Lessons From Antagonizing the Cellular Effect of Thrombin–Coronary Artery Disease - LANCELOT–CAD

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. LANCELOT−CAD was a phase II trial designed to study the safety and efficacy of atopaxar in patients with chronic coronary artery disease (CAD).

Hypothesis:

Atopaxar would be safe and efficacious, as compared with placebo, in the treatment of patients admitted with high-risk chronic CAD.

Study Design

  • Placebo Controlled
  • Blinded
  • Randomized
  • Parallel

Patient Populations:

  • Previous acute coronary syndrome (including MI or unstable angina) at least 4 weeks previously
  • Percutaneous coronary revascularization at least 12 weeks previously
  • Angina with documented ischemia by provocative testing or angiographically evident coronary artery disease (>70%) and at least one high-risk indicator (high-sensitivity C-reactive protein >3.0 mg/L, diabetes mellitus, peripheral arterial disease, stroke [>1 year earlier], or carotid arterial disease) at the time of enrollment
  • On antiplatelet therapy with aspirin (75-325 mg daily) and/or a thienopyridine (clopidogrel or ticlopidine) for 1 month before screening

    Number of enrollees: 720
    Duration of follow-up: 28 weeks
    Median patient age: 64 years
    Percentage female: 24%

Exclusions:

  • Increased risk of bleeding (bleeding diathesis, major trauma, or surgery within 30 days; pathological bleeding within 6 months; history of intracranial or retinal hemorrhage, stroke, or TIA within 1 year; known intracranial vascular pathology; INR >1.5; partial thromboplastin time >1.5x ULN; platelet count <100,000/µL; hemoglobin <10 g/dl)
  • New York Heart Association class III or IV congestive heart failure
  • Cardiovascular instability, as evidenced by events or cardiovascular medication dose modifications within 30 days of screening
  • Surgery within 30 days of screening or planned during the course of the study
  • ALT or aspartate aminotransferase (AST) >3 ULN
  • Total bilirubin >1.5x ULN
  • Creatinine clearance <30 ml/min
  • Use of oral antiplatelet agents other than aspirin (≤325 mg daily), clopidogrel (75 mg daily), or ticlopidine (250 mg twice daily); oral anticoagulants; fibrinolytics; long-term nonsteroidal anti-inflammatory drugs or cyclooxygenase-2 inhibitors; potent and moderate CYP3A4 inhibitors; or other investigational agents

Primary Endpoints:

  • Any bleeding, as per CURE definition

Secondary Endpoints:

  • Major adverse cardiac events at 24 weeks
  • Platelet function studies
  • QTc change
  • Laboratory values
  • Adverse events

Drug/Procedures Used:

Patients were randomized in a 1:1:1:1 fashion to receive either placebo, or atopaxar 50 mg daily, 100 mg daily, or 200 mg daily for 24 weeks.

Concomitant Medications:

Aspirin (93%), clopidogrel (39%), lipid-lowering agent (94%), beta-blocker (79%), and renin-angiotensin-aldosterone antagonists (81%)

Principal Findings:

A total of 720 patients were randomized, 177 to placebo, 182 to atopaxar 50 mg daily, 174 to atopaxar 100 mg daily, and 187 to atopaxar 200 mg daily. Baseline characteristics were fairly similar between the four arms. About 67% had diabetes mellitus, 63% had prior myocardial infarction (MI), 63% had prior percutaneous coronary intervention, 43% had prior coronary artery bypass grafting, and 11% had experienced prior stroke/transient ischemic attack (TIA).

The primary endpoint of bleeding (as defined in the Clopidogrel in Unstable Angina to Prevent Recurrent Events [CURE] trial) was higher in the atopaxar arms compared with placebo (3.9% vs. 0.6%, p = 0.03). There was a trend toward higher bleeding with higher doses of atopaxar (3.9% vs. 1.7% vs. 5.9%, p = 0.01). This was mainly due to an increase in minor bleeding in the atopaxar arms compared with placebo (3.0% vs. 0.6%, p = 0.08). There was no difference in the incidence of major bleeding (0.9% vs. 0%, p = NS).

When analyzed by the Thrombolysis in Myocardial Infarction (TIMI) definitions for major, minor, and minimal bleeding, no differences were noted between the four arms. The incidence of cardiovascular death, stroke, MI, or recurrent ischemia was similar between the placebo and active control arms (4.6% vs. 1.7% vs. 2.9% vs. 3.2%, p = 0.77). Individual endpoints including cardiovascular death, MI, stroke, and recurrent ischemia were similar between the four arms.

Platelet function studies were assessed in 80 patients. Rapid and nearly complete inhibition of platelet aggregation (IPA) was achieved within 4-6 hours (as measured with 15 µM of thrombin receptor-activated peptide [TRAP]) with the 100 and 200 mg doses (90%, 96% mean IPA, respectively). High levels were maintained for 24 hours. In patients treated with 50 mg, 38% IPA was achieved by 4-6 hours, but inhibition diminished over time and was indistinguishable from placebo by 24 hours. After 2 weeks, all three atopaxar arms demonstrated high levels of IPA, although troughs and peaks were noted in the 50 mg arm. At study completion, the 50 mg arm had IPA levels that were similar to placebo at 3 days, whereas the 100 mg arm had similar IPA levels at 7 days.

There was a dose-related increase in the incidence of alanine aminotransferase (ALT) ≥3x upper limit of normal (ULN) with higher doses of atopaxar (1.1% vs. 2.9% vs. 5.5%) compared with placebo (0%) (p < 0.0001). Mean QTc was similar between the three atopaxar doses (410 vs. 416 vs. 414 msec) and placebo (415 msec) (p = 0.67). However, QTc prolongation >30 msec, as compared with baseline, was higher with higher doses of atopaxar (4.6% vs. 8.3% vs. 10.2%, p = 0.07).

Interpretation:

The results of the phase II LANCELOT−CAD trial demonstrate that atopaxar results in a dose-dependent increase in total bleeding, as compared with placebo, with no difference in the incidence of major bleeding, on a background of aspirin monotherapy, with about 40% also on clopidogrel. Platelet studies demonstrated a very rapid onset of platelet inhibition with the 100 and 200 mg doses, which was maintained for 24 hours after the initial dose. Higher doses were associated with a higher incidence of transaminitis, and a trend toward greater QTc prolongation. The trial was underpowered to study clinical outcomes, but they seemed to be similar between the placebo and atopaxar arms. Similar results have been noted in the LANCELOT−ACS and J-LANCELOT trials.

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

References:

Wiviott SD, Flather MD, O’Donoghue ML, et al. Randomized Trial of Atopaxar in the Treatment of Patients With Coronary Artery Disease: The Lessons From Antagonizing the Cellular Effect of Thrombin–Coronary Artery Disease Trial. Circulation 2011;123:1854-63.

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

Keywords: Coronary Artery Disease, Myocardial Infarction, Stroke, Acute Coronary Syndrome, Follow-Up Studies, Ischemic Attack, Transient, Platelet Aggregation Inhibitors, Receptors, Proteinase-Activated, Receptors, Thrombin, Peripheral Arterial Disease, Carotid Artery Diseases, Ticlopidine, Blood Platelets, Purinergic P2Y Receptor Antagonists, Percutaneous Coronary Intervention, C-Reactive Protein, Peptides, Coronary Artery Bypass, Diabetes Mellitus


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