title: Real-time dose adjustment using point-of-care platelet reactivity testing in a double-blind study of prasugrel in children with sickle cell anaemia.
abstract: Patients with sickle cell anaemia (SCA) have vaso-occlusive crises resulting from occlusive hypoxic-ischaemic injury. Prasugrel inhibits platelet activation and aggregation involved in SCA pathophysiology. Determining Effects of Platelet Inhibition on Vaso-Occlusive Events (DOVE) was a phase 3, double-blind, randomised, placebo-controlled trial assessing prasugrel efficacy. DOVE sought to bring patients' P2Y12 reaction unit (PRU) value within a targeted range via prasugrel dose adjustments using encrypted VerifyNow P2Y12®(VN-P2Y12) point-of-care testing and an interactive voice-response system (IVRS). After PRU determination, randomised patients received 0.08 mg/kg/day prasugrel or placebo. Encrypted PRUs and IVRS provided double-blind dose adjustments to achieve a defined PRU target range of 136-231; placebo patients had mock titrations. Of 341 randomised patients, 166 placebo and 160 prasugrel patients reached the fully titrated dose (FTD). Most prasugrel patients (n=104, 65 %) remained on the initial 0.08 mg/kg dose; doses escalations occurred in 23 % of patients (n=36). Mean PRUs for the pharmacodynamic population at baseline were similar in the prasugrel (273 ± 44.9) and placebo groups (273 ± 51.7), with significant reductions in PRU (p<0.001) for prasugrel patients at the FTD and at 9 months. Concomitant use of hydroxyurea did not affect platelet reactivity at any time. The majority of prasugrel patients (n=135, 84.4 %) at the FTD were within the target range of 136-231 PRUs. Mean VN-P2Y12 percentage inhibition at baseline was similar in the prasugrel (2.8  ± 5.4 %) and placebo groups (2.0 ± 4.7 %); prasugrel patients had significant increases in inhibition (p<0.001) at FTD and at 9 months. Patients with higher PRU values at baseline required higher prasugrel doses to bring PRU within the prespecified range. DOVE is the first study to successfully employ double-blind, real-time, encrypted, point-of-care platelet testing and IVRS to dose-adjust antiplatelet therapy to a targeted range of platelet inhibition.
authors.affiliation: Joseph A. Jakubowski, PhD, Eli Lilly and Company, Indianapolis, IN 46285, USA, Tel.: +1 317 276 9036, Fax: +1 317 433 1996, E-mail: jayacjay@aol.com.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Jakubowski
authors.forename: Carolyn C
authors.initials: CC
authors.lastname: Hoppe
authors.forename: Chunmei
authors.initials: C
authors.lastname: Zhou
authors.forename: Brendan E
authors.initials: BE
authors.lastname: Smith
authors.forename: Patricia B
authors.initials: PB
authors.lastname: Brown
authors.forename: Lori E
authors.initials: LE
authors.lastname: Heath
authors.forename: Baba
authors.initials: B
authors.lastname: Inusa
authors.forename: David C
authors.initials: DC
authors.lastname: Rees
authors.forename: David S
authors.initials: DS
authors.lastname: Small
authors.forename: Neehar
authors.initials: N
authors.lastname: Gupta
authors.forename: Suqin
authors.initials: S
authors.lastname: Yao
authors.forename: Matthew
authors.initials: M
authors.lastname: Heeney
authors.forename: Julie
authors.initials: J
authors.lastname: Kanter
mesh_terms: D000293:Adolescent; D000755:Anemia, Sickle Cell / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy*; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D004311:Double-Blind Method; D054796:Drug Dosage Calculations; D016903:Drug Monitoring / Q000379:methods*; D005260:Female; D006801:Humans; D008297:Male; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D010979:Platelet Function Tests; D000067716:Point-of-Care Testing; D000068799:Prasugrel Hydrochloride / Q000008:administration & dosage* / Q000009:adverse effects; D011237:Predictive Value of Tests; D058921:Purinergic P2Y Receptor Antagonists / Q000008:administration & dosage* / Q000009:adverse effects; D058925:Receptors, Purinergic P2Y12 / Q000097:blood / Q000187:drug effects; D013997:Time Factors; D016896:Treatment Outcome; D014652:Vascular Diseases / Q000097:blood / Q000175:diagnosis / Q000517:prevention & control*
chemical_list: C548576:P2RY12 protein, human; D010975:Platelet Aggregation Inhibitors; D058921:Purinergic P2Y Receptor Antagonists; D058925:Receptors, Purinergic P2Y12; D000068799:Prasugrel Hydrochloride
keywords: Prasugrel; VerifyNow; antiplatelet; clinical trial; platelets