Lesson From Antagonizing the Cellular Effects of Thrombin–Acute Coronary Syndromes - LANCELOT–ACS

Description:

Atopaxar is a novel protease-activated receptor-1 (PAR-1) antagonist (formerly known as E5555) that has shown promising results in early clinical studies. The LANCELOT−ACS trial was a phase II trial designed to study the safety and efficacy of atopaxar in patients admitted with acute coronary syndrome (ACS).

Hypothesis:

Atopaxar would be safe and efficacious, as compared with placebo, in the treatment of patients admitted with ACS.

Study Design

  • Blinded
  • Parallel
  • Placebo Controlled
  • Randomized

Patient Populations:

  • Male or female; ages 18-80 years
  • Presenting with features of unstable angina or non-ST-elevation MI
  • At least one of the following:
    o Troponin T or I or creatine kinase-myocardial band ≥ULN
    o ECG changes compatible with ischemia (i.e., ST depression at least 1 mm in two contiguous leads or T-wave inversion >3 mm or any dynamic ST shift or transient ST elevation)
    o Randomization and treatment ≤72 hours of the onset of symptoms

    Number of enrollees: 603
    Duration of follow-up: 12 weeks
    Median patient age: 61 years
    Percentage female: 32%

Exclusions:

  • Increased risk of bleeding, anemia (hemoglobin <10 g/dl), thrombocytopenia (<100 x 103/μL), history of pathological intracranial findings
  • Planned elective major surgery
  • Planned use of oral anticoagulants (e.g., warfarin), fibrinolytics, or regular nonsteroidal anti-inflammatory drugs
  • Known hepatic disease or creatinine clearance <30 ml/min

Primary Endpoints:

  • Major bleeding, as per CURE definition

Drug/Procedures Used:

Patients presenting with ACS were randomized in a 1:1:1:1 fashion to receive either placebo, or atopaxar 400 mg loading dose followed by 50 mg daily maintenance dose, atopaxar 400 mg loading dose followed by 100 mg daily maintenance dose, or atopaxar 400 mg loading dose followed by 200 mg daily maintenance dose.

Concomitant Medications:

Aspirin (97%), thienopyridine (82%), statin (88%), beta-blocker (85%), and glycoprotein IIb/IIIa inhibitor (15%)

Principal Findings:

A total of 603 patients were randomized, 142 to placebo, 156 to atopaxar 50 mg daily, 157 to atopaxar 100 mg daily, and 148 to atopaxar 200 mg daily. Baseline characteristics were fairly similar between the four arms. About 22% had diabetes mellitus, 27% had prior myocardial infarction (MI), 3% had prior stroke, and 5% had known peripheral arterial disease.

The primary endpoint of major bleeding (as defined in the Clopidogrel in Unstable Angina to Prevent Recurrent Events [CURE] trial) was noted to be similar between the placebo, atopaxar 50 mg, 100 mg, and 200 mg arms, respectively (0% vs. 0.7% vs. 3.2% vs. 1.4%, p = 0.28).The rate of major bleeding for all doses of atopaxar combined was 1.8% vs. 0% for placebo (p = 0.12). CURE-defined minor bleeding was also similar for placebo versus the three ascending doses of atopaxar (2.2% vs. 0.7% vs. 2.6% vs. 0.7%, p = 0.81). Similar results were noted when analyzed by the Thrombolysis in Myocardial Infarction (TIMI) definitions for major, minor, and minimal bleeding. The incidence of cardiovascular death, stroke, MI, or recurrent ischemia at 12 weeks was similar between the four arms (7.8% vs. 3.9% vs. 10.8% vs. 9.5%, p = 0.26). The incidence of ischemia, as detected by 48-hour Holter monitoring, was lower in the combined atopaxar arm, as compared with placebo (18.7% vs. 28.1%, p = 0.02). Two ischemic strokes were noted, one in the 100 mg arm and one in the 200 mg arm; one hemorrhagic stroke was also noted in the 100 mg arm. There were no strokes in the placebo arm.

Platelet function studies demonstrated a dose-dependent inhibition of platelet aggregation (as measured with 15 µM of thrombin receptor-activated peptide) with the 50 mg, 100 mg, and 200 mg maintenance doses of atopaxar (77% vs. 90% vs. 95% at 2 weeks, and 63% vs. 79% vs. 97% at 8 weeks). Significant inhibition of platelet aggregation with the loading dose of 400 mg was seen within 1-3 hours of administration (74%).

There was a dose-related increase in the incidence of alanine aminotransferase ≥3x upper limit of normal (ULN) with higher doses of atopaxar (2.2% vs. 2.2% vs. 5.5%; p = 0.14) compared with placebo (2.5%). Mean QTc was higher across the three atopaxar doses (410.9 vs. 414.4 vs. 417.8 msec), as compared with placebo (409.4 msec), although no malignant arrhythmias or syncope were noted.

Interpretation:

The results of the phase II LANCELOT−ACS trial demonstrate the safety of atopaxar in terms of major bleeding in patients with ACS, as compared with placebo (on a background of aspirin and a thienopyridine), although higher doses were associated with a higher incidence of transaminitis and QTc prolongation. The trial was underpowered to study clinical outcomes, but they seemed to be similar between the placebo and atopaxar arms. A high level of platelet aggregation inhibition was achieved with the 400 mg loading dose within 1-3 hours of administration, and this was sustained with the maintenance doses in a dose-response fashion. Similar safety and efficacy results were noted in the J-LANCELOT trial in Japanese patients with ACS, coronary artery disease, or high-risk clinical characteristics.

Atopaxar is a PAR-1 antagonist and, thus, has a novel mechanism of antiplatelet action. Further phase III trials are awaited.

References:

O’Donoghue ML, Bhatt DL, Wiviott SD, et al. Safety and Tolerability of Atopaxar in the Treatment of Patients With Acute Coronary Syndromes: The Lessons From Antagonizing the Cellular Effects of Thrombin–Acute Coronary Syndromes Trial. Circulation 2011;123:1843-53.

Presented by Dr. Michelle O’Donoghue at the Transcatheter Cardiovascular Therapeutics Meeting (TCT 2010), Washington, DC, September 2010.

Clinical Topics: Acute Coronary Syndromes, Arrhythmias and Clinical EP, Vascular Medicine, SCD/Ventricular Arrhythmias, Atrial Fibrillation/Supraventricular Arrhythmias

Keywords: Coronary Artery Disease, Myocardial Infarction, Stroke, Acute Coronary Syndrome, Follow-Up Studies, Creatine Kinase, Platelet Aggregation Inhibitors, Troponin T, Syncope, Receptors, Thrombin, Peripheral Arterial Disease, Ticlopidine, Pyridines, Blood Platelets, Peptides, Imines, Electrocardiography, Ambulatory, Diabetes Mellitus


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