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Clinica Chimica Acta 341 (2004) 41 – 48
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Head-to-head comparison of the diagnostic utility of BNP
and NT-proBNP in symptomatic and asymptomatic
structural heart disease
Thomas Mueller a, Alfons Gegenhuber b, Werner Poelz c, Meinhard Haltmayer a,*
a
Department of Laboratory Medicine, Konventhospital Barmherzige Brueder, Seilerstaette 2, A-4021 Linz, Austria
b
Department of Internal Medicine, Konventhospital Barmherzige Brueder Linz, Austria
c
Department of Applied System Sciences and Statistics, University of Linz, Austria
Received 4 June 2003; received in revised form 14 October 2003; accepted 16 October 2003
Abstract
Background: B-type natriuretic peptide (BNP) and the amino-terminal fragment of the BNP prohormone (NT-proBNP) are
markers for functional cardiac impairment and are elevated in heart failure (HF). Aim of the present study was to perform a
head-to-head comparison of the diagnostic utility of BNP and NT-proBNP in symptomatic and asymptomatic structural heart
disease. Methods: We prospectively classified 180 consecutive subjects according to ACC/AHA guidelines. Blood
concentrations of BNP and NT-proBNP were determined by two fully automated chemiluminescent assays (Bayer and Roche
method). Diagnostic utilities were tested by ROC analyses and logistic regression. Results: ROC curves of BNP and NTproBNP in patients with symptomatic HF (n = 43) and asymptomatic subjects (n = 137) did not differ significantly (AUC 0.930
vs. 0.918, p = 0.650), but comparison of patients with asymptomatic structural heart disease (n = 56) and subjects without
structural disorder of the heart (n = 81) revealed different AUCs for the respective assays (0.735 vs. 0.839, p = 0.009). In the
population studied, age, sex and renal function had no impact on the diagnostic performance of both tests when compared by
logistic regression models. Conclusions: Both assays facilitate diagnosis of symptomatic and asymptomatic structural heart
disease. BNP and NT-proBNP may be equally useful as an aid in the differential diagnosis of probable signs or symptoms of
HF. In contrast, NT-proBNP might be a more discerning marker of early cardiac dysfunction than BNP.
D 2004 Elsevier B.V. All rights reserved.
Keywords: Diagnosis; Echocardiography; Heart failure; Natriuretic peptides
1. Introduction
Assays for the cardiac peptides atrial natriuretic
peptide (ANP) and B-type natriuretic peptide (BNP)
have received considerable attention as potential
* Corresponding author. Tel.: +43-732-7897-2201; fax: +43732-7897-2299.
E-mail address: [email protected] (M. Haltmayer).
0009-8981/$ - see front matter D 2004 Elsevier B.V. All rights reserved.
doi:10.1016/j.cccn.2003.10.027
screening tests for symptomatic and asymptomatic
heart disease [1– 3]. These looped peptides and the
amino-terminal fragments of their precursor hormones
(NT-proANP and NT-proBNP) are secreted by the
hemodynamically stressed heart, mainly in response
to myocardial stretch induced by volume overload [4].
Both ANP and BNP promote natriuresis and diuresis,
inhibit the renin – angiotensin – aldosterone axis and
act as vasodilators [5]. In contrast to ANP, regulation
42
T. Mueller et al. / Clinica Chimica Acta 341 (2004) 41–48
of BNP synthesis and excretion occurs mainly at the
level of gene expression, suggesting that ANP and
BNP form a dual, integrated natriuretic peptide system, and BNP may be a backup hormone activated
only after prolonged ventricular overload [1]. NTproANP and NT-proBNP occur mainly in their high
mass molecular form with longer half-life than the
respective active hormones, but may also be cleaved
into smaller fragments in vivo. However, a possible
biological function of NT-proANP and NT-proBNP
and their split products is still under debate [4,6].
Nevertheless, available clinical data indicate that
both BNP and NT-proBNP appear to be useful
diagnostic and prognostic markers with respect to
heart failure (HF) and may be superior to ANP and
NT-proANP [4]. Currently potential advantages of
either BNP or NT-proBNP in diagnosing symptomatic HF or asymptomatic cardiac dysfunction remain
unclear because available direct head-to-head comparisons of BNP and NT-proBNP are rare and were
mainly related to functional variables of cardiac
impairment [7 – 12]. In addition, these studies measuring BNP and/or NT-proBNP used older generation
assays, which have limitations with respect to their
analytical/clinical sensitivity, analytical specificity
(accuracy) and practicability [6]. Newer generation
assays for measurement of BNP and NT-proBNP
may overcome these problems. Thus, using the
approach of classifying subjects according to the
‘ACC/AHA Guidelines for the Evaluation and Management of Chronic Heart Failure in the Adult’ [13],
aim of the present investigation was to perform a
direct head-to-head comparison of the diagnostic
utility of BNP and NT-proBNP as measured by two
fully automated chemiluminescent assays (Bayer and
Roche method) with respect to symptomatic and
asymptomatic structural heart disease.
2. Materials and methods
The present study, carried out prospectively for a
period of 12 weeks (August to November 2002) at the
Division of Internal Medicine, Department of Cardiology, St. John of God Hospital Linz/Austria, was
approved by the local ethics committee in accordance
to the Helsinki Declaration; all study participants gave
written informed consent. The study population,
which has been described in detail previously [14],
comprised 157 consecutive patients admitted for extensive cardiac evaluation and further 23 consecutive
patients with symptomatic HF admitted for inpatient
treatment. Primary evaluation of patients was done by
thorough survey of the patients’ history and physical
examination, by initial and ongoing assessment of
patients’ ability to perform routine and desired activities of daily living and by 12-lead electrocardiogram
and chest radiography. Each patient was subjected to
blood sampling for determination of BNP, NTproBNP, NT-proANP and other routine laboratory
parameters such as complete blood count, serum
electrolytes, blood urea nitrogen, serum creatinine,
blood glucose, liver function test and thyroid-stimulating hormone. In all subjects, echocardiography
coupled with colour-flow, continuous-wave and
pulsed-wave Doppler studies of the aortic and mitral
valve was performed by one of three registered
diagnostic cardiac sonographers on the same echocardiographic instrument (Sonos 2000, Hewlett-Packard,
USA). Normal ventricular function (i.e., subjects
without structural disorder of the heart) was defined
by a left ventricular end-diastolic diameter (LVEDD)
< 56 mm, without left ventricular hypertrophy or
without wall motion abnormities, a right ventricular
systolic pressure (RVSP) < 35 mm Hg and a left
ventricular ejection fraction (LVEF) >60%. Isolated
diastolic dysfunction as measured by echocardiography was not defined in this study because early
diastolic dysfunction per se (e.g., without left ventricular hypertrophy) is not related to structural abnormities according to the ACC/AHA Guidelines [13]. In
addition, there are currently no universally accepted
minimal criteria for the diagnosis of diastolic dysfunction [15]. Pathogenesis of ventricular abnormities
was classified in either hypertensive, ischemic, dilated
or valvular. Drug therapy (i.e., ACE-inhibitors, betablockers, digitalis and diuretics) was recorded at the
day of blood collection and was modified in the
sequel.
Based on the above-described evaluation, study
subjects were classified according to the ‘ACC/AHA
Guidelines for the Evaluation and Management of
Chronic Heart Failure in the Adult’ [13] to one of the
four following categories by one experienced cardiologist: (a) healthy subjects (n = 42), (b) patients at high
risk for developing HF but without structural disorder
T. Mueller et al. / Clinica Chimica Acta 341 (2004) 41–48
of the heart (HF stage a, n = 39), (c) patients with
structural disorder of the heart but without symptoms
of HF (HF stage b, n = 56) and (d) patients with past
or current symptoms of HF associated with underlying
structural heart disease (HF stage c, n = 43). None of
the study participants belonged to HF stage d according to the above guidelines (patients with end-stage
disease requiring specialized treatment strategies).
43
The patient evaluation and classification was done
blinded to natriuretic peptide values. Clinical characteristics and demographic information of the study
population according to the ACC/AHA classification
[13] are summarized in Table 1.
Blood for measurement of BNP and NT-proBNP
concentrations was collected by venipuncture in polyethylene therephthalate glycol (PET) Vacuette clot
Table 1
Patient characteristics according to heart failure classification (total number = 180)
HF stage A (n = 39)
HF stage B (n = 56)
HF stage C (n = 43)
Demographic and clinical features
Male/female
39/3
Age (years)
39.6 (29.2 – 52.0)
BMI (kg/m2)
25.9 (22.9 – 27.4)
Arterial hypertension
0
Diabetes mellitus
0
Known CAD
0
NYHA I
–
NYHA II
–
NYHA III
–
NYHA IV
–
Healthy (n = 42)
31/8
52.1 (45.6 – 64.0)
27.8 (25.5 – 30.0)
37
2
8
–
–
–
–
48/8
64.9 (53.8 – 76.8)
26.4 (24.2 – 29.6)
43
11
31
–
–
–
–
41/2
60.8 (55.0 – 67.4)
27.3 (25.1 – 30.7)
19
15
32
0
38
5
0
Echocardiographic data
Impaired LVEF
Enlarged LVEDD
LV hypertrophy
Pulmonary hypertension
Wall motion abnormities
–
–
–
–
–
26
9
26
0
23
43
39
2
11
32
Pathogenesis of ventricular abnormities
Hypertensive CMP
–
Ischemic CMP
–
Dilated CMP
–
Valvular CMP
–
–
–
–
–
25
26
2
3
0
32
10
1
Drug therapy
ACE-inhibitors
Beta-blockers
Digitalis
Diuretics
0
0
0
0
22
22
0
9
22
32
0
11
37
30
7
26
Biochemical markers
Creatinine (mg/dl)
eGFR (ml/min)
NT-proANP (pmol/l)
BNP (pg/ml)
NT-proBNP (pg/ml)
1.1 (1.0 – 1.2)
100 (89 – 114)
50 (50 – 749)
9.0 (5.3 – 17.9)
32.9 (14.1 – 54.1)
1.1 (0.9 – 1.2)
91 (74 – 112)
50 (50 – 1589)
11.7 (6.8 – 25.1)
60.6 (30.7 – 101)
1.1 (1.0 – 1.2)
76 (58 – 94)
460 (50 – 1927)
24.2 (13.3 – 71.9)
166 (82.8 – 376)
1.1 (0.9 – 1.3)
85 (61 – 116)
3679 (1737 – 6748)
232 (137 – 431)
776 (337 – 1609)
–
–
–
–
–
Abbreviations: HF = heart failure, BMI = body mass index, NYHA = New York Heart Association classes of HF, eGFR = estimated glomerular
filtration rate. Study subjects were classified according to the ACC/AHA Guidelines (see Ref. [13]). HF stage A: patients who are at high risk
for developing HF but without structural heart disease; HF stage B: patients with structural heart disease but who have never developed
symptoms of HF; HF stage C: patients with past or current symptoms of HF associated with underlying structural heart disease. Age, BMI and
biochemical markers are presented as median (25th – 75th percentile).
44
T. Mueller et al. / Clinica Chimica Acta 341 (2004) 41–48
activator tubes and EDTA tubes (Greiner Bio-One,
Austria) after an overnight fast, with the study participants in supine position for at least 20 min. Blood
samples were centrifuged at 3500 g for 10 min at 4
jC immediately after collection, and serum/plasma
was separated for the determination of each assay.
Roche assays for determination of serum NT-proBNP
were done on the same day within 4 h after specimen
collection on an Elecsys 2010 analyzer. The Roche
assay is a fully automated two-site sandwich immunoassay incorporating polyclonal antibodies against
the N-terminal (amino acids 1– 21) and mid-region
(amino acids 39 – 50) of NT-proBNP [14]. Total coefficients of variation for the Roche NT-proBNP assay
were less than 3.0% (determined with controls provided by the manufacturer, target values 215 and 4010
pg/ml). Plasma samples for the Bayer BNP assay were
stored at
70 jC until analysis (for up to 3.5
months), which was done on an ADVIA Centaur
analyzer using investigational test kits not approved
for routine clinical application. The Bayer assay (also
a fully automated two-site sandwich immunoassay)
incorporates two monoclonal antibodies that recognize the sterically remote sites, C-terminus region and
the intramolecular ring structure of BNP (using the
same antibodies as the Shionogi RIA). The Bayer
assay was calibrated based on clinical trials to be
harmonized with the Triage BNP test decision threshold of 100 pg/ml. For the Bayer BNP assay, total
coefficients of variation at three concentrations were
less than 5.0% (determined with controls provided by
the manufacturer, target values 43, 432 and 1585 pg/
ml) in our laboratory. The Biomedica proANP ELISA
[16] was used for determination of serum NT-proANP.
Since NT-proANP values of 82 subjects were below
the detection limit of 50 pmol/l, they were classified
as having 50 pmol/l. All three assays were performed
according to the manufacturer’s recommendations,
each sample with a single determination. Control
samples were supplied by the manufacturers and were
used to accept or reject individual runs. Serum creatinine values were routinely obtained by Jaffè kinetic
on a COBAS Integra 700 analyzer on the day of blood
collection. Estimated glomerular filtration rate (eGFR)
was calculated using the Cockgroft and Gault [17]
formula.
Statistical analysis was performed with the SPSS
(ver. 10.0) and the MedCalc (ver. 7.2.0.2) software.
Fig. 1. ROC plots for BNP and NT-proBNP. Solid lines indicate
ROC curves for BNP, and dotted lines are ROC curves for NTproBNP. (a) Patients with symptomatic structural heart disease (HF
stage C, n = 43) compared to subjects without symptoms of HF
(n = 137), AUC for BNP 0.930, AUC for NT-proBNP 0.918,
difference not statistically significant ( p = 0.650). (b) Patients with
asymptomatic structural heart disease (HF stage B, n = 56)
compared to subjects without structural disorder of the heart
(n = 81), AUC for BNP 0.735, AUC for NT-proBNP 0.839,
difference statistically significant ( p = 0.009).
T. Mueller et al. / Clinica Chimica Acta 341 (2004) 41–48
Dichotomous variables are given as prevalence in
number (%), and continuous data are expressed as
median (25th – 75th percentile). Receiver-operating
characteristic (ROC) plot analysis was carried out to
test the diagnostic utility of BNP and NT-proBNP
assays under several conditions. Comparisons between the areas under curve were assessed according
to the method by Hanley and McNeil [18]. In order to
determine odds ratios (unadjusted and controlling for
age, sex and eGFR) for the detection of symptomatic
and asymptomatic structural heart disease with respect
to BNP and NT-proBNP thresholds of highest accuracy, logistic regression analysis without variable
selection technique was performed. Dichotomous variables were coded with an indicator variable of 1 for
having the disease and 0 for its absence. All probabilities were two-tailed and p values less than 0.05
were regarded as statistically significant.
3. Results
In order to determine performance characteristics
of BNP and NT-proBNP for identifying symptomatic
HF, the entire study population was divided into two
groups. The first group consisted of all patients with
HF stage C (n = 43, NYHA II – III), and the second
45
group comprised all asymptomatic subjects (n = 137,
i.e., 81 subjects without structural disorder of the heart
plus 56 patients with asymptomatic structural heart
disease). ROC curve analysis as given in Fig. 1a
revealed an area under curve (AUC) of 0.930 (standard error 0.028, 95% CI 0.882 – 0.962) for BNP and
an AUC of 0.918 (standard error 0.030, 95% CI
0.868 – 0.954) for NT-proBNP. The related difference
of 0.012 was not statistically significant ( p = 0.650).
In the sample studied, optimal cutoff values (i.e.,
points of the ROC curves, in which the sum of false
negative and false positive results is lowest) for
detecting symptomatic HF were 113 pg/ml (sensitivity
81%, specificity 96%) for BNP and 211 pg/ml (sensitivity 93%, specificity 82%) for NT-proBNP.
To determine AUCs of both peptides for the
diagnosis of asymptomatic structural heart disease,
we used patients with HF stage B as diseased group
(n = 56, patients with structural disorder of the heart
without symptoms of HF) and patients without structural disorder of the heart as the nondiseased (n = 81,
i.e., 42 healthy subjects plus 39 patients with HF stage
A). Under this condition, the BNP assay displayed an
AUC of 0.735 (standard error 0.045, 95% CI 0.653 –
0.806), and the NT-proBNP assay displayed an AUC
of 0.839 (standard error 0.037, 95% CI 0.767 –0.896),
with the difference of 0.104 being statistically signif-
Table 2
Results of logistic regression analysis
Independent variable
Cutoff value (see text, pg/ml)
Odds ratio (95% CI, p value)
Diagnostic accuracy
Incorrect classification
False positive
False negative
n=6
n = 25
n=8
n=3
Prediction of symptomatic structural heart disease—adjusted model (controlling for age, sex and eGFR)
BNP
113
117 (32 – 429, < 0.001)
92%
NT-proBNP
211
83 (19 – 354, < 0.001)
84%
n=5
n = 19
n=9
n=9
Prediction of asymptomatic structural heart disease—unadjusted model
BNP
13.4
5.4 (2.5 – 11, < 0.001)
NT-proBNP
70.2
13.3 (5.8 – 31, < 0.001)
n = 29
n = 19
n = 14
n = 11
n = 13
n = 16
n = 18
n = 11
Prediction of symptomatic structural heart disease—unadjusted model
BNP
113
96 (31 – 293, < 0.001)
NT-proBNP
211
60 (17 – 209, < 0.001)
92%
84%
69%
78%
Prediction of asymptomatic structural heart disease—adjusted model (controlling for age, sex and eGFR)
BNP
13.4
3.4 (1.4 – 8.0, 0.006)
77%
NT-proBNP
70.2
7.1 (2.8 – 18, < 0.001)
80%
Observed frequencies: prediction of symptomatic structural heart disease (43 diseased vs. 137 nondiseased, n = 180), prediction of asymptomatic
structural heart disease (56 diseased vs. 81 nondiseased, n = 137). Abbreviations: eGFR = estimated glomerular filtration rate.
46
T. Mueller et al. / Clinica Chimica Acta 341 (2004) 41–48
icant ( p = 0.009). Given these ROC curves as plotted
in Fig. 1b, cutoff values with the highest accuracy
were 13.4 pg/ml (sensitivity 75%, specificity 64%) for
BNP and 70.2 pg/ml (sensitivity 80%, specificity
77%) for NT-proBNP.
Univariate odds ratios for the detection of both
symptomatic and asymptomatic structural heart disease were calculated with BNP or NT-proBNP as
independent variables dichotomized according to the
above-determined thresholds. In addition, odds ratios
for symptomatic and asymptomatic structural heart
disease with respect to BNP and NT-proBNP adjusted
for age, sex and eGFR were also determined in order
to estimate the influence of these potential confounders in our study population. Results of these analyses
are specified in Table 2.
4. Discussion
Aim of the present study was to perform a head-tohead comparison of BNP and NT-proBNP as measured by new generation chemiluminescent immunoassays with respect to their diagnostic utility for the
diagnosis of symptomatic and asymptomatic structural heart disease. The main finding was that both tests
may be useful as a diagnostic aid in structural heart
disease with symptoms of HF (HF stage c), as
indicated by comparable AUCs in ROC analysis.
However, NT-proBNP seems to be minimally advantageous compared to BNP for the detection of structural heart disease without symptoms of HF (HF stage
B), but both assays generally seem to have a diminished diagnostic performance for HF stage B compared to HF stage C. Because of a slower plasma
clearance of NT-proBNP compared to the biologically
active peptide BNP, the circulating concentrations of
NT-proBNP have been reported to be much higher
[6], although both peptides are released by cardiomyocytes on an equimolar basis [1]. As a consequence, NT-proBNP might undergo a greater
proportional rise in early disease state than BNP
which could be the biologic rationale for NT-proBNP
being the preferable biomarker for asymptomatic
structural heart disease. Our data may be in accordance with the literature since authors of a previous
study on BNP and NT-proBNP suggested that NTproBNP might be a more discerning marker of early
cardiac dysfunction than BNP [7]. In addition, a headto-head comparison of NT-proBNP and BNP measurements did not show significant diagnostic differences for both parameters in the detection of a more
severely impaired LVEF < 40% in patients with
chronic stable HF [8].
As demonstrated by logistic regression analysis,
no relevant influences of age, sex and renal function
(eGFR) on the diagnostic performance of both assays
could be observed in our study; the diagnostic
accuracy of both tests for the prediction of HF stage
B and C did not change noteworthy when calculating
a model unadjusted for potential confounders and the
model controlling for age, sex and eGFR. This is
important since previous studies described an association of natriuretic peptide concentrations with age,
sex and renal function, in particular in patients with
cardiac impairment [7,12,19]. In the present study,
this relationship had no relevant impact on the
diagnostic performance of BNP and NT-proBNP.
However, regarding renal function, our statement is
restricted to eGFR, and it has to be mentioned that
the median of eGFR values was 90 ml/min (25th –
75th percentile, 70– 110 ml/min) in the entire study
population, with only 17 patients having an
eGFR < 50 ml/min (for further information, see also
Table 1).
One of the limitations of our study may be the fact
that subjects were undergoing cardiac investigations
in a hospital setting. Such a population may be
different from the general population where screening
for BNP and/or NT-proBNP would be more useful. In
addition, the sample size of 180 persons may be too
small for determining the effective diagnostic utility
of a certain test, and the prevalence of each heart
failure class may have been fixed by the subject
selection and may therefore not be representative of
routine practice. Next, study subjects showed a wide
range of age not equally distributed among the study
groups, and furthermore, some study subjects received
angiotensin-converting enzyme inhibitor therapy and
used diuretics, beta-blockers or digoxin. Concerns had
been expressed that these drugs might modify circulating concentrations of natriuretic peptides and limit
their potential as markers for left ventricular dysfunction [3]. These facts may have imposed a certain bias
related to the absolute size of AUCs in ROC analysis.
However, the relative proportions of AUCs related to
T. Mueller et al. / Clinica Chimica Acta 341 (2004) 41–48
the two methods should not be affected by the above
limitations.
To date, there is no agreement on the best procedure for measuring BNP and NT-proBNP because
determination by older generation competitive assay
methods (such as RIA or EIA) is affected by several
analytical problems as reviewed recently [6]. Noncompetitive assays (such as IRMA and ELISA) for
determination of BNP and NT-proBNP generally have
a better degree of sensitivity, precision and specificity
than the respective competitive immunoassays. Therefore, this second generation of generally ‘two-site’
(sandwich) immunometric assays, using two specific
antibodies prepared against sterically remote epitopes
of the peptide chain, should be preferred. However,
these methods are still time-consuming (an assay
typically requires from 5 to 36 h) and cannot be used
in a fully automated analytical system. Third-generation assays can be directly used in fully automated
analytical systems and permit the measurement of
BNP and NT-proBNP concentrations in a few
minutes. Two of these third-generation assays are
the Roche NT-proBNP method and the Bayer BNP
assay (total duration of assays: 15 – 20 min), both
being more convenient for a more widespread use of
BNP and/or NT-proBNP in clinical laboratories and
clinical practice.
In conclusion, both BNP and NT-proBNP as
measured by the investigated newer generation
assays should be equally useful as an aid to differentiate dyspnoea of cardial or pulmonary origin. The
approach of BNP or NT-proBNP measurement in the
evaluation of acute dyspnoea has already been suggested in recent studies [20 – 22]. In contrast, a
minimal performance advantage for the NT-proBNP
assay may be advocated with respect to the prediction of asymptomatic structural heart disease (HF
stage B). In this context, it has to be pointed out that
the diagnostic accuracy of BNP and NT-proBNP is
probably lower under this condition. Nevertheless,
both tests could be useful for selecting patients for
further cardiac evaluation, which has already been
recommended for BNP in previous publications
[23,24]. For a more detailed approach to asymptomatic structural heart disease and natriuretic peptides,
it would be necessary to investigate a larger population also facilitating subgroup analyses of different
echocardiographic findings.
47
Acknowledgements
This work was supported in part by a grant for
scientific research from the Upper Austrian Government. We thank Bayer Diagnostics, Vienna and Roche
Diagnostics, Vienna for technical assistance and
providing reagents free of charge. Neither of these
institutions played part in study design, data collection, data analysis, data interpretation, writing the
report or decision to submit the manuscript for
publication. We also wish to thank Martina Stuetz
from our laboratory for performing the Biomedica
NT-proANP ELISA analyses.
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