Conen, David

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EDITORIALEdoxaban and amiodarone: interactionson multiple levelsDavid Conen*Division of Internal Medicine, Department of Medicine and Cardiovascular Research Institute Basel, University Hospital, Basel, SwitzerlandThis paper was guest edited by Anthony N. DeMaria, M.D. (University of California; ademaria@ucsd.edu).This editorial refers to ‘Edoxaban vs. warfarin in patientswith atrial fibrillation on amiodarone: a subgroup analysisof the ENGAGE AF-TIMI 48 trial’†, by J. Steffel et al., onpage 2239.Stroke prevention using oral anticoagulation is a highly effectiveintervention to improve outcomes among patients with atrial fibril-lation (AF), the most common cardiac arrhythmia in the popula-tion.1,2 Compared with placebo, the use of vitamin K antagonistsreduces the risk of stroke by 64% in patients with AF, but significantlyincreases the risk of major and life-threatening bleeding.3 In recentyears, new oral anticoagulants with a more favourable risk–benefitprofile have been developed and tested in large randomizedtrials, further improving anticoagulation treatment among patientswith AF.One of these studies was the Effective Anticoagulation withFactor Xa Next Generation in Atrial Fibrillation–Thrombolysis inMyocardial Infarction 48 (ENGAGE AF-TIMI 48) trial, a large rando-mized trial comparing the efficacy and safety of two dosing regimensof edoxaban with warfarin among AF patients at increased risk ofstroke. Compared with warfarin, this trial established the non-inferiority of both regimens with regard to prevention of strokeand systemic embolism, with the advantage of significantly lowerrates of major bleeding associated with both dosing strategies.4However, the low-dose edoxaban strategy was associated with ahighly significant 41% increased risk of ischemic stroke, making theclinical use of this regimen less straightforward, despite its profoundreduction of bleeding complications and a significant reduction inall-cause mortality.Thus interventions to improve the efficacy of the low-dose edox-aban strategy without compromising too much its safety could havean important impact on clinical practice.Drug–drug interactions that moderately increase edoxaban drugconcentrationsmay help to achieve this goal. In this issue of the jour-nal, a subgroup analysis of the ENGAGE AF-TIMI 48 trial is pre-sented that investigated the effect of amiodarone, a widely usedantiarrhythmic drug with multiple drug–drug interactions, on theefficacy and safety of edoxaban for stroke prevention in AF pa-tients.5 The authors of this study showed that among the 2492 par-ticipants (11.8%) receiving amiodarone at baseline, low-doseedoxaban was associated with a significant reduction in the risk ofstroke or systemic embolism [hazard ratio (HR) 0.60, 95% confi-dence interval (CI) 0.36, 0.99], without increasing the risk of ische-mic stroke (HR 0.96, 95% CI 0.54, 1.70). In contrast, the risk ofstroke or systemic embolism was significantly higher among patientsin the low-dose edoxaban arm not taking amiodarone (HR 1.20,95% CI 1.03, 1.40; P-value for interaction 0.01). On the otherhand, the principal safety endpoint of major bleeding was similaramong patients taking or not taking amiodarone (HR 0.35, 95% CI0.21, 0.59 and HR 0.53, 95% CI 0.46, 0.61; P-value for interaction0.13). As expected, concomitant use of amiodarone increasededoxaban concentrations in the low-dose arm (27.3+24.5 ng/mLvs. 21.9+ 20.8 ng/mL, P, 0.001) and in the high-dose arm(58.5+53.2 ng/ml vs. 43.2+ 41.1 ng/mL, P, 0.001).Now the key question is whether concomitant use of amiodaroneand low-dose edoxaban achieves a “sweet spot” between protec-tion from ischemic events and bleeding, as suggested by the authors,or whether the observed findings can be explained by chance. In myview, the second option is more likely for several reasons. First, asappropriately stated by the authors, study participants were not ran-domized to amiodarone treatment, and the amiodarone subgroupwas relatively small and only one of several subgroups that were as-sessed, such that chance, bias or confounding may have contributedto these differential findings. Second, the significant interaction in ef-ficacy in the low-dose edoxaban group was not observed in thehigh-dose group despite a larger difference in edoxaban concentra-tions between amiodarone users and non-users. In addition,co-administration of amiodarone had no effect on the incidenceof major bleeding events, the principal safety endpoint. The authorshypothesize that the increase in plasma levels caused byco-administration of amiodarone and low-dose edoxaban occursat an inflection point in the dose–response curve for efficacy butfalls within the flatter part of the dose–response curve for bleeding,while the increase in concentration in high-dose edoxaban patientstaking amiodarone occurs during the flat portion of the dose–The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology.† doi:10.1093/eurheartj/ehv201.*Corresponding author. Department of Medicine, University Hospital, Petersgraben 4, 4031 Basel, Switzerland. Tel: +41 61 265 2525, Fax: +41 61 265 5734, E-mail: david.conen@usb.chPublished on behalf of the European Society of Cardiology. All rights reserved. & The Author 2015. For permissions please email: journals.permissions@oup.com.European Heart Journal (2015) 36, 2210–2211doi:10.1093/eurheartj/ehv245response curve for efficacy. While appealing, this hypothesis seemsnot to be consistent with the findings of a recently published paperfrom the ENGAGEAF-TIMI 48 trial, where therewas a linear dose–response curve for both efficacy and safety across a wide range ofedoxaban concentrations, without evidence of an inflection pointor saturation effect.6 In this analysis, the dose–response curve forbleeding was actually steeper than that for stroke or systemic em-bolism, suggesting that a relevant effect of amiodarone shouldhave been observed primarily for the bleeding endpoint. Third,while differences in edoxaban concentrations were statistically sig-nificant, they were rather small on an absolute scale. Being on high-dose vs. low-dose edoxaban had a far greater impact on edoxabanconcentrations than being on amiodarone vs. no amiodarone asindicated above. Nevertheless, differences in the absolute rates ofthe primary endpoint among those taking and not taking amiodar-one in the low-dose arm (1.12% per year vs. 2.16% per year) areon the same order of magnitude as those between the 60-mgdose and the 15-mg dose (1.0% per year vs. 2.36% per year), wheredifferences in mean edoxaban concentrations were far greater (48.5vs. 16.0 ng/mL).6Nonetheless, the current article is still of clinical importance forseveral reasons. First, it shows that co-prescription of amiodaronedoes not have any visible adverse effects on the efficacy and safetyof edoxaban. This is a very reassuring finding for those AF patientswho need both amiodarone and effective stroke prevention.Although post-marketing studies are usually not randomized andtherefore subject to bias, they will be an important tool to furtherincrease our reassurance of edoxaban use in clinical practice, as hasbeen nicely shown for dabigatran.7 Second, although the interactionbetween edoxaban and amiodarone seems to be less of an issue, thecurrent article still highlights the importance of taking into accountdrug–drug interactions in clinical practice. While the novel oralanticoagulants have fewer interactions than vitamin K antagonists,we cannot ignore this important issue when prescribing thesedrugs to patients who often have several co-morbidities and co-medications.8 Finally, this article nicely illustrates the challengeswe face in the translation of trial findings to everyday patient care.If the interpretation of interaction P-values and subgroup effectsremains difficult and controversial despite the availability of a largerandomized trial in a well-characterized patient population, thenfinding the right drug for an individual patient is an even more daunt-ing task. Only with carefully performed analyses from large studiessuch as ENGAGE AF-TIMI 48 we will be able to make the rightdecisions for our patients with whom we interact every day inclinical practice.Conflict of interest: D.C. has received research grants fromBayer, Daiichi-Sankyo and BMS/Pfizer and scientific advisory boardsfees from Bayer, Daiichi-Sankyo, BMS/Pfizer and BoehringerIngelheim.References1. Conen D, Chae CU, Glynn RJ, Tedrow UB, Everett BM, Buring JE, Albert CM. Riskof death and cardiovascular events in initially healthy women with new-onset atrialfibrillation. JAMA 2011;305:2080–2087.2. Krijthe BP, Kunst A, Benjamin EJ, Lip GY, Franco OH, Hofman A, Witteman JC,Stricker BH, Heeringa J. Projections on the number of individuals with atrial fibrilla-tion in the European Union, from 2000 to 2060. Eur Heart J 2013;34:2746–2751.3. Hart RG, Pearce LA, Aguilar MI. Meta-analysis: antithrombotic therapy to preventstroke in patients who have nonvalvular atrial fibrillation. Ann Intern Med 2007;146:857–867.4. Giugliano RP, Ruff CT, Braunwald E, Murphy SA,Wiviott SD, Halperin JL, Waldo AL,Ezekowitz MD, Weitz JI, Spinar J, Ruzyllo W, Ruda M, Koretsune Y, Betcher J, Shi M,Grip LT, Patel SP, Patel I, Hanyok JJ, Mercuri M, Antman EM, Investigators EA-T.Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2013;369:2093–2104.5. Steffel J, Giugliano RP, Braunwald E, Murphy SA, Atar D, Heidbuchel H, Camm AJ,Antman EM, Ruff CT. Edoxaban vs. warfarin in patients with atrial fibrillation onamiodarone: a subgroup analysis of the ENGAGE AF-TIMI 48 trial. Eur Heart J2015;36:2239–2245.6. Ruff CT, Giugliano RP, Braunwald E, Morrow DA, Murphy SA, Kuder JF,Deenadayalu N, Jarolim P, Betcher J, Shi M, Brown K, Patel I, Mercuri M,Antman EM. Association between edoxaban dose, concentration, anti-Factor Xaactivity, and outcomes: an analysis of data from the randomised, double-blindENGAGE AF-TIMI 48 trial. Lancet 2015;385:2288–2295.7. Graham DJ, Reichman ME, Wernecke M, Zhang R, Southworth MR, Levenson M,Sheu TC, Mott K, Goulding MR, Houstoun M, MaCurdy TE, Worrall C,Kelman JA. Cardiovascular, bleeding, and mortality risks in elderly Medicare patientstreated with dabigatran or warfarin for nonvalvular atrial fibrillation. Circulation 2015;131:157–164.8. Heidbuchel H, Verhamme P, Alings M, Antz M, Hacke W, Oldgren J, Sinnaeve P,Camm AJ, Kirchhof P, European Heart Rhythm Association. European HeartRhythm Association practical guide on the use of new oral anticoagulants in patientswith non-valvular atrial fibrillation. Europace 2013;15:625–651.Editorial 2211

Edoxaban and amiodarone: interactions on multiple levels

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Edoxaban and amiodarone: interactions on multiple levels

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