Inaccuracy of international normalized ratio (INR) measurements and suggestions for improved WHO guidelines for calibration of reference preparations – a statistical study

Abstract

Summary. Numerous empirical studies show that the accuracy of international normalized ratio (INR) measurements is unsatisfactory and worse than generally expected. We demonstrate that a plausible reason for this large inaccuracy is a conventional calibration procedure of reference preparations with (i) an erroneous assumption that the line relating logarithmic prothrombin times (log PTs) of patients passes through the mean log PT of the 'normal' population (mean normal PT); (ii) non-perceived interactions between patients and PT systems; and (iii) systematic exclusions of 'outliers'. The same conventional procedure also results in serious overestimation of the accuracy of INR measurements, thus leading to a false sense of security in oral anticoagulant therapy. In an example with data from WHO guidelines, we show that the systematic overprediction of INR (which is believed to be 0) may be as large as 5%, when prediction is performed under the conventional WHO model. Under the same model the CV of the predicted vs. the true INR is believed to be only about 1% when it in reality is more than 4%. We suggest that the conventional calibration procedure is modified in order to reduce the twofold negative impact of lower true accuracy and overestimated reported accuracy on oral anticoagulant therapy and to allow for an unambiguous definition of true INR values. Keywords: accuracy, calibration, international normalized ratio (INR).The international normalized ratio (INR) is recommended by the World Health Organization (WHO) for reporting prothrombin time (PT) in patients on stable oral anticoagulant therapy [1,2]. However, reports on inconsistent INR measurements suggest that the accuracy of these are overestimated [3][4][5][6][7][8][9]. In a recent study [10], we found that for blood samples with true INR 2 and 4, the 95% prediction intervals for INR measurements obtained directly by the second generation international reference preparation (IRP) RBT/79 are 1.7-2.4, and 3.2-5.0, respectively. These intervals are large compared, e.g. with the therapeutic range of 2-3 for patients with mechanical heart valves. In routine use the prediction interval is even larger, since routine INR estimates are obtained by commercial thromboplastins which have had their international sensitivity index (ISI) assigned either by the use of plasma calibrators with INR determined against an IRP, or by successive calibrations against a house standard and an IRP. Moreover the inaccuracy of IRPs will generally increase with the distance from the primary IRP 67/40.The aim of the present study was to investigate how some critical statistical assumptions of the WHO guidelines [2] for calibration of international reference preparations or secondary standards affect the validity of INR measurements. The focus is on a single calibration exercise within a single laboratory, but the results may be further generalized to multicenter calibrations and serial calibrations. The results can be used to optimize future calibrations in order to maximize the va...

Discrepancies in International Normalized Ratio Results between Instruments: A Model to Split the Variation into Subcomponents

“…All instruments used in this study were calibrated against an IRP or methods traceable to an IRP in accordance with WHO guidelines (2 ). However, it has been shown that the calibration procedure does not necessarily harmonize with the INR results (3,5 ). Differences in calibration were taken into account by correction of all results by use of linear regression.…”

“…Agreement in results between laboratory INR instruments and methods improved after the introduction of WHO guidelines that launched new calibration procedures (2 ). Nevertheless, harmonization of results from different laboratories remains challenging (3)(4)(5). Different types and sensitivities of thromboplastins (2 ) and interactions between thromboplastin and coagulation factors of individual patients may influence the accuracy of the instruments (4,6,7 ).…”

Self-Management of Oral Anticoagulant Therapy: A Review

“…the use of a sensitive tromboplastin, method for clot detection, full-blood versus plasma analysis, precision and method used for the calibration process, and the stability of the patients OAT [45][46][47][48]. INR determined in the laboratory using a standardized and quality controlled method (with internal and external quality assurance) is often referred to as the golden standard [49], to which all other methods should be compared.…”

Evaluation of Different Thromboplastins and Coagulometers on International Normalize Ratio (INR) Readings for Patients under Stable Oral Anticoagulant Therapy

“…Variations between various thromboplastin preparations have in the past led to decreased accuracy of INR readings, and a study suggested that despite international calibration efforts (by INR) there were still statistically significant differences between various kits [6]. Harmonization of results from different laboratories remains challenging [7]. Different types and sensitivities of thromboplastins [5] and interactions between thromboplastins and coagulation factors of individual patients may influence the accuracy of the instruments [8][9][10].…”