The study, dubbed the Regulation of Coagulation in Orthopaedic Surgery to Prevent Deep Venous Thrombosis and Pulmonary Embolism 2 (RECORD2), compared oral rivaroxaban 10 mg once daily for 31-39 days (n = 1252) plus placebo injection for 10-14 days with oral rivaroxaban or enoxaparin 40 mg once daily subcutaneously for 31-39 days (n = 1257) with placebo tablet for 10-14 days.
The final analysis included 864 patients in the rivaroxaban group and 869 in the enoxaparin arm. The primary outcome (a composite of deep vein thrombosis, nonfatal pulmonary embolism, and all-cause mortality up to days 30 to 42) occurred in 17 patients (2%) in the rivaroxaban group and in 81 patients (9.3%) in the enoxaparin group, resulting in an absolute risk reduction of 7.3% for the rivaroxaban group.
Overall, patients in the enoxaparin group were more than four times as likely to suffer deep vein thrombosis, nonfatal pulmonary embolism, or die as those in the rivaroxaban group. Bleeding events during treatment were similar for both groups.
Current guidelines recommend enoxaparin for a minimum of 10 days, and up to 35 days, after surgery but such preventive treatment is not used much once the patient is discharged. As a result, <50% of patients receive thromboprophylaxis for at least 28 days, the Lancet study authors point out.
Practice-changing findings
In an accompanying editorial2 John Eikelboom, MBBS, MSc and Jeffrey Weitz, MD, of McMaster University in Hamilton, Ontario, Canada, called rivaroxaban "an obvious choice for simplified thromboprophylaxis after hip or knee arthroplasty."
Dr. Eikelboom told MSKreport.com that the new study will have wide-reaching implications.?"I suspect these results will have an important impact on practice, particularly extended outpatient prophylaxis. The reasons are that rivaroxaban is simple to use because it can be given orally and does not require monitoring, it is more effective than low weight molecular heparin, and it does not increase bleeding."
The trials do not identify any patient groups who should not receive rivaroxaban, Dr. Eikleboom said. "However, they excluded patients with severe liver or kidney disease as well as patients considered to be at high risk of bleeding, [and] the latter groups of patients as well as those taking certain medications (eg, HIV protease inhibitors) should not be treated with rivaroxaban."
Rivaroxaban versus dabigatran
"Rivaroxaban provides a very important new option for extended prophylaxis against VTE after total hip arthroplasty or total knee arthroplasty," he said. However, there is another drug, dabigatran (Pradaxa, Boehringer Ingelheim Pharmaceuticals, Inc) that has recently also been shown to be effective for extended duration prophylaxis. Rivaroxaban has not been directly compared with dabigatran. "Between these two new drugs, it appears that a new standard of care for extended duration thromboprophylaxis has been established."
NEJM studies of >7000 people strengthen the evidence
Rivaroxaban is significantly more effective than enoxaparin for preventing venous thrombosis in patients undergoing major orthopaedic surgery, according to two phase III studies published in the New England Journal of Medicine.3,4
In one study, dubbed RECORD1, 3153 patients were assigned to rivaroxaban 10 mg once daily plus placebo injection, beginning after surgery, or to enoxaparin 40 mg once daily plus placebo tablet, beginning the evening before surgery. Treatments were continued through postoperative day 35.
The primary efficacy outcome was the composite of deep vein thrombosis, nonfatal pulmonary embolism, or death from any cause at 36 days. This occurred in 1.1% of patients in the rivaroxaban group and in 3.7% in the enoxaparin group. Moreover, major VTE occurred in 0.2% and 2%, respectively, the study showed. Rates of major bleeding were 0.3% with rivaroxaban and 0.1% with enoxaparin, but this was not statistically significant.
In the RECORD3 study, researchers used the same dosing schedule as in RECORD1 for 10-14 days after total knee arthroplasty. The study comprised 824 patients assigned to rivaroxaban and 878 assigned to enoxaparin.
The composite efficacy outcome by day 17 occurred in 9.6% of patients in the rivaroxaban group and in 18.9% in the enoxaparin group. Rates of major VTE were 1% and 2.6%, respectively. Rates of major bleeding were 0.6% in the rivaroxaban group and 0.5% in the enoxaparin group, the study showed.
Other hurdles to overcome
In an editorial accompanying the NEJM studies,5 Jens Lohrmann,MD, at the University of Freiburg in Germany, and Dr. Richard C. Becker, MD, at Duke University Medical Center in Durham, North Carolina, point out that even the safest and most effective anticoagulants are still used in <60% of orthopaedic patients despite efficacy and recommendations to the contrary.
"Electronic alerts for anticoagulation do increase the rate of prophylaxis but they are not 100% effective, which suggests that an integrated approach, up to the level of 'order entry' and strict performance metrics, will be required to achieve greater success and optimal patient care."
References
1. Kakkar AK, Brenner B, Dahl OE, et al. Extended duration rivaroxaban versus short-term enoxaparin for the prevention of venous thromboembolism after total hip arthroplasty: a double-blind, randomized, controlled trial. [published online ahead of print June 25, 2008]. Lancet. 2008; doi:10.1016/50140-6736(08)60880-6.
2. Eikelboom JW, Weitz JI. Selective factor Xa inhibition for thromboprophylaxis. [published online ahead of print June 25, 2008]. Lancet. 2008; doi:10.1016/50140-6736(08)60879-X .
3. Eriksson BI, Borros LC, Friedman RJ, et al Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty. NEJM. 2008;358:2765-2775.
4. Lassen MR, Ageno W, Borros LC, et al. Rivaroxaban versus enoxaparin for thrombopropylaxis after total knee arthroplasty. NEJM. 2008;358:2776-2886.
5. Lohrmann J, Becker RC. New anticoagulants?the path from discovery to clinical practice. NEJM. 2008;358:2827-2828.
PubMed: Related Articles