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Letter to the Editor| Volume 90, P125-126, August 2021

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The debated issue of direct oral anticoagulants correct dosing: When even the reviewer is confused

Published:June 02, 2021DOI:https://doi.org/10.1016/j.ejim.2021.05.009
The debated issue of direct oral anticoagulants correct dosing: When even the reviewer is confused
Previous ArticleGender distribution in boards of internal medicine societies
      While the rejection of a paper submitted to a journal is an inevitable event in the activity of a researcher and must be accepted, sometimes the motivations for such rejection appear questionable or even in contrast to accepted recommendations. This is the case of an article we recently submitted to a prestigious, high-ranked, cardiology journal in which we discussed about the use of the two different doses of each direct oral anticoagulant (DOAC) in non-valvular atrial fibrillation (NVAF). Based on the different design of the phase III clinical trials, and in particular of RE-LY [
      • Connolly S.J.
      • Ezekowitz M.D.
      • Yusuf S.
      • Eikelboom J.
      • Oldgren J.
      • Parekh A.
      • Pogue J.
      • Reilly P.A.
      • Themeles E.
      • Varrone J.
      • Wang S.
      • Alings M.
      • Xavier D.
      • Zhu J.
      • Diaz R.
      • Lewis B.S.
      • Darius H.
      • Diener H.C.
      • Joyner C.D.
      • Wallentin L.
      RE-LY Steering Committee and Investigators
      Dabigatran versus warfarin in patients with atrial fibrillation.
      N Engl J Med. 2009; 361: 1139-1151https://doi.org/10.1056/NEJMoa0905561
      ] with dabigatran compared to ROCKET AF [
      • Patel M.R.
      • Mahaffey K.W.
      • Garg J.
      • Pan G.
      • Singer D.E.
      • Hacke W.
      • Breithardt G.
      • Halperin J.L.
      • Hankey G.J.
      • Piccini J.P.
      • Becker R.C.
      • Nessel C.C.
      • Paolini J.F.
      • Berkowitz S.D.
      • Fox K.A.
      • Califf R.M.
      ROCKET AF Investigators
      Rivaroxaban versus warfarin in nonvalvular atrial fibrillation.
      N Engl J Med. 2011; 365: 883-891https://doi.org/10.1056/NEJMoa1009638
      ], ARISTOTLE [
      • Granger C.B.
      • Alexander J.H.
      • McMurray J.J.
      • Lopes R.D.
      • Hylek E.M.
      • Hanna M.
      • Al-Khalidi H.R.
      • Ansell J.
      • Atar D.
      • Avezum A.
      • Bahit M.C.
      • Diaz R.
      • Easton J.D.
      • Ezekowitz J.A.
      • Flaker G.
      • Garcia D.
      • Geraldes M.
      • Gersh B.J.
      • Golitsyn S.
      • Goto S.
      • Hermosillo A.G.
      • Hohnloser S.H.
      • Horowitz J.
      • Mohan P.
      • Jansky P.
      • Lewis B.S.
      • Lopez-Sendon J.L.
      • Pais P.
      • Parkhomenko A.
      • Verheugt F.W.
      • Zhu J.
      • Wallentin L.
      ARISTOTLE Committees and Investigators
      Apixaban versus warfarin in patients with atrial fibrillation.
      N Engl J Med. 2011; 365: 981-992https://doi.org/10.1056/NEJMoa1107039
      ] and ENGAGE AF-TIMI 48 [
      • Giugliano R.P.
      • Ruff C.T.
      • Braunwald E.
      • Murphy S.A.
      • Wiviott S.D.
      • Halperin J.L.
      • Waldo A.L.
      • Ezekowitz M.D.
      • Weitz J.I.
      • Špinar J.
      • Ruzyllo W.
      • Ruda M.
      • Koretsune Y.
      • Betcher J.
      • Shi M.
      • Grip L.T.
      • Patel S.P.
      • Patel I.
      • Hanyok J.J.
      • Mercuri M.
      • Antman E.M.
      ENGAGE AF-TIMI 48 Investigators. Edoxaban versus warfarin in patients with atrial fibrillation.
      N Engl J Med. 2013; 369: 2093-2104https://doi.org/10.1056/NEJMoa1310907
      ] with the factor-Xa inhibitors rivaroxaban, apixaban, and edoxaban respectively, we argued that the administration of the lower dose of dabigatran should be essentially at the prescriber's discretion, whereas that of factor-Xa inhibitors should be strictly dependent on specific clinical and/or laboratory patient's characteristics, in the absence of which such posology needs to be considered off-label and generally avoided. As consistently reported in the Literature [
      • Steinberg B.A.
      • Shrader P.
      • Thomas L.
      • Ansell J.
      • Fonarow G.C.
      • Gersh B.J.
      • Kowey P.R.
      • Mahaffey K.W.
      • Naccarelli G.
      • Reiffel J.
      • Singer D.E.
      • Peterson E.D.
      • Piccini J.P.
      ORBIT-AF Investigators and Patients
      Off-label dosing of non-vitamin K antagonist oral anticoagulants and adverse outcomes: the ORBIT-AF II registry.
      J Am Coll Cardiol. 2016; 68: 2597-2604https://doi.org/10.1016/j.jacc.2016.09.966
      ,
      • Camm A.J.
      • Cools F.
      • Virdone S.
      • Bassand J.P.
      • Fitzmaurice D.A.
      • Fox K.A.A.
      • Goldhaber S.Z.
      • Goto S.
      • Haas S.
      • Mantovani L.G.
      • Kayani G.
      • Grierson Turpie A.G.
      • Antoon Verheugt F.W.
      • Kakkar A.K.
      • Investigators GARFIELD-AF
      Mortality in patients with atrial fibrillation receiving nonrecommended doses of direct oral anticoagulants.
      J Am Coll Cardiol. 2020; 76: 1425-1436https://doi.org/10.1016/j.jacc.2020.07.045
      ], the off-label administration of the lower doses of factor-Xa inhibitors may indeed be advantageous in terms of safety, but adequate efficacy cannot be guaranteed. Only by using factor-Xa inhibitors, and in general all DOAC, according to the same modalities applied in the corresponding phase III trial, it is possible to anticipate that the results observed therein will be reproduced in clinical practice.

      Keywords

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      References

        • Connolly S.J.
        • Ezekowitz M.D.
        • Yusuf S.
        • Eikelboom J.
        • Oldgren J.
        • Parekh A.
        • Pogue J.
        • Reilly P.A.
        • Themeles E.
        • Varrone J.
        • Wang S.
        • Alings M.
        • Xavier D.
        • Zhu J.
        • Diaz R.
        • Lewis B.S.
        • Darius H.
        • Diener H.C.
        • Joyner C.D.
        • Wallentin L.
        • RE-LY Steering Committee and Investigators
        Dabigatran versus warfarin in patients with atrial fibrillation.
        N Engl J Med. 2009; 361: 1139-1151https://doi.org/10.1056/NEJMoa0905561
        View in Article
        • Patel M.R.
        • Mahaffey K.W.
        • Garg J.
        • Pan G.
        • Singer D.E.
        • Hacke W.
        • Breithardt G.
        • Halperin J.L.
        • Hankey G.J.
        • Piccini J.P.
        • Becker R.C.
        • Nessel C.C.
        • Paolini J.F.
        • Berkowitz S.D.
        • Fox K.A.
        • Califf R.M.
        • ROCKET AF Investigators
        Rivaroxaban versus warfarin in nonvalvular atrial fibrillation.
        N Engl J Med. 2011; 365: 883-891https://doi.org/10.1056/NEJMoa1009638
        View in Article
        • Granger C.B.
        • Alexander J.H.
        • McMurray J.J.
        • Lopes R.D.
        • Hylek E.M.
        • Hanna M.
        • Al-Khalidi H.R.
        • Ansell J.
        • Atar D.
        • Avezum A.
        • Bahit M.C.
        • Diaz R.
        • Easton J.D.
        • Ezekowitz J.A.
        • Flaker G.
        • Garcia D.
        • Geraldes M.
        • Gersh B.J.
        • Golitsyn S.
        • Goto S.
        • Hermosillo A.G.
        • Hohnloser S.H.
        • Horowitz J.
        • Mohan P.
        • Jansky P.
        • Lewis B.S.
        • Lopez-Sendon J.L.
        • Pais P.
        • Parkhomenko A.
        • Verheugt F.W.
        • Zhu J.
        • Wallentin L.
        • ARISTOTLE Committees and Investigators
        Apixaban versus warfarin in patients with atrial fibrillation.
        N Engl J Med. 2011; 365: 981-992https://doi.org/10.1056/NEJMoa1107039
        View in Article
        • Giugliano R.P.
        • Ruff C.T.
        • Braunwald E.
        • Murphy S.A.
        • Wiviott S.D.
        • Halperin J.L.
        • Waldo A.L.
        • Ezekowitz M.D.
        • Weitz J.I.
        • Špinar J.
        • Ruzyllo W.
        • Ruda M.
        • Koretsune Y.
        • Betcher J.
        • Shi M.
        • Grip L.T.
        • Patel S.P.
        • Patel I.
        • Hanyok J.J.
        • Mercuri M.
        • Antman E.M.
        ENGAGE AF-TIMI 48 Investigators. Edoxaban versus warfarin in patients with atrial fibrillation.
        N Engl J Med. 2013; 369: 2093-2104https://doi.org/10.1056/NEJMoa1310907
        View in Article
        • Steinberg B.A.
        • Shrader P.
        • Thomas L.
        • Ansell J.
        • Fonarow G.C.
        • Gersh B.J.
        • Kowey P.R.
        • Mahaffey K.W.
        • Naccarelli G.
        • Reiffel J.
        • Singer D.E.
        • Peterson E.D.
        • Piccini J.P.
        • ORBIT-AF Investigators and Patients
        Off-label dosing of non-vitamin K antagonist oral anticoagulants and adverse outcomes: the ORBIT-AF II registry.
        J Am Coll Cardiol. 2016; 68: 2597-2604https://doi.org/10.1016/j.jacc.2016.09.966
        View in Article
        • Camm A.J.
        • Cools F.
        • Virdone S.
        • Bassand J.P.
        • Fitzmaurice D.A.
        • Fox K.A.A.
        • Goldhaber S.Z.
        • Goto S.
        • Haas S.
        • Mantovani L.G.
        • Kayani G.
        • Grierson Turpie A.G.
        • Antoon Verheugt F.W.
        • Kakkar A.K.
        • Investigators GARFIELD-AF
        Mortality in patients with atrial fibrillation receiving nonrecommended doses of direct oral anticoagulants.
        J Am Coll Cardiol. 2020; 76: 1425-1436https://doi.org/10.1016/j.jacc.2020.07.045
        View in Article
        • Steffel J.
        • Collins R.
        • Antz M.
        • Cornu P.
        • Desteghe L.
        • Haeusler K.G.
        • Oldgren J.
        • Reinecke H.
        • Roldan-Schilling V.
        • Rowell N.
        • Sinnaeve P.
        • Vanassche T.
        • Potpara T.
        • Camm A.J.
        • Heidbüchel H.
        • reviewers: External
        • Lip G.Y.H.
        • Deneke T.
        • Dagres N.
        • Boriani G.
        • Chao T.F.
        • Choi E.K.
        • Hills M.T.
        • Santos I.S.
        • Lane D.A.
        • Atar D.
        • Joung B.
        • Cole O.M.
        • Field M
        European Heart Rhythm Association practical guide on the use of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation.
        Europace. 2021; (Apr 25)https://doi.org/10.1093/europace/euab065
        View in Article
        • Douxfils J.
        • Adcock D.
        • Bates S.M.
        • Favaloro E.J.
        • Gouin-Thibault I.
        • Guillermo C.
        • Kawai Y.
        • Lindhoff-Last P.D.E.
        • Kitchen S.
        • Gosselin R.C.
        Update of the international council for standardization in hematology recommendations for laboratory measurement of direct oral anticoagulants.
        Thromb Haemost. 2021; (2021 Mar 19)https://doi.org/10.1055/a-1450-8178
        View in Article
        • Gulpen A.J.W.
        • Ten Cate H.
        • Henskens Y.M.C.
        • van Oerle R.
        • Wetzels R.
        • Schalla S.
        • Crijns H.J.
        • Ten Cate-Hoek A.J
        The daily practice of direct oral anticoagulant use in patients with atrial fibrillation; an observational cohort study.
        PLoS ONE. 2019; 14e0217302https://doi.org/10.1371/journal.pone.0217302
        View in Article

      Article info

      Publication history

      Published online: June 02, 2021
      Accepted: May 6, 2021
      Received: May 1, 2021

      Identification

      DOI: https://doi.org/10.1016/j.ejim.2021.05.009

      Copyright

      © 2021 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.

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