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

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.

Figure 1

CONSORT flow diagram. INR, international normalized ratio; VKA, vitamin K antagonist.

Figure 2

Box and whiskers plots of plasma concentration of AR-H067637 (μmol/L) for each AZD0837 treatment group. Boxes show interquartile range with median indicated. Whiskers extend to the most extreme data point which is not more than 1.5 times the interquartile range. Values outside these limits are individually depicted. The 2-, 12-, and 36-week samples were taken pre-dose (trough values), and at the 2-week visit also at 2 and 4 h post-dose; otherwise, samples were allowed to be taken at any time but were predominantly collected at pre-dose.

Figure 3

(A) Activated partial thromboplastin time (s) vs. plasma concentration of AR-H067637 (μmol/L); (B) Ecarin clotting time (s) vs. plasma concentration of AR-H067637 (μmol/L).

Figure 4

d-Dimer level by treatment and time in (A) vitamin K antagonist (VKA)-naïve patients and (B) VKA pre-treated patients.