Safety of Dabigatran in Secondary Prevention of Venous Thromboembolism in Pediatric Patients

Study Methodology and Population Evaluated

A total of 203 pediatric patients (55.7% boys) older than 3 months and younger than 18 years, with a diagnosis of venous thromboembolism confirmed by imaging, were enrolled in the open-label multicenter prospective single-arm study. Due to a persistent risk factor (RF), they used dabigatran (a direct thrombin inhibitor) for up to 12 months as part of secondary prevention. The most common RFs included congenital heart defect (6%), hematologic malignancy (5.5%), central venous catheter (5.5%), or genetically determined procoagulant state (44.8%; Leiden mutation, prothrombin gene mutation, antithrombin or protein C/S deficiency, etc.).

Patients were treated with the standard of care (SOC) for ≥ 3 months before entering the study or had completed treatment with dabigatran in another study (DIVERSITY), where they had been treated with either SOC or dabigatran. The dose of dabigatran was always adjusted according to the patient’s weight, age, and estimated renal function.

Monitored Parameters

The primary monitored parameters included recurrence of venous thromboembolism, incidence of major bleeding (defined as fatal bleeding, clinically evident bleeding /drop in hemoglobin concentration in blood by at least 20 g/l in 24 hours/, retroperitoneal, pulmonary, and CNS bleeding or bleeding requiring surgery), clinically relevant or minor bleeding, and death (overall or thromboembolic-related) at 6 and 12 months after starting treatment.

Secondary monitored parameters included newly diagnosed post-thrombotic syndrome or its progression, the proportion of patients requiring dabigatran dose adjustment, and tolerance of the drug formulation.

Findings

Patients used dabigatran for an average of 36.3 weeks. Capsules or pellets were used as the drug form by 171 (84.2%) and 32 (15.8%) participants, respectively. Treatment was discontinued in 32 children due to the resolution of the procoagulant state, and in 25 children due to failure to reach the target concentration of dabigatran even after dose adjustment. 115 chronically anticoagulated patients (56.7%) newly started using dabigatran, and 88 were included from the DIVERSITY study, with 59 (29.1%) treated with dabigatran and 29 (14.3%) with standard therapy.

Venous thromboembolism recurred in 2 (1%) patients, and bleeding occurred in 40 (19.7%) children. Of these, 3 (1.5%) were major bleedings, 2 (1.0%) were clinically relevant, and 37 (18.2%) were minor bleedings. The probability of no recurrence was 0.955 (95% confidence interval [CI] 0.951–0.997), and for no bleeding, it was 0.852 (95% CI 0.672–0.815). No deaths were reported during the study. Post-thrombotic syndrome was diagnosed in 2 out of 162 children (1.2%) with deep vein thrombosis. The probability of not developing it was 0.985 (95% CI 0.939–0.996).

Dabigatran dose adjustment was necessary in 26.1% of patients. Capsules and pellets as drug formulations were tolerated by 98.4% and 94.1% of participants, respectively. Adverse events related to dabigatran use were reported in 152 (74.9%) patients, most commonly nasopharyngitis, headaches, and abdominal pain. Serious adverse events occurred in 25 (12.3%) children. 12 (5.9%) participants discontinued treatment due to adverse events.

Pharmacokinetic and pharmacodynamic parameters were comparable to adult patients.

Conclusion

Dabigatran in this study demonstrated a favorable safety profile in pediatric patients older than 3 months in secondary prevention of venous thromboembolism in the presence of persistent risk factors.

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Source: Brandao L.R., Albisetti M., Halton J. et al. Safety of dabigatran etexilate for the secondary prevention of venous thromboembolism in children. Blood 2020; 135 (7): 491–504, doi: 10.1182/blood.2019000998.