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New Landmark Study Confirms Potential for Exanta (ximelagatran) in Prevention of Stroke in Atrial Fibrillation.

American Heart Association Scientific Sessions 2003, ORLANDO, Florida, November 11 /PRNewswire/ -- Results from the SPORTIF V(1)(a) study, presented today, support the potential for Exanta(TM) (ximelagatran), the first oral treatment in a new class of direct thrombin inhibitors (DTIs), to be an effective and predictable replacement for warfarin in the prevention of stroke and systemic embolic events (SEE) in patients with atrial fibrillation (AF), without the limitations of warfarin treatment. SPORTIF V, together with the recently presented SPORTIF III(2)(b) study, is part of the largest stroke prevention in atrial fibrillation study programme to date, involving 7329 patients. These studies will now be submitted to regulatory authorities in the US and Europe as part of the regulatory application for Exanta in this indication.

SPORTIF V was designed as a non-inferiority(c) study to compare oral Exanta with the current standard treatment, dose-adjusted warfarin in preventing stroke and systemic embolic events (SEE) in atrial fibrillation, and the results support the findings of the SPORTIF III study. The primary efficacy endpoint was met, showing that fixed dose twice daily 36mg oral Exanta is non-inferior to dose-adjusted warfarin in preventing stroke and SEE: 51 Exanta patients with events (1.6%/yr) vs 37 for warfarin (1.2%/yr), confirming non-inferiority based on the same criteria used in the SPORTIF III study. Importantly, this result was seen despite excellent control of warfarin treatment in the study: patients were within the INR(d) range of 2.0-3.0 for 68% of time. When the results from both studies are pooled, 91 patients with events were seen for Exanta compared with 93 for warfarin (1.6%/yr vs 1.6%/yr), supporting the efficacy of Exanta in prevention of strokes and thromboembolic events in patients with atrial fibrillation.

"If a person can take warfarin and take it well, it is highly effective at preventing strokes. It is a real problem, however, to deliver the drug consistently to patients, particularly the elderly, as it requires close coagulation monitoring and dose titration", comments Dr Jonathan L. Halperin, Professor of Medicine at the Mount Sinai School of Medicine, New York, and SPORTIF V Lead Investigator. "The risk of stroke, as well as the difficulties of using warfarin - particularly the increased risk of bleeding - increases with age, leaving too many patients under-treated. Ximelagatran represents an exciting new approach to anticoagulation, as the SPORTIF V results show. We may be able to offer our patients a much-needed, consistently efficacious alternative to warfarin treatment that does not have the limitations inherent in coagulation monitoring or dose titration."

Patients were treated for an average of 20 months in SPORTIF V, providing further long-term data to support the emerging benefit-risk profile for Exanta. Despite no coagulation monitoring or dose titration in the Exanta group, a lower number of patients in SPORTIF V experienced major bleeding (2.4% Exanta vs 3.1% warfarin; p=n.s.). Warfarin was well controlled with careful ongoing coagulation monitoring, dose adjustment and dose titration, yet Exanta demonstrated significantly less total (major and/or minor) bleeding rates than well-controlled warfarin (37% Exanta vs 47% warfarin p<0.0001) with no significant increase in event rate.

An elevation of liver enzymes (ALAT >3XULN) was observed in 6% of patients treated with Exanta in SPORTIF V, a consistent level to that seen in other long-term Exanta studies. An incidence of elevated bilirubin > 2XULN following ALAT > 3XULN was seen in 9 Exanta patients vs 1 warfarin patient. When assessed alongside SPORTIF III as pooled data, the overall incidence of liver enzymes for Exanta in the SPORTIF programme is 6.1%, compared with 0.8% of patients in the warfarin group. These elevations are typically transient (occurring within first 2-6 months), decrease towards normal with treatment continuation or discontinuation and are not associated with specific clinical symptoms in the SPORTIF programme overall.

Overall, a statistically significant net clinical benefit is seen for Exanta from the pooled data of both the SPORTIF V and SPORTIF III studies. In an assessment of the combined rates of deaths, primary events and major bleeding while on treatment in both studies, 5.2% events were seen with Exanta compared with 6.2% with warfarin (p=0.038). This finding demonstrates that patients can benefit from a predictable and effective treatment to prevent morbidity and mortality, whilst avoiding the limitations that are associated with warfarin.

"SPORTIF V supports the overall clinical benefit of Exanta in this important area of unmet medical need", comments Dr Hamish Cameron, Vice President, Head of Exanta, AstraZeneca. "The SPORTIF programme will represent the key element of our regulatory submissions supporting the use of the drug in the prevention of stroke and SEE in patients with atrial fibrillation. The submission, which is planned for the end of the year, will also include a full evaluation of Exanta's risk benefit profile based on the extensive data we have generated from clinical studies in more than 30,000 patients."

Stroke is a leading cause of death in adults in industrialised countries, with five million fatal events per year(3). Atrial fibrillation has been found to increase the risk of stroke fivefold, accounting for around 15% of all strokes(4)(5). Despite studies showing that the risk of stroke can be reduced by 62% in patients taking oral anticoagulant therapy(5), around 50% of eligible patients do not receive optimal treatment(6).

Exanta is the first oral anticoagulant to reach late stage clinical development in almost 60 years, and has been the subject of the most extensive clinical study programme to date, involving around 30,000 patients. Regulatory submissions for Exanta in the prevention of stroke in patients with atrial fibrillation indication will take place in US and Europe by the end of 2003.

Notes to Editors

Exanta is a trademark of the AstraZeneca group of companies.

AstraZeneca is a major international healthcare business engaged in the research, development, manufacture and marketing of prescription pharmaceuticals and the supply of healthcare services. It is one of the top five pharmaceutical companies in the world with healthcare sales of over US$17.8 billion and leading positions in sales of gastrointestinal, oncology, anaesthesia (including pain management), cardiovascular, central nervous system (CNS) and respiratory products. AstraZeneca is listed in the Dow Jones Sustainability Index (Global and European) as well as the FTSE4Good Index.

(a) SPORTIF: Stroke Prevention using an ORal Thrombin Inhibitor in atrial Fibrillation. SPORTIF V is a randomised, double blind, parallel group study involving 3,922 people aged 18 or over from 409 sites in North America (Canada and the US) (1960 in Exanta group; 1962 in warfarin group). 36mg fixed dose oral Exanta twice daily was compared with dose-adjusted warfarin (INR 2.0-3.0) once daily. Patients in the study had non-valvular atrial fibrillation (AF) and at least one additional risk factor for stroke, which included: previous stroke or transient ischaemic attack; previous systemic embolism; hypertension; left ventricular dysfunction; age greater than or equal to 75 years; age greater than or equal to 65 and coronary artery disease; age > 65 and diabetes mellitus

(b) SPORTIF III is a multi-national, randomised, open-label parallel-group study with blinded event assessment, involving 3407 patients from 259 centres across Europe, Australia and Asia.

(c) Non-inferiority: Placebo-controlled trials are often now considered unethical due to the large number of highly effective available treatments. Therefore, the concept of non-inferiority testing is now increasingly common where the objective of a study is to demonstrate that a treatment is 'not inferior to' a gold standard treatment. This pre-defined criteria was used for both the SPORTIF III and SPORTIF V studies to demonstrate the benefits of Exanta compared with warfarin, which although very effective when well managed, has extensive limitations.

(d) INR: International Normalised Ratio: target range of blood coagulation defined to minimise the risk of events. Below INR 2.0, the risk of stroke increases and above 3.0 the risk of bleeding increases exponentially.

A webcast of the SPORTIF V late-breaking clinical presentation will go live on the American Heart Association Scientific Sessions website www.scientificsessions.org from 10.45 EST Wednesday 12 November 2003.

References:

(1) SPORTIF V: Presentation at Late-breaking Clinical Trial Session, American Heart Association Scientific Sessions 2003, 11 November 2003.

(2) SPORTIF III: The Lancet 2003 in press.

(3) The European Stroke Initiative: European Stroke Initiative Recommendations for Stroke Management - Update 2003. Cerebrovascular Disease 2003;16:311-337.

(4) Wolf, P.A. et al: Atrial fibrillation as an independent risk factor for stroke: the Framingham Study. Stroke. 1991;22:983-988.

(5) Hart RG, Benavente O, McBride R, Pearce LA. Antithrombotic therapy to prevent stroke in patients with atrial fibrillation: a meta-analysis. Ann Intern Med 199; 131:492-501

(6) Buckingham, T.A. et al: Anticoagulants for atrial fibrillation: why is the treatment rate so low? Clin. Cardiol 2002;25:447-454

For further information, please see www.astrazenecapressoffice.com

Contact: Julie Saunders, Global PR Manager, AstraZeneca, mobile: + 46 708 46 76 33, office: + 44 1625 231319/+ 46 31 70 64865, email: julie.saunders@astrazeneca.com or Amanda Sefton (Ketchum), +44 7958 228 097, or Ross Wilkie (Ketchum), office: +44 (0)20 7611 3603
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