few adverse effects or drug interactions. Rivaroxaban shows good efficacy in preliminary studies, with low rates of bleeding complications and no need for clinical monitoring. Future studies with other patient populations will further delineate other uses with rivaroxaban.

Lisa K. Lohr, PharmD, BCPS, BCOP, is a Clinical Pharmacist in Oncology and Bone Marrow Transplantation in the Department of Pharmacy Services at the University of Minnesota Medical Center and is a HemOnc Today Editorial Board member.

For more information:

• Abrams PJ. Pharmacotherapy. 2009;29:167-181.
• Erikkson BJ. N Engl J Med. 2008;358:2765-2775.
• Gulseth MP. Am J Health-Syst Pharm. 2008;65:1520-1529.
• Kakkar AK. Lancet. 2008;372:31-39.
• Lassen MR. N Engl J Med. 2008;358:2776-2786.
• Turpie AGG. Blood. 2008;112:Abstract 35.