(228 days)
Not Found
No
The device description and performance studies focus on the analytical and clinical performance of an immunoassay using electrochemiluminescence technology. There is no mention of AI or ML in the device description, intended use, or performance evaluation sections. The analysis is based on quantitative determination of a biomarker, not on algorithmic interpretation of complex data using AI/ML.
No
This device is an in vitro diagnostic test used to measure a biomarker (NT-proBNP) to aid in the diagnosis and risk stratification of heart failure, which is a diagnostic function, not a therapeutic one.
Yes
The "Intended Use / Indications for Use" section explicitly states that the assay "is used as an aid in the diagnosis of individuals suspected of having heart failure" and "as an aid in the diagnosis of acute decompensated heart failure (ADHF)."
No
The device is an in vitro diagnostic immunoassay kit that relies on chemical reactions and specialized hardware (cobas e family of analyzers) to measure NT-proBNP levels in biological samples. It is not a software-only device.
Yes, this device is an IVD (In Vitro Diagnostic).
The "Intended Use / Indications for Use" section explicitly states: "Immunoassay for the in vitro quantitative determination of N-terminal pro-Brain natriuretic peptide in human serum and plasma." and "This assay is used as an aid in the diagnosis of individuals suspected of having heart failure."
The "Device Description" also describes it as an "in vitro quantitative determination".
These statements clearly indicate that the device is intended for use outside of the body to examine specimens (serum and plasma) for diagnostic purposes, which is the definition of an In Vitro Diagnostic device.
N/A
Intended Use / 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.
The electrochemiluminescence immunoassay "ECLIA" is intended for use on cobas e immunoassay analyzers.
Product codes (comma separated list FDA assigned to the subject device)
NBC
Device Description
Elecsys proBNP II and proBNP II STAT are second-generation assays by Roche Diagnostics for the in vitro quantitative determination of N-terminal pro-Brain natriuretic peptide (NT-proBNP) in human serum and plasma. The STAT and the 18 Minute assays are intended for use on the cobas e 601.
The cobas e family of analyzers emplovs the electrochemiluminescence immunoassay "ECLIA" technology. The assays are sandwich principle methods using two monoclonal antibodies which are specifically directed against NT-proBNP. For the neutralization of free biotin in serum and plasma, Roche developed an antibody, which binds to free biotin. The antibodies are specific for free biotin and do not bind to or interact with the biotin-linker conjugates.
Mentions image processing
Not Found
Mentions AI, DNN, or ML
Not Found
Input Imaging Modality
Not Found
Anatomical Site
Not Found
Indicated Patient Age Range
Subjects were > 22 years of age
Intended User / Care Setting
emergency department (ED)
Description of the training set, sample size, data source, and annotation protocol
Not Found
Description of the test set, sample size, data source, and annotation protocol
To assess the performance of positive and negative cut-points for ADHF in patients presenting with signs and symptoms of ADHF to the ED, a multi-center trial was performed in the United States. 1485 subjects were enrolled at 17 sites, 744 males and 741 females. Subjects were > 22 years of age with symptoms of suspected acute decompensated HF, presenting with dyspnea of a duration no longer than several days. 275 (19 %) were found to have acutely decompensated HF, based on adjudication by a clinical events committee.
Summary of Performance Studies (study type, sample size, AUC, MRMC, standalone performance, key results)
PRECISION (CLSI EP05-A3)
Study Type: Precision study
Sample Size: Not specified for total samples, but 8 serum samples and 2 controls were tested in single determinations in four separate aliquots (divided into two runs per day) for 21 operating days (n=84).
Key Results: The results of precision studies performed with the Elecsys proBNP II assay met predetermined acceptance criteria.
ANALYTICAL SENSITIVITY - Limit of Blank (LoB) and Limit of Detection (LoD) (CLSI EP17-A2)
Study Type: Analytical sensitivity study
Sample Size: LoB: 60 determinations of an analyte-free sample. LoD: Five low level human serum samples measured.
Key Results: LoB will be set to ≤ 8 pg/mL. LoD will be set to ≤ 10 pg/mL.
Limit of Quantitation (LoQ) (CLSI EP17-A2)
Study Type: Limit of Quantitation study
Sample Size: 10 native, unaltered serum samples, tested in 5 replicates, once per day for 5 days (n=25 measured values per sample).
Key Results: The LoQ claim in the labeling will be set to 36 pg/mL.
Linearity/Reportable Range (CLSI EP06-Ed2)
Study Type: Linearity study (weighted least square regression by pooled variance)
Sample Size: 10 levels, 3 replicates each.
Key Results: The recommended measuring range is 36 to 35000 pg/mL. Linearity specifications were met.
Endogenous Interferences (CLSI EP07-A3)
Study Type: Endogenous interference study
Sample Size: Three different analyte concentration levels (low ~130 pg/mL, medium ~900 pg/mL, high ~20000 pg/mL) in human native serum.
Key Results: No interference up to: Bilirubin ≤ 428 µmol/L or ≤25 mg/dL; Hemoglobin ≤ 0.621 mmol/L or ≤1000 mg/dL; Lipemia ≤ 1500 mg/dL; Biotin ≤ 3500 ng/mL; Rheumatoid Factor ≤ 1500 IU/mL.
CLINICAL PERFORMANCE EVALUATION - Expected values: Acute care setting
Study Type: Multi-center clinical trial
Sample Size: 1485 subjects
Key Results:
- Median proBNP II: Subjects without ADHF: 105 pg/mL (IQR: 38.64 - 400.38 pg/mL); Subjects with ADHF: 3012 pg/mL (IQR: 1258.50 - 6673.50 pg/mL).
- Median proBNP II STAT: Subjects without ADHF: 105 pg/mL (IQR: 37.86 - 402.80 pg/mL); Subjects with ADHF: 3054 pg/mL (IQR: 1255.50 - 6759.00 pg/mL).
- Likelihood ratio (LR) for gray zone (228 subjects): 0.91 (95% CI: 0.66-1.25) suggesting no additive diagnostic value.
- Positive likelihood ratios (LR+) and negative likelihood ratios (LR-) were calculated across different age groups and genders for both Elecsys proBNP II and Elecsys proBNP II STAT assays, demonstrating their strength as an aid in diagnosing ADHF.
- Renal cohort (eGFR age-specific cut-point):
- Actual ADHF: 220
- No ADHF: 173
- Total: 393
- Post-test Probability of ADHF: 220/393 = 56.0% (95%-CI: 50.9-61.0)
- LR+: 3.03 (95%-CI: 2.59-3.55)
- Gray test result (NT-proBNP ≥ 300 pg/mL and ≤ age-specific cut-point):
- Actual ADHF: 39
- No ADHF: 189
- Total: 228
- Post-test Probability of ADHF: 39/228 = 17.1% (95%-CI: 12.3-22.9)
- LR: 0.81 (95%-CI: 0.58-1.12)
- Negative test result (NT-proBNP
§ 862.1117 B-type natriuretic peptide test system.
(a)
Identification. The B-type natriuretic peptide (BNP) test system is an in vitro diagnostic device intended to measure BNP in whole blood and plasma. Measurements of BNP are used as an aid in the diagnosis of patients with congestive heart failure.(b)
Classification. Class II (special controls). The special control is “Class II Special Control Guidance Document for B-Type Natriuretic Peptide Premarket Notifications; Final Guidance for Industry and FDA Reviewers.”
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July 21, 2023
Roche Diagnostics Jane Phillips Sr. Regulatory Program Manager 9115 Hague Road Indianapolis, IN 46250
Re: K223637
Trade/Device Name: Elecsys proBNP II, Elecsys proBNP II STAT Regulation Number: 21 CFR 862.1117 Regulation Name: B-type natriuretic peptide test system Regulatory Class: Class II Product Code: NBC Dated: June 20, 2023 Received: June 21, 2023
Dear Jane Phillips:
We have reviewed your Section 510(k) premarket notification of intent to market the device referenced above and have determined the device is substantially equivalent (for the indications for use stated in the enclosure) to legally marketed predicate devices marketed in interstate commerce prior to May 28, 1976, the enactment date of the Medical Device Amendments, or to devices that have been reclassified in accordance with the provisions of the Federal Food, Drug, and Cosmetic Act (Act) that do not require approval of a premarket approval application (PMA). You may, therefore, market the device, subject to the general controls provisions of the Act. Although this letter refers to your product as a device, please be aware that some cleared products may instead be combination products. The 510(k) Premarket Notification Database located at https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpmn/pmn.cfm identifies combination product submissions. The general controls provisions of the Act include requirements for annual registration, listing of devices, good manufacturing practice, labeling, and prohibitions against misbranding and adulteration. Please note: CDRH does not evaluate information related to contract liability warranties. We remind you, however, that device labeling must be truthful and not misleading.
If your device is classified (see above) into either class II (Special Controls) or class III (PMA), it may be subject to additional controls. Existing major regulations affecting your device can be found in the Code of Federal Regulations, Title 21, Parts 800 to 898. In addition, FDA may publish further announcements concerning your device in the Federal Register.
Please be advised that FDA's issuance of a substantial equivalence determination does not mean that FDA has made a determination that your device complies with other requirements of the Act or any Federal statutes and regulations administered by other Federal agencies. You must comply with all the Act's requirements, including, but not limited to: registration and listing (21 CFR Part 807); labeling (21 CFR Part 801 and Part 809); medical device reporting of medical device-related adverse events) (21 CFR
1
- for devices or postmarketing safety reporting (21 CFR 4, Subpart B) for combination products (see https://www.fda.gov/combination-products/guidance-regulatory-information/postmarketing-safety-reportingcombination-products); good manufacturing practice requirements as set forth in the quality systems (QS) regulation (21 CFR Part 820) for devices or current good manufacturing practices (21 CFR 4, Subpart A) for combination products; and, if applicable, the electronic product radiation control provisions (Sections 531-542 of the Act); 21 CFR 1000-1050.
Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21 CFR Part 807.97). For questions regarding the reporting of adverse events under the MDR regulation (21 CFR Part 803), please go to https://www.fda.gov/medical-device-safety/medical-device-reportingmdr-how-report-medical-device-problems.
For comprehensive regulatory information about mediation-emitting products, including information about labeling regulations, please see Device Advice (https://www.fda.gov/medicaldevices/device-advice-comprehensive-regulatory-assistance) and CDRH Learn (https://www.fda.gov/training-and-continuing-education/cdrh-learn). Additionally, you may contact the Division of Industry and Consumer Education (DICE) to ask a question about a specific regulatory topic. See the DICE website (https://www.fda.gov/medical-device-advice-comprehensive-regulatoryassistance/contact-us-division-industry-and-consumer-education-dice) for more information or contact DICE by email (DICE@fda.hhs.gov) or phone (1-800-638-2041 or 301-796-7100).
Sincerely.
Paula V. Caposino -S
Paula Caposino, Ph.D. Acting Deputy Director Division of Chemistry and Toxicology Devices OHT7: Office of In Vitro Diagnostics Office of Product Evaluation and Ouality Center for Devices and Radiological Health
Enclosure
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K223637 Elecsys proBNP II and proBNP II STAT 510(k) Summary
This summary of 510(k) safety and effectiveness information is being submitted in accordance with the requirements of 21 CFR 807.92.
In accordance with 21 CFR 807.87, Roche Diagnostics hereby submits official notification as required by Section 510(k) of the Federal Food, Drug and Cosmetics Act of our intention to market the device described in this Premarket Notification 510(k).
The purpose of this Traditional 510(k) Premarket Notification is to obtain FDA review and clearance for the new cut-offs for patients presenting with dyspnea to the emergency department for the Elecsys proBNP II STAT and the Elecsys proBNP.
| Submitter Name | Roche Diagnostics |
|---|---|
| Address | 9115 Hague Road |
| P.O. Box 50416 | |
| Indianapolis, IN 46250-0457 | |
| Contact | Jane Phillips, PhD |
| Phone: (317) 521 3338 | |
| Email: jane.phillips@roche.com | |
| Date Prepared | November 30th, 2022 |
| Proprietary Name | Elecsys proBNP II and Elecsys proBNP II STAT |
| Common Name | proBNP II and proBNP II STAT |
| Classification Name | B-type natriuretic peptide test system |
| Product Codes, | |
| Regulation Numbers | NBC, 862.1117 |
| Predicate Devices | Elecsys proBNP II and Elecsys proBNP II STAT (K210546) |
4
| Item | Elecsys proBNP II
K210546 | Elecsys proBNP II
Candidate Device | Change description |
|------------------|------------------------------------------------------|------------------------------------------------------|--------------------|
| Proprietary name | Elecsys proBNP II | Elecsys proBNP II | None |
| Technology | ECLIA | ECLIA | None |
| Test format | Sandwich | Sandwich | None |
| Test type | Quantitative | Quantitative | None |
| Assay protocol | R1 + R2 + sample, incubation, +
beads, incubation | R1 + R2 + sample, incubation, +
beads, incubation | None |
| Measuring Range | 36-35000 pg/mL | 36-35000 pg/mL | None |
Table 1: Similarities and Differences between the Elecsys proBNP II
Table 2: Similarities and Differences between the Elecsys proBNP STAT
| ltem | Elecsys proBNP II STAT
K210546 | Elecsys proBNP II STAT
Candidate Device | Change description |
|------------------|-----------------------------------------|--------------------------------------------|--------------------|
| Proprietary name | Elecsys proBNP II STAT | Elecsys proBNP II STAT | None |
| Technology | ECLIA | ECLIA | None |
| Test format | Sandwich | Sandwich | None |
| Test type | Quantitative | Quantitative | None |
| Assay protocol | R1 + R2 + sample + beads,
incubation | R1 + R2 + sample + beads,
incubation | None |
| Measuring Range | 36-35000 pg/ml | 36-35000 pg/ml | None |
5
DEVICE DESCRIPTION 1.
Elecsys proBNP II and proBNP II STAT are second-generation assays by Roche Diagnostics for the in vitro quantitative determination of N-terminal pro-Brain natriuretic peptide (NT-proBNP) in human serum and plasma. The STAT and the 18 Minute assays are intended for use on the cobas e 601
The cobas e family of analyzers emplovs the electrochemiluminescence immunoassay "ECLIA" technology. The assays are sandwich principle methods using two monoclonal antibodies which are specifically directed against NT-proBNP. For the neutralization of free biotin in serum and plasma, Roche developed an antibody, which binds to free biotin. The antibodies are specific for free biotin and do not bind to or interact with the biotin-linker conjugates.
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.
The electrochemiluminescence immunoassay "ECLIA" is intended for use on cobas e immunoassay analyzers.
3. PREDICATE DEVICE
The predicate for this submission are the Elecsys proBNP II and the Elecsys proBNP II STAT Immunoassays which we cleared in K210546. No changes have been made to the assay since clearance.
6
ANALYTICAL PERFORMANCE EVALUATION 4.
Analytical experiments were run on the cobas e 601 using the Elecsys proBNP II.
PRECISION (CLSI EP05-A3)
Precision was evaluated on a single cobas e 601 for Elecsys proBNP II. The experiment was conducted according to CLSI guideline EP05-A3.
The protocol consisted of testing the 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). Testing was conducted at one internal site.
Results
Elecsys proBNP II
Lot MP01: Elecsys proBNP II
| cobas e 601 analyzer | |||||||||
|---|---|---|---|---|---|---|---|---|---|
| Repeatability | Intermediate precision | ||||||||
| Sample | |||||||||
| (Serum) | Mean | ||||||||
| pg/mL | SD | ||||||||
| pg/mL | SD 95% | ||||||||
| UCL | |||||||||
| pg/mL | CV | ||||||||
| % | CV 95% | ||||||||
| UCL | |||||||||
| % | SD | ||||||||
| pg/mL | SD | ||||||||
| 95% | |||||||||
| UCL | |||||||||
| pg/mL | CV | ||||||||
| % | CV 95% | ||||||||
| UCL | |||||||||
| % | |||||||||
| Human serum 1 | 68.3 | 1.96 | 2.39 | 2.9 | 3.5 | 3.26 | 4.05 | 4.8 | 5.9 |
| Human serum 2 | 145 | 3.24 | 3.96 | 2.2 | 2.7 | 5.95 | 7.42 | 4.1 | 5.1 |
| Human serum 3 | 314 | 4.31 | 5.27 | 1.4 | 1.7 | 11.5 | 14.7 | 3.7 | 4.7 |
| Human serum 4 | 467 | 12.8 | 15.7 | 2.7 | 3.4 | 17.6 | 21.2 | 3.8 | 4.5 |
| Human serum 5 | 1004 | 20.0 | 24.4 | 2.0 | 2.4 | 34.6 | 42.0 | 3.5 | 4.2 |
| Human serum 6 | 2075 | 38.9 | 47.6 | 1.9 | 2.3 | 68.6 | 84.8 | 3.3 | 4.1 |
| Human serum 7 | 15985 | 371 | 454 | 2.3 | 2.8 | 579 | 712 | 3.6 | 4.5 |
| Human serum 8 | 34624 | 609 | 744 | 1.8 | 2.1 | 1367 | 1725 | 3.9 | 5.0 |
| PreciControl | |||||||||
| Cardiac II 1 | 140 | 2.48 | 3.03 | 1.8 | 2.2 | 4.94 | 6.13 | 3.5 | 4.4 |
| PreciControl | |||||||||
| Cardiac II 2 | 4721 | 70.2 | 85.8 | 1.5 | 1.8 | 156 | 198 | 3.3 | 4.2 |
Conclusion
The results of precision studies performed with the Elecsys proBNP II assay met predetermined acceptance criteria.
7
ANALYTICAL SENSITIVITY
Limit of Blank (LoB) and Limit of Detection (LoD) (CLSI EP17-A2)
LoB of the Elecsys proBNP II on the cobas e 601 was determined according to CLSI EP17-A2. Limit of Blank determines the highest observed measurement values for samples free of analyte. The Limit of Blank was determined as the 95th percentile of measurements of blank samples.
LoD of the Elecsys proBNP II on the cobas e 601 analyzer was determined according to CLSI EP17-A2. The LoD determines the lower limit for samples with analyte. The LoD was determined as the lowest amount of analyte in a sample that can be detected with a 95% probability.
Methods LoB
In total 60 determinations of an analyte-free sample were obtained on one instrument over ≥ three days in 6 runs with 10-fold determination per run. Three lots of reagent were used in the experiment design.
As the analyzer does not report negative sample concentrations, the data set was truncated and the data were evaluated as the linear interpolation of the 57th ranked observation.
Methods LoD
Five low level human serum samples were measured on one instrument over ≥ three days in 6 runs with a two-fold determination per run. In total sixty determinations per reagent lot. The experiment was conducted using three reagent lots.
A pooled estimate of the precision (SD total) for the 5 low level samples was calculated.
LoD was calculated according to EP17-A2, chapter 5.3.3.2 as:
LoD = LoB + 1.653 x SD total (of low analyte samples)
8
Results
Elecsys proBNP II
| Instrument 1 | |||||||
|---|---|---|---|---|---|---|---|
| Date Run | 31-Jul-2019 | ||||||
| 1 | 31-Jul-2019 | ||||||
| 2 | 31-Jul-2019 | ||||||
| 3 | 01-Aug-2019 | ||||||
| 4 | 22-Aug-2019 | ||||||
| 5 | 23-Aug-2019 | ||||||
| 6 | |||||||
| Analyte-free | Value_1 | 0.0000 | 0.0000 | 0.0000 | 0.0000 | 0.0000 | 0.966 |
| Value_2 | 0.0000 | 0.0000 | 0.0000 | 0.145 | 0.0000 | 0.0000 | |
| Value_3 | 0.0000 | 0.0000 | 0.783 | 0.0000 | 0.0000 | 0.844 | |
| Value_4 | 0.0000 | 0.0000 | 0.0000 | 0.343 | 0.407 | 1.44 | |
| Value_5 | 0.0000 | 0.0000 | 0.0000 | 0.0000 | 0.0000 | 0.0000 | |
| Value_6 | 0.0000 | 0.0000 | 0.0000 | 0.145 | 0.721 | 1.21 | |
| Value_7 | 0.0000 | 0.0000 | 0.0000 | 0.0000 | 0.0000 | 0.0000 | |
| Value_8 | 0.0000 | 0.0000 | 0.0000 | 0.0000 | 0.0000 | 1.56 | |
| Value_9 | 0.0000 | 0.0000 | 0.0000 | 0.0000 | 0.0000 | 0.0000 | |
| Value_10 | 0.0000 | 0.0000 | 0.471 | 0.0000 | 0.0000 | 0.0000 | |
| Analyte-low | Date Run | 31-Jul-2019 | |||||
| 1 | 31-Jul-2019 | ||||||
| 2 | 31-Jul-2019 | ||||||
| 3 | 01-Aug-2019 | ||||||
| 4 | 22-Aug-2019 | ||||||
| 5 | 23-Aug-2019 | ||||||
| 6 | |||||||
| Value_1 | 5.11 | 6.25 | 7.86 | 6.95 | 7.80 | 7.49 | |
| Value_2 | 7.70 | 4.41 | 4.52 | 5.27 | 5.64 | 5.64 | |
| Value_3 | 6.68 | 3.59 | 6.74 | 6.57 | 7.16 | 5.05 | |
| Value_4 | 4.46 | 6.41 | 5.16 | 5.22 | 6.01 | 6.36 | |
| Value_5 | 3.26 | 2.60 | 6.79 | 6.68 | 6.41 | 4.03 | |
| Value_6 | 6.03 | 4.45 | 3.70 | 4.62 | 4.41 | 6.47 | |
| Value_7 | 7.91 | 5.48 | 5.69 | 5.43 | 5.96 | 6.75 | |
| Value_8 | 5.54 | 7.11 | 9.18 | 8.71 | 7.91 | 8.81 | |
| Value_9 | 5.69 | 4.79 | 7.91 | 7.91 | 7.65 | 5.59 |
Lot MP01 Elecsys proBNP II (concentrations in pg/mL)
| calculation
| factor (Cβ) | 1.653 |
|---|---|
| SD value 1/2 | 1.30 |
| SD value 3/4 | 1.08 |
| SD value 5/6 | 1.46 |
| SD value 7/8 | 1.43 |
| SD value 9/10 | 1.14 |
| SD total | 1.29 |
| SD total x Cβ | 2.13 |
| LoD | 3.22 |
| Result: | LoB | 1.48 | LoD | 2.57 | pg/mL |
|---|---|---|---|---|---|
| --------- | ----- | ------ | ----- | ------ | ------- |
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Conclusion
The LoD claim in the labeling will be set to ≤ 10 pg/mL. LoB will be set to ≤ 8 pg/mL.
Limit of Quantitation (LoQ) (CLSI EP17-A2)
LoQ determines the lowest amount of analyte that can be quantitatively determined with stated accuracy and stated experimental conditions. The LoQ was determined as the lowest concentration of analyte which can be reproducibly measured with an intermediate precision of 20% CV.
Methods LoQ
A low level sample set of 10 native, unaltered serum samples using the cobas e 601 analyzer of known measurand concentration was tested in 5 replicates (aliquots) on one instrument in singleton per day, over 5 days with 1 run per day. Three lots of reagent were used in the LoQ experiment. A total of n=25 measured values were obtained for each sample. The mean value and the intermediate precision as coefficient of variation (CV) and standard deviation (SD) were calculated for each LoQ sample.
Results
Elecsys proBNP II
Lot MP01: Elecsys proBNP II
| Day 1 | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Date Run | 11-Feb-2019 | |||||||||
| Sample | ||||||||||
| Type | Sample | |||||||||
| _1 | Sample | |||||||||
| _2 | Sample | |||||||||
| _3 | Sample | |||||||||
| _4 | Sample | |||||||||
| _5 | Sample | |||||||||
| _6 | Sample | |||||||||
| _7 | Sample | |||||||||
| _8 | Sample | |||||||||
| _9 | Sample | |||||||||
| _10 | ||||||||||
| Replicate | NT-proBNP concentrations in pg/mL | |||||||||
| 1 | 12.1 | 11.6 | 17.3 | 16.4 | 30.1 | 46.2 | 53.0 | 74.1 | 63.9 | 77.4 |
| 2 | 11.9 | 8.70 | 19.8 | 17.1 | 29.8 | 47.4 | 56.1 | 68.6 | 60.7 | 80.9 |
| 3 | 8.26 | 11.8 | 16.2 | 17.2 | 33.6 | 48.7 | 55.5 | 59.0 | 71.8 | 98.9 |
| 4 | 10.4 | 10.5 | 23.5 | 16.3 | 29.7 | 47.6 | 58.4 | 66.9 | 73.8 | 97.3 |
| 5 | 9.25 | 13.7 | 18.4 | 22.7 | 33.3 | 46.7 | 57.3 | 60.4 | 72.4 | 99.2 |
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| Day 2 | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Date Run | 12-Feb-2019 | |||||||||
| Sample | ||||||||||
| Type | Sample | |||||||||
| _1 | Sample | |||||||||
| _2 | Sample | |||||||||
| _3 | Sample | |||||||||
| _4 | Sample | |||||||||
| _5 | Sample | |||||||||
| _6 | Sample | |||||||||
| _7 | Sample | |||||||||
| _8 | Sample | |||||||||
| _9 | Sam | |||||||||
| ple - | ||||||||||
| _10 | ||||||||||
| Replicate | NT-proBNP concentrations in pg/mL | |||||||||
| 1 | 13.1 | 14.1 | 18.3 | 22.0 | 33.1 | 45.5 | 59.6 | 65.9 | 80.8 | 103 |
| 2 | 9.64 | 10.5 | 19.2 | 18.6 | 30.2 | 45.8 | 58.5 | 63.9 | 82.8 | 103 |
| 3 | 10.1 | 10.3 | 21.4 | 24.1 | 33.9 | 46.8 | 60.6 | 64.9 | 82.6 | 105 |
| 4 | 13.9 | 10.6 | 22.2 | 22.8 | 29.9 | 49.7 | 55.2 | 63.1 | 78.6 | 107 |
| 5 | 10.5 | 10.1 | 20.1 | 13.7 | 22.6 | 30.1 | 49.6 | 57.8 | 64.6 | 78.9 |
| Day 3 | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Date Run | 13-Feb-2019 | |||||||||
| Sample | ||||||||||
| Type | Sample | |||||||||
| _1 | Sample | |||||||||
| _2 | Sample | |||||||||
| _3 | Sample | |||||||||
| _4 | Sample | |||||||||
| _5 | Sample | |||||||||
| _6 | Sample | |||||||||
| _7 | Sample | |||||||||
| _8 | Sample | |||||||||
| _9 | Sample | |||||||||
| _10 | ||||||||||
| replicate | NT-proBNP concentrations in pg/mL | |||||||||
| 1 | 12.1 | 12.0 | 18.1 | 21.3 | 31.5 | 42.6 | 54.9 | 58.3 | 76.0 | 99.8 |
| 2 | 11.4 | 8.64 | 18.8 | 21.7 | 31.7 | 42.8 | 54.2 | 60.1 | 77.4 | 99.6 |
| 3 | 8.37 | 12.5 | 17.7 | 21.7 | 27.9 | 46.5 | 52.9 | 65.4 | 76.1 | 98.4 |
| 4 | 12.3 | 12.5 | 21.1 | 22.0 | 33.2 | 45.9 | 53.1 | 60.3 | 79.5 | 102 |
| 5 | 8.98 | 12.5 | 16.8 | 18.2 | 33.4 | 46.3 | 57.0 | 62.9 | 79.4 | 101 |
| Day 4 | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| Date Run | 14-Feb-2019 | ||||||||||
| Sample | |||||||||||
| Type | Sample | ||||||||||
| _1 | Sample | ||||||||||
| _2 | Sample | ||||||||||
| _3 | Sample | ||||||||||
| _4 | Sample | ||||||||||
| _5 | Sample | ||||||||||
| _6 | Sample | ||||||||||
| _7 | Sample | ||||||||||
| _8 | Sample | ||||||||||
| _9 | Sam | ||||||||||
| ple | |||||||||||
| _10 | |||||||||||
| Replicate | NT-proBNP concentrations in pg/mL | ||||||||||
| 1 | 9.31 | 10.0 | 20.7 | 21.7 | 29.0 | 48.8 | 57.8 | 64.6 | 77.2 | 103 | |
| 2 | 12.9 | 13.4 | 21.4 | 18.2 | 33.4 | 50.1 | 56.2 | 65.7 | 82.3 | 108 | |
| 3 | 9.42 | 10.6 | 18.2 | 22.0 | 29.4 | 50.6 | 56.5 | 66.9 | 83.4 | 105 | |
| 4 | 13.1 | 14.1 | 18.8 | 19.8 | 32.4 | 46.2 | 57.1 | 64.8 | 80.1 | 108 | |
| 5 | 10.0 | 13.2 | 19.1 | 23.1 | 33.3 | 47.5 | 60.2 | 63.3 | 81.9 | 104 |
11
| Day 5 | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Date Run | 18-Feb-2019 | |||||||||
| Sample | ||||||||||
| Type | Sample | |||||||||
| _1 | Sample | |||||||||
| _2 | Sample | |||||||||
| _3 | Sample | |||||||||
| _4 | Sample | |||||||||
| _5 | Sample | |||||||||
| _6 | Sample | |||||||||
| _7 | Sample | |||||||||
| _8 | Sample | |||||||||
| _9 | Sample | |||||||||
| _10 | ||||||||||
| Replicate | NT-proBNP concentrations in pg/mL | |||||||||
| 1 | 12.4 | 9.14 | 21.7 | 18.7 | 31.4 | 48.1 | 53.8 | 62.8 | 78.8 | 102 |
| 2 | 10.0 | 9.69 | 21.1 | 21.0 | 33.1 | 45.1 | 54.6 | 60.5 | 75.4 | 104 |
| 3 | 8.87 | 12.6 | 17.6 | 21.2 | 29.0 | 48.6 | 54.9 | 65.2 | 81.7 | 98.1 |
| 4 | 9.53 | 12.9 | 21.4 | 21.5 | 29.4 | 49.6 | 58.0 | 65.9 | 80.6 | 107 |
| 5 | 12.8 | 13.6 | 21.8 | 18.6 | 28.0 | 51.3 | 56.2 | 65.1 | 78.1 | 104 |
| Sample
Type | Sample
_1 | Sample
_2 | Sample
_3 | Sample
_4 | Sample
_5 | Sample
_6 | Sample
_7 | Sample
_8 | Sample
_9 | Sam
ple
_10 |
|---------------------------------------|--------------|--------------|--------------|--------------|--------------|--------------|--------------|--------------|--------------|-------------------|
| Measured
conc
Mean of 5
days | 10.8 | 11.6 | 19.6 | 20.1 | 30.9 | 46.6 | 56.0 | 63.9 | 76.8 | 99.9 |
| SD of 5
days | 1.70 | 1.70 | 1.91 | 2.60 | 2.59 | 4.05 | 2.55 | 3.59 | 6.09 | 8.43 |
| Conc.
CV%
of 5 days | 15.7 | 14.7 | 9.7 | 13.0 | 8.4 | 8.7 | 4.6 | 5.6 | 7.9 | 8.4 |
Conclusion
The LoQ claim in the labeling will be set to 36 pg/mL.
Linearity/Reportable Range (CLSI EP06-Ed2)
The linearity study was conducted on the proBNP II assays to demonstrate that measurements across the claimed measuring range for each parameter are linear. The study was performed according to CLSI guideline EP06-Ed2.
Methods
The experiment was initially designed for evaluation with the preceding edition of the guideline, i.e. CLSI guideline EP06-A. The evaluation was repeated according to the current guideline CLSI EP06-Ed2 using in-house software tool BioWarp.
12
A weighted least square regression by pooled variance was performed. As one high analyte human, native serum sample above measuring range was diluted with analyte free serum (CLSI Design A1), a regression without intercept was chosen. As variance increases with concentration, weighted linear regression was used. As only 3 replicates are available at each dilution step, the weights were computed based on the pooled variance including also the replicates of the next higher as well as the next lower dilution step ("moving window").
Results
| Category | Name | Value | |
|---|---|---|---|
| Unit | pg/mL | ||
| Max Number of Replicates | 3 | ||
| Input Data | Number of Levels | 10 | |
| Range of Levels | 0.000640 - 1.00 | ||
| Measured Range | 24.3 - 35902 | ||
| CLSI Design | Al | ||
| Model | Weighting | yes | |
| Precision Specs | Prec. Acc. Limits | Passed | |
| SubRange 1 (21.9 - 50.0) | 10.0 SD | 1 | |
| SubRange 2 (50.0 - 100) | 20.0 CV | 1 | |
| SubRange 3 (100 - 35000) | 10.0 CV | 8 | |
| ADL Specs | Allowed Deviation | Passed | |
| SubRange 1 (21.9 - 50.0) | 10.0 [pg/mL] abs | 1 | |
| SubRange 2 (50.0 - 35000) | 20.0 [%] rel | 9 | |
| Linearity evaluation | between: 24.3 - 35902 [pg/mL] | PASSED |
Linearity Evaluation Summary
Results of the linear regression analysis
| Level | Relative
Concentration | Mean | Expected | Predicted | SubRange | Diff. abs | Diff. rel | Criteria | Specs
met |
|-------|---------------------------|-------|----------|-----------|----------|-----------|-----------|----------|--------------|
| 1 | 1.00 | 35902 | 35902 | 34218 | 2 | 1684 | 4.92 | 22 years of age with symptoms of suspected acute decompensated HF, presenting with dyspnea of a duration no longer than several days. 275 (19 %) were found to have acutely decompensated HF, based on adjudication by a clinical events committee.
As reported in previous studies, the age-based positive cut-points, and the negative cut-point for all ages were determined to be:
| Age Group | Elecsys proBNP II/
Elecsys proBNP II STAT
Cut-Points | Interpretation |
|----------------|------------------------------------------------------------|-------------------------------------------------|
| 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 |
| Elecsys proBNP II/
Elecsys proBNP II STAT
| Cut-Point | Interpretation |
|---|---|
| 300 pg/mL | NT-proBNP 450 |
| 900 | |
| 50-75 | Gray |
| 50-75 | Negative |
| >75 | Gray |
| >75 | Negative |
A total of only 228 subjects (15%) had NT-proBNP levels that fell into the gray zone between cutpoints with Elecsys proBNP II. This analysis was performed to better understand the performance of the assay for values that fall between the cut-off for positive and the cut-off for negative.
The likelihood ratio (LR) for all 228 subjects (any age) who fell into the gray zone was 0.91 (95% CI: 0.66-1.25) suggesting no additive diagnostic value. For them, other clinical or diagnostic information would be necessary for the differential diagnosis of acute decompensated HF in patients presenting with acute dyspnea in the emergency department.
The performance of the NT-proBNP-based diagnosis of ADHF through the triple age-specific positive cut-points and the single universal negative cut-point was demonstrated through the calculation of Likelihood ratios (positive likelihood ratios (LR+) and negative likelihood ratios (LR-). Likelihood ratios can provide a quantification of the diagnostic capabilities of the assay for both subjects with reactive Elecsys NT-proBNP results (LR+) and non-reactive Elecsys NTproBNP results (LR-). The likelihood ratio can be used to project the change in the probability of having ADHF from the general disease prevalence (the pre-test probability) to the probability after the test results are interpreted (the post-test probability). Establishing the likelihood ratios for the Elecsys proBNP II and proBNP II STAT assays performed on the cobas e 601 analyzer demonstrated the strength of the assays as an aid in diagnosing ADHF and the ability to understand the implications of the diagnosis in patients presenting emergently with dyspnea.
Analyses were conducted separately for each gender and age sub-population, as well for all agegroups combined and all genders combined.
20
Acutely decompensated cutoff performance
| Age
Group | Test Result
Interpretation | ADHF | No
ADHF | Total |
|--------------|-------------------------------|------|------------|-------|
| 75 | Positive | 43 | 31 | 74 |
| | Gray | 14 | 52 | 66 |
| | Negative | 0 | 25 | 25 |
| | Total | 57 | 108 | 165 |
| All | Positive | 220 | 173 | 393 |
| | Gray | 39 | 189 | 228 |
| | Negative | 16 | 848 | 864 |
| | Total | 275 | 1210 | 1485 |
Three-by-Two Contingency Table for the ICON Cut-Points - Elecsys proBNP II 18min Assay - All Evaluable US Subjects
21
Pre- and Post-Test Probabilities as well as informative LRs for NT-proBNP Cut-Points for the Diagnosis or Exclusion of Acute Decompensated Heart Failure - Elecsys proBNP II 18min Assay - All Evaluable US Subjects
| Likelihood Ratio | ||||||||
|---|---|---|---|---|---|---|---|---|
| Prevalence of | Post-test Probability of ADHF | Post-test Probability of No ADHF | (ADHF) | |||||
| Age Group | ADHF | |||||||
| (%) (n/N) | Test Result | |||||||
| Interpretation | Estimate (%) | |||||||
| (n/N) | 95%-CI (%) c) | Estimate (%) | ||||||
| (n/N) | 95%-Cl (%) c) | LR d) | 95%-CI e) | |||||
| 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 | 0.00 | 0.00- | ||||||
| NaN |
c) Wilson score confidence intervals with continuity correction
d) LR = likelihood ratios
e) log method confidence intervals
f) Positive: > age-specific cut-point
g) Gray: ≥ 300 pg/mL and ≤ age-specific cut-point
h) NaN (Not a Number) due to empty cells
i) Negative: 75 | Positive | 15 | 17 | 32 |
| | Gray | 6 | 26 | 32 |
| | Negative | 0 | 10 | 10 |
| | Total | 21 | 53 | 74 |
| All | Positive | 86 | 77 | 163 |
| | Gray | 17 | 87 | 104 |
| | Negative | 7 | 467 | 474 |
| | Total | 110 | 631 | 741 |
23
Pre- and Post-Test Probabilities as well as informative LRs for NT-proBNP Cut-Points for the Diagnosis or Exclusion of ADHF - Elecsys proBNP II 18min Assay - Females
| | Prevalence of | | Post-test Probability of ADHF | | Post-test Probability of No ADHF | | Likelihood Ratio
(ADHF) | |
|-----------|-------------------|-------------------------------|-------------------------------|---------------|----------------------------------|---------------|----------------------------|-----------------|
| Age Group | ADHF
(%) (n/N) | Test Result
Interpretation | Estimate (%)
(n/N) | 95%-CI (%) c) | Estimate (%)
(n/N) | 95%-CI (%) c) | LR d) | 95%-Cl e) |
| 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 | 81.3
(26/32) | 63.0-
92.1 | 0.58 | 0.28-
1.21 |
| | | Negative | -- | -- | 100
(10/10) | 65.5-
100 | 0.00 | 0.00-
NaN |
24
Three-by-Two Contingency Table for the ICON Cut-Points - Elecsys proBNP II 18min Assay - Males
| Age Group | Test Result
Interpretation | ADHF | No ADHF | Total |
|-----------|-------------------------------|------|---------|-------|
| 75 | Positive | 28 | 14 | 42 |
| | Gray | 8 | 26 | 34 |
| | Negative | 0 | 15 | 15 |
| | Total | 36 | 55 | 91 |
| All | Positive | 134 | 96 | 230 |
| | Gray | 22 | 102 | 124 |
| | Negative | 9 | 381 | 390 |
| | Total | 165 | 579 | 744 |
25
Pre- and Post-Test Probabilities as well as informative LRs for NT-proBNP Cut-Points for the Diagnosis or Exclusion of ADHF - Elecsys proBNP II 18min Assay- Males
| Likelihood Ratio | ||||||||
|---|---|---|---|---|---|---|---|---|
| Prevalence of | Post-test Probability of ADHF | Post-test Probability of No ADHF | (ADHF) | |||||
| ADHF | Test Result | Estimate (%) | Estimate (%) | |||||
| Age Group | (%) (n/N) | Interpretation | (n/N) | 95%-CI (%) c) | (n/N) | 95%-CI (%) c) | LR d) | 95%-CI e) |
| 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 | |||||
| (15/15) | 74.7- | |||||||
| 100 | 0.00 | 0.00- | ||||||
| NaN |
26
Three-by-Two Contingency Table for the ICON Cut-Points - Elecsys proBNP II STAT Assay - All Evaluable US Subjects
| Age Group | Test Result
Interpretation | ADHF | No ADHF | Total |
|-----------|-------------------------------|------|---------|-------|
| 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 |
27
Pre- and Post-Test Probabilities as well as informative LRs for NT-proBNP Cut-Points for the Diagnosis or Exclusion of ADHF - Elecsys proBNP II STAT Assay - All Evaluable US Subjects
| | Prevalence of | | Post-test Probability of ADHF | | Post-test Probability of No ADHF | | Likelihood Ratio
(ADHF) | |
|-----------|-------------------|-------------------------------|-------------------------------|----------------|----------------------------------|----------------|----------------------------|-----------------|
| Age Group | ADHF
(%) (n/N) | Test Result
Interpretation | Estimate (%)
(n/N) | 95%-CI (%) c) | Estimate (%)
(n/N) | 95%-CI (%) c) | LR d) | 95%-CI e) |
| 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 |
c) Wilson score confidence intervals with continuity correction
d) LR = likelihood ratios
e) log method confidence intervals
f) Positive: > age-specific cut-point
g) Gray: ≥ 300 pg/mL and ≤ age-specific cut-point
h) NaN (Not a Number) due to empty cells
i) Negative: 75 | Positive | 15 | 17 | 32 |
| | Gray | 6 | 26 | 32 |
| | Negative | 0 | 10 | 10 |
| | Total | 21 | 53 | 74 |
| All | Positive | 86 | 77 | 163 |
| | Gray | 17 | 86 | 103 |
| | Negative | 7 | 468 | 475 |
| | Total | 110 | 631 | 741 |
29
Pre- and Post-Test Probabilities as well as informative LRs for NT-proBNP Cut-Points for the Diagnosis or Exclusion of ADHF - Elecsys proBNP II STAT Assay - Females
| | Prevalence of ADHF | | Post-test Probability of ADHF | | Post-test Probability of No ADHF | | Likelihood Ratio
(ADHF) | |
|-----------|--------------------|----------------------------|-------------------------------|---------------|----------------------------------|----------------|----------------------------|-----------------|
| Age Group | (%) (n/N) | Test Result Interpretation | Estimate (%)
(n/N) | 95%-CI (%) c) | Estimate (%)
(n/N) | 95%-CI (%) c) | LR d) | 95%-CI e) |
| 61.9
(13/21) | 38.7-
81.0 | -- | -- | 27.30 | 13.42-
55.54 |
| | | Gray g) | 0.0
(0/15) | 0.0-
25.3 | 100.0
(15/15) | 74.7-
100.0 | 0.00 | 0.00-
NaN h) |
| | | Negative i) | -- | -- | 99.1
(229/331) | 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 | 81.3
(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 |
30
| Age Group | Test Result Interpretation | ADHF | No ADHF | Total |
|---|---|---|---|---|
| 75 | Positive | 28 | 14 | 42 |
| Gray | 8 | 26 | 34 | |
| Negative | 0 | 15 | 15 | |
| Total | 36 | 55 | 91 | |
| All | Positive | 134 | 95 | 229 |
| Gray | 22 | 106 | 128 | |
| Negative | 9 | 378 | 387 |
Three-by-Two Contingency Table for the ICON Cut-Points - Elecsys proBNP II STAT Assay - Males
31
Pre- and Post-Test Probabilities as well as informative LRs for NT-proBNP Cut-Points for the Diagnosis or Exclusion of ADHF - Elecsys proBNP II STAT Assay - Males
| | Prevalence of
ADHF
(%) (n/N) | Test Result
Interpretation | Post-test Probability of ADHF | | Post-test Probability of No ADHF | | Likelihood Ratio
(ADHF) | |
|-----------|------------------------------------|-------------------------------|-------------------------------|---------------|----------------------------------|----------------|----------------------------|-----------------|
| Age Group | | | Estimate (%)
(n/N) | 95%-CI (%) c) | Estimate (%)
(n/N) | 95%-CI (%) c) | LR d) | 95%-CI e) |
| 48.6
(18/37) | 32.2-
65.3 | -- | -- | 8.57 | 5.41-
13.59 |
| | | Gray g) | 0.0
(0/8) | 0.0-
40.2 | 100.0
(8/8) | 59.8-
100.0 | 0.00 | 0.00-
NaN h) |
| | | Negative i) | -- | -- | 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 |
32
Renal cohort (ED)
Renal disease can alter NT-proBNP values because the peptide is known to be cleared by the kidneys. Below are analyses of performance in patients with and without compromised renal function.
Pre- and Post-Test Probabilities as well as informative LRs for NT-proBNP Cut-Points for the Diagnosis or Exclusion of ADHF - Elecsys proBNP II 18min Assay - Renal Disease (eGFR 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 |
i) Wilson score confidence intervals with continuity correction
- k) LR = likelihood ratios
I) log method confidence intervals
m) Positive: > age-specific cut-point
n) Gray: ≥ 300 pg/mL and ≤ age-specific cut-point
o) NaN (Not a Number) due to empty cells
33
Pre- and Post-Test Probabilities as well as informative LRs for NT-proBNP Cut-Points for the Diagnosis or Exclusion of ADHF - Elecsys proBNP II 18min Assay - No Renal Disease (eGFR ≥ 60 mL/min/1.73 m²)
| | Prevalence of
ADHF
(%) (n/N) | Test Result
Interpretation | Post-test Probability of ADHF
Estimate (%)
(n/N) | 95%-CI (%) j) | Post-test Probability of No ADHF
Estimate (%)
(n/N) | 95%-CI (%) j) | Likelihood Ratio
(ADHF)
LR k) | 95%-CI I) |
|-------|------------------------------------|-------------------------------|--------------------------------------------------------|---------------|-----------------------------------------------------------|----------------|-------------------------------------|-----------------|
| 75 | | Positive | 50.0
(9/18) | 29.0-
71.0 | -- | -- | 2.72 | 1.29-
5.76 |
| | 26.9
(18/67) | 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 |
Of note, the overall positive likelihood ratio (LR+) with the Elecsys proBNP II STAT was found to be lower in patients with renal disease compared to patients without renal disease (LR+ 2.61 and 6.42, respectively). In this population, more false positives are observed. Caution should be used when interpreting NT-proBNP or Elecsys proBNP II STAT results in patients with renal dysfunction.
34
Body mass index (ED)
Prior studies concluded that the concentrations of BNP6 and NT-proBNP7 are lower in obese people, both without and with HF. The most likely biological reason for the lower natriuretic peptide level has been described by the lower release of natriuretic peptides in obesity and also involving pericardial fat, rather than increase in their clearance. The observed natriuretic peptide reduction in obese (vs non-obese) patients was 10-50 %. In line, the overall negative likelihood ratio (LR-) with the Elecsys proBNP II was observed to be higher (i.e., worse) in patients with high BMI compared to patients with low BMI (LR- 0.13 and 0.00, respectively). This is due to the fact that false negatives were characterized by a high BMI. 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).
In the context of obesity, natriuretic peptides should be interpreted with caution. For diagnostic purposes, the results should always be assessed in conjunction with the patient's medical history, clinical examination and other findings.
| | Prevalence of
ADHF
(%) (n/N) | Test Result
Interpretation | Post-test Probability of ADHF | | Post-test Probability of No ADHF | | Likelihood Ratio
(ADHF) | |
|-----------|------------------------------------|-------------------------------|-------------------------------|---------------|----------------------------------|----------------|----------------------------|-----------------|
| Age Group | | | Estimate (%)
(n/N) | 95%-CI (%) q) | Estimate (%)
(n/N) | 95%-CI (%) q) | LR r) | 95%-CI s) |
| 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 |
q) Wilson score confidence intervals with continuity correction
r) LR = likelihood ratios
s) log method confidence intervals
t) Positive: > age-specific cut-point
u) Gray: ≥ 300 pg/mL and ≤ age-specific cut-point
v) NaN (Not a Number) due to empty cells
w) Negative: 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 |
| | | | | | (186/186) | 100.0 | | NaN |
History of heart failure (ED)
Heart failure is a chronic progressive disease. Below are the analyses showing the performance of NT-proBNP in patients with a previous diagnosis of heart failure when presenting to the ED with a suspicion of ADHF.
In addition, 346 subjects in this cohort had a previous diagnosis of heart failure.
| Three-by-Two Contingency Table for the ICON Cut-Points - Elecsys proBNP II 18 Minute |
|---|
| Assay – All Subjects with a Previous Diagnosis of Heart Failure |
| Age Group | Test Result
Interpretation | ADHF | No ADHF | Total |
|-----------|-------------------------------|------|---------|-------|
| 75 | Positive | 29 | 15 | 44 |
| | Gray | 6 | 16 | 22 |
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| Age Group | Test Result
Interpretation | ADHF | No ADHF | Total |
|-----------|-------------------------------|------|---------|-------|
| | Negative | 0 | 3 | 3 |
| | Total | 35 | 34 | 69 |
| All | Positive | 147 | 70 | 217 |
| | Gray | 19 | 40 | 59 |
| | Negative | 10 | 60 | 70 |
| | Total | 176 | 170 | 376 |
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Pre- and Post-Test Probabilities as well as informative LRs for NT-proBNP Cut-Points for the Diagnosis or Exclusion of ADHF - Elecsys proBNP II 18 Minute Assay - History of HF
| | Prevalence of | | Post-test Probability of ADHF | | Post-test Probability of No ADHF | | Likelihood Ratio
(ADHF) | |
|-----------|-------------------|----------------|-------------------------------|---------------|----------------------------------|---------------|----------------------------|-----------|
| | ADHF | Test Result | Estimate (%) | | Estimate (%) | | | |
| Age Group | (%) (n/N) | Interpretation | (n/N) | 95%-Cl (%) x) | (n/N) | 95%-Cl (%) x) | LR y) | 95%-CI z) |
| 75 | 50.7
(35/69) | Positive | 65.9 | 50.0- | -- | -- | 1.88 | 1.25- |
| | | | (29/44) | 79.1 | | | | 2.82 |
| | | Gray | 27.3 | 11.6- | 72.7 | 49.6- | 0.36 | 0.16- |
| | | | (6/22) | 50.4 | (16/22) | 88.4 | | 0.82 |
| | | Negative | -- | -- | 100.0 | 31.0- | 0.00 | 0.00- |
| | | | | | (3/3) | 100.0 | | NaN |
x) Wilson score confidence intervals with continuity correction
y) LR = likelihood ratios
z) log method confidence intervals
aa) Positive: > age-specific cut-point
ab) Gray: ≥ 300 pg/mL and ≤ age-specific cut-point
ac) NaN (Not a Number) due to empty cells
ad) Negative: 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 | 0.80 | 0.40-
1.59 |
| | | Negative | -- | -- | 100.0
(22/22) | 81.5-
100.0 | 0.00 | 0.00-
NaN |
Patients with a history of prior HF have a substantially lower performance for rule-in 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. Use caution when interpreting test results in these patients due to a higher false positive and false negative rate.
6. CONCLUSIONS
The information provided in this 510(k) Premarket Notification supports the determination that the supplementation of the additional cut-points provides adequate performance when aiding in the diagnosis of acutely decompensated heart failure.
40
The information submitted in this Premarket Notification supports a substantial equivalent decision.
7. REFERENCES
- McDonagh TA, Metra M, Adamo M, et al. 2021 ESC Guidelines for the diagnosis and treatment of acute 1. and chronic heart failure. Eur Heart J. 2021;42(36):3599-3726.
- Writing Committee M, Members AAJC. 2022 AHA/ACC/HFSA Guideline for the Management of Heart 2. Failure. J Card Fail. 2022;28(5):e1-e167.
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- Daniels LB, Clopton P, Bhalla V, et al. How obesity affects the cut-points for B-type natriuretic peptide in the diagnosis of acute heart failure. Results from the Breathing Not Properly Multinational Study. Am Heart J. 2006;151(5):999-1005.
-
- Kozhuharov N, Martin J, Wussler D, et al. Clinical effect of obesity on N-terminal pro-B-type natriuretic peptide cut-off concentrations for the diagnosis of acute heart failure. Eur J Heart Fail. 2022;24(9):1545-1554.
-
- Mueller C, McDonald K, de Boer RA, et al. Heart Failure Association of the European Society of Cardiology practical guidance on the use of natriuretic peptide concentrations. Eur J Heart Fail. 2019;21(6):715-731.
-
- Daniels LB, Clopton P, Bhalla V, et al. How obesity affects the cutpoints for B-type natriuretic peptide in the diagnosis of acute heart failure. Results from the Breathing Not Properly Multinational Study. Am Heart J. 2006;151(5):999-1005.
-
- Kozhuharov N, Martin J, Wussler D, et al. Clinical effect of obesity on N-terminal pro-B-type natriuretic peptide cut-off concentrations for the diagnosis of acute heart failure. Eur J Heart Fail. 2022;24(9):1545-1554.
-
- Mueller C, McDonald K, de Boer RA, et al. Heart Failure Association of the European Society of Cardiology practical guidance on the use of natriuretic peptide concentrations. Eur J Heart Fail. 2019;21(6):715-731.