“As part of the ENGAGE AF-TIMI 48 trial, we administered a reduced edoxaban dose to patients with pre-specified clinical factors known to increase the risk of bleeding due to higher drug exposure.
“This is the first analysis of a novel oral anticoagulant that evaluates edoxaban dose, concentration, anti-factor Xa activity and the relationship with efficacy and bleeding outcomes,” said Christian Ruff, MD, MPH, Investigator, TIMI Study Group, Associate Physician, Brigham and Women’s Hospital, Assistant Professor of Medicine, Harvard Medical School, Boston, MA. A lower incidence of major bleeding was observed in patients receiving edoxaban 30 mg compared to warfarin (HR, 0.55 95% CI, 0.46 to 0.65) and in patients receiving dose reduced edoxaban 15 mg compared to warfarin (HR, 0.31 95% CI, 0.23 to 0.42), with a greater relative reduction seen in the dose reduced 15 mg arm (edoxaban p-interaction=0.002). In the low-dose regimen of edoxaban, compared to warfarin, the relative risk of stroke or SEE observed in patients receiving 30 mg (HR, 1.07 95% CI, 0.86 to 1.34) was consistent with that seen in patients receiving dose-reduction to 15 mg (HR, 1.07 95% CI, 0.79 to 1.46) (edoxaban p-interaction=0.99). A numerically lower incidence of major bleeding was observed in patients receiving edoxaban 60 mg compared to warfarin (HR 0.88 95% CI, 0.76 to1.03) and in patients receiving dose reduced edoxaban 30 mg compared to warfarin (HR 0.63 95% CI, 0.50 to 0.81), with a greater relative reduction seen in the dose reduced 30 mg arm (edoxaban p-interaction=0.02). The pre-specified analysis found that in the high-dose regimen of edoxaban, compared with warfarin, the relative risk reduction of stroke or SEE observed in patients receiving 60 mg (hazard ratio, 0.78 95% confidence interval, 0.61 to 0.99) was consistent with that seen in patients receiving dose-reduction to 30 mg (HR, 0.81 CI, 0.58 to 1.13) (edoxaban p-interaction=0.85). A 4-fold edoxaban dose range (15 mg-60 mg) was associated with a 3-fold gradient of the mean edoxaban trough concentration and a 2.4-fold gradient of mean anti-factor Xa activity.1Įdoxaban 50% dose reduction in selected patients with NVAF resulted in a decrease in mean edoxaban trough concentration by 29% and 35%, and a decrease in mean anti-factor Xa activity by 25% and 20% in the high-dose and low-dose regimens, respectively.
In patients who were eligible for inclusion in this subgroup analysis, trough edoxaban concentration was measured in 6,780 patients and anti-factor Xa activity was measured in 2,865 patients. Regardless of treatment received (edoxaban or warfarin), patients who met pre-specified clinical criteria for dose reduction had higher rates of stroke or SEE and major bleeding. Of patients randomized to edoxaban, 25.4% were dose reduced based on pre-specified clinical factors known to potentially increase the risk of bleeding due to higher drug exposure. The ENGAGE AF-TIMI 48 study compared two once-daily edoxaban treatment strategies, a high-dose regimen (60 mg or 30 mg dose-reduced) and a low-dose regimen (30 mg or 15 mg dose-reduced), with warfarin for a median of 2.8 years. The analysis also compared rates of major bleeding and efficacy outcomes of edoxaban versus warfarin, stratified by dose reduction status.
#ENGAGE AF TIMI 48 UPDATE#
Results presented during ESC Congress 2014 Clinical Trial Update Hot Line sessionīarcelona, Spain – Daiichi Sankyo Company, Limited (hereafter, Daiichi Sankyo) today announced data from a subgroup analysis of the phase 3 ENGAGE AF-TIMI 48 study, that explores the relationship between edoxaban dose, concentration and anti-factor Xa activity in patients with non-valvular atrial fibrillation (NVAF).
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