The role of NT-proBNP in the management of suspected heart failure

disease focus
C ardiovascular Disease
As published in CLI - September 2006
The role of NT-proBNP in the management
of suspected heart failure
by Dr P. Hildebrandt
Chronic heart failure is often under- or mis-diagnosed due to lack of diagnostic resources. Measurement of NT-proBNP level
for screening patients with symptoms suggestive of chronic heart failure has been shown to have a very high sensitivity and
an acceptable specificity, making it ideal for such screening, as well as allowing a reduction in the number of echocardiographies
carried out. In acute heart failure patients NT-proBNP level has proved to be very valuable for clinicians making decisions
on appropriate action at initial presentation, during treatment and at discharge. In the acute setting additional markers
such as troponin T, CK MB and haemoglobin are frequently indicated for evaluating other cardiac conditions, e.g. myocardial
infarction. These analyses can be carried out either on a laboratory platform or using PoC testing.
One of the major challenges in modern cardiology
is the appropriate treatment of heart failure
patients. Heart failure can occur in chronic (CHF)
[1] and acute (AHF) forms [2], the latter including
patients with de novo heart failure as well as
patients with an acute exacerbation of CHF. Both
of these disease expressions present the clinician
with diagnostic and screening challenges, for
which levels of B-type natriuretic peptides have
proved to be valuable.
Chronic heart failure (CHF) - background
The aetiology of CHF is most often ischaemic, but
the condition can also be the result of hypertension
or valve diseases. CHF is a common disease
with a prevalence of approximately 1% of the
population, a prevalence which is increasing, presumably
due to better treatment of patients with
acute heart failure as well as ischaemic heart disease,
leading to an increased survival of patients
with chronic heart disease. CHF is a serious disease
with a very high risk of mortality, equivalent
to many cancers, and is furthermore an expensive
disease for society because of the many hospital
readmissions. On the positive side, the emergence
of modern pharmacological and mechanical treatment
options has reduced morbidity and mortality.Unfortunately,
a major problem in the management
of heart failure is the large incidence of
under- and mis-diagnoses.
Chronic heart failure - definition and diagnosis
The most commonly used definition of heart failure
is the presence of symptoms suggestive of
heart failure (most often dyspnoea, peripheral
oedema or fatigue) as well as objective evidence of
impaired cardiac function. The most commonly
used method for evaluation of cardiac function is
echocardiography, an investigation which requires
expensive equipment and trained sonographers.
Because the symptoms of heart failure are rather
nonspecific, and also occur in other illnesses and
in deconditioning, there is a risk that patients will
not be appropriately investigated. The diagnosis
of heart failure may be missed, or patients diagnosed
with heart failure without proper evaluation
may be treated for the condition when they
are not suffering from it.
In order to identify patients with heart failure
some algorithms have been used but without great
success. Symptoms and electrocardiography
(ECG) have been used most frequently for screening.
During recent years biochemical markers
have been evaluated for screening purposes, especially
neurohormonal markers, as in heart failure
the neurohormonal system in general is activated.
The ideal marker should be effective for screening,
have a high sensitivity, have prognostic impact, be
stable and simple to use and
not be too expensive. More
recently some very useful
markers have emerged,
namely the natriuretic peptides.
The natriuretic peptides
The natriuretic peptides
have been known for
decades, especially atrial
natriuretic peptide (ANP)
and brain or B-type natriuretic
peptide (BNP). After
commercial analysis became
available, information on the
use of these markers in clinical
practice increased substantially.
From a clinical
point of view the interest is mainly concentrated
on BNP and its inactive stable split product N-terminal
pro-BNP (NT-proBNP). BNP is secreted
from the left ventricular myocardium and to a
lesser degree from the atria and the right ventricle,
the stimulus for secretion being wall stress.
Studies have shown that BNP and NT-proBNP are
very effective prognostic markers of cardiovascular
morbidity and mortality for many cardiovascular
diseases in several populations [3], but currently
their role as risk markers has not yet been
established in the clinic. The current use of BNP
and NT-proBNP is primarily concentrated on
screening for acute and chronic heart failure.
Natriuretic peptides and CHF
As mentioned previously one of the main problems
in CHF patient management is the effective screening
of symptomatic patients prior to carrying out further
diagnostic procedures. Measurement of BNP and
Figure 1. Screening strategy for patients poresenting with symptoms of CHF.

Figure 2. Proposed use of NT-proBNP in AHF patients.
NT-proBNP levels have been shown to be highly suitable
for this purpose.
Generally speaking heart failure is caused by systolic
failure, diastolic failure, heart valve disease and
arrhythmias. The most frequent, and best evaluated
cause of the condition in terms of diagnosis and
treatment, is systolic failure.
Several investigations demonstrate that systolic heart
failure with normal BNP / NT-proBNP level is very
unusual, although it is observed in rare cases of
patients with CHF and reduced systolic LV function,
who are asymptomatic or only slightly symptomatic
when given optimal heart failure treatment.
In patients with symptoms suggestive of heart failure,
who are referred for echocardiography by general
practitioners, an elevated BNP / NT-proBNP level
below the cut-off value of 125 pg/mL has been generally
validated for ruling-out CHF, with a sensitivity for substantial
cardiac dysfunction and systolic dysfunction of
97 - 100% and a specificity of approximately 50% [4, 5].
This very high sensitivity results in a very low risk of
overlooking patients with heart failure, which is
required for a good screening method. One essential
reason for this screening value is the fact that BNP / NTproBNP
levels are normal even in patients with severe
pulmonary disease. It is only necessary to carry out
echocardiography in patients with values above the
aforementioned cut-off levels, which would be cost
effective as it could result in approximately 40% less
echocardiographies being carried out.
As mentioned previously, several investigations have
demonstrated the very high prognostic
value of measuring BNP /
NT-proBNP levels in mild as well
as severe heart failure. In most of
these studies the prognostic value
is considerably greater than with
traditional risk markers for this
disease, which include New York
Heart Association Class and LV
ejection fraction. The very high
prognostic value of measuring
BNP / NT-proBNP levels supports
the use of such screening, as
an increased level is highly indicative
that further investigation is
warranted, in order to find a
potentially reversible cardiac aetiology
or to intensify the treatment
being given. Screening
according to the scheme shown
in Figure 1 is relevant for patients presenting to the GP
with symptoms of CHF. Tests can be carried out in
either the central laboratory, or at the point of care.
Alleged errors
It is important to stress that BNP / NT-proBNP levels
increase with age even in subjects without cardiac disease
[6]. The reasons for this could be the age-related
changes which occur in the metabolism of natriuretic
peptides, age-dependent changes in the heart, or the
decrease in renal function which occurs with age. It is a
subject of discussion whether the cut-off values for
screening symptomatic patients should be age-dependent,
but until now no consensus concerning this has
been reached. BNP / NT-proBNP levels increases with
decreasing renal function, primarily in patients with
serum creatinin levels above 200 mol/L. In general values
are higher in females than males and lower in obese
subjects, though the magnitudes of these differences are
fairly small and are of minimal importance in clinical
screening. Values are increased in patients with left
ventricular hypertrophy, atrial fibrillation, severe aortic
stenosis and presumably also with milder form of aortic
stenosis, as well as in patients with other valve diseases.
BNP / NT-proBNP levels are influenced by medical
treatment, thus ACE inhibitors, angiotensin II antagonists,
spironolactone and diuretics reduce the level, while
betablockers induce a very small increase or decrease.
Natriuretic peptides in monitoring therapy
A promising new application for NT-proBNP measurement
in CHF could be its use in guiding and
monitoring treatment. Several studies on this topic
are ongoing, utilising laboratory platforms as well as
point of care testing. In an ongoing study in the
Danish Network of Heart Failure Clinics stable CHF
patients are randomised for follow up by GPs, follow
up by Heart Failure Clinics with standard care or follow
up in Heart Failure Clinics utilising NT-proBNP
level, measured either by the Elecsys platform or
using the Roche Cardiac proBNP test.
Acute heart failure (AHF)
Admissions for AHF are frequent and expensive. In
Denmark the annual admission rate is approximately
2 per 1000 inhabitants, making AHF the fourth
most costly disease for hospitals. A rapid and effective
diagnosis, prompt and effective treatment and a
reduced hospital stay are important for both improving
the prognosis and reducing costs. In order to do
this it is important that dyspnoea due to AHF and
dyspnoea resulting from another disease (usually a pulmonary
disease) can be differentiated in the emergency
room. This differentiation has generally been made
based on clinical judgement, but recently measurement
of NT-proBNP levels has been shown to very helpful
either alone or combined with clinical judgement [7].
This has been demonstrated in academic settings, but
its value would presumably be even greater in more
rural areas, where there are fewer trained doctors in
emergency rooms.
It has been proposed that by utilising NT-proBNP
level, patients can be divided into three groups: one
group with a high level of NT-proBNP (>450 - 1800
pg/mL, dependent on age) and a very high risk for
AHF, one group with a low NT-proBNP (< 300 pg/mL,
age-independent) and very low risk for AHF, and a relatively
small intermediate grey zone group. Using these
values results in a high sensitivity of 90 - 95% while still
retaining a good specificity of 60% [7], the sensitivity
being highest in younger subjects.
The Basel study [8] demonstrated that BNP guided
management of AHF resulted in significantly shorter
in-patient hospital stays, and lower costs of approximately
80% of usual patient management costs.
A proposal for the use of NT-proBNP level in AHF
patient management [based on 7] is shown in Figure 2.
It is of importance that the cut-off values for NTproBNP
level are in general three times higher than the
cut-off values for patients with chronic heart failure. If
NT-proBNP level is used for this purpose, tested either
in the central lab or in a PoC setting, results should be
rapidly available to allow a quick decision on the need
for admission and treatment, and to optimise patient
management for maximum benefit.

Central analysis or Point-of-Care (PoC) testing
NT-proBNP measurement can be carried out either on
laboratory platform or using PoC testing, according to
the local logistics. The recently developed Roche
Cardiac proBNP shows excellent correlation with the
laboratory method.
One potential draw-back for PoC testing could be the
measuring range of up to 3000 pg/mL only. However
when used as a screening test for CHF this is of no
importance, as patients with values above 125 pg/mL
(or perhaps somewhat higher in older patients) should
undergo additional cardiac evaluation. The use of
either a laboratory platform or PoC testing should primarily
depend on local tradition and logistics, e.g. it
could be time-saving for the patient to have the PoC
test in the GP’s or the specialist’s facility.
Using a laboratory platform or PoC testing in the acute
setting has advantages and disadvantages, the primary
advantage of PoC testing being the speed of analysis,
allowing the result to be available rapidly enough for
acute decisions to be made. If the result from the central
laboratory is quickly available this is equally satisfactory.
The measurement upper limit of only 3000 pg/mL is not
a problem in acute evaluation of the patient. In further
patient work-up, especially if NT-proBNP guided follow
up is warranted, the upper cut-off limit could be a problem
and the use of a laboratory platform could be
necessary.
Conclusions
Sufficient evidence exists from measurement of
NT-proBNP level in patients with suspected heart
failure to support the implementation of this
screening test in patients with symptoms suggestive
of chronic heart failure. Further diagnostic tests
such as echocardiography only need to be performed
in patients with elevated levels of NTproBNP.
In patients with acute dyspnoea, there is
substantial evidence supporting the use of NTproBNP
level to aid in decisions on treatment, hospitalisation
and discharge. NT-proBNP level can be
measured either in a centralised lab or point of care
setting, according to local practice and convenience.
References
1. The Task Force on Chronic Heart Failure of the
European Society of Cardiology. Executive summary of
the Guidelines on the diagnosis and treatment of Chronic
Heart Failure. Eur Heart J 2005; 26: 1115-40.
2. The Task Force on Acute Heart Failure of the European
Society of Cardiology. Executive summary of the
Guidelines on the diagnosis and treatment of Acute Heart
Failure. Eur Heart J 2005; 26: 384-416.
3. Kistorp C, Raymond I, Pedersen F et al. N-terminal probrain
natriuretic peptide, C-reactive protein an urinary
albumin levels as predictor of mortality and cardiovascular
events in older adults. JAMA 2005; 293: 1609-16.
4. Gustafsson F, Steensgaard-Hansen F, Badskjaer J,
Poulsen AH, Corell P, Hildebrandt P. Diagnostic and prognostic
performance of N-terminal proBNP in primary
care patients with suspected heart failure. J Card Fail 2005;
11(5 suppl): S15-20.
5. Zaphiriou A, Robb S, Murray-Thomas T, Mendez G,
Fox, McDonagh T, Hardman SM, Dargie HJ, Cowie MR.
The diagnostic accuracy of plasma BNP and NT-proBNP
in patients reffered from primary care with suspected
heart failure: results of the UK natriuretic peptide study.
Eur J Heart Fail 2005; 7: 537-41.
6. Raymond I, Groenning BA, Hildebrandt P, Nilsson JC,
Bauman M, Trawinski J, Pedersen F. The influence of age,
sex and other variables on the plasma level of N-terminal
pro brain natriuretic peptide in a large sample of the general
population. Heart 2003; 89: 745-51.
7. Januzzi JL, Jr, Camargo CA, Anwaruddin S, Baggish AL,
Chen AA, Krauser DG, Tung R, Cameron R, Nagurney JT,
Chae CU, Lloyd-Jones DM, Brown DF, Foran-Melanson S,
Sluss PM, Lee-Lewandrowski E, Lewandrowski KB. The N-
terminal pro-BNP investigation of dyspnea in the emergency
department (PRIDE) study. Am J Cardiol 2005; 95:
948-54.
8. Mueller C, Scholer A, Laule-ilian K, Martina B,
Schindler C, Buser P, Pfisterer M, Perruchoud A. Use of B-
type natriuretic peptide in the evaluation and management
of acute dyspnea. NEJM 2004; 350: 647-54.
The author
Per Hildebrandt, DMSci,
Assistant professor,
Director of internal medicine and cardiology services,
Roskilde University hospital,
Kogevej 7 - 13,
DK-4000 Roskilde,
Denmark.
e-mail: rspehi@ra.dk