Shortened anticoagulation after provoked VTE safe, effective in young patients: Kids-DOTT
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Among young patients with provoked venous thromboembolism, shorter duration of anticoagulation is noninferior to current standard of care, according to the results of the Kids-DOTT randomized trial.
Published in JAMA, the results of this trial indicated that risk for recurrent VTE or bleeding events is low in this population and that just 6 weeks of anticoagulation was similarly safe and effective as the currently recommended 3-month duration.
“For more than a decade, hematologists taking care of VTE patients less than 21 years old have occasionally used shorter than conventional courses of anticoagulation — eg, 6 weeks total,” Neil A. Goldenberg, MD, PhD, associate dean for clinical and translational research and director of the Johns Hopkins All Children’s Institute for Clinical and Translational Research, told Healio. “However, the standard of care in young patients has been a 3-month course of anticoagulation for provoked VTE based entirely on randomized clinical trials performed in older adults. Given key differences in risk factors and outcomes between older adults and young patients, we felt that this fundamental question on duration of therapy for patients less than 21 years old with VTE needed a devoted randomized trial.”
The goal of the trial was to compare the clinical benefit of an abbreviated duration of anticoagulant therapy of 6 weeks with the conventional 3-month duration for the treatment of first-episode acute provoked VTE in 297 young patients (mean age, 8 years; 49% female).
Participants at 42 centers across five countries were randomly assigned to 6-week or 3-month anticoagulant duration. The most commonly used anticoagulants were low-molecular-weight heparins. Participants were excluded if there were severe anticoagulant deficiencies or a prior VTE.
The primary efficacy endpoint was symptomatic recurrent VTE, and the primary safety endpoint was clinically relevant bleeding events within 1 year. The primary analysis was noninferiority in the per-protocol population.
“Although this was not studied in the trial, cutting in half the duration of treatment with anticoagulant medication that these young patients undergo can be anticipated to result not only in significant savings in health care costs, but also better quality of life — and the ability to return sooner to normal routines, age-appropriate activities and sports,” Goldenberg told Healio.
6-week vs. 3-month anticoagulation
Researchers reported that the estimated 1-year cumulative incidence of symptomatic recurrent VTE was 0.66% in the 6-week duration group (95% CI, 0-1.95) and 0.7% in the 3-month duration group (95% CI, 0-2.07; absolute difference, 0.04; 95% CI, 3.81 to 3.56).
For the primary safety endpoint, the researchers reported a 1-year cumulative incidence of 0.65% for the 6-week duration group (95% CI, 0-1.91) and 0.7% in the 3-month duration group (95% CI, 0-2.06; absolute difference, 0.05; 95% CI, 3.78 to 3.54).
“We were pleasantly surprised that the signal was so clear and consistent, with respect to the stringent criteria that we had set up in advance for drawing conclusions from the trial. In order to draw a definitive ‘positive’ conclusion from the trial’s findings, the analyses had to meet criteria for noninferiority in both the per-protocol population and among all randomized patients,” Goldenberg told Healio. “Whatever the results — whether or not they supported non-inferiority — it was important that they be definitive, and that the per-protocol analysis and the intention-to-treat analysis were concordant; we were fortunate that that was the case.”
Based on the absolute risk differences for both the primary safety and efficacy endpoint, the researchers determined that an abbreviated 6 weeks of anticoagulation following first provoked VTE was noninferior to a 3-month duration among patients younger than 21 years.
Trials evaluating both efficacy and safety
In a related editorial, Benoît Mâsse, PhD, professor of biostatistics at the Université de Montréal, and colleagues discussed how the design if the present trial may inform the design of future randomized clinical trials.
“The findings suggest that anticoagulant therapy could be stopped sooner than currently recommended and that doing so is likely to be as safe as longer treatment. Quality of life may be improved in many children by decreasing the duration of subcutaneous injections,” the editorial authors wrote. “The trial of Goldenberg et al suggests that there are instances when a randomized clinical trial must consider both efficacy and safety. What remains to be determined is when this analytic approach should be used in studies that evaluate when to start and when to stop a treatment for potentially serious conditions.”
For more information:
Neil A. Goldenberg, MD, PhD, can be reached at neil@jhmi.edu.
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