Lower-dose edoxaban significantly reduced stroke or systemic embolic events compared with warfarin in atrial fibrillation patients on amiodarone (HR 0.60; 95% CI 0.36-0.99; P interaction <0.01).
RCT (n=2,492)
randomized
Does edoxaban reduce stroke or systemic embolic events compared to warfarin in patients with atrial fibrillation on amiodarone?
Amiodarone use at randomization significantly improved the relative efficacy of lower-dose edoxaban compared to warfarin for stroke prevention in atrial fibrillation, likely due to increased edoxaban plasma levels via P-glycoprotein inhibition.
Effect estimate: HR 0.60 (95% CI 0.36-0.99)
p-value: p=<0.01
BACKGROUND: In the ENGAGE AF-TIMI 48 trial, the higher-dose edoxaban (HDE) regimen had a similar incidence of ischaemic stroke compared with warfarin, whereas a higher incidence was observed with the lower-dose regimen (LDE). Amiodarone increases edoxaban plasma levels via P-glycoprotein inhibition. The current pre-specified exploratory analysis was performed to determine the effect of amiodarone on the relative efficacy and safety profile of edoxaban. METHODS AND RESULTS: At randomization, 2492 patients (11.8%) were receiving amiodarone. The primary efficacy endpoint of stroke or systemic embolic event was significantly lower with LDE compared with warfarin in amiodarone treated patients vs. patients not on amiodarone (hazard ratio HR 0.60, 95% confidence intervals CIs 0.36-0.99 and HR 1.20, 95% CI 1.03-1.40, respectively; P interaction <0.01). In patients randomized to HDE, no such interaction for efficacy was observed (HR 0.73, 95% CI 0.46-1.17 vs. HR 0.89, 95% CI 0.75-1.05, P interaction = 0.446). Major bleeding was similar in patients on LDE (HR 0.35, 95% CI 0.21-0.59 vs. HR 0.53, 95% CI 0.46-0.61, P interaction = 0.131) and HDE (HR 0.94, 95% CI 0.65-1.38 vs. HR 0.79, 95% CI 0.69-0.90, P interaction = 0.392) when compared with warfarin, independent of amiodarone use. CONCLUSIONS: Patients randomized to the LDE treated with amiodarone at the time of randomization demonstrated a significant reduction in ischaemic events vs. warfarin when compared with those not on amiodarone, while preserving a favourable bleeding profile. In contrast, amiodarone had no effect on the relative efficacy and safety of HDE.
Steffel et al. (Wed,) conducted a rct in atrial fibrillation (n=2,492). Edoxaban vs. warfarin was evaluated on stroke or systemic embolic event (HR 0.60, 95% CI 0.36-0.99, p=<0.01). Lower-dose edoxaban significantly reduced stroke or systemic embolic events compared with warfarin in atrial fibrillation patients on amiodarone (HR 0.60; 95% CI 0.36-0.99; P interaction <0.01).