The direct oral anticoagulant (DOAC) edoxaban is a potential alternative mode of thromboprophylaxis in children with cardiac disease showing low rates of clinically relevant bleeding (CRB) and thromboembolism (TE), with advantages of once-daily dosing and infrequent monitoring requirement versus standard of care, according to new data from the ENNOBLE-ATE trial.
Data from the Phase 3, multinational, prospective, randomized, open-label, blinded-endpoint trial were published online Monday and will appear in the Dec. 13 issue of Journal of the American College of Cardiology, concluding that the oral factor Xa inhibitor edoxaban, administered once daily, is a “reasonable alternative” anticoagulant for children with cardiac disease.
Led by Michael A. Portman, MD, from the University of Washington, Seattle, the study notes that historically, low-molecular-weight heparin and vitamin K antagonists (VKAs) have been a mainstay of anticoagulant therapy and prevention for TE in children.
However, Portman and colleagues noted that low-molecular-weight heparin requires twice-daily subcutaneous administration, "which is suboptimal, particularly in young children.”
“Meanwhile, oral VKAs in children exhibit delayed onset of action, narrow therapeutic index, unpredictable pharmacological response, multiple food and drug interactions, and the need for frequent blood monitoring,” they noted.
The study added that the DOAC edoxaban has been shown to have pharmacokinetic properties including rapid peak plasma concentration, low cytochrome P450 metabolism, limited protein binding, and linear pharmacokinetics.
“These properties allow for once-daily dosing, a distinct advantage for pediatric patients compared with other DOACs that have been administered in twice daily doses during clinical trials,” they said.
“However, no prior published study has specifically compared DOACs to SOC [standard-of-care] anticoagulation for primary or secondary thromboprophylaxis in children with cardiac disease.”
The trial was funded solely by Daiichi-Sankyo, Inc., the manufacturer of edoxaban.
Portman and colleagues noted that the primary aim of the ENNOBLE-ATE (Edoxaban for Prevention of Blood Vessels Being Blocked by Clots [Thrombotic Events] in Children at Risk Because of Cardiac Disease) multinational randomized clinical trial was to compare 3-month bleeding safety of once-daily, age- and weight-adjusted, oral edoxaban to SOC anticoagulants in children.
A total of 168 patients were randomized 2:1 to age and weight-based oral edoxaban once daily vs SOC for 3 months (main study period), stratified by cardiac diagnosis.
In total, 58 patients received SOC while 109 received edoxaban, noted the team – adding that one patient, although randomized to edoxaban, never received the drug because of logistics related to the COVID-19 pandemic.
Demographic and baseline characteristics were similar between the treatment arms. Approximately 44% of the study population had a history of Fontan surgery, 22% had Kawasaki disease, and 4% had heart failure.
Both groups could continue in an open-label edoxaban extension arm through 1 year, noted the team, adding that the primary endpoint was set as adjudicated CRB while the main secondary endpoint was symptomatic TE or asymptomatic intracardiac thrombosis.
The modified intention-to-treat cohort included 167 children, noted the researchers, adding that one patient per group experienced a nonmajor CRB in the main period.
Treatment-emergent adverse events occurred in 46.8% (51 of 109) with edoxaban and 41.4% (24 of 58) with SOC, while one SOC patient experienced two TE events (deep vein thrombosis with pulmonary embolism).
Among 147 children in the extension, one CRB event (0.7%) and four TEs occurred (2.8%; 2 strokes and 2 of 33 Kawasaki disease patients with coronary artery thromboses and/or myocardial infarctions).
“Overall, the study findings support the contention that edoxaban is an appropriate and perhaps attractive alternative to SOC anticoagulants (low-molecular-weight heparins and VKAs) in these pediatric patients,” said Portman and colleagues.
“Edoxaban provided once daily would remove stress and burden on families with children, who require thromboprophylaxis,” they said.
However, the team also noted that further studies of the pharmacokinetics of edoxaban in infants and children are necessary to refine dosing recommendations.
Writing in an accompanying editorial comment, Nadine F. Choueiter, MD, from the Children’s Hospital at Montefiore, Albert Einstein College of Medicine, Bronx, New York, noted that the study provides “exciting and crucial” initial evidence to inform practical use of edoxaban and DOACs in children with cardiac disease.
“As a pediatric cardiologist, I find that the cohort represents, for the most part, the real-world general population of children older than 2 years of age who I would consider offering anticoagulation for either venous or arterial thrombosis prevention,” said Choueiter.
However, she noted that the study is neither designed nor powered to test the superiority or inferiority of edoxaban compared with anticoagulants: “Pediatric thrombosis research remains challenging, and the main limitation of this study is the rarity of the primary and secondary outcomes (although well defined),” she said.
The editorialist added that collaboration of health care providers with other important stakeholders, including the industry, regulatory, and funding agency – as well as patients and their families – can help overcome those challenges, especially in children with cardiac disease.
“The results of these efforts will truly reduce the need for long-term treatment of children with parenteral anticoagulants or long-term monitoring of children on oral vitamin K antagonists,” she said.
Portman MA, Jacobs JP, Newburger JW, et al. Edoxaban for Thromboembolism Prevention in Pediatric Patients With Cardiac Disease. J Am Coll Cardiol 2022;80:2301–2310.
Choueiter NF. Advancing Anticoagulation for Children With Cardiac Disease. J Am Coll Cardiol 2022;80:2311–2313.
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