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Why the four non-vitamin K-antagonist oral anticoagulants are actually five

  • Andrea Rubboli
    Correspondence
    Corresponding author. Department of Cardiovascular Diseases - AUSL Romagna, Division of Cardiology, Ospedale S. Maria delle Croci, Viale Randi 5, 48121 Ravenna, Italy
    Affiliations
    Department of Cardiovascular Diseases - AUSL Romagna, Division of Cardiology, S. Maria delle Croci Hospital, Viale Randi 5, 48121 Ravenna, Italy
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Published:April 18, 2020DOI:https://doi.org/10.1016/j.ejim.2020.04.010
      The four currently available non-vitamin K-antagonist oral anticoagulants (NOAC) include dabigatran, apixaban, edoxaban, and rivaroxaban. Because however of the different design of the randomized clinical trials in which they were compared with warfarin for the prevention of stroke and/or systemic embolism in patients with non-valvular atrial fibrillation (NVAF), NOAC should more properly be considered to be five. In the ARISTOTLE [
      • Granger CB
      • Alexander JH
      • McMurray JJ
      • Lopes RD
      • Hylek EM
      • Hanna M
      • Al-Khalidi HR
      • Ansell J
      • Atar D
      • Avezum A
      • Bahit MC
      • Diaz R
      • Easton JD
      • Ezekowitz JA
      • Flaker G
      • Garcia D
      • Geraldes M
      • Gersh BJ
      • Golitsyn S
      • Goto S
      • Hermosillo AG
      • Hohnloser SH
      • Horowitz J
      • Mohan P
      • Jansky P
      • Lewis BS
      • Lopez-Sendon JL
      • Pais P
      • Parkhomenko A
      • Verheugt FW
      • Zhu J
      • Wallentin L
      ARISTOTLE Committees and Investigators. Apixaban versus warfarin in patients with atrial fibrillation.
      ], ENGAGE AF-TIMI 48 [
      • Giugliano RP
      • Ruff CT
      • Braunwald E
      • Murphy SA
      • Wiviott SD
      • Halperin JL
      • Waldo AL
      • Ezekowitz MD
      • Weitz JI
      • Špinar J
      • Ruzyllo W
      • Ruda M
      • Koretsune Y
      • Betcher J
      • Shi M
      • Grip LT
      • Patel SP
      • Patel I
      • Hanyok JJ
      • Mercuri M
      • Antman EM
      ENGAGE AF-TIMI 48 Investigators. Edoxaban versus warfarin in patients with atrial fibrillation.
      ] and ROCKET AF [
      • Patel MR
      • Mahaffey KW
      • Garg J
      • Pan G
      • Singer DE
      • Hacke W
      • Breithardt G
      • Halperin JL
      • Hankey GJ
      • Piccini JP
      • Becker RC
      • Nessel CC
      • Paolini JF
      • Berkowitz SD
      • Fox KA
      • Califf RM
      ROCKET AF Investigators. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation.
      ] trials with the factor-Xa inhibitors (FXa) apixaban, edoxaban, and rivaroxaban, respectively, a single drug dose was contemplated at baseline, namely, 5 mg twice daily for apixaban, 60 mg once daily for edoxaban, and 20 mg once daily for rivaroxaban. In specific subpopulations with peculiar clinical and/or laboratory characteristics, including two out of three criteria among age ≥80 years, creatinine ≥1.5 ml/min, and body weight ≤60 kg for apixaban, at least one of creatinine clearance (CrCl) 30-50 ml/min, body weight ≤60 kg and concomitant use of potent glycoprotein-P inhibitors for edoxaban, and CrCl 30-50 ml/min for rivaroxaban [
      • Granger CB
      • Alexander JH
      • McMurray JJ
      • Lopes RD
      • Hylek EM
      • Hanna M
      • Al-Khalidi HR
      • Ansell J
      • Atar D
      • Avezum A
      • Bahit MC
      • Diaz R
      • Easton JD
      • Ezekowitz JA
      • Flaker G
      • Garcia D
      • Geraldes M
      • Gersh BJ
      • Golitsyn S
      • Goto S
      • Hermosillo AG
      • Hohnloser SH
      • Horowitz J
      • Mohan P
      • Jansky P
      • Lewis BS
      • Lopez-Sendon JL
      • Pais P
      • Parkhomenko A
      • Verheugt FW
      • Zhu J
      • Wallentin L
      ARISTOTLE Committees and Investigators. Apixaban versus warfarin in patients with atrial fibrillation.
      ,
      • Giugliano RP
      • Ruff CT
      • Braunwald E
      • Murphy SA
      • Wiviott SD
      • Halperin JL
      • Waldo AL
      • Ezekowitz MD
      • Weitz JI
      • Špinar J
      • Ruzyllo W
      • Ruda M
      • Koretsune Y
      • Betcher J
      • Shi M
      • Grip LT
      • Patel SP
      • Patel I
      • Hanyok JJ
      • Mercuri M
      • Antman EM
      ENGAGE AF-TIMI 48 Investigators. Edoxaban versus warfarin in patients with atrial fibrillation.
      ,
      • Patel MR
      • Mahaffey KW
      • Garg J
      • Pan G
      • Singer DE
      • Hacke W
      • Breithardt G
      • Halperin JL
      • Hankey GJ
      • Piccini JP
      • Becker RC
      • Nessel CC
      • Paolini JF
      • Berkowitz SD
      • Fox KA
      • Califf RM
      ROCKET AF Investigators. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation.
      ], all of them ultimately leading to an increased exposure to (and therefore effect of) the drug, dose reduction to 2.5 mg twice daily for apixaban, 30 mg once daily for edoxaban, and 15 mg once daily for rivaroxaban, was mandated (Fig. 1). At variance, in the RE-LY [
      • Connolly SJ
      • Ezekowitz MD
      • Yusuf S
      • Eikelboom J
      • Oldgren J
      • Parekh A
      • Pogue J
      • Reilly PA
      • Themeles E
      • Varrone J
      • Wang S
      • Alings M
      • Xavier D
      • Zhu J
      • Diaz R
      • Lewis BS
      • Darius H
      • Diener HC
      • Joyner CD
      • Wallentin L
      RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation.
      ] trial with the thrombin inhibitor dabigatran two different drug doses, namely, 150 mg twice daily and 110 mg twice daily, were contemplated at baseline and independently tested against warfarin in two identical populations (and therefore in a same population) with no adjustment based on any patient characteristics (Fig. 1). As a consequence, the two arms of the RE-LY [
      • Connolly SJ
      • Ezekowitz MD
      • Yusuf S
      • Eikelboom J
      • Oldgren J
      • Parekh A
      • Pogue J
      • Reilly PA
      • Themeles E
      • Varrone J
      • Wang S
      • Alings M
      • Xavier D
      • Zhu J
      • Diaz R
      • Lewis BS
      • Darius H
      • Diener HC
      • Joyner CD
      • Wallentin L
      RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation.
      ] trial could be considered as two independent studies.
      Fig. 1
      Fig. 1Design of the randomized clinical trials comparing the non-vitamin K-antagonist oral anticoagulants dabigatran apixaban, edoxaban, and rivaroxaban vs. warfarin in non-valvular atrial fibrillation. BID: twice daily; OD: once daily; CrCl: creatinine clearance.
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