(266 days)
VITROS® NT-proBNP II – K201312
No
The device is a standard immunoassay for measuring a specific biomarker, and the description focuses on the chemical and analytical methods used, not on AI/ML for interpretation or diagnosis. The performance studies evaluate the assay's accuracy in relation to clinical outcomes and other assays, not the performance of an AI/ML algorithm.
No
Explanation: This device is an in vitro diagnostic (IVD) assay designed to quantitatively determine N-terminal pro B-type natriuretic peptide levels. Its intended use is to aid in diagnosis, assessment of severity, and risk stratification of heart failure and acute coronary syndrome. It does not directly treat or prevent a disease, which is the function of a therapeutic device.
Yes
Explanation: The "Intended Use / Indications for Use" section explicitly states that the device aids in the "diagnosis of patients suspected of having acute heart failure in the Emergency Department."
No
The device is an immunoassay kit that requires physical reagents and an automated immunoassay analyzer (DxI 9000) to function, indicating it is a hardware-dependent medical device, not software-only.
Yes, this device is an IVD (In Vitro Diagnostic).
Here's why:
- Intended Use: The intended use explicitly states that the assay is for the "quantitative determination of N-terminal pro B-type natriuretic peptide levels in human serum and plasma." This involves testing biological samples (serum and plasma) in vitro (outside the body).
- Device Description: The description details a laboratory-based immunoassay process that analyzes blood samples. It describes the reagents, the automated analyzer, and the measurement of light generated from a chemical reaction with the sample. This is a classic description of an in vitro diagnostic test.
- Care Setting: The intended user and care setting are described as a "Clinical laboratory setting / Emergency Department," which is where in vitro diagnostic tests are performed.
- Performance Studies: The performance studies involve analyzing patient samples to evaluate the assay's ability to aid in the diagnosis and risk stratification of heart failure, which are clinical applications of in vitro diagnostic results.
The core function of the device is to analyze a biological sample (blood) in vitro to provide information about a patient's health status, which is the definition of an In Vitro Diagnostic device.
N/A
Intended Use / Indications for Use
The Access NT-proBNP assay is a paramagnetic particle, chemiluminescent immunoassay for the quantitative determination of N-terminal pro B-type natriuretic peptide levels in human serum and plasma using the automated DxI Access Immunoassay Analyzers to aid in the following:
- diagnosis of patients suspected of having acute heart failure in the Emergency Department
- assessment of heart failure severity
- risk stratification of patients with heart failure
- risk stratification of patients with acute coronary syndrome
Product codes
NBC
Device Description
The Access NT-proBNP assay is a paramagnetic particle, chemiluminescent immunoassay for the quantitative determination of N-terminal pro B-type natriuretic peptide levels in human serum and plasma using the automated Dxl 9000 Access Immunoassay Analyzers to aid in the following: 1) diagnosis of patients suspected of acute heart failure in the Emergency Department, 2) assessment of heart failure severity, 3) risk stratification of patients with heart failure, 4) risk stratification of patients with acute coronary syndrome.
The Access NT-proBNP is a two-site immunoenzymatic (sandwich) assay. Paramagnetic particles coated with monoclonal anti-NT-proBNP antibody and monoclonal anti-NTproBNP antibody conjugated to alkaline phosphatase are added to a reaction vessel along with a surfactant-containing buffer and serum or plasma sample. The human NTproBNP binds to the anti-NT-proBNP antibody on the solid phase, while the anti-NTproBNP antibody-alkaline phosphatase conjugate reacts with a different antigenic site on the NT-proBNP molecule. After incubation, materials bound to the solid phase are held in a magnetic field while unbound materials are washed away. Then the chemiluminescent substrate is added to the vessel and light generated by the reaction is measured with a luminometer. The light production is directly proportional to the concentration of analyte in the sample. Analyte concentration is automatically determined from a stored calibration.
Other items required to use the assay include calibrators, Lumi-Phos PRO, and wash buffer. The Access NT-proBNP reagent packs. Access NT-proBNP calibrators, along with the Access wash buffer, and Lumi-Phos PRO are designed for use on the Dxl 9000 Access Immunoassay Analyzers in a clinical laboratory setting.
Mentions image processing
Not Found
Mentions AI, DNN, or ML
Not Found
Input Imaging Modality
Not Found
Anatomical Site
Not Found
Indicated Patient Age Range
The clinical performance evaluation was conducted on adults aged 21 and older.
The healthy population reference interval study included subjects under 50 years, 50-75 years, and over 75 years of age.
Intended User / Care Setting
Clinical laboratory setting
Description of the training set, sample size, data source, and annotation protocol
Not Found
Description of the test set, sample size, data source, and annotation protocol
A multicenter prospective study was conducted to validate clinical performance of the established diagnostic cutoffs and evaluate the clinical utility of the Access NT-proBNP assay on the Dxl 9000 Immunoassay Analyzer as an aid in the diagnosis of adults aged 21 and older presenting to the Emergency Department with a clinical suspicion of acute heart failure. NT-proBNP concentrations were determined in samples from 2,384 patients presenting to the Emergency Department with clinical suspicion of acute heart failure (AHF). Final diagnoses were adjudicated by an independent committee of medical doctors who decided on presence of acute heart failure. Adjudicators were blinded to the Access NT-proBNP assay results. The AHF incidence was 44.4% (1059/2384) consisting of 48.2% Females (1149/2384) and 51.8% (1235/2384) Males, 57.8% White or Caucasian (1377/2384), 35.7% Black or African American (850/2384), and 6.5% Asian (155/2384). Two subjects did not have their races reported.
Summary of Performance Studies (study type, sample size, AUC, MRMC, standalone performance, key results)
Study Type: Non-clinical studies (Imprecision, High Dose Hook Effect, Limit of Blank (LoB), Limit of Detection (LoD), and Limit of Quantitation (LoQ), Linearity, Matrix Comparison, Interfering Substances, Cross Reactivity, Expected Values) and Clinical Performance Evaluation (Clinical Sensitivity, Correlation to NYHA functional classification, Comparison to Other Commercially Available NT-proBNP Assays, Risk Stratification of Patients with Heart Failure and Acute Coronary Syndrome).
Sample Size:
- Imprecision Study: Not specified, but multiple samples were tested in duplicate in 2 runs per day for a minimum of 20 days. Example samples (N=86, N=84, N=83, N=84, N=85, N=86, N=86) are shown in a table.
- High Dose Hook Effect: Not specified.
- LoB, LoD, LoQ: Not specified.
- Linearity: Not specified.
- Matrix Comparison: Sixty-eight (68) matched serum, lithium heparin and EDTA plasma samples.
- Interfering Substances: Not specified.
- Cross Reactivity: Not specified.
- Expected Values (Reference Interval Study): A total of 306 males were included with 39.6% 75 years of age. (Table 7 also shows N=675 for All Subjects, N=306 for Males, and N=369 for Females).
- Clinical Sensitivity (Emergency Department Study): 2,384 patients.
- NYHA Correlation Study: 1043 subjects adjudicated to acute HF (450 Female and 593 Male).
- Comparison to Other Assays: Samples from the prospective multicenter study (2,384 patients).
AUC:
- Clinical Sensitivity (Rule-Out):
- All Subjects: 0.8692 (95% CI: 0.8549 - 0.8835)
- Clinical Sensitivity (Rule-In):
- 75 years: 0.8122 (95% CI: 0.7779 - 0.8465)
- Comparison to Other Commercially Available NT-proBNP Assays:
- Access NT-proBNP: 0.8536 (95% CI: 0.8362 - 0.8710)
- Roche Elecsys proBNP II: 0.8562 (95% CI: 0.8361 - 0.8762)
Standalone Performance:
- Imprecision: Within-laboratory precision showed CVs ranging from 3.5% to 7.0%.
- High Dose Hook Effect: No high dose hook effect observed up to 400,000 ng/L.
- LoB, LoD, LoQ: LoB: 1.1 ng/L, LoD: 4.8 ng/L, LoQ: 4.8 ng/L.
- Linearity: Within ± 10% for values > 50 ng/L and within ± 5.0 ng/L for values ≤ 50 ng/L across analytical measuring range (10.0 - 35,000 ng/L).
- Matrix Comparison: All sample types (serum, lithium heparin, EDTA plasma) are suitable for use.
- Interfering Substances: No significant interference (> 10% shift) observed with tested substances.
- Cross Reactivity: No significant cross-reactivity (> 10%) observed with tested substances.
Key Results:
- Clinical Sensitivity: The device demonstrates acceptable clinical performance as an aid in the diagnosis of acute heart failure. Posttest probabilities and likelihood ratios were provided across different age groups.
- Correlation to NYHA functional classification: A significant trend relationship was observed between NT-proBNP values and NYHA classification for all subjects, females, and males (p-value 75 years: 71.9%
- All Subjects: 73.4%
- Posttest Probability of Non-HF (Negative Result):
- 75 years: 93.8%
- All Subjects: 94.7%
- Likelihood Ratio Positive (HF):
- 75 years: 2.42
- All Subjects: 3.45
- Likelihood Ratio (Grey Zone):
- 75 years: 0.42
- All Subjects: 0.58
- Likelihood Ratio (Negative):
- 75 years: 0.06
- All Subjects: 0.07
Predicate Device(s): If the device was cleared using the 510(k) pathway, identify the Predicate Device(s) K/DEN number used to claim substantial equivalence and list them here in a comma separated list exactly as they appear in the text. List the primary predicate first in the list.
Elecsys® proBNP II - K072437
Reference Device(s): Identify the Reference Device(s) K/DEN number and list them here in a comma separated list exactly as they appear in the text.
VITROS® NT-proBNP II – K201312
Predetermined Change Control Plan (PCCP) - All Relevant Information for the subject device only (e.g. presence / absence, what scope was granted / cleared under the PCCP, any restrictions, etc).
Not Found
§ 862.1117 B-type natriuretic peptide test system.
(a)
Identification. The B-type natriuretic peptide (BNP) test system is an in vitro diagnostic device intended to measure BNP in whole blood and plasma. Measurements of BNP are used as an aid in the diagnosis of patients with congestive heart failure.(b)
Classification. Class II (special controls). The special control is “Class II Special Control Guidance Document for B-Type Natriuretic Peptide Premarket Notifications; Final Guidance for Industry and FDA Reviewers.”
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Image /page/0/Picture/0 description: The image contains the logo of the U.S. Food and Drug Administration (FDA). On the left is the Department of Health & Human Services logo. To the right of that is the FDA logo, which is a blue square with the letters "FDA" in white. To the right of the blue square is the text "U.S. FOOD & DRUG ADMINISTRATION" in blue.
April 12, 2024
Beckman Coulter Inc. Kate Oelberg Senior Staff Quality and Regulatory Affairs 1000 Lake Hazeltine Drive Chaska, Minnesota 55331
Re: K232164
Trade/Device Name: Access NT-proBNP Regulation Number: 21 CFR 862.1117 Regulation Name: B-Type Natriuretic Peptide Test System Regulatory Class: Class II Product Code: NBC Dated: March 15, 2024 Received: March 15, 2024
Dear Kate Oelberg:
We have reviewed your section 510(k) premarket notification of intent to market the device referenced above and have determined the device is substantially equivalent (for the indications for use stated in the enclosure) to legally marketed predicate devices marketed in interstate commerce prior to May 28, 1976, the enactment date of the Medical Device Amendments, or to devices that have been reclassified in accordance with the provisions of the Federal Food, Drug, and Cosmetic Act (the Act) that do not require approval of a premarket approval application (PMA). You may, therefore, market the device, subject to the general controls provisions of the Act. Although this letter refers to your product as a device, please be aware that some cleared products may instead be combination products. The 510(k) Premarket Notification Database available at https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpmn/pmn.cfm identifies combination product submissions. The general controls provisions of the Act include requirements for annual registration, listing of devices, good manufacturing practice, labeling, and prohibitions against misbranding and adulteration. Please note: CDRH does not evaluate information related to contract liability warranties. We remind you, however, that device labeling must be truthful and not misleading.
If your device is classified (see above) into either class II (Special Controls) or class III (PMA), it may be subject to additional controls. Existing major regulations affecting your device can be found in the Code of Federal Regulations, Title 21, Parts 800 to 898. In addition, FDA may publish further announcements concerning your device in the Federal Register.
Additional information about changes that may require a new premarket notification are provided in the FDA guidance documents entitled "Deciding When to Submit a 510(k) for a Change to an Existing Device" (https://www.fda.gov/media/99812/download) and "Deciding When to Submit a 510(k) for a Software Change to an Existing Device" (https://www.fda.gov/media/99785/download).
1
2
Your device is also subject to, among other requirements, the Quality System (QS) regulation (21 CFR Part 820), which includes, but is not limited to, 21 CFR 820.30, Design controls; 21 CFR 820.90, Nonconforming product; and 21 CFR 820.100, Corrective and preventive action. Please note that regardless of whether a change requires premarket review, the QS regulation requires device manufacturers to review and approve changes to device design and production (21 CFR 820.30 and 21 CFR 820.70) and document changes and approvals in the device master record (21 CFR 820.181).
Please be advised that FDA's issuance of a substantial equivalence determination does not mean that FDA has made a determination that your device complies with other requirements of the Act or any Federal statutes and regulations administered by other Federal agencies. You must comply with all the Act's requirements, including, but not limited to: registration and listing (21 CFR Part 807); labeling (21 CFR Part 801 and Part 809); medical device reporting of medical device-related adverse events) (21 CFR Part 803) for devices or postmarketing safety reporting (21 CFR Part 4, Subpart B) for combination products (see https://www.fda.gov/combination-products/guidance-regulatory-information/postmarketing-safetyreporting-combination-products); good manufacturing practice requirements as set forth in the quality systems (QS) regulation (21 CFR Part 820) for devices or current good manufacturing practices (21 CFR Part 4, Subpart A) for combination products; and, if applicable, the electronic product radiation control provisions (Sections 531-542 of the Act); 21 CFR Parts 1000-1050.
Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21 CFR 807.97). For questions regarding the reporting of adverse events under the MDR regulation (21 CFR Part 803), please go to https://www.fda.gov/medical-device-safety/medical-device-reportingmdr-how-report-medical-device-problems.
For comprehensive regulatory information about mediation-emitting products, including information about labeling regulations, please see Device Advice (https://www.fda.gov/medicaldevices/device-advice-comprehensive-regulatory-assistance) and CDRH Learn (https://www.fda.gov/training-and-continuing-education/cdrh-learn). Additionally, you may contact the Division of Industry and Consumer Education (DICE) to ask a question about a specific regulatory topic. See the DICE website (https://www.fda.gov/medical-device-advice-comprehensive-regulatoryassistance/contact-us-division-industry-and-consumer-education-dice) for more information or contact DICE by email (DICE@fda.hhs.gov) or phone (1-800-638-2041 or 301-796-7100).
Sincerely,
Paula V. Caposino -S
Paula Caposino, Ph.D. Acting Deputy Director Division of Chemistry and Toxicology Devices OHT7: Office of In Vitro Diagnostics Office of Product Evaluation and Quality Center for Devices and Radiological Health
2
Indications for Use
510(k) Number (if known) K232164
Device Name Access NT-proBNP
| Indications for Use (Describe) |
|---|
| ---------------------------------------------- |
The Access NT-proBNP assay is a paramagnetic particle, chemiluminescent immunoassay for the quantitative determination of N-terminal pro B-type natriuretic peptide levels in human serum and plasma using the automated DxI Access Immunoassay Analyzers to aid in the following:
-
- diagnosis of patients suspected of having acute heart failure in the Emergency Department
-
- assessment of heart failure severity
-
- risk stratification of patients with heart failure
-
- risk stratification of patients with acute coronary syndrome
| Type of Use (Select one or both, as applicable) | |
|---|---|
| ------------------------------------------------- | -- |
X Prescription Use (Part 21 CFR 801 Subpart D)
| Over-The-Counter Use (21 CFR 801 Subpart C)
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Image /page/3/Picture/0 description: The image shows the logo for Beckman Coulter. On the left is a red oval with two white curved lines inside. To the right of the oval is the company name, "BECKMAN COULTER", in black, with "BECKMAN" on the top line and "COULTER" on the bottom line.
510(k) Summary
This summary of 510(k) safety and effectiveness information is being submitted in accordance with the requirements of SMDA 1990 and 21 CFR 807.92.
510(k) Number: K232164
Date Prepared: April 12, 2024
Staff Regulatory Affairs Specialist
Email: rclark01@beckman.com
Alternate Contact:
Phone: (336) 327-2336
Rachel Clark
Submitter Name and Address:
Beckman Coulter, Inc 1000 Lake Hazeltine Drive Chaska, MN 55318
Primary Contact:
Kate Oelberg Senior Staff Quality and Regulatory Affairs Phone: (612) 431-7315 Email: kmoelberg@beckman.com
Trade Device Name: Access NT-proBNP Common Name: Access NT-proBNP Classification name: B-Type natriuretic peptide test system Classification Regulation: 21 CFR 862.1117 Classification Product Code: NBC
Predicate Device: Elecsys® proBNP II - K072437
Reference Device: VITROS® NT-proBNP II – K201312
Device Description
The Access NT-proBNP assay is a paramagnetic particle, chemiluminescent immunoassay for the quantitative determination of N-terminal pro B-type natriuretic peptide levels in human serum and plasma using the automated Dxl 9000 Access Immunoassay Analyzers to aid in the following: 1) diagnosis of patients suspected of acute heart failure in the Emergency Department, 2) assessment of heart failure severity, 3) risk stratification of patients with heart failure, 4) risk stratification of patients with acute coronary syndrome.
4
The Access NT-proBNP is a two-site immunoenzymatic (sandwich) assay. Paramagnetic particles coated with monoclonal anti-NT-proBNP antibody and monoclonal anti-NTproBNP antibody conjugated to alkaline phosphatase are added to a reaction vessel along with a surfactant-containing buffer and serum or plasma sample. The human NTproBNP binds to the anti-NT-proBNP antibody on the solid phase, while the anti-NTproBNP antibody-alkaline phosphatase conjugate reacts with a different antigenic site on the NT-proBNP molecule. After incubation, materials bound to the solid phase are held in a magnetic field while unbound materials are washed away. Then the chemiluminescent substrate is added to the vessel and light generated by the reaction is measured with a luminometer. The light production is directly proportional to the concentration of analyte in the sample. Analyte concentration is automatically determined from a stored calibration.
Other items required to use the assay include calibrators, Lumi-Phos PRO, and wash buffer. The Access NT-proBNP reagent packs. Access NT-proBNP calibrators, along with the Access wash buffer, and Lumi-Phos PRO are designed for use on the Dxl 9000 Access Immunoassay Analyzers in a clinical laboratory setting.
Intended use
The Access NT-proBNP assay is a paramagnetic particle, chemiluminescent immunoassay for the quantitative determination of N-terminal pro B-type natriuretic peptide levels in human serum and plasma using the automated Dxl Access Immunoassay Analyzers to aid in the following:
-
- diagnosis of patients suspected of having acute heart failure in the Emergency Department
-
- assessment of heart failure severity
-
- risk stratification of patients with heart failure
-
- risk stratification of patients with acute coronary syndrome
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Image /page/5/Picture/0 description: The image shows the logo for Beckman Coulter. The logo consists of a red circle with two white curved lines inside, resembling a stylized wave or flow. To the right of the circle, the words "BECKMAN" and "COULTER" are stacked on top of each other in a bold, sans-serif font. The overall design is clean and modern.
Table 1: Device Comparison
| Device
Characteristics | New Device
Access NT-proBNP | Predicate Device
Elecsys® NT-pro BNP II
K072437 | Reference Device
VITROS® NT-proBNP II
K201312 | Comment |
|------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Intended Use /
Indications for
Use | Rx ONLY
For in vitro diagnostic use only.
The Access NT-proBNP assay is
a paramagnetic particle,
chemiluminescent immunoassay
for the quantitative determination
of N-terminal pro B-type
natriuretic peptide levels in
human serum and plasma using
the automated Dxl Access
Immunoassay Analyzers to aid in
the following:
- diagnosis of patients
suspected of having acute heart
failure in the Emergency
Department - assessment of heart failure
severity - risk stratification of patients
with heart failure - risk stratification of patients
with acute coronary syndrome | Rx ONLY
For in vitro diagnostic use only.
For the quantitative determination
of N terminal pro-Brain natriuretic
peptide in human serum and
plasma. Elecsys® proBNP II
assay is used as an aid in the
diagnosis of individuals
suspected of having congestive
heart failure. The test is further
indicated for the risk stratification
of patients with acute coronary
syndrome and congestive heart
failure. The test may also serve
as an aid in the assessment of
increased risk of cardiovascular
events and mortality in patients at
risk for heart failure who have
stable coronary artery disease.
The electrochemiluminescence
immunoassay "ECLIA" is
intended for use on Elecsys and
cobas e immunoassay analyzers. | Rx ONLY
For in vitro diagnostic use
only.
For the quantitative
measurement of N-terminal
pro Brain Natriuretic Peptide
(NT-proBNP) in human
serum and plasma (K₂
EDTA or Lithium Heparin)
using VITROS 3600
Immunodiagnostic System to
aid in the diagnosis of heart
failure. The test can also be
used in the assessment of
heart failure severity in
patients diagnosed with
heart failure. | Similar |
| Analyte
Measured | NT-proBNP | NT-proBNP | NT-proBNP | Same |
| Antibody | Monoclonal anti-NT-proBNP | Monoclonal anti-NT-proBNP | Monoclonal anti-NT-proBNP | Same |
| Device
Characteristics | New Device
Access NT-proBNP | Predicate Device
Elecsys® NT-pro BNP II
K072437 | Reference Device
VITROS® NT-proBNP II
K201312 | Comment |
| Sample Type | Human Serum and Plasma
(Lithium Heparin and EDTA) | Human Serum and Plasma | Human Serum and Plasma | Same |
| Method | The Access NT-proBNP assay is
used in association with the
automated Dxl Access
Immunoassay Analyzer | Elecsys and cobas e
immunoassay analyzers | VITROS 3600
Immunodiagnostic System | Different |
| Format | Chemiluminescent | Electrochemiluminescent | Immunometric | Different |
| Assay Principle | Sandwich | Sandwich | Sandwich | Same |
| Measuring Range | 10.0 ng/L - 35,000 ng/L (pg/mL) | 5 - 35,000 pg/mL | 20.0 -30,000 pg/mL | Similar |
| Traceability | The Access NT-proBNP
Calibrator is traceable to
manufacturer's working
calibrators. Traceability process
is based on EN ISO 17511 | Standardized against the Elecsys
NT-proBNP assay | Standardized against the
Elecsys NT-proBNP II assay | There is no
internationally
recognized
standard for NT-
proBNP specific
antibody. The
Elecsys proBNP
assay reference
materials are
proprietary to
Roche
Diagnostics. |
| High Dose Hook
Effect | No high dose hook effect
observed up to 400,000 ng/L
(pg/mL) | Hook effect studies demonstrated
no effect up to 300,000 pg/mL | no high dose hook effect up
to a concentration of
300,000 pg/mL | Similar |
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| Device
Characteristics | New Device
Access NT-proBNP | Predicate Device
Elecsys® NT-pro BNP II
K072437 | Reference Device
VITROS® NT-proBNP II
K201312 | Comment | | | | | | | | | | | | | | | | | | |
|----------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------|-----------------------------------------------------|------------------------------------------------------------------------------------------------------------|--|--|--|------------------------------------------------------------------------------------------------------------------------------------------------------------|--|--|--|--|--|--|-------------------------------------------------------------------------------------------------------------------------------------|--|--|--|--|--|--|---------|
| Reagent Storage
and Stability | Access NT-proBNP
Reagent Stability Unopened at
2 -10°C Up to stated Expiration Date After Opening
at 2-10°C 61 days On analyzer 61 days | | | | | | | Elecsys NT-proBNP II
Reagent Stability Unopened at 2
-8°C Up to stated Expiration Date After Opening
at 2-8°C 12 weeks On analyzers 8 weeks | | | | | | | VITROS NT-proBNP II
Reagent Stability Unopened 2-
8°C Expiration Date Open on
system ≤ 8 weeks Opened 2-8°C ≤8 weeks | | | | | | | Similar |
| | See Table A. below | 125 pg/mL for patients, 75 years;
450 pg/mL for patients ≥ 75 years | See Table B. below | Same for Access
NT-proBNP and
VITROS® NT-
proBNP II
Different from
Elecsys NT-
proBNP II | | | | | | | | | | | | | | | | | | |
8
| Table A. Access NT-proBNP |
|---|
| --------------------------- |
| Expected Values | All Subjects ng/L (pg/mL) | |||
|---|---|---|---|---|
| Age (years) | 75 | All ages | ||
| N | 267 | 256 | 152 | 675 |
| Mean | 48 | 94 | 158 | 90 |
| SD | 43 | 79 | 103 | 85 |
| Median | 37 | 69 | 129 | 64 |
| IQR: 25th - 75th percentile | 19 - 65 | 36 - 125 | 85 - 190 | 30 - 121 |
| 95th percentile ULN | 118 | 273 | 413 | 252 |
| 97.5th percentile ULN | 162 | 311 | 457 | 358 |
| % 50 ng/L (pg/mL) . |
A study based on CLSI EP05-A3 performed on the Dxl 9000 Access Immunoassay Analyzer tested multiple samples in duplicate in 2 runs per day for a minimum of 20 days.
| | | Mean | Repeatability
(Within Run) | | Between Run | | Between Day | | Within Laboratory
precision | |
|----------|----|--------|-------------------------------|-----|--------------|-----|--------------|-----|--------------------------------|-----|
| Sample | N | (ng/L) | SD
(ng/L) | %CV | SD
(ng/L) | %CV | SD
(ng/L) | %CV | SD
(ng/L) | %CV |
| Sample 1 | 86 | 31 | 0.7 | 2.3 | 0.5 | 1.5 | 0.7 | 2.2 | 1.1 | 3.5 |
| Sample 2 | 84 | 129 | 2.9 | 2.2 | 7.2 | 5.6 | 0.0 | 0.0 | 7.8 | 6.0 |
| Sample 3 | 83 | 266 | 5.3 | 2.0 | 15.8 | 5.9 | 0.0 | 0.0 | 16.7 | 6.3 |
| Sample 4 | 84 | 377 | 7.7 | 2.0 | 25.3 | 6.7 | 0.0 | 0.0 | 26.4 | 7.0 |
| Sample 5 | 85 | 1,777 | 45.1 | 2.5 | 63.2 | 3.6 | 44.5 | 2.5 | 89.5 | 5.0 |
| Sample 6 | 86 | 12,076 | 225.5 | 1.9 | 638.0 | 5.3 | 0.0 | 0.0 | 676.7 | 5.6 |
| Sample 7 | 86 | 26,126 | 534.1 | 2.0 | 1,418.9 | 5.4 | 1.5 | 0.0 | 1516.1 | 5.8 |
Table 2: Access NT-proBNP Imprecision, Dxl 9000
10
High Dose Hook Effect
The study was performed using samples containing increasing concentrations of NT-pro antigen in a range greater than > 400,000 ng/L exceeding the dose of the S6 Calibrator. Access NT-proBNP assay has no high dose hook effect observed up to 400,000 ng/L.
Limit of Blank (LoB), Limit of Detection (LoD), and Limit of Quantitation (LoQ)
Limit of Blank (LoB), Limit of Detection (LoD), and Limit of Quantitation (LoQ) studies were conducted on the Dxl 9000 Access Immunoassay Analyzer following CLSI EP17-A2,Evaluation of Detection Capability for Clinical Laboratory Measurement Procedures; Approved Guideline - Second Edition. The LoB study included multiple reagent lots and 3 instruments for 3 days. The LoD and LoQ studies included multiple reagent lots and 3 instruments up to 5 days.
Table 4: Access NT-proBNP LoB, LoD and LoQ
| Maximum Observed Result | Design Criteria | |
|---|---|---|
| ng/L (pg/mL) | ng/L (pg/mL) | |
| Limit of Blank (LoB) | 1.1 | 50 ng/L and is within ± 5.0 ng/L for values ≤ 50 ng/L. The assay demonstrates acceptable non-linearity across the analytical measuring range (10.0 -35,000 ng/L). |
Matrix Comparison
Lithium heparin plasma and serum are preferred sample types. EDTA plasma is also an acceptable sample type. A sample type comparison study was performed on the Access NT-proBNP assay. The study included sixty-eight (68) matched serum, lithium heparin and EDTA plasma samples spanning range that were analyzed in replicates of three (3). The results of the study demonstrate all sample types are suitable for use on the Access NTproBNP assay.
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Interfering Substances
Lithium heparin plasma samples that contained NT-proBNP concentrations of approximately 125 and 1,800 ng/L (pg/mL) were spiked with the substances listed in Table 5. The spiked samples were run on the Dxl 9000 Access Immunoassay Analyzer. The values were calculated based upon CLSI EP07-A3 guidelines. The interference was determined by testing controls (with no interfering substance added) and matched test samples (with interfering substance added). None of the compounds tested were found to cause significant interference (as defined by a shift in dose > 10%) using the test concentrations provided in the following table.
| Substance | Concentration | Substance | Concentration |
|---|---|---|---|
| (+)-cis-Diltiazem hydrochloride | 120 ug/mL | Hydralazine | 20 µg/mL |
| Acetaminophen | 1456 umol/L | Hydrochlorothiazide | 20 µg/mL |
| Alkaline Phosphatase | 2000 U/L | Ibuprofen | 2425 umol/L |
| Allopurinol | 240 ug/mL | Indomethacin | 36 µg/mL |
| Amiodarone | 4.2 mg/dL | Intralipid | 1600 mg/dL |
| Amlodipine besylate | 4 ug/mL | Isosorbide dinitrate | 0.593 mg/dL |
| Ampicillin | 200 ug/mL | L-Ascorbic Acid | 376 umol/L |
| Ascorbic acid | 20 mg/dL | Levothyroxine | 0.042 mg/dL |
| Atenolol | 40 ug/mL | Lidocaine | 1.5 mg/dL |
| Atorvastatin calcium trihydrate | 32 ug/mL | Lisinopril x 2H2O | 16 µg/mL |
| Bilirubin, conjugated | 19 mg/dL | Losartan potassium | 130 µmol/L |
| Bilirubin, unconjugated | 15 mg/dL | Lovastatin | 0.021 mg/dL |
| Biotin | 30,000 ng/mL | Methyldopa | |
| sesquihydrate | 100 ug/mL | ||
| Caffeine | 10.8 mg/dL | Metoprolol hemitartrate | 18.7 umol/L |
| Captopril | 40 ug/mL | Naproxen sodium | 2170 umol/L |
| Carvedilol | 74 umol/L | Nicotine | 1.6 µg/mL |
| Chloramphenicol | 7.8 mg/dL | Nicotinic acid | 40 µg/mL |
| Cholesterol | 400 mg/dL | Nifedipine | 36 ug/mL |
| Clopidogrel hydrogen sulfate | 30 ug/mL | Nitrofurantoin | 40 µg/mL |
| Creatinine | 15 mg/dL | Oxazepam | 12 µg/mL |
Table 5: Interfering Substances
13
Table 5: Interfering Substances
| Substance | Concentration | Substance | Concentration |
|---|---|---|---|
| Cyclosporine | 40 ug/mL | Oxytetracycline | 100 µg/mL |
| Diclofenac sodium salt | 60 ug/mL | Phenobarbital | 69 mg/dL |
| Digitoxin | 60 ug/mL | Phenytoin | 6.00 mg/dL |
| Digoxin | 0.0039 mg/dL | Probenecid | 600 µg/mL |
| Disopyramide | 1.68 mg/dL | Procainamide | 4.80 mg/dL |
| Dobutamine | 100 µg/mL | Propranolol | 64 µg/mL |
| Dopamine hydrochloride | 116 µg/mL | Quinidine | 20 µg/mL |
| Dipyridamole | 30 ug/mL | Ramipril | 14.4 µmol/L |
| Enalaprilat dihydrate | 16 ug/mL | Rheumatoid Factor | 500 IU/mL |
| Erythromycin | 13.8 mg/dL | Salicylic acid | 200 ug/mL |
| Fenofibrate | 45 µg/mL | Simvastatin | 32 µg/mL |
| Fibrinogen | 1000 mg/dL | Spironolactone | 600 mg/dL |
| Furosemide | 199 µmol/L | Sulfamethoxazole | 1.7 µmol/L |
| Hemoglobin | 1000 mg/dL | Theophylline | 6 mg/dL |
| Heparin | 330 units/dL | Trasylol/Aprotinin | 100 KIE/mL |
| Human anti-Mouse Antibodies | |||
| (HAMA) | 800 µg/L | Trimethoprim | 64 µg/mL |
| Human gamma-globulin | 30 g/L | Verapamil | |
| hydrochloride | 96 ug/mL | ||
| Human Serum Albumin | 60 g/L | Warfarin | 7.5 mg/dL |
14
Cross Reactivity
A study evaluated the potential for cross-reactivity of substances that are similar in structure to NT-proBNP. Lithium heparin samples that contain NT-proBNP concentrations of 125 ng/L (pg/mL) and 1,800 ng/L (pg/mL) were spiked with concentrations of the substances listed in Table 6. The spiked samples were run on the Dxl 9000 Access Immunoassay Analyzer. The values were calculated based upon CLSI EP07-A3 guidelines. No significant cross-reactivity (>10%) was observed when the listed substances were tested at the indicated concentrations.
| Substance | High
Concentration | Substance | High
Concentration |
|-----------------|-----------------------|--------------------------------------|-----------------------|
| Adrenomedullin | 1.0 ng/mL | CNP22 | 2.2 ug/mL |
| Aldosterone | 0.6 ng/mL | Endothelin I | 2000 pg/mL |
| Angiotensin I | 0.6 ng/mL | NT-proANP1-30
(preproANP26-55) | 3.5 ug/mL |
| Angiotensin II | 0.6 ng/mL | NT-proANP31-67
(preproANP56-92) | 1.0 ng/mL |
| Angiotensin III | 1.0 ng/mL | NT-proANP79-98
(preproANP104-123) | 1.0 ng/mL |
| ANP28 | 3.1 ug/mL | Renin | 50 ng/mL |
| Arg-Vasopressin | 1.0 ng/mL | Urodilatin | 3.5 ug/mL |
| BNP32 | 3.5 ug/mL | | |
Table 6: Access NT-proBNP Cross Reactivity
15
Expected Values
Each laboratory should validate or establish its own reference intervals to assure proper representation of specific populations.
A multicenter prospective reference interval study was conducted to establish the upper limit of normal (ULN) for Access NT-proBNP in a population of apparently healthy adults. A total of 306 males were included with 39.6% 75 years of age.
Subjects were surveyed and were excluded if they met any of the following criteria:
- · Disease(s) of/or affecting the cardiovascular system
- Poorly controlled hypertension (defined as current blood pressure ≥ 140 mm Hg systolic, or ≥ 85 mm Hg diastolic)
- · Currently taking medication for cardiovascular disease (except medications to control hypertension)
- Body-mass index (BMI) ≥ 30 kg/m2
- Diabetes
- Chronic kidney disease.
- · Other serious chronic disease(s) (e.g. cancer, COPD, HIV, lupus erythematosus, etc.)
- Acute bacterial or viral infection
Additional surrogate biomarkers were screened, and subjects were also excluded based on abnormal estimated glomerular filtration rate (eGFR) and high-sensitivity cardiac troponin (hsTnl). Descriptive statistics for NT-proBNP concentrations are shown in Table 9.
16
| All Subjects ng/L (pg/mL) | ||||
|---|---|---|---|---|
| Age (years) | 75 | All ages | ||
| N | 267 | 256 | 152 | 675 |
| Mean | 48 | 94 | 158 | 90 |
| SD | 43 | 79 | 103 | 85 |
| Median | 37 | 69 | 129 | 64 |
| IQR: 25th - 75th percentile | 19 - 65 | 36 - 125 | 85 - 190 | 30 - 121 |
| 95th percentile ULN | 118 | 273 | 413 | 252 |
| 97.5th percentile ULN | 162 | 311 | 457 | 358 |
| % 75 | All ages | |||
| N | 132 | 111 | 63 | 306 |
| Mean | 33 | 68 | 130 | 66 |
| SD | 38 | 71 | 82 | 72 |
| Median | 23 | 48 | 115 | 41 |
| IQR: 25th - 75th percentile | 13 - 39 | 28 - 77 | 77 - 148 | 20 - 84 |
| 95th percentile ULN | 84 | 188 | 243 | 188 |
| 97.5th percentile ULN | 103 | 284 | 434 | 267 |
| % 75 | All ages | |||
| N | 135 | 145 | 89 | 369 |
| Mean | 63 | 114 | 178 | 111 |
| SD | 42 | 80 | 111 | 89 |
| Median | 54 | 91 | 154 | 82 |
| IQR: 25th - 75th percentile | 32 - 80 | 54 - 155 | 93 - 216 | 49 - 149 |
| 95th percentile ULN | 152 | 282 | 443 | 294 |
| 97.5th percentile ULN | 178 | 317 | 457 | 370 |
| % 75 | All ages | 75 | ||
| N | 1044 | 308 | 440 | 296 |
| Mean | 5377 | 4119 | 5659 | 6266 |
| SD | 5511 | 4868 | 5442 | 6008 |
| Median | 3,776 | 2,466 | 4,111 | 4,291 |
| IQR: 25th - 75th percentile | 1406-7483 | 959-5745 | 1539-8222 | 2077-8394 |
| Min | 75 | Positive | 240 | 94 |
| (47/143) | (25.7-40.9%) | 67.1% | ||
| (96/143) | (59.1-74.3%) | 0.51 | (0.37, 0.71) | |
| Grey Zone | 59 | 132 | 191 | |
| (268/287) | (89.9-95.7%) | 0.07 | (0.05, 0.11) | |
| Negative | 4 | 61 | 65 | |
| (303/590) | Positive | 71.9% | ||
| (240/334) | (66.8-76.4%) | - | - | 2.42 |
| Total | 303 | 287 | 590 | |
| (59/191) | (24.8-37.8%) | 69.1% | ||
| (132/191) | (62.2-75.2%) | 0.42 | (0.33, 0.55) | |
| All | Positive | 899 | 326 | 1225 |
| Grey Zone | 118 | 253 | 371 | |
| Subjects | 44.4% (1059/2384) | Positive | 73.4% | |
| (899/1225) | (70.8-75.8%) | - | - | 3.45 |
| Negative | 42 | 746 | 788 | |
| (118/371) | (27.3-36.7%) | 68.2% | ||
| (253/371) | (63.3-72.7%) | 0.58 | (0.48, 0.71) | |
| Total | 1059 | 1325 | 2384 | |
| (746/788) | (92.9-96.0%) | 0.07 | (0.05, 0.09) |
The pretest probability of acute heart failure (prevalence of heart failure in the subject adjudicated diagnosis), posttest probabilities, likelihood ratios and the two-tailed 95% confidence interval of the Access NT-proBNP test result were determined across the age groups using the age-independent rule-out (300 ng/L) cutoffs and agedependent rule-in (450 ng/L for subjects 75 years old). Table 10 displays data for all subjects by age group.
20
Table 10: Access NT-proBNP of all subjects (LiHep samples)
*Wilson Score confidence intervals **log method confidence intervals
21
Sensitivity and specificity are also calculated and plotted in separate receiver operation curves (ROC) for both an overall age-independent analysis and individual age-dependent groups separately. Area under the curve (AUC) is also reported with 95% 2-sided confidence intervals. The ROC results for the Rule-Out sensitivity and 1-specificity data are provided in Table 12.
| Age Group | Area Under the Curve | Standard Error | Lower 95% CI | Upper 95% CI |
|---|---|---|---|---|
| All Subjects (Rule-Out) | 0.8692 | 0.00729 | 0.8549 | 0.8835 |
| 75 years (Rule-In) | 0.8122 | 0.0175 | 0.7779 | 0.8465 |
Table 11: The Area Under the Curve (AUC) for Rule-Out and Rule-In cutoffs with Upper / Lower Cls
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Access NT-proBNP Correlation to New York Heart Association (NYHA) functional classification in patients diagnosed with acute HF
There was an even distribution of classifications across the 1043 subject group adjudicated to acute HF with a clinical ED site NYHA evaluation and represents the accurate performance estimates for this claim. The population consisted of 450/1043 (43.14%) females and 593/1043 (56.86%) males. The descriptive statistics for the Access NT-proBNP results (ng/L) were determined across gender and are summarized in Table 12.
The JT test of trending was conducted on the 1043 all-subject group, resulting in a Z statistic of 4.1991 and a one-sided p-value