ADVIA Centaur® NT-proBNPII (PBNPII)
Device Facts
| Record ID | K220265 |
|---|---|
| Device Name | ADVIA Centaur® NT-proBNPII (PBNPII) |
| Applicant | Siemens Healthcare Diagnostics, Inc. |
| Product Code | NBC · Clinical Chemistry |
| Decision Date | Sep 24, 2023 |
| Decision | SESE |
| Submission Type | Traditional |
| Regulation | 21 CFR 862.1117 |
| Device Class | Class 2 |
Indications for Use
The ADVIA Centaur® NT-proBNPII (PBNPII) assay is for in vitro diagnostic use in the quantitative determination of N-terminal pro-brain natriuretic peptide (NT-proBNP) in human serum and plasma (EDTA and lithium heparin) using the ADVIA Centaur® XP system. In the Emergency Department (ED) and Outpatient (OP) populations, 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.
Device Story
The ADVIA Centaur NT-proBNP (PBNPII) is a 1-step sandwich immunoassay for the quantitative measurement of NT-proBNP in human serum and plasma. It utilizes monoclonal sheep anti-human NT-proBNP antibodies; one labeled with acridinium ester and the other biotinylated and bound to streptavidin magnetic particles. The device is used on the ADVIA Centaur XP system in clinical settings. The system processes samples to produce a chemiluminescent signal proportional to the NT-proBNP concentration. Healthcare providers use these quantitative results to aid in the diagnosis of heart failure in patients presenting with clinical symptoms. The device assists in clinical decision-making by providing objective biomarker data to rule-in or rule-out heart failure, potentially improving diagnostic accuracy and patient management.
Clinical Evidence
Clinical performance was evaluated in a prospective multi-site study. ED population (N=3128) and OP population (N=1033) were assessed against an independent central adjudication panel of cardiologists. For the ED population, performance was evaluated using age-dependent rule-in/rule-out cut-offs. For the OP population, a single 125 pg/mL cut-off yielded 86.0% sensitivity and 64.3% specificity (AUC 0.839). Analytical performance included precision (CLSI EP05-A3), linearity (CLSI EP06-Ed2), and interference/cross-reactivity testing (CLSI EP07-ed3).
Technological Characteristics
Chemiluminescent immunoassay; reagents include monoclonal sheep anti-human NT-proBNP antibodies (F(ab')2 fragment and biotinylated), streptavidin magnetic particles, and acridinium ester label. Measuring range: 35–35,000 pg/mL. Automated system (ADVIA Centaur XP). Complies with CLSI guidelines (EP05-A3, EP06, EP07, EP17-A2, EP28-A3c, EP37).
Indications for Use
Indicated for use in ED and OP populations with clinical suspicion of new onset or worsening heart failure (HF) to aid in diagnosis. Applicable to all ages.
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
- Roche Elecsys proBNP II assay (K072437)
Related Devices
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- K232164 — Access NT-proBNP · Beckman Coulter, Inc. · Apr 12, 2024
- K031038 — ADVIA CENTAUR B-TYPE NATRIURETIC PEPTIDE (BNP) ASSAY · Bayer Healthcare, LLC · Jun 23, 2003
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
K220265
B Applicant
Siemens Healthcare Diagnostics Inc.
C Proprietary and Established Names
ADVIA Centaur® NT-proBNPII (PBNPII)
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:
N-terminal pro-brain natriuretic peptide (NT-proBNP)
C Type of Test:
Quantitative, Chemiluminescence immunoassay
Food and Drug Administration
10903 New Hampshire Avenue
Silver Spring, MD 20993-0002
www.fda.gov
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K220265 - Page 2 of 22
# III Intended Use/Indications for Use:
## A Intended Use(s):
See Indications for Use below.
## B Indication(s) for Use:
The ADVIA Centaur® NT-proBNPII (PBNPII) assay is for in vitro diagnostic use in the quantitative determination of N-terminal pro-brain natriuretic peptide (NT-proBNP) in human serum and plasma (EDTA and lithium heparin) using the ADVIA Centaur® XP system.
In the Emergency Department (ED) and Outpatient (OP) populations, 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.
## C Special Conditions for Use Statement(s):
Rx - For Prescription Use Only
## D Special Instrument Requirements:
ADVIA Centaur® XP system
# IV Device/System Characteristics:
## A Device Description:
The candidate device is comprised of an assay kit which includes the ADVIA Centaur PBNPII ReadyPack primary reagent pack, ADVIA Centaur PBNPII Ancillary Reagent ReadyPack, ADVIA Centaur® PBNPII Calibrators, ADVIA Centaur PBNPII CAL calibrator assigned value cards, and ADVIA Centaur PBNPII master curve card.
| ADVIA Centaur® PBNPII ReadyPack primary reagent pack | ADVIA Centaur PBNPII Lite Reagent:
Monoclonal sheep anti-human NT-proBNP F(ab')2 fragment antibody (~0.36 μg/mL) labeled with acridinium ester in buffer; bovine serum albumin; bovine gamma globulin; preservatives. |
| --- | --- |
| | ADVIA Centaur PBNPII Solid Phase Reagent:
Monoclonal sheep anti-human NT-proBNP antibody (~2 μg/mL) labeled with biotin bound to streptavidin magnetic particles (~220 mg/L) in buffer; bovine serum albumin; bovine gamma globulin; sheep gamma globulin; preservatives. |
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K220265 - Page 3 of 22
| ADVIA Centaur PBNPII
Ancillary Reagent | Buffer with bovine serum albumin; bovine gamma globulin; sheep gamma globulin; preservatives. |
| --- | --- |
| ADVIA Centaur PBNPII
Low and High Calibrators | After reconstitution, low or high levels of NT-proBNP antigen; buffer; bovine serum albumin; preservatives. |
| --- | --- |
Materials required but not provided in the assay kit:
ADVIA Centaur Wash
ADVIA Centaur Probe Wash
## B Principle of Operation:
The candidate device is an automated two-site sandwich immunoassay using chemiluminescent detection. The binding reaction relies on a biotinylated monoclonal sheep antibody specific to human NT-proBNP and conjugated to streptavidin magnetic microparticles; and an acridinium-ester-labeled monoclonal sheep F(ab')2 antibody fragment specific to NT-proBNP.
## V Substantial Equivalence Information:
## A Predicate Device Name(s):
Elecsys proBNP II Immunoassay
## B Predicate 510(k) Number(s):
K072437
## C Comparison with Predicate(s):
| Device & Predicate Device(s): | K220265 | K072437 |
| --- | --- | --- |
| Device Trade Name | ADVIA Centaur® NT-proBNPII (PBNPII) | Elecsys proBNP II Immunoassay |
| General Device Characteristic Similarities | | |
| Intended Use | Quantitative determination of N-terminal pro-brain natriuretic peptide (NT-proBNP) in human serum and plasma | Same |
| General Device Characteristic Differences | | |
| Measuring range | 35 to 35,000 pg/mL | 5 to 35,000 pg/mL |
| | | |
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VI Standards/Guidance Documents Referenced:
Class II Special Control Guidance Document for B-Type Natriuretic Peptide Premarket Notifications; Final Guidance for Industry and FDA Reviewers, issued on November 30, 2000.
CLSI EP05-A3 Evaluation of Precision of Quantitative Measurement Procedures; Approved Guideline - Third Edition
CLSI EP06 Evaluation of Linearity of Quantitative Measurement Procedures. 2nd Edition.
CLSI EP07 Interference Testing in Clinical Chemistry: Approved Guideline. 3rd Edition.
CLSI EP17-A2 Evaluation of Detection Capability for Clinical Laboratory Measurement Procedures; Approved Guideline - Second Edition.
CLSI EP28-A3c Defining, Establishing, and Verifying Reference Intervals in the Clinical Laboratory; Approved Guideline -Third Edition.
CLSI EP37 Supplemental Tables for Interference Testing in Clinical Chemistry. 1st Edition
VII Performance Characteristics (if/when applicable):
A Analytical Performance:
1. Precision/Reproducibility:
The precision performance of the ADVIA Centaur® NT-proBNPII (PBNPII) assay run on the ADVIA Centaur XP system was established in several studies following the recommendations of CLSI EP05-A3.
Within-Lab Precision
The within-lab performance was established. In the study, six native serum sample pools spanning approximately each medical decision level and three controls were assayed in replicates of two per run, two runs per day over 20 days using one reagent lot for a total of 80 measurements. The data were analyzed for repeatability and within-lab %CV using the ANOVA method consistent with the recommendations of CLSI EP05-A3. The results are summarized below.
| Sample | Mean pg/mL | Repeatability | | Within-Lab | |
| --- | --- | --- | --- | --- | --- |
| | | SD | %CV | SD | %CV |
| Serum 1 | 116 | 6.1 | 5.3 | 7.8 | 6.7 |
| Serum 2 | 271 | 9.6 | 3.5 | 10.8 | 4.0 |
| Serum 3 | 380 | 5.4 | 1.4 | 8.9 | 2.3 |
| Serum 4 | 806 | 15.3 | 1.9 | 16.7 | 2.1 |
| Serum 5 | 1597 | 25.7 | 1.6 | 31.6 | 2.0 |
| Serum 6 | 25073 | 416 | 1.7 | 690 | 2.8 |
| QC 1 | 144 | 5.6 | 3.9 | 6.1 | 4.2 |
| QC 2 | 418 | 8.7 | 2.1 | 12.1 | 2.9 |
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| Sample | Mean pg/mL | Repeatability | | Within-Lab | |
| --- | --- | --- | --- | --- | --- |
| | | SD | %CV | SD | %CV |
| QC 3 | 4778 | 93.0 | 1.9 | 134.7 | 2.8 |
Between-Lab reproducibility
The reproducibility performance was established with a multi-site precision evaluation. Samples for testing were comprised of 8 native patient serum pools and three controls. In the study, each sample was tested at three sites using the same three lots of reagents. Each sample was assayed in replicates of three per run, two runs per day over five days for 30 measurements per lot per site, or for a total of 270 measurements across the three sites. The data was analyzed using a random effects model to estimate the variance components of within-run, between run, between day, between lot, and between sites.
All Sites Combined:
| Sample | Mean pg/mL | Between Site | | Between Lot | | Between Day | | Between Run | | Repeatability | | Reproducibility | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | | SD | %CV | SD | %CV | SD | %CV | SD | %CV | SD | %CV | SD | %CV |
| Control | 142 | 4.2 | 2.9% | 3.5 | 2.5% | 1.0 | 0.7% | 0.6 | 0.4% | 4.9 | 3.4% | 7.4 | 5.2% |
| Control | 420 | 11.4 | 2.7% | 8.8 | 2.1% | 3.8 | 0.9% | 3.3 | 0.8% | 8.6 | 2.0% | 17.5 | 4.2% |
| Control | 4842 | 118.0 | 2.4% | 105.1 | 2.2% | 32.3 | 0.7% | 30.9 | 0.6% | 91.3 | 1.9% | 187.9 | 3.9% |
| serum | 139 | 4.4 | 3.1% | 1.9 | 1.3% | 1.4 | 1.0% | 0.0 | 0.0% | 4.5 | 3.2% | 6.7 | 4.8% |
| serum | 319 | 7.3 | 2.3% | 4.3 | 1.3% | 2.5 | 0.8% | 0.0 | 0.0% | 8.0 | 2.5% | 12.0 | 3.8% |
| serum | 482 | 11.9 | 2.5% | 4.9 | 1.0% | 3.8 | 0.8% | 0.0 | 0.0% | 10.6 | 2.2% | 17.0 | 3.5% |
| serum | 809 | 17.2 | 2.1% | 12.3 | 1.5% | 5.7 | 0.7% | 4.1 | 0.5% | 15.6 | 1.9% | 27.1 | 3.4% |
| serum | 1611 | 35.3 | 2.2% | 26.2 | 1.6% | 0.0 | 0.0% | 7.2 | 0.4% | 30.0 | 1.9% | 53.7 | 3.3% |
| serum | 10230 | 281.8 | 2.8% | 160.2 | 1.6% | 61.2 | 0.6% | 62.6 | 0.6% | 216.3 | 2.1% | 399.4 | 3.9% |
| serum | 19230 | 630.3 | 3.3% | 181.4 | 0.9% | 98.0 | 0.5% | 117.4 | 0.6% | 391.7 | 2.0% | 779.1 | 4.1% |
| serum | 28557 | 834.3 | 2.9% | 248.9 | 0.9% | 139.2 | 0.5% | 0.0 | 0.0% | 702.2 | 2.5% | 1127.2 | 3.9% |
2. Linearity:
The linearity performance of the ADVIA Centaur® NT-proBNPII (PBNPII) assay run on the ADVIA Centaur XP system was established in a study following the recommendations of CLSI EP06, 2nd Edition. Samples for testing were comprised of two linearity panels each with 10 concentration levels. Each linearity panel was a dilution series prepared by intermixing known volumes of high and low sample pools of native human serum. The low pool was a non-zero sample. In the study, each sample (of the 20 total) was assayed in replicates of seven on one instrument using each of three reagent lots. The linearity was analyzed separately for each reagent lot. Using a weighted linear regression model, the difference between the mean observed value and the value predicted by the weighted linear regression model was derived. At each concentration, the deviation from linearity was less than 10%. The sponsor concluded that the assay yields a linear response over the claimed NT-proBNP measuring range of 35 to 35,000 pg/mL.
Sample Dilution
Serum and plasma samples with concentrations up to 63,128 pg/mL can be measured after a 5-fold dilution or 10-fold dilution. The percent recovery of diluted samples ranged from 80.5% to 87.2%.
3. Analytical Specificity/Interference:
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The analytical specificity performance of the ADVIA Centaur® NT-proBNPII (PBNPII) was established by conducting a cross-reactivity study and interference testing for endogenous and exogenous substances, consistent with CLSI EP07, 3rd Edition and CLSI EP37, 1st Edition.
## Endogenous substances
Interference from endogenous substances was assessed using serum samples with NT-proBNP at approximate concentrations of 125 pg/mL and 2000 pg/mL. Each of the two samples was further divided into two aliquots for a control sample (with no added interferent) and test sample (with added interferent). For screening, each sample was assayed in replicates of 8 using three lots of reagent packs on one instrument. No significant interference, defined by the sponsor as within ±10% difference in the mean for the test sample versus the mean of the control sample, was observed at the following concentrations:
| Substance | Highest concentration tested at which no significant interference is observed |
| --- | --- |
| Albumin | 6.00 g/dL |
| Cholesterol | 500 mg/dL |
| Conjugated Bilirubin | 60 mg/dL |
| Unconjugated Bilirubin | 60 mg/dL |
| Creatinine | 30.0 mg/dL |
| Hemoglobin | 1000 mg/dL |
| Human anti-mouse antibodies (HAMA) | 800 μg/L |
| Immunoglobulin G (IgG) | 5.00 g/dL |
| Lipemia (Intralipid®) | 3000 mg/dL |
| Protein, total | 11.1 g/dL |
| Rheumatoid factor (RF) | 1500 IU/mL |
| Triglyceride | 1000 mg/dL |
## Exogenous substances
Interference from exogenous substances was assessed using samples with NT-proBNP concentrations of 125 pg/mL and 2000 pg/mL following the same procedure as for endogenous substances. No significant interference, defined by the sponsor as within ±10% difference in the mean for the test sample versus the mean of the control sample was observed at the following concentrations:
| Substance | Highest concentration tested at which no significant interference is observed |
| --- | --- |
| Abciximab | 21.0 μg/mL |
| Acetaminophen | 20.0 mg/dL |
| Allopurinol | 2.50 mg/dL |
| Amiodarone | 2.0 mg/dL |
| Acetylcysteine | 15.0 mg/dL |
| Amiodarone | 4.2 mg/dL |
| Ampicillin | 7.50 mg/dL |
| Amlodipine Besylate | 4.00 μg/mL |
| Ascorbic Acid | 5.00 mg/dL |
| Atenolol | 1.00 mg/dL |
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| Substance | Highest concentration tested at which no significant interference is observed |
| --- | --- |
| Atorvastatin | 32.0 mg/dL |
| Bisoprolol | 0.0258 mg/dL |
| Biotin | 3510 ng/mL |
| Caffeine | 10.8 mg/dL |
| Captopril | 5.00 mg/dL |
| Chlordiazepoxide | 1.00 mg/dL |
| Cinnarizine | 3.00 mg/dL |
| Clopidogrel bisulfate | 30.0 µg/mL |
| Cyclosporine | 4000 ng/mL |
| Calcium dobesilate | 6.00 mg/dL |
| Carvedilol | 4.32 mg/dL |
| Cefoxitin | 660 mg/dL |
| Chloramphenicol | 7.80 mg/dL |
| Digitoxin | 7.5 µg/dL |
| Digoxin | 0.039 mg/dL |
| Diltiazem | 120 µg/mL |
| Dipyridamole | 30.0 µg/mL |
| Disopyramide | 40.0 µg/mL |
| Dopamine | 16.0 mg/dL |
| Doxycycline | 1.80 mg/dL |
| Enalapril maleate | 16.0 µg/mL |
| Erythromycin | 13.8 mg/dL |
| Epinephrine | 0.050 mg/dL |
| Furosemide | 6.00 mg/dL |
| Gentamycin sulfate | 3.51 mg/dL |
| Heparin | 3.00 U/mL |
| Hydralazine | 20.0 µg/mL |
| Hydrochlorothiazide | 20.0 µg/mL |
| Indomethacin | 16.0 µg/mL |
| Isosorbide dinitrate | 6.00 mg/dL |
| Insulin | 0.160 mg/dL |
| Lisinopril | 16.0 µg/mL |
| Lovastatin | 16.0 µg/mL |
| L-Thyroxine | 60.0 µg/dL |
| L-dopa (Levodopa) | 0.750 mg/dL |
| Lidocaine | 8.00 mg/dL |
| Methyldopa | 2.50 mg/dL |
| Milrinone lactate | 2.40 µg/mL |
| Methylprednisolone | 0.783 mg/dL |
| Metoprolol tartrate | 15.0 mg/dL |
| Metronidazole | 12.3 mg/dL |
| Molsidomine | 0.018 mg/dL |
| Nicotine | 0.100 mg/dL |
| Nifedipine | 6.00 mg/dL |
| Nitrofurantoin | 40.0 µg/mL |
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| Substance | Highest concentration tested at which no significant interference is observed |
| --- | --- |
| Nitroglycerine | 0.160 μg/mL |
| Oxazepam | 12.0 μg/mL |
| Oxytetracycline | 100 μg/mL |
| Phenytoin | 5.00 mg/dL |
| Probenecid | 200 μg/mL |
| Propranolol | 0.150 mg/dL |
| Phenprocoumon | 1.50 mg/dL |
| Phenobarbital | 69.0 mg/dL |
| Phenylbutazone | 32.1 mg/dL |
| Phenytoin | 6.00 mg/dL |
| Pravastatin | 0.021 mg/dL |
| Propafenone HCL | 30.0 mg/dL |
| Quinidine | 20.0 μg/mL |
| Retavase (reteplase) | 3.33 mg/dL |
| Rifampicin (Rifampin) | 4.80 mg/dL |
| Salicylic Acid | 60.0 mg/dL |
| Simvastatin | 32.0 μg/mL |
| Sotalol hydrochloride | 0.510 mg/dL |
| Spironolactone | 7.50 mg/dL |
| Streptokinase | 150,000 U/L |
| Theophylline | 4.00 mg/dL |
| Trimethoprim | 64.0 μg/mL |
| Tolbutamide | 150 mg/dL |
| Torsemide | 1.50 mg/dL |
| Urokinase | 150,000 U/L |
| Verapamil | 96.0 μg/mL |
| Warfarin | 8.00 mg/dL |
## Cross-reactivity
A study was conducted to evaluate the performance of the ADVIA Centaur NT-proBNPII (PBNPII) in the presence of cross reactants. In the study, two samples were prepared from human serum pools- low and high. Each serum pool was then spiked with cross-reactive substance to form a test sample or spiked with solvent to form a control sample. Each sample was assayed in replicates of 8. The % cross-reactivity was calculated as:
$$
\% \text{ cross-reactivity} = 100\% \times (\text{test conc.} - \text{control conc.}) / (\text{cross-reactant conc.})
$$
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| Cross-reactant | Concentration | Control (pg/mL) | Test (pg/mL) | % Cross-reactivity |
| --- | --- | --- | --- | --- |
| Adrenomedullin | 1.0 ng/mL | 3 | 8 | ND |
| | | 126 | 127 | 0.1% |
| Aldosterone | 0.6 ng/mL | 3 | 2 | ND |
| | | 139 | 143 | 0.7% |
| Angiotensin I | 0.6 ng/mL | 3 | 4 | ND |
| | | 126 | 128 | 0.3% |
| Angiotensin II | 0.6 ng/mL | 9 | 18 | ND |
| | | 143 | 147 | 0.7% |
| Angiotensin III | 1.0 ng/mL | 2 | 5 | ND |
| | | 139 | 134 | -0.5% |
| ANP28 | 3.1 μg/mL | 2 | 1 | ND |
| | | 139 | 138 | 0.0% |
| Arg-Vasopressin | 1.0 ng/mL | 9 | 11 | ND |
| | | 143 | 144 | 0.1% |
| BNP32 (Natrecor®) | 3.5 μg/mL | 2 | 1 | ND |
| | | 139 | 135 | 0.0% |
| CNP32 | 2.2 μg/mL | 2 | 1 | ND |
| | | 139 | 138 | 0.0% |
| DNP | 1.0 ng/mL | 2 | 1 | ND |
| | | 139 | 138 | -0.1% |
| Endothelin | 20 pg/mL | 2 | 7 | ND |
| | | 139 | 138 | -5.0% |
| proBNP (non-glycosylated) | 3000 pg/mL | 5 | 398 | 13% |
| | | 158 | 1060 | 30% |
| proBNP (glycosylated) | 3000 pg/mL | 5 | 43 | 1% |
| | | 158 | 732 | 19% |
| preproANP26-55 | 3.5 μg/mL | 2 | 2 | ND |
| | | 139 | 138 | 0.0% |
| preproANP56-92 | 1.0 ng/mL | 2 | 2 | ND |
| | | 139 | 137 | -0.2% |
| preproANP104-123 | 1.0 ng/mL | 3 | 4 | ND |
| | | 126 | 124 | -0.2% |
| Renin | 50 ng/mL | 2 | 5 | ND |
| | | 141 | 123 | 0.0% |
| Urodilatin | 3.5 μg/mL | 2 | 2 | ND |
| | | 141 | 124 | 0.0% |
| VNP | 1.0 ng/mL | 2 | 2 | ND |
| | | 139 | 137 | -0.2% |
The results showed cross-reactivity of proBNP (glycosylated) and proBNP (nonglycosylated). Cross-reactivity of NT-proBNP assays to proBNP has been documented previously.
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High dose hook effect
The ADVIA Centaur® NT-proBNPII (PBNPII) assay was evaluated for high dose hook effect using 10 concentration levels of NT-proBNP. The results support that the ADVIA Centaur® NT-proBNPII (PBNPII) assay does not show a high dose hook effect up to 300,000 pg/mL of NT-proBNP.
4. Assay Reportable Range:
35 to 35,000 pg/mL
5. Traceability, Stability, Expected Values (Controls, Calibrators, or Methods):
Metrological traceability
The metrological traceability of the ADVIA Centaur® NT-proBNPII (PBNPII) assay was reviewed and found acceptable.
Sample Stability
The sponsor provided data to support sample stability at different temperatures and conditions:
- After centrifugation, serum specimens stored on the clot are stable for up to 24 hours at 2–8°C.
- Separated samples are stable for up to 3 days at room temperature, and for up to 4 days at 2–8°C.
- Separated samples are stable at ≤ -20°C for up to 12 months.
6. Detection Limit:
The detection capability of the ADVIA Centaur® NT-proBNPII (PBNPII) run on the ADVIA Centaur XP system was evaluated for limit of blank (LoB), limit of detection (LoD), and limit of quantitation (LoQ) following the recommendations in CLSI EP17-A2.
LoB
Samples for LoB testing consisted of four blank native human serum samples preselected for low NT-proBNP levels. In the study, LoB was determined separately for each of three reagent lots using one instrument. With each lot, the four samples were each assayed in 12 replicates per run, one run per day over 5 days for a total of 60 measurements per sample per reagent lot. The LoB was calculated non-parametrically. The LoB was calculated separately for each reagent lot and the highest value was taken as the LoB value; 13 pg/mL.
LoD
Samples for the LoD study consisted of 10 low NT-proBNP in native human serum and pooled human serum. In the study, LoD was determined separately for each of three reagent lots using one instrument. With each lot, the samples were each assayed in replicates of 8 per run, with one run per day over five days for a total of 40 measurements per sample per reagent lot. The parametric approach described in EP17-A2 was followed to determine the
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LoD. The highest observed LoD of the three lots was the reported LoD for the assay; 20 pg/mL.
## LoQ
Samples for the LoQ study consisted of 10 low NT-proBNP in native human serum and pooled human serum. In the study, LoQ was determined separately for each of three reagent lots using one instrument. With each lot, the samples were each assayed in replicates of 8 per run, with one run per day over five days for a total of 40 measurements per sample per reagent lot. For each reagent lot, the within-laboratory precision for each sample, expressed as %CV, was plotted against the mean concentration obtained for each sample. LoQ was determined by the concentration where a power function model fit to the data equaled 20% CV. The largest estimate across all reagent lots was 35 pg/mL.
The summary results for LoB, LoD and LoQ are shown below.
| LoB | LoD | LoQ | Claimed Measuring Range |
| --- | --- | --- | --- |
| 13 pg/mL | 20 pg/mL | 21 pg/mL | 35 to 35,000 pg/mL |
## 7. Assay Cut-Off:
See Section VII D.
## B Comparison Studies:
### 1. Method Comparison with Predicate Device:
Not Applicable: see clinical studies in Section C.
### 2. Matrix Comparison:
The assay is intended for use with serum and plasma (EDTA and lithium heparin).
A matrix equivalency study to serum (no gel barrier) was conducted to support use of the ADVIA Centaur® NT-proBNPII (PBNPII) run on the ADVIA Centaur XP system with additional specimen matrix types claimed in the product labeling: Serum (no gel barrier), SST serum tube (gel barrier), RST serum tube (gel barrier), K2 EDTA plasma, and lithium heparin plasma. In the study, 50 donor matched venous specimens of the aforementioned were collected. Each specimen was tested in singlicate using one lot of the reagent kit and one instrument, and the results compared to the mean of singlicate serum measurements. The results were analyzed by Passing-Bablok linear regression with the concentration from each donor's evaluation tube (y-axis) versus the mean concentration of the serum results (x-axis).
| | Slope | Intercept | Concentration range, pg/mL | r |
| --- | --- | --- | --- | --- |
| K2EDTA plasma | 1.00 | 1 | 50 - 30134 | 1.000 |
| Lithium heparin plasma | 1.00 | 4 | 57 - 30390 | 0.999 |
| BD Vacutainer SST™ Tube | 1.00 | -2 | 54 - 30122 | 1.000 |
| BD Vacutainer RST™ Tube | 1.00 | 4 | 53 - 30237 | 1.000 |
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The study results support the sponsor's claim that serum and plasma (EDTA and lithium heparin) are acceptable sample types to be used with this assay.
## C Clinical Studies:
1. Clinical Sensitivity:
See Section VII C.3.
2. Clinical Specificity:
See Section VII C.3.
3. Other Clinical Supportive Data:
Clinical studies were performed in the emergency department and in outpatient settings.
## Emergency Department (ED)
A clinical study across 30 sites in the United States was conducted to establish the clinical performance characteristics of the ADVIA Centaur NT-proBNPII (PBNPII) run on the ADVIA Centaur XP system. In the study, subjects 22 years and older presenting with signs and symptoms that raise clinical suspicion of heart failure (HF), such as dyspnea, that were not related to trauma, were enrolled. For each patient enrollment, a serum sample was collected for determination of their NT-proBNP concentration. Data supporting the stability of the samples for the storage time and condition were provided by the sponsor. A diagnosis of whether or not acute HF for each subject was assessed by an independent, central adjudication panel. Individuals in the population were African American (45.8%) and white (50.1%), with the remaining 4.2% represented by other races.
From the 3128 subjects enrolled in the study, a total of 1148 subjects were adjudicated as acute HF and 1980 subjects were adjudicated as without acute HF.
| | Subject with Acute Heart Failure (N=1148) | Subject Without Acute Heart Failure (N=1980) |
| --- | --- | --- |
| Age Group | | |
| <50 | 20.0% (230/1148) | 34.2% (678/1980) |
| 50-75 | 41.9% (481/1148) | 41.4% (820/1980) |
| >75 | 38.1% (437/1148) | 24.3% (482/1980) |
| | | |
| Sex | | |
| Female | 41.5% (476/1148) | 52.4% (1038/1980) |
| Male | 58.5% (672/1148) | 47.6% (942/1980) |
The pretest probability of HF (prevalence of HF in the study), posttest probabilities, likelihood ratios and the two-tailed 95% CIs of the test result versus adjudicated diagnosis were determined using the age-dependent positive cut-offs (450 pg/mL for subjects 22-<50 years old; 900 pg/mL for subjects 50-<75 years old; 1800 pg/mL for subjects ≥75 years old)
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and age-independent negative (300 pg/mL) cutoff and are summarized in the following tables:
All subjects
| Age Group (years) | NT-proBNP | Cut-off (pg/mL) | Adjudicated Diagnosis | | Total | Post-test Risk (%) of HF | 95% CI Post-test Risk (%) of HF | LR+ | 95% CI LR+ |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | | | Positive | Negative | | | | | |
| <50 | Positive | >450 | 209 | 123 | 332 | 63.0% (209/332) | 57.5%,68.2% | 5.01 | 4.25, 5.91 |
| | Indeterminate | 300 – ≤450 | 8 | 19 | 27 | 29.6% (8/27) | 13.8%,50.2% | 1.24 | 0.55, 2.80 |
| | Negative | <300 | 13 | 536 | 549 | 2.4% (13/549) | 1.3%,4.0% | 0.07 | 0.04, 0.12 |
| | Total | | 230 | 678 | 908 | Pre-Test Risk of HF= 25.3% (230/908) | | | |
| 50-75 | Positive | >900 | 403 | 185 | 588 | 68.5% (403/588) | 64.6%,72.3% | 3.71 | 3.25, 4.24 |
| | Indeterminate | 300 – ≤900 | 54 | 160 | 214 | 25.2% (54/214) | 19.6%,31,6% | 0.58 | 0.43, 0.77 |
| | Negative | <300 | 24 | 475 | 499 | 4.8% (24/499) | 3.1%,7.1% | 0.09 | 0.06, 0.13 |
| | Total | | 481 | 820 | 1301 | Pre-Test Risk of HF= 37.0% (481/1301) | | | |
| >75 | Positive | >1800 | 375 | 174 | 549 | 68.3% (375/549) | 64.2%,72.2% | 2.38 | 2.10, 2.69 |
| | Indeterminate | 300 – ≤1800 | 55 | 186 | 241 | 22.8% (55/241) | 17.7%,27.7% | 0.33 | 0.25, 0.43 |
| | Negative | <300 | 7 | 122 | 129 | 5.4% (7/129) | 2.2%,10.9% | 0.06 | 0.03, 0.13 |
| | Total | | 437 | 482 | 919 | Pre-Test Risk of HF= 47.6% (437/919) | | | |
Female subjects
| Age Group (years) | NT-proBNP | Cut-off (pg/mL) | Adjudicated Diagnosis | | Total | Post-test Risk (%) of HF | 95% CI Post-test Risk (%) of HF | LR+ | 95% CI LR+ |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | | | Positive | Negative | | | | | |
| <50 | Positive | >450 | 71 | 54 | 125 | 56.8% (71/125) | 47.6%, 65.6% | 5.71 | 4.39, 7.43 |
| | Indeterminate | 300 – ≤450 | 4 | 12 | 16 | 25.0% (4/16) | 7.3%, 52.4% | 1.45 | 0.48, 4.38 |
| | Negative | <300 | 9 | 299 | 308 | 2.9% (9/308) | 1.3%, 5.5% | 0.13 | 0.07, 0.24 |
| | Total | | 84 | 365 | 449 | Pre-Test Risk of HF = 18.7% (84/449) | | | |
| 50-75 | Positive | >900 | 155 | 81 | 236 | 65.7% (155/236) | 59.2%, 71.7% | 3.97 | 3.23, 4.89 |
| | Indeterminate | 300 – ≤900 | 28 | 69 | 97 | 28.9% (28/97) | 20.1%, 39.0% | 0.84 | 0.56, 1.26 |
| | Negative | <300 | 14 | 259 | 273 | 5.1% (14/273) | 2.8%, 8.5% | 0.11 | 0.07, 0.19 |
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| Age Group (years) | NT-proBNP | Cut-off (pg/mL) | Adjudicated Diagnosis | | Total | Post-test Risk (%) of HF | 95% CI Post-test Risk (%) of HF | LR+ | 95% CI LR+ |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | | | Positive | Negative | | | | | |
| | Total | | 197 | 409 | 606 | Pre-Test Risk of HF = 32.5% (197/606) | | | |
| >75 | Positive | >1800 | 170 | 91 | 261 | 65.1% (170/261) | 59.0%, 70.9% | 2.53 | 2.12, 3.01 |
| | Indeterminate | 300 – ≤1800 | 21 | 97 | 118 | 17.8% (21/118) | 11.4%, 25.9% | 0.29 | 0.19, 0.45 |
| | Negative | <300 | 4 | 76 | 80 | 5.0% (4/80) | 1.4%, 12.3% | 0.07 | 0.03, 0.19 |
| | Total | | 195 | 264 | 459 | Pre-Test Risk of HF= 42.5% (195/459) | | | |
Male subjects
| Age Group (years) | NT-proBNP | Cut-off (pg/mL) | Adjudicated Diagnosis | | Total | Post-test Risk (%) of HF | 95% CI Post-test Risk (%) of HF | LR+ | 95% CI LR+ |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | | | Positive | Negative | | | | | |
| <50 | Positive | >450 | 138 | 69 | 207 | 66.7% (138/207) | 59.8%, 73.1% | 4.29 | 3.47, 5.30 |
| | Indeterminate | 300 – ≤450 | 4 | 7 | 11 | 36.4% (4/11) | 10.9%, 69.2% | 1.23 | 0.36, 4.12 |
| | Negative | <300 | 4 | 237 | 241 | 1.7% (4/241) | 0.5%, 4.2% | 0.04 | 0.01, 0.10 |
| | Total | | 146 | 313 | 459 | Pre-Test Risk of HF = 31.8% (146/459) | | | |
| 50-75 | Positive | >900 | 248 | 104 | 352 | 70.5% (248/352) | 65.4%, 75.2% | 3.45 | 2.91, 4.10 |
| | Indeterminate | 300 – ≤900 | 26 | 91 | 117 | 22.2% (26/117) | 15.1%, 30.8% | 0.41 | 0.27, 0.62 |
| | Negative | <300 | 10 | 216 | 226 | 4.4% (10/226) | 2.1%, 8.0% | 0.07 | 0.04, 0.12 |
| | Total | | 284 | 411 | 695 | Pre-Test Risk of HF= 40.9% (284/695) | | | |
| >75 | Positive | >1800 | 205 | 83 | 288 | 71.2% (205/288) | 65.6%, 76.3% | 2.22 | 1.86, 2.66 |
| | Indeterminate | 300 – ≤1800 | 34 | 89 | 123 | 27.6% (34/123) | 20.0%, 36.4% | 0.34 | 0.24, 0.49 |
| | Negative | <300 | 3 | 46 | 49 | 6.1% (3/49) | 1.3%, 16.9% | 0.06 | 0.02, 0.19 |
| | Total | | 242 | 218 | 460 | Pre-Test Risk of HF = 52.6% (242/460) | | | |
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Subjects WITH History of HF
| Age Group (years) | NT-proBNP | Cut-off (pg/ml) | Adjudicated Diagnosis | | Total | Post-test Risk (%) of HF | 95% CI Post-test Risk (%) of HF | LR+ | 95% CI LR+ |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | | | Positive | Negative | | | | | |
| <50 | Positive | >450 | 157 | 63 | 220 | 71.4% (157/220) | 64.9%, 77.2% | 1.72 | 1.44, 2.05 |
| | Indeterminate | 300 – ≤450 | 5 | 8 | 13 | 38.5% (5/13) | 13.9%, 68.4% | 0.43 | 0.14, 1.29 |
| | Negative | <300 | 12 | 49 | 61 | 19.7% (12/61) | 10.6%, 31.8% | 0.17 | 0.09, 0.30 |
| | Total | | 174 | 120 | 294 | Pre-Test Risk of HF = 59.2% (174/294) | | | |
| 50-75 | Positive | >900 | 312 | 94 | 406 | 76.8% (312/406) | 72.4%, 80.9% | 2.15 | 1.83, 2.54 |
| | Indeterminate | 300 – ≤900 | 44 | 49 | 93 | 47.3% (44/93) | 36.9%, 57.9% | 0.58 | 0.40, 0.85 |
| | Negative | <300 | 20 | 101 | 121 | 16.5% (20/121) | 10.4%, 24.4% | 0.13 | 0.08, 0.20 |
| | Total | | 376 | 244 | 620 | Pre-Test Risk of HF = 60.6% (376/620) | | | |
| >75 | Positive | >1800 | 265 | 86 | 351 | 75.5% (265/351) | 70.7%, 79.9% | 1.68 | 1.44, 1.95 |
| | Indeterminate | 300 – ≤1800 | 30 | 63 | 93 | 32.3% (30/93) | 22.9%, 42.7% | 0.26 | 0.18, 0.38 |
| | Negative | <300 | 4 | 14 | 18 | 22.2% (4/18) | 6.4%, 47.6% | 0.16 | 0.05, 0.47 |
| | Total | | 299 | 163 | 462 | Pre-Test Risk of HF = 64.7% (299/462) | | | |
Subjects with NO History of HF
| Age Group (years) | NT-proBNP | Cut-off (pg/mL) | Adjudicated Diagnosis | | Total | Post-test Risk (%) of HF | 95% CI Post-test Risk (%) of HF | LR+ | 95% CI LR+ |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | | | Positive | Negative | | | | | |
| <50 | Positive | >450 | 47 | 53 | 100 | 47.0% (47/100) | 36.9%, 57.2% | 8.94 | 6.84, 1.68 |
| | Indeterminate | 300 – ≤450 | 3 | 10 | 13 | 23.1% (3/13) | 5.0%, 53.8% | 3.02 | 0.86, 0.64 |
| | Negative | <300 | 1 | 451 | 452 | 0.2% (1/452) | 0.0%, 1.2% | 0.02 | 0.00, 0.16 |
| | Total | | 51 | 514 | 565 | Pre-Test Risk of HF = 9.0% (51/565) | | | |
| 50-75 | Positive | >900 | 87 | 80 | 167 | 52.1% (87/167) | 44.2%, 59.9% | 5.73 | 4.62, 7.11 |
| | Indeterminate | 300 – ≤900 | 10 | 102 | 112 | 8.9% (10/112) | 4.4%, 15.8% | 0.52 | 0.28, 0.95 |
| | Negative | <300 | 3 | 345 | 348 | 0.9% (3/348) | 0.2%, 2.5% | 0.05 | 0.02, 0.14 |
| | Total | | 100 | 527 | 627 | Pre-Test Risk of HF = 15.9% (100/627) | | | |
| >75 | Positive | >1800 | 106 | 83 | 189 | 56.1% (106/189) | 48.7%, 63.3% | 2.83 | 2.31, 3.47 |
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Subjects with eGFR <60 mL/min/1.73m²
| Age Group (years) | NT-proBNP | Cut-off (pg/mL) | Adjudicated Diagnosis | | Total | Post-test Risk (%) of HF | 95% CI Post-test Risk (%) of HF | LR+ | 95% CI LR+ |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | | | Positive | Negative | | | | | |
| <50 | Positive | >450 | 72 | 39 | 111 | 64.9% (72/111) | 55.2%, 73.7% | 1.68 | 1.35, 2.08 |
| | Indeterminate | 300 – ≤450 | 3 | 3 | 6 | 50.0% (3/6) | 11.8%, 88.2% | 0.91 | 0.19, 4.35 |
| | Negative | <300 | 1 | 27 | 28 | 3.6% (1/28) | 0.1%, 18.3% | 0.03 | 0.00, 0.24 |
| | Total | | 76 | 69 | 145 | Pre-Test Risk of HF = 52.4% (76/145) | | | |
| 50-75 | Positive | >900 | 176 | 82 | 258 | 68.2% (176/258) | 62.2%, 73.9% | 2.08 | 1.75, 2.48 |
| | Indeterminate | 300 – ≤900 | 19 | 36 | 55 | 34.5% (19/55) | 22.2%, 48.6% | 0.51 | 0.30, 0.86 |
| | Negative | <300 | 7 | 78 | 85 | 8.2% (7/85) | 3.4%, 16.2% | 0.09 | 0.04, 0.18 |
| | Total | | 202 | 196 | 398 | Pre-Test Risk of HF = 50.8% (202/398) | | | |
| >75 | Positive | >1800 | 260 | 105 | 365 | 71.2% (260/365) | 66.3%, 75.8% | 1.99 | 0.73, 2.30 |
| | Indeterminate | 300 – ≤1800 | 22 | 88 | 110 | 20.0% (22/110) | 13.0%, 28.7% | 0.20 | 0.13, 0.31 |
| | Negative | <300 | 0 | 34 | 34 | 0.0% (0/34) | NA | NA | NA |
| | Total | | 282 | 227 | 509 | Pre-Test Risk of HF = 55.4% (282/509) | | | |
Subjects with eGFR ≥60 mL/min/1.73m²
| Age Group (years) | NT-proBNP | Cut-off (pg/mL) | Adjudicated Diagnosis | | Total | Post-test Risk (%) of HF | 95% CI Post-test Risk (%) of HF | LR+ | 95% CI LR+ |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | | | Positive | Negative | | | | | |
| <50 | Positive | >450 | 137 | 83 | 220 | 62.3% (137/220) | 55.5%, 68.7% | 6.22 | 5.07, 7.64 |
| | Indeterminate | 300 – ≤450 | 4 | 15 | 19 | 21.1% (4/19) | 6.1%, 45.6% | 1.01 | 0.34, 2.99 |
| | Negative | <300 | 11 | 475 | 486 | 2.3% (11/486) | 1.1%, 4.0% | 0.09 | 0.05, 0.15 |
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| Age Group (years) | NT-proBNP | Cut-off (pg/mL) | Adjudicated Diagnosis | | Total | Post-test Risk (%) of HF | 95% CI Post-test Risk (%) of HF | LR+ | 95% CI LR+ |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | | | Positive | Negative | | | | | |
| | Total | | 152 | 573 | 725 | Pre-Test Risk of HF = 21.0% (152/725) | | | |
| 50-75 | Positive | >900 | 223 | 101 | 324 | 68.8% (223/324) | 63.5%, 73.8% | 4.87 | 4.04, 5.87 |
| | Indeterminate | 300 – ≤900 | 34 | 122 | 156 | 21.8% (34/156) | 15.6%, 29.1% | 0.61 | 0.43, 0.87 |
| | Negative | <300 | 17 | 381 | 398 | 4.3% (17/398) | 2.5%, 6.8% | 0.10 | 0.06, 0.16 |
| | Total | | 274 | 604 | 878 | Pre-Test Risk of HF = 31.2% (274/878) | | | |
| >75 | Positive | >1800 | 113 | 67 | 180 | 62.8% (113/180) | 55.3%, 69.9% | 2.77 | 2.21, 3.47 |
| | Indeterminate | 300 – ≤1800 | 32 | 97 | 129 | 24.8% (32/129) | 17.6%, 33.2% | 0.54 | 0.38, 0.77 |
| | Negative | <300 | 7 | 86 | 93 | 7.5% (7/93) | 3.1%, 14.9% | 0.13 | 0.06, 0.28 |
| | Total | | 152 | 250 | 402 | Pre-Test Risk of HF = 37.8% (152/402) | | | |
Subjects with BMI $\geq 30\mathrm{kg / m2}$
| Age Group (years) | NT-proBNP | Cut-off (pg/mL) | Adjudicated Diagnosis | | Total | Post-test Risk (%) of HF | 95% CI Post-test Risk (%) of HF | LR+ | 95% CI LR+ |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | | | Positive | Negative | | | | | |
| <50 | Positive | >450 | 147 | 69 | 216 | 68.1% (147/216) | 61.4%, 74.2% | 5.13 | 4.11, 6.40 |
| | Indeterminate | 300 – ≤450 | 7 | 10 | 17 | 41.2% (7/17) | 18.4%, 67.1% | 1.69 | 0.65, 4.35 |
| | Negative | <300 | 13 | 323 | 336 | 3.9% (13/336) | 2.1%, 6.5% | 0.10 | 0.06, 0.16 |
| | Total | | 167 | 402 | 569 | Pre-Test Risk of HF = 29.3% (167/569) | | | |
| 50-75 | Positive | >900 | 217 | 67 | 284 | 76.4% (217/284) | 71%, 81.2% | 4.81 | 3.83, 6.05 |
| | Indeterminate | 300 – ≤900 | 46 | 86 | 132 | 34.8% (46/132) | 26.8%, 43.6% | 0.79 | 0.57, 1.10 |
| | Negative | <300 | 23 | 272 | 295 | 7.8% (23/295) | 5.0%, 11.5% | 0.13 | 0.08, 0.19 |
| | Total | | 286 | 425 | 711 | Pre-Test Risk of HF = 40.2% (286/711) | | | |
| >75 | Positive | >1800 | 111 | 38 | 149 | 74.5% (111/149) | 66.7%, 81.3% | 3.02 | 2.26, 4.04 |
| | Indeterminate | 300 – ≤1800 | 30 | 61 | 91 | 33.0% (30/91) | 23.5%, 43.6% | 0.51 | 0.35, 0.74 |
| | Negative | <300 | 5 | 52 | 57 | 8.8% (5/57) | 2.9%, 19.3% | 0.10 | 0.04, 0.24 |
| | Total | | 146 | 151 | 297 | Pre-Test Risk of HF = 49.2% (146/297) | | | |
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Subjects with BMI $< 30\mathrm{kg} / \mathrm{m}^2$
| Age Group (years) | NT-proBNP | Cut-off (pg/mL) | Adjudicated Diagnosis | | Total | Post-test Risk (%) of HF | 95% CI Post-test Risk (%) of HF | LR+ | 95% CI LR+ |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | | | Positive | Negative | | | | | |
| <50 | Positive | >450 | 52 | 52 | 104 | 50.0% (52/104) | 40.0%, 60.0% | 4.77 | 3.75, 6.07 |
| | Indeterminate | 300 – ≤450 | 0 | 8 | 8 | 0.0% (0/8) | NA | NA | NA |
| | Negative | <300 | 0 | 188 | 188 | 0.0% (0/188) | NA | NA | NA |
| | Total | | 52 | 248 | 300 | Pre-Test Risk of HF = 17.3% (52/300) | | | |
| 50-75 | Positive | >900 | 168 | 101 | 269 | 62.5% (168/269) | 56.4%, 68.3% | 3.45 | 2.92, 4.08 |
| | Indeterminate | 300 – ≤900 | 6 | 71 | 77 | 7.8% (6/77) | 2.9%, 16.2% | 0.18 | 0.08, 0.40 |
| | Negative | <300 | 0 | 189 | 189 | 0.0% (0/189) | NA | NA | NA |
| | Total | | 174 | 361 | 535 | Pre-Test Risk of HF = 32.5% (174/535) | | | |
| >75 | Positive | >1800 | 240 | 131 | 371 | 64.7% (240/371) | 59.6%, 69.6% | 2.12 | 1.85, 2.42 |
| | Indeterminate | 300 – ≤1800 | 21 | 107 | 128 | 16.4% (21/128) | 10.5%, 24.0% | 0.23 | 0.15, 0.35 |
| | Negative | <300 | 1 | 65 | 66 | 1.5% (1/66) | 0.0%, 8.2% | 0.02 | 0.00, 0.13 |
| | Total | | 262 | 303 | 565 | Pre-Test Risk of HF = 46.4% (262/565) | | | |
Subjects WITH Comorbidities (Diabetes, Hypertension, Kidney Disease/Renal Dysfunction)
| Age Group (years) | NT-proBNP | Cut-off (pg/mL) | Adjudicated Diagnosis | | Total | Post-test Risk (%) of HF | 95% CI Post-test Risk (%) of HF | LR+ | 95% CI LR+ |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | | | Positive | Negative | | | | | |
| <50 | Positive | >450 | 173 | 89 | 262 | 66.0% (173/262) | 59.9%, 71.7% | 3.99 | 3.30, 4.82 |
| | Indeterminate | 300 – ≤450 | 7 | 13 | 20 | 35.0% (7/20) | 15.4%, 59.2% | 1.11 | 0.45, 2.72 |
| | Negative | <300 | 11 | 290 | 301 | 3.7% (11/301) | 1.8%, 6.4% | 0.08 | 0.04, 0.14 |
| | Total | | 191 | 392 | 583 | Pre-Test Risk of HF = 32.8% (191/583) | | | |
| 50-75 | Positive | >900 | 374 | 160 | 534 | 70.0% (374/534) | 66.0%, 73.9% | 3.67 | 3.18, 4.23 |
| | Indeterminate | 300 – ≤900 | 52 | 141 | 193 | 26.9% (52/193) | 20.8%, 33.8% | 0.58 | 0.43, 0.78 |
| | Negative | <300 | 24 | 405 | 429 | 5.6% (24/429) | 3.6%, 8.2% | 0.09 | 0.06, 0.14 |
| | Total | | 450 | 706 | 1156 | Pre-Test Risk of HF = 38.9% (450/1156) | | | |
| >75 | Positive | >1800 | 351 | 155 | 506 | 69.4% (351/506) | 65.1%, 73.4% | 2.41 | 2.11, 2.76 |
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| Age Group (years) | NT-proBNP | Cut-off (pg/mL) | Adjudicated Diagnosis | | Total | Post-test Risk (%) of HF | 95% CI Post-test Risk (%) of HF | LR+ | 95% CI LR+ |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | | | Positive | Negative | | | | | |
| | Indeterminate | 300 –≤1800 | 52 | 168 | 220 | 23.6% (52/220) | 18.2%, 29.8% | 0.33 | 0.25, 0.44 |
| | Negative | <300 | 7 | 114 | 121 | 5.8% (7/121) | 2.4%, 11.6% | 0.07 | 0.03, 0.14 |
| | Total | | 410 | 437 | 847 | Pre-Test Risk of HF = 48.4% (410/847) | | | |
Subjects WITHOUT Comorbidities (Diabetes, Hypertension, Kidney Disease/Renal Dysfunction)
| Age Group (years) | NT-proBNP | Cut-off (pg/mL) | Adjudicated Diagnosis | | Total | Post-test Risk (%) of HF | 95% CI Post-test Risk (%) of HF | LR+ | 95% CI LR+ |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | | | Positive | Negative | | | | | |
| <50 | Positive | >450 | 29 | 31 | 60 | 48.3% (29/60) | 35.2%, 61.6% | 7.72 | 5.44, 10.94 |
| | Indeterminate | 300 – ≤450 | 1 | 6 | 7 | 14.3% (1/7) | 0.4%, 57.9% | 1.38 | 0.17, 11.06 |
| | Negative | <300 | 2 | 227 | 229 | 0.9% (2/229) | 0.1%, 3.1% | 0.07 | 0.02, 0.28 |
| | Total | | 32 | 264 | 296 | Pre-Test Risk of HF = 10.8% (32/296) | | | |
| 50-75 | Positive | >900 | 25 | 23 | 48 | 52.1% (25/48) | 37.2%, 66.7% | 4.23 | 2.90, 6.16 |
| | Indeterminate | 300 – ≤900 | 2 | 18 | 20 | 10.0% (2/20) | 1.2%, 31.7% | 0.43 | 0.11, 1.75 |
| | Negative | <300 | 0 | 64 | 64 | 0.0% (0 /64) | NA | NA | NA |
| | Total | | 27 | 105 | 132 | Pre-Test Risk of HF = 20.5% (27/132) | | | |
| >75 | Positive | >1800 | 22 | 18 | 40 | 55.0% (22/40) | 38.5%, 70.7% | 2.10 | 1.44, 3.08 |
| | Indeterminate | 300 – ≤1800 | 3 | 17 | 20 | 15.0% (3/20) | 3.2%, 37.9% | 0.30 | 0.10, 0.93 |
| | Negative | <300 | 0 | 8 | 8 | 0.0% (0/8) | NA | NA | NA |
| | Total | | 25 | 43 | 68 | Pre-Test Risk of HF = 36.8% (25/68) | | | |
The sponsor included the following statements in their instructions for use concerning the performance of their device in ED settings in certain clinical subgroups:
- Patients with BMI $\geq 30\mathrm{kg / m2}$ had a higher rate of false negatives compared to those patients with BMI $< 30\mathrm{kg / m2}$ . Of the total false negatives (44/1148), 41 (93%) came from patients with BMI $\geq 30\mathrm{kg / m2}$ , 1 (2.2%) came from a patient with a BMI $< 30\mathrm{kg / m2}$ , and 2 (4.4%) were from patients with unknown BMI.
- Patients with eGFR $< 60 \mathrm{~mL} / \mathrm{min} / 1.73 \mathrm{~m}^{2}$ had a higher rate of false positives compared to those patients with eGFR $\geq 60 \mathrm{~mL} / \mathrm{min} / 1.73 \mathrm{~m}^{2}$ . Of the 492 total patients with eGFR $< 60 \mathrm{~mL} / \mathrm{min} / 1.73 \mathrm{~m}^{2}$ adjudicated as no acute HF, 226 (45.9%) had PBNPII concentrations $\geq$ ASC. Of
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the 1427 total patients with eGFR ≥60 mL/min/1.73m2 adjudicated as no acute HF, 251 (17.6%) had PBNPII concentrations ≥ ASC. Sixty-one (61) patients adjudicated as no acute HF (3.1%), had unknown eGFR.
- Patients with a history of HF had a higher rate of false positives compared to those patients with no history of HF. Of the 527 total patients with a history of HF adjudicated as no acute HF, 243 (46.1%) had PBNPII concentrations ≥ ASC. Of the 1338 total patients with no history of HF adjudicated as no acute HF, 216 (16.1%) had PBNPII concentrations ≥ ASC. Of the 1980 patients adjudicated as no acute HF, 115 (5.8%) had unknown history of HF.
Variation in NT-proBNP concentrations due to high BMI, low GFR, and history of HF are extensively discussed in published literature on Natriuretic Peptides.
## Outpatient (OP)
A clinical study across 28 OP sites in the United States was conducted to establish the clinical performance characteristics of the ADVIA Centaur® NT-proBNPII (PBNPII) run on the ADVIA Centaur XP system. In the study, subjects 22 years and older presenting with signs and symptoms that raise clinical suspicion of heart failure (HF), such as dyspnea, that were not related to trauma, were enrolled in the study. For each patient, a serum sample was collected for determination of their NT-proBNP concentration. Data supporting the stability of the samples for the storage time and condition were provided by the sponsor. A diagnosis of new onset of HF or not was assessed by an independent, central adjudication panel. Individuals in the population were African American (19.7%) and white (78.4%), with the remaining 1.8% represented by other races. The clinical performance of the device using cutoff of 125 pg/mL was evaluated. From the 1033 subjects enrolled in the study, a total of 185 subjects were adjudicated as new onset HF and 848 subjects were adjudicated as without HF. The clinical performance of the device is summarized below:
| Group | | Sensitivity | Specificity | PPV | NPV |
| --- | --- | --- | --- | --- | --- |
| Males ≤75 years | Estimate | 85.5% (53/62) | 68.9% (179/260) | 39.6% (53/134) | 95.2% (179/188) |
| | 95% CI | 74.2%, 93.1% | 62.8%, 74.4% | 31.2%, 48.4% | 91.1%, 97.8% |
| Females ≤75 years | Estimate | 79.2% (57/72) | 70.8% (335/473) | 29.2% (57/195) | 95.7% (335/350) |
| | 95% CI | 67.5%, 87.8% | 67.0%, 74.9% | 23.0%, 36.2% | 93.0%, 97.6% |
| Males >75 years | Estimate | 90.5% (19/21) | 37.2% (16/43) | 41.3% (19/46) | 88.9% (16/18) |
| | 95% CI | 69.6%, 98.8% | 22.8%, 51.7% | 27.0%, 56.8% | 65.3%, 98.6% |
| Females >75 years | Estimate | 100% (30/30) | 20.8% (15/72) | 34.5% (30/87) | 100% (15/15) |
| | 95% CI | 88.4%, 100% | 2.2%, 32.0% | 24.6%, 45.4% | 78.2%, 100% |
| Group | | Sensitivity | Specificity | PPV | NPV |
| --- | --- | --- | --- | --- | --- |
| BMI <30 kg/m² | Estimate | 88.2% (67/76) | 60.6% (238/393) | 30.2% (67/222) | 96.4% (238/247) |
| | 95% CI | (87.7%, 99.6%) | (63.5%, 75.0%) | (31.9%, 49.1%) | (96.1%, 99.9%) |
| BMI ≥30 kg/m² | Estimate | 84.4% (92/109) | 67.5% (303/449) | 38.7% (92/238) | 94.7% (303/320) |
| | 95% CI | (76.2%, 90.6%) | (62.9%, 71.8%) | (32.4%, 45.2%) | (91.6%, 96.9%) |
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| Group | | Sensitivity | Specificity | PPV | NPV |
| --- | --- | --- | --- | --- | --- |
| Comorbidities present | Estimate | 86.4% (153/177) | 60.7% (396/652) | 37.4% (153/409) | 94.3% (396/420) |
| | 95% CI | (80.5%, 91.1%) | (56.9%, 64.5%) | (32.7%, 42.3%) | (91.6%, 96.3%) |
| Comorbidities not present | Estimate | 75.0% (6/8) | 76.0% (136/179) | 12.2% (6/49) | 98.6% (136/138) |
| | 95% CI | (34.9, 96.8%) | (69.0%, 82.0%) | (4.6%, 24.8%) | (94.9%, 99.8%) |
| Group | | Sensitivity | Specificity | PPV | NPV |
| --- | --- | --- | --- | --- | --- |
| eGFR <60 mL/min/1.73 m² | Estimate | 100.0% (33/33) | 32.7% (18/55) | 47.1% (33/70) | 100.0% (18/18) |
| | 95% CI | (89.4%, 100.0%) | (20.7%, 46.7%) | (35.1%, 59.5%) | (81.5%, 100.0%) |
| eGFR ≥60 mL/min/1.73 m² | Estimate | 96.4% (4/56) | 69.5% (182/262) | 40.3% (54/134) | 98.9% (182/184) |
| | 95% CI | (87.7%, 99.6%) | (63.5%, 75.0%) | (31.9%, 49.1%) | (96.1%, 99.9%) |
## D Clinical Cut-Off:
The sponsor describes the following cut-offs for patients presenting to ED settings where HF is suspected:
| Age Group (Years) | PBNPII Results (pg/mL) | Interpretation |
| --- | --- | --- |
| All | <300 | Negative: Heart Failure Unlikely |
| <50 | ≥ 300 - ≤ 450 | Gray Zone: Result Indeterminate – Consider other reasons for NT-proBNP elevation |
| 50-75 | ≥ 300 - ≤ 900 | |
| >75 | ≥ 300 - ≤ 1800 | |
| <50 | > 450 | Positive: Heart Failure Likely |
| 50-75 | > 900 | |
| >75 | > 1800 | |
For patients presenting to outpatient facilities where HF is suspected (but has not been previously diagnosed), the following cut-off is described:
| Age Group (Years) | PBNPII Results (pg/mL) | Interpretation |
| --- | --- | --- |
| All | < 125 | Negative: Heart Failure Unlikely |
| All | ≥ 125 | Positive: Heart Failure Likely |
## E Expected Values/Reference Range:
The expected values of NT-proBNP in healthy adults was established in a study conducted in accordance with CLSI EP28-A3c.
In the study, serum levels of NT-proBNP were assayed with the ADVIA Centaur® NT-proBNPII (PBNPII) on a total of 723 apparently healthy subjects (362 females and 361 males) without HF. These apparently healthy subjects were self-reported without heart failure or disease. The results were subgrouped by gender, with each group of females and males was stratified into three age groups of: < 50 years, 50-75 years, and > 75 years. The data was analyzed by a non-parametric method and summarized as follows.
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| Sex | Age years | N | Mean pg/mL | SD pg/mL | Median pg/mL | 95th Percentile pg/mL |
| --- | --- | --- | --- | --- | --- | --- |
| Male | <50 | 120 | 56 | 95. | <35 | 124 |
| | 50-75 | 121 | 78 | 136.4 | <35 | 322 |
| | >75 | 120 | 56 | 50.6 | <35 | 154 |
| Female | <50 | 122 | 57 | 33.1 | 37 | 133 |
| | 50-75 | 120 | 77 | 124.0 | 40 | 192 |
| | >75 | 120 | 89 | 216.4 | 43 | 178 |
| Overall | Overall | 723 | 6 | 124.9 | <35 | 163 |
# VIII Proposed Labeling:
The labeling does support the finding of substantial equivalence for this device.
# IX Conclusion:
The submitted information in this premarket notification is complete and does support a substantial equivalence decision.
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