Effects of dalteparin on anti-XA levels cannot be predicted in critically ill COVID-19 patients

ABSTRACT

Background: Critically ill patients with COVID-19 are at high risk of thromboembolic events, despite thromboprophylaxis with lowmolecular weight heparins (LWMH), while increased-intensity thromboprophylaxis in this patient population is associated with bleeding. This raises the question whether pharmacokinetic (PK) effects of LMWHs are predictable in these patients. Aims: To investigate whether a dosing algorithm for dalteparin administration could be designed based on clinical parameters, using PK modeling with anti-Xa levels as readout. Methods: In this explorative, observational study, we prospectively included 15 adult COVID-19 patients admitted to the intensive care unit receiving dalteparin in prophylactic-intensity (5000 IU dalteparin once daily (OD) for those <100 kg, 5000 IU dalteparin bidaily (BD) for those ≥100 kg) and therapeutic-intensity (100 IU/kg BD). A minimum of 4 anti-Xa samples per day were collected on regular timepoints over 1-3 days. PK analysis of dalteparin was performed by nonlinear mixed-effect modeling (NONMEM v7.4). The final model was used to perform Monte Carlo simulations to predict anti-Xa levels with different dalteparin regimens. The study was approved by the local medical ethics committee. Results: The data were well-fitted to a linear one compartment model. Wide interindividual variation in the parameters absorption (78%) and clearance (34%) of dalteparin was observed, not explained by clinical covariates such as creatinine clearance for elimination rate. Simulations show that prophylactic dosing in individuals <100 kg result in anti-Xa levels within generally used prophylactic targets, while increased-prophylactic dosing in those ≥100 kg result in supraprophylactic levels in 40% of patients. With therapeuticintensity dosing in secondary thromboprophylaxis, 22% of patients would be subtherapeutically, and 19% patients supratherapeutically dosed. Conclusions: Anti-Xa levels during dalteparin treatment in the critically ill COVID-19 patient are difficult to predict and often off-target. Until data from randomized clinical trials conclude on the best dosing, this suggests that anti-Xa measurements are needed to guide high-intensity dosing in the individual patient.