A Phase II, double-blind, randomized, parallel group, dose-finding study of the safety and tolerability of darexaban compared with warfarin in patients with non-valvular atrial fibrillation: The oral factor Xa inhibitor for prophylaxis of stroke in atrial fibrillation study 2 (OPAL-2)

G. Y H Lip, J. L. Halperin, P. Petersen, G. M. Rodgers, D. Páll, R. W. Renfurm

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

Background: Darexaban (YM150) is a novel oral anticoagulant that directly inhibits factor Xa. Objectives: To investigate the optimal daily dose regimen of YM150 in subjects with non-valvular atrial fibrillation (NVAF). Methods: In this multicenter, double-blind, double-dummy, randomized, parallel-group, dose-confirmation study (NCT00938730), patients with NVAF were randomized to darexaban 15 mg bid, 30 mg qd, 30 mg bid, 60 mg qd, 60 mg bid or 120 mg qd, or warfarin qd. The primary endpoint was the incidence of adjudicated major and/or clinically relevant non-major bleeding events. Secondary endpoints included efficacy, pharmacodynamics, safety and tolerability. Results: A total of 1297 patients were randomized and finally included in the trial (median age, 66 [range 30-89] years; 68.8% male): 981 completed treatment for a median of 28 weeks (interquartile range, 24-36). At daily doses of 30-60 mg, darexaban bid resulted in fewer bleeding events than darexaban qd. For darexaban 120 mg, the bid regimen produced more bleeding events than the qd regimen. Although few efficacy endpoints occurred, these decreased with increasing daily darexaban dose. Darexaban decreased plasma D-dimer levels (index of thrombogenesis) after 4 weeks of treatment by 21.5-33.8% compared with baseline, which was comparable with warfarin at the higher darexaban doses. Darexaban was well tolerated with no liver toxicity. Conclusions: In this Phase II study in patients with NVAF, a lower bleeding rate was observed in the 120 mg daily darexaban group compared with warfarin with a reduction in plasma D-dimer as marker for hemostasis. Further investigation of the optimal dose of darexaban for the prevention of stroke in patients with NVAF would need to be considered.

Original languageEnglish
Pages (from-to)1405-1413
Number of pages9
JournalJournal of Thrombosis and Haemostasis
Volume13
Issue number8
DOIs
Publication statusPublished - Aug 1 2015

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Warfarin
Atrial Fibrillation
Stroke
Safety
Hemorrhage
darexaban
Factor Xa Inhibitors
Hemostasis
Anticoagulants

Keywords

  • Anticoagulants
  • Atrial fibrillation
  • Clinical trial
  • Hemorrhage
  • Stroke

ASJC Scopus subject areas

  • Hematology

Cite this

@article{cc8d45ea073943c1bc09017d481229a1,
title = "A Phase II, double-blind, randomized, parallel group, dose-finding study of the safety and tolerability of darexaban compared with warfarin in patients with non-valvular atrial fibrillation: The oral factor Xa inhibitor for prophylaxis of stroke in atrial fibrillation study 2 (OPAL-2)",
abstract = "Background: Darexaban (YM150) is a novel oral anticoagulant that directly inhibits factor Xa. Objectives: To investigate the optimal daily dose regimen of YM150 in subjects with non-valvular atrial fibrillation (NVAF). Methods: In this multicenter, double-blind, double-dummy, randomized, parallel-group, dose-confirmation study (NCT00938730), patients with NVAF were randomized to darexaban 15 mg bid, 30 mg qd, 30 mg bid, 60 mg qd, 60 mg bid or 120 mg qd, or warfarin qd. The primary endpoint was the incidence of adjudicated major and/or clinically relevant non-major bleeding events. Secondary endpoints included efficacy, pharmacodynamics, safety and tolerability. Results: A total of 1297 patients were randomized and finally included in the trial (median age, 66 [range 30-89] years; 68.8{\%} male): 981 completed treatment for a median of 28 weeks (interquartile range, 24-36). At daily doses of 30-60 mg, darexaban bid resulted in fewer bleeding events than darexaban qd. For darexaban 120 mg, the bid regimen produced more bleeding events than the qd regimen. Although few efficacy endpoints occurred, these decreased with increasing daily darexaban dose. Darexaban decreased plasma D-dimer levels (index of thrombogenesis) after 4 weeks of treatment by 21.5-33.8{\%} compared with baseline, which was comparable with warfarin at the higher darexaban doses. Darexaban was well tolerated with no liver toxicity. Conclusions: In this Phase II study in patients with NVAF, a lower bleeding rate was observed in the 120 mg daily darexaban group compared with warfarin with a reduction in plasma D-dimer as marker for hemostasis. Further investigation of the optimal dose of darexaban for the prevention of stroke in patients with NVAF would need to be considered.",
keywords = "Anticoagulants, Atrial fibrillation, Clinical trial, Hemorrhage, Stroke",
author = "Lip, {G. Y H} and Halperin, {J. L.} and P. Petersen and Rodgers, {G. M.} and D. P{\'a}ll and Renfurm, {R. W.}",
year = "2015",
month = "8",
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doi = "10.1111/jth.13025",
language = "English",
volume = "13",
pages = "1405--1413",
journal = "Journal of Thrombosis and Haemostasis",
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TY - JOUR

T1 - A Phase II, double-blind, randomized, parallel group, dose-finding study of the safety and tolerability of darexaban compared with warfarin in patients with non-valvular atrial fibrillation

T2 - The oral factor Xa inhibitor for prophylaxis of stroke in atrial fibrillation study 2 (OPAL-2)

AU - Lip, G. Y H

AU - Halperin, J. L.

AU - Petersen, P.

AU - Rodgers, G. M.

AU - Páll, D.

AU - Renfurm, R. W.

PY - 2015/8/1

Y1 - 2015/8/1

N2 - Background: Darexaban (YM150) is a novel oral anticoagulant that directly inhibits factor Xa. Objectives: To investigate the optimal daily dose regimen of YM150 in subjects with non-valvular atrial fibrillation (NVAF). Methods: In this multicenter, double-blind, double-dummy, randomized, parallel-group, dose-confirmation study (NCT00938730), patients with NVAF were randomized to darexaban 15 mg bid, 30 mg qd, 30 mg bid, 60 mg qd, 60 mg bid or 120 mg qd, or warfarin qd. The primary endpoint was the incidence of adjudicated major and/or clinically relevant non-major bleeding events. Secondary endpoints included efficacy, pharmacodynamics, safety and tolerability. Results: A total of 1297 patients were randomized and finally included in the trial (median age, 66 [range 30-89] years; 68.8% male): 981 completed treatment for a median of 28 weeks (interquartile range, 24-36). At daily doses of 30-60 mg, darexaban bid resulted in fewer bleeding events than darexaban qd. For darexaban 120 mg, the bid regimen produced more bleeding events than the qd regimen. Although few efficacy endpoints occurred, these decreased with increasing daily darexaban dose. Darexaban decreased plasma D-dimer levels (index of thrombogenesis) after 4 weeks of treatment by 21.5-33.8% compared with baseline, which was comparable with warfarin at the higher darexaban doses. Darexaban was well tolerated with no liver toxicity. Conclusions: In this Phase II study in patients with NVAF, a lower bleeding rate was observed in the 120 mg daily darexaban group compared with warfarin with a reduction in plasma D-dimer as marker for hemostasis. Further investigation of the optimal dose of darexaban for the prevention of stroke in patients with NVAF would need to be considered.

AB - Background: Darexaban (YM150) is a novel oral anticoagulant that directly inhibits factor Xa. Objectives: To investigate the optimal daily dose regimen of YM150 in subjects with non-valvular atrial fibrillation (NVAF). Methods: In this multicenter, double-blind, double-dummy, randomized, parallel-group, dose-confirmation study (NCT00938730), patients with NVAF were randomized to darexaban 15 mg bid, 30 mg qd, 30 mg bid, 60 mg qd, 60 mg bid or 120 mg qd, or warfarin qd. The primary endpoint was the incidence of adjudicated major and/or clinically relevant non-major bleeding events. Secondary endpoints included efficacy, pharmacodynamics, safety and tolerability. Results: A total of 1297 patients were randomized and finally included in the trial (median age, 66 [range 30-89] years; 68.8% male): 981 completed treatment for a median of 28 weeks (interquartile range, 24-36). At daily doses of 30-60 mg, darexaban bid resulted in fewer bleeding events than darexaban qd. For darexaban 120 mg, the bid regimen produced more bleeding events than the qd regimen. Although few efficacy endpoints occurred, these decreased with increasing daily darexaban dose. Darexaban decreased plasma D-dimer levels (index of thrombogenesis) after 4 weeks of treatment by 21.5-33.8% compared with baseline, which was comparable with warfarin at the higher darexaban doses. Darexaban was well tolerated with no liver toxicity. Conclusions: In this Phase II study in patients with NVAF, a lower bleeding rate was observed in the 120 mg daily darexaban group compared with warfarin with a reduction in plasma D-dimer as marker for hemostasis. Further investigation of the optimal dose of darexaban for the prevention of stroke in patients with NVAF would need to be considered.

KW - Anticoagulants

KW - Atrial fibrillation

KW - Clinical trial

KW - Hemorrhage

KW - Stroke

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