Phase III clinical trial results released today underscore that rivaroxaban, the oral, once-daily, investigational anticoagulant, was significantly more effective than enoxaparin, the standard of care, in preventing venous thromboembolism (VTE) in patients undergoing total hip or knee replacement surgery. Rivaroxaban-treated patients consistently experienced lower rates of VTE events compared to enoxaparin-treated patients across three large studies as well as demonstrating a similar rate of major bleeding events. Rivaroxaban is being jointly developed by Johnson & Johnson Pharmaceutical Research & Development, L.L.C. and Bayer HealthCare AG.Data from the RECORD1 and RECORD2 studies, evaluating rivaroxaban in total hip replacement surgery, were presented at the 49th Annual Meeting of the American Society of Hematology. Additional data from the head-to-head RECORD3 study, which showed similar statistically significant results for rivaroxaban compared with enoxaparin in total knee replacement surgery, also were presented.
Studies presented include:
- RECORD1 (n=4,541), which demonstrated a 70 percent relative risk reduction
(RRR) (p<0.001) in total VTE when compared with enoxaparin and an 88
percent RRR (p<0.001) in major VTE - RECORD2 (n=2,509), which demonstrated a 79 percent RRR (p<0.001) in
total VTE when compared with enoxaparin, again with an 88 percent RRR
(p<0.001) in major VTE - RECORD3 (n=2,531), which demonstrated a 49 percent RRR (p<0.001) in
total VTE when compared with enoxaparin, and a 62 percent RRR (p=0.016) in
major VTE - Major bleeding rates were similar for both drugs (less than or equal to 0.6
percent) and differences were not statistically significant - No routine blood monitoring was required in the Phase III RECORD program at
the 10mg dose, based on the Phase II data and pharmacokinetic profile
"In RECORD1, 2 and 3 we have three Phase III trials showing unprecedented results in major orthopedic surgery for the prevention of VTE, and this is genuinely exciting," said Dr. A.G.G. Turpie, Principal Investigator in the RECORD program, Professor of Medicine, McMaster University, Canada. "In three different trials across large patient populations, we have seen rivaroxaban outperform the current standard of care, enoxaparin, without compromising on safety. This is strong clinical evidence that we are making a major leap forward in oral anticoagulation in orthopedic surgery."
A key secondary endpoint of the study measuring the reduction of symptomatic VTE, also showed clinically meaningful results in favor of rivaroxaban. For this endpoint, the trials showed an RRR of 45 percent (p=0.222) in RECORD1, an 80 percent RRR (p=0.004) in RECORD2 and a 66 percent RRR (p=0.005) in RECORD3, compared to the standard regimen.
"The symptomatic VTE findings in the RECORD trials are extraordinary," added Dr. Turpie. "Previous trials were successful in identifying trends towards reducing symptomatic VTE, but with RECORD2 and 3 we are seeing clinically relevant reductions in symptomatic VTE for the first time in orthopedic surgery. These results are a major milestone in the evolution of anticoagulation therapy."
Rivaroxaban is a novel, oral, once-daily direct Factor Xa inhibitor in advanced clinical development for a range of patients who could benefit from prevention and/or treatment of blood clots. Rivaroxaban works at a pivotal stage in the coagulation process to directly inhibit the enzyme Factor Xa.
Detailed Study Results
Data presented at the ASH meeting are from RECORD (Regulation of Coagulation in major Orthopedic surgery reducing the Risk of DVT and PE), a global program of four pivotal trials involving more than 12,000 patients comparing oral, once-daily rivaroxaban, with subcutaneous enoxaparin in the prevention of VTE after elective, major orthopedic surgery. Following are summary results from RECORD1, RECORD2 and RECORD3:
RECORD1 (Abstract #6)
The RECORD1 trial compared the safety and efficacy of rivaroxaban with enoxaparin in patients undergoing total hip replacement surgery. The duration of thromboprophylaxis in both treatments was five weeks. The study met its primary endpoint, and demonstrated a 70 percent RRR (p<0.001) in total VTE (composite of deep vein thrombosis, non-fatal pulmonary embolism and all-cause mortality), for patients treated with rivaroxaban compared with those treated with enoxaparin (1.1 percent and 3.7 percent, respectively). In addition, against the secondary endpoint, an 88 percent RRR (p<0.001) in major VTE (composite of proximal deep vein thrombosis, non-fatal pulmonary embolism and VTE-related death) was observed in patients treated with rivaroxaban (0.2 percent and 2.0 percent, respectively). Rivaroxaban also demonstrated a similar rate of major bleeding to enoxaparin (0.3 percent and 0.1 percent, respectively, p=0.178).
RECORD2 (Abstract #307)
The RECORD2 study evaluated the safety and efficacy of rivaroxaban compared with enoxaparin and placebo. The duration of thromboprophylaxis in patients undergoing total hip replacement was 35+/- 4 days (extended prophylaxis) for rivaroxaban or 10-14 days for those receiving enoxaparin, followed by placebo. The primary and secondary endpoints were the same as for RECORD1 with a 79 percent RRR (p<0.001) in total VTE and an 88 percent RRR (p<0.001) in major VTE for patients treated with rivaroxaban compared with those treated with enoxaparin. Rivaroxaban demonstrated a similar rate of major bleeding compared to enoxaparin (0.1 percent and 0.1 percent, respectively, p=0.980), despite the greater treatment duration with rivaroxaban in this study.
RECORD3 (Abstract #308)
The RECORD3 trial compared the safety and efficacy of rivaroxaban with enoxaparin in patients undergoing total knee replacement surgery. Enoxaparin was initiated 12 hours before surgery, and rivaroxaban was initiated 6-8 hours after surgery; both treatments were continued for 10-14 days. Primary and secondary endpoints were the same as for RECORD1 and there was a 49 percent RRR (p<0.001) in total VTE and a 62 percent RRR (p=0.016) in major VTE for patients treated with rivaroxaban compared with those treated with enoxaparin. Rivaroxaban demonstrated similar rates of major bleeding to enoxaparin (0.6 percent and 0.5 percent, respectively, p=0.774).
Copies of the abstracts may be viewed online at the ASH website: www.hematology.org/meetings/abstracts.cfm
Unmet Needs in Venous Thromboembolism (VTE)
VTE, a disease process that begins with a blood clot in a vein, includes both deep vein thrombosis (DVT) and pulmonary embolism (PE). Patients undergoing major orthopedic surgery are at risk for VTE because, during the surgery the large veins of the leg that carry blood back to the heart can be damaged, significantly increasing the risk of coagulation and thrombosis.
Each year approximately 700,000 people elect to have hip and knee replacement surgeries in the U.S. and a blood clot is the most common cause of re-hospitalization for this patient group. In fact, VTE is considered the most frequent preventable serious and potentially fatal complication following major orthopedic surgery. But the threat stretches beyond orthopedic surgeries. Blood clots are one of the leading causes of global mortality and a concern for many patient populations, including those with atrial fibrillation at risk for stroke; those at risk for acute myocardial infarction (heart attack); those undergoing major orthopedic surgery; and acutely medically ill patients.
About Rivaroxaban
To date, rivaroxaban is the most studied oral, direct Factor Xa inhibitor in clinical development. More than 20,000 patients have been evaluated in the completed Phase II programs and enrolled thus far in the Phase III programs. Almost 50,000 patients are expected to be evaluated in the total clinical development program.
Bayer HealthCare submitted a regulatory filing to the European Agency for the Evaluation of Medicinal Products (EMEA) at the end of October 2007 for approval to market rivaroxaban in the EU for the prevention of VTE in patients undergoing major orthopedic surgery of the lower limbs. Upon regulatory approval, rivaroxaban will be commercialized in Europe by Bayer Schering Pharma. A filing for rivaroxaban for a similar indication in the U.S. is planned in 2008, where upon approval, it will be will commercialized by Scios Inc. and Ortho-McNeil, Inc., both of which are wholly-owned subsidiaries of Johnson & Johnson.
Johnson & Johnson Pharmaceutical Research and Development
Johnson & Johnson Pharmaceutical Research & Development, L.L.C. (J&JPRD), is part of Johnson & Johnson, the world's most broadly based producer of health care products. J&JPRD is headquartered in Raritan, NJ, and has facilities throughout Europe and the United States. J&JPRD is leveraging drug discovery and drug development in a variety of therapeutic areas to address unmet medical needs worldwide.
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