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Four Weeks With Arixtra (Fondaparinux) Significantly Reduces The Risk Of Deep Venous Thrombosis And Pulmonary Embolism In Hip Fracture Surgery Patients: Presented at SICOT

Results of the Penthifra Plus Trial Presented Today at the 12^th World Congress Of the International Society of Orthopaedic Surgery and Traumatology (SICOT) Meeting in San Diego, California

SAN DIEGO, CA -- August 30, 2002 -- Treating patients undergoing hip fracture surgery with the new synthetic agent fondaparinux (ArixtraŽ), a selective Factor Xa inhibitor, for four weeks compared to one week markedly reduces the incidence of thromboembolic complications from 35% to 1.4%, a reduction of 96%, according to findings presented today at the SICOT meeting in San Diego. The Penthifra Plus trial is the first study to evaluate the benefit of four weeks of prophylaxis of deep-vein thrombosis and pulmonary embolism following hip fracture surgery.

"The very high efficacy of fondaparinux prophylaxis given for four weeks in the Penthifra Plus study will induce a dramatic change of the DVT prevention procedures in orthopedic surgery. In my opinion, this level of treatment effect for patients is similar in magnitude to that experienced when antibiotic therapy was first introduced," said Bengt Eriksson, MD, PhD, Orthopaedic Surgeon at Sahlgrenska University Hospital /Ostra, Goteborg, Sweden and lead Investigator of the study. "After a short one week of therapy is given to these patients, one third of the patients still experienced a thromboembolic event during the following month. Our study shows that four weeks of prophylaxis with fondaparinux reduces these events very substantially. This significantly improves the management of patients undergoing surgery for hip fracture, where the risk remains very high for at least four weeks."

Hip Fracture Surgery: A very high and prolonged risk of venous thromboembolism
Patients undergoing hip fracture surgery experience the highest levels of deep-vein thrombosis and pulmonary embolism (venous thromboembolism).(1,2) Pulmonary embolism occurs much more frequently after hip fracture surgery than in patients undergoing elective hip replacement due to osteoarthrosis.(1,3-6) Without prophylaxis, fatal pulmonary embolism occurs in 4 to 13% of patients,(1) and despite the use of current prophylactic therapies, given for a period of 7 to 10 days, rates of fatal pulmonary embolism up to 2% are still observed.(3) Antithrombotic therapy is usually given for one week following surgery, but several studies have shown that patients experience a persistent risk of embolism for a longer period after orthopaedic surgery and that they can benefit from prophylaxis for at least four weeks.(7,8)

Penthifra Plus Study: Methods and Results
This placebo-controlled study evaluated for a period of seven days versus 28 days the safety and efficacy of thromboprophylaxis with fondaparinux in patients undergoing surgery for fracture of the upper third of the femur. In the study, 656 patients from 57 centers in 16 countries undergoing surgery for hip fracture received 2.5 mg fondaparinux daily for seven days, beginning after 6 hours after surgery. On day seven, patients were randomized and treated in the double-blind period with either continued fondaparinux prophylaxis or with placebo for an additional 21 days. Screening with venography was systematically performed at the end of the double blind period, or earlier if thrombosis was clinically suspected. Patients with symptoms of PE underwent objective testing.

The incidence of VTE events observed at the end of the double blind period was 1.4% for the fondaparinux group versus 35% for the placebo group with a highly significant relative risk reduction of 96% in favor of fondaparinux (p=4x10(-22)). Similarly, the number of patients with symptomatic events of DVT and PE was significantly reduced from 2.7% to 0.3%. There was no difference in terms of clinically relevant bleeding between placebo and fondaparinux.

Fondaparinux: An innovative antithrombotic agent
Although antithrombotic drugs have been available for decades, fondaparinux is the first synthetic agent to selectively inhibit a specific key enzyme in the coagulation process called Factor Xa ("Ten A"). This drug represents an important advance in antithrombotic therapy. Fondaparinux has recently been approved for the prevention of venous thromboembolism (VTE) in patients undergoing major orthopaedic surgery of the lower limbs such as hip fracture, major knee or hip replacement surgery. The four phase III trials performed in major orthopaedic surgery have been recently published.(4-6,9) They demonstrate a significant overall reduction of more than 50% in the rate of VTE events i.e. proximal and distal deep-vein thrombosis (DVT) and pulmonary embolism (PE) compared to the low-molecular-weight heparin, enoxaparin with a similar safety profile.(10,11)

Fondaparinux is undergoing further development in the prophylaxis and treatment of venous and arterial thromboembolic diseases.

The Penthifra Plus study was supported by a grant from Sanofi-Synthelabo and NV Organon.

References
1. Geerts WH, Heit JA, Clagett GP, Pineo GF, Colwell CW, Anderson FA, Wheeler HB. Sixth ACCP Consensus Conference on antithrombotic therapy. Prevention of venous thromboembolism. Chest 2001;119:132S-175S.
2. Nicolaides AN. Prevention of venous thromboembolism. International Consensus Statement. Guidelines compiled in accordance with the scientific evidence. Int Angiol 2001;20:1-37.
3. Frostick SP. Death after joint replacement. Haemostasis 2000;30(Suppl):84-87.
4. Eriksson BI, Bauer KA, Lassen MR, Turpie AGG. Fondaparinux Compared with Enoxaparin for the Prevention of Venous Thromboembolism after Hip-Fracture Surgery. N Engl J Med 2001;345:1298-1304.
5. Lassen MR, Bauer KA, Eriksson BI, Turpie AG. Postoperative fondaparinux versus preoperative enoxaparin for prevention of venous thromboembolism in elective hip-replacement surgery: a randomized double-blind comparison. Lancet 2002;359:1715-1720.
6. Turpie AGG, Bauer KA, Eriksson BI, Lassen MR. Postoperative fondaparinux versus postoperative enoxaparin for prevention of venous thromboembolism after elective hip-replacement surgery: a randomized double-blind trial. Lancet 2002;359:1721-26.
7. Eikelboom JW, Quinlan DJ, Douketis JD. Extended-duration prophylaxis against venous thromboembolism after total hip or knee replacement: a meta-analysis of the randomized trials. Lancet 2001;358:9-15.
8. Hull RD, Pineo GF, Stein PD, Mah AF, et al. Extended out-of-hospital low-molecular-weight heparin prophylaxis against deep venous thrombosis in patients after elective hip arthroplasty: a systematic review. Ann Intern Med 2001;135:858-869.
9. Bauer KA, Eriksson BI, Lassen MR, Turpie AGG. Fondaparinux compared with enoxaparin for the prevention of venous thromboembolism after elective major knee surgery. N Engl J Med 2001;345:1305-10.
10. Turpie AGG. Overview of the clinical results of pentasaccharide in major orthopedic surgery. Haematologica 2001;86(Suppl):59-62.
11. Turpie A.G.G, Bauer K.A, Eriksson B.I, Lassen M.R. Fondaparinux versus enoxaparin for the prevention of venous thromboembolism in major orthopedic surgery: A meta-analysis of four randomized double-blind studies. Arch. Intern. Med In Press 2002

SOURCE: Goteborg University

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