title: High-dose aspirin in dogs increases vascular resistance with limited additional anti-platelet effect when combined with potent P2Y12 inhibition.
abstract: BACKGROUND
  With the arrival of the potent P2Y12 antagonists, ticagrelor and prasugrel, the need for co-treatment with aspirin in acute coronary syndromes must be re-examined. This study assessed whether high-dose aspirin: a) provides additional anti-platelet efficacy, assessed in vivo and ex vivo, when combined with P2Y12 inhibition; and/or b) has a negative effect on vascular function.
  
  
  METHODS
  Using an anaesthetized dog model of thrombosis, the effects of aspirin (50mg/kg) in addition to clopidogrel and ticagrelor were evaluated at two levels of P2Y12 inhibition, maximal (≥96%) and sub-maximal (~80%), as assessed by ex vivo ADP-induced whole blood impedence aggregometry.
  
  
  RESULTS
  In the absence of aspirin, maximal and sub-maximal P2Y12 inhibition inhibited arachidonic acid-induced platelet aggregation by approximately 80% and 24%, respectively, without affecting platelet TXA2 formation. During maximal P2Y12 inhibition, aspirin provided less additional inhibition of ex vivo arachidonic acid- and collagen-induced platelet aggregation, as compared with sub-maximal P2Y12 inhibition, without additional anti-thrombotic effect in vivo. Aspirin significantly decreased in vivo PGI2 production (27%) and increased vascular resistance (16%), independently of P2Y12 antagonism.
  
  
  CONCLUSIONS
  In the dog, P2Y12 antagonists inhibit TXA2-mediated platelet-aggregation independently of aspirin. Aspirin provides less additional anti-platelet effects during maximal compared with sub-maximal P2Y12 inhibition but increases vascular resistance.
authors: AstraZeneca R&D Mölndal, Sweden.
authors: Jan-Arne
authors: JA
authors: Björkman
authors: Helen
authors: H
authors: Zachrisson
authors: Gun-Britt
authors: GB
authors: Forsberg
authors: Helena
authors: H
authors: von Bahr
authors: Göran I
authors: GI
authors: Hansson
authors: Timothy D
authors: TD
authors: Warner
authors: Sven
authors: S
authors: Nylander
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D016718:Arachidonic Acid / Q000494:pharmacology; D001241:Aspirin / Q000494:pharmacology*; D000077144:Clopidogrel; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D008297:Male; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D058921:Purinergic P2Y Receptor Antagonists / Q000494:pharmacology*; D058925:Receptors, Purinergic P2Y12 / Q000378:metabolism*; D013927:Thrombosis / Q000188:drug therapy; D000077486:Ticagrelor; D013988:Ticlopidine / Q000031:analogs & derivatives / Q000494:pharmacology; D014655:Vascular Resistance / Q000187:drug effects
chemical_list: D010975:Platelet Aggregation Inhibitors; D058921:Purinergic P2Y Receptor Antagonists; D058925:Receptors, Purinergic P2Y12; D016718:Arachidonic Acid; D000077144:Clopidogrel; D000077486:Ticagrelor; D000241:Adenosine; D013988:Ticlopidine; D001241:Aspirin