State of the art: Using natriuretic peptide levels in clinical practice
Alan Maisela,i,⁎, Christian Muellerb, Kirkwood Adams Jr.
Nadia Aspromontee, John G.F. Clelandf, Alain Cohen-Solalg, Ulf Dahlstromh,
Anthony DeMariai, Salvatore Di Sommaj, Gerasimos S. Filippatosk, Gregg C. Fonarowl,
Patrick Jourdainm, Michel Komajdan, Peter P. Liuo, Theresa McDonaghp,
Kenneth McDonaldq, Alexandre Mebazaar, Markku S. Nieminens, W. Frank Peacockt,
Marco Tubarou, Roberto Vallev, Marc Vanderhydenw, Clyde W. Yancyx,
Faiez Zannady, Eugene Braunwaldz
c, Stefan D. Ankerd,
aVA San Diego Healthcare System, United States
bUniversity Hospital Basel, Switzerland
cUniversity of North Carolina, Chapel Hill, United States
dCharite, Campus Virchow-Klinikum, Berlin Germany
eSan Spirito Hospital, Rome Italy
fCastle Hill Hospital, University of Hull, Kingston-upon-Hull, UK
gHopital Lariboisiere, Paris France
hLinkoping University Hospital, Linkoping Sweden
iUniversity of California, San Diego, United States
jSant'Andrea Hospital University La Sapienza, Rome Italy
kAthens University Hospital Attikon, Athens Greece
lUniversity of California, Los Angeles, United States
mParis Descartes University, Paris France
nUniversity Pierre & Marie Curie, Paris 6, Department of Cardiology, Pitie Salpetriere Hospital, Paris France
oUniversity of Toronto, Canada
pRoyal Brompton Hospital, London UK
qSt. Vincents University Hospital, Dublin Ireland
rUniversity Paris 7 Diderot, Hopital Lariboisiere, Paris France
sHelsinki University Central Hospital, Helsinki, Finland
tThe Cleveland Clinic, Cleveland Ohio, United States
uSan Filippo Neri Hospital, Rome Italy
vCentro per lo Scompenso Ospedale Civile, San Dona di Piave, Italy
wOnze Lieve Vrouwe Ziekenhuis, Aalst Belgium
xBaylor University Medical Center, Dallas Texas, United States
yInserm Centre d'Investigation Cliniques, Nancy France
zBrigham and Women's Hospital, Boston Massachusetts, United States
Received 30 June 2008; received in revised form 14 July 2008; accepted 17 July 2008
Available online 29 August 2008
Natriuretic peptide (NP) levels (B-type natriuretic peptide (BNP) and N-terminal proBNP) are now widely used in clinical practice and
cardiovascular research throughout the world and have been incorporated into most national and international cardiovascular guidelines for
European Journal of Heart Failure 10 (2008) 824–839
⁎Corresponding author. VASDHS Cardiology 9111-A, 3350 La Jolla Village Drive, San Diego, CA 92161, United States.
E-mail address: email@example.com (A. Maisel).
1388-9842/$ - see front matter. Published by Elsevier B.V. on behalf of European Society of Cardiology.
heart failure. The role of NP levels in state-of-the-art clinical practice is evolving rapidly. This paper reviews and highlights ten key messages
• NP levels are quantitative plasma biomarkers of heart failure (HF).
• NP levels are accurate in the diagnosis of HF.
• NP levels may help risk stratify emergency department (ED) patients with regard to the need for hospital admission or direct ED discharge.
• NP levels help improve patient management and reduce total treatment costs in patients with acute dyspnoea.
• NP levels at the time of admission are powerful predictors of outcome in predicting death and re-hospitalisation in HF patients.
• NP levels at discharge aid in risk stratification of the HF patient.
• NP-guided therapy may improve morbidity and/or mortality in chronic HF.
• The combination of NP levels together with symptoms, signs and weight gain assists in the assessment of clinical decompensation in HF.
• NP levels can accelerate accurate diagnosis of heart failure presenting in primary care.
• NP levels may be helpful to screen for asymptomatic left ventricular dysfunction in high-risk patients.
Published by Elsevier B.V. on behalf of European Society of Cardiology.
Keywords: Natriuretic peptides; Clinical practice; Diagnosis
The FDA clearance of B-type natriuretic peptide in the
fall of 2000 as an adjunct to the diagnosis of heart failure
(HF) has generated both excitement and controversy. The
rapid adoption of both BNP and N-terminal proBNP
(natriuretic peptides (NP)) suggests that their clinical
application exceeds their use as rule-out blood tests for
heart failure. Indeed, there are data suggesting that at some
level, with consideration for the confounders of chronic
elevations and non-HF disease states that may elevate NPs,
an elevated NP level may represent a reasonable “rule-in”
biomarker that is also highly prognostic for clinically
relevant outcomes in both HF and acute coronary syndrome.
There is also early support for the concept that NP levels are
modulated by medications and may help guide treatment in
both the inpatient and outpatient setting.
The widespread promulgation of relatively straightfor-
ward and easily accessible tests, including NPs, has a
potential downside — too many tests are ordered for reasons
beyond the intended use. Physicians have voiced appropriate
concern over how best to integrate NP testing into the
clinical arena so that they can make informed decisions in
diagnosing and managing patients. Extrapolation from peer-
reviewed literature is required when considering individual
patients, and it is here that clinical acumen and user
experience play an important role.
The purpose of this review is to provide clinicians with
advice on the use of NP levels in their daily practice. The
recommendations presented are consensus based, i.e. based
on evidence combined with the clinical judgment of the
majority of a group of experts. Some recommendations
could be criticized for leaning to one side or the other of a
controversial issue. However, the authors are all intimately
involved in the area of HF,and many use NP levels on a daily
basis. As general recommendations apply to both BNP and
NT-proBNP, examples will be given with both peptides.
Although the levels correlate with each other, the individual
values of the two NPs are NOT interchangeable. They have
different half-lives, different modes of degradation, and most
important, different ranges and cut-off values. However,
their similarities far outweigh their differences, and for the
purpose of the reader, the two should be considered basically
History of B-type natriuretic peptide testing
1988 Sudoh et al. isolate BNP from porcine brain tissue 
1991 Mukoyama et al. demonstrate that BNP is a normal cardiac hormone
secreted primarily by the ventricles 
1993 Shionogi & Co, Ltd. develop the first commercial BNP assay (RIA)
1994 Davis et al. provide the first report suggesting that BNP is useful in
diagnosing HF in dyspnoeic patients 
1994 Multiple reports of elevated BNP levels in HF [7,8]
1995 Hunt et al. — first report of NT-proBNP circulating in human plasma
1997 Cowie et al. show that BNP has high accuracyto diagnoseCHF in the
primary care setting 
1998 McDonagh et al. demonstrate that BNP is reliable in the detection of
left ventricular dysfunction 
2000 Biosite, Inc. introduces the BNP point-of-care assay
2001 Maisel et al. publish the first point-of-care BNP in the ED and
hospital settings [12,13]
2002 Breathing Not Properly Study published 
2003 Lainchbury et al. — first report of NT-proBNP in the diagnosis of HF
2003 Central lab assays become available: Bayer Healthcare, LLC,
Diagnostics Div., ADVIA Centaur, ShionoRIA BNP assay in US
(central lab) and Roche Elecys
2004 BASEL trial showing reduction in morbidity and treatment cost with
BNP published 
2005 Beckman central lab (Biosite antibody) and Abbott Diagnostics,
AxSYM BNP assay (central lab) becomes available
2005 PRIDE study on NT-proBNP in AHF published 
2005 ESC Guidelines for acute and chronic Heart Failure Endorse BNP
2006 Biosite Triage BNP Test receives CLIAwaiver for whole blood use.
AHA/ACC Guidelines for Heart Failure Endorse Class II a
recommendation for NPs. (Level of evidence A) 
825 A. Maisel et al. / European Journal of Heart Failure 10 (2008) 824–839
equal. Two important principles should underlie the clinical
use of NPs. First, a NP level is NOT a stand-alone test. It is
always of greatest value when it complements the physi-
cian's clinical skills along with other available diagnostic
tools and should always be interpreted in consideration of
renal function and body mass index (BMI). Second, NP
levels should be interpreted and used as continuous variables
in order to make full use of the biological information
provided by the measurement (like for example calculated
glomerular filtration rate or LDL-cholesterol). Cut-off levels
may still be useful to make the application of NP easy for
physicians without extensive experience with NP testing.
2. Natriuretic peptides — history and physiology
initially was isolated and named after the porcine “brain”.
However, with the primary site of synthesis localized to the
cardiac ventricular myocytes, the term “B-type” natriuretic
peptide is now favoured. The best current understanding
suggests that in the setting of volume expansion or pressure
BNP in the ventricular myocardium , although some have
volumes and NP levels .
After synthesis, the peptide is cleaved first to proBNP,
then to the biologically active BNP and the inactive amino-
terminal fragment, NT-proBNP. The release of BNP results
in improved myocardial relaxation and serves an important
regulatory role in response to acute increases in ventricular
volume by opposing the vasoconstriction, sodium retention,
and antidiuretic effects of the activated renin–angiotensin–
aldosterone system .
Fig. 1 illustrates the haemodynamic determinants of BNP.
A given level of BNP is a summation of many inputs and is a
measure of many aspects of cardiac function.
3. Use of natriuretic peptide levels in patients presenting
with acute dyspnoea
In many industrialized nations, HF, a progressive disease
with a mortality exceeding most cancers, represents one of
the most expensive disorders to the medical system .
Most patients with HF eventually present to the emergency
department (ED) or hospital. Because HF occurs predomi-
nantly in older subjects, its presentation is often complicated
by multiple co-morbidities that are common in this
population. This is unfortunate, since the most common
presentation of HF is dyspnoea, a complaint that is neither
specific nor sensitive for predicting the presence of HF.
Thus, the challenge for the emergency physician is to triage
rapidly and accurately patients presenting with dyspnoea due
to HF from those with many other common aetiologies with
NP testing improves diagnostic accuracy and thus has
become a standard part of the evaluation in patients
Fig. 1. Haemodynamic determinants of BNP.
826A. Maisel et al. / European Journal of Heart Failure 10 (2008) 824–839
presenting to the ED with dyspnoea. NP levels improve the
accuracy of physician decision-making; errors decline, and a
occurred if NP levels were considered as part of the initial
As a quantitative marker of HF, NP levels are best
interpreted as a continuous variable. The higher the NP
value the greater the likelihood that the dyspnoea is due to
HF. While the use of cut points can be criticized, for
clinical usefulness specific cut-off values can provide
benchmarks correlating with relevant statistical thresh-
olds. When BNP is low (b100 pg/ml), it is unlikely that
HF is contributing to the clinical presentation. On the
other hand, a high BNP (N400 pg/ml) suggests that HF is a
contributor to the patient's symptoms with specificity
exceeding 90% (Fig. 2). The “rule-out” level (BNP
b100 pg/ml) can exclude HF from the differential
diagnosis. However to “rule in” HF (BNPN400 pg/ml)
is more complex. This requires addressing the fact that
BNP may be persistently elevated in chronic HF and may
Fig. 2. BNP Consensus Algorithm.
Fig. 3. Optimal cut points for NT-proBNP in the ED.
827A. Maisel et al. / European Journal of Heart Failure 10 (2008) 824–839
not be representative of an acute haemodynamic change.
Other conditions that result in an increased BNP should
also be considered, including both those that result in
myocardial stretch (acute pulmonary embolus, acute
coronary syndrome, primary pulmonary hypertension,
etc.) and renal failure.
While a 2 cut-point approach provides high diagnostic
accuracy, this does leave a “grey zone” of BNP values
between100 and 400 pg/ml where clinical acumen and
ancillary testing are often required to make a correct
diagnosis. If a large proportion of patients with acute
breathlessness had values in the grey zone this could reduce
the clinical utility of NP but, in practice, 75% of patients
have values above or below these cut-off values
A recent pooled analysis examined the utility of NT-
proBNP in the diagnosis of heart failure . When using
NT-proBNP, a cut point of 300 pg/ml is proposed to “rule
out” a diagnosis of HF, while higher age-dependent cut
points are suggested to “rule in” HF  (Fig. 3). Patients
with NT-proBNP levels N450 pg/ml (b50 years), N900 pg/
ml (50–75 years), and N1800 pg/ml (N75 years) all have a
high likelihood of heart failure as the diagnosis.
As a quantitative marker of HF, the use of NP levels is not
only helpful for diagnosis, but also for risk stratification and
may therefore assist in triage decisions. Initial ED NP levels
identify the risk of death or readmission within 30 days.
Inpatient mortality has been shown to be related to admission
BNP in a linear manner [24,25]. Patients with a BNP at
presentation N1730 pg/ml (fourth quartile) had an in-hospital
mortality rate that was more than three-times that of patients
with BNP levelsb430 pg/ml (first quartile). . NT-
proBNP levels in the EDN1000 pg/ml are associated with
severe heart failure and an adverse prognosis. .
Results from two large randomised controlled studies
provide further support for the use of NP testing in the ED
[14,26,27]. In the BASEL study, a single measurement of
BNP in the ED added to the clinical evaluation, reduced the
time to the initiation of the correct treatment, reduced in-
hospital days and reduced overall cost by 26%. Importantly
the improvement in outcome and the reduction in total costs
persisted at six months . Therefore, in patients presenting
with dyspnoea the use of NP levels is not only cost-effective
but also cost saving. Recent data from the Canadian
IMPROVE-CHF study confirmed that the findings of the
BASEL study also apply in a universal health coverage
system . The knowledge of NT-proBNP levels (mea-
sured at presentation and at 72 h) in IMPROVE-CHF
reduced the duration of the ED visit by 21%, the number of
patients re-hospitalised over 60 days by 35%, and direct
medical cost of all ED visits, hospitalisations, and sub-
sequent outpatient services at 60 days by 15%.
Therefore, NP testing should be considered for most
patients within the “at risk for heart failure” demographic and
presenting to the ED with acute dyspnoea. For logistic and
practical reasons, this approach seems preferable to selective
testing. Even in those patients in whom the diagnosis seems
certain, a NP level in the ED gives important information
concerning short and intermediate-term prognosis. Despite
this apparent recommendation for near global assessment of
NPs in patients presenting with dyspnoea, the likelihood of a
test is related to the pre-test probability of disease. If the
clinical scenario is overwhelmingly consistent with HF or
more importantly is clearly unrelated to HF, there is no need
to perform the assay for diagnostic purposes. For example, in
a patient in whom dyspnoea is associated with a known
cause, such as an adult presenting with trauma or a paediatric
patient with known asthma, a NP level is not needed.
NP levels may guide the intensity of ED treatment, aid in
the decision to admit or not admit a patient to the hospital,
and clarify the urgency of post-discharge follow-up. For
example the non-obese patient with HF whose BNP level is
b250 pg/ml is generally at low risk for subsequent adverse
cardiac events and may be discharged from the ED after
relief of symptoms, as long as problems other than HF
requiring admission are not present . Conversely, the
greater the NP level, the worse the severity of HF and the
higher the incidence of short and long-term mortality.
3.1. Caveats in using NP levels
3.1.1. “Grey zone”
The grey zone is defined as follows:
BNP NT-proBNP 
b50 years old 300 450 pg/ml
50–75 years 300–900 pg/ml
N75 years 300–1800 pg/ml
The grey zone needs extra physician attention and
ancillary testing. While the final diagnosis is often mild to
moderate HF [14,28], other causes of a modest rise in NP
level should be considered. This includes non-cardiac
pathology that causes myocardial stress, and includes
pulmonary hypertension and RV dysfunction secondary to
pulmonary embolism, acute coronary syndrome, atrial
fibrillation, or chronic obstructive pulmonary disease with
cor pulmonale . Patients with pneumonia can also have
modest increases in NP levels. Renal dysfunction will be
discussed below. The medium-term prognosis for dyspnoeic
patients with LV dysfunction and BNP levels in the grey
zone is fairly good but outcome may also be determined by
the severity of any co-morbid condition. The grey zone
levels are far more strongly associated with heart failure
when concomitant clinical features are present, such as a
history of heart failure, jugular venous pressure, and prior
diuretic use .
3.1.2. Pulmonary disease
In patients with chronic pulmonary disease, differentiat-
ing between pulmonary causes of dyspnoea versus con-
founding cardiac disease can be clinically challenging.
828 A. Maisel et al. / European Journal of Heart Failure 10 (2008) 824–839
Although the presence of pulmonary hypertension and RV
dysfunction may increase NP levels into the grey zone, few
patients with moderate COPD have a BNPN100 pg/ml or
NT-proBNP levelsN350 pg/ml. In patients with pulmonary
hypertension and RV dysfunction (e.g. in severe chronic
obstructive pulmonary disease, pneumonia, and primary
pulmonary hypertension), NP levels are often in the grey
zone and occasionally in the diagnostic zone for HF,
reflecting the existence of major RV stress and, in effect,
right heart failure [31–36]. The accuracy of NP to diagnose
HF is unchanged in the presence of pre-existing pulmonary
disease [36,37]. Data from the BASEL study suggest that
monitoring of NP levels also improves patient management
and reduces treatment costs in this important patient
NP levels may also be increased into the grey zone, and
possibly higher, in the setting of acute right ventricular
strain as a result of a pulmonary embolism. NP levels
should not replace the standard diagnostic process when
this condition is suspected; it is elevated in ~30% of
patients and is associated with a worse outcome, especially
when it occurs in the presence of elevated troponin levels
3.1.3. Renal disease
There is an important interrelationship between cardiac
and renal dysfunction. About one third of outpatients with
chronic HF have renal insufficiency, defined by an eGFR
(estimated glomerular filtration rate, MDRD formula) less
than 60 ml/min . Current data suggest that the cause of
elevated NP levels in renal failure is multifactorial,
representing in part a true counter-regulatory response
from the heart to the kidney, and not simply diminished
passive renal clearance [40–43].
In order to maintain optimal diagnostic performance, the
cut point for detecting HF may need to be raised when eGFR
is less than 60 ml/min . It is important to note that due to
the lack of data, NP testing for heart failure should be
discouraged in patients on dialysis.
Importantly, high NP levels should not be ignored in the
setting of renal dysfunction. Given the strong relationship
between cardiac and renal disease, clearly elevated NP
values suggest that cardiac disease is present and should
influence clinical decision-making.
NP levels (both BNP and NT-proBNP) are lower in obese
people, both with and without HF [44–47]. Although the
reason for this interaction remains undetermined, the
increased concentration of the NP Receptor-C clearance
receptor on adipocytes has led some to postulate that
increased clearance might be the reason for lower NP levels
[48,49]. To optimize diagnostic accuracy, lower cut-off
values should be used. As there seems to be a linear decrease
in NP levels with increasing BMI, the higher the BMI the
lower the cut-off level which provides the highest accuracy
[50,51]. Avery low BNP cut-off level (b50 pg/ml) should be
used to rule out HF in obese patients (BMIN35 kg/m2). For
reasons of simplicity, it seems justified to conversely double
the NP value of an obese patient to correct for the increased
BMI. Despite the lower circulating levels, NP levels retain a
prognostic capacity in obese patients .
With regard to NT-proBNP, an analysis of the ICON study
demonstrated that rule-out values remained robust irrespec-
tive of BMI .
3.1.5. Diastolic dysfunction
The severity of diastolic dysfunction is correlated to
increased levels of both BNP and NT-proBNP [52,53]. NP
levels by themselves cannot be used to differentiate systolic
from “diastolic dysfunction” in the ED. In fact, the inverse
relationship between ejection fraction and NP levels is poor,
with an area under the curve (AUC) of the receiver operated
characteristic (ROC) curve in the 0.6–0.7 ranges. This is
consistent with the known physiology of BNP, which reflects
ventricular stress rather than contractility or mass.
Diagnosing “diastolic dysfunction” in asymptomatic or
minimally symptomatic individuals is still a work in
progress, as age, gender, and gold standards for diastolic
dysfunction come into play. There is further discussion
below in the section on screening for cardiovascular
3.2. Caveats: low levels of natriuretic peptides
3.2.1. HF due to causes upstream from the LV
When HF is due to a cause upstream from the LV, for
example in mitral stenosis or acute mitral regurgitation, NP
levels may not be very high despite severe symptoms. The
absence of a significant rise in LV wall stress in these acute
settings explains the lack of marked NP production, and
while NP levels may still be higher than normal, they will not
rise to the same degree as when the HF occurs with a
concomitant overload on the LV. Similarly, pericardial
abnormalities, such as constriction and tamponade, can
sometimes cause symptoms of HF; however, since the
myocardial wall is not abnormally stressed, NP levels are
typically normal or only slightly elevated [54,55].
3.2.2. Flash pulmonary oedema
NP levels may be relatively low in patients presenting
with HF symptoms that develop abruptly, within approxi-
mately 1 h. In this setting, the time interval between the
initial trigger and the measurement of NP levels is so short
that it precedes the up-regulated peptide synthesis. Since
only very small quantities of BNP (compared to ANP) are
stored in secretory granules, the development of elevated NP
levels in “flash” pulmonary oedema is dependent upon the
de novo synthesis and secretion of the peptide . The
incidence of this phenomenon seems to be very low
[14,16,17]. Perhaps ANP levels might someday be a better
marker in this condition.
829A. Maisel et al. / European Journal of Heart Failure 10 (2008) 824–839
3.3. Practical points and recommendations
• A NP level can be used to quantify the severity of HF,
reflecting systolic and diastolic left ventricular dysfunc-
tion, as well as valvular heart disease and right ventricular
• Patients presenting with dyspnoea, especially of uncertain
origin, to emergency services should undergo a history,
physical examination, chest X-ray, ECG and blood should
be sampled for a NP and renal function measurement.
• NP level should be interpreted as a continuous variable.
When using cut-off values for BNP in patients with acute
dyspnoea, apply two values: one to “rule out” (b100 pg/
ml) and one to “rule in” HF (N400 pg/ml). When
considering BNP to rule in HF, chronic HF elevations and
non-HF pathology that may increase BNP must be
considered. The grey zone between 100 and 400 pg/ml
needs additional physician interpretation. When using
NT-proBNP, apply one rule-out value (b300 pg/ml) and
one of three rule-in values based on age. Other clinical
features may be of great assistance in obtaining the
diagnosis of HF.
• The rule-out values for both BNP and NT-proBNP in the
acutely dyspnoeic patient do not need to be adjusted for
age or sex. To optimize diagnostic accuracy with either
NP, adjustments should be made for renal dysfunction and
• The knowledge of a patient's baseline NP level may
further improve ED physician diagnostic accuracy.
• The grey zone is observed in 25% of dyspnoeic patients,
three-quarters of whom have HF as the ultimate
diagnosis. These patients usually have mild HF and a
• There appears to be a linear inverse relationship between
BMI and BNP levels. Patients who are obese
(BMIN30 kg/m2) should have their BNP doubled to use
the standard cut points. Alternatively, the rule-out value
for BNP in obese patients presenting with acute dyspnoea
is lower than the standard rule-out values. Thus far, there
have been no suggested corrections for NT-proBNP and
4. NP levels in the inpatient setting
One third or more of patients with a discharge diagnosis
of HF will be readmitted within 3–6 months and this
greatly adds to the cost of care [57,58]. Patients who are
admitted to the hospital with decompensated HF usually
respond symptomatically to treatment, but there has been
no good method to evaluate the relationship between acute
response and long-term outcome before NPs. The fact that
NPs have a short half-life, are easily measured, and
provide a quantitative marker of HF severity and
prognosis, suggests that they might be a useful guide to
therapy in acute HF.
Overall, the use of NP testing once a patient has been
admitted has been studied less extensively as compared to
the use in the ED. In particular, we lack data from
randomised controlled trials.
Although some studies question the relationship between
pulmonary artery wedge pressure (PAWP) and NP levels
[59–61], elevated levels commonly indicate an increased
PAWP in patients admitted with volume overloaded,
decompensated HF. Although this relationship has not
been duplicated in all evaluations, a treatment that reduces
PAWP will frequently lead to a fall in NP levels, as long as
the patient is maintaining an adequate urine output .
Conceptually, the NP level of a patient who is admitted
with decompensated HF is comprised of two components,
that of a baseline, optivolaemic (dry) NP level and that
occurring from acute pressure or volume overload (the wet)
NP level. At the point of decompensation, a patient's NP
Fig. 4. Wet versus optivolaemic BNP levels (optivolaemic = baseline).
830 A. Maisel et al. / European Journal of Heart Failure 10 (2008) 824–839
level is the sum of the baseline NP level plus what volume
overload adds (Fig. 4).
Blood levels of NPs rise to very high levels in the setting
of acute HF. Nevertheless, recent studies support the idea
that HF patients actually manifest a state of BNP
insufficiency, due to both a deficiency of biologically active
BNP and resistance to its effects . Evidence for a state of
deficiency comes from molecular analysis of BNP in
subjects with acute HF, which reveals two distinct circulating
forms of BNP: a high-molecular weight form, thought to be
the biologically inactive proBNP, and a low-molecular
weight form, the 32-amino acid active BNP . Abnormal
processing of proBNP into less active forms may also factor
into the state of relative BNP insufficiency .
Although there is little objective data defining why NP
levels do not decline in some patients despite treatment,
several clinical scenarios should be considered. First and
most importantly, a high NP level may actually be the
patient's optivolaemic (dry) NP level due to persistent
increased ventricular wall stress, even after resolution of
acute episodes of volume overload. It is also possible that
with excessive parenteral diuretic treatment, intravascular
dehydration results in a pre-renal state. While in normal
patients the kidney partially clears BNP and NT-proBNP,
with decreasing GFR, increased levels of both NPs are well
described. In fact, NP levels can be markedly elevated in
anephric dialysis patients, compared to those with normal
renal function. Therefore, worsening azotaemia from
excessive diuresis may result in increasing NP levels.
Another possible scenario is that a patient with concomitant
right-sided HF and significant ascites and/or oedema might
diurese many litres before NP levels actually drop. This is
likely due to mobilization of third-space fluid rather than
lowering of cardiac filling pressures. Continuing diuresis
and/or vasodilatation should eventually lower “wet” NP
levels. Finally, in some cases treatment simply does not
effectively reduce central cardiac haemodynamics and
therefore does not improve cardiomyocyte stress and one
should not expect to see a decline in this setting.
We suggest to measure NP levels routinely at the time of
admission and prior to discharge when optivolaemic status is
achieved. The latter measurement is supported by studies
the level measured at admission [66,67]. Repeat NP measure-
ments should be considered in the event of clinical deteriora-
tion or to evaluate adequacy of therapy, but is currently not
indicated in the vast majority of inpatients with HF.
Some studies have found that the lower the discharge
optivolaemic NP level is, the lower the risk of death and
re-hospitalisation [66,67]. We suggest that this is because a
relatively low NP level usually represents a more stable
patient (NYHA I–II) and one that is more likely to be in a
true euvolaemic state. However, the literature is not
consistent and a precise relationship between discharge
BNP levels and long-term outcomes is unclear. Some large
clinical trials report that despite a reduction in mean BNP
there were no differences in long-term benefits [68,69]. In
the randomised IMPROVE-CHF study, with follow-up NP
data available, clinical benefit was demonstrated. Unfortu-
nately there was limited investigation as to how the data
was used to guide therapy, and the authors hypothesized
that the majority of benefit derived from accurate HF
detection at the time of presentation. It is still debated
whether the baseline or final NP is the most important
parameter for hospitalised patients, or whether they may
reflect similar information since the range of “risk” can be
quite large and should be interpreted as a continuous
variable. Overall, we believe that knowing a patients'
baseline optivolaemic NP level is likely to be important in
monitoring the patient in the first thirty days after
While some studies have shown that a relative drop
(approximately 30%) in the NP level is associated with a
good short-term prognosis , the absolute NP level at
discharge appears to be a better reflection of the state of the
ventricle and whether optivolaemic status has been reached
(b350 pg/ml for BNP and b4000 pg/ml for NT-proBNP). A
patient in whom NP has risen during hospitalisation or has
dropped but is still in the 600–700-pg/ml range for BNP and
N7000 pg/ml for NT-proBNP at discharge has an increased
risk of cardiovascular events . Changing therapy based
on measured NP levels has not yet been shown to be
beneficial, but more aggressive monitoring and therapy may
be wise. Pre-discharge NP levels appear to be more cost-
effective than comprehensive Doppler-echocardiographic
examination for the prediction of future cardiac death or HF
4.1. Practical points and recommendations
• NP levels substantially above previous levels (N50%)
usually reflect volume overload.
• A patient admitted with acute breathlessness due to HF
and a high BNP level (generally N600 pg/ml for BNP and
6000 pg/ml for proBNP) usually has high filling pressures
secondary to volume overload, and a treatment-induced
decrease in PCWP will commonly lead to a rapid drop in
• Altered forms of BNP might account for some of the
apparent increase in BNP levels measured with conven-
tional assays in patients with decompensated HF.
• NP levels should always be interpreted together with a
measure of renal function.
• NP levels should be measured routinely on admission and
prior to discharge when the patient is considered
• While a drop in NP level in response to treatment is
important, the final NP level seems to be the most
accurate predictor of death or readmission.
• BNPb350–400 pg/ml or NT-proBNP b4000 pg/ml at the
time of discharge, especially in the setting of optivolae-
mia, predicts a stable post-hospital course.
831A. Maisel et al. / European Journal of Heart Failure 10 (2008) 824–839
• If NP levels fail to decrease with appropriate and
intensive therapy or remain elevated at the time of
discharge, anticipate a poor prognosis. Consider more
aggressive in-hospital treatment and careful post-dis-
5. The use of NP levels in the intensive care unit
The diagnostic problems in the intensive care unit (ICU)
are at least as challenging as in the ED. Major differences in
patient characteristics, disease severity, co-morbidity, and
therapies between the ICU and the ED require that the
potential clinical use of NP levels in the ICU be defined by
specific ICU studies.
Despite decades of clinical use of invasive haemody-
namic measurements and echocardiographic examinations,
we are just beginning to appreciate the syndrome of HF in
the ICU. While NP levels seem to have high accuracy in the
identification for cardiac dysfunction in the ICU, the rule-out
levels may be higher, around N150 pg/ml in the case of BNP,
to maintain specificity . In a consecutive series of ICU
patients, a BNP of b150 pg/ml had a negative predictive
value of 97% for the presence of cardiac dysfunction.
Because patients with cardiac pulmonary oedema have
substantially higher NP levels than patients with the acute
respiratory distress syndrome, NP levels are fairly accurate
(AUC 0.8) in the differential diagnosis of cardiogenic versus
non-cardiogenic pulmonary oedema .
NP levels are elevated not only in cardiogenic shock, but
also in severe sepsis and septic shock. This is most likely due
to sepsis-induced inflammatory myocardial dysfunction
. Furthermore, NP levels do not reliably predict
pulmonary capillary wedge pressure in consecutive ICU
patients, even less so in patients with shock [74,75]. Thus,
NPs DO NOT seem to be useful diagnostically when the
differential diagnosis includes shock of any type .
NP levels may assist in ventilator weaning. Plasma NP is
higher in patients who fail a weaning trial as compared to
those with successful weaning . It may also identify
patients in whom treatment should be intensified or changed
prognostic information regarding perioperative complication
rates in patients undergoing cardiac or vascular surgery, and
predict length of stay, morbidity, and mortality .
In conclusion, despite a clear clinical need, currently
available data are insufficient to define precisely the role of
NP levels in the clinical ICU routine. Diagnosis of
respiratory failure and timing of extubation seem to be the
most promising indications .
5.1. Practical points and recommendations
• NP levels identify cardiac dysfunction in the ICU but at
higher rule-out values.
• NP levels may be useful in distinguishing between
cardiogenic and non-cardiogenic pulmonary oedema.
• NP levels are elevated in severe sepsis, septic shock, and
cardiogenic shock. Therefore, they are not useful in the
differential diagnosis of shock. NP levels cannot reliably
predict PCWP in those conditions.
• NP levels may be helpful in the timing of extubation.
• NP levels predict perioperative cardiac complications.
6. Monitoring NP levels post-hospitalisation: implications
for NP-guided outpatient treatment
6.1. Variability and decompensation
Interpretation of NP levels requires an understanding of
the variability of these peptides. When a change in a NP
level is not accompanied by a change in clinical status, this
might reflect biological variability or a change in cardiac
or renal function that has not yet resulted in symptoms or
signs. As a result of both analytical and biological
variabilities (haemodynamic, renal, etc.), reference change
values (RCV) have been reported to be large for both BNP
and NT-proBNP, varying from 40–130% [79–81]. As
these studies assumed that unchanged symptoms equalled
unchanged cardiac status, considerable uncertainty
remains regarding these estimates. As emphasized for all
indications, incorporating the NP measurement into the
overall clinical assessment is also very important in the
outpatient setting. For patients in a heart failure pro-
gramme who have NP levels measured when stable, an
increase in NP of e.g. 50% over baseline values
accompanied by appropriate symptoms and signs confirms
a clinical diagnosis of decompensation.
It must also be considered that less than a 50% change in
NP level may be within the range of biological variability in
some patients, and not representative of a clinical event. In
establishing whether a patient has worsening heart failure
one needs to be aware of their optivolaemic NP level before
interpreting a value in the setting of possible clinical
deterioration. Although there is limited evidence-based
data to support the impact of hospitalisation avoidance
with NP levels, the consensus of authors suggest that one of
the best ways to keep a person out of the hospital is not to let
the discharge NP level rise. Early after discharge, elevations
in NP levels are often associated with volume overload and
diuretics may need adjustment.
The combination of symptoms, weight gain, and NP
levels may be the best way to diagnose early decompensa-
tion. A proposed algorithm for detecting decompensation is
illustrated in Fig. 5 (right-hand figure) for patients perform-
ing daily weight monitoring in a telemedicine programme.
Please note that the cut-off values suggested are to a large
extent not based on prospective studies, but on expert
opinion on how to balance possible variability against
prospective data indicating that changes in NP of as little as
25% do have prognostic importance. If weight is increased
and either shortness of breath or oedema is present, an
adjustment in medications (usually diuretics) is made over
832A. Maisel et al. / European Journal of Heart Failure 10 (2008) 824–839
the telephone. If not present, a NP level is drawn in the lab or
possibly in the near future, by finger-stick at home. In HF
patients, a 50% increase over their optivolaemic baseline is
considered significant and requires intervention. A 25–50%
increase calls for continued clinical judgment and considera-
tion of the biological variation of NPs. When the increase in
NP level is negligible (b25%), other causes of weight gain
are sought. A similar algorithm can be used in patients
presenting to clinics with worsening symptoms of HF
(Fig. 5, left-hand figure). As for inpatients, proper adjust-
ment of HF management requires NP to be measured
together with renal function.
6.2. Outpatient titration
The relationship between the drop in the NP level and the
improvement in patient's symptoms and subsequent out-
come suggests that NP-guided treatment might assist in
adjusting chronic therapy. There are precedents for using
surrogates to titrate treatment in conditions such as
hypertension (measuring blood pressure), diabetes (glucose
and haemoglobin A1c measurements), kidney disease
(creatinine), and lipid disorders (lipid profile). But thus far
there has been no effective surrogate for HF treatment that is
reliable, objective, easy to use, and cost-effective. Since NP
levels may reflect end-diastolic wall stress, which is elevated
by both increased filling pressures and by LV dilation ,
measuring serial levels over time may provide a way, in
conjunction with clinical acumen, to monitor the effects of
drug therapy on LV remodelling .
In a pilot study of 69 patients with HF and systolic LV
dysfunction randomised to receive therapy guided by NP
levels or standard care, NP-guided treatment reduced total
cardiovascular events and delayed time to first event .
Similarly, the STARS-BNP trial, a multicentre study under
the auspices of the Heart Failure working group of the
French Society of Cardiology conducted a randomised trial
to assess the benefits of titration of therapy in an attempt to
achieve BNP values of b100 pg/ml. They showed that this
approach reduced the composite primary endpoint of HF
deaths and HF hospitalisation  compared to guideline-
directed therapy. The authors suggested that 300 pg/ml was a
more attainable and still useful target BNP level to aim for,
rather than 100 pg/ml. While we recommend that the best
Fig. 5. Algorithms for outpatient management.
833 A. Maisel et al. / European Journal of Heart Failure 10 (2008) 824–839
outcomes may be obtained by driving the BNP to b100–
300 pg/ml, this is based on extrapolation and the most
appropriate way to achieve this goal remains under
discussion as higher diuretic doses may lead to the
possibility of worse outcomes as well. Furthermore, the
precise ranges and time intervals of testing are still under
intense investigation. Results of currently enrolling studies
will help to define these parameters. Not all studies have
demonstrated that changes in BNP levels are associated with
improved outcomes. In a study by Miller et al.  190
patients were followed for 2 years with serial BNP measures.
The authors noted that an elevation of BNP from normal, at
any time during the study, was associated with a poor
outcome. However, once BNP was elevated, further changes
(either increases or decreases) remained associated with the
same risk of adverse events (hazard ratio, 5.09; Pb0.001).
It is possible that NP-guided therapy is successful simply
because it serves as a reminder to physicians to give
evidence-based treatment; in the previously mentioned
STARS-BNP trial many patients were not yet receiving
appropriate doses of guideline-directed therapy. The rele-
vance of these trials is generally limited by the selective
enrolment of relatively young patients with systolic HF and
little co-morbidity. Ongoing studies will provide further
insights into the potential benefit of NP-guided therapy in
older populations and in the elderly with diastolic HF .
It appears that ACE inhibitors, angiotensin receptor
blockers, spironolactone, and perhaps long-term beta-blockers
(in the short-term beta-blockers increase NP levels) drive NP
levels down [8–93]. In the Valsartan Heart Failure Trial (Val-
HeFT) and CARE-HF studies, changes in BNP over time
induced by pharmacological or device therapy were shown to
predict morbidity and mortality better than initial values
[92,93]. From an economic perspective, there are currently
insufficient data to determine whether regular assessment of
NP levels is cost-effective for outpatient titration . Finally
an important analysis from the COMET trial demonstrated the
prognostic importance of plasma NT-proBNP in chronic heart
failure patients taking beta-blockers .
6.2.1. Key findings
• NP levels are commonly reduced by treatment with
diuretics, ACE inhibitors, angiotensin receptor blockers,
aldosterone antagonists and cardiac resynchronization
therapy (CRT). Beta-blockers may increase NP levels in
the first weeks and months after administration but after
6–12 months may cause NP levels to fall.
• Several small controlled trials using NP-guided therapy
demonstrate a significant reduction in the primary
combined endpoint of HF death and re-hospitalisation.
• Regular assessment of renal function is required to avoid
deterioration in renal function when using this approach.
6.2.2. Practical points and recommendations
• NP levels drawn early after discharge may confirm the
adequacy of outpatient therapy. Increases in NP levels
following hospital discharge may reflect inadequate
• There is considerable day-to-day variation in NP levels. A
50% increase in NP levels, compared to those taken when
the patient was stable, suggests decompensation when
appropriate symptoms and/or signs are present. An
increase of 25–50% may represent decompensation but
clinical judgment should be the deciding factor. An
increase in NP level of b25% (or a decrease) may be the
result of biological variation unrelated to a change in
clinical status and suggests that decompensation has not
occurred or may be reflective of early physiological
changes. Ultimately clinical judgment must adjudicate
these possibilities. The baseline sample should be drawn
when the patient is clinically stable to permit interpreta-
tion in this manner.
may be the best way to predict early decompensation.
• Tailoring therapy to achieve a target BNP/NT-proBNP is
a promising approach but further research is required.
6.3. Screening for sub-clinical disease
Many people with substantial LV dysfunction do not have
symptoms [95–97] but might be identified by a simple
screening test such as BNP/NT-proBNP. Although echocar-
diography is the current gold standard for detection of LV
dysfunction and many other structural cardiac abnormalities,
its cost and limited availability make it an impractical choice
for mass screening. Also, the echocardiographic detection
and quantification of LV diastolic dysfunction can be
challenging in clinical practice.
The success of a population-based screening pro-
gramme for a disease condition is dependent on disease
prevalence, the availability of a screening test that is
acceptable, safe and inexpensive, the presence of effective
treatment for detected disease, as well as the existence of,
and compliance with, a follow-up care system for people at
risk or with positive tests [98,99]. NPs are attractive
candidates for screening the general population for sub-
clinical disease for several reasons. First, LV dysfunction
and the other cardiovascular diseases that are detectable by
elevated NP levels are common and cause significant
morbidity and mortality . Second, NP levels may be
elevated early in the disease process, allowing for timely
detection of disease prior to symptom onset . Third,
early treatment of latent disease with medications such as
angiotensin converting enzyme inhibitors improves out-
comes by preventing the development of symptomatic HF
. Finally, several studies have shown that, in the right
setting, screening with NPs may prove cost-effective
Several investigations have evaluated the use of NP
levels to identify asymptomatic subjects with poor
ventricular function. Most concluded that due to the
relatively low prevalence of disease, the best potential
834 A. Maisel et al. / European Journal of Heart Failure 10 (2008) 824–839
application for NPs is to utilize their high negative
predictive value for “ruling out” disease [106–108].
Other studies looking to screen for a broader range of
sub-clinical cardiovascular disorders also found excellent
negative predictive value .
NPs may be useful for detecting a range of clinical
disorders. In the Framingham Offspring Study of 3346
asymptomatic middle-aged subjects, Wang et al. found that
BNP levels independently predicted mortality, heart failure,
stroke or transient ischaemic attack, and atrial fibrillation,
even after adjusting for traditional risk factors . BNP
levels above the 80th percentile (~20 pg/ml) carried a 62%
increased risk of death and a 76% increased risk of a first
major cardiovascular event. With each increment of one
standard deviation in log BNP levels, there was a 27%
increase in risk of death, a 77% increase in risk of HF, a
66% increase in the risk of atrial fibrillation, and a 53%
increase in the risk of stroke or transient ischaemic attack.
Thus, even small elevations of BNP levels (in the 20–
100 pg/ml range), significantly less than traditional cut
points for acutely dyspnoeic patients, may serve as an early
warning sign, aiding in the timely detection of cardiovas-
screening the population for asymptomatic left ventricular
dysfunction (ASLVD) alters the natural history of the
for other conditions have shown in a randomised trial that
6.3.1. Practical points and recommendations
• NP testing might be appropriate for screening large
asymptomatic populations for left ventricular systolic
dysfunction either at low or high risk (post-MI patients,
diabetic patients, poorly controlled hypertension, people
aged N70 years) with echocardiographic assessment of
patients with high levels.
• Optimal cut points for excluding HF in the office are BNP
b20 pg/ml and NT-proBNP: 125 or 450 pg/ml for b75
and N75 years of age.
7. BNP in current guidelines
As with every new diagnostic or treatment modality,
there is often a lag between the evidence and the
integration into national and international guidelines.
However, it is very encouraging to see that only a few
years after introduction into clinical practice, all major
cardiovascular guidelines recommend the use of NP levels
in some context.
8. Directions for future research
While there have been significant strides in NP research
over the past five years, there are still many important areas
to explore. The following is a partial list of research needs
with regards to NP levels.
8.1. Emergency department
• Define target values for NP levels for response to therapy
in the ED.
• Randomised clinical trials (RCT) to evaluate safety and
efficacy of NP-guided management regarding hospital
admission versus ED management.
• Determine whether NP levels, used in a multimarker
panel, may aid in the early diagnosis or rule out of ACS.
• Better define caveats for using NPs for the diagnosis/
management of HF in the very elderly.
• Determine if the use of NPs in the pre-hospital arena by
emergency medical technicians results in improved
8.2. Diastolic function
• Use NP levels for patient inclusion in studies evaluating
treatment of patients with diastolic dysfunction.
• Explore the combination of a NP level plus echocardio-
graphy as a potential gold standard for the diagnosis of
• Better define cut points for establishing severity of
8.3. Inpatient monitoring of NP levels
• Define target values for NP levels for response to therapy.
• Conduct RCT to evaluate safety and efficacy of NP-
guided hospital management regarding treatment and
• Determine the value that NP levels can serve as a
surrogate for dyspnoea in clinical trials.
8.4. Outpatient monitoring
• Determine the value of NPs for deciding on the strategy of
care (i.e. persistent high NP leads to intensive specialist
follow-up; low NP leads to more community physician
and HF nurse follow-up).
• Conduct further RCTs to evaluate safety and efficacy of
• Determine whether reduction in NP levels (absolute or
percent reduction) or achieving a target level is the most
appropriate treatment goal.
• Determine if patient-directed NP-guided treatment
is feasible, cost-effective and results in improved out-
comes (similar to glucose monitoring in diabetics).
• Conduct studies to demonstrate that screening-using NP
improves patient outcome.
835 A. Maisel et al. / European Journal of Heart Failure 10 (2008) 824–839
8.6. Acute coronary syndromes
• Use of NP to stratify risk and target high-risk patients
needing aggressive intervention.
NP levels can help clinicians manage patients in a great
exclude cardiovascular disease, for the differential diagnosis
of symptoms that might be due to HF and are astonishingly
powerful prognostic tools. Each assay gives different values
for BNP and NT-proBNP and the clinician should become
familiarwithjust one, at least initially.Plasma concentrations
should be interpreted in the context of the clinical setting and
in conjunction with a test of renal function. Serial measure-
ment determines whether a patient's prognosis has changed
in response to therapy but it is not yet clear whether and how
this should be used to guide treatment.
Alan Maisel, MD — Research support: Roche, Biosite,
and Bayer. Consultant: Biosite.
Christian Mueller, MD — Research grants: The Swiss
National Science Foundation, the Swiss Heart Founda-
tion, the Novartis Foundation, the Krokus Foundation,
Abbott, Biosite, BRAHMS, Roche, and the University of
Kirkwood Adams Jr, MD — No conflicts.
Stefan Anker, MD, PhD — Consultant/research grants:
BRAHMS, and Roche Diagnostics.
Nadia Aspromonte, MD — No conflicts.
John GF Cleland, MD — Research support: Roche.
Alain Cohen-Solal, MD, PhD — Honorarium: Biosite.
Anthony DeMaria, MD — Research support: GE
Salvatore DiSomma, MD — Consultant: Biosite.
Ulf Dahlstrom, MD — Research support: Biosite.
Gerasimos S. Filippatos, MD — Research support:
Biosite, BRAHMS, and Roche.
Gregg C. Fonarow, MD — Research support, consultant,
Patrick Jourdain, MD — No conflicts.
Michel Komajda, MD — No conflicts.
Peter P. Liu, MD — No conflicts.
Theresa McDonagh, MD — No conflicts.
Kenneth McDonald, MD — Honorarium: Biosite.
Alexandre Mebazaa MD, PhD — Honoraria: Biosite.
Markku S. Nieminen, MD — Consultant: Scios,
Medtronic, St. Jude, Orion Pharma, Abbott, Bayer, and
W. Frank Peacock, MD — Scientific advisory board:
Abbott, Beckman-Coulter, Biosite, Inverness, Ortho Clinical
Diagnostics, and Response Biomedical. Research grants:
Abbott, Biosite, and Inverness.
Marco Tubaro, MD — No conflicts.
Roberto Valle, MD — No conflicts.
Marc Vanderhyden, MD — No conflicts.
Clyde W. Yancy, MD — Research support: Scios. Con-
sultant: Biosite and Scios.
Faiez Zannad, MD, PhD — I have participated
occasionally (max 2–3/year) in symposia/advisory board
meetings/consultancies for the following companies for
which I receive an honorarium (always b$10,000) and
reimbursement of travel-related expenses. Daiichi Sankyo,
Pfizer, Otsuka, Servier Novartis, and Boehringer Ingelheim.
Eugene Braunwald, MD — Chairman of the TIMI Study
Group at the Brigham and Women's Hospital. Salary
derived entirely from the TIMI Study Group Account at
the Brigham and Women's Hospital: AstraZeneca Pharma-
ceuticals LP, Johnson & Johnson, Bristol Myers Squibb
Pharmaceutical Research Institute, CV Therapeutics, Eli
Lilly, Genentech, Integrated Therapeutics Group, Merck &
Co., Inc., Novartis, Pfizer, Inc., Roche Diagnostics Corp.,
Sanofi Aventis, and Schering-Plough Research Institute.
Honoraria/advisory board/consultant: Bayer AG, Daiichi
Sankyo, Eli Lilly, Merck & Co., Momenta, Pfizer, DLA
Piper Inc (Law firm representing Pfizer), Schering-Plough,
and Sanofi Aventis.
Special thanks to Scott Mader and CLINDEVOR360, Inc
for assisting in the trafficking, editorial process and
management of this project and the interchange among this
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