(262 days)
The Alere NT-proBNP for Alinity i assay is a chemiluminescent microparticle immunoassay (CMIA) used for the in vitro quantitative determination of N-terminal pro B-type natriuretic peptide (NT-proBNP) in human serum and plasma on the Alinity i system.
In the emergency department, measurements of NT-proBNP are used as an aid in the diagnosis of heart failure (HF) in patients with clinical suspicion of new onset or worsening HF.
The Alere NT-proBNP for Alinity i assay is an automated, two-step immunoassay for the in vitro quantitative determination of NT-proBNP in human serum and plasma using chemiluminescent microparticle immunoassay (CMIA) technology. Sample and anti-NT-proBNP coated paramagnetic microparticles are combined and incubated. The NT-proBNP present in the sample binds to the anti-NT-proBNP coated microparticles. The mixture is washed. Anti-NT-proBNP acridinium-labeled conjugate is added to create a reaction mixture and incubated. Following a wash cycle, Pre-Trigger and Trigger Solutions are added. The resulting chemiluminescent reaction is measured as a relative light unit (RLU). There is a direct relationship between the amount of NT-proBNP in the sample and the RLU detected by the system optics.
Despite the request for acceptance criteria and study proving the device meets said criteria, the provided document is a 510(k) summary for a diagnostic test (Alere NT-proBNP for Alinity i Reagent Kit). This type of document focuses on demonstrating substantial equivalence to a predicate device, and thus does not explicitly list "acceptance criteria" for performance in the same way one might find for a new medical device claiming superiority or non-inferiority.
Instead, the document details various performance characteristics of the device, comparing them to relevant standards (CLSI guidelines) and providing statistical data. It aims to show that the new device performs acceptably and similarly to a previously cleared device.
Therefore, I cannot extract a table of "acceptance criteria" as such a table is not explicitly presented. However, I can infer the implied acceptance criteria from the reported performance, specifically from the "No Significant Interference" and "within acceptable performance" statements in the nonclinical performance section, and the effectiveness of the cutoffs for diagnosis in the clinical performance. The "reported device performance" will be the actual numbers provided in the document.
Here's a summary of the available information, structured to address your points as much as possible given the document type:
Implied Acceptance Criteria and Reported Device Performance
As this is a 510(k) submission, explicit quantitative acceptance criteria are not stated in a dedicated table format. Instead, the device's performance characteristics are presented as evidence of substantial equivalence to a predicate device and adherence to recognized standards. The implied acceptance criteria are that the device demonstrates acceptable accuracy, precision, and clinical utility for its stated indications for use.
Here's a table summarizing key performance indicators that would implicitly serve as acceptance criteria given standard diagnostic device requirements:
| Performance Characteristic | Implied Acceptance Criterion | Reported Device Performance |
|---|---|---|
| Analytical Measuring Interval (AMI) | The range over which results can be reliably quantified. | 15.8 to 35,000.0 pg/mL (1.9 to 4130.0 pmol/L). Extended Measuring Interval (EMI) up to 350,000 pg/mL (41,300.0 pmol/L) for diluted samples. |
| Linearity | Device should demonstrate linear response across AMI. | Linear across the AMI of 15.8 to 35,000.0 pg/mL. |
| Within-Laboratory Precision (Overall CV) | Low variability; specific CV targets for different concentration levels. | Low Control: 6.2% CVMedium Control: 4.1% CVHigh Control: 4.0% CVPanels A-F: 3.6% - 10.0% CVPanel G: 4.0% CVPanel H (Supplemented): 7.7% CV |
| Reproducibility (Overall CV) | Low variability across sites, days, and lots. | Low Control: 4.7% CVMedium Control: 4.8% CVHigh Control: 6.7% CVPanel 1: 18.9% CVPanels 2-6: 4.3% - 6.0% CVPanel 7 (Supplemented): 6.6% CVPanel 8 (Supplemented): 7.2% CV |
| Lower Limits of Measurement (LoQ) | Detect and quantify analyte at low concentrations with acceptable precision. | LoQ: 15.8 pg/mL (1.9 pmol/L) (defined as lowest concentration at which 20% CV was met).LoB: 0.1 pg/mLLoD: 3.6 pg/mL (0.4 pmol/L) |
| Analytical Specificity (Interference) | Interference within ±10.0% for listed substances/drugs. | No significant interference (within ±10.0%): Bilirubin, Biotin, Cholesterol, HAMA, Hemoglobin, IgG, Intralipid, RF (up to 600 IU/mL), Total Protein (up to 12.6 g/dL), and a comprehensive list of 50+ drugs at specified concentrations. Interference beyond ±10.0% observed for: RF at 1520 IU/mL (-8.9% to -11.4%), Total Protein at 15.2 g/dL (-12.7%). |
| Cross-Reactivity | % recovery within 100% ± 10% for listed cross-reactants. | All evaluated cross-reactants (e.g., Adrenomedullin, Aldosterone, Angiotensin I/II/III, ANP, BNP, CNP, Endothelin, NT-proANP, Renin, Urodilatin) showed % recovery within 100% ± 10%. |
| High Dose Hook | No hook effect up to a specified high concentration. | No hook effect observed up to 372,620 pg/mL. |
| Clinical Performance (Posttest Probability for HF) | Positive test result to show high posttest probability of HF; Negative test result to show high posttest probability of Non-HF. | All Subjects (Positive): 75.2% (708/942) posttest probability of HF.All Subjects (Negative): 94.0% (794/845) posttest probability of Non-HF.Grayzone: 35.6% posttest probability of HF.Similar detailed results provided for various age groups, sexes, eGFR, BMI, and comorbidity subgroups. |
| Clinical Performance (Likelihood Ratios for HF) | High LR (Positive), Low LR (Negative). | All Subjects (Positive): 4.29 (3.80, 4.83)All Subjects (Negative): 0.09 (0.07, 0.12)Grayzone: 0.78 (0.64, 0.96) Similar detailed results provided for various age groups, sexes, eGFR, BMI, and comorbidity subgroups. |
Study Details:
-
Sample sizes used for the test set and the data provenance:
- Clinical Performance Study (test set): 2127 Emergency Department (ED) subjects.
- Provenance: Multi-center prospective study across 17 collection sites in the US.
- Demographics: 1030 (48.4%) female, 1097 (51.6%) male, age 19-97 years. Predominantly White (53.1%) and Black/African American (39.5%). 90.9% non-Hispanic/Latino.
- Nonclinical Performance (examples):
- Within-Laboratory Precision: 240 replicates (controls/panels).
- Reproducibility: 360 replicates (controls/panels) per assay (across 3 sites).
- Lower Limits of Measurement: n ≥ 60 replicates for LoB, LoD, LoQ.
- Analytical Specificity/Interference: Each substance tested at 2 analyte levels (approximately 125 pg/mL and 2000 pg/mL).
- Clinical Performance Study (test set): 2127 Emergency Department (ED) subjects.
-
Number of experts used to establish the ground truth for the test set and the qualifications of those experts:
- The ground truth for the clinical study was an "adjudicated diagnosis" determined by a panel of board-certified cardiologists. The exact number of cardiologists on the panel is not specified in the provided text.
-
Adjudication method (e.g. 2+1, 3+1, none) for the test set:
- The document states "An adjudicated diagnosis was determined by a panel of board-certified cardiologists." It does not specify the exact adjudication method (e.g., majority vote, sequential review, etc.).
-
If a multi reader multi case (MRMC) comparative effectiveness study was done, If so, what was the effect size of how much human readers improve with AI vs without AI assistance:
- No, this document describes the validation of a quantitative in vitro diagnostic (IVD) reagent kit for measuring NT-proBNP levels using an automated chemiluminescent immunoassay (CMIA) system. It is not an AI-assisted diagnostic imaging device, so an MRMC study is not relevant to this submission. The "readers" are the automated analyzers and laboratory personnel interpreting numerical results.
-
If a standalone (i.e., algorithm only without human-in-the-loop performance) was done:
- This device is a standalone diagnostic test in the sense that it provides a quantitative NT-proBNP result. The assay itself is a fully automated process on the Alinity i system. The performance data presented (precision, linearity, limits, specificity, clinical performance tables) represent the performance of the device "standalone" in generating these quantitative results, which are then used by clinicians as an "aid in diagnosis." There isn't a "human-in-the-loop" component to the measurement itself, though medical professionals interpret the results in a clinical context.
-
The type of ground truth used (expert consensus, pathology, outcomes data, etc.):
- For the clinical performance study, the ground truth for Heart Failure (HF) diagnosis was established by expert consensus (adjudicated diagnosis by a panel of board-certified cardiologists).
-
The sample size for the training set:
- This document describes a 510(k) submission for an in vitro diagnostic reagent kit. Unlike AI/ML software, such devices typically undergo analytical and clinical validation studies with defined test sets but do not have a "training set" in the sense of machine learning algorithms. The development and optimization of the assay would have involved various internal samples and experiments, but these are not explicitly termed "training sets" and their size is not reported in this context.
-
How the ground truth for the training set was established:
- As explained above, the concept of a "training set" with established ground truth, as typically applied to machine learning or AI models, does not directly apply to the regulatory submission type for this diagnostic reagent kit. The assay is based on chemical and biological principles (CMIA) rather than learned algorithms from large datasets.
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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 in blue, with the words "U.S. FOOD & DRUG" stacked on top of the word "ADMINISTRATION".
January 16, 2025
Axis-Shield Diagnostics Limited Claire Dora Associate Director, Regulatory Affairs 17 Luna Place, The Technology Park Dundee. Scotland DD 1XA United Kingdom
Re: K241176
Trade/Device Name: Alere NT-proBNP for Alinity i Reagent Kit Regulation Number: 21 CFR 862.1117 Regulation Name: B-Type Natriuretic Peptide Test System Regulatory Class: Class II Product Code: NBC Dated: December 11, 2024 Received: December 11, 2024
Dear Claire Dora:
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"
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(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).
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 OS 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.
All medical devices, including Class I and unclassified devices and combination product device constituent parts are required to be in compliance with the final Unique Device Identification System rule ("UDI Rue"). The UDI Rule requires, among other things, that a device bear a unique device identifier (UDI) on its label and package (21 CFR 801.20(a)) unless an exception or alternative applies (21 CFR 801.20(b)) and that the dates on the device label be formatted in accordance with 21 CFR 801.18. The UDI Rule (21 CFR 830.300(a) and 830.320(b)) also requires that certain information be submitted to the Global Unique Device Identification Database (GUDID) (21 CFR Part 830 Subpart E). For additional information on these requirements, please see the UDI System webpage at https://www.fda.gov/medical-device-advicecomprehensive-regulatory-assistance/unique-device-identification-system-udi-system.
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.
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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. Division 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
Enclosure
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Indications for Use
510(k) Number (if known) K241176
Device Name Alere NT-proBNP for Alinity i
The Alere NT-proBNP for Alinity i assay is a chemiluminescent microparticle immunoassay (CMIA) used for the in vitro quantitative determination of N-terminal pro B-type natriuretic peptide (NT-proBNP) in human serum and plasma on the Alinity i system.
In the emergency departments of NT-proBNP are used as an aid in the diagnosis of heart failure (HF) in patients with clinical suspicion of new onset or worsening HF.
| Type of Use (Select one or both, as applicable) | |
|---|---|
| ☑ Prescription Use (Part 21 CFR 801 Subpart D) | ☐ Over-The-Counter Use (21 CFR 801 Subpart C) |
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Indications for Use (Describe)
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Administrative Documentation - 510(k) Summary
This summary of the 510(k) safety and effectiveness information is being submitted in accordance with the requirements of SMDA 1990 and 21 CFR §807.92.
I. 510(k) Number
II. Applicant Name
Axis-Shield Diagnostics Limited Luna Place, The Technology Park, Dundee DD2 1XA United Kingdom
Primary contact:
Claire Dora, Associate Director, Regulatory Affairs Axis-Shield Diagnostics Ltd Phone: +44(0)790994098 Email: claire.dora@abbott.com
Date Summary Prepared: January 16, 2025
III. Device Name
Trade Name: Alere NT-proBNP for Alinity i
Alere NT-proBNP for Alinity i Device Classification: Class II Classification Name: BNP Test System Governing Regulation: 21 CFR Part 862.1117 Product Code: NBC
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IV. Predicate Device
Roche Elecsys proBNP II (K092649)
V. Description of Device
A. Reagents
The various configurations of the Alere NT-proBNP for Alinity i Reagent Kit are described below.
| List Number | ||
|---|---|---|
| 04S7921 | 04S7931 | |
| Tests per cartridge | 100 | 500 |
| Number of cartridges per kit | 2 | 2 |
| Tests per kit | 200 | 1000 |
| Microparticle volume | 6.7 mL | 27.0 mL |
| Conjugate volume | 6.1 mL | 26.5 mL |
Microparticles: Anti-NT-proBNP (sheep, monoclonal) coated microparticles in Bis-TRIS buffer with protein (bovine) stabilizer, non-specific binding blocking agents, and surfactant. Minimum concentration: 0.05% solids. Preservative: sodium azide.
Conjugate: Anti-NT-proBNP (mouse, monoclonal) acridinium-labeled conjugate in MES buffer with protein (bovine) stabilizer and surfactant. Minimum concentration: 0.12 ug/mL. Preservatives: antimicrobial agents.
B. Biological Principles of the Procedure
The Alere NT-proBNP for Alinity i assay is an automated, two-step immunoassay for the in vitro quantitative determination of NT-proBNP in human serum and plasma using chemiluminescent microparticle immunoassay (CMIA) technology.
Sample and anti-NT-proBNP coated paramagnetic microparticles are combined and incubated. The NT-proBNP present in the sample binds to the anti-NT-proBNP coated microparticles. The mixture is washed. Anti-NT-proBNP acridinium-labeled conjugate is added to create a reaction mixture and incubated. Following a wash cycle,
Pre-Trigger and Trigger Solutions are added.
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The resulting chemiluminescent reaction is measured as a relative light unit (RLU). There is a direct relationship between the amount of NT-proBNP in the sample and the RLU detected by the system optics.
Assay Standardization
There is currently no international recognized reference method or reference material for standardization. The Alere NT-proBNP for Alinity i Calibrators are traceable to internal reference standards at every concentration level that were value assigned on and made traceable to the predicate device by transference, as described by Clinical and Laboratory Standards Institute (CLSI) Document EP32-R.*
C. Interpretation of Results
Emergency Department
For patients presenting to the emergency department (ED) with clinical suspicion of heart failure (HF), the results should be interpreted as indicated in the table below.
| Age Group(Years) | NT-proBNP | ||
|---|---|---|---|
| (pg/mL) | (pmol/L) | Interpretation | |
| All | < 300.0 | < 35.4 | Negative: HF unlikely |
| 18 to < 50 | ≥ 300.0 to < 450.0 | ≥ 35.4 to < 53.1 | Grayzone: Indeterminate |
| 50 to 75 | ≥ 300.0 to < 900.0 | ≥ 35.4 to < 106.2 | Consider other causes ofNT-proBNP elevation. |
| > 75 | ≥ 300.0 to < 1800.0 | ≥ 35.4 to < 212.4 | |
| 18 to < 50 | ≥ 450.0 | ≥ 53.1 | Positive: HF likely |
| 50 to 75 | ≥ 900.0 | ≥ 106.2 | |
| > 75 | ≥ 1800.0 | ≥ 212.4 |
" Clinical and Laboratory Standards Institute (CLSI). Metrological Traceability and Its Implementation; A Report. CLSI document EP32-R. Wayne, PA: CLSI; 2006.
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VI. Intended Use of the Device
The Alere NT-proBNP for Alinity i assay is a chemiluminescent microparticle immunoassay (CMIA) used for the in vitro quantitative determination of N-terminal pro B-type natriuretic peptide (NT-proBNP) in human serum and plasma on the Alinity i system.
In the emergency department, measurements of NT-proBNP are used as an aid in the diagnosis of heart failure (HF) in patients with clinical suspicion of new onset or worsening HF.
VII. Comparison with the Predicate Device
The similarities and differences between the subject device and the predicate device are presented in the table below.
| Subject Device:Alere NT-proBNP for Alinity i | Predicate Device:Roche Elecsys proBNP II (K092649) | |
|---|---|---|
| General Device Characteristic Similarities | ||
| IntendedUse/Indicationsfor Use | Immunoassay used for the in vitroquantitative determination of N-terminalpro B-type natriuretic peptide(NT-proBNP) in human serum andplasma.In the emergency department,measurements of NT-proBNP are usedas an aid in the diagnosis of heart failure(HF) in patients with clinical suspicionof new onset or worsening HF. | Immunoassay for the in vitro quantitativedetermination of N-terminal pro-Brainnatriuretic peptide in human serum andplasma.This assay is used as an aid in the diagnosis ofindividuals suspected of having congestiveheart failure.The test is further indicated for the riskstratification of patients with acute coronarysyndrome and congestive heart failure.The test may also serve as an aid in theassessment of increased risk of cardiovascularevents and mortality in patients at risk forheart failure who have stable coronary arterydisease. |
| Specimen Type | Human serum and plasma | Same |
| Test Principle | Sandwich immunoassay | Same |
| MeasurementType | Quantitative | Same |
| Analyte | NT-proBNP | Same |
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| Subject Device:Alere NT-proBNP for Alinity i | Predicate Device:Roche Elecsys proBNP II (K092649) | |
|---|---|---|
| DetectionTechnology | Chemiluminescence | Same |
| General Device Differences | ||
| Principle ofOperation | CMIA | Electro chemiluminescent microparticleimmunoassay (ECLIA) |
| Intended UseSetting | Emergency department | Not specified |
| MeasuringInterval | Analytical Measuring Interval (AMI):15.8 to 35,000.0 pg/mL(1.9 to 4130.0 pmoL/L) | 5 to 35,000 pg/mL |
| Hook Effect | No hook effect up to 372,620 pg/mL | No hook effect up to 300,000 pg/mL |
| ResultsInterpretation | Negative: HF unlikely for all patients:< 300.0 pg/mL | 125 pg/mL for < 75 years450 pg/mL for ≥ 75 years |
| Gray Zone: Indeterminate; consider othercauses of NT-proBNP elevation: | ||
| Age (Years) NT-proBNP (pg/mL)18 to < 50 ≥ 300.0 to < 450.050 to 75 ≥ 300.0 to < 900.0> 75 ≥ 300.0 to < 1800.0 | ||
| Positive: HF likely: | ||
| Age (Years) NT-proBNP (pg/mL)18 to < 50 ≥ 450.050 to 75 ≥ 900.0> 75 ≥ 1800.0 |
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VIII. Summary of Nonclinical Performance
A. Reportable Interval
Based on representative data for the limit of quantitation (LoQ), the ranges over which results can be reported are provided below.
| pg/mL | pmol/L | |
|---|---|---|
| Analytical MeasuringInterval (AMI)a | 15.8 - 35,000.0 | 1.9 - 4130.0 |
| Extended MeasuringInterval (EMI)b | 35,000.0 - 350,000.0 | 4130.0 - 41,300.0 |
| Reportable Intervalc | 15.8 - 350,000.0 | 1.9 - 41,300.0 |
ª AMI: The AMI extends from the LoQ to the upper limit of quantitation (ULoQ). This is determined by the range of values in pg/mL (pmol/L) that demonstrated acceptable performance for linearity, imprecision, and bias.
b EMI: The EMI extends from the ULoQ to the ULoQ × dilution factor. The value reflects a 1:10 dilution factor.
^ The reportable interval extends from the LoQ to the upper limit of the EMI.
B. Within-Laboratory Precision (20-Day)
A study was performed based on guidance from CLSI EP05-A3. * Testing was conducted using 3 lots of the Alere NT-proBNP for Alinity i reagents, 1 lot of the Alere NT-proBNP for Alinity i Calibrators, 1 lot of the Alere NT-proBNP for Alinity i Controls, and 1 instrument. Three controls and 8 human plasma panels (7 native panels and 1 panel supplemented with NT-proBNP analyte) were tested in 2 replicates at 2 separate times per day on 20 days.
* Clinical and Laboratory Standards Institute (CLS). Evaluation of Quantitative Measurement Procedures; Approved Guideline—Third Edition. CLSI Document EP05-A3. Wayne, PA: CLSI; 2014.
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| Mean | Repeatability | Within-Laboratorya | Between-Lot | Overall Within-Laboratoryb | ||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Sample | n | (pg/mL) | SD | %CV | SD | %CV | SD | %CV | SD | %CV |
| Low Control | 240 | 143.0 | 6.40 | 4.5 | 7.63 | 5.3 | 4.42 | 3.1 | 8.82 | 6.2 |
| Medium Control | 240 | 503.4 | 16.26 | 3.2 | 18.21 | 3.6 | 9.29 | 1.8 | 20.44 | 4.1 |
| High Control | 240 | 5144.2 | 177.02 | 3.4 | 202.18 | 3.9 | 21.47 | 0.4 | 203.32 | 4.0 |
| Panel A | 240 | 18.8 | 1.39 | 7.4 | 1.72 | 9.2 | 0.75 | 4.0 | 1.88 | 10.0 |
| Panel B | 240 | 55.6 | 2.64 | 4.7 | 3.02 | 5.4 | 1.60 | 2.9 | 3.41 | 6.1 |
| Panel C | 240 | 130.4 | 4.28 | 3.3 | 5.44 | 4.2 | 4.87 | 3.7 | 7.30 | 5.6 |
| Panel D | 240 | 449.1 | 13.10 | 2.9 | 18.68 | 4.2 | 14.02 | 3.1 | 23.36 | 5.2 |
| Panel E | 240 | 1011.4 | 28.31 | 2.8 | 34.49 | 3.4 | 21.92 | 2.2 | 40.87 | 4.0 |
| Panel F | 240 | 1938.0 | 54.02 | 2.8 | 65.28 | 3.4 | 22.56 | 1.2 | 69.07 | 3.6 |
| Panel G | 240 | 14,939.8 | 417.56 | 2.8 | 518.88 | 3.5 | 296.61 | 2.0 | 597.67 | 4.0 |
| Panel H(Supplemented) | 240 | 31,711.0 | 989.02 | 3.1 | 1185.11 | 3.7 | 2118.19 | 6.7 | 2427.19 | 7.7 |
ª Includes repeatability (within-run), between-run, and between-day variability.
b Includes repeatability (within-run), between-run, between-day, and between-lot variability.
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C. Linearity
A study was performed based on guidance from CLSI EP06, 2nd ed. This assay is linear across the AMI of 15.8 to 35,000.0 pg/mL (1.9 to 4130.0 pmol/L).
D. Lower Limits of Measurement
A study was performed based on guidance from CLSI EP17-A2. T Testing was conducted using 3 lots of the Alere NT-proBNP for Alinity i reagents on each of 2 instruments over a minimum of 3 days. The maximum observed limit of blank (LoB), limit of detection (LoD), and limit of quantitation (LoQ) values are summarized below.
| pg/mL | pmol/L | |
|---|---|---|
| LoBa | 0.1 | 0.0 |
| LoDb | 3.6 | 0.4 |
| LoQc | 15.8 | 1.9 |
a The LoB represents the 95th percentile from n ≥ 60 replicates of zero-analyte samples.
b The LoD represents the lowest concentration at which the analyte can be detected with 95% probability based on n ≥ 60 replicates of low-analyte level samples.
6 The LoQ is defined as the lowest concentration at which a maximum allowable precision of 20 %CV was met and was determined from n ≥ 60 replicates of low-analyte level samples.
E. Analytical Specificity
1. Potentially Interfering Endogenous Substances
A study was performed based on guidance from CLSI EP07, 3rd ed. + Each substance was tested at 2 levels of the analyte (approximately 125 pg/mL and 2000 pg/mL).
* Clinical and Laboratory Standards Institute (CLSI). Evaluation of the Linearity of Quantitative Measurement Procedures. 2nd ed. CLSI Guideline EP06. Wayne, PA: CLSI; 2020.
T Clinical and Laboratory Standards Institute (CLSI). Evaluation of Detection Capability for Clinical Measurements; Approved Guideline-Second Edition. CLSI Document EP17-A2. Wayne, PA: CLSI; 2012.
+ Clinical and Laboratory Standards Institute (CLSI). Interference Testing in Clinical Chemistry. 3rd ed. CLSI Guideline EP07. Wayne, PA: CLSI; 2018.
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No significant interference (interference within ± 10.0%) was observed at the following concentrations.
| No Significant Interference (Interference within ± 10.0%) | |
|---|---|
| Potentially Interfering Substance | Interferent Level |
| Bilirubin (conjugated) | 60 mg/dL |
| Bilirubin (unconjugated) | 60 mg/dL |
| Biotin | 4250 ng/mL |
| Cholesterol | 700 mg/dL |
| Human Anti-mouse Antibodies (HAMA) | 1500 ng/mL |
| Hemoglobin | 1 g/dL |
| IgG | 6 g/dL |
| Intralipid | 3000 mg/dL |
| Rheumatoid Factor (RF) | 600 IU/mL |
| Total Protein | 12.6 g/dL |
Interference beyond ± 10.0% (based on 95% confidence interval [CI]) was
observed at the concentrations shown below for the following substances.
| Interference beyond ± 10.0% (based on 95% CI) | |||
|---|---|---|---|
| Potentially InterferingSubstance | Interferent Level | Analyte Level | % Interference(95% CI) |
| RF | 1520 IU/mL | 125 pg/mL | -8.9%(-10.4%, -7.5%) |
| 1520 IU/mL | 2000 pg/mL | -11.4%(-12.4%, -10.4%) | |
| Total Protein | 15.2 g/dL | 125 pg/mL | -12.7%(-14.7%, -10.7%) |
| 15.5 g/dL | 2000 pg/mL | -9.9%(-11.4%, -8.5%) |
{13}------------------------------------------------
2. Potentially Interfering Drugs
A study was performed based on guidance from CLSI EP07, 3rd ed. * Each substance was tested at 2 levels of the analyte (approximately 125 pg/mL and 2000 pg/mL).
No significant interference (interference within ± 10.0%) was observed at the following concentrations.
| No Significant Interference (Interference within ± 10.0%) | |||
|---|---|---|---|
| Potentially InterferingDrug | Interferent Level | Potentially InterferingDrug | Interferent Level |
| Acetaminophen | 15.6 mg/dL | Lidocaine | 8.0 mg/dL |
| Acetylsalicylic Acid | 60 mg/dL | Lisinopril | 1.6 mg/dL |
| Allopurinol | 6.0 mg/dL | Lithium | 4.20 mg/dL |
| Amikacin | 15 mg/dL | Losartan potassium | 5.99 mg/dL |
| Amiodarone | 4.2 mg/dL | Lovastatin | 2.0 mg/dL |
| Amlodipine Besylate | 0.4 mg/dL | L-Thyroxine | 0.06 mg/dL |
| Ampicillin | 7.5 mg/dL | Methyldopa | 2.5 mg/dL |
| Ascorbic acid | 5.25 mg/dL | Methylprednisolone | 0.75 mg/dL |
| Atenolol | 1.0 mg/dL | Metoprolol | 1.5 mg/dL |
| Atorvastatin | 32 mg/dL | Milrinone | 0.183 mg/dL |
| Caffeine | 10.8 mg/dL | Naproxen | 49.97 mg/dL |
| Captopril | 5.0 mg/dL | Nicotine | 0.1 mg/dL |
| Carbamazepine | 4.5 mg/dL | Nicotinic acid | 4.0 mg/dL |
| Carvedilol | 3.75 mg/dL | Nifedipine | 6.0 mg/dL |
| Chloramphenicol | 7.8 mg/dL | Nitrofurantoin | 4.0 mg/dL |
| Chlordiazepoxide | 1.0 mg/dL | Nitroglycerin | 0.016 mg/dL |
| Chlorpromazine | 0.33 mg/dL | Oxazepam | 1.2 mg/dL |
| Cimetidine | 3.0 mg/dL | Oxytetracycline | 10 mg/dL |
| No Significant Interference (Interference within ± 10.0%) | |||
| Potentially InterferingDrug | Interferent Level | Potentially InterferingDrug | Interferent Level |
| Cinnarizine | 3.1 mg/dL | Penicillin G | 25 U/mL |
| Clopidogrel bisulfate | 7.5 mg/dL | Pentobarbital | 12.6 mg/dL |
| Creatinine | 30 mg/dL | Phenobarbitol | 69 mg/dL |
| Cyclosporine A | 0.4 mg/dL | Phenprocoumon(Marcumar) | 1.53 mg/dL |
| Dextran 40 | 6000 mg/dL | Phenytoin | 6.0 mg/dL |
| Diazepam | 3.0 mg/dL | Primidone | 5.7 mg/dL |
| Diclofenac | 6.0 mg/dL | Probenecid | 60 mg/dL |
| Digoxin | 0.025 mg/dL | Procainamide | 4.8 mg/dL |
| Diltiazem | 12 mg/dL | Propafenone | 30 mg/dL |
| Dipyridamole | 8.0 mg/dL | Propanolol | 0.2 mg/dL |
| Disopyramide | 4.0 mg/dL | Propoxyphene | 0.321 mg/dL |
| Dobutamine | 10 mg/dL | Quinidine | 2.0 mg/dL |
| Dopamine | 65 mg/dL | Ramipril | 0.6 mg/dL |
| Enalapril Maleate | 1.6 mg/dL | Retaplase | 3.33 mg/dL |
| Epinephrine | 0.05 mg/dL | Simvastatin | 3.2 mg/dL |
| Erythromycin | 13.8 mg/dL | Spironolactone | 7.5 mg/dL |
| Ethanol | 600 mg/dL | Sulfamethoxazole | 112 mg/dL |
| Ethosuximide | 30 mg/dL | Theophylline | 6.0 mg/dL |
| Fenofibrate | 4.5 mg/dL | Tolbutamide | 150 mg/dL |
| Furosemide | 6.0 mg/dL | Torasemide | 1.5 mg/dL |
| Gentamicin | 12 mg/dL | Trandolapril | 4.0 mg/dL |
| Heparin | 8 U/mL | Trasylol/Aprotinin | 501.8 KIE/mL |
| Hydralazine | 2.0 mg/dL | Trimethoprim | 6.4 mg/dL |
| Hydrochlorothiazide | 2.0 mg/dL | Uric Acid | 23.5 mg/dL |
| Insulin | 0.16 mg/dL | Valproic Acid | 50 mg/dL |
| Ibuprofen | 50 mg/dL | Verapamil | 24 mg/dL |
| No Significant Interference (Interference within ± 10.0%) | |||
| Potentially InterferingDrug | Interferent Level | Potentially InterferingDrug | Interferent Level |
| Indomethacin | 3.6 mg/dL | Warfarin | 7.5 mg/dL |
| Isosorbide dinitrate | 6.0 mg/dL |
* Clinical and Laboratory Standards Institute (CLSI). Interference Testing in Clinical Chemistry. 3rd ed. CLSI Guideline EP07. Wayne, PA: CLSI; 2018.
{14}------------------------------------------------
{15}------------------------------------------------
3. Cross-Reactants
A study was performed based on guidance from CLSI EP07, 3rd ed. * Samples with NT-proBNP target concentrations of 125 pg/mL and 2000 pg/mL containing the cross-reactants at the concentration listed below were tested with the Alere NT-proBNP for Alinity i assay on the Alinity i system. For each cross-reactant, the % recovery was calculated as: (NT-proBNP concentration with cross-reactant) / (NT-proBNP concentration without cross-reactant) × 100%. The observed % recovery of NT-proBNP was within 100% ± 10% for all cross-reactants evaluated at each analyte level.
| Potential Cross-Reactant | Cross-Reactant Concentration |
|---|---|
| Adrenomedullin | 1000 pg/mL |
| Aldosterone | 600 pg/mL |
| Angiotensin I | 600 pg/mL |
| Angiotensin II | 600 pg/mL |
| Angiotensin III | 1000 pg/mL |
| ANP 28 | 3100 ng/mL |
| Arg-Vasopressin | 1000 pg/mL |
| BNP 32 | 3500 ng/mL |
| CNP 22 | 2200 ng/mL |
| Endothelin | 20 pg/mL |
| NT-proANP 1-30 (preproANP26-55) | 3500 ng/mL |
* Clinical and Laboratory Standards Institute (CLSI). Interference Testing in Clinical Chemistry. 3rd ed. CLSI Guideline EP07. Wayne, PA: CLSI; 2018.
{16}------------------------------------------------
| Potential Cross-Reactant | Cross-Reactant Concentration |
|---|---|
| NT-proANP 31-67 (preproANP56-92) | 1000 pg/mL |
| NT-proANP 79-98 (preproANP104-123) | 1000 pg/mL |
| Renin | 50,000 pg/mL |
| Urodilatin | 3500 ng/mL |
F. High Dose Hook
High dose hook effect was not observed on samples up to 372,620 pg/mL.
G. Expected Values (Reference Interval)
A reference interval study was performed based on guidance from CLSI EP28-A3c. Testing was performed with a US-based general population from apparently healthy individuals (≥ 18 years old). The specimens were tested with the Alere NT-proBNP for Alinity i assay on the Alinity i system. Based on the results, the 95% reference interval of an apparently healthy population for each sex and age range was determined to be as follows:
| Reference Interval | ||||
|---|---|---|---|---|
| Median | (2.5th to 97.5th Percentile) | |||
| Age Range | Sex | n | (pg/mL) | (pg/mL) |
| 18 to < 50 years old | Female | 181 | 30.7 | < 15.8 to 104.8 |
| Male | 137 | < 15.8 | < 15.8 to 180.3 | |
| 50 to 75 years old | Female | 134 | 51.7 | <15.8 to 334.1 |
| Male | 146 | 39.9 | < 15.8 to 451.6 | |
| > 75 years old | Female | 127 | 81.4 | < 15.8 to 956.1 |
| Male | 136 | 65.1 | < 15.8 to 683.0 |
Clinical and Laboratory Standards Institute (CLSI). Defining, Establishing, and Verifying Reference Intervals in the Clinical Laboratory; Approved Guideline—Third Edition. CLSI document EP28-A3c. Wayne, PA: CLSI; 2008.
{17}------------------------------------------------
IX. Summary of Clinical Performance
A. Reproducibility
A study was performed based on guidance from CLSI EP05-A3. * Testing was conducted at each of 3 testing sites using 3 lots of the Alere NT-proBNP for Alinity i reagents, 2 lots of the Alere NT-proBNP for Alinity i Calibrators, 2 lots of the Alere NT-proBNP for Alinity i Controls, and 1 instrument. Three controls and 8 human plasma panels (6 native panels and 2 panels supplemented with NT-proBNP analyte) were tested in a minimum of 3 replicates at 2 separate times per day on 5 different days.
* Clinical and Laboratory Standards Institute (CLSI). Evaluation of Quantitative Measurement Procedures; Approved Guideline-Third Edition. CLSI Document EP05-A3. Wayne, PA: CLSI; 2014.
{18}------------------------------------------------
| Sample | n | Mean(pg/mL) | RepeatabilitySD | Repeatability%CV | Within-LaboratoryaSD | Within-Laboratorya%CV | Between-SiteSD | Between-Site%CV | Between-LotSD | Between-Lot%CV | OverallReproducibilitybSD | OverallReproducibilityb%CV |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Low Control | 360 | 136.6 | 4.75 | 3.5 | 5.75 | 4.2 | 2.63 | 1.9 | 1.45 | 1.1 | 6.49 | 4.7 |
| Medium Control | 360 | 477.1 | 12.24 | 2.6 | 15.35 | 3.2 | 14.20 | 3.0 | 8.88 | 1.9 | 22.72 | 4.8 |
| High Control | 359 | 4932.2 | 201.01 | 4.1 | 311.08 | 6.3 | 105.17 | 2.1 | 0.00 | 0.0 | 328.38 | 6.7 |
| Panel 1 | 359 | 14.5 | 2.10c | 14.5 | 2.74c | 18.9 | 0.00 | 0.0 | 0.00 | 0.0 | 2.74c | 18.9 |
| Panel 2 | 360 | 51.9 | 2.14 | 4.1 | 3.07 | 5.9 | 0.49 | 0.9 | 0.00 | 0.0 | 3.11 | 6.0 |
| Panel 3 | 360 | 127.1 | 4.67 | 3.7 | 5.95 | 4.7 | 1.36 | 1.1 | 0.78 | 0.6 | 6.15 | 4.8 |
| Panel 4 | 360 | 436.9 | 10.46 | 2.4 | 18.67 | 4.3 | 3.18 | 0.7 | 0.00 | 0.0 | 18.94 | 4.3 |
| Panel 5 | 360 | 996.5 | 21.86 | 2.2 | 43.45 | 4.4 | 17.12 | 1.7 | 0.00 | 0.0 | 46.70 | 4.7 |
| Panel 6 | 360 | 1891.1 | 33.18 | 1.8 | 79.86 | 4.2 | 35.96 | 1.9 | 0.00 | 0.0 | 87.58 | 4.6 |
| Panel 7(Supplemented) | 359 | 15,664.6 | 319.91 | 2.0 | 974.61 | 6.2 | 281.81 | 1.8 | 217.28 | 1.4 | 1037.54 | 6.6 |
| Panel 8(Supplemented) | 360 | 25,630.5 | 601.42 | 2.3 | 1654.86 | 6.5 | 220.39 | 0.9 | 807.19 | 3.1 | 1854.37 | 7.2 |
Includes repeatability (within-run), between-run, and between-day variability. a
b Includes repeatability (within-run), between-run, between-site, and between-lot variability.
င An outlying run was observed. Based on guidance from CLSI EPO5-A3, a replacement run was performed and the results are shown in the preceding table. Without the replacement run, the repeatability SD was 9.5 pg/mL (1.12 pmol2), within-laboratory precision SD was 9.64 pg/mL (1.14 pmoVL), and the overall reproducibility SD was 9.64 pg/mL (1.14 pmol/L).
{19}------------------------------------------------
B. Clinical Performance
A multi-center prospective study including 17 collection sites across the US was conducted to establish the performance characteristics of the Alere NT-proBNP for Alinity i assay. Subjects 18 years and older presenting to the ED with signs and symptoms consistent with a clinical suspicion of new onset or acute exacerbation of HF were included in the study. Subjects with renal insufficiency requiring dialysis or known estimated glomerular filtration rate (eGFR) < 15.0 mL/min/1.73 m² and subjects with dyspnea after chest trauma were excluded from the study. An adjudicated diagnosis was determined by a panel of board-certified cardiologists.
The results were determined from 2127 ED subjects. Of the 2127 ED subjects, 1030 (48.4%) were female and 1097 (51.6%) were male, ranging in age from 19 to 97 years. Individuals in the population were White (53.1%), Black or African American (39.5%), Asian (1.7%), American Indian or Alaska Native (0.8%), Native Hawaiian or Other Pacific Islander (0.3%), or represented by other races (0.9%), with the remaining 3.6% of Unknown / Not Reported race. A total of 1934 (90.9%) ED subjects were not Hispanic or Latino, and 168 (7.9%) ED subjects were Hispanic or Latino, with the remaining 25 (1.2%) ED subjects of Unknown / Not Reported ethnicity.
The descriptive statistics for the Alere NT-proBNP for Alinity i test results (pg/mL) were determined within and across sex by age group and are summarized in the following table.
| AdjudicatedDiagnosis | HF | Non-HF | ||||||
|---|---|---|---|---|---|---|---|---|
| Age Group(Years) | < 50 | 50 to 75 | > 75 | All | < 50 | 50 to 75 | > 75 | All |
| All Subjects | ||||||||
| N | 160 | 553 | 167 | 880 | 300 | 799 | 148 | 1247 |
| Mean | 4354.5 | 6092.9 | 6891.3 | 5928.3 | 437.9 | 760.4 | 1738.8 | 798.9 |
| SD | 5454.61 | 8144.69 | 6860.32 | 7521.45 | 1686.57 | 1833.48 | 3494.96 | 2100.93 |
| Median | 2664.9 | 3297.2 | 4787.6 | 3420.7 | 70.1 | 198.9 | 565.9 | 181.8 |
{20}------------------------------------------------
| AdjudicatedDiagnosis | HF | Non-HF | ||||||
|---|---|---|---|---|---|---|---|---|
| Age Group(Years) | < 50 | 50 to 75 | > 75 | All | < 50 | 50 to 75 | > 75 | All |
| Minimum | 22.8 | 19.8 | 158.9 | 19.8 | 0.0 | 0.0 | 4.2 | 0.0 |
| Maximum | 38,880.9 | 60,716.9 | 38,938.4 | 60,716.9 | 24,737.1 | 17,988.9 | 31,154.0 | 31,154.0 |
| Female Subjects | ||||||||
| N | 55 | 236 | 85 | 376 | 165 | 407 | 82 | 654 |
| Mean | 4034.7 | 5370.1 | 6814.2 | 5501.2 | 273.5 | 614.8 | 1320.8 | 617.2 |
| SD | 6302.82 | 7732.10 | 7042.32 | 7417.01 | 732.64 | 1543.13 | 2403.63 | 1556.92 |
| Median | 1851.5 | 2541.7 | 4787.6 | 2786.4 | 73.1 | 174.9 | 499.7 | 161.2 |
| Minimum | 22.8 | 24.9 | 158.9 | 22.8 | 0.0 | 0.9 | 25.7 | 0.0 |
| Maximum | 38,880.9 | 47,385.1 | 38,938.4 | 47,385.1 | 5633.9 | 14,849.5 | 18,827.7 | 18,827.7 |
| Male Subjects | ||||||||
| N | 105 | 317 | 82 | 504 | 135 | 392 | 66 | 593 |
| Mean | 4522.0 | 6631.0 | 6971.2 | 6247.0 | 638.8 | 911.6 | 2258.0 | 999.4 |
| SD | 4977.78 | 8410.52 | 6708.84 | 7590.10 | 2369.85 | 2084.06 | 4464.35 | 2557.26 |
| Median | 2780.1 | 4066.5 | 4773.9 | 3904.3 | 64.1 | 221.0 | 701.8 | 203.2 |
| Minimum | 58.3 | 19.8 | 186.9 | 19.8 | 0.0 | 0.0 | 4.2 | 0.0 |
| Maximum | 26,986.3 | 60,716.9 | 32,286.4 | 60,716.9 | 24,737.1 | 17,988.9 | 31,154.0 | 31,154.0 |
The pretest probability of adjudicated HF (prevalence of adjudicated HF in the study), posttest probabilities, and likelihood ratios of the Alere NT-proBNP for Alinity i result vs adjudicated diagnosis (along with the 95% CIs) were determined based on guidance from CLSI EP12, 3rd ed., * for all subjects and by sex using the age-dependent positive cutoffs (450 pg/mL for subjects 18 to < 50 years of age, 900 pg/mL for subjects 50 to 75 years of age, and 1800 pg/mL for subjects > 75 years of age) and age-independent negative cutoff (300 pg/mL).
* Clinical and Laboratory Standards Institute (CLSI). Evaluation of Qualitative, Binary Output Examination Performance. 3rd ed. CLSI Guideline EP12. Wayne, PA: CLSI; 2023.
{21}------------------------------------------------
| All Subjects | ||||||||
|---|---|---|---|---|---|---|---|---|
| NT-proBNPResult | AdjudicatedDiagnosis | PosttestProbability ofHF % (n/N)(95% CI)a | PosttestProbability ofNon-HF %(n/N)(95% CI)a | LikelihoodRatio (HF)(95% CI)b | ||||
| HF | Non-HF | Total | ||||||
| Age Group: 18 to < 50 YearsPretest Probability of HF (Prevalence of HF in Study): 34.78% (160/460) | ||||||||
| Positive | 140 | 48 | 188 | 74.5(140/188)(67.8, 80.2) | - | 5.47(4.19, 7.13) | ||
| Grayzone | 7 | 13 | 20 | 35.0(7/20)(18.1, 56.7) | 65.0(13/20)(43.3, 81.9) | 1.01(0.41, 2.48) | ||
| Negative | 13 | 239 | 252 | - | 94.8(239/252)(91.4, 97.0) | 0.10(0.06, 0.17) | ||
| Total | 160 | 300 | 460 | |||||
| Age Group: 50 to 75 YearsPretest Probability of HF (Prevalence of HF in Study): 40.90% (553/1352) | ||||||||
| Positive | 437 | 148 | 585 | 74.7(437/585)(71.0, 78.1) | - | 4.27(3.67, 4.96) | ||
| Grayzone | 80 | 147 | 227 | 35.2(80/227)(29.3, 41.7) | 64.8(147/227)(58.3, 70.7) | 0.79(0.61, 1.01) | ||
| Negative | 36 | 504 | 540 | - | 93.3(504/540)(90.9, 95.1) | 0.10(0.07, 0.14) | ||
| Total | 553 | 799 | 1352 |
The results for all subjects are presented in the following table.
Age Group: > 75 Years
Pretest Probability of HF (Prevalence of HF in Study): 53.02% (167/315)
{22}------------------------------------------------
| All Subjects | ||||||
|---|---|---|---|---|---|---|
| Adjudicated Diagnosis | PosttestProbability ofHF % (n/N)(95% CI)a | PosttestProbability ofNon-HF %(n/N)(95% CI)a | LikelihoodRatio (HF)(95% CI)b | |||
| NT-proBNPResult | HF | Non-HF | Total | |||
| Positive | 131 | 38 | 169 | 77.5(131/169)(70.6, 83.2) | - | 3.06(2.30, 4.06) |
| Grayzone | 34 | 59 | 93 | 36.6(34/93)(27.5, 46.7) | 63.4(59/93)(53.3, 72.5) | 0.51(0.36, 0.73) |
| Negative | 2 | 51 | 53 | - | 96.2(51/53)(87.2, 99.0) | 0.03(0.01, 0.14) |
| Total | 167 | 148 | 315 | |||
| All Subjectsc | ||||||
| Pretest Probability of HF (Prevalence of HF in Study): 41.37% (880/2127) | ||||||
| Positive | 708 | 234 | 942 | 75.2(708/942)(72.3, 77.8) | - | 4.29(3.80, 4.83) |
| Grayzone | 121 | 219 | 340 | 35.6(121/340)(30.7, 40.8) | 64.4(219/340)(59.2, 69.3) | 0.78(0.64, 0.96) |
| Negative | 51 | 794 | 845 | - | 94.0(794/845)(92.2, 95.4) | 0.09(0.07, 0.12) |
| Total | 880 | 1247 | 2127 |
The results for female subjects are presented in the following table.
{23}------------------------------------------------
| Female Subjects | ||||||
|---|---|---|---|---|---|---|
| NT-proBNPResult | AdjudicatedDiagnosis | Total | PosttestProbability ofHF % (n/N)(95% CI)a | PosttestProbability ofNon-HF %(n/N)(95% CI)a | LikelihoodRatio (HF)(95% CI)b | |
| HF | Non-HF | |||||
| Age Group: 18 to < 50 Years | ||||||
| Pretest Probability of HF (Prevalence of HF in Study): 25.00% (55/220) | ||||||
| Positive | 45 | 20 | 65 | 69.2(45/65)(57.2, 79.1) | - | 6.75(4.39, 10.37) |
| Grayzone | 3 | 7 | 10 | 30.0(3/10)(10.8, 60.3) | 70.0(7/10)(39.7, 89.2) | 1.29(0.34, 4.80) |
| Negative | 7 | 138 | 145 | - | 95.2(138/145)(90.4, 97.6) | 0.15(0.08, 0.31) |
| Total | 55 | 165 | 220 | |||
| Age Group: 50 to 75 Years | ||||||
| Pretest Probability of HF (Prevalence of HF in Study): 36.70% (236/643) | ||||||
| Positive | 173 | 56 | 229 | 75.5(173/229)(69.6, 80.7) | - | 5.33(4.13, 6.88) |
| Grayzone | 35 | 76 | 111 | 31.5(35/111)(23.6, 40.7) | 68.5(76/111)(59.3, 76.4) | 0.79(0.55, 1.15) |
| Negative | 28 | 275 | 303 | - | 90.8(275/303)(87.0, 93.5) | 0.18(0.12, 0.25) |
| Total | 236 | 407 | 643 | |||
| Age Group: > 75 Years | ||||||
| Pretest Probability of HF (Prevalence of HF in Study): 50.90% (85/167) | ||||||
| Positive | 64 | 19 | 83 | 77.1(64/83)(67.0, 84.8) | - | 3.25(2.15, 4.91) |
| Female Subjects | ||||||
| AdjudicatedDiagnosis | ||||||
| NT-proBNPResult | HF | Non-HF | Total | PosttestProbability ofHF % (n/N)(95% CI)a | PosttestProbability ofNon-HF %(n/N)(95% CI)a | LikelihoodRatio (HF)(95% CI)b |
| Grayzone | 20 | 34 | 54 | 37.0(20/54)(25.4, 50.4) | 63.0(34/54)(49.6, 74.6) | 0.57(0.36, 0.90) |
| Negative | 1 | 29 | 30 | - | 96.7(29/30)(83.3, 99.4) | 0.03(0.00, 0.24) |
| Total | 85 | 82 | 167 | |||
| All Female Subjectsc | ||||||
| Pretest Probability of HF (Prevalence of HF in Study): 36.50% (376/1030) | ||||||
| Positive | 282 | 95 | 377 | 74.8(282/377)(70.2, 78.9) | - | 5.16(4.25, 6.27) |
| Grayzone | 58 | 117 | 175 | 33.1(58/175)(26.6, 40.4) | 66.9(117/175)(59.6, 73.4) | 0.86(0.65, 1.15) |
| Negative | 36 | 442 | 478 | - | 92.5(442/478)(89.7, 94.5) | 0.14(0.10, 0.19) |
| Total | 376 | 654 | 1030 |
Administrative Documentation – 510(k) Summary
Administrative Documentation – 510(k) Summary
Page 20 of 42
{24}------------------------------------------------
The results for male subjects are presented in the following table.
{25}------------------------------------------------
| Male Subjects | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| NT-proBNPResult | AdjudicatedDiagnosis | PosttestProbability of | PosttestProbability ofNon-HF % | Likelihood | ||||||
| HF | Non-HF | Total | HF % (n/N)(95% CI)a | (n/N)(95% CI)a | Ratio (HF)(95% CI)b | |||||
| Age Group: 18 to < 50 Years | ||||||||||
| Pretest Probability of HF (Prevalence of HF in Study): 43.75% (105/240) | ||||||||||
| Positive | 95 | 28 | 123 | 77.2(95/123)(69.1, 83.8) | - | 4.36(3.12, 6.10) | ||||
| Grayzone | 4 | 6 | 10 | 40.0(4/10)(16.8, 68.7) | 60.0(6/10)(31.3, 83.2) | 0.86(0.25, 2.96) | ||||
| Negative | 6 | 101 | 107 | - | 94.4(101/107)(88.3, 97.4) | 0.08(0.03, 0.17) | ||||
| Total | 105 | 135 | 240 | |||||||
| Age Group: 50 to 75 Years | ||||||||||
| Pretest Probability of HF (Prevalence of HF in Study): 44.71% (317/709) | ||||||||||
| Positive | 264 | 92 | 356 | 74.2(264/356)(69.4, 78.4) | - | 3.55(2.95, 4.27) | ||||
| Grayzone | 45 | 71 | 116 | 38.8(45/116)(30.4, 47.9) | 61.2(71/116)(52.1, 69.6) | 0.78(0.56, 1.10) | ||||
| Negative | 8 | 229 | 237 | - | 96.6(229/237)(93.5, 98.3) | 0.04(0.02, 0.09) | ||||
| Total | 317 | 392 | 709 | |||||||
| Age Group: > 75 Years | ||||||||||
| Pretest Probability of HF (Prevalence of HF in Study): 55.41% (82/148) | ||||||||||
| Positive | 67 | 19 | 86 | 77.9(67/86) | - | 2.84(1.92, 4.20) |
(68.1, 85.4)
{26}------------------------------------------------
| Male Subjects | ||||||
|---|---|---|---|---|---|---|
| NT-proBNPResult | Adjudicated Diagnosis | PosttestProbability ofHF % (n/N)(95% CI)a | PosttestProbability ofNon-HF %(n/N)(95% CI)a | LikelihoodRatio (HF)(95% CI)b | ||
| HF | Non-HF | Total | ||||
| Grayzone | 14 | 25 | 39 | 35.9(14/39)(22.7, 51.6) | 64.1(25/39)(48.4, 77.3) | 0.45(0.26, 0.80) |
| Negative | 1 | 22 | 23 | - | 95.7(22/23)(79.0, 99.2) | 0.04(0.01, 0.26) |
| Total | 82 | 66 | 148 | |||
| All Male Subjectsc | ||||||
| Pretest Probability of HF (Prevalence of HF in Study): 45.94% (504/1097) | ||||||
| Positive | 426 | 139 | 565 | 75.4(426/565)(71.7, 78.8) | - | 3.61(3.10, 4.19) |
| Grayzone | 63 | 102 | 165 | 38.2(63/165)(31.1, 45.8) | 61.8(102/165)(54.2, 68.9) | 0.73(0.54, 0.97) |
| Negative | 15 | 352 | 367 | - | 95.9(352/367)(93.4, 97.5) | 0.05(0.03, 0.08) |
| Total | 504 | 593 | 1097 |
The pretest probability of adjudicated HF (prevalence of adjudicated HF in the study), posttest probabilities, and likelihood ratios of the Alere NT-proBNP for Alinity i result vs adjudicated diagnosis (along with the 95% CIs) were also determined for relevant clinical subgroups using the age-dependent positive cutoffs and age-independent negative cutoff.
The results for subjects with a history of HF are presented in the following table.
{27}------------------------------------------------
| Subjects With History of HF | ||||||
|---|---|---|---|---|---|---|
| NT-proBNPResult | AdjudicatedDiagnosis | PosttestProbability ofHF % (n/N)(95% CI)a | PosttestProbability ofNon-HF %(n/N)(95% CI)a | LikelihoodRatio (HF)(95% CI)b | ||
| HF | Non-HF | Total | ||||
| Age Group: 18 to < 50 Years | ||||||
| Pretest Probability of HF (Prevalence of HF in Study): 71.70% (114/159) | ||||||
| Positive | 103 | 17 | 120 | 85.8(103/120)(78.5, 91.0) | - | 2.39(1.64, 3.50) |
| Grayzone | 5 | 3 | 8 | 62.5(5/8)(30.6, 86.3) | 37.5(3/8)(13.7, 69.4) | 0.66(0.16, 2.64) |
| Negative | 6 | 25 | 31 | - | 80.6(25/31)(63.7, 90.8) | 0.09(0.04, 0.22) |
| Total | 114 | 45 | 159 | |||
| Age Group: 50 to 75 Years | ||||||
| Pretest Probability of HF (Prevalence of HF in Study): 65.09% (427/656) | ||||||
| Positive | 344 | 82 | 426 | 80.8(344/426)(76.7, 84.2) | - | 2.25(1.88, 2.69) |
| Grayzone | 58 | 45 | 103 | 56.3(58/103)(46.7, 65.5) | 43.7(45/103)(34.5, 53.3) | 0.69(0.48, 0.99) |
| Negative | 25 | 102 | 127 | - | 80.3(102/127)(72.6, 86.3) | 0.13(0.09, 0.20) |
| Total | 427 | 229 | 656 | |||
| Age Group: > 75 Years | ||||||
| Pretest Probability of HF (Prevalence of HF in Study): 69.31% (131/189) | ||||||
| Positive | 107 | 22 | 129 | 82.9 | - | 2.15 |
| Subjects With History of HF | ||||||
| AdjudicatedDiagnosis | PosttestProbability of | PosttestProbability ofNon-HF % | Likelihood | |||
| NT-proBNPResult | HF | Non-HF | Total | HF % (n/N)(95% CI)a | (n/N)(95% CI)a | Ratio (HF)(95% CI)b |
| Grayzone | 24 | 21 | 45 | 53.3(24/45)(39.1, 67.1) | 46.7(21/45)(32.9, 60.9) | 0.51(0.31, 0.83) |
| Negative | 0 | 15 | 15 | - | 100.0(15/15)(79.6, 100.0) | 0.01(0.00, 0.24) |
| Total | 131 | 58 | 189 | |||
| All Subjects With History of HFc | ||||||
| Pretest Probability of HF (Prevalence of HF in Study): 66.93% (672/1004) | ||||||
| Positive | 554 | 121 | 675 | 82.1(554/675)(79.0, 84.8) | - | 2.26(1.95, 2.62) |
| Grayzone | 87 | 69 | 156 | 55.8(87/156)(47.9, 63.3) | 44.2(69/156)(36.7, 52.1) | 0.62(0.47, 0.83) |
| Negative | 31 | 142 | 173 | - | 82.1(142/173)(75.7, 87.1) | 0.11(0.07, 0.16) |
| Total | 672 | 332 | 1004 |
(75.5, 88.5)
{28}------------------------------------------------
The results for subjects without a history of HF are presented in the following table.
{29}------------------------------------------------
| Subjects Without History of HF | |||||||
|---|---|---|---|---|---|---|---|
| NT-proBNP Result | Adjudicated Diagnosis | Total | Posttest Probability of HF % (n/N) (95% CI)a | Posttest Probability of Non-HF % (n/N) (95% CI)a | Likelihood Ratio (HF) (95% CI)b | ||
| Age Group: 18 to < 50 YearsPretest Probability of HF (Prevalence of HF in Study): 15.28% (46/301) | |||||||
| Positive | 37 | 31 | 68 | 54.4(37/68)(42.7, 65.7) | - | 6.62(4.62, 9.48) | |
| Grayzone | 2 | 10 | 12 | 16.7(2/12)(4.7, 44.8) | 83.3(10/12)(55.2, 95.3) | 1.11(0.25, 4.90) | |
| Negative | 7 | 214 | 221 | - 96.8(214/221)(93.6, 98.5) 0.18(0.09, 0.36) | |||
| Total | 46 | 255 | 301 | ||||
| Age Group: 50 to 75 YearsPretest Probability of HF (Prevalence of HF in Study): 18.10% (126/696) | |||||||
| Positive | 93 | 66 | 159 | 58.5(93/159)(50.7, 65.9) | - | 6.37(4.97, 8.18) | |
| Grayzone | 22 | 102 | 124 | 17.7(22/124)(12.0, 25.4) | 82.3(102/124)(74.6, 88.0) | 0.98(0.64, 1.48) | |
| Negative | 11 | 402 | 413 | - | 97.3(402/413)(95.3, 98.5) | 0.12(0.07, 0.22) | |
| Total | 126 | 570 | 696 | ||||
| Age Group: > 75 YearsPretest Probability of HF (Prevalence of HF in Study): 28.57% (36/126) | |||||||
| Positive | 24 | 16 | 40 | 60.0(24/40) | - | 3.75(2.27, 6.19) | |
| Subjects Without History of HF | |||||||
| NT-proBNP Result | Adjudicated Diagnosis | Posttest Probability of HF % (n/N) (95% CI)a | Posttest Probability of Non-HF % (n/N) (95% CI)a | Likelihood Ratio (HF) (95% CI)b | |||
| HF | Non-HF | Total | |||||
| Grayzone | 10 | 38 | 48 | 20.8 (10/48) (11.7, 34.3) | 79.2 (38/48) (65.7, 88.3) | 0.66 (0.37, 1.17) | |
| Negative | 2 | 36 | 38 | - | 94.7 (36/38) (82.7, 98.5) | 0.14 (0.04, 0.55) | |
| Total | 36 | 90 | 126 | ||||
| All Subjects Without History of HFc | |||||||
| Pretest Probability of HF (Prevalence of HF in Study): 18.52% (208/1123) | |||||||
| Positive | 154 | 113 | 267 | 57.7 (154/267) (51.7, 63.5) | - | 6.00 (4.96, 7.25) | |
| Grayzone | 34 | 150 | 184 | 18.5 (34/184) (13.5, 24.7) | 81.5 (150/184) (75.3, 86.5) | 1.00 (0.71, 1.40) | |
| Negative | 20 | 652 | 672 | 97.0 (652/672) (95.4, 98.1) | 0.13 (0.09, 0.21) | ||
| Total | 208 | 915 | 1123 |
(44.6, 73.7)
{30}------------------------------------------------
Patients with a history of HF had a higher rate of false positives compared to patients without a history of HF. Of the 332 total patients with a history of HF and adjudicated as non-HF, 121 (36.4%) had NT-proBNP concentrations greater than or equal to agedependent cutoffs. Of the 915 total patients with no history of HF and adjudicated as non-HF, 113 (12.3%) had NT-proBNP concentrations greater than or equal to agedependent cutoffs. This difference is likely due to long-standing chronic elevation of NT-proBNP in patients with a previous diagnosis of HF. Results should always be
{31}------------------------------------------------
assessed in conjunction with patient's medical history, clinical examination, and other findings.
The results for subjects with an eGFR less than 60 mL/min/1.73 m² are presented in the following table. This group was comprised of 548 patients with an eGFR between 30 and less than 60 mL/min/1.73 m² and 80 patients with an eGFR less than 30 mL/min/1.73 m².
| Subjects With eGFR < 60 mL/min/1.73 m² | ||||||
|---|---|---|---|---|---|---|
| NT-proBNPResult | AdjudicatedDiagnosis | PosttestProbability ofHF % (n/N)(95% CI)a | PosttestProbability ofNon-HF %(n/N)(95% CI)a | LikelihoodRatio (HF)(95% CI)b | ||
| HF | Non-HF | Total | ||||
| Age Group: 18 to < 50 Years | ||||||
| Pretest Probability of HF (Prevalence of HF in Study): 72.22% (39/54) | ||||||
| Positive | 37 | 5 | 42 | 88.1(37/42)(75.0, 94.8) | - | 2.85(1.39, 5.84) |
| Grayzone | 1 | 0 | 1 | 100.0(1/1)(20.7, 100.0) | 0.0(0/1)(0.0, 79.3) | 1.18(0.05, 27.37) |
| Negative | 1 | 10 | 11 | - | 90.9(10/11)(62.3, 98.4) | 0.04(0.01, 0.28) |
| Total | 39 | 15 | 54 | |||
| Age Group: 50 to 75 Years | ||||||
| Pretest Probability of HF (Prevalence of HF in Study): 57.11% (237/415) | ||||||
| Positive | 201 | 58 | 259 | 77.6(201/259)(72.1, 82.3) | - | 2.60(2.09, 3.24) |
| Grayzone | 27 | 50 | 77 | 35.1(27/77)(25.3, 46.2) | 64.9(50/77)(53.8, 74.7) | 0.41(0.26, 0.62) |
| Subjects With eGFR < 60 mL/min/1.73 m² | ||||||
| NT-proBNPResult | AdjudicatedDiagnosis | Total | PosttestProbability ofHF % (n/N)(95% CI)a | PosttestProbability ofNon-HF %(n/N)(95% CI)a | LikelihoodRatio (HF)(95% CI)b | |
| HF | Non-HF | |||||
| Negative | 9 | 70 | 79 | - | 88.6(70/79)(79.7, 93.9) | 0.10(0.05, 0.19) |
| Total | 237 | 178 | 415 | |||
| Age Group: > 75 YearsPretest Probability of HF (Prevalence of HF in Study): 59.12% (94/159) | ||||||
| Positive | 78 | 22 | 100 | 78.0(78/100)(68.9, 85.0) | - | 2.45(1.72, 3.49) |
| Grayzone | 16 | 22 | 38 | 42.1(16/38)(27.9, 57.8) | 57.9(22/38)(42.2, 72.1) | 0.50(0.29, 0.88) |
| Negative | 0 | 21 | 21 | - | 100.0(21/21)(84.5, 100.0) | 0.02(0.00, 0.26) |
| Total | 94 | 65 | 159 | |||
| All Subjects With eGFR < 60 mL/min/1.73 m² cPretest Probability of HF (Prevalence of HF in Study): 58.92% (370/628) | ||||||
| Positive | 316 | 85 | 401 | 78.8(316/401)(74.5, 82.5) | - | 2.59(2.17, 3.10) |
| Grayzone | 44 | 72 | 116 | 37.9(44/116)(29.6, 47.0) | 62.1(72/116)(53.0, 70.4) | 0.43(0.30, 0.60) |
| Negative | 10 | 101 | 111 | - | 91.0(101/111)(84.2, 95.0) | 0.07(0.04, 0.13) |
| Total | 370 | 258 | 628 | |||
| Subjects With eGFR ≥ 60 mL/min/1.73 m² | ||||||
| NT-proBNP Result | Adjudicated Diagnosis | Posttest Probability of HF % (n/N) (95% CI)a | Posttest Probability of Non-HF % (n/N) (95% CI)a | Likelihood Ratio (HF) (95% CI)b | ||
| HF | Non-HF | Total | ||||
| Age Group: 18 to < 50 YearsPretest Probability of HF (Prevalence of HF in Study): 30.25% (121/400) | ||||||
| Positive | 103 | 43 | 146 | 70.5(103/146)(62.7, 77.3) | - | 5.52(4.15, 7.34) |
| Grayzone | 6 | 13 | 19 | 31.6(6/19)(15.4, 54.0) | 68.4(13/19)(46.0, 84.6) | 1.06(0.41, 2.73) |
| Negative | 12 | 223 | 235 | - | 94.9(223/235)(91.3, 97.1) | 0.12(0.07, 0.21) |
| Total | 121 | 279 | 400 | |||
| Age Group: 50 to 75 YearsPretest Probability of HF (Prevalence of HF in Study): 33.51% (312/931) | ||||||
| Positive | 232 | 90 | 322 | 72.0(232/322)(66.9, 76.7) | - | 5.11(4.18, 6.26) |
| Grayzone | 53 | 97 | 150 | 35.3(53/150)(28.1, 43.3) | 64.7(97/150)(56.7, 71.9) | 1.08(0.80, 1.47) |
| Negative | 27 | 432 | 459 | - | 94.1(432/459)(91.6, 95.9) | 0.12(0.09, 0.18) |
| Total | 312 | 619 | 931 | |||
| Subjects With eGFR ≥ 60 mL/min/1.73 m² | ||||||
| NT-proBNP Result | Adjudicated Diagnosis | Posttest Probability of HF % (n/N) (95% CI)a | Posttest Probability of Non-HF % (n/N) (95% CI)a | Likelihood Ratio (HF) (95% CI)b | ||
| HF | Non-HF | Total | ||||
| Positive | 52 | 16 | 68 | 76.5(52/68)(65.1, 85.0) | - | 3.75(2.36, 5.95) |
| Grayzone | 18 | 37 | 55 | 32.7(18/55)(21.8, 45.9) | 67.3(37/55)(54.1, 78.2) | 0.56(0.35, 0.89) |
| Negative | 2 | 30 | 32 | - | 93.8(30/32)(79.9, 98.3) | 0.08(0.02, 0.31) |
| Total | 72 | 83 | 155 | |||
| All Subjects With eGFR ≥ 60 mL/min/1.73 m² c | ||||||
| Pretest Probability of HF (Prevalence of HF in Study): 33.98% (505/1486) | ||||||
| Positive | 387 | 149 | 536 | 72.2(387/536)(68.3, 75.8) | - | 5.05(4.32, 5.89) |
| Grayzone | 77 | 147 | 224 | 34.4(77/224)(28.5, 40.8) | 65.6(147/224)(59.2, 71.5) | 1.02(0.79, 1.31) |
| Negative | 41 | 685 | 726 | - | 94.4(685/726)(92.4, 95.8) | 0.12(0.09, 0.16) |
| Total | 505 | 981 | 1486 |
{32}------------------------------------------------
{33}------------------------------------------------
The results for subjects with an eGFR greater than or equal to 60 mL/min/1.73 m² are presented in the following table.
Age Group: > 75 Years
Pretest Probability of HF (Prevalence of HF in Study): 46.45% (72/155)
{34}------------------------------------------------
Patients with an eGFR less than 60 mL/min/1.73 m² had a higher rate of false positives compared to patients with an eGFR greater than or equal to 60 mL/min/1.73 m². Of the 258 total patients with an eGFR less than 60 mL/min/1.73 m² and adjudicated as non-HF, 85 (32.9%) had NT-proBNP concentrations greater than or equal to agedependent cutoffs. Of the 981 total patients with an eGFR greater than or equal to
{35}------------------------------------------------
60 mL/min/1.73 m² and adjudicated as non-HF, 149 (15.2%) had NT-proBNP concentrations greater than or equal to age-dependent cutoffs. Eight patients adjudicated as non-HF (0.6%) had an unknown eGFR. Patients with an eGFR less than 60 mL/min/1.73 m² had a higher rate of false negatives (9.0% [10/111]) compared to patients with an eGFR greater than or equal to 60 mL/min/1.73 m² (5.6% [41/726]). All 10 of the false negatives in the eGFR less than 60 mL/min/1.73 m² group were from patients with a BMI greater than or equal to 30 kg/m2. In patients with eGFR less than 60 mL/min/1.73 m², caution should be used when interpreting NT-proBNP results. Results should always be assessed in conjunction with the patient's medical history, clinical examination, and other findings.
The results for subjects with a BMI greater than or equal to 30 kg/m² are presented in the following table.
| Subjects With BMI ≥ 30 kg/m² | |||||||
|---|---|---|---|---|---|---|---|
| NT-proBNPResult | Adjudicated Diagnosis | PosttestProbability ofHF % (n/N)(95% CI)a | PosttestProbability ofNon-HF %(n/N)(95% CI)a | LikelihoodRatio (HF)(95% CI)b | |||
| HF | Non-HF | Total | |||||
| Age Group: 18 to < 50 Years | |||||||
| Pretest Probability of HF (Prevalence of HF in Study): 40.75% (108/265) | |||||||
| Positive | 90 | 26 | 116 | 77.6(90 / 116)(69.2, 84.2) | - | 5.03(3.51, 7.22) | |
| Grayzone | 7 | 8 | 15 | 46.7(7 / 15)(24.8, 69.9) | 53.3(8 / 15)(30.1, 75.2) | 1.27(0.48, 3.40) | |
| Negative | 11 | 123 | 134 | - | 91.8(123 / 134)(85.9, 95.4) | 0.13(0.07, 0.23) | |
| Total | 108 | 157 | 265 | ||||
| Subjects With BMI ≥ 30 kg/m² | |||||||
| Adjudicated Diagnosis | PosttestProbability ofHF % (n/N)(95% CI)a | PosttestProbability ofNon-HF %(n/N)(95% CI)a | LikelihoodRatio (HF)(95% CI)b | ||||
| NT-proBNPResult | HF | Non-HF | Total | ||||
| Positive | 231 | 54 | 285 | 81.1(231 / 285)(76.1, 85.2) | - | 4.84(3.74, 6.25) | |
| Grayzone | 67 | 64 | 131 | 51.1(67 / 131)(42.7, 59.5) | 48.9(64 / 131)(40.5, 57.3) | 1.18(0.87, 1.61) | |
| Negative | 30 | 253 | 283 | - | 89.4(253 / 283)(85.3, 92.5) | 0.13(0.09, 0.19) | |
| Total | 328 | 371 | 699 | ||||
| Age Group: > 75 Years | |||||||
| Pretest Probability of HF (Prevalence of HF in Study): 59.81% (64/107) | |||||||
| Positive | 48 | 5 | 53 | 90.6(48 / 53)(79.7, 95.9) | - | 6.45(2.80, 14.88) | |
| Grayzone | 16 | 19 | 35 | 45.7(16 / 35)(30.5, 61.8) | 54.3(19 / 35)(38.2, 69.5) | 0.57(0.33, 0.97) | |
| Negative | 0 | 19 | 19 | - | 100.0(19/19)(83.2, 100.0) | 0.02(0.00, 0.28) | |
| Total | 64 | 43 | 107 | ||||
| All Subjects With BMI ≥ 30 kg/m2 c | |||||||
| Pretest Probability of HF (Prevalence of HF in Study): 46.69% (500/1071) |
Age Group: 50 to 75 Years
Pretest Probability of HF (Prevalence of HF in Study): 46.92% (328/699)
{36}------------------------------------------------
| Positive | 369 | 85 | 454 | 81.3 | 4.96 |
|---|---|---|---|---|---|
| (369/454) | (4.05, 6.07) | ||||
| (77.4, 84.6) |
{37}------------------------------------------------
| NT-proBNPResult | Subjects With BMI ≥ 30 kg/m² | ||||||||
|---|---|---|---|---|---|---|---|---|---|
| AdjudicatedDiagnosis | PosttestProbability ofHF % (n/N)(95% CI)a | PosttestProbability ofNon-HF %(n/N)(95% CI)a | LikelihoodRatio (HF)(95% CI)b | ||||||
| Grayzone | HF | 90 | Non-HF | 91 | Total | 181 | 49.7(90/181)(42.5, 56.9) | 50.3(91/181)(43.1, 57.5) | 1.13(0.87, 1.47) |
| Negative | HF | 41 | Non-HF | 395 | Total | 436 | - | 90.6(395/436)(87.5, 93.0) | 0.12(0.09, 0.16) |
| Total | HF | 500 | Non-HF | 571 | Total | 1071 |
The results for subjects with a BMI less than 30 kg/m² are presented in the following table.
| Subjects With BMI < 30 kg/m² | ||||||||
|---|---|---|---|---|---|---|---|---|
| Adjudicated Diagnosis | Posttest Probability ofHF % (n/N)(95% CI)ª | Posttest Probability ofNon-HF % (n/N)(95% CI)ª | LikelihoodRatio (HF)(95% CI)b | |||||
| NT-proBNPResult | HF | Non-HF | Total | |||||
| Age Group: 18 to < 50 Years | ||||||||
| Pretest Probability of HF (Prevalence of HF in Study): 30.41% (45/148) | ||||||||
| Positive | 44 | 16 | 60 | 73.3(44/60)(61.0, 82.9) | - | 6.29(4.00, 9.90) | ||
| Grayzone | 0 | 4 | 4 | 0.0(0/4)(0.0, 49.0) | 100.0(4/4)(51.0, 100.0) | 0.25(0.01, 4.60) | ||
| Negative | 1 | 83 | 84 | - | 98.8(83/84)(93.6, 99.8) | 0.03(0.00, 0.19) | ||
| Total | 45 | 103 | 148 | |||||
| NT-proBNPResult | AdjudicatedDiagnosis | |||||||
| HF | Non-HF | Total | PosttestProbability ofHF % (n/N)(95% CI)a | PosttestProbability ofNon-HF %(n/N)(95% CI)a | LikelihoodRatio (HF)(95% CI)b | |||
| Age Group: 50 to 75 Years | ||||||||
| Pretest Probability of HF (Prevalence of HF in Study): 36.46% (198/543) | ||||||||
| Positive | 185 | 80 | 265 | 69.8(185/265)(64.0, 75.0) | - | 4.03(3.31, 4.90) | ||
| Grayzone | 9 | 69 | 78 | 11.5(9/78)(6.2, 20.5) | 88.5(69/78)(79.5, 93.8) | 0.23(0.12, 0.45) | ||
| Negative | 4 | 196 | 200 | - | 98.0(196/200)(95.0, 99.2) | 0.04(0.01, 0.09) | ||
| Total | 198 | 345 | 543 | |||||
| Age Group: > 75 Years | ||||||||
| Pretest Probability of HF (Prevalence of HF in Study): 51.08% (95/186) | ||||||||
| Positive | 76 | 31 | 107 | 71.0(76/107)(61.8, 78.8) | - | 2.35(1.73, 3.18) | ||
| Grayzone | 17 | 32 | 49 | 34.7(17/49)(22.9, 48.7) | 65.3(32/49)(51.3, 77.1) | 0.51(0.30, 0.85) | ||
| Negative | 2 | 28 | 30 | - | 93.3(28/30)(78.7, 98.2) | 0.07(0.02, 0.28) | ||
| Total | 95 | 91 | 186 | |||||
| All Subjects With BMI < 30 kg/m2 c | ||||||||
| Pretest Probability of HF (Prevalence of HF in Study): 38.54% (338/877) | ||||||||
| Positive | 305 | 127 | 432 | 70.6(305/432) | - | 3.83 | ||
| NT-proBNPResult | Subjects With BMI < 30 kg/m2 | |||||||
| AdjudicatedDiagnosis | PosttestProbability ofHF % (n/N)(95% CI)a | PosttestProbability ofNon-HF %(n/N)(95% CI)a | LikelihoodRatio (HF)(95% CI)b | |||||
| HF | Non-HF | Total | ||||||
| Grayzone | 26 | 105 | 131 | 19.8(26/131)(13.9, 27.5) | 80.2(105/131)(72.5, 86.1) | 0.39(0.26, 0.59) | ||
| Negative | 7 | 307 | 314 | - | 97.8(307/314)(95.5, 98.9) | 0.04(0.02, 0.08) | ||
| Total | 338 | 539 | 877 | |||||
| NT-proBNPResult | Adjudicated Diagnosis | Subjects With Comorbidities | ||||||
| HF | Non-HF | Total | PosttestProbability ofHF % (n/N)(95% CI)a | PosttestProbability ofNon-HF %(n/N)(95% CI)a | LikelihoodRatio (HF)(95% CI)b | |||
| Age Group: 18 to < 50 Years | Pretest Probability of HF (Prevalence of HF in Study): 43.67% (131/300) | |||||||
| Positive | 115 | 34 | 149 | 77.2(115/149)(69.8, 83.2) | - | 4.36(3.21, 5.93) | ||
| Grayzone | 7 | 10 | 17 | 41.2(7/17)(21.6, 64.0) | 58.8(10/17)(36.0, 78.4) | 0.90(0.35, 2.31) | ||
| Negative | 9 | 125 | 134 | - | 93.3(125/134)(87.7, 96.4) | 0.09(0.05, 0.18) | ||
| Total | 131 | 169 | 300 | |||||
| Age Group: 50 to 75 Years | Pretest Probability of HF (Prevalence of HF in Study): 43.23% (527/1219) | |||||||
| Positive | 415 | 136 | 551 | 75.3(415/551)(71.6, 78.7) | - | 4.01(3.42, 4.69) | ||
| Grayzone | 78 | 133 | 211 | 37.0(78/211)(30.7, 43.7) | 63.0(133/211)(56.3, 69.3) | 0.77(0.60, 0.99) | ||
| Negative | 34 | 423 | 457 | - | 92.6(423/457)(89.8, 94.6) | 0.11(0.08, 0.15) | ||
| Total | 527 | 692 | 1219 | |||||
| Age Group: > 75 Years |
{38}------------------------------------------------
(66.1, 74.7)
{39}------------------------------------------------
Patients with a BMI greater than or equal to 30 kg/m2 had a higher rate of false negatives compared to patients with a BMI less than 30 kg/m². Of the total observed false negatives (51/880), 41 (80.4%) were from patients with a BMI greater than or equal to 30 kg/m², 7 (13.7%) were from patients with a BMI less than 30 kg/m², and 3 (5.9%) were from patients with an unknown BMI. In patients with a BMI less than 30 kg/m2, the age greater than 75 years group had a higher rate of false negatives (6.7% [2/30]) than the other age groups. Results should always be assessed in conjunction with the patient's medical history, clinical examination, and other findings. In patients with obesity, natriuretic peptides should be interpreted with caution.
The results for subjects with comorbidities are presented in the following table. Comorbidities include at least one of the following: diabetes, renal dysfunction (eGFR less than 60 mL/min/1.73 m²), hypertension, and/or chronic obstructive pulmonary disease (COPD). Patients with these comorbidities had a higher rate of false positives compared to patients without these comorbidities.
{40}------------------------------------------------
| Positive | 128 | 36 | 164 | 78.0 | - | 2.88 |
|---|---|---|---|---|---|---|
| (128/164) | (2.15, 3.85) | |||||
| (71.1, 83.7) |
{41}------------------------------------------------
| Subjects With Comorbidities | ||||||
|---|---|---|---|---|---|---|
| NT-proBNPResult | AdjudicatedDiagnosis | PosttestProbability ofHF % (n/N)(95% CI)a | PosttestProbability ofNon-HF %(n/N)(95% CI)a | LikelihoodRatio (HF)(95% CI)b | ||
| HF | Non-HF | Total | ||||
| Grayzone | 33 | 48 | 81 | 40.7(33/81)(30.7, 51.6) | 59.3(48/81)(48.4, 69.3) | 0.56(0.38, 0.81) |
| Negative | 2 | 48 | 50 | - | 96.0(48/50)(86.5, 98.9) | 0.03(0.01, 0.14) |
| Total | 163 | 132 | 295 | |||
| All Subjects With Comorbiditiesc | ||||||
| Pretest Probability of HF (Prevalence of HF in Study): 45.26% (821/1814) | ||||||
| Positive | 658 | 206 | 864 | 76.2(658/864)(73.2, 78.9) | - | 3.86(3.41, 4.38) |
| Grayzone | 118 | 191 | 309 | 38.2(118/309)(32.9, 43.7) | 61.8(191/309)(56.3, 67.1) | 0.75(0.61, 0.92) |
| Negative | 45 | 596 | 641 | - | 93.0(596/641)(90.7, 94.7) | 0.09(0.07, 0.12) |
| Total | 821 | 993 | 1814 | |||
| Subjects Without Comorbidities | ||||||
| NT-proBNP Result | Adjudicated DiagnosisHF | Non-HF | Total | Posttest Probability of HF % (n/N)(95% CI)a | Posttest Probability of Non-HF % (n/N)(95% CI)a | Likelihood Ratio (HF)(95% CI)b |
| Age Group: 18 to < 50 Years | ||||||
| Pretest Probability of HF (Prevalence of HF in Study): 18.13% (29/160) | ||||||
| Positive | 25 | 14 | 39 | 64.1(25/39)(48.4, 77.3) | - | 8.07(4.81, 13.51) |
| Grayzone | 0 | 3 | 3 | 0.0(0/3)(0.0, 56.1) | 100.0(3/3)(43.9, 100.0) | 0.64(0.03, 12.00) |
| Negative | 4 | 114 | 118 | - | 96.6(114/118)(91.6, 98.7) | 0.16(0.06, 0.39) |
| Total | 29 | 131 | 160 | |||
| Age Group: 50 to 75 Years | ||||||
| Pretest Probability of HF (Prevalence of HF in Study): 19.55% (26/133) | ||||||
| Positive | 22 | 12 | 34 | 64.7(22/34)(47.9, 78.5) | - | 7.54(4.32, 13.18) |
| Grayzone | 2 | 14 | 16 | 12.5(2/16)(3.5, 36.0) | 87.5(14/16)(64.0, 96.5) | 0.59(0.14, 2.43) |
| Negative | 2 | 81 | 83 | - | 97.6(81/83)(91.6, 99.3) | 0.10(0.03, 0.39) |
| Total | 26 | 107 | 133 | |||
| Age Group: > 75 Years | ||||||
| Pretest Probability of HF (Prevalence of HF in Study): 20.00% (4/20) | ||||||
| Positive | 3 | 2 | 5 | 60.0(3/5)(23.1, 88.2) | - | 6.00(1.46, 24.69) |
The results for subjects without comorbidities are presented in the following table.
{42}------------------------------------------------
{43}------------------------------------------------
| Subjects Without Comorbidities | |||||||
|---|---|---|---|---|---|---|---|
| NT-proBNPResult | AdjudicatedDiagnosis | PosttestProbability ofHF % (n/N)(95% CI)a | PosttestProbability ofNon-HF %(n/N)(95% CI)a | Likelihood Ratio(HF)(95% CI)b | |||
| HF | Non-HF | Total | |||||
| Grayzone | 1 | 11 | 12 | 8.3(1/12)(1.5, 35.4) | 91.7(11/12)(64.6, 98.5) | 0.36(0.06, 2.05) | |
| Negative | 0 | 3 | 3 | - | 100.0(3/3)(43.9, 100.0) | 0.52(0.03, 8.39) | |
| Total | 4 | 16 | 20 | ||||
| All Subjects Without Comorbiditiesc | Pretest Probability of HF (Prevalence of HF in Study): 18.85% (59/313) | ||||||
| Positive | 50 | 28 | 78 | 64.1(50/78)(53.0, 73.9) | - | 7.69(5.33, 11.08) | |
| Grayzone | 3 | 28 | 31 | 9.7(3/31)(3.3, 24.9) | 90.3(28/31)(75.1, 96.7) | 0.46(0.15, 1.47) | |
| Negative | 6 | 198 | 204 | - | 97.1(198/204) | 0.13(0.06, 0.28) |
a The Wilson score method was used to calculate 95% CI for posttest probability.
313
b The log method was used to calculate 95% CI for likelihood ratio.
254
રેત્રે રહે
Total
c The analysis across age groups used the pooled result based on age-dependent positive cutoff and age-independent rule-out cutoff.
The formulas below were used to calculate the pretest probabilities, posttest probabilities, and likelihood ratios in the tables above.
| Adjudicated Diagnosis | ||
|---|---|---|
| Alere NT-proBNP for Alinity i Result | HF | Non-HF |
| Positive (≥ age-dependent cutoff) | A | B |
| Grayzone (≥ 300 pg/mL to < age-dependent cutoff) | C | D |
(93.7, 98.6)
{44}------------------------------------------------
| Adjudicated Diagnosis | ||
|---|---|---|
| Alere NT-proBNP for Alinity i Result | HF | Non-HF |
| Negative (<300 pg/mL [age-independent rule-out cutoff]) | E | F |
Posttest probability of HF:
- Posttest probability of HF for positive test results = A((A+B) .
- . Posttest probability of HF for grayzone test results = C/(C+D)
Posttest probability of non-HF:
- . Posttest probability of non-HF for grayzone test results = D/(C+D)
- Posttest probability of non-HF for negative test results = F/(E+F)
Likelihood ratios of HF given Alere NT-proBNP for Alinity i test result category:
- . Positive: (A/(A+C+E))/(B/(B+D+F))
- Grayzone: (C/(A+C+E)/(D/(B+D+F))
- . Negative: (E/(A+C+E))/(F/(B+D+F))
New York Heart Association (NYHA) Functional Classification
A total of 880 subjects had an NYHA functional classification. Descriptive statistics for the Alere NT-proBNP for Alinity i test results (pg/mL) by NYHA classification for subjects adjudicated to have HF are presented in the table below.
| NYHA Functional Classa | |||
|---|---|---|---|
| Descriptive Statistics | II | III | IV |
| All Subjects | |||
| N | 12 | 369 | 499 |
| Mean | 5535.8 | 5187.5 | 6485.6 |
| SD | 6834.18 | 7056.92 | 7829.43 |
| Minimum | 89.5 | 27.1 | 19.8 |
| 5th Percentile | 89.5 | 244.0 | 303.0 |
| 25th Percentile | 1319.5 | 989.4 | 1492.8 |
| Median | 2846.4 | 2817.5 | 3928.2 |
| 75th Percentile | 7399.7 | 6230.9 | 8349.3 |
| 95th Percentile | 23734.0 | 20653.1 | 22086.6 |
| Maximum | 23734.0 | 60716.9 | 59178.1 |
| Female Subjects |
{45}------------------------------------------------
| NYHA Functional Classa | |||
|---|---|---|---|
| Descriptive Statistics | II | III | IV |
| N | 4 | 163 | 209 |
| Mean | 5667.6 | 4216.4 | 6500.1 |
| SD | 6135.91 | 6073.57 | 8222.56 |
| Minimum | 264.5 | 27.1 | 22.8 |
| 5th Percentile | 264.5 | 149.2 | 159.4 |
| 25th Percentile | 492.6 | 749.2 | 1266.5 |
| Median | 4542.9 | 2172.1 | 3713.5 |
| 75th Percentile | 11967.5 | 5022.1 | 8159.8 |
| 95th Percentile | 13320.3 | 19295.7 | 24566.4 |
| Maximum | 13320.3 | 38880.9 | 47385.1 |
| Male Subjects | |||
| N | 8 | 206 | 290 |
| Mean | 5469.9 | 5955.9 | 6475.2 |
| SD | 7566.03 | 7674.86 | 7547.84 |
| Minimum | 89.5 | 166.7 | 19.8 |
| 5th Percentile | 89.5 | 365.8 | 375.5 |
| 25th Percentile | 1954.8 | 1221.8 | 1599.4 |
| Median | 2846.4 | 3702.6 | 4094.2 |
| 75th Percentile | 5415.8 | 7202.5 | 8515.5 |
| 95th Percentile | 23734.0 | 21410.7 | 21598.1 |
| Maximum | 23734.0 | 60716.9 | 59178.1 |
ª No NYHA Class I subjects were included in the study.
X. Conclusion
The information presented in this 510(k) premarket notification demonstrate that the subject device, Alere NT-proBNP for Alinity i (List Number 04S79), is substantially equivalent to the predicate device, Roche Elecsys proBNP II (K092649).
§ 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.”