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

AimsTo 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).MethodsIn 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.ResultsBleeding 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.ConclusionsDarexaban 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

More, More, More: Reducing Thrombosis in Acute Coronary Syndromes Beyond Dual Antiplatelet Therapy—Current Data and Future Directions

“…The control arms in the reported trials, against which TT was compared, have mostly included patients receiving a combination of aspirin and clopidogrel,21, 22, 23, 28, 29, 30, 31, 45 but current guidelines recommend ticagrelor or prasugrel over clopidogrel in ACS 15, 20, 26, 38. Consequently, any new combination regimen should be compared with “current best.” The combination of a non–vitamin K oral anticoagulant with DAPT that includes these more effective P2Y 12 inhibitors may increase bleeding compared with clopidogrel, but this has never been tested.…”

“…The addition of darexaban, another FXa inhibitor, to DAPT in ACS patients was examined in the phase II RUBY‐1 (Study Evaluating Safety, Tolerability, and Efficacy of YM150 in Subjects With Acute Coronary Syndromes) trial 29. Darexaban dose‐dependently increased TIMI major bleeding compared with placebo (0.6% versus 0.3%; 95% CI, 1.13–4.60; P =0.022), and although not powered to assess efficacy outcomes, there was no observed difference between groups (5.6% versus 4.4%; P value not significant).…”

Application of Rivaroxaban in Acute Coronary Syndrome: Evidence and Current Guidelines

“…Еще один блокатор Xa фактора дарексабан без-успешно изучен у больных с ОКС: исследование RUBY-1 из-за избытка кровотечений прекращено (на уровне II-й фазы) [14]. К концу 2015г успешно изученным и одобренным к использованию при ОКС из антикоагулянтов, пред-назначенных для длительного приема внутрь, явля-ется только ривароксабан.…”

Novel anticoagulants in the therapy of peripheral arterial and coronary artery disease

“…Darexaban, another Factor IIa Inhibitor, was evaluated for safety and tolerability for the prevention of ischemic events in acute coronary syndromes (34). Darexaban, when added to dual antiplatelet therapy, produced a dose-related 2-to 4-fold increase in bleeding versus placebo, with no other safety concerns, but also with no efficacy.…”