CLARINET trial

Wessel, D. et al.
(Presented at AHA 2010)

Background: Infants with cyanotic congenital heart disease (CCHD) palliated with a systemic-to-pulmonary artery (PA) shunt are at increased risk for shunt thrombosis and mortality.

Methods: We conducted a multi-center, randomized, double-blind, placebo-controlled trial to determine whether the addition of clopidogrel, 0.2mg/kg/day, to conventional therapy reduces all-cause mortality and shunt-related morbidity in infants with CCHD palliated with a PA shunt. The clopidogrel dose was selected to inhibit ADP-induced platelet aggregation by 30-50%, similar to the 75 mg adult dose. The primary efficacy outcome event was the first occurrence of any component of the composite endpoint of death, shunt thrombosis or a cardiac procedure before 120 days of age following an event considered of thrombotic nature. This event-driven trial conducted in 32 countries had 80% power to detect a 30% relative reduction in the primary event rate with 172 events and .05 overall type I error rate.

Results: 906 infants <3 months of age who had undergone a PA shunt were randomly assigned to receive clopidogrel (467, 51.5%) or placebo (439, 48.5%) in addition to conventional therapy. Median duration of treatment was 162 days. Concomitant aspirin was administered in 88% of subjects.

The primary composite outcome rate did not differ significantly between the clopidogrel vs. placebo groups: 19.1% vs. 20.5%, respectively, with relative risk reduction = 11.1% (95%CI: –19.2, 33.6; p=.43).

Components of the composite primary outcome, analyzed separately, also did not differ significantly between clopidogrel and placebo groups: mortality rate was 11.8% vs 13.9%; shunt thrombosis was 5.8% vs. 4.8%, and cardiac-related interventions occurred in 4.5% vs. 3.2%, respectively.
Clopidogrel treatment was not significantly beneficial within any subgroups, specific cardiac defect groups or shunt types. The percentage of subjects in the clopidogrel vs. placebo groups with any bleeding event (18.8% vs. 20.2%) and with severe bleeding events (4.1% vs. 3.4%) was similar.

Conclusion: Clopidogrel treatment of infants < 3 months of age with CCHD palliated with a PA shunt and predominantly receiving concomitant aspirin therapy does not reduce all-cause mortality or shunt-related morbidity.