TY - JOUR
T1 - Effects of dalteparin on anti-Xa activities cannot be predicted in critically ill COVID-19 patients
AU - van der Heijden, Charlotte D.C.C.
AU - ter Heine, Rob
AU - Kooistra, Emma J.
AU - Brüggemann, Roger J.
AU - Walburgh Schmidt, Jesper W.J.
AU - de Grouw, Elke P.L.M.
AU - Frenzel, Tim
AU - Pickkers, Peter
AU - Leentjens, Jenneke
N1 - © 2021 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.
PY - 2022/6
Y1 - 2022/6
N2 - Critically ill COVID-19 patients are at high risk of thromboembolic events despite routine-dosed low-molecular-weight heparin thromboprophylaxis. However, in recent randomized trials increased-intensity thromboprophylaxis seemed futile and possibly even harmful. In this explorative pharmacokinetic (PK) study we measured anti-Xa activities on frequent timepoints in 15 critically ill COVID-19 patients receiving dalteparin and performed PK analysis by nonlinear mixed-effect modelling. A linear one-compartment model with first-order kinetics provided a good fit. However, wide interindividual variation in dalteparin absorption (variance 78%) and clearance (variance 34%) was observed, unexplained by routine clinical covariates. Using the final PK model for Monte Carlo simulations, we predicted increased-intensity dalteparin to result in anti-Xa activities well over prophylactic targets (0.2-0.4 IU/mL) in the majority of patients. Therapeutic-intensity dalteparin results in supratherapeutic anti-Xa levels (target 0.6-1.0 IU/mL) in 19% of patients and subtherapeutic levels in 22%. Therefore, anti-Xa measurements should guide high-intensity dalteparin in critically ill COVID-19 patients.
AB - Critically ill COVID-19 patients are at high risk of thromboembolic events despite routine-dosed low-molecular-weight heparin thromboprophylaxis. However, in recent randomized trials increased-intensity thromboprophylaxis seemed futile and possibly even harmful. In this explorative pharmacokinetic (PK) study we measured anti-Xa activities on frequent timepoints in 15 critically ill COVID-19 patients receiving dalteparin and performed PK analysis by nonlinear mixed-effect modelling. A linear one-compartment model with first-order kinetics provided a good fit. However, wide interindividual variation in dalteparin absorption (variance 78%) and clearance (variance 34%) was observed, unexplained by routine clinical covariates. Using the final PK model for Monte Carlo simulations, we predicted increased-intensity dalteparin to result in anti-Xa activities well over prophylactic targets (0.2-0.4 IU/mL) in the majority of patients. Therapeutic-intensity dalteparin results in supratherapeutic anti-Xa levels (target 0.6-1.0 IU/mL) in 19% of patients and subtherapeutic levels in 22%. Therefore, anti-Xa measurements should guide high-intensity dalteparin in critically ill COVID-19 patients.
KW - anti-Xa
KW - COVID-19
KW - critical care
KW - dalteparin
KW - low-molecular weight heparin
KW - pharmacokinetics
KW - therapeutic drug monitoring
KW - Anticoagulants
KW - COVID-19 Drug Treatment
KW - Humans
KW - Critical Illness/therapy
KW - Heparin, Low-Molecular-Weight
KW - Factor Xa Inhibitors/pharmacokinetics
KW - Dalteparin/adverse effects
KW - Venous Thromboembolism/chemically induced
UR - http://www.scopus.com/inward/record.url?scp=85122749418&partnerID=8YFLogxK
U2 - 10.1111/bcp.15208
DO - 10.1111/bcp.15208
M3 - Article
C2 - 34965610
AN - SCOPUS:85122749418
SN - 0306-5251
VL - 88
SP - 2982
EP - 2987
JO - British Journal of Clinical Pharmacology
JF - British Journal of Clinical Pharmacology
IS - 6
ER -