Randomised, parallel-group, multicentre, multinational phase 2 study comparing edoxaban, an oral factor Xa inhibitor, with warfarin for stroke prevention in patients with atrial fibrillation

Abstract

The primary objective of this study was to compare the safety of four fixed-dose regimens of edoxaban with warfarin in patients with non-valvular atrial fibrillation (AF). In this 12-week, parallel-group, multicentre, multinational study, 1,146 patients with AF and risk of stroke were randomised to edoxaban 30 mg qd, 30 mg bid, 60 mg qd, or 60 mg bid or warfarin dose-adjusted to a target international normalised ratio of 2.0-3.0. The study was double-blind to edoxaban dose, but open-label to warfarin. Primary outcomes were occurrence of major and/or clinically relevant non-major bleeding and elevated hepatic enzymes and/or bilirubin. Mean age was 65 +/- 8.7 years and 64.4% were warfarin-naïve. Whereas major plus clinically relevant non-major bleeding occurred in 3.2% of patients randomised to warfarin, the incidence of bleeding was significantly higher with the edoxaban 60 mg bid (10.6%; p=0.002) and 30 mg bid regimens (7.8%; p=0.029), but not with the edoxaban 60 mg qd (3.8%) or 30 mg qd regimens (3.0%). For the same total daily dose of 60 mg, both bleeding frequency and trough edoxaban concentrations were higher in the 30-mg bid group than in the 60-mg qd group. There were no significant differences in hepatic enzyme elevations or bilirubin values among the groups. The safety profiles of edoxaban 30 and 60 mg qd in patients with AF were similar to warfarin. In contrast, the edoxaban bid regimens were associated with more bleeding than warfarin. These results suggest that in this three-month study, edoxaban 30 or 60 mg qd are safe and well-tolerated.

Oral anticoagulants for primary prevention, treatment and secondary prevention of venous thromboembolic disease, and for prevention of stroke in atrial fibrillation: systematic review, network meta-analysis and cost-effectiveness analysis

“…There are 14 studies 12,95,99,101,102,106,108,[110][111][112][113]115,120,122,123,128,129,131 reporting outcomes in this format. Of these, only three studies 111,122,128,131 report mean follow-up time, t, which can be used in the likelihood as described above.…”

“…The remaining eight studies 12,95,101,102,108,110,113,115 report only the study duration, which, we know from those studies reporting both study duration and mean or median follow-up, greatly overestimates mean follow-up time. In studies that report both, the mean follow-up time, as a proportion of the study duration, ranges from 36% to 69%.…”

Laboratory measurement of the anticoagulant activity of edoxaban: a systematic review

“…The mean APTT increased by only 21 and 4 % at 1.5 and 12 h, respectively, after ingestion of a single 60 mg dose [10]. In an in vitro study of normal spiked plasma, an edoxaban concentration of 500 ng/mL (well above the peak levels of 120–250 ng/mL noted in patients taking edoxaban 60 mg daily [5] ) was required to double the APTT from baseline [15]. …”

“…As yet, there are scant data on the relationship between plasma edoxaban levels and clinical outcomes [5] and no evidence to support routine monitoring and dose adjustment. Nevertheless, measurement may be useful in three circumstances: (1) to determine if any clinically relevant anticoagulant effect is present (e.g.…”

“…Edoxaban has been studied as a once daily drug at a dose of 30 or 60 mg in phase III clinical trials [1, 2]. In a pharmacokinetic analysis involving predominantly Caucasian patients with NVAF, the interquartile range for steady-state peak and trough levels was approximately 60–120 and 5–20 ng/mL for subjects receiving edoxaban 30 mg daily and 120–250 and 10–40 ng/mL for subjects receiving 60 mg daily [5]. Exposure was somewhat greater in Asian patients with NVAF [6].…”