ST AIA-PACK BNP
Device Facts
| Record ID | K192380 |
|---|---|
| Device Name | ST AIA-PACK BNP |
| Applicant | Fujirebio Diagnostics,Inc. |
| Product Code | NBC · Clinical Chemistry |
| Decision Date | Aug 24, 2020 |
| Decision | SESE |
| Submission Type | Traditional |
| Regulation | 21 CFR 862.1117 |
| Device Class | Class 2 |
Intended Use
The Tosoh ST AIA-PACK BNP assay is designed for IN VITRO DIAGNOSTIC USE ONLY for the quantitative measurement of BNP in human K2EDTA plasma on Tosoh AIA System analyzers. BNP is used as an aid in the diagnosis of heart failure (HF) in patients presenting to the emergency department (ED) with clinical suspicion of new onset HF, acutely decompensated or exacerbated HF.
Device Story
The ST AIA-PACK BNP is a two-site immunoenzymometric assay performed in test cups on Tosoh AIA System analyzers. It uses magnetic beads coated with anti-BNP mouse monoclonal antibody and enzyme-labeled monoclonal antibody to bind BNP in human K2EDTA plasma. After washing, a fluorogenic substrate (4MUP) is added; the resulting fluorescence is directly proportional to the BNP concentration. The device is used in clinical and hospital laboratories by trained personnel. Results are used by clinicians as an aid in diagnosing heart failure in emergency department patients. The assay provides quantitative BNP measurements, which help clinicians assess heart failure status and severity, potentially improving diagnostic accuracy for patients with suspected cardiac decompensation.
Clinical Evidence
Prospective study of 724 evaluable patients presenting to the ED with suspected heart failure. Performance evaluated against an independent central adjudication panel diagnosis. At a 100 pg/mL cutoff, sensitivity was 88.4% (95% CI: 84.5-91.5%) and specificity was 70.6% (95% CI: 66.0-74.9%). AUC was 0.881. Subgroup analyses by age and gender were performed.
Technological Characteristics
Two-site immunoenzymometric assay. Components: magnetic lyophilized beads coated with anti-BNP mouse monoclonal antibody; anti-BNP mouse monoclonal antibody conjugated to alkaline phosphatase. Energy source: fluorogenic substrate (4-methylumbelliferyl phosphate). Form factor: test cups for use on Tosoh AIA-2000 analyzer. Assay range: 4.0–2000 pg/mL. One-step sandwich assay principle.
Indications for Use
Indicated for patients presenting to the emergency department with clinical suspicion of new onset, acutely decompensated, or exacerbated heart failure.
Regulatory Classification
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.
Special Controls
*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.”
Predicate Devices
- SIEMENS ADVIA Centaur® BNP Assay (K031038)
Related Devices
- K211199 — ST AIA-PACK BNP Assay · Tosoh Bioscience, Inc. · Nov 8, 2021
- K033606 — ABBOTT AXSYM B-TYPE NATRIURETIC PEPTIDE (BNP) MICROPARTICLE ENZYME IMMUNOASSAY (MEIA) TEST · Axis-Shield Diagnostics, Ltd. · Jan 30, 2004
Submission Summary (Full Text)
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FDA
U.S. FOOD & DRUG
ADMINISTRATION
# 510(k) SUBSTANTIAL EQUIVALENCE DETERMINATION DECISION SUMMARY
ASSAY ONLY
## I Background Information:
A 510(k) Number
K192380
B Applicant
Fujirebio Diagnostics, Inc.
C Proprietary and Established Names
ST AIA-PACK BNP
D Regulatory Information
| Product Code(s) | Classification | Regulation Section | Panel |
| --- | --- | --- | --- |
| NBC | Class II | 21 CFR 862.1117 - B-Type Natriuretic Peptide Test System | CH - Clinical Chemistry |
## II Submission/Device Overview:
A Purpose for Submission:
New Device
B Measurand:
B-type Natriuretic Peptide (BNP)
C Type of Test:
Quantitative Immunoenzymometric Assay
Food and Drug Administration
10903 New Hampshire Avenue
Silver Spring, MD 20993-0002
www.fda.gov
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K192380 - Page 2 of 17
## III Intended Use/Indications for Use:
### A Intended Use(s):
See Indications for Use below.
### B Indication(s) for Use:
The Tosoh ST AIA-PACK BNP assay is designed for IN VITRO DIAGNOSTIC USE ONLY for the quantitative measurement of BNP in human K2EDTA plasma on Tosoh AIA System analyzers. BNP is used as an aid in the diagnosis of heart failure (HF) in patients presenting to the emergency department (ED) with clinical suspicion of new onset HF, acutely decompensated or exacerbated HF.
### C Special Conditions for Use Statement(s):
Rx - For Prescription Use Only
The ST AIA-PACK BNP should only be used for patients presenting to the emergency department (ED)
### D Special Instrument Requirements:
TOSOH AIA Analyzer 2000
## IV Device/System Characteristics:
### A Device Description:
The ST AIA-PACK BNP set consists of 5 trays x 20 test cups. Each kit contains plastic test cups containing twelve magnetic lyophilized beads coated with anti-BNP mouse monoclonal antibody and 100 µL of anti-BNP mouse monoclonal antibody conjugated to alkaline phosphatase with sodium azide as a preservative.
### B Principle of Operation:
The ST AIA-PACK BNP is a two-site immunoenzymometric assay which is performed entirely in the ST AIA-PACK BNP test cups. BNP present in the test sample is bound with monoclonal antibody immobilized on magnetic beads and enzyme-labeled monoclonal antibody. The magnetic beads are washed to remove unbound enzyme-labeled monoclonal antibody and are then incubated with a fluorogenic substrate, 4-methylumbelliferyl phosphate (4MUP). The amount of enzyme-labeled monoclonal antibody that binds to the beads is directly proportional to the BNP concentration in the test sample. A standard curve is constructed, and unknown sample concentrations are calculated using the curve.
### V Substantial Equivalence Information:
#### A Predicate Device Name(s):
Advia Centaur B-type Natriuretic Peptide (BNP) Assay
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B Predicate 510(k) Number(s):
K031038
C Comparison with Predicate(s):
| Device & Predicate Device(s): | K192380 | K031038 |
| --- | --- | --- |
| Device Trade Name | ST AIA-PACK BNP | SIEMENS ADVIA Centaur BNP |
| General Device Characteristic Similarities | | |
| Intended Use/Indications for Use | For in vitro diagnostic use only for the quantitative measurement of BNP in human (EDTA) plasma | Same |
| Cut-off | 100 pg/mL | Same |
| Type of Specimen | Human EDTA plasma | Same |
| General Device Characteristic Differences | | |
| Instrument System | TOSOH AIA Analyzer 2000 | ADVIA Centaur and ADVIA Centaur XP Systems |
| Principle of Operation | Immunoenzymometric Assay | Chemiluminescence immunoassay |
| Assay Range | 4.0 – 2000pg/mL | <2.0 – 5000pg/mL |
| Test Principle | One-step sandwich assay | Delayed one-step sandwich assay |
| Intended Use Setting | For use on patients presenting to the Emergency Department (ED) | Not specified |
VI Standards/Guidance Documents Referenced:
CLSI EP28-A3c: Defining, Establishing and Verifying Reference Intervals in the Clinical Laboratory; Approved Guideline
CLSI EP06-A: Evaluation of Linearity of Quantitative Measurement Procedures, A Statistical Approach: Approved Guideline
CLSI EP07: Interference Testing in Clinical Chemistry; Approved Guideline – Third Edition
CLSI EP37: Supplemental Tables for Interference Testing in Clinical Chemistry; Approved Guideline – First Edition
CLSI EP17-A: Protocols for Determination of Limits of Detection and Limits of Quantitation; Approved Guideline
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CLSI EP05-A3: Evaluation of Precision of Quantitative Measurement Procedures; Approved Guideline – Third Edition
Guidance on Informed Consent for In Vitro Diagnostic Device Studies Using Leftover Human Specimens that are Not Individually Identifiable; Guidance for Sponsors, Institutional Review Boards, Clinical Investigators, and Food and Drug Administration Staff (April 25, 2006) Class II Special Control Guidance Document for B-Type Natriuretic Peptide Premarket Notifications; Final Guidance for Industry and FDA Reviewers. Document issued on: November 30, 2000
## VII Performance Characteristics (if/when applicable):
## A Analytical Performance:
### 1. Precision/Reproducibility:
The study was conducted at 1 site using three lots of ST AIA-PACK BNP Reagents and Calibrator Sets on three AIA-2000 analyzers to assess the precision of the ST AIA-PACK BNP assay. Six EDTA plasma samples were tested. A high concentration sample was prepared by spiking an EDTA plasma base pool with BNP. This sample was then diluted using a base EDTA plasma pool to create 3 pools with BNP concentrations of approximately 500, 1000, and 2000 pg/mL. The lower concentration samples were patient samples with approximate BNP concentrations of 10, 50 and 100 pg/mL. The six samples were tested in replicates of two, at two separate times per day, for twenty days. The two runs per day were separated by a minimum of two hours.
Within run, between run, between day and total precision was calculated for each lot and all lots combined. Results for a representative lot and the combined lots are shown below.
ST AIA-PACK BNP Precision one lot (n=80)
| Sample | | EDTA Plasma-1 | EDTA Plasma-2 | EDTA Plasma-3 | EDTA Plasma-4 | EDTA Plasma-5 | EDTA Plasma-6 |
| --- | --- | --- | --- | --- | --- | --- | --- |
| Mean Conc. (pg/mL) | | 10.896 | 49.919 | 104.864 | 495.956 | 988.208 | 1951.419 |
| Within Run | SD | 0.609 | 1.450 | 1.997 | 11.611 | 25.244 | 33.062 |
| | %CV | 5.6 | 2.9 | 1.9 | 2.3 | 2.6 | 1.7 |
| Between Run | SD | 0.000 | 0.307 | 1.777 | 7.232 | 15.589 | 21.281 |
| | %CV | 0.0 | 0.6 | 1.7 | 1.5 | 1.6 | 1.1 |
| Between Day | SD | 0.361 | 0.722 | 0.541 | 0.000 | 5.415 | 13.418 |
| | %CV | 3.3 | 1.4 | 0.5 | 0.0 | 0.5 | 0.7 |
| Total | SD | 0.708 | 1.648 | 2.728 | 13.679 | 30.159 | 41.546 |
| | %CV | 6.5 | 3.3 | 2.6 | 2.8 | 3.1 | 2.1 |
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ST AIA-PACK BNP Precision Combined Lots (n=240)
| Sample | Overall Mean (pg/mL) | Source of Variation | SD | %CV |
| --- | --- | --- | --- | --- |
| EDTA Plasma-1 | 10.588 | Within Run | 0.547 | 5.2 |
| | | Between Run | 0.000 | 0.0 |
| | | Between Day | 0.217 | 2.0 |
| | | Between Lot | 0.982 | 9.3 |
| Total | | | 1.145 | 10.8 |
| EDTA Plasma-2 | 49.873 | Within Run | 1.592 | 3.2 |
| | | Between Run | 0.000 | 0.0 |
| | | Between Day | 0.219 | 0.4 |
| | | Between Lot | 0.807 | 1.6 |
| Total | | | 1.798 | 3.6 |
| EDTA Plasma-3 | 106.718 | Within Run | 2.637 | 2.5 |
| | | Between Run | 0.739 | 0.7 |
| | | Between Day | 0.000 | 0.0 |
| | | Between Lot | 1.700 | 1.6 |
| Total | | | 3.223 | 3.0 |
| EDTA Plasma-4 | 519.429 | Within Run | 10.127 | 1.9 |
| | | Between Run | 5.613 | 1.1 |
| | | Between Day | 0.000 | 0.0 |
| | | Between Lot | 23.664 | 4.6 |
| Total | | | 26.346 | 5.1 |
| EDTA Plasma-5 | 1050.712 | Within Run | 21.451 | 2.0 |
| | | Between Run | 13.823 | 1.3 |
| | | Between Day | 3.329 | 0.3 |
| | | Between Lot | 58.632 | 5.6 |
| Total | | | 64.031 | 6.1 |
The EDTA Plasma-6 sample was excluded from this analysis because the results with all lots combined were above the measuring range of the assay.
2. Linearity:
The claimed assay range is 4.0 to 2000 pg/mL. A study was conducted to determine the linearity of the Tosoh ST AIA-PACK BNP assay using low and high EDTA plasma samples. The low sample was prepared by making a 1:99 dilution of a higher EDTA plasma sample. The ST AIA-PACK BNP sample diluting solution was used to prepare the dilutions. The high sample was spiked EDTA plasma. The intermediate concentrations were made by dilutions that would be related to each other and the high and low samples by constant intervals. A total of fourteen (14) samples each for EDTA plasma ranging from 3.1 – 2271.54 pg/mL were assayed on one (1) Tosoh AIA-2000 analyzer in replicates of four (4).
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The sponsor performed the analyses recommended in the CLSI guideline EP06-A and the results support that the assay is linear from 4.0 to 2000 pg/mL.
## 3. Analytical Specificity/Interference:
### Endogenous Interfering Substances:
Studies were conducted to evaluate the potential interference from the endogenous substance summarized below with the Tosoh ST AIA-PACK BNP assay. EDTA plasma samples with known concentrations of BNP, at approximately 35 pg/mL, 90 pg/mL and 1,000 pg/mL were spiked with varying concentrations of the potential interferents. The criterion for no interference was defined as a mean percent recovery for each interferent within 100±10% of the control. When the substances listed below were tested, no interference was observed up to the concentration listed in the table.
| Substance | Highest Concentration Tested With No Interference |
| --- | --- |
| Hemoglobin | 130 mg/dL |
| Unconjugated (Free) Bilirubin | 15 mg/dL |
| Conjugated bilirubin | 19 mg/dL |
| Lipemia (represented by triglycerides) | 1600 mg/dL |
| Protein (represented by human albumin) | 14 g/dL |
| Rheumatoid factor | 500 IU/mL |
| Ascorbic Acid | 20 mg/dL |
| Human IgG | 5.3 g/dL |
| Creatinine | 15 mg/dL |
| Cholesterol | 400 mg/dL |
| Alkaline Phosphatase | 2000 U/L |
| HAMA IgG | 500 ng/mL |
In addition, the labeling includes the following limitations:
- Hemolyzed samples should be avoided for the measurement due to the possibility to give erroneously lower concentrations.
- Lipemia has an insignificant effect on the assay except in the case of gross lipemia where spatial interference may occur.
- Tosoh Automated Immunoassays utilizing alkaline phosphatase-based technologies should not be used with samples from patients under Asfotase Alfa treatment.
- Patient samples may also contain human anti-mouse antibody (HAMA) due to either natural antibody production or antibodies produced in response to therapy regimens. HAMA may cause either false-positive or false-negative results in assays using
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mouse monoclonal antibodies. Other heterophile antibodies are also known to interfere in assays of this type. ST AIA-PACK BNP has been designed to minimize the effects of heterophile antibodies, but interference from high titers cannot be ruled out.
## Cross reactants:
Studies were conducted to evaluate the potential interference from various compounds with the Tosoh ST AI-PACK BNP assay. EDTA plasma samples of known BNP concentrations targeting 100 pg/mL and 300-500pg/mL were spiked with each cross reactant at a concentration of 50, 600 or 1000 pg/mL. Results are summarized below.
| Cross Reactant | Concentration (pg/mL) | % Cross Reactivity |
| --- | --- | --- |
| Adrenomedullin 52 Human | 1000 | 0.17 |
| Aldosterone | 1000 | 0.11 |
| Angiotensin I | 600 | 0.02 |
| Angiotensin II | 600 | 0.13 |
| Angiotensin III | 1000 | 0.37 |
| ANP | 1000 | 0.03 |
| Arg^{8}-Vasopressin | 1000 | 0.02 |
| CNP | 1000 | 0.00 |
| DNP | 1000 | 0.43 |
| Endothelin | 1000 | 0.08 |
| NT-proBNP | 1000 | 0.05 |
| Renin | 50 | 0.18 |
| Urodilatin | 1000 | 0.00 |
| VNP | 1000 | 5.09 |
## Drug Interference:
Studies were conducted to evaluate the potential interference from therapeutic drugs with the Tosoh ST AIA-PACK BNP assay. Interference testing was performed with 2 different EDTA samples of known BNP concentrations, targeting 100 pg/mL and 300 - 500 pg/mL. The criterion for no interference was defined as a mean percent recovery for each therapeutic within 100±10% of the control. When the substances listed below were tested, no interference was observed up to the concentration listed in the table.
| Compound | Highest Concentration Tested With No Interference |
| --- | --- |
| Acetaminophen (4-Acetamidophenol) | 1456 μmol/L |
| Acetylsalicylic Acid | 200 μg/mL |
| Allopurinol | 240 ug/mL |
| Amiodarone | 4.2 mg/dL |
| Amlodipine besylate | 4 μg/mL |
| Ampicillin | 200 μg/mL |
| L-Ascorbic Acid | 376 μmol/L |
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| Compound | Highest Concentration Tested With No Interference |
| --- | --- |
| Atenolol | 40 µg/mL |
| Atorvastatin | 32 µg/mL |
| Biotin | 30 µg/mL |
| Caffeine | 10.8 mg/dL |
| Carvedilol | 74 µmol/L |
| Captopril | 40 µg/mL |
| Chloramphenicol | 7.8 mg/dL |
| Clopidogrel Bisulfate | 30 µg/mL |
| Cyclosporine | 40 µg/mL |
| Diclofenac sodium salt | 60 µg/mL |
| Digitoxin | 60 µg/mL |
| Digoxin | 0.0039 mg/dL |
| (+)-cis-Diltiazem hydrochloride | 120 µg/mL |
| Dipyridamole | 30 µg/mL |
| Disopyramide | 1.68 mg/dL |
| Dobutamine | 100 µg/mL |
| Dopamine hydrochloride | 116 µg/mL |
| Enalaprilat dehydrate (hydrolyzed from enalapril maleate) | 16 µg/mL |
| Erythromycin | 13.8 mg/dL |
| Fenofibrate | 45 µg/mL |
| Furosemide | 199 µmol/L |
| Heparin | 330 units/dL |
| Hydralazine | 20 µg/mL |
| Hydrochlorothiazide | 20 µg/mL |
| Ibuprofen | 2425 µmol/L |
| Indomethacin | 36 µg/mL |
| Isosorbide dinitrate | 0.593 mg/dL |
| Levothyroxine | 0.042 mg/dL |
| Lidocaine | 1.5 mg/dL |
| Lisinopril x 2H2O | 16 µg/mL |
| Losartan potassium | 130 µmol/L |
| Lovastatin | 0.021 mg/dL |
| Methyldopa | 100 µg/mL |
| (±)-Metoprolol (+)-tartrate salt | 18.7 µmol/L |
| Naproxen | 2170 µmol/L |
| Nicotine | 1.6 µg/mL |
| Nicotinic acid | 40 µg/mL |
| Nifedipine | 36 µg/mL |
| Nitrofuratoin | 40 µg/mL |
| Oxazepam | 12 µg/mL |
| Oxytetracycline | 100 µg/mL |
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| Compound | Highest Concentration Tested With No Interference |
| --- | --- |
| Phenobarbital | 69 mg/dL |
| Phenytoin | 6.00 mg/dL |
| Probenecid | 600 μg/mL |
| Procainamide | 4.80 mg/dL |
| Propanolol | 64 μg/mL |
| Quinidine | 20 μg/mL |
| Ramipril | 14.4 μmol/L |
| Simvastatin | 32 μg/mL |
| Spironolactone | 600 μg/mL |
| Sulfamethoxazole | 1.7 μmol/L |
| Theophylline | 6.00 mg/dL |
| Trymethoprim | 64 μg/mL |
| Verapamil hydrochloride | 96 μg/mL |
| Warfarin | 7.5 mg/dL |
| Trasylol/Aprotinin | 100 KIE/mL |
**High-Dose Hook Effect:**
Hook effect was evaluated using one (1) BNP positive EDTA plasma sample spiked to 60,000 pg/mL and diluted 1:2, 1:5, and 1:10 with ST AIA-PACK BNP sample diluting solution. No high dose hook effect was observed when samples up to approximately 50,000 pg/mL of BNP were assayed.
The following information will be included in the limitations section of the labeling.
- The ST AIA-PACK BNP has been designed so that the high dose “hook effect” is not a problem for the vast majority of samples. The “hook effect” phenomenon may occur at BNP concentrations higher than 50,000 pg/mL.
4. **Assay Reportable Range:**
4.0 – 2000 pg/mL
5. **Traceability, Stability, Expected Values (Controls, Calibrators, or Methods):**
**Traceability:**
The ST AIA-PACK BNP CALIBRATOR SET contains assigned concentrations of BNP. The assigned value is determined on a lot-by-lot basis and is designed to provide an assay calibration range of 4.0 to 2,000 pg/mL of BNP. The calibrators are prepared through serial dilution of a gravimetrically prepared internal reference standards made with commercially available BNP.
**Sample Stability:**
The sponsor provided data to support sample stability at different temperatures:
Refrigerated samples 35.6 – 46.4 °F (2 - 8 °C) are stable for up to 8 hours.
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Room Temperature samples are stable for up to 3 hours.
Frozen plasma at –4 °F (–20 °C) are stable for 65 days.
6. Detection Limit:
The CLSI EP17-A guideline was used to design the limit of blank (LoB), limit of detection (LoD) and limit of quantitation (LoQ) studies.
LoB was determined by running sixty replicates of Calibrator 1 (Buffered Solution; Blank Sample) over five days, measuring one run per day, three replicates per run and four lots using the Tosoh ST AIA-PACK BNP assay on one Tosoh AIA-2000 instrument. Non-parametric principle based on ordered values was used.
Low level samples selected from concentrations in the range from 1.3 to 17.0 pg/mL (LoB to 4x LoB) were prepared by dilution of specimens with known BNP concentrations. The samples were assayed in replicates of two (2) over five (5) days on one instrument for a total of ten (10) replicates per sample. The standard deviation (SD) and coefficient of variation (CV%) were calculated.
LoQ was calculated as the functional sensitivity at 20% CV. To determine the functional sensitivity, a precision profile was plotted using the values of CV% and the mean concentration of the samples in pg/mL from the LoD study.
The data provided supports the following claims:
LoB = 0.9 pg/mL
LoD = 1.9 pg/mL
LoQ = 3.5 pg/mL.
7. Assay Cut-Off:
See Clinical Cutoff in Section D.
B Comparison Studies:
1. Method Comparison with Predicate Device:
Not Applicable: see clinical studies in Section C.
2. Matrix Comparison:
Not Applicable: human K2 EDTA plasma is the only sample type claimed for use with this assay.
C Clinical Studies:
1. Clinical Sensitivity:
See section 3 below.
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2. Clinical Specificity:
See section 3 below.
3. Other Clinical Supportive Data (When 1. and 2. Are Not Applicable):
A study was conducted in the U.S. to support the use of the assay. Compared to clinical studies for previously cleared BNP devices, this study prospectively recruited males and females who presented to the ED with clinical suspicion of new onset HF, acutely decompensated or exacerbated HF. A total of 825 samples were assayed for BNP using the Tosoh AIA 2000 Analyzer were recruited from 8 different ED sites. The analysis is based on 724 patients that met the inclusion criteria and the outcome (new onset HF, acutely decompensated or exacerbated HF) was based on adjudication. The samples were frozen prior to analysis. Data supporting the stability of the samples for the storage time and conditions were provided by the sponsor.
The cross tabulation of results between HF and BNP at the cutoff of 100 pg/mL is below.
| Adjudicated | BNP | | |
| --- | --- | --- | --- |
| | ≥100 pg/mL | <100 pg/mL | Total |
| HF | 291 | 38 | 329 |
| Not HF | 116 | 279 | 395 |
| Total | 407 | 317 | 724 |
Using the traditional single cutoff of 100 pg/mL, the sensitivity of the ST AIA-PACK BNP assay is 88.4% and the specificity is 70.6%. The Positive Predictive Value (PPV) is 71.5% and the Negative Predictive Value (NPV) is 88.0%.
| Measure | Value | Low CI | High CI |
| --- | --- | --- | --- |
| Sensitivity | 88.4% | 84.5% | 91.5% |
| Specificity | 70.6% | 66.0% | 74.9% |
| Sensitivity + Specificity | 159.1% | 153.0% | 164.3% |
| Concordance | 78.7% | 75.6% | 81.6% |
| PPV, CI | 71.5% | 66.9% | 75.7% |
| NPV, CI | 88.0% | 84.0% | 91.1% |
| Positive Likelihood Ratio (PLR), CI | 3.012 | 2.572 | 3.527 |
| Negative Likelihood Ratio (NLR), CI | 0.164 | 0.120 | 0.222 |
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The performance for the device in the cohort was calculated for age above and below 75 years old. The clinical performance of the ST AIA-PACK BNP assay using the cutoff of 100 pg/mL for the two different age groups is described below.
| | Age <75 | Age ≥75 |
| --- | --- | --- |
| Sensitivity | 86.9% | 90.8% |
| 95% CI | (172/198) | (119/131) |
| | (81.5-90.9%) | (84.7-94.7%) |
| Specificity | 78.1% | 52.6% |
| 95% CI | (218/279) | (61/116) |
| | (72.9-82.6%) | (43.6-61.4%) |
| PPV | 73.8% | 68.4% |
| 95% CI | (172/233) | (119/174) |
| | (67.8-79.0%) | (61.1-74.8%) |
| NPV | 89.3% | 83.6% |
| 95% CI | (218/244) | (61/73) |
| | (84.8-92.6%) | (73.4-90.3%) |
| Prevalence | 41.5% | 53.0% |
| 95% CI | (37.2-46.0%) | (46.8-59.2%) |
| 1-Prevalence | 58.5% | 47.0% |
| 95% CI | (54.0-62.8%) | (40.8-53.2%) |
| PLR | 3.973 | 1.916 |
| 95% CI | (3.162-4.992) | (1.570-2.338) |
| NLR | 0.168 | 0.174 |
| 95% CI | (0.117-0.242) | (0.099-0.307) |
The performance for the device in the cohort was calculated for sex. The clinical performance of the ST AIA-PACK BNP assay using the cutoff of 100 pg/mL for males and females is described below.
| | Females | Males |
| --- | --- | --- |
| Sensitivity | 89.1% | 88.0% |
| 95% CI | (122/137) | (169/192) |
| | (82.7-93.3%) | (82.7-91.9%) |
| Specificity | 67.4% | 73.7% |
| 95% CI | (128/190) | (151/205) |
| | (60.4-73.6%) | (67.2-79.2%) |
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| | Females | Males |
| --- | --- | --- |
| PPV | 66.3% | 75.8% |
| | (122/184) | (169/223) |
| 95% CI | (59.2-72.7%) | (69.8-80.9%) |
| NPV | 89.5% | 86.8% |
| | (128/143) | (151/174) |
| 95% CI | (83.4-93.5%) | (80.9-91.0%) |
| Prevalence | 41.9% | 48.4% |
| 95% CI | (36.7-47.3%) | (43.5-53.3%) |
| 1-Prevalence | 58.1% | 51.6% |
| 95% CI | (52.7-63.3%) | (46.7-56.5%) |
| PLR | 2.729 | 3.342 |
| 95% CI | (2.206-3.375) | (2.642-4.226) |
| NLR | 0.163 | 0.163 |
| 95% CI | (0.100-0.265) | (0.110-0.241) |
The performance was further broken down by history of heart failure, BMI and Estimated Glomerular Filtration Rate (eGFR) values. The clinical performance is summarized in the following tables.
| | History of HF | No History of HF |
| --- | --- | --- |
| Sensitivity | 89.5% | 87.1% |
| 95% CI | (170/190) | (121/139) |
| | (84.3-93.1%) | (80.5-91.6%) |
| Specificity | 44.9% | 80.2% |
| 95% CI | (48/107) | (231/288) |
| | (35.8-54.3%) | (75.2-84.4%) |
| PPV | 74.2% | 68.0% |
| 95% CI | (170/229) | (121/178) |
| | (68.2-79.5%) | (60.8-74.4%) |
| NPV | 70.6% | 92.8% |
| 95% CI | (48/68) | (231/249) |
| | (58.9-80.1%) | (88.9-95.4%) |
| Prevalence | 64.0% | 32.6% |
| 95% CI | (58.4-69.2%) | (28.3-37.1%) |
| 1-Prevalence | 36.0% | 67.4% |
| 95% CI | (30.8-41.6%) | (62.9-71.7%) |
| PLR | 1.623 | 4.398 |
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| | History of HF | No History of HF |
| --- | --- | --- |
| 95% CI | (1.358-1.938) | (3.456-5.598) |
| NLR | 0.235 | 0.161 |
| 95% CI | (0.147-0.373) | (0.105-0.249) |
| | eGFR <60* | eGFR ≥60 |
| --- | --- | --- |
| Sensitivity | 89.4% | 87.6% |
| 95% CI | (135/151) | (156/178) |
| | (83.5-93.4%) | (82.0-91.7%) |
| Specificity | 58.7% | 74.1% |
| 95% CI | (54/92) | (223/301) |
| | (48.5-68.2%) | (68.9-78.7%) |
| PPV | 78.0% | 66.7% |
| 95% CI | (135/173) | (156/234) |
| | (71.3-83.6%) | (60.4-72.4%) |
| NPV | 77.1% | 91.0% |
| 95% CI | (54/70) | (223/245) |
| | (66.0-85.4%) | (86.8-94.0%) |
| Prevalence | 62.1% | 37.2% |
| 95% CI | (55.9-68.0%) | (33.0-41.6%) |
| 1-Prevalence | 37.9% | 62.8% |
| 95% CI | (32.0-44.1%) | (58.4-67.0%) |
| PLR | 2.165 | 3.382 |
| 95% CI | (1.686-2.778) | (2.772-4.126) |
| NLR | 0.181 | 0.167 |
| 95% CI | (0.110-0.296) | (0.112-0.248) |
* patients with eGFR values < 30 were excluded from the study
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| | BMI <30 | BMI 30-36 | BMI ≥37 |
| --- | --- | --- | --- |
| Sensitivity | 96.1% | 90.3% | 75.3% |
| 95% CI | (124/129) | (84/93) | (64/85) |
| | (91.2-98.3%) | (82.6-94.8%) | (65.2-83.2%) |
| Specificity | 65.5% | 74.2% | 74.4% |
| 95% CI | (114/174) | (72/97) | (64/86) |
| | (58.2-72.2%) | (64.7-81.9%) | (64.3-82.5%) |
| PPV | 67.4% | 77.1% | 74.4% |
| 95% CI | (124/184) | (84/109) | (64/86) |
| | (60.3-73.7%) | (68.3-84.0%) | (64.3-82.5%) |
| NPV | 95.8% | 88.9% | 75.3% |
| 95% CI | (114/119) | (72/81) | (64/85) |
| | (90.5-98.2%) | (80.2-94.0%) | (65.2-83.2%) |
| Prevalence | 42.6% | 48.9% | 49.7% |
| 95% CI | (37.1-48.2%) | (41.9-56.0%) | (42.3-57.1%) |
| 1-Prevalence | 57.4% | 51.1% | 50.3% |
| 95% CI | (51.8-62.9%) | (44.0-58.1%) | (42.9-57.7%) |
| PLR | 2.788 | 3.505 | 2.943 |
| 95% CI | (2.265-3.431) | (2.484-4.944) | (2.012-4.306) |
| NLR | 0.059 | 0.130 | 0.332 |
| 95% CI | (0.025-0.141) | (0.069-0.245) | (0.224-0.491) |
There are potentially confounding comorbidities that may influence BNP results. These comorbidities include diabetes, renal insufficiency, hypertension (HTN) and/or chronic obstructed pulmonary disease (COPD). Among the 724 patients in the study, 577 patients presented with comorbidities and 147 presented with no comorbidities. Performance of the BNP, broken down by the presence or absence of these comorbidities. In the subset of patients without comorbidities the sensitivity was $89.3\%$ and the specificity was $74.7\%$ . Conversely in the patients with comorbidities the sensitivity and specificity were $88.3\%$ and $69.4\%$ respectively.
| | Without comorbidities | With comorbidities |
| --- | --- | --- |
| Sensitivity | 89.3% | 88.3% |
| 95% CI | (50/56) | (241/273) |
| | (78.5-95.0%) | (83.9-91.6%) |
| Specificity | 74.7% | 69.4% |
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| | Without comorbidities | With comorbidities |
| --- | --- | --- |
| 95% CI | (68/91)
(64.9-82.5%) | (211/304)
(64.0-74.3%) |
| PPV | 68.5% | 72.2% |
| | (50/73) | (241/334) |
| 95% CI | (57.1-78.0%) | (67.1-76.7%) |
| NPV | 91.9% | 86.8% |
| | (68/74) | (211/243) |
| 95% CI | (83.4-96.2%) | (82.0-90.5%) |
| Prevalence | 38.1% | 47.3% |
| 95% CI | (30.6-46.2%) | (43.3-51.4%) |
| 1-Prevalence | 61.9% | 52.7% |
| 95% CI | (53.8-69.4%) | (48.6-56.7%) |
| PLR | 3.533 | 2.886 |
| 95% CI | (2.453-5.088) | (2.423-3.437) |
| NLR | 0.143 | 0.169 |
| 95% CI | (0.067-0.308) | (0.121-0.236) |
The following limitations are in the device labeling:
- This test has low sensitivity (76%) in patients with severe obesity (BMI ≥37). In the study, 24% of patients with an adjudicated diagnosis of new onset heart failure, exacerbated heart failure or acutely decompensated heart failure and a BMI ≥37 had BNP values below the cut-off (false negatives)
- This test has low specificity (59%) in patients with eGFR < 60. In the study, 41% of patients without an adjudicated diagnosis of new onset heart failure, exacerbated heart failure or acutely decompensated heart failure and eGFR < 60 had BNP values above the cut-off (false positives).
- This test has low specificity (53%) in patients in the higher age group (age ≥75). In the study, 47% of patients with an adjudicated diagnosis of new onset heart failure, exacerbated heart failure or acutely decompensated heart failure and aged ≥75 years had BNP values above the cut-off (false positives)
- This test has low specificity (45%) in patients with a history of HF. In the study, 55% of patients with an adjudicated diagnosis of new onset heart failure, exacerbated heart failure or acutely decompensated heart failure and a history of HF had BNP values above the cut-off (false positives)
D Clinical Cut-Off:
As recommended in the American Heart Association guidelines for acute heart failure (Weintraub NL, et al. Acute Heart Failure Syndromes: Emergency Department Presentation, Treatment, and Disposition: Current Approaches and Future Aims: A Scientific Statement from the American
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Heart Association. Circulation. 2010; 122:1975-1996.), 100 pg/mL has been used as the cutoff for this assay.
## E Expected Values/Reference Range:
To establish the reference range for subjects without HF BNP, concentrations from a total of 430 apparently healthy individuals were evaluated. The descriptive statistics for BNP concentrations in the population without heart failure are shown below.
| Age | All | <45 | 45-54 | 55-64 | 65-74 | 75+ |
| --- | --- | --- | --- | --- | --- | --- |
| N | 430 | 92 | 83 | 88 | 87 | 80 |
| Mean pg/ml | 34.6 | 10.4 | 11.9 | 15.1 | 58.1 | 81.6 |
| SD pg/ml | 73.8 | 11.0 | 11.2 | 18.1 | 106.6 | 110.2 |
| Median pg/ml | 10.8 | 5.9 | 7.9 | 8.5 | 14.7 | 39.1 |
| 95 percentile pg/ml | 143.2 | 26.0 | 39.8 | 42.5 | 241.2 | 273.6 |
| % < 100 pg/ml | 91.4 | 100.0 | 100.0 | 98.9 | 82.8 | 73.8 |
| Minimum pg/ml | <4 | <4 | <4 | <4 | <4 | <4 |
| Maximum pg/ml | 627.5 | 80.0 | 51.6 | 121.3 | 619.1 | 627.5 |
## VIII Proposed Labeling:
The labeling supports the finding of substantial equivalence for this device.
## IX Conclusion:
The submitted information in this premarket notification is complete and supports a substantial equivalence decision.
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