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

Ph Gabriel Steg; Shamir R Mehta; J Wouter Jukema; Gregory Y.H. Lip; C Michael Gibson; Frantisek Kovar; Petr Kala; Alberto Garcia-Hernandez; Ronny W Renfurm; Christopher B Granger; RUBY-1 Investigators; Christian Tobias Torp-Pedersen

doi:http://dx.doi.org/10.1093/eurheartj/ehr334

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

Ph Gabriel Steg, Shamir R Mehta, J Wouter Jukema, Gregory Y.H. Lip, C Michael Gibson, Frantisek Kovar, Petr Kala, Alberto Garcia-Hernandez, Ronny W Renfurm, Christopher B Granger, RUBY-1 Investigators, Christian Tobias Torp-Pedersen

151 Citations (Scopus)

Abstract

Aims: 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).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: 1.134.60, 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. Conclusion: 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.

Original language	English
Journal	European Heart Journal (Online)
Volume	32
Issue number	20
Pages (from-to)	2541-54
Number of pages	14
ISSN	1522-9645
DOIs	https://doi.org/10.1093/eurheartj/ehr334
Publication status	Published - Oct 2011

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Steg, P. G., Mehta, S. R., Jukema, J. W., Lip, G. Y. H., Gibson, C. M., Kovar, F., Kala, P., Garcia-Hernandez, A., Renfurm, R. W., Granger, C. B., RUBY-1 Investigators, & Torp-Pedersen, C. T. (2011). 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. European Heart Journal (Online), 32(20), 2541-54. https://doi.org/10.1093/eurheartj/ehr334

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. / Steg, Ph Gabriel; Mehta, Shamir R; Jukema, J Wouter et al.

In: European Heart Journal (Online), Vol. 32, No. 20, 10.2011, p. 2541-54.

Research output: Contribution to journal › Journal article › Research › peer-review

Steg, PG, Mehta, SR, Jukema, JW, Lip, GYH, Gibson, CM, Kovar, F, Kala, P, Garcia-Hernandez, A, Renfurm, RW, Granger, CB, RUBY-1 Investigators & Torp-Pedersen, CT 2011, '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', European Heart Journal (Online), vol. 32, no. 20, pp. 2541-54. https://doi.org/10.1093/eurheartj/ehr334

@article{5a4d2dfe64b641c8bfb293953fb6e31f,

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 = "Aims: 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).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: 1.134.60, 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. Conclusion: 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.",

author = "Steg, {Ph Gabriel} and Mehta, {Shamir R} and Jukema, {J Wouter} and Lip, {Gregory Y.H.} and Gibson, {C Michael} and Frantisek Kovar and Petr Kala and Alberto Garcia-Hernandez and Renfurm, {Ronny W} and Granger, {Christopher B} and Torp-Pedersen, {Christian Tobias} and Torp-Pedersen, {Christian Tobias}",

year = "2011",

month = oct,

doi = "http://dx.doi.org/10.1093/eurheartj/ehr334",

language = "English",

volume = "32",

pages = "2541--54",

journal = "European Heart Journal",

issn = "0195-668X",

publisher = "Oxford University Press",

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T1 - RUBY-1

T2 - 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

AU - Steg, Ph Gabriel

AU - Mehta, Shamir R

AU - Jukema, J Wouter

AU - Lip, Gregory Y.H.

AU - Gibson, C Michael

AU - Kovar, Frantisek

AU - Kala, Petr

AU - Garcia-Hernandez, Alberto

AU - Renfurm, Ronny W

AU - Granger, Christopher B

AU - RUBY-1 Investigators

AU - Torp-Pedersen, Christian Tobias

PY - 2011/10

Y1 - 2011/10

N2 - Aims: 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).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: 1.134.60, 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. Conclusion: 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.

AB - Aims: 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).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: 1.134.60, 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. Conclusion: 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.

U2 - http://dx.doi.org/10.1093/eurheartj/ehr334

DO - http://dx.doi.org/10.1093/eurheartj/ehr334

M3 - Journal article

SN - 0195-668X

VL - 32

SP - 2541

EP - 2554

JO - European Heart Journal

JF - European Heart Journal

IS - 20

ER -

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

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