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

      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.
      ] 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.
      ], 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.
      ] 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.
      ] 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.
      ,
      • 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.
      ], 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.

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