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Prothrombin Time Significant Change

Use of the international normalized ratio (INR) has greatly standardized and improved the monitoring of oral anticoagulant therapy. However 25-30% of INR values fall outside the therapeutic range, raising the issue of warfarin dose adjustment. Random variation of INR values may occur in a patient, despite stable intensity of oral anticoagulant therapy, as a result of both biological variation (such as minor changes in diet or intestinal vitamin K absorption) and analytic variation (such as minor changes in blood drawing or processing). A recent study addressed the important issue of how to evaluate whether a change in INR represents random variation, not requiring a warfarin dose change, or whether it represents a significant clinically relevant change, requiring an adjustment of the warfarin dose (Clinical Chemistry 1995; 41:1171-76).

The authors determined that combined analytical and biological variation within a subject on a stable dose of warfarin amounts to approximately 10%. Taking this random variation into account, they calculated that a significant change in INR in a patient on fixed dose and steady state warfarin therapy can be expressed as a change (increase or decrease) of greater than 0.28 times the previous INR (for a 95% level of significance). For example, if the previous INR was 2.5, a significant change in the INR value necessitating a change in warfarin dose would be greater than +/- 0.7 (0.28 x 2.5). The table shows the values for significant changes in INR and ranges of acceptable INR variation at various previous INR values, using this formula. Please note that these values apply only to patients who are on a fixed dose of warfarin, having achieved a steady state of anticoagulation. The authors do caution that if the INR value is unacceptably high, indicating an increased risk for hemorrhage, reduction of dose must be considered solely on the basis of clinical judgment.

The authors claim that use of these guidelines is likely to avoid the “ping-pong” effect on the INR of inappropriately changing the warfarin dose up and down in response to minor random variations in that value, which may result in under- or over-anticoagulation. In summary, using this approach in patients stably anticoagulated with warfarin may provide some guidance in determining whether a change in warfarin dose is warranted, thus improving oral anticoagulant control.

Previous INR

Significant change in INR would be greater than

Range of acceptable INR variation



1.4 - 2.6



1.8 - 3.2



2.2 - 3.8



2.5 - 4.5

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