• Cardiology Clinical Trials
• Coronary Artery Disease

Results from the RUBY-I trial [NCT00994292] showed a dose-related, 2- to 4-fold increase in bleeding when the factor Xa inhibitor darexaban was added to standard treatment (aspirin with or without clopidogrel) for the secondary prevention of ischemic vascular events in patients with recent acute coronary syndrome (ACS). These result are consistent with the findings of other factor Xa inhibitor trials in patients with ACS and, thus, not unexpected in this Phase 2 dose-ranging safety trial that compared darexaban with placebo. Gabriel Steg, MD, Hôpital Bichat, Université Paris Diderot, Paris, France, who presented the results of the RUBY-1 trial, stated that “investigating the potential role of low-dose darexaban in preventing major cardiac events after ACS will require a large Phase 3 trial to test whether or not it might achieve clinical efficacy on top of dual antiplatelet therapy (DAPT) without an unacceptable increase in the risk of bleeding.”

The RUBY-1 trial was a prospective Phase 2, multicenter, double-blind, randomized, multiple-dose, placebo-controlled, parallel-group, 26-week study in 1279 patients with recent non-ST-segment elevation (NSTEMI) and ST-segment elevation (STEMI). Patients with NSTEMI were also required to have one additional risk factor for recurrent ischemic events. Key exclusion criteria included the need for ongoing anticoagulant therapy, fibrinolytic administration, glycoprotein llb/lllA antagonists or other antiplatelet drugs (aspirin and clopidogrel were allowed), heightened bleeding risk, stroke or transient ischemic attack within 12 months prior to index event, and persistent systolic blood pressure ≥160 mm Hg and/or diastolic blood pressure ≥100 mm Hg at baseline. After discontinuation of parenteral antithrombotic therapy, subjects received one of six regimens of darexaban (5 mg BID, 10 mg QD, 15 mg BID, 30 mg QD and BID, 60 mg QD) or placebo in addition to DAPT. The primary study outcome was the incidence of major or clinically relevant nonmajor bleeding events. Secondary endpoints included a composite of all-cause mortality, nonfatal myocardial infarction (MI), nonfatal stroke, and severe recurrent ischemia.

Approximately 70% of subjects had STEMI and nearly three-quarters had undergone PCI for their index event prior to study enrollment. The mean subject age was 57 years, and 80% was male. Approximately 96% of subjects were on DAPT with aspirin + clopidogrel. Of the 23% of patients who discontinued prematurely, 137 (11%) did so because of adverse events (AEs), which were more frequent in the groups that received high doses of darexaban. Overall AEs were similar between arms, including alanine transaminase, aspartate transaminase, and bilirubin levels.

Major and clinically relevant nonmajor bleeding events at 6 months were numerically higher in all darexaban arms compared with the placebo group (pooled HR, 2.28; 95% CI, 1.13 to 4.60; p=0.022) [Steg PG et al. Eur Heart J 2011]. There was a dose-response relationship (p=0.009) for increased bleeding rates with increasing darexaban dose. Furthermore, BID dosing was associated with numerically higher bleeding rates compared with the same QD dose across the three total study doses (10 mg, 30 mg, 60 mg). Relative to placebo (3.1%), the increase in bleeding was statistically significant (p=0.002) for the darexaban 30-mg BID dose (11.3%). No cases of fatal bleeding or intracranial hemorrhage were reported in either study group. TIMI major bleeding rates were low in all groups; however, the rate for any TIMI bleeding followed the same dose-dependent increase as was seen for the primary endpoint. There was no difference in the composite efficacy endpoint of all-cause mortality, nonfatal MI, nonfatal stroke, and severe recurrent ischemia in any of the darexaban dose groups, individually or combined, when compared with placebo (p=NS).

Darexaban is a novel anti-Xa anticoagulant, similar to rivaroxaban and apixaban, which have already been evaluated in Phase 2 studies. While the Phase 3 APPRAISE-2 trial that evaluated apixaban in ACS was halted early due to excess bleeding risk, the ATLAS-2 trial (rivaroxaban in ACS) is ongoing. Insights from these Phase 3 trials will help clinicians understand whether there is a role for oral anticoagulant therapy in addition to antiplatelet therapy in patients with ACS and how to dose these new agents appropriately.

• © 2011 MD Conference Express