Once-daily oral drug shows efficacy over enoxaparin in preventing VTE in TKA patients

Patients treated with rivaroxaban showed a 62% risk reduction for major venous thromboembolism vs. to those receiving enoxaparin.

GENEVA — Results of a phase 3 clinical trial show that once-daily treatment with rivaroxaban provides significantly better protection against venous thromboembolism compared to enoxaparin in patients who undergo total knee arthroplasty.

Rivaroxaban is an oral direct Factor Xa inhibitor in phase 3 clinical development for preventing and treating thrombosis in acute and chronic settings. The drug is being jointly developed by Johnson & Johnson Pharmaceutical Research & Development LLC and Bayer HealthCare AG. Pending regulatory approval, it is expected to receive the trade name Xarelto, according to a press release from the two companies.

In the current study, called RECORD3, investigators found that patients treated with rivaroxaban showed a 49% relative risk reduction in the composite primary endpoint of deep vein thrombosis (DVT), non-fatal pulmonary embolism (PE) and all-cause mortality compared to patients treated with enoxaparin (P<.001).

In addition, patients treated with the drug showed a 62% risk reduction (P=.01) for developing major venous thromboembolism (VTE), which represents the study's secondary endpoint and is a composite of proximal DVT, non-fatal PE and VTE-related death, according to the release.

Rivaroxaban-treated patients also had a 0.6% rate of major bleeding, similar to the 0.5% rate seen for patients treated with enoxaparin, the release noted.

The RECORD3 study is a phase 3, double-blind trial involving 2,531 elective total knee arthroplasty (TKA) patients. The study evaluated the safety and efficacy of 10 mg oral, once-daily rivaroxaban administered 6 to 8 hours after surgery vs. 40 mg subcutaneous, once-daily enoxaparin started the evening before surgery. Both treatment regimens were continued for 10 to 14 days postop.

The primary efficacy endpoint of the study was the composite of DVT, as diagnosed by mandatory venography, non-fatal PE and all-cause mortality. The primary safety endpoint was major bleeding.

Lead investigator Michael R. Lassen, MD, of Hoersholm Hospital, University of Copenhagen, Denmark, presented the results of the study at the 21st Congress of the International Society on Thrombosis and Haemostasis.

Investigators found that DVT, non-fatal PE and death occurred in 79 of 824 (9.6%) patients treated with rivaroxaban vs. 166 of 878 (18.9%) patients treated with enoxaparin, resulting in a 49% relative risk reduction of 49% (P<.001), according to the release.

Rivaroxaban-treated patients also had significantly lower rates of major VTE and symptomatic VTE.

Major VTE occurred in 1% of rivaroxaban-treated patients vs. 2.6% of enoxaparin-treated patients, for a 62% relative risk reduction. Symptomatic VTE occurred in 1% of rivaroxaban-treated patients vs. 2.7% of enoxaparin-treated patients, for a 64% relative risk reduction, according to the release.

Major bleeding occurred in 0.6% of rivaroxaban- and 0.5% of enoxaparin-treated patients. Any bleeding occurred in 4.9% of rivaroxaban- and 4.8% of enoxaparin-treated patients, according to the release.

Upon regulatory approval, rivaroxaban will be commercialized in the United States by Scios Inc. and Ortho-McNeil Inc. Bayer Schering Pharma will market the drug throughout the rest of the world.

Bayer and Johnson & Johnson plan to submit regulatory filings for the prevention of VTE in orthopedic surgery in late 2007 in Europe and in 2008 in the United States, the release said.

Phase 2 studies reported

Also recently, another group of investigators found promising results with the oral Factor Xa inhibitor rivaroxaban in three phase 2 trials. Ola E. Dahl, MD, and colleagues studied more than 1,000 patients who received either oral rivaroxaban (2.5 mg to 30 mg) or enoxaparin for 5 to 9 days following total hip or total knee arthroplasty. They reported their results at the 8th European Federation of National this May in Florence.

In those studies the investigators found comparable safety and efficacy between enoxaparin and 5-mg to 20-mg daily doses of rivaroxaban. Moreover, they discovered no link between patients' weight, gender or age and the dose/response between the treatment and clinically relevant bleeding or DVT, PE or death, according to their abstract.

"Dose adjustment for age, gender and body weight will not be necessary with rivaroxaban, excluding the extremes (eg, mega-fat and very thin)," Dahl told Orthopaedics Today International.

To determine the efficacy of rivaroxaban, the investigators studied the rates of DVT, PE or death in 1,380 patients. To assess for safety, they noted any cases of clinically relevant bleeding in 1,854 patients who took the medication.

"Overall, logistic regression showed a positive dose/response relationship with rivaroxaban for clinically relevant bleeding (P<.001), and a flat relationship for the primary efficacy endpoint (P=.115)," the investigators wrote.

Age may impact VTE risk

They also found that age increased the risk of VTE. While DVT, PE or all-cause mortality occurred in 20.2% to 26.6% of patients older than 70 years, it was only noted in 9.4% to 17.3% of patients younger than 60 years. Similarly, 5.7% to 15.4% of patients over 70 had clinically relevant bleeding compared to 1.4% to 12% of those younger than 60 years.

After adjusting for age, the investigators found higher rates of DVT, PE and mortality in women, but found less frequent rates of clinical bleeding.

They also discovered no significant correlation between weight and safety and efficacy after adjusting for gender, age and study, and reported that weight did not impact.

While Dahl said that he did not know why weight did not change the dose/response relationship, he and his colleagues saw similar findings with other modern anticoagulants. "I have a simple speculation that blood volume in adult humans is roughly independent of weight," he said.

For more information:
Please see follow-up article in September/October 2008 issue of Orthopaedics Today International; www.orthosupersite.com/view.asp?rid=31356.
Dahl OE, Eriksson BI, Homering M, et al. The effect of patient age, gender and weight on the efficacy and safety of Rivaroxaban (BAY 59-7939) for the prevention of venous thromboembolism after major orthopaedic surgery. #F385. Presented at the 8th European Federation of National Associations of Orthopaedics and Traumatology Congress. May 11-15, 2007. Florence.
Lassen MR, Turpie AG, Rosencher N, et al. Late breaking clinical trial: Rivaroxaban: An oral, direct factor Xa Inhibitor for the prevention of venous thromboembolism in total knee replacement surgery - results of the RECORD3 study. O-S-006B. Presented at the 21st Congress of the International Society on Thrombosis and Haemostasis. July 6-12, 2007. Geneva.