In the ENGAGE AF-TIMI 48 trial, the higher-dose Edoxaban ( HDE; Lixiana, Savaysa ) regimen had a similar incidence of ischaemic stroke compared with Warfarin ( Coumadin ), whereas a higher incidence was observed with the lower-dose regimen ( LDE ).
Amiodarone ( Cordarone ) 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.
At randomization, 2492 patients ( 11.8% ) were receiving Amiodarone.
The primary efficacy endpoint of stroke or systemic embolic event was significantly lower with lower-dose regimen compared with Warfarin in Amiodarone treated patients versus 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 less than 0.01 ).
In patients randomized to higher-dose Edoxaban, 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 lower-dose regimen ( HR 0.35, 95% CI 0.21-0.59 vs. HR 0.53, 95% CI 0.46-0.61, P interaction = 0.131 ) and higher-dose Edoxaban ( 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.
In conclusion, patients randomized to the lower-dose regimen treated with Amiodarone at the time of randomization have demonstrated a significant reduction in ischaemic events versus 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 higher-dose regimen. ( Xagena )
Steffel J et al, Eur Heart J 2015; Epub ahead of print