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”
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.
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.
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.
Michelson AD, Frelinger AL, Furman MI. Resistance to antiplatelet drugs. Eur Heart J Supplements. 2006; 8 (suppl G): G53–G58.