Age-Dependent Heterogeneity in the Efficacy of Prophylaxis With Enoxaparin Against Catheter-Associated Thrombosis in Critically Ill Children: A Post Hoc Analysis of a Bayesian Phase 2b Randomized Clinical Trial

Abstract

Objectives: We explored the age-dependent heterogeneity in the efficacy of prophylaxis with enoxaparin against central venous catheter-associated deep venous thrombosis in critically ill children.

Design: Post hoc analysis of a Bayesian phase 2b randomized clinical trial.

Setting: Seven PICUs.

Patients: Children less than 18 years old with newly inserted central venous catheter.

Interventions: Enoxaparin started less than 24 hours after insertion of central venous catheter and adjusted to anti-Xa level of 0.2-0.5 international units/mL versus usual care.

Measurements and main results: Of 51 children randomized, 24 were infants less than 1 year old. Risk ratios of central venous catheter-associated deep venous thrombosis with prophylaxis with enoxaparin were 0.98 (95% credible interval, 0.37-2.44) in infants and 0.24 (95% credible interval, 0.04-0.82) in older children greater than or equal to 1 year old. Infants and older children achieved anti-Xa level greater than or equal to 0.2 international units/mL at comparable times. While central venous catheter was in situ, endogenous thrombin potential, a measure of thrombin generation, was 223.21 nM.min (95% CI, 8.78-437.64 nM.min) lower in infants. Factor VIII activity, a driver of thrombin generation, was also lower in infants by 45.1% (95% CI, 15.7-74.4%). Median minimum platelet count while central venous catheter was in situ was higher in infants by 39 × 103/mm3 (interquartile range, 17-61 × 103/mm3). Central venous catheter:vein ratio was not statistically different. Prophylaxis with enoxaparin was less efficacious against central venous catheter-associated deep venous thrombosis at lower factor VIII activity and at higher platelet count.

Conclusions: The relatively lesser contribution of thrombin generation on central venous catheter-associated thrombus formation in critically ill infants potentially explains the age-dependent heterogeneity in the efficacy of prophylaxis with enoxaparin.

Trial registration: ClinicalTrials.gov NCT03003390.

Conflict of interest statement

Drs. Faustino and Spinella received funding to conduct the Catheter-Related Early Thromboprophylaxis with Enoxaparin Trial. Dr. Faustino’s institution received funding from National Institutes of Health (NIH) and the American Heart Association to conduct the trial (16RNT31180018). Drs. Faustino and Spinella received funding from the NIH/Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) to conduct the trial (R21HD089131). Drs. Faustino, Hanson, Pinto, Shabanova, and McPartland received support for article research from the NIH. Drs. Faustino, Raffini, Hanson, Kandil, McPartland, and Spinella disclosed off-label product use of enoxaparin (investigational new drug approval from the U.S. Food and Drug Administration was received). Dr. Raffini received funding from Bayer, Genetech, Xa-Tek, and HemaBiologics. Dr. Hanson’s institution received funding from the NIH. Dr. Kandil received funding from Children’s Hospital Collaborative, Improving Pediatric Sepsis Outcomes. Dr. Shabanova’s institution received funding from Prevention of Central Venous Catheter-Associated Thrombosis in Critically Ill Children NICHD: R21HD089131; she 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. The remaining authors have disclosed that they do not have any potential conflicts of interest.

Copyright © 2020 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Figures

Figure 1.

Posterior distributions of the risk ratio of central venous catheter-associated deep venous thrombosis (CADVT) with prophylaxis with enoxaparin in critically ill infants and older children. The vertical line represents the posterior median of the probability distribution of the risk ratio. CrI – credible interval.

Figure 2.

Kaplan-Meier curves of the probabilities of receiving enoxaparin (A) and achieving anti-Xa level ≥0.2 IU/mL (B) between critically ill infants and older children.

Figure 3.

Endogenous thrombin potential (ETP; A), factor VIII activity (B) and D-dimer level (C) across different sampling times in critically ill infants and older children.

Figure 4.

Effect of factor VIII activity (A) and platelet count (B and C) on the risk ratio of CVC-associated DVT (CADVT) with prophylaxis with enoxaparin. Higher risk ratios of CADVT with prophylaxis with enoxaparin, i.e., risk ratios that approached 1, indicated minimal reductions in the risk of CADVT with prophylaxis with enoxaparin and less efficacy. Conversely, lower risk ratios, i.e., risk ratios that approached 0, indicated significant reductions in the risk of CADVT with prophylaxis with enoxaparin and greater efficacy.