Abstract | 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) 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.
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Authors | Gregory Y H Lip, Lars H Rasmussen, S Bertil Olsson, Eva C Jensen, Anders L Persson, Ulf Eriksson, Karin F C Wåhlander, Steering Committee |
Journal | European heart journal
(Eur Heart J)
Vol. 30
Issue 23
Pg. 2897-907
(Dec 2009)
ISSN: 1522-9645 [Electronic] England |
PMID | 19690349
(Publication Type: Clinical Trial, Phase II, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
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Chemical References |
- Anticoagulants
- Antifibrinolytic Agents
- Biomarkers
- Fibrin Fibrinogen Degradation Products
- fibrin fragment D
- Vitamin K
- Thrombin
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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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