Clopidogrel in Critically Ill Patients

Christian Schoergenhofer; Eva-Luise Hobl; Peter Schellongowski; Gottfried Heinz; Walter S Speidl; Jolanta M Siller-Matula; Monika Schmid; Raute Sunder-Plaßmann; Thomas Stimpfl; Matthias Hackl; Bernd Jilma

doi:10.1002/cpt.878

Clopidogrel in Critically Ill Patients

Clin Pharmacol Ther. 2018 Feb;103(2):217-223. doi: 10.1002/cpt.878. Epub 2017 Nov 3.

Affiliations

¹ Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria.
² Department of Medicine I, Hematology, and Oncology, Medical University of Vienna, Vienna, Austria.
³ Department of Medicine II, Cardiology, Medical University of Vienna, Vienna, Austria.
⁴ Department of Medicine III, Gastroenterology, and Hepatology, Medical University of Vienna, Vienna, Austria.
⁵ Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria.
⁶ TAmiRNA GmbH, Vienna, Austria.

PMID: 28913918
PMCID: PMC5813104
DOI: 10.1002/cpt.878

Abstract

Only limited data are available regarding the treatment of critically ill patients with clopidogrel. This trial investigated the effects and the drug concentrations of the cytochrome P450 (CYP450) activated prodrug clopidogrel (n = 43) and the half-life of the similarly metabolized pantoprazole (n = 16) in critically ill patients. ADP-induced aggregometry in whole blood classified 74% (95% confidence intervals 59-87%) of critically ill patients as poor responders (n = 43), and 65% (49-79%) responded poorly according to the vasodilator-stimulated phosphoprotein phosphorylation (VASP-P) assay. Although the plasma levels of clopidogrel active metabolite normally exceed the inactive prodrug ∼30-fold, the parent drug levels even exceeded those of the metabolite 2-fold in critically ill patients. The half-life of pantoprazole was several-fold longer in these patients compared with reference populations. The inverse ratio of prodrug/active metabolite indicates insufficient metabolization of clopidogrel, which is independently confirmed by the ∼5-fold increase in half-life of pantoprazole. Thus, high-risk patients may benefit from treatment with alternative platelet inhibitors.

Publication types

Clinical Trial
Comparative Study
Research Support, Non-U.S. Gov't

MeSH terms

Activation, Metabolic
Aged
Austria
Biomarkers / blood
Blood Platelets / drug effects*
Blood Platelets / metabolism
Cell Adhesion Molecules / blood
Clopidogrel / administration & dosage
Clopidogrel / adverse effects
Clopidogrel / blood
Clopidogrel / pharmacokinetics*
Critical Illness*
Cytochrome P-450 CYP2C19 / genetics
Cytochrome P-450 CYP2C19 / metabolism
Down-Regulation
Drug Monitoring / methods
Drug Resistance
Female
Half-Life
Humans
Male
Microfilament Proteins / blood
Middle Aged
Pantoprazole / administration & dosage
Pantoprazole / adverse effects
Pantoprazole / blood
Pantoprazole / pharmacokinetics*
Phosphoproteins / blood
Platelet Aggregation / drug effects*
Platelet Aggregation Inhibitors / administration & dosage
Platelet Aggregation Inhibitors / adverse effects
Platelet Aggregation Inhibitors / blood
Platelet Aggregation Inhibitors / pharmacokinetics*
Platelet Function Tests
Proton Pump Inhibitors / administration & dosage
Proton Pump Inhibitors / adverse effects
Proton Pump Inhibitors / blood
Proton Pump Inhibitors / pharmacokinetics*

Substances

Biomarkers
Cell Adhesion Molecules
Microfilament Proteins
Phosphoproteins
Platelet Aggregation Inhibitors
Proton Pump Inhibitors
vasodilator-stimulated phosphoprotein
Clopidogrel
Pantoprazole
CYP2C19 protein, human
Cytochrome P-450 CYP2C19