Vitamin K antagonist drugs remain the cornerstone of oral anticoagulation for prevention of stroke and other thromboembolic events in patients with atrial fibrillation, mechanical heart valves and for venous thromboembolism prophylaxis. When time within therapeutic range (TTR) of the prothrombin time International Normalised Ratio (INR) is maximised, safety, efficacy, and cost-effectiveness of warfarin treatment is unsurpassed.

Introduction

The innovative microINR system (iLine Microsystems, Spain) has been designed to exploit the advantages of both microfluidics and the Lab-on-a-Chip (LOC) technological concepts under the company’s proprietary technology. Following the activation of the coagulation cascade by a micro dispensed amount of recombinant tissue factor reagent, INR determination is carried out through capillary blood flow monitoring along microfluidic channels through an embedded Machine Vision System (MVS). When clotting, blood undergoes a sudden viscosity increase and thus a sudden flow rate decay, which is detected, measured as prothrombin time and converted into INR using lot-specific calibration parameters micro printed on the Chip surface.

New POC systems for INR determination using blood samples should be calibrated and validated before they are used by anticoagulant clinics and patients for self-testing and self-management. According to World Health Organization (WHO) Guidelines, a specific procedure is recommended for the calibration of whole-blood coagulometers [1]. For validation of the INR displayed by the POC system, the INR bias will be calculated relative to the mean INR determined with the International Standard. The INR bias should be 10 % or less.

The purpose of the study was to evaluate the accuracy of the microINR system by comparison to the International Standard for recombinant human thromboplastin (coded rTF/09) at the internationally renowned LUMC (Leiden University Medical Centre) in Leiden (The Netherlands). Additionally the parameter repeatability (precision) was assessed from duplicate determinations on each individual blood specimen.

Material & Methods

80 subjects, 60 VKA patients and 20 healthy volunteers, were recruited from the LUMC (Coagulation Reference Laboratory). INR values ranged from 0.9 to 5.3

In the present study, three analyzers and 250 chips with lot number 47170, provided by iLine Microsystems, were used. The reference laboratory provided the International Standard rTF/09 and equipment for blood collection and PT testing in the laboratory.

The clotting time determinations were performed on 8 days. On each day, blood specimens were collected from 10 individuals (8 VKA patients and 2 healthy volunteers) and analyzed with the whole blood coagulometer (duplicate measurements) in order to calculate the coagulometer’s precision. Citrated plasma samples from the same individuals were analyzed with the International Standard in the laboratory.

INR results from microINR system vs INR results from the reference Standard International System
Figure 1. Linear regression plot, INR results from microINR system vs INR results from the reference Standard International System.

Scatterplot showing the relation between the mean INR and the difference in INR
Figure 2. Scatterplot showing the relation between the mean INR and the difference in INR.

Bland-Altman plot showing the relation between the International Standard INR and the BIAS
Figure 3. Bland-Altman plot showing the relation between the International Standard INR and the BIAS.

Data Analysis & Results

Accuracy performance was evaluated by comparing results on the microINR system to reference results on the Standard International from citrated venous blood processed to plasma.

Linear regression analysis between the results of the microINR system and the reference system that appears in Figure 1 showed strong correlation. The correlation coefficient was 0.9284 with a slope of 0.9611.

Furthermore, Figure 2 clearly demonstrates an excellent accuracy to the reference rTF/09 with an overall BIAS of 0.7% and an SD of 11%. The mean BIAS at INR 2.0 was 4.34%, at INR 3.0 was 0.83% and at INR 4.5 was -2.56%.

The Bland-Altman representation in Figure 3, shows fully compliance with the ISO 17593:2007 criteria since all the data fall inside the ±0.5 INR difference for INRs bellow 2.0 and ±30% difference for INRs between 2.0 and 4.5. The ±0.5 INR and ±30% criteria are represented by a thick dark line.

Conclusion

The microINR system is fully complying with the ISO 17593:2007 requirements: “the INR bias will be calculated relative to the mean INR determined with the International Standard and should be 10% or less”, and these results confirm the suitability of the system for managing patients receiving warfarin. Due to these results, microINR System was approved for use by the Netherlands Thrombosis Services.

Furthermore, these obtained results in accuracy demonstrate a BIAS lower than the ones published recently for the Coaguchek XS system in the same evaluation carry out by LUMC [2].

Previous evaluation done on the microINR system from Pf. Van den Besselaar’s team [3] was done with a non-standard product that included a R&D driven alternative calibration. The present study counteracts this publication demonstrating the microINR system’s standard product performance.

Further Information

If you’d like to find out more about the microINR analyser contact POCD on 1800 640 075 or click the button below to view the product webpage.

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References

  1. WHO Expert Committee on Biological Standardization. Guidelines for thromboplastins and plasma used to monitor oral anticoagulant therapy with vitamin K antagonists. WHO Technical Report Series 2013; 979:271-316.
  2. Van den Besselaar AMHP, et al. Point-of-care monitoring of vitamin K- antagonists: validation of CoaguCheck XS test strips with International Standard thromboplastin, J Clin Pathol 2012; 65:1031-1035.
  3. Van den Besselaar AMHP, van der Meer FJM, Abdoel CF, Witteveen E, Analytical accuracy and precision of two novel Point-of-Care systems for INR determination, Thrombosis Research (2015).