Aspirin and thienopyridine antiplatelet therapy (such as clopidogrel) are standard care in the treatment of acute coronary syndrome (ACS) and even in stable coronary artery disease (CAD) after coronary intervention with stent. However, effective antiplatelet agents are needed which do not increase the risk of bleeding. Two J-LANCELOT (Japanese Lessons from Antagonizing the Cellular Effect of Thrombin) trials were designed to evaluate a new protease-activated receptor 1 (PAR-1) inhibitor known as E5555 in Japanese patients; the primary purpose of the trials was to assess the safety and tolerability of E5555, and secondary purpose to determine its effects on major adverse cardiac events (MACE) and platelet aggregation in ACS and CAD.
Principal investigator Professor Shinya Goto from Tokai University School of Medicine, Japan, reported that the two trials separately showed that E5555 may have the potential to reduce MACE (CV death, MI, stroke, or recurrent ischemia) with no increase in serious bleeding events even with addition to standard care in both ACS and CAD patients.
ACS patients (unstable angina pectoris or non-ST elevation MI, n = 241) received a loading dose of 400 mg E5555 on day 1, followed by 50 mg, 100 mg, 200 mg E5555 or placebo per day for 12 weeks (>90% of patients also received aspirin and a thienopyridine). Patients with high-risk CAD (n = 263) received placebo, and 50 mg, 100 mg, or 200 mg E5555 once daily for 24 weeks (all patients were on aspirin and approximately 40% thienopyridine).
Bleeding was assessed according to CURE ("clopidogrel in unstable angina to prevent recurrent evets") and TIMI ("thrombolysis in MI") criteria. Though there was a numerical trend towards an increase in any bleeding incidence with increasing treatment dose of E5555, this was not statistically significant. Clinically significant bleeding consisting of TIMI major, minor and minimal bleeding requiring medical attention was almost the same between the placebo and combined active groups, 1.5% vs 1.5% in CAD and 6.6% vs 5.0% in ACS patients, respectively.
There was a numerically lower incidence of MACE in the active group than in the placebo group in the CAD trial (1.0% vs. 4.5%,>
E5555 produced strong inhibition of platelet aggregation via PAR-1 blockade. At trough levels, over 90% mean inhibition of platelet aggregation was achieved with doses of 100 mg and 200 mg, and 20-60% inhibition was achieved with a dose of 50 mg E5555 in both study groups.
Professor Goto said: "E5555 was generally well tolerated with regard to bleeding complications and has potential for reduction of MACE in patients with ACS or high risk CAD. While E5555 did not increase the incidence of clinically significant bleeding, there was a dose-dependent trend for increased minimal bleeding.
"From these results, PAR-1 receptor antagonism may be an attractive pathway in the treatment of atherothrombosis. But we need further adequately powered trials to determine the efficacy and safety of E5555."