Reduced Anticoagulant Duration for VTE Noninferior in Patients Younger Than 21 Years

Neil A. Goldenberg, MD, PhD

Little is known regarding the optimal duration of anticoagulant therapy for venous thromboembolism (VTE) among patients younger than 21 years of age.

Thus, the primary aim of a recent randomized controlled trial was to compare the noninferiority of a shortened duration of anticoagulant therapy (6 weeks) to a conventional duration (3 months) for the treatment of first-episode acute provoked VTE in this patient population.

A team led by Neil A. Goldenberg, MD, PhD, Institute for Clinical and Translational Research, Johns Hopkins All Children’s Hospital found the reduced anticoagulant therapy duration met noninferiority criteria, based on trade-offs observed between recurrent VTE risk and clinically relevant bleeding events within 1 year.

Methods

Data was collected in the Multicenter Evaluation of the Duration of Therapy for Thrombosis in Children (Kids-DOTT trial), a RCT conducted at 42 children’s hospitals and academic medical centers in 5 countries.

Eligibility for enrollment included patients ≥21 years of age with acute VTE confirmed radiologically with a provoking factor, such as recent hospitalization or traumatic injury identified by investigators. The main exclusions were severe anticoagulant deficiencies or prior VTE.

Those without persistent antiphospholipid antibodies and whose thrombi were resolved upon repeat imaging at 6 weeks after diagnosis underwent randomization. Randomization was a 1:1 ratio with stratification by age group (<30 days, 30 days - <13 years, and 13 years - <21 years) and anatomical site of thrombosis.

Patients were assigned to discontinue anticoagulant therapy versus continuing anticoagulant therapy for a total of 3 months following diagnosis, with follow-up at 3 months, 6 months, 1 year, and 2 years for the development of recurrent VTE or clinically relevant bleeding events.

The primary efficacy endpoint was centrally adjudicated symptomatic recurrent VTE, while the primary safety endpoint was centrally adjudicated clinically relevant bleeding events within 1 year after diagnosis of index VTE.

Then, the primary analysis was noninferiority in the per-protocol population, where the non inferiority boundary incorporated a bivariate trade-off that included an absolute increase of 0% in symptomatic recurrent VTE with an absolute risk reduction of 4% in bleeding events.

Findings

A total of 417 patients underwent randomization, with the final visit for primary end points occurring in January 2021. Among this population, 297 patients (median age, 8.3 years; 49% female) met criteria for the primary per-protocol analysis.

The most used anticoagulant therapies were low-molecular-weight heparins, administered to 84% of participants during the acute treatment period and to 86% of patients during the subacute treatment period.

Data show the primary efficacy outcome occurred in 1 patient in the 6-week group and in 2 patients in the 3-month group, while the safety outcome occurred in 1 patient in the 6-week group and 1 patient in the 3-month group.

The Kaplan-Meier estimate for the 1-year cumulative incidence of the primary efficacy outcome of symptomatic recurrent VTE was 0.66% (95% CI, 0% - 1.95%) for the 6-week anticoagulant therapy group and 0.70% (95% CI, 0% - 2.07%) in the 3-month anticoagulant therapy group. An absolute risk difference of -0.04% (95% CI, -3.81 - 3.56) was shown.

For the primary safety outcome, the incidence was 0.65% (95% CI, 0% - 1.91%) in the 6-week group and 0.70% (95% CI, 0% - 2.06%) in the 3-month group, with an absolute risk difference of -0.05% (95% CI, -3.78 - 3.54%).

In the primary analysis, Goldenberg and colleagues found noninferiority was demonstrated based on absolute risk difference in recurrent VTE and clinically relevant bleeding events between groups.

Takeaways

“Taken together, data from these recent RCTs suggest that the risks of recurrent venous thromboembolism and clinically relevant bleeding events in young patients receiving anticoagulation for the treatment of acute venous thromboembolism are lower than previously reported from observational studies— particularly among patients with provoked venous thromboembolism,” investigators wrote.

The study, “Effect of Anticoagulant Therapy for 6 Weeks vs 3 Months on Recurrence and Bleeding Events in Patients Younger Than 21 Years of Age With Provoked Venous Thromboembolism: The Kids-DOTT Randomized Clinical Trial,” was published in JAMA.