Chronic anticoagulation with apixaban is a safe alternative to vitamin K antagonists or low-molecular-weight heparin in children with congenital or acquired heart disease at risk of thromboembolism, according to new trial data. The study, published online Monday and in the Dec. 12 issue of the Journal of the American College of Cardiology, noted that children with congenital or acquired heart disease are frequently at risk for clinically significant thrombosis including intracardiac, intravascular and coronary thromboses. Indeed, thrombotic complications are increasingly recognized as important factors contributing to morbidity and mortality in pediatric heart disease, said the researchers behind the study, led by R. Mark Payne, MD, from the Wells Center for Pediatric Research at the Indiana University School of Medicine, Indianapolis. “The current standard of care (SOC), vitamin K antagonists (VKA) or low-molecular-weight heparin (LMWH), has significant disadvantages in children,” said the team, adding that VKAs such as warfarin have a narrow therapeutic window requiring frequent therapeutic monitoring, interactions with medications and some foods, and a lack of liquid formulations, while long-term bone density is also potentially adversely affected. Payne and colleagues noted that direct oral anticoagulants (DOACs) such as the direct factor Xa (FXa) inhibitor apixaban do not require antithrombin and have recently been suggested to be an important therapeutic alternative for anticoagulation of children, including those with heart disease. “However, there remains a pressing need for improved understanding of the pharmacokinetics (PK) and pharmacodynamics (PD) of DOACs with age-appropriate pediatric formulations,” they said As a result, the authors sought to describe safety, PK, PD and efficacy of apixaban for prevention of thromboembolism in children with congenital or acquired heart disease. Study details The SAXOPHONE study is a prospective, randomized, open-label, parallel-arm, phase 2 trial using the SOC (VKA or LMWH) as a comparator to assess the safety, PK, PD, and efficacy of apixaban for the prevention of thromboembolism in children with a broad range of congenital or acquired heart disease requiring chronic thromboprophylaxis. Payne and colleagues randomly assigned patients 2:1 to receive either apixaban or SOC (129 apixaban and 63 SOC) for 1 year with intention-to-treat analysis. The primary endpoint was a composite of adjudicated major or clinically relevant nonmajor bleeding, while secondary endpoints were PK, PD, quality of life, and exploration of efficacy. Diagnoses of patients included single ventricle (74%), Kawasaki disease (14%) and other heart disease (12%), they added. The team reported that one apixaban participant (0.8%) and three with SOC (4.8%) had major or clinically relevant nonmajor bleeding; a percentage difference of -4.0% (95% confidence interval [CI]: -12.8 to 0.8). Furthermore, the team noted that apixaban pediatric PK steady-state exposures were consistent with adult levels. No thromboembolic events or deaths occurred in either arm, they said, adding that the apixaban incidence rate for all bleeding events was nearly twice the rate of SOC (100.0 vs 58.2 per 100 person-years), driven by 12 participants with four or more minor bleeding events. “In this pediatric multinational, randomized trial, bleeding and thromboembolism were infrequent on apixaban and SOC,” concluded Payne and colleagues, noting that apixaban PK data correlated well with adult trials that demonstrated efficacy. “These results support the use of apixaban as an alternative to SOC for thromboprophylaxis in pediatric heart disease,” the authors said, adding that future studies should explore a diversity of long-term outcomes, including quality of life and bone density, associated with the use of target-specific oral anticoagulants in pediatric patients with cardiovascular disease. Important dosing data Writing in an accompanying editorial, Craig A. Mullen, MD, PhD, from the University of Rochester, New York, said the trial provides very important data on the use of apixaban for the prevention of thromboembolism in pediatric heart disease. “It will prove useful not only to pediatric cardiologists but all pediatricians who need to treat pediatric patients with anticoagulation,” he noted, adding that while the finding is not surprising, it is important because the the SAXOPHONE trial provides good data on the PK and PD of apixaban in children dosed according to weight. “As is often the case in drug development, the original pharmacokinetic and pharmacodynamic data were derived from studies in adults who typically weigh 60 to 100 kg (a roughly 2-fold range),” he said, adding that pediatric patients range from 3 kg to around 70kg – a roughly 20-fold range. “Now pediatric cardiologists and hematologists have very useful data on how to safely dose apixaban in children.” However, Mullen noted some “practical problems” that may slow the replacement of warfarin by apixaban in pediatric heart disease and other pediatric conditions – noting that at present, the 0.1-mg capsule and 0.5-mg tablets used in the trial are not commercially available. “One hopes that because the manufacturer of apixaban, Bristol Myers Squibb, provided all the financing and drug for this trial, that such forms will be made available,” said the editorialist, adding that a second practical but important consideration is cost and cost-effectiveness of the treatments, including the efficacy of the treatments, and costs associated with ongoing monitoring, further events and treatment failures. “In adults, apixaban and other DOACs have generally shown a bit more efficacy in preventing events (eg, deep vein thrombosis, stroke) and also lead to less bleeding. These are the considerations that drive the superior cost-effectiveness of apixaban. The pediatric study reported here was not powered to show and did not show either superior efficacy or reduced bleeding with apixaban,” the expert commented. Sources: Payne RM, Burns KM, Glatz AC, et al. Apixaban for Prevention of Thromboembolism in Pediatric Heart Disease. J Am Coll Cardiol 2023;82:2296-2309. Mullen CA. Apixaban for Children With Heart Disease. J Am Coll Cardiol 2023;82:2310-2311. Image Credit: Soni's – stock.adobe.com