Therapeutic monitoring of warfarin: The appropriate response marker

Warfarin is a 4-hydroxycoumarin anticoagulant drug used for the prevention and management of thromboembolic and vascular diseases. It acts through the inhibition of the vitamin K-dependent transcarboxylation reactions that co nvert precursors of clotting factors into their active form. Appropriate us e of warfarin requires patient monitoring and dosage adjustments, to ensure its safety and efficacy. The aim of this work was to clarify the relations hip between traditional (prothrombin time, usually expressed as the interna tional normalized ratio; INR) and alternative (clotting factors II and X) w arfarin response markers to establish their usefulness for therapeutic drug monitoring. Seventy adult outpatients, aged between 31 and 86 years old, were involved in the study. All subjects received warfarin in a monotherapy regimen and h ad been on a stable dosing schedule for at least two weeks to assure a stea dy-state condition. A total of 81 prothrombin times (expressed as INR), and factor II and factor X activity were simultaneously determined. Eleven pat ients presented repeated measurements at different time periods under the s ame dosing regimen. The results obtained from regression and cluster analys is showed a close relationship between factors II and X (r = 0.73), a weak correlation between INR and both factor II (r = -0.35) and factor X (r = -0 .36), and a very slight dependency between warfarin and the response marker s used. In addition, it seems that independent of the selected response mar ker, in long-term warfarin therapy, reproducible responses can be obtained over time if a steady-state condition is achieved. The coefficients of vari ation for factors II and X were greater (35.44 and 37.93%, respectively) th an INR (14.50%), indicating that INR is a more precise measure than either factor II or factor X. In conclusion, INR appears to be the most appropriate warfarin response mar ker for therapeutic drug monitoring due to its universality, objectivity as a direct physiological effect measurement, and the available information r egarding appropriate endpoints. However, when INR values are not in accorda nce with patient response therapy, factor II and factor X should be conside red as an alternative to optimize warfarin therapy.