Use and Outcomes of Secondary Anticoagulation in Patients <21 Years Old Following Completion of a Primary Course of Anticoagulation for Treatment of Acute Provoked VTE: Findings from the Multinational Kids-DOTT Trial

Background: Although the rate of venous thromboembolism (VTE) recurrence is low among pediatric patients with provoked VTE, children with a history of VTE who have persistent prothrombotic risk factors such as central venous catheters (CVCs), thrombophilia and cancer have been shown to have increased risk for recurrent VTE (e.g., Brandao et al., Lancet Hematology 2020). Prospective multicenter data on the use of secondary anticoagulation in patients with a first provoked VTE are limited.

Objective: We sought to characterize the use and outcomes of secondary anticoagulation in patients <21 years old with provoked VTE, via the multinational Kids-DOTT trial. We hypothesized that older patient age is associated with use of secondary anticoagulation among patients with provoked VTE who have persistent prothrombotic risk factors following completion of a primary course of anticoagulation for treatment of acute provoked VTE, and that frequencies of clinically relevant bleeding and recurrent VTE are low in this setting.

Methods: We conducted a secondary analysis of patients enrolled in the NIH-sponsored, multinational randomized controlled Kids-DOTT trial (NCT00687882; Goldenberg et al., JAMA 2022) who received secondary anticoagulation. We defined secondary anticoagulation as anticoagulant use beyond the initial treatment period of 6-12 weeks for the purpose of secondary VTE prevention, as captured in case report forms. “Chronic” secondary anticoagulation was defined as that which began within 2 weeks of the prescribed treatment course; otherwise, secondary anticoagulation was defined as “episodic”. The presence of new and/or recurrent prothrombotic risk factors was captured in association with each episode. Variables were summarized as counts and percentages for categorical variables and medians with interquartile ranges (IQR) for continuous variables. To compare groups that did versus did not receive secondary anticoagulation, Mann-Whitney U test was used for continuous variables and chi-square, or Fisher's exact test was used for categorical variables, with alpha <0.05 considered significant. All statistical analyses were performed using R version 4.1.2 (R Core Team, 2021).

Results: Among 532 patients enrolled in the Kids-DOTT trial, 18 (3.4%) received secondary anticoagulation, all of whom had persistence or recurrence of prothrombotic risk factors (Table 1). The most frequent prothrombotic risk factors associated with use of secondary anticoagulation were a new or persistent central venous catheter (28%, N=5) and infection (17%, N=3). Despite having persistence or recurrence of prothrombotic risk factors, only 1 patient who received secondary anticoagulation developed recurrent VTE and 2 patients experienced clinically relevant bleeding during a median follow-up of 1.99 years [IQR 1.06-2.02], none of which was temporally related to secondary anticoagulation use. As shown in Table 2, patients who received secondary anticoagulation were older (median 12.9 years [IQR 7.6-15.5 years] vs. 8 years [1-15 years], P=0.05) and more likely to have upper extremity deep vein thrombosis (50% vs. 29%; P=0.003) when compared to those who did not receive secondary anticoagulation.

Conclusion: These findings suggest that use of secondary anticoagulation is low among patients <21 years old with provoked VTE. However, among those who receive secondary anticoagulation for persistent or recurrent prothrombotic risk factors, the risks of recurrent VTE and clinically relevant bleeding may be low. Furthermore, focused study of use and outcomes of chronic and episodic secondary anticoagulation is warranted to inform future practice on secondary prevention in children, adolescents, and young adults with a history of provoked VTE.