CHICAGO — Clopidogrel at a dose of 0.2 mg/kg in infants and toddlers achieves a platelet inhibition level similar to the 75 mg/day that's standard in adults for prevention and treatment of major cardiac events, Dr. Jennifer S. Li said at the annual scientific sessions of the American Heart Association.
This was the main finding of the phase II Platelet Aggregation In Children (PICOLO) study, the first randomized, double-blind, multicenter clinical trial to look at the pharmacokinetics of clopidogrel in children age 0–24 months at increased risk of thrombotic events because of congenital heart disease, explained Dr. Li of the Duke Clinical Research Institute, Durham, N.C.
The antiplatelet drug isn't at present approved for use in young children, although it's often used off-label in those at increased thrombotic risk. PICOLO was undertaken in order to identify the optimal dose for platelet inhibition in such patients. Pinning down the correct dose was a priority because extrapolating adult dosing to children at roughly 1 mg/kg has been reported to result in life-threatening hemorrhage.
“This may be because extrapolated dosing doesn't account for physiologic or metabolic differences in children,” she said.
PICOLO involved 73 evaluable 0− to 24-month-olds at increased thrombotic risk due to a systemic-to-pulmonary artery shunt, stent placement, or Kawasaki disease. They were randomized to 7–28 days of clopidogrel at 0.01, 0.1, or 0.2 mg/kg per day or placebo.
The goal was to find the dose that achieved 30%–50% platelet inhibition by light transmission aggregometry. That's what 75 mg/day accomplishes in adults, for whom there is extensive evidence to show that this degree of platelet inhibition results in a marked reduction in thrombotic events.
The optimal dose in children proved to be 0.2 mg/kg. It achieved 49% inhibition of the maximum extent of platelet aggregation and 44% inhibition of the rate of aggregation. Lesser doses didn't even come close to the target.
Clopidogrel at all doses was well tolerated. No hemorrhagic events occurred.
Effective platelet inhibition can't be assumed to be a surrogate for clinical efficacy in children. Clinical outcomes are being assessed in the ongoing Clopidogrel To Lower Arterial Thrombotic Risk For Neonates and Infants Trial (CLARINET). Both PICOLO and CLARINET are sponsored by Sanofi-Aventis and Bristol-Myers Squibb.