— Are there better options than warfarin and heparins?
Crystal Phend, Contributing Editor, MedPage Today
November 26, 2022
Children with cardiomyopathy are one of the highest-risk pediatric groups for developing thrombosis, along with kids with Fontan circulation, systemic-to-pulmonary artery shunt-dependent functionally univentricular circulation, central lines, and Kawasaki disease with coronary aneurysms.
Prophylaxis to prevent thromboembolism and associated complications for children with cardiac disease is most commonly done with antiplatelets (such as aspirin and clopidogrel) and anticoagulants (such as low-molecular-weight heparin and vitamin K antagonists [VKAs]).
The American College of Chest Physicians (CHEST) 2012 guidelines on pediatric thromboembolism recommended that dilated cardiomyopathy be treated with a VKA no later than the child’s activation on a cardiac transplant waiting list, though this was a grade 2C recommendation based on a relative paucity of data.
Like most areas of pediatric medicine, it’s been hard to get data for a variety of reasons, including rarity of events, lack of pediatric-specific dosing, and questionable generalizability from adults.
Mechanisms that lead to thromboembolic events are typically different in children than adults — for example, blood stasis seen in cardiomyopathy and heart failure patients, noted Nadine F. Choueiter, MD, of the Children’s Hospital at Montefiore in New York City, in a recent commentary in the Journal of the American College of Cardiology.
However, heparins and VKAs, such as warfarin, have drawbacks for children, said Michael Portman, MD, of Seattle Children’s Research Institute.
“Warfarin is very labile in children,” he told MedPage Today in an interview monitored by his institution’s media relations.
The CHEST guidelines suggested targeting an international normalized ratio (INR) of 2.5, with point-of-care monitoring when possible, when using VKAs.
However, studies have suggested that children stay in the target range only about 40% to 45% of the time.
“Warfarin is affected substantially by diet, which is constantly changing in children, so it’s a burden on parents in particular — they have to watch really closely what their children eat, so it won’t affect their anticoagulation medicine,” Portman said. “My heart failure patients, they tell me it’s always a big issue for them.”
Furthermore, many families don’t have the capacity to do home monitoring of INR or insurance that will pay for it, he added. That means trips to the lab at least monthly.
Direct-acting oral anticoagulants (DOACs) are an appealing option, said Choueiter. “They can be administered orally, are antithrombin independent, have a rapid onset and offset of action, few drug and food interactions, and linear pharmacokinetics with no need of routine monitoring.”
Among the DOACs, rivaroxaban (Xarelto) and edoxaban (Savaysa, Lixiana) are typically once-daily drugs, which offers advantages for families to give the drug in the morning and then not worry about it through the school day and after-school activities, Portman noted.
Dabigatran (Pradaxa) and rivaroxaban were the first DOACs to gain FDA approvals for pediatric venous thromboembolism treatment last year, and rivaroxaban gained an indication in thromboprophylaxis for children ages 2 years and older with congenital heart disease who have undergone the Fontan procedure.
Most of the limited DOAC use to date in children, though, has been off-label, with research evaluating their use in pediatrics just starting to emerge over the past 2 to 3 years, Portman said.
At the recent American Heart Association annual meeting in Chicago, Portman’s group reported the results from the randomized ENNOBLE-ATE trial, which included 167 children with cardiac disease who were randomly assigned to open-label treatment with age- and weight-based oral edoxaban once daily versus standard of care for 3 months, with an open-label edoxaban extension arm through 1 year. While Fontan and Kawasaki disease indications predominated, 4% of the patients were enrolled due to heart failure.
For the primary endpoint of adjudicated clinically relevant bleeding, one patient in each group had an event, both non-major bleeding. For the main secondary endpoint of symptomatic thromboembolism or asymptomatic intracardiac thrombosis, one patient in the standard-of-care arm experienced deep vein thrombosis with pulmonary embolism. One clinically relevant bleeding event occurred among the 147 children in the extension phase, for a rate of 0.7%. The rate of thromboembolism in the extension phase was 2.8%, with two strokes and two of the 33 Kawasaki disease patients experiencing coronary artery thromboses or myocardial infarction.
Choueiter called the trial “exciting and crucial initial evidence to inform practical use of edoxaban and DOACs in children with cardiac disease,” though she cautioned that there were too few events to really infer either superiority or noninferiority for efficacy or safety endpoints.
“Each institution has to decide whether they’ll allow the use of DOACs,” Portman acknowledged. “And many want to see at least published papers. Those are starting to emerge.”
For his pediatric patients, some of whom have been on a DOAC for 3 or 4 years now, families have indicated a definite boost in quality of life after switching.
The difference is even more stark for patients switching from twice-daily injections of low-molecular-weight heparin, Portman noted.
“The patients who are usually on that are small children less than 2 years of age, because in that age group, the warfarin lability is even more problematic,” he explained. “With enoxaparin [low-molecular-weight heparin], those kids are just covered with bruises from their injections, those bruises disappear, and children don’t look like they’re abused anymore. And the parents, they all tell me that the quality of life is dramatically improved.”
Adherence is another potential benefit, he added, as the compliance rate was 94% in the edoxaban arm of his trial compared with 45% in the standard-of-care group (all but three of whom were on VKAs). That rate dropped to 55% in the extension period with edoxaban, perhaps in part due to the onset of the COVID-19 pandemic.
According to Choueiter, one important consideration that could impact long-term adherence to DOACs, “especially in adolescent girls, is the heavy menstrual bleeding seen in women on apixaban [Eliquis] or edoxaban compared to vitamin K antagonists. In contrast, with dabigatran, a risk reduction in uterine bleeding was seen compared to vitamin K antagonists.”
Choueiter reported no relevant conflicts of interest.
Portman disclosed serving on the steering committee of Daiichi-Sankyo for his study, which was funded by the company.