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Volume 14, Number 4, pp. 520-531
© 2003, AACN
The Measurement of Brain
Natriuretic Peptide
in Heart Failure
Precision, Accuracy, and Implications
for Practice
Jill N. Howie, RN, MS, NP; Mary A. Caldwell, RN, PhD, MBA;
Kathleen Dracup, RN, DNSc
Heart failure (HF) is a major public health
problem in the United States. Approximately
4.8 million individuals are diagnosed with
this syndrome and an estimated 550,000 new
cases are identified each year.1 Advanced HF
continues to be one of the most disabling
medical conditions and common causes of
death in the United States.1 After HF is diagnosed, the 1-year mortality rate increases by
almost 20%.1 The magnitude of the HF epidemic will worsen as the population ages
and individuals survive the cardiovascular
precursors of HF (eg, acute myocardial infarction, valvular disease, hypertension). The
cost of caring for patients with HF is staggering, with $3.6 billion paid to Medicare beneficiaries annually.2
Diagnosing and treating those with HF has
been a clinical challenge. Patients with HF are
asymptomatic in the early phases or may
have symptoms such as shortness of breath,
fatigue, or ankle swelling that they may not
identify as serious. In addition, many patients
will present to a clinical setting (physician’s
office, emergency department [ED], urgent
■ Although advances have been made in
the management of heart failure (HF),
hospital readmission rates remain high.
Finding a simple blood test to identify HF
would dramatically impact the diagnosis
and treatment of this syndrome. A better
understanding of the pathophysiology of
HF may result in improved treatment
measures. Current guidelines do not
target any clinical or hemodynamic criteria
to achieve before discharge. Most efforts
to reduce readmissions have been
focused on drugs, technology, and the use
of specialty HF clinics. Brain natriuretic
peptide (BNP) levels have the potential of
providing diagnostic, prognostic, and
therapeutic information. In addition, BNP
levels appear to be associated with future
cardiac events such as hospital
readmission. The purpose of this article is
to review the precision and accuracy of
BNP measurement in those with HF, and
to describe how measurement of BNP can
be used in clinical practice. Ultimately,
BNP testing may improve the accuracy of
the diagnosis of HF and guide best
treatment practices. (KEYWORDS: Brain
natriuretic peptide, heart failure,
hospitalization, predictors)
▪▪▪▪▪▪▪▪▪▪
From UCSF School of Nursing, San Francisco, Calif.
Reprint requests to: Jill Howie, Department of
Physiological Nursing, Box 0610, N631G, UCSF School
of Nursing, San Francisco, CA 94143 (jill.howie@nursing.ucsf.edu).
520
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521
care clinic) with shortness of breath where
many other diagnoses need to be excluded.
When HF is suspected, the patient must undergo testing that is time consuming, costly,
uncomfortable, and not without risks. Those
with chronic HF have episodic exacerbations
where diagnostic testing is again necessary
for identification of acute decompensation.
Finding a simple blood test to identify HF
would have a dramatic impact on diagnosis
and treatment, with earlier diagnosis and a
better understanding of the pathophysiology
of HF leading to improved treatment.
Brain natriuretic peptide (BNP) is a 32amino acid polypeptide involved in the regulation of blood pressure and fluid volume.3
BNP was first identified in porcine brain tissue, hence the confusing term “brain” natriuretic peptide, but is now known to be predominately synthesized and secreted in the
cardiac ventricles.3 The terms BNP and Btype natriuretic peptide are now preferred.
BNP is one of a “family” of natriuretic peptides, atrial natriuretic peptide (ANP or Atype natriuretic peptide), and C-type natriuretic peptide. The release of BNP occurs in
response to increases in ventricular pressure
and is directly proportional to ventricular expansion.4 BNP levels abruptly rise when HF
worsens. They may also be mildly to moderately elevated in chronic HF and left ventricular (LV) dysfunction because of sustained elevations in LV pressure.3,4 Debate regarding
the interpretation of elevated levels of BNP
continues, but in general, it is thought that elevated BNP levels in acute HF warrant adjustment in diuretic therapy. For moderately
elevated BNP levels associated with chronic
HF, treatment is aggressively aimed at diminishing the effects of ventricular remodeling.
BNP is becoming more widely utilized
underscoring the importance for clinicians to
understand the strengths and weaknesses of
this test. Therefore, the purpose of this article is to review the precision and accuracy of
BNP measurement in those with HF, and to
describe how measurement of BNP can be
utilized in clinical practice.
radiometric assay (IRMA), and immunofluorometric (Triage [Biosite Diagnostics, San
Diego, Calif] or IMFA method). Generally,
the test is performed using the RIA method,
but investigators also report the use of a
commercial IRMA method (Shinoria BNP,
Shinogi and Co., Ltd., Osaka, Japan). The
RIA method is the less desirable method because it has a lower sensitivity and specificity, and is less precise and practical for the
technician to use, but is less costly.5 The limitations to the RIA method spurred interest in
the development of a more precise and practical method of BNP measurement.6
Briefly, the IRMA method uses monoclonal antibodies and 125I-labeled anti-BNP
antibody solution to bind BNP and count its
presence with a gamma counter. This laboratory method of testing is precise, but it is
also costly, not automated, and requires approximately 36 hours to complete.7 The immunofluorometric assay or Triage method
uses two murine antibodies against the biologically active portion of the BNP amino
acid. 7 The Triage method utilizes a kit that
resembles a blood glucose meter, although
the kits require more blood than is provided
by a lancet. Therefore, venipuncture is necessary for this point-of care test. Whole
blood is added to the sample port, red blood
cells are filtered out, and plasma enters the
reaction chamber where it reacts with fluorescent antibodies. Finally, the fluorescentbound BNP traverses a detection lane and is
counted. The test takes 15 minutes, is fully
automated, and costs less than $30.
A laboratory test that provides information quickly, noninvasively, and easily is the
most desirable type of test.8 For example,
troponin level is a test that provides diagnostic information quickly and spurs decision
making. The BNP Triage method for diagnosing HF has garnered the most attention
from clinicians because it provides the possibility for rapid diagnostic information. In this
article, discussion will be limited to the
Triage method of testing because it is most
practical for clinical settings.
Description of the Instruments
Precision of the Triage Method
BNP levels can be measured using three
methods: radioimmunoassay (RIA), immuno-
When new instruments are developed for
clinical use or research purposes the instru-
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Figure 1. Accuracy and Precision: When new instruments are developed for clinical use or research purposes
the instrument must be fully tested to ensure that the instrument is actually measuring the desired phenomena.
Laboratory tests are rigorously tested for their accuracy and precision. However, accuracy and precision may not
coincide. In the example of the above target, (A) neither accuracy nor precision is present. In B, the example is
precise because it hits the target in the same place each time (reliable), but not accurate because the center is
missed. In C, the example is accurate because it hits the target, but not precise because the same part of the target is not hit each time. In D, the example is precise and accurate because the target is struck each time (accurate) and in the same place (precise).
ment must be fully tested to ensure that the
instrument is actually measuring the desired
phenomenon, in this case, volume overload.
Thousands of instruments have been developed by nurses, physicians, sociologists, and
psychologists to measure phenomena such
as quality of life, social support, and perceived control, for example. These instruments undergo rigorous testing for reliability
and validity. Clinical laboratory tests must
also undergo testing, but the terms most often used to describe them are precision and
accuracy. Testing for precision and accuracy
is performed often by clinical laboratory
physicians.
During the past decade, researchers have
studied BNP testing methods for precision
and accuracy (see Figure 1). Precision de-
scribes the consistency or reproducibility between measurements of a physiologic instrument8 (see Table 1). An example of precision
relates to a patient having a BNP level drawn
and the sample divided in half. The method
should provide the same BNP value from
each sample from that particular patient.
As previously mentioned, the IRMA
method for BNP testing has been tested and
found to be precise and accurate. Del Ry, Giannessi, and Clerico then compared the precision between the IRMA and Triage methods.7 To examine precision, the authors
examined blood samples from 182 healthy
adults to use as reference values. Because
BNP was a new measurement, the “normal”
value is still being debated; therefore, the
authors had to establish a “normal” value for
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their samples. They identified this value by
noting the range in the samples for both the
Triage and the IRMA assay methods; a value
above the 95th percentile was the cut-off
for a normal range. When between assay
imprecision or variability was measured, it
was found that more variability exists using
the Triage method than the IRMA method.
In addition, the Triage method measured
some samples with a reported “0” value
while the IRMA method measured values
up to 10 pg/mL. This finding suggested that
Triage method had a lower sensitivity than
the IRMA method at the low range and was
somewhat less precise. Fortunately, BNP levels at the 0-10 pg/mL level have no clinical
significance. The results of this study are
consistent with others suggesting that the
Triage method is less precise and more variable at low ranges than other methods, but
provides useful information for therapy.9,10
Maisel and colleagues compared the
Triage and RIA methods with patients in
whom abnormal LV function was suspected.11
They hypothesized that BNP might predict
abnormal LV function. Echocardiography was
used to confirm suspected LV dysfunction
and then compared to BNP levels. Interestingly, accuracy (as seen below) was reported
in this study whereas precision was not.
Accuracy of the Triage Method
Del Ry, Giannessi, and Clerico also compared the accuracy between the IRMA and
Triage methods.7 Accuracy is most often established by comparing the measured value
to an accepted standard 8 (see Table 1). To
establish the accuracy of the two methods,
the investigators measured BNP levels in 37
normal adults and 37 adults with varying degrees of HF. They found a close linear relationship with the two methods at concentrations ranging from 0-1300 pg/mL. A
Bland-Altman plot revealed that the IRMA
method had better sensitivity at the lower
range than the Triage method. A Bland-Altman plot is defined in Table 1, but briefly
this plot compares the value of two measures to display the variability between the
measures.12 In this case, there should be
very little or no variability between the IRMA
method and the Triage. Furthermore, similar
523
values were obtained in all subjects (patients
with or without HF) using both methods.
The mean BNP values found in healthy subjects using both methods were similar
(10.3⫾11.6 pg/mL and 9.6⫾ 13.1 pg/mL, respectively). The mean BNP values in cardiac
subjects were also similar (328.6⫾379.4pg/mL
with the IRMA method and 344.2⫾369.1
pg/mL with the Triage method). These data
suggest that both methods have similar
power to discriminate between normal subjects and patients with HF.
Maisel used the Triage method to compare BNP levels in those who were referred
with suspected abnormal LV function.11
There were 105 patients with normal cardiac
function and 95 patients with abnormal LV
function identified by echocardiography.
The mean BNP levels were 29.5 ⫾ 62.4
pg/mL and 489 ⫾ 75 pg/mL, respectively.
The group difference was significant (p
⬍0.001). A value of 38.5pg/mL was 95% sensitive for the detection of LV dysfunction
with a negative predictive value of 93%. A
BNP of 75 pg/mL exhibited a 98% specificity,
98% positive predictive value, and 93% accuracy (see Table 1). BNP levels of ⬎100
pg/mL were seen in only 1% of those with
normal heart function and 80% of those with
abnormal function. These findings indicate
that the Triage method is highly sensitive,
specific, and selective in identifying those
with abnormal LV dysfunction, which is a
precursor to and/or indicator of HF.
Biologic Variability and Brain
Natriuretic Peptide
There is strong evidence to suggest that BNP
levels vary across certain patient conditions
and diseases.5,13,14 Some patient conditions
or characteristics such as gender and age are
known to cause variations in BNP levels. Female gender is associated with higher BNP
levels compared to males and BNP levels increase with age in both genders.13 These differences by age and gender appear to be
even more pronounced when LV dysfunction is present or when the patient is on hormone replacement therapy.13,14 Redfield and
colleagues13 found that plasma BNP was
21% higher in females on hormone replacement therapy (HRT) than in those not on
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TABLE 1 Biochemical Measurement Terms
Term
Definition
Accuracy
The difference between the measured value and the true value.32 Accuracy is most
often established by comparing the measured value to a standard. In studies
using nonphysiologic measures accuracy can be termed validity. Accuracy is
partially determined by the sensitivity and specificity of the measure in
physiologic measurements and using statistical measures.8
Diagnostic studies must be precise, ie, must find the same result upon repeat
examination. A Bland-Altman plot will compare the differences between two
measures using a plot (observation 1 vs observation 2). The closer the agreement
between the two measures, the smaller the variation and the more precise the
measure.12
Sources of error in physiologic measures. Error may be preanalytic, analytic and
postanalytic.8
Describes the consistency or reproducibility between measurements made by a
physiologic instrument.8 In studies using nonphysiologic measures, precision can be
termed reliability. Precision is determined by utilizing Levy-Jenning’s charts,
duplicate measures, mean absolute difference, imprecision profiles, and other
methods.
The precision profile is a valuable tool for analyzing assays. It allows researchers to
judge assay precision quickly.33 The precision profile monitors precision,
sensitivity and working range of an assay. It consists of three different curves on
the same plot: 1) Within batch profile of the current assay, based on counting error
of the samples, 2) Within batch precision profile of the current assay run, based
on the replicate error of the sample, and 3) Between batch profile of all the
previous assay runs, based on replicate error of the samples. This provides a
graphical representation of amount of error inherent at various analyte
concentrations. Two curves are plotted representing the error which allows
determination of the working range of the assay. The researcher can also
interpolate the estimated error (coefficient of variation) at any concentration value.
The primary goal of a precision profile is to gain information about the random
errors of measurement which leads to imprecision.
Defines how sensitive and specific a measure is, but can only be used with
dichotomous variables such as, with disease present vs without disease. It is a
graphical way of observing an instrument. Sensitivity and specificity are plotted
on a curve with the higher curve representing the more accurate measure.8
The probability that a patient with a given disease will have a positive test result, or the
true positive rate.8
The probability that a patient without the disease will have a negative test result, or
true negative rate.8
Bland-Altman Plot
Error
Precision
Precision Profile
Receiver Operating
Characteristic
Curves
Sensitivity
Specificity
HRT using the Triage assay. However, using
the IRMA assay, the difference was present
but not significant. This difference in assay
values suggests that there may be different
normal values between the Triage and the
IRMA assay methods. In addition, females
and those on HRT may have higher normal
values than males.
Morrison and colleagues examined BNP
levels in 321 patients who presented to an urgent care facility with dyspnea.15 While patients with HF had significantly higher BNP
levels than those with pulmonary disease,
BNP levels were ⬎200 pg/mL in several cases
of pulmonary embolism secondary to in-
creased right atrial and ventricular pressures.10,16 Further exploration of BNP levels in
pulmonary embolism and other pulmonary
diseases is needed. Biologic variability in BNP
measurement will need exploration to determine if there are other factors that influence
changes in levels such as cultural variations,
medications, or genetic variations.
Summary of Precision and
Accuracy
Studies to date suggest that the Triage
method is a precise, accurate, and appropri-
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ate measure of BNP. A lower degree of precision and accuracy exists at low BNP levels,
but this limitation has little clinical relevance.
Accuracy is demonstrated with specificity
and sensitivity levels all ⱖ82%. Researchers
have reported increased levels of BNP with
female gender and increasing age, suggesting that biologic variability exists.13 Future
studies will need to address precision in the
Triage method more closely. All future studies need to be completed on large samples
with diversity in ethnicity, age, body position, fasting, time of day, assay method, genetic factors, and gender factors considered.
Clinical Studies Utilizing Brain
Natriuretic Peptide in Heart Failure
Patients—The Emergency
Department
The clinical usefulness of BNP is beginning
to be studied and appreciated. In the urgent
care and emergency room setting, BNP levels have been obtained in patients presenting with dyspnea to identify HF. Dyspnea in
the elderly patient with underlying medical
problems such as chronic obstructive pulmonary disease (COPD) or other lung disease can suggest exacerbation of an existing
medical problem or one of a multitude of
possible problems. Echocardiography is the
gold standard for verifying the diagnosis of
HF but is expensive and not always readily
accessible. In addition, echocardiography is
technically difficult in severely dyspneic patients as well as in obese patients and those
with obstructive lung diseases.
In an early study Davis and colleagues17
assessed the diagnostic value of BNP in 52
patients who were admitted acutely to the
hospital from the emergency room with dyspnea. They compared the BNP levels with
LV ejection fraction, a standard indicator of
LV function. Patients were either diagnosed
with lung disease, HF, or both. Interestingly,
severity of dyspnea was subjectively reported as similar in all patients. A comparison of the patients revealed that BNP had
higher sensitivity and specificity in identifying HF than ejection fraction.17
As mentioned previously, Morrison and
colleagues15 studied 321 dyspneic patients
presenting to an ED to determine if BNP lev-
525
els could accurately differentiate CHF from
pulmonary etiologies. A BNP value of 94
pg/mL had a sensitivity of 86% and specificity of 98% for differentiating CHF from
pulmonary disease.
Dao and colleagues 18 examined BNP levels in 250 patients presenting to an urgent
care facility with dyspnea. Using the pointof-care Triage method, the authors sought to
determine whether BNP had an impact on
the diagnosis of HF. Patient records were reviewed retrospectively and BNP results were
not known to reviewers. Patients with HF
had significantly higher BNP levels than
those with pulmonary or other conditions.
Fifteen patients were incorrectly diagnosed
at the time of their visit. Patients with HF had
a mean BNP value of 1076 pg/mL. Had a
cutoff value of 80 pg/mL been utilized, 29 of
the 30 misdiagnosed patients would have
been diagnosed correctly.
In another ED study, researchers investigated utilizing the BNP level with other clinical information to establish or exclude the
diagnosis of HF.19 This large multicenter
study examined the baseline characteristics
of dyspneic patients, including New York
Heart Association (NYHA) class and BNP
level. Investigators found that the best clinical predictor of HF was increased heart size
on chest roentgenogram. Rales were the
most accurate finding on physical examination. BNP values, however, were the single
most accurate predictor of the presence or
absence of HF. Amazingly, a BNP level >100
pg/mL was more accurate (83%) than either
the National Health and Nutrition Examination Survey (NHANES) or Framingham criteria, the two most commonly used sets of criteria for diagnosing HF.
In a large, multisite, international study
examining dyspneic ED patients, knowledge
of BNP value improved clinical diagnostic
ability.20 In a group of patients where diagnosis was more difficult, BNP correctly identified 74% of patients and only misidentified
7%. BNP measurement discriminated between those with diastolic HF and obstructive lung disease, a distinction that remains
challenging. In another study involving dyspneic patients, 26 NYHA class III patients
were evaluated for LV systolic and diastolic
dysfunction.21 Of those patients, 17 patients
were diagnosed with COPD and 9 with dias-
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TABLE 2 Brain Natriuretic Peptide Levels in Emergency Department Patients
With Dyspnea
Author
BNP Level
Sensitivity
Specificity
Morrison et al: Utility of a rapid
B-natriuretic peptide assay
in differentiating congestive
heart failure from lung disease
in patients presenting with
dyspnea15
Dao et al: Utility of B-type
natriuretic peptide in the
diagnosis of congestive
heart failure18
Maisel et al: Rapid
measurement of B-Type
natriuretic peptide in the
emergency diagnosis of
heart failure19
Average BNP level in
patients with CHF
was 731 pg/mL
BNP level of 94 pg/mL
had 91% accuracy
86% (for BNP level of 94)
98% (for BNP level
of 94)
1076 + 138 pg/mL in
98% (for BNP level of 80)
patients with CHF
BNP level of 80 pg/mL
had 95% accuracy
675 + 450 pg/mL in
90% (for BNP level
patients with CHF
of >100)
BNP level of 100pg/mL
had 83.4% diagnostic
accuracy
BNP level > 100 pg/mL 94 % (for BNP level of
had 81.5% accuracy
>100)
92% (for BNP level
of 80)
McCullough et al: B-type
natriuretic peptide and
clinical judgment in
emergency diagnosis of
heart failure20
Cabanes et al: Brain natriuretic
peptide blood levels in the
differential diagnosis of
dyspnea21
Davis et al: Plasma brain
natriuretic peptide in
assessment of acute
dyspnea17
76% (for BNP level
of >100)
70% (for BNP level
of >100)
224 + 240 pg/mL
found in patients
with diastolic HF
NR
NR
>22 pmol/L
93%
90%
CHF, congestive heart failure; NR, not reported; pmol/L, picomols per liter. Picomols per liter cannot be compared pg/mL or
picograms per milliliter.
tolic HF. BNP levels were significantly higher
in patients with diastolic HF when compared
to those with COPD. A summary of these
studies is presented in Table 2.
Clinical Studies Using Brian
Natriuretic Peptide in Patients With
Heart Failure
The Acute and Critical Care Setting
While the studies above provide evidence
that BNP levels are useful in diagnosing HF,
investigators have also hypothesized that
BNP may be valuable in guiding therapy in
the acute setting. In a small study in the critical care setting, investigators hypothesized
that levels of BNP would decline in association with falling wedge pressures.22 They asserted that the development of a simple and
reliable method for assessment of filling
pressures would provide a useful gauge for
titration of therapy. Twenty patients with
acutely decompensated HF and a wedge
pressure of ⬎20mmHg were included. Investigators found that there was a significant
correlation between percent change in
wedge pressure from baseline to treatment
and change in BNP level. In addition, dying
patients had higher final BNP levels. The researchers suggested that BNP monitoring
may be an effective way to improve the inhospital management of patients with
acutely decompensated HF.
In an effort to assess patient outcomes, 72
patients with acutely decompensated HF
were studied.9 The investigators examined
BNP levels upon admission and throughout
the patients’ hospital stay with physicians
blinded to BNP results. Patients who died or
were readmitted had either no change or an
increase in their BNP level during the course
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of hospitalization. Those patients with a successful outcome had a decline in their overall BNP level. These studies provide evidence that falling BNP values not only
exhibit improving clinical condition but provide a useful method for titrating therapy.
The Primary Care Setting
Diagnosing HF in the primary care setting remains challenging as the symptoms are nonspecific and the clinical signs are not sensitive. 23 The diagnostic challenge is even
greater in the early stages of HF. Monitoring
BNP levels may help the clinician identify
patients who are likely to have HF and require further clinical assessment and/or referral to a cardiologist.
A population-based study examined the
predictive value of BNP in 122 patients with a
suspected new diagnosis of HF.16 Of the 122
patients referred, 35 (29%) were found to
have HF based on the definition from the
Working Group on HF of the European Society of Cardiology.24 Concentrations of BNP
were significantly higher for those with HF.
Brain natriuretic peptide values ⬎21.2pmol/L
had sensitivity, specificity, and positive predictive values of 97%, 84%, and 70%, respectively. The authors concluded that BNP was a
useful tool for determining which patients
with suspected HF required further clinical
assessment. In addition, another group of investigators evaluated the value of BNP to assess the severity of HF in a cardiology clinic.25
The researchers determined that plasma concentrations of BNP significantly increased in
acute HF in relation to its severity.
The Prognostic Value
While the diagnostic value of BNP now appears undisputed, researchers are beginning to study its prognostic value. Readmission after hospitalization for HF is
common, with an estimated 44% of
Medicare patients experiencing rehospitalization at 6 months. 26 Having a tool for
predicting rehospitalization, morbidity, and
mortality events could provide useful information for patients, physicians, and nurses.
Table 2 summarizes studies that have utilized BNP levels in patients with HF in an
effort to assess prognosis.
527
Researchers have examined the utility of
BNP as a method of risk stratifying HF patients for future cardiac events such as rehospitalization and mortality (see Table 2). As
previously mentioned, 72 patients with
acutely decompensated HF were studied
prospectively to assess outcomes.9 The authors examined patient medical records at 30
days after discharge for readmission, or
death, and measured BNP levels daily. BNP
levels tended to increase during hospitalization in patients who were rehospitalized or
died. In addition, univariate analysis revealed
that the predischarge BNP level was strongly
associated with outcomes. Also, discharge
BNP levels of ⬍430 pg/mL had a strong negative predictive value for hospital readmission. Interestingly, although NYHA class improved in those who were readmitted to the
hospital, there were only minimal decreases
in BNP levels during hospitalization.
Investigators have also examined survival
in HF patients over the age of 65, comparing
discharge BNP levels with future cardiac
events.27 Their findings revealed that discharge BNP levels of ⬍132 pg/mL were associated with significantly fewer cardiac
events than those with higher BNP levels. In
a study examining HF patients over time, investigators assessed the prognostic power of
BNP by following 78 stable HF clinic patients for a mean time of 398 days.28 A HF
survival score (HFSS) was created based on
a multivariable prognostic model. Results indicated that higher levels of BNP correlated
with a high-risk HFSS and low BNP values
correlated with a low HFSS score. BNP provided the ability to discriminate patients with
chronic clinical events from patients without
clinical events, with a cut-off value of 107.5
pg/mL, given a specificity of 75% and sensitivity of 88%.
Berger et al29 evaluated the predictive
value of BNP for determining sudden cardiac
death in HF patients. During a 3-year period,
452 patients were followed. A total of 44 patients experienced cardiac death and in a
multivariate model, BNP was the only independent predictor of sudden death. Selvais
and colleagues25 also determined that BNP
concentration was an independent predictor
of prognosis in patients with HF. Patients with
BNP values ⬎106 pg/mL had an increased
risk of mortality. These studies provide evi-
Description
Findings
Cheng et al: A Rapid
Bedside Test for B-Type
Peptide Predicts Treatment
Outcomes in Patients
Admitted for Decompensated
HF: A Pilot Study9
2001
72
males
NYHA class III patients admitted
for decompensated HF; BNP
levels measured daily;
determined association
between initial and pre-discharge
BNP levels and subsequent
adverse outcomes.
BNP levels tended to increase during hospitalization in those who
were rehospitalized or died; univariate analysis revealed that
the predischarge BNP level was strongly associated with
rehospitalization or mortality; in surviving patients, BNP
levels were strong predictors of subsequent readmission;
although NYHA class decreased in those who were readmitted
to the hospital, there were only minimal decreases in BNP levels
during hospitalization.
Koglin et al: Role of
BNP in Risk
Stratification of Patients
with Congestive HF28
2001
78
(69 males)
BNP levels were obtained from HF
clinic patients; clinical course
followed for mean of 398 days.
A risk stratification model provided a survival score (HRSS) and
stratified patients into low-risk, medium-risk, and high-risk
groups; BNP levels and HFSS showed a significant inverse
correlation; a high HFSS indicating a low risk for adverse
outcome was related to low BNP levels; changes in BNP levels
were significantly related to changes in limitations in physical
activity; a cut-off BNP value of 107.5 pg/mL was able to
discriminate patients with, from those without, clinical events.
Tamura et al: Prognostic
Impact of Plasma BNP for
Cardiac Events in Elderly
Patients with Congestive
HF27
2001
48
elderly
Patients admitted for first episode HF;
clinical characteristics, BNP,
ejection fraction, left ventricular
mass index were compared to
patients without recurrent cardiac
events.
12 cardiac events were observed; NYHA class was higher in
patients with cardiac events than those without. BNP levels
in those patients with cardiac events were significantly
higher; cardiac event rate was significantly higher in
those with BNP levels ⬎132pg/mL using Kaplan-Meier analysis.
Berger et al: B-Type Natriuretic
Peptide Predicts Sudden Death
in Patients With Chronic HF29
2001
452
(57
females)
BNP levels, clinical and hemodynamic
variables in those with ejection
fraction <35%; Patients without
heart transplant or mechanical assist
devices were followed for sudden
cardiac death.
Selvais et al: Cardiac Natriuretic
Peptides for Diagnosis and Risk
Stratification in HF: Influences of
Left Ventricular Dysfunction and
Coronary Artery Disease on
Cardiac Hormonal Activation 25
1998
27
controls,
32 CAD
101 HF
BNP, ANF, N-pro ANF, and LVEF were
compared in all patients to evaluate
the diagnostic ability, severity of HF
and predict 2 year mortality.
Sudden cardiac failure occurred in 44 patients (49%) and pump
failure in 31 patients; 293 survived without transplant or
device up to 3 years, 89 died, 65 had transplant, 14 died from
other causes; in a multivariate model only log BNP level
was an independent predictor of sudden death; using a
cut-off point of log BNP <130 pg/mL, death-free survival rates
were significantly higher (99%) in patients below compared
with patients above (81%).
Concentrations of ANF, N-proANF, and BNP increased in relation
to HF severity; only N-proANF was able to distinguish between
controls, CAD, and HF patients; BNP was able to
distinguish HF severity; N-proANF and BNP were the
best independent predictors of outcome and mortality.
ANF, atrial natriuretic factor; N-proANF, atrial natriuretic factor prohormone; LVEF, left ventricular ejection fraction; CAD, coronary artery disease.
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dence that BNP levels can present predictive
information about the course of HF.
BNP for Everyone?
Given the success of BNP measurements in
primary and acute care, a reasonable question
to ask is, “Should mass screenings for HF utilizing BNP be undertaken?” The results from
the Framingham Heart Study indicate that
BNP screening may not be helpful in this setting.30 In a large prospective cohort study,
3177 participants (1707 female) underwent
testing to determine if BNP was a useful
screening test for LV hypertrophy and systolic
dysfunction. Each subject underwent echocardiography and venipuncture for BNP. Receiver
operating characteristic curves (ROC) were
obtained with echocardiography results plotted as the dependent variable and log BNP
levels plotted as the independent variable.
Briefly, ROC curves (see Table 1) plot sensitivity and specificity on a graph that defines the
area under the curve (AUC). AUC is used to
determine global test performance, with an
AUC ⬍.5 indicating no discriminative ability.
Overall, the ROC curves for elevated LV mass
or systolic dysfunction were ⱕ.75, far below
the desired high specificity level of .95. Of
note, men and women were compared separately with men having higher discrimination
than women. Thus, it appears that BNP is not
appropriate as a mass screening test.
Future Recommendations
This review provides strong evidence that
BNP measurements are a useful part of the diagnostic work-up for individual patients in a
variety of settings. BNP levels are sensitive
and specific for the diagnosis of abnormal
heart function and HF. In addition, declining
BNP levels appear to correlate with falling
wedge pressures in acutely decompensated
patients, with declining BNP levels better predictive outcomes. In the primary care setting,
BNP levels might provide a useful indicator of
which patients are likely to have HF and require further assessment. Future cardiac
events may also be predicted by knowledge
of BNP levels. Indeed, BNP levels may provide more useful information for the future
529
care of patients with HF than any other rapid
diagnostic test.
In 2001 the European Society of Cardiology convened a taskforce for the diagnosis
and treatment of congestive HF.31 The group
published guidelines stating that BNP levels
can be helpful in the diagnostic process, especially in untreated patients. Patients suspected of having HF, especially in primary
care, can be selected for further investigation
if BNP levels are elevated. Epidemiological
studies have demonstrated that BNP levels
have a high predictive value (low rate of
false positives), thereby improving the diagnostic work-up process. In addition, the
guidelines also suggest that high levels of
BNP identify those at risk for future cardiovascular events including death.
Future studies are necessary to provide
more information regarding cut-off points
for normal, abnormal, and HF values in specific assays such as IRMA and Triage. Gender-specific studies are needed to further explore the normal values for women and
those on HRT. Additional research should include larger sample sizes and be conducted
in more diverse populations. Lastly, researchers need to focus on the predictive
power of BNP and the possibility of developing admission and discharge criteria utilizing both clinical symptoms and BNP.
As technology advances, BNP levels may
reach the point of a very rapid assay, as in
the measurement of blood glucose levels.
Will BNP measures be feasible and helpful
for patients in their own homes? If such a
rapid assay is developed, will prehospital
use be added to Advanced Cardiac Life Support? Will medical and nursing care of patients who are managed in skilled nursing
homes be improved by BNP testing? Often,
these patients are the most challenging to diagnose as they may not be able to describe
symptoms because of dementia and they often have comorbidities that put them at risk
for acute HF. A rapid assay may be able to
provide information for diuretic therapy and
fend off a hospitalization event.
Conclusion
The Triage method is desirable because it is
rapid, convenient, and now shown to detect
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HOWIE ET AL
HF and abnormal LV dysfunction. Finding a
blood test for HF that is precise and accurate
would change the future for diagnosing and
treating patients with HF. In a variety of settings such as the ED, cardiology clinic, primary care clinic, and the intensive care unit,
BNP levels provide information regarding
the presence of HF, severity, and resolution
of acute exacerbation. Furthermore, several
studies present beginning evidence that BNP
levels at time of hospital discharge and over
time provide predictive information regarding hospital readmission rates and mortality.
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