Safety of Dabigatran in the Secondary Prevention of Venous Thromboembolism in Children

Study Methodology and Population

A total of 203 patients (55.7% boys) under the age of 18 were enrolled in the open-label, single-arm prospective cohort study by March 2019. They were divided into three groups based on age: the first group included patients aged 12 to 18 years (n = 153), the second group included those aged 2 to 12 years (n = 42), and the third group included those aged 3 months to 2 years (n = 8).

The inclusion criteria for the study were as follows:

• VTE diagnosis confirmed by ultrasound, CT, or MRI
• persistent risk factor for thromboembolism requiring anticoagulation
• at least 3 months of standard anticoagulation therapy (SOC) (56.7% of patients) or 3 months of dabigatran use (29.1%) or administration of low molecular weight heparin or warfarin as SOC (14.3%) in the DIVERSITY study

The most common persistent risk factors for thromboembolism were hereditary thrombophilia (44.8% of patients), congenital heart disease (6.0%), hematologic malignancy (5.5%), central venous catheter (CVC) insertion (5.5%), and “unprovoked” venous thromboembolism (14.3%).

Before enrollment in the study, the majority of patients (74.9%) received low molecular weight heparin (LMWH) as anticoagulation therapy. The most frequently reported VTE diagnosis was deep vein thrombosis outside the CVC and central nervous system (CNS) (75.9% of patients). Post-thrombotic syndrome was reported in 17.6% of patients.

After dose adjustment according to estimated glomerular filtration rate, patients took dabigatran in the form of capsules (84.2%) or pellets (15.8%) for 12 months (shorter if the risk factor was eliminated). They were then switched to standard treatment and monitored for another 28 days.

Evaluated Parameters

After 6 and 12 months of dabigatran use, the following primary parameters were evaluated:

• recurrence of VTE
• major bleeding events (MBEs) defined as fatal or clinically significant bleeding (with a reduction in hemoglobin concentration in the blood by ≥ 20 g/L within 24 hours), retroperitoneal, pulmonary, CNS, or perioperative bleeding
• non-major clinically relevant bleeding events (CRNMBEs) requiring transfusion or medical intervention
• minor bleeding not meeting MBE and CRNMBE criteria
• mortality

The following secondary parameters were monitored:

• new diagnosis/progression of post-thrombotic syndrome
• need for dose adjustment
• tolerability of the drug form

Results

Recurrence of venous thromboembolism was reported in 2 patients (1%) during dabigatran use. The probability of it not occurring during 12 months of use was determined to be 0.988 (95% confidence interval [CI] 0.951−0.997). Bleeding occurred in 40 patients (19.7%)—specifically 3 (1.5%) major bleeding events, 2 (1%) CRNMBEs, and 37 (18.2%) minor bleeding events. The probability that bleeding would not occur during 12 months of dabigatran use is therefore 0.752 (95% CI 0.672−0.815). No deaths were reported.

Post-thrombotic syndrome was reported in 2 patients (1.2%). The probability that it would not develop during 12 months of dabigatran use was 0.985 (95% CI 0.939−0.996). Dose adjustment was required in 26.1% of patients. Almost all study participants accepted the drug form.

Adverse events occurred in 152 patients (74.9%). The most common were nasopharyngitis (16.7% of cases), headache (16.3%), and abdominal pain (10.3%). Severe adverse events occurred in 25 cases (12.3%), and treatment had to be interrupted in 12 of them (15.9%).

Discussion and Conclusion

Dabigatran appears to be safe for secondary prevention of venous thromboembolism in children over 3 months old with persistent risk factors. After dose adjustment for age and body weight, its pharmacokinetic and pharmacodynamic profile is comparable to that in adults, and plasma level monitoring is not necessary. Moreover, the DIVERSITY study demonstrated efficacy and safety comparable to standard treatment (low molecular weight heparin and warfarin). However, due to the low number of subjects, these data cannot be applied with absolute certainty to patients under 2 years old.

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Source: Brandão 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.