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

Abstract

Importance: Among patients younger than 21 years of age, the optimal duration of anticoagulant therapy for venous thromboembolism is unknown.

Objective: To test the hypothesis that a 6-week duration of anticoagulant therapy for provoked venous thromboembolism is noninferior to a conventional 3-month therapy duration in patients younger than 21 years of age.

Design, setting, and participants: Randomized clinical trial involving 417 patients younger than 21 years of age with acute, provoked venous thromboembolism enrolled at 42 centers in 5 countries from 2008-2021. The main exclusions were severe anticoagulant deficiencies or prior venous thromboembolism. Patients without persistent antiphospholipid antibodies and whose thrombi were resolved or not completely occlusive upon repeat imaging at 6 weeks after diagnosis underwent randomization. The final visit for the primary end points occurred in January 2021.

Interventions: Total duration for anticoagulant therapy of 6 weeks (n = 207) vs 3 months (n = 210) for provoked venous thromboembolism.

Main outcomes and measures: The primary efficacy and safety end points were centrally adjudicated symptomatic recurrent venous thromboembolism and clinically relevant bleeding events within 1 year blinded to treatment group. The primary analysis was noninferiority in the per-protocol population. The noninferiority boundary incorporated a bivariate trade-off that included an absolute increase of 0% in symptomatic recurrent venous thromboembolism with an absolute risk reduction of 4% in clinically relevant bleeding events (1 of 3 points on the bivariate noninferiority boundary curve).

Results: Among 417 randomized patients, 297 (median age, 8.3 [range, 0.04-20.9] years; 49% female) met criteria for the primary per-protocol population analysis. The Kaplan-Meier estimate for the 1-year cumulative incidence of the primary efficacy outcome was 0.66% (95% CI, 0%-1.95%) in the 6-week anticoagulant therapy group and 0.70% (95% CI, 0%-2.07%) in the 3-month anticoagulant therapy group, and for the primary safety outcome, the incidence was 0.65% (95% CI, 0%-1.91%) and 0.70% (95% CI, 0%-2.06%). Based on absolute risk differences in recurrent venous thromboembolism and clinically relevant bleeding events between groups, noninferiority was demonstrated. Adverse events occurred in 26% of patients in the 6-week anticoagulant therapy group and in 32% of patients in the 3-month anticoagulant therapy group; the most common adverse event was fever (1.9% and 3.4%, respectively).

Conclusions and relevance: Among patients younger than 21 years of age with provoked venous thromboembolism, anticoagulant therapy for 6 weeks compared with 3 months met noninferiority criteria based on the trade-off between recurrent venous thromboembolism risk and bleeding risk.

Trial registration: ClinicalTrials.gov Identifier: NCT00687882.

Figure 1.. Screening, Randomization, and Follow-up of Patients in the Kids-DOTT Trial

Kids-DOTT indicates Multicenter Evaluation of the Duration of Therapy for Thrombosis in Children. ^aThe findings related to the observational cohort aims will be published separately. ^bTwo additional deaths occurred per group that were outside the per-protocol population. ^cIncluded withdrawal by site principal investigator (n = 1 per group); informed consent no longer in effect due to change in child custody (n = 1 per group); and eligibility criteria no longer met due to underlying disease diagnosis (n = 1 per group). ^dCalculated as the number of patients randomized minus the number of patients not completing the follow-up visit at 6 months or later, minus the additional number of patients who received less than 80% of prescribed doses of anticoagulant therapy.

Figure 2.. Bivariate Noninferiority Analysis Reflecting the Trade-off Between Adjudicated Symptomatic Recurrent Venous Thromboembolism (Primary Efficacy End Point) and Clinically Relevant Bleeding Events (Primary Safety End Point)

The absolute risk differences (anticoagulant therapy for 6 weeks minus anticoagulant therapy for 3 months) for both primary end points yield point estimates in a 2-dimensional plane. The 95% CIs for the 2-dimensional point estimates form 95% confidence rectangles. ^aConstructed using the following points for between-group absolute risk differences in symptomatic recurrent venous thromboembolism and clinically relevant bleeding events, respectively: 1% and -12%; 0% and -4%; -5% and 4%. Noninferiority is demonstrated in the per-protocol population and confirmed among all randomized patients by the fact that in each case the entire 95% confidence rectangle lies within the noninferiority zone (white background) to the southwest of the noninferiority boundary. Additional details on the bivariate end point methods appear in Supplement 3 and have been described by Hu et al.