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Personalised Warfarin Dosing in Children Post-cardiac Surgery
Basma Zuheir Al-Metwali1,2,3, Peter Rivers1, Larry Goodyer1
1School of Pharmacy, De Montfort University, Leicester, UK.
Insights
A new warfarin dosing algorithm improved anticoagulation control in children, especially during initial treatment. This personalized approach, using genetic information, showed faster stabilization and better time in therapeutic range compared to standard methods.
Area of Science:
- Pharmacology
- Pediatric Cardiology
- Genetics
Background:
- Warfarin dosing presents challenges due to individual pharmacokinetic (PK) and pharmacodynamic (PD) variations.
- Genetic factors, including CYP2C9 and VKORC1 genotypes, significantly influence warfarin metabolism and response.
- Optimizing warfarin therapy in children, particularly post-cardiac surgery, is crucial for effective anticoagulation.
Purpose of the Study:
- To evaluate a novel, personalized warfarin dosing algorithm for children based on a PK/PD model incorporating genetic data.
- To compare the efficacy of the model-based dosing algorithm against conventional weight-based dosing in pediatric patients.
Main Methods:
- A prospective, observational study involving two groups of children post-cardiac surgery.
- Group 1: Warfarin-naïve patients received model-estimated loading and maintenance doses, compared to historical controls.
- Group 2: Patients on maintenance therapy underwent a crossover study comparing model-based versus conventional dosing.
Main Results:
- In Group 1, model-based dosing led to a shorter time to stable anticoagulation (29.0 vs. 96.5 days) and a higher percentage of time in therapeutic range (83.4% vs. 62.3%).
- Group 1 also showed a longer time to first therapeutic INR (5 vs. 2 days) and over-anticoagulation (15.0 vs. 4.0 days) compared to controls.
- No significant differences in INR control were observed between model-based and conventional dosing in Group 2 (mean %ITR 68.82% vs. 67.9%; mean %TTR 85.47% vs. 80.2%).
Conclusions:
- Model-based warfarin dosing, incorporating genetic information, shows potential to enhance anticoagulation control in pediatric patients, particularly during initiation and stabilization.
- Further larger-scale studies are warranted to validate these findings and confirm the benefits of personalized warfarin dosing algorithms in children.
- The study highlights the need for advanced dosing strategies to overcome warfarin's complex PK/PD profile in pediatric populations.
Abstract:
Warfarin dosing is challenging due to a multitude of factors affecting its pharmacokinetics (PK) and pharmacodynamics (PD). A novel personalised dosing algorithm predicated on a warfarin PK/PD model and incorporating CYP2C9 and VKORC1 genotype information has been developed for children. The present prospective, observational study aimed to compare the model with conventional weight-based dosing. The study involved two groups of children post-cardiac surgery: Group 1 were warfarin naïve, in whom loading and maintenance doses were estimated using the model over a 6-month duration and compared to historical case-matched controls. Group 2 were already established on maintenance therapy and randomised into a crossover study comparing the model with conventional maintenance dosing, over a 12-month period. Five patients enrolled in Group 1. Compared to the control group, the median time to achieve the first therapeutic INR was longer (5 vs. 2 days), to stable anticoagulation was shorter (29.0 vs. 96.5 days), to over-anticoagulation was longer (15.0 vs. 4.0 days). In addition, median percentage of INRs within the target range (%ITR) and percentage of time in therapeutic range (%TTR) was higher; 70% versus 47.4% and 83.4% versus 62.3%, respectively. Group 2 included 26 patients. No significant differences in INR control were found between model and conventional dosing phases; mean %ITR was 68.82% versus 67.9% (p = 0.84) and mean %TTR was 85.47% versus 80.2% (p = 0.09), respectively. The results suggest model-based dosing can improve anticoagulation control, particularly when initiating and stabilising warfarin dosing. Larger studies are needed to confirm these findings.
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