title: Oral direct thrombin inhibitor AZD0837 for the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation: a Phase II study of AZD0837 in patients who are appropriate for but unable or unwilling to take vitamin K antagonist therapy.
abstract: BACKGROUND
  Some patients with atrial fibrillation (AF) cannot be treated with vitamin K antagonists (VKAs) and will therefore not receive effective thromboprophylaxis. The primary objective of the present Phase II trial (NCT00623779) was to assess the feasibility of conducting a study with a novel oral anticoagulant, the direct thrombin inhibitor AZD0837, in patients with AF unable or unwilling to take warfarin, by evaluation of dropout rates and compliance.
  
  
  METHODS
  Patients were randomised to receive AZD0837 extended-release tablets 150 mg (n=43) or 300 mg (n = 42) once daily, or standard therapy (no treatment, aspirin 75-325 mg or clopidogrel 75 mg once daily; n = 46) for a median treatment duration of 6 weeks.
  
  
  RESULTS
  Reasons for patients not being treated with warfarin were: refusal or permanent cessation decided by the patient (64.8%), inability to keep international normalised ratio 2-3 over a 3-month period (23.2%), physician assessment that VKA was inappropriate (20.4%) and warfarin allergy (2.8%). Compliance with treatment (mean ± SD) was 97.0 ± 16.5% for AZD0837 150 mg and 99.8 ± 1.4% for 300 mg. Compliance with study visits was high (mean 93-98%). The numbers of dropouts were four, six and three, whilst minor or clinically significant minor bleeds were reported in zero, five and two patients in the AZD0837 150 mg, 300 mg and standard-therapy groups, respectively. No major bleeds were reported. Both doses of AZD0837 reduced levels of fibrin D-dimer and prolonged activated partial thromboplastin time, ecarin clotting time and thrombin clotting time.
  
  
  CONCLUSIONS
  AZD0837 had a good safety profile during this study, including a low incidence of bleeding events, with effective anticoagulation on pharmacodynamic parameters. A larger study in AF patients unable or unwilling to take warfarin is feasible, as judged by compliance and dropout rates.
authors.affiliation: University of Birmingham Centre for Cardiovascular Sciences, City Hospital, Birmingham, UK. g.y.h.lip@bham.ac.uk
authors.forename: Gregory Y H
authors.initials: GY
authors.lastname: Lip
authors.forename: Lars H
authors.initials: LH
authors.lastname: Rasmussen
authors.forename: S Bertil
authors.initials: SB
authors.lastname: Olsson
authors.forename: Sofia
authors.initials: S
authors.lastname: Zetterstrand
authors.forename: Christina
authors.initials: C
authors.lastname: Stahre
authors.forename: Anders
authors.initials: A
authors.lastname: Bylock
authors.forename: Maria
authors.initials: M
authors.lastname: Aunes-Jansson
authors.forename: Ulf
authors.initials: U
authors.lastname: Eriksson
authors.forename: Karin
authors.initials: K
authors.lastname: Wåhlander
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000578:Amidines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D000925:Anticoagulants / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D001281:Atrial Fibrillation / Q000097:blood / Q000150:complications / Q000188:drug therapy*; D001384:Azetidines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D004617:Embolism / Q000097:blood / Q000209:etiology / Q000517:prevention & control*; D005260:Female; D005338:Fibrin Fibrinogen Degradation Products / Q000378:metabolism; D006801:Humans; D008297:Male; D055118:Medication Adherence; D008875:Middle Aged; D020521:Stroke / Q000097:blood / Q000209:etiology / Q000517:prevention & control*; D016896:Treatment Outcome
chemical_list: C551586:AZD 0837; D000578:Amidines; D000925:Anticoagulants; D001384:Azetidines; D005338:Fibrin Fibrinogen Degradation Products; C036309:fibrin fragment D