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
(2009) In European Heart Journal 30(23). p.2897-2907- 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 >= 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.... (More)
- 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 >= 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 naive 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-naive subjects with treatment, whereas in VKA pre-treated patients, D-dinner levels started tow 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 similar to 10% from baseline and returned to baseline following treatment cessation. The frequency of serum alanine aminotransferase >= 3 x 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. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/1533572
- author
- Lip, Gregory Y. H. ; Rasmussen, Lars H. ; Olsson, Bertil LU ; Jensen, Eva C. ; Persson, Anders L. ; Eriksson, Ulf and Wahlander, Karin F. C.
- organization
- publishing date
- 2009
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- Direct thrombin inhibitor, AZD0837, Atrial fibrillation, Vitamin K antagonists (VKAs), Stroke prevention
- in
- European Heart Journal
- volume
- 30
- issue
- 23
- pages
- 2897 - 2907
- publisher
- Oxford University Press
- external identifiers
-
- wos:000272454800025
- scopus:71649109346
- pmid:19690349
- ISSN
- 1522-9645
- DOI
- 10.1093/eurheartj/ehp318
- language
- English
- LU publication?
- yes
- id
- 24dc0397-a991-4e3f-a25a-0c96c698f745 (old id 1533572)
- date added to LUP
- 2016-04-01 13:42:04
- date last changed
- 2022-02-04 08:53:24
@article{24dc0397-a991-4e3f-a25a-0c96c698f745,
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 >= 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 naive 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-naive subjects with treatment, whereas in VKA pre-treated patients, D-dinner levels started tow 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 similar to 10% from baseline and returned to baseline following treatment cessation. The frequency of serum alanine aminotransferase >= 3 x 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.}},
author = {{Lip, Gregory Y. H. and Rasmussen, Lars H. and Olsson, Bertil and Jensen, Eva C. and Persson, Anders L. and Eriksson, Ulf and Wahlander, Karin F. C.}},
issn = {{1522-9645}},
keywords = {{Direct thrombin inhibitor; AZD0837; Atrial fibrillation; Vitamin K antagonists (VKAs); Stroke prevention}},
language = {{eng}},
number = {{23}},
pages = {{2897--2907}},
publisher = {{Oxford University Press}},
series = {{European Heart Journal}},
title = {{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}},
url = {{http://dx.doi.org/10.1093/eurheartj/ehp318}},
doi = {{10.1093/eurheartj/ehp318}},
volume = {{30}},
year = {{2009}},
}