J Steffel1, R P Giugliano2, E Braunwald2, S A Murphy2, D Atar3, H Heidbuchel4, A J Camm5, E M Antman2, C T Ruff6. 1. Department of Cardiology, University Heart Center Zurich, Zurich, Switzerland. 2. Cardiovascular Division, Brigham and Women's Hospital, TIMI Study Group, 350 Longwood Avenue, 1st Floor Offices, Boston 02115, MA, USA. 3. Department of Cardiology B, Oslo University Hospital Ulleval, University of Oslo, Oslo, Norway. 4. Hasselt University and Heart Center, Jessa Hospital, Hasselt, Belgium. 5. Division of Clinical Sciences, St. George's University of London, Cranmer Terrace, London SW17 0RE, UK. 6. Cardiovascular Division, Brigham and Women's Hospital, TIMI Study Group, 350 Longwood Avenue, 1st Floor Offices, Boston 02115, MA, USA cruff@partners.org.
Abstract
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 receivingamiodarone. 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. Published on behalf of the European Society of Cardiology. All rights reserved.
RCT Entities:
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. Published on behalf of the European Society of Cardiology. All rights reserved.
Authors: David Sanborn; Alan Sugrue; Mustapha Amin; Ramila Mehta; Medhat Farwati; Abhishek J Deshmukh; Haarini Sridhar; Azza Ahmed; Samuel J Asirvatham; Narith N Ou; Peter A Noseworthy; Ammar M Killu; Siva K Mulpuru; Malini Madhavan Journal: Am J Cardiol Date: 2021-10-27 Impact factor: 2.778
Authors: Hans-Christoph Diener; James Aisenberg; Jack Ansell; Dan Atar; Günter Breithardt; John Eikelboom; Michael D Ezekowitz; Christopher B Granger; Jonathan L Halperin; Stefan H Hohnloser; Elaine M Hylek; Paulus Kirchhof; Deirdre A Lane; Freek W A Verheugt; Roland Veltkamp; Gregory Y H Lip Journal: Eur Heart J Date: 2017-03-21 Impact factor: 29.983