E Vincent S Faustino1, Veronika Shabanova1, Leslie J Raffini2, Sarah B Kandil1, Simon Li3, Matthew G Pinto3, Jill M Cholette4, Sheila J Hanson5, Marianne E Nellis6, Cicero T Silva7, Ranjit Chima8, Anjali Sharathkumar9, Kimberly A Thomas10, Tara McPartland11, Joana A Tala12, Philip C Spinella10. 1. Department of Pediatrics, Yale School of Medicine, New Haven, CT. 2. Department of Pediatrics, Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA. 3. Department of Pediatrics, New York Medical College, Maria Fareri Children's Hospital, Valhalla, NY. 4. Department of Pediatrics, University of Rochester Golisano Children's Hospital, Rochester, NY. 5. Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI. 6. Department of Pediatrics, NY Presbyterian Hospital - Weill Cornell Medicine, New York, NY. 7. Department of Diagnostic Radiology, Yale School of Medicine, New Haven, CT. 8. Division of Critical Care Medicine, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH. 9. Stead Family Department of Pediatrics, University of Iowa Carver College of Medicine, Iowa City, IA. 10. Department of Pediatrics, Washington University in St. Louis, St. Louis, MO. 11. Yale Center for Clinical Investigation, Yale School of Medicine, New Haven, CT. 12. Pediatric Intensive Care Unit, Yale-New Haven Children's Hospital, New Haven, CT.
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.
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.
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