title: 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.
abstract: BACKGROUND
  Thrombin is a key mediator of platelet activation. Atopaxar is a reversible protease-activated receptor-1 antagonist that interferes with thrombin-mediated platelet effects. The phase II Lessons From Antagonizing the Cellular Effect of Thrombin-Coronary Artery Disease (LANCELOT-CAD) trial examined the safety and tolerability of prolonged therapy with atopaxar in subjects with CAD.
  
  
  RESULTS
  Subjects with a qualifying history were randomized in a double-blind fashion to 3 dosing regimens of atopaxar (50, 100, or 200 mg daily) or matching placebo for 24 weeks and followed up for an additional 4 weeks. The key safety end points were bleeding according to the Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) and Thrombolysis in Myocardial Infarction (TIMI) classifications. Secondary objectives included platelet aggregation and major adverse cardiac events. Seven hundred and twenty subjects were randomized. Overall bleeding rates tended to be higher with atopaxar compared with placebo by CURE criteria (placebo, 0.6%; atopaxar, 3.9%; relative risk, 6.82, P=0.03; 50 mg, 3.9%; 100 mg, 1.7%; 200 mg, 5.9%; P for trend=0.01) and TIMI criteria (placebo, 6.8%; atopaxar, 10.3%; relative risk, 1.52, P=0.17; 50 mg, 9.9%; 100 mg, 8.1%; 200 mg, 12.9%; P for trend=0.07). There was no difference in major bleeding. Major adverse cardiac events were numerically lower in the atopaxar subjects. All atopaxar regimens achieved high levels of platelet inhibition. A transient elevation in liver transaminases and dose-dependent QTc prolongation without apparent complications were observed in higher-dose atopaxar treatment groups.
  
  
  CONCLUSIONS
  In this dose-ranging study of patients with CAD, treatment with atopaxar resulted in platelet inhibition, more minor bleeding, and numerically but not statistically fewer ischemic events. Larger-scale trials are needed to determine whether these patterns translate into clinically meaningful effects.
  
  
  BACKGROUND
  URL: http://www.ClinicalTrials.gov. Unique identifier: NCT00312052.
authors.affiliation: Cardiovascular Division, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115, USA. swiviott@partners.org
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Wiviott
authors.forename: Marcus D
authors.initials: MD
authors.lastname: Flather
authors.forename: Michelle L
authors.initials: ML
authors.lastname: O'Donoghue
authors.forename: Shinya
authors.initials: S
authors.lastname: Goto
authors.forename: Desmond J
authors.initials: DJ
authors.lastname: Fitzgerald
authors.forename: Fernando
authors.initials: F
authors.lastname: Cura
authors.forename: Philip
authors.initials: P
authors.lastname: Aylward
authors.forename: Victor
authors.initials: V
authors.lastname: Guetta
authors.forename: Dariusz
authors.initials: D
authors.lastname: Dudek
authors.forename: Charles F
authors.initials: CF
authors.lastname: Contant
authors.forename: Dominick J
authors.initials: DJ
authors.lastname: Angiolillo
authors.forename: Deepak L
authors.initials: DL
authors.lastname: Bhatt
mesh_terms: D000368:Aged; D015415:Biomarkers; D001792:Blood Platelets / Q000187:drug effects; D003324:Coronary Artery Disease / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006470:Hemorrhage / Q000139:chemically induced; D006801:Humans; D007097:Imines / Q000008:administration & dosage* / Q000009:adverse effects; D008297:Male; D008875:Middle Aged; D015539:Platelet Activation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D011725:Pyridines / Q000008:administration & dosage* / Q000009:adverse effects; D018179:Receptors, Thrombin / Q000037:antagonists & inhibitors*
chemical_list: D015415:Biomarkers; C540445:E 5555; D007097:Imines; D010975:Platelet Aggregation Inhibitors; D011725:Pyridines; D018179:Receptors, Thrombin