We read with interest the 2012 evidence-based management of anticoagulant therapy on clinical practice guidelines of the American College of Chest Physicians (ACCP) , published recently in Chest. When discussing how and when vitamin K should be used to reverse over-anticoagulation, the guidelines recommended the following: (i) ‘for patients taking VKAs with an INR between 4.5 and 10 and with no evidence of bleeding, we suggest against the routine use of vitamin K (Grade 2B)’; and (ii) ‘for patients taking VKAs with INR > 10.0 and with no evidence of bleeding, we suggest that oral vitamin K be administered (Grade 2C)’.
We wish to comment on the numerical significance of the International Normalized Ratio (INR) as stated by the recommendation. According to the 1999 guidelines for thromboplastins and plasma used to control oral anticoagulant therapy issued by the World Health Organization (WHO) , the INR scale for reporting prothrombin time (PT) results has well-defined limitations, some of which are strictly pertinent to the ACCP recommendations.
The INR scale is most accurate within the interval of 1.5–4.5 . To appreciate why this is so, it is worth reporting briefly how a working thromboplastin is calibrated. Twenty or more healthy subjects (not taking anticoagulants and free from diseases known to alter coagulation) and 60 or more patients stabilized on vitamin K antagonists (VKAs) for at least 6 weeks should be selected and included in the calibration if their INRs are within the range of 1.5–4.5. Plasma is then subjected to PT measurements with the working and standard thromboplastins, and paired PTs are plotted on a double-log scale (standard thromboplastin on the vertical axis). After checking for linearity, the best-fit line that describes patients and normal data points is drawn, and eventually the slope of the line is estimated by orthogonal regression analysis. The slope of the line (after appropriate correction) is taken as the International Sensitivity Index (ISI), which represents a measure of the responsiveness of the thromboplastin being calibrated relative to the international standard. The above procedure implies that the ISI and therefore the INR that is derived thereafter (i.e. INR = (PTpatient/PTnormal]ISI) is accurate within the limits of INR from 1.5 to 4.5 (i.e. the INR of the patients selected for calibration). Therefore, the accuracy of INR values in excess of 4.5 is questionable, as there is no assurance that the calibration line beyond that value is still linearly related to the increasing PT prolongation. Furthermore, it is possible that different thromboplastins (even if they have been calibrated correctly) will display different INRs. Hence, grading the recommendation on the use of vitamin K to reverse anticoagulation on the basis of INR values from 4.5 to 10.0 or beyond 10.0, as stated in the ACCP recommendation, contrasts with the WHO guidelines, lacks evidence, and might be misleading, depending on the thromboplastin used for testing. Furthermore, the use of point-of-care coagulometers for self-testing, which is recommended for selected patients by the ACCP guidelines , would make impossible the practical application of the recommended use of vitamin K, because, according to Leichsenring et al. , portable coagulometers reliably measure INR only up to 8.0. Although no definite conclusions can be drawn, a more pragmatic approach would be to recommend vitamin K administration when the INR is > 8.0. Although there is no assurance that an INR from 4.5 to 8.0 is accurate, it is certainly much more accurate than an INR of ≥ 10.0.