期刊
EUROPEAN HEART JOURNAL
卷 32, 期 20, 页码 2541-2554出版社
OXFORD UNIV PRESS
DOI: 10.1093/eurheartj/ehr334
关键词
Anticoagulant; Acute coronary syndrome; Secondary prevention; Darexaban
资金
- Astellas Pharma
- Servier
- Amgen
- Astellas
- AstraZeneca
- Bayer
- Boehringer Ingelheim
- Bristol-Myers Squibb
- Daiichi Sankyo/Eli Lilly alliance
- GlaxoSmithKline
- Medtronic
- Merck Sharpe
- Dohme
- Roche
- sanofi-aventis
- Medicines Company
- Eli Lilly
- Eisai
- Biotronik
- Boston Scientific
- Cordis
- Daiichi Sankyo
- Lilly
- Genzyme, Medtronic
- Merck
- Schering-Plough
- Orbus Neich
- Novartis
- Netherlands Heart Foundation
- Inter-University Cardiology Institute of the Netherlands
- European Community
- Johnson and Johnson
- Astellas Pharma US
- Medtronic Vascular, Inc.
- Merck Co.
- Hoffman-La Roche
- Otsuka
To establish the safety, tolerability and most promising regimen of darexaban (YM150), a novel, oral, direct factor Xa inhibitor, for prevention of ischaemic events in acute coronary syndrome (ACS). In a 26-week, multi-centre, double-blind, randomized, parallel-group study, 1279 patients with recent high-risk non-ST-segment or ST-segment elevation ACS received one of six darexaban regimens: 5 mg b.i.d., 10 mg o.d., 15 mg b.i.d., 30 mg o.d., 30 mg b.i.d., or 60 mg o.d. or placebo, on top of dual antiplatelet treatment. Primary outcome was incidence of major or clinically relevant non-major bleeding events. The main efficacy outcome was a composite of death, stroke, myocardial infarction, systemic thromboembolism, and severe recurrent ischaemia. Bleeding rates were numerically higher in all darexaban arms vs. placebo (pooled HR: 2.275; 95 CI: 1.134.60, P 0.022). Using placebo as reference (bleeding rate 3.1), there was a doseresponse relationship (P 0.009) for increased bleeding with increasing darexaban dose (6.2, 6.5, and 9.3 for 10, 30, and 60 mg daily, respectively), which was statistically significant for 30 mg b.i.d. (P 0.002). There was no decrease (indeed a numerical increase in the 30 and 60 mg dose arms) in efficacy event rates with darexaban, but the study was underpowered for efficacy. Darexaban showed good tolerability without signs of liver toxicity. Darexaban when added to dual antiplatelet therapy after ACS produces an expected dose-related two- to four-fold increase in bleeding, with no other safety concerns but no signal of efficacy. Establishing the potential of low-dose darexaban in preventing major cardiac events after ACS requires a large phase III trial. ClinicalTrials.gov Identifier: NCT00994292.
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