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National Public Health Service
Brain natriuretic peptide
Rapid review of the
evidence for targeted
brain natriuretic peptide
testing in the detection
of cardiac failure in
primary care
populations
Author: Dr M Webb, Public Health Practitioner
Date: October 2008
Version: 2
Status: Final
Intended Audience: Monmouth Local Health Board; Cardiac networks
Purpose and Summary of Document: Brain natriuretic peptide (BNP)
assays for ruling out heart failure may be more effective and cost effective if
targeted at certain ‘risk’ groups. The present document summarises the
evidence on effectiveness and cost effectiveness of targeted BNP testing for
three groups in which the patients have different risk factors and where
clinical suspicion would vary.
Publication/Distribution: ?
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Contents
Page
Number
EXECUTIVE SUMMARY
1. BACKGROUND
2. AIMS
3. RESEARCH QUESTIONS
4. METHODS
4.1 Identifying existing and ongoing research
4.1i Literature searching
5. RESULTS
5.1 BNP levels in cardiac and non cardiac diseases
5.2 Targeted diagnosis of heart failure in primary care
populations
5.3 Cut-off values and risk scores
5.4 Economic aspects
6 CONCLUSIONS
7 REFERENCES
Appendix 1 Main search strategy
Appendix 2 High level search strategy
Appendix 3 Evidence levels and quality grading
4
4
4
5
5
5
6
6
7
9
12
13
15
19
19
20
Copyright of this draft © 2008 National Public Health Service for Wales
All rights reserved
Any unauthorised copying without prior permission will constitute an
infringement of copyright.
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Glossary
ACS
AUC
BNP
NT-pro BNP
CE
CI
DOR
ECG
HF
HTA
LVSD
MI
QALY
SOB
Version 2
Author Dr Mary Webb
Acute coronary syndrome
Area under the curve
Brain natriuretic peptide
N terminal pro brain natriuretic
peptide
Cost effectiveness
Confidence interval
Diagnostic odds ratio
Electrocardiogram
Heart failure
Health technology assessment
Left ventricular systolic dysfunction
Myocardial infarction
Quality adjusted life year
Shortness of breath
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Executive summary





There is increasing interest in the use of brain natriuretic peptides
(BNP) to improve the diagnosis of heart failure (HF) in primary care and
to reduce inappropriate referrals to secondary care. Clinical guidelines
recommend the use of BNP assays in conjunction with other diagnostic
tests in primary care, but uptake in primary care has been slow.
Recently the practical application of BNP tests in primary care has
been questioned.
The cardiac networks in Wales have considered in detail the use of
BNP in primary care and have considered the suggestion made by
some cardiologists that BNP assays for ruling out HF are more
effective and cost effective if targeted at certain ‘risk’ groups. The
National Public Health Service was asked to perform a rapid review of
the literature to assess the evidence on effectiveness and cost
effectiveness of targeted BNP testing for three groups in which the
patients have different risk factors and where clinical suspicion would
vary.
Validated methods to maximise retrieval of Level 1 and Level 2
literature were used.
There was a lack of good quality evidence to answer the research
questions and most of the published studies were performed in
secondary care. Two good quality systematic reviews had been
recently published and these were used to inform the present evidence
review. Supplementary relevant evidence, not included in these two
reviews, was also appraised. The published literature clearly illustrated
the wide variation of BNP levels in both cardiac and non-cardiac
disease and with age and gender. The lack of defined cut-off BNP
values appeared to be contributing to the inconsistent evidence for the
effectiveness of BNP testing. Considerable efforts are being made to
clarify the issue of cut-off values and there was data indicating that with
a level of <100pg/ml that shortness of breath was unlikely to be due to
significant heart failure. The combination of risk scores with BNP
testing may be an effective approach.
The cost effectiveness studies were also inconclusive, but a good
quality systematic review with a comprehensive economic analysis,
indicated that diminishing returns could occur with BNP testing being
used in primary care and that the use of such assays should be limited
to patients in whom the cause of shortness of breath is very doubtful.
There was some data to suggest that hand held/portable
echocardiography may be potentially cost effective.
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1.
Brain natriuretic peptide
Background
In primary care the burden of heart failure (HF) is exacerbated by problems
with inaccurate diagnosis that may result in inappropriate referrals for
echocardiography. Echocardiography is generally recognised as the ‘gold
standard’ test.1 2, but in Wales, as in some other countries, the demand for
out-patient and in-patient echocardiography, both for HF and other cardiac
conditions already exceeds the capacity of current services.3
Some
guidelines suggest that brain natriuretic peptides (BNP) and N terminal pro
brain natriuretic peptide (NT-proBNP) and electrocardiography (ECG) can be
used as diagnostic tools to support general practitioners in their assessment
of patients with suspected heart failure and possible reduce the demand for
echocardiography. 1 4 Concern has been expressed however, that there is a
lack of good evidence that the use in primary care of BNP measurement, as a
filter for echocardiography, significantly reduces the number of referrals for
echocardiograms 5 6 and other international guidelines do not recommend
routine BNP testing. 7
The cardiac networks in Wales are considering the use of BNP to diagnose
HF in primary care and an Expert Group has produced several key
documents. 8 Recently the SE Wales Cardiac Network has suggested that
BNP testing may be more effective if it could be targeted at different risk
groups and has identified three groups of patients with different risk factors
and where clinical suspicion would vary.
2.
3.
Aims

To determine the evidence for the effectiveness and cost-effectiveness
of differential application of BNP testing for cardiac failure in primary
care populations presenting with clinically identified high, medium and
low risk symptoms.

To identify additional information for BNP cut-off points in each of the
risk groups and any data on portable echocardiography as an
alternative or adjunct to the diagnosis of heart failure.
Research question
The aims in Section 2 were converted to structured questions for searching
using the Population, Intervention, Comparison and Outcome (PICO) 9 format
Populations: High risk - Patients with shortness of breath (SOB) and a history of
myocardial infarction and other coronary heart diseases who would
‘always’ require full assessment with echocardiography.
 Intermediate risk - Patients with SOB and hypertension with abnormalities
on ECG.
 Lower risk - Patients with SOB and no known heart failure risk factors
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Intervention – BNP assay in primary care.
Comparators – standard clinical assessment; ECG
Outcome – reduction in inappropriate referrals for echocardiography and/or
secondary care.
4.
Methods
4.1
Identifying existing and ongoing research
4.1. 1
Literature searching
Systematic searching:
As per the protocol contained in The Evidence Checklist 10 a scoping search
was initially performed to identify major papers on published evidence and
refine the final search strategy. For the present overview, search terms
contained in the search strategies were used from published reviews and they
were kept broad to maximise retrieval of references. The basic search
strategy is shown in Appendix 1. The amount and type of literature on BNP
testing necessitated the use of a pragmatic approach to searching for
evidence in order to achieve production of the review, within the very short
timescale for delivery. It is clear that there had to be a balance between
timeliness and rigour and high quality evidence and systematic reviews, metaanalyses, health technology assessments and clinical guidelines were
identified first. It should be emphasised therefore that this review is not a
systematic review of primary studies but is the result of searches for best
evidence.
High level searching: It is well known that the classical databases for
medical literature, such as Medline, do not adequately index all relevant
literature. The reviewer used validated methods that involved the use of
meta-search engines and other databases for ‘high level’ searching to quickly
identify relevant evidence. (Appendix 2)
For critical appraisal, the tables recommended for use in the National Institute
for Health and Clinical Excellence Guideline Development Methods manual 11
were modified to accept the type of studies identified for the use of BNP
testing in the diagnosis of HF. The data relevant to the research question was
entered into an evidence table. The quality of the evidence was graded using
the NICE hierarchy of evidence and the quality checklists. Evidence was
rejected if graded as poor quality, apart from where it was of Level 1 type (see
Appendix 3 for explanation of evidence grading system) and was highly
relevant to the questions. Due to practical limitations a single reviewer
performed the final selection, critical appraisal and data extraction.
Inclusion Criteria
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Adults presenting to primary care with symptoms described in the three risk
groups in Section 3.
Search period January 2000 – May 2008
Papers in English, German, French or Spanish
Interventions relating to the use of BNP testing in patient populations with
differing symptoms presenting to primary care with the possible diagnosis of
HF.
Randomised controlled trials (RCT)
Systematic reviews
Meta-analyses
Guidelines
Observational studies (where higher quality evidence was not available)
5.
Results
The scoping search revealed two recent high quality health technology
assessments (HTAs) /systematic reviews 12 13 (Level 1-) that were of
relevance and these were used extensively to inform the present report.
Other pertinent evidence, not included in these HTAs was also appraised.
5.1
BNP levels in cardiac and non cardiac diseases
For the effective use of BNP in patients with different symptoms suggestive of
HF, the levels of BNP in different diseases are relevant. In general, all the 21
cardiac diseases considered in one HTA12 were associated with an increase
in BNP and NT-pro BNP. These included diastolic dysfunction14 15, cardiac
decompensation 16acute right HF 17 and cardiac pulmonary oedema. 17 Acute
right HF without cardiac pulmonary decompensation was not related to BNP
concentration. Patients with cardiac pulmonary oedema had higher levels of
BNP than patients with obstructive lung disease. Patients with diastolic
dysfunction had raised BNP levels but they were not as elevated as patients
with systolic dysfunction. 14 15
.
Patients with acute coronary syndrome (ACS) had elevated NT-proBNP
levels, 18 but there was no difference between patients with and without
ischemic heart disease, unless the patients had cardiovascular risk factors. 19
20 Acute myocardial infarction (MI)19 21, or previous MI22 23 were associated
with increased levels of BNP. Stable angina was not associated with a
difference in B-type natriuretic peptides in one study 19 that included
hypertensive patients, but was positively associated in patients with non STelevation myocardial infarction (NSTEMI) ACS. 24 There was no difference
between patients with dilated cardiomyopathy and previous MI.25 Arrhythmia
26 was associated with elevated levels of B-type natriuretic peptides; however,
there was no difference between atrial fibrillation and sinus rhythm 27 valvular
disease 26 and all severities of aortic stenosis 28 were positively associated
with B-type natriuretic peptides levels.
The effect of 11 non-cardiac diseases on B-type natriuretic peptide levels was
mixed. Non-cardiac causes of dyspnoea, 29 30 31 diabetic nephropathy,32 and
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stroke 33 were all associated with increased levels of B-type natriuretic
peptides. Lung disease compared with HF34 or HF plus lung disease 35 had
lower BNP and NT-proBNP levels respectively. Diabetic retinopathy 36 and
cerebrovascular disease (including stroke and transient ischemic attack) 19 33
did not show association with B-type natriuretic peptide levels. Four of five
studies that evaluated hypertension 37 38 39 showed a positive association with
B-type natriuretic peptides; duration of hypertension was not associated with
BNP levels. 37 There was no difference in NT-proBNP levels between patients
with peripheral vascular disease compared with patients without risk factors
for cardiovascular disease. 19
5.1 CONCLUSION – The levels of BNP are variable in both cardiac and
non cardiac disease and the need for characterisation of cut-off values
for each clinical condition present in the different risk populations is
vital.
5.2 Targeted diagnosis of heart failure in primary care
populations
The majority of published evidence was from studies performed in the acute
or secondary care setting and there was a lack of direct high quality evidence
from studies performed in primary care to answer the research questions. It
proved difficult to determine the symptoms of the patients described in the
published studies and therefore to assign them to the three chosen risk
groups for the present review; a linked evidence approach was therefore
adopted.
One good quality HTA 12 included a total of seven papers (data could be
abstracted from only five), that selected patients from a primary care setting.
Five of these studies were cross-sectional in design 38 26 35 40 41 and one was a
RCT. 42 There was one study that selected patients randomly and identified a
high risk cohort group that is possibly equivalent to the intermediate risk group
in the present review and one group with established HF that corresponds to
the high risk group. 43 Two studies evaluated BNP with cut-off points ranging
from 10 to 115 pg/ml and reported sensitivities from 66 to 92%, specificities
from 18 to 88%, the area under the curve (AUC) from 0.70 to 0.88, LR+ from
1.12 to 5.7, and LR- from 0 to 0.27. Meta-analysis gave a summary DOR of 2
(95 % CI: 1 to 6). The three studies evaluating NT-proBNP with cut-off points
from 67 to 338 pg/ml reported sensitivities from 67 to 100%, specificities from
18 to 84% , AUC from 0.70 to 0.93, LR+ from 1.22 to 5.7, and LR- from 0 to
0.27. Meta-analysis gave a summary diagnostic odds ratio (DOR) of 17 (95 %
CI: 9 to 32) The authors suggested that the wide variation in specificity may
be due to the effect of determinants such as age, obesity, other diseases
(e.g., hypertension, diabetes, renal failure) or drugs (e.g., beta blockers,
diuretics, angiotensin converting enzyme (ACE) inhibitor) on BNP levels. The
included studies were of good quality.
The Australian HTA 13 included a more recent study 44(Level 2+) not included
in the American HTA 12 described above, which contained higher quality data
but was not a randomised study. The evidence on the diagnostic accuracy of
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BNP tests in primary care indicated that the test is likely to aid in the earlier
identification of alternative diagnoses for those patients ‘ruled out’ from having
HF and most of these alternative diagnoses (pulmonary diseases, asthma,
anaemia) have established treatments. When this alternative pathology is
severe enough, early identification and treatment is likely to benefit the
patient. The clinical impact of the test is however unknown.
The HTA13 considered evidence for NT-pro BNP assays separately and the
conclusions from the results were similar to those of BNP apart from the
possible indication that NT-proBNP assays may be more useful in ruling out
HF more frequently in those patients presenting with dyspnoea and/or
oedema of recent onset and suspected of HF. The Australian Medical
Services Advisory Committee has recommended that public funding be
supported for the use of BNP assays in the diagnosis of HF in the hospital
emergency setting but not in the non-hospital setting. It would appear that this
decision was taken because it is currently unknown what impact the
introduction of the tests will have on the current echocardiography referral rate
for those who test positive
The good quality meta-analysis ( Level 1+) published by Battaglia in 200645
summarised the evidence on the diagnosis of HF and also compared the
performance of a rapid enzyme linked immunoabsorbent assay (ELISA) with
the standard radioimmunoabsorbent (RIA) test and included studies ranging
from asymptomatic patients in the community to patients presenting with
acute dyspnoea in emergency departments. The authors concluded that
negative results of both tests accurately rule out the diagnosis if patients are
at relatively low risk of chronic HF and that the use of BNP tests in low-risk
patients in primary care settings could reduce demand for echocardiography
and referrals of patients to specialists. The ELISA test, which allows bedside
testing and provides results in a few minutes, performed somewhat better
than the RIA tests, which must be sent to a laboratory, but it is more costly
than RIA. The effect of introduction of such tests on patient outcomes or cost
is as yet unknown. One methodological problem with this study was that it
was only possible to adjust for information that was aggregated at study level
since individual patient data was not available.
The systematic review of Latour-Perez et al.46 (Level 1- ) concluded that BNP
was less useful for ruling out left ventricular systolic dysfunction (LVSD) than it
was for ruling out HF; this study is however of poor quality and the
conclusions should be viewed with caution. Another study 47(Level 1- ) also
looked at the diagnostic value of BNP and indicated that a BNP level of
80pg/ml is useful in diagnosing heart failure in symptomatic patients without a
history of heart failure. This study also has methodological problems
The findings of Fuat et al 200648 ( Level 2- ) should be viewed in the context of
the systematic review of diagnostic tests (BNP, NT-proBNP and ECG) in the
assessment of LVSD. 49 (Level 1- ) In this review of 32 studies BNP, NTproBNP and ECG were equivalent in terms of ruling out a diagnosis of LVSD.
Although the negative predictive values of BNP and NT-proBNP are higher
than ECG in the Fuat study, the precision of these estimates as measured by
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the 95% confidence interval around the point estimates do overlap to a large
extent. 50
The HTA from the NHS in Scotland51 (Level 2 ++) was primarily concerned
with the effectiveness of different tests that can be used by GPs for an initial
assessment/diagnosis of patients with signs and symptoms suggestive of HF.
The assessment did not consider the use of BNP tests in patients with other
diseases. The authors acknowledged that further research on audit of
practice is required but indicate that BNP has potential for ruling out HF and
that the estimated annual resource savings are £0.6 million to £1.4 million.
These figures were however, extrapolated from a Swiss study and need
verification within a UK primary care setting.
5.2 CONCLUSION - The evidence was inconsistent with regard to the
effectiveness of using BNP assays in the three risk groups.
It was
difficult to determine the patient characteristics of the risk groups
described in the published literature. It appeared that the majority of
authors considered that there was not enough good quality evidence
from community studies to conclusively recommend BNP testing in
primary care.
There was some Level 1 evidence that the targeted
approach to patients with different risk factors may be clinically
effective.
5.3
Cut-off values and risk scores
The practical application of BNP measurement in primary care has been
limited by problems in defining a cut-off threshold for effective diagnosis of
HF. This has led some researchers to try and develop scoring systems in
primary care that could permit the identification of patients with a poor
prognosis, without relying solely on a single cut-off threshold value for BNP.
In one study 52 (Level 2- ), 532 patients were followed up for 6.4 years and
multivariate analysis was used to generate a prognostic scoring system that
included such items as age, sex, angina, diabetes. The authors acknowledge
the limitations of their study but suggest that such an approach may be useful
in primary care to manage patients at different risk for HF. The cut-off scores
for risk groups were 25th percentile, 411pg/ml; 50th percentile, 475pg/ml; 75th
percentile, 524pg/ml. The ruling out of LVSD after MI by BNP measurement is
still controversial and a recent paper from Germany suggests that evaluation
of clinical information and the development of risk scores are as least as
effective as NT-proBNP testing. 53
Maisel54 found that in patients referred from primary to acute care that a
negative predictive value of BNP level of <100 pg/ml was the strongest
feature of this peptide. Although the positive predictive value in a given
patient at a cut-off of 100pg/ml is 80%, most patients with significant chronic
HF as a cause of their dyspnoea will have levels of 400pg/ml. Thus, in
patients presenting with levels between 100 and 400 pg/ml, one needs to
exclude baseline LV dysfunction without exacerbation, pulmonary embolism,
and cor pulmonale.
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Thus it has been concluded that:55

With a cut-off of <100pg/ml: significant HF as cause of SOB can be
excluded

Most patients with significant HF will have a BNP> 400pg/ml

BNP 100-400pg/ml: will exclude non relevant baseline LVD,
pulmonary embolism & cor pulmonale.
The diagram below gives an indication of the diagnostic accuracy of BNP
testing to rule out SOB caused by HF. 55
Receiver-Operating-Characteristic Curve for Various cut-off levels of
BNP in differentiating between SOB due to HF and SOB due to other
causes. i
i
Taken from Reference 55. Permission to copy applied for.
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The South West London Cardiac Network56 has interpreted the published cutoff data and recommended levels for use locally. (see Table 1)
Table 1
AGE in years
<60
60-75
>75
Cut-off value
50
97.9
49.9
99.3
100
95.4
48.9
98.3
250
94.4
49.1
99.7
Sensitivity %
Specificity%
NPV%
Fuat 57 (Level 2 - ) reported on the use of NT-proBNP by general practitioners
in 600 patients with suspected heart failure using a single recommended cutoff point of 150pg/ml. 396 (66%) of assays were above the limit, of which 348
patients were assessed in clinics and 84 had LVSD (14% of the total cohort).
The age range for all patients was 35 to 95 with a median of 77 years and 368
(61%) were women. Of the 249 (75%) without LVSD, the majority had
cardiovascular causes for a raised NT-proBNP level. Introduction of the
assay increased waiting times for one-stop diagnostic clinics from 2 to 8
weeks and was not of cost benefit. The authors concluded that the optimum
cut-point for use in real life primary care prior to referral for echocardiography
has yet to be resolved.
The preliminary results of the international collaborative study of NT-proBNP
in patients referred from primary care to secondary care have some indirect
relevance to the research questions in that they indicate possible cut-off
values for BNP/NT-proBNP. Data was obtained from 4604 patients (2575
males, 2029 females) from 16 centres in the UK, Europe and the US. The
median age was 61 years (range 18.4 to 94.4 years, interquartile range 53 to
70 years) with a disease prevalence of 14.8%. Individual AUCs ranged from
0.974 to 0.835 according to the prior probability of disease in the population
studied (2.2 to 26.6%). Overall, the AUC for the pooled data was 0.898
(confidence interval 0.886-0.911). Analysing the data according to age
intervals produced AUC's for ages <50, 50-75 and >75 years respectively of
0.950 (0.927-0.973); 0.909 (0.894-0.924); 0.855 (0.815-0.894). The optimised
decision thresholds were respectively, 79, 102 and 225 pg/L. Using optimised
age and sex specific reference limits from a previous study produced
sensitivities and negative predictive values (NPV) of:



Males < 60 years: sensitivity 93.9%, NPV 98.2%
Females <60 years: sensitivity 90.4%, NPV 88.2%;
Males > 60 years: sensitivity 91.3%, NPV 96.1%;
Females > 60 years: sensitivity 88.3%, NPV 90.3%.
.
5.3 CONCLUSION - There was a lack of consistency in the literature on
the cut-off levels for BNP to diagnose HF and other diseases in primary
care and it was acknowledged that this is limiting the use of BNP in the
community. There was data suggesting that a cut-off value of <100pg/ml
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could exclude significant HF as a cause of SOB, which may have
relevance to the ‘low risk’ group. The combination of BNP assays with
risk scores may have clinical potential. One problem with the published
studies was that they often considered patients already triaged to
secondary care and therefore may not include all patients presenting to
primary care.
5.4
Economic aspects
There have been few economic evaluations of BNP testing in primary care.
The extent of the effectiveness in terms of quality adjusted life years (QALYs)
depends on the extent to which BNP tests hasten the correct definitive
diagnosis, as well as on the influence of a correct diagnosis on the disease
outcome. The cost effectiveness (CE) rests on the value of the additional
information made available by the assays in terms of health gain and resource
savings compared with the cost of the tests. In the Australian HTA 13 one
analysis was largely based on symptomatic patients i.e. those presenting with
SOB and/or oedema of recent onset and suspected of HF. In the absence of
any RCT in primary care with health outcome as the primary outcome, it was
impossible to estimate an incremental CE ratio based on life years saved or
QALYs in this setting. One way sensitivity analysis indicated that diminishing
marginal returns could arise if the testing is extended to GP populations that
have a high probability of HF. Such diminished returns could also arise if
testing is performed on increasing proportions of patients with minor levels of
symptoms without clinically important pathology. It is therefore very important
that the test is only ordered for patients with dyspnoea and/or oedema of
recent onset in whom there is genuine uncertainty about whether the
symptoms are caused by HF or an alternative pathology.
The HTA report from Scotland51 included an economic analysis, which
suggested that if GPs’ decisions to refer patients for echocardiography, made
without the assistance of BNP testing, had a specificity better than 50%, the
addition of BNP would add to cost, but that the cost of £500 per additional true
positive detected might be acceptable. This report has been criticised
because it does not present an explicit underlying economic model and
contains a number of flaws. For example, it uses the number of true-positive
cases detected alone as the diagnostic effectiveness measure and the
interpretation of its results depend upon how much the decision makers would
be willing to pay for each additional true-positive result – a parameter unlikely
to be known. Moreover, the analysis does not take all patient groups to a
definitive diagnosis: real-life strategies would incur subsequent costs, when
patients who, for example, had false-negative test results returned to primary
care with unresolved symptoms requiring further investigation. 58
Goode et al.59 suggested that preliminary screening of high-risk primary-care
patients using electrocardiogram QRS width or NT-proBNP alone was
insufficiently precise to be clinically useful. However, including NT-proBNP
and QRS width in a logistic regression model, together with evidence of prior
myocardial infarction and symptoms of breathlessness or peripheral oedema
gave significant reductions in the number of false positive referrals and the
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cost per diagnosis of clinically significant left ventricular systolic dysfunction.
Furthermore, Lim and colleagues60 found that while initial NT-proBNP
estimation may be cost-effective in detecting any causes of heart failure,
portable echocardiography remains the most cost effective strategy to assess
patients with heart failure from the community. Galasko et al. 61 in a UK
community study compared the effectiveness and cost effectiveness of ECG,
NT-proBNP and hand held echocardiography (HE) with traditional
echocardiography (TE) in screening for LVSD. The study, which has some
selection bias, found that ECG, NT-proBNP and HE pre-screening prior to TE
all produced considerable cost savings compared with TE screening alone.
The authors suggest that because interpretation of ECGs is sometimes
difficult in primary care that natriuretic peptide driven screening may be
preferable.
The modelling study reported by Scott et al 58 used a deterministic costconsequences analysis to compare alternative diagnostic strategies such as
ECGs interpreted by hospital consultants with BNP testing. The authors
concluded that the model demonstrates that for the base-case scenario, an
initial diagnostic strategy of BNP was superior to ECG in terms of diagnosis of
symptomatic heart failure in patients presenting to primary care, despite more
initial false negatives and higher costs. The editorial accompanying the article
5 questioned whether the results of published economic studies are
generalisable to primary care because there are differences in performance
(and ease of use by GPs) of a point-of-care BNP assay versus a laboratorybased BNP or NT-proBNP assay; different decision cut-off points between the
studies, assay cost differences and importantly the fact that in all these
studies the ECG was read by experienced secondary care clinicians rather
than GPs. These factors may significantly alter the cost-consequence
assumptions being made. Furthermore, the studies looked at patients already
triaged to secondary care and may not include all patients presenting to
primary care. Thus before BNP/NT-proBNP is recommended, a prospective
controlled trial in primary care of the use of both point-of-care and laboratory
assays that take all patients with suspected heart failure to a definitive
diagnosis is required.
5.4 CONCLUSION - The cost effectiveness data on the use of BNP in
primary care was inconclusive and little published data was found that
was directly relevant to the three risk groups. One good quality
systematic review concluded that in order to prevent diminishing
economic returns that BNP testing should be limited to patients with
recent onset dyspnoea and/or oedema, where it is uncertain if the
symptoms are caused by HF. There is data that is suggestive that hand
held/portable echocardiography may be cost effective.
6.
Conclusions

The rapid review of the evidence did not find conclusive high quality
evidence on the effectiveness or cost effectiveness of BNP assays in
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the targeted diagnosis of HF in primary care and further research is
required.

There was evidence that was suggestive that the targeted approach in
different risk groups may have potential clinically, but at present there
appears to be a lack of good data from primary care and future
research is required. The mixed results of the pilot studies, being
performed within the UK, reported by the NHS Heart Improvement
Programme2 confirmed this view.

There was a lack of consistency on what BNP cut-off values should be
used, but some data suggested that a value of < 100pg/ml will exclude
SOB caused by significant HF. The potential use of risk scores is
currently being investigated by researchers in the field.

High quality cost effectiveness data was lacking, but one good quality
systematic review indicated that in order to prevent diminishing returns
BNP testing should only be used in patients where there is doubt over
the cause of the SOB. There was some data that hand held/portable
echocardiography may be of use in screening patients in primary care
in combination with ECG and NT-proBNP.
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7.
Brain natriuretic peptide
References
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of valvular aortic stenosis Am J Cardiol 2004; 94: 740. Cited in Ref 12. Abstract read.
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ventricular dysfunction Eur J Heart Fail 2004; 6: 301. Cited in Ref 12. Abstract read.
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Logeart D; Saudubray C; Beyne P et al. Comparative value of Doppler echocardiography and B-type
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Tarnow L; Hildebrandt P; Hansen BV et al. Plasma N-terminal pro-brain natriuretic peptide as an
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James SK; Lindahl B; Siegbahn A et al. N-terminal pro-brain natriuretic peptide and other risk
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Bettencourt P; Ferreira A; Sousa T et al. Brain natriuretic peptide as a marker of cardiac involvement
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congestive heart failure. Arch Intern Med 2006; 166:1073.
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a real life study. Heart 2005; 91(Suppl I): A22.
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Lim TK, Dwivedi G, Hayat et al. Cost effectiveness of the B type natriuretic peptide,
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Galasko GI; Barnes SC; Collinson P et al. what is the most cost-effective strategy to screen for left
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Appendix 1
Brain natriuretic peptide
Main search strategy
The facility available on the HOWIS website to search simultaneously across multiple
databases was used. Ovid Medline, Embase, Cochrane Database of Systematic
Reviews, ACP Journal Club EBM reviews; Database of Abstracts of Reviews of
Effects; British Nursing Index and Cinahl, were searched
Search terms included subject headings and text words based on: natriuretic peptide,
brain/ 2. bnp.mp. [mp=title, original title, abstract, name of substance word, subject
heading word];3. nt-probnp.mp; brain-type natriuretic peptide.mp; probnp.mp;
natriuretic factor; natriuretic peptide type-b.mp; type-b natriuretic peptide.mp;
ventricular natriuretic peptide; heart failure.mp. [mp=title, original title, abstract,
name of substance word; exp heart failure; exp myocardial infarction; exp dyspnoea;
exp coronary heart disease; exp hypertension
The search terms meta.ab; synthesis.ab; literature.ab; randomized.hw; published.ab;
meta-analysis pt; trials.hw; controlled.hw; medline.ab; selection.ab; sources.ab;
trials.ab; review.ab; review.pt; articles.ab; reviewed.ab were used to retrieve RCTs,
metanalyses and systematic reviews from Medline.
Appendix 2
High level search strategy
Agency for Healthcare Research and Quality Chronic Care (AHRQ)
Agency for Quality in Medicine (AZQ)
Canadian Coordinating Office for Health Technology Assessment (CCOHTA)
Centre for Health Services Research - Population and Health Sciences - University of
Newcastle
Centre for Reviews & Dissemination
Clinical Evidence
Department of Health
Effective Practice & Organisation of Care Group
Guidelines International Network
Google
Google scholar
Health Evidence Bulletin Wales
Health Management Information Consortium
Health Technology Assessment Programme
Kings Fund
National Assembly for Wales
National Library for Health ( NLH) – Cardiovascular Specialist Library
National Guideline Clearinghouse
National Institute for Health and Clinical Excellence
National Public Health Service for Wales
NHS Centre for Reviews and Dissemination
NHS Improvement Agency
Scottish Intercollegiate Guidelines Network (SIGN)
SUMSearch
Turning Research Into Practice (TRIP) Database
UpToDate
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Brain natriuretic peptide
Appendix 3 Evidence levels and quality grading (modified
from NICE Guideline Methodology Manual) ref 7
Level of Evidence
1++
1+
12++
2+
2-
3
4
Type of evidence
High-quality meta-analyses, systematic
reviews of RCTs, or
RCTs with a very low risk of bias
Well-conducted meta-analyses,
systematic reviews of RCTs,or RCTs
with a low risk of bias
Meta-analyses, systematic reviews of
RCTs, or RCTs with a high risk of bias
High-quality systematic reviews of case–
control or cohort studies. High-quality
case–control or cohort studies with a very
low risk of confounding, bias, or chance
and a high probability that the
relationship is causal
Well-conducted case–control or cohort
studies with a low risk of confounding,
bias, or chance and a moderate
probability that the relationship is causal
Case–control or cohort studies with a
high risk of confounding bias, or chance
and a significant risk that the relationship
is not causal
Non-analytic studies (for example, case
reports, case series)
Expert opinion, formal consensus
Quality grading
++ = good quality
+ = fair
+/- = fair to poor
- = poor
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