In a recent randomised controlled trial, an age-adjusted, weight-adjusted dabigatran dosing algorithm was found to be appropriate in children under 18 years old with venous thromboembolism (VTE). Writing in Lancet: Haematology, Jacqueline Halton (University of Ottawa, Ottawa, Canada) and colleagues report that dabigatran was non-inferior to standard of care in terms of efficacy—with similar pharmacokinetic–pharmacodynamic relationships as those seen in adults—and suggest that it might be a suitable alternative to the standard of care.
The authors detail that dabigatran etexilate is “a direct oral anticoagulant with potential to overcome the limitations of standard of care in children with VTE”. In this clinical trial, they aimed to study the appropriateness of a paediatric dabigatran dosing algorithm, and the efficacy and safety of dabigatran dosed according to that algorithm versus standard of care in treating children with VTE.
Halton et al describe the DIVERSITY (Dabigatran etexilate for the treatment of acute venous thromboembolism in children) study as a randomised, controlled, open-label, parallel-group, phase 2b/3 non-inferiority trial conducted in 65 centres across 26 countries.
They write that the standard of care (low-molecular-weight heparins, unfractionated heparin, vitamin K antagonists, or fondaparinux) was compared with a paediatric oral dabigatran dosing regimen (an age-adjusted and weight-adjusted nomogram) in children younger than 18 years with acute VTE initially treated (5–21 days) with parenteral anticoagulation, requiring anticoagulation therapy for at least three months.
Patients were randomised 1:2 (standard of care:dabigatran) and stratified by age (12 to <18 years, 2 to <12 years, and birth to <2 years) via interactive response technology, the authors relay.
Halton and colleagues note that the primary composite efficacy endpoint (intention-to-treat analysis) was the proportion of children with complete thrombus resolution, and freedom from recurrent VTE and VTE-related death. They add that secondary endpoints included safety (determined by major bleeding events [time-to-event analysis on the treated set]) and pharmacokinetic–pharmacodynamics relationships.
Writing in Lancet: Haematology, Halton et al communicate that 328 children were enrolled in the study between 18 February 2014 and 14 November 2019, and that the median exposure to standard of care was 85 days (interquartile range [IQR] 80–90) and to dabigatran was 84.5 days (78–89).
They report that similar proportions of children treated with standard of care and dabigatran met the composite efficacy endpoint (38 [42%] of 90 vs. 81 [46%] of 177; Mantel-Haenszel weighted difference, -0.04; 90% confidence interval -0.14–0.07; p<0.0001 for non-inferiority).
On-treatment bleeding events were recorded in 22 (24%) of 90 children receiving standard of care and 38 (22%) of 176 children receiving dabigatran (hazard ratio [HR] 1.15, 95% CI 0.68–1.94; p=0.61); major bleeding events were similar between the groups (two [2%] of 90 and four [2%] of 176; HR 0.94, 95% CI 0.17–5.16; p=0.95).
In addition, the authors mention that pharmacokinetic–pharmacodynamic curves showed a linear relationship between total dabigatran plasma concentration and diluted thrombin time and ecarin clotting time, and a non-linear relationship with activated partial thromboplastin time; curves were similar to those for adults.
Finally, they relay that serious adverse events were reported for 18 (20%) of 90 children receiving standard of care and 22 (13%) of 176 children receiving dabigatran. The most common severe adverse events were vascular disorders (standard of care three [3%] of 90, dabigatran two [1%] of 176), and gastrointestinal disorders (standard of care two [2%] of 90 and dabigatran five [3%] of 176). One on-treatment death occurred in the standard to care group (retroperitoneal bleeding, not considered treatment related by the study investigators).
Considering the value of this study, the authors remark that DIVERSITY “provides level II evidence that the efficacy and safety, and pharmacokinetic–pharmacodynamic relationships, of dabigatran are similar to those reported in randomised clinical trials evaluating dabigatran in adults with acute VTE. They postulate: “The results of DIVERSITY might help to extend findings of adult clinical trials of venous thromboembolism to children with more certainty”.
In the discussion of their findings, Halton et al recognise certain limitations, including the fact that a double-blind design “was not possible for ethical and operational reasons,” and that the exclusion criteria “limit the external validity of the DIVERSITY findings to the broader acute venous thromboembolism paediatric population”. They stress that further data in the real-world setting based on dabigatran capsules, pellets, and oral solution are required.
