A Promising New Option to Prevent Thromboembolism in Pediatric Heart Disease

Research study background   

Children with certain types of congenital or acquired heart disease, including single ventricle disease and Kawasaki disease, are at high risk for thromboembolism. Prophylaxis with a vitamin K antagonist (VKA), such as warfarin, or low-molecular-weight heparin (LMWH) is the current standard of care for these patients. Neither therapy is ideal for children. VKAs have many drug interactions and require dietary restrictions and frequent lab testing. LMWHs must be injected twice daily and also require frequent lab testing. Apixaban, part of a new class of anticoagulant drugs called direct oral anticoagulants (DOACs) found to be safe and effective in adults, has potential as an alternative to VKA and LMWH for preventing thromboembolism in children. This phase 2, open-label, multinational trial was the first to assess the safety and efficacy of apixaban in children with heart disease, as well as evaluate the pharmacokinetics and pharmacodynamics of age-appropriate pediatric formulations of the drug. Children’s Hospital Colorado was one of the participating sites, led by a pediatric cardiologist who developed the hospital’s multidisciplinary Cardiac Antithrombosis Management Program and Cardiac Thrombosis Clinic.

The trial included patients as young as 28 days old and up to 18 years old. After recruitment and enrollment, participants were randomized 2:1; the majority took daily weight-based doses of apixaban, and the rest proceeded with the standard of care. Participants had a broad range of diagnoses including single ventricle disease (74%), Kawasaki disease (14%) and other heart disease (12%).

The mean duration of drug exposure was 330.6 days for all participants, and adherence to both treatments was high. There were few incidences of major or clinically relevant nonmajor bleeding, occurring in one patient taking apixaban and three patients receiving the standard of care. The rate of all bleeding events, including minor bleeding events like nosebleeds, was similar between the two treatment groups at 37%. The incidence of adverse events was no different between both groups (20.6% with apixaban vs. 21.0% with the standard of care). There were no thromboembolic events detected by imaging or clinical diagnosis in either treatment group, consistent with adult trial results. The levels of apixaban in children at steady state were also comparable to the adults. Importantly, quality of life surveys conducted during the study suggested child-reported lower anxiety when taking apixaban compared to VKAs or LMWHs.

Clinical implications

Study findings support the use of apixaban for chronic thromboprophylaxis in children with heart disease as a safe and well-tolerated alternative to VKAs and LMWHs. Comparable conclusions were reported in a recent meta-analysis of patients with Fontan circulation, as well as other pediatric studies of DOACs in children with venous thromboembolism.

A limitation of the trial is that newborns were not included since DOACs were not frequently used in this group when it was designed. Future research should prioritize investigating diverse long-term outcomes linked with DOACs.