Download Health Technology Assessment Report 6 the Use of B Type

Health Technology Assessment Report 6
The use of B-type natriuretic peptides (BNP and NT-proBNP) in the
investigation of patients with suspected heart failure
Authors: Craig J, Bradbury I, Cummins E, Downie S, Foster L, Stout A.
1
© NHS Quality Improvement Scotland 2005
ISBN 1-903961-49-1
NHS Quality Improvement Scotland (NHS QIS) consents to the photocopying,
electronic reproduction by ‘uploading’ or ‘downloading’ from the website,
retransmission, or other copying of this report on the Health Technology
Assessment for educational and ‘not-for-profit’ purposes. No reproduction by
or for commercial organisations is permitted without the express written
permission of NHS QIS.
www.nhshealthquality.org
2
Contents
1
2
3
4
5
Executive summary ................................................................................ 10
Introduction ............................................................................................. 17
Background on NHS Quality Improvement Scotland .............................. 18
Setting the scene .................................................................................... 19
Clinical effectiveness .............................................................................. 25
5.1
Methodology ........................................................................... 25
5.1.1
Sources of evidence ................................................................. 26
5.1.1.1 Literature search..................................................................... 26
5.1.1.2 Study selection criteria............................................................ 26
5.1.2
Overview of diagnostic studies ................................................. 27
5.1.3
Evaluation of sensitivity, specificity and pooled diagnostic
odds ratio.................................................................................. 28
5.1.4
Analysis .................................................................................... 29
5.2
Results.................................................................................... 29
5.2.1
BNP for heart failure ................................................................. 30
5.2.2
BNP for LVSD .......................................................................... 33
5.2.3
NT-proBNP for heart failure...................................................... 35
5.2.4
NT-proBNP for LVSD ............................................................... 36
5.2.5
ECG for heart failure (cardiologist read) ................................... 37
5.2.6
ECG for heart failure (machine read)........................................ 38
5.2.7
ECG for LVSD (cardiologist read)............................................. 38
5.2.8
ECG for LVSD (machine read) ................................................. 39
5.2.9
Joint diagnostic value of ECG and BNP or NT-proBNP............ 40
5.2.10 Comparative studies for heart failure in primary care ............... 41
5.2.11 Referral rates............................................................................ 42
5.2.12 Sequential use of ECG and BNP.............................................. 44
5.3
B-type natriuretic peptide in diastolic heart failure (DHF)........ 44
5.4
B-type natriuretic peptide performance in different settings.... 44
5.5
Suggested cut-offs.................................................................. 44
5.5.1
Other reasons for elevated BNP............................................... 45
5.6
Discussion .............................................................................. 47
5.7
Conclusions ............................................................................ 49
6 Cost effectiveness .................................................................................. 51
6.1
Methodology ........................................................................... 51
6.1.1
Sources of evidence ................................................................. 51
6.1.1.1 Literature search..................................................................... 51
6.1.1.2 Study selection criteria............................................................ 51
6.1.2
Overview of studies .................................................................. 52
6.1.3
Economic model for primary care ............................................. 53
6.1.3.1 Model inputs: clinical effectiveness data................................. 55
6.1.3.2 Model inputs: prevalence rate of heart failure......................... 56
6.1.3.3 Model inputs: cost of tests, drugs and waiting times............... 56
6.2
Results.................................................................................... 57
6.2.1
Base-case interpretation of results ........................................... 57
6.2.2
Base-case results ..................................................................... 58
6.2.3
Sensitivity analyses .................................................................. 59
6.2.3.1 Prevalence rate of heart failure............................................... 59
3
6.2.3.2 Accuracy of B-type natriuretic peptide testing and ECG
readings.................................................................................. 60
6.2.3.3 Point-of-care testing................................................................ 63
6.2.3.4 Lower cost of laboratory tests ................................................. 64
6.2.3.5 The cost of echocardiography ................................................ 64
6.2.3.6 Use and cost of ECGs by GPs ............................................... 65
6.2.3.7 The cost of additional tests for false-negative patients ........... 65
6.2.3.8 Results for diagnosis of LVSD ................................................ 66
6.2.3.9 Joint testing using a combination of diagnostic tests .............. 67
6.3
Discussion .............................................................................. 68
6.4
Conclusions ............................................................................ 69
7 Other issues relevant to clinical and cost effectiveness evidence .......... 71
7.1
Organisational issues ............................................................. 71
7.1.1
Surveys of use of B-type natriuretic peptide testing and
echocardiography facilities ....................................................... 71
7.1.1.1 Use of B-type natriuretic peptide testing ................................. 71
7.1.1.2 Use of echocardiography........................................................ 71
7.1.2
Provision of B-type natriuretic peptide testing services in the
acute sector .............................................................................. 72
7.1.2.1 Potential benefits of B-type natriuretic peptide tests in the acute
care sector .............................................................................. 72
7.1.2.2 Organisational aspects of a B-type natriuretic peptides service
in the acute care sector .......................................................... 72
7.1.3
Provision of B-type natriuretic peptide testing services in primary
care .......................................................................................... 74
7.1.3.1 Potential benefits of B-type natriuretic peptide tests in general
practice ................................................................................... 74
7.1.3.2 Organisational challenges of a B-type natriuretic peptide testing
service in general practice ...................................................... 74
7.1.4
Consultant-led ECG service ..................................................... 74
7.1.5
Discussion ................................................................................ 75
7.2
Patient issues ......................................................................... 76
8 Principal findings, limitations and recommendations .............................. 78
8.1
Principal findings..................................................................... 78
8.1.1
Scope of the HTA ..................................................................... 78
8.1.2
Summary of findings................................................................. 78
8.2
Further research ..................................................................... 80
8.3
Limitations and uncertainties .................................................. 81
8.4
Recommendations.................................................................. 82
8.5
Resource implications of recommendations ........................... 84
8.5.1
Incidence of heart failure .......................................................... 84
8.5.2
Potential number of B-type natriuretic peptide tests in acute
setting....................................................................................... 84
8.5.3
Diagnostic setting: primary care ............................................... 85
8.5.4
Sensitivity analysis ................................................................... 86
8.5.5
Additional costs in hospitals and primary care.......................... 86
8.5.6
Total costs of implementing B-type natriuretic peptide testing.. 87
8.5.7
Potential resources released .................................................... 87
8.5.8
Comparison of costs and resources released .......................... 88
8.6
Challenges for implementation ............................................... 89
4
9
10
11
12
Acknowledgements................................................................................. 90
References ............................................................................................. 91
Appendices ........................................................................................... 102
Glossary ............................................................................................... 139
5
List of tables
Table 4 - 1
Table 4 - 2
Table 5 - 1
Table 5 - 2
Table 5 - 3
Table 5 - 4
Table 5 - 5
Table 5 - 6
Table 6 - 1
Table 6 - 2
Table 6 - 3
Table 6 - 4
Table 6 - 5
Table 6 - 6
Table 6 - 7
Table 6 - 8
Table 6 - 9
Table 6 - 10
Table 6 - 11
Table 6 - 12
Table 6 - 13
Table 6 - 14
Table 6 - 15
Table 6 - 16
Table 6 - 17
Table 6 - 18
Table 6 - 19
New York Heart Association classification of heart failure
symptoms .................................................................................20
Comparison of BNP and NT-proBNP .......................................23
Sensitivity and specificity of tests .............................................29
Summary of results for different combinations of tests and
target diagnoses .......................................................................30
Estimated NPV for each test/condition combination assuming
fixed test performance and varying pre-test prevalence ...........30
Sensitivity and specificity of B-type natriuretic peptide assays
at various cut-off points and compared with ECGs read by
cardiologists .............................................................................42
Referral patterns for 1,000 patients with symptoms
suggestive of heart failure (Wright et al., 2003) ........................42
Referral patterns for 1,000 patients (diagnosed by GP) with
heart failure (Zaphiriou et al., unpublished) ..............................43
Comparison of using BNP and standard care in the
emergency setting ....................................................................53
Sensitivities and specificities of tests for heart failure...............56
Cost of tests, therapy and waiting times ...................................57
Base-case results for 100 patients presenting to a GP surgery
with symptoms suggestive of heart failure................................58
Results ordered by costs ..........................................................59
Sensitivity analysis: prevalence of 48% for heart failure...........60
Sensitivity analysis: 90% sensitivity and 73% specificity of
B-type natriuretic peptides........................................................60
Sensitivity analysis: 93% sensitivity and 63% specificity of
consultant-led ECG service ......................................................61
Sensitivity analysis: 85% sensitivity and 60% specificity for
GP-read ECG ...........................................................................61
Sensitivity analysis: 87% sensitivity and 26% specificity for
machine-read ECGs .................................................................62
Sensitivity analysis: 82% sensitivity and 76% specificity for
GP-read ECGs .........................................................................62
Sensitivity analysis: 92% sensitivity and 37% specificity for
machine-read ECGs .................................................................63
Sensitivity analysis: point-of-care tests 50 annual throughput
and £37.50 per test...................................................................63
Sensitivity analysis: point-of-care tests 200 annual throughput
and £30 per test .......................................................................63
Sensitivity analysis: echocardiography cost of £60 ..................64
Sensitivity analysis: echocardiography cost of £150.................64
Sensitivity analysis: one additional GP visit for false-negative
patients.....................................................................................66
Sensitivity analysis: three additional GP visits for falsenegative patients ......................................................................66
Sensitivity analysis: LVSD prevalence of 18% and basecase accuracies of tests for LVSD............................................67
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Table 6 - 20 Sensitivity analysis: 83% sensitivity for LVSD and 21%
specificity for GP-read ECG .....................................................67
Table 6 - 21 Sensitivity and specificity of a combination of diagnostic tests .67
Table 6 - 22 Sensitivity analysis: comparison of joint tests and B-type
natriuretic peptide tests ............................................................68
Table 8 - 1 Base case minimum and maximum number of tests in
primary care setting ..................................................................85
Table 8 - 2 Range of number and costs of B-type natriuretic peptide
tests..........................................................................................86
Table 8 - 3 Range of echocardiography savings ........................................87
Table 8 - 4 Comparison of costs and savings from B-type natriuretic
peptide tests by setting: first year and steady state
(All £ millions) ...........................................................................88
Table 11 - 1 All BNP studies – patient characteristics ................................110
Table 11 - 2 B-type natriuretic peptide studies – results and comments ....112
Table 11 - 3 All NT-proBNP studies – patient characteristics .....................113
Table 11 - 4 NT-proBNP studies – results and comments..........................114
Table 11 - 5 ECG studies – patient characteristics.....................................115
Table 11 - 6 ECG studies – results and comments ....................................116
Table 11 - 7 Cost of B-type natriuretic peptide tests...................................131
Table 11 - 8 Cost of echocardiography.......................................................132
Table 11 - 9 Cost of consultant-led ECG service........................................132
Table 11 - 10 Number of echocardiographs performed during the previous
12 months on patients referred with suspected heart failure
by GPs....................................................................................136
Table 11 - 11 Waiting time for direct access echocardiography...................136
Table 11 - 12 Waiting time for an outpatient clinic appointment
(unprioritised) .........................................................................137
Table 11 - 13 Waiting time for echocardiography (unprioritised)..................137
Table 11 - 14 Cases where echocardiogram provides insufficient
diagnostic information.............................................................138
7
List of figures
Figure 4 - 1 Algorithm for assessment of suspected heart failure in primary
care ..........................................................................................21
Figure 5 - 1 Pooled sensitivity of BNP for heart failure ................................32
Figure 5 - 2 Pooled specificity of BNP for heart failure ................................32
Figure 5 - 3 Pooled diagnostic OR for BNP in heart failure..........................32
Figure 5 - 4 BNP sensitivity for LVSD ..........................................................34
Figure 5 - 5 BNP specificity for LVSD ..........................................................34
Figure 5 - 6 BNP diagnostic OR for LVSD ...................................................34
Figure 5 - 7 NT-proBNP sensitivity for heart failure .....................................35
Figure 5 - 8 NT-proBNP specificity for heart failure .....................................35
Figure 5 - 9 NT-proBNP diagnostic OR for heart failure ..............................36
Figure 5 - 10 NT-proBNP sensitivity for LVSD ..............................................36
Figure 5 - 11 NT-proBNP specificity for LVSD ..............................................36
Figure 5 - 12 NT-proBNP diagnostic OR for LVSD .......................................36
Figure 5 - 13 ECG sensitivity for heart failure (cardiologist read)..................37
Figure 5 - 14 ECG specificity for heart failure (cardiologist read)..................37
Figure 5 - 15 ECG diagnostic OR for heart failure (cardiologist read)...........38
Figure 5 - 16 ECG sensitivity for LVSD (cardiologist read) ...........................39
Figure 5 - 17 ECG specificity for LVSD (cardiologist read) ...........................39
Figure 5 - 18 ECG diagnostic OR for LVSD (cardiologist read) ....................39
Figure 5 - 19 ECG sensitivity for LVSD (machine read)................................40
Figure 5 - 20 ECG specificity for LVSD (machine read)................................40
Figure 5 - 21 ECG diagnostic OR for LVSD (machine read) .........................40
Figure 6 - 1 Algorithm for the diagnosis of heart failure ...............................54
Figure 11 - 1 Summary ROC curve for BNP in heart failure ........................117
Figure 11 - 2 Summary ROC curve for BNP in LVSD..................................117
Figure 11 - 3 Summary ROC curve for NT-proBNP in heart failure .............118
Figure 11 - 4 Summary ROC curve for NT-proBNP in LVSD.......................118
Figure 11 - 5 Summary ROC curve for ECG in Heart Failure ......................119
Figure 11 - 6 BNP sensitivity for heart failure in hospital setting ..................119
Figure 11 - 7 BNP specificity for heart failure in hospital setting ..................119
Figure 11 - 8 BNP diagnostic OR for heart failure in hospital setting ...........120
Figure 11 - 9 BNP sensitivity for LVSD in hospital setting ...........................120
Figure 11 - 10 BNP specificity for LVSD in hospital setting..........................120
Figure 11 - 11 BNP diagnostic OR for LVSD in hospital setting...................120
Figure 11 - 12 NT-proBNP sensitivity for heart failure in hospital setting .....121
Figure 11 - 13 NT-proBNP specificity for heart failure in hospital setting .....121
Figure 11 - 14 NT-proBNP diagnostic OR for heart failure in hospital
setting...................................................................................121
Figure 11 - 15 NT-proBNP sensitivity for LVSD in hospital setting ..............122
Figure 11 - 16 NT-proBNP specificity for LVSD in hospital setting ..............122
Figure 11 - 17 NT-proBNP diagnostic OR for LVSD in hospital setting........122
Figure 11 - 18 BNP sensitivity for heart failure in primary setting ................123
Figure 11 - 19 BNP specificity for heart failure in primary setting ................123
Figure 11 - 20 BNP diagnostic OR for heart failure in primary setting..........123
Figure 11 - 21 BNP sensitivity for LVSD in primary care setting ..................124
Figure 11 - 22 BNP specificity for LVSD in primary care setting ..................124
Figure 11 - 23 BNP diagnostic OR for LVSD in primary care setting ...........124
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Figure 11 - 24 NT-proBNP sensitivity for heart failure in primary care
setting...................................................................................125
Figure 11 - 25 NT-proBNP specificity for heart failure in primary care
setting...................................................................................125
Figure 11 - 26 NT-proBNP diagnostic OR for heart failure in primary care
setting ..................................................................................125
Figure 11 - 27 NT-proBNP sensitivity for LVSD in primary care setting .......126
Figure 11 - 28 NT-proBNP specificity for LVSD in primary care setting .......126
Figure 11 - 29 NT-proBNP diagnostic OR for LVSD in primary care setting 126
Figure 11 - 30 Pooled sensitivity for heart failure .........................................127
Figure 11 - 31 Pooled specificity for heart failure .........................................127
Figure 11 - 32 Pooled diagnostic OR for heart failure ..................................128
Figure 11 - 33 Pooled summary ROC curve for heart failure .......................128
Figure 11 - 34 Pooled sensitivity for LVSD ..................................................129
Figure 11 - 35 Pooled specificity for LVSD ..................................................129
Figure 11 - 36 Pooled diagnostic OR for LVSD ...........................................129
List of appendices
Appendix
Appendix
Appendix
Appendix
Appendix
Appendix
Appendix
Appendix
1
2
3
4
5
6
7
8
Experts and peer reviewers....................................................102
Strategy for literature searches ..............................................103
Literature selection process for clinical effectiveness .............109
Diagnostic test studies............................................................110
Graphical representations of diagnostic tests.........................117
Cost of tests ...........................................................................131
Organisation of healthcare in Scotland...................................133
Analysis of questionnaire results ............................................135
9
Executive Summary
1 Executive summary
Summary of HTA recommendations
Use of B-type natriuretic peptide tests in primary care
1. GPs who do not record ECGs in their own practice, or who are not
confident in confirming an automated ECG report produced in their own
practice, should adopt B-type natriuretic peptide tests when deciding which
patients to refer for further assessment for heart failure. The test result
should be used to rule-out a possible diagnosis of heart failure. Initially,
patient data should be audited by Health Boards to ensure the resultant
decisions are clinically appropriate.
2. There is no strong evidence base to support GPs who accurately interpret
ECGs changing their current practice of referring all patients with a newa
relevant ECG abnormality, in the presence of clinical signs and symptoms
suggestive of heart failure, for further clinical assessment.
Use of B-type natriuretic peptide tests in acute care
3. B-type natriuretic peptide tests should not replace echocardiography for
the diagnosis of heart failure.
4. Physicians in admission units should use B-type natriuretic peptide tests,
in conjunction with other clinical information, for patients in whom there is
genuine diagnostic uncertainty after standard evaluation, and no timely
access to echocardiography. The test result should be used to rule-out
heart failure. Initially, this approach should be audited to establish the cost
effectiveness of the service in Scotland.
B-type natriuretic peptide cut-offs
5. B-type natriuretic peptide concentrations rise with age in the normal
population and the recommended cut-off levels should reflect this. If agerelated cut-offs are not available, then clinicians should note that B-type
natriuretic peptide tests might have a reduced specificity in a
predominantly older age group of patients with suspected heart failure.
6. Clinicians and laboratory managers should co-operate at NHS Board level
(or across Scotland) to validate that the manufacturers’ recommended cutoffs for B-type natriuretic peptide concentrations are appropriate for their
own population and that the cut-offs are sufficiently sensitive to identify all
patients with mild heart failure.
a
‘New’ is defined as an abnormality without documented previous investigation.
10
Executive Summary
Type of B-type natriuretic peptide test
7. The type of B-type natriuretic peptide testing service (point-of-care or
laboratory service) offered in the acute setting should be decided locally by
laboratory, clinical and managerial staff working collaboratively, such that
quality-assured results meet the needs of the clinical decision maker. All
services should adhere to the procedures required by accreditation and
regulatory agencies.
Protocols
8. B-type natriuretic peptide testing should not be used for therapeutic
decision making until large, prospective studies have reported. Studies
indicate that the level of B-type natriuretic peptide concentrations has
prognostic value but further evidence is required on threshold.
9. Managed clinical networks that currently include GPs who do not record
ECGs in their practice (and thus who should adopt B-type natriuretic
peptide tests), should develop robust heart failure referral protocols, that
include B-type natriuretic peptide test results, to manage referrals for
further clinical assessment and echocardiography. The use of these
protocols should be monitored and deviations addressed.
10. Healthcare professionals should explain clearly and timeously to patients
and carers what their diagnosis is and how it was made, and ensure that
this is supported by written information.
Further research
Further research is necessary to establish:
•
the additional benefit of B-type natriuretic peptide tests to rule-out heart
failure where GPs already read ECGs accurately (this is currently under
way)
•
the clinical effectiveness of commencing patients on pharmacological
therapy who present at their GP with a clinical history and signs and
symptoms of heart failure, and who have raised B-type natriuretic peptides
and there is limited access to echocardiography; such research should
seek to establish the clinical benefit of commencing treatment in advance
of confirming the diagnosis
•
the utility of B-type natriuretic peptide testing in informing the diagnosis of
diastolic heart failure.
These recommendations should be reviewed as new evidence arises.
11
Executive Summary
Introduction
This health technology assessment (HTA) is primarily concerned with the
clinical and cost effectiveness of B-type natriuretic peptide (BNP) tests and
electrocardiograms for use by physicians in the initial diagnostic work-up of
patients with signs and symptoms suggestive of heart failure. Information from
these initial investigations should be used to decide which patients to refer for
further clinical assessment and echocardiography.
Heart failure is a complex clinical syndrome in which a cardiac abnormality
reduces the ability of the heart to pump blood. Symptoms of heart failure
typically include breathlessness or fatigue, either at rest or during exertion, or
ankle swelling, but these are often difficult to interpret. This means that
diagnosis of heart failure by clinical means alone is inadequate. Non-specialist
physicians in admission units in the acute sector or general practitioners
(GPs) in the community usually make the initial clinical assessment. Studies
show that over 50% of patients diagnosed with suspected heart failure in
primary care do not have a diagnosis of heart failure confirmed on further
evaluation by a specialist.
Guidelines recommend that therapy should not be initiated until a diagnosis
has been established with reasonable certainty, usually by echocardiography.
However, in some areas waiting times for echocardiography are up to 30
weeks. Historically, only about 30% of heart failure patients diagnosed in
general practice received echocardiography. Further development of, and
indeed maintaining the current service, is constrained by the lack of trained
echocardiographers. Thus, in practice many patients with suspected heart
failure receive treatment without appropriate confirmation of the diagnosis.
The prognosis for patients with heart failure is poor if the underlying problem
cannot be rectified by therapy. Uncertainty of diagnosis, delays in confirming
diagnosis and level of misdiagnosis are major concerns for patients with heart
failure and patient groups. Given that the disease may be reversible if treated
at an early stage, patients have a strong preference for an early and certain
diagnosis and appropriate medication. Inappropriate diagnosis at best leads
to patients receiving medication that will not improve their condition but which
may indeed harm them.
Each year in Scotland, 30,000 patients with heart failure make about 63,000
visits to their GPs and over 12,000 patients will be admitted to hospital with
this condition. The average age for patients attending GPs with a diagnosis of
heart failure is over 77 years and many will have difficulties in accessing care.
Thus pathways of care are variable, depending on many factors including the
availability of investigative services such as echocardiography, location of the
patient relative to such services and patient preferences.
In patients with heart failure, the protein B-type (or brain) natriuretic peptide
(BNP) is released by the heart into the bloodstream. The main stimuli for its
secretion are changes in left ventricular wall stretch and volume overload. Its
production causes dilation of the blood vessels which reduces blood pressure
and stimulates sodium and water excretion. BNP plasma concentrations are
12
Executive Summary
therefore raised in patients with heart failure, and generally the higher the
concentration, the more severe the disease.
Laboratory and point-of-care assays that measure BNP and the inactive
peptide N terminal-proBNP (NT-proBNP) concentrations in the blood are now
commercially available. BNP and NT-proBNP are known collectively as B-type
natriuretic peptides.
Primary objective and scope of the HTA
There is increasing interest from GPs and hospital physicians in Scotland
about the use of B-type natriuretic peptides to improve the diagnostic process
for heart failure and, in particular, to reduce the number of inappropriate
referrals from GPs to heart failure specialists. However, there is considerable
uncertainty about whether, where and how it should be used. This HTA was
therefore undertaken to establish the place of B-type natriuretic peptide tests
in the diagnostic algorithm for heart failure. Specifically, the HTA investigated
whether or not a normal B-type natriuretic peptide result can reliably rule-out
heart failure:
•
•
in the primary care setting to inform the decision on whether or not to send
a patient to a specialist or for echocardiography
in admission units to inform decisions around treatment and placement of
patients.
The assessment does not consider the use of B-type natriuretic peptide tests
in other potential areas, for example for patients with acute coronary
syndrome, screening of asymptomatic people, or guiding therapy in patients
with heart failure.
Methods
This HTA takes account of the evidence on clinical and cost effectiveness of
B-type natriuretic peptide testing and considers the potential impact on
patients and the NHS in Scotland.
Evidence identified by literature searching, together with evidence provided by
experts, patient interest groups and manufacturers, was critically appraised
and expert staff undertook robust analyses. Questionnaires were undertaken
to ascertain the current use of B-type natriuretic peptide assays and
availability of echocardiography.
An economic model of the primary care setting compared the clinical and cost
effectiveness of the current diagnostic pathway (assessment of signs and
symptoms using physical examination, laboratory tests and an
electrocardiogram (ECG), followed by echocardiography if there is clinical
suspicion of heart failure) for patients with suspected heart failure with the
following alternatives:
1. a specialist-led ECG service, whereby GPs record the ECG and send the
recording for interpretation by experienced clinicians in the acute sector. If
13
Executive Summary
the ECG shows relevant abnormalities, then the patient would be referred
to a specialist and receive echocardiography.
2. the addition of a B-type natriuretic peptide test to the current diagnostic
pathway, with referral to a specialist if BNP results are abnormal.
Peer review and wide public consultation ensured that all views were
considered.
Results and conclusions
A survey showed that in Scotland only one hospital uses a point-of-care BNP
service in accident and emergency (A&E) and on other wards. Subsequently,
a second Health Board has introduced a laboratory NT-proBNP service for
use in general practice, mainly for patients who had a working diagnosis of
heart failure that had not been confirmed by echocardiography.
The clinical evidence showed that for diagnosing heart failure, a cardiologist
report of an abnormal ECG and B-type natriuretic peptide tests have similar
sensitivities but the latter have higher specificity. An automated report of
abnormal ECG has a similar sensitivity but a much lower specificity than Btype natriuretic peptide tests. There is very little published data on how
accurately GPs interpret ECGs; a study with this objective is planned.
There is no evidence that the accuracy of BNP differs from that of NTproBNP. However, more studies have been conducted using BNP, and
behaviour in concomitant disease and in the elderly is better characterised.
The accuracy of B-type natriuretic peptide assays is greatest in patients with
more severe disease and poorest in patients who are already receiving
therapy for heart failure. B-type natriuretic peptide tests are best used to ruleout heart failure. The assays are not diagnostic if used in isolation from other
tests as heart failure is not the only condition which can cause a rise in these
peptides. Thus further tests, particularly echocardiography, are necessary to
confirm the diagnosis, inform on the patient’s aetiology and hence the
appropriate treatment strategy.
There is evidence that the availability of rapid B-type natriuretic peptide
results in admission units, in addition to the standard initial clinical
assessment, may improve the evaluation and treatment of patients. This could
reduce the length of stay and total treatment costs compared with current
practice.
The evidence on the addition of B-type natriuretic peptide tests to existing
clinical assessment suggests that providing GPs who do not record ECGs in
their practice or who are not confident in confirming an automated ECG report
produced locally, with a patient’s B-type natriuretic peptide concentration
could reduce the number of patients who are referred inappropriately for
further cardiac assessment and echocardiography.
14
Executive Summary
In practice, where access to echocardiography is limited and patients with
clinical signs and symptoms of heart failure are started on pharmacological
therapy in advance of the echocardiography result, then the availability of a Btype natriuretic peptide result may improve the selection of patients for such
treatment. However, B-type natriuretic peptides rise for reasons other than
heart failure and there is no trial to provide evidence for the effectiveness of
commencing therapy on the basis of a B-type natriuretic peptide level.
Therefore, no evidence based recommendations can be made in relation to
this.
Currently, the very limited clinical evidence suggests there may be benefit
from GPs referring all patients with a new relevant ECG abnormality and
those with normal ECG but abnormal B-type natriuretic peptides. This
assumes all patients with suspected heart failure will receive an accurately
read ECGb. A study currently under way may provide better data to inform this
decision. If the analyses cannot be used for this purpose, then a randomised
study comparing referral decisions made by a GP on the initial visit, with or
without the benefit of a B-type natriuretic peptide result should be undertaken.
The cost effectiveness of such a strategy has not been proven.
Modelling suggests that using B-type natriuretic peptide tests could be cost
saving if the specificity of diagnostic tests currently used to inform on whether
or not to refer patients for further assessment and echocardiography is less
than 50%. However, recognising the impracticality of measuring such a
specificity, the recommendations use confidence in confirming an automated
ECG report as a proxy for a specificity of under 50%.
In addition to acquiring the B-type natriuretic peptide assays, any change to
current practice would inevitably require considerable investment in:
•
•
•
educating and training doctors and nurses on taking and interpreting the
tests
developing and revising referral protocols
undertaking audit.
The total cost and the timeliness of obtaining a quality-assured result should
inform decisions on whether the B-type natriuretic peptide assay should be
undertaken in a laboratory setting or at the point of delivery of care.
From a patient perspective, honest and accurate information is of paramount
importance. Many patients reported a long wait for a diagnosis and others
were unsure if they had been given a diagnosis of heart failure or not.
Therefore, patients are likely to value avoiding unnecessary anxiety if a
simple, relatively non-invasive blood test can rule-out heart failure.
b
To the average accuracy levels observed by cardiologists
15
Executive Summary
Resource implications of recommendations
The annual cost of implementing the recommendations on the use of B-type
natriuretic peptide testing in primary and secondary care are estimated at
between £0.20 million and £0.55 million, with a further £0.3 million in the first
year for training and protocol development. The main factors influencing the
costs are the numbers of symptomatic patients who present with signs and
symptoms of heart failure for diagnosis, whether they present to GPs or
hospital and the number of GPs who do not record ECGs in their own practice
or are not confident in confirming an automated ECG report produced locally.
The estimated annual resource savings are from:
•
•
a reduction in echocardiography, saving £0.6 million to £1.4 million
lower admissions and shorter length of stays, saving £0.1 million to £0.6
million.
Introducing B-type natriuretic peptide tests in primary care should release
echocardiography resources that have a similar value to the cost of the
additional tests. Estimated savings comfortably exceed costs in the hospital
setting. These are however extrapolations from a Swiss study and still need to
be piloted in Scotland to establish whether they are appropriate for the
admissions setting.
16
2 Introduction
This document makes recommendations to NHSScotland based on a
completed Health Technology Assessment (HTA) on The use of B-type
natriuretic peptides in the investigation of patients with suspected heart failure
by NHS Quality Improvement Scotland (NHS QIS).
The initial sections of this document provide background information on NHS
QIS and on the HTA process (Section 3), and introduce the topic (Section 4).
The clinical evidence gathered is summarised in Section 5 and economic
analyses are presented in Section 6.
Organisational issues and patient issues are explored in Section 7.
Section 8 discusses the results and presents the recommendations that have
been informed by these results.
17
3 Background on NHS Quality Improvement Scotland
NHS QIS was set up by the Scottish Parliament in 2003 to take the lead in
improving the quality of care and treatment delivered by NHSScotland.
NHS QIS does this by setting standards and monitoring performance, and by
providing NHSScotland with advice, guidance and support on effective clinical
practice and service improvements.
Health technology assessment
HTA is an internationally recognised process used by NHS QIS to advise the
NHS in Scotland about a specific health intervention, eg medicine, equipment
or diagnostic test. HTA evaluates the clinical and cost effectiveness of the
various ways in which the health intervention can be used, comparing
alternative interventions where appropriate. Patient and organisational
aspects are also considered.
Evidence is identified by literature searching, together with evidence provided
by experts, patient interest groups and manufacturers. It is then critically
appraised and robust analyses are undertaken by expert staff. Surveys may
be undertaken to ascertain current clinical practice.
With considerable input from healthcare professionals who are expert in this
area of medicine (see Appendix 1), NHS QIS staff from a variety of disciplines
conduct the assessment. Peer review and wide public consultation ensures
that all views are considered in the process.
18
4 Setting the scene
Heart failure
Heart failure is a complex clinical syndrome in which the ability of the heart to
pump blood is reduced. The European Society of Cardiology (ESC) considers
the essential features of heart failure to be breathlessness or fatigue either at
rest or during exertion, and oedema (Remme et al., 2001). The signs and
symptoms, when present, are neither sensitive nor specific, making heart
failure difficult to diagnose accurately (De Lemos et al., 2003).
Diagnosis relies on clinical judgement of whether symptoms of heart failure
are present and evidence of cardiac dysfunction. Clinical judgement is
informed by a history, physical examination and appropriate investigations
(Remme et al., 2001). Non-specialist physicians in admission units or GPs
usually make the initial clinical assessment using ECG and X-rays but signs
are difficult to interpret, particularly among elderly patients, the obese and
women (Remme et al., 2001). Thus diagnosing heart failure is a considerable
challenge for these clinicians, particularly since most physicians working in
A&E or in admission units are not cardiologists (Packer, 2004).
Echocardiography is necessary to confirm the diagnosis and is the ‘gold
standard’ test for heart failure.
Within general practice, an ECG may be interpreted either by the GP or with
the assistance of an automated ECG report, or the GP may refer the patient
to a secondary care setting for the ECG. Historically, more than half of cases
diagnosed in primary care are found not to be heart failure when investigated
by echocardiography (Wright et al., 2003).
If heart failure is confirmed by echocardiography, the severity of the condition,
precipitating factors and the type of cardiac dysfunction should also be
assessed in order to make a full diagnosis and to choose appropriate
treatment (Cowie & Hobbs, 2002). However, historically only about 30% of
heart failure patients diagnosed in general practice in Scotland received
echocardiography (Scottish Health Purchasing Information Centre, 1998).
The New York Heart Association (NYHA) classification provides a measure of
the severity of symptoms and functional impact of heart failure on an
individual patient. This four-level scale is presented in Table 4 - 1.
19
Table 4 - 1 New York Heart Association classification of heart failure
symptoms
Class
Class I
Class II
Symptoms
No restriction at all – asymptomatic
Slight limitation by symptoms – comfortable at rest but ordinary activity results in
symptoms
Class III Marked limitation by symptoms – comfortable at rest but less than ordinary activity
gives symptoms
Class IV Unable to undertake any activity without symptoms – symptoms at rest
Reprinted from the European Heart Journal, 22, Remme WJ et al., Guidelines for the
diagnosis and treatment of chronic heart failure, 1527–1560, Copyright (2001) with
permission from The European Society of Cardiology.
Ischaemic heart disease is the most common cause of heart failure. As such,
most heart failure is associated with evidence of left ventricular systolic
dysfunction (LVSD), although diastolic impairment is a common if not
universal accompaniment. The majority of patients with heart failure and
impairment of diastolic function also have impaired systolic function (Remme
et al., 2001). This reflects the fact that systolic and diastolic phases and
function are interdependent (Chatterjee, 2002). When heart failure is
accompanied by a predominant or isolated abnormality in diastolic function,
this clinical syndrome is called diastolic heart failure (Zile & Brutsaert, 2002).
In 1999, the Scottish Intercollegiate Guidelines Network (SIGN) published a
guideline on the diagnosis and treatment of heart failure due to LVSD
(Scottish Intercollegiate Guidelines Network, 1999). The recommended
algorithm for assessment of heart failure in primary care is shown in Figure
Figure 4 - 1.
20
Figure 4 - 1 Algorithm for assessment of suspected heart failure in
primary care
Reprinted from Scottish Intercollegiate Guidelines Network (1999)
Recommended pharmacological treatments for heart failure included
angiotensin converting enzyme (ACE) inhibitors, β-adrenoceptor antagonists,
diuretic therapy, spironolactone and digoxin. Recommended non
pharmacological interventions included dietary measures, exercise, smoking
cessation and moderation in alcohol consumption. The measures have been
shown to improve symptoms and prognosis and are incorporated into other
guidelines, particularly National Institute for Clinical Excellence (NICE)
(National Institute for Clinical Excellence, 2003) and ESC guidelines (Remme
et al., 2001).
The prognosis associated with untreated heart failure is worse than most
cancers. Results from study by Stewart et al. (2001) showed that, with the
exception of lung cancer, heart failure was associated with a poorer survival
rate than myocardial infarction and most common types of cancer.
21
Heart failure is the end stage of all diseases of the heart and is a major cause
of morbidity and mortality. The incidence and prevalence of the syndrome is
difficult to ascertain accurately as studies on epidemiology are complicated by
the lack of a universal agreement on the definition of heart failure (Davis et al.,
2000). The MONICA (monitoring trends and determinants in cardiovascular
disease) study defined heart failure as symptomatic LVSD based on clinical
judgement and echocardiography (ejection fraction (EF) 30% or less).
According to this definition, in a population of men and women aged 25–74
years from North Glasgow, 1.5% had heart failure. The MONICA study also
determined that asymptomatic LVSD is at least as common as symptomatic
heart failure (McDonagh & Morrison, 1997). Early treatment of asymptomatic
LVSD is beneficial as it can prevent progression to heart failure (Cowie &
Hobbs, 2002).
It is well established that the prevalence of heart failure increases rapidly with
age. The syndrome is becoming more prevalent because of the ageing
population and advances in the treatment of coronary heart disease; more
people are surviving a myocardial infarction but are left with residual heart
damage (Stewart et al., 2003).
Heart failure accounts for more than 4% of all general medical and cardiology
admissions (Stewart et al., 2002). The combined total direct cost of heart
failure to the NHS in the UK was estimated to be £905 million in the year 2000
– equivalent to 1.91% of total NHS expenditure – with hospitalisation being
the predominant cost component (Stewart et al., 2002).
According to ISD data, 30,000 patients with heart failure visit their GPs about
63,000 times annually; this is equivalent to about 60 visits per practice, and an
increase of 5% on the previous year. Eccles et al.(1998) estimated that each
GP with a list size of 2,000 patients will see about 10 new patients with heart
failure each year.
ISD data also show that annually Scottish hospitals admit over 12,000
patients with heart failure, of whom 7,260 are emergency admissions. This
number has fallen steadily over the last five years from over 8,700 at year
ending 31 March 1999. A similar decline is observed in elective admissions.
Admitting departments will triage significantly more patients who present with
signs and symptoms of heart failure such as breathlessness, swelling and
fatigue.
B-type natriuretic peptide
Brain natriuretic peptide (BNP) and N terminal-pro-BNP (NT-proBNP) are
peptide hormones produced in the heart by breakdown of a pre-cursor protein
(pro-BNP). BNP causes natriuresis, diuresis, vasodilation and muscle
relaxation; NT-proBNP is inactive (Cowie et al., 2003). Important differences
between the two tests are summarised in Table 4 - 2.
22
Table 4 - 2 Comparison of BNP and NT-proBNP
Characteristics
Hormonally active
Half life
Clearance mechanism
BNP
Yes
22 min
Neutral endopeptidase
clearance receptors
+
-0.20
Increases with aging
Correlation with glomerular
filtration rate
Approved cut-off(s) for
100 pg/ml
diagnosis of chronic heart
failure
(Adapted from Weber et al. (2005)).
NT-proBNP
No
120 min
Renal clearance
+++
-0.60
Age < 75 years: 125 pg/ml
Age ≥ 75 years: 450 pg/ml
Plasma BNP and NT-proBNP concentrations are raised in patients with
increased cardiac chamber wall stretch, an expanded fluid volume or reduced
clearance of peptides. Raised concentrations are thus associated with various
conditions to include heart failure and renal failure. In heart failure, the
concentrations rise with NYHA class. Concentrations also vary by age,
gender, co-morbidity and drug therapy (Cowie et al., 2003).
Measurement of plasma concentration of BNP and NT-proBNP is approved
by the American Food and Drug Administration (FDA) as a blood test to aid in
the diagnosis of heart failure.
In Scotland, BNP assays are marketed for laboratory settings (Abbott and
Bayer) and for point-of-care testing (BioSite). An assay for NT-proBNP is also
available (Roche Diagnostics). This is currently only for laboratory settings.
Other assays are expected to be available from Dade Behring and Diagnostic
Products (Dr P Collinson, Consultant Chemical Pathologist, St George’s
Hospital, London. Personal communication, September 2004).
In response to a questionnaire distributed by NHS QIS, only one laboratory in
Scotland indicated that it provides BNP testing (using the BioSite assay). This
service is provided for secondary care and A&E settings. Subsequently, a
laboratory NT-proBNP assay has been introduced for use in primary care
mainly in patients who were awaiting an echocardiography. In addition, at
least one managed clinical network (MCN) to date has budgeted to pilot BNP
use.
Primary objective and scope of the HTA
There is increasing interest from GPs and hospital physicians in Scotland
about the use of B-type natriuretic peptide tests, but uncertainty about
whether and how they should be used. The NICE guideline on chronic heart
failure, published in 2003, recommended that health professionals should
seek to exclude a diagnosis of heart failure through the use of 12-lead ECG
and/or BNP or NT-proBNP where available. If one or both are abnormal, the
patients should receive echocardiography; if the diagnosis is still unclear after
these, and other tests, then the patient should be referred to a specialist
(National Institute for Clinical Excellence, 2003).
23
This HTA was undertaken to establish the place of B-type natriuretic peptides
in the diagnosis of heart failure in Scotland. More specifically, the HTA
investigated whether or not a normal BNP or NT-proBNP result should be
used for patients with signs and symptoms of possible heart failure:
1. in the primary care setting to inform the decision to refer a patient to a
specialist or for echocardiography
2. in the admissions setting to inform decisions around treatment and
placement of patients.
Clinicians in primary and secondary care are assumed to use an ECG for
such patients.
As explained previously, B-type natriuretic peptide concentration can be
affected by drug therapy. For this reason, the HTA focuses on studies of
patients with new symptoms who have had no treatment for heart failure.
Patients with a historical diagnosis of heart failure which has not been
confirmed by echocardiography are not considered in detail. B-type natriuretic
peptides are likely to be lower in such patients because many will have been
treated with diuretics and ACE inhibitors (Cowie, 2004).
B-type natriuretic peptides may also be used in patients with symptoms
suggestive of acute coronary syndromes, as a screening tool in asymptomatic
people or for monitoring the treatment given to patients with heart failure.
However, these issues have not been considered in this HTA.
24
5 Clinical effectiveness
5.1
Methodology
This chapter assesses the clinical-effectiveness evidence for the use of Btype natriuretic peptide tests in diagnosing heart failure in the primary care
and emergency settings.
As described in Section 4, clinical presentations of heart failure include
patients with evidence of LVSD and patients with normal or near normal
systolic function but an abnormal diastolic dysfunction. A diagnosis of LVSD is
usually established by determining the EF by echocardiographyc. The gold
standard for defining diastolic dysfunction is left heart catheterisation and
evaluation of pressure-volume curves at rest and during exercise (Banerjee et
al., 2002). However, this procedure is invasive and therefore not practicable
as a diagnostic tool for the majority of patients. For this reason, many of the
published studies use a target diagnosis of LVSD. Sensitivity and specificity
are therefore estimated for the following combinations of test and target
diagnosis:
•
•
•
•
BNP, heart failure
BNP, LVSD
NT-proBNP, heart failure
NT-proBNP, LVSD.
In clinical practice, BNP, NT-proBNP and an ECG can be used as part of the
clinical assessment of patients to inform referral decisions for further
diagnostic tests, particularly echocardiography. Throughout this chapter,
sensitivity and specificity should refer to a target of ‘appropriate referral’, and
ideally would be presented for a combination of the tests under consideration
and clinical features. However, the evidence available from the literature only
permits the accuracy of these individual tests to be determined, and the
complex relationship of these tests to clinical features must remain a matter
for clinical judgement.
It is likely that a number of patient characteristics, specifically age, gender,
grade of disease, prior drug therapy and pre-existing renal impairment will
affect the diagnostic accuracy of B-type natriuretic peptides. The majority of
studies do not present data in sufficient detail to allow these issues to be
addressed formally in the statistical analysis; however these are discussed in
Sections 5.5.1 and 5.6.
In order to provide data for the economic assessment, the accuracy of an
ECG for providing evidence of conditions consistent with the aetiology of heart
failure and LVSD was also assessed.
c
Other tests such as radionuclide ventriculography or catheterisation may be necessary if the
echocardiogram cannot be interpreted.
25
5.1.1 Sources of evidence
Evidence was obtained from a variety of sources including published and grey
literature and information from manufacturers and clinical experts.
5.1.1.1 Literature search
Initial scoping searches to identify high-level evidence such as HTAs,
systematic reviews and ongoing research relevant to the question were
undertaken in June 2003 and updated in January 2004. Sources used
included, for example, the HTA database, the Cochrane Database of
Systematic Reviews and the Database of Abstracts of Reviews of Effects
(DARE).
The systematic literature search for primary studies was undertaken between
February and June 2004. Three searches were undertaken, which combined
the concept of heart failure with each of the diagnostic tests. Also, to focus the
retrieval on diagnostic accuracy studies, a methodological filter adapted from
McKibbon et al.(1999) was used. Due to the large number of studies
retrieved, the decision was made to restrict the ECG and echocardiography
searches to retrieve systematic reviews. An in-house systematic reviews filter
was used. In addition, searches to identify studies relating to the natural
history and disease progression of heart failure were also undertaken. No
language or date restrictions were applied to any searches.
The following sources were used for all searches and were accessed via
OVID:
•
•
•
•
MEDLINE
EMBASE
MEDLINE IN PROCESS
CINAHL.
The British Library’s table of contents service ‘Zetoc’ was used. Relevant
journal title and keyword searches were set up, with results emailed and
disseminated daily from April 2004 until the end of March 2005. In addition,
bibliographies were scanned for relevant studies and citation searching on
key papers and authors was undertaken using Web of Science.
A list of sources searched and a copy of the search strategies, including the
diagnostic accuracy and systematic reviews filters, are included in Appendix
2. All included strategies were those used to search MEDLINE. These
strategies were adapted to search the other listed databases. A complete
listing of all strategies can be obtained by contacting NHS QIS.
5.1.1.2 Study selection criteria
The following studies were included:
•
•
studies with a target diagnosis of LVSD or heart failure
primary studies.
26
Studies were excluded if:
•
•
•
accuracy estimates were based on the comparison of clearly diseased
patients against a healthy control group
they did not present sufficient information to allow sensitivity and specificity
to be calculated
sufficient data to estimate accuracy was not presented in the paper.
A total of 2,941 studies were identified in the literature search and 2,141 were
excluded using these criteria (Appendix 3). In total, 1,090 potentially relevant
articles were reviewed and 118 articles were referenced in the report.
5.1.2 Overview of diagnostic studies
BNP
Twenty-three studies of BNP are included in this review (see Table 11 - 1,
Appendix 4). Of these, 11 consider heart failure, 10 consider LVSD and two
consider the diagnosis of ‘left ventricular dysfunction’ including both systolic
and diastolic dysfunction. The latter two are excluded from the meta-analyses.
The study by Sparrow et al. (2003) is also excluded from the meta-analyses,
as inclusion in this study was limited to patients already receiving loop
diuretics, which is known to reduce BNP levels (Kazanegra et al., 2001).
Studies results are shown in Table 11 - 2 (see Appendix 4).
NT-proBNP
Thirteen studies of NT-proBNP are included in this review (eight in heart
failure, the remainder in LVSD). Study details are shown in Table 11 - 3 and
results in Table 11 - 4 (see Appendix 4).
ECG
A normal ECG is rare in a patient with chronic heart failure (Remme et al.,
2001). Although ECG abnormalities are unlikely to be specific for heart failure
or LVSD, the use of an ECG as a tool to select patients for further referral is
frequently current clinical practice, and its ‘diagnostic’ accuracy will therefore
be estimated.
Twelve peer-reviewed studies of ECG diagnosis are included in this review
(three in heart failure, the remainder in LVSD). Study details are shown in
Table 11 - 5 and results in Table 11 - 6 (see Appendix 4).
In addition, data from an unpublished study are used (Struthers, unpublished).
27
Study quality and applicability
Generally, the studies of B-type natriuretic peptides appear to have
reasonable internal validity; in all but eight studies it was reported that the
reference and index tests were read independently. The blind status was not
reported in the remaining studies.
However, some concerns remain over generalising from these results;
particularly over their applicability to the primary care setting considered in the
economic evaluation.
Of particular concern, the two types of study population which dominate these
studies are:
•
•
patients presenting to the emergency department with acute
breathlessness
patients already selected by GPs for referral to a cardiology unit/heart
failure clinic.
It is likely that both these populations may contain more severely ill patients
than would be typical of the group initially presenting to a GP. Moreover, the
accuracy of any test will vary with severity of illness. Thus the observed
sensitivity and specificity of these tests, based on groups containing more
severely ill patients, may be higher than achievable in normal practice.
Additionally, the definition of LVSD varies among studies (ranging from an EF
of below 30% to one of below 50%).
Similar concerns apply to the ECG studies. A further concern with
generalising from these studies is that the ECGs have been interpreted by
either consultant cardiologists or GPs with sufficient interest and skill to
participate in such studies. It is not clear that the resultant accuracy will apply
to ECGs read by GPs outside the study setting.
5.1.3 Evaluation of sensitivity, specificity and pooled diagnostic odds ratio
The ‘accuracy’ of a diagnostic test is normally described by two quantities, the
sensitivity and specificity (or equivalently the true-positive rate [=sensitivity]
and the false-positive rate [=1 – specificity]).
Sensitivity is the probability that a test result is positive given the subject has
the disease. In a suitable experiment, the sensitivity can be estimated by:
true-positive/(true-positive + false-negative).
Specificity is the probability that a test result is negative given the subject
does not have the disease. In a suitable experiment, the specificity can be
estimated by: true-negative/(true-negative + false-positive).
The sensitivity and specificity of tests are illustrated in Table 5 - 1.
28
Table 5 - 1 Sensitivity and specificity of tests
Diagnostic test
Positive
Negative
Total
With disease
a
c
a+c
Without disease
b
d
b+d
Total
a+b
c+d
a+b+c+d
Therefore, sensitivity is expressed as a/a+c, and specificity is expressed as
d/b+d.
The diagnostic odds ratio (OR) is used to assess the risk of a particular
outcome, and is a relative measure of risk of having the disease given a
positive test compared with those having the disease given a negative test. It
is commonly used as a measure for the discriminative power of a diagnostic
test. It is the ratio of the odds of a positive test result among diseased to the
odds of a positive test result among the non-diseased (Moses et al., 1993).
OR =
sensitivity (1 − sensitivity )
(1 − specificity ) specificity
The negative predictive value (NPV) of each test will also be presented for a
range of prevalences of heart failure (5%, 15%, 25% and 50%). The NPV of a
test in a population with prior (pre-test) prevalence of p is given by:
(1 − p ) * specificity
(1 − p ) * specificity + p * (1 − sensitivity )
NPV =
5.1.4 Analysis
Data from the studies were combined using a meta-analysis approach
(Dersimonian & Laird, 1986). Analyses were performed separately for each of
the combinations of test and target diagnosis described in Section 5.1. Both
assay type (supplier) and assay cut-off varied among studies. Therefore, in
addition to pooling the sensitivity and specificity separately using a randomeffects model, summary receiver operating characteristic (ROC) curves
(Moses et al., 1993) were constructed. Summary ROC curves allow results
from several diagnostic studies to be combined, where each reports an
estimated false-positive rate (FPR) and an estimated true-positive rate (TPR).
Analyses were performed using the MetaDiSC software. Additionally, the five
studies which assessed the diagnostic accuracy of BioSite BNP for heart
failure using a common cut-off (100 pg/ml) were combined, since this group of
studies could be expected to be reasonably homogeneous.
The ROC curves for BNP and NT-proBNP are shown for heart failure and
LVSD and ECG in heart failure (Figures 11 - 1 to 11 - 4, Appendix 4).
5.2
Results
The main results are summarised in Table 5 - 2 and Table 5 - 3, and
discussed in greater detail in Sections 5.2.1 to 5.5.1.
29
Table 5 - 2 Summary of results for different combinations of tests and
target diagnoses
Test and target
diagnosis
Pooled sensitivity
(95% CI)
0.91 (0.90–0.93)
0.88 (0.84–0.91)
0.91 (0.88–0.93)
0.84 (0.80–0.88)
Pooled
specificity
(95% CI)
0.73 (0.71–0.75)
0.62 (0.60–0.63)
0.76 (0.75–0.77)
0.65 (0.64–0.67)
Pooled
diagnostic OR
(95% CI)
36 (17–74)
11 (7–18)
40 (18–88)
15 (11–21)
BNP, heart failure
BNP, LVSD
NT-proBNP, heart failure
NT-proBNP, LVSD
ECG, heart failure
(cardiologist read)
ECG, heart failure
(machine read)d
ECG, LVSD (cardiologist
read)
ECG, LVSD (machine
read)
0.85 (0.79–0.90)
0.60 (0.56–0.65)
10 (5–21)
0.86 (0.68–0.98)
0.26 (0.20–0.31)
2
0.90 (0.88–0.92)
0.58 (0.56–0.60)
12 (7–21)
0.83 (0.74–0.91)
0.21 (0.17–0.25)
1 (0.5–4)
Table 5 - 3 Estimated NPV for each test/condition combination assuming
fixed test performance and varying pre-test prevalence
Test and target
diagnosis
BNP for heart
failure
BNP for LVSD
NT-proBNP for
heart failure
NT-proBNP for
LVSD
ECG for heart
failure
(cardiologist
read)
ECG for LVSD
(cardiologist
read)
Pre-test prevalence
5%
15%
25%
50%
99%
98%
96%
89%
99%
97%
94%
84%
99%
98%
96%
89%
99%
96%
92%
80%
99%
96%
92%
80%
99%
97%
95%
85%
5.2.1 BNP for heart failure
Graphical summaries for this analysis are shown in Figures 5 - 1 to 5 - 3.
Although the sensitivity values appear homogeneous, and the overall
sensitivity estimate of 91% is therefore a reasonable summary, the
specificities vary substantially among studies. Three studies have
considerably lower specificities than the remainder. The abstract report by
Misuraca et al. (2002) does not contain sufficient information to allow an
explanation of their low specificity, but some explanation is possible for the
two remaining studies. The study by Knusden et al. (2004) contains a
relatively high proportion of patients over 75 (average age of 76 years, versus
average age of 63 years in the study by Dao et al. (2001) and 65 years in the
study by Maisel et al. (2001)). The Logeart et al. (2002) study of patients with
d
Single study only.
30
acute severe dyspnoea contains patients with pulmonary embolism and
severe chronic obstructive pulmonary disease (COPD) who had BNP levels in
excess of 100 pg/ml.
31
Figure 5 - 1 Pooled sensitivity of BNP for heart failure
Figure 5 - 2 Pooled specificity of BNP for heart failure
Figure 5 - 3 Pooled diagnostic OR for BNP in heart failure
32
It should be noted, however, that the design of many of these studies could
usefully be improved upon, and that some doubt must remain over the exact
usefulness of BNP in the diagnosis of heart failure. Specifically, the studies do
not exclude patients in whom no important diagnostic uncertainty exists (ie
patients in whom heart failure is essentially certain). The sensitivity may be
lower in studies restricted to patients with substantial uncertainty. For
example, of the patients included in the Maisel et al. (2001) study, a
retrospective analysis determined that the emergency physician faced real
diagnostic uncertainty in about 28% of patients (Maisel et al., 2001).
The study by Villacorta et al. (2002) recruited a large proportion of NYHA
Grade IV patients, and only one cardiologist was involved in making the
diagnosis.
BNP has a greater than 90% NPV in the patient groups observed in general
practice and outpatients where prevalence rates are under, for example, 30%;
and about 90% for groups with higher prevalence rates, for example in the
acute setting.
5.2.2 BNP for LVSD
Graphical summaries for this analysis are shown in Figures 5 - 4 to 5 - 6. Two
points should be noted:
•
Hutcheon et al. (2002) and Landray et al. (2000), two of the three included
studies with markedly lower specificities, contain high proportions of
elderly patients. The remaining low specificity study (Ng et al., 2003)
deliberately reported the specificity corresponding to a sensitivity of 100%,
arguing that this corresponded best to their preferred usage of BNP.
•
The specificity of BNP for the detection of LVSD is lower than that for heart
failure. This may in part reflect the fact that not all heart failure patients
have reduced EF and so the result accords with clinical expectations.
The NPV for BNP for LVSD exceeds 90% at prevalence rates below 25%.
33
Figure 5 - 4 BNP sensitivity for LVSD
Figure 5 - 5 BNP specificity for LVSD
Figure 5 - 6 BNP diagnostic OR for LVSD
34
5.2.3 NT-proBNP for heart failure
Graphical summaries for this analysis are shown in Figures 5 - 7 to 5 - 9. It
should be noted that the pooled OR for NT-proBNP and NPVs in this
indication are essentially the same as that for BNP (40 versus 36) suggesting
that there is little important difference between the performance of the two
tests. This view is supported by the results of Ng et al. (2003) and HammererLercher et al. (2001). It should also be noted that the criticisms of BNP studies
also apply to these studies (see Section 5.2.1).
The study by Hobbs et al. (2004) contained patients who were being treated
for heart failure, and so presumably were at least ‘strongly suspected’ of
having the target disease.
Figure 5 - 7 NT-proBNP sensitivity for heart failure
Figure 5 - 8 NT-proBNP specificity for heart failure
35
Figure 5- 9 NT-proBNP diagnostic OR for heart failure
5.2.4 NT-proBNP for LVSD
Graphical summaries for this analysis are shown in Figures 5 - 10 to 5 - 12.
Again, the results are comparable with those obtained for BNP (see Section
5.2.2).
Figure 5 - 10 NT-proBNP sensitivity for LVSD
Figure 5 - 11 NT-proBNP specificity for LVSD
Figure 5 - 12 NT-proBNP diagnostic OR for LVSD
36
5.2.5 ECG for heart failure (cardiologist read)
Graphical summaries for three of the four studies analysed are shown in
Figure 5 - 13 to Figure 5 - 15. The fourth study (Fonseca et al., 2004) was not
included because the stated specificity (51%) is inconsistent with that
calculated from the raw data in the paper (35%).
The studies analysed also include unpublished data for cardiologist-read ECG
from a study currently under way in Dundee (Struthers, unpublished). Note
that the results reported here refer to the accuracy of ECG results as reported
by cardiologists or experienced GPs.
The ECG has a slightly lower sensitivity and specificity than BNP or NTproBNP. It has a similar NPV to B-type natriuretic peptide tests at the low
prevalence rates that might be observed in GPs’ clinics but has a poorer NPV
in settings with higher prevalence rates.
However, abnormalities on an ECG are linked to a range of cardiac conditions
including arrhythmias, acute coronary syndrome and ventricular strain, in
addition to heart failure. Referral to specialist is appropriate for such
conditions. Thus the lower specificity may not be a clinical drawback but
rather in accordance with good clinical practice.
Figure 5 - 13 ECG sensitivity for heart failure (cardiologist read)
Figure 5 - 14 ECG specificity for heart failure (cardiologist read)
37
Figure 5 - 15 ECG diagnostic OR for heart failure (cardiologist read)
5.2.6 ECG for heart failure (machine read)
The only study of machine-interpreted ECGs for heart failure (Struthers,
unpublished) showed a similar sensitivity (86%) but considerably lower
specificity (26%). The ECG used was an E-lite 6.34® with an interpretation
package using Minnesota criteria.e
5.2.7 ECG for LVSD (cardiologist read)
Graphical summaries for the seven studies of ECG in LVSD are shown in
Figures 5 - 16 to 5 - 18. The diagnostic performance of ECG appears similar
for this indication to the performance of BNP and NT-proBNP. It should be
noted, however that this generally refers to the performance of ECG as read
by cardiologists or ‘specifically experienced’ GPs and may not be easily
replicated outside these trials.
Its NPV is also similar to the performance of BNP and NT-proBNP other than
for populations with high prevalence rates.
e
Normal was defined as sinus rhythm 60–100/min, axis -30° to +90°, PR interval <0.2 s, QRS
duration <0.12 s, QTc interval <0.42 s with normal P wave, QRS complex as well as normal
ST segment and T wave.
38
Figure 5 - 16 ECG sensitivity for LVSD (cardiologist read)
Figure 5 - 17 ECG specificity for LVSD (cardiologist read)
Figure 5 - 18 ECG diagnostic OR for LVSD (cardiologist read)
5.2.8 ECG for LVSD (machine read)
Graphical summaries for the two studies of machine-read ECG in LVSD are
shown in Figure 5 - 19 to 5 - 21. The sensitivity is similar to that of
cardiologist-read ECG, but with substantially lower specificity (0.21).
39
Figure 5 - 19 ECG sensitivity for LVSD (machine read)
Figure 5 - 20 ECG specificity for LVSD (machine read)
Figure 5 - 21 ECG diagnostic OR for LVSD (machine read)
5.2.9 Joint diagnostic value of ECG and BNP or NT-proBNP
The three studies reported here (Hutcheon et al., 2002; Wright et al., 2003;
Zaphiriou et al., unpublished) assess the joint value of BNP or NT-proBNP
and ECG in diagnosing heart failure or LVSD. Hutcheon et al. (2002) found no
additional value in BNP measurement in addition to ECG, for the definition of
LVSD in their elderly patient population. In contrast, Wright et al. (2003)
reported that GPs obtained significantly more correct diagnoses of heart
failure (70% versus 59.5%) when provided with NT-proBNP results in addition
to existing clinical assessment results. Finally, Zaphiriou et al. (unpublished)
found that ECG (coded as normal/abnormal) does not add predictive value if
the NT-proBNP level is known.
Interestingly, Hedberg et al. (2004) showed that in randomly selected 75-year
old men and women, although the assay used (Shionona BNP kit, Shionogi &
Co, Osaka, Japan) was less accurate than ECG in diagnosis of LVSD, BNP is
of diagnostic value in patients with an abnormal ECG (35% of subjects with a
40
major ECG anomaly and raised BNP had LVSD, versus 3% with a major ECG
anomaly and normal BNP).
These studies suggest that some information is likely to be obtained from
peptide values that is additional to the information from the ECG results, at
least when the target diagnosis is that of heart failure. It would be valuable to
confirm this in the primary setting.
5.2.10 Comparative studies for heart failure in primary care
Two studies (Wright et al., 2003; Zaphiriou et al., unpublished) allow direct
comparison of B-type natriuretic peptides with either ECG or standard clinical
assessment in patients drawn from primary care and assessed for heart
failure. These studies therefore provide the most immediately relevant
comparisons to the objectives of this HTA.
The first study (Wright et al., 2003) was a direct, randomised comparison of
GP clinical assessment with or without NT-proBNP. It was not clear from the
paper whether any additional examinations (eg ECG) formed part of the GPs’
routine clinical assessment. In this randomised study involving just over 300
patients (average age of 72 years), of whom 77 (25%) were diagnosed finally
as heart failure, the sensitivity of the two groups was identical (91% in both),
but the specificity was higher in the group of GPs given access to the NTproBNP results compared with the group without access (61% versus 50%).
Two points should be noted. First, the GPs were given a 30-minute training
session on the interpretation of NT-proBNP. Secondly, the study may not
exactly mirror the likely practice in Scotland should B-type natriuretic peptide
assays be introduced. Specifically, patients were invited for a review visit by
GPs (median time from first visit to review was 24 days); whereas in practice,
it is likely that patients would be referred for echocardiography immediately
after the B-type natriuretic peptide test result becomes available. It is plausible
that without the review period, the apparent advantage of B-type natriuretic
peptides would be larger than an 11% improvement in specificity.
The Zaphiriou et al. (unpublished) study compared the accuracies of BNP,
NT-proBNP and ECG in diagnosing heart failure among 306 patients (average
age 74 years) who were referred by GPs to an open-access
echocardiography clinic with suspected heart failure. The diagnosis of heart
failure was confirmed in 34% of patients.
The sensitivity and specificity of the various tests in this population are shown
in Table 5 - 4.
41
Table 5 - 4 Sensitivity and specificity of B-type natriuretic peptide
assays at various cut-off points and compared with ECGs read by
cardiologists
Test
NT-proBNP
BNP
Cut-off
125 pg/ml
100 pg/ml
65 pg/ml
30 pg/ml
Sensitivity
0.98
0.79
0.87
0.95
Specificity
0.35
0.72
0.57
0.35
0.81
0.60
ECG read by
cardiologists
These data (see Table 5 - 4) suggest that at the manufacturers’
recommended cut-offs, the BNP assay has a slightly poorer sensitivity than
ECG. As the cut-off level is reduced, sensitivity improves but specificity
declines.
5.2.11 Referral rates
The data provided by Wright et al. (2003) allow us to construct Table 5 - 5
which shows how referral patterns could be altered for 1,000 patients
exhibiting dyspnea or oedema, with the same referral characteristics of GPs
as found by Wright et al.(2003)f. As discussed above, the benefit of NTproBNP may be underestimated by the Wright et al. (2003) study, compared
with likely practice. However, the data presented suggest that approximately
83 echocardiography referrals would be saved per 1,000 additional NTproBNP tests. If we assumed that all the changes from the initial to the review
visit observed by Wright were caused by the NT-proBNP measurement, this
would increase to approximately 187 saved referrals per 1,000 NT-proBNP
tests.
Table 5 - 5 Referral patterns for 1,000 patients with symptoms
suggestive of heart failure (Wright et al., 2003)
Patient sub-groups
Referred – not heart failure
Referred – heart failure
Not referred – not heart failure
Not referred – heart failure
Avoided referrals – not heart failure (estimate)
Additional missed referrals with heart failure (estimate)
Number of patients
374
230
373
23
83
0
A similar calculation of benefit from the Zaphiriou et al. (unpublished) study
has been made assuming that B-type natriuretic peptide testing would only be
used by GPs in the patient group described in this study, ie those currently
referred to rapid-access echocardiography, and that GPs would interpret the
B-type natriuretic peptide results rigidly in accordance with pre-specified cutoffs.
f
Initial diagnostic impression based on patient history and examination was that 70% of
patients had heart failure. However, only 25% were allocated a diagnosis of heart failure by a
panel.
42
The analysis in Table 5 - 6 shows how referral patterns would be altered for
1,000 patients currently referred for rapid-access echocardiography as in the
Zaphiriou paper, assuming a true prevalence in this group of 25.2% (that is,
the GP specificity for diagnosis of heart failure is 0.252; this is in line with
other reports of rapid-access clinics, such as Fox et al. (2000)). This table
suggests that based on these assumptions, 1,000 NT-proBNP tests at the
manufacturer’s recommended cut-off could yield a saving of 261 referrals for
further assessment and echocardiography. This is unlikely to completely
reflect the true situation; some tests will probably be performed on patients
not currently referred, contributing both additional costs and potentially
additional true-positive findings.
Table 5 - 6 Referral patterns for 1,000 patients (diagnosed by GP) with
heart failure (Zaphiriou et al., unpublished)
Patient sub-group
No BNP
Referred – not heart failure
Referred – heart failure
NT-proBNP >125 pg/ml
Avoided referrals – not heart failure
Missed referrals with heart failure
BNP – 100 pg/ml
Avoided referrals – not heart failure
Missed referrals with heart failure
BNP – 30 pg/ml
Avoided referrals – not heart failure
Missed referrals with heart failure
ECG
Avoided referrals – not heart failure
Missed referrals with heart failure
Number of patients
747
252
261
5
538
53
261
13
448
48
Wright et al. (2003) provides some evidence that NT-proBNP is able to
identify cases of heart failure which are missed by GP clinical assessment;
the Zaphiriou et al. (unpublished) study does not allow this topic to be
addressed.
The actual benefit of B-type natriuretic peptide testing in Scottish primary care
could be assessed by undertaking a randomised study of similar design to the
Wright et al. (2003) study, but with referral decisions based solely upon the
first visit and B-type natriuretic peptide level. Such a study could also estimate
the most appropriate cut-off point for B-type natriuretic peptides in primary
care, and provide evidence on the disposition of ‘B-type natriuretic peptide
false-positive’ patients. It is plausible that this group may include patients
requiring cardiologist or related specialist care and thus the GP was correct to
refer for further cardiac assessment.
A study currently nearing completion in Darlington may provide the data
needed to assess the use of B-type natriuretic peptide tests in patients
showing normal ECGs (Dr A Fuat, Clinical Lead, CHD, Darlington Primary
Care Trust. Personal communication, October 2004).
43
5.2.12 Sequential use of ECG and BNP
One study (Zaphiriou et al., unpublished) allows estimates to be made of the
value of BNP among two groups of patients, namely those with a normal ECG
and those with an abnormal ECG. Although this suggests that there may be
some merit in supplementing normal ECG results with BNP testing, because
this is only one study in a relatively small number of patients, clear
conclusions on this issue must await further studies.
5.3
B-type natriuretic peptide in diastolic heart failure (DHF)
As the diagnostic OR for BNP is greater when assessed against clinical
criteria than against LVSD, BNP may also be detecting patients with DHF.
Further support is lent to this hypothesis by a small study (Yamaguchi et al.,
2004) in which BNP (Shinogi) levels of a group of 16 patients meeting the
diagnostic criteria of DHFg and a group of 22 hypertensive patients of similar
age, EF and left ventricular mass index but without any evidence of heart
failure were compared. BNP values were significantly (p<0.01) higher in the
DHF group.
These results suggest that a large prospective study of the utility of BNP or
NT-proBNP in diagnosing DHF would be valuable, especially in view of the
difficulty of diagnosing DHF by other routinely available methods.
5.4
B-type natriuretic peptide performance in different settings
It is likely that the performance of BNP or NT-proBNP may be different in the
hospital as opposed to the primary care setting. For example, it may be that
patients presenting to A&E may be acutely ill compared with those consulting
their GP. Separate meta-analyses were undertaken to address this possibility.
However, this results in attempting to combine small numbers of rather
heterogeneous studies, and the results presented must be treated with
considerable caution.
The results are presented graphically in Figures 11 - 6 to 11 - 29 (Appendix
4). There is however little persuasive evidence of any difference between the
settings in these studies, and pooled results will be used in the baseline
economic evaluation. The resultant pooled values for the sensitivity,
specificity, OR and ROC for heart failure and LVSD are shown in Figures 11 30 to 11 - 37 (Appendix 4).
5.5
Suggested cut-offs
Although simple single value cut-offs for the diagnosis of heart failure have
been suggested by manufacturers, it is clear from the literature that a more
realistic interpretation of BNP and NT-proBNP is to suggest that very low
g
Symptoms of heart failure present at admission and reduce by diuretic treatment, in the
presence of preserved EF (>45%) and no evidence of congenital heart disease, renal
disease, severe valve disease or acute coronary syndromes.
44
values rule-out heart failure, very high values make heart failure extremely
likely in the absence of other causes of raised BNP and that intermediate
values should be regarded as indeterminate.
A wide range of ‘optimal’ cut-offs has been suggested, generally on the basis
of a retrospective search for the best attainable discrimination. For example,
the BNP investigators (Maisel et al., 2003) suggested 100 pg/ml as the
optimal cut-off point, whereas Lainchbury et al. (2003) using the same assay,
suggested a cut-off of 208 pg/ml and Logeart et al. (2002) commented that in
their population ‘values of BNP between 80 pg/ml and 300 pg/ml were nondiagnostic’.
Hohl et al. (2003) in reviewing the BNP study, (Maisel et al., 2003) suggested
that a more useful approach might be to regard BNP <50 pg/ml as negative
for heart failure, values above 150 pg/ml as positive and intermediate values
as ‘indeterminate’ (note though that results from Logeart et al. (2002) would
suggest a lower value of 300 pg/ml for the minimum positive value, and
McCullogh et al. (2003) in a recent review paper suggested 400 pg/ml).
Currently, unpublished work (Zaphiriou et al., unpublished) suggests that in
patients referred to rapid-access echocardiography, a low cut-off for Biosite
BNP (30 pg/ml) is needed to retain high sensitivity.
It is likely that a similar approach will be needed for NT-proBNP. In this case,
the appropriate cut-off is likely to be age related. The current recommendation
from Roche suggests that the appropriate cut-off for heart failure detection
increases at the age of 75 from 125 to 450 pg/ml.
It is clear that more research is needed to define the appropriate cut-off
values, particularly in primary care.
More generally, the possibility of substantial rises in BNP due to, for example
pulmonary embolism (values of 1,000 pg/ml reported by Kucher et al. (2003)),
suggests that in some patients not even extremely high BNP would be
diagnostic of heart failure.
5.5.1 Other reasons for elevated BNP
BNP and NT-proBNP have been shown to be elevated in a variety of other
clinical conditions. These are discussed here. These studies confirm that BNP
and NT-proBNP are non-specific markers of ventricular dysfunction; rather
they identify patients at risk who require further assessment.
45
Pulmonary embolism
Pruszczyk et al. (2003) showed that NT-proBNP was elevated in 66/79
patients with acute pulmonary embolism (APE), and appeared to be predictive
of death or adverse events. Thirteen patients without NT-proBNP elevation
had uncomplicated recoveries, whereas 15 deaths and 24 adverse events
occurred in those with elevated NT-proBNP.
Kucher et al. (2003) showed that 42/73 patients with APE had (BioSite) BNP
levels above 90 pg/ml. They also showed however that only BNP levels below
50 pg/ml appear ‘definitely’ predictive of a benign course.
Renal disease
Siebenhofer et al. (2003) showed that NT-proBNP is significantly higher in
patients with diabetic nephropathy than in patients with Type 1 diabetes but
without evidence of nephropathy.
Luchner et al. (2002) showed that NT-proBNP is raised after myocardial
infarction to a similar level both in patients with left ventricular dysfunction,
defined as EF <35% (182.8 ± 41.9 pmol/l), and in patients with renal
dysfunction, defined as glomerular filtrate rate (GFR) <50 ml/min (210.3 ±
51.4 pmol/l). The authors commented that cut-off concentrations for NTproBNP to diagnose LVSD must depend on renal function.
Similarly, McCullough et al. (2003) showed that in patients with non-cardiac
dyspnoea, the average BNP level exceeds 200 pg/ml for patients with a GFR
below 60 ml/min.
Given the established relationship between B-type natriuretic peptide
concentrations and renal failure, measuring creatinine and B-type natriuretic
peptide concentrations simultaneously would aid the interpretation of the test
result.
Sepsis
Jones & Kline (2003) reported on three patients who presented with
symptoms suggestive of heart failure and BNP (BioSite) levels in excess of
1,000 pg/ml. Two of the three patients had normal left ventricular function, the
third had some evidence of impairment. In all three, the final diagnosis was
septic shock (Pseudomonas aeruginosa in two patients, and Escherichia coli
in one patient).
46
Acute coronary syndrome
A meta-analysis (Galvani et al., 2004) showed that both BNP and NT-proBNP
are raised in acute coronary syndromes, and indeed are predictive of clinical
outcomes.
B-type natriuretic peptide was also found to predict both exercise induced
(Sadanandan et al., 2004) and dobutamine-induced (Asada et al., 2004)
myocardial ischaemia and the extent of coronary artery disease in patients
with stable angina (Weber et al., 2004).
Severe acute dyspnoea
Logeart et al. (2002) reported that some patients with acute severe dyspnoea
(requiring urgent hospitalisation) but with no evidence of heart failure had
BNP levels in excess of 100 pg/ml.
5.6
Discussion
A few points are clear from these analyses.
First, the diagnostic performance of BNP and NT-proBNP is similar. There is
no clinically significant evidence of any difference in diagnostic accuracy for
clinical heart failure, although there is some suggestion from four comparative
studies of a small advantage for NT-proBNP in the detection of lesser degrees
of LVSD (EF <50%) (Seino et al., 2004; Pfister et al., 2004; HammererLercher et al., 2001; Mueller et al., 2004).
Second, both BNP and NT-proBNP are more accurate in identifying heart
failure than in identifying LVSD; the specificity is much lower in the latter
indication.
Third, the ECG (as read by consultants and experienced GPs) appears to
have similar diagnostic value for LVSD to BNP or NT-proBNP. However, the
ECG (as read by consultants and specifically experienced GPs) has a similar
sensitivity but somewhat lower specificity than BNP or NT-proBNP for heart
failure.
Fourth, because BNP and NT-proBNP are non-specific markers of ventricular
dysfunction and can be raised by a variety of conditions, levels must be
interpreted along with other clinical and biochemical findings. Raised B-type
natriuretic peptide concentrations identify patients at risk of further adverse
events and require further assessment.
Finally, the specificity of BNP to detect LVSD (and possibly heart failure)
appears lower in studies with patients of older mean age. This is not
significant by meta-regression, but accords with biological considerations and
empirical studies in healthy volunteers (Wang et al., 2002; Redfield et al.,
2002).
The study reported by Wright et al. (2003) suggests that the major advantage
from NT-proBNP is in allowing heart failure to be ruled out in more patients
47
than is the case for ECG alone. However, the applicability of this result to the
task of selecting patients for echocardiography and cardiologist review is
unclear for two reasons. First, the results presented by Zaphiriou et al.
(unpublished) suggested that in fact BNP and NT-proBNP have lower
specificity than ECG and second, it is unclear whether GPs could avoid
referring a patient presenting with new ECG anomalies to a cardiologist,
regardless of their BNP status. These data suggest that a study could usefully
be undertaken to determine whether the greatest benefit of BNP may be, in
fact, to allow patients with heart failure and a normal ECG to be referred
timeously.
There is substantial evidence that the BNP level rises with NYHA grade, as
shown for example in the BNP study (Maisel et al., 2002), by Selvais et al.
(1998) and by Seino et al. (2004). Clearly, BNP (and NT-proBNP) will also be
more sensitive (for a fixed specificity) for higher grades of heart failure. This is
in accordance with the results obtained from screening asymptomatic groups
for mild LVSD, for example in Vasan et al. (2002) and Luchner et al. (2000).
This of course also implies that the sensitivity will be less high than the
reported values in patients with lower NYHA grades.
Two papers (in addition to the diagnostic study reported by Sparrow et al.
(2003)) specifically addressed the accuracy of B-type natriuretic peptides in
patients with established treatment for heart failure. Tang et al. (2003)
reported that 106 of 449 symptomatic heart failure patients (NYHA II or III)
and 60 of 109 asymptomatic heart failure (NYHA I) had BNP levels (BioSite)
below 100 pg/ml. Ninety-four percent of patients were receiving diuretics, 83%
ACE inhibitors or angiotensin-receptor blockers and 57% β-blockers.
McGeoch et al. (2002) showed that in a group of 100 patients treated for heart
failure for at least 3 months (largely ACE inhibitor ± diuretic), 37 had a BNP
value below 50 pmol/l (the local cut-off for the BNP assay used). This work,
together with earlier studies showing that BNP levels fall after treatment with
diuretics (Kazanegra et al., 2001), ACE inhibitors (Murdoch et al., 1999; Van
Veldhuisen et al., 1998) and valsartan (Latini et al., 2002). These results
suggest that BNP will be more effective as a diagnostic tool in patients not
already receiving therapy for heart failure. It should be noted, however, that
Wright et al. (2003) report that NT-proBNP retained diagnostic significance
even in pre-treated patients, although their results are not reported in detail.
48
Effect of B-type natriuretic peptides in the prognosis of heart failure
A recent systematic review of the prognostic utility of B-type natriuretic
peptide in patients with heart failure (Doust et al., 2005) found 19 studies in
patients with symptomatic heart failure and five studies in asymptomatic
patients. Despite the acknowledged difficulties of avoiding publication and
other biases, the authors concluded that B-type natriuretic peptide is a strong
predictor of prognosis, both of death and of cardiac events. Indeed, it appears
that B-type natriuretic peptide is at least as powerful a predictor as left
ventricular ejection fraction (LVEF), and may have additive predictive value
with LVEF.
They also note that in two studies in asymptomatic people, levels of BNP or
NT-proBNP well below the cut-offs currently used for heart failure appear to
predict poorer outcomes.
5.7
•
•
•
•
•
•
•
•
•
Conclusions
There is no evidence that for clinical purposes the accuracy of BNP differs
from that of NT-proBNP based on the results of this HTA. However, more
studies have been conducted using BNP, and behaviour in concomitant
disease and in the elderly is better characterised.
B-type natriuretic peptide levels alone are unlikely to be diagnostic,
because of the possibility of rises due to pulmonary embolism, renal
disease, sepsis and other causes. Instead, they are best used as a ‘ruleout’ test for heart failure.
For heart failure, a cut-off between 30 and 50 pg/ml (BioSite) identifies
patients who are unlikely to have acutely decompensated heart failure.
Rises in BNP above 150 pg/ml are associated both with acutely
decompensated heart failure and a variety of similarly serious conditions,
so although not diagnostic for heart failure, would prompt further
investigation.
Both BNP and NT-proBNP assays are less accurate for diagnosing LVSD
than for heart failure and have similar accuracy for LVSD compared with
ECGs read by consultants and specifically experienced GPs.
B-type natriuretic peptide tests have similar sensitivity but slightly greater
specificity for heart failure compared with ECGs read by cardiologists and
specifically experienced GPs.
The accuracy of the assays is greatest in severe disease.
The accuracy of B-type natriuretic peptides is poorer in patients who are
receiving therapy for heart failure.
The evidence on the addition of B-type natriuretic peptide tests to existing
clinical assessment suggests that providing GPs with the assay results
could reduce the number of patients who receive an initial diagnosis of
heart failure, which is not confirmed by echocardiography. However, this
should be confirmed by further studies designed to match the clinical
setting in Scotland.
Currently, very limited evidence from one study suggests that in primary
care, the optimal clinical referral strategy could be to refer all patients with
abnormal ECGs, and those with normal ECG but abnormal B-type
49
•
•
•
natriuretic peptides. This assumes all patients with suspected heart failure
will receive an ECG. A study currently under way may provide better data
to inform this decision. If the results of this study are not adequate for this
purpose, a further randomised study of referral decisions based solely
upon the first visit and B-type natriuretic peptide level will be needed.
Further work is required to establish relevant cut-offs and how these are
affected by age, sex and possibly co-morbid conditions.
BNP or NT-proBNP may be of value in the diagnosis of DHF. This should
be explored by further prospective study.
Studies indicate that the level of B-type natriuretic peptide concentrations
has prognostic value.
50
6 Cost effectiveness
6.1
Methodology
This chapter evaluates the cost effectiveness of B-type natriuretic peptide
testing in acute and primary care settings.
The methodology adopted is set out in Guidance to manufacturers (Health
Technology Board for Scotland, 2002). Best practice recommends that
economic evaluations adopt a societal perspective (Drummond & McGuire,
2001). However, this economic evaluation is based on diagnostic strategies in
heart failure; relevant variables include the diagnostic impact on patients and
changes to the use of subsequent tests. This means that the narrower
perspective of NHSScotland and the patient is used.
6.1.1 Sources of evidence
Evidence was obtained from a variety of sources including published and grey
literature and information from manufacturers and clinical experts.
6.1.1.1 Literature search
Initial scoping searches were undertaken in June 2003 and updated in
January 2004 to identify economic evaluations relating to the use of B-type
natriuretic peptides in the diagnosis of heart failure. The following databases
were searched: the NHS Economic Evaluation Database (NHS EED) and the
Health Economics Evaluation Database (HEED). In addition, websites of the
world’s major health economics research units were searched for relevant
economic evaluations.
Searches were undertaken in the major bibliographic databases (MEDLINE,
EMBASE, MEDLINE IN PROCESS, CINAHL, all via OVID) during April 2004
to identify further economic evaluations and costing information relating to the
use of BNP, ECG and echocardiography in the diagnosis of heart failure.
Three searches were undertaken, which combined heart failure with each of
the diagnostic tests. An in-house economics filter was also used as part of the
search strategy. The BNP and ECG searches were limited by date. Studies
pre-1998 were not retrieved. The echocardiography search retrieved a large
volume of articles, and was also restricted by date; only articles published
from 2000 onwards were retrieved. This particular search was also restricted
to English language papers. No language restrictions were applied to the BNP
or ECG searches.
A list of the sources searched and a copy of the strategy used to search the
MEDLINE database is given in Appendix 2. This strategy was adapted to
search all other databases. A complete listing of all strategies can be obtained
by contacting NHS QIS.
6.1.1.2 Study selection criteria
Studies were excluded if:
51
•
•
no data were reported on the costs and outcomes from using B-type
natriuretic peptides to assist in diagnosing patients with symptoms of heart
failure
the populations were not relevant to Scotland.
No formal data extraction or syntheses were performed.
6.1.2 Overview of studies
Acute care setting
One study using BNP tests in an emergency setting met the inclusion criteria.
Mueller et al. (2004) reported a prospective, randomised controlled study of
452 patients who presented with acute breathing difficulties to an emergency
department in Basel, Switzerland. Two hundred and twenty-five patients were
assigned to a diagnostic strategy including a BNP point-of-care test and the
remainder were assigned to the standard protocol. The BNP cohort had a
lower admission rate (75% versus 85% for control; p=0.008) and fewer
patients were placed in intensive care (24% versus 15%; p=0.01). In the BNP
group, the median time to discharge was shorter (8.0 days versus 11.0 days;
p=0.001) and the cost of treatment was lower ($5,410, 95% CI $4,516–$6,304
compared with $7,264, 95% CI $6,301–$8,227; p=0.006). The 30-day
mortality rates were 10% and 12% for the BNP and control groups
respectively (p=0.45).
Assuming the two patients groups were well matched, the authors concluded
that in the emergency setting, the availability of rapid BNP results in
conjunction with other clinical information improves the evaluation and
treatment of patients, thereby reducing length of stay and total treatment
costs.
Applying Scottish costs and length of stay
Mueller et al. (2004) used hospital charges as an estimate of treatment costs
and did not deduct the costs of conducting the BNP tests from the savings in
reduced hospitalisation rates and shorter length of stay, to establish the net
savings from using BNP.
Table 6 - 1 shows the potential savings that could accrue if the clinicaleffectiveness data from the Swiss study are replicated in the Scottish setting.
These assume two cohorts, each of 100 patients, one receiving a BNP test as
part of standard care and the second standard care only. Treatment costs for
the BNP group were calculated by multiplying 100 by the admission rate and
the time to discharge from the Swiss study, and the mean Scottish daily bed
costs of £255. This is calculated based on the actual bed days used for each
speciality group; for example if a patient is admitted to cardiology and
transferred to general medicine, then a weighted average of the two costs is
computed. Information Services (ISD) of NHS National Services Scotland
provided this information. Treatment costs for the standard care group were
calculated by multiplying 100 by the observed admission rate in the Swiss
52
study, time to discharge and Scottish daily bed costs (the latter variables from
ISD).
Table 6 - 1 Comparison of using BNP and standard care in the
emergency setting
Number of patients
Admission rate
Average length of stay
Treatment costs
(Cost per day £255)
Total cost including BNP test @ £30 per test
Total savings
Saving per patient
B-type natriuretic
peptides group
100
75%
8 days
Standard care
(control group)
100
85%
9.2 days
£153,000
£156,000
£43,400
£434
£199,400
£199,400
The total treatment costs were £153,000 for the BNP group and £199,400 for
the standard care group. Adding the cost of conducting 100 point-of-care tests
at £30 each gives a total cost for the BNP group of £156,000. This suggests if
the Swiss results generalise to Scotland, then there could be a potential cost
saving of about £430 per patient from adopting BNP testing in acute care.
This is the only study of cost effectiveness in this setting and these cost
comparisons do not provide robust evidence. Thus, it would be essential to
pilot using these tests on typical patients presenting to A&E to enable clinical
and cost effectiveness to be validated using Scottish protocols, diagnostic and
discharge procedures.
Primary care setting
McDonagh et al. (2004a) compared the cost effectiveness of screening highrisk patients for LVSD using B-type natriuretic peptides or hospital outpatient
ECG or echocardiography. The costs assumed for each procedure were £16,
£84 and £121 respectively. The results showed that pre-screening by BNP
gives rise to more false positives than using ECG (3,025 versus 889) but that
B-type natriuretic peptide testing is the more cost-effective option.
These results are not directly relevant to the study question because this HTA
is interested in symptomatic patients only.
6.1.3 Economic model for primary care
A simple economic model for primary care compared the clinical and cost
effectiveness of the current diagnostic pathway as shown in Figure 6 - 1
(assessment of signs and symptoms using ECG followed by referral to a
specialist and echocardiography if there is clinical suspicion of heart failure)
with the following alternatives:
•
a consultant-led ECG service, whereby GPs take the ECG and send the
image to a cardiology service for interpretation by trained technicians and
cardiologists, followed by referral to a specialist and echocardiography if
ECG results are abnormal.
53
•
addition of a B-type natriuretic peptide test to the current diagnostic
pathway followed by referral to a specialist and echocardiography if B-type
natriuretic peptide results are abnormal.
Figure 6 - 1 Algorithm for the diagnosis of heart failure
Reprinted from Remme et al. (2001) with permission from the European Society of
Cardiology.
Some GPs send the patient to a referral centre to have the ECG taken and
interpreted. This variation of the first option would increase the cost of the
ECG but it is assumed the accuracy of the test would not change.
As explained in Section 4, historically only about 30% of heart failure patients
diagnosed in primary care receive an echocardiogram. However, the
introduction of a clinical indicator in the GMS contract (NHS Confederation &
British Medical Association, 2003) is anticipated to materially increase the use
of echocardiography to confirm a diagnosis of LVD. The model assumed all
patients referred receive echocardiography.
The model focused on the number and cost of correct ECG and B-type
natriuretic peptide abnormalg results, with the test results confirmed using
echocardiography as the ‘gold standard’. This is described as the number of
true-positive results.
The principal outcome was the marginal cost of each correct abnormal test
result confirmed by echocardiography.
g
An abnormal result, referred to as a positive result, for B-type natriuretic peptides is defined
as a result that is higher than a pre-defined cut-off. A normal result, referred to as a negative
result, for B-type natriuretic peptides is a result which is below the pre-defined cut-off.
54
Costs included:
•
•
•
•
the laboratory and reagent cost of B-type natriuretic peptide tests
the additional costs of a consultant-led ECG service compared with a GPbased service
the cost of managing patients who have a negative test result but who do
have the disease (false-negative patients)
the cost of echocardiography and 2 months of diuretics for patients
referred for an echocardiogram on the basis of the initial test result but
who have normal echocardiography (false-positive patients).
No costs were included for echocardiography scans which confirm an
abnormal test result. If the costs were to be included, it would increase the
cost base of all options by the cost of echocardiography for all true-positive
patients.
These costs are likely to understate the patient disbenefit of an unnecessary
referral to echocardiography. For example, such patients may suffer anxiety
whilst awaiting the echocardiogram and be delayed in receiving treatment for
their true underlying condition.
The costs used were therefore limited to the diagnostic process, but included
the costs of false-positive and false-negative results. No model of the impact
of B-type natriuretic peptide tests on the entire pathway for treating patients
with heart failure, or of their impact on patients’ quality of life and life
expectancy is presented. The literature search failed to find any robust data
quantifying the effect of small changes in the timing and cost of diagnostic
tests on the total costs of managing patients with heart failure and patient
outcomes. This means that the analysis was limited to examining the definite
benefits, as measured by improving the use of limited healthcare resources,
afforded by the different diagnostic tests.
6.1.3.1 Model inputs: clinical-effectiveness data
Section 5.2 presents the clinical effectiveness evidence for BNP, NT-proBNP
and ECG. This shows that BNP and NT-proBNP, whether laboratory or pointof-care, have similar accuracies. The sensitivities and specificities for BNP
and NT-proBNP have thus been combined to give a single sensitivity and
specificity for B-type natriuretic peptides (see Table 6 - 2; and Figures 11 - 30
and 11 - 31, Appendix 4).
The model assumed that GPs reading ECGs have an accuracy level
equivalent to the accuracy of the pooled consultant-read studies and an ECG
machine. There is considerable uncertainty around this key assumption. A
study of the accuracy of GP-read ECGs is under way and its results should
inform this assumption (Prof. A Struthers, Professor of Cardiovascular
Medicine and Therapies, University of Dundee and Ninewells Hospital.
Personal communication, June 2004).
55
Table 6 - 2 Sensitivities and specificities of tests for heart failure
Test
Sensitivitya
Specificitya
B-type natriuretic peptides
91%
(laboratory and point-ofcare)
Consultant-led ECG
85%
GP-read ECG
85%
a
Rounded to the nearest whole number.
75%
60%
49%
6.1.3.2 Model inputs: prevalence rate of heart failure
The literature search identified two studies with prevalence rates for heart
failure in a symptomatic group. Cowie et al. (1997) asked a group of London
GPs to refer all newly suspected heart failure patients to their clinic over a 15month period. Among 122 newly suspected heart failure patients, 35 were
found to have heart failure, giving a prevalence rate of 29%.
Of 1,586 patients presenting to hospital with shortness of breath in the study
by Wu et al. (2004), 47% had heart failure.
A third study by Landray et al. (2000) of 126 patients with suspected heart
failure (mean age 74.4 years), referred by GPs to a clinic, found 32% had
LVSD.
The Cowie et al. (1997) results are for a similar presenting population to that
modelled in this HTA; possibly the observed prevalence will be higher than
the rate in general practice because the population in the Cowie et al. (1997)
study was selected and did not include the wider group of patients with signs
and symptoms suggestive of heart failure. Both groups should have lower
prevalence rates than found in a hospital setting because acutely ill patients
will present at hospital. The Landray et al. (2000) study included a high
proportion of elderly patients and did not define LVSD. Many elderly patients
will have impaired EF so a high prevalence LVSD can be expected.
The base case adopted a prevalence rate of 29% for heart failure. The
Landray data are used to inform the sensitivity analyses.
6.1.3.3 Model inputs: cost of tests, drugs and waiting times
The base case assumed all new patients presenting with symptoms of heart
failure receive an ECG as part of the GP’s initial assessment. Thus, the
costings assumed no marginal costs for a GP-read ECG. The cost per test
and cost of therapy are provided in Table 6 - 3, with details in Appendix 6.
56
Table 6 - 3 Cost of tests, therapy and waiting times
Cost item
B-type natriuretic
peptides laboratory
test
GP-read ECG
Consultant-led ECG
Echocardiography
Therapy
Description of costs
Reagent cost per testa plus transport,
laboratory, staff time and communication with
patient
All patients receive an ECG.
GP ECG, 90% read by a medical technical
officer grade 4 and 10% by a cardiologist, plus
communications to GP and from GP to patient
Clinic costs, scan, read and report, patient travel
time and communications from consultant to GP
and to patient
Waiting time
Patients receive diuretic prior to
echocardiography
Marginal cost or time
£21
£0
£12
£109
2 months
£1 per month
£56.40 (of which
£14.40 is patient travel
cost)
Time to re-presentation
3 months
a
Costs include quality control and calibration: these are indicative costs from the
manufacturer and assumed throughput of 1,000 tests per year.
False-negative
patients
Costs of two further GP visits before receiving
an echocardiography
Univariate sensitivity analyses are presented on most of the variables
presented in Table 6- 3, reflecting uncertainties around variation in service
delivery and patient numbers.
6.2
Results
6.2.1 Base-case interpretation of results
In the subsequent tables, the diagnostic tests are ordered by cost to assist the
comparison of outcomes and cost effectiveness. If one test has a lower cost
and higher number of true-positive results, it is said to ‘dominate’ the other
more costly but less effective strategy.
However, sometimes a more expensive strategy yields more true-positive
results than a cheaper strategy. In such cases, the more expensive strategy
could be cost effective. To inform this decision, the additional cost for each
additional true-positive result is calculated. The resultant incremental cost per
additional true-positive result can then be compared with the value of the
benefit.
The value NHSScotland should be willing to pay for the benefit of an
additional true-positive result depends upon the cost effectiveness of
treatment and the impact that earlier treatment has upon quality of life and
longevity in heart failure patients.
The main clinical benefit from B-type natriuretic peptides is that the test
identifies patients who are unlikely to have decompensated heart failure and
thus require echocardiography to complete the diagnosis. For this group, the
clinical focus should be on alternative diagnoses. Being able to rule-out heart
failure sooner should reduce the period of diagnostic uncertainty, thereby
enabling earlier treatment for some patients and reducing patient anxiety.
57
These benefits could be realised with 100% sensitivity by sending all
suspected heart failure patients to echocardiography. An upper boundary to
the willingness to pay for each additional true-positive result can thus be
approximated by comparing the current service structure of referring those
patients with a positive ECG with the currently unrealised option of referring
all patients to echocardiography. This upper boundary of willingness to pay is
determined by the accuracy of the ECG, being:
•
•
•
£900 if ECGs reach the accuracy of a consultant-led service
£830 if ECGs reach the accuracy of a GP-read service
£490 if ECGs reach the accuracy of a machine-read service.
Given the current healthcare setting, the upper boundary on the willingness to
pay per additional true-positive result was taken to be around £500 for the
base case. This is a low value, but reflects in part the uncertainty around the
current accuracy of GP-read ECGs in diagnosing heart failure. As is clear
from the above, this value is sensitive to the assumed comparator. For
example, comparing the cost effectiveness of sending all patients to
echocardiography, with a consultant-led service gives a willingness to pay of
£900 for each additional true-positive result.
6.2.2 Base-case results
The results for a base case of 100 patients presenting to a GP surgery with
symptoms suggestive of heart failure are presented in Table 6 - 4.
Table 6 - 4 Base-case results for 100 patients presenting to a GP surgery
with symptoms suggestive of heart failure
Test results for heart failure
True-positives
False-positives
True-negatives
False-negatives
Cost analysis
Additional diagnostic tests
Incorrect echocardiography
referrals
Incorrect diuretic use
Further tests in false-negative
patients
Total costs
B-type
natriuretic
peptides
26.4
17.8
53.3
2.6
Consultantled ECG
GP-read ECG
24.7
28.4
42.6
4.4
24.7
36.2
34.8
4.4
£2,100
£1,200
£0
£1,935
£3,096
£3,947
£36
£57
£72
£147
£245
£245
£4,217
£4,598
£4,265
58
Table 6 - 5 Results ordered by costs
Tests ordered
by cost
Cost
Marginal
cost/
truepositive
..
Dominated
Truepositive
results
b
Correct
a
results
Marginal cost/
correct result
BNP
£4,217
26.4
79.6
..
GP-read ECG
£4,265
24.7
59.4
Dominated
Consultant-led
£4,598
24.7
Dominated
67.3
Dominated
ECG
a
The number of true positives plus number of true negatives.
b
In these and subsequent tables, ‘B-type natriuretic peptides’ is abbreviated to ‘BNP’
Under the base case, B-type natriuretic peptide testing is the lowest cost
option. The greater specificity of B-type natriuretic peptide tests leads to cost
savings from fewer incorrect referrals to echocardiography, and these savings
offset the additional testing costs. However, the cost differences are very
small, about 1% and well within the margin of error.
The consultant-led ECG service is more costly overall than either the GP-read
ECG service or B-type natriuretic peptide testing, as it has a higher cost per
test than a GP-read ECG but poorer specificity than B-type natriuretic peptide
testing. As B-type natriuretic peptide testing also detects more true-positive
results, it consequently dominates the consultant-led ECG service.
6.2.3 Sensitivity analyses
Sensitivity analyses are essential to test the robustness of the results to
variations in the assumptions on costs, epidemiology and clinical
effectiveness (Busse et al., 2001). The sensitivity of the base-case results to
the following uncertainties were tested:
•
•
•
•
•
•
•
•
different prevalence rates for heart failure
different test accuracies using the confidence intervals
laboratory B-type natriuretic peptides and consultant-led ECG requiring an
additional patient visit to communicate the test results
using point-of-care B-type natriuretic peptide testing within GP practices
different costs of echocardiograms and ECGs
different costs of additional testing of false-negative patients
applying the results for diagnosing LVSD rather than for heart failure
joint testing for heart failure.
6.2.3.1 Prevalence rate of heart failure
Landray et al. (2000) found that 32% of patients with suspected heart failure
were diagnosed with LVSD from echocardiography. If the balance between
LVSD and heart failure as reported in Maisel et al. (2001) is applied to the
LVSD prevalence of Landray et al. (2000); this implies a much higher
prevalence of heart failure in the presenting population of around 50%. The
results of sensitivity analysis with a prevalence of 48% for heart failure are
shown in Table 6 - 6.
59
Table 6 - 6 Sensitivity analysis: prevalence of 48% for heart failure
Tests ordered
by cost
GP-read ECG
BNP
Consultant-led
ECG
Cost
Truepositive
results
£3,350
£3,787
40.8
43.7
Marginal
cost/truepositive
result
..
£152
£3,915
40.8
Dominated
66.3
82.7
Marginal
cost/
correct
result
..
£27
72.0
Dominated
Correct
results
The greater sensitivity of B-type natriuretic peptides results in more truepositive results than either type of ECG service, but the higher prevalence of
heart failure within the presenting population reduces the importance of tests
having a high specificity. The greater specificity of B-type natriuretic peptides
still results in fewer incorrect referrals for echocardiography, but the resultant
savings are insufficient to outweigh the additional test costs.
The prevalence rate at which B-type natriuretic peptide testing becomes more
expensive than a GP-read ECG is around 31%. This means that if less than
31% of patients presenting with symptoms of heart failure have the disease,
B-type natriuretic peptides dominate the ECG-led services.
6.2.3.2 Accuracy of B-type natriuretic peptide testing and ECG readings
Section 5.2 outlines the uncertainty around the pooled estimates for the
accuracy of BNP and NT-proBNP in detecting heart failure. The 95%
confidence interval for the pooled sensitivity is 90% to 93%, while the 95%
confidence interval for the pooled specificity is 74% to 76%. The results from
adopting the most pessimistic values of 90% sensitivity and 73% specificity
are shown in Table 6 - 7.
Table 6 - 7 Sensitivity analysis: 90% sensitivity and 74% specificity of Btype natriuretic peptides
Tests ordered
by cost
GP-read ECG
BNP
Consultant-led
ECG
Cost
Truepositive
results
£4,265
£4,391
24.7
26.1
Marginal
cost/truepositive
result
..
£87
£4,598
24.7
Dominated
Correct
results
Marginal
cost/correct
result
59.4
77.9
..
£7
67.3
Dominated
B-type natriuretic peptide testing still detects more true-positive and truenegative patients than either ECG option, but the lower specificity compared
with the base case slightly increases the costs arising from incorrect
echocardiography referrals. This marginally increases the cost per additional
true-positive result, but the £87 lies well within the upper boundary of the
willingness to pay.
Table 6 - 8 applies the Misuraca et al. (2002) results of a sensitivity of 93%
and specificity of 63% for consultant-led ECGs for heart failure, while retaining
60
all other base-case assumptions. At these levels of accuracy, the consultantled option is as cost effective as B-type natriuretic peptide testing.
Table 6 - 8 Sensitivity analysis: 93% sensitivity and 63% specificity of
consultant-led ECG service
Tests ordered
by cost
BNP
Consultant-led
ECG
GP-read ECG
Cost
Truepositive
results
£4,217
26.4
Marginal
cost/truepositive
result
..
£4,230
27.0
£4,265
24.7
Correct
results
Marginal
cost/correct
result
79.6
..
£22
71.7
Dominated
Dominated
59.4
Dominated
These analyses indicate that the ordering of the tests is sensitive to
uncertainty around the clinical-effectiveness data. There is considerable
uncertainty about the accuracy of ECG readings within the GP setting. The
accuracy of the consultant-led ECG service provides an upper boundary to
that which could be expected from GPs. Machine-read ECG accuracy levels
will apply to some GPs, but other GPs may have greater interpretative skills. If
GPs can perform as accurately as the consultant-led ECG service (85%
sensitivity and 60% specificity) without incurring the additional £12 per test,
this significantly improves the number of true-positive results, while also
realising savings from fewer incorrect echocardiography referrals as shown in
Table 6 - 9.
Table 6 - 9 Sensitivity analysis: 85% sensitivity and 60% specificity for
GP-read ECG
Tests
ordered by
cost
GP-read
ECG
BNP
Consultantled ECG
Cost
Truepositive
results
Marginal
cost/truepositive
result
Correct
results
Marginal
cost/correct
result
£3,398
24.7
..
67.3
..
£4,217
26.4
£471
79.6
£66
£4,598
24.7
Dominated
67.3
Dominated
If a GP-read ECG service could attain a consultant level of accuracy at no
extra cost, B-type natriuretic peptide testing would not be cost effective.
However, it is difficult to see how this could be attained at no extra cost given
the initial and continuing training requirement. If training costs were less than
£9 per GP-read ECG to achieve a consultant level of accuracy, then this
would be the most cost-effective option.
Applying the sensitivity and specificity estimates of machine-read ECGs of
87% and 26% respectively to the GP setting would result in the findings in
Table 6 - 10.
61
Table 6 - 10 Sensitivity analysis: 87% sensitivity and 26% specificity for
machine-read ECGs
Tests
ordered by
cost
BNP
Consultantled ECG
Machineread ECG
Cost
Truepositive
results
£4,217
26.4
Marginal
cost/truepositive
result
..
£4,598
24.7
£6,045
25.2
Correct
results
Marginal
cost/correct
result
79.6
..
Dominated
67.3
Dominated
Dominated
43.7
Dominated
The machine-read ECG attains a higher level of sensitivity than the
consultant-led ECG service, but the additional cost of £12 for the consultantled ECG service is more than offset by its higher specificity and fewer
incorrect echocardiography referrals. The consultant-led ECG service is thus
more cost effective than the GP-read machine ECG. However, B-type
natriuretic peptide testing is the most cost effective strategy with the lowest
cost and highest true-positive results.
Additional data from an unpublished pilot study (Struthers, unpublished)
compared six GPs’ readings, and a machine reading, of 90 ECGs with those
of a cardiologist. The results were:
•
•
mean GP-read ECGs: sensitivity 82% (range 65–93%) and specificity 76%
(range 37–97%)
machine-read ECGs: sensitivity 92% and specificity 37%.
These six volunteer GPs may or may not be representative of the accuracy
levels in general practice. Moreover, interpreting ECGs for abnormalities is
not a test for the accuracy of diagnosing heart failure. However, to inform the
sensitivity analysis, the results using these accuracies are shown in
Table 6 - 11.
Table 6 - 11 Sensitivity analysis: 82% sensitivity and 76% specificity for
GP-read ECGs
Tests ordered
by cost
GP-read ECG
BNP
Consultant-led
ECG
Cost
Truepositive
results
£2,186
£4,217
23.8
26.4
Marginal
cost/truepositive
result
..
£778
£4,598
24.7
Dominated
Correct
results
Marginal
cost/correct
result
77.7
79.6
..
£1,069
67.3
Dominated
If GPs can achieve these accuracies, then using B-type natriuretic peptide
testing is unlikely to be cost effective. The cost per additional true-positive
result of around £800 from transferring to B-type natriuretic peptide testing
from an ECG reading exceeds the willingness-to-pay threshold.
Table 6 - 12 shows that after applying the higher accuracies for machine-read
ECGs, B-type natriuretic peptide testing still dominates. It is therefore unlikely
62
that, under these assumptions, the machine-read ECG is cost effective
compared with B-type natriuretic peptide testing.
Table 6 - 12 Sensitivity analysis: 92% sensitivity and 37% specificity for
machine-read ECGs
Tests ordered
by cost
BNP
Consultant-led
ECG
Machine-read
ECG
Cost
Truepositive
results
£4,217
26.4
Marginal
cost/truepositive
result
..
£4,598
24.7
£5,096
26.7
Correct
results
Marginal
cost/correct
result
79.6
..
Dominated
67.3
Dominated
£3,029
53.0
Dominated
6.2.3.3 Point-of-care testing
Point-of-care B-type natriuretic peptide testing could be performed within GP
practices. The costs depend on number of tests used (see Appendix 6).
Results are presented assuming an annual throughput of only 50 patients,
with a resultant cost per test of £37.50 (Table 6 - 13), falling to £30 if the
practice undertakes 200 tests (Table 6 - 14).
Table 6 - 13 Sensitivity analysis: point-of-care tests 50 annual
throughput and £37.50 per test
Tests ordered
by cost
GP-read ECG
Consultant-led
ECG
BNP point-ofcare tests
Cost
Truepositive
results
£4,265
24.7
Marginal
cost/truepositive
result
..
£4,598
24.7
£5,867
26.4
Correct
results
Marginal
cost/correct
result
59.4
..
Dominated
67.3
£43
£921
79.6
£102
Table 6 - 14 Sensitivity analysis: point-of-care tests 200 annual
throughput and £30 per test
Tests ordered
by cost
GP-read ECG
Consultant-led
ECG
BNP point-ofcare tests
Cost
Truepositive
results
£4,265
24.7
Marginal
cost/truepositive
result
..
£4,598
24.7
£5,117
26.4
Correct
results
Marginal
cost/correct
result
59.4
..
Dominated
67.3
£43
£490
79.6
£42
Table 6 - 13 and Table 6 - 14 underline the sensitivity of results to the cost of
the B-type natriuretic peptide test. Even with a reasonably high annual
throughput of 200 tests, the additional cost per test is at the upper boundary
of the willingness to pay per additional true-positive result.
63
These results compare point-of-care testing in the GP setting with the
estimates for the average GP accuracy. The same ordering would apply if Btype natriuretic peptide point-of-care testing were compared with machineread ECGs in the GP setting.
6.2.3.4 Lower cost of laboratory tests
Under the base-case cost of £21 per laboratory test, B-type natriuretic peptide
testing was the most cost-effective option. Howver, if the cost of a laboratory
B-type natriuretic peptide test rises by £1, the GP-read ECG becomes the
most cost-effective option. Thus recommendations on usage are very
sensitive to the cost of the tests.
6.2.3.5 The cost of echocardiography
While the cost of B-type natriuretic peptide tests relative to ECG is important,
so too is its cost relative to echocardiography. Significant uncertainty
surrounds the cost of an echocardiogram, as its use within the NHS in
Scotland varies considerably. The annual number of scans per operator and
the skill mix between the different grades of technical operators and
consultant input vary. Moreover, current use may not guide future use
following the adoption of echocardiography as a clinical indicator within the
new GP contract (NHS Confederation & British Medical Association, 2003).
Assuming different throughputs and skill mix, a range of echocardiography
costs from £60 to £150 are possible. The results of sensitivity analyses using
these ranges are shown in Table 6 - 15 and Table 6 - 16.
Table 6 - 15 Sensitivity analysis: echocardiography cost of £60
Tests ordered
by cost
GP-read ECG
Consultant-led
ECG
BNP
Cost
Truepositive
results
£2,490
24.7
Marginal
cost/truepositive
result
..
£3,206
24.7
£3,348
26.4
Correct
results
Marginal
cost/correct
result
59.4
..
Dominated
67.3
£92
£493
79.6
£11
Table 6 - 16 Sensitivity analysis: echocardiography cost of £150
Tests ordered
by cost
BNP
GP-read ECG
Consultant-led
ECG
Cost
Truepositive
results
£4,945
£5,749
26.4
24.7
Marginal
cost/truepositive
result
..
Dominated
£5,762
24.7
Dominated
Correct
results
Marginal
cost/correct
result
79.6
59.4
..
Dominated
67.3
Dominated
As anticipated, a lower echocardiography cost renders the more expensive
but more specific options (consultant-led ECG and B-type natriuretic peptides
tests) less cost effective. There is less benefit to be gained from avoiding
incorrect referrals if these are relatively inexpensive. If the cost of £60 per
64
echocardiogram applies and the consultant-led ECG option is deemed not to
be practical, the cost per additional true-positive result of moving from GPread ECG to B-type natriuretic peptide testing is about £500, at the upper end
of the willingness-to-pay threshold.
The reverse applies if echocardiograms are more expensive, and the higher
specificity of B-type natriuretic peptide tests results in a lower overall cost.
Given its higher sensitivity, this reinforces the cost effectiveness of B-type
natriuretic peptide testing.
Due to the poor specificity of the GP-read option, its overall costs and thus
ranking are particularly sensitive to the cost of echocardiography.
6.2.3.6
Use and cost of ECGs by GPs
The base case assumes that all GPs use an ECG to provide information on
the cardiac function of all patients presenting with symptoms suggestive of
heart failure. Moreover, because the ECG is used in all options on all patients,
the model attributes no cost to this activity. (Khunti et al., 2002; Fuat et al.,
2003) note that not all GPs request an ECG when assessing such patients.
If ECGs are not used by most GPs in diagnosing heart failure, then it would
be appropriate to include a cost for an ECG in the GP-read ECG option. The
cost of the GP-read ECG option could rise by £20 per test (being the
published Department of Health cost for an ECG). This would cause B-type
natriuretic peptide testing to convincingly dominate the ECG option (ie be
more cost effective).
Since B-type natriuretic peptide testing is more cost effective than the
consultant-led ECG service in the base case, any rise in the cost of
consultant-led ECGs beyond the £12 of the base case would reinforce this.
Within the consultant-led ECG service, the cost per ECG would have to fall to
around £8 for it not to be dominated by B-type natriuretic peptide testing. At
this level of cost per consultant-led ECG, B-type natriuretic peptide testing
would remain cost effective due to its higher sensitivity. The cost per
consultant-led ECG would be required to fall to under £1 for the incremental
cost effectiveness of moving to B-type natriuretic peptide testing to rise to
around £500 per additional true-positive result.
6.2.3.7
The cost of additional tests for false-negative patients
Just as changing the cost of incorrect referrals emphasises the importance of
the specificity of the tests, changing the cost of incorrectly ruling-out heart
failure (false-negative results) emphasises the importance of the sensitivities
of the tests. In the base case, the cost of additional tests among falsenegative patients was taken to be equivalent to two GP visits. To test the
sensitivity of the base-case result, two cases are explored by using the costs
of one and three GP visits. The results are shown in Table 6 - 17 and Table 6
- 18.
65
Table 6 - 17 Sensitivity analysis: one additional GP visit for falsenegative patients
Tests ordered
by cost
GP-read ECG
BNP
Consultant-led
ECG
Cost
Truepositive
results
£4,142
£4,144
24.7
26.4
Marginal
cost/truepositive
result
..
£1
£4,475
24.7
Dominated
Correct
results
Marginal
cost/correct
result
59.4
79.6
..
£0
67.3
Dominated
Table 6 - 18 Sensitivity analysis: three additional GP visits for falsenegative patients
Tests ordered
by cost
BNP
GP-read ECG
Consultant-led
ECG
Cost
Truepositive
results
£4,365
£4,510
26.4
24.7
Marginal
cost/truepositive
result
..
Dominated
£4,843
24.7
Dominated
Correct
results
Marginal
cost/correct
result
79.6
59.4
..
Dominated
67.3
Dominated
For one additional GP visit for false-negative patients, the B-type natriuretic
peptides testing and GP-read options are virtually identical in terms of cost
effectiveness. Increasing the cost of managing false-negatives increases the
relative cost effectiveness of B-type natriuretic peptide testing.
6.2.3.8 Results for diagnosis of LVSD
As discussed in Section 5.1, many clinical trials used a primary end point of
LVSD, not heart failure. The pooled sensitivities and specificities for BNP and
NT-proBNP for LVSD are 86% and 63% respectively compared with 91% and
75% values for heart failure. The accuracy of experts interpreting ECG in
published trials for LVSD shows a sensitivity and specificity of 90% and 58%
respectively. The two studies of machine-interpreted ECGs show a sensitivity
and specificity of 83% and 21% respectively for GP-read ECG machines for
LVSD. Pooling the data suggests an average GP-read accuracy of 85%
sensitivity and 46% specificity.
Applying the prevalence data from Section 6.1.3.2 to give a prevalence rate of
LVSD of 18% and using LVSD accuracies outlined above gives the results in
Table 6 - 19.
66
Table 6 - 19 Sensitivity analysis: LVSD prevalence of 18% and base-case
accuracies of tests for LVSD
Tests ordered
by cost
GP-read ECG
Consultant-led
ECG
BNP
Cost
Truepositive
results
£5,067
15.3
Marginal
cost/truepositive
result
..
£5,124
16.2
£5,610
15.5
Correct
results
Marginal
cost/correct
result
53.0
..
£63
63.8
£5
Dominated
67.1
£144
If LVSD was the principal condition of concern, then GP-read ECGs would
appear to be the most cost-effective option. However, it must be recognised
that the estimate for GP-read ECG accuracy for LVSD is a simple pooling of
expert and machine-level accuracy, and is therefore uncertain.
If GPs were to only attain machine-read ECG levels of accuracy, for which an
evidence base exists, the findings in Table 6 - 20 would apply.
Table 6 - 20 Sensitivity analysis: 83% sensitivity for LVSD and 21%
specificity for GP-read ECG
Tests
ordered by
cost
Consultantled ECG
BNP
Machineread ECG
Cost
Truepositive
results
Marginal
cost/truepositive
result
Correct
results
Marginal
cost/correct
result
£5,124
16.2
..
63.8
..
£5,610
15.5
Dominated
67.1
£144
£7,363
14.9
Dominated
32.2
Dominated
6.2.3.9 Joint testing using a combination of diagnostic tests
The sensitivity analyses have considered applying each diagnostic test
separately. GPs could use a decision rule whereby if either test is positive,
then the patient should be referred for echocardiography. There are no robust
data on the accuracy of joint testing so the only means of assessing this is to
assume independence between the tests. Thus for two tests, A and B:
•
•
the joint sensitivity is: sensitivityA + ([1 – sensitivityA ] x sensitivityB)
the joint specificity is: specificityA x specificityB.
The resultant sensitivities and specificities are shown in Table 6 - 21.
Table 6 - 21 Sensitivity and specificity of a combination of diagnostic
tests
Combination of diagnostic tests
B-type natriuretic peptides and consultant-led ECG
B-type natriuretic peptides and machine-read ECG
Sensitivity
99%
99%
Specificity
45%
37%
These provide an upper boundary for the joint sensitivity and a lower
boundary for the joint specificity. However, it seems extremely unlikely that
67
the test results will be independent. The sensitivity of test B among the falsenegative results from test A is likely to be higher than that amongst all
presenting heart failure patients. A similar argument applies to the joint
specificity.
Within the base-case analysis of single testing, B-type natriuretic peptide
testing dominated the ECG services (see Table 6 - 22). This compares the
results from the joint tests with the single B-type natriuretic peptide testing
strategy.
Table 6 - 22 Sensitivity analysis: comparison of joint tests and B-type
natriuretic peptide tests
Tests ordered by cost
Cost
Truepositive
results
BNP
BNP and GP-read ECG
BNP and consultant-led
ECG
£4,217
£7,107
26.4
28.6
Marginal
cost/truepositive
result
..
£1,302
£7,657
28.6
£1,550
Correct
results
Marginal
cost/correct
result
79.6
54.7
..
Dominated
60.6
Dominated
The values for the cost per additional true-positive result for the joint
strategies suggest these are unlikely to be cost effective. Indeed, the total
cost of the joint strategies is only marginally less than that of the 100%
sensitive strategy of simply sending all suspected heart failure patients
straight to echocardiography. Given the uncertainty around the low joint
specificity and high joint sensitivity, this result needs to be interpreted with
extreme caution.
These results suggest there is value in further research into the benefit of
adding B-type natriuretic peptide tests into the referral pathway for the group
of GPs who are already highly competent in interpreting ECGs.
6.3
Discussion
There is limited evidence from the literature on the cost effectiveness of using
B-type natriuretic peptides compared with standard practice in primary care
for patients with suspected heart failure. A study is under way which might
provide this data (Dr A Fuat, Clinical Lead, CHD, Darlington Primary Care
Trust. Personal communication, October 2004). The economic model can only
indicate the range of variables conducive to moving from a GP-read ECG
service to a B-type natriuretic peptide testing service or a consultant-led ECG
service.
The base case and sensitivity analyses suggest that if GPs are taking
decisions to refer patients for echocardiography using a diagnostic test with a
specificity of less than 50%, then it is cost effective to adopt a more accurate
test. The savings primarily stem from reducing the number of inappropriate
referrals to echocardiography.
If the specificity of a GP-read ECG is higher than 50% (assuming a sensitivity
of over 80%), then using B-type natriuretic peptide testing is not cost saving
68
but rather there are marginal costs incurred in detecting each additional
patient diagnosed with heart failure using echocardiography.
The sensitivity analysis of the joint tests suggests that where GPs have a high
accuracy in reading ECGs, then B-type natriuretic peptide testing should not
be adopted without rigorous piloting against standard practice.
Realistically, measuring the specificity of each GP in reading ECGs is not
feasible. Hence the recommendations use the term ‘confident in confirming an
automated ECG report’ as a proxy for a low specificity.
The base case assumed all GPs have access to a 12-lead ECG machine to
assist in assessing patients with suspected heart failure in order to detect a
range of cardiac abnormalities. Since this test is common to all the options, no
cost has been included for its use. However, several sources indicate that all
GPs may not use an ECG for patients with suspected heart failure. For these
GPs, there are considerable clinical and economic benefits from adopting
laboratory B-type natriuretic peptide testing.
The base case assumes all patients with abnormal ECGs or B-type natriuretic
peptide levels receive echocardiography following referral to secondary care.
The Scottish Health Purchasing Information Centre (1998) reported that
historically only 30% of heart failure patients in general practice received
echocardiography. Low referral rates reduce the benefits from using accurate
tests to avoid incorrect referrals. GPs are now being given incentives to
confirm a diagnosis of LVSD by an echocardiography (NHS Confederation &
British Medical Association, 2003). This action should move standard practice
closer to the base-case scenario, assuming capacity is provided to meet the
additional demand.
The cost-effectiveness analysis does not fully reflect patient benefits, such as
the reduced anxiety and inconvenience of an unnecessary echocardiography.
Section 7.2 discusses these and other potential patient benefits from having a
reliable and quick test to provide access to further assessments. Moreover, if
fewer inappropriate referrals are made, then access should be improved for
those patients who require a timely diagnosis that enables them to receive
earlier treatment (see Section 7.1).
6.4
Conclusions
There is evidence that in the emergency setting, the availability of rapid BNP
results, in conjunction with other clinical information, can improve the
evaluation and treatment of patients with heart failure compared with current
practice, thereby reducing length of stay and total treatment costs. A study
should investigate whether this cost-effectiveness evidence generalises to
Scottish patients in the acute setting, using Scottish diagnostic and treatment
protocols.
The economic model suggests that using B-type natriuretic peptide tests in
primary care could be cost saving if the specificity of the tests GPs currently
use to refer patients for echocardiography is less than 50%. Such tests
69
include using ECG machines for interpretative purposes and response to
drugs. Practically, where GPs are not confident in confirming ECGs, then
access to B-type natriuretic peptide tests is likely to be cost effective.
Additionally, the results are sensitive to many variables, including prevalence
rates and the cost of echocardiography. Audit data from GP practices that do
employ B-type natriuretic peptide tests should be used to inform on
prevalence rates. Individual hospitals may wish to cost their own
echocardiography service, particularly following its introduction as a clinical
indicator in the GMS contract.
An alternative to B-type natriuretic peptide testing is to have a cardiologist-led
ECG service. The clinical and cost-effectiveness data suggests there is little
difference between these strategies. Organisational issues, including the
timeliness and quality of the service, may preclude developing and sustaining
such services.
In some settings, introducing B-type natriuretic peptide testing could result in
higher absolute costs compared with the costs of existing diagnostic tests.
NHSScotland should be willing to pay this marginal cost if it is less than the
value of the benefits to patients from improved quality of life and longevity.
This willingness to pay is estimated to have an upper boundary of about £500
per patient.
70
7 Other issues relevant to clinical and cost effectiveness
evidence
7.1
Organisational issues
This chapter describes the current provision of B-type natriuretic peptide
testing and echocardiography in Scotland, as evaluated by surveys conducted
by NHS QIS (Section 7.1.1). It outlines some of the organisational issues that
could arise from providing B-type natriuretic peptide testing services in the
acute sector (Section 7.1.2) and in primary care (Section 7.1.3), and from the
provision of a cardiologist-led ECG service to primary care (Section 7.1.4). A
discussion of these issues is provided in Section 7.1.5. Section 7.2 describes
patient issues pertaining to B-type natriuretic peptide testing. Appendix 7
provides an overview of the organisation of the NHS in Scotland.
No formal systematic literature searching on the organisation of B-type
natriuretic peptide testing services was undertaken but relevant literature from
the clinical and cost-effectiveness searches was used, in addition to
information from manufacturers and patient groups, expert knowledge and the
survey results.
7.1.1 Surveys of use of B-type natriuretic peptide testing and
echocardiography facilities
7.1.1.1 Use of B-type natriuretic peptide testing
A survey of 22 Scottish laboratories identified one laboratory that provides Btype natriuretic peptide testing using a point-of-care device in A&E and other
wards. Five laboratories indicated that they are planning to introduce the test.
Lack of finance was cited as the main reason for not using the test.
Subsequently, a second Health Board has introduced an NT-proBNP testing
service for use in general practice.
In addition to the survey, manufacturers were asked to describe the use of Btype natriuretic peptide testing in Scotland and worldwide. All manufacturers
of these tests reported that no sites in Scotland are reporting B-type
natriuretic peptide test results routinely, which contrasts with the situation in
England, Ireland and Wales.
7.1.1.2 Use of echocardiography
Of the 21 hospitals with echocardiography facilities that responded to the
survey, 12 reported that they provide direct-access echocardiography, with a
waiting time for this service of between 0 and 12 weeks. The wait for
echocardiography via an outpatient clinic appointment can take up to a
maximum of 30 weeks, although more than half of the clinics that responded
indicated that they would prioritise appointments on the basis of factors such
as severity of symptoms. The majority of respondents indicated that the
demand for echocardiography services exceeds the available capacity in
terms of staff, equipment and/or accommodation.
71
Fuller details of the surveys of Scottish laboratories and hospitals are
provided in Appendix 7.
No survey of clinicians was undertaken to establish the perceived need for Btype natriuretic peptide testing.
7.1.2 Provision of B-type natriuretic peptide testing services in the acute
sector
7.1.2.1 Potential benefits of B-type natriuretic peptide tests in the acute care
sector
Given the high sensitivity and specificity of BNP (92% and 74%) and NTproBNP (97% and 82%) for diagnosing heart failure in patients presenting to
A&E with acute breathlessness (Figures 11 - 6,11 - 7, 11 - 12, and 11 - 13
respectively, Appendix 4), these tests are useful in improving the accuracy of
diagnosis. Additionally, B-type natriuretic peptide testing can assist in
admission and treatment decisions (Maisel et al., 2004; Wu et al., 2004).
The benefits of B-type natriuretic peptide testing arise if the tests have a
greater diagnostic accuracy than ECGs read by general physicians or other
healthcare professionals, or provide additional information to that from an
ECG. However, there is conflicting evidence (Prasad et al., 1996;
Montgomery et al., 1994) on the ability of healthcare staff to interpret an ECG
for evidence of cardiac malfunction. Introducing a B-type natriuretic peptides
service is likely to be of greatest benefit where medical staff have low
interpretive skills and high staff turnover precludes training to improve these
skills.
7.1.2.2 Organisational aspects of a B-type natriuretic peptides service in the
acute care sector
Some of the organisational aspects of using B-type natriuretic peptide tests in
this setting are now considered. Once the decision to adopt B-type natriuretic
peptide tests has been made, the next key decision is whether to use a
laboratory service or point-of-care testing service. Factors to consider include
the need for timely quality-assured test results to inform clinical decision
making, and the cost and practicality of providing these results. The timeliness
of a test result is likely to be a key driver in decisions relating to admission
and placement. Point-of-care test results can be available within 15 minutes
from taking a blood sample. Laboratory tests take a similar time to process
but samples need to be transported to the laboratory, and there has to be
systems in place to receive, test and report the sample urgently.
The Medicines and Healthcare products Regulatory Agency (formerly the
Medical Devices Agency) (Medical Devices Agency, 2002) provides guidance
on the management of a point-of-care testing service in a hospital setting. In
addition, the recommendations regarding the organisation of a troponin
testing service made by Craig et al. (2004) are relevant to a B-type natriuretic
peptide testing service.
72
Laboratories introducing B-type natriuretic peptide testing will need to develop
technical protocols to address issues such as collection, transport and storage
of samples, recording and reporting of results, recognising that there is some
uncertainty about the characterisation of the assays. Their use should be
monitored.
Laboratories and clinical leads, preferably at NHS Board level (or across
Scotland) should work collaboratively to validate that the manufacturers’
recommended cut-offs for B-type natriuretic peptide concentrations are
appropriate for their own population. This is to ensure that the cut-offs are
sufficiently sensitive to identify all patients with mild heart failure and will
require the absolute levels of B-type natriuretic peptide concentrations in the
‘normal population’ for this setting.
There are still several biochemistry issues to be resolved around the use of Btype natriuretic peptide assays, including:
•
•
•
•
•
•
antibody specificity
influence of specimen type
calibration material verification
specimen storage conditions
imprecision characteristics
reference limit information (Jaffe et al., 2004).
Collinson et al. (2004) identified that NT-proBNP tests are stable under a
range of conditions but no similar study on BNP tests has been identified in
the literature.
Relevant clinical protocols which outline specific circumstances for testing
should be established and their use monitored. These should be supported by
training.
Adopting B-type natriuretic peptide testing should also facilitate greater
standardisation of clinical decision making by reducing diagnostic ambiguity
(Wu et al., 2004). Data should be collected and reviewed to ensure B-type
natriuretic peptide tests are improving outcomes for patients and hospitals.
Hospitals should also identify the information patients may wish to have about
the test and develop suitable educational materials to meet these needs.
Finally, hospitals will need additional funding for the tests. Savings from fewer
echocardiograms and cardiology referrals will not result in cash savings but
enable existing patient needs to be met more rapidly.
73
7.1.3 Provision of B-type natriuretic peptide testing services in primary care
7.1.3.1 Potential benefits of B-type natriuretic peptide tests in general
practice
Providing patients are not receiving therapy for heart failure (see Section 5.6),
clinical evidence suggests that ‘normal’ levels of B-type natriuretic peptides (ie
less than 100 pg/ml) could ‘rule-out’ heart failure in the GP setting (Cowie et
al., 2003). Improving the accuracy of the initial work-up diagnosis could
potentially result in the reduction in the number of inappropriate referrals for
echocardiography.
The benefits of a B-type natriuretic peptide testing service are greatest where
GPs use diagnostic tools that have significantly lower levels of accuracy,
particularly specificity.
7.1.3.2 Organisational challenges of a B-type natriuretic peptide testing
service in general practice
Introducing B-type natriuretic peptide testing in general practice presents
similar issues to those in the acute setting. For example, the decision about
whether to use a laboratory or a point-of-care testing service will be influenced
by the cost and timeliness of obtaining a quality-assured result. However, in
primary care, a key factor to consider in the cost-effectiveness analysis is
whether a further GP appointment is required to inform patients of their test
results.
An additional consideration for primary care is the need for a standardised
process across MCNs in terms of cut-off levels and diagnostic protocols.
Currently, such standardisation is not possible because GPs have different
approaches to echocardiography referrals. The CHD MCNs also need to
decide whether, for example, heart failure nurses in the community could
benefit from accessing B-type natriuretic peptide results.
If B-type natriuretic peptide testing is introduced, it will be important to audit
the outcome of referrals, including echocardiography results and B-type
natriuretic peptide concentrations. The audit should also ensure that the tests
are only being used when there is diagnostic uncertainty.
The introduction of B-type natriuretic peptide testing services in primary care
will require additional funding. If a B-type natriuretic peptide point-of-care
testing service is adopted, savings are likely to arise in echocardiography
services in the acute sector. If a laboratory service is used, costs will largely
be incurred by laboratories, and to a lesser extent by GP practices.
7.1.4 Consultant-led ECG service
Where GPs recognise that their current approach to echocardiography
referrals is sub-optimal, an alternative to B-type natriuretic peptide testing
could be a consultant-led ECG service. This service would involve accredited
technicians leading on ECG interpretation, and a cardiologist available for
74
specialist advice. The availability of technical and clinical skills in the acute
sector is therefore necessary to provide a quality-assured and timely ECGreading service. However, responses to the survey (see Section 7.1.1)
indicate that the lack of these skills is a significant barrier to increasing the
capacity of echocardiography services. It is anticipated that these are likely to
be the same staff that would operate a consultant-led ECG service.
To ensure this service is practicable, several GP practices may need to jointly
agree to use this service, ECG training for GPs and practice nurses may be
required and good communication between healthcare professionals in
primary and secondary care is essential. Steps to ensure a quality-assured
process need to be put in place as the risk of losing paper/scans and
frequency of incomprehensible scans may be high.
Funding is also a significant factor in setting up this service, with the majority
of the costs and benefits incurred in the secondary sector.
Experience shows that this type of service is extremely difficult to maintain –
for example, a consultant-led service at the Royal Infirmary Edinburgh was
disbanded (Dr P Padfield, Deputy Medical Director and Consultant
Physician/Reader in Medicine, Western General Hospital, Edinburgh.
Personal communication, October 2004) – and therefore is unlikely to be
feasible.
7.1.5 Discussion
Some common themes emerge from Sections 7.1.2, 7.1.3 and 7.1.4. First,
one of the major difficulties in diagnosing heart failure is that most of the
decision makers (including GPs) are general medical physicians without
expertise in cardiology, with variable skills in using diagnostic tests such as an
ECG. Measuring the accuracy of the current diagnostic tests and comparing
this level with the accuracy of a B-type natriuretic peptide testing service is
necessary before taking the decision to adopt B-type natriuretic peptide
testing.
Second, prior to the introduction of a B-type natriuretic peptide testing service,
CHD MCNs should agree:
•
•
which patient groups should be tested
who is to be informed in primary and secondary care of B-type natriuretic
peptide test results, how it is to be communicated and what is its content
(eg should letters from GPs requesting a clinic appointment contain B-type
natriuretic peptide levels, should such data be in the discharge letter,
should heart failure nurses be informed of the test results, is it kept on
patient electronic and paper-based records?).
Steps must be taken to monitor use of the tests in both primary care and
acute services to ensure that only those patients who will receive greatest
benefit from them are tested and that data flows are in accordance with
protocols.
75
Third, any B-type natriuretic peptide testing service must be quality-assured
and timeous to ensure results are available for clinical decision making.
Clinical guidelines and protocols should clearly show the role of B-type
natriuretic peptide testing, and such information should be communicated to
patients and carers to re-assure them about the purpose of the blood test.
Fourth, a consultant-led ECG service could be as clinically effective as B-type
natriuretic peptide testing but may be difficult to sustain, within a qualityassured process because of staff constraints.
Fifth, NHS Boards should consider further training for existing GPs and staff in
key areas, such as medical staff in A&E, in order to improve their accuracy in
interpreting ECGs. Existing medical training should be reviewed to ensure
sufficient time is devoted to this.
Finally, introducing any B-type natriuretic peptide testing or enhanced service
will require additional funding. Assuming the service is cost effective, savings
should accrue from fewer echocardiograms or fewer admissions. However,
such savings will not release cash but rather free up resources to be used in
other activities. The investment will not be cash neutral. Moreover, if GPs
adopt point-of-care tests because they are proven to be clinically and cost
effective in their setting, then the investment takes place within primary care
but the benefits are accrued in secondary care. Incentives must be in place to
facilitate rationale decision making between the sectors.
7.2
Patient issues
The recent NICE Guideline on chronic heart failure (National Institute for
Clinical Excellence, 2003) was informed by representation from the
Cardiomyopathy Association, the British Heart Foundation and a patient and
carer focus group. Several issues emerged that are pertinent to this HTA.
These have been explored and developed in this section with input from
Chest Heart and Stroke Scotland, British Heart Foundation and Ms Libby
Paton, Heart Failure Nurse for East Ayrshire. Information available on the
DIPEX website (www.dipex.org) regarding the diagnosis of heart failure has
also been used.
Honest and accurate information is of paramount importance to patients. For
example, patients reported they were unsure whether they had been given a
diagnosis, or only received a diagnosis when they asked questions. Others
had long waits for a diagnosis. Such experiences are consistent with the
findings of Ng et al. (2003); that there are several obstacles to diagnosis in
primary care, including lack of facilities for appropriate investigations,
particularly echocardiography. Thus GPs may seem to lack confidence
because they have not had the initial diagnosis confirmed by an objective test.
As stated in Section 4, in 50% of people who are given a diagnosis of heart
failure in primary care, a subsequent echocardiogram reveals that they do not
actually have the condition. The patient groups explained that a diagnosis of
heart failure causes anxiety that may lead to feeling depressed. Reducing this
burden of misdiagnosis is essential from their standpoint.
76
The results presented in Section 5.2 show that B-type natriuretic peptide
testing would reduce the proportion of people who are incorrectly assessed in
primary care as having a cardiac disorder and thereby reduce the number
who require to be referred for echocardiography.
Both aspects have considerable patient benefits. Many of the patients are
elderly and have breathing difficulties which may make attending clinics
difficult. Any patient who has an inappropriate diagnosis of heart failure is
prescribed medication that will not improve their condition and may indeed
harm them. Furthermore, delays for echocardiography can be up to 30 weeks
(survey response, August 2004). Reducing the number of people requiring
echocardiography should reduce waiting lists and enable those with the
disease to receive a confirmed diagnosis more quickly and therefore start
treatment earlier. Given this disease may be stabilised if treated at an early
stage, this has considerable potential benefit to patients.
Confidence and the ability to cope with the illness are affected by the attitude
of the healthcare professional and their willingness to spend time explaining
the condition and care process. A B-type natriuretic peptide test gives the GP
more certainty over the diagnosis, which in turn will give the patient more
confidence in the GP and may help ensure adherence to therapy.
A normal B-type natriuretic peptide result can establish that a patient does not
have heart failure. If the test is undertaken in primary care, then a normal
result avoids the need for a patient to travel to hospital for further cardiac
testing and eliminates the associated anxiety. If undertaken in A&E, it may
reduce admissions and length of stay by reducing diagnostic uncertainty.
These benefits, notably in respect of reducing inappropriate referrals to
secondary care, may have particular value to patients in rural areas.
Furthermore, given the age and morbidity of these patients, many may be
vulnerable to the risk of hospital-associated infections. Thus, such patients
may have a strong preference for a B-type natriuretic peptide test in A&E,
compared with admission followed by echocardiography the next day.
Although some patients may be reluctant to undergo medical tests (eg for
insurance reasons), patients rarely object to a simple, relatively non-invasive
blood test and are likely to feel relief if it can rule-out heart failure.
Many participants in the NICE focus group felt that the various healthcare
professionals involved in their care did little to communicate with one another
appropriately. A GP could readily communicate a B-type natriuretic peptide
result to secondary care colleagues, for example by documenting the result
on a patient-held record, such as the ‘My Heart’ record used in Glasgow.
77
8 Principal findings, limitations and recommendations
This chapter considers the principal findings (Section 8.1), the need for further
research (Section 8.2), the limitations and uncertainties (Section 8.3), and
makes evidence-based recommendations (Section 8.4). The resource
implications of the recommendations and challenges for implementation are
addressed in Sections 8.5 and 8.6.
8.1
Principal findings
8.1.1 Scope of the HTA
The HTA focuses on the optimal use in Scotland of B-type natriuretic peptides
within the diagnostic pathway for patients with suspected heart failure in the
admissions setting and primary care. It considers the clinical effectiveness,
cost effectiveness, patients’ needs and preferences and organisational issues
surrounding the adoption of B-type natriuretic peptide tests or introducing a
consultant-led ECG service, compared with standard practice. The evidence
and conclusions from these four sections are now synthesised.
8.1.2 Summary of findings
The clinical evidence shows that for selecting appropriate patients for referral
for echocardiography or further assessment for heart failure, cardiologists
reading ECGs and B-type natriuretic peptide tests have similar sensitivities
but the latter has somewhat higher specificity. The machine-read ECG has
similar sensitivity to BNP but a much lower specificity. There is no evidence
that the accuracy of BNP differs from that of NT-proBNP.
The accuracy of B-type natriuretic peptide assays is greatest in patients with
more severe disease and poorest in patients who are already receiving
therapy for heart failure. The assays are less accurate for LVSD than for heart
failure.
There is some evidence that B-type natriuretic peptide assays may be of
benefit in diagnosing DHF. This should be confirmed by large prospective
studies.
In all settings, B-type natriuretic peptide tests can only be a ‘rule-out’ test of
cardiac abnormality. B-type natriuretic peptide concentrations are raised in
several conditions other than heart failure, such as pulmonary embolism and
renal disease. Patients with abnormal B-type natriuretic peptide tests require
further investigations by echocardiography. Other causes of the symptoms
should be considered in patients with normal B-type natriuretic peptide
concentrations.
The cut-off concentrations for use as a rule-out test are not well defined and
more work is required to optimise these, particularly in the GP setting. These
patients are likely to be elderly, with co-morbidities and on multiple drug
therapies. Such groups have not been included in many of the trials to inform
cut-offs.
78
There is some evidence that it is clinically and cost effective to adopt B-type
natriuretic peptide tests in an emergency setting, in addition to the standard
initial clinical assessment. Further work is necessary to establish whether the
results generalise to a Scottish setting.
The relevant setting will depend on the decisions made in the emergency and
admissions departments. Some hospitals may find the main benefit is in A&E,
to rule-out the need for patient admission and inform placement decisions;
other hospitals may find physicians on the admissions ward would find it
beneficial to have a B-type natriuretic peptide level available to inform the
initial diagnostic work-up of patients in whom there is genuine diagnostic
uncertainty and no timely access to echocardiography.
Limited evidence from the general practice setting shows that providing GPs
with information on a patient’s B-type natriuretic peptide concentration, as part
of the standard clinical assessment, can reduce the number of patients who
receive an initial diagnosis of heart failure which is not confirmed by
echocardiography. GPs who are not confident in interpreting ECGs to inform
referral decisions will find the greatest clinical and economic benefit from
adopting B-type natriuretic peptide tests.
The evidence from one trial (Zaphiriou, unpublished) suggests that in primary
care, fewer referrals to echocardiography could be made if GPs refer:
•
•
all patients with abnormal ECGs
all patients with a normal ECG but an abnormal B-type natriuretic peptide
test.
This is consistent with the standard diagnostic pathway recommended in
Maisel et al. (2004) and assumes all patients suspected of heart failure will
receive an ECG. However, neither the study, nor the economic modelling
undertaken in this HTA has shown this referral strategy to be cost effective.
A study currently under way may provide better data to inform this decision
(Dr A Fuat, Clinical Lead, CHD, Darlington Primary Care Trust. Personal
communication, December 2004). If the analyses cannot be used for this
purpose, then a further randomised study of referral decisions based solely
upon the first visit and B-type natriuretic peptide level is needed.
Modelling suggests that using B-type natriuretic peptide tests could be cost
saving if the specificity of tests currently used to inform whether or not to refer
patients for further assessment including echocardiography is less than 50%.
It is impractical to measure the specificity of GPs interpreting an ECG for this
purpose. A proxy measure based on whether the GP feels confident in
confirming an automated ECG report is thus adopted in the
recommendations. Thus, where GPs do not use ECG or are not confident with
their interpretation of an ECG, they should use B-type natriuretic peptide tests
to inform rule-out decisions on heart failure.
Any such change to current practice would inevitably involve organisational
considerations, such as education, training, developing and modifying existing
79
referral protocols and undertaking audit. The total cost and the timeliness of
obtaining a quality-assured result should inform decisions on whether the Btype natriuretic peptide testing service, if adopted, should be laboratory based
or undertaken at the point of care.
From a patient perspective, honest, accurate and timely information is of
paramount importance. Many patients reported a long wait for a diagnosis and
others were unsure if they had been given a diagnosis or not. Therefore,
patients are likely to value avoiding unnecessary anxiety if a simple, relatively
non-invasive blood test can rule-out heart failure.
The economic model only considered two options to improve the accuracy of
existing diagnostic tests: B-type natriuretic peptide assays or a consultant-led
ECG service. However, other options exist. For example, there may be wider
clinical benefits if all regular users of ECGs, such as general physicians and
GPs, receive additional training to improve their skill base. The Royal College
of General Practitioners (Scotland) has advised that it would support
enhancing this training within the continuing professional development
programme.
For primary care, a laboratory B-type natriuretic peptide testing service is
likely to be much easier to organise and quality assure than a consultant-led
ECG service and may also ensure consistency of decision making and equity
of access to echocardiography. Indeed, experience shows a consultant-led
service is very difficult to sustain (Dr P Padfield, Deputy Medical Director and
Consultant Physician/Reader in Medicine, Western General Hospital,
Edinburgh. Personal communication, October 2004).
The cost effectiveness of either a laboratory service or a consultant-led ECG
service improves if GPs do not initiate a second consultation to discuss the
results with the patient. A point-of-care service avoids this potential cost but is
only likely to be cost effective if several GP practices can share access to an
assay. This would enable them to achieve a throughput of approximately 200
tests a year and avoid the significant premium per test charged for smaller
throughputs.
The needs and preferences of patients with suspected heart failure clearly
demonstrate that a high value is placed on receiving a timely and accurate
diagnosis. Adopting more sensitive ‘rule-out’ tests and rationalising access to
echocardiography using the results of these tests is consistent with these
patient needs. Patient outcomes are also likely to be enhanced if waiting
times for echocardiography are shortened, enabling therapy to commence
sooner. However, there may be other, cheaper ways of achieving this.
8.2
Further research
An audit of the costs and benefits of adopting B-type natriuretic peptide
testing in Scottish emergency/admission settings should be undertaken to
ensure that the benefits seen in Switzerland (Mueller et al., 2004) generalise
to Scotland.
80
A study currently under way may inform the optimal clinical pathway to adopt
in primary care, assuming ECGs are accurately interpreted (Dr A Fuat,
Clinical Lead, CHD, Darlington Primary Care Trust. Personal communication
September 2004). If not, then a further study, similar to that conducted by
Wright et al. (2003), should be undertaken, with one arm being GPs using the
results from B-type natriuretic peptide tests on the initial visit.
The possible use of B-type natriuretic peptides to inform a clinical diagnosis
and empirical treatment strategy, avoiding the need for urgent
echocardiography, cannot be supported from the available evidence and
should be studied in prospective trials.
Further evidence on the accuracy of GPs reading ECGs will be available from
the Struthers study (Prof. A Struthers, Professor of Cardiovascular Medicine
and Therapies, University of Dundee and Ninewells Hospital. Personal
communication, September 2004) and this should help to inform the accuracy
of standard practice in primary care.
Further study of the B-type natriuretic peptide assays as indicated in Section
7.1.2.2 is also required to reduce uncertainty about the characterisation of the
assays. Laboratories and manufacturers should work to establish relevant cutoffs and ascertain how these are affected by age, sex and drug therapy.
Moreover, there is still considerable uncertainty about the appropriate cut-off
levels for using the test results to rule-out heart failure and how these may
change for different clinical settings.
Research should also continue into alternative technologies to improve
diagnostic accuracy for heart failure such as hand-held echocardiography.
Further research should take place to determine the utility of B-type natriuretic
peptide in the diagnosis of DHP.
8.3
Limitations and uncertainties
There are deficiencies in the published clinical evidence base, in particular on
the accuracy of existing diagnostic tests undertaken in general practice. For
example, there are few studies on the accuracy of ECGs in this patient group
and little evidence on the use of B-type natriuretic peptides and ECG, together
with clinical judgement, in patients with symptoms suggestive of heart failure
in whom there is genuine uncertainty about their diagnosis.
The cost-effectiveness analysis assumed that the clinical-effectiveness
accuracies observed in trials generalise to patients in Scotland. However, the
trials were not homogenous, having a range of entry criteria and varying cutoff levels for the concentration of B-type natriuretic peptides.
The cost-effectiveness analysis has derived a willingness to pay value of
about £500 per additional patient detected with heart failure. This value is very
sensitive to assumptions about the accuracy of tests, values that are
themselves uncertain.
81
The analysis assumed that secondary care can re-prioritise resources to
organise a consultant-led ECG service. Previous attempts to sustain such
services have not always been successful. The analysis also assumed that a
trained medical technical officer grade 4 could achieve the same accuracy as
a cardiologist for 90% of ECGs, with only 10% being referred to a consultant
for interpretation. If such technical officers have lower accuracies, then the
case for a consultant-led service is weakened.
8.4
Recommendations
3. GPs who do not record ECGs in their own practice, or who are not
confident in confirming an automated ECG report produced in their own
practice, should adopt B-type natriuretic peptide tests when deciding which
patients to refer for further assessment for heart failure. The test result
should be used to rule-out a possible diagnosis of heart failure. Initially,
patient data should be audited by Health Boards to ensure the resultant
decisions are clinically appropriate.
4. There is no strong evidence base to support GPs who accurately interpret
ECGs changing their current practice of referring all patients with a newh
relevant ECG abnormality, in the presence of clinical signs and symptoms
suggestive of heart failure, for further clinical assessment.
Use of B-type natriuretic peptide tests in acute care
5. B-type natriuretic peptide tests should not replace echocardiography for
the diagnosis of heart failure.
6. Physicians in admission units should use B-type natriuretic peptide tests,
in conjunction with other clinical information, for patients in whom there is
genuine diagnostic uncertainty after standard evaluation, and no timely
access to echocardiography. The test result should be used to rule-out
heart failure. Initially, this approach should be audited to establish the cost
effectiveness of the service in Scotland.
B-type natriuretic peptide cut-offs
7. B-type natriuretic peptide concentrations rise with age in the normal
population and the recommended cut-off levels should reflect this. If agerelated cut-offs are not available, then clinicians should note that B-type
natriuretic peptide tests might have a reduced specificity in a
predominantly older age group of patients with suspected heart failure.
8. Clinicians and laboratory managers should co-operate at NHS Board level
(or across Scotland) to validate that the manufacturers’ recommended cutoffs for B-type natriuretic peptide concentrations are appropriate for their
own population and that the cut-offs are sufficiently sensitive to identify all
patients with mild heart failure.
h
‘New’ is defined as an abnormality without documented previous investigation.
82
Type of B-type natriuretic peptide test
9. The type of B-type natriuretic peptide testing service (point-of-care or
laboratory service) offered in the emergency setting should be decided
locally by laboratory, clinical and managerial staff working collaboratively,
such that quality-assured results meet the needs of the clinical decision
maker. All services should adhere to the procedures required by
accreditation and regulatory agencies.
Protocols
10. B-type natriuretic peptide testing should not be used for therapeutic
decision making until large, prospective studies have reported. Studies
indicate that the level of B-type natriuretic peptide concentrations has
prognostic value but further evidence is required on threshold.
11. Managed clinical networks that currently include GPs who do not record
ECGs in their practice (and thus who should adopt B-type natriuretic
peptide tests), should develop robust heart failure referral protocols, that
include B-type natriuretic peptide test results, to manage referrals for
further clinical assessment and echocardiography. The use of these
protocols should be monitored and deviations addressed.
12. Healthcare professionals should explain clearly and timeously to patients
and carers what their diagnosis is and how it was made, and ensure that
this is supported by written information.
Further research
Further research is necessary to establish:
•
the additional benefit of B-type natriuretic peptide tests to rule-out heart
failure where GPs already read ECGs accurately (this is currently under
way)
•
the clinical effectiveness of commencing pharmacological therapy on
patients presenting at GPs with a clinical history and signs and symptoms
of heart failure who have raised B-type natriuretic peptides and who have
limited access to echocardiography; such research should seek to
establish the clinical benefit of commencing treatment in advance of
confirming the diagnosis; and
•
the utility of B-type natriuretic peptide testing in informing the diagnosis of
diastolic heart failure.
These recommendations should reviewed as new evidence arises.
83
8.5
Resource implications of recommendations
The main factors influencing changes in resource use from adopting B-type
natriuretic peptide testing in NHSScotland are:
•
•
•
•
the number of GPs who do not record ECGs or who are not confident in
confirming an automated ECG report
the number of patients who present to such GPs with symptoms
suggestive of heart failure
the number of patients who present to hospital with symptoms suggestive
of heart failure in whom there is genuine diagnostic uncertainty after
standard clinical evaluation and no access to timely echocardiography
avoided echocardiography referrals and inappropriate use of inpatient
resources.
8.5.1 Incidence of heart failure
ISD data from GP practices show a prevalence rate for heart failure of around
30,000 (0.6%) have a diagnosis of heart failure in Scotland. The ISD rate is at
the low end of the prevalence ranges in the clinical literature. It is lower than
the 1% prevalence rate reported in Eccles et al. (1998), who also reported an
annual incidence rate of 0.5%. Applying this figure to the ISD data suggests
around 15,000 patients are newly diagnosed with heart failure in Scotland
each year.
McDonagh (2002) found a prevalence rate of 1.4% for symptomatic LVSD
among 25–74 year olds in Glasgow. Adjusting this for a general population
and for the Maisel et al. (2001) ratio for LVSD to heart failure suggests a
prevalence of about 1.4% for symptomatic heart failure in Glasgow’s general
population.
Not all of these people will present for diagnosis. Using 1% as an upper figure
for the potential prevalence of diagnosed heart failure in the Scottish
population, and applying the Eccles et al. (1998) ratio between incidence and
prevalence suggests a maximum incidence of 25,000 new cases of heart
failure in Scotland each year.
The differences between the observed rates from clinical studies and the ISD
data may partially be explained by the fact that heart failure is often not the
final diagnosis, with echocardiography enabling physicians to identify the
underlying cause of the heart failure (Remme et al., 2001).
8.5.2 Potential number of B-type natriuretic peptide tests in acute setting
The ISD data identify that in Scotland about 12,000 patients present to
hospital each year with heart failure, of whom about 7,300 are emergency
admissions and over 4,000 are repeat admissions. If the 7,300 emergency
admissions are undiagnosed patients, then that suggests a maximum of
between 30% and 50% of patients receive a diagnosis of heart failure through
hospital attendance. Seven thousand (7,000) will be adopted as an upper limit
84
for numbers of patients diagnosed with heart failure in hospital and half of this
figure (3,500) as a lower limit.
A normal ECG is uncommon in patients with acute heart failure and thus the
ECG should identify the majority of patients with this condition (Nieminen et
al., 2005).The literature search identified one paper by Fonseca et al. (2004)
which found 25% of patients with chronic heart failure in a primary care setting
had normal ECG or chest X-ray. The equivalent rate in an acute setting will be
lower, given the greater severity of the disease. The number of patients with
genuine diagnostic uncertainty after an ECG is assumed to have a lower
value of 5% and upper value of 20%, equivalent to a range of 175 to 1,400
patients.
Applying the prevalence rate of 47% (Wu et al., 2004) for the emergency
setting (see Section 6.1.3.2), this gives a range of potential patient numbers
who might benefit from the B-type natriuretic peptide test in the hospital
setting of between 375 and 2,975.
8.5.3 Diagnostic setting: primary care
No estimate of the number of GPs who might feel more confident using B-type
natriuretic peptide tests rather than an ECG is available. The only study of six
GPs interpreting ECGs, compared with the gold standard interpretation by a
cardiologist (Struthers, unpublished) showed that one of the six GPs had a
low specificity (37%). The economic modelling indicates such GPs should
adopt BNP. This group of selected GPs may have greater confidence in
reading ECGs than an unselected group. The costings will adopt a
conservative estimate ie, that 25% of GPs will adopt the recommendation to
use B-type natriuretic peptide testing, with a sensitivity analysis assuming
50%.
The resulting minimum and maximum of potential tests in primary care for the
base case is shown in Table 8 - 1.
Table 8 - 1 Base case minimum and maximum number of tests in
primary care setting
Number of new heart failure cases
15,000
25,000
Number of patients who
present in hospital
Number of patients who
present in primary care
Prevalence rate
(Section 6.1.3.2)
% of GPs using BNP tests
Number of tests in primary
care (rounded)i
7,000
3,500
8,000
21,500
29%
29%
25%
25%
6,900
18,535
i
Number of tests in primary care multiplied by number of GPs using BNP divided by
prevalence rate.
85
If 50% of GPs adopt B-type natriuretic peptide testing, then the potential
number of tests increases two fold, to between 13,790 and 37,070.
Based upon the number of tests required, and a test cost of £25j this would
imply a budgetary requirement of the following order (see Table 8 - 2).
Table 8 - 2 Range of number and costs of B-type natriuretic peptide tests
Number of tests
Incidence of heart failure
15,000
25,000
Number of tests
GP
Hospital
Total tests
Costs
GP
Hospital
Total test costs
6,900
375
7,275
18,535
2,975
21,510
£172,500
£9,375
£181,875
£463,375
£74,375
£537,750
Additionally, if all patients receive an information leaflet costing 10 pence
each, the annual costs would rise by about £2,000.
8.5.4 Sensitivity analysis
If 50% of GPs, rather than the 25% assumed in the base case, adopt B-type
natriuretic peptide tests then the total costs rise to between £0.35 and £1
million. Indeed, a range of sensitivity tests using different prevalence rates
and hospital/GP mixes suggest that the range of costs of between £0.15
million and £1 million is a robust estimate of the cost of introducing B-type
natriuretic peptides testing.
8.5.5 Additional costs in hospitals and primary care
The main costs of implementing B-type natriuretic peptide testing within
hospitals will be:
•
•
training the test operators (probably nurses on admission wards) and
clinicians
developing, implementing and monitoring the relevant laboratory and
clinical protocols, to include within MCNs.
Drawing upon the conclusions by Craig et al. (2004) for a troponin testing
service, an overall cost of around £1,600 for training and £1,300 for protocol
development in each hospital is appropriate. If the tests were introduced at
each of the 33 hospitals that admit more than 50 patients annually with heart
failure, the incremental costs would be about £96,000.
j
Secondary care may employ point-of-care testing, but given reasonable throughputs, a figure
of £25 per test should be achievable.
86
In primary care, 25% of the 4,300 GPs and at least two nurses from each of
the 1,000 practices would require approximately 1 hour of training, at a cost of
£100 per hour per GP and £20 per hour per nurse. Training would therefore
cost around £187,500, rising to almost £300,000 if 50% of GPs require
training.
8.5.6 Total costs of implementing B-type natriuretic peptide testing
The costs to implement B-type natriuretic peptide tests in the first year are
estimated to be between £0.47 million and £0.83 million comprising:
•
•
•
B-type natriuretic peptide test cost
Hospital training and protocols
GP practice costs
£0.18 million to £0.54 million
£0.10 million
£0.19 million
Thereafter, the costs should fall to the cost of the tests plus some training of
new GPs, nurses and physicians and continued training for others.
8.5.7 Potential resources released
Using B-type natriuretic peptide tests should reduce the number of referrals
for clinical assessment and echocardiography. Given a specificity of B-type
natriuretic peptides of 75% (see Figure 11 - 31) and a consultant-led ECG
service specificity of 60% (see Section 5.2.5), this suggests a potential
improvement of 14%k within the hospital setting. Assuming a specificity of
49% (see Section 6.1.3.1) for a GP-read ECG, then the improvement within
the GP setting is estimated to be about 25%. Removing patient travel costs
from the cost for an echocardiogram gives a cost of £102 per
echocardiogram. Applying these rates and costs gives the following potential
resources savings (see Table 8 - 3).
Table 8 - 3 Range of echocardiography savings
Settings
GP
Hospital
Total savings
Cost savings
Incidence of heart failure
15,000
25,000
£175,865
£472,630
£4,970
£39,450
£180,835
£512,080
These resources should be available for alternative use but it is unlikely that
actual cash savings will be made. Moreover, these savings assume that
currently all patients with an initial diagnosis of heart failure are referred for
echocardiography. The savings are overstated if the referral rate is less than
100%. The results are also very sensitive to the assumed prevalence rate of
29% in the GP setting. As this rate increases, the potential savings fall.
k
Difference due to rounding.
87
As reported in Section 6.1.2, Mueller et al. (2004) achieved hospital-related
savings of about £465 per emergency patient from adopting B-type natriuretic
peptide testing. The potential savings range from £0.08 million to £0.65
million, assuming 3,500 and 7,000 patients respectively are diagnosed with
heart failure annually in the acute sector.
Further savings were found in the Swiss study from the lower admission rate
to intensive care from using B-type natriuretic peptide testing, 15% as
opposed to 24% (p=0.01). However, this saving has not been costed because
there is insufficient information on the admission rate to intensive care for
patients with suspected heart failure in Scotland.
In summary, the estimated annual resource savings range from £0.26 million
to £1.16 million, comprising of £0.18 million to £0.51 million for reduced for
echocardiography referrals and £0.08 million to £0.65 million for
hospitalisation.
8.5.8 Comparison of costs and resources released
Table 8 - 4 compares the annual costs and savings from introducing B-type
natriuretic peptide tests for the first year later years by setting, assuming 25%
uptake of testing by GPs.
Table 8 - 4 Comparison of costs and savings from B-type natriuretic
peptide tests by setting: first year and steady state (All £ millions)
Setting
GP
Hospital
Total
GP
Hospital
Total
For first year
For steady state
Total
Total
Total
Total
Net
Net
gross
gross
gross
gross
l
j
cost/saving
cost/saving
costs
savings
costs
savings
Heart failure incidence of 15,000 patients
£0.36
£0.18
£0.18
£0.17
£0.17
£0.00
£0.11
£0.09
£0.02
£0.01
£0.09
-£0.08
£0.47
£0.27
£0.20
£0.18
£0.26
-£0.08
Heart failure incidence of 25,000 patients
£0.65
£0.47
£0.18
£0.46
£0.47
-£0.01
£0.17
£0.69
-£0.52
£0.07
£0.69
-£0.62
£0.82
£1.16
-£0.34
£0.53
£1.16
-£0.63
Assuming an annual incidence of 15,000 patients, the introduction of B-type
natriuretic peptide testing would require an investment for training, developing
protocols and providing tests of under £0.5 million in the first year. Non-cash
resource savings of just over half of this sum are forecast to be achievable,
giving a net cost to the service of around £0.2 million. Thereafter, the annual
cash expenditure on tests is forecast to be about £0.2 million. Non-cash
resource savings are forecast to exceed these costs by about £0.08 million,
with almost all the savings being in the acute sector.
l
Negative value represents a net saving.
88
Assuming an annual incidence of 25,000 patients, the introduction of B-type
natriuretic peptide tests would require a cash investment of over £0.8 million.
Forecast resource savings from avoided echocardiography avoided and
reduced length of stays exceed £1 million pounds, with all the net savings
being in the acute sector. These savings are however extrapolations from a
Swiss study and still need to be piloted in Scotland to establish whether they
generalise to the Scottish admission setting. Thereafter, annual savings are
forecast to exceed costs in the acute sector. However, the costs and savings
are very similar in primary care, with no forecast net saving.
The model assumed that only tests required by the algorithm are undertaken;
experience with other tests suggests that this is an optimistic assumption (Dr
P Padfield, Deputy Medical Director and Consultant Physician/Reader in
Medicine, Western General Hospital, Edinburgh. Personal communication,
October 2004). Thus without careful monitoring of the use of these tests in
clinical practice, the cost base may underestimate the out-turn costs.
8.6
Challenges for implementation
The main challenges for implementation of the HTA recommendations are
likely to include encouraging and motivating GPs who are using inaccurate
diagnostic techniques (eg machine-read ECG or response to drugs) to adopt
B-type natriuretic peptide testing. This will require education, training and
support but it is not clear how these will be organised.
The funding of tests is also a concern. Introducing B-type natriuretic peptides
tests into primary care should save resources but these resources will be in
secondary care. Moreover, the saved resources will not be in cash but rather
primarily from reducing the workload of existing echocardiography services.
It is not anticipated that introducing a laboratory B-type natriuretic peptide
testing service will present major organisational challenges; the process will
be similar to that adopted for other blood tests. A challenge could arise if it is
cost effective to adopt a point-of-care testing service, especially if laboratory
quality assurance and quality control is difficult to achieve.
Education and training for medical practitioners on the ‘decision rules’
required for any new diagnostic system would need to be put in place.
Existing protocols within MCNs may also require updating but these should
not be onerous.
89
9 Acknowledgements
NHS QIS is grateful to all experts and peer reviewers (Appendix 1) who have
given generously of their precious time to scope the project, appraise the
evidence and in the writing of this HTA Report.
Thanks to all manufacturers who submitted evidence at the outset of the
project and to those who provided access to information during the
assessment.
Thanks to all patient and carer organisations who participated in scoping the
project and in providing evidence.
Thanks to the Royal College of General Practitioners, the Royal College of
Physicians and Surgeons (Glasgow) and the Scottish Cardiac Society Royal
Colleges in Scotland who published the Consultation Report on their
websites.
Finally, thanks also to all healthcare professionals and service users who
responded to the surveys and submitted responses during the consultation
period.
90
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11 Appendices
Appendix 1 Experts and peer reviewers
EXPERTS
Dr David Davidson
General Practitioner
(MCN lead for CHD)
Paisley
Dr Hamish Greig
Out-of hours General Practitioner
Brechin
Dr Andrew Henderson
Consultant Physician
Lorn and Islands District General
Hospital, Oban
Dr Theresa McDonagh
Consultant Cardiologist
Royal Brompton Hospital, London
Ms Elizabeth Paton
Heart Failure Project Nurse
East Ayrshire Local Healthcare Cooperative)
Mr Alan Reid
Biochemist
The Victoria Infirmary, Glasgow
Dr Richard Spooner
Biochemist
Gartnavel General Hospital,
Glasgow
Professor Alan Struthers
Professor of Cardiovascular Medicine
and Therapies
University of Dundee and Ninewells
Hospital
Dr P O Collinson
Consultant Chemical Pathologist
St George's Hospital, London
Professor Martin Cowie
Chair in Cardiology
(Health Services Research)
National Heart and Lung Institute,
London
Dr Frank Dunn
Clinical Director
Stobhill Hospital, Glasgow
Dr Steve Engleman
Health Economist
Edinburgh
Dr Paul Padfield
Deputy Medical Director and
Consultant Physician/Reader in
Medicine
Western General Hospital,
Edinburgh
PEER REVIEWERS
102
Appendix 2 Strategy for
literature searches
Clinical effectiveness:
Secondary literature
•
An initial search was undertaken in
June 2003, and updated in January
2004, to identify HTAs, systematic
reviews and other evidence-based
reports using the following sources:
•
•
•
•
•
•
•
•
•
•
•
National Institute for Clinical
Excellence (NICE)
http://www.nice.org.uk
National Coordinating Centre
for Health Technology
Assessment (NCCHTA)
http://www.ncchta.org/
Health Technology Assessment
Database (HTA) via the
Cochrane Library (Internet)
Cochrane Database of
Systematic Reviews (CDSR) via
the Cochrane Library (Internet)
Database of Abstracts of
Reviews of Effects (DARE) via
the Cochrane Library (Internet)
NHS Centre for Reviews and
Dissemination, University of
York
http://www.york.ac.uk/inst/crd/
West Midlands Health
Technology Assessment
Collaboration, Department of
Public Health & Epidemiology,
University of Birmingham
http://www.publichealth.bham.a
c.uk/wmhtag/
ScHARR, University of Sheffield
http://www.shef.ac.uk/scharr
South and West R&D
Directorate, DEC reports
http://www.hta.nhsweb.nhs.uk/r
apidhta
British Columbia Office of
Health Technology Assessment
(BCOHTA)
•
•
•
•
•
•
•
•
•
•
•
•
•
103
http://www.chspr.ubc.ca/cgibin/pub?program=bcohta&by=d
ate
Health Services Utilization and
Research Commission,
Saskatchewan
http://www.saskatoonhealthregi
on.ca/
Institute for Clinical and
Evaluative Sciences, Ontario
http://www.ices.on.ca
Manitoba Centre for Health
Policy,
http://www.umanitoba.ca/centre
s/mchp
ECRI
http://www.ecri.org/
HSTAT,
http://www.ncbi.nlm.nih.gov/boo
ks/bv.fcgi?rid=hstat
SIGN (Scottish Intercollegiate
Guidelines Network)
http://www.sign.ac.uk
Health Services Research Unit
http://www.abdn.ac.uk/hsru/
ARIF (Aggressive Research
Intelligence Facility)
http://www.bham.ac.uk/arif/
Health Evidence Bulletins
Wales
http://www.hebw.uwcm.ac.uk/
Clinical Evidence (BMJ)
http://www.clinicalevidence.com
Centre for Clinical
Effectiveness, Monash Institute
of Public Health
http://www.med.monash.edu.au
/healthservices/cce/
Prodigy
http://www.prodigy.nhs.uk
TriP database
http://www.tripdatabase.com/
Bandolier
http://www.jr2.ox.ac.uk/bandolie
r/
Ongoing Reviews database
•
http://www.updatesoftware.com/National/
Medical Research Council –
funded research
http://fundedresearch.cos.com/
MRC/
9. systole/
10. ((ventric$ or diastol$ or systol$)
adj2 (function$ or dysfunction$ or
fail$)).tw
11. (lvsd or rvsd or lvd or rvd).tw
12. or/1-11
13. exp natriuretic agents/
14. (natriuretic$ adj peptide$).tw
15. bnp.tw
16. ((biological or biochemical or
cardiac) adj marker$).tw
17. (biomarker$ or bio-marker$).tw
18. or/13-17
19. 12 and 18
Clinical Effectiveness:
Primary literature
The following sources were
searched, via OVID, between
February 2004 and June 2004:
•
•
•
•
MEDLINE
EMBASE
MEDLINE In Process
CINAHL
Search 2: Diagnostic accuracy of
ECG
Details of the three main searches
relating to the diagnostic accuracy
of BNP, ECG and
echocardiography are listed below.
All strategies are those used to
search MEDLINE. Search 1
combined the concepts of heart
failure and BNP. This strategy was
then combined with the diagnostic
accuracy filter. Searches 2 and 3,
combining the concept of ECG and
heart failure, and echocardiography
and heart failure respectively, were
combined with a diagnostic
accuracy filter, and to further refine
the results, a systematic reviews
filter. For details of additional
strategies, please contact NHS
QIS.
1. exp heart failure, congestive/
2. ((heart$ or cardiac$ or cardial$
or coronar$) adj2 fail$).tw
3. hf.tw
4. exp ventricular dysfunction/
5. exp ventricular function/
6. hypertrophy, left ventricular/
7. hypertrophy, right ventricular/
8. diastole/
9. systole/
10. ((ventric$ or diastol$ or systol$)
adj2 (function$ or dysfunction$ or
fail$)).tw
11. (lvsd or rvsd or lvd or rvd).tw
12. or/1-11
13. exp electrocardiography/
14. electrocardio$.tw
15. (ecg? or ekg?).tw
16. or/13-15
17. 12 and 16
Search 1: Diagnostic accuracy of
BNP
Search 3: Diagnostic accuracy of
echocardiography
1. exp heart failure, congestive/
2. ((heart$ or cardiac$ or cardial$
or coronar$) adj2 fail$).tw
3. hf.tw.
4. exp ventricular dysfunction/
5. exp ventricular function/
6. hypertrophy, left ventricular/
7. hypertrophy, right ventricular/
8. diastole/
1. exp heart failure, congestive/
2. ((heart$ or cardiac$ or cardial$
or coronar$) adj2 fail$).tw
3. hf.tw.
4. exp ventricular dysfunction/
5. exp ventricular function/
6. hypertrophy, left ventricular/
7. hypertrophy, right ventricular/
8. diastole/
104
9. systole/
10. ((ventric$ or diastol$ or systol$)
adj2 (function$ or dysfunction$ or
fail$)).tw
11. (lvsd or rvsd or lvd or rvd).tw.
12. or/1-11
13. exp echocardiography/
14. (cardioechogra$ or echocardio$
or (echo adj cardio$)).tw.
15. echo?.tw.
16. or/13-15
17. 12 and 16
12. MEDLINE/
13. (medline or medlars or embase
or cochrane or cinahl or psycinfo or
psychinfo or psyclit or psychlit or
science citation index or scisearch
or web of science or pubmed).tw.
14. (handsearch$ or (hand adj2
search$)).tw.
15. (manual$ adj2 search$).tw.
16. or/1-15
17. Letter.pt.
18. Editorial.pt.
19. Comment.pt.
20. Case Reports.pt.
21. or/17-20
22. 16 not 21
Diagnostic accuracy filter
1. exp "sensitivity and specificity"/
2. exp diagnostic errors/
3. likelihood functions/
4. Reproducibility of results/
5. sensitiv$.tw.
6. specificit$.tw.
7. accurac$.tw.
8. (predictive adj2 value$).tw.
9. (false$ adj2 (positive$ or
negative$ or rate$)).tw.
10. roc.tw.
11. (receiver operat$ adj2 (curve$
or characteristic$)).tw
12. (likelihood$ adj2 (ratio$ or
function$)).tw
13. or/1-12
Meta-analyses and Systematic
review filter
1. Meta-analysis.pt.
2. Review, academic.pt.
3. exp Review Literature/
4. Meta-Analysis/
5. (metaanaly$ or metanaly$ or
(meta adj2 analy$)).tw.
6. (review$ or overview$).ti.
7. (systematic$ adj4 (review$ or
overview$)).tw.
8. ((quantitative$ or qualitative$)
adj4 (review$ or overview$)).tw.
9. ((studies or trial$) adj1 (review$
or overview$)).tw.
10. (integrat$ adj2 (research or
review$ or literature)).tw.
11. (pool$ adj1 (analy$ or data)).tw.
105
Economic evaluation: Secondary
literature
•
An initial search was undertaken in
June 2003, and updated in January
2004, to identify economic
evaluations, using the following
sources:
•
•
•
•
•
•
•
•
•
•
•
•
NHS Economic Evaluation
database (NHS EED) via the
Cochrane Library (Internet)
Health Economic Evaluations
Database (HEED),
www.ohe.org/HEED.htm (by
subscription)
Health Economics Research
Unit, Aberdeen
http://www.abdn.ac.uk/heru
Centre for Health Economics,
York
http://www.york.ac.uk/inst/che/
Health Economics Research
Centre, Oxford
http://www.herc.ox.ac.uk
Health Economics Research
Group, Brunel
http://www.brunel.ac.uk/about/a
cad/herg
Centre for Health Services
Research, University of
Newcastle
http://www.ncl.ac.uk/chsr/resear
ch/economics
SCHARR School of Health and
Related Research, Sheffield
http://www.shef.ac.uk/uni/acade
mic/R-Z/scharr/
Health Economics Group, East
Anglia
http://www.med.uea.ac.uk/resea
rch/research_econ/HEG_Intro.h
tm
Institute of Health Economics
IHE, Alberta, Canada
http://www.ihe.ab.ca
LSE London School of
Economics and Political
Science
http://www.lse.ac.uk/
•
•
•
•
•
•
Southampton University
Economics Department
http://www.economics.soton.ac.
uk
Centre for Health Economics
Research and Development
CHERE, University of Sydney
and Central Sydney Area
Health Service
http://www.chere.uts.edu.au
Institute of Health Economics
(IHE), Alberta, Canada
http://www.ihe.ab.ca
International Health Economics
Association iHEA,
http://www.healtheconomics.org
Centre for Health Economics
and Policy Analysis (CHEPA),
McMaster University
http://www.chepa.org
Centre for Health Economics
(CHPE), University of
Melbourne and Monash
University, Australia
http://www.buseco.monash.edu.
au/centres/che
NetEc
http://www.netec.mcc.ac.uk/Net
Ec.html
IDEAS Internet Documents in
Economics Access Service
http://ideas.repec.org
Economics evaluation: Primary
literature
The following sources were
searched, via OVID, during April
2004:
•
•
•
•
MEDLINE
EMBASE
MEDLINE In Process
CINAHL
There were three searches
undertaken to identify economic
evaluations of BNP, ECG and
echocardiography. The strategies
for MEDLINE are presented below:
106
42. monte carlo.tw
43. (decision adj2 (tree$ or analys$
or model$)).tw
44. ((clinical or critical or patient)
adj (path? or pathway?)).tw
45. (managed adj2 (care or
network?)).tw.
46. or/17-45
47. 10 and 16 and 46
48. Limit 47 to yr=1998-2004
Search 1: Economic evaluation
of BNP
1.exp heart failure, congestive/
2. ((heart$ or cardiac$ or cardial$
or coronar$) adj2 fail$).tw.
3. hf.tw.
4. exp ventricular dysfunction/
5. exp ventricular function/
6. hypertrophy, left ventricular/
7. hypertrophy, right ventricular/
8. (ventric$ adj2 (function$ or
dysfunction$ or fail$)).tw
9. (lvsd or rvsd or lvd or rvd).tw
10. or/1-9
11. exp natriuretic agents/
12. (natriuretic$ adj peptide$).tw
13. bnp.tw
14. ((biological or biochemical or
cardiac) adj marker$).tw
15. (biomarker$ or bio-marker$).tw
16. or/11-15
17. exp economics/
18. quality of life/
19. value of life/
20. quality adjusted life years/
21. models, economic/
22. markov chains/
23. monte carlo method/
24. decision tree/
25. economic$.tw
26. (cost? or costing? or costly or
costed).tw
27. (price? or pricing?).tw
28. (pharmacoeconomic? or
(pharmaco adj economic?)).tw
29. budget$.tw
30. expenditure$.tw
31. (value adj1 (money or
monetary)).tw
32. (fee or fees).tw
33. "quality of life".tw
34. qol$.tw
35. hrqol$.tw
36. "quality adjusted life year$".tw
37. qaly$.tw
38. cba.tw
39. cea.tw
40. cua.tw
41. markov$.tw
Search 2: Economic evaluation
of ECG
1.exp heart failure, congestive/
2. ((heart$ or cardiac$ or cardial$
or coronar$) adj2 fail$).tw.
3. hf.tw.
4. exp ventricular dysfunction/
5. exp ventricular function/
6. hypertrophy, left ventricular/
7. hypertrophy, right ventricular/
8. (ventric$ adj2 (function$ or
dysfunction$ or fail$)).tw.
9. (lvsd or rvsd or lvd or rvd).tw.
10. or/1-9
11. exp electrocardiography/
12. electrocardio$.tw.
13. (ecg? or ekg?).tw.
14. or/11-13
15. exp economics/
16. quality of life/
17. value of life/
18. quality adjusted life years/
19. models, economic/
20. markov chains/
21. monte carlo method/
22. decision tree/
23. economic$.tw.
24. (cost? or costing? or costly or
costed).tw.
25. (price? or pricing?).tw.
26. (pharmacoeconomic? or
(pharmaco adj economic?)).tw.
27. budget$.tw.
28. expenditure$.tw.
29. (value adj1 (money or
monetary)).tw.
30. (fee or fees).tw.
31. "quality of life".tw.
107
32. qol$.tw.
33. hrqol$.tw.
34. "quality adjusted life year$".tw.
35. qaly$.tw.
36. cba.tw.
37. cea.tw.
38. cua.tw.
39. markov$.tw.
40. monte carlo.tw.
41. (decision adj2 (tree$ or analys$
or model$)).tw
42. ((clinical or critical or patient)
adj (path? or pathway?)).tw
43. (managed adj2 (care or
network?)).tw
44. or/15-43
45. 10 and 14 and 44
46. Limit 45 to yr=1998-2004
24. Limit 23 to yr=2000-2004
25. Limit 24 to English language
Further details about the search
and a copy of all search strategies
can be obtained by contacting NHS
QIS.
Search 3: Economic evaluation
of echocardiography
1. exp heart failure, congestive/
2. ((heart$ or cardiac$ or cardial$
or coronar$) adj2 fail$).tw.
3. hf.tw.
4. exp ventricular dysfunction/
5. exp ventricular function/
6. hypertrophy, left ventricular/
7. hypertrophy, right ventricular/
8. (ventric$ adj2 (function$ or
dysfunction$ or fail$)).tw.
9. (lvsd or rvsd or lvd or rvd).tw.
10. or/1-9
11. exp echocardiography/
12. (cardioechogra$ or echocardio$
or (echo adj cardio$)).tw.
13. echo?.tw.
14. or/11-13
15. exp economics/
16. economic$.tw.
17. (cost? or costing? or costly or
costed).tw.
18. (value adj1 (money or
monetary)).tw.
19. cba.tw.
20. cea.tw.
21. cua.tw.
22. or/15-21
23. 10 and 14 and 22
108
Appendix 3 Literature selection process for clinical effectiveness
109
Appendix 4 Diagnostic test studies
Table 11 - 1 All BNP studies – patient characteristics
Lead author
Cowie (1997)
Dao (2001)
Lubien (2002)
Sim (2003)
Knudsen (2004)
Kruger (2004)
Maisel (2002)
Morrison (2002)
Davis (1994)
Sparrow (2003)
Landray (2000)
Lainchbury (2003)
Villacorta (2002)
Maisel (2001)
Davidson (1996)
Yamamoto (2000)
Logeart (2002)
Ng (2003)
McDonagh (1998)
Setting
GP referral/open-access
echocardiography
Emergency department
Other
GP referral/open-access
echocardiography
Emergency department
Cardiology clinic
Emergency department
Emergency department
Emergency department
Other
GP referral/open-access
echocardiography
Emergency department
Emergency department
GP referral/open-access
echocardiography
Other
GP referral/open-access
echocardiography
Emergency department
GP referral/open-access
echocardiography
GP referral/open-access
echocardiography
Target
diagnosis
Diagnostic
method
Total
number
evaluated
for assay
Number
assayed
and
target
disease
HF
Consensus
106
29
HF
LVDD
Consensus
Echo
236
294
97
119
LVSD
Echo
83
26
HF
LVSD
HF
HF
HF
LVSD
Consensus
Echo
Consensus
Consensus
Consensus
Echo
155
128
1,586
321
52
621
75
66
744
134
32
314
LVSD
Echo
126
40
HF
Consensus
Single
cardiologist
205
LVD
EF cutoff
Prospective
Manufacturer
Mean
age
Yes
Peninsula
NR
NR
Yes
Yes
Biosite
Biosite
63
60
0.35
Yes
Local system
72
0.40
Yes
Yes
Yes
Yes
Yes
Yes
Biosite
Biosite
Biosite
Biosite
Local system
Not described
76
61
64
NR
74
75
NR
Yes
Shionoria
74
70
Yes
Biosite
70
70
36
Yes
Biosite
72
Echo
200
95
Yes
Biosite
65
LVSD
Nuclear
medicine
87
22
0.35
Yes
Peninsula
64
LVSD
Echo
466
51
0.45
Yes
Shionoria
65
HF
Consensus
163
115
Yes
Biosite
65
LVSD
Echo
13
17
0.35
Yes
Peninsula
63
LVSD
Echo
1,252
37
0.30
Yes
Peninsula
51
HF
110
0.50
Lead author
Hutcheon (2002)
Misuraca (2002)
Smith (2000)
Zaphiriou
(unpublished)
Setting
Other (Day Hospital for
elderly)
GP referral/open-access
echocardiography
GP referral/open-access
echocardiography
GP referral/open-access
echocardiography
Target
diagnosis
Diagnostic
method
Total
number
evaluated
for assay
Number
assayed
and
target
disease
EF cutoff
Prospective
NR
Yes
Peninsula
79
Yes
NR
70
Yes
Peninsula
76
Yes
Biosite
74
LVSD
Echo
299
31
HF
Consensus
83
45
LVSD
Echo
155
12
HF
Consensus
301
104
HF = Heart Failure
LVDD = Left Ventricular Diastolic Dysfunction
LVSD = Left Ventricular Systolic Dysfunction
EF = Ejection Fraction
NR = Not Reported
111
NR
Manufacturer
Mean
age
Table 11 - 2 B-type natriuretic peptide studies – results and comments
Lead author
Cowie (1997)
Dao (2001)
Lubien (2002)
Sim (2003)
Knudsen (2004)
Kruger (2004)
Maisel (2002)
Morrison (2002)
Davis (1994)
Sparrow (2003)
Landray (2000)
Lainchbury (2003)
Villacorta (2002)
Maisel (2001)
Davidson (1996)
Yamamoto (2000)
Logeart (2002)
Ng (2003)
McDonagh (1998)
Hutcheon (2002)
Misuraca (2002)
Smith (2000)
Zaphiriou
(unpublished)
Sensitivity
0.97
0.94
0.85
0.88
0.94
0.89
0.90
0.94
0.93
0.55
0.88
0.94
1.00
0.92
1.00
0.79
0.96
1.00
0.76
0.97
Specificity
0.84
0.94
0.83
0.60
0.45
0.55
0.73
0.84
0.90
0.56
0.34
0.70
0.97
0.86
0.58
0.64
0.31
0.44
0.87
0.38
0.93
0.92
0.34
0.65
0.79
0. 72
Comments
QRS prolongation >0.1 s gives 0.84, 0.63.
All on loop diuretics already. Not consecutive series of patients
EF cut-off point not specified.
52% with dyspnoea.
33% symptomatic.
Random sample of population rather than symptomatic presenting patients.
Elderly patients examined for various reasons (decreased mobility the most common).
Italian study (reported in Italian, English abstract).
Series of elderly patients (not necessarily symptomatic).
112
Table 11 - 3 All NT-proBNP studies – patient characteristics
Lead author
Jose (2003)
Gustafson (2003)
Nielsen (2004)
Nielsen (2004)
Bayes-Genis (2004)
Talwar (1999)
Wright (2003)
Ng (2003)
Pfister (2004)
McDonagh (2004b)
Bay (2003)
Hobbs (2002)
Zaphiriou
(unpublished)
Setting
Emergency
department
GP referral/
open-access echo
GP referral/
open-access echo
GP referral/
open-access echo
Emergency
department
Other
GP referral/
open-access echo
GP referral/
open-access echo
Emergency
department
GP referral/
open-access echo
Emergency
department
GP referral/
open-access echo
GP referral/
open-access echo
Target
diagnosis
Diagnostic
method
Total
number
evaluated
for assay
Number
assayed
and target
disease
HF
Other
119
73
LVSD
Echo
367
33
HF
Consensus
146
HF
Consensus
HF
EF
cutoff
Prospective
Manufacturer
Mean
age
Yes
Biomedica
Yes
Local system
47
Yes
Roche
65
141
34
Yes
Roche
65
Consensus
89
74
0.45
Yes
Roche
62
LVSD
Echo
243
96
NR
Yes
Local system
73
HF
Consensus
305
77
Yes
Local system
72
LVSD
Echo
13
17
0.35
Yes
Local system
63
LVSD
Echo
339
24
0.4
Yes
Roche
HF
Other
3,051
94
Yes
Roche
Yes
ELISA (No
detail)
LVSD
Echo
HF
HF
0.40
2,193
157
Consensus
591
52
Yes
Roche
Consensus
302
104
Yes
Roche
HF = Heart Failure
LVSD = Left Ventricular Systolic Dysfunction
113
0.40
54
68.8
66
56
73
66
74
Table 11 - 4 NT-proBNP studies – results and comments
Lead author
Jose (2003)
Gustafson (2003)
Nielsen (2004)
Nielsen (2004)
Bayes-Genis (2004)
Talwar (1999)
Wright (2003)
Ng (2003)
Pfister (2004)
McDonagh (2004b)
Bay (2003)
Hobbs (2002)
Zaphiriou
(unpublished)
Sensitivity
0.97
0.97
0.96
0.94
0.96
0.94
0.80
1.00
0.92
0.75
0.73
1.00
Specificity
0.89
0.46
0.67
0.69
0.60
0.55
0.90
0.46
0.61
0.79
0.82
0.70
0.98
0.35
Comments
Framingham criteria for diagnosis-not clear whether >1 assessor. High proportion of heart failure.
Males only, grade of dyspnea also recorded.
Females only.
EF cut-off point not specified.
Epidemiological study, not symptomatic presenting patients.
Random sample – not symptomatic presenting patients.
Symptomatic patients referred from GP.
114
Table 11 - 5 ECG studies – patient characteristics
Lead author
Davie (1996)
Gillespie (1997)
Nielsen (2000)
Hutcheon (2002)
Misuraca (2002)
Houghton (1997)
Ng (2003)
Zaphiriou
(unpublished)
Khandekar (1996)
Sandler (2000)
Lindsay (2000)
Struthers
(Unpublished)
Fonseca (2004)
Setting
GP referral/open-access
echo
Emergency department
GP referral/open-access
echo
Other (Day Hospital for
elderly)
GP referral/open-access
echo
GP referral/open-access
echo
GP referral/open-access
echo
GP referral/open-access
echo
GP referral/open-access
echo
GP referral/open-access
echo
GP referral/open-access
echo
GP referral/open-access
echo
GP-based
epidemiological study
Target
diagnosis
Diagnostic
method
Total
number
evaluated
for assay
Number
assayed
and target
disease
EF cut-off
Prospective
Mean age
LVSD
Echo
534
96
NR
Yes
NR
LVSD
Echo
71
45
NR
Yes
73
LVSD
Consensus
126
15
0.45
Yes
LVSD
Echo
299
31
NR
Yes
79
HF
Consensus
83
45
Yes
70
LVSD
Echo
200
165
0.4
Yes
65
LVSD
Echo
1,331
17
0.35
Yes
63
HF
Consensus
302
104
Yes
74
LVSD
Echo
137
50
NR
NR
65
LVSD
Echo
240
71
0.4
No
NR
LVSD
Echo
416
97
NR
No
NR
HF
Single
cardiologist
407
54
Yes
NR
HF
Consensus
1,034
539
Yes
NR
HF = Heart Failure
LVSD = Left Ventricular Systolic Dysfunction
NR= Not reported
115
71
Table 11 - 6 ECG studies – results and comments
Lead author
Sensitivity
Specificity
Comments
Davie (1996)
Gillespie (1997)
Nielsen (2000)
Hutcheon (2002)
Misuraca (2002)
Houghton (1997)
Houghton (1997)
Houghton (1997)
Ng (2003)
Zaphiriou
(unpublished)
Khandekar
(1996)
Sandler (2000)
Lindsay (2000)
Struthers
(Unpublished)
Struthers
(Unpublished)
Fonseca (2004)
(reported
summary results)
0.94
0.98
0.87
0.97
0.93
0.89
0.92
0.90
0.88
0.61
0.69
0.56
0.50
0.63
0.46
0.54
0.49
0.61
0.81
0.60
0.78
0.20
Machine read
0.73
0.91
0.55
0.65
Not clear – possibly read by GP.
Cardiologist
0.95
0.52
Cardiologist
0.94
0.22
Machine
0.81
0.51
Cardiologist – not included in analysis – raw
data in paper suggests specificity = 35%
Highly-selected group, high prevalence.
Cardiologist
GP number 1
GP number 2
Cardiologist
116
Appendix 5 Graphical representations of diagnostic tests
Figure 11- 1 Summary ROC curve for BNP in heart failure
Figure 11- 2 Summary ROC curve for BNP in LVSD
117
Figure 11- 3 Summary ROC curve for NT-proBNP in heart failure
Figure 11- 4 Summary ROC curve for NT-proBNP in LVSD
118
Figure 11- 5 Summary ROC curve for ECG in Heart Failure
Figure 11- 6 BNP sensitivity for heart failure in hospital setting
Figure 11- 7 BNP specificity for heart failure in hospital setting
119
Figure 11- 8 BNP diagnostic OR for heart failure in hospital setting
Figure 11- 9 BNP sensitivity for LVSD in hospital setting
Figure 11- 10 BNP specificity for LVSD in hospital setting
Figure 11- 11 BNP diagnostic OR for LVSD in hospital setting
120
Figure 11- 12 NT-proBNP sensitivity for heart failure in hospital setting
Figure 11- 13 NT-proBNP specificity for heart failure in hospital setting
Figure 11- 14 NT-proBNP diagnostic OR for heart failure in hospital
setting
121
Figure 11- 15 NT-proBNP sensitivity for LVSD in hospital setting
Figure 11- 16 NT-proBNP specificity for LVSD in hospital setting
Figure 11- 17 NT-proBNP diagnostic OR for LVSD in hospital setting
122
Figure 11- 18 BNP sensitivity for heart failure in primary setting
Figure 11- 19 BNP specificity for heart failure in primary setting
Figure 11- 20 BNP diagnostic OR for heart failure in primary setting
123
Figure 11- 21 BNP sensitivity for LVSD in primary care setting
Figure 11- 22 BNP specificity for LVSD in primary care setting
Figure 11- 23 BNP diagnostic OR for LVSD in primary care setting
124
Figure 11- 24 NT-proBNP sensitivity for heart failure in primary care
setting
Figure 11- 25 NT-proBNP specificity for heart failure in primary care
setting
Figure 11- 26 NT-proBNP diagnostic OR for heart failure in primary care
setting
125
Figure 11- 27 NT-proBNP sensitivity for LVSD in primary care setting
Figure 11- 28 NT-proBNP specificity for LVSD in primary care setting
Figure 11- 29 NT-proBNP diagnostic OR for LVSD in primary care setting
126
Figure 11- 30 Pooled sensitivity for heart failure
Figure 11- 31 Pooled specificity for heart failure
127
Figure 11- 32 Pooled diagnostic OR for heart failure
Figure 11- 33 Pooled summary ROC curve for heart failure
128
Figure 11- 34 Pooled sensitivity for LVSD
Figure 11- 35 Pooled specificity for LVSD
Figure 11- 36 Pooled diagnostic OR for LVSD
129
Figure 11-37 Pooled summary ROC for LVSD
130
Appendix 6 Cost of tests
B-type natriuretic peptides tests
The manufacturers provided costs (before discounts) of B-type natriuretic
peptide testing reagents for different throughputs. Where necessary, the costs
of quality control and calibration were added. Additional costs were included
for clinicians taking the test, administration, transport and communicating the
results to patients. The laboratory staff costs to undertake the tests were
taken from Craig et al. (2004). GP consultation costs and the cost of patients
travel were taken from Netten et al. (2003). Point-of-care tests were assumed
to require additional time during the initial GP appointment at a cost of £7.50.
The cost of B-type natriuretic peptide tests are presented in Table 11 - 7.
Table 11 - 7 Cost of B-type natriuretic peptide tests
Cost of B-type natriuretic peptide tests
Annual throughput
Range of assay costs
Laboratory staff
Other test related costs
Additional clinician/nurse
time
Total base case
2,000
laboratory
tests
£15.05–
£16.50
£1.00
£2.00
1,000
laboratory
tests
£17.75–
£18.70
£1.00
£2.00
200 pointof-care
tests
50
point-ofcare tests
£22.50
£30.00
N/A
N/A
N/A
N/A
£1.50
£1.50
£7.50
£7.50
£19.55–
£21.00
£22.25–
£23.20
£30.00
£37.50
N/A=Not Applicable
These estimated costs were compared with the actual cost incurred by a
Scottish Health Board that recently introduced NT-proBNP laboratory costs.
Following discussion with this Health Board, the base-case was assumed to
be £21 for each laboratory-based B-natriuretic peptide test and £30 for a
point-of-care test.
Echocardiography
The components of the echocardiography costs and associated assumptions
are set out in Table 11 - 8.
131
Table 11 - 8 Cost of echocardiography
Item
Costa
Capital cost per scan
£14
Read costs per scan
£52
Clinic costs
£12
Cardiologist/consultant cost
£12
Letter to GP
£10
Letter from GP to patient
Patient travel costs for
echocardiograph
Total costs
a
All costs rounded to nearest pound.
£2
Source
Manufacturer capital costs
and 2,140 scans annually
(Buckle & Chambers, 2000)
MTO4 salary + oncosts
PSSRU: number of scans
887 (Buckle & Chambers,
2000) + 20% quality
assurance
Marginal cost of booking
echocardiography
Cardiologist review and
assessment
Letter to GP and update
electronic and paper records
(Netten et al., 2003)
£7
£109
Consultant-led ECG service
The costs of a consultant-led ECG service are presented in Table 11 - 9.
Table 11 - 9 Cost of consultant-led ECG service
Item
90% read by MTO4: 10% consultant
read
Admin to fax to and from surgery
Letter from GP to patient
Total
Cost
£6
£4
£2
£12
132
Appendix 7 Organisation of healthcare in Scotland
The NHSScotland was restructured on 1 April 2004. There are now 15 NHS
Boards and 8 Special Heath Boards. NHS Boards have established
Community Health Partnerships which bring together partners to plan,
develop and provide the community health services which are the
responsibility of the relevant board.
Like the NHS in other parts of the UK, the NHS in Scotland provides
comprehensive healthcare for its citizens, and is free at the point of use. It is
funded mainly by direct taxation in the form of income tax and national
insurance contributions, with a small proportion of funding coming from patient
charges, such as for dental care and prescriptions. A key feature of the UK’s
funding system is its concept of fairness, providing maximum separation
between an individual’s financial contributions and their use of healthcare.
After social security payments, health is the biggest single component of
public expenditure (Wanless, 2002).
Mortality and morbidity rates are higher in Scotland than in England, reflecting
differences in their populations and environmental and socio-economic
factors. However, alongside these greater health needs, Scotland has more
healthcare resources. Funding per head, the number of hospital beds and
professional healthcare staff are all above the levels in England (Wanless,
2002).
NHSScotland has core aims of improving the health of the population and
reducing inequalities in health. There are currently 12 national priorities to
include coronary heart disease and stroke, cancer and mental health.
In 2002–2003, over £7 billion was spent in Scotland on healthcare services.
Spending on hospitals and acute care accounted for over £2 billion, with £800
million on mental health services, £200 million on maternity services, £320
million on continuing care, £460 million on community services and £360
million on other healthcare. Spending per head is set to rise to £1,700 in
2005–2006, and is higher than in England, matching the EU levels (Audit
Scotland, 2004).
NHSScotland has around 147,000 staff, including more than 63,000 nurses,
midwives and health visitors and over 8,500 doctors. There are also more
than 7,000 GPs, including doctors, dentists, opticians and community
pharmacists, who are independent contractors providing a range of services
within the NHS in return for various fees and allowances
(www.show.scot.nhs.uk/public/publicindex.htm).
SEHD leads the central management of NHSScotland, overseeing the work of
the 15 NHS Boards responsible for delivering health services for people in
their areas.
The eight Special Health Boards have Scotland-wide remits for specific
functions. For example, NHS Education Scotland commissions education and
training for some NHS staff, and NHS QIS sets standards and monitors
133
performance, and provides NHSScotland with advice, guidance and support
on effective clinical practice and service improvements.
More information about the health service in Scotland can be obtained from
http://www.show.scot.nhs.uk and
http://www.show.scot.nhs.uk/publicationsindex.htm
134
Appendix 8 Analysis of questionnaire results
11.1 Survey results of B-type natriuretic peptide testing services and
echocardiography facilities
To assess the current availability and use of B-type natriuretic peptide testing
and echocardiography facilities in Scotland, questionnaire surveys of hospital
laboratories and cardiology departments were carried out. Postal
questionnaires were sent to named individuals in these settings for
completion, and attempts were made to follow up non-responders by
telephone.
11.1.1 Survey of laboratories
Twenty-two laboratories were identified and surveyed, and 17 laboratories
(77%) returned a completed questionnaire. A telephone follow up of the five
non-responders asked only one question (whether they offer B-type natriuretic
peptide testing).
One laboratory indicated that it provides B-type natriuretic peptide testing.
This service is provided for secondary care and A&E settings, and the test
used is the Biosite Triage®.
A total of 21 laboratories (16 from completed questionnaires and five from the
telephone follow up) advised that they do not offer B-type natriuretic peptide
testing. Reasons given for this, by those who returned a completed
questionnaire, were lack of finance (13), clinicians not wishing to use it (2) or
not requesting it (2), a lack of both time and staff (1), and B-type natriuretic
peptide testing seen as a low Health Board priority (1). Of the 13 laboratories
that responded to the question, five indicated that they are planning to
introduce B-type natriuretic peptide testing.
11.1.2 Survey of cardiology departments
Thirty-four hospitals with cardiology departments were identified. A
questionnaire was sent to a named consultant cardiologist in each hospital to
be forwarded, where necessary, for completion by the consultant most closely
involved with the echocardiography service. A total of 23 replies (68%) were
received. One hospital responded that it does not have the information
requested, and another indicated that it does not have echocardiography
facilities. Results from the remaining 21 hospitals were analysed.
11.1.2.1
Number of echocardiograms
Fourteen hospitals provided information regarding the number of
echocardiograms performed during the previous 12 months on patients
referred with suspected heart failure by GPs. The number of echocardiograms
ranges from 50 to 1,000 (see Table 11 - 10).
135
Table 11 - 10 Number of echocardiograms performed during the
previous 12 months on patients referred with suspected heart failure by
GPs
Number of hospitals
11.1.2.2
Number of echocardiograms
201–
401–
601–
400
600
800
2
4
3
200 or
less
3
801–
1,000
2
Cannot
specify or not
given
6
Direct-access echocardiography
Twelve of the 21 hospitals provide a direct-access echocardiography service
for patients with suspected heart failure referred by GPs. Among these 12
hospitals, the waiting time for this service ranges from 0 to 12 weeks (see
Table 11 - 11).
Table 11 - 11 Waiting time for direct-access echocardiography
Waiting time (weeks)
Number of
hospitals
11.1.2.3
<1
1–2
3–4
5–6
7–8
9–10
11-12
1
3
1
1
1
4
1
Outpatient clinic appointments
In 11 of the 18 hospitals for which information was provided, it was reported
that the heart failure outpatient clinic prioritises appointments. However, a
number of those who indicated that prioritisation takes place (6), as well as of
those who did not respond to the question (3), commented that there is no
specific heart failure clinic as such. Eight hospitals indicated that they
prioritise on the basis of severity, and prioritisation was also reported to be
based upon an assessment of urgency by the GP (3) and the consultant (2),
on symptoms (1), or on ‘other relevant information’ (1). One respondent
indicated that highest priority would be given to decompensated heart failure,
and lowest priority given to breathlessness with an unknown cause.
Of the 11 hospitals that reported prioritisation of outpatient clinic
appointments, 10 provided separate figures for highest and lowest priority
waiting times. The highest priority waiting time ranges from less than one
week to nine weeks, and the lowest priority waiting time from less than one
week to approximately 30 weeks.
Of the seven hospitals that reported no prioritisation of outpatient clinic
appointments, six gave a single, ‘general’ waiting time figure, ranging from 1
to 20 weeks (see Table 11 - 12).
136
Table 11 - 12 Waiting time for an outpatient clinic appointment
(unprioritised)
<5
Number of
hospitals
11.1.2.4
1
Waiting time (weeks)
6–10
11–15
3
1
16–20
1
Echocardiography appointment
Of the 19 hospitals that responded to the question, 15 reported that all
patients referred from GPs with suspected heart failure receive an
echocardiogram. One individual who did not respond to the question
commented that patients would receive an echocardiogram if they were
referred to direct-access echocardiography, but not if they were referred to the
outpatient clinic and the problem was clearly COPD or obesity.
When patients do receive an echocardiogram, 13 of the 20 hospitals that
responded stated that this would take place at the initial outpatient
appointment, three stated that it would not, and four indicated that this would
only sometimes be the case (although one expanded on this to say ‘almost
always’). The seven respondents who stated that the echocardiogram would
not, or would only sometimes, take place at the initial appointment were asked
a further question about the subsequent wait for echocardiography. One
respondent gave figures for highest and lowest priority waiting times
separately (1 week and 4 weeks respectively), and one gave a lowest priority
waiting time figure only (16 weeks). Five respondents gave a single, ‘general’
waiting time figure, ranging from 2 to 10 weeks (see Table 11 - 13).
Table 11 - 13 Waiting time for echocardiography (unprioritised)
Waiting times
(weeks)
<5
6–10
Number of
hospitals
11.1.2.5
2
3
Echocardiography resources
Sixteen of the 21 respondents indicated that the current demand for
echocardiography services exceeds the available capacity. This was
attributed to shortages of technical staff (14), clinical staff (9), equipment (7)
and accommodation (4).
Seventeen hospitals provided information on the staff resource used per
individual echocardiogram. The following combinations of staff were reported:
a technician working alone (7), with a consultant/specialist registrar/staff
grade (7), with a member of clerical staff (1), or with another technician (1);
and a medical scientist working with a medical secretary (1). Time spent
ranges from 15 to 240 minutes for a technician, and from 5 to 15 minutes for a
consultant/specialist registrar/staff grade.
137
11.1.2.6
Diagnostic information from echocardiography and other
investigations
Sixteen hospitals provided information regarding the percentage of patients
with suspected heart failure for whom the echocardiogram provides
insufficient diagnostic information. The responses given range from 2% to
90% (see Table 11 - 14). Those who did not respond to the question
commented that ‘multiple factors’ are involved (1), the figure ‘depends on how
many low probability referrals are made by GPs for echo’ (1),
echocardiography is only one part of a comprehensive assessment (1), and
that they thought the figure would be ‘fairly high’ (1). One respondent stressed
that although the echocardiogram provides insufficient diagnostic information
in 90% of patients, it ‘rarely provides “no” information’.
Table 11 - 14 Cases where echocardiogram provides insufficient
diagnostic information
Percentage of cases
Number of hospitals
≤20%
21–40%
41–60%
61–80%
10
3
1
0
81–
100%
2
Cannot
specify or not
given
5
In the event that an echocardiogram being undertaken for suspected heart
failure provides insufficient diagnostic information for that individual, it was
reported that the following additional investigations are undertaken:
radionuclide angiography (13), myocardial perfusion scintigraphy using
SPECT (4), chest X-ray (3), B-type natriuretic peptide testing (1), cardiac
catheterisation (2), ECG (2), trial of treatment (2), cardiac magnetic resonance
imaging (1), contrast echocardiography (1), pulmonary function tests (1),
transoesophageal echo (1) and the treadmill exercise test (1).
138
12 Glossary
ACE inhibitors
acute coronary
syndromes
antibodies
antigen
assay
asymptomatic
BNP
cardiologist
catheterisation
CI
clinical
effectiveness
COPD
coronary heart
disease
cost effectiveness
cut-off
decompensated
DHF
diagnosis
diuresis
dyspnoea
Angiotensin-converting enzyme inhibitors. A group of
drugs which lower blood pressure and expand blood
vessels.
A collective term for the spectrum of acute coronary
disease associated with myocardial ischaemia.
Special blood proteins produced in response to an
antigen.
Any substance that the body regards as foreign or
potentially dangerous, against which antibodies are
produced.
A test to measure the amount of a specific constituent
of a solution.
Without symptoms.
B-type (or brain) natriuretic peptide. A hormone
produced by the heart involved in the regulation of
heart and blood vessels. It is an indicator of heart
failure.
Specialist doctor who treats patients with heart
conditions.
Refers to the insertion of a flexible tube into a narrow
opening, used to visualise the coronary arteries or to
perform angioplasty.
Confidence interval. An interval likely to contain the true
value of an unknown quantity (eg the true sensitivity of
a test). For a 95% CI, if the experiment were repeated
many times, 95% of the intervals would contain the
value of the unknown quantity that is being estimated.
The evaluation of the balance between benefits and
risks in a standard clinical setting using outcomes of
importance to the patient.
Chronic obstructive pulmonary disease.
Disease, such as angina, coronary thrombosis or heart
attack, caused by the narrowing or blockage of the
coronary arteries by atheroma.
Used in its broadest form, this term encompasses all
forms of economic analysis.
A boundary value for a test variable which distinguishes
normal from abnormal results.
The heart has failed to maintain adequate circulation.
Diastolic heart failure. Predominant or isolated
abnormality in diastolic function.
Identification and classification of an illness by means
of its signs, symptoms and the results of investigations.
This involves ruling out other illnesses and causal
factors for clinical manifestations.
An increase in the secretion of urine by the kidneys.
Breathing difficulties.
139
ECG
echocardiography
EF
empirical
epidemiology
ESC
false negative
FDA
GFR
gold standard
GP
grey literature
heart failure
heterogeneous
homogeneous
HTA
incidence
invasive
ischaemic heart
disease
left ventricular
dysfunction
loop diuretics
Electrocardiogram. A diagnostic test that monitors the
electrical activity of the heart.
Ultrasound technique used to obtain an image and
measurement of the heart.
Ejection fraction. A measure of the heart’s capacity to
contract and pump blood.
Pertaining to observations and the collection of data.
The scientific study of the natural history of diseases
and factors associated with diseases. It may involve
purely observational studies or interventions in
populations.
European Society of Cardiology.
A test result which indicates that a patient does not
have the disease of interest, when in fact they do.
Food and Drug Administration.
Glomerular filtrate rate.
Widely recognised as the best available.
General practitioner.
Although the most likely sources of evidence for
assessment are databases of the mainstream journal
literature, useful evidence can be found in symposium
proceedings, government monographs, industry
reports, unpublished studies and other non-traditional
sources.
A condition in which the pumping action of the heart is
impaired.
When pertaining to meta-analysis, means that the
results of any individual trial are not compatible with
those of any of the other trials.
When pertaining to meta-analysis, means that the
results of any individual trial are compatible with those
of any of the other trials.
Health Technology Assessment. It is a multidisciplinary
field of policy analysis which studies the medical,
social, ethical and economic implications of
development, diffusion and the use of health
technology.
The number of new cases of a disease in a year.
When pertaining to treatment, involves breaking the
skin, or insertion of an instrument into the body.
Disease of the heart associated with deficient blood
supply caused by functional constriction or obstruction
within the blood vessels.
Disordered pumping action of the main chamber of the
heart. It can occur due to myocardial infarction or
previous damage and is the most powerful predictor of
subsequent major coronary events.
A class of drugs which act on a particular part of the
kidney to cause an increase in urine secretion.
140
LVSD
MCN
meta-regression
morbidity
mortality
myocardial
infarction
natriuresis
nephropathy
NHS QIS
NHSScotland
NICE
NPV
NT-proBNP
NYHA
oedema
OR
peptides
point-of-care test
prevalence
primary care
Left ventricular systolic dysfunction (see left ventricular
dysfunction).
Managed clinical networks. A formally organised
network of clinicians. The main function is to audit
performance on the basis of standards and guidelines,
with the aim of improving healthcare across a wide
geographical area, or for specific conditions. Each
managed clinical network must have a qualityassurance framework describing the standards the
service will meet.
A method to investigate the results of heterogeneous
studies.
The frequency (incidence and/or prevalence) of a
particular disease or group of diseases.
The death rate.
Damage that occurs to the heart muscle when the
oxygen supply is disrupted. This is usually as a result of
an occluded coronary artery.
An increase in the amount of sodium excreted in urine.
Disease of the kidney.
NHS Quality Improvement Scotland. It is a statutory
body, established as a Special Health Board in January
2003. Its role is to focus on improving the quality of
patient care and the health of patients. It will have a
particular emphasis on the quality of care and the
patient journey for vulnerable groups.
Website: www.nhshealthquality.org
National Health Service in Scotland.
National Institute of Clinical Excellence.
Negative predictor value. Percentage of patients with a
negative test who do not have the disease.
N-terminal-pro-BNP. An inactive peptide hormone
produced in the heart.
New York Heart Association.
An excess accumulation of fluids in the body.
Odds ratio. The association between a random event
(E) and some condition (A), expressed as the odds that
E occurs when A is true divided by the odds that E
occurs when A is not true.
Short chains of amino acids.
A diagnostic procedure performed in the vicinity of the
patient. It is also described as ‘near patient test’ and
‘bedside test’.
The overall proportion of the population who have the
disease.
The conventional first point of contact between a
patient and the NHS. This is the component of care
delivered to patients outside hospitals and is typically,
though by no means exclusively, delivered through
141
prognosis
pulmonary
embolism
ROC curve
sensitivity
sepsis
SIGN
specificity
syndrome
systolic heart
failure
true positive
vasodilation
general practices. Primary care services are the most
frequently used of all services provided by
NHSScotland. Primary care encompasses a range of
family health services provided by family doctors,
dentists, pharmacists, optometrists and ophthalmic
medical practitioners.
An assessment of the expected future course and
outcome of a person’s disease.
A blood clot in the lungs.
Receiver operating characteristic curve. Used to
evaluate the accuracy of any method of predicting
different outcomes.
The probability that a test result is positive, given that a
person has the disease.
An illness caused by a bacteria infection of the
bloodstream.
Scottish Intercollegiate Guidelines Network.
The probability that a test result is negative, given that
a person does not have the disease.
A collection of signs or symptoms.
The inability to pump an adequate volume of blood
and/or to do so only from an abnormally elevated filling
pressure.
A test result which correctly indicates that a patient has
the disease of interest.
Widening of blood vessels.
142