title: The new INNOVANCE® PFA P2Y cartridge is sensitive to the detection of the P2Y₁₂ receptor inhibition.
abstract: Insufficient response on antiplatelet medication has become an intensively discussed issue because of the risk factor of recurrent adverse cardiovascular events. However, the monitoring of antiplatelet therapy requires appropriate, robust and reliable test methods. For the measurement of thienopyridine effects, the manufacturer of the PFA-100® System provides the INNOVANCE® PFA P2Y * cartridge. We tested this cartridge for its capacity to detect the inhibition of the P2Y₁₂ receptor, which is the target for thienopyridine medication (e.g. clopidogrel). We compared the INNOVANCE® PFA P2Y * results with those obtained by the receptor specific flow cytometric vasodilator stimulated phosphoprotein (VASP) assay that expresses the status of the P2Y₁₂ receptor as "platelet reactivity index" (PRI). The in vitro addition of the P2Y₁₂ receptor antagonist cangrelor (AR-C69931MX) to citrated human whole blood resulted in a dose-dependent prolongation of closure times (CTs) of the INNOVANCE® PFA P2Y * cartridge correlating with decreased PRI levels. In volunteers, the intake of a 600 mg clopidogrel loading dose caused an increase of the CTs in all volunteers, although some of these volunteers were identified as "poor responders" by the VASP assay (no significant reduction of PRI levels). In 50 patients with stable coronary artery disease undergoing percutaneous coronary intervention (PCI) and under dual antiplatelet therapy, the new cartridge had a detection rate of 84% (CT 106 s as cut-off) for clopidogrel medication. After dividing the 50 patients into two groups according to their response to clopidogrel INNOVANCE® PFA P2Y * recognized all "responders" (defined by a PRI > 50%) using >106 s as cut-off but the specificity for a "good response" was only 42% because several "poor responders" (defined by a PRI > 50%) also showed CTs above the cut-off. The best correlation (substantial agreement) between the results of INNOVANCE® PFA P2Y * and of the VASP phosphorylation assay was achieved using CT > 200 s and PRI < 55% as cut-offs. Then, the sensitivity of INNOVANCE® PFA P2Y * was 97% and the specificity for a "good response" 65%. In summary, INNOVANCE® PFA P2Y * showed a high sensitivity for the detection of P2Y₁₂ receptor blockade, but had only a limited specificity for a "good response" to clopidogrel. Therefore, this new cartridge is a useful tool to rule out P2Y₁₂ receptor inhibition, if normal or only slightly prolonged CTs are obtained. Its predictive value for risk assessment of thromboembolic events, e.g. after coronary stent implantation, needs to be evaluated in clinical trials.
authors.affiliation: Institut fuer Klinische Biochemie und Pathobiochemie mit Zentrallabor, Universitaetsklinikum Wuerzburg, Wuerzburg, Germany. j.koessler@medizin.uni-wuerzburg.de
authors.forename: Juergen
authors.initials: J
authors.lastname: Koessler
authors.forename: Anna L
authors.initials: AL
authors.lastname: Kobsar
authors.forename: Mirjana S
authors.initials: MS
authors.lastname: Rajkovic
authors.forename: Andreas
authors.initials: A
authors.lastname: Schafer
authors.forename: Ulrike
authors.initials: U
authors.lastname: Flierl
authors.forename: Stephanie
authors.initials: S
authors.lastname: Pfoertsch
authors.forename: Johann
authors.initials: J
authors.lastname: Bauersachs
authors.forename: Udo
authors.initials: U
authors.lastname: Steigerwald
authors.forename: Andreas R
authors.initials: AR
authors.lastname: Rechner
authors.forename: Ulrich
authors.initials: U
authors.lastname: Walter
mesh_terms: D000249:Adenosine Monophosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001681:Biological Assay; D015415:Biomarkers / Q000097:blood; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism; D016022:Case-Control Studies; D015815:Cell Adhesion Molecules / Q000378:metabolism; D000077144:Clopidogrel; D003324:Coronary Artery Disease / Q000188:drug therapy; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D008297:Male; D008840:Microfilament Proteins / Q000378:metabolism; D008875:Middle Aged; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D011237:Predictive Value of Tests; D058919:Purinergic P2 Receptor Antagonists / Q000494:pharmacology* / Q000627:therapeutic use; D018048:Receptors, Purinergic P2 / Q000097:blood; D012680:Sensitivity and Specificity; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D055815:Young Adult; D000098662:Vasodilator-Stimulated Phosphoprotein
chemical_list: D015415:Biomarkers; D015815:Cell Adhesion Molecules; D008840:Microfilament Proteins; D010750:Phosphoproteins; D010975:Platelet Aggregation Inhibitors; D058919:Purinergic P2 Receptor Antagonists; D018048:Receptors, Purinergic P2; D000098662:Vasodilator-Stimulated Phosphoprotein; D000249:Adenosine Monophosphate; C117446:cangrelor; D000077144:Clopidogrel; D013988:Ticlopidine