Nice, France (May 30, 2008) -- Results from a pivotal Phase III clinical trial presented today demonstrate that rivaroxaban, an oral, once-daily, investigational anticoagulant medication, was superior in preventing venous blood clots in patients who underwent total knee replacement (TKR) surgery. The head-to-head study compared rivaroxaban with the U.S.-approved dosing regimen for enoxaparin, the current standard of care.
Data from the RECORD4 clinical trial were presented at the annual meeting of the European Federation of National Associations of Orthopaedics & Traumatology (EFORT). Rivaroxaban is being jointly developed by Johnson & Johnson Pharmaceutical Research & Development, L.L.C. and Bayer HealthCare AG.
The RECORD4 data show that rivaroxaban (10mg once-daily) provided TKR surgery patients a statistically significant 31% relative risk reduction (RRR) in total venous thromboembolism (VTE) events - defined in the study as the composite of all deep vein thrombosis, non-fatal pulmonary embolism and all-cause mortality - compared to enoxaparin (30mg twice-daily) (6.9% and 10.1%, respectively, p =0.012). Rates of major bleeding, the main safety endpoint, were low in both treatment groups, yet numerically greater in rivaroxaban-treated patients. This difference was not statistically significant from the rate of major bleeding in enoxaparin-treated patients (0.7% and 0.3% respectively; p=0.110). RECORD4 is the third of three, direct, head-to-head comparisons within the RECORD program to demonstrate the superior efficacy of rivaroxaban over enoxaparin with a similar adverse event profile.
"The superior efficacy and similar adverse event profile of rivaroxaban demonstrated in RECORD4 are in line with the outstanding results of the earlier RECORD studies," said Dr. A.G.G. Turpie, Professor of Medicine, McMaster University, Canada and Principal Investigator for the RECORD program. "The success of this trial strengthens my belief that direct Factor Xa inhibition with rivaroxaban has the potential to revolutionize the way we prevent the formation of dangerous blood clots."
RECORD4 is part of the RECORD program (REgulation of Coagulation in major Orthopedic surgery reducing the Risk of DVT and PE), which involved more than 12,500 total hip or knee replacement surgery patients, and is the first RECORD trial to evaluate rivaroxaban against enoxaparin 30mg twice-daily, which is the Food and Drug Administration (FDA)-approved dosing regimen for enoxaparin in knee replacement surgery. The RECORD1, 2 and 3 studies compared rivaroxaban against enoxaparin dosed once-daily at 40mg. The full RECORD data set will be used to support the new drug application for rivaroxaban to the FDA, which is planned for submission in the third quarter 2008.
RECORD4 Study Details
RECORD4 compared rivaroxaban to enoxaparin for the prevention of VTE following TKR surgery in 3,148 patients. Rivaroxaban (10mg once-daily) was orally administered 6-8 hours post surgery, compared to enoxaparin (30mg twice-daily), which was initiated by subcutaneous injection 12-24 hours post surgery. The study achieved its primary endpoint, demonstrating a 31% RRR in total VTE for patients treated with rivaroxaban, compared to those treated with enoxaparin (6.9% and 10.1%, respectively; p = 0.012). The rate of major bleeding, the main safety endpoint, was numerically greater in rivaroxaban-treated patients, yet rates were low in both treatment groups (0.7% in rivaroxaban-treated patients and 0.3% in enoxaparin-treated patients). This difference between treatment groups was not statistically significant (p=0.110). Major VTE (composite of proximal deep vein thrombosis, non-fatal pulmonary embolism and VTE-related death) and symptomatic VTE, secondary efficacy endpoints, occurred less frequently with rivaroxaban, but the differences did not reach statistical significance.
Unmet Needs in Venous Thromboembolism (VTE)
Annually in the U.S., more than 900,000 people suffer from VTE events, and 300,000 people die from VTE. VTE includes deep vein thrombosis (DVT), a blood clot in a deep vein (usually in the leg), and pulmonary embolism (PE), a blood clot in the lungs, both of which are serious, life-threatening - but often preventable - conditions. These clots often break apart and travel through the bloodstream, blocking blood flow to vital organs.
Patients undergoing major orthopedic surgery are at high risk for VTE because during hip or knee replacement procedures, the large veins of the leg that carry blood back to the heart are damaged, significantly increasing the risk of VTE. In fact, venous blood clots occur in 40-60% of patients undergoing major orthopedic surgery who do not receive preventative care. Each year, approximately 700,000 Americans elect to have hip and knee replacement surgeries, and a blood clot is the most common cause of re-hospitalization for this patient group.
About the RECORD Program
RECORD is a global program of clinical trials that involved more than 12,500 patients and compared rivaroxaban to enoxaparin for the prevention of VTE in patients undergoing either total knee or hip replacement surgery.
- In RECORD1, rivaroxaban demonstrated a 70% RRR in total VTE in patients undergoing total hip replacement (THR) surgery compared to enoxaparin, with a similar safety profile. The duration of thromboprophylaxis in both treatments was five weeks.
- In RECORD2, extended-duration rivaroxaban (35+/-4 days) demonstrated a 79% RRR in total VTE and a similar rate of major bleeding in patients undergoing THR surgery compared to patients dosed with short-duration enoxaparin (10 days) followed by placebo.
- In RECORD3, rivaroxaban demonstrated a 49% RRR in total VTE in patients undergoing TKR surgery compared to enoxaparin, with a similar safety profile. Enoxaparin was initiated 12 hours before surgery, and rivaroxaban was initiated 6 hours after surgery. Both treatments were continued for 10 days.
- In RECORD4, 10mg once-daily rivaroxaban was compared to the U.S.-approved dosing regimen for enoxaparin in knee replacement surgery, 30mg twice-daily. Rivaroxaban demonstrated a 31% RRR in total VTE in patients undergoing TKR surgery compared to enoxaparin, with a similar safety profile. Rivaroxaban was initiated 6 hours after surgery, while enoxaparin was initiated 12-24 hours after surgery. Both treatments were continued for 10 days.
Rivaroxaban is being jointly developed by Johnson & Johnson Pharmaceutical Research & Development, L.L.C and Bayer HealthCare. The extensive clinical trial program for rivaroxaban makes it the most studied, oral, direct Factor Xa inhibitor in the world today. Almost 50,000 patients are expected to be evaluated in the total clinical development program.
Bayer HealthCare, which holds marketing rights for the compound in countries outside the U.S., has 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. To date, the drug has been filed in more than 10 countries, including Canada and China, and is expected to be filed for approval of a similar indication in the U.S. in the third quarter of 2008. If approved by the FDA, Scios Inc. and Ortho-McNeil, Inc., both of which are wholly-owned subsidiaries of Johnson & Johnson, will market the drug in the U.S.
Johnson & Johnson Pharmaceutical Research & Development, L.L.C.
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