ACS:180 AND ADVIA CENTAUR B-TYPE NATRIURETIC PEPTIDE (BNP) ASSAYS

K043228 · Bayer Healthcare, LLC · NBC · Apr 22, 2005 · Clinical Chemistry

Device Facts

• Record ID: K043228
• Device Name: ACS:180 AND ADVIA CENTAUR B-TYPE NATRIURETIC PEPTIDE (BNP) ASSAYS
• Applicant: Bayer Healthcare, LLC
• Product Code: NBC · Clinical Chemistry
• Decision Date: Apr 22, 2005
• Decision: SESE
• Submission Type: Traditional
• Regulation: 21 CFR 862.1117
• Device Class: Class 2

Indications for Use

For in vitro diagnostic use in the quantitative determination of B-type natriuretic peptide (BNP) in human plasma using the ADVIA Centaur® System. This assay is indicated for the measurement of plasma BNP as an aid in the diagnosis and assessment of severity of heart failure. In patients with acute coronary syndromes (ACS), this test, in conjunction with other known risk factors, can also be used to predict survival as well as to predict the likelihood of future heart failure. This assay is not intended for use on any other system. For in vitro diagnostic use in the quantitative determination of B-type natriuretic peptide (BNP) in human plasma using the ACS:180® System. This assay is indicated for the measurement of plasma BNP as an aid in the diagnosis and assessment of severity of heart failure. In patients with acute coronary syndromes (ACS), this test, in conjunction with other known risk factors, can also be used to predict survival as well as to predict the likelihood of future heart failure. This assay is not intended for use on any other system.

Device Story

Fully automated two-site sandwich chemiluminescence immunoassay; uses acridinium ester-labeled monoclonal mouse anti-BNP and biotinylated monoclonal mouse anti-BNP coupled to streptavidin-coated paramagnetic particles. Sample incubated with reagents; unbound conjugates washed away; chemiluminescent signal measured in luminometer. Signal intensity proportional to BNP concentration. Used in clinical laboratories by technicians; results interpreted by physicians to aid heart failure diagnosis, severity assessment, and prognosis in ACS patients. Benefits include rapid, objective quantification of BNP levels to inform clinical decision-making.

Clinical Evidence

No clinical study data provided in the summary document; substantial equivalence based on analytical performance characteristics including precision (1.8-9.9% CV), analytical sensitivity, dilution recovery, and lack of interference from common substances (hemoglobin, triglycerides, cholesterol, urea, creatinine, bilirubin, IgG).

Technological Characteristics

Chemiluminescence immunoassay; two-site sandwich format. Reagents: monoclonal mouse anti-human BNP antibodies. Energy source: automated system-based chemiluminescence detection. Sample type: EDTA plasma. Connectivity: Integrated with ADVIA Centaur or ACS:180 systems. Sterilization: N/A (reagent-based).

Indications for Use

Indicated for quantitative determination of BNP in human plasma as an aid in diagnosis and severity assessment of heart failure. In patients with acute coronary syndromes (ACS), used with other risk factors to predict survival and likelihood of future heart failure.

Regulatory Classification

Identification

The B-type natriuretic peptide (BNP) test system is an in vitro diagnostic device intended to measure BNP in whole blood and plasma. Measurements of BNP are used as an aid in the diagnosis of patients with congestive heart failure.

Special Controls

*Classification.* Class II (special controls). The special control is “Class II Special Control Guidance Document for B-Type Natriuretic Peptide Premarket Notifications; Final Guidance for Industry and FDA Reviewers.”

Predicate Devices

• Bayer Diagnostics ADVIA® Centaur® BNP Assay (k031038)
• Bayer Diagnostics ACS:180® BNP Assay (k040425)

Submission Summary (Full Text)

{0}

1

# 510(k) SUBSTANTIAL EQUIVALENCE DETERMINATION DECISION SUMMARY ASSAY ONLY TEMPLATE

A. 510(k) Number:
k043228

B. Purpose for Submission:
Labeling changes, Indications for Use modified to include: In patients with acute coronary syndromes (ACS) this test, in conjunction with other known risk factors, can also be used to predict survival, as well as to predict the likelihood of future heart failure.

C. Measurand:
B-type natriuretic peptide test system (BNP)

D. Type of Test:
Quantitative

E. Applicant:
Bayer HealthCare LLC

F. Proprietary and Established Names:
Bayer Diagnostics ADVIA® Centaur® BNP Assay, Bayer Diagnostics ACS:180® BNP Assay

G. Regulatory Information:
1. Regulation section:
21 CFR 862.1117 B-type natriuretic peptide test system
2. Classification:
Class II
3. Product code:
NBC

{1}

4. Panel:

75 Chemistry

## H. Intended Use:

1. Intended use(s):

For in vitro diagnostic use in the quantitative determination of B-type natriuretic peptide (BNP) in human plasma using the ADVIA Centaur® System. This assay is indicated for the measurement of plasma BNP as an aid in the diagnosis and assessment of severity of heart failure. In patients with acute coronary syndromes (ACS), this test, in conjunction with other known risk factors, can also be used to predict survival as well as to predict the likelihood of future heart failure. This assay is not intended for use on any other system.

For in vitro diagnostic use in the quantitative determination of B-type natriuretic peptide (BNP) in human plasma using the ACS:180® System. This assay is indicated for the measurement of plasma BNP as an aid in the diagnosis and assessment of severity of heart failure. In patients with acute coronary syndromes (ACS), this test, in conjunction with other known risk factors, can also be used to predict survival as well as to predict the likelihood of future heart failure. This assay is not intended for use on any other system.

2. Indication(s) for use:

See intended use above

3. Special conditions for use statement(s):

For prescription use only

4. Special instrument requirements:

Bayer Diagnostics ADVIA® Centaur®, Bayer Diagnostics ACS:180®

## I. Device Description:

ADVIA Centaur® BNP:

5 ReadyPack ® primary reagent packs containing ADVIA Centaur® BNP Lite Reagent (monoclonal mouse anti-human BNP fragment antibody labeled with acridium ester in buffer with bovine gamma globulin, mouse gamma globulin and preservatives) and Solid Phase (monoclonal mouse anti-human BNP antibody in bovine gamma globulin, mouse gamma globulin and preservatives), ADVIA Centaur® Master Curve card for 500 tests or 1 ReadyPack ® primary reagent pack containing ADVIA Centaur® BNP Lite Reagent and Solid Phase, ADVIA Centaur® Master Curve card for 100 tests

{2}

ACS:180® BNP:

6 vials of ACS:180® BNP Lite Reagent, 6 vials of ACS:180® Solid Phase, ACS:180® BNP Master Curve Card or 1 vial of ACS:180® BNP Lite Reagent, 1 vial of ACS:180® Solid Phase, ACS:180® BNP Master Curve Card

## J. Substantial Equivalence Information:

1. Predicate device name(s):

Bayer Diagnostics ADVIA® Centaur® BNP Assay, Bayer Diagnostics ACS:180® BNP Assay

2. Predicate 510(k) number(s):

k031038, k040425

3. Comparison with predicate:

| Similarities | | |
| --- | --- | --- |
| Item | Device | Predicate |
| Assay principle | Chemiluminescence immunoassay | Same |
| Traceability | Synthetic human BNP in buffer based matrix | Same |
| Sample type | EDTA plasma | Same |
| Differences | | |
| Item | Device | Predicate |
| Indications for Use | For in vitro diagnostic use in the quantitative determination of B-type natriuretic peptide (BNP) in human plasma using the ADVIA Centaur® and ACS:180® Systems. This assay is indicated for the measurement of plasma BNP as an aid in the diagnosis and assessment of severity of heart failure. In patients with acute coronary syndromes (ACS), this test, in conjunction with other known risk factors, can also be used to predict survival as well as to predict the likelihood of future heart failure. | For in vitro diagnostic use in the quantitative determination of B-type natriuretic peptide (BNP) in human plasma using the ADVIA Centaur® and ACS:180® Systems. This assay is indicated for the measurement of plasma BNP as an aid in the diagnosis and assessment of severity of heart failure. This test, in conjunction with other known risk factors, can also be used to predict survival in patients after myocardial infarction. |

{3}

4

| Assay cut-off | Age and gender matched descriptive statistics provided.
Decision threshold of 100 pg/mL recommended for diagnosis of heart failure. Decision threshold of 80 pg/mL recommended for predicting survival and future heart failure in patients with ACS. | Age and gender matched descriptive statistics provided.
Decision threshold of 100 pg/mL recommended for diagnosis of heart failure. Decision threshold of 80 pg/mL recommended for prediction of survival after myocardial infarction. |
| --- | --- | --- |

K. Standard/Guidance Document Referenced (if applicable):

NCCLS EP5, NCCLS EP7-P

L. Test Principle:

The ADVIA Centaur and ACS:180 BNP assays are fully automated two-site sandwich immunoassays using direct chemiluminescent technology, which uses constant amounts of two monoclonal antibodies. The first antibody, in the Lite Reagent, is an acridinium ester labeled monoclonal mouse anti-human BNP F(ab')₂ fragment specific to the ring structure of BNP. The second antibody, in the Solid Phase, is a biotinylated monoclonal mouse anti-human antibody specific to the C-terminal portion of BNP, which is coupled to streptavidin magnetic particles. A direct relationship exists between the amount of BNP present in the patient sample and the amount of relative light units (RLUs) detected by the system.

M. Performance Characteristics (if/when applicable):

1. Analytical performance:

a. Precision/Reproducibility:

Previously established for k031038

ADVIA Centaur: Six samples were assayed 4 times in 20 runs on 2 systems (n = 160 for each sample), over a period of 20 days. Two separate studies were performed, each with a separate lot of reagents. Within run precision % CV ranged from 4.3 % at 29.4 pg/mL to 2.1% at 1736 pg/mL, with total precision of 4.7 % and 2.9 %, respectively.

ACS:180: Six samples were assayed 3 times in 20 runs on 2 systems (n = 120 for each sample) over a period of 20 days. Within run precision % CV ranged from 7.9 % at 51.5 pg/mL to 2.5% at 1783 pg/mL, with total precision of 9.9 % and 3.8 %, respectively.

{4}

b. Linearity/assay reportable range:

Linearity was previously established for k031038. Reportable range: ADVIA Centaur <2 to 5000 pg/mL, ACS 180 < 7.5 to 5000 pg/mL. Patient samples with high BNP levels were mixed in various proportions with patient samples containing low levels of BNP. When compared to the expected value, the measured (recovered) values of BNP averaged 103% with a range of 93 to 113% for the ADVIA Centaur and averaged 98% with a range of 96 to 102% for the ACS:180.

c. Traceability, Stability, Expected values (controls, calibrators, or methods):

The ADVIA Centaur and ACS:180 BNP assays are traceable to an internal standard manufactured using synthetic human BNP (amino acid 77-108). Assigned calibrator doses and ranges for quality control material are traceable to this standardization.

d. Detection limit:

The detection was previously established for k031038. The functional sensitivity is defined as the lowest BNP concentration determined at a coefficient of variation of 20%. The functional sensitivity was determined to be 2.5 pg/mL for the ADVIA Centaur and 11.0 pg/mL for the ACS:180. The minimum detectable concentration (MDC) of the assay is < 2 pg/mL for the ADVIA Centaur and < 7.5 pg/mL for the ACS:180. The MDC is defined as the concentration of BNP that corresponds to the relative light units (RLU's) that are 2 SD > the mean RLU's of 20 replicate determinations of the BNP zero standard. This response is an estimate of the MDC with 95% confidence.

e. Analytical specificity:

The analytical specificity was previously established for k031038. Less than a 5% change in results was seen in results for specimens with up to 1000 mg/dL hemoglobin, 800 mg/dL triglycerides, 1000 mg/dL cholesterol, 200 mg/dL urea, 2.5 mg/dL creatinine, and 25 mg/dL unconjugated bilirubin. Less than a 7% change was seen in results for specimens with up to 25 mg/dL conjugated bilirubin and 5.3 mg/dL human IgG.

A total of 55 commonly used pharmaceutical drugs were added to human plasma-based samples at two times the maximum therapeutic dosage and evaluated for potential interference. The results demonstrated ≤ 10% interference from each drug.

The drug Neseritide is a synthetic form of BNP-32 which is thought to be virtually identical to the endogenous active hormone BNP. The Bayer BNP assays measure Neseritide as BNP. The following statement in the labeling addresses the use of the test with patients receiving Neseritide:

{5}

It has been reported that patients with acute decompensated heart failure who are candidates for nesiritide (recombinant BNP) infusion should have a baseline BNP measurement taken prior to initiation of therapy. Measurements taken during infusion are reflective of the dose of nesiritide. Because of the short half-life of BNP (20 minutes), measurements taken 2 hours after the cessation of treatment again reflect the level of endogenous BNP. It has also been reported that following infusion, endogenous BNP levels return to baseline by 1-2 hours and continue to drop at 6 hours to about 80% of preinfusion levels, suggesting a resetting of the neuro-hormonal axis and improvement in ventricular wall tension as a result of treatment. The ADVIA Centaur and ACS:180 BNP assays are not approved for nesiritide monitoring.

f. Assay cut-off:

See clinical cut-off below

2. Comparison studies:

a. Method comparison with predicate device:

The method comparison was previously established for the ADVIA Centaur in k031038. For 949 samples in the range of 0 to 1290 pg/mL, the relationship between the ADVIA Centaur BNP assay and a predicate device is described by the Passing & Bablok regression equation:

$$
\text{ADVIA Centaur BNP} = 0.74 \times (\text{Predicate Device}) - 0.60 \times \text{pg/mL}
$$
Correlation coefficient (r) = 0.90

For 730 samples in the range of < 7.5 to 4135 pg/mL, the relationship between the ACS:180 BNP assay and the ADVIA Centaur BNP assay is described by the Passing & Bablok regression equation:

$$
\text{ACS:180 BNP} = 1.03 \times (\text{ADVIA Centaur BNP}) - 0.10 \times \text{pg/mL}
$$
Correlation coefficient (r) = 1.0

{6}

b. Matrix comparison:

EDTA plasma is the only recommended sample type

3. Clinical studies:

a. Clinical Sensitivity:

The clinical sensitivity was previously established for k031038. The clinical sensitivity and specificity of the ADVIA Centaur BNP assay using a decision threshold of 100 pg/mL for various age groups within each gender are presented in the following tables:

Clinical Sensitivity and Specificity vs. Age and Gender

| Males | | | | | |
| --- | --- | --- | --- | --- | --- |
| | Age Group | | | | |
| | <45 years | 45-54 years | 55-64 years | 65-74 years | 75 + years |
| % Sensitivity | 58.7 | 49.2 | 69.9 | 83.7 | 88.6 |
| 95% Confidence Interval | 40.4 - 71.0 | 36.4 - 62.1 | 61.0 - 77.9 | 75.1 - 90.2 | 80.9 - 93.9 |
| % Specificity | 100 | 100 | 99.5 | 96.8 | 94.6 |
| 95% Confidence Interval | 97.2 - 100 | 97.4 - 100 | 97.6 - 100 | 93.2 - 98.8 | 85.1 - 98.9 |

Females

| | Age Group | | | | |
| --- | --- | --- | --- | --- | --- |
| | <45 years | 45-54 years | 55-64 years | 65-74 years | 75 + years |
| % Sensitivity | 45.5 | 56.3 | 60.4 | 68.9 | 87.2 |
| 95% Confidence Interval | 24.4 - 67.8 | 37.7 - 73.7 | 45.3 - 74.2 | 53.4 - 81.8 | 79.7 - 92.6 |
| % Specificity | 99.5 | 99.3 | 97.8 | 97.2 | 79.8 |
| 95% Confidence Interval | 97.1 - 100 | 96.4 - 100 | 94.4 - 99.4 | 93.5 - 99.0 | 69.9 - 87.6 |

{7}

b. Clinical specificity:

See clinical sensitivity above.

c. Other clinical supportive data (when a. and b. are not applicable):

4. Clinical cut-off:

The decision threshold for diagnosing heart failure was determined based on the BNP level at the 95th percentile of the Reference Group. The most appropriate decision threshold for diagnosing heart failure apparent from these distributions is 100 pg/mL. This BNP value translates into a general specificity of the test of greater than 97 %.

The decision threshold for predicting survival and future heart failure in patients with acute coronary syndromes is 80 pg/mL.

Prognostic Utility in Patients with Acute Coronary Syndromes:

Two independent retrospective studies have demonstrated the prognostic utility of BNP. In the first study, BNP was assayed on 438 patients with myocardial infarction (MI) from the ENTIRE-TIMI 23 multi-national trial.45 The baseline BNP level was significantly higher in patients who died within 30 days (n=15, 89 pg/mL; 25th-75th, 40-192 pg/mL) compared to survivors (n = 423, 15 pg/mL; 25th-75th, 8.8-32 pg/mL, p&lt;0.0001). BNP levels greater than 80 pg/mL were associated with a substantially higher risk of death through 30 days of follow-up (17.4% vs. 1.8%, p&lt;0.0001). The odds ratio for death within 30 days for patients with BNP levels greater than 80 pg/mL was 11.5. The odds ratio for death within 30 days for patients with BNP levels greater than 80 pg/mL, adjusted for age, history of hypertension, and prior angina, was 8.3 with a 95% confidence interval of 2.7 to 25.8. Patients with elevated BNP levels also had an increased risk of composite end points for death and heart failure combined (23.9% vs. 5.1%, p&lt;0.0001). The odds ratio for death or heart failure within 30 days for patients with BNP levels greater than 80 pg/mL was 5.8. The odds ratio for death or heart failure within 30 days for patients with BNP levels greater than 80 pg/mL, adjusted for age, history of heart failure, history of hypertension, and prior angina, was 3.6 with a 95% confidence interval of 1.5 to 8.8. Elevated levels of BNP at initial presentation are associated with an increased risk of mortality in patients with MI.

Another study was performed on 2525 patients with acute coronary syndromes (ACS). Patients with a BNP level of more than 80 pg/ml were significantly more likely to die, have a new recurrent infarction, or have new or progressive heart failure than those with a level of 80 pg/ml or less. After adjustment for other independent predictors of the long-term risk of death, a BNP level of more than 80 pg/ml remained significantly associated with an increased 10-month mortality rate (P= 0.04).

8

{8}

5. Expected values/Reference range:

The expected results for the ADVIA Centaur BNP assay were previously established in k031038. These results were confirmed for the ACS:180 by analyzing 730 samples (see method comparison). The circulating BNP concentration was determined from 1521 individuals without heart failure (785 women and 736 men). This population included apparently healthy individuals and individuals with hypertension, diabetes, renal insufficiency, and chronic obstructive pulmonary disease. The descriptive statistics for BNP concentrations in the population without heart failure are shown in the following tables. These values are representative of the results obtained from clinical studies. Clinical studies indicate that BNP levels increase with age in the general population with the highest values seen in individuals greater than 75 years of age. In this subgroup of patients, age needs to be taken into consideration for accurate interpretation of test results.

| All | | | | | | |
| --- | --- | --- | --- | --- | --- | --- |
| | Age Group | | | | | |
| | All | <45 years | 45-54 years | 55-64 years | 65-74 years | 75 + years |
| Mean, pg/mL | 23.2 | 11.9 | 15.6 | 19.5 | 28.3 | 60.3 |
| SD, pg/mL | 32.5 | 12.9 | 15.9 | 22.6 | 25.4 | 73.0 |
| Median, pg/mL | 14.5 | 8.6 | 10.4 | 13.8 | 22.1 | 43.7 |
| 95th Percentile, | 70.8 | 33.3 | 46.7 | 53.2 | 72.3 | 176 |
| % < 100 pg/mL | 97.4 | 99.7 | 99.7 | 98.8 | 97.0 | 85.5 |
| Minimum, pg/mL | <2 | <2 | <2 | <2 | <2 | <2 |
| Maximum, pg/mL | 576 | 128 | 119 | 286 | 164 | 576 |
| N | 1521 | 317 | 291 | 403 | 365 | 145 |
| Males | | | | | | |
| --- | --- | --- | --- | --- | --- | --- |
| | Age Group | | | | | |
| | All | <45 years | 45-54 years | 55-64 years | 65-74 years | 75 + years |
| Mean, pg/mL | 17.9 | 9.1 | 11.2 | 14.5 | 25.8 | 41.9 |
| SD, pg/mL | 22.9 | 9.4 | 11.8 | 13.9 | 25.1 | 48.8 |
| Median, pg/mL | 11.3 | 5.9 | 7.6 | 11.9 | 17.8 | 26.1 |
| 95th Percentile, | 54.3 | 29.4 | 32.8 | 38.8 | 67.6 | 121 |
| % < 100 pg/mL | 98.6 | 100 | 100 | 99.5 | 96.8 | 94.6 |
| Minimum, pg/mL | <2 | <2 | <2 | <2 | <2 | <2 |
| Maximum, pg/mL | 250 | 56.6 | 88.9 | 132 | 151 | 250 |
| N | 736 | 129 | 140 | 223 | 188 | 56 |

{9}

10

Females

| | Age Group | | | | | |
| --- | --- | --- | --- | --- | --- | --- |
| | All | <45 years | 45-54 years | 55-64 years | 65-74 years | 75 + years |
| Mean, pg/mL | 28.1 | 13.8 | 19.8 | 25.6 | 31.0 | 71.9 |
| SD, pg/mL | 38.8 | 14.6 | 18.0 | 29.0 | 25.5 | 82.9 |
| Median, pg/mL | 18.5 | 10.4 | 14.8 | 19.4 | 25.7 | 54.3 |
| 95th Percentile, pg/mL | 86.1 | 35.9 | 56.7 | 75.5 | 72.9 | 167 |
| % < 100 pg/mL | 96.3 | 99.5 | 99.3 | 97.8 | 97.1 | 79.8 |
| Minimum, pg/mL | <2 | <2 | <2 | <2 | <2 | <2 |
| Maximum, pg/mL | 576 | 128 | 119 | 286 | 164 | 576 |
| N | 785 | 188 | 151 | 180 | 177 | 89 |

## Patients with Heart Failure

To establish the expected results for the ADVIA Centaur BNP assay in individuals with heart failure, plasma samples were obtained from 722 patients diagnosed with heart failure (264 women and 458 men). The descriptive statistics for BNP concentrations in patients with heart failure are presented in the following tables. These values are representative of the results obtained from clinical studies. In addition, laboratories should be aware of their respective institution’s current practice for the evaluation of heart failure.

## Heart Failure Population – All

| NYHA Functional Class | | | | | |
| --- | --- | --- | --- | --- | --- |
| | All | NYHA I | NYHA II | NYHA III | NYHA IV |
| Mean, pg/mL | 505 | 178 | 270 | 525 | 1134 |
| SD, pg/mL | 711 | 347 | 402 | 576 | 1141 |
| Median, pg/mL | 262 | 64.3 | 130 | 355 | 843 |
| 5th percentile, pg/mL | 10.8 | 1.6 | 5.4 | 21.1 | 109 |
| 95th percentile, pg/mL | 1873 | 772 | 999 | 1696 | 3157 |
| % ≥ 100 pg/mL | 72.6 | 43.1 | 58.7 | 82.0 | 95.8 |
| Minimum, pg/mL | <2 | <2 | <2 | <2 | 4.0 |
| Maximum, pg/mL | 6989 | 2310 | 3107 | 4052 | 6989 |
| N | 722 | 72 | 242 | 289 | 119 |

{10}

Heart Failure Population – Males

| NYHA Functional Class | | | | | |
| --- | --- | --- | --- | --- | --- |
| | All | NYHA I | NYHA II | NYHA III | NYHA IV |
| Mean, pg/mL | 518 | 121 | 308 | 542 | 1214 |
| SD, pg/mL | 726 | 135 | 475 | 588 | 1200 |
| Median, pg/mL | 245 | 77.7 | 135 | 339 | 950 |
| 5^{th} percentile, pg/mL | 10.7 | 3.9 | 4.4 | 23.2 | 71.5 |
| 95^{th} percentile, pg/mL | 1946 | 400 | 1280 | 1852 | 3157 |
| % ≥ 100 pg/mL | 72.9 | 44.7 | 61.3 | 81.4 | 93.9 |
| Minimum, pg/mL | <2 | <2 | <2 | <2 | 33.7 |
| Maximum, pg/mL | 6989 | 552 | 3107 | 3503 | 6989 |
| N | 458 | 47 | 150 | 194 | 66 |
| NYHA Functional Class | | | | | |
| --- | --- | --- | --- | --- | --- |
| | All | NYHA I | NYHA II | NYHA III | NYHA IV |
| Mean, pg/mL | 482 | 285 | 207 | 492 | 1034 |
| SD, pg/mL | 687 | 551 | 228 | 556 | 1068 |
| Median, pg/mL | 291 | 62.5 | 117 | 355 | 779 |
| 5^{th} percentile, pg/mL | 11.0 | 0 | 9.5 | 15.9 | 115 |
| 95^{th} percentile, pg/mL | 1575 | 1447 | 552 | 1518 | 2970 |
| % > 100 pg/mL | 72.0 | 40.0 | 54.3 | 83.2 | 98.1 |
| Minimum, pg/mL | <2 | <2 | <2 | 4.8 | 4.0 |
| Maximum, pg/mL | 5845 | 2310 | 1231 | 4052 | 5845 |
| N | 264 | 25 | 92 | 94 | 53 |

Heart Failure Population – Females

{11}

These results show that there is a relationship between the severity of the clinical signs and symptoms of heart failure and the median BNP concentrations of each NYHA functional class.

**N. Proposed Labeling:**

The labeling is sufficient and it satisfies the requirements of 21 CFR Part 809.10.

**O. Conclusion:**

The submitted information in this premarket notification is complete and supports a substantial equivalence decision.

12