title: 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.
abstract: BACKGROUND
  Atopaxar (E5555) is a reversible protease-activated receptor-1 thrombin receptor antagonist that interferes with platelet signaling. The primary objective of the Lessons From Antagonizing the Cellular Effects of Thrombin-Acute Coronary Syndromes (LANCELOT—ACS) trial was to evaluate the safety and tolerability of atopaxar in patients with ACS.
  
  
  RESULTS
  Six hundred and three subjects were randomized within 72 hours of non-ST-elevation ACS to 1 of 3 doses of atopaxar (400-mg loading dose followed by 50, 100, or 200 mg daily) or matching placebo. The incidence of Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) major or minor bleeding did not differ significantly between the combined atopaxar and placebo groups (3.08% versus 2.17%, respectively; P=0.63), and there was no dose-related trend (P=0.80). The incidence of CURE major bleeding was numerically higher in the atopaxar group compared with the placebo group (1.8% versus 0%; P=0.12). The incidence of cardiovascular death, myocardial infarction, stroke, or recurrent ischemia was similar between the atopaxar and placebo arms (8.03% versus 7.75%; P=0.93). The incidence of CV death, MI, or stroke was 5.63% in the placebo group and 3.25% in the combined atopaxar group (P=0.20). Dose-dependent trends for efficacy were not seen. Atopaxar significantly reduced ischemia on continuous ECG monitoring (Holter) at 48 hours compared with placebo (relative risk, 0.67; P=0.02). Transient dose-dependent transaminase elevation and relative QTc prolongation were observed with the highest doses of atopaxar.
  
  
  CONCLUSIONS
  In patients after ACS, atopaxar significantly reduced early ischemia on Holter monitoring without a significant increase in major or minor bleeding. Larger trials are required to fully establish the efficacy and safety of atopaxar.
  
  
  BACKGROUND
  URL: http://www.ClinicalTrials.gov. Unique identifier: NCT00548587.
authors.affiliation: Brigham and Women's Hospital, Boston, MA 02115, USA. modonoghue@partners.org
authors.forename: Michelle L
authors.initials: ML
authors.lastname: O'Donoghue
authors.forename: Deepak L
authors.initials: DL
authors.lastname: Bhatt
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Wiviott
authors.forename: Shaun G
authors.initials: SG
authors.lastname: Goodman
authors.forename: Desmond J
authors.initials: DJ
authors.lastname: Fitzgerald
authors.forename: Dominick J
authors.initials: DJ
authors.lastname: Angiolillo
authors.forename: Shinya
authors.initials: S
authors.lastname: Goto
authors.forename: Gilles
authors.initials: G
authors.lastname: Montalescot
authors.forename: Uwe
authors.initials: U
authors.lastname: Zeymer
authors.forename: Philip E
authors.initials: PE
authors.lastname: Aylward
authors.forename: Victor
authors.initials: V
authors.lastname: Guetta
authors.forename: Dariusz
authors.initials: D
authors.lastname: Dudek
authors.forename: Rafal
authors.initials: R
authors.lastname: Ziecina
authors.forename: Charles F
authors.initials: CF
authors.lastname: Contant
authors.forename: Marcus D
authors.initials: MD
authors.lastname: Flather
mesh_terms: D054058:Acute Coronary Syndrome / Q000188:drug therapy* / Q000401:mortality; D000368:Aged; D016757:Death, Sudden, Cardiac / Q000453:epidemiology; D005260:Female; D006470:Hemorrhage / Q000453:epidemiology; D006801:Humans; D007097:Imines / Q000008:administration & dosage* / Q000009:adverse effects; D015994:Incidence; D008107:Liver Diseases / Q000453:epidemiology; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000453:epidemiology; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D011725:Pyridines / Q000008:administration & dosage* / Q000009:adverse effects; D018179:Receptors, Thrombin / Q000037:antagonists & inhibitors*; D012307:Risk Factors; D055502:Secondary Prevention; D020521:Stroke / Q000453:epidemiology
chemical_list: C540445:E 5555; D007097:Imines; D010975:Platelet Aggregation Inhibitors; D011725:Pyridines; D018179:Receptors, Thrombin