Nice, France - The new oral anticoagulant rivaroxaban (Johnson & Johnson/Bayer) showed superior efficacy compared with the US-approved dosing regimen of enoxaparin in preventing venous thromboembolism (VTE) in patients who had undergone total-knee-replacement surgery in the RECORD4 trial [1].

Dr Alexander Turpie

Rivaroxaban is one of several potential new oral anticoagulants in development. 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 patients and for the treatment of acute coronary syndromes.

The RECORD4 trial was presented on June 1, 2008, at the annual meeting of the European Federation of National Associations of Orthopaedics & Traumatology (EFORT), by Dr Alexander Turpie (McMaster University, Hamilton, ON). It involved 3148 patients who were assigned to rivaroxaban (10 mg once daily orally) starting six to eight hours postsurgery or to enoxaparin (30 mg twice daily by subcutaneous injection), 12 to 24 hours postsurgery. Both treatments were continued for 10 to 14 days. Patients were followed for 40 days, after which time venograms of all extremities were performed.

The primary end point—total VTE events (defined as the composite of all deep vein thrombosis, nonfatal pulmonary embolism, and all-cause mortality)—was significantly reduced in the rivaroxaban group.

Secondary efficacy end points—major VTE (composite of proximal deep vein thrombosis, nonfatal pulmonary embolism, and VTE-related death) and symptomatic VTE—also occurred numerically less frequently with rivaroxaban, but the differences did not reach statistical significance.

The rate of major bleeding, the main safety end point, was numerically greater in rivaroxaban-treated patients, but this was not statistically significant.

Rivaroxaban showed a similar safety profile to enoxaparin, and there was no sign of any liver toxicity, which blighted AstraZeneca's similar drug, ximelagatran (Exanta).

The RECORD program has evaluated rivaroxaban vs enoxaparin in more than 12 500 total-hip- or knee-replacement-surgery patients in four trials. RECORD4 is the only trial in this series to evaluate rivaroxaban against enoxaparin 30 mg twice-daily (the FDA-approved dosing regimen in knee-replacement surgery). The RECORD1, 2, and 3 studies, which compared rivaroxaban against enoxaparin dosed once-daily at 40 mg, also suggested benefit for the new oral drug.

A RECORD4 steering committee member, orthopedic surgeon Dr Louis Kwong (Harbor-UCLA Medical Center, Torrance, CA), commented to heartwire: "This trial was a much tougher test for rivaroxaban, as it was going against a 50% higher dose of enoxaparin than that included in the previous RECORD studies. But it still showed superiority."

"I will definitely use this drug when it becomes available, as it has superior efficacy to what we have at present, but its greatest advantage is its simple oral administration, which will do away with the need for injections, and no monitoring is required. There are plus points all the way round," Kwong added.

Johnson & Johnson notes that more than 900 000 people suffer from VTE events and 300 000 people die from VTE each year in the US. Patients undergoing major orthopedic surgery are at particularly high risk, with VTE occurring in 40% to 60% of such patients who do not receive preventive care.

Bayer, which has rights to rivaroxaban outside the US, submitted an approval application for the product in the European Union last October for the prevention of VTE in patients undergoing major orthopedic surgery of the lower limbs. To date, applications for drug have been filed in more than 10 countries, including Canada and China, and are expected to be filed for approval of a similar indication in the US in the third quarter of 2008. If approved by the FDA, rivaroxaban will be marketed by Scios and Ortho-McNeil, both subsidiaries of Johnson & Johnson. 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.