New England Journal of Medicine Publishes Results from Two of the Landmark Phase III RECORD Studies with Rivaroxaban

Update: Xarelto (rivaroxaban) Now FDA Approved - July 1, 2011

Head-to-Head trials involving over 7000 patients after Major Orthopedic Surgery / Rivaroxaban superior to Enoxaparin in Preventing Venous Blood Clots / Bleeding rates were low and comparable between the treatment arms


BERLIN, June 26, 2008 – Data from two Phase III clinical trials published today in the New England Journal of Medicine (NEJM), demonstrated that the investigational anticoagulant rivaroxaban (Xarelto®), taken as one tablet daily, is significantly more effective than enoxaparin, a current standard of care, in preventing venous blood clots in total hip and knee replacement surgery patients. Bleeding rates in both studies were low and comparable between the two treatment arms.

NEJM has also published an accompanying editorial by Dr. Jens Lohrmann and Dr. Richard C. Becker entitled, “New Anticoagulants — The Path from Discovery to Clinical Practice“ which provides an additional independent perspective on these data and how they may impact thrombosis management.

Venous blood clots, also known as venous thromboembolism or VTE, are potentially deadly complications of major orthopedic surgery. Rivaroxaban is being jointly developed by Bayer HealthCare AG and Johnson & Johnson Pharmaceutical Research & Development, L.L.C..

“Today's publications on rivaroxaban have the potential to change clinical practice in this field,” said Bengt Eriksson, M.D., Ph.D., Department of Orthopaedics, at the Sahlgrenska University Hospital, Sweden, Principal Investigator of the RECORD1 clinical trial. “The results demonstrate that we now seem to have an effective and safe oral anticoagulant for convenient prophylaxis of venous thromboembolism. This is of great importance since patients undergoing major surgery of the hip and knee are at high risk of developing such potentially life threatening complications and the risk of VTE extends beyond hospitalisation."

The first study, RECORD1 (REgulation of Coagulation in major Orthopedic surgery reducing the Risk of DVT and PE), showed that rivaroxaban, a direct Factor Xa inhibitor, provided patients undergoing total hip replacement surgery with a 70% relative risk reduction (RRR) in total VTE from 3.7% in those administered enoxaparin to 1.1% for those on rivaroxaban — without increasing bleeding rates. Top-line results from RECORD1 were first presented at the annual meeting of the American Society of Hematology (ASH) in December 2007.

The second study, RECORD3, showed that rivaroxaban provided patients undergoing total knee replacement surgery with a 49% RRR in total VTE from 18.9% in those administered enoxaparin to 9.6% for those on rivaroxaban — without increasing bleeding rates. Top-line results from RECORD3 were first presented at the International Society on Thrombosis and Haemostasis (ISTH) Congress in July 2007.

“The RECORD1 and RECORD3 study results show that rivaroxaban has the potential to set a new clinical standard in the treatment of blood clots and reduce the global burden of VTE” said Frank Misselwitz, M.D., PhD, Head of Cardiovascular Clinical Development, Bayer HealthCare AG. “The fact that rivaroxaban is significantly superior to enoxaparin in the prevention of VTE, with similar bleeding rates, not only offers patients relief from the inconveniences associated with today’s therapies, but also demonstrates that we may have found the right target along the complicated coagulation cascade.”

Current treatments such as vitamin K antagonists ( e.g., warfarin and acenocoumarol) and heparins have been the mainstays of anticoagulant treatment for many years; however, in the outpatient setting and for long-term use, each class has disadvantages. This has highlighted the need for new anticoagulants to be developed that are safe, effective and do not require regular injections or routine blood monitoring.

New Data to be Presented on June 27th at the International Congress on Thrombosis (ICT)
Five oral presentations and nine posters will be presented on rivaroxaban at the 20th ICT which is being held in Athens, Greece from 25 to 28 June 2008. Amongst the highlights will be the new and pre-specified pooled data-analysis of the RECORD1, 2 and 3 studies:
“A meta-analysis of three pivotal studies of rivaroxaban – a novel, oral, direct Factor Xa inhibitor – for thromboprophylaxis after orthopedic surgery” by Alexander Turpie, Michael Lassen, and Ajay Kakkar, et al., to be presented at 08:30–10:00 on Friday 27 June.

All of the accepted abstracts are to be published in a supplement of Pathophysiology of Haemostasis and Thrombosis.

Notes to editors:

Unmet Needs in Venous Thromboembolism (VTE)
In the EU, blood clots exceed 1.5 million events annually and are responsible for killing 544,000 people each year – more than breast cancer, prostate cancer, HIV/AIDS and road traffic accidents combined.
VTE is a serious life-threatening condition. It 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. These clots often break apart and travel through the bloodstream, blocking blood flow to vital organs. During hip or knee replacement procedures, the large veins of the leg that carry blood back to the heart are damaged which significantly increases the VTE risk for patients undergoing such major orthopedic surgery. In fact, venous blood clots occur in 40-60% of patients undergoing major orthopedic surgery and not receiving preventative care.

An estimated 815,000 hip replacement procedures were performed in the US and Europe in 2005 while the number of knee replacement procedures was estimated to be 761,000. But the threat stretches beyond orthopedic surgeries: Blood clots are one of the leading causes of global disease and death in many patient populations, including those with atrial fibrillation at risk for stroke, those at risk for acute myocardial infarction (heart attack) and acutely ill hospitalized patients, such as those with cancer.

To learn more about VTE please visit www.thrombosisadviser.com

About RECORD1
RECORD1 compared the safety and efficacy of rivaroxaban with enoxaparin in 4,541 patients undergoing total hip replacement surgery. Patients were randomized to receive oral rivaroxaban 10 mg once-daily or subcutaneous enoxaparin injection 40 mg once-daily for five weeks. Overall, RECORD1 showed superiority for rivaroxaban, demonstrating a 70% relative risk reduction (RRR) (p<0.001) in total VTE (the primary efficacy endpoint which encompasses the composite of deep vein thrombosis, non-fatal pulmonary embolism and all-cause mortality) when compared with enoxaparin, and an 88% RRR (p<0.001) in major VTE (the main secondary efficacy endpoint which focuses on VTE-related events).

The primary safety endpoint was major bleeding. The superior efficacy of rivaroxaban was not associated with any significant differences in the incidence of major bleeding between rivaroxaban and enoxaparin groups (0.3% and 0.1% respectively, p=0.178). Rivaroxaban has not been associated with compromised liver function.

About RECORD3
RECORD3 compared the safety and efficacy of rivaroxaban with enoxaparin in 2,531 patients undergoing total knee replacement surgery. Patients were randomized to receive either oral rivaroxaban 10 mg once-daily for 10-14 days or subcutaneous enoxaparin injection 40 mg once-daily for 12 +/- 2 days.

Overall, RECORD3 demonstrated a 49% relative risk reduction (RRR) (p<0.001) in total VTE (the primary efficacy endpoint which encompasses the composite of deep vein thrombosis, non-fatal pulmonary embolism and all-cause mortality) for rivaroxaban when compared with enoxaparin, and a 62% RRR (p=0.016) in major VTE (the main secondary efficacy endpoint which focuses on VTE-related events).

The primary safety endpoint was major bleeding. The superior efficacy of rivaroxaban was not associated with any significant differences in the incidence of major bleeding between rivaroxaban and enoxaparin groups (0.6% and 0.5% respectively, p=0.774). Rivaroxaban has not been associated with compromised liver function.

About the RECORD program
RECORD (REgulation of Coagulation in major Orthopedic surgery reducing the Risk of DVT and PE), is a global program of clinical trials involving 12,729 patients, comparing rivaroxaban with enoxaparin in patients following either total knee or hip replacement surgery.

In RECORD1, rivaroxaban demonstrated a 70% relative risk reduction (RRR) in total VTE in patients undergoing total hip replacement (THR) surgery compared with 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 therapy with enoxaparin (10–14 days) followed by placebo. The results of RECORD2 were published online in The Lancet on 25 June.
In RECORD3, rivaroxaban demonstrated 49% RRR in total VTE in patients undergoing total knee replacement (TKR) surgery compared to enoxaparin, with a similar safety profile. Both treatments were dosed for 10–14 days.
In RECORD4, 10mg once-daily rivaroxaban was compared to the U.S.-approved regimen for enoxaparin of 30mg injected twice-daily. Rivaroxaban demonstrated a 31% RRR in total VTE in patients undergoing TKR surgery compared to enoxaparin, with a similar safety profile. Both treatments were continued for 10–14 days. Results from this study were presented in May at the 9th Annual Meeting of the European Federation of National Associations of Orthopaedics & Traumatology (EFORT) in Nice, France.
About Rivaroxaban
Rivaroxaban is being jointly developed by Bayer HealthCare and Johnson & Johnson Pharmaceutical Research & Development, L.L.C.. The extensive clinical trial program for rivaroxaban makes it the most studied, oral, direct Factor Xa inhibitor in the world today. Based on the clinical evidence in more than 20,000 patients, rivaroxaban has not been associated with compromised liver function. A more definitive statement will be made once the data from long-term exposure to rivaroxaban in the VTE treatment and stroke prevention in atrial fibrillation (SPAF) programs are available. 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. To date, the drug has been filed in more than 10 countries, including Canada and China, and is also expected to be filed for approval in the U.S. in mid 2008, where if approved, it will be commercialized by Scios Inc. and Ortho-McNeil, Inc., both of which are wholly-owned subsidiaries of Johnson & Johnson.

The trade name of rivaroxaban is expected to be Xarelto®, pending health authority approval.

About Bayer HealthCare

The Bayer Group is a global enterprise with core competencies in the fields of health care, nutrition and high-tech materials. Bayer HealthCare, a subsidiary of Bayer AG, is one of the world’s leading, innovative companies in the healthcare and medical products industry and is based in Leverkusen, Germany. The company combines the global activities of the Animal Health, Consumer Care, Diabetes Care and Pharmaceuticals divisions. The pharmaceuticals business operates under the name Bayer Schering Pharma. Bayer HealthCare’s aim is to discover and manufacture products that will improve human and animal health worldwide. Find more information at www.bayerhealthcare.com.

Bayer Schering Pharma is a worldwide leading specialty pharmaceutical company. Its research and business activities are focused on the following areas: Diagnostic Imaging, General Medicine, Specialty Medicine and Women's Healthcare. With innovative products, Bayer Schering Pharma aims for leading positions in specialized markets worldwide. Using new ideas, Bayer Schering Pharma aims to make a contribution to medical progress and strives to improve the quality of life. Find more information at www.bayerscheringpharma.de.

Forward-Looking Statements

This release may contain forward-looking statements based on current assumptions and forecasts made by Bayer Group or subgroup management. Various known and unknown risks, uncertainties and other factors could lead to material differences between the actual future results, financial situation, development or performance of the company and the estimates given here. These factors include those discussed in Bayer’s public reports which are available on the Bayer website at www.bayer.com. The company assumes no liability whatsoever to update these forward-looking statements or to conform them to future events or developments.


Contact

 

Name: Dr. Jost Reinhard 
  Head Global R&D und Scientific Communication
 
Address: Bayer Schering Pharma AG
Germany-13342 Berlin
 
Telephone: +49 30 468 15062
Telefax: +49 30 468 16646
E-Mail: jost.reinhard@bayerhealthcare.com

Posted: June 2008

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