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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
Study Questions:
What is the safety, tolerability, and most promising regimen of darexaban (YM150), a novel, oral, direct factor Xa inhibitor, for prevention of ischemic events in acute coronary syndrome (ACS)?
Methods:
In a 26-week, multicenter, double-blind, randomized, parallel-group study, 1,279 patients with recent high-risk non-ST-segment or ST-segment elevation ACS received one of six darexaban regimens: 5 mg BID, 10 mg QD, 15 mg BID, 30 mg QD, 30 mg BID, or 60 mg QD, or placebo, on top of dual antiplatelet treatment. Primary outcome was incidence of major or clinically relevant nonmajor bleeding events. The main efficacy outcome was a composite of death, stroke, myocardial infarction, systemic thromboembolism, and severe recurrent ischemia.
Results:
Bleeding rates were numerically higher in all darexaban arms versus placebo (pooled hazard ratio, 2.275; 95% confidence interval, 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 BID (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:
The authors concluded that 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.
Perspective:
This dose-ranging study showed that the frequency of major bleeding events during 6 months of double-blind treatment (on top of dual antiplatelet therapy) after ACS was two- to four-fold higher with the various doses of darexaban than with placebo. There was an increase in bleeding rates with increasing increments in the total daily dose. There was no significant difference in the composite of nonfatal MI, nonfatal stroke, severe recurrent ischemia, and death due to any cause during 6 months of double-blind treatment. Additional studies are indicated to test whether darexaban may achieve better clinical efficacy on top of dual antiplatelet therapy without an unacceptable increase in the risk of bleeding, but it should be noted that prior studies with other agents have failed to show superior efficacy with triple antithrombotic agent therapy.
Keywords: Myocardial Infarction, Stroke, Acute Coronary Syndrome, Fibrinolytic Agents, Azepines, Ribonucleases, Thromboembolism, Incidence, Coronary Angiography, Liver, Factor Xa, Benzamides, Confidence Intervals, Hemorrhage
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