Effect on perfusion chamber thrombus size in patients with atrial fibrillation during anticoagulant treatment with oral direct thrombin inhibitors, AZD0837 or ximelagatran, or with vitamin K antagonists.

Abstract

INTRODUCTION:

AZD0837 and ximelagatran are oral direct thrombin inhibitors that are rapidly absorbed and bioconverted to their active forms, AR-H067637 and melagatran, respectively. This study investigated the antithrombotic effect of AZD0837, compared to ximelagatran and the vitamin K antagonist (VKA) phenprocoumon (Marcoumar), in a disease model of thrombosis in patients with non-valvular atrial fibrillation (NVAF).

METHODS:

Open, parallel-group studies were performed in NVAF patients treated with VKA, which was stopped aiming for an international normalized ratio (INR) of ≤ 2 before randomization. Study I: 38 patients randomized to AZD0837 (150,250 or 350 mg) or ximelagatran 36 mg twice daily for 10-14 days. Study II: 27 patients randomized to AZD0837 250 mg twice daily or VKA titrated to an INR of 2-3 for 10-14 days. A control group of 20 healthy elderly subjects without NVAF or anticoagulant treatment was also studied. Size of thrombus formed on pig aorta strips was measured after a 5-minute perfusion at low shear rate with blood from the patient/control subject.

RESULTS:

Thrombus formation was inhibited by AZD0837 and ximelagatran. Relative to untreated patients, a 50% reduction of thrombus size was estimated at plasma concentrations of 0.6 and 0.2 μmol/L for AR-H067637 and melagatran, respectively. For patients receiving VKA treatment, the thrombus size was about 15% lower compared with healthy elderly controls.

CONCLUSIONS:

Effects of AZD0837 and ximelagatran on thrombus formation were similar or greater than for VKA therapy and correlated with plasma concentrations of their active forms.

• Authors: Michael Wolzt, Ulf G Eriksson, Ghazaleh Gouya, Nicolai Leuchten, Stylianos Kapiotis, Margareta Elg, Kajs-Marie Schützer, Sofia Zetterstrand, Malin Holmberg, Karin Wåhlander
• Journal: Thrombosis research (Thromb Res) Vol. 129 Issue 4 Pg. e83-91 (Apr 2012) ISSN: 1879-2472 [Electronic] United States
• PMID: 21925716 (Publication Type: Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 Elsevier Ltd. All rights reserved.

Chemical References

• AZD 0837
• Amidines
• Anticoagulants
• Antithrombins
• Azetidines
• Benzylamines
• Vitamin K
• ximelagatran

Topics

• Administration, Oral
• Aged
• Amidines (administration & dosage)
• Animals
• Anticoagulants (administration & dosage)
• Antithrombins (administration & dosage)
• Atrial Fibrillation (complications, diagnosis, drug therapy)
• Azetidines (administration & dosage)
• Benzylamines (administration & dosage)
• Female
• Humans
• In Vitro Techniques
• Male
• Middle Aged
• Swine
• Thrombosis (complications, diagnosis, prevention & control)
• Treatment Outcome
• Vitamin K (antagonists & inhibitors)