Harmonizing the International Normalized Ratio (INR) : Standardization of Methods and Use of Novel Strategies to Reduce Interlaboratory Variation and Bias.

OBJECTIVES: To reduce interlaboratory variation and bias in international normalized ratio (INR) results, as used to monitor patients receiving vitamin K antagonist therapy, including warfarin, in a large pathology network (n = 27 laboratories) by procedural standardization and harmonization. METHODS: Network consensus to standardize to common instrument and reagent platforms was established, following development of hemostasis test specifications. Subsequent installations and implementation occurred after conclusion of a government tender process. Network-wide application of simple novel process of verification harmonization of local international sensitive index and mean normal prothrombin time initiated for each new lot of INR reagent that does not require ongoing use of reference thromboplastin or calibration/certified plasma sets. RESULTS: We achieved reduction of different instrument manufacturers (from four to one), instrument types (10 to three), reagent types (four to one), and instrument/reagent combinations (12 to three), plus substantial reduction in INR variability and bias. CONCLUSIONS: Results infer significant improvement in local patient management, with positive implications for other laboratories. For the United States in particular, lack of US Food and Drug Administration-cleared certified plasmas may compromise INR accuracy, and our novel approach may provide a workable alternative for laboratories and networks.

Improving the inter-laboratory harmonization of the international normalized ratio (INR): utilizing the concept of transference to estimate and/or validate international sensitivity index (ISI) and mean normal prothrombin time (MNPT) values and/or to eliminate measurement bias.

BACKGROUND: The Prothrombin Time (PT) assay is clinically the most often requested coagulation test, as used primarily for monitoring of Vitamin K antagonist therapy where results are typically expressed as an International Normalized Ratio (INR). The INR reflects the patient's PT adjusted for the specific test reagent and instrument combination used by applying two correction factors, namely the International Sensitivity Index (ISI) and the Mean Normal Prothrombin Time (MNPT), according to the formula: INR = (patient PT/MNPT)ISI. When the manufacturer provides an ISI, laboratories are encumbered to check or locally validate the assigned value. Where a manufacturer does not provide an ISI, the laboratory needs to define its own (local ISI) value. The MNPT typically has to be locally defined, based on the population being tested. The main current CLSI recommendation for defining ISI values comprises use of commercial reference ('certified') plasma calibration sets, but FDA cleared material is limited, and different results may arise using different products. The MNPT can be defined using a WHO/CLSI recommended procedure requiring 20 normal individuals or with some calibration sets. Overall, there is limited data to validate the performance of these processes in laboratory practice, and ongoing evidence from external quality assurance (proficiency testing) programs indicates continued failure in INR harmonization, suggesting that ISI and MNPT values used by laboratories (and presumably assessed using current recommended processes) continue to be inaccurate. OBJECTIVE: To assess some novel approaches to the laboratory estimation and/or validation of ISI and MNPT values for use in the INR calculation, and including the process of 'transference', normally used to assess the comparability of analytical systems or to transfer reference intervals between comparable systems. RESULTS: We have successfully adapted these comparative procedures, including 'transference', to permit ongoing estimation and/or validation of ISI and MNPT values for use in INR calculations for a range of instrumentation, which has led to improved harmonization of INR values obtained in our pathology network. These processes do not require the use of any normal individual plasmas or calibrator sets and greatly simplifies the INR process. Evidence for validation of the processes used is provided by ongoing satisfactory performance in external quality assurance (proficiency testing).

Improving the harmonisation of the International Normalized Ratio (INR): time to think outside the box?

The prothrombin time (PT) assay is the most often requested coagulation test and used primarily for monitoring Vitamin K antagonist therapy, where results may be expressed as an International Normalised Ratio (INR). The INR is the patient's PT 'mathematically adjusted' or 'standardised' to take into account the specific test system used (i.e., comprising the test reagent/instrument combination). This standardisation or 'adjustment' is achieved by applying two 'correction factors', respectively defined by the 'International Sensitivity Index' (ISI) and the 'mean normal prothrombin time' (MNPT), according to the formula: INR=[patient PT/MNPT](ISI). While some manufacturers provide assigned ISI values for specific PT reagents and instrumentation, the vast number of possible reagent/instrument combinations usually precludes this in most situations. Even when an ISI is provided by the manufacturer, laboratories need to check or validate the assigned value. When a manufacturer does not provide an ISI, the laboratory needs to define its own (local ISI) value. The MNPT usually has to be locally defined, based on the population being tested. Current recommendations for defining ISI values include the classical, but prohibitively complex, World Health Organization (WHO) recommended procedure, and more recently the use of commercial reference-plasma calibration sets. The MNPT can also be defined using the WHO recommended procedure or with calibration sets. However, there is limited information to validate the performance of these in laboratory practice, and there are several unrecognised problems that limit the validity and utility of the ISI and MNPT values that are determined. Thus, it is perhaps time to start thinking outside the box, and to utilise additional methods for determining and/or validating ISI and MNPT values. This may include the use of regression analysis to assess ongoing peer-related performance in external quality assurance programmes, and to compare the behaviour of proposed replacement reagents with that of existing reagents. Such strategies have proven of considerable benefit to local laboratory practice, and should therefore enable other laboratories to optimise their practice in order to provide INRs that better reflect a patient's anticoagulant status, and thus assist in their clinical therapeutic management.

Time to think outside the box? Prothrombin time, international normalised ratio, international sensitivity index, mean normal prothrombin time and measurement of uncertainty: a novel approach to standardisation.

BACKGROUND: The prothrombin time (PT) assay is the most clinically ordered coagulation test, and most often used for monitoring of vitamin K antagonist therapy (e.g., warfarin), where results are expressed as an international normalised ratio (INR). The INR is in essence the patient's PT 'mathematically adjusted' to a standardised value taking into account the peculiarities of the test system as defined by an ISI (international sensitivity index) and MNPT (mean normal prothrombin time). Although some manufacturers provide assigned ISI values for specific PT reagents and instrumentation, it is still recommended practice that laboratories check or validate these ISIs, as well as estimate the MNPT. Where an ISI is not provided by a manufacturer, the laboratory needs to estimate its own value. Current recommendations suggest the use of commercial reference-plasma calibration sets, but there is limited information on the performance of these in the field. RESULTS: We report a comparative study that assessed the utility of three such commercial calibration plasma sets, used as recommended, as well as alternate or supplementary procedures for estimation of ISI and MNPT. The latter included one novel approach using comparative data of 'existing' versus 'replacement' reagent, as well as assessment of external quality assurance data. Although MNPT value estimates were not grossly disparate, a wide variety of ISI values (e.g., 1.12-1.30 for our primary instrument) was obtained with the different plasma sets. CONCLUSION: Because of the above, further verification checks are required prior to acceptance of ISI and MNPT estimates generated from commercial plasma calibration sets. We also provide some recommendations regarding the process of standardisation of INR testing.