San Francisco (December 7, 2008) –– Results from a pre-specified pooled analysis of the RECORD clinical trial program showed that the novel, investigational, oral anticoagulant rivaroxaban was superior to enoxaparin treatment regimens for the prevention of venous thromboembolism (VTE) after total knee or hip replacement surgery. The data also show that rates of major bleeding were low and not statistically different from the comparator.
Pooled results from the four RECORD trials, involving more than 12,500 patients, were presented today at the 50th Annual Meeting of the American Society of Hematology (ASH). RECORD is the largest clinical trial program ever conducted of an oral anticoagulant in the prevention of VTE after such surgeries.
“Swelling in the leg and shortness of breath are symptoms that can herald venous thromboembolism, which, in turn, can result in long-term complications or death,” said Dr. A.G.G. Turpie, Professor of Medicine, McMaster University, Canada, and Principal Investigator for the RECORD program. “As a physician, one of my goals is to reduce patients’ risk of complications, and these data show that rivaroxaban has the ability to reduce the composite of symptomatic VTE and all cause mortality by half when compared to enoxaparin.”
The RECORD studies (REgulation of Coagulation in major Orthopedic surgery reducing the Risk of DVT and PE) evaluated 10 mg of rivaroxaban given once daily in the prevention of VTE following elective total knee replacement surgery (TKR) or total hip replacement surgery (THR). The pooled analysis had a primary composite efficacy endpoint of symptomatic VTE [symptomatic deep vein thrombosis (DVT) and symptomatic non-fatal pulmonary embolism (PE)] and all-cause mortality, which was analyzed in the following time windows:
In each of the three time windows, patients treated with rivaroxaban demonstrated a statistically significant reduction of more than 50% in the composite primary efficacy endpoint compared to patients treated with enoxaparin. Specifically, there was a 51% relative risk reduction (RRR) in those treated with rivaroxaban vs. those treated with enoxaparin (0.8% vs. 1.6%, respectively, p<0.001) in the total study duration pool; a 58% RRR in the total treatment duration pool (0.6% vs. 1.3%, respectively, p<0.001) and a 52% RRR for those treated with rivaroxaban vs. those treated with enoxaparin (0.5% vs. 1.0%, respectively, p<0.001) in the head-to-head treatment pool.
The four pre-specified treatment-emergent bleeding safety endpoints in the pooled analysis were assessed at two time points: the total treatment duration pool and in the head-to-head treatment pool.
Rivaroxaban demonstrated low bleeding rates that were not statistically significantly different in comparison to enoxaparin for three of the four pre-specified safety endpoints (major bleeding, major bleeding including surgical site bleeding, and any bleeding).
· Rates of major bleeding in the total treatment duration pool were 0.4% (n=24) vs. 0.2% (n=13), (p=0.076) and were 0.3% (n=21) vs. 0.2% (n=13), (p=0.175) in the head-to-head treatment pool for rivaroxaban and enoxaparin, respectively.
· Combined rates of surgical site bleeding and major bleeding in total treatment duration pool were 1.8% (n=111) vs. 1.4% (n=85), (p=0.063); rates in the head-to-head pool were 1.7% (n=108) vs. 1.4% (n=84), (p=0.082) for rivaroxaban and enoxaparin, respectively.
· Rates of any bleeding in the total treatment duration pool were 7.0% (n=434) vs. 6.5% (n=401), (p=0.255) and 6.6% (n=409) vs. 6.2% (n=384), (p=0.376) for rivaroxaban and enoxaparin, respectively in the head-to-head treatment pool.
Rates for the composite endpoint of major and clinically relevant non-major bleeding in the pooled analysis were also low but statistically significantly different; 3.2% (n=197) for rivaroxaban vs. 2.5% (n=158) for enoxaparin, (p=0.039) in the total treatment duration pool. However, rates were not statistically significantly different in the head-to-head treatment pool of 12±2 days, which included the majority of reported bleeding cases in these criteria; 2.8% (n=176) for rivaroxaban vs. 2.5% (n=152) for enoxaparin, (p=0.186).
These findings confirm the results of the four individual RECORD studies, which demonstrated the superior efficacy of rivaroxaban for preventing total VTE [composite of DVT, non-fatal PE, all-cause mortality], both in head-to-head comparisons with enoxaparin (RECORD1, 3 and 4) as well as when comparing extended-duration (5 weeks) rivaroxaban with short-duration (2 weeks) enoxaparin in RECORD2. In all four studies, rivaroxaban and enoxaparin had similar safety profiles.
“The combination of the efficacy and the safety profile of rivaroxaban may help change clinical practice to more accurately reflect established anticoagulation guidelines which are in place to protect patient lives,” said Dr. Turpie. “All the results reported from the RECORD program strengthen my belief that direct Factor Xa inhibition with rivaroxaban has the potential to revolutionize the way we prevent the formation of dangerous blood clots.”
Copies of the abstracts may be viewed online at www.hematology.org/meetings/abstracts.cfm
Rivaroxaban is being developed jointly by Johnson & Johnson Pharmaceutical Research & Development, L.L.C. (J&JPRD) and Bayer HealthCare AG.
The extensive clinical trial program supporting rivaroxaban makes it the most studied oral, direct Factor Xa inhibitor in the world today. More than 60,000 patients are expected to be enrolled into the rivaroxaban clinical development program, which will evaluate the product in the prevention and treatment of a broad range of disorders where blood clotting plays a major role. In July 2008, J&JPRD submitted a New Drug Application to the U.S. Food and Drug Administration for the use of rivaroxaban to prevent DVT and PE in patients undergoing hip or knee replacement surgery. If approved by the FDA, Ortho-McNeil, a Division of Ortho-McNeil-Janssen Pharmaceuticals, Inc., will commercialize rivaroxaban in the U.S.
Johnson & Johnson Pharmaceutical Research & Development, L.L.C.
Johnson & Johnson Pharmaceutical Research & Development, L.L.C. (J&JPRD) is a wholly-owned subsidiary of Johnson & Johnson, the world's most broadly based producer of health care products. J&JPRD is headquartered in Raritan, N.J., and has facilities throughout Europe, the United States and Asia. J&JPRD is leveraging drug discovery and drug development in a variety of therapeutic areas, including CNS, Internal Medicine and Oncology, to address unmet medical needs worldwide. More information can be found at http://www.jnjpharmarnd.com.
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