Variations in Prothrombin Time and International Normalized Ratio over 24 Hours in Warfarin‐Treated Patients

Study Objective. To determine the variation of prothrombin times and international normalized ratio (INR) over 24 hours in humans. Design. Prospective, parallel study. Setting. University‐affiliated general clinical research center. Patients. Six patients receiving long‐term warfarin therapy and six sex‐matched controls. Interventions. Warfarin was administered to the patients at 6:00 P.M. Measurements and Main Results. Prothrombin times and INR were determined every 2 hours over 24 hours. Time of study entry, meals, and sleep cycles were controlled. A significant cosinor rhythm for prothrombin times and INR (p≤0.03) occurred in warfarin‐treated patients, suggesting that diurnal variation occurs. The mean difference between the peak and trough prothrombin times was 1.8 ± 0.9 seconds (range 0.8‐3 sec) with a mean change of 9.3% ± 3.7%. The peak prothrombin time and INR values occurred between 4:00 A.M. and 8:00 A.M. in five patients, and trough values between 6:00 P.M. and midnight in five. No significant cosinor rhythm was noted for controls (p>0.5). Conclusion. Significant variations in prothrombin time and INR occurred in patients receiving warfarin therapy, with the highest values occurring in the morning and the lowest in the evening. These results may have clinical implications for patients receiving either high‐ or low‐intensity warfarin therapy. 1995 Pharmacotherapy Publications Inc.