title: Does the VerifyNow P2Y12 assay overestimate "therapeutic response" to clopidogrel? Insights using short thrombelastography.
abstract: In contrast to short thrombelastography (s-TEG) which utilises adenosine diphosphate (ADP) alone, the VerifyNow P2Y12 assay (VN-P2Y12) additionally uses prostaglandin E1 (PGE1) as agonist to assess response to P2Y12 inhibitors. Based upon previous observations, we hypothesised that VN-P2Y12 overestimates the therapeutic effects of clopidogrel. Simultaneous assay with s-TEG and VN-P2Y12 was performed in 43 healthy volunteers and 170 patients either on or off clopidogrel. Furthermore, in 27 patients on clopidogrel 75 mg we compared the effects of adding 22 nM PGE1 to ADP on platelet aggregation in s-TEG to ADP alone. A higher proportion of individuals had a result indicating high platelet reactivity (HPR) with s-TEG than VN-P2Y12 in (i) 43 clopidogrel naïve volunteers (95.3% vs 81.4%, p = NS); (ii) 28 volunteers loaded with clopidogrel 600 mg (39.3% vs 10.7 %, p = < 0.01); (iii) 123 clopidogrel naïve patients (93.5% vs 78%, p = < 0.0001); (iv) 47 patients on clopidogrel 75 mg (42.6% vs 4.3%, p = < 0.0001). In 59 patients loaded with clopidogrel 600 mg/900 mg, a greater proportion had a "therapeutic response" with VN-P2Y12 compared to s-TEG, regardless of the threshold for defining HPR with VN-PY12 (P2Y12 reaction units ≥ 230 or 208). Furthermore, adding PGE1 to ADP in s-TEG potentiated the anti-aggregatory effects of clopidogrel compared with ADP alone. In conclusion, VN-P2Y12 overestimates the functional effects of clopidogrel in some individuals, possibly because it utilises PGE1 in addition to ADP. This could have implications for the ability of VN-P2Y12 to stratify patients as "responders" or "non-responders" to clopidogrel.
authors.forename: Vikram
authors.initials: V
authors.lastname: Khanna
authors.forename: Alex
authors.initials: A
authors.lastname: Hobson
authors.forename: Rand
authors.initials: R
authors.lastname: Mikael
authors.forename: Nalyaka
authors.initials: N
authors.lastname: Sambu
authors.forename: Nicola
authors.initials: N
authors.lastname: Englyst
authors.affiliation: Prof. N. Curzen, Wessex Cardiothoracic Unit, University Hospital Southampton NHS Foundation Trust, Southampton SO16 6YD, United Kingdom, Tel.: +44 2380794972, Fax: +44 2380795174, E-mail:nick.curzen@uhs.nhs.uk.
authors.forename: Nick
authors.initials: N
authors.lastname: Curzen
mesh_terms: D000244:Adenosine Diphosphate / Q000008:administration & dosage; D000527:Alprostadil / Q000008:administration & dosage; D000077144:Clopidogrel; D004357:Drug Synergism; D006801:Humans; D010974:Platelet Aggregation / Q000187:drug effects; D010979:Platelet Function Tests / Q000379:methods* / Q000706:statistics & numerical data; D058921:Purinergic P2Y Receptor Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D058925:Receptors, Purinergic P2Y12 / Q000097:blood*; D013916:Thrombelastography / Q000379:methods* / Q000706:statistics & numerical data; D013988:Ticlopidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: C548576:P2RY12 protein, human; D058921:Purinergic P2Y Receptor Antagonists; D058925:Receptors, Purinergic P2Y12; D000244:Adenosine Diphosphate; D000077144:Clopidogrel; D000527:Alprostadil; D013988:Ticlopidine
keywords: Clopidogrel; VerifyNow P2Y12 assay; high platelet reactivity; prostaglandin E1; thrombelastography