Access NT-proBNP
Device Facts
| Record ID | K232164 |
|---|---|
| Device Name | Access NT-proBNP |
| Applicant | Beckman Coulter, Inc. |
| Product Code | NBC · Clinical Chemistry |
| Decision Date | Apr 12, 2024 |
| Decision | SESE |
| Submission Type | Traditional |
| Regulation | 21 CFR 862.1117 |
| Device Class | Class 2 |
Intended Use
The Access NT-proBNP assay is a paramagnetic particle, chemiluminescent immunoassay for the quantitative determination of N-terminal pro B-type natriuretic peptide levels in human serum and plasma using the automated Dxl Access Immunoassay Analyzers to aid in the following: 1. diagnosis of patients suspected of having acute heart failure in the Emergency Department 2. assessment of heart failure severity 3. risk stratification of patients with heart failure 4. risk stratification of patients with acute coronary syndrome
Device Story
Access NT-proBNP is a two-site sandwich chemiluminescent immunoassay for quantitative measurement of NT-proBNP in human serum/plasma. It uses paramagnetic particles coated with monoclonal anti-NT-proBNP antibodies and an alkaline phosphatase-conjugated monoclonal anti-NT-proBNP antibody. The device operates on automated Dxl Access Immunoassay Analyzers in clinical laboratory settings. During analysis, the analyte binds to the solid-phase antibody and the conjugate; after magnetic separation and washing, a chemiluminescent substrate is added. Light output, measured by a luminometer, is directly proportional to analyte concentration. Results are used by clinicians to aid in diagnosing acute heart failure, assessing disease severity, and performing risk stratification for heart failure and acute coronary syndrome. The device provides objective data to support clinical decision-making, potentially improving patient management and outcomes.
Clinical Evidence
Prospective multicenter study of 2,384 patients presenting to the ED with suspected acute heart failure. Adjudicated diagnosis by independent committee. AUC for rule-out was 0.8692 (95% CI: 0.8549-0.8835). Rule-in AUCs: <50 years (0.8919), 50-75 years (0.8802), >75 years (0.8122). Comparison to predicate showed comparable diagnostic accuracy (Access AUC 0.8536 vs. Elecsys AUC 0.8562). Significant trend relationship (p<0.0001) between NT-proBNP values and NYHA functional classification.
Technological Characteristics
Paramagnetic particle, chemiluminescent sandwich immunoassay. Materials: monoclonal anti-NT-proBNP antibodies, alkaline phosphatase conjugate, chemiluminescent substrate. Form factor: reagent packs for automated Dxl Access Immunoassay Analyzers. Connectivity: standalone analyzer system. Standards: CLSI EP05-A3 (precision), EP06-ED2 (linearity), EP17-A2 (detection capability), EP07-A3 (interference).
Indications for Use
Indicated for patients 22 years and older presenting with signs and symptoms of acute heart failure in the Emergency Department. Excludes patients with stage 4 or 5 chronic kidney disease, chronic dialysis, or dyspnea not secondary to 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
- Elecsys®proBNP II Immunoassay (K072437)
Related Devices
- K072189 — PATHFAST NTPROBNP AND D-DIMER TESTS · Mitsubishi Kagaku Iatron · Feb 5, 2008
- K241176 — Alere NT-proBNP for Alinity i Reagent Kit · Axis-Shield Diagnostics, Ltd. · Jan 16, 2025
- K220265 — ADVIA Centaur® NT-proBNPII (PBNPII) · Siemens Healthcare Diagnostics, Inc. · Sep 24, 2023
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
K232164
B Applicant
Beckman Coulter Inc.
C Proprietary and Established Names
Access NT-proBNP
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 Assay
B Measurand:
N-terminal pro B-type natriuretic peptide (NT-proBNP)
C Type of Test:
Chemiluminescent Assay
Food and Drug Administration
10903 New Hampshire Avenue
Silver Spring, MD 20993-0002
www.fda.gov
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K232164 - Page 2 of 30
# III Intended Use/Indications for Use:
## A Intended Use(s):
See Indications for Use below.
## B Indication(s) for Use:
The Access NT-proBNP assay is a paramagnetic particle, chemiluminescent immunoassay for the quantitative determination of N-terminal pro B-type natriuretic peptide levels in human serum and plasma using the automated DxI Access Immunoassay Analyzers to aid in the following:
1. diagnosis of patients suspected of having acute heart failure in the Emergency Department
2. assessment of heart failure severity
3. risk stratification of patients with heart failure
4. risk stratification of patients with acute coronary syndrome
## C Special Conditions for Use Statement(s):
Rx - For Prescription Use Only
## D Special Instrument Requirements:
DxI 9000 Access Immunoassay Analyzer
# IV Device/System Characteristics:
## A Device Description:
The Access NT-proBNP assay is a paramagnetic particle, chemiluminescent immunoassay for the quantitative determination of NT-proBNP levels in human serum and plasma using the automated DxI Access immunoassay.
The Access NT-proBNP reagent pack is ready to use. Each kit contains 2x100 test reagent packs (cartridge). Each cartridge consists of the following reagents:
| Well | Contents | Ingredients |
| --- | --- | --- |
| R1a | 3.37 mL | Dynabeads® paramagnetic particles coated with rabbit anti-human NT-proBNP monoclonal antibody in TRIS buffered saline with surfactant, protein (bovine), < 0.1% sodium azide, and 0.1% ProClin 300. |
| R1b | 12.70 mL | MOPS buffered saline with surfactant, protein (bovine, murine, rabbit), < 0.1% sodium azide, and 0.1% ProClin 300. |
| R1c | 8.75 mL | 0.10N Sodium Hydroxide |
| R1d | 3.10 mL | Human-mouse anti-NT-proBNP chimeric monoclonal antibody alkaline phosphatase conjugate in MES buffered saline with |
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Materials needed but not supplied with the reagent kit include Access NT-proBNP calibrators, quality control materials (commercial control material), Lumi-Phos PRO, and UniCel DxI wash buffer II.
## B Principle of Operation:
The Access NT-proBNP is a two-site immuno-enzymatic (“sandwich”) assay. Paramagnetic particles coated with monoclonal anti-NT-proBNP antibody and monoclonal anti-NT-proBNP antibody conjugated to alkaline phosphatase are added to a reaction vessel along with a surfactant-containing buffer and serum or plasma samples. The human NT-proBNP binds to the anti-NT-proBNP antibody on the solid phase, while the anti-NT-proBNP antibody-alkaline phosphatase conjugate reacts with a different antigenic site on the NT-proBNP molecule.
After incubation, materials bound to the solid phase are held in a magnetic field while unbound materials are washed away. Then the chemiluminescent substrate is added to the vessel and light generated by the reaction is measured with a luminometer. The light production is directly proportional to the concentration of analyte in the sample. Analyte concentration is automatically determined from a stored calibration.
## 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): | K232164 | K072437 |
| --- | --- | --- |
| Device Trade Name | Access NT-proBNP | Elecsys® proBNP II Immunoassay |
| General Device Characteristic Similarities | | |
| Intended Use/Indications For Use | For the quantitative determination of N-terminal pro B-type natriuretic peptide (NT- | Same |
K232164 - Page 3 of 30
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| Device & Predicate Device(s): | K232164 | K072437 |
| --- | --- | --- |
| | proBNP) levels in human serum and plasma | |
| Antibody | Monoclonal anti-NT-proBNP | Same |
| Sample Type | Serum and Plasma | Same |
| General Device Characteristic Differences | | |
| High Dose Hook Effect | No high dose hook effect observed up to 400,000 ng/L (pg/mL) | No high dose hook effect observed up to 300,000 pg/mL |
| Measuring Range | 10.0 – 35,000 ng/L (pg/mL) | 5 – 35,000 pg/mL |
VI Standards/Guidance Documents Referenced:
Clinical & Laboratory Standards Institute (CLSI) EP-09c Measurement Procedure Comparison and Bias Estimation Using Patient Samples
CLSI EP05-A3: Evaluation of Precision of Quantitative Measurement Procedures; 3rd Edition
CLSI EP17-A2: Evaluation of Detection Capability for Clinical Laboratory Measurement Procedures; 2nd Edition
CLSI EP 07: Interference Testing In Clinical Chemistry; 3rd Edition
CLSI EP25-A: Evaluation of Stability of In Vitro Diagnostic Reagents; Approved Guideline; 2009.
CLSI EP 06: Evaluation of the Linearity of Quantitative Measurement Procedures; 2nd Edition
Class II Special Control Guidance Document for B-Type Natriuretic Peptide Premarket Notifications; Final Guidance for Industry and FDA Reviewers (November 30, 2000).
K232164 - Page 4 of 30
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# VII Performance Characteristics (if/when applicable):
# A Analytical Performance:
# 1. Precision/Reproducibility:
Single - Site Precision Study
A single site precision study was performed following the CLSI guideline EP05-A3. A panel of seven (7) lithium heparin samples, seven (7) serum samples and seven (7) $\mathrm{K}_2$ EDTA plasma samples with concentrations of NT-proBNP spanning the measuring range were used in the study. Samples were assayed for twenty-three (23) days with two runs per day and two replicates per run using one (1) DxI 9000 Access Immunoassay Analyzer. Each sample was tested across three (3) reagent pack lots and one (1) calibrator lot. The overall estimate includes within-run, between-run, between-day and between reagent lot variance components.
| Sample | Sample Type | N | Mean (ng/L) | Repeatability (Within Run) | | Between Run | | Between Day | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | | | | SD | %CV | SD | %CV | SD | %CV |
| 1 | K2EDTA | 258 | 31 | 0.7 | 2.4 | 0.6 | 2.0 | 0.5 | 1.7 |
| 2 | | 252 | 132 | 2.8 | 2.1 | 6.8 | 5.2 | 0.0 | 0.0 |
| 3 | | 272 | 272 | 5.3 | 1.9 | 15.9 | 5.8 | 0.0 | 0.0 |
| 4 | | 251 | 387 | 8.7 | 2.2 | 25.6 | 6.6 | 0.0 | 0.0 |
| 5 | | 257 | 1912 | 48.7 | 2.5 | 73.5 | 3.8 | 52.0 | 2.7 |
| 6 | | 258 | 12426 | 233.1 | 1.9 | 635.4 | 5.1 | 0.0 | 0.0 |
| 7 | | 258 | 27061 | 534.1 | 2.0 | 1465.7 | 5.4 | 0.0 | 0.0 |
| 1 | LiHep | 254 | 38 | 1.0 | 2.7 | 1.4 | 3.8 | 0.7 | 1.8 |
| 2 | | 252 | 129 | 2.8 | 2.2 | 2.7 | 2.1 | 1.5 | 1.2 |
| 3 | | 252 | 290 | 6.0 | 2.1 | 6.3 | 2.2 | 0.0 | 0.0 |
| 4 | | 257 | 437 | 9.6 | 2.2 | 9.6 | 2.2 | 6.5 | 1.5 |
| 5 | | 258 | 1705 | 46.3 | 2.7 | 54.7 | 3.2 | 21.7 | 1.3 |
| 6 | | 258 | 10780 | 178.0 | 1.7 | 416 | 3.9 | 0.0 | 0.0 |
| 7 | | 258 | 23014 | 403.0 | 1.8 | 942.5 | 4.1 | 0.0 | 0.0 |
| 1 | Serum | 258 | 33 | 0.9 | 2.8 | 0.8 | 2.4 | 0.7 | 2.0 |
| 2 | | 257 | 118 | 2.9 | 2.5 | 2.5 | 2.1 | 2.5 | 2.1 |
| 03 | | 258 | 288 | 6.2 | 2.2 | 12.5 | 4.4 | 0.0 | 0 |
| 4 | | 252 | 450 | 16.0 | 3.6 | 13.5 | 3.0 | 0.0 | 0 |
| 5 | | 258 | 1988 | 49.5 | 2.5 | 75.4 | 3.8 | 0.0 | 0 |
| 6 | | 257 | 11497 | 188.9 | 1.6 | 475.5 | 4.1 | 0.0 | 0 |
| 7 | | 252 | 25260 | 514.9 | 2.0 | 393.6 | 1.6 | 269.0 | 1.1 |
K232164 - Page 5 of 30
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| Sample | Sample Type | N | Mean (ng/L) | Between-Reagent Lot | | Overall | |
| --- | --- | --- | --- | --- | --- | --- | --- |
| | | | | SD | %CV | SD | %CV |
| 1 | K2EDTA | 258 | 31 | 0.6 | 2.0 | 1.3 | 4.0 |
| 2 | | 252 | 132 | 2.3 | 1.7 | 7.7 | 5.8 |
| 3 | | 272 | 272 | 6.2 | 2.3 | 17.9 | 6.6 |
| 4 | | 251 | 387 | 9.2 | 2.4 | 28.6 | 7.4 |
| 5 | | 257 | 1912 | 114.1 | 6.0 | 153.3 | 8.0 |
| 6 | | 258 | 12426 | 390.2 | 3.1 | 781.2 | 6.3 |
| 7 | | 258 | 27061 | 880.8 | 3.3 | 1791.5 | 6.6 |
| 1 | LiHep | 254 | 38 | 0.5 | 1.4 | 2.0 | 5.2 |
| 2 | | 252 | 129 | 1.8 | 1.4 | 4.5 | 3.5 |
| 3 | | 257 | 290 | 6.5 | 2.3 | 10.9 | 3.8 |
| 4 | | 258 | 437 | 14.1 | 3.2 | 20.6 | 4.7 |
| 5 | | 258 | 1705 | 90.1 | 5.3 | 117.2 | 6.9 |
| 6 | | 258 | 10780 | 324.3 | 3.0 | 556.7 | 5.2 |
| 7 | | 258 | 23014 | 755.6 | 3.3 | 1273.4 | 5.5 |
| 1 | Serum | 258 | 33 | 0.5 | 1.6 | 1.5 | 4.5 |
| 2 | | 257 | 118 | 2.3 | 1.9 | 5.1 | 4.3 |
| 3 | | 258 | 288 | 3.8 | 1.3 | 14.5 | 5.0 |
| 4 | | 252 | 450 | 15.4 | 3.4 | 26.0 | 5.8 |
| 5 | | 258 | 1988 | 110.7 | 5.6 | 142.8 | 7.2 |
| 6 | | 257 | 11497 | 369.6 | 3.2 | 631.2 | 5.5 |
| 7 | | 252 | 25260 | 862.3 | 3.4 | 1111.7 | 4.4 |
## Multi - Site Precision Study
The reproducibility performance was established with a multi-site precision evaluation. The study was performed at three sites. Samples for testing were comprised of samples with 7 concentration levels for each sample matrix type with concentrations of NT-proBNP spanning the assay measuring range. Samples were assayed in duplicate per run, two (2) runs per day for five (5) days (n=20 per sample per site per sample type). Two calibrator lots and three reagent lots were used at three (3) sites, with each site receiving one reagent lot. The results are all summarized below.
K232164 - Page 6 of 30
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All Sites Combined Lithium Heparin Reproducibility
| Sample | N | Mean (ng/L) | Repeatability | | Between Run | | Between Day | | Between Site/Lot | | Reproducibility | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | | | SD | %CV | SD | %CV | SD | %CV | SD | %CV | SD | %CV |
| 1 | 60 | 38.24 | 1.3 | 3.5 | 0.7 | 1.7 | 0.0 | 0.0 | 2.6 | 6.9 | 3.0 | 7.9 |
| 2 | 59 | 127.31 | 3.6 | 2.9 | 0.0 | 0.0 | 0.8 | 0.6 | 7.1 | 5.6 | 8.0 | 6.3 |
| 3 | 59 | 288.19 | 7.8 | 2.7 | 2.0 | 0.7 | 4.7 | 1.6 | 14.0 | 4.9 | 16.8 | 5.8 |
| 4 | 60 | 428.00 | 6.5 | 1.5 | 7.3 | 1.7 | 0.0 | 0.0 | 17.4 | 4.1 | 20.0 | 4.7 |
| 5 | 60 | 1708.42 | 33.7 | 2.0 | 29.5 | 1.7 | 23.2 | 1.4 | 5.2 | 0.3 | 50.7 | 3.0 |
| 6 | 60 | 11096.6 | 191.6 | 1.7 | 135.2 | 1.2 | 91.7 | 0.8 | 159.7 | 1.4 | 298.2 | 2.7 |
| 7 | 60 | 23848.6 | 527.5 | 2.2 | 367.5 | 1.5 | 0.0 | 0.0 | 344.0 | 1.4 | 724.4 | 3.0 |
All Sites Combined Serum Reproducibility
| Sample | N | Mean (ng/L) | Repeatability (Within Run) | | Between Run | | Between Day | | Between Site/Lot | | Reproducibility | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | | | SD | %CV | SD | %CV | SD | %CV | SD | %CV | SD | %CV |
| 1 | 60 | 32.21 | 1.1 | 3.4 | 0.3 | 0.9 | 0.5 | 1.5 | 1.7 | 5.2 | 2.1 | 6.5 |
| 2 | 60 | 113.33 | 2.7 | 2.4 | 2.3 | 2.0 | 1.2 | 1.0 | 0.0 | 0.0 | 3.8 | 3.3 |
| 3 | 60 | 278.48 | 7.7 | 2.8 | 4.8 | 1.7 | 0.0 | 0.0 | 4.7 | 1.7 | 10.2 | 3.7 |
| 4 | 60 | 440.96 | 9.8 | 2.2 | 7.0 | 1.6 | 0.0 | 0.0 | 8.5 | 1.9 | 14.8 | 3.3 |
| 5 | 59 | 1965.83 | 49.3 | 2.5 | 38.1 | 1.9 | 0.0 | 0.0 | 0.0 | 0.0 | 62.4 | 3.2 |
| 6 | 60 | 11809.4 | 196.7 | 1.7 | 155.9 | 1.3 | 0.0 | 0.0 | 66.7 | 0.6 | 259.7 | 2.2 |
| 7 | 60 | 25997.2 | 487.6 | 1.9 | 221.9 | 0.9 | 488.9 | 1.9 | 557.0 | 2.1 | 914.5 | 3.5 |
All Sites Combined K2 EDTA Reproducibility
| Sample | N | Mean (ng/L) | Repeatability | | Between Run | | Between Day | | Between Site/Lot | | Reproducibility | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | | | SD | %CV | SD | %CV | SD | %CV | SD | %CV | SD | %CV |
| 1 | 60 | 30.30 | 1.0 | 3.2 | 0.0 | 0.0 | 0.3 | 0.8 | 1.7 | 5.6 | 2.0 | 6.5 |
| 2 | 59 | 129.15 | 3.3 | 2.6 | 1.1 | 0.9 | 1.5 | 1.1 | 3.4 | 2.6 | 5.1 | 3.9 |
| 3 | 60 | 268.19 | 6.5 | 2.4 | 3.1 | 1.1 | 4.1 | 1.5 | 7.7 | 2.9 | 11.3 | 4.2 |
| 4 | 60 | 384.61 | 7.6 | 2.0 | 4.7 | 1.2 | 5.1 | 1.3 | 8.3 | 2.2 | 13.3 | 3.4 |
| 5 | 60 | 1870.66 | 64.6 | 3.5 | 41.0 | 2.2 | 0.0 | 0.0 | 25.7 | 1.4 | 80.7 | 4.3 |
| 6 | 60 | 12905.6 | 238.5 | 1.8 | 145.5 | 1.1 | 75.2 | 0.6 | 114.4 | 0.9 | 311.1 | 2.4 |
| 7 | 60 | 28459.3 | 702.7 | 2.5 | 88.8 | 0.3 | 133.7 | 0.5 | 595.6 | 2.1 | 935.1 | 3.3 |
K232164 - Page 7 of 30
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K232164 - Page 8 of 30
2. Linearity:
The linearity performance of the Access NT-proBNP assay run on the DxI 9000 Access Immunoassay Analyzer was established for serum, lithium heparin plasma and $\mathrm{K}_2\mathrm{EDTA}$ plasma respectively in a study following the recommendations of the CLSI EP06, $2^{\mathrm{nd}}$ Edition guideline. One high sample pool above the measuring range ( $>35,000~\mathrm{ng / L}$ ) was prepared by pooling high concentration native patient samples for the serum sample. The EDTA and lithium heparin plasma high pools required spiking with additional NT-proBNP antigen to achieve the desired concentration. One low sample pool below the limit of quantification was prepared by pooling low concentration native samples of each respective sample type. The low and high pool samples from each sample type condition were mixed in pre-defined rations to create an additional seven samples for each sample type. Each sample was measured on each of three reagent pack lots and a single calibrator lot on one DxI 9000 Access Immunoassay Analyzer. The low pool from each sample type/panel was run in replicates of eight and all other samples were run in replicates of four. The linearity was analyzed separately for each reagent lot per sample type. 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 $10~\mathrm{ng / L}$ to $35,000~\mathrm{ng / L}$ .
3. Analytical Specificity/Interference:
The analytical specificity performance of the Access pro-BNP assay was established by conducting a cross-reactivity study and interference testing for endogenous and exogenous substances following the CLSI EP 07, $3^{\mathrm{rd}}$ Edition guideline.
Endogenous substances
Interference from endogenous substances was assessed using lithium heparin plasma samples with NT-proBNP at approximate concentrations of $125\mathrm{ng / L}$ and $1800\mathrm{ng / L}$ . Each of the two samples was divided into two aliquots for a control sample (with no added interferent) and a test sample (with added interferent). Each sample was measured on one DxI 9000 Access Immunoassay Analyzer across three reagent lots and one calibrator lot. No significant interference, defined by the sponsor as a difference within $\pm 10\%$ between the mean for the test sample versus the mean of the control samples, was observed at the following concentrations:
| Substance | Highest concentration tested at which no significant interference is observed |
| --- | --- |
| Bilirubin, conjugated | 19 mg/dL |
| Bilirubin, unconjugated | 15 mg/dL |
| Cholesterol | 400 mg/dL |
| Creatinine | 15 mg/dL |
| Hemoglobin | 1000 mg/dL |
| Intralipid | 1600 mg/dL |
| Human Serum Albumin | 60 g/L |
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K232164 - Page 9 of 30
| Substance | Highest concentration tested at which no significant interference is observed |
| --- | --- |
| Human gamma-globulin | 30g/L |
| Rheumatoid factors | 500 IU/mL |
| HAMA | 800 μg/L |
| Alkaline Phosphatase | 2000 U/L |
## Exogenous substances
Interference from exogenous substances was assessed using lithium heparin plasma samples with NT-proBNP at approximate concentrations of 125 ng/L and 1800 ng/L following the same procedure as for the endogenous substance testing. No significant interference, defined by the sponsor as a difference within ± 10% between the mean for the test sample versus the mean of the control samples, was observed at the following concentrations:
| Substance | Highest concentration tested at which no significant interference is observed |
| --- | --- |
| (+)-cis-Diltiazem hydrochloride | 120 μg/mL |
| Acetaminophen | 1456 μmol/L |
| Allopurinol | 240 μg/mL |
| Amiodarone | 4.2 mg/dL |
| Amlodipine besylate | 4 μg/mL |
| Ampicillin | 200 μg/mL |
| Ascorbic acid | 20 mg/dL |
| Atenolol | 40 μg/mL |
| Atorvastatin calcium trihydrate | 32 μg/mL |
| Biotin | 30,000 ng/mL |
| Caffeine | 10.8 mg/dL |
| Captopril | 40 μg/mL |
| Carvedilol | 74 μmol/L |
| Chloramphenicol | 7.8 mg/dL |
| Clopidogrel hydrogen sulfate | 30 μg/mL |
| Cyclosporine | 40 μg/mL |
| Diclofenac sodium salt | 60 μg/mL |
| Digitoxin | 60 μg/mL |
| Digoxin | 0.0039 mg/dL |
| Disopyramide | 1.68 mg/dL |
| Dobutamine | 100 μg/mL |
| Dopamine hydrochloride | 116 μg/mL |
| Dipyridamole | 30 μg/mL |
| Enalaprilat dihydrate | 16 μg/mL |
| Erythromycin | 13.8 mg/dL |
| Fenofibrate | 45 μg/mL |
| Fibrinogen | 1000 mg/dL |
| Furosemide | 199 μmol/L |
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| Substance | Highest concentration tested at which no significant interference is observed |
| --- | --- |
| Heparin | 330 units/dL |
| Hydralazine | 20 μg/mL |
| Hydrochlorothiazide | 20 μg/mL |
| Ibuprofen | 2425 μmol/L |
| Isosorbide dinitrate | 0.593 mg/dL |
| L-Ascorbic Acid | 376 μmol/L |
| Levothyroxine | 0.042 mg/dL |
| Lidocaine | 1.5 mg/dL |
| Lisinopril x 2H₂O | 16 μg/mL |
| Losartan potassium | 130 μmol/L |
| Lovastatin | 0.021mg/dL |
| Methyldopa sesquihydrate | 100 μg/mL |
| Metoprolol hemitartrate | 18.7 μmol/L |
| Naproxen sodium | 2170 μmol/L |
| Nicotine | 1.6 μg/mL |
| Nicotinic acid | 40 μg/mL |
| Nifedipine | 36 μg/mL |
| Nitrofurantoin | 40 μg/mL |
| Oxazepam | 12 μg/mL |
| Oxytetracycline | 100 μg/mL |
| Phenobarbital | 69 mg/dL |
| Phenytoin | 6 mg/dL |
| Probenecid | 600 μg/dL |
| Propranolol | 64 μg/mL |
| Quinidine | 20 μg/mL |
| Ramipril | 14.4 μmol/L |
| Salicylic acid | 200 μg/mL |
| Simvastatin | 32 μg/mL |
| Spironolactone | 600 mg/dL |
| Sulfamethoxazole | 1.7 μmol/L |
| Theophylline | 6 mg/dL |
| Trasylol/Aprotinin | 100 KIE/mL |
| Trimethoprim | 64 μg/mL |
| Verapamil hydrochloride | 96 μg/mL |
| Warfarin | 7.5 mg/dL |
## Cross-reactivity
A study was conducted to evaluate the performance of the Access pro-BNP assay in the presence of cross reactants. In this study, two lithium heparin plasma samples with NT-proBNP concentrations at 125 ng/L and 1800 ng/L were used. Each sample was then spiked with the potential cross-reactive substance to form a test sample or spiked with solvent to
K232164 - Page 10 of 30
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form a control sample. Each sample was assayed in replicates of 5 on a single DxI 9000 Access Immunoassay Analyzer across three (3) reagent pack lots and one calibrator lot. The % cross-reactivity was calculated as:
% cross-reactivity = 100 x (test conc. - control conc.)/cross-reactant conc.
The results of the cross-reactivity studies are summarized below:
| Cross-reactant | Concentration | Percent cross reactivity |
| --- | --- | --- |
| ANP28 | 3.1 μg/mL | 0% |
| | | 0% |
| Adrenomedullin | 1 ng/mL | 0% |
| | | 0% |
| Aldosterone | 0.6 ng/mL | 0% |
| | | 3% |
| Angiotensin I | 0.6 ng/mL | 0% |
| | | 4% |
| Angiotensin II | 0.6 ng/mL | -1% |
| | | 5% |
| Angiotensin III | 1 ng/mL | 0% |
| | | -2% |
| Arg-Vasopressin | 1 ng/mL | 0% |
| | | 1% |
| BNP 32 | 3.5 μg/mL | 0% |
| | | 0% |
| CNP 22 | 2.2 μg/mL | 0% |
| | | 0% |
| Endothelin | 2 ng/mL | 0% |
| | | 2% |
| NT-proANP 1-30 | 3.5 μg/mL | 0% |
| | | 0% |
| NT-proANP 31-67 | 1 ng/mL | 0% |
| | | -2% |
| NT-proANP 79-98 | 1 ng/mL | 0% |
| | | -2% |
| Renin | 50 ng/mL | 0% |
| | | 0% |
| Urodilatin | 3.5 μg/mL | 0% |
| | | 0% |
## High dose hook effect
The Access NT-proBNP Reagent Pack was evaluated for high dose hook effect using lithium heparin plasma samples with 5 concentration levels of NT-proBNP. Each sample was tested in replicates of five (5) using three reagent lots and one calibrator lot on one DxI 9000
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Access Immunoassay Analyzer. The results support that the Access NT-proBNP reagent pack does not show a high dose hook effect up to 400,000 ng/L (pg/mL) of NT-proBNP.
## 4. Assay Reportable Range:
The claimed measuring range is 10.0 to 35,000 ng/L.
## 5. Traceability, Stability, Expected Values (Controls, Calibrators, or Methods):
### Metrological traceability
The Access NT-proBNP calibrator is traceable to the manufacturer’s working calibrators.
### Sample Stability
The sponsor has provided information to support the following claims in their labeling:
- Separated samples are stable for up to 24 hours at room temperature, and for up to 3 days at 2-10°C.
- Separated samples are stable at -15°C for up to 30 days.
The sponsor also provided data to support that samples stored frozen at ≤ -15°C may be subjected to one freeze-thaw cycle.
## 6. Detection Limit:
The detection capability of the Access NT-proBNP assay run on the Dxl 9000 Access Immunoassay Analyzer was evaluated. The limit of blank (LoB), limit of detection (LoD), and limit of quantification (LoQ) were established following the recommendations in the CLSI EP17-A2 guideline.
### Limit of Blank (LoB)
The LoB study was performed on four non-analyte samples using three reagent pack lots and one calibrator lot. Each sample was analyzed across three (3) days with one run per day and five replicates per run per reagent lot on one (1) Dxl 9000 Access Immunoassay Analyzer for a total of 180 replicates. The LoB was determined non-parametrically for each reagent lot separately and the highest value obtained from three lots was taken as the LoB value.
- The LoB for the Access NT-proBNP assay is estimated to be 1.1 ng/L
### Limit of Detection (LoD)
The LoD study was performed using five (5) serum, six (6) EDTA, and six (6) lithium heparin plasma native samples containing low levels of NT-proBNP analyte. In the study, LoD was determined separately for each of three reagent pack lots using one calibrator lot on one (1) Dxl 9000 Access Immunoassay Analyzer. With each lot, the samples were each assayed in replicates of five per run, two runs per day over 5 days for a total of 50
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measurements per sample per reagent lot. The parametric approach described in EP17-A2 was followed to determine the LoD. The highest observed LoD of the three lots was the reported LoD for the assay.
- The LoD for the Access NT-proBNP assay is estimated to be 4.8 ng/L (serum), 3.2 ng/L (K₂EDTA) and 4.3 ng/dL (LiHep)
## Limit of Quantification (LoQ)
The LoQ study was performed using ten (10) serum, nine (9) EDTA and nine (9) Lithium Heparin plasma samples containing low levels of NT-proBNP analyte. In the study, the LoQ was determined separately for each of three reagent pack lots using one calibrator lot on one (1) Dxl 9000 Access Immunoassay Analyzer. With each lot, the samples were each assayed in replicates of five per run, two runs per day over 5 days for a total of 50 measurement per sample per reagent lot. The LoQ was determined as the lowest concentration of analyte which can be measured with a within-laboratory precision of 20% CV, and the highest value obtained from three lots was the reported LoQ for the assay.
- The LoQ for the Access NT-proBNP assay is estimated to be 4.8 ng/L (serum), 3.2 ng/L (K₂EDTA), and 4.3 ng/L (LiHep).
These studies support the following detection capability claims in the labeling:
- Limit of Blank (LoB): 1.1 ng/L
- Limit of Detection (LoD): 4.8 ng/L
- Limit of Quantitation (LoQ) (≤ 20% within-lab CV): 4.8 ng/L
## 7. Assay Cut-Off:
See section D. for Clinical Cut-off information.
## 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 (K₂-EDTA and lithium heparin). In addition to precision, linearity and clinical studies, a matrix equivalency study was conducted to support the use of serum and K₂ EDTA samples with the Access NT-proBNP on the DxI 9000 Access Immunoassay Analyzer. In the study, 68 donor matched samples of the aforementioned were collected. For each combination, each sample was tested in three replicates using one DxI 9000 Access Immunoassay Analyzer. The results were analyzed using Passing-Bablok regression analysis comparing the first replicate of the test tube to the mean of the control tube. The results support the use of K₂-EDTA plasma, lithium heparin plasma and serum on the Access NT-proBNP assay.
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C Clinical Studies:
1. Clinical Sensitivity:
See Section VII. C.3.
2. Clinical Specificity:
See Section VII.C.3.
3. Other Clinical Supportive Data (When 1. and 2. Are Not Applicable):
Clinical Performance Studies in the Emergency Department
A multi-center prospective study including 17 clinical collection sites and 3 clinical laboratory testing sites across in the United States was conducted to establish the clinical performance characteristics of the Access NT-proBNP assay run on the DxI 9000 Access Immunoassay Analyzer. In this study, subjects 22 years and older presenting with signs and symptoms that raise clinical suspicion of acute heart failure were enrolled in the study. Subjects with stage 4 or 5 chronic kidney disease (CKD), chronic dialysis and subjects with dyspnea clearly not secondary to HF (e.g., primary lung disease or chest trauma) were excluded from the study. For each patient enrollment, a serum, a K₂-EDTA, and a lithium heparin sample were collected for determination of their NT-proBNP concentration. The Access NT pro-BNP assay results were determined on the DxI 9000 Access Immunoassay Analyzer using stored frozen samples collected from 2384 ED subjects consisting of 48.2% (1149/2384) female subjects and 51.8% (1235/2384) male subjects. Individuals in the population were 35.7% Black or African American, 57.8% White or Caucasian, and 6.5% Asian. The sponsor provided information to support the use of the frozen samples in their study.
The descriptive statistics for the Access NT-proBNP results were determined within and across sex and age groups. The results are summarized below.
Female
| | Subjects with Acute Heart Failure* | | | | Subjects without Acute Heart Failure* | | | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
| Age (years) | All Ages | <50 | 50-75 | >75 | All Ages | <50 | 50-75 | >75 |
| N | 450 | 138 | 164 | 148 | 692 | 349 | 209 | 134 |
| Mean (ng/L) | 5264 | 3786 | 5597 | 6272 | 982 | 705 | 948 | 1758 |
| SD (ng/L) | 5795 | 5257 | 5753 | 6076 | 2341 | 2287 | 2325 | 2349 |
| Median (ng/L) | 3342 | 1835 | 3420 | 4178 | 193 | 108 | 193 | 842 |
| IQR 25th – 75th percentile (ng/L) | 1125-7291 | 840-4976 | 1243-8463 | 2028-8691 | 62-725 | 47-322 | 69-572 | 312-2137 |
| Min(ng/L) | 26 | 26 | 33 | 210 | <10 | <10 | <10 | 26 |
| Max(ng/L) | 34973 | 34973 | 28037 | 33866 | 23996 | 23996 | 23968 | 12651 |
*only the subjects with numerical values were included in the descriptive statistical analysis.
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Male
| | Subjects with Acute Heart Failure* | | | | Subjects without Acute Heart Failure* | | | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
| Age (years) | All Ages | <50 | 50-75 | >75 | All Ages | <50 | 50-75 | >75 |
| N | 594 | 170 | 276 | 148 | 632 | 220 | 260 | 152 |
| Mean (ng/L) | 5463 | 4389 | 5696 | 6261 | 1181 | 735 | 1058 | 2035 |
| SD (ng/L) | 5289 | 4526 | 5259 | 5959 | 2375 | 2129 | 2251 | 2692 |
| Median (ng/L) | 4049 | 3261 | 4352 | 4408 | 263 | 92 | 214 | 981 |
| IQR 25th – 75th percentile (ng/L) | 1680-7533 | 1203-6289 | 1735-8030 | 2164-8284 | 68-1055 | 26-373 | 74-850 | 343-2441 |
| Min(ng/L) | <10 | <10 | 66 | 188 | <10 | <10 | <10 | 16 |
| Max(ng/L) | 33611 | 27795 | 33611 | 32848 | 20485 | 20485 | 17542 | 16253 |
All subjects
| | Subjects with Acute Heart Failure* | | | | Subjects without Acute Heart Failure* | | | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
| Age (years) | All Ages | <50 | 50-75 | >75 | All Ages | <50 | 50-75 | >75 |
| N | 1044 | 308 | 440 | 296 | 1324 | 569 | 469 | 286 |
| Mean (ng/L) | 5377 | 4119 | 5659 | 6266 | 1077 | 716 | 1009 | 1905 |
| SD (ng/L) | 5511 | 4868 | 5442 | 6008 | 2358 | 2226 | 2282 | 2537 |
| Median (ng/L) | 3776 | 2466 | 4111 | 4291 | 218 | 106 | 204 | 926 |
| IQR 25th – 75th percentile (ng/L) | 1406-7483 | 959-5745 | 1539-8222 | 2077-8394 | 63-904 | 39-347 | 72-670 | 335-2325 |
| Min (ng/L) | <10 | <10 | 33 | 188 | <10 | <10 | <10 | 16 |
| Max (ng/L) | 34973 | 34973 | 33611 | 33866 | 23996 | 23966 | 23968 | 16253 |
A diagnosis of acute HF or no acute HF was determined for each subject by an independent central adjudication panel consisting of medical doctors with a specialty in cardiology or heart failure. For the 2384 subjects enrolled in the study, a total of 1059 subjects were adjudicated as subjects with acute HF and 1325 subjects were adjudicated as subjects without acute HF.
| | Subject with Acute Heart Failure | Subject without Acute Heart Failure |
| --- | --- | --- |
| Age Group | | |
| < 50 | 35.3% (310/879) | 64.7% (569/879) |
| 50-75 | 48.7% (446/915) | 51.2% (469/915) |
| >75 | 51.4% (303/590) | 48.6% (287/590) |
| | | |
| Sex | | |
| Female | 39.7% (456/1149) | 60.3% (693/1149) |
| Male | 48.8% (603/1235) | 51.1% (632/1235) |
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Access NT-proBNP results versus adjudicated diagnosis
| Age (years) | Access NT-proBNP Result | Adjudicated Diagnosis | | Total |
| --- | --- | --- | --- | --- |
| | | HF | No HF | |
| <50 | Positive | 279 | 127 | 406 |
| | Gray Zone | 12 | 25 | 37 |
| | Negative | 19 | 417 | 436 |
| | Total | 310 | 569 | 879 |
| 50-75 | Positive | 380 | 105 | 485 |
| | Gray Zone | 47 | 96 | 143 |
| | Negative | 19 | 268 | 287 |
| | Total | 446 | 469 | 915 |
| >75 | Positive | 240 | 94 | 334 |
| | Gray Zone | 59 | 132 | 191 |
| | Negative | 4 | 61 | 65 |
| | Total | 303 | 287 | 590 |
| All | Positive | 899 | 326 | 1225 |
| | Gray Zone | 118 | 253 | 371 |
| | Negative | 42 | 746 | 788 |
| | Total | 1059 | 1325 | 2384 |
The pretest probabilities of HF (prevalence of HF in the clinical study), posttest probabilities, likelihood ratios, and the two-tailed 95% CI of the test results versus adjudicated diagnosis were determined using the age-dependent positive cut-offs (450 ng/L for subjects 22 - < 50 years old; 900 ng/L for subjects 50 - ≤ 75 years old; 1800 ng/L for subjects >75 years old) and age-independent negative (300 ng/mL) cutoff and are summarized in the following tables:
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Access NT-proBNP - All subjects (LiHep samples)
| Age Group | Prevalence of HF (% (n/N)) | Access NT-ProBNP results | Posttest Probability of HF | | Posttest Probability of non-HF | | Likelihood Ratio and CI | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | | | Estimate % (n/N) | 95% CI | Estimate (% (n/N)) | 95% CI (%)* | LR | 95%-CI** |
| <50 | 35.3% (310/879) | Positive | 68.7% (279/406) | (64.1-73.0%) | | | 4.03 | (3.44, 4.72) |
| | | Grey Zone | 32.4% (12/37) | (19.6-48.5%) | 67.6% (25/37) | (51.5-80.4%) | 0.88 | (0.45,1.73) |
| | | Negative | | | 95.6% (417/436) | (93.3-97.2%) | 0.08 | (0.05, 0.13) |
| 50-75 | 48.7% (446/915) | Positive | 78.4% (380/485) | (74.5-81.8%) | | | 3.81 | (3.20, 4.52) |
| | | Grey Zone | 32.9% (47/143) | (25.7-40.9%) | 67.1% (96/143) | (59.1-74.3%) | 0.51 | (0.37,0.71) |
| | | Negative | | | 93.4% (268/287) | (89.9-95.7%) | 0.07 | (0.05, 0.11) |
| >75 | 51.4% (303/590) | Positive | 71.9% (240/334) | (66.8-76.4%) | | | 2.42 | (2.03, 2.88) |
| | | Grey Zone | 30.9% (59/191) | (24.8-37.8%) | 69.1% (132/191) | (62.2-75.2%) | 0.42 | (0.33, 0.55) |
| | | Negative | | | 93.8% (61/65) | (85.2-97.6%) | 0.06 | (0.02, 0.16) |
| All | 44.4% (1059/2384) | Positive | 73.4% (899/1225) | (70.8-75.8%) | | | 3.45 | (3.13, 3.80) |
| | | Grey Zone | 31.8% (118/371) | (27.3-36.7%) | 68.2% (253/371) | (63.3-72.7%) | 0.58 | (0.48, 0.71) |
| | | Negative | | | 94.7% (746/788) | (92.9-96.0%) | 0.07 | (0.05, 0.09) |
*Wilson Score confidence interval
** log method confidence intervals
K232164 - Page 17 of 30
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Access NT-proBNP - Female Subjects (LiHep Samples)
| Age Group | Prevalence of HF (% (n/N)) | Access NT-ProBNP results | Posttest Probability of HF | | Posttest Probability of non-HF | | Likelihood Ratio and CI | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | | | Estimate % (n/N) | 95% CI | Estimate (% (n/N)) | 95% CI (%)* | LR | 95%-CI** |
| <50 | 28.5% (139/488) | Positive | 60.9% (123/202) | (54.0-67.4%) | | | 3.91 | (3.19, 4.79) |
| | | Grey Zone | 31.3% (5/16) | (14.2-55.6%) | 68.8% (11/16) | (44.4-85.8%) | 1.14 | (0.40, 3.22) |
| | | Negative | | | 95.9% (259/270) | (92.9-97.7%) | 0.11 | (0.06, 0.19) |
| 50-75 | 44.1% (165/374) | Positive | 76.0% (133/175) | (69.2-81.7%) | | | 4.01 | (3.03, 5.31) |
| | | Grey Zone | 30.6% (19/62) | (20.6-43.0%) | 69.4% (43/62) | (57.0-79.4%) | 0.56 | (0.34, 0.92) |
| | | Negative | | | 90.5% (124/137) | (84.4-94.4%) | 0.13 | (0.08, 0.22) |
| >75 | 53.0% (152/287) | Positive | 73.9% (119/161) | (66.6-80.1%) | | | 2.52 | (1.93, 3.28) |
| | | Grey Zone | 32.6% (30/92) | (23.9-42.7%) | 67.4% (62/92) | (57.3-76.1%) | 0.43 | (0.30, 0.62) |
| | | Negative | | | 91.2% (31/34) | (77.0-97.0%) | 0.09 | (0.03, 0.25) |
| All | 39.7% (456/1149) | Positive | 69.7% (375/538) | (65.7-73.4%) | | | 3.50 | (3.04, 4.03) |
| | | Grey Zone | 31.8% (54/170) | (25.2-39.1%) | 68.2% (116/170) | (60.9-74.8%) | 0.71 | (0.52, 0.96) |
| | | Negative | | | 93.9% (414/441) | (91.2-95.7%) | 0.10 | (0.07, 0.14) |
K232164 - Page 18 of 30
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Access NT-proBNP - Male Subjects (LiHep Samples)
| Age Group | Prevalence of HF (% (n/N)) | Access NT-ProBNP results | Posttest Probability of HF | | Posttest Probability of non-HF | | Likelihood Ratio and CI | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | | | Estimate % (n/N) | 95% CI | Estimate (% (n/N)) | 95% CI * | LR | 95%-CI** |
| <50 | 43.7% (171/391) | Positive | 76.5% (156/204) | (70.2-81.8%) | | | 4.18 | (3.24, 5.39) |
| | | Grey Zone | 33.3% (7/21) | (17.2-54.6%) | 66.7% (14/21) | (45.4-82.8%) | 0.64 | (0.27, 1.56) |
| | | Negative | | | 95.2% (158/166) | (90.8-97.5%) | 0.07 | (0.03, 0.13) |
| 50-75 | 51.9% (281/541) | Positive | 79.7% (247/310) | (74.8-83.8%) | | | 3.63 | (2.91, 4.52) |
| | | Grey Zone | 34.6% (28/81) | (25.1-45.4%) | 65.4% (53/81) | (54.6-74.9%) | 0.49 | (0.32, 0.75) |
| | | Negative | | | 96.0% (144/150) | (91.5-98.2%) | 0.04 | (0.02, 0.08) |
| >75 | 49.8% (151/303) | Positive | 69.9% (121/173) | (62.7-76.3%) | | | 2.34 | (1.85, 2.96) |
| | | Grey Zone | 29.3% (29/99) | (21.2-38.9%) | 70.7% (70/99) | (61.1-78.8%) | 0.42 | (0.29, 0.60) |
| | | Negative | | | 96.8% (30/31) | (83.8-99.4%) | 0.03 | (0.00, 0.23) |
| All | 48.8% (603/1235) | Positive | 76.3% (524/687) | (73.0-79.3%) | | | 3.37 | (2.94, 3.86) |
| | | Grey Zone | 31.8% (64/201) | (25.8-38.6%) | 68.2% (137/201) | (61.4-74.2%) | 0.49 | (0.37, 0.64) |
| | | Negative | | | 95.7% (332/347) | (93.0-97.4%) | 0.05 | (0.03, 0.08) |
K232164 - Page 19 of 30
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Access NT-proBNP - Subjects with HF history (LiHep)
| Age Group | Prevalence of HF (% (n/N)) | Access NT-ProBNP results | Posttest Probability of HF | | Posttest Probability of non-HF | | Likelihood Ratio and CI | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | | | Estimate % (n/N) | 95% CI (%) | Estimate (% (n/N)) | 95% CI (%)* | LR | 95%-CI** |
| <50 | 63.4% (208/328) | Positive | 79.0% (188/238) | (73.4-83.7%) | | | 2.17 | (1.75, 2.69) |
| | | Grey Zone | 43.8% (7/16) | (23.1-66.8%) | 56.3% (9/16) | (33.2-76.9%) | 0.45 | (0.17, 1.17) |
| | | Negative | | | 82.4% (61/74) | (72.2-89.4%) | 0.12 | (0.07, 0.20) |
| 50-75 | 71.0% (323/455) | Positive | 85.0% (278/327) | (80.7-88.5%) | | | 2.32 | (1.85, 2.91) |
| | | Grey Zone | 47.8% (33/69) | (36.5-59.4%) | 52.2% (36/69) | (40.6-63.5%) | 0.37 | (0.24, 0.57) |
| | | Negative | | | 79.7% (47/59) | (67.7-88.0%) | 0.10 | (0.06, 0.17) |
| >75 | 66.9% (202/302) | Positive | 78.7% (170/216) | (72.8-83.6%) | | | 1.83 | (1.47, 2.28) |
| | | Grey Zone | 41.1% (30/73) | (30.5-52.6%) | 58.9% (43/73) | (47.4-69.5%) | 0.35 | (0.23, 0.52) |
| | | Negative | | | 84.6% (11/13) | (57.8-95.7%) | 0.09 | (0.03, 0.32) |
| All | 67.6% (733/1085) | Positive | 81.4% (636/781) | (78.6-84.0%) | | | 2.11 | (1.85, 2.39) |
| | | Grey Zone | 44.3% (70/158) | (36.8-52.1%) | 55.7% (88/158) | (47.9-63.2%) | 0.38 | (0.29, 0.51) |
| | | Negative | | | 81.5% (119/146) | (74.4-87.0%) | 0.11 | (0.08, 0.15) |
K232164 - Page 20 of 30
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Access NT-proBNP - Subjects with no HF history (LiHep)
| Age Group | Prevalence of HF (% (n/N)) | Access NT-ProBNP results | Posttest Probability of HF | | Posttest Probability of No non-HF | | Likelihood Ratio and CI | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | | | Estimate % (n/N) | 95% CI * | Estimate (% (n/N)) | 95% CI * | LR | 95%-CI** |
| <50 | 18.4% (101/550) | Positive | 53.9% (90/167) | (46.3-61.3%) | | | 5.20 | (4.19, 6.44) |
| | | Grey Zone | 23.8% (5/21) | (10.6-45.1%) | 76.2% (16/21) | (54.9-89.4%) | 1.39 | (0.52, 3.70) |
| | | Negative | | | 98.3% (356/362) | (96.4-99.2%) | 0.07 | (0.03, 0.16) |
| 50-75 | 26.8% (123/459) | Positive | 65.0% (102/157) | (57.2-72.0%) | | | 5.07 | (3.93, 6.54) |
| | | Grey Zone | 18.9% (14/74) | (11.6-29.3%) | 81.1% (60/74) | (70.7-88.4%) | 0.64 | (0.37, 1.10) |
| | | Negative | | | 96.9% (221/228) | (93.8-98.5%) | 0.09 | (0.04, 0.18) |
| >75 | 35.0% (100/286) | Positive | 59.0% (69/117) | (49.9-67.5%) | | | 2.67 | (2.03, 3.53) |
| | | Grey Zone | 24.8% (29/117) | (17.8-33.3%) | 75.2% (88/117) | (66.7-82.2%) | 0.61 | (0.44, 0.86) |
| | | Negative | | | 96.2% (50/52) | (87.0-98.9%) | 0.07 | (0.02, 0.29) |
| All | 25.0% (324/1295) | Positive | 59.2% (261/441) | (54.5-63.7%) | | | 4.35 | (3.77, 5.01) |
| | | Grey Zone | 22.6% (48/212) | (17.5-28.7%) | 77.4% (164/212) | (71.3-82.5%) | 0.88 | (0.65, 1.18) |
| | | Negative | | | 97.7% (627/642) | (96.2-98.6%) | 0.07 | (0.04, 0.12) |
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Access NT-proBNP - Subjects with eGFR $< 60~\mathrm{mL / min} / 1.73~\mathrm{m}^2$ of BSA (LiHep)
| Age Group | Prevalence of HF(%) (n/N)) | Access NT-ProBNP results | Posttest Probability of HF | | Posttest Probability of non-HF | | Likelihood Ratio and CI | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | | | Estimate % (n/N) | 95% CI (%) | Estimate (% (n/N)) | 95% CI (%)* | LR | 95%-CI** |
| <50 | 38.9% (102/262) | Positive | 68.1% (96/141) | (60.0-75.2%) | | | 3.35 | (2.60, 4.31) |
| | | Grey Zone | 40.0% (4/10) | (16.8-68.7%) | 60.0% (6/10) | (31.3-83.2%) | 1.05 | (0.30, 3.62) |
| | | Negative | | | 98.2% (109/111) | (93.7-99.5%) | 0.03 | (0.01, 0.11) |
| 50-75 | 58.6% (249/425) | Positive | 80.9% (224/277) | (75.8-85.1%) | | | 2.99 | (2.38, 3.76) |
| | | Grey Zone | 28.8% (17/59) | (18.8-41.4%) | 71.2% (42/59) | (58.6-81.2%) | 0.29 | (0.17,0.49) |
| | | Negative | | | 91.0% (81/89) | (83.3-95.4%) | 0.07 | (0.04-0.14) |
| >75 | 57.9% (205/354) | Positive | 77.9% (169/217) | (71.9-82.9%) | | | 2.56 | (2.01, 3.26) |
| | | Grey Zone | 30.8% (33/107) | (22.9-40.1%) | 69.2% (74/107) | (59.9-77.1%) | 0.32 | (0.23, 0.46) |
| | | Negative | | | 90.0% (27/30) | (74.4-96.5%) | 0.08 | (0.03, 0.24) |
| All | 53.4% (556/1041) | Positive | 77.0% (489/635) | (73.6-80.1%) | | | 2.92 | (2.54, 3.36) |
| | | Grey Zone | 30.7% (54/176) | (24.3-37.8%) | 69.3% (122/176) | (62.2-75.7%) | 0.39 | (0.29, 0.52) |
| | | Negative | | | 94.3% (217/230) | (90.6-96.7%) | 0.05 | (0.03, 0.09) |
K232164 - Page 22 of 30
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Access NT-proBNP - Subjects with eGFR ≥60 mL/min/1.73 m² of BSA (LiHep)
| Age Group | Prevalence of HF (% (n/N)) | Access NT-ProBNP results | Posttest Probability of HF | | Posttest Probability of No non-HF | | Likelihood Ratio and CI | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | | | Estimate % (n/N) | 95% CI (%) | Estimate (% (n/N)) | 95% CI (%)* | LR | 95%-CI** |
| <50 | 33.7% (208/617) | Positive | 69.1% (183/265) | (63.3-74.3%) | | | 4.39 | (3.59, 5.36) |
| | | Grey Zone | 29.6% (8/27) | (15.9-48.5%) | 70.4% (19/27) | (51.5-84.1%) | 0.83 | (0.37, 1.86) |
| | | Negative | | | 94.8% (308/325) | (91.8-96.7%) | 0.11 | (0.07, 0.17) |
| 50-75 | 40.2% (197/490) | Positive | 75.0% (156/208) | (68.7-80.4%) | | | 4.46 | (3.45, 5.77) |
| | | Grey Zone | 35.7% (30/84) | (26.3-46.4%) | 64.3% (54/84) | (53.6-73.7%) | 0.83 | (0.55, 1.24) |
| | | Negative | | | 94.4% (187/198) | (90.3-96.9%) | 0.09 | (0.05, 0.15) |
| >75 | 41.5% (98/236) | Positive | 60.7% (71/117) | (51.6-69.1%) | | | 2.17 | (1.67, 2.83) |
| | | Grey Zone | 31.0% (26/84) | (22.1-41.5%) | 69.0% (58/84) | (58.5-77.9%) | 0.63 | (0.43, 0.93) |
| | | Negative | | | 97.1% (34/35) | (85.5-99.5%) | 0.04 | (0.01, 0.28) |
| All | 37.5% (503/1343) | Positive | 69.5% (410/590) | (65.7-73.1%) | | | 3.80 | (3.32-4.36) |
| | | Grey Zone | 32.8% (64/195) | (26.6-39.7%) | 67.2% (131/195) | (60.3-73.4%) | 0.82 | (0.62, 1.08) |
| | | Negative | | | 94.8% (529/558) | (92.6-96.4%) | 0.09 | (0.06, 0.13) |
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Access NT-proBNP - Subjects with BMI $\geq 30\mathrm{kg / m^2}$ (LiHep)
| Age Group | Prevalence of HF (% (n/N)) | Access NT-ProBNP results | Posttest Probability of HF | | Posttest Probability of No non-HF | | Likelihood Ratio and CI | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | | | Estimate % (n/N) | 95% CI * | Estimate (% (n/N)) | 95% CI * | LR | 95%-CI** |
| <50 | 41.5% (228/549) | Positive | 76.3% (200/262) | (70.8-81.1%) | | | 4.54 | (3.61, 5.71) |
| | | Grey Zone | 36.7% (11/30) | (21.9-54.5%) | 63.3% (19/30) | (45.5-78.1%) | 0.82 | (0.40, 1.68) |
| | | Negative | | | 93.4% (240/257) | (89.7-95.8%) | 0.10 | (0.06, 0.16) |
| 50-75 | 52.3% (266/509) | Positive | 85.0% (210/247) | (80.0-88.9%) | | | 5.18 | (3.83, 7.02) |
| | | Grey Zone | 42.4% (39/92) | (32.8-52.6%) | 57.6% (53/92) | (47.4-67.2%) | 0.67 | (0.46, 0.98) |
| | | Negative | | | 90.0% (153/170) | (84.6-93.7%) | 0.10 | (0.06, 0.16) |
| >75 | 60.7% (130/214) | Positive | 88.6% (93/105) | (81.1-93.3%) | | | 5.01 | (2.93, 8.55) |
| | | Grey Zone | 39.8% (33/83) | (29.9-50.5%) | 60.2% (50/83) | (49.5-70.1%) | 0.43 | (0.30, 0.60) |
| | | Negative | | | 84.6% (22/26) | (66.5-93.8%) | 0.12 | (0.05, 0.29) |
| All | 49.1% (624/1272) | Positive | 81.9% (503/614) | (78.7-84.8%) | | | 4.71 | (3.96, 5.60) |
| | | Grey Zone | 40.5% (83/205) | (34.0-47.3%) | 59.5% (122/205) | (52.7-66.0%) | 0.71 | (0.55, 0.91) |
| | | Negative | | | 91.6% (415/453) | (88.7-93.8) | 0.10 | (0.07, 0.13) |
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Access NT-proBNP - Subjects with BMI $< 30\mathrm{kg} / \mathrm{m}^2$ (LiHep)
| Age Group | Prevalence of HF (% (n/N)) | Access NT-ProBNP results | Posttest Probability of HF | | Posttest Probability of No non-HF | | Likelihood Ratio and CI | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | | | Estimate % (n/N) | 95% CI (%) | Estimate (% (n/N)) | 95% CI (%)* | LR | 95%-CI** |
| <50 | 24.8% (82/330) | Positive | 54.9% (79/144) | (46.7-62.8%) | | | 3.68 | (2.97, 4.55) |
| | | Grey Zone | 14.3% (1/7) | (2.6-51.3%) | 85.7% (6/7) | (48.7-97.4%) | 0.50 | (0.06, 4.13) |
| | | Negative | | | 98.9% (177/179) | (96.0-99.7%) | 0.03 | (0.01, 0.13) |
| 50-75 | 44.3% (180/406) | Positive | 71.4% (170/238) | (65.4-76.8%) | | | 3.14 | (2.57, 3.84) |
| | | Grey Zone | 15.7% (8/51) | (8.2-28.0%) | 84.3% (43/51) | (72.0-91.8%) | 0.23 | (0.11, 0.48) |
| | | Negative | | | 98.3% (115/117) | (94.0-99.5%) | 0.02 | (0.01, 0.09) |
| >75 | 46.0% (173/376) | Positive | 64.2% (147/229) | (57.8-70.1%) | | | 2.10 | (1.76, 2.51) |
| | | Grey Zone | 24.1% (26/108) | (17.0-32.9%) | 75.9% (82/108) | (67.1-83.0%) | 0.37 | (0.25, 0.55) |
| | | Negative | | | 100% (39/39) | (91.0-100.0%) | 0.00 | (0.00, 0.00) |
| All | 39.1% (435/1112) | Positive | 64.8% (396/611) | (60.9-68.5%) | | | 2.87 | (2.56, 3.21) |
| | | Grey Zone | 21.1% (35/166) | (15.6-27.9%) | 78.9% (131/166) | (72.1-84.4%) | 0.42 | (0.29, 0.59) |
| | | Negative | | | 98.8% (331/335) | (97.0-99.5%) | 0.02 | (0.01,0.05) |
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Access NT-proBNP - Subjects with comorbidities*** (LiHep)
| Age Group | Prevalence of HF (% (n/N)) | Access NT-ProBNP results | Posttest Probability of HF | | Posttest Probability of non-HF | | Likelihood Ratio and CI | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | | | Estimate % (n/N) | 95% CI (%) | Estimate (% (n/N)) | 95% CI * | LR | 95%-CI** |
| <50 | 46.3% (240/518) | Positive | 75.0% (213/284) | (69.7-79.7%) | | | 3.48 | (2.83, 4.27) |
| | | Grey Zone | 37.9% (11/29) | (22.7-56.0%) | 62.1% (18/29) | (44.0-77.3%) | 0.71 | (0.34, 1.47) |
| | | Negative | | | 92.2% (189/205) | (87.7-95.1%) | 0.10 | (0.06, 0.16) |
| 50-75 | 50.7% (401/791) | Positive | 79.3% (340/429) | (75.2-82.8%) | | | 3.72 | (3.08, 4.48) |
| | | Grey Zone | 35.8% (44/123) | (27.9-44.6%) | 64.2% (79/123) | (55.4-72.1%) | 0.54 | (0.39, 0.76) |
| | | Negative | | | 92.9% (222/239) | (88.9-95.5%) | 0.07 | (0.05, 0.12) |
| >75 | 51.8% (284/548) | Positive | 71.6% (224/313) | (66.3-76.3%) | | | 2.34 | (1.96, 2.80) |
| | | Grey Zone | 32.2% (56/174) | (25.7-39.4%) | 67.8% (118/174) | (60.6-74.3%) | 0.44 | (0.34, 0.58) |
| | | Negative | | | 93.4% (57/61) | (84.3-97.4%) | 0.07 | (0.03, 0.17) |
| All | 49.8% (925/1857) | Positive | 75.7% (777/1026) | (73.0-78.3%) | | | 3.14 | (2.82, 3.51) |
| | | Grey Zone | 34.0% (111/326) | (29.1-39.4%) | 66.0% (215/326) | (60.6-70.9%) | 0.52 | (0.42, 0.64) |
| | | Negative | | | 92.7% (468/505) | (90.1-94.6%) | 0.08 | (0.06, 0.11) |
*** The comorbidity group was defined as having one or more of the following non-cardiac medical history conditions (within 90 days prior to presentation at the emergency department): Metabolic disorders (e.g., diabetes or nonalcoholic fatty liver disease), renal insufficiency (defined as eGFR <60 to ≥30 mL/min/1.73m² BSA), systemic hypertension, and/or pulmonary disease requiring a chronic steroid therapy and/or supplemental home oxygen.
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Access NT-proBNP - Subjects without comorbidities (LiHep)
| Age Group | Prevalence of HF (% (n/N)) | Access NT-ProBNP results | Posttest Probability of HF | | Posttest Probability of non-HF | | Likelihood Ratio and CI | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | | | Estimate % (n/N) | 95% CI (%) | Estimate (% (n/N)) | 95% CI (%)* | LR | 95%-CI** |
| <50 | 19.4% (70/361) | Positive | 54.1% (66/122) | (45.3-62.7%) | | | 4.90 | (3.85, 6.24) |
| | | Grey Zone | 12.5% (1/8) | (2.2-47.1%) | 87.5% (7/8) | (52.9-97.8%) | 0.59 | (0.07, 4.75) |
| | | Negative | | | 98.7% (228/231) | (96.3, 99.6%) | 0.05 | (0.02, 0.17) |
| 50-75 | 36.3% (45/124) | Positive | 71.4% (40/56) | (58.5-81.6%) | | | 4.39 | (2.80, 6.88) |
| | | Grey Zone | 15.0% (3/20) | (5.2-36.0%) | 85.0% (17/20) | (64.0-94.8%) | 0.31 | (0.10, 1.00) |
| | | Negative | | | 95.8% (46/48) | (86.0-98.8%) | 0.08 | (0.02, 0.29) |
| >75 | 45.2% (19/42) | Positive | 76.2% (16/21) | (54.9-89.4%) | | | 3.87 | (1.74, 8.62) |
| | | Grey Zone | 17.6% (3/17) | (6.2-41.0%) | 82.4% (14/17) | (59.0-93.8%) | 0.26 | (0.09, 0.77) |
| | | Negative | | | 100.0% (4/4) | (51.0-100.0%) | 0.00 | (0.00, 0.00) |
| All | 25.4% (134/527) | Positive | 61.3% (122/199) | (54.4-67.8%) | | | 4.65 | (3.78, 5.72) |
| | | Grey Zone | 15.6% (7/45) | (7.7-28.8%) | 84.4% (38/45) | (71.2-92.3%) | 0.54 | (0.25, 1.18) |
| | | Negative | | | 98.2% (278/283) | (95.9-99.2%) | 0.05 | (0.02, 0.12) |
The sponsor included information in the clinical study section of the labeling regarding the false positives and false negatives in certain subgroups.
Correlation of the Access NT-proBNP assay results with New York Heart Association (NYHA) functional classification in patients diagnosed with HF:
The Assess NT-proBNP results were determined from samples from 1043 subjects with heart failure. The population consisted of 450 females and 593 males. The descriptive statistics for the Access NT-proBNP results (ng/L) were determined across sex and are summarized in the following table:
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All Subjects
| Statistics | NYHA Functional Classification | | | |
| --- | --- | --- | --- | --- |
| | NYHA Class I | NYHA Class II | NYHA Class III | NYHA Class IV |
| N | 91 | 271 | 485 | 196 |
| Mean | 3485 | 4718 | 5656 | 6460 |
| SD | 3499 | 4539 | 5939 | 6087 |
| Median | 2350 | 3547 | 3717 | 5073 |
| 5th Percentile | 425 | 345 | 382 | 185 |
| 95th Percentile | 11643 | 13291 | 18446 | 18290 |
Jonckheere-Terpstra test of trend p <0.0001
Female
| Statistics | NYHA Functional Classification | | | |
| --- | --- | --- | --- | --- |
| | NYHA Class I | NYHA Class II | NYHA Class III | NYHA Class IV |
| N | 37 | 112 | 213 | 88 |
| Mean | 2282 | 4659 | 5297 | 7206 |
| SD | 1857 | 4465 | 5987 | 7144 |
| Median | 1546 | 3698 | 3173 | 4533 |
| 5th Percentile | 343 | 294 | 291 | 150 |
| 95th Percentile | 7384 | 12706 | 17152 | 26226 |
Jonckheere-Terpstra test of trend p =0.0005
Male
| Statistics | NYHA Functional Classification | | | |
| --- | --- | --- | --- | --- |
| | NYHA Class I | NYHA Class II | NYHA Class III | NYHA Class IV |
| N | 54 | 159 | 272 | 108 |
| Mean | 4309 | 4761 | 5938 | 5852 |
| SD | 4093 | 4604 | 5896 | 5020 |
| Median | 2948 | 3422 | 4173 | 5149 |
| 5th Percentile | 425 | 432 | 606 | 379 |
| 95th Percentile | 12527 | 13402 | 20869 | 14584 |
Jonckheere-Terpstra test of trend p =0.0033
In the labeling, the sponsor states the following:
The JT test of trending was conducted on the 1043 subjects with an enrollment site NYHA evaluation and an adjudicated acute HF diagnosis resulting in a Z statistic of 4.1991 and p-value < 0.001. These results indicate that there is a statistically significant relationship between Access NT-proBNP results and HF severity as determined by NYHA class.
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Risk stratification of patient with heart failure (HF) and risk stratification of acute coronary syndrome (ACS).
The sponsor provided information to support the risk stratification of heart failure and acute coronary syndrome claims based on the following three peer-reviewed literature references:
Reference 1: N-Terminal Pro-Brain Natriuretic Peptide and Other Risk Markers for the Separate Prediction of Mortality and Subsequent Myocardial Infarction in Patients with Unstable Coronary Artery Disease, GUSTO IV Substudy, James, S.K. et al, Circulation 2003, 108(3): 275-281.
Reference 2: N-Terminal Pro-Brain Natriuretic Peptide on Admission for Early Risk Stratification of Patients with Chest Pain and No ST-Segment Elevation, Jernberg, T. et al. Journal of the American College of Cardiology, 2002, 40(3): 437-445.
Reference 3: N-Terminal pro B type natriuretic peptide, but not the new putative cardiac hormone relaxin, predicts prognosis in patients with chronic heart failure. Fisher, C. et al. Heart, 2003, 89 (8):879-881
## D Clinical Cut-Off:
For patients in the Emergency Department (ED) settings, the Access NT-proBNP assay results should be interpreted as indicated in the table below.
| Age Group (Years) | NT-proBNP Results (ng/L) | Interpretation |
| --- | --- | --- |
| All | < 300 ng/L | Heart Failure Unlikely |
| <50 | ≥ 300 - < 450 | Grey Zone: Results Indeterminate-consider other reasons for NT-proBNP elevation |
| 50-75 | ≥300 - <900 | |
| >75 | ≥300 - <1800 | |
| <50 | ≥450 | Heart Failure Likely |
| 50-75 | ≥900 | |
| >75 | ≥1800 | |
## 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-A3.
In the study, lithium heparin, serum and $\mathrm{K}_2\mathrm{EDTA}$ levels of NT-proBNP were assayed with the Access NT-proBNP assay on a total of 675 apparently healthy subjects (369 females and 306 males) without HF. The results were subgrouped by sex, with each group of females and males were stratified into three age groups of: $< 50$ years, 50-75 years, and $>75$ years. The exclusion criteria used were:
- Disease(s) of /or affecting the cardiovascular system.
- Poorly controlled hypertension (defined as current blood pressure $\geq 140 \mathrm{~mmHg}$ systolic, or $\geq 85 \mathrm{~mmHg}$ diastolic).
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- Current taking mediation for cardiovascular disease (except medications to control hypertension).
- Body-mass index (BMI) $\geq 30 \, \mathrm{kg/m}^2$
- Diabetes
- Chronic kidney disease
- Other serious chronic disease(s) (e.g., cancer, COPD, HIV, lupus erythematosus, etc).
- Acute bacterial or viral infection.
Representative data from lithium heparin samples is summarized in the following tables:
Female ng/L (LiHep)
| Age (years) | <50 | 50-75 | >75 | All ages |
| --- | --- | --- | --- | --- |
| N | 135 | 145 | 89 | 369 |
| Mean | 63 | 114 | 178 | 111 |
| SD | 42 | 80 | 111 | 89 |
| Median | 54 | 91 | 154 | 82 |
| IQR (25th -75th percentile) | 32-80 | 54-155 | 93-216 | 49-149 |
| 95th percentile ULN | 152 | 282 | 443 | 294 |
| 97.5% percentile ULN | 178 | 317 | 457 | 670 |
| %<125 ng/L | 91.1% | 65.5% | 33.7% | 67.2% |
Male ng/L (LiHep)
| Age (years) | <50 | 50-75 | >75 | All ages |
| --- | --- | --- | --- | --- |
| N | 132 | 111 | 63 | 306 |
| Mean | 33 | 68 | 130 | 66 |
| SD | 38 | 71 | 82 | 72 |
| Media | 23 | 48 | 115 | 41 |
| IQR (25th -75th percentile) | 13-39 | 28-77 | 77-148 | 20-84 |
| 95th percentile ULN | 84 | 188 | 243 | 188 |
| 97.5% percentile ULN | 103 | 284 | 434 | 267 |
| %<125 ng/L | 99.2% | 87.4% | 58.7% | 86.6% |
## 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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