Assessment of Clinical Substantial Equivalence of Xprecia Stride Coagulation Analyzer

Introduction

Fast, reliable prothrombin time/international normalized ratio (PT/INR) test results are essential for point-of-care (POC) locations such as urgent care and primary care to support oral anticoagulant therapy (OAT). Siemens Healthcare Diagnostics offers a handheld POC device called the Xprecia Stride™ Coagulation Analyzer* to produce rapid PT/INR test results from fingerstick samples.

In this external validation study performed under ICH/GCP guidelines, the clinical substantial equivalence of the Xprecia Stride analyzer PT/INR test was evaluated against a proven laboratory hemostasis method (BCS® XP System from Siemens Healthcare Diagnostics).

Summary

The Xprecia Stride analyzer showed a very good correlation (r2 = 0.89) and 0.0 PT/INR bias at medical decision levels with the BCS XP System. Reproducibility/intermediate precision showed that liquid quality control (LQC) satisfied the industry-standard acceptance criterion of ≤10%.

Moreover, repeatability was also well within the same acceptance criterion. Using the data and the following analysis, the intended clinical use of the Xprecia Stride Coagulation Analyzer is validated for near-patient PT/INR testing using capillary blood.

               

The increasing demand for oral anticoagulant therapy (OAT)

OAT is given on a long-term basis for patients who are at high risk of developing blood clots or for those who are suffering from recurrent abnormal blood clotting.

For instance, people having atrial fibrillation (AF), which is a common cardiac arrhythmia affecting over 2.6 million in the USA and 6 million people in Europe,1 are at high risk of developing clots, including those that lead to ischemic stroke. OAT is often prescribed to mitigate these stroke risks, but frequent patient PT/INR monitoring is essential as part of the medications.

In a year, over 800 million PT/INR tests are carried out worldwide.2 A growing population of patients on warfarin (COUMADIN) therapy and the decreasing trend of using the central laboratory for testing have increased the demand for PT/INR tests at the point of care:

  • POC PT/INR test settings comprise of the outpatient clinics, the physician’s office and diverse hospital locations, including the operating rooms, the emergency room, the radiography department and the coronary care unit
  • PT/INR testing at POC helps rapid interventions that may help improve patient therapy

Clinical utility

The Xprecia Stride Coagulation Analyzer is an accurate, user-friendly and convenient handheld instrument designed for near-patient monitoring of PT/INR testing on capillary blood samples. With better safety features, the system is intended to protect operators during the testing process:

  • Small, 6 µL sample size
  • Rapid results across the 0.8–4.5 INR reporting range
  • User-friendly color touchscreen interface and clear display of results as INR units
  • Integrated bar-code scanner that facilitates rapid, error-free data capture
  • Push-button ejection of used test strips to reduce biohazard exposure
  • Seamless, secure bidirectional data transfer via USB connection

Test technology

The Xprecia Stride analyzer measures the prothrombin time using single-use reagent test strips and electrochemical technology. A sample chamber in the test strip is filled with the blood sample by capillary action.

The strip includes dried reagents containing thromboplastin, an electroactive thrombin substrate, as well as other reagents. The thrombin substrate releases an electroactive group, which is determined electrochemically at the electrodes in the strip; the coagulation time is determined by analyzing the current generated, using an algorithm.

Two on-strip quality control checks are used to analyze each test strip by applying a sample to check whether adequate test sample and reagents are present on the test strip and for degradation of test strips caused by exposure to environmental factors. If either control fails, an error will be reported by the analyzer and subsequently, the test will be cancelled.

LQC material provides users the option to perform testing as outlined in local, state, federal or national guidelines. Siemens Healthineers has been a major player in laboratory hemostasis solutions for over three decades and now can offer a POC system for coagulation testing. The Xprecia Stride Coagulation Analyzer extends Siemens’ hemostasis expertise into the POC arena and provides customers the option of an extensive portfolio of analyzers from the same provider.

The Xprecia Stride analyzer employs the Dade® Innovin® reagent, which is the same reagent employed by Siemens Healthineers lab analyzers — eliminating a potential area for variability between POC and lab test results.

Study purpose

The PT/INR test using the Xprecia Stride Coagulation Analyzer must show clinical substantial equivalence to the clinical reference method. Obtaining accurate results in terms of low bias and high precision facilitates the analyzer to be used optimally for clinical decision making.

The study analyzed:

  • Agreement versus an established reference laboratory method used for PT/INR testing
  • Repeatability
  • Reproducibility/intermediate precision (LQC levels 1 and 2)
  • Expected INR range for study subjects not on anticoagulation therapy

Methods

General

A group of 364 study subjects, including patients going through warfarin therapy and those not on warfarin therapy, were enrolled over an 11 month period at four clinical sites. At every site, two separate whole-blood capillary samples were collected from subjects through finger puncture for immediate PT/INR testing by qualified POC operators using the Xprecia Stride Coagulation Analyzer.

In a citrated tube, a whole-blood sample was also collected from each subject. After centrifuging these samples to generate platelet-poor plasma, they were frozen. The frozen samples were then shipped to a laboratory§ for PT/INR testing using the reference Siemens Healthcare Diagnostics BCS XP System and Dade Innovin reagent.

The same aliquot of sample was measured twice and the INR results were averaged to provide the laboratory INR value. Subsequently, Universal Biosensors Pty Ltd (Rowville, Victoria, Australia) performed the data analysis.

The study was performed with analyzers, reagent test strips and INR liquid quality control materials manufactured on validated lines.

Method comparison study

The bias and agreement in INR measurement were determined using the results from the first drop of fingerstick whole blood from study subjects (n = 364). The method comparison was performed using the Xprecia Stride analyzer results across two INR ranges (<2.0, and 2.0-4.5).

These ranges provided a distribution of subject results across the measuring range. The allocation of study subjects to a range was based on their averaged laboratory INR reference value.

A Passing-Bablok regression was performed using the results from both analytical methods, calculating the coefficient of determination (r2), correlation coefficient (r), slope (95% CI) and y-intercept (95% CI). Passing-Bablok regression acceptance criteria up to 4.5 INR were defined as:

  • Coefficient of determination (r2) ≥0.82
  • Slope: 95% confidence interval within 0.80–1.20
  • Intercept: +0.3 to -0.3

Bias of the Xprecia Stride analyzer PT/INR test was calculated at two medical decision points (INR = 2.0 and INR = 4.5; see Table 1).

Reproducibility/intermediate precision study

At each site, qualified operators generated reproducibility/intermediate precision data by performing tests using the Xprecia Stride analyzer, with LQC levels 1 and 2 in duplicate at the beginning and end of 20 days of testing.

Three lots of PT liquid quality control kits and three lots of reagent test strips were used to perform testing across the four sites. Table 3 shows the multiple parameters estimated from complete datasets for each site analyzer at each LQC level.

Repeatability study

The difference between results from pairs of capillary samples obtained from two separate fingersticks and tested on the same analyzer was used to assess repeatability. Repeatability data analysis was performed using the valid pairs obtained from 364 study subjects (all clinical sites).

The standard deviation, mean INR and the %CV were determined across three INR ranges (<2.0, 2.0-3.0, and 3.1-4.5; see Table 2).

Expected range

For nontherapeutic individuals, the expected range was evaluated using the Xprecia Stride analyzer PT/INR test results (n = 120, 84 results sourced from this study, combined with 36 results from an in-house study). The normal range was stated as lower and upper INR values enclosing 95% of the results.

Results

Method comparison study

A plot of the Passing-Bablok regression applied on capillary blood PT/INR results obtained from Xprecia Stride analyzers against the PT/INR results obtained using the reference BCS XP System is shown in Figure 1. Method comparison regression statistics and calculated bias are presented in Table 1.

             

Figure 1. Plot of Passing-Bablok regression fit (red) and line of identity (gray).

The study results showed that the Xprecia Stride Coagulation Analyzer PT/INR test has a very good correlation (r2 = 0.89) with the reference laboratory BCS XP System method.3

Table 1. Xprecia Stride analyzer versus BCS XP System method comparison regression statistics and calculated bias.

Slope (95% CI)

Intercept (95% CI)

Correlation Coefficient (r)

Coefficient of Determination (r2)

Calculated Bias at 2.0 INR

Calculated Bias at 4.5 INR

1.0 (0.95 to 1.00)

0.0 (0.0 to 0.1)

0.944

0.89

0.0

0.0

 

The study also showed the low bias of the test compared with laboratory BCS XP System INR measurement. At the medical decision points of 2.0 INR and 4.5 INR, 0.0 INR bias was observed, well within the acceptance criterion defined as not to exceed a median bias of ±0.3.

Repeatability study

Table 2. INR results for the Xprecia Stride analyzer on paired samples of capillary blood.

Summary of Repeatability SDs and %CVs for Xprecia Stride Analyzer PT/INR Results

Site-PT/INR Range (BCS XP)

INR

(<2.0)

INR

(2.0–3.0)

INR

(3.1–4.5)

 

 

Xprecia Stride Analyzer Within Run

Xprecia Stride Analyzer Within Run

Xprecia Stride Analyzer Within Run

 

 

N

SD

%CV

N

SD

%CV

N

SD

%CV

 

Combined Sites

168

0.06

5.8

418

0.14

5.3

120

0.15

4.5

 

Data analysis showed that repeatability %CVs were ≤5.8 across the three INR ranges, well below the industry-standard criterion of acceptance of %CV ≤10%.

Expected range

For subjects that are not on oral anticoagulation therapy, the Xprecia Stride analyzer INR test range of 0.9 to 1.1 enclosed 95% of results for capillary blood.

Reproducibility/intermediate precision study

Table 3. Reproducibility/intermediate precision of PT liquid quality control (LQC) testing across study locations.

 

Repeatability (formerly called Within Run)

Within Laboratory (formerly called Total)

Control Level

Site

N

Mean

SD

%CV

SD

%CV

 

PT Control 1

1

80

1.27

0.03

2.5

0.05

3.9

2

80

1.29

0.03

2.3

0.04

2.8

3

80

1.20

0.02

1.8

0.02

1.9

4

80

1.24

0.04

3.3

0.06

5.0

 

PT Control 2

1

80

3.18

0.06

1.8

0.15

4.7

2

80

3.22

0.07

2.2

0.10

3.1

3

80

3.18

0.05

1.6

0.09

2.7

4

80

3.11

0.11

3.6

0.26

8.3

 

Discussion and conclusions

Here, the validation of the Xprecia Stride Coagulation Analyzer was carried out in line with its intended use with capillary blood, clearing all test acceptance criteria over the measuring range with the Passing-Bablok regression results as follows:

  • Coefficient of determination (r2) ≥0.89
  • Slope: 1.0 (95% CI 0.95 to 1.0)
  • Intercept: 0.0 (95% CI 0.0 to 0.1)

Compared to the PT/INR test carried out using the reference BCS XP System, the Xprecia Stride analyzer PT/INR test demonstrated equivalency. Bias was very low at two key PT/INR medical decision points (2.0 PT/INR and 4.5 PT/INR, bias 0.0). Reproducibility/intermediate precision was ≤8.3% CV, satisfying an acceptance criterion of ≤10% CV. Test repeatability was ≤5.8% CV, which is also well below this criterion of acceptance.3

The performance of the Xprecia Stride analyzer PT/INR test is equivalent to a reference laboratory test. Trained healthcare practitioners can confidently use the Xprecia Stride analyzer PT/INR test at POC to monitor patients receiving warfarin oral anticoagulant therapy.

The Xprecia Stride Coagulation Analyzer delivers reliable, laboratory-quality performance, which is complemented by its simplicity, speed, efficiency and overall practicality in POC settlings.

Acknowledgements

Produced from materials originally authored by Fernando R,1 Jacobson AK,1 Kennedy S,2 Lessard C,2 Scribner A.3

1Loma Linda VA Healthcare System, Loma Linda, CA.

2Siemens Healthcare Diagnostics Inc., Norwood, MA.

3DCOL Center for Research, Longview, TX

References

  1. Kannel WB, Benjamin EJ. Status of the epidemiology of atrial fibrillation. Med Clin North Am. 2008;92:17-40.
  2. Jackson CM, Esnouf MP. Clin Chem. 2005;51(3):483-85.
  3. Clinical laboratory testing and in vitro medical devices— Requirements for in vitro monitoring systems for self-testing of oral anticoagulant therapy. ISO 17593:2007.

About Siemens Healthineers Point of Care Diagnostics

Point-of-care solutions are designed to provide immediate, convenient, and easy-to-use diagnostic testing. From the ED to the physician’s office, clinical management decisions can be made immediately and result in improved patient safety, clinical outcomes, and overall patient satisfaction.


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Last updated: Jul 14, 2018 at 7:09 PM

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