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European Heart Journal Advance Access published online on August 18, 2009
European Heart Journal, doi:10.1093/eurheartj/ehp318
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2009. For permissions please email: journals.permissions@oxfordjournals.org
The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that the original authorship is properly and fully attributed; the Journal, Learned Society and Oxford University Press are attributed as the original place of publication with correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact journals.permissions@oxfordjournals.org

Oral direct thrombin inhibitor AZD0837 for the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation: a randomized dose-guiding, safety, and tolerability study of four doses of AZD0837 vs. vitamin K antagonists

Gregory Y.H. Lip1,*, Lars H. Rasmussen2, S. Bertil Olsson3, Eva C. Jensen4, Anders L. Persson4, Ulf Eriksson4, Karin F.C. Wåhlander4 on behalf of the Steering Committee

1 University of Birmingham Centre for Cardiovascular Sciences, City Hospital, Dudley Road, Birmingham B18 7QH, UK
2 Department of Cardiology, Aarhus University Hospital, Aalborg Hospital, Aalborg, Denmark
3 Department of Cardiology, Lund University Hospital, Sweden
4 AstraZeneca Research and Development, Mölndal, Sweden

Received 26 March 2009; revised 9 June 2009; accepted 3 July 2009 * Corresponding author. Tel: +44 121 5075080, Fax: +44 121 554 4083, Email: g.y.h.lip{at}bham.ac.uk

Aims: Oral anticoagulation with vitamin K antagonists (VKAs) for stroke prevention in atrial fibrillation (AF) is effective but has significant limitations. AZD0837, a new oral anticoagulant, is a prodrug converted to a selective and reversible direct thrombin inhibitor (AR-H067637). We report from a Phase II randomized, dose-guiding study (NCT00684307 [ClinicalTrials.gov] ) to assess safety, tolerability, pharmacokinetics, and pharmacodynamics of extended-release AZD0837 in patients with AF.

Methods and results: Atrial fibrillation patients (n = 955) with ≥1 additional risk factor for stroke were randomized to receive AZD0837 (150, 300, or 450 mg once daily or 200 mg twice daily) or VKA (international normalized ratio 2–3, target 2.5) for 3–9 months. Approximately 30% of patients were naïve to VKA treatment. Total bleeding events were similar or lower in all AZD0837 groups (5.3–14.7%, mean exposure 138–145 days) vs. VKA (14.5%, mean exposure 161 days), with fewer clinically relevant bleeding events on AZD0837 150 and 300 mg once daily. Adverse events were similar between treatment groups; with AZD0837, the most common were gastrointestinal disorders (e.g. diarrhoea, flatulence, or nausea). D-Dimer, used as a biomarker of thrombogenesis, decreased in all groups in VKA-naïve subjects with treatment, whereas in VKA pre-treated patients, D-dimer levels started low and remained low in all groups. As expected, only a few strokes or systemic embolic events occurred. In the AZD0837 groups, mean S-creatinine increased by ~10% from baseline and returned to baseline following treatment cessation. The frequency of serum alanine aminotransferase ≥3x upper limit of normal was similar for AZD0837 and VKA.

Conclusion: AZD0837 was generally well tolerated at all doses tested. AZD0837 treatment at an exposure corresponding to the 300 mg od dose in this study provides similar suppression of thrombogenesis at a potentially lower bleeding risk compared with dose-adjusted VKA.

This study is registered with ClinicalTrials.gov, number NCT00684307 [ClinicalTrials.gov] .

Key Words: Vitamin K antagonists (VKAs) • Stroke prevention • Atrial fibrillation • Direct thrombin inhibitor • AZD0837


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