Abstract 5621: A Phase 2 Feasibility Trial of the Oral Direct Thrombin Inhibitor AZD0837 in the Prevention of Stroke and Systemic Embolic Events in Patients With Atrial Fibrillation, Who Are Unable or Unwilling to Take Warfarin Therapy
Many patients with atrial fibrillation (AF) cannot be treated with vitamin K antagonists (VKA) such as warfarin for various reasons, and will therefore not receive effective thromboprophylaxis. Development of a novel oral anticoagulant with an improved safety profile while maintaining the efficacy of VKA would represent a significant advance in the management of AF. The primary objective of the present Phase 2 trial (NCT00623779) was to assess the feasibility of conducting a study in patients with AF unable or unwilling to take warfarin, by evaluation of drop-out rate and compliance with treatment and study procedures. Secondary objectives included assessment of safety/tolerability (including bleeding), and pharmacodynamic properties of AZD0837. Patients were randomised to receive AZD0837 extended-release tablets 150 mg (n=41) or 300 mg (n=42) once daily, or standard therapy (no treatment, ASA 75–325 mg or clopidogrel 75 mg once daily) (n=45). The study was blinded to AZD0837 dose. Treatment duration was between 4 weeks and 6 months (median 6 weeks). Reasons for patients not being treated with warfarin were: permanent cessation or refusal by the patient (62%), physicians assessment that VKA was inappropriate (21%), inability to keep INR between 2.0 –3.0 over a 3-month period (24%), and warfarin allergy (2%). 40% of patients were warfarin-naïve. Compliance with study treatment (mean±SD) was 96.9±16.5% for AZD0837 150 mg and 99.8±11.4% for 300 mg. Compliance with study visits was 93.3±15.0% for AZD0837 150 mg, 95.6±10.4% for 300 mg and 97.5±6.8% for standard therapy. The number of drop-outs were 4, 6 and 3, whilst minor or clinically significant minor bleeds were reported in 0, 5 and 2 with AZD0837 150 mg, 300 mg and standard therapy, respectively. No major bleeding events were reported. Both doses of AZD0837 showed relevant anticoagulation effects in terms of reduced levels of fibrin D-Dimer, and prolongation of ECT and APTT. This Phase 2 trial indicates that a larger study in this group of AF patients in need of effective thromboprophylaxis may be feasible, as judged by compliance and drop-out rates. The oral direct thrombin inhibitor AZD0837 has a favorable safety profile including a low incidence of bleeding events, and seems to offer effective anticoagulation.