Efficacy of Early Prophylaxis Against Catheter-Associated Thrombosis in Critically Ill Children: A Bayesian Phase 2b Randomized Clinical Trial

Abstract

Objectives: We obtained preliminary evidence on the efficacy of early prophylaxis on the risk of central venous catheter-associated deep venous thrombosis and its effect on thrombin generation in critically ill children.

Design: Bayesian phase 2b randomized clinical trial.

Setting: Seven PICUs.

Patients: Children less than 18 years old with a newly inserted central venous catheter and at low risk of bleeding.

Intervention: Enoxaparin adjusted to anti-Xa level of 0.2-0.5 international units/mL started at less than 24 hours after insertion of central venous catheter (enoxaparin arm) versus usual care without placebo (usual care arm).

Measurements and main results: At the interim analysis, the proportion of central venous catheter-associated deep venous thrombosis on ultrasonography in the usual care arm, which was 54.2% of 24 children, was significantly higher than that previously reported. This resulted in misspecification of the preapproved Bayesian analysis, reversal of direction of treatment effect, and early termination of the randomized clinical trial. Nevertheless, with 30.4% of 23 children with central venous catheter-associated deep venous thrombosis on ultrasonography in the enoxaparin arm, risk ratio of central venous catheter-associated deep venous thrombosis was 0.55 (95% credible interval, 0.24-1.11). Including children without ultrasonography, clinically relevant central venous catheter-associated deep venous thrombosis developed in one of 27 children (3.7%) in the enoxaparin arm and seven of 24 (29.2%) in the usual care arm (p = 0.02). Clinically relevant bleeding developed in one child randomized to the enoxaparin arm. Response profile of endogenous thrombin potential, a measure of thrombin generation, was not statistically different between trial arms.

Conclusions: These findings suggest the efficacy and safety of early prophylaxis that should be validated in a pivotal randomized clinical trial.

Trial registration: ClinicalTrials.gov NCT03003390.

Conflict of interest statement

Drs. Faustino and Spinella received funding from the National Institutes of Health (NIH)/Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) to conduct the trial (R21HD089131). Dr. Faustino received funding from the American Heart Association to conduct the trial (16RNT31180018). Dr. Shabanova received funding through the Clinical and Translational Science Award Grant Number UL1 RR024139 from the National Center for Research Resources and the National Center for Advancing Translational Science, components of the NIH, and NIH roadmap for Medical Research. Drs. Faustino’s and Shabanova’s institutions received funding from NICHD, American Heart Association, and the National Center for Advancing Translational Science. Drs. Faustino, Shabanova, Hanson, Sharathkumar, and Thomas received support for article research from the NIH. Dr. Faustino, Dr. Raffini, Dr. Kandil, Dr. Hanson, and Ms. McPartland disclosed off-label product use of enoxaparin. Dr. Raffini received funding from CSL Behring, XaTek, and Bayer. Dr. Pinto’s institution received funding from the NIH. Dr. Hanson’s institution received funding from NIH/Eunice Kennedy Shriver NICHD. Dr. Thomas’ institution received funding from Yale University. The remaining authors have disclosed that they do not have any potential conflicts of interest.

Copyright © 2021 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Figures

Figure 1.

CONSORT diagram. 1All children, regardless of the presence of ultrasonography, were analyzed for the other outcome measures.

Figure 2.

Posterior distribution of the risk ratio of central venous catheter-associated deep venous thrombosis (CADVT) with early prophylaxis with enoxaparin. The vertical line represents the posterior median of the probability distribution of the risk ratio while the shaded area represents the posterior probability that the risk ratio is

Figure 3.

Response profiles of endogenous thrombin potential (ETP; A), factor VIII activity (B) and D-dimer level (C) across sampling days and between trial arms. None of the response profiles were statistically different between trial arms. CVC – central venous catheter; IQR – interquartile range.