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

E. Vincent S. Faustino; Veronika Shabanova; Leslie J. Raffini; Sarah B. Kandil; Simon Li; Matthew G. Pinto; Jill M. Cholette; Sheila J. Hanson; Marianne E. Nellis; Cicero T. Silva; Ranjit Chima; Anjali Sharathkumar; Kimberly A. Thomas; Tara McPartland; Joana A. Tala; Philip C. Spinella

doi:10.1097/CCM.0000000000004784

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

E. Vincent S. Faustino, Veronika Shabanova, Leslie J. Raffini, Sarah B. Kandil, Simon Li, Matthew G. Pinto, Jill M. Cholette, Sheila J. Hanson, Marianne E. Nellis, Cicero T. Silva, Ranjit Chima, Anjali Sharathkumar, Kimberly A. Thomas, Tara McPartland, Joana A. Tala, Philip C. Spinella

Division of Critical Care Medicine

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25 Scopus citations

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.

Original language	English
Pages (from-to)	E235-E246
Journal	Critical care medicine
Volume	49
Issue number	3
DOIs	https://doi.org/10.1097/CCM.0000000000004784
State	Published - Mar 1 2021

Keywords

Bayesian statistics
bleeding
central venous catheter
deep venous thrombosis
enoxaparin
pediatric intensive care unit

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10.1097/CCM.0000000000004784

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Faustino, E. V. S., Shabanova, V., Raffini, L. J., Kandil, S. B., Li, S., Pinto, M. G., Cholette, J. M., Hanson, S. J., Nellis, M. E., Silva, C. T., Chima, R., Sharathkumar, A., Thomas, K. A., McPartland, T., Tala, J. A., & Spinella, P. C. (2021). Efficacy of Early Prophylaxis Against Catheter-Associated Thrombosis in Critically Ill Children: A Bayesian Phase 2b Randomized Clinical Trial. Critical care medicine, 49(3), E235-E246. https://doi.org/10.1097/CCM.0000000000004784

@article{6e8a32ee194a47839fa8d5a927428046,

title = "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.",

keywords = "Bayesian statistics, bleeding, central venous catheter, deep venous thrombosis, enoxaparin, pediatric intensive care unit",

author = "Faustino, {E. Vincent S.} and Veronika Shabanova and Raffini, {Leslie J.} and Kandil, {Sarah B.} and Simon Li and Pinto, {Matthew G.} and Cholette, {Jill M.} and Hanson, {Sheila J.} and Nellis, {Marianne E.} and Silva, {Cicero T.} and Ranjit Chima and Anjali Sharathkumar and Thomas, {Kimberly A.} and Tara McPartland and Tala, {Joana A.} and Spinella, {Philip C.}",

year = "2021",

month = mar,

day = "1",

doi = "10.1097/CCM.0000000000004784",

language = "English",

volume = "49",

pages = "E235--E246",

journal = "Critical care medicine",

issn = "0090-3493",

number = "3",

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Faustino, EVS, Shabanova, V, Raffini, LJ, Kandil, SB, Li, S, Pinto, MG, Cholette, JM, Hanson, SJ, Nellis, ME, Silva, CT, Chima, R, Sharathkumar, A, Thomas, KA, McPartland, T, Tala, JA & Spinella, PC 2021, 'Efficacy of Early Prophylaxis Against Catheter-Associated Thrombosis in Critically Ill Children: A Bayesian Phase 2b Randomized Clinical Trial', Critical care medicine, vol. 49, no. 3, pp. E235-E246. https://doi.org/10.1097/CCM.0000000000004784

TY - JOUR

T1 - Efficacy of Early Prophylaxis Against Catheter-Associated Thrombosis in Critically Ill Children

T2 - A Bayesian Phase 2b Randomized Clinical Trial

AU - Faustino, E. Vincent S.

AU - Shabanova, Veronika

AU - Raffini, Leslie J.

AU - Kandil, Sarah B.

AU - Li, Simon

AU - Pinto, Matthew G.

AU - Cholette, Jill M.

AU - Hanson, Sheila J.

AU - Nellis, Marianne E.

AU - Silva, Cicero T.

AU - Chima, Ranjit

AU - Sharathkumar, Anjali

AU - Thomas, Kimberly A.

AU - McPartland, Tara

AU - Tala, Joana A.

AU - Spinella, Philip C.

PY - 2021/3/1

Y1 - 2021/3/1

N2 - 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.

AB - 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.

KW - Bayesian statistics

KW - bleeding

KW - central venous catheter

KW - deep venous thrombosis

KW - enoxaparin

KW - pediatric intensive care unit

UR - http://www.scopus.com/inward/record.url?scp=85102219870&partnerID=8YFLogxK

U2 - 10.1097/CCM.0000000000004784

DO - 10.1097/CCM.0000000000004784

M3 - Article

C2 - 33372745

AN - SCOPUS:85102219870

SN - 0090-3493

VL - 49

SP - E235-E246

JO - Critical care medicine

JF - Critical care medicine

IS - 3

ER -

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

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Keywords

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