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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 ThromboembolismThe Kids-DOTT Randomized Clinical Trial

Educational Objective
To learn about anticoagulant therapy for the prevention of recurrent venous thromboembolism.
1 Credit CME
Key Points

Question  Among patients younger than 21 years of age with acute provoked venous thromboembolism, is a 6-week duration of anticoagulant therapy noninferior to a conventional 3-month duration?

Findings  In this randomized clinical trial that included 417 patients with provoked venous thromboembolism, anticoagulant therapy for 6 weeks vs 3 months resulted in symptomatic recurrent venous thromboembolism in 0.66% vs 0.70%, respectively, and clinically relevant bleeding events in 0.65% vs 0.70% within 1 year. The differences met the criteria for noninferiority.

Meaning  Among patients younger than 21 years of age with provoked venous thromboembolism, anticoagulant therapy for 6 weeks compared with 3 months met noninferiority based on a combination of recurrent venous thromboembolism risk and bleeding risk.

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

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CME Disclosure Statement: Unless noted, all individuals in control of content reported no relevant financial relationships. If applicable, all relevant financial relationships have been mitigated.

Article Information

Corresponding Author: Neil A. Goldenberg, MD, PhD, Institute for Clinical and Translational Research, Johns Hopkins All Children’s Hospital, 600 Fifth St S, Ste 3200, St Petersburg, FL 33701 (neil@jhmi.edu).

Correction: This article was corrected March 22, 2022, to revise Figure 1 because underneath the randomization oval, the second row of boxes, which contain information about the follow-up visits, were inadvertently flipped and should have appeared on the opposite sides of the diagram and to fix an incorrect number in the figure.

Accepted for Publication: December 8, 2021.

Author Contributions: Drs Goldenberg and Bonaca had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Kittelson, Abshire, Bonaca, Casella, Halperin, Kessler, Manco-Johnson, Spyropoulos, Steg, Turpie.

Acquisition, analysis, or interpretation of data: Goldenberg, Schulman, Kittelson, Bonaca, Dale, Halperin, Hamblin, Kessler, Manco-Johnson, Sidonio, Steg.

Drafting of the manuscript: Goldenberg, Kittelson, Bonaca, Casella, Hamblin, Spyropoulos.

Critical revision of the manuscript for important intellectual content: Schulman, Kittelson, Abshire, Bonaca, Casella, Dale, Halperin, Kessler, Manco-Johnson, Sidonio, Steg, Turpie.

Statistical analysis: Kittelson, Bonaca, Dale, Kessler.

Administrative, technical, or material support: Goldenberg, Bonaca, Casella, Sidonio.

Supervision: Kittelson, Abshire, Bonaca, Halperin.

Conflict of Interest Disclosures: Dr Goldenberg reported receiving personal fees from Anthos, Bristol Myers Squibb, Bayer, Daiichi-Sankyo, Pfizer, and Novartis. Dr Kittelson reported receiving personal fees from Bayer and Janssen Pharmaceuticals. Dr Bonaca reported receiving grants from EverlyWell, Virta, Wraser, Amgen, ARCA Biopharma, AstraZeneca/MedImmune, Bayer, Better Therapeutics, CellResearch, Heartflow, Janssen, Novo Nordisk, Osiris, Regio Bio, and HDL Therapeutics. Dr Halperin reported receiving personal fees from Johnson & Johnson (Ortho-McNeil-Janssen), Bayer, and Boehringer Ingelheim. Dr Sidonio reported receiving personal fees from Grifols, Bayer, Pfizer, Biomarin, Novo Nordisk, Catalyst, and Sanofi and receiving grants from Genentech, Octapharma, and Takeda. Dr Spyropoulos reported receiving personal fees from Janssen, Boehringer Ingelheim, Bristol Myers Squibb, Sanofi, Portola, and Bayer and receiving grants from Janssen and Boehringer Ingelheim. Dr Steg reported receiving grants from Amarin, AstraZeneca, Bayer, Sanofi, and Servier and receiving personal fees from Amarin, Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Idorsia, Merck, Novartis, Novo Nordisk, Pfizer, PhaseBio, Regeneron, Sanofi, and Servier. Dr Schulman reported receiving grants from Octapharma and receiving personal fees from Boehringer Ingelheim, Bayer, Sanofi, and Daiichi-Sankyo. No other disclosures were reported.

Funding/Support: This work was funded by grants 1U01HL130048 and 1K23HL084055 from the National Heart, Lung, and Blood Institute; the Bridge Award from the American Society of Hematology; the Thrombosis Studies Award from the Hemophilia and Thrombosis Research Society of North America; an investigator-initiated studies award from Eisai Inc; and an institutional research award from the Johns Hopkins All Children’s Foundation.

Role of the Funder/Sponsor: The funders/sponsors had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. The National Heart, Lung, and Blood Institute was represented on the executive steering committee and independently ran the data and safety monitoring board.

Group Information: A list of the Kids-DOTT Trial Investigators and the ATLAS Group members appears in Supplement 4.

Data Sharing Statement: See Supplement 5.

Additional Contributions: We thank the Kids-DOTT Trial Investigators, the clinical research coordinators, and the research nurses at all participating centers for their partnership in conducting the multicenter trial. We are indebted to the late Will Hiatt, MD (University of Colorado), who served on the executive steering committee and directed the data coordinating center through 2020, and contributed substantively to early versions of the manuscript; Andrei Kindzelski, MD, PhD (program director, Division of Blood Diseases and Resources, National Heart, Lung, and Blood Institute and representative on the executive steering committee; received no compensation for contribution); and Laurel McDevitt, MS (Johns Hopkins All Children’s Hospital; received salary support for contribution), for assistance in formatting and submission of the manuscript, Tables, Figures, and Supplements. We also thank the members of the clinical end point adjudication committee and the data and safety monitoring committee; the project management team at the clinical coordinating center for pediatric multicenter studies at the Institute for Clinical and Translational Research, Johns Hopkins All Children’s Hospital; the data coordinating center at CPC Clinical Research; the research administration staff at the Department of Research and Grants Administration, Johns Hopkins All Children’s Hospital; the grants administration staff at the Office of Research Administration, School of Medicine, Johns Hopkins University; CPC Clinical Research; and the Office of Grants and Contracts, University of Colorado Anschutz Medical Campus.

AMA CME Accreditation Information

Credit Designation Statement: The American Medical Association designates this Journal-based CME activity activity for a maximum of 1.00  AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Successful completion of this CME activity, which includes participation in the evaluation component, enables the participant to earn up to:

  • 1.00 Medical Knowledge MOC points in the American Board of Internal Medicine's (ABIM) Maintenance of Certification (MOC) program;;
  • 1.00 Self-Assessment points in the American Board of Otolaryngology – Head and Neck Surgery’s (ABOHNS) Continuing Certification program;
  • 1.00 MOC points in the American Board of Pediatrics’ (ABP) Maintenance of Certification (MOC) program;
  • 1.00 Lifelong Learning points in the American Board of Pathology’s (ABPath) Continuing Certification program; and
  • 1.00 credit toward the CME of the American Board of Surgery’s Continuous Certification program

It is the CME activity provider's responsibility to submit participant completion information to ACCME for the purpose of granting MOC credit.

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