Elecsys proBNP II, Elecsys proBNP II STAT
Device Facts
| Record ID | K223637 |
|---|---|
| Device Name | Elecsys proBNP II, Elecsys proBNP II STAT |
| Applicant | Roche Diagnostics |
| Product Code | NBC · Clinical Chemistry |
| Decision Date | Jul 21, 2023 |
| Decision | SESE |
| Submission Type | Traditional |
| Regulation | 21 CFR 862.1117 |
| Device Class | Class 2 |
Indications for Use
Immunoassay for the in vitro quantitative determination of N-terminal pro-Brain natriuretic peptide in human serum and plasma. This assay is used as an aid in the diagnosis of individuals suspected of having heart failure. It can be used as an aid in the diagnosis of acute decompensated heart failure (ADHF) in patients presenting with signs and symptoms of ADHF to the emergency department (ED). The test is further indicated for the risk stratification of patients with acute coronary syndrome and heart failure. The test may also serve as an aid in the assessment of increased risk of cardiovascular events and mortality in patients at risk for heart failure who have stable coronary artery disease.
Device Story
Quantitative immunoassay (ECLIA) for NT-proBNP in human serum/plasma. Input: 15 µL sample; biotinylated monoclonal antibody; ruthenium-labeled monoclonal antibody. Process: Sandwich complex formation; magnetic capture on streptavidin-coated microparticles; chemiluminescent emission via voltage application to electrode; photomultiplier detection. Used in clinical laboratories on cobas e immunoassay analyzers. Output: NT-proBNP concentration (pg/mL) determined via calibration curve. Results aid clinicians in diagnosing ADHF, risk-stratifying acute coronary syndrome/HF, and assessing cardiovascular risk. Provides age-dependent cut-offs for ADHF diagnosis in emergency settings.
Clinical Evidence
Multi-center prospective study (17 US sites, 1,485 ED subjects, age 22-97). Evaluated clinical performance of age-dependent cut-offs for ADHF diagnosis. Results provided as posttest probabilities and likelihood ratios across age groups (<50, 50-75, >75), sex, and comorbidities (eGFR, BMI, history of HF). Analytical performance (precision, linearity, LoB/LoD/LoQ) established via bench testing on cobas e 601 analyzer.
Technological Characteristics
Electrochemiluminescence immunoassay (ECLIA). Reagents: Streptavidin-coated microparticles, biotinylated monoclonal anti-NT-proBNP antibody, ruthenium-labeled monoclonal anti-NT-proBNP antibody. Measuring range: 36-35,000 pg/mL. Analyzers: cobas e 601. Calibration: 2-point calibration with master curve via barcode. Software: Automated analysis on cobas e platform.
Indications for Use
Indicated for individuals suspected of having heart failure, including patients presenting to the emergency department with signs and symptoms of acute decompensated heart failure (ADHF). Also indicated for risk stratification of patients with acute coronary syndrome and heart failure, and assessment of cardiovascular event/mortality risk in patients at risk for heart failure with stable coronary artery disease.
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, Elecsys proBNP II STAT (K210546)
Related Devices
- K072437 — ELECSYS PROBNP II, PRECICONTROL CARDIAC II, PROBNP II CALSET · Roche Diagnostics · Feb 5, 2008
- K210546 — Elecsys proBNP II, Elecsys proBNP II STAT · Roche Diagnostics · Mar 31, 2022
- K051382 — ELECSYS PROBNP IMMUNOASSAY · Roche Diagnostics Corp. · Dec 5, 2005
Submission Summary (Full Text)
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K223637 - Page 1 of 20
# 510(k) SUBSTANTIAL EQUIVALENCE DETERMINATION DECISION SUMMARY
ASSAY ONLY
## I Background Information:
A 510(k) Number
K223637
B Applicant
Roche Diagnostics
C Proprietary and Established Names
Elecsys proBNP II, Elecsys proBNP II STAT
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:
Expansion of the intended use
B Measurand:
N-terminal pro Brain Natriuretic Peptide (NT-proBNP)
C Type of Test:
Quantitative immunoassay
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III Intended Use/Indications for Use:
A Intended Use(s):
See Indications for Use below.
B Indication(s) for Use:
Both the Elecsys proBNP II and Elecsys proBNP II STAT have the following indications for use:
Immunoassay for the in vitro quantitative determination of N-terminal pro-Brain natriuretic peptide (NT-proBNP) in human serum and plasma. This assay is used as an aid in the diagnosis of individuals suspected of having heart failure (HF). It can be used as an aid in the diagnosis of acute decompensated heart failure (ADHF) in patients presenting with signs and symptoms of ADHF to the emergency department (ED). The assay is further indicated for the risk stratification of patients with acute coronary syndrome and HF. The test may also serve as an aid in the assessment of increased risk of cardiovascular events and mortality in patients at risk for HF who have stable coronary artery disease.
The electrochemiluminescence immunoassay “ECLIA” is intended for use on the cobas e immunoassay analyzers.
C Special Conditions for Use Statement(s):
Rx - For Prescription Use Only
D Special Instrument Requirements:
Performance data for this submission was generated using the cobas e 601 immunoassay analyzer
IV Device/System Characteristics:
A Device Description:
The Elecsys proBNP II and the Elecsys proBNP II STAT consist of three reagents in separate bottles labeled M, R1, and R2:
- M: Streptavidin-coated microparticles (transparent cap), 1 bottle, 6.5 mL: Streptavidin-coated microparticles 0.72 mg/mL; preservative
- R1: Anti-NT-proBNP-Ab~biotin (gray cap), 1 bottle, 9 mL: Biotinylated monoclonal anti-NT-proBNP antibody (mouse) 1.1 µg/mL; phosphate buffer 40 mmol/L, pH 5.8; preservative
- R2: Anti-NT-proBNP-Ab~Ru(bpy) (black cap), 1 bottle, 9 mL: Monoclonal anti-NT-proBNP antibody (sheep) labeled with ruthenium complex 1.1 µg/mL; Biotin scavenger antibody 1.5 mg/mL; phosphate buffer 40 mmol/L, pH 5.8; preservative
K223637 - Page 2 of 20
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K223637 - Page 3 of 20
## B Principle of Operation:
The Elecsys proBNP II assay follows the procedure below:
1st incubation: Antigen in the sample (15 µL), a biotinylated monoclonal NT-proBNP-specific antibody, and a monoclonal NT-proBNP-specific antibody labeled with a ruthenium complex (Tris(2,2'-bipyridyl)ruthenium(II)-complex (Ru(bpy)₃²⁺)) form a sandwich complex.
2nd incubation: After addition of streptavidin-coated microparticles, the complex becomes bound to the solid phase via interaction of biotin and streptavidin.
The reaction mixture is aspirated into the measuring cell where the microparticles are magnetically captured onto the surface of the electrode. Unbound substances are then removed with ProCell/ProCell M. Application of a voltage to the electrode then induces chemiluminescent emission which is measured by a photomultiplier.
Results are determined via a calibration curve which is generated by 2-point calibration and a master curve provided via the reagent barcode or e-barcode.
The Elecsys proBNP II STAT assay follows a similar procedure outlined above except that the first and second incubations are combined into a single step. The total assay run time for the Elecsys proBNP II is 18 min and for the Elecsys proBNP II STAT is 9 min.
## V Substantial Equivalence Information:
### A Predicate Device Name(s):
Elecsys proBNP II, Elecsys proBNP II STAT
### B Predicate 510(k) Number(s):
K210546
### C Comparison with Predicate(s):
| Device & Predicate Device(s): | K223637 | K210546 |
| --- | --- | --- |
| Device Trade Name | Elecsys proBNP II, Elecsys proBNP II STAT | Elecsys proBNP II, Elecsys proBNP II STAT |
| General Device Characteristic Similarities | | |
| Intended Use | For the quantitative determination of NT-proBNP in human serum and plasma. | Same |
| Test principle | Quantitative immunoassay | Same |
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| Device & Predicate Device(s): | K223637 | K210546 |
| --- | --- | --- |
| General Device Characteristic Differences | | |
| Result interpretation | Emergency Department setting for ADHF:
**Negative**
< 300 pg/mL for all age groups
**Indeterminate**
• ≥ 300 to ≤ 450 pg/mL for < 50 years of age
• ≥ 300 to ≤ 900 pg/mL for 50-75 years of age
• ≥ 300 to ≤ 1800 pg/mL for > 75 years of age
**Positive**
• > 450 pg/mL for < 50 years of age
• > 900 pg/mL for 50-75 years of age
• >1800 pg/mL for > 75 years of age | **Positive**
• 125 pg/mL for < 75 years of age
• 450 pg/mL for patients ≥ 75 years of age |
VI Standards/Guidance Documents Referenced:
Clinical and Laboratory Standards Institute (CLSI) EP05-A3: Evaluation of Precision of Quantitative Measuring Procedures-Third Edition.
CLSI EP06: Evaluation of the Linearity of Quantitative Measurement Procedure - Second Edition.
CLSI EP17-A2: Evaluation of Detection Capability for Clinical Laboratory Measurement Procedures-Second Edition.
B-Type Natriuretic Peptide Premarket Notifications - Final Class II Special Control Guidance Document for Industry and FDA Reviewers
K223637 - Page 4 of 20
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VII Performance Characteristics (if/when applicable):
The performance characteristics of the Elecsys ProBNP II STAT on the cobas e 601 analyzer are described in K210456.
A Analytical Performance:
1. Repeatability and Intermediate Precision:
The precision of the Elecsys proBNP II assay was evaluated on one cobas e 601 analyzer at one internal site with three reagent lots over 21 days.
Testing was conducted with eight serum samples and two controls in single determinations in four separate aliquots (divided into two runs per day) for 21 operating days (n=84). Repeatability, Between-Run, Between-Day, and Within-Laboratory Precision were calculated per the recommendations in the CLSI EP05-A3 guideline.
Human serum samples 1, 2, 3, 4, 5, and 6 are pooled unaltered human serum samples. Samples 7 and 8 are human serum sample pools spiked with a synthetic NT-proBNP peptide. Results from a representative lot are described below.
| | | Repeatability | | Within laboratory precision | |
| --- | --- | --- | --- | --- | --- |
| Sample | Mean pg/mL | SD pg/mL | CV % | SD pg/mL | CV % |
| Human serum 1 | 68.3 | 1.96 | 2.9 | 3.26 | 4.8 |
| Human serum 2 | 145 | 3.24 | 2.2 | 5.95 | 4.1 |
| Human serum 3 | 314 | 4.31 | 1.4 | 11.5 | 3.7 |
| Human serum 4 | 467 | 12.8 | 2.7 | 17.6 | 3.8 |
| Human serum 5 | 1004 | 20.0 | 2.0 | 34.6 | 3.5 |
| Human serum 6 | 2075 | 38.9 | 1.9 | 68.6 | 3.3 |
| Human serum 7 | 15985 | 371 | 2.3 | 579 | 3.6 |
| Human serum 8 | 34624 | 609 | 1.8 | 1367 | 3.9 |
| PreciControl Cardiac II 1 | 140 | 2.48 | 1.8 | 4.94 | 3.5 |
| PreciControl Cardiac II 2 | 4721 | 70.2 | 1.5 | 156 | 3.3 |
2. Linearity:
The linearity study was conducted using the Elecsys proBNP II on the cobas e 601 analyzer following the recommendations in the CLSI guideline EP06 second edition. One high analyte human native serum sample with a NT-proBNP concentration above the measuring rage was diluted with analyte free serum. A total of 10 concentrations were prepared that spanned the measuring range. Samples were assayed in 3-fold determination within a single run.
The maximum deviation from linearity observed within the claimed measuring range for the Elecsys proBNP II was -16.8%.
K223637 - Page 5 of 20
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The results of the linearity study support the claimed measuring range of 36 pg/mL to 35000 pg/mL
3. Analytical Specificity/Interference:
Analytical specificity studies were conducted using the Elecsys proBNP II assay on the cobas e 601 analyzer and support the same analytical specificity claims established in K210546 for the Elecsys proBNP II assay on the e 411 analyzer.
4. Assay Reportable Range:
The claimed assay reportable range is 36-35,000 pg/mL.
5. Traceability, Stability, Expected Values (Controls, Calibrators, or Methods):
The traceability of the assays is the same as described in K210546.
6. Detection Limit:
LoB (Limit of blank), LoD (Limit of detection) and Limit of Quantitation (LoQ) of the Elecsys proBNP II on the cobas e 601 analyzer were determined according to CLSI EP17-A2 and support the claims described in K210546 for the Elecsys proBNP II assay on the e 411 analyzer.
7. Assay Cut-Off:
See clinical cut-off (Section VII.D.) below.
B Comparison Studies:
1. Method Comparison with Predicate Device:
A method comparison was conducted using the Elecsys NT proBNP II assay on the cobas e 411 and the cobas e 601 analyzers. One hundred fifty-seven (157) human serum samples containing between 54 and 33,544 pg/mL of NTproBNP were tested in the study. One hundred fifty-three (153) samples were native and 4 samples were spiked. There were no diluted samples.
The results of the Passing-Bablok regression analysis are summarized below:
| Slope | 95% CI | Intercept | 95% CI | Pearsons r |
| --- | --- | --- | --- | --- |
| 0.988 | 0.980 to 0.995 | 1.03 | -2.98 to 4.96 | 0.999 |
2. Matrix Comparison:
The sponsor claims the same matrix types for the Elecsys proBNP II on the cobas e 601 as described in K210546.
K223637 - Page 6 of 20
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# C Clinical Studies:
1. Clinical Sensitivity:
See Section VII.C.3. below.
2. Clinical Specificity:
See Section VII.C.3. below.
3. Other Clinical Supportive Data (When 1. And 2. Are Not Applicable):
A multi-center prospective study including 17 sites in the United States was conducted to establish the clinical performance characteristics of the Elecsys proBNP II and Elecsys proBNP II STAT assays. Subjects 22 years and older admitted to the emergency department (ED) suspected of or with symptoms of acute decompensated heart failure (ADHF) that included acute dyspnea of a duration no longer than several days were enrolled in the study. Subjects with renal insufficiency requiring dialysis or known estimated glomerular filtration rate (eGFR) $< 15.0 \, \text{mL/min/1.73 m}^2$ and subjects with dyspnea after chest trauma were excluded from the study. The final clinical diagnosis was adjudicated by cardiologists or ED physicians. The Elecsys proBNP II and Elecsys proBNP II STAT results were determined on the Roche cobas e601 immunoassay analyzer using samples collected from 1485 ED subjects consisting of 741 (49.9%) female subjects and 744 (50.1%) male subjects ranging in age from 22 to 97 years. Individuals in the population were Caucasian (57.4%), Black or African American (37.2%), Asian (1.3%), American Indian or Alaska Native (0.3%), Native Hawaiian or Other Pacific Islander (0.6%), or other race (1.3%) with the remaining 1.9% of unknown race. 1238 (83.4%) ED subjects were not Hispanic or Latino and 190 (12.8%) ED subjects were Hispanic or Latino with the remaining 57 (3.8%) ED subjects of unknown ethnicity.
The descriptive statistics for the Elecsys proBNP II and Elecsys proBNP II STAT results $(\mathrm{pg} / \mathrm{mL})$ were determined within and across sex by age group. The results using the Elecsys proBNP II STAT assay are summarized below and are similar to the results obtained using the Elecsys proBNP II:
Elecsys proBNP II STAT - All subjects
| | ADHF | | | | No ADHF | | | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
| Age group | < 50 | 50-75 | >75 | All | < 50 | 50-75 | >75 | All |
| N | 36 | 182 | 57 | 275 | 442 | 660 | 108 | 1210 |
| Mean (SD) | 3175.8(2640.3) | 5204.3(6569.9) | 7689.5(8796.2) | 5453.8(6854.2) | 159.8(428.6) | 819.0(2721.4) | 1751.5(2472.2) | 661.4(2203.7) |
| Median | 2554.0 | 2832.0 | 4473.0 | 3054.0 | 45.1 | 148.7 | 847.2 | 104.9 |
| Min - Max | 90.4 -9900.0 | 36.0 -33746.0 | 316.4 -35000.0 | 36.0 -35000.0 | 36.0 -5921.0 | 36.0 -35000.0 | 39.4 -16896.0 | 36.0 -35000.0 |
K223637 - Page 7 of 20
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Elecsys proBNP II STAT - Females
| | ADHF | | | | No ADHF | | | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
| Age group | <50 | 50-75 | >75 | All | <50 | 50-75 | >75 | All |
| N | 15 | 74 | 21 | 110 | 252 | 326 | 53 | 631 |
| Mean (SD) | 3559.7
(3173.3) | 5106.0
(7371.8) | 9179.4
(10912.0) | 5672.8
(7920.7) | 132.8
(399.0) | 761.0
(2638.8) | 1972.5
(2877.1) | 611.8
(2144.3) |
| Median | 2990.0 | 2762.5 | 4941.0 | 2912.5 | 54.5 | 124.8 | 885.7 | 98.8 |
| Min - Max | 202.5 - 9900.0 | 67.6 - 32615.0 | 929.1 - 35000.0 | 67.6 - 35000.0 | 36.0 - 5921.0 | 36.0 - 35000.0 | 60.7 - 16896.0 | 36.0 - 35000.0 |
Elecsys proBNP II STAT - Males
| | ADHF | | | | No ADHF | | | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
| Age group | <50 | 50-75 | >75 | All | <50 | 50-75 | >75 | All |
| N | 21 | 108 | 36 | 165 | 190 | 334 | 55 | 579 |
| Mean (SD) | 2901.6
(2227.4) | 5271.6
(5994.1) | 6820.3
(7324.4) | 5307.9
(6061.3) | 195.7
(463.7) | 875.6
(2802.5) | 1538.6
(2011.4) | 715.5
(2267.4) |
| Median | 2470.0 | 2907.5 | 4143.0 | 3123.0 | 36.0 | 182.9 | 840.0 | 112.8 |
| Min - Max | 90.4 - 7544.0 | 36.0 - 33746.0 | 316.4 - 34670.0 | 36.0 - 34670.0 | 36.0 - 3405.0 | 36.0 - 35000.0 | 39.4 - 10326.0 | 36.0 - 35000.0 |
Elecsys proBNP II STAT results versus adjudicated diagnosis
| Age (years) | Elecsys proBNP II STAT Test Result Interpretation | Adjudicated diagnosis | | Total |
| --- | --- | --- | --- | --- |
| | | ADHF | No ADHF | |
| <50 | Positive | 31 | 27 | 58 |
| | Gray | 0 | 23 | 23 |
| | Negative | 5 | 392 | 397 |
| | Total | 36 | 442 | 478 |
| 50-75 | Positive | 146 | 114 | 260 |
| | Gray | 25 | 117 | 142 |
| | Negative | 11 | 429 | 440 |
| | Total | 182 | 660 | 842 |
| >75 | Positive | 43 | 31 | 74 |
| | Gray | 14 | 52 | 66 |
| | Negative | 0 | 25 | 25 |
| | Total | 57 | 108 | 165 |
| All | Positive | 220 | 172 | 392 |
| | Gray | 39 | 192 | 231 |
| | Negative | 16 | 846 | 862 |
| | Total | 275 | 1210 | 1485 |
K223637 - Page 8 of 20
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The pretest probability of ADHF (prevalence of ADHF in the study), posttest probabilities, likelihood ratios and the 95% confidence intervals (CIs) of the Elecsys proBNP II result versus adjudicated diagnosis and the Elecsys proBNP II STAT result versus adjudicated diagnosis were determined across and within sex using the age-dependent positive (450 pg/mL for subjects < 50 years of age; 900 pg/mL for subjects 50–75 years of age; 1800 pg/mL for subjects > 75 years of age) and age-independent negative (300 pg/mL) cutoffs. The results using the Elecsys proBNP II STAT assay are summarized below and are similar to the results obtained using the Elecsys proBNP II:
Elecsys proBNP II STAT all subjects
| Age Group | Prevalence of ADHF (% (n/N)) | Test Result Interpretation | Posttest Probability of ADHF | | Posttest Probability of No ADHF | | Likelihood Ratio (ADHF) | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | | | Estimate (% (n/N)) | 95% CI (%)* | Estimate (% (n/N)) | 95% CI (%)* | LR | 95%-CI** |
| <50 | 7.5 (36/478) | Positive | 53.4 (31/58) | 40.0-66.5 | - | - | 14.10 | 9.56-20.79 |
| | | Gray | 0.0 (0/23) | 0.0-17.8 | 100.0 (23/23) | 82.2-100.0 | 0.00 | 0.00-NaN |
| | | Negative | - | - | 98.7 (392/397) | 96.9-99.5 | 0.16 | 0.07-0.35 |
| 50-75 | 21.6 (182/842) | Positive | 56.2 (146/260) | 49.9-62.2 | - | - | 4.64 | 3.87-5.57 |
| | | Gray | 17.6 (25/142) | 11.9-25.1 | 82.4 (117/142) | 74.9-88.1 | 0.77 | 0.52-1.16 |
| | | Negative | - | - | 97.5 (429/440) | 95.4-98.7 | 0.09 | 0.05-0.17 |
| >75 | 34.5 (57/165) | Positive | 58.1 (43/74) | 46.1-69.3 | - | - | 2.63 | 1.89-3.66 |
| | | Gray | 21.2 (14/66) | 12.5-33.3 | 78.8 (52/66) | 66.7-87.5 | 0.51 | 0.31-0.84 |
| | | Negative | - | - | 100.0 (25/25) | 83.4-100.0 | 0.00 | 0.00-NaN |
N/A = not applicable. NaN = not a number due to empty cells.
*Wilson Score confidence intervals with continuity correction
**Log method confidence intervals
K223637 - Page 9 of 20
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Elecsys proBNP II STAT - Females
| Age Group | Prevalence of ADHF (%) (n/N) | Test Result Interpretation | Posttest Probability of ADHF | | Posttest Probability of No ADHF | | Likelihood Ratio (ADHF) | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | | | Estimate (%) (n/N) | 95%-CI (%)* | Estimate (%) (n/N) | 95%-CI (%)* | LR | 95%-CI** |
| <50 | 5.6 (15/267) | Positive | 61.9 (13/21) | 38.7-81.0 | -- | -- | 27.3 0 | 13.42-55.54 |
| | | Gray | 0.0 (0/15) | 0.0-25.3 | 100.0 (15/15) | 74.7-100.0 | 0.00 | 0.00-NaN |
| | | Negative | -- | -- | 99.1 (229/231) | 96.6-99.8 | 0.15 | 0.04-0.53 |
| 50-75 | 18.5 (74/400) | Positive | 52.7 (58/110) | 43.0-62.2 | -- | -- | 4.91 | 3.73-6.48 |
| | | Gray | 19.6 (11/56) | 10.7-32.8 | 80.4 (45/56) | 67.2-89.3 | 1.08 | 0.59-1.98 |
| | | Negative | -- | -- | 97.9 (229/234) | 94.8-99.2 | 0.10 | 0.04-0.22 |
| >75 | 28.4 (21/74) | Positive | 46.9 (15/32) | 29.5-65.0 | -- | -- | 2.23 | 1.38-3.58 |
| | | Gray | 18.8 (6/32) | 7.9-37.0 | (26/32) | 63.0-92.1 | 0.58 | 0.28-1.21 |
| | | Negative | -- | -- | 100.0 (10/10) | 65.5-100.0 | 0.00 | 0.00-NaN |
NaN due to empty cells
*Wilson Score confidence intervals with continuity correction
**log method confidence intervals
Elecsys proBNP II STAT - Males
| Age Group | Prevalence of ADHF (%) (n/N) | Test Result Interpretation | Posttest Probability of ADHF | | Posttest Probability of No ADHF | | Likelihood Ratio (ADHF) | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | | | Estimate (%) (n/N) | 95%-CI (%)* | Estimate (%) (n/N) | 95%-CI (%)* | LR | 95%-CI** |
| <50 | 10.0 (21/211) | Positive | 48.6 (18/37) | 32.2-65.3 | -- | -- | 8.57 | 5.41-13.59 |
| | | Gray | 0.0 (0/8) | 0.0-40.2 | 100.0 (8/8) | 59.8-100.0 | 0.00 | 0.00-NaN |
K223637 - Page 10 of 20
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| Age Group | Prevalence of ADHF (%) (n/N) | Test Result Interpretation | Posttest Probability of ADHF | | Posttest Probability of No ADHF | | Likelihood Ratio (ADHF) | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | | | Estimate (%) (n/N) | 95%-CI (%)* | Estimate (%) (n/N) | 95%-CI (%)* | LR | 95%-CI** |
| | | Negative | -- | -- | 98.2 (163/166) | 94.4-99.5 | 0.17 | 0.06-0.48 |
| 50-75 | 24.4 (108/442) | Positive | 58.7 (88/150) | 50.3-66.6 | -- | -- | 4.39 | 3.45-5.59 |
| | | Gray | 16.3 (14/86) | 9.5-26.1 | 83.7 (72/86) | 73.9-90.5 | 0.60 | 0.35-1.02 |
| | | Negative | -- | -- | 97.1 (200/206) | 93.5-98.8 | 0.09 | 0.04-0.20 |
| >75 | 39.6 (36/91) | Positive | 66.7 (28/42) | 50.4-80.0 | -- | -- | 3.06 | 1.88-4.96 |
| | | Gray | 23.5 (8/34) | 11.4-41.6 | 76.5 (26/34) | 58.4-88.6 | 0.47 | 0.24-0.92 |
| | | Negative | -- | -- | 100.0 (15/15) | 74.7-100.0 | 0.00 | 0.00-NaN |
NaN due to empty cells
*Wilson Score confidence intervals with continuity correction
**log method confidence intervals
The pretest probability of ADHF (prevalence of ADHF in the study), posttest probabilities, likelihood ratios and the $95\%$ CIs of the Elecsys proBNP II result versus adjudicated diagnosis and Elecsys proBNP II STAT result versus adjudicated diagnosis were determined for the relevant clinical subgroups using the age-dependent positive $(450~\mathrm{pg / mL}$ for subjects $< 50$ years of age; $900~\mathrm{pg / mL}$ for subjects 50-75 years of age; $1800~\mathrm{pg / mL}$ for subjects $\geq 75$ years of age) and age-independent negative $(300~\mathrm{pg / mL})$ cutoffs. The results using the Elecsys proBNP II STAT assay are summarized below and are similar to the results obtained using the Elecsys proBNP II:
K223637 - Page 11 of 20
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Elecsys proBNP II STAT – Subjects with a history of heart failure
| Age Group | Prevalence of ADHF (%) (n/N) | Test Result Interpretation | Posttest Probability of ADHF | | Posttest Probability of No ADHF | | Likelihood Ratio (ADHF) | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | | | Estimate (%) (n/N) | 95%-CI (%)* | Estimate (%) (n/N) | 95%-CI (%)* | LR | 95%-CI** |
| <50 | 45.2 (28/62) | Positive | 67.2 (25/37) | 50.1-81.4 | -- | -- | 2.53 | 1.58-4.06 |
| | | Gray | 0.0 (0/6) | 0.0-48.3 | 100.0 (6/6) | 51.7-100 | 0.00 | 0.00-NaN |
| | | Negative | -- | -- | 84.2 (16/19) | 59.5-95.8 | 0.23 | 0.07-0.7 |
| 50-75 | 52.6 (113/215) | Positive | 68.9 (93/135) | 60.3-76.4 | -- | -- | 2.00 | 1.56-2.56 |
| | | Gray | 40.6 (13/32) | 24.2-59.2 | 59.4 (19/32) | 40.8-75.8 | 0.62 | 0.32-1.19 |
| | | Negative | -- | -- | 85.4 (41/48) | 71.6-93.5 | 0.15 | 0.07-0.33 |
| >75 | 50.7 (35/69) | Positive | 65.9 (29/44) | 50.0-79.1 | -- | -- | 1.88 | 1.25-2.82 |
| | | Gray | 27.3 (6/22) | 11.6-50.4 | 72.7 (16/22) | 49.6-88.4 | 0.36 | 0.16-0.82 |
| | | Negative | -- | -- | 100.0 (3/3) | 31.0-100.0 | 0.00 | 0.00-NaN |
NaN due to empty cells
*Wilson Score confidence intervals with continuity correction
**log method confidence intervals
K223637 - Page 12 of 20
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Elecsys proBNP II STAT – Subjects with no history of heart failure
| Age Group | Prevalence of ADHF (%) (n/N) | Test Result Interpretation | Posttest Probability of ADHF | | Posttest Probability of No ADHF | | Likelihood Ratio (ADHF) | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | | | Estimate (%) (n/N) | 95%-CI (%)* | Estimate (%) (n/N) | 95%-CI (%)* | LR | 95%-CI** |
| <50 | 1.8 (7/396) | Positive | 26.3 (5/19) | 10.1-51.4 | -- | -- | 19.85 | 9.9-39.8 |
| | | Gray | 0.0 (0/17) | 0.0-22.9 | 100.0 (17/17) | 77.1-100 | 0.00 | 0.00-NaN |
| | | Negative | -- | -- | 99.4 (358/360) | 97.8-99.9 | 0.31 | 0.10-1.00 |
| 50-75 | 10 (57/569) | Positive | 40 (42/105) | 30.7-50 | -- | -- | 5.99 | 4.53-7.91 |
| | | Gray | 12 (12/100) | 6.6-20.4 | 88 (88/100) | 79.6-93.4 | 1.22 | 0.72-2.1 |
| | | Negative | -- | -- | 99.2 (361/364) | 97.4-99.8 | 0.07 | 0.02-0.22 |
| >75 | 20.0 (16/80) | Positive | 45.5 (10/22) | 25.1-67.3 | -- | -- | 3.33 | 1.77-6.29 |
| | | Gray | 16.7 (6/36) | 7.0-33.5 | 83.3 (30/36) | 66.5-93 | 0.80 | 0.4-1.59 |
| | | Negative | -- | -- | 100.0 (22/22) | 81.5-100.0 | 0.00 | 0.00-NaN |
NaN due to empty cells
*Wilson Score confidence intervals with continuity correction
**log method confidence intervals
The sponsor included the following information in the labeling.
"Patients with a history of prior HF have a substantially lower performance for positive cutpoints compared to the performance in all evaluable subjects of the ICON-Reloaded cohort, which is likely due to a chronic biological elevation of NT-proBNP in these conditions. Higher false positive rates were observed in all subjects and higher false negative rates were seen in
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those subjects who were less than 50 and between 50-75 years of age. Use caution when interpreting test results in these patients due to a higher false positive and false negative rate."
Elecsys proBNP II STAT - Subjects with eGFR $< 60~\mathrm{mL / min} / 1.73~\mathrm{m2}$
| Age Group | Prevalence of ADHF (%) (n/N) | Test Result Interpretation | Posttest Probability of ADHF | | Posttest Probability of No ADHF | | Likelihood Ratio (ADHF) | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | | | Estimate (%) (n/N) | 95%-CI (%)* | Estimate (%) (n/N) | 95%-CI (%)* | LR | 95%-CI** |
| <50 | 40.9 (9/22) | Positive | 81.8 (9/11) | 47.8-96.8 | -- | -- | 6.50 | 1.82-23.26 |
| | | Gray | 0.0 (0/4) | 0.0-60.4 | 100.0 (4/4) | 39.6-100.0 | 0.00 | 0.00-NaN |
| | | Negative | - | -- | 100.0 (7/7) | 56.1-100.0 | 0.00 | 0.00-NaN |
| 50-75 | 40.5 (85/210) | Positive | 64.2 (77/120) | 54.8-72.6 | -- | -- | 2.63 | 2.05-3.39 |
| | | Gray | 22.6 (7/31) | 10.3-41.5 | 77.4 (24/31) | 58.5-89.7 | 0.43 | 0.19-0.95 |
| | | Negative | - | -- | 98.3 (58/59) | 89.7-99.9 | 0.03 | 0.00-0.18 |
| >75 | 40.4 (38/94) | Positive | 60.0 (33/55) | 45.9-72.7 | -- | -- | 2.21 | 1.56-3.13 |
| | | Gray | 16.1 (5/31) | 6.1-34.5 | 83.9 (26/31) | 65.5-93.9 | 0.28 | 0.12-0.67 |
| | | Negative | - | -- | 100.0 (8/8) | 59.8-100.0 | 0.00 | 0.00-NaN |
NaN due to empty cells
*Wilson Score confidence intervals with continuity correction
**log method confidence interval
Elecsys proBNP II STAT - Subjects with eGFR $\geq 60~\mathrm{mL / min} / 1.73~\mathrm{m2}$
| Age Group | Prevalence of ADHF (%) (n/N) | Test Result Interpretation | Posttest Probability of ADHF | | Posttest Probability of No ADHF | | Likelihood Ratio (ADHF) | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | | | Estimate (%) (n/N) | 95%-CI (%)* | Estimate (%) (n/N) | 95%-CI (%)* | LR | 95%-CI** |
| <50 | 6.9 (25/361) | Positive | 48.8 (21/43) | 33.6-64.3 | -- | -- | 12.8 3 | 8.27-19.89 |
| | | Gray | 0.0 (0/16) | 0.0-24.1 | 100.0 (16/16) | 75.9-100.0 | 0.00 | 0.00-NaN |
| | | Negative | -- | -- | 98.7 (298/302) | 96.4-99.6 | 0.18 | 0.07-0.44 |
| 50-75 | 15.5 (92/592) | Positive | 50.0 (65/130) | 41.5-58.5 | -- | -- | 5.43 | 4.18-7.06 |
| | | Gray | 16.4 (18/110) | 10.2-24.9 | 83.6 (92/110) | 75.1-89.8 | 1.06 | 0.68-1.67 |
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| Age Group | Prevalence of ADHF (%) (n/N) | Test Result Interpretation | Posttest Probability of ADHF | | Posttest Probability of No ADHF | | Likelihood Ratio (ADHF) | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | | | Estimate (%) (n/N) | 95%-CI (%)* | Estimate (%) (n/N) | 95%-CI (%)* | LR | 95%-CI** |
| | | Negative | -- | -- | 97.4 (343/352) | 95.0-98.7 | 0.14 | 0.08-0.27 |
| >75 | 26.9 (18/67) | Positive | 50.0 (9/18) | 29.0-71.0 | -- | -- | 2.72 | 1.29-5.76 |
| | | Gray | 27.3 (9/33) | 13.9-45.8 | 72.7 (24/33) | 54.2-86.1 | 1.02 | 0.59-1.76 |
| | | Negative | -- | -- | 100.0 (16/16) | 75.9-100.0 | 0.00 | 0.00-NaN |
NaN due to empty cells
*Wilson Score confidence intervals with continuity correction
**log method confidence intervals
Elecsys proBNP II STAT - Subjects with BMI $\geq 30\mathrm{kg / m2}$
| Age Group | Prevalence of ADHF (%) (n/N) | Test Result Interpretation | Posttest Probability of ADHF | | Posttest Probability of No ADHF | | Likelihood Ratio (ADHF) | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | | | Estimate (%) (n/N) | 95%-CI (%)* | Estimate (%) (n/N) | 95%-CI (%)* | LR | 95%-CI** |
| <50 | 11.8 (30/255) | Positive | 62.5 (25/40) | 45.8-76.8 | -- | - | 12.50 | 7.47-20.91 |
| | | Gray | 0.0 (0/11) | 0.0-32.1 | 100.0 (11/11) | 67.9-100.0 | 0.00 | 0.00-NaN |
| | | Negative | -- | -- | 97.5 (199/204) | 94.1-99.1 | 0.19 | 0.08-0.42 |
| 50-75 | 25.6 (104/407) | Positive | 60.2 (77/128) | 51.1-68.6 | -- | - | 4.40 | 3.34-5.79 |
| | | Gray | 25.8 (17/66) | 16.1-38.2 | 74.2 (49/66) | 61.8-83.9 | 1.01 | 0.61-1.67 |
| | | Negative | -- | -- | 95.3 (203/213) | 91.3-97.6 | 0.14 | 0.08-0.26 |
| >75 | 32.3 (20/62) | Positive | 55.0 (11/20) | 32.0-76.2 | -- | - | 2.57 | 1.27-5.18 |
| | | Gray | 29.0 (9/31) | 14.9-48.2 | 71.0 (22/31) | 51.8-85.1 | 0.86 | 0.49-1.51 |
| | | Negative | -- | -- | 100.0 (11/11) | 67.9-100.0 | 0.00 | 0.00-NaN |
NaN due to empty cells
*Wilson Score confidence intervals with continuity correction
**log method confidence intervals
K223637 - Page 15 of 20
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Elecsys proBNP II STAT – Subjects with BMI <30 kg/m²
| Age Group | Prevalence of ADHF (%) (n/N) | Test Result Interpretation | Posttest Probability of ADHF | | Posttest Probability of No ADHF | | Likelihood Ratio (ADHF) | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | | | Estimate (%) (n/N) | 95%-CI (%)* | Estimate (%) (n/N) | 95%-CI (%)* | LR | 95%-CI** |
| <50 | 2.8 (5/177) | Positive | 33.3 (5/15) | 13.0-61.3 | -- | -- | 17.20 | 9.43-31.39 |
| | | Gray | 0.0 (0/12) | 0.0-30.1 | 100.0 (12/12) | 69.9-100.0 | 0.00 | 0.00-NaN |
| | | Negative | - | -- | 100.0 (150/150) | 96.9-100.0 | 0.00 | 0.00-NaN |
| 50-75 | 18.9 (70/370) | Positive | 51.6 (63/122) | 42.5-60.7 | -- | -- | 4.58 | 3.59-5.83 |
| | | Gray | 11.1 (7/63) | 5.0-22.2 | 88.9 (56/63) | 77.8-95.0 | 0.54 | 0.26-1.12 |
| | | Negative | - | -- | 100.0 (185/185) | 97.5-100.0 | 0.00 | 0.00-NaN |
| >75 | 36.6 (37/101) | Positive | 59.3 (32/54) | 45.1-72.1 | -- | -- | 2.52 | 1.75-3.61 |
| | | Gray | 15.2 (5/33) | 5.7-32.7 | 84.8 (28/33) | 67.3-94.3 | 0.31 | 0.13-0.73 |
| | | Negative | - | -- | 100.0 (14/14) | 73.2-100.0 | 0.00 | 0.00-NaN |
NaN due to empty cells
*Wilson Score confidence intervals with continuity correction
**log method confidence intervals
The sponsor included the following information in the labeling:
"In this study, 15 of the 16 subjects with false negative results had an elevated BMI. In turn, however, patients with low BMI that were tested negative are characterized by a high NPV of 100% (95% CI 98.7-100.0)".
K223637 - Page 16 of 20
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Elecsys proBNP II STAT – Subjects with Comorbidities (i.e., subjects with at least one of the following: diabetes, renal insufficiency (eGFR values < 60), hypertension and/or chronic obstructive pulmonary disease (COPD)).
| Age Group | Prevalence of ADHF (%) (n/N) | Test Result Interpretation | Posttest Probability of ADHF | | Posttest Probability of No ADHF | | Likelihood Ratio (ADHF) | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | | | Estimate (%) (n/N) | 95%-CI (%)* | Estimate (%) (n/N) | 95%-CI (%)* | LR | 95%-CI** |
| <50 | 14 (31/221) | Positive | 57.8 (26/45) | 42.2-72 | -- | -- | 8.39 | 5.33-13.2 |
| | | Gray | 0.0 (0/18) | 0.0-21.9 | 100.0 (18/18) | 78.1-100.0 | 0.00 | 0.00-NaN |
| | | Negative | - | -- | 96.8 (153/158) | 92.4-98.8 | 0.20 | 0.00-NaN |
| 50-75 | 23.8 (161/677) | Positive | 57 (127/223) | 50.2-63.5 | -- | -- | 4.24 | 3.48-5.17 |
| | | Gray | 20.5 (24/117) | 13.8-29.2 | 79.5 (93/117) | 70.8-86.2 | 0.83 | 0.55-1.25 |
| | | Negative | - | -- | 97 (327/337) | 94.4-98.5 | 0.10 | 0.05-0.18 |
| >75 | 35.8 (53/148) | Positive | 63.5 (40/63) | 50.4-75 | -- | -- | 3.12 | 2.12-4.59 |
| | | Gray | 21.3 (13/61) | 12.3-34 | 78.7 (48/61) | 66-87.7 | 0.49 | 0.29-0.81 |
| | | Negative | - | -- | 100.0 (24/24) | 82.8-100 | 0.00 | 0.00-NaN |
NaN due to empty cells
*Wilson Score confidence intervals with continuity correction
**log method confidence intervals
proBNP II STAT - Subjects without Comorbidities
| Age Group | Prevalence of ADHF (%) (n/N) | Test Result Interpretation | Posttest Probability of ADHF | | Posttest Probability of No ADHF | | Likelihood Ratio (ADHF) | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | | | Estimate (%) (n/N) | 95%-CI (%)* | Estimate (%) (n/N) | 95%-CI (%)* | LR | 95%-CI** |
| <50 | 1.7 (4/232) | Positive | 36.4 (4/11) | 12.4-68.4 | -- | -- | 32.57 | 15.7-67.5 |
| | | Gray | 0.0 (0/5) | 0.0-53.7 | 100.0 (5/5) | 46.3-100 | 0.00 | 0.00-NaN |
| | | Negative | - | -- | 100 (216/216) | 97.8-100 | 0.00 | 0.00-NaN |
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| Age Group | Prevalence of ADHF (%) (n/N) | Test Result Interpretation | Posttest Probability of ADHF | | Posttest Probability of No ADHF | | Likelihood Ratio (ADHF) | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | | | Estimate (%) (n/N) | 95%-CI (%)* | Estimate (%) (n/N) | 95%-CI (%)* | LR | 95%-CI** |
| 50-75 | 12 (15/125) | Positive | 52 (13/25) | 31.8-71.7 | -- | -- | 7.94 | 4.49-14.04 |
| | | Gray | 5.6 (1/18) | 0.3-29.4 | 94.4 (17/18) | 70.6-99.7 | 0.43 | 0.06-3.01 |
| | | Negative | - | -- | 98.8 (81/82) | 92.5-99.9 | 0.09 | 0.01-0.60 |
| >75 | 0.0 (0/7) | Positive | 0.0 (0/6) | 0.0-48.3 | -- | -- | NaN | NaN-NaN |
| | | Gray | NaN (0/0) | NA-NA | NaN (0/0) | NA-NA | NaN | NaN-NaN |
| | | Negative | -- | -- | 100.0 (1/1) | 5.5-100 | NaN | NaN-NaN |
NaN due to empty cells
*Wilson Score confidence intervals with continuity correction
**log method confidence intervals
## New York Heart Association (NYHA) Functional Classification
586 subjects had a NYHA functional classification. NT-proBNP values in this group are presented below for the Elecsys proBNP II STAT assay. The results based on the Elecsys proBNP II were similar.
All Subjects:
| proBNP II STAT | All HF | NYHA II | NYHA III | NYHA IV |
| --- | --- | --- | --- | --- |
| Mean | 1400 | 1067 | 1485 | 1631 |
| SD | 3712 | 3087 | 3044 | 4973 |
| Median | 155 | 111 | 270 | 161 |
| 5th Percentile | 36 | 36 | 36 | 36 |
| 95th Percentile | 7781 | 4952 | 8585 | 7774 |
| % above cut-point | 26.3 | 20.8 | 31.7 | 24.4 |
| Minimum | 36 | 36 | 36 | 36 |
| Maximum | 35000 | 27776 | 21402 | 35000 |
| N | 586 | 178 | 240 | 168 |
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Female Subjects:
| proBNP II STAT | All HF | NYHA II | NYHA III | NYHA IV |
| --- | --- | --- | --- | --- |
| Mean | 1090 | 522 | 1175 | 1558 |
| SD | 3317 | 1247 | 2486 | 5077 |
| Median | 115 | 105 | 121 | 132 |
| 5th Percentile | 36 | 36 | 36 | 36 |
| 95th Percentile | 5160 | 2426 | 6310 | 7750 |
| % above cut-point | 20.3 | 13.7 | 27 | 18.9 |
| Minimum | 36 | 36 | 36 | 36 |
| Maximum | 35000 | 9832 | 14061 | 35000 |
| N | 301 | 95 | 111 | 95 |
Male Subjects:
| proBNP II STAT | All HF | NYHA II | NYHA III | NYHA IV |
| --- | --- | --- | --- | --- |
| Mean | 1727 | 1692 | 1752 | 1725 |
| SD | 4068 | 4248 | 3441 | 4867 |
| Median | 279 | 115 | 403 | 228 |
| 5th Percentile | 36 | 36 | 36 | 36 |
| 95th Percentile | 8852 | 9793 | 8768 | 7030 |
| % above cut-point | 32.6 | 28.9 | 35.7 | 31.5 |
| Minimum | 36 | 36 | 36 | 36 |
| Maximum | 34670 | 27776 | 21402 | 34670 |
| N | 285 | 83 | 129 | 73 |
The sponsor also provided information to support the use of the frozen samples in this study.
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# D Clinical Cut-Off:
In this submission, the sponsor added the following cut-offs for use as an aid in the diagnosis of ADHF in patients presenting to emergency departments:
| Age Group | Elecsys proBNP II / Elecsys proBNP II STAT Cut-Points | Interpretation |
| --- | --- | --- |
| All ages | 300 pg/mL | NT-proBNP < 300 pg/mL indicates ADHF not likely |
| < 50 years | 450 pg/mL | NT-proBNP > 450 pg/mL indicates ADHF is likely |
| 50 to 75 years | 900 pg/mL | NT-proBNP > 900 pg/mL indicates ADHF is likely |
| > 75 years | 1800 pg/mL | NT-proBNP > 1800 pg/mL indicates ADHF is likely |
| All ages | Results within the gray zone for the patient’s age group | Indeterminate. Further clinical information is needed to determine if ADHF is present |
# E Expected Values/Reference Range:
Reference ranges for individuals without heart failure were previously established in K022516.
Also see Section VII.C.3., which describes NT-proBNP levels in subjects without ADHF presenting to the ED.
# 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.
