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Prospective Comparison of Point-of-Care Device and Standard Analyzer for Monitoring of International Normalized Ratio in Outpatient Oral Anticoagulant Clinic

Point-of-care testing (POCT) coagulometers are increasingly being used in the hospital setting and patients’ self-testing. We determined the agreement of prothrombin time international normalized ratio (INR) results by POCT coagulometer and laboratory instrument through a comparative analysis and investigated whether the results of POCT coagulometer can reliably be used without being confirmed by standard laboratory analyzer. A total of 200 INR measurements by POCT coagulometer (CoaguChek XS Pro) and laboratory analyzer (Sysmex CS2000i) were compared using Passing-Bablok regression analysis and Bland-Altman plot. Agreement of the INR measurement was further analyzed in relation to dosing decision. The correlation of INR measurements between CoaguChek XS Pro and Sysmex CS2000i was excellent (correlation coefficient = 0.973). The overall mean difference was 0.21 INR ± 0.32 (range: 1.7-0.44). The mean difference was found to get increased as INR results increased and was 0.09 in the subtherapeutic range (≤1.9 INR), 0.29 INR in the therapeutic range (2.0-3.0 INR), while 0.4 INR in the supratherapeutic range (>3.0 INR). The overall agreement was excellent (κ = 0.916) and overall 11 (5.5%) of 200 INR measurements showed a difference in dosing decision between the 2 instruments. The positive bias of POC-INR is evident in the supratherapeutic range which could affect the dosing decision requiring confirmation with the laboratory INR measurement.


Introduction
Point-of-care tests (POCT) are the tests performed at or near patient site of care. Their application is increasing as they enable swift clinical decisions due to rapid therapeutic turnaround time. 1 In hemostasis field, a number of POCTs (activated clotting time, thromboelastography, platelet function, D-dimer, and so on) are available but measurement of international normalized ratio (INR) for monitoring warfarin therapy is the main test of this domain. 2 Despite the emergence of novel oral anticoagulants, warfarin is still the most commonly used oral anticoagulant worldwide. 3 Warfarin is monitored through INR which is a mathematical calculation based on prothrombin time. Owing to complex pharmacokinetics and pharmacodynamics of warfarin, it is necessary to keep the patient in a narrow therapeutic index (INR of 2-3) to prevent clot formation or expansion. 4 To determine INR, POCT could be performed easily with less frequent visits to the laboratory either at anticoagulation clinic or at home. Additionally, INR-POCT allows reduction of problems related to venipuncture, particularly in patients with difficult venous access and therefore can minimize errors in results of blood coagulation. 5 It also provides greater convenience for patients living in remote locations 6 and has been advocated for home monitoring and self-dose adjustment. 7 Quality assurance for POCT is no less important than for conventional laboratory-based analyses and incorporates all measures that are taken to ensure the reliability of testing and reporting. Therefore, general applicability of POCT-INR to particular patient populations requires validation. Hence, it is extremely important to compare INR results from point-of-care device with the results as generated by laboratory instrument. In 2013, anticoagulation clinic was initiated at our institute. We planned to monitor anticoagulation with POCT device in this clinic and therefore needed validation of the new tool. This study was undertaken to perform comparative evaluation of POCT-INR with the INR obtained in laboratory by standardized automated method to determine the agreement between 2 test results.

Study Design and Study Population
This comparative study was conducted at Aga Khan University Hospital, Pakistan, from July 2013 to March 2014. A total of 100 individuals (20 healthy controls and 80 patients on warfarin) were enrolled. During study period, patients were recruited from outpatient anticoagulation clinic who visited for routine monitoring of oral anticoagulation therapy with warfarin prescribed either for treatment or prophylaxis of venous thromboembolism. Controls were the healthy individuals visiting our blood bank for donating blood. Study population was 18 years and older. The median age of study population was 36 years (range: 18-62) with 71 males and 29 females. All individuals were included after informed consent.

Sample Collection and INR Measurements
Two drops of capillary whole blood and 3 mL of venous blood (in a tube containing 3.2% buffered sodium citrate) was collected from each individual for estimation of INR on point-of-care device (CoaguChek XS Pro; Roche Diagnostics GmbH, Mannheim, Germany) and laboratory instrument (Sysmex CS 2000i; Sysmex Corporation, Kobe, Japan), respectively. The venous sampling was performed by trained phlebotomist and samples were sent to laboratory where INR testing was performed within 2 hours of sample collection while the capillary blood testing was performed by trained nursing staff at the anticoagulation clinic. Both the capillary blood testing on POC device and laboratory instrument was determined in duplicate.
The CoaguChek XS Pro uses a human recombinant thromboplastin (International sensitivity index [ISI] ¼ 1.01) and employs electrochemical current detection to measure clot formation. In capillary whole blood testing, the mean coefficient of variation of the CoaguChek XS Pro INR determination was claimed to be less than 4.5% by the manufacturer, and the analytic measurement range was 0.8 to 8.0 INR.
The citrated venous blood samples Sysmex CS2000i were processed and analyzed according to the routine procedures of the laboratory. Sysmex CS 2000i utilizes a clotting-based assay for prothrombin time estimation using Innovin (Dade Innovin, Siemens Healthcare Diagnostics Products GmbH, Germany)as thromboplastin reagent with an ISI of 0.9. The laboratory measurements using Sysmex CS2000i was considered the reference standard method.
Quality control. Manufacturer's recommendation for calibration was followed and it was assured that both the test and the comparative methods remain in proper quality control throughout the evaluation period. Two levels of internal control were provided by the manufacturer: levels 1 and 2 with respective INR of 1.18 + 0.04 and 2.95 + 0.12, respectively. Operators ran 2 levels of control upon starting and toward the end of container of test strips as recommended by manufacturer.

Statistical Analysis
The INR measurements were analyzed using Pearson correlation coefficient, Passing-Bablok regression analysis, and Bland-Altman plot. Bland-Altman plot was used to identify mean difference and 95% limits of agreement of the INR results between CoaguChek XS Pro and Sysmex CS2000i. The overall correlation and difference were compared in a total of 200 measurements and were further compared in 3 INR ranges (<1.9 INR, 1.0-2.0 INR, and 2.0-3.0 INR). Agreement of INR measurements was also assessed according to the 3 ranges of dosing decision (subtherapeutic, therapeutic, and supratherapeutic ranges) with cutoff values of <1.9 INR, 2.0-3.0 INR, and >3.0 INR, respectively. Cohen k value was used for assessing agreement. Statistical analysis was performed using Excel Stat Biomed 2017, SAS 9.3, and SPSS 21 version, and P values less than .05 were considered statistically significant.

Ethical Approval
The study was initiated after ethical approval from institutional ethical review committee [#2569-Pat-ERC-13]. Informed consent was taken from each individual before enrollment in study. The study results were not neither discussed nor disclosed to the manufacturer.

Results
A total of 400 INR measurements were performed from 100 anticoagulated patients through duplicate testing on each

Clinical Evaluation
The agreement of INR measurements between CoaguChek XS Pro and Sysmex CS2000i was further assessed according to the 3 INR ranges (subtherapeutic, therapeutic, and supratherapeutic ranges) related to dosing decision. The overall agreement was excellent (k ¼ 0.916; 95% CI: 0.862-0.964), and 11 (5.5%) of 200 INR measurements showed a difference in dosing decision between the 2 instruments (Table 1).

Discussion
Point-of-care INR devices were initially implemented to monitor oral anticoagulation by vitamin K antagonist, [8][9][10][11] and thereafter, its use has been extended to monitor coagulation state in the operating room, 12 emergency department, 13 and for patient self-testing at home.
The performance evaluation of POC-INR devices have been conducted in a number of studies in the past several years with varying results of precision and accuracy. In a review by Christensen and Larsen, the precision and accuracy of POCT coagulometers were found to be acceptable for use in clinical settings. 3 15,16 In addition to the overall correlation and agreement, we further compared the INR results in subtherapeutic (<1.9 INR), therapeutic (2-3 INR), and supratherapeutic (>3.1 INR) range and found bias not only in the supratherapeutic but therapeutic range as well (Figures 2 and 3 15 With the availability of more convenient and cost-effective microfluidics technology of POC-INR, it has become the standard of care for patients on chronic warfarin therapy. It enables health-care providers to perform prompt warfarin dosing adjustment decision-making and face-to-face education with the patient. Dose adjustment rests on INR results, hence POC-INR results need to be accurate.
As for the clinical decision is concerned, we found no change in decision-making for dose adjustment in 2 instruments results for INR less than 1.9. However, positive bias observed in the therapeutic as well as supratherapeutic INR range suggests that it should be confirmed through standard laboratory analyzer. This study is limited in that the sample size in the >3.0 INR range was small as compared to the subtherapeutic and therapeutic range. Further studies with equal randomization in different INR ranges would delineate the performance evaluation of POC-INR. It might be convenient using POC-INR where facility of laboratory INR is not available. However, to minimize clinical problems arising from implementation of this technology, collaboration between manufacturers, pathology laboratories, and general practice and adherence to a recognized external quality assurance scheme is essential.

Conclusion
CoaguChek XS Pro shows an excellent agreement with Sysmex CS2000i for INR results. The minimal positive bias of POC-INR is evident in the therapeutic and supratherapeutic range which could affect the dosing decision and therefore needs to be confirmed with the laboratory INR measurement.