Edoxaban effects on bleeding following punch biopsy and reversal by a 4-factor prothrombin complex concentrate.
BACKGROUND
The oral factor Xa inhibitor edoxaban has demonstrated safety and efficacy in stroke prevention in patients with atrial fibrillation and in the treatment and secondary prevention of venous thromboembolism. This study investigated the reversal of edoxaban's effects on bleeding measures and biomarkers by using a 4-factor prothrombin complex concentrate (4F-PCC).


RESULTS
This was a phase 1 study conducted at a single site. This was a double-blind, randomized, placebo-controlled, 2-way crossover study to determine the reversal effect of descending doses of 4F-PCC on bleeding duration and bleeding volume following edoxaban treatment. A total of 110 subjects (17 in part 1, 93 in part 2) were treated. Intravenous administration of 4F-PCC 50, 25, or 10 IU/kg following administration of edoxaban (60 mg) dose-dependently reversed edoxaban's effects on bleeding duration and endogenous thrombin potential, with complete reversal at 50 IU/kg. Effects on prothrombin time were partially reversed at 50 IU/kg. A similar trend was seen for bleeding volume.


CONCLUSIONS
The 4F-PCC dose-dependently reversed the effects of edoxaban (60 mg), with complete reversal of bleeding duration and endogenous thrombin potential and partial reversal of prothrombin time following 50 IU/kg. Edoxaban alone and in combination with 4F-PCC was safe and well tolerated in these healthy subjects. A dose of 50 IU/kg 4F-PCC may be suitable for reversing edoxaban anticoagulation.


BACKGROUND
http://www.clinicaltrials.gov. Unique identifier: NCT02047565.
From Daiichi Sankyo Pharma Development, Edison, NJ (H.Z., K.S.B., A.G.V., M.D., V.D., W.F., L.H., M.A.G., H.J.L.); Daiichi Sankyo Inc., Parsippany, NJ (J.-F.M.); Quintiles Inc., Overland, KS (B.L.); CSL Behring GmbH, Marburg, Germany (A.F.); and Brigham and Women's Hospital, Harvard Medical School, Boston, MA (E.M.A.). hzahir@dsi.com.
Hamim
H
Zahir
From Daiichi Sankyo Pharma Development, Edison, NJ (H.Z., K.S.B., A.G.V., M.D., V.D., W.F., L.H., M.A.G., H.J.L.); Daiichi Sankyo Inc., Parsippany, NJ (J.-F.M.); Quintiles Inc., Overland, KS (B.L.); CSL Behring GmbH, Marburg, Germany (A.F.); and Brigham and Women's Hospital, Harvard Medical School, Boston, MA (E.M.A.).
Karen S
KS
Brown
From Daiichi Sankyo Pharma Development, Edison, NJ (H.Z., K.S.B., A.G.V., M.D., V.D., W.F., L.H., M.A.G., H.J.L.); Daiichi Sankyo Inc., Parsippany, NJ (J.-F.M.); Quintiles Inc., Overland, KS (B.L.); CSL Behring GmbH, Marburg, Germany (A.F.); and Brigham and Women's Hospital, Harvard Medical School, Boston, MA (E.M.A.).
Alexander G
AG
Vandell
From Daiichi Sankyo Pharma Development, Edison, NJ (H.Z., K.S.B., A.G.V., M.D., V.D., W.F., L.H., M.A.G., H.J.L.); Daiichi Sankyo Inc., Parsippany, NJ (J.-F.M.); Quintiles Inc., Overland, KS (B.L.); CSL Behring GmbH, Marburg, Germany (A.F.); and Brigham and Women's Hospital, Harvard Medical School, Boston, MA (E.M.A.).
Madhuri
M
Desai
From Daiichi Sankyo Pharma Development, Edison, NJ (H.Z., K.S.B., A.G.V., M.D., V.D., W.F., L.H., M.A.G., H.J.L.); Daiichi Sankyo Inc., Parsippany, NJ (J.-F.M.); Quintiles Inc., Overland, KS (B.L.); CSL Behring GmbH, Marburg, Germany (A.F.); and Brigham and Women's Hospital, Harvard Medical School, Boston, MA (E.M.A.).
Jen-Fue
JF
Maa
From Daiichi Sankyo Pharma Development, Edison, NJ (H.Z., K.S.B., A.G.V., M.D., V.D., W.F., L.H., M.A.G., H.J.L.); Daiichi Sankyo Inc., Parsippany, NJ (J.-F.M.); Quintiles Inc., Overland, KS (B.L.); CSL Behring GmbH, Marburg, Germany (A.F.); and Brigham and Women's Hospital, Harvard Medical School, Boston, MA (E.M.A.).
Victor
V
Dishy
From Daiichi Sankyo Pharma Development, Edison, NJ (H.Z., K.S.B., A.G.V., M.D., V.D., W.F., L.H., M.A.G., H.J.L.); Daiichi Sankyo Inc., Parsippany, NJ (J.-F.M.); Quintiles Inc., Overland, KS (B.L.); CSL Behring GmbH, Marburg, Germany (A.F.); and Brigham and Women's Hospital, Harvard Medical School, Boston, MA (E.M.A.).
Barbara
B
Lomeli
From Daiichi Sankyo Pharma Development, Edison, NJ (H.Z., K.S.B., A.G.V., M.D., V.D., W.F., L.H., M.A.G., H.J.L.); Daiichi Sankyo Inc., Parsippany, NJ (J.-F.M.); Quintiles Inc., Overland, KS (B.L.); CSL Behring GmbH, Marburg, Germany (A.F.); and Brigham and Women's Hospital, Harvard Medical School, Boston, MA (E.M.A.).
Annette
A
Feussner
From Daiichi Sankyo Pharma Development, Edison, NJ (H.Z., K.S.B., A.G.V., M.D., V.D., W.F., L.H., M.A.G., H.J.L.); Daiichi Sankyo Inc., Parsippany, NJ (J.-F.M.); Quintiles Inc., Overland, KS (B.L.); CSL Behring GmbH, Marburg, Germany (A.F.); and Brigham and Women's Hospital, Harvard Medical School, Boston, MA (E.M.A.).
Wenqin
W
Feng
From Daiichi Sankyo Pharma Development, Edison, NJ (H.Z., K.S.B., A.G.V., M.D., V.D., W.F., L.H., M.A.G., H.J.L.); Daiichi Sankyo Inc., Parsippany, NJ (J.-F.M.); Quintiles Inc., Overland, KS (B.L.); CSL Behring GmbH, Marburg, Germany (A.F.); and Brigham and Women's Hospital, Harvard Medical School, Boston, MA (E.M.A.).
Ling
L
He
From Daiichi Sankyo Pharma Development, Edison, NJ (H.Z., K.S.B., A.G.V., M.D., V.D., W.F., L.H., M.A.G., H.J.L.); Daiichi Sankyo Inc., Parsippany, NJ (J.-F.M.); Quintiles Inc., Overland, KS (B.L.); CSL Behring GmbH, Marburg, Germany (A.F.); and Brigham and Women's Hospital, Harvard Medical School, Boston, MA (E.M.A.).
Michael A
MA
Grosso
From Daiichi Sankyo Pharma Development, Edison, NJ (H.Z., K.S.B., A.G.V., M.D., V.D., W.F., L.H., M.A.G., H.J.L.); Daiichi Sankyo Inc., Parsippany, NJ (J.-F.M.); Quintiles Inc., Overland, KS (B.L.); CSL Behring GmbH, Marburg, Germany (A.F.); and Brigham and Women's Hospital, Harvard Medical School, Boston, MA (E.M.A.).
Hans J
HJ
Lanz
From Daiichi Sankyo Pharma Development, Edison, NJ (H.Z., K.S.B., A.G.V., M.D., V.D., W.F., L.H., M.A.G., H.J.L.); Daiichi Sankyo Inc., Parsippany, NJ (J.-F.M.); Quintiles Inc., Overland, KS (B.L.); CSL Behring GmbH, Marburg, Germany (A.F.); and Brigham and Women's Hospital, Harvard Medical School, Boston, MA (E.M.A.).
Elliott M
EM
Antman
D061605:Administration, Intravenous; D000293:Adolescent; D000328:Adult; D001707:Biopsy, Needle / Q000009:adverse effects*; D001777:Blood Coagulation / Q000187:drug effects*; D001779:Blood Coagulation Factors / Q000494:pharmacology*; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D065427:Factor Xa Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D005260:Female; D006470:Hemorrhage / Q000517:prevention & control*; D006801:Humans; D008297:Male; D008875:Middle Aged; D011517:Prothrombin Time; D011725:Pyridines / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D013844:Thiazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D013997:Time Factors; D055815:Young Adult
D001779:Blood Coagulation Factors; D065427:Factor Xa Inhibitors; D011725:Pyridines; D013844:Thiazoles; C025667:prothrombin complex concentrates; C552171:edoxaban
anticoagulants; hemodynamics; pharmacology; thrombin