Darexaban added to dual antiplatelet therapy after ACS increased major or clinically relevant non-major bleeding compared to placebo (pooled HR 2.275; 95% CI 1.13-4.60; P=0.022).
RCT (n=1,279)
double-blind
randomized
Yes
Does darexaban added to dual antiplatelet therapy increase bleeding or improve efficacy outcomes in patients with recent high-risk ACS?
Darexaban added to dual antiplatelet therapy after ACS significantly increases bleeding risk without an apparent efficacy benefit, though the study was underpowered for efficacy.
Hazard Ratio: 2.275 (95% CI 1.13–4.6)
p-value: p=0.022
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). 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.
Steg et al. (2011) conducted an RCT in acute coronary syndrome (ACS) (n=1,279). darexaban (YM150) vs. placebo was evaluated on incidence of major or clinically relevant non-major bleeding events (HR 2.275, 95% CI 1.13-4.60, p=0.022). Darexaban added to dual antiplatelet therapy after ACS increased major or clinically relevant non-major bleeding compared to placebo (pooled HR 2.275; 95% CI 1.13-4.60; P=0.022).