Edoxaban vs. Warfarin in Patients With Atrial Fibrillation on Amiodarone

Subgroup Analysis of the Engage AF-TIMI 48 Trial

J. Steffel; R.P. Giugliano; E. Braunwald; S.A. Murphy; D. Atar; H. Heidbuchel; A.J. Camm; E.M. Antman; C.T. Ruff


Eur Heart J. 2015;36(33):2239-2245. 

In This Article

Abstract and Introduction


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.


In the effective anti-coagulation with factor Xa next generation in atrial fibrillation (AF)–thrombolysis in myocardial infarction 48 (ENGAGE AF-TIMI 48) trial, two dosing regimens of the direct factor Xa inhibitor edoxaban were found to be non-inferior to well-managed warfarin for the prevention of stroke or systemic embolic events (SEEs) in patients with AF.[1] In addition, both regimens of edoxaban significantly reduced the risk of major bleeding and cardiovascular death when compared with warfarin. The lower-dose (LD) regimen of edoxaban, however, was associated with a 41% relative increase in ischaemic stroke when compared with warfarin.

Edoxaban acts as a substrate for the efflux transporter p-glycoprotein (P-gp), located primarily in the intestine, which limits systemic absorption of drugs by pumping them back into the intestinal lumen.[2–4] Edoxaban underwent extensive preclinical testing to determine the optimal dosing for patients co-treated with P-gp inhibitors. Co-administration of edoxaban with strong P-gp inhibitors verapamil, quinidine, and dronedarone significantly increased maximal edoxaban drug levels (Cmax), the area under the curve, and trough (Cmin) plasma levels.[5] Based on these findings, as well as on further modelling and simulation of edoxaban exposure and response relationships,[5] a 50% dose reduction was implemented in the ENGAGE AF-TIMI 48 trial for patients taking these drugs. In contrast, amiodarone is a weaker P-gp inhibitor; based on drug–drug interaction studies there was no dose reduction implemented in the ENGAGE AF-TIMI 48 trial for concomitant amiodarone use.

Amiodarone is one of the most frequently used anti-arrhythmic drugs in patients with AF, in spite of its pronounced side effect profile as well as numerous drug–drug interactions.[6] Amiodarone decreases hepatic metabolism of warfarin by inhibiting cytochrome P450-dependent elimination pathways, necessitating frequent dose adjustments to counterbalance its potentiating effect on the degree of anti-coagulation. In view of its widespread use, potential interactions with non-vitamin K oral anti-coagulants (NOACs) such as edoxaban are of great clinical importance for a large number of patients. In the current pre-specified exploratory analysis, we evaluated the efficacy and safety of edoxaban in patients co-treated with amiodarone in the ENGAGE AF-TIMI 48 trial.[1] Since a prior analysis of edoxaban concentration in this trial demonstrated correlations with clinical efficacy and safety,[7] we also explored the impact of concomitant amiodarone use on edoxaban concentration and outcomes.