title: RUBY-1: a randomized, double-blind, placebo-controlled trial of the safety and tolerability of the novel oral factor Xa inhibitor darexaban (YM150) following acute coronary syndrome.
abstract: OBJECTIVE
  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).
  
  
  METHODS
  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.
  
  
  RESULTS
  Bleeding rates were numerically higher in all darexaban arms vs. placebo (pooled HR: 2.275; 95% CI: 1.13-4.60, P = 0.022). Using placebo as reference (bleeding rate 3.1%), there was a dose-response 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.
  
  
  CONCLUSIONS
  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.
authors: INSERM U-698, Paris, France. gabriel.steg@bch.aphp.fr
authors: Ph Gabriel
authors: PG
authors: Steg
authors: Shamir R
authors: SR
authors: Mehta
authors: J Wouter
authors: JW
authors: Jukema
authors: Gregory Y H
authors: GY
authors: Lip
authors: C Michael
authors: CM
authors: Gibson
authors: Frantisek
authors: F
authors: Kovar
authors: Petr
authors: P
authors: Kala
authors: Alberto
authors: A
authors: Garcia-Hernandez
authors: Ronny W
authors: RW
authors: Renfurm
authors: Christopher B
authors: CB
authors: Granger
mesh_terms: D054058:Acute Coronary Syndrome / Q000188:drug therapy*; D000284:Administration, Oral; D001381:Azepines / Q000008:administration & dosage / Q000009:adverse effects; D001549:Benzamides / Q000008:administration & dosage / Q000009:adverse effects; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D065427:Factor Xa Inhibitors; D005260:Female; D006470:Hemorrhage / Q000139:chemically induced; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000209:etiology; D017202:Myocardial Ischemia / Q000517:prevention & control; D012307:Risk Factors; D055502:Secondary Prevention; D020521:Stroke / Q000209:etiology; D013923:Thromboembolism / Q000209:etiology; D016896:Treatment Outcome
chemical_list: D001381:Azepines; D001549:Benzamides; D065427:Factor Xa Inhibitors; C569750:darexaban