Subgroup Analysis of ENGAGE AF-TIMI 48 explores the relationship between edoxaban dose, concentration, anti-factor Xa activity and outcomes

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). The analysis also compared rates of major bleeding and efficacy outcomes [stroke and systemic embolic events (SEE)] of edoxaban versus warfarin, stratified by dose reduction status.

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. 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 [creatinine clearance 30-50 mL/min, body weight < 60 kg, or concomitant use of certain P-glycoprotein inhibitors (verapamil, quinidine)]. 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.¹

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. 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.¹

Edoxaban 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.¹

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 [HR], 0.78; 95% confidence interval [CI], 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 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).¹

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 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).¹

“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. “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 analysis showed that while edoxaban concentrations and anti-factor Xa activity were decreased in these patients, the rates of stroke or SEE were consistent with those who did not receive a dose reduction, with greater relative reductions in bleeding compared to warfarin.

“The findings from this exploratory analysis are interesting, as they provide additional insights on how edoxaban dose reduction impacted treatment concentration, anti-factor Xa activity and outcomes in patients in the ENGAGE AF-TIMI 48 study,” said Mahmoud Ghazzi, MD, PhD, Executive Vice President and Global Head of Development for Daiichi Sankyo.

These analyses were performed using paired measurements of edoxaban concentration and anti-factor Xa activity at a single point in time (one month post-randomization) in a subset of patients from the ENGAGE AF-TIMI 48 trial. As this was an exploratory analysis, there are limitations to correlating the finding of the sub-study with the overall clinical outcomes of ENGAGE AF-TIMI 48 and the results may not be representative of the entire population.

1.  Ruff, C et al. Relationship Between Edoxaban Dose, Anti-Factor Xa Activity, and Outcomes in the ENGAGE AF-TIMI 48 Trial. Presented at ESC Congress 2014. 2014. Presentation number 5684.