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Rivaroxaban for Thromboprophylaxis After Joint Replacement

In two large, randomized studies, rivaroxaban was superior to enoxaparin in preventing venous thrombosis.

During the past few years, low-molecular-weight heparins and fondaparinux (Arixtra) have supplanted unfractionated heparin and warfarin as the favored options for preventing venous thromboembolism (VTE) after joint replacement. These anticoagulants are given subcutaneously once or twice daily for as long as 1 month after surgery. In Europe, treatment is started 1 day before surgery, whereas, in North America, it is generally begun the day after surgery. Although these prophylactic regimens have greatly lowered the incidence of VTE, they are associated with a small but definite risk for bleeding, and they require that either the patient or a caregiver perform injections. Therefore, efforts have been under way to develop oral anticoagulants that are as safe and effective as the subcutaneous agents.

One such oral agent, rivaroxaban — a small-molecule inhibitor of activated clotting-factor X — was shown in dose-finding studies to be both safe and effective in preventing VTE in patients who underwent joint-replacement surgery (Clin Pharmacokinet 2008; 47:203). Now, two multinational, industry-supported, randomized, double-blind phase III trials of rivaroxaban have been completed. One study involved more than 4500 patients who were undergoing hip arthroplasty; in the other, researchers enrolled 2500 patients who were undergoing total-knee arthroplasty. In both studies, patients received either daily rivaroxaban (10 mg orally beginning 6–8 hours after surgery) or enoxaparin (40 mg injected 12 hours before surgery, 6–8 hours after surgery, and then once daily). In the hip study, bilateral venography was performed the day after the last dose of either study drug (generally day 35). In the knee study, bilateral venography was performed between day 11 and day 15 after surgery, after which the study drug was discontinued; clinical observation continued for 30 to 35 days after the last dose.

In the hip study, major VTE — defined as a composite endpoint of proximal deep venous thrombosis, nonfatal pulmonary embolism, and death from VTE — occurred in fewer patients who received rivaroxaban than in patients who received enoxaparin (0.2% vs. 2.0%; P<0.001). In the knee study, major VTE also occurred in fewer patients who received rivaroxaban (1.0% vs. 2.6%; P=0.01); distal-vein thrombosis was also less common in that group (8.5% vs. 15.9%; P<0.001). In both studies, major bleeding and elevations in transaminase values occurred in small numbers of patients, and the between-group differences in incidence were insignificant.

Comment: These two studies demonstrate the safety and efficacy of rivaroxaban for thromboprophylaxis in patients who are undergoing hip or knee arthroplasty. Although both trials showed that rivaroxaban was more protective than was enoxaparin, the dose of enoxaparin used was only 40 mg daily, whereas clinical practice in North America is to give 30 mg twice daily. Nevertheless, the low rates of thromboembolism in patients who received rivaroxaban testify to its effectiveness. In addition to the benefit of oral administration, rivaroxaban likely will be less expensive than the injectable low-molecular-weight heparins. Although FDA approval could happen soon, proof of safety and effectiveness will rest on postmarketing surveillance of large numbers of patients considered to be candidates for this drug.

— David Green, MD, PhD

Published in Journal Watch Oncology and Hematology June 25, 2008

Citation(s):

Eriksson BI et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty. N Engl J Med 2008 Jun 26; 358:2765. (http://dx.doi.org/10.1056/NEJMoa0800374)

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Lassen MR et al. Rivaroxaban for thromboprophylaxis after total knee arthroplasty. N Engl J Med 2008 Jun 26; 358:2776. (http://dx.doi.org/10.1056/NEJMoa076016)

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• Medline abstract (Free)