Clopidogrel in Critically Ill Patients

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.

Figure 1

ADP‐induced whole blood aggregometry. Upper panel: ADP‐induced whole blood aggregometry before (0 h) intake of daily 75 mg clopidogrel, as well as 2 h and 24 h thereafter, as well as results from patients with stable coronary artery disease (CAD).18 Lower panel: Platelet reactivity index as results of vasodilator‐stimulated phosphoprotein phosphorylation assay in patients in the intensive care unit (ICU) and in patients with stable CAD.18 Presented are medians (solid line), quartiles (dashed line), and individual geometric means. The gray symbols show ICU‐patients with platelet counts <75 G/L. The horizontal line shows the cutoff of 46 U and 42%, respectively (n = 43 at 0 h and 2 h, n = 37 at 24 h).

Figure 2

Plasma concentrations of clopidogrel and clopidogrel active metabolite. Presented are medians ± quartiles. Upper panel shows clopidogrel and clopidogrel active metabolite (n = 43) before (0 h) and 2 h and 24 h (n = 37) after intake of 75 mg clopidogrel. The lower panel shows the ratio of clopidogrel active metabolite concentrations and clopidogrel 2 h after intake of 75 mg clopidogrel subdivided by the different genotypes (n = 43) and in comparison with healthy volunteers who received 600 mg clopidogrel.12