. 2025 Jan 1;26(1):e95-e105.

doi: 10.1097/PCC.0000000000003648. Epub 2024 Nov 20.

Protocol for the Catheter-Related Early Thromboprophylaxis With Enoxaparin (CRETE) Studies

E Vincent S Faustino¹, Sarah B Kandil¹, Matthew K Leroue², Anthony A Sochet³, Michele Kong⁴, Jill M Cholette⁵, Marianne E Nellis⁶, Matthew G Pinto⁷, Madhuradhar Chegondi⁸, Michelle Ramirez⁹, Hilary Schreiber¹⁰, Elizabeth W J Kerris¹¹, Christie L Glau¹², Amanda Kolmar¹³, Teddy M Muisyo¹⁴, Anjali Sharathkumar⁸, Lee Polikoff¹⁵, Cicero T Silva¹⁶, Lauren Ehrlich¹⁶, Oscar M Navarro^{17

18}, Philip C Spinella¹⁹, Leslie Raffini²⁰, Sarah N Taylor¹, Tara McPartland²¹, Veronika Shabanova^{1

22}; Catheter-Related Early Thromboprophylaxis with Enoxaparin (CRETE) Studies Investigators and the Pediatric Critical Care Blood Research Network (BloodNet) of the Pediatric Acute Lung Injury and Sepsis Investigators Network (PALISI)

Affiliations

¹ Department of Pediatrics, Yale School of Medicine, New Haven, CT.
² Department of Pediatrics, University of Colorado, Aurora, CO.
³ Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Johns Hopkins All Children's Hospital, St. Petersburg, FL.
⁴ Division of Pediatric Critical Care Medicine, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL.
⁵ Department of Pediatrics, University of Rochester, Rochester, NY.
⁶ Division of Critical Care Medicine, Department of Pediatrics, Weill Cornell Medicine, New York, NY.
⁷ Department of Pediatrics, New York Medical College, Maria Fareri Children's Hospital, Valhalla, NY.
⁸ Stead Family Department of Pediatrics, University of Iowa, Iowa City, IA.
⁹ Division of Pediatric Critical Care, NYU Langone Medical Center, Hassenfeld Children's Hospital, New York, NY.
¹⁰ Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI.
¹¹ Department of Pediatrics, Penn State College of Medicine, Penn State Health Children's Hospital, Hershey, PA.
¹² Department of Anesthesiology and Critical Care Medicine, The University of Pennsylvania Perelman School of Medicine, Children's Hospital of Philadelphia, Philadelphia, PA.
¹³ Division of Critical Care, Department of Pediatrics, Washington University School of Medicine in St. Louis, St. Louis, MO.
¹⁴ Section of Pediatric Critical Care, Department of Pediatrics, Oklahoma Children's Hospital, University of Oklahoma Health Sciences Center, Oklahoma City, OK.
¹⁵ Division of Critical Care Medicine, Department of Pediatrics, The Warren Alpert Medical School of Brown University, Providence, RI.
¹⁶ Department of Radiology and Biomedical Imaging, Yale School of Medicine, New Haven, CT.
¹⁷ Department of Diagnostic and Interventional Radiology, The Hospital for Sick Children, Toronto, ON, Canada.
¹⁸ Department of Medical Imaging, University of Toronto, Toronto, ON, Canada.
¹⁹ Trauma and Transfusion Medicine Center, Department of Surgery, University of Pittsburgh, Pittsburgh, PA.
²⁰ Department of Pediatrics, University of Pennsylvania, Children's Hospital of Philadelphia, Philadelphia, PA.
²¹ Yale Center for Clinical Investigation, Yale School of Medicine, New Haven, CT.
²² Department of Biostatistics, Yale School of Public Health, New Haven, CT.

PMID: 39560771
PMCID: PMC11717624 (available on 2026-01-01)
DOI: 10.1097/PCC.0000000000003648

Protocol for the Catheter-Related Early Thromboprophylaxis With Enoxaparin (CRETE) Studies

E Vincent S Faustino et al. Pediatr Crit Care Med. 2025.

. 2025 Jan 1;26(1):e95-e105.

doi: 10.1097/PCC.0000000000003648. Epub 2024 Nov 20.

Authors

Affiliations

¹ Department of Pediatrics, Yale School of Medicine, New Haven, CT.
² Department of Pediatrics, University of Colorado, Aurora, CO.
³ Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Johns Hopkins All Children's Hospital, St. Petersburg, FL.
⁴ Division of Pediatric Critical Care Medicine, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL.
⁵ Department of Pediatrics, University of Rochester, Rochester, NY.
⁶ Division of Critical Care Medicine, Department of Pediatrics, Weill Cornell Medicine, New York, NY.
⁷ Department of Pediatrics, New York Medical College, Maria Fareri Children's Hospital, Valhalla, NY.
⁸ Stead Family Department of Pediatrics, University of Iowa, Iowa City, IA.
⁹ Division of Pediatric Critical Care, NYU Langone Medical Center, Hassenfeld Children's Hospital, New York, NY.
¹⁰ Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI.
¹¹ Department of Pediatrics, Penn State College of Medicine, Penn State Health Children's Hospital, Hershey, PA.
¹² Department of Anesthesiology and Critical Care Medicine, The University of Pennsylvania Perelman School of Medicine, Children's Hospital of Philadelphia, Philadelphia, PA.
¹³ Division of Critical Care, Department of Pediatrics, Washington University School of Medicine in St. Louis, St. Louis, MO.
¹⁴ Section of Pediatric Critical Care, Department of Pediatrics, Oklahoma Children's Hospital, University of Oklahoma Health Sciences Center, Oklahoma City, OK.
¹⁵ Division of Critical Care Medicine, Department of Pediatrics, The Warren Alpert Medical School of Brown University, Providence, RI.
¹⁶ Department of Radiology and Biomedical Imaging, Yale School of Medicine, New Haven, CT.
¹⁷ Department of Diagnostic and Interventional Radiology, The Hospital for Sick Children, Toronto, ON, Canada.
¹⁸ Department of Medical Imaging, University of Toronto, Toronto, ON, Canada.
¹⁹ Trauma and Transfusion Medicine Center, Department of Surgery, University of Pittsburgh, Pittsburgh, PA.
²⁰ Department of Pediatrics, University of Pennsylvania, Children's Hospital of Philadelphia, Philadelphia, PA.
²¹ Yale Center for Clinical Investigation, Yale School of Medicine, New Haven, CT.
²² Department of Biostatistics, Yale School of Public Health, New Haven, CT.

PMID: 39560771
PMCID: PMC11717624 (available on 2026-01-01)
DOI: 10.1097/PCC.0000000000003648

Abstract

Objectives: In post hoc analyses of our previous phase 2b Bayesian randomized clinical trial (RCT), prophylaxis with enoxaparin reduced central venous catheter (CVC)-associated deep venous thrombosis (CADVT) in critically ill older children but not in infants. The goal of the Catheter-Related Early Thromboprophylaxis with Enoxaparin (CRETE) Studies is to investigate this newly identified age-dependent heterogeneity in the efficacy of prophylaxis with enoxaparin against CADVT in critically ill children.

Design: Two parallel, multicenter Bayesian superiority explanatory RCTs, that is, phase 3 for older children and phase 2b for infants, and an exploratory mechanistic nested case-control study (Trial Registration ClinicalTrials.gov NCT04924322, June 7, 2021).

Setting: At least 15 PICUs across the United States.

Patients: Older children 1-17 years old ( n = 90) and infants older than 36 weeks corrected gestational age younger than 1 year old ( n = 168) admitted to the PICU with an untunneled CVC inserted in the prior 24 hours. Subjects with or at high risk of clinically relevant bleeding will be excluded.

Interventions: Prophylactic dose of enoxaparin starting at 0.5 mg/kg then adjusted to anti-Xa range of 0.2-0.5 international units (IU)/mL for older children and therapeutic dose of enoxaparin starting at 1.5 mg/kg then adjusted to anti-Xa range of greater than 0.5-1.0 IU/mL or 0.2-0.5 IU/mL for infants while CVC is in situ.

Measurements and main results: Randomization is 2:1 to enoxaparin or usual care (no enoxaparin) for older children and 1:1:1 to either of 2 anti-Xa ranges of enoxaparin or usual care for infants. Ultrasonography will be performed after removal of CVC to assess for CADVT. Subjects will be monitored for bleeding. Platelet poor plasma will be analyzed for markers of thrombin generation. Samples from subjects with CADVT will be counter-matched 1:1 to subjects without CADVT from the opposite trial arm. Institutional Review Board approved the "CRETE Studies" on July 1, 2021. Enrollment is ongoing with planned completion in July 2025 for older children and July 2026 for infants.

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Conflict of interest statement

Dr. Faustino’s institution received funding from the National Center for Advancing Translational Sciences (NCATS). Drs. Faustino’s, Glau’s and Shabanova’s institutions received funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD). Drs. Faustino, Leroue, Sochet, Kong, Nellis, Pinto, Chegondi, Ramirez, Schreiber, Kerris, Glau, Kolmar, Muisyo, Silva, McPartland, and Shabanova received support for article research from the National Institutes of Health (NIH). Drs. Faustino, Kandil, Kerris, Glau, Silva, McPartland, and Shabanova disclosed off-label use of Enoxaparin. Dr. Kandil’s institution received funding from the NICHD (R01 HD106326) and the NCATS (UL1 TR001863); she received funding from the NIH (1R18HS027401-01A1) and the Children’s Hospital Association’s Improving Pediatric Sepsis Outcomes Steering Committee. Drs. Sochet’s, Kong’s, Schreiber’s, Kerris’, Kolmar’s, and Silva’s institutions received funding from the NIH. Dr. Glau received funding from the Medical University of South Carolina. Dr. Sharathkumar is a site investigator for a Pfizer study. Dr. Polikoff received funding from Novavax. Dr. Taylor’s institution received funding from Prolacta Bioscience and Ferring Pharmaceuticals; she received funding from Mother’s Milk Is Best. The remaining authors have disclosed that they do not have any potential conflicts of interest.

References

1. O’Brien SH, Stanek JR, Witmer CM, et al. The continued rise of venous thromboembolism across US children’s hospitals. Pediatrics 2022;149(3):e2021054649. - PubMed
1. Raffini L, Huang YS, Witmer C, et al. Dramatic increase in venous thromboembolism in children’s hospitals in the United States from 2001 to 2007. Pediatrics 2009;124(4):1001–1008. - PubMed
1. Mahajerin A, Branchford BR, Amankwah EK, et al. Hospital-associated venous thromboembolism in pediatrics: A systematic review and meta-analysis of risk factors and risk assessment models. Haematologica 2015;100(8):1045–1050. - PMC - PubMed
1. Faustino EVS, Shabanova V, Raffini LJ, et al. Efficacy of early prophylaxis against catheter-associated thrombosis in critically ill children: A Bayesian phase 2b randomized clinical trial. Crit Care Med 2021;49(3):e235–e246. - PMC - PubMed
1. Faustino EV, Lawson KA, Northrup V, et al. Mortality-adjusted duration of mechanical ventilation in critically ill children with symptomatic central venous line-related deep venous thrombosis. Crit Care Med 2011;39(5):1151–1156. - PMC - PubMed

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Protocol for the Catheter-Related Early Thromboprophylaxis With Enoxaparin (CRETE) Studies

Affiliations

Protocol for the Catheter-Related Early Thromboprophylaxis With Enoxaparin (CRETE) Studies

Authors

Affiliations

Abstract

Conflict of interest statement

References

Publication types

MeSH terms

Substances

Associated data

Grants and funding

LinkOut - more resources

Full Text Sources

Medical