Treatment with the direct factor Xa inhibitor edoxaban (Lixiana) resulted in low rates of clinically relevant bleeding and thromboembolism (TE) compared with standard-of-care (SOC) anticoagulants in children with cardiac diseases requiring thromboprophylaxis, in the phase 3 ENNOBLE-ATE trial.
Among 167 children in the modified intention-to-treat cohort, there was one adjudicated clinically relevant bleeding event in the edoxaban group at 15 days (epistaxis) and one in the SOC group at 54 days (hematochezia).
There were no adjudicated TE events with edoxaban and one with SOC (both deep vein thrombosis and a pulmonary embolism).
Among 147 children treated in a 9-month edoxaban extension phase, there was 1 clinically relevant bleeding event (0.7%; an abdominal bleed due to traumatic injury-related liver laceration) and 4 TEs (2.8%; 2 strokes and 2 coronary artery thromboses and/or myocardial infarctions).
After lock of the adjudication database, a primary hemorrhagic stroke adjudicated as a TE was further reviewed by the clinical event committee chair and determined to meet criteria for a major bleed event. If this determination is included, there were 2 (1.4%) safety and 3 (2.1%) efficacy events during the extension period.
“Overall, the study findings support the contention that edoxaban is an appropriate and perhaps attractive alternative to SOC anticoagulants (low molecular weight heparins and vitamin K antagonists) in these pediatric patients,” Michael A. Portman, MD, Seattle Children’s Research Institute, University of Washington, and colleagues conclude.
Thromboprophylaxis is especially challenging in children, they note, because aspirin has shown suboptimal efficacy in groups at increased TE risk, low molecular weight heparin (LMWH) requires twice-daily injections, and vitamin K antagonists (VKAs) have a delayed onset of action, narrow therapeutic index, multiple food and drug interactions, and require frequent blood monitoring.
Edoxaban is administered once daily, whereas the approved pediatric dosing for other direct oral anticoagulants (DOACs) ranges from twice daily to three times per day, he noted.
ENNOBLE-ATE is the first published study to compare a DOAC with SOC anticoagulation for primary or secondary thromboprophylaxis in children with cardiac disease, the authors report.
The DOACs dabigatran (Pradaxa) and rivaroxaban (Xarelto) were previously found noninferior to standard anticoagulants for efficacy in the treatment of acute venous thromboembolism and in thromboprophylaxis in the 2021 DIVERSITY trial and 2019 EINSTEIN-Jr trial, respectively.
To put the present findings in context, the clinically relevant bleeding rate was 0.9% in the present trial, 3% in EINSTEIN-Jr, and 1% in DIVERSTY for the drug treatment groups during similar 3-month main treatment periods, Portman reported.
The ENNOBLE-ATE results were published online October 31 in the Journal of the American College of Cardiology and will be presented November 6 in an outstanding research awards in pediatric cardiology session at the upcoming American Heart Association (AHA) Scientific Sessions 2022.
The multinational study included 168 children (> 38 weeks to < 18 years of age) with cardiac diseases who were at risk for TE complications and required at least 3 months of anticoagulant prophylaxis. They were randomly assigned 2:1 to oral once-daily edoxaban or SOC anticoagulation for 3 months with the option to continue in an open-label edoxaban extension for up to 9 additional months.
In the SOC group, 3 patients received twice-daily LMWH and 47 patients received VKA treatment with a mean time in therapeutic range of 45%. Edoxaban adherence (receiving 80%-120% of prescribed doses) was 94% in the main study but dropped to 55% in the extension phase, which the authors suggest is likely because part of the study was conducted during the COVID-19 pandemic.
During the main treatment period, treatment-emergent adverse events occurred in 51 patients (47%) in the edoxaban group and 24 patients (41%) in the SOC anticoagulation group.
Five patients (2.6%) in the edoxaban group and 3 patients (5.2%) in the SOC group experienced serious adverse events, none deemed related to study intervention.
There were no deaths during the main treatment period and 2 deaths in the extension period; one attributed to cardiac disease progression and the other to development of a fatal hemorrhagic stroke while edoxaban was withheld due to an acquired hemolytic disease not attributed to drug treatment.
“An Important Milestone”
“The study design and implementation represent an important milestone in the study of thromboprophylaxis in children with cardiac disease,” Nadine Choueiter, MD, a pediatric cardiologist at Children’s Hospital at Montefiore, Bronx, New York, says in an accompanying editorial.
Not surprising, 44% of patients with congenital heart disease had a history of a Fontan procedure and 33% of those with acquired heart disease had a history of Kawasaki disease, of which two-thirds had giant coronary artery aneurysms, she said. “This represents the referral base of large participating centers and adds to the strength of the study as this population is at risk for arterial thrombosis as opposed to the venous thrombosis often seen in general pediatric thrombosis studies.”
Choueiter said there’s a lot to be learned, however, about edoxaban absorption and safety in children with cardiac disease younger than 2 years, as they comprised less than 10% of the edoxaban group.
An important consideration that might impact long-term adherence to DOACs especially in adolescent girls is the heavy menstrual bleeding seen in women on apixaban or edoxaban compared with VKAs, she added. In contrast, a risk reduction in uterine bleeding has been seen with dabigatran vs VKAs.
“In summary this study provides exciting and crucial initial, evidence to inform practical use of edoxaban and DOACs in children with cardiac disease,” Choueiter concluded. “Yet it is neither designed nor powered to test the superiority or inferiority of edoxaban in comparison to anticoagulants. Pediatric thrombosis research remains challenging and the main limitation of this study is the rarity of the primary and secondary outcomes though well defined.”
J Am Coll Cardiol. Published online October 31, 2022. Abstract, Editorial
American Heart Association (AHA) Scientific Sessions 2022. Session 316. To be presented November 6, 2022.
The trial was funded by Daiichi Sankyo. Portman, Jacobs, Berger, Newburger, and Goldenberg served on the study steering committee for Daiichi Sankyo. Dugal and Grosso and Ben Tao are employees of Daiichi Sankyo . Choueiter reports no relevant financial relationships.
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