title: Inhibition of platelet aggregation by AZD6140, a reversible oral P2Y12 receptor antagonist, compared with clopidogrel in patients with acute coronary syndromes.
abstract: OBJECTIVE
  In a substudy of DISPERSE (Dose confIrmation Study assessing anti-Platelet Effects of AZD6140 vs. clopidogRel in non-ST-segment Elevation myocardial infarction)-2, we compared the antiplatelet effects of AZD6140 and clopidogrel and assessed the effects of AZD6140 in clopidogrel-pretreated patients.
  
  
  BACKGROUND
  Clopidogrel, in combination with aspirin, reduces cardiovascular events in patients with acute coronary syndromes (ACS). However, patients with poor inhibition of platelet aggregation with clopidogrel may be less well protected. AZD6140 is a reversible oral P2Y(12) receptor antagonist that has been studied in ACS patients in comparison with clopidogrel (DISPERSE-2 study).
  
  
  METHODS
  Patients were randomized to receive either AZD6140 90 mg twice a day, AZD6140 180 mg twice a day, or clopidogrel 75 mg once a day for up to 12 weeks in a double-blind, double-dummy design. One-half the patients allocated AZD6140 received a 270-mg loading dose. Patients randomized to receive clopidogrel were given a 300-mg loading dose unless they had already been treated with clopidogrel. Adenosine diphosphate-induced platelet aggregation was assessed by optical aggregometry on day 1 and at 4-week intervals.
  
  
  RESULTS
  AZD6140 inhibited platelet aggregation in a dose-dependent fashion and both doses achieved greater levels of inhibition than clopidogrel (e.g., 4 weeks, 4-h postdose [mean (+/-SD)]: clopidogrel 64% [+/-22%], AZD6140 90 mg 79% [+/-22%], AZD6140 180 mg 95% [+/-8%]. AZD6140 also produced further suppression of platelet aggregation in patients previously treated with clopidogrel.
  
  
  CONCLUSIONS
  AZD6140 exhibited greater mean inhibition of platelet aggregation than a standard regimen of clopidogrel in ACS patients. In addition, AZD6140 further suppressed platelet aggregation in clopidogrel pretreated patients.
authors.affiliation: Cardiovascular Research Unit, University of Sheffield, Sheffield, United Kingdom. r.f.storey@sheffield.ac.uk
authors.forename: Robert F
authors.initials: RF
authors.lastname: Storey
authors.forename: Steen
authors.initials: S
authors.lastname: Husted
authors.forename: Robert A
authors.initials: RA
authors.lastname: Harrington
authors.forename: Stanley
authors.initials: S
authors.lastname: Heptinstall
authors.forename: Robert G
authors.initials: RG
authors.lastname: Wilcox
authors.forename: Gary
authors.initials: G
authors.lastname: Peters
authors.forename: Mark
authors.initials: M
authors.lastname: Wickens
authors.forename: Håkan
authors.initials: H
authors.lastname: Emanuelsson
authors.forename: Paul
authors.initials: P
authors.lastname: Gurbel
authors.forename: Peer
authors.initials: P
authors.lastname: Grande
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Cannon
mesh_terms: D054058:Acute Coronary Syndrome / Q000188:drug therapy*; D000284:Administration, Oral; D000368:Aged; D000077144:Clopidogrel; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004562:Electrocardiography / Q000187:drug effects*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000188:drug therapy*; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D058919:Purinergic P2 Receptor Antagonists; D058925:Receptors, Purinergic P2Y12; D013988:Ticlopidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*
chemical_list: C548576:P2RY12 protein, human; D010975:Platelet Aggregation Inhibitors; D058919:Purinergic P2 Receptor Antagonists; D058925:Receptors, Purinergic P2Y12; D000077144:Clopidogrel; D013988:Ticlopidine