Adler, Marcel

Nagler, Michael

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LETTERS TOTHE EDITORdoi:10.1093/europace/euv107Published online 4 June 2015Adherence to treatment withnon-vitamin K antagonistanticoagulants: once- vs.twice-daily regimensWith great interest, we read the article byVrijens and Heidbuchel, recently published inEuropace1 focusing on adherence to non-vitamin K antagonists (NOACs) and translatingstudies on modelling HIV treatment toNOACs. We congratulate the authors fortheir excellent work. Indeed, reduced adher-ence might increase thrombo-embolic andbleeding complications and seriously impairthe value of NOACs in clinical practice. Wefully agree with the authors that clinicalstudies on predictors and consequences ofnon-adherence are urgently needed.However, conclusions for or against a par-ticular dosing regimen based on theoreticalconsiderations might be premature due toseveral reasons. First, patients with atrial fibril-lation areoften in need of concomitantmedica-tion. Limiting the overall number of tabletstaken per day might increase both, adherenceand persistence, to all drugs prescribed. In add-ition, there is consistent evidence based onclinical data that adherence in once-daily (QD)regimen is superior to twice-daily (BID) appli-cation, in particular with regard to drugsused to treat cardiovascular diseases. This wasconfirmed in a recentmeta-analysis comprisingall trials of drugs used in this setting.2 Secondly,the pharmacokinetic model mentioned wascreated in the context of HIV drugs. However,overall treatment outcomes for QD and BIDregimen in thesepatientswere similar ina rando-mized controlled trial, andbenefits for BIDwereshown in a subgroup of patients only.3 In thecase of rivaroxaban, pharmacokinetics of QDand BID treatments were extensively testedand no significant difference in terms of CmaxandCtroughwas established.4 Finally, inter-patientvariability of drug levels in NOACs is consider-able5 and no critically low trough-level is estab-lished. Since implementation of low molecularweight heparins we are aware that constanthigh drug levels are not absolutely necessary toachieve an effective anticoagulant treatment.In conclusion, we fully agree with theauthors that extent of adherence to NOACsas well as predictors and consequences of non-adherence are unclear. Clinical studies addres-sing these issues are urgently needed.Conflict of interest: M.A. declares that nocompeting interests exist. M.N. has receivedresearch grants or lecture fees from Pfizer,Novo Nordisk, Bayer, Bristol-Myers Squibb,CSL Behring, Sanofi-aventis, Roche Diagnos-tics, and Axonlab.References1. Vrijens B, Heidbuchel H. Non-vitamin K antagonistoral anticoagulants: considerations on once- vs.twice-daily regimens and their potential impact onmedication adherence. Europace 2015;17:514–23.2. Coleman CI, Roberts MS, Sobieraj DM, Lee S, Alam T,Kaur R. Effect of dosing frequency on chronic cardio-vascular disease medication adherence. Curr Med ResOpin 2012;28:669–80.3. Flexner C, Tierney C, Gross R, Andrade A, Lalama C,Eshleman SH et al. Comparison of once-daily ver-sus twice-daily combination antiretroviral therapyin treatment-naive patients: results of AIDS clinicaltrials group (ACTG) A5073, a 48-week randomizedcontrolled trial. Clin Infect Dis 2010;50:1041–52.4. Mueck W, Borris LC, Dahl OE, Haas S, Huisman MV,Kakkar AK et al. Population pharmacokineticsand pharmacodynamics of once- and twice-daily rivar-oxaban for the prevention of venous thromboembol-ism in patients undergoing total hip replacement.Thromb Haemost 2008;100:453–61.5. Mueck W, Stampfuss J, Kubitza D, Becka M. Clinicalpharmacokinetic and pharmacodynamic profile of riv-aroxaban. Clin Pharmacokinet 2014;53:1–16.Marcel Adler1 and Michael Nagler2,3,*1Department of Haematology and CentralHaematology Laboratory, Inselspital,Bern University, Bern, Switzerland;2Laboratory of Clinical Thrombosis andHaemostasis, and Cardiovascular ResearchInstitute, Maastricht University Medical Center,P.O. Box 616, Maastricht 6229 ER,The Netherlands;3Division of Haematology and CentralHaematology Laboratory, LuzernerKantonsspital,Lucerne 16 CH-6000, Switzerland*Corresponding author. Tel: +31 433 88 42 63;fax +31 433 88 41 59. E-mail address:m.nagler@maastrichtuniversity.nldoi:10.1093/europace/euv108Published online 4 June 2015Medication adherence andnon-vitamin K antagonist oralanticoagulants: what do wereally know?In their publication in EP-Europace, Vrijens andHeidbuchel1 conclude twice-daily (BID) dosingof non-vitamin K antagonist (VKA) oral anticoa-gulants ‘may be more forgiving in patients withsuboptimal adherence’ than once-daily (OD)dosing. The authors submit the above conclusionis ‘exemplified’ by the PLATO trial, which com-pared OD clopidogrel to BID ticagrelor in acutecoronary syndrome patients; suggesting thereduced rate of cardiovascular events with BIDticagrelor was the result of a ‘greater degree ofcontinuity of drug action’ in the presence of sub-optimal adherence.1,2 This theory ignores poten-tial differences in antiplatelet potency betweenagents, in addition to, likely inferior platelet inhib-ition in some clopidogrel patientswithCYP2C19genetic polymorphisms.3 These points are morelikely to explain differences in PLATOevent ratesthan variances in blood concentrations/activitysubsequent to suboptimal adherence.Weagreewith the authors that timing adher-ence (considering both the correct number ofdoses taken and their timing) is an importantadherence metric to consider. If one embracestiming adherence, the authors statement thatthe pharmacological equivalent of missing asingle dose of a QD regimen is missing threeconsecutive doses of a BID regimen (Figure 2,panel C) becomes representative of only anextreme instance of suboptimal adherence.1The European Heart RhythmAssociation guid-ance4 on new oral anticoagulants advises a for-gotten dose can be taken as long as no morethan half the dosing interval has passed. Thismeans a patient taking an OD regimen needonly remember to take their missed dosewithin 12-h of when it was scheduled to catchup; and consequently, need not go a full 48-hwithout a dose as depicted in panel C. It is alsonoteworthy that Figure 2 is stated to representa single hypothetical drug givenODvs. BID, andnot a comparison of different non-VKA oralanticoagulants.Perhaps most importantly, it is unclear whateffect fluctuations in non-VKAoral anticoagula-tion (measured by drug concentration in theblood or degrees of factor Xa and/or thrombininhibition) will have on efficacy and safety.Unlike antibiotics, for example, there is apaucity of data regarding what pharmacoki-netic/pharmacodynamic parameters are mostimportant in preventing thrombosis or bleed-ing. Perhaps the peak-to-trough ratio of theanticoagulant is most important (a kin to ami-noglycoside antibiotics), or maybe only aminimal trough level of anticoagulation activityabove a certain threshold is required toprevent or treat thrombosis?Published on behalf of the European Society of Cardiology. All rights reserved.& The Author 2015. For permissions please email: journals.permissions@oup.com.

Adherence to treatment with non-vitamin K antagonist anticoagulants: once- vs. twice-daily regimens

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Adherence to treatment with non-vitamin K antagonist anticoagulants: once- vs. twice-daily regimens

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