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Original Articles

Evaluation of the Accuracy of the LumiraDx INR Test Using Patients in Receipt of Phenprocoumon Anticoagulation Therapy

Völler, Heinz MD, PhD∗,†; Heyne, Karen

Author Information
Point of Care: The Journal of Near-Patient Testing & Technology: September 2020 - Volume 19 - Issue 3 - p 72-76
doi: 10.1097/POC.0000000000000207
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Abstract

After the initial development of warfarin, a coumarin anticoagulant, in the 1950s,1 a number of derivatives have been developed, most notably the 4-hydroxycoumarins, phenprocoumon, and acenocoumarol. Collectively, these coumarin anticoagulants are known as vitamin K antagonists (VKAs) owing to their mechanisms of action in inhibiting vitamin K epoxide reductase, leading to the depletion of functional vitamin K-dependent clotting factors. These VKAs are now widely prescribed to reduce blood clotting by decreasing the action of vitamin K, for example, in patients with atrial fibrillation, venous thromboembolism, and those who have mechanical heart valves.2–4 Research has shown that, with VKA therapies, there are prescribing differences between countries, especially within Europe. For example, warfarin is predominantly prescribed in the United Kingdom and Italy; phenprocoumon in Germany, Austria, and Switzerland; and acenocoumarol in Spain.5,6

Currently, the standard method for monitoring VKA therapy is prothrombin time (PT) testing. To harmonize the results between different thromboplastin reagents, the PT is expressed as an international normalized ratio (INR).7,8 It is well established that VKA drugs have a narrow therapeutic window. When the dose is too low, the risk of thrombotic events remains high, whereas when the dose is too high, the risk of bleeding increases. However, the inability to predict interindividual variabilities (eg, age, body mass index, genetic differences, and concomitant diseases) and response to environmental factors (eg, diet, alcohol intake, and drug–drug interactions) means that determining the daily dose required to maintain therapeutic anticoagulation can be very difficult.9,10 Therefore, the anticoagulant effect of VKAs must be closely monitored to maintain patients with mechanical heart valves within an INR target range of 2.5 to 3.5, and patients with venous thromboembolism and atrial fibrillation within a target range of 2.0 to 3.0.10,11 A prerequisite to optimal VKA therapy is the correct measurement of a patient's INR, which is dependent on high accuracy and precision of the method and device used.12

The LumiraDx INR Test is a point-of-care (POC) test designed for use at or near the site of patient care using capillary blood from fingersticks. In a previous study, the precision and accuracy of the LumiraDx INR Test were evaluated in comparison to a criterion standard laboratory test, the IL ACL Elite Pro (Instrumentation Laboratory). The study results indicated that INR results of 366 patients, tested in multiple clinical settings, correlated well with laboratory testing, as well as between the different application methods and test strip lots.13 The study recruited patients taking warfarin (Coumadin). The objective of the current study was to evaluate the accuracy of the LumiraDx INR Test in patients taking phenprocoumon in a German clinic, compared with the INR results obtained using 2 different laboratory reference instruments, the IL ACL Elite Pro and the Sysmex CS-5100.

METHOD

Study Population

This study was conducted in a rehabilitation clinic for cardiovascular diseases in Germany. Patients were identified for the study by the investigator or clinical site staff (nurses) from patients who were regularly attending the anticoagulation clinic for INR monitoring. Potential participants were given a patient information sheet detailing all information relevant to participation in the study. The study protocol complied with the Declaration of Helsinki (2013) and was conducted under the approval of Landesärztekammer Brandenburg, Geschäftsstelle Cottbus, Referat Ethikkommission (reference: AS19(6B)/2019). All participants gave their written informed consent for POC and laboratory testing. This study was registered at ClinicalTrials.gov (NCT04074980).

This study was an observational, cross-sectional study with patients enrolled between May and August 2019. Devices used in this study were CE marked for INR measurement by healthcare professionals. All patients were 18 years and older, willing and able to provide written informed consent, deemed medically appropriate for study participation by the investigator (eg, patients without known inherited [eg, hemophilia or von Willebrand disease] or acquired [eg, liver cirrhosis] conditions that are likely to be associated with coagulopathy), and currently prescribed phenprocoumon VKA therapy (Falithrom and Marcumar). Patients were excluded if they were within 4 weeks of the first prescription of phenprocoumon (most patients are initiated on phenprocoumon therapy using a slow-induction protocol and rarely achieve therapeutic INR levels during the first few weeks of treatment), were taking a direct oral anticoagulant, were receiving non-phenprocoumon VKA therapy, or had confirmed or suspected pregnancy.

Study Design

This study was composed of 2 parts: For part 1 of the study, 1 venous whole blood draw was taken from the patients. Samples were centrifuged to plasma at 1500 rcf for 15 minutes. The pooled plasma was decanted, aliquoted, and frozen at −80°C. The frozen plasma samples were shipped to the LumiraDx UK Ltd laboratory in Stirling, UK, for paired analysis of INR using the LumiraDx INR Test and the IL ACL Elite Pro (Instrumentation Laboratory) laboratory reference system. For part 2 of the study, trained clinical site staff obtained 1 fingerstick sample of capillary blood from each patient for direct analysis on the LumiraDx INR Test. During the same study visit, a venous blood sample was processed to plasma by centrifugation. A portion of the plasma sample was analyzed on the Sysmex CS-5100 at a hospital in the United Kingdom and a second portion transferred to the LumiraDx laboratory for measurement with the IL ACL Elite Pro. The IL ACL Elite Pro used lyophilized recombinant thromboplastin (RecombiPlasTin 2G [HemosIL]) and the Sysmex CS-5100 used Siemens Dade Innovin reagent.

Investigative Device

The LumiraDx INR Test is an in vitro diagnostic medical test that is intended for professional POC use for the monitoring of patients on anticoagulation therapy with VKA drugs. The test is used to provide INR based on the quantitative PT of capillary whole blood. When a blood sample is applied to the Test Strip, the clotting cascade leads to the conversion of prothrombin to thrombin, which in turn recognizes a peptide sequence on the substrate. Following cleavage of this peptide sequence, the substrate becomes unquenched and emits a fluorescence signal detectable by the LumiraDx instrument. The amount of signal detected over a specific time is converted into INR and the result is displayed on the touchscreen of the instrument.14

Samples used for the study should cover the range of INR results from 2.5 to 4.5, but samples outside this range were also included in the analysis (CE-marked range for the LumiraDx INR Test is INR 0.8–7.5). The INR test results are typically displayed in 60 to 90 seconds. The LumiraDx INR Test was calibrated using the World Health Organization international standard rTF/09 to provide traceability to reference systems and the LumiraDx INR Test. More information regarding operational characteristics (performance characteristics and precision assay) of the LumiraDx instrument can be found in the LumiraDx Platform User Manual15 and INR Test Strip Product Insert.14

A complete description of the LumiraDx Platform and INR Test can be found at the LumiraDx website.10

Statistical Analysis

For part 1 of the study, a Passing–Bablok regression analysis with Excel was used to compare the plasma INR results measured by the LumiraDx INR Test to results of the IL ACL Elite Pro reference instrument to determine the accuracy of the LumiraDx INR Test. A Passing–Bablok regression analysis was also used to determine the accuracy of capillary blood measured on the LumiraDx INR Test with plasma samples measured with the IL ACL Elite Pro and Sysmex CS-5100.

RESULTS

A total of 102 patients were enrolled in this study from a rehabilitation clinic for cardiovascular diseases in Germany. Of these, 25 patients participated in part 1 of the study and 77 patients in part 2. The patients had a mean age of 64 years and 9 months (range, 36–88 years) and a mean INR of 2.62. The demographics of the 2 study populations are listed in Table 1.

TABLE 1 - Demographic Data Relating to Age and Sex of Recruited Individuals Receiving Phenprocoumon
Study Gender n Age Mean Time on Therapy INR (ACL) INR (LumDx)
Mean Min Max Mean CI Mean CI
Part 1 Falithrom Female 1 76 y 1 mo 76 y 1 mo 76 y 1 mo 4 mo 2.87 3.00
Male 10 60 y 6 mo 43 y 80 y 5 mo 2 y 8 mo 2.78 2.13–3.43 2.81 2.13–3.48
Combined 11 61 y 11 mo 43 y 80 y 5 mo 2 y 6 mo 2.79 2.21–3.37 2.82 2.22–3.43
Part 1 Marcumar Female 3 65 y 11 mo 47 y 4 mo 83 y 4 mo 7 y 6 mo 3.11 1.68–4.54 2.93 2.17–3.69
Male 11 67 y 52 y 2 mo 79 y 2 mo 5 y 1 mo 2.3 1.93–2.67 2.27 1.86–2.69
Combined 14 66 y 9 mo 47 y 4 mo 83 y 4 mo 5 y 7 mo 2.47 2.11–2.84 2.41 2.06–2.77
Part 1 combined 25 64 y 8 mo 43 y 83 y 4 mo 4 y 3 mo 2.61 2.30–2.92 2.59 2.28–2.91
Part 2 Falithrom Female 6 76 y 7 mo 63 y 10 mo 86 y 3 mo 1 y 5 mo 2.41 1.75–3.08 2.67 1.84–3.50
Male 37 61 y 43 y 88 y 2 mo 1 y 11 mo 2.77 2.45–3.09 2.68 2.36–3.00
Combined 43 63 y 2 mo 43 y 88 y 2 mo 1 y 10 mo 2.72 2.44–3.01 2.68 2.39–2.96
Part 2 Marcumar Female 13 67 y 8 mo 41 y 5 mo 81 y 1 mo 3 y 7 mo 2.34 1.85–2.83 2.32 1.82–2.81
Male 20 65 y 3 mo 36 y 10 mo 80 y 8 mo 4 y 2.63 2.36–2.90 2.64 2.38–2.90
Combined 33 66 y 2 mo 36 y 10 mo 81 y 1 mo 3 y 10 mo 2.52 2.28–2.76 2.51 2.27–2.75
Phenprocoumon acis Female 1 85 y 4 mo 85 y 4 mo 85 y 4 m 5 y 2 mo 2.29 2.65
Part 2 combined 77 64 y 9 mo 36 y 10 mo 88 y 2 mo 2 y 9 mo 2.64 2.44–2.81 2.61 2.42–2.79
All combined 102 64 y 9 mo 36 y 10 mo 88 y 2 mo 3 y 1 mo 2.62 2.47–2.78 2.44 2.25–2.63
ACL, IL ACL Elite Pro; CI, confidence interval; LumDx, LumiraDx.

Patients participating in part 1 of the study (n = 25) had their plasma tested in replicates of 2 on the LumiraDx INR Test device and the IL ACL Elite Pro reference instrument at the LumiraDx laboratory. Accuracy of result agreement was determined between the 2 methods, and the INR results from the LumiraDx INR Test were plotted against the results from the reference instrument. Results showed a high agreement between the 2 methods (r = 0.981) (Fig. 1).

FIGURE 1
FIGURE 1:
Method comparison of INR measurements of plasma samples from patients taking phenprocoumon, obtained using the LumiraDx INR Test and the IL ACL Elite Pro. INR, international normalized ratio; Int CI, intercept confidence interval; Slp CI, slope confidence interval.

In part 2 of the study, the accuracy of INR result agreement was analyzed by comparing capillary whole blood samples measured using the LumiraDx INR Test at the anticoagulation clinic to paired venous plasma samples measured using the IL ACL Elite Pro (n = 74) and Sysmex CS-5100 (n = 73) instruments at the reference laboratories. For the IL ACL Elite Pro measurements, paired plasma samples from 3 patients were unavailable, whereas for the Sysmex CS-5100, paired plasma samples from 4 patients were unavailable. When compared with the IL ACL Elite Pro, results showed a strong correlation (r = 0.949) between the LumiraDx INR Test and the reference method across the INR range (Fig. 2). Further comparison of results from the LumiraDx Test and from the Sysmex CS-5100 instrument also showed a strong correlation between the 2 methods across the INR range (r = 0.950) (Fig. 3).

FIGURE 2
FIGURE 2:
Method comparison of INR measurements of capillary whole blood samples versus venous plasma samples from patients taking phenprocoumon, obtained using the LumiraDx INR Test and the IL ACL Elite Pro, respectively. INR, international normalized ratio; Int CI, intercept confidence interval; Slp CI, slope confidence interval.
FIGURE 3
FIGURE 3:
Method comparison of INR measurements of capillary whole blood samples versus venous plasma samples from patients taking phenprocoumon, obtained using the LumiraDx INR Test and the Sysmex CS-5100, respectively. INR, international normalized ratio; Int CI, intercept confidence interval; Slp CI, slope confidence interval.

DISCUSSION

This study aimed to evaluate the accuracy of the LumiraDx INR Test when testing plasma and whole capillary blood samples in a cohort of patients receiving phenprocoumon VKA therapy. Comparison of INR results from plasma samples of 25 patients receiving phenprocoumon, measured using the LumiraDx INR Test versus a criterion laboratory instrument, the IL ACL Elite Pro, showed a good correlation between the 2 methods. When comparing INR obtained from fingerstick capillary blood samples using the LumiraDx INR Test to INR measured on the IL ACL Elite Pro and the Sysmex CS-5100 reference instruments, results demonstrated very good agreement between these methods and the LumiraDx INR Test.

Results from this study agreed with findings from a previous study investigating the accuracy and precision of the LumiraDx INR Test in patients taking warfarin (Coumadin), which demonstrated that the coumarin therapy prescribed did not influence the accuracy of the LumiraDx INR Test results.13

Coagulometers are commonly used for POC testing of INR in an anticoagulation clinic setting, and some are also approved for patient self-testing or patient self-management.8 Results from this study and that previously published on the LumiraDx INR Test13 show similar results for accuracy and precision when compared with laboratory reference methods as found with other POC coagulometers such as CoaguChek XS, MicroINR, and Xprecia Stride.16–18

Overall, based on the tests performed, the LumiraDx INR Test gives accurate results compared with 2 commonly used laboratory reference methods. The findings indicate that the LumiraDx INR Test can be used by healthcare professionals at the POC to provide reliable INR monitoring of patients who are receiving VKA therapy.

ACKNOWLEDGMENTS

Writing support was provided by Viola Kooij, integrated medhealth communication (imc), London, UK. The authors thank K. Stolze for patient management and testing at the clinic. The authors would like to thank K. Taggart of University Hospital Wishaw, NHS Lanarkshire, UK, for the Sysmex analyses.

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Keywords:

international normalized ratio; LumiraDx Platform; LumiraDx INR Test; oral anticoagulation; point-of-care; vitamin K antagonist therapy; phenprocoumon

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