RUBY-1

Study evaluating safety, tolerability and efficacy of darexaban in subjects with acute coronary syndromes (2011)

Condition

Secondary prevention of ischemic events in acute coronary syndrome (ACS)

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Objective

To evaluate the safety and tolerability of of different doses and dose regimens of darexaban on top of standard treatment with ASA with or without clopidogrel for secondary prevention of ischemic vascular events in patients with recent ACS

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Trial design

Randomized, double-blind, placebo-controlled, dose-ranging phase II study
Active treatment: six different darexaban regimens: 5 mg twice daily (n=159), 10 mg once daily (n=159), 15 mg twice daily (n=159), 30 mg once daily (n=156), 30 mg twice daily (n=153), 60 mg once daily (n=153) on top of antiplatelet treatment with ASA and/or clopidogrel, for 26 weeks
Control treatment: placebo tablets once or twice daily on top of antiplatelet treatment with ASA and/or clopidogrel (n=319)

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Endpoints

Primary safety endpoint: incidence of major and clinically relevant nonmajor bleeding events (according to a modified ISTH definition) during the 6 months of double-blind treatment
Secondary safety endpoint: TIMI major bleeding events
Primary efficacy endpoint: composite of all-cause mortality, non-fatal myocardial infarction (MI), non-fatal stroke, and severe recurrent ischaemia

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Trial participants

1258 patients with recent high-risk non-ST-segment or ST-segment elevation ACS

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Results

Safety outcome: The primary outcome of the study (major or clinically relevant non-major bleeding events) was numerically higher in all darexaban arms than in the placebo group, with hazard ratios ranging from 1.8 to 3.8. (pooled hazard ratio 2.275; p=0.022). Using placebo as reference (with a bleeding rate of 3.1%), there was a dose-response relationship for increased bleeding rates with increasing darexaban dose, since the cumulative incidence of bleeding was 6.2, 6.5, and 9.3% for patients receiving total daily doses of 10, 30, and 60 mg darexaban, respectively. This increase was statistically significant for the 30 mg twice daily dose (p=0.002). The rates of bleeding were similar for patients receiving twice daily vs. once daily dosing with darexaban (8.4 vs. 6.1%, respectively, p=0.310). There were no other significant drug-related safety concerns associated with darexaban
Efficay outcome: At 6 months, there was no decrease in rates of efficacy outcome (composite of all-cause death, non-fatal myocardial infarction, non-fatal stroke, and severe recurrent ischaemia) with darexaban versus placebo. The cumulative incidence of this composite efficacy outcome was numerically higher in the darexaban 30 and 60 mg daily dose arms compared with placebo, and numerically lower with the lowest dose (10 mg daily)

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Summary

Safety outcome: Darexaban, when added to dual antiplatelet therapy after ACS, produces an expected, dose-related 2- to 4-fold increase in bleeding:

  • Bleeding rates were numerically higher in all darexaban arms versus placebo
  • There was a dose-response relationship for increased bleeding with increasing darexaban dose, which was statistically significant for darexaban 30 mg twice daily

Darexaban was well tolerated, with no signs of liver toxicity
Efficacy outcome: There was no decrease in efficacy event rates with darexaban. However, as with most phase II dose-ranging trials of antithrombotic drugs, this study was underpowered for efficacy

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Reference

Steg PG, Mehta SR, Jukema JW, Lip GY, Gibson CM, Kovar F, Kala P, Garcia-Hernandez A, Renfurm RW, Granger CB, on behalf of the RUBY-1 Investigators. 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. Eur Heart J 2011;32:2541-2554

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Corresponding author

Prof. Philippe Gabriel Steg, INSERM U-698 ‘Recherche Clinique en Athérothrombose’, Université Paris VII-Denis Diderot, Centre Hospitalier Bichat-Claude Bernard, 46 rue Henri Huchard, 75877 Paris Cedex 18, France, e-mail: gabriel.steg@bch.aphp.fr

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