AAOS 2009: Rivaroxaban Impressive in Reducing Risk for VTE After Total Knee Replacement

March 2, 2009 (Las Vegas, Nevada) - The oral anticoagulant rivaroxaban was significantly better at reducing the incidence of venous thromboembolism (VTE) after total knee-replacement surgery than the US Food and Drug Administration (FDA)-approved dosing regimen of enoxaparin, according to research presented from the RECORD4 trial here at the American Academy of Orthopaedic Surgeons (AAOS) 2009 Annual Meeting.

"The trial demonstrates that rivaroxaban at 10 mg daily can greatly reduce the risk of VTE, compared with enoxaparin at 30 mg twice daily, with a low rate of complications," said lead researcher Alexander Turpie, MD, professor of medicine at McMaster University, in Hamilton, Ontario.

However, at least some orthopaedic surgeons at the meeting questioned whether the new medication was an appropriate solution after knee-replacement surgery, because of its greater risk for bleeding.

Data from the RECORD4 trial were first presented in June 2008 at the annual meeting of the European Federation of National Associations of Orthopaedics and Traumatology, as reported on Medscape Orthopaedics at the time.

The RECORD trials have compared rivaroxaban and enoxaparin in more than 12,500 total hip- and knee-replacement surgery patients. The RECORD4 trial is the first to test the new oral drug against enoxaparin at 30 mg twice daily - the FDA-approved dosing regimen for knee-replacement surgery. Previous RECORD trials have compared the new anticoagulant against the European standard of enoxaparin dosed once daily at 40 mg.

In the multicenter trial, 3148 patients were randomized to receive either oral rivaroxaban at 10 mg once daily 6 to 8 hours after surgery, or 30 mg of enoxaparin administered subcutaneously twice daily 12 to 24 hours after total knee replacement. Treatments were maintained for 10 to 14 days, and patients were followed for 40 days, after which they underwent a mandatory bilateral venography. The trial took place at 131 sites worldwide. No differences in demographics were noted between the 2 groups. Most patients were white with an average body mass index of 30 kg/m2 or above.

Total VTE Events Significantly Reduced With Rivaroxaban.

Results indicated that total VTE events - defined as all deep vein thrombosis, nonfatal pulmonary embolisms, and all-cause mortality - were significantly lower in the rivaroxaban group than in the enoxaparin group. The rate of total VTE events was 6.9% in the rivaroxaban group and 10.1% in the enoxaparin group, providing a relative risk reduction of 31.4% for those on the oral anticoagulant, Dr. Turpie said.

The trial's secondary end points - major VTE (a composite of proximal deep vein thrombosis, nonfatal pulmonary embolism, and VTE-related death) and symptomatic VTE - also occurred less frequently in the rivaroxaban group, although this trend did not reach statistical significance.

There were also more bleeding events in the rivaroxaban group than the enoxaparin group, although this did not reach statistical significance. The rate of major bleeding in the rivaroxaban group was 0.7%, compared with 0.3% in the enoxaparin group, and the rate of all bleeding events was 10.5% and 9.4%, respectively.

Bleeding a Prime Concern

"Bleeding is a prime concern for orthopaedic surgeons, so we carefully assessed major bleeding, including bleeding events that were fatal, critical, or that required reoperation. We also assessed extra-surgical site bleeding, but found no significant differences between the 2 groups," Dr. Turpie said. There were also no significant differences in elevation of liver enzymes, and all elevations seen during the study dropped at the end of treatment.

"This is a drug that has the potential to provide effective prophylaxis of VTE after knee -replacement surgery," Dr. Turpie concluded.

Yet some orthopaedic surgeons at the AAOS meeting remain unconvinced. "Preventing VTE is an issue that's important to surgeons, hospitals, and patients. But the present study did not clearly address issues such as wound-healing complications," said Keith Berend, MD, who moderated the session at which the study was presented. Dr. Berend is clinical assistant professor of orthopaedics at Ohio State University, in Columbus. "The bottom line is that when you give patients a drug that means they don't clot, they also bleed. Although rivaroxaban is exciting because it's an oral drug, I don't think we have all the answers yet about it," Dr. Berend said.

Dr. Turpie has disclosed paid presentations and consultant fees from Bayer Healthcare, Johnson & Johnson. Dr. Berend has disclosed no relevant financial relationships.

American Academy of Orthopaedic Surgeons (AAOS) 2009 Annual Meeting: Abstract 540. Presented February 27, 2009.