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(Circulation. 2008;117:553-559.)
© 2008 American Heart Association, Inc.

Pediatric Cardiology

Dosing of Clopidogrel for Platelet Inhibition in Infants and Young Children

Primary Results of the Platelet Inhibition in Children On cLOpidogrel (PICOLO) Trial

Jennifer S. Li, MD, MHS; Eric Yow, MS; Katherine Y. Berezny, MPH; Paula M. Bokesch, MD; Matsato Takahashi, MD; Thomas P. Graham, Jr, MD; Stephen P. Sanders, MD; Daniel Sidi, MD; Damien Bonnet, MD; Peter Ewert, MD; Lisa K. Jennings, PhD; Alan D. Michelson, MD, for the PICOLO Investigators

From the Division of Pediatric Cardiology (J.S.L., E.Y., K.Y.B.), Department of Pediatrics, Duke University Medical Center and Duke Clinical Research Institute, Durham, NC; Children’s Healthcare of Atlanta (P.M.B.), Cardiac Research Department, Atlanta, Ga; Children’s Hospital of Los Angeles (M.T.), Los Angeles, Calif; Division of Cardiology (T.P.G.), Vanderbilt Children’s Hospital, Nashville, Tenn; Ospedale Pediatrico Bambino Gesu (S.P.S.), Rome, Italy; Départment de Pédiatrie (D.S., D.B.), Pediatric Cardiology Unit, Hospital Necker Enfants Malades, Université Paris V, Paris, France; Abteilung für angeborene Herzfehler (P.E.), Deutsches Herzzentrum Berlin, Berlin, Germany; Vascular Biology Center of Excellence (L.K.J.), University of Tennessee Health Science Center, Memphis, Tenn; and Center for Platelet Function Studies (A.D.M.), Department of Pediatrics, University of Massachusetts Medical School, Worcester, Mass.

Correspondence to Jennifer S. Li, MD, MHS, PO Box 17969, Duke Clinical Research Institute, Durham NC 27705. E-mail jennifer.li{at}duke.edu

Received May 16, 2007; accepted October 22, 2007.

Background— Infants and young children with certain types of heart disease are at increased risk for thromboses. Clopidogrel 75 mg/d is used in adults to prevent thrombotic events. The dose to achieve similar platelet inhibition in children is unknown. The objectives of the present study were (1) to determine the dose of clopidogrel needed in infants and young children to achieve a mean 30% to 50% inhibition of 5-µmol/L ADP–induced platelet aggregation (ie, inhibition similar to that observed with 75 mg in adults) and (2) to assess the safety and tolerability of clopidogrel in infants and young children.

Methods and Results— We performed a prospective, multicenter, randomized, placebo-controlled trial evaluating the pharmacodynamics of clopidogrel in children (0 to 24 months) with a cardiac condition at risk for arterial thrombosis. Patients were randomized to clopidogrel versus placebo in a 3:1 ratio in 4 sequential groups (0.01, 0.10, 0.20, and 0.15 mg/kg) for 7 and 28 days. Platelet aggregation was assessed at baseline and steady state by light-transmission aggregometry. Of 116 patients enrolled, 92 (50% neonates, 50% infants/toddlers) were randomized, and 73 completed the study. A total of 79% of the randomized and treated patients were taking aspirin. Compared with placebo, clopidogrel 0.20 mg · kg^–1 · d^–1 resulted in a mean 49.3% (95% confidence interval 25.7% to 72.8%) inhibition of the maximum extent of platelet aggregation and a mean 43.9% (95% confidence interval 18.6% to 69.2%) inhibition of the rate of platelet aggregation. There was marked interpatient variability in the degree of platelet aggregation inhibition within each treatment-dose group and age group. No serious bleeding events occurred.

Conclusions— Clopidogrel 0.20 mg · kg^–1 · d^–1 in children 0 to 24 months of age achieves a platelet inhibition level similar to that in adults taking 75 mg/d. Clopidogrel is well tolerated in infants and young children at this dose.

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