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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.

AbstractAIMS:
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) to assess safety, tolerability, pharmacokinetics, and pharmacodynamics of extended-release AZD0837 in patients with AF.
METHODS AND RESULTS:
Atrial fibrillation patients (n = 955) with > or =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 approximately 10% from baseline and returned to baseline following treatment cessation. The frequency of serum alanine aminotransferase > or =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.
AuthorsGregory Y H Lip, Lars H Rasmussen, S Bertil Olsson, Eva C Jensen, Anders L Persson, Ulf Eriksson, Karin F C Wåhlander,
JournalEuropean heart journal (Eur Heart J) Vol. 30 Issue 23 Pg. 2897-907 (Dec 2009) ISSN: 1522-9645 [Electronic] England
PMID19690349 (Publication Type: Clinical Trial, Phase II, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
Chemical References
  • Anticoagulants
  • Antifibrinolytic Agents
  • Biomarkers
  • Fibrin Fibrinogen Degradation Products
  • fibrin fragment D
  • Vitamin K
  • Thrombin
Topics
  • Adult
  • Aged
  • Aged, 80 and over
  • Anticoagulants (therapeutic use)
  • Antifibrinolytic Agents (therapeutic use)
  • Atrial Fibrillation (complications, drug therapy)
  • Biomarkers (metabolism)
  • Bleeding Time
  • Embolism (prevention & control)
  • Female
  • Fibrin Fibrinogen Degradation Products (metabolism)
  • Humans
  • Male
  • Middle Aged
  • Stroke (prevention & control)
  • Thrombin (antagonists & inhibitors, metabolism)
  • Vitamin K (antagonists & inhibitors, metabolism)

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