title: A Bayesian dose-individualization method for warfarin.
abstract: BACKGROUND
  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.
  
  
  OBJECTIVE
  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.
  
  
  METHODS
  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 (INR(ss)) was achieved. The predicted INR(ss) values were determined using the first zero to six serially collected INR observations. Observed and predicted INR(ss) 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 INR(ss) values between 2 and 3 when zero to six serially collected INR observations were available.
  
  
  RESULTS
  A total of 55 patients were recruited between March and November 2011. When no observed INR values were available the resulting INR(ss) 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 INR(ss) 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.
  
  
  CONCLUSIONS
  The TCIWorks warfarin dosing method produced accurate and precise INR(ss) 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.
authors: School of Pharmacy, University of Otago, PO Box 56, Dunedin, 9054, New Zealand. dan.wright@otago.ac.nz
authors: Daniel F B
authors: DF
authors: Wright
authors: Stephen B
authors: SB
authors: Duffull
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000925:Anticoagulants / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D001499:Bayes Theorem; D004305:Dose-Response Relationship, Drug; D005260:Female; D006470:Hemorrhage / Q000139:chemically induced / Q000517:prevention & control; D006801:Humans; D019934:International Normalized Ratio; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D008954:Models, Biological; D011446:Prospective Studies; D012984:Software; D014859:Warfarin / Q000008:administration & dosage* / Q000493:pharmacokinetics*
chemical_list: D000925:Anticoagulants; D014859:Warfarin