New anticoagulant significantly reduces risk of VTE in TKA

A prospective randomized study showed the relative risk of venous thromboembolism in total knee arthroplasty was reduced by 31%.

LAS VEGAS – The latest clinical trial looking at rivaroxaban (Xarelto; Bayer Schering/Ortho-McNeil) showed a relative risk reduction of 31% compared with enoxaparin (Lovenox; Sanofi Aventis) in patients undergoing total knee arthroplasty.

“The oral factor X inhibitor, in the regimen tested, is more effective than the current grade 1 recommended regimen of enoxaparin in North America,” Alexander G. Turpie, MD, said at the American Academy of Orthopaedic Surgeons 76th Annual Meeting.

Rivaroxaban is an orally delivered active factor X inhibitor that has been evaluated for the prevention of thrombosis in major orthopedic surgery in four randomized clinical trials – two for hip replacement and two for knee replacement, Turpie said.

The study presented here, RECORD 4, was a prospective, double-blind, randomized controlled trial looking at 3,148 patients undergoing knee replacement surgery.

The first three randomized controlled trials (RECORD 1, 2 and 3), compared rivaroxaban with the European regimen of enoxaparin 40 mg once a day, and all three trials demonstrated that rivaroxaban resulted in greater reduction in the risk of venous thromboembolism (VTE) compared with enoxaparin.

RECORD 4

: “The oral factor X inhibitor, in the regimen tested, is more effective than the current grade 1 recommended regimen of enoxaparin in North America.”; — Alexander G. Turpie, MD

Patients in the RECORD 4 study were given either 10 mg/day of rivaroxaban orally beginning 6 to 8 hours postoperatively or the North American regimen of 30 mg of enoxaparin subcutaneously twice a day beginning 12 to 24 hours postoperatively. Treatment lasted approximately 2 weeks.

Although patients were recruited worldwide, most were from North America, with almost half of the patients being from the United States.

There was no difference in patient demographics between the two treatment groups. Average age was about 64 years and average weight was about 84 kg.

The primary efficacy point was total VTE, which was a composite of any deep vein thrombosis (DVT), nonfatal pulmonary embolism (PE) and all-cause mortality. The researchers also considered a variety of clinically important secondary outcomes: major VTE, which is proximal DVT, nonfatal PE and VTE-related death, and symptomatic VTE, which is important to orthopedic surgeons, Turpie said.

Because of its impact on orthopedic surgery, bleeding was assessed as the main safety end point, he said. The main bleeding assessment was major bleeding, which was fatal, bleeding into a critical organ, bleeding that required reoperation, and extrasurgical site bleeding with a hemoglobin fall of greater than 2 g/dL or a transfusion of two or more units of blood.

“We emphasized extrasurgical site bleeding, ... but that is not to say we ignore bleeding into the surgical site,” which was assessed in other bleeding, Turpie said. He emphasized that this assessment is different than what is done in other contemporary clinical trials.

Patients were followed for 3 months to monitor for adverse events.

The primary analysis was a noninferiority analysis of the per-protocol population and, if noninferiority was met, a superiority analysis was carried out.

Results

Analysis of the primary efficacy outcome showed that the enoxaparin group had a 10.1% rate of total VTE and the rivaroxaban group, 6.9%.

“That is a [relative] risk reduction of 31%, which is highly statistically significant,” Turpie said.

Looking at major VTE and symptomatic VTE, there are nonsignificant reductions in both.

In the rivaroxaban group, 10 patients had bleeds, whereas four patients had bleeds in the enoxaparin group; however, this difference was not statistically significant, Turpie said. The rate of any bleeding was 10.5% in the rivaroxaban group and 9.4% in the enoxaparin group. Major bleeding was 0.7% for rivaroxaban and 0.3% for enoxaparin. Nonmajor bleeding was also similar, with clinically relevant nonmajor bleeding at 2.6% for rivaroxaban and 2% for enoxaparin.

There were other adverse events, Turpie said, but none of them clinically important. Important cardiovascular events, such as myocardial infarction, stroke and arterial problems, were 0.7% with enoxaparin and 0.5% with rivaroxaban.

: “We now have the potential for an orally active drug to provide effective prophylaxis without the requirement of monitoring.”; — Alexander G. Turpie, MD

From the orthopedic surgeon’s point of view, “There was really no difference of very low rates of wound-related infections and no mortality difference,” Turpie said.

In addition, he said the researchers assessed the hepatic enzyme changes, given the experience with the direct thrombin inhibitor ximelagatran (Exanta), which did not receive FDA approval for any indication because of concerns regarding elevated liver enzyme measurements.

“If anything, there were fewer patients who had abnormalities of hepatic enzymes with test drug rivaroxaban in comparison to enoxaparin,” Turpie said. “Importantly, these elevations were not characteristic of the abnormalities noted with ximelagatran and all disappeared at the end of the study treatment.”

With these results, Turpie said rivaroxaban is a promising drug that could greatly affect VTE and DVT prophylaxis in the future.

“This is the first time we have seen a reduction with a new orally active agent administered without monitoring when compared with the North American enoxaparin regimen, ... a 31% reduction in the risk of all venous thromboembolism and consistent with reductions of both major VTE and symptomatic VTE, and no significant difference in bleeding,” he said.

“The conclusions are that rivaroxaban has superior efficacy with respect to the primary efficacy outcome — low rates of major symptomatic VTE events — with a similar safety profile to enoxaparin. So we now have the potential for an orally active drug to provide effective prophylaxis without the requirement of monitoring.”

For more information:

Alexander G. Turpie, MD, FRCP, FACC, Hamilton Health Sciences-General Hospital, 237 Barton St., East Hamilton, ON L8L 2X2, Canada; 905-528-9946; fax: 905-521-1551; e-mail: turpiea@mcmaster.ca. He has financial relationships with Bayer HealthCare, Johnson & Johnson and Sanofi-Aventis.

Reference:

Turpie AG. Thromboprophylaxis with rivaroxaban versus enoxaparin after total knee replacement: RECORD4. Paper#540. Presented at the American Academy of Orthopaedic Surgeons 76th Annual Meeting. Feb. 25-28, 2009. Las Vegas.