CHANGES IN PLASMA WARFARIN LEVELS AND VARIATIONS IN STEADY-STATE PROTHROMBIN TIMES

Objective: To determine the relative contribution of changes in the pl asma warfarin level to variation in the serial steady-state prothrombi n times. Methods: This was a prospective observational cohort study pe rformed at two outpatient anticoagulation clinics. Serial prothrombin times and paired plasma total warfarin levels were determined in a con venience sample of otherwise healthy patients who required long-term o ral anticoagulation therapy with warfarin. Results: Serial measurement s were obtained from 129 patients, 60 of whom provided three or more s erial samples. Analysis of covariance showed a highly significant (p = 0.0001) relationship between the anticoagulant effect and the logarit hm of the warfarin concentration (R(2) = 0.75), with 15.3% of the tota l variance attributable to the effect of warfarin and 31.1% attributab le to individual variation in sensitivity to warfarin, In an analysis of the subjects who had three or more serial measurements, the mean we ighted correlation coefficient for the relationship between the logari thm of the warfarin concentration and the anticoagulant response varie d widely, from strongly negative to strongly positive, and as the rang e of observed prothrombin times increased, stronger positive correlati on was observed. Conclusions: In this cohort, the plasma warfarin leve l was a strong predictor of observed changes in serial prothrombin tim e measurements. However, the correlation between clotting times and wa rfarin levels varied widely among subjects, particularly when the rang e of observed prothrombin times was moderate, This suggests that in th ese subjects, other factors, such as measurement error or pharmacodyna mic changes, played a major role.