Hamilton, ON - Three trials of the new oral anticoagulant rivaroxaban, showing impressive results in the prevention of venous thromboembolism (VTE) in patients undergoing orthopedic surgery, were published last week. A pooled analysis from RECORD1, 2, and 3 has also shown superiority of rivaroxaban over enoxaparin in preventing VTE without increasing bleeding.

The RECORD1 and 3 trials are published in the June 26, 2008, issue of the New England Journal of Medicine [1,2], while the RECORD2 trial is published online in the Lancet on June 25, 2008 [3]. All three trials have been presented previously (and reported by heartwire) at various medical meetings. A fourth similar trial (RECORD4) was presented earlier this month at the 2008 Congress of the European Federation of National Associations of Orthopaedics and Traumatology.

Rivaroxaban is one of several potential new oral anticoagulants in development that are set to become the long-awaited replacements for warfarin. First indications will be in preventing VTE after surgery, but these agents are also being developed as replacements for warfarin for the prevention of stroke in atrial-fibrillation (AF) patients and for the treatment of acute coronary syndromes (ACS).

Both the current New England Journal of Medicine and Lancet papers are accompanied by editorials enthusing over the benefits of the new oral agents [4,5]. In the Lancet editorial, Drs John W Eikelboom and Jeffrey I Weitz (McMaster University, Hamilton, ON) note that for over 60 years, vitamin-K antagonists such as warfarin have been the only available oral anticoagulants, and although effective, these drugs are challenging to use, with unpredictable anticoagulant responses necessitating monitoring and frequent dose adjustments, which is inconvenient for patients and costly for healthcare systems.

In contrast, they point out that rivaroxaban is orally active and produces such a predictable anticoagulant response that no monitoring is required. They report that the four phase 3 RECORD trials together compared rivaroxaban with enoxaparin (Lovenox, Sanofi-Aventis) for prevention of venous thromboembolism after hip or knee arthroplasty in more than 12 500 patients. Eikelboom and Weitz summarize the results of the four trials in the table.

They point that the RECORD1, 3, and 4 trials, which all compared similar durations of enoxaparin and rivaroxaban, suggest that the new oral agent is more effective than enoxaparin (given once or twice daily) and that this benefit occurred without an increase in bleeding events. "With superior efficacy, no compromise in safety, and a convenient once-daily regimen, rivaroxaban seems an obvious choice for simplified thromboprophylaxis after hip or knee arthroplasty," they write.

Eikelboom and Weitz say that the RECORD2 results add to the evidence that an extended duration of thromboprophylaxis after total-hip arthroplasty is more effective than short-term therapy. Noting that current guidelines already recommend extended thromboprophylaxis after total-hip arthroplasty, they report that such treatment is underused after hospital discharge because low-molecular-weight heparin and fondaparinux (Arixtra, GlaxoSmithKline) must be given by subcutaneous injection, whereas vitamin-K antagonists need monitoring. "With fixed oral dosing and no monitoring, rivaroxaban will streamline out-of-hospital thromboprophylaxis," they add.

The editorialists also note that is no evidence of liver toxicity (which led to the withdrawal of the oral thrombin inhibitor ximelagatran) with rivaroxaban as yet, but data on exposure in more patients and for longer durations than are currently available are needed to confirm the drug's safety. In RECORD2, the small excess in the number of cardiovascular events after stopping rivaroxaban treatment (five on drug, none on control) raises concerns about rebound activation of coagulation, and further data are needed to exclude this possibility, they comment.

Eikelboom and Weitz point out that another new anticoagulant, dabigatran etexilate (Pradaxa/ Pradax, Boehringer Ingelheim), which has recently been approved in Europe and Canada, has been shown to be noninferior to an equal duration of subcutaneous enoxaparin for prevention of venous thromboembolism after total-hip arthroplasty, but the efficacy and safety of rivaroxaban and dabigatran etexilate have yet to be compared directly. They conclude: "The promising results with rivaroxaban and dabigatran etexilate for prevention of venous thromboembolism bring a replacement for warfarin one step closer."

Rivaroxaban is awaiting approval in Europe, Canada, and China for the prevention of VTE in patients undergoing major orthopedic surgery of the lower limbs. An application for a similar indication is expected to be filed in the US later this year. The drug will be marketed in the US by Scios and Ortho-McNeil, both subsidiaries of Johnson & Johnson. Bayer has rights to the product outside the US. The drug is also in phase 3 trials for the prevention of stroke in AF patients and in phase 2 trials for the treatment of ACS.