Japanese-Lesson from Antagonizing the Cellular Effect of Thrombin - J-LANCELOT


The goal of the trial was to evaluate treatment with the novel protease-activated receptor-1 (PAR-1) antagonist E5555 (atopaxar) compared with placebo among Japanese patients with an acute coronary syndrome (ACS) or coronary artery disease (CAD). PAR-1 binding inhibits platelet activation.


E5555 will be associated with an acceptable rate of bleeding.

Study Design

  • Placebo Controlled
  • Randomized
  • Blinded
  • Parallel

Patient Populations:

  • Patients with CAD or recent/current ACS
  • Documented CAD defined as percutaneous coronary intervention (>4 weeks prior to enrollment), coronary artery bypass grafting (>12 weeks prior to enrollment), or stable CAD
  • Patients with diabetes, peripheral arterial disease, or prior stroke/transient ischemic attack were also eligible for enrollment

    Number of enrollees: 504
    Duration of follow-up: 12 weeks
    Age range: mean 64-67 years across different groups
    Percentage female: 12-20% across different groups


  • ST-elevation myocardial infarction

Primary Endpoints:

  • Bleeding events

Secondary Endpoints:

  • MACE defined as cardiovascular death, myocardial infarction, stroke, or recurrent ischemia
  • Platelet aggregation induced by thrombin receptor-activating peptide (TRAP)

Drug/Procedures Used:

Eligible Japanese patients were randomized to one of four treatment groups: 1) E5555 200 mg daily (n = 129), 2) E5555 100 mg daily (n = 131), 3) E5555 50 mg daily (n = 117), or 4) placebo (n = 127). Patients initially received a loading dose of E5555 400 mg or placebo on day 1.

ACS patients were treated with study drug for 12 weeks, whereas the other patients were treated for 24 weeks.

Concomitant Medications:

All patients received aspirin 75-325 mg daily.

Principal Findings:

In the ACS E5555 200 mg cohort, mean age was 64 years, 26% were women, mean weight was 65 kg, 36% had diabetes, and 75% had hypertension. The use of aspirin was 98%, and thienopyridine 89%.

There were no Thrombolysis in Myocardial Infarction (TIMI) major bleeds in any group. In the ACS cohort, any TIMI bleed (major, minor, or minimal) was 23.0% with the E5555 200 mg dose versus 16.4% with placebo (p = 0.40), and in the CAD cohort, any TIMI bleed was 13.2% versus 4.5% (p = 0.081), respectively.

In the ACS cohort, major adverse cardiac events (MACE) were 5.0% in the combined E5555 group versus 6.6% with placebo (p = 0.73), and in the CAD cohort, MACE were 1.0% versus 4.5% (p = 0.066), respectively.

In the ACS cohort, treatment-related adverse events were 44% in the combined E5555 group versus 28% with placebo (p = 0.024), and in the CAD cohort, treatment-related adverse events were 32% versus 14% (p = 0.003), respectively. This was mainly due to a dose-dependent increase in liver function abnormalities. Platelet aggregation was more than 90% with 100 mg and 200 mg E5555, and 20-60% with 50 mg E5555.


Among patients with ACS, CAD, or high-risk clinical characteristics, the use of E5555 (atopaxar) on a background of aspirin and clopidogrel may be effective. This novel agent prevented platelet activation in a dose-dependent manner by blocking the PAR-1 receptor. Nonmajor bleeding events were nonsignificantly increased with E5555, whereas MACE were nonsignificantly decreased. Liver enzyme abnormalities were increased with this experimental agent. Further study is needed to more precisely characterize the efficacy and safety of E5555.


Goto S, Ogawa H, Takeuchi M, Flather MD, Bhatt DL, on behalf of the J-LANCELOT(Japanese-Lesson from Antagonizing the Cellular Effect of Thrombin) Investigators. Double-blind, placebo-controlled Phase II studies of the protease-activated receptor 1 antagonist E5555 (atopaxar) in Japanese patients with acute coronary syndrome or high-risk coronary artery disease. Eur Heart J 2010;Aug 30:[Epub ahead of print].

Presented by Dr. Shinya Goto at the European Society of Cardiology Congress, Stockholm, Sweden, August 2010.

Clinical Topics: Acute Coronary Syndromes, Cardiac Surgery, Invasive Cardiovascular Angiography and Intervention, Prevention, Vascular Medicine, Atherosclerotic Disease (CAD/PAD), Aortic Surgery, Interventions and ACS, Interventions and Coronary Artery Disease, Interventions and Vascular Medicine, Hypertension

Keywords: Coronary Artery Disease, Myocardial Infarction, Stroke, Acute Coronary Syndrome, Ischemic Attack, Transient, Follow-Up Studies, Peripheral Arterial Disease, Ticlopidine, Pyridines, Percutaneous Coronary Intervention, Receptor, PAR-1, Platelet Aggregation, Liver, Imines, Coronary Artery Bypass, Hypertension, Diabetes Mellitus

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