Warfarin is a difficult drug to dose accurately and safely due to large inter-individual variability in dose requirements. Current dosing strategies appear to be sub-optimal, with reports indicating that patients achieve international normalized ratios (INRs) within the therapeutic range only 40–65 % of the time. The consequences of poor INR control are potentially severe with INRs below 2 carrying an increased risk of clotting while INRs >4 increase the risk of major bleeding events. Bayesian forecasting methods have the potential to improve INR control.
The aims of this study were to (1) prospectively assess the predictive performance of a Bayesian dosing method for warfarin implemented in TCIWorks; and (2) determine the expected time in the therapeutic range (TTR) of INRs predicted using TCIWorks.
Patients who were initiating warfarin therapy were prospectively recruited from Dunedin Hospital, Dunedin, New Zealand. Warfarin doses were entered into TCIWorks from the first day of therapy until a stable steady-state INR (INRss) was achieved. The predicted INRss values were determined using the first zero to six serially collected INR observations. Observed and predicted INRss values were compared using measures of bias (mean prediction error [MPE]) and imprecision (root mean square error [RMSE]). The TTR was determined by calculating the percentage of predicted INRss values between 2 and 3 when zero to six serially collected INR observations were available.
A total of 55 patients were recruited between March and November 2011. When no observed INR values were available the resulting INRss predictions were positively biased (MPE 0.52 [95 % CI 0.30, 0.73]); however, this disappeared once observed INR values were entered into TCIWorks. The precision of the predicted INRss values improved dramatically once three or more observed INR values were available (RMSE <0.53) compared with no INRs (RMSE 0.96). These results suggest that TCIWorks will be effective at maintaining the INR within the therapeutic INR range (2–3) 65 % of the time when three INR measurements are available and 80 % of the time when six INR measurements are available.
The TCIWorks warfarin dosing method produced accurate and precise INRss predictions. We predict that the method will provide an INR value within the therapeutic range 65–80 % of the time once three or more INR observations are available, making this a useful tool for clinicians and warfarin clinics. Further research to assess the impact of this method on long-term INR control is warranted.
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The authors wish to thank the Pharmacy Department at Dunedin Hospital, Professor Andre van Rij and the staff of the Otago Vascular Diagnostics Unit for assistance with patient recruitment. The authors are grateful to Lionel van den Berg from the University of Queensland and Professor Carl Kirkpatrick from Monash University for invaluable assistance with TCIWorks. We wish to thank Anna Karin Hamberg from the University of Uppsala for generous assistance with the warfarin model and for helpful comments on the manuscript. This study was funded by a research grant from the New Zealand Pharmacy and Education Research Foundation (NZPERF), PO Box 11-640, Manners Street, Wellington, New Zealand. At the time of writing, Dan Wright was the recipient of a University of Otago PhD scholarship.
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The authors have no conflicts of interest that are directly relevant to the content of this study.
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Wright, D.F.B., Duffull, S.B. A Bayesian Dose-Individualization Method for Warfarin. Clin Pharmacokinet 52, 59–68 (2013). https://doi.org/10.1007/s40262-012-0017-6
- International Normalize Ratio
- Warfarin Therapy
- Dose Method
- International Normalize Ratio Control