title: Clopidogrel pharmacokinetics and pharmacodynamics in out-of-hospital cardiac arrest patients with acute coronary syndrome undergoing target temperature management.
abstract: BACKGROUND
  Target temperature management (TTM) after cardiac arrest (CA) improves outcome in patients with acute coronary syndrome (ACS). Previous data point to an interaction between hypothermia and drug metabolism, potentially impacting on platelet function in patients on antiplatelet therapy.
  
  
  OBJECTIVE
  To compare clopidogrel metabolism and platelet function in clopidogrel naïve ACS patients treated with TTM (33°C, n=15) and in ACS patients (troponin positive) without TTM (n=18).
  
  
  METHODS
  Platelet function was measured by multiple electrode platelet aggregometry (MEA), light transmittance aggregometry (LTA) and VASP analysis before and after administration of a 600mg clopidogrel loading dose. Plasma levels of clopidogrel and its metabolites were measured. All patients were screened for CYP2C19*2 polymorphism and scheduled for PCI. TTM was carried out for 24h at a target temperature of 33°C using a computer feedback surface cooling device in cardiac arrest patients.
  
  
  RESULTS
  Plasma concentration of clopidogrel and metabolites was lower in the TTM group after 2 and 4h, respectively (all p<0.005 vs. controls), and platelet function tests revealed an attenuated response to clopidogrel with respect to baseline platelet activity in the TTM group. This was significant for MEA, LTA and VASP analysis (all p<0.05). Moreover, there was no significant difference in genotype and platelet function determined ex vivo at 33 or 37°C, respectively.
  
  
  CONCLUSIONS
  Inhibition of platelet function is significantly lessened in TTM at 33°C, likely due to reduced clopidogrel absorption. Patients with TTM might thus have a higher risk for further cardiovascular events despite antiplatelet therapy with clopidogrel.
authors.affiliation: Department of Medicine/Cardiology, Deutsches Herzzentrum Berlin, Augustenburger Platz 1, 13353 Berlin, Germany. Electronic address: jkaufmann@DHZB.de.
authors.forename: Jan
authors.initials: J
authors.lastname: Kaufmann
authors.affiliation: Department of Medicine/Cardiology, Deutsches Herzzentrum Berlin, Augustenburger Platz 1, 13353 Berlin, Germany.
authors.forename: Ernst
authors.initials: E
authors.lastname: Wellnhofer
authors.affiliation: Department of Nephrology/Intensive Care Medicine, Cardiac Arrest Center of Excellence, Charité University Hospital Berlin, Campus Virchow, Augustenburger Platz 1, 13353 Berlin, Germany.
authors.forename: Helena
authors.initials: H
authors.lastname: Stockmann
authors.affiliation: Department of Medicine I, Jüdisches Krankenhaus Berlin, Heinz-Galinski-Str 1, 13347 Berlin, Germany.
authors.forename: Kristof
authors.initials: K
authors.lastname: Graf
authors.affiliation: Department of Medicine/Cardiology, Deutsches Herzzentrum Berlin, Augustenburger Platz 1, 13353 Berlin, Germany.
authors.forename: Eckart
authors.initials: E
authors.lastname: Fleck
authors.affiliation: Department of Nephrology/Intensive Care Medicine, Cardiac Arrest Center of Excellence, Charité University Hospital Berlin, Campus Virchow, Augustenburger Platz 1, 13353 Berlin, Germany.
authors.forename: Tim
authors.initials: T
authors.lastname: Schroeder
authors.affiliation: Department of Medicine/Cardiology, Deutsches Herzzentrum Berlin, Augustenburger Platz 1, 13353 Berlin, Germany.
authors.forename: Philipp
authors.initials: P
authors.lastname: Stawowy
authors.affiliation: Department of Nephrology/Intensive Care Medicine, Cardiac Arrest Center of Excellence, Charité University Hospital Berlin, Campus Virchow, Augustenburger Platz 1, 13353 Berlin, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Storm
mesh_terms: D054058:Acute Coronary Syndrome / Q000097:blood / Q000150:complications* / Q000188:drug therapy; D000368:Aged; D016887:Cardiopulmonary Resuscitation / Q000379:methods*; D000077144:Clopidogrel; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007036:Hypothermia, Induced / Q000379:methods*; D008297:Male; D058687:Out-of-Hospital Cardiac Arrest / Q000097:blood / Q000209:etiology / Q000628:therapy*; D010975:Platelet Aggregation Inhibitors / Q000493:pharmacokinetics; D011446:Prospective Studies; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D016896:Treatment Outcome
chemical_list: D010975:Platelet Aggregation Inhibitors; D000077144:Clopidogrel; D013988:Ticlopidine
keywords: Acute coronary syndrome; Clopidogrel metabolism; Hypothermia; Platelet aggregation