The Lancet Publishes RECORD4 Study Demonstrating Superior Efficacy for the Prevention of Venous Blood Clots

• Head-to-head study shows once-daily Xarelto is the only oral anticoagulant to significantly reduce VTE event rates compared to twice-daily injectable enoxaparin, whilst maintaining a similar low rate of major bleeding
• RECORD4 Confirms Results of RECORD1, 2 and 3

May 6, 2009 – Data from the pivotal Phase III RECORD4 (REgulation of Coagulation in major Orthopedic surgery reducing the risk of Deep Vein Thrombosis and Pulmonary Embolism) clinical trial, published online today in The Lancet demonstrate that Bayer’s novel anticoagulant Xarelto® (rivaroxaban), taken as one tablet, once-daily, was significantly more effective in reducing the occurrence of venous blood clots following elective total knee replacement surgery (TKR) than twice-daily injectable enoxaparin. ¹ These results make Xarelto the only oral anticoagulant to have demonstrated superior efficacy compared to enoxaparin at its higher U.S.-approved dosing regimen of 30mg twice-daily for venous thromboembolism (VTE) prevention in patients undergoing TKR, the current standard of care in the U.S. ¹ In addition the study also demonstrated that Xarelto maintained a similar low rate of major bleeding as seen with enoxaparin.

Xarelto is being jointly developed by Bayer HealthCare AG and Johnson & Johnson Pharmaceutical Research & Development, L.L.C. RECORD4 forms part of the RECORD clinical trial program, which involved more than 12,500 total hip or knee replacement surgery patients. Data from the RECORD program supported the approval of Xarelto by the European Commission in September 2008 for the prevention of VTE in adult patients undergoing elective hip or knee surgery. The full RECORD data set was used to support the new drug application for Xarelto in the U.S. in 2008, as well as additional filings that are under review with regulatory agencies around the world.

RECORD4 was a multicenter, randomized, double-blind trial that compared Xarelto (10 mg tablet once-daily) with the U.S.-approved treatment regimen for the prevention of VTE following TKR surgery of enoxaparin (30 mg injection twice-daily) in 3,148 patients.1 Xarelto provided patients with s statistically significant reduction in total VTE rates (composite of deep vein thrombosis, non-fatal pulmonary embolism and all-cause mortality), 6.9 % vs. 10.1 % for enoxaparin, (p = 0.012), corresponding to a relative risk reduction (RRR) of 31 %. ¹

Furthermore, Xarelto maintained a similar low rate of major bleeding that was not statistically different to the rate of major bleeding in the enoxaparin-treated patients, (0.7 % and 0.3 % respectively; p = 0.110). ¹

“Rivaroxaban is the first oral anticoagulant to demonstrate superiority over the current standard treatment, and as such it has the potential to become a new clinical standard for the prevention of serious blood clots following major orthopedic surgery,” said Dr. A.G.G. Turpie, Professor of Medicine, McMaster University, Hamilton, Canada and Principal Investigator for the RECORD program. “It is well documented that many patients find the regimen of self-injection associated with current anticoagulation therapies difficult to comply with. Rivaroxaban, as a once-a-day tablet, could significantly increase patient compliance and reduce the incidence of, and costs associated with, treating post-surgical blood clots.”

Developments in Thrombophrophylaxis Treatments
Venous blood clots are serious complications that can impact patients undergoing major orthopedic surgery due to vascular damage and reduced mobility. ² If prophylactic measures are not taken, VTE can occur in up to 60 % of these patients and cause death in 7.5 %. ³ Current treatments, such as vitamin K antagonists and heparins, have been the foundation of anticoagulation treatment for years. However they have significant disadvantages both in the outpatient setting and for long-term use. This highlights the need for development of new anticoagulants that are well tolerated and effective, but do not require regular injections or routine blood monitoring. Xarelto is taken as one tablet, once-daily (at home and in hospital), and requires no routine coagulation monitoring. ⁴ It works by targeting a pivotal stage in the blood clotting process and directly inhibits the enzyme Factor Xa. ^4,5

The efficacy of Xarelto and the statistically similar low risk of bleeding to enoxaparin demonstrated in the RECORD4 trial results were also seen in the RECORD1, 2 and 3 studies that compared Xarelto against enoxaparin (40 mg injected once-daily) after major orthopedic surgery. ^6,7,8

“The publication of the RECORD4 data highlights again how Xarelto continues to exceed our expectations, and is a testament to the consistently strong results generated across the full RECORD program,” said Frank Misselwitz, MD, Head of Cardiovascular Development, Bayer Schering Pharma. “With its unique targeted inhibition of Factor Xa and favourable benefit-risk profile, Xarelto could transform treatment approaches for the prevention of potentially life-threatening blood clots following hip or knee replacement surgery.”

RECORD4 Study Details ¹
RECORD4 compared Xarelto with enoxaparin for the prevention of VTE following TKR surgery in 3,148 patients. Xarelto (10 mg tablet once-daily) was administered 6-8 hours post surgery, compared to enoxaparin (30 mg injection twice-daily) which was administered 12-24 hours post surgery for 10-14 days, in accordance with the U.S. approved regiment. The study demonstrated a 31 % RRR in total VTE, the primary endpoint of this trial for patients treated with Xarelto compared with those treated with enoxaparin (6.9 % and 10.1 %, respectively; p = 0.012). Event rates for the secondary efficacy endpoints were consistently lower in the Xarelto treated patients, but did not reach statistical significance. The rate of major bleeding in the Xarelto treated patients was low and not statistically different to the rate of major bleeding in the enoxaparin-treated patients, (0.7 % and 0.3 % respectively; p = 0.110)

Unmet Needs in Venous Thromboembolism (VTE)
Blood clots can break apart and travel through the bloodstream, blocking blood flow to vital organs. VTE, which annually impacts an estimated 6.5 million people worldwide, ⁹ includes DVT, a blood clot in a deep vein (usually in the leg), and PE, a blood clot in the lung, both of which are serious, life-threatening – but often preventable – conditions. ¹⁰ Blood clots are a major global health problem causing over 500,000 deaths in the EU and an estimated 300,000 deaths in the US each year – more than breast cancer, prostate cancer, HIV/AIDS and road traffic accidents combined. ^11,12 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 can be damaged, significantly increasing the risk of developing a clot. ¹⁰ In fact, venous blood clots occur in up to 60 percent of patients undergoing major orthopedic surgery who do not receive preventive care. ¹³

About Xarelto
Xarelto was invented in Bayer’s Wuppertal laboratories in Germany, and is being jointly developed by Bayer HealthCare and Johnson & Johnson Pharmaceutical Research & Development, L.L.C. Xarelto is approved in the European Union for the prevention of VTE in adult patients undergoing elective hip or knee replacement surgery, where it is marketed under the brand name Xarelto. Additional approvals have been granted in other countries, including Australia, Canada, China, Mexico and Singapore. To date, Xarelto has been launched in more than 25 countries around the world by Bayer Schering Pharma.

The extensive clinical trial program supporting Xarelto 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 Xarelto clinical development program, which will evaluate the product in the prevention and treatment of a broad range of acute and chronic blood-clotting disorders, including VTE treatment, stroke prevention in patients with atrial fibrillation, secondary prevention of acute coronary syndrome, and VTE prevention in hospitalized, medically ill patients.

To learn more about thrombosis, please visit www.thrombosisadviser.com

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, Bayer Schering Pharma, Consumer Care and Medical Care divisions. 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.

References:
1. Turpie AGG, Lassen MR, Davidson BL et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty (RECORD4): a randomised trial. The Lancet 2009
2. Di Minno G, Agnes R; Tufano A. Venous thromboembolism: which patients are truly at risk? Acta Biomed 2005; 76 (Suppl 1): 31-2.
3. Geerts WH, Pineo GF, Heit JA et al. Prevention of venous thromboembolism. The seventh ACCP conference on antithrombotic and thrombolytic therapy. Chest. 2004; 126 Suppl.3:338S-400S.
4. Turpie AGG. Oral, direct factor Xa inhibitors in development for the prevention and treatment of thromboembolic diseases. Arterioscler Thromb Vasc Biol. 2007;27:1238-47.
5. Perzborn E, Strassburger J, Wilmen A, et al. In vitro and in vivo studies of the novel antithrombotic agent BAY 59-7939—an oral, direct Factor Xa inhibitor. J Thromb Haemost. 2005;3:514-21.
6. Eriksson BI, Borris LC, Friedman RJ, et al. Oral rivaroxaban compared with subcutaneous enoxaparin for extended thromboprophylaxis after total hip arthroplasty: the RECORD1 trial. Abstract 2367 presented at American Society of Hematology 49th Annual Meeting in Atlanta, Georgia, 8–11 December 2007.
7. Kakkar AK, Brenner B, Dahl OE, et al. Extended thromboprophylaxis with rivaroxaban compared with short-term thromboprophylaxis with enoxaparin after total hip arthroplasty: the RECORD2 trial. Abstract 307 presented at American Society of Hematology 49th Annual Meeting in Atlanta, Georgia, 8–11 December 2007.
8. Lassen MR, Turpie AG, Rosencher N, et al. Rivaroxaban – an oral, direct Factor Xa inhibitor – for thromboprophylaxis after total knee arthroplasty: the RECORD3 trial. Abstract 308 presented at American Society of Hematology 49th Annual Meeting in Atlanta, Georgia, 8–11 December 2007.
9. Heit JA. Poster 68 presented at: American Society of Hematology, 47th Annual Meeting, Atlanta, GA, December 10-13, 2005.
10. Turpie AG, Chin BS, Lup GY. Venous Thromboembolism: pathophysiology, clinical features, and prevention. BMJ. 2002;325(7369):887-890.
11. Cohen AT, Agnelli G, Anderson FA, et al. Venous thromboembolism (VTE) in Europe. The number of VTE events and associated morbidity and mortality. Thromb Haemost. 2007;98:756-64.
12. Heit JA. Cohen AT, Anderson FA, on behalf of the VTE Impact Assessment Group. Estimated annual number of incident and recurrent, non-fatal and fatal venous thromboembolism (VTE) events in the US. Abstract 68 presented at American Society of Hematology 47th Annual Meeting in Atlanta, Georgia, 10–13 December 2005.
13. Choi BY. J Surg Orthop Adv 2007; 16: 31-5.

Contact:
Anna-Carin Stark, Tel.: +46 732 096 471
E-mail: anna-carin.stark@bayerhealthcare.com