Clopidogrel in Infants With Systemic-to-Pulmonary-Artery Shunts

Study Questions:

Does the addition of clopidogrel to standard therapy reduce all-cause mortality and shunt-related morbidity in infants with cyanotic congenital heart disease palliated with systemic-to-pulmonary-artery shunts?

Methods:

CLARINET (Clopidogrel to Lower Arterial Thrombotic Risk in Neonates and Infants Trial), a multicenter, double-blind, placebo-controlled trial was performed. Infants 92 days of age or younger with cyanotic congenital heart disease with systemic-to-pulmonary-artery shunt (including modified Blalock-Taussig [BT] shunt, right ventricular-to-pulmonary artery shunt, central shunt, or stent of ductus arteriosus) were randomized to clopidogrel 0.2 mg/kg (467 infants) or placebo (439 infants). Patients in both groups were continued on conventional therapy (including aspirin in 87.9% of infants). The primary efficacy endpoint was a composite of death or heart transplantation, shunt thrombosis, or performance of a cardiac procedure due to thrombotic event before 120 days of age.

Results:

The majority of patients in the study (509/906) had undergone placement of modified BT shunt without Norwood procedure. Of patients in the study with Norwood procedure, 113 had undergone modified BT shunt, whereas 114 had undergone right ventricular-to-pulmonary shunt. The rate of the composite primary endpoint did not differ between the clopidogrel group (19.1%) and the placebo group (20.5%) (absolute risk difference of 1.4% percentage points). The relative risk reduction with clopidogrel was 11.1% (95% confidence interval [CI], -19.2 to 33.6; p = 0.43). Shunt thrombosis occurred at a rate of 5.8% in the clopidogrel group and 4.8% in the placebo group (relative risk reduction, -16.1; 95% CI, -105.3 to 34.4; p = 0.61). There was no significant benefit of clopidogrel in any subgroup, including subgroups defined by shunt type. In per-protocol analysis, adverse events occurred in 73.9% of patients in the clopidogrel group and 66.9% of patients in the placebo group (p = 0.04).

Conclusions:

Clopidogrel in addition to conventional therapy for infants with cyanotic congenital heart disease palliated with systemic-to-pulmonary-artery shunt did not reduce either all-cause mortality or shunt-related morbidity.

Perspective:

This paper reported the results of CLARINET, a large, randomized, industry-supported trial of clopidogrel for infants with systemic-to-pulmonary-artery shunts. The study population was a representative sample of infants with cyanotic congenital heart disease, including patients with single- and two-ventricle congenital heart disease. The single-ventricle patients were evenly split between modified BT shunts and right ventricle-to-pulmonary-artery shunts. There was no difference in all-cause mortality or shunt thrombosis between the clopidogrel and placebo group. This well-designed study joins other recent randomized, multicenter trials for infants with congenital heart disease. While it reinforces with feasibility of such studies, it continues to highlight the challenges of studying therapies in infants with congenital heart disease. Despite industry funding and enrollment at 134 sites, the study did reach statistical power to test the equivalence of clopidogrel and placebo.

Clinical Topics: Cardiac Surgery, Congenital Heart Disease and Pediatric Cardiology, Invasive Cardiovascular Angiography and Intervention, Cardiac Surgery and CHD & Pediatrics, Cardiac Surgery and Heart Failure, Congenital Heart Disease, CHD & Pediatrics and Interventions, CHD & Pediatrics and Prevention, Heart Transplant, Interventions and Structural Heart Disease

Keywords: Norwood Procedures, Infant, Newborn, Heart Defects, Congenital, Ductus Arteriosus, Thrombosis, Risk Reduction Behavior, Blalock-Taussig Procedure, Pulmonary Artery, Stents, Heart Transplantation


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