Medications approved for adults often have additional uses in pediatric patients. Such is the case — as described by Wessel and colleagues — for clopidogrel, an agent that blocks the P2Y12 component of adenosine diphosphate (ADP) receptors on the surface of platelets. ADP receptors prevent the activation of the glycoprotein IIb/IIIa receptor complex, thereby reducing aggregation. Clopidogrel is used most commonly as a prophylactic antiplatelet therapy in adults with atherosclerotic cardiovascular disease, but is increasingly employed in the pediatric population, particularly in those with cardiac disease. Pediatric cardiovascular practitioners are using clopidogrel (along with the standard aspirin) to prevent the thrombosis of systemic-to-pulmonary-artery shunts in patients with complex cyanotic heart disease; however, the safety and efficacy of this practice have never been looked at prospectively. In the June 20 issue of The New England Journal of Medicine, investigators created a multicenter, event-driven trial to evaluate clopidogrel’s effect on infants.

The study, Clopidogrel to Lower Arterial Thrombotic Risk in Neonates and Infants Trial (CLARINET), was a double-blinded, randomized, placebo-controlled trial. Infants of 92 days or younger were recruited from one of 134 sites all over the world if they had cyanotic congenital heart disease that was palliated with a systemic-to-pulmonary-artery shunt. These infants were then randomly assigned to receive clopidogrel or placebo (most subjects in both groups were taking aspirin). The primary end point was defined as the earliest occurrence of any of the following: death or heart transplant, shunt thrombosis, or a cardiac procedure performed before 120 days of age because of a thrombotic event.  Adverse events, particularly bleeding episodes, also were tracked. Although this study was sponsored by the drug’s manufacturers Sanofi-Aventis and Bristol-Myers Squibb, the authors noted that statisticians not employed by either company were responsible for validating the final end point.

A total of 906 subjects were enrolled, 467 in the clopidogrel group and 439 in the placebo group. The authors found that adding clopidogrel to conventional therapies (i.e., aspirin) did not affect mortality from any cause or shunt-thrombosis-related morbidity. Although no statistically significant differences were detected in total subjects with adverse events, the authors found more neurologic events in the clopidogrel group versus the placebo group.

The authors proposed that the lack of an effect could be attributed to decreased baseline aggregation rate in infants compared to adults, possibly rendering clopidogrel‘s effect on ADP less protective in preventing thrombosis. Regardless of the reason, this study should give practitioners pause before prescribing clopidogrel in cyanotic infants with systemic-to-pulmonary-artery shunts.

This Concise Critical Appraisal is authored by SCCM member Daniel E. Sloniewsky, MD. Each installment highlights journal articles most relevant to the critical care practitioner.