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(Circulation. 2008;118:e121.)
© 2008 American Heart Association, Inc.

Correspondence

Response to Letter Regarding Article, "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

Duke University, Durham, NC

Paula M. Bokesch, MD

Children’s Healthcare of Atlanta, Atlanta, Ga

Matsato Takahashi, MD

Children’s Hospital of Los Angeles, Los Angeles, Calif

Thomas P. Graham, Jr, MD

Vanderbilt University, Nashville, Tenn

Stephen P. Sanders, MD

Ospedale Pediatrico Bambino Gesu, Rome, Italy

Daniel Sidi, MD; Damien Bonnet, MD

Hospital Necker Enfants Malades, Paris, France

Peter Ewert, MD

Abteilung für angeborene Herzfehler Deutsches Herzzentrum Berlin, Berlin, Germany

Lisa K. Jennings, PhD

University of Tennessee Heath Science Center, Memphis, Tenn

Alan D. Michelson, MD

University of Massachusetts Medical School, Worcester, Mass

	Introduction

Top Introduction Disclosures References

 
We thank Caruthers and Dorsch for their interest in the Platelet Inhibition in Children On cLOpidogrel (PICOLO) trial.¹ The variability in inhibition of ADP-induced platelet aggregation by clopidogrel reported for pediatric patients in PICOLO (Figure 2 of our article¹) is similar to the well-described variability in inhibition of ADP-induced platelet aggregation by clopidogrel observed in adult patients.²

Caruthers and Dorsch’s main concern is that because clopidogrel undergoes metabolism through CYP3A4, lower CYP3A4 activity in neonates may explain the variability in our results. This theory assumes that lower CYP3A4 activity in neonates compared with infants would result in lower levels of the circulating metabolite of clopidogrel and, therefore, less inhibition of ADP-induced platelet aggregation. Their theory is of interest, as neonates tended to have higher, though statistically nonsignificant, inhibition of maximum extent of platelet aggregation at all doses evaluated, even though the mean aggregation response of each group before clopidogrel exposure was almost identical (40%). Thus, these data would contradict the supposition that significantly less active metabolite was being generated in the neonate cohort. As with adults, it has been postulated that variability of clopidogrel responsiveness may be due to differences in CYP3A4 activity and polymorphisms of the P2Y12 receptor, as well as baseline reactivity or pathophysiological status of individual patients.

Caruthers and Dorsch go on to state that "Clinical experience with clopidogrel has shown a need for higher doses to achieve 30% to 50% inhibition of 5 µmol/L ADP-induced platelet aggregation in the early years of life." However, only prospective, multicenter, randomized, placebo-controlled trials such as the PICOLO trial¹ can provide definitive conclusions in this regard.

Caruthers and Dorsch conclude by stating that, "It also seems reasonable to start with a dose based on this subset data and then check periodic platelet aggregation based on simple point-of-care tests to confirm the 30% to 50% inhibition." However, there is no established or validated relationship between any simple point-of-care tests and platelet aggregometry.^3,4 Furthermore, studies in neither children nor adults have demonstrated benefit by guiding the dose of clopidogrel based on the results of platelet function testing.

	Disclosures

Top Introduction Disclosures References

 
Drs Bokesch, Graham, Takahashi, and Sanders served on the steering committee and received honoraria from Sanofi-aventis. All authors indicate that their institutions have received research grants from Bristol-Myers Squibb and Sanofi-aventis.

	References

Top Introduction Disclosures References

 
1. Li JS, Yow E, Berezny KY, Bokesch PM, Takahashi M, Graham TP Jr, Sanders SP, Sidi D, Bonnet D, Ewert P, Jennings LK, Michelson AD. Dosing of clopidogrel for platelet inhibition in infants and young children: primary results of the Platelet Inhibition in Children On cLOpidogrel (PICOLO) trial. Circulation. 2008; 117: 553–559.[Abstract/Free Full Text]

2. Michelson AD, Frelinger AL, Furman MI. Resistance to antiplatelet drugs. Eur Heart J Supplements. 2006; 8 (suppl G): G53–G58.[Abstract/Free Full Text]

3. Gurbel PA, Becker RC, Mann KG, Steinhubl SR, Michelson AD. Platelet function monitoring in patients with coronary artery disease. J Am Coll Cardiol. 2007; 50: 1822–1834.[Abstract/Free Full Text]

4. Harrison P, Frelinger AL 3rd, Furman MI, Michelson AD. Measuring antiplatelet drug effects in the laboratory. Thromb Res. 2007; 120: 323–336.[CrossRef][Medline] [Order article via Infotrieve]

This Article Extract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Li, J. S. Articles by Michelson, A. D. Search for Related Content PubMed Articles by Li, J. S. Articles by Michelson, A. D. Related Collections Aggregation Acute myocardial infarction Platelets