Health Technology Assessment Report 6

The use of B-type natriuretic peptides (BNP and NT-proBNP) in theinvestigation of patients with suspected heart failure

Authors: Craig J, Bradbury I, Cummins E, Downie S, Foster L, Stou

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© 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

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Contents

1 Executive summary ................................................................................10 2 Introduction.............................................................................................17 3 Background on NHS Quality Improvement Scotland ..............................18 4 Setting the scene ....................................................................................19 5 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 ..................................................................................50 6.1 Methodology ...........................................................................50

6.1.1 Sources of evidence.................................................................50 6.1.1.1 Literature search.....................................................................50 6.1.1.2 Study selection criteria............................................................50

6.1.2 Overview of studies ..................................................................51 6.1.3 Economic model for primary care.............................................52

6.1.3.1 Model inputs: clinical effectiveness data.................................54 6.1.3.2 Model inputs: prevalence rate of heart failure.........................55 6.1.3.3 Model inputs: cost of tests, drugs and waiting times...............55

6.2 Results....................................................................................56 6.2.1 Base-case interpretation of results ...........................................56 6.2.2 Base-case results .....................................................................57 6.2.3 Sensitivity analyses ..................................................................58

6.2.3.1 Prevalence rate of heart failure...............................................58

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6.2.3.2 Accuracy of B-type natriuretic peptide testing and ECG readings..................................................................................59

6.2.3.3 Point-of-care testing................................................................62 6.2.3.4 Lower cost of laboratory tests.................................................63 6.2.3.5 The cost of echocardiography ................................................63 6.2.3.6 Use and cost of ECGs by GPs ...............................................64 6.2.3.7 The cost of additional tests for false-negative patients ...........64 6.2.3.8 Results for diagnosis of LVSD ................................................65 6.2.3.9 Joint testing using a combination of diagnostic tests ..............66

6.3 Discussion ..............................................................................67 6.4 Conclusions ............................................................................68

7 Other issues relevant to clinical and cost effectiveness evidence ..........70 7.1 Organisational issues .............................................................70

7.1.1 Surveys of use of B-type natriuretic peptide testing and echocardiography facilities .......................................................70

7.1.1.1 Use of B-type natriuretic peptide testing .................................70 7.1.1.2 Use of echocardiography........................................................70

7.1.2 Provision of B-type natriuretic peptide testing services in the acute sector..............................................................................71

7.1.2.1 Potential benefits of B-type natriuretic peptide tests in the acute care sector..............................................................................71

7.1.2.2 Organisational aspects of a B-type natriuretic peptides service in the acute care sector ..........................................................71

7.1.3 Provision of B-type natriuretic peptide testing services in primary care ..........................................................................................73

7.1.3.1 Potential benefits of B-type natriuretic peptide tests in general practice ...................................................................................73

7.1.3.2 Organisational challenges of a B-type natriuretic peptide testing service in general practice ......................................................73

7.1.4 Consultant-led ECG service .....................................................73 7.1.5 Discussion ................................................................................74

7.2 Patient issues .........................................................................75 8 Principal findings, limitations and recommendations ..............................77

8.1 Principal findings.....................................................................77 8.1.1 Scope of the HTA .....................................................................77 8.1.2 Summary of findings.................................................................77

8.2 Further research .....................................................................79 8.3 Limitations and uncertainties ..................................................80 8.4 Recommendations..................................................................81 8.5 Resource implications of recommendations ...........................83

8.5.1 Incidence of heart failure ..........................................................83 8.5.2 Potential number of B-type natriuretic peptide tests in acute

setting.......................................................................................83 8.5.3 Diagnostic setting: primary care ...............................................84 8.5.4 Sensitivity analysis ...................................................................85 8.5.5 Additional costs in hospitals and primary care..........................86 8.5.6 Total costs of implementing B-type natriuretic peptide testing..86 8.5.7 Potential resources released ....................................................86 8.5.8 Comparison of costs and resources released ..........................87

8.6 Challenges for implementation ...............................................88

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9 Acknowledgements.................................................................................90 10 References .............................................................................................91 11 Appendices...........................................................................................102 12 Glossary ...............................................................................................139

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List of tables

Table 4 - 1 New York Heart Association classification of heart failure symptoms .................................................................................20

Table 4 - 2 Comparison of BNP and NT-proBNP .......................................23 Table 5 - 1 Sensitivity and specificity of tests .............................................29 Table 5 - 2 Summary of results for different combinations of tests and

target diagnoses.......................................................................30 Table 5 - 3 Estimated NPV for each test/condition combination assuming

fixed test performance and varying pre-test prevalence ...........30 Table 5 - 4 Sensitivity and specificity of B-type natriuretic peptide assays

at various cut-off points and compared with ECGs read by cardiologists .............................................................................42

Table 5 - 5 Referral patterns for 1,000 patients with symptoms suggestive of heart failure (Wright et al., 2003) ........................42

Table 5 - 6 Referral patterns for 1,000 patients (diagnosed by GP) with heart failure (Zaphiriou et al., unpublished) ..............................43

Table 6 - 1 Comparison of using BNP and standard care in the emergency setting ....................................................................52

Table 6 - 2 Sensitivities and specificities of tests for heart failure...............55 Table 6 - 3 Cost of tests, therapy and waiting times ...................................56 Table 6 - 4 Base-case results for 100 patients presenting to a GP surgery

with symptoms suggestive of heart failure................................57 Table 6 - 5 Results ordered by costs ..........................................................58 Table 6 - 6 Sensitivity analysis: prevalence of 48% for heart failure...........59 Table 6 - 7 Sensitivity analysis: 90% sensitivity and 73% specificity of

B-type natriuretic peptides........................................................59 Table 6 - 8 Sensitivity analysis: 93% sensitivity and 63% specificity of

consultant-led ECG service ......................................................60 Table 6 - 9 Sensitivity analysis: 85% sensitivity and 60% specificity for

GP-read ECG ...........................................................................60 Table 6 - 10 Sensitivity analysis: 87% sensitivity and 26% specificity for

machine-read ECGs.................................................................61 Table 6 - 11 Sensitivity analysis: 82% sensitivity and 76% specificity for

GP-read ECGs .........................................................................61 Table 6 - 12 Sensitivity analysis: 92% sensitivity and 37% specificity for

machine-read ECGs.................................................................62 Table 6 - 13 Sensitivity analysis: point-of-care tests 50 annual throughput

and £37.50 per test...................................................................62 Table 6 - 14 Sensitivity analysis: point-of-care tests 200 annual throughput

and £30 per test .......................................................................62 Table 6 - 15 Sensitivity analysis: echocardiography cost of £60 ..................63 Table 6 - 16 Sensitivity analysis: echocardiography cost of £150.................63 Table 6 - 17 Sensitivity analysis: one additional GP visit for false-negative

patients.....................................................................................65 Table 6 - 18 Sensitivity analysis: three additional GP visits for false-

negative patients ......................................................................65 Table 6 - 19 Sensitivity analysis: LVSD prevalence of 18% and base-

case accuracies of tests for LVSD............................................66

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Table 6 - 20 Sensitivity analysis: 83% sensitivity for LVSD and 21% specificity for GP-read ECG .....................................................66

Table 6 - 21 Sensitivity and specificity of a combination of diagnostic tests .66 Table 6 - 22 Sensitivity analysis: comparison of joint tests and B-type

natriuretic peptide tests ............................................................67 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..........................................................................................85 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) ...........................................................................87

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

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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 ...............................53 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 126Figure 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 1 Experts and peer reviewers....................................................102 Appendix 2 Strategy for literature searches ..............................................103 Appendix 3 Literature selection process for clinical effectiveness .............109 Appendix 4 Diagnostic test studies............................................................110 Appendix 5 Graphical representations of diagnostic tests.........................117 Appendix 6 Cost of tests ...........................................................................131 Appendix 7 Organisation of healthcare in Scotland...................................133 Appendix 8 Analysis of questionnaire results ............................................135

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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 NHS 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 age-related 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 cut-offs 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.

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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 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 be reviewed as new evidence arises.

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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

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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

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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 B-type 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 NT-proBNP. 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 rule-out 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.

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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 B-type 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

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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.

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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.

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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.

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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.

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Table 4 - 1 New York Heart Association classification of heart failure symptoms Class Symptoms Class I No restriction at all – asymptomatic Class II 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.

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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.

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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.

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Table 4 - 2 Comparison of BNP and NT-proBNP Characteristics BNP NT-proBNP

Hormonally active Yes No Half life 22 min 120 min Clearance mechanism Neutral endopeptidase

clearance receptors Renal clearance

Increases with aging + +++ Correlation with glomerular filtration rate

-0.20 -0.60

Approved cut-off(s) for diagnosis of chronic heart failure

100 pg/ml Age < 75 years: 125 pg/ml Age ≥ 75 years: 450 pg/ml

(Adapted from Weber et al. (2005)). 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).

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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.

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5 Clinical effectiveness

5.1 Methodology

This chapter assesses the clinical-effectiveness evidence for the use of B-type 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.

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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.

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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).

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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.

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Table 5 - 1 Sensitivity and specificity of tests Diagnostic test With disease Without disease Total Positive a b a + b Negative c d c + d Total a + c b + 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).

( )( ) yspecificityspecificit

ysensitivitysensitivitOR−

−=

11

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:

( )( ) ( )ysensitivitpyspecificitp

yspecificitpNPV−+−

−=

1**1*1

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 random-effects 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.

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Table 5 - 2 Summary of results for different combinations of tests and target diagnoses

Test and target diagnosis

Pooled sensitivity (95% CI)

Pooled specificity (95% CI)

Pooled diagnostic OR

(95% CI) BNP, heart failure 0.91 (0.90–0.93) 0.73 (0.71–0.75) 36 (17–74) BNP, LVSD 0.88 (0.84–0.91) 0.62 (0.60–0.63) 11 (7–18) NT-proBNP, heart failure 0.91 (0.88–0.93) 0.76 (0.75–0.77) 40 (18–88) NT-proBNP, LVSD 0.84 (0.80–0.88) 0.65 (0.64–0.67) 15 (11–21) ECG, heart failure (cardiologist read) 0.85 (0.79–0.90) 0.60 (0.56–0.65) 10 (5–21)

ECG, heart failure (machine read)d 0.86 (0.68–0.98) 0.26 (0.20–0.31) 2

ECG, LVSD (cardiologist read) 0.90 (0.88–0.92) 0.58 (0.56–0.60) 12 (7–21)

ECG, LVSD (machine read) 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 Pre-test prevalence

5% 15% 25% 50% BNP for heart failure 99% 98% 96% 89%

BNP for LVSD 99% 97% 94% 84% NT-proBNP for heart failure 99% 98% 96% 89%

NT-proBNP for LVSD 99% 96% 92% 80%

ECG for heart failure (cardiologist read)

99% 96% 92% 80%

ECG for LVSD (cardiologist read)

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.

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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

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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%.

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Figure 5 - 4 BNP sensitivity for LVSD

Figure 5 - 5 BNP specificity for LVSD

Figure 5 - 6 BNP diagnostic OR for LVSD

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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 Hammerer-Lercher 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

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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

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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 NT-proBNP. 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)

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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.

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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).

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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

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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 NT-proBNP 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.

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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 Cut-off Sensitivity Specificity NT-proBNP 125 pg/ml 0.98 0.35

100 pg/ml 0.79 0.72 65 pg/ml 0.87 0.57

BNP 30 pg/ml 0.95 0.35 ECG read by cardiologists 0.81 0.60

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 NT-proBNP 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 NT-proBNP 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 Number of patients Referred – not heart failure 374 Referred – heart failure 230 Not referred – not heart failure 373 Not referred – heart failure 23 Avoided referrals – not heart failure (estimate) 83 Additional missed referrals with heart failure (estimate) 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 cut-offs.

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.

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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 Number of patients No BNP Referred – not heart failure 747 Referred – heart failure 252 NT-proBNP >125 pg/ml Avoided referrals – not heart failure 261 Missed referrals with heart failure 5 BNP – 100 pg/ml Avoided referrals – not heart failure 538 Missed referrals with heart failure 53 BNP – 30 pg/ml Avoided referrals – not heart failure 261 Missed referrals with heart failure 13 ECG Avoided referrals – not heart failure 448 Missed referrals with heart failure 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).

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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.

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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 non-diagnostic’.

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.

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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 NT-proBNP 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).

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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; Hammerer-Lercher 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

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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.

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.

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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 ‘rule-out’ 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 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.

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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:

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• 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 clinical-effectiveness 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

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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

B-type natriuretic peptides group

Standard care (control group)

Number of patients 100 100 Admission rate 75% 85% Average length of stay 8 days 9.2 days Treatment costs (Cost per day £255)

£153,000

£199,400

Total cost including BNP test @ £30 per test £156,000 £199,400 Total savings £43,400 Saving per patient £434

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 high-risk 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.

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• 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

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.

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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.

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 GP-

based 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 point-of-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

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inform this assumption (Prof. A Struthers, Professor of Cardiovascular Medicine and Therapies, University of Dundee and Ninewells Hospital. Personal communication, June 2004).

Table 6 - 2 Sensitivities and specificities of tests for heart failure Test Sensitivitya Specificitya

B-type natriuretic peptides (laboratory and point-of-care)

91% 75%

Consultant-led ECG 85% 60% GP-read ECG 85% 49% a Rounded to the nearest whole number.

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 15-month 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.

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Table 6 - 3 Cost of tests, therapy and waiting times Cost item Description of costs Marginal cost or time

B-type natriuretic peptides laboratory test

Reagent cost per testa plus transport, laboratory, staff time and communication with patient

£21

GP-read ECG All patients receive an ECG. £0

Consultant-led 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

£12

Clinic costs, scan, read and report, patient travel time and communications from consultant to GP and to patient

£109 Echocardiography

Waiting time 2 months

Therapy Patients receive diuretic prior to echocardiography £1 per month

Costs of two further GP visits before receiving an echocardiography

£56.40 (of which £14.40 is patient travel

cost)

False-negative patients 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.

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.

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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 B-type

natriuretic peptides

Consultant-led ECG GP-read ECG

True-positives 26.4 24.7 24.7 False-positives 17.8 28.4 36.2 True-negatives 53.3 42.6 34.8 False-negatives 2.6 4.4 4.4 Cost analysis Additional diagnostic tests £2,100 £1,200 £0 Incorrect echocardiography referrals £1,935 £3,096 £3,947

Incorrect diuretic use £36 £57 £72 Further tests in false-negative patients £147 £245 £245

Total costs £4,217 £4,598 £4,265

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Table 6 - 5 Results ordered by costs

Tests ordered by cost Cost

True- positive results

Marginal cost/ true-

positive

Correct resultsa

Marginal cost/ correct result

BNPb £4,217 26.4 .. 79.6 .. GP-read ECG £4,265 24.7 Dominated 59.4 Dominated Consultant-led ECG £4,598 24.7 Dominated 67.3 Dominated

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.

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Table 6 - 6 Sensitivity analysis: prevalence of 48% for heart failure

Tests ordered by cost Cost

True- positive results

Marginal cost/true- positive result

Correct results

Marginal cost/

correct result

GP-read ECG £3,350 40.8 .. 66.3 .. BNP £3,787 43.7 £152 82.7 £27 Consultant-led ECG £3,915 40.8 Dominated 72.0 Dominated

The greater sensitivity of B-type natriuretic peptides results in more true- positive 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 74% specificity are shown in Table 6 - 7.

Table 6 - 7 Sensitivity analysis: 90% sensitivity and 74% specificity of B-type natriuretic peptides

Tests ordered by cost Cost

True- positive results

Marginal cost/true-positive result

Correct results

Marginal cost/correct

result

GP-read ECG £4,265 24.7 .. 59.4 .. BNP £4,391 26.1 £87 77.9 £7 Consultant-led ECG £4,598 24.7 Dominated 67.3 Dominated

B-type natriuretic peptide testing still detects more true-positive and true-negative 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

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all other base-case assumptions. At these levels of accuracy, the consultant-led 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 Cost

True- positive results

Marginal cost/true-positive result

Correct results

Marginal cost/correct

result

BNP £4,217 26.4 .. 79.6 .. Consultant-led ECG £4,230 27.0 £22 71.7 Dominated

GP-read ECG £4,265 24.7 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 Cost

True- positive results

Marginal cost/true-positive result

Correct results

Marginal cost/correct

result

GP-read ECG £3,398 24.7 .. 67.3 ..

BNP £4,217 26.4 £471 79.6 £66 Consultant-led ECG £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.

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Table 6 - 10 Sensitivity analysis: 87% sensitivity and 26% specificity for machine-read ECGs

Tests ordered by

cost Cost

True- positive results

Marginal cost/true-positive result

Correct results

Marginal cost/correct

result

BNP £4,217 26.4 .. 79.6 .. Consultant-led ECG £4,598 24.7 Dominated 67.3 Dominated

Machine-read ECG £6,045 25.2 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 consultant-led 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 Cost

True- positive results

Marginal cost/true-positive result

Correct results

Marginal cost/correct

result

GP-read ECG £2,186 23.8 .. 77.7 .. BNP £4,217 26.4 £778 79.6 £1,069 Consultant-led ECG £4,598 24.7 Dominated 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

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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 Cost

True- positive results

Marginal cost/true-positive result

Correct results

Marginal cost/correct

result

BNP £4,217 26.4 .. 79.6 .. Consultant-led ECG £4,598 24.7 Dominated 67.3 Dominated

Machine-read ECG £5,096 26.7 £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 Cost

True- positive results

Marginal cost/true-positive result

Correct results

Marginal cost/correct

result

GP-read ECG £4,265 24.7 .. 59.4 .. Consultant-led ECG £4,598 24.7 Dominated 67.3 £43

BNP point-of-care tests £5,867 26.4 £921 79.6 £102

Table 6 - 14 Sensitivity analysis: point-of-care tests 200 annual throughput and £30 per test

Tests ordered by cost Cost

True- positive results

Marginal cost/true-positive result

Correct results

Marginal cost/correct

result

GP-read ECG £4,265 24.7 .. 59.4 .. Consultant-led ECG £4,598 24.7 Dominated 67.3 £43

BNP point-of-care tests £5,117 26.4 £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.

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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 B-type natriuretic peptide point-of-care testing were compared with machine-read 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 Cost

True- positive results

Marginal cost/true-positive result

Correct results

Marginal cost/correct

result

GP-read ECG £2,490 24.7 .. 59.4 .. Consultant-led ECG £3,206 24.7 Dominated 67.3 £92

BNP £3,348 26.4 £493 79.6 £11

Table 6 - 16 Sensitivity analysis: echocardiography cost of £150

Tests ordered by cost Cost

True- positive results

Marginal cost/true-positive result

Correct results

Marginal cost/correct

result

BNP £4,945 26.4 .. 79.6 .. GP-read ECG £5,749 24.7 Dominated 59.4 Dominated Consultant-led ECG £5,762 24.7 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

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echocardiogram applies and the consultant-led ECG option is deemed not to be practical, the cost per additional true-positive result of moving from GP-read 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 false-negative patients was taken to be equivalent to two GP visits. To test the sensitivity of the base-case, 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.

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Table 6 - 17 Sensitivity analysis: one additional GP visit for false-negative patients

Tests ordered by cost Cost

True- positive results

Marginal cost/true-positive result

Correct results

Marginal cost/correct

result

GP-read ECG £4,142 24.7 .. 59.4 .. BNP £4,144 26.4 £1 79.6 £0 Consultant-led ECG £4,475 24.7 Dominated 67.3 Dominated

Table 6 - 18 Sensitivity analysis: three additional GP visits for false- negative patients

Tests ordered by cost Cost

True- positive results

Marginal cost/true-positive result

Correct results

Marginal cost/correct

result

BNP £4,365 26.4 .. 79.6 .. GP-read ECG £4,510 24.7 Dominated 59.4 Dominated Consultant-led ECG £4,843 24.7 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.

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Table 6 - 19 Sensitivity analysis: LVSD prevalence of 18% and base-case accuracies of tests for LVSD

Tests ordered by cost Cost

True- positive results

Marginal cost/true-positive result

Correct results

Marginal cost/correct

result

GP-read ECG £5,067 15.3 .. 53.0 .. Consultant-led ECG £5,124 16.2 £63 63.8 £5

BNP £5,610 15.5 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 Cost

True- positive results

Marginal cost/true-positive result

Correct results

Marginal cost/correct

result

Consultant-led ECG £5,124 16.2 .. 63.8 ..

BNP £5,610 15.5 Dominated 67.1 £144 Machine-read ECG £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 Sensitivity Specificity B-type natriuretic peptides and consultant-led ECG 99% 45% B-type natriuretic peptides and machine-read ECG 99% 37%

These provide an upper boundary for the joint sensitivity and a lower boundary for the joint specificity. However, it seems extremely unlikely that

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the test results will be independent. The sensitivity of test B among the false- negative 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 True-

positive results

Marginal cost/true-positive result

Correct results

Marginal cost/correct

result

BNP £4,217 26.4 .. 79.6 .. BNP and GP-read ECG £7,107 28.6 £1,302 54.7 Dominated BNP and consultant-led ECG £7,657 28.6 £1,550 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

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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

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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.

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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 B-type 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 B-type 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.

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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 B-type 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 NT-proBNP (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.

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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 B-type 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.

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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

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specialist advice. The availability of technical and clinical skills in the acute sector is therefore necessary to provide a quality-assured and timely ECG-reading 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.

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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 quality- assured 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.

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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.

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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.

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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

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referral protocols and undertaking audit. The total cost and the timeliness of obtaining a quality-assured result should inform decisions on whether the B-type 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.

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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 cut-offs 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 cut-off 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.

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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

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 NHS 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 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

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 age-related 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 cut-offs for B-type natriuretic peptide concentrations are appropriate for their

h ‘New’ is defined as an abnormality without documented previous investigation.

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own population and that the cut-offs are sufficiently sensitive to identify all patients with mild heart failure.

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 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.

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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 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

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hospital attendance. Seven thousand (7,000) will be adopted as an upper limit 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.

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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 7,000 3,500

Number of patients who present in primary care 8,000 21,500

Prevalence rate (Section 6.1.3.2) 29% 29%

% of GPs using BNP tests 25% 25% Number of tests in primary care (rounded)i 6,900 18,535

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 6,900 18,535 Hospital 375 2,975 Total tests 7,275 21,510 Costs GP £172,500 £463,375 Hospital £9,375 £74,375 Total test costs £181,875 £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 million 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

i Number of tests in primary care multiplied by number of GPs using BNP divided by prevalence rate.

j Secondary care may employ point-of-care testing, but given reasonable throughputs, a figure of £25 per test should be achievable.

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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.

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 £0.18 million to £0.54 million • Hospital training and protocols £0.10 million • GP practice costs £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

k Difference due to rounding.

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echocardiogram. Applying these rates and costs gives the following potential resources savings (see Table 8 - 3).

Table 8 - 3 Range of echocardiography savings Cost savings

Incidence of heart failure Settings 15,000 25,000

GP £175,865 £472,630 Hospital £4,970 £39,450 Total savings £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. 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)

For first year For steady state

Setting Total gross costs

Total gross

savings Net

cost/savingl

Total gross costs

Total gross

savings Net

cost/savingj

Heart failure incidence of 15,000 patients l Negative value represents a net saving.

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GP £0.36 £0.18 £0.18 £0.17 £0.17 £0.00 Hospital £0.11 £0.09 £0.02 £0.01 £0.09 -£0.08 Total £0.47 £0.27 £0.20 £0.18 £0.26 -£0.08

Heart failure incidence of 25,000 patients GP £0.65 £0.47 £0.18 £0.46 £0.47 -£0.01 Hospital £0.17 £0.69 -£0.52 £0.07 £0.69 -£0.62 Total £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.

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.

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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.

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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.

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10 References

Asada J, Tsuji H, Iwasaka T, Thomas J and Lauer M. 2004. Usefulness of plasma brain natriuretic peptide levels in predicting dobutamine-induced myocardial ischemia. Am J Cardiol, 93(6), 702-704.

Audit Scotland. 2004. An overview of the performance of the NHS in Scotland. Edinburgh: Audit Scotland.

Banerjee P, Banerjee T, Khand A, Clark AL and Cleland JGF. 2002. Diastolic heart failure: neglected or misdiagnosed? J Am Coll Cardiol, 39(1), 138-141.

Bay M, Kirk V, Parner J, Hassager C, Nielsen H, Krogsgaard K, Trawinski J, Boesgaard S and Aldershvile J. 2003. NT-proBNP: a new diagnostic screening tool to differentiate between patients with normal and reduced left ventricular systolic function. Heart (British Cardiac Society), 89(2), 150-154.

Bayes-Genis A, Santalo-Bel M, Zapico ME, Lopez L, Cotes C, Bellido J, Leta R, Casan P and Ordonez-Llanos J. 2004. N-terminal probrain natriuretic peptide (NT-proBNP) in the emergency diagnosis and in-hospital monitoring of patients with dyspnoea and ventricular dysfunction. Eur J Heart Fail, 6(3), 301-308.

Buckle R and Chambers J. 2000. A survey of echocardiography in the South Thames region. Br J Cardio, 7(8)

Busse R, Orvain J, Drummond M, Gurtner F, Jorgensen T, Jovell A, Malone J, Perleth M, Wild C and European Centre for Health Technology Assessment. 2001. Best practice in undertaking and reporting health technology assessments. Stockholm: ECHTA.

Chatterjee K. 2002. Primary diastolic heart failure. Am J Ger Cardiol, 11(3), 178-189.

Collinson PO, Barnes SC, Gaze DC, Galasko G, Lahiri A and Senior R. 2004. Analytical performance of the N terminal pro B type natriuretic peptide (NT-proBNP) assay on the Elecsys 1010 and 2010 analysers. Eur J Heart Fail, 6(3), 365-368.

Cowie MR, Struthers AD, Wood DA, Coats AJ, Thompson SG, Poole-Wilson PA and Sutton GC. 1997. Value of natriuretic peptides in assessment of patients with possible new heart failure in primary care. Lancet, 350(9088), 1349-1353.

Cowie MR and Hobbs R. 2002. Best practice: evidence from the clinical trials. Heart (British Cardiac Society), 88(2), ii2-ii4.

Cowie MR, Jourdain P, Maisel A, Dahlstrom U, Follath F, Isnard R, Luchner A, McDonagh T, Mair J, Nieminen M and Francis G. 2003. Clinical applications of B-type natriuretic peptide (BNP) testing. Eur Heart J, 24(19), 1710-1718.

91

Cowie M. 2004. B type natriuretic peptide testing: where are we now? Heart, 90(7), 725-726.

Craig J, Bradbury I, Collinson P, Emslie C, Findlay I, Hunt K, Kohli H, Kulkarni U, Macpherson K, Riches E, Single A and Tochel C. 2004. The organisation of troponin testing services in acute coronary syndromes. Glasgow: NHS Quality Improvement Scotland.

Dao Q, Krishnaswamy P, Kazanegra R, Harrison A, Amirnovin R, Lenert L, Clopton P, Alberto J, Hlavin P and Maisel AS. 2001. Utility of B-type natriuretic peptide in the diagnosis of congestive heart failure in an urgent-care setting. J Am Coll Cardiol, 37(2), 379-385.

Davidson NC, Naas AA, Hanson JK, Kennedy NS, Coutie WJ and Struthers AD. 1996. Comparison of atrial natriuretic peptide, B-type natriuretic peptide, and N-terminal proatrial natriuretic peptide as indicators of left ventricular systolic dysfunction. Am J Cardiol, 77(10), 828-831.

Davie A, Francis C, Love M, Caruana L, Starkey I, Shaw T, Sutherland G and McMurray J. 1996. Value of the electrocardiogram in identifying heart failure due to left ventricular systolic dysfunction. BMJ, 312(7025), 222

Davis M, Espiner E, Richards G, Billings J, Town I, Neill A, Drennan C, Richards M, Turner J and Yandle T. 1994. Plasma brain natriuretic peptide in assessment of acute dyspnoea. Lancet, 343(8895), 440-444.

Davis R, Hobbs F and Lip G. 2000. ABC of heart failure: history and epidemiology. BMJ, 320(7226), 39-42.

De Lemos JA, McGuire DK and Drazner MH. 2003. B-type natriuretic peptide in cardiovascular disease. Lancet, 360(9380), 316-322.

Dersimonian R and Laird N. 1986. Meta-analysis in clinical trials. Ctrl Clin Trial, 7(3), 177-188.

Doust J, Pietrzak E, Dobson A and Glasziou P. 2005. How well does b-type natriuretic peptide predict death and cardiac events in patients with heart failure: systematic review. BMJ, 330(7492), 625-633.

Drummond M and McGuire A. 2001. Economic evaluation in health care: merging the theory with practice. Oxford: Oxford University Press.

Eccles M, Freemantle N and Mason J. 1998. North of England evidence based development project: guideline for angiotensin converting enzyme inhibitors in primary care management of adults with symptomatic heart failure. BMJ, 316(7141), 1369-1375.

Fonseca C, Mota T, Morais H, Matias F, Coasta C, Oliveria A and Ceia F. 2004. The value of electrocardiogram and chest x-ray for confirming or refuting a suspected diagnosis of heart failure in the community. Eur J Heart Fail, 6(6), 807-812.

92

Fox KF, Cowie MR, Wood DA, Coats AJ, Poole-Wilson PA and Sutton GC. 2000. A rapid access heart failure clinic provides a prompt diagnosis and appropriate management of new heart failure presenting in the community. Eur J Heart Fail, 2(4), 423-429.

Fuat A, Hungin APS and Murphy JJ. 2003. Barriers to accurate diagnosis and effective management of heart failure in primary care: qualitative study. BMJ, 326(7382), 196-200.

Galvani M, Ferrini D and Ottani F. 2004. Natriuretic peptides for risk stratification of patients with acute coronary syndromes. Eur J Heart Fail, 6(3), 327-333.

Gillespie N, McNeill G, Pringle T, Ogston S, Struthers A and Pringle S. 1997. Cross sectional study of contribution of clinical assessment and simple cardiac investigations to diagnosis of left ventricular systolic dysfunction in patients admitted with acute dyspnoea. BMJ, 314(7085), 936-940.

Gustafsson F, Badskjaer J, Hansen FS, Poulsen AH and Hildebrandt P. 2003. Value of N-terminal proBNP in the diagnosis of left ventricular systolic dysfunction in primary care patients referred for echocardiography. Heartdrug, 3(3), 141-146.

Hammerer-Lercher A, Neubauer E, Muller S, Pachinger O, Puschendorf B and Mair J. 2001. Head-to-head comparison of N-terminal pro-brain natriuretic peptide, brain natriuretic peptide and N-terminal pro-atrial natriuretic peptide in diagnosing left ventricular dysfunction. Clin Chim Acta, 310(2), 193-197.

Health Technology Board for Scotland. 2002. Guidance for manufacturers on submission of evidence to health technology assessments. Glasgow: HTBS.

Hedberg P, Lonnberg I, Jonason T, Nilsson G, Pehrsson K and Ringqvist I. 2004. Electrocardiogram and b-type natriuretic peptide as screening tools for left ventricular systolic dysfunction in a population-based sample of 75-year-old men and women. Am Heart J, 148(3), 524-529.

Hobbs FD, Davis RC, Roalfe AK, Hare R, Davies MK and Kenkre JE. 2002. Reliability of N-terminal pro-brain natriuretic peptide assay in diagnosis of heart failure: cohort study in representative and high risk community populations. BMJ, 324(7352), 1498-1500.

Hobbs F, Davis R, Roalfe A, Hare R and Davies M. 2004. Reliability of N-terminal proBNP assay in diagnosis of left ventricular systolic dysfunction within representative and high risk populations. Heart, 90(8), 866-870.

Hohl C, Mitelman B, Wyer P and Lang E. 2003. Should emergency physicians use b-type natriuretic peptide testing in patients with unexplained dyspnea? Can J Emerg Med, 5(3), 162-165.

Houghton A, Sparrow N, Toms E and Cowley A. 1997. Should general practitioners use the electrocardiogram to select patients with suspected heart failure for echocardiography? Int J Cardiol, 62(1), 31-36.

93

Hutcheon SD, Gillespie ND, Struthers AD and McMurdo MET. 2002. B-type natriuretic peptide in the diagnosis of cardiac disease in elderly day hospital patients. Age & Ageing, 31(4), 295-301.

Jaffe A, Apple F and Babuin L. 2004. Why we don't know the answer may be more important than the specific question. Clin Chem, 50(9), 1495-1497.

Jones AE and Kline JA. 2003. Elevated brain natriuretic peptide in septic patients without heart failure. Ann Emerg Med, 42(5), 714-715.

Jose JV, Gupta SN and Selvakumar D. 2003. Utility of N-terminal pro-brain natriuretic peptide for the diagnosis of heart failure. Indian Heart J, 55(1), 35-39.

Kazanegra R, Cheng V, Garcia A, Krishnaswamy P, Gardetto N, Clopton P and Maisel A. 2001. A rapid test for b-type natriuretic peptide correlates with falling wedge pressures in patients treated for decompensated heart failure: a pilot study. J Card Fail, 7(1), 21-29.

Khandekar S, Murphy J and Bossingham C. 1996. Value of ECGs in identifying heart failure due to left ventricular systolic dysfunction: echocardiography is still necessary. BMJ, 312(7039), 1160-1161.

Khunti K, Hearnshaw H, Baker R and Grimshaw G. 2002. Heart failure in primary care: qualitative study of current management and perceived obstacles to evidence-based diagnosis and management by general practitioners. Eur J Heart Fail, 4(6), 771-777.

Knudsen CW, Riis JS, Finsen AV, Eikvar L, Muller C, Westheim A and Omland T. 2004. Diagnostic value of a rapid test for B-type natriuretic peptide in patients presenting with acute dyspnoe: effect of age and gender. Eur J Heart Fail, 6(1), 55-62.

Kruger S, Filzmaier K, Graf J, Kunz D, Stickel T, Hoffmann R, Hanrath P and Janssens U. 2004. QRS prolongation on surface ECG and brain natriuretic peptide as indicators of left ventricular systolic dysfunction. J Intern Med, 255(2), 206-212.

Kucher N, Printzen G, Doernhoefer T, Windecker S, Meier B and Hess OM. 2003. Low pro-brain natriuretic peptide levels predict benign clinical outcome in acute pulmonary embolism. Circulation, 107(12), 1576-1578.

Lainchbury JG, Campbell E, Frampton CM, Yandle TG, Nicholls MG and Richards AM. 2003. Brain natriuretic peptide and n-terminal brain natriuretic peptide in the diagnosis of heart failure in patients with acute shortness of breath. J Am Coll Cardiol, 42(4), 728-735.

Landray MJ, Lehman R and Arnold I. 2000. Measuring brain natriuretic peptide in suspected left ventricular systolic dysfunction in general practice: cross-sectional study. BMJ, 320(7240), 985-986.

94

Latini R, Masson S, Anand I, Judd D, Maggioni A, Chiang Y, Bevilacqua M, Salio M, Cardano P, Dunselman P, Holwerda N, Tognoni G, Cohn J and Valsartan Heart Failure Trial Investigators. 2002. Effects of valsartan on circulating brain natriuretic peptide and norephinephrine in symptomatic chronic heart failure: the valsartan heart failure trial (Val-HeFT). Circulation, 106(19), 2454-2458.

Lindsay M, Goodfield N, Hogg K and Dunn F. 2000. Optimising direct access echo referral in suspected heart failure. Scot Med J, 45(2), 43-44.

Logeart D, Saudubray C, Beyne P, Thabut G, Ennezat PV, Chavelas C, Zanker C, Bouvier E and Solal AC. 2002. Comparative value of doppler echocardiography and B-type natriuretic peptide assay in the etiologic diagnosis of acute dyspnea. J Am Coll Cardiol, 40(10), 1794-1800.

Lubien E, DeMaria A, Krishnaswamy P, Clopton P, Koon J, Kazanegra R, Gardetto N, Wanner E and Maisel AS. 2002. Utility of B-natriuretic peptide in detecting diastolic dysfunction: comparison with doppler velocity recordings. Circulation, 105(5), 595-601.

Luchner A, Burnett JC, Jr., Jougasaki M, Hense HW, Heid IM, Muders F, Riegger GA and Schunkert H. 2000. Evaluation of brain natriuretic peptide as marker of left ventricular dysfunction and hypertrophy in the population. J Hypertens, 18(8), 1121-1128.

Luchner A, Hengstenberg C, Lowel H, Trawinski J, Baumann M, Riegger GA, Schunkert H and Holmer S. 2002. N-terminal pro-brain natriuretic peptide after myocardial infarction: a marker of cardio-renal function. Hypertension, 39(1), 99-104.

Maisel AS. 2001. B-type natriuretic peptide (BNP) levels: diagnostic and therapeutic potential. Rev Cardiovasc Med, 2,S13-8.

Maisel AS, Koon J, Krishnaswamy P, Kazenegra R, Clopton P, Gardetto N, Morrisey R, Garcia A, Chiu A and De Maria A. 2001. Utility of B-natriuretic peptide as a rapid, point-of-care test for screening patients undergoing echocardiography to determine left ventricular dysfunction. Am Heart J, 141(3), 367-374.

Maisel A, Krishnaswamy P, Nowak R, McCord J, Hollander J, Duc P, Omland T, Storrow A, Abraham W, Wu A, Clopton P, Steg P, Westheim A, Knudsen C, Perez A, Kazanegra R, Hermann H and McCullough P. 2002. Rapid measurement of b-type natriuretic peptide in the emergency diagnosis of heart failure. N Engl J Med, 347(3), 161-167.

Maisel AS, McCord J, Nowak RM, Hollander JE, Wu AH, Duc P, Omland T, Storrow AB, Krishnaswamy P, Abraham WT, Clopton P, Steg G, Aumont MC, Westheim A, Knudsen CW, Perez A, Kamin R, Kazanegra R, Herrmann HC, McCullough PA and Breathing Not Properly Multinational Study Investigators. 2003. Bedside b-type natriuretic peptide in the emergency diagnosis of heart

95

failure with reduced or preserved ejection fraction: results from the breathing not properly multinational study. J Am Coll Cardiol, 41(11), 2010-2017.

Maisel A. 2004. Updated algorithms for using b-type natriuretic peptide (BNP) levels in the diagnosis and management of congestive heart failure. Crit Path Cardiol, 3(3), 144-149.

Maisel A, Hollander J, Guss D, McCullough P, Nowak R, Green G, Saltzberg M, Ellison S, Bhalla M, Bhalla V, Clopton P and Jesse R. 2004. Primary results of the rapid emergency department heart failure outpatient trial (REDHOT): a multicenter study of b-type natriuretic peptide levels, emergency department decision making, and outcomes in the patients presenting with shortness of breath. J Am Coll Cardiol, 44(6), 1328-1333.

McCullough PA, Duc P, Omland T, McCord J, Nowak RM, Hollander JE, Herrmann HC, Steg PG, Westheim A, Knudsen CW, Storrow AB, Abraham WT, Lamba S, Wu AH, Perez A, Clopton P, Krishnaswamy P, Kazanegra R, Maisel AS and Breathing Not Properly Multinational Study Investigators. 2003. B-type natriuretic peptide and renal function in the diagnosis of heart failure: an analysis from the breathing not properly multinational study. Am J Kidney Dis, 41(3), 571-579.

McDonagh T and Morrison C. 1997. Symptomatic and asymptomatic left-ventricular systolic dysfunction in an urban population. Lancet, 350(9081), 829-833.

McDonagh TA, Robb SD, Murdoch DR, Morton JJ, Ford I, Morrison CE, Tunstall-Pedoe H, McMurray JJ and Dargie HJ. 1998. Biochemical detection of left-ventricular systolic dysfunction. Lancet, 351(9095), 9-13.

McDonagh TA. 2002. Screening for left ventricular dysfunction: a step too far? Heart (British Cardiac Society), 88,S4.

McDonagh T, Robb S, Neilsen O, Morrison C, Morton J and Dargie H. 2004a. A comparsion of the cost effectiveness of screening for left ventricular dysfunction using brain natriuretic peptide or echocardiography. Edinburgh: Chief Scientists Office.

McDonagh TA, Holmer S, Raymond I, Luchner A, Hildebrant P and Dargie HJ. 2004b. NT-proBNP and the diagnosis of heart failure: a pooled analysis of three European epidemiological studies. Eur J Heart Fail, 6(3), 269-273.

McGeoch G, Lainchbury J, Town GI, Toop L, Espiner E and Richards AM. 2002. Plasma brain natriuretic peptide after long-term treatment for heart failure in general practice. Eur J Heart Fail, 4(4), 479-483.

McKibbon A, Eady A and Marks S. 1999. PDQ evidence-based principles and practice. London: B.C. Decker Inc.

Medical Devices Agency. 2002. Management and use of IVD point of care test devices. London: Medical Devices Agency.

96

Misuraca G, Serafini O, Caporale R, Battista F and Plastina F. 2002. Diagnosis of heart failure in general medicine: role of the brain natriuretic peptide: results of a pilot study of a population sample from Calabria. Ital Heart J, 3(9), 928-932.

Montgomery H, Hunter S, Morris S, Naughton-Morgan R and Marshall R. 1994. Interpretation of electrocardiograms by doctors. BMJ, 309(6968), 1551-1552.

Morrison LK, Harrison A, Krishnaswamy P, Kazanegra R, Clopton P and Maisel A. 2002. Utility of a rapid B-natriuretic peptide assay in differentiating congestive heart failure from lung disease in patients presenting with dyspnea. J Am Coll Cardiol, 39(2), 202-209.

Moses L, Shapiro D and Littenberg B. 1993. Combining independent studies of a diagnostic test into a summary ROC curve: data-analytic approaches and some additional considerations. Stat Med, 12(14), 1293-1316.

Mueller C, Scholer A, Laule-Kilian K, Martina B, Schindler C, Buser P, Pfisterer M and Perruchoud A. 2004. Use of b-type natriuretic peptide in the evaluation and management of acute dyspnea. N Engl J Med, 350(7), 647-654.

Murdoch D, McDonagh T, Byrne J, Blue L, Farmer R, Morton J and Dargie H. 1999. Titration of vasodilator therapy in chronic heart failure according to plasma brain natriuretic peptide concentration: randomized comparison of the neuroendocrine effects of tailored versus empirical therapy. Am Heart J, 138(6), 1-12.

National Institute for Clinical Excellence. 2003. Chronic heart failure: national clinical guideline for diagnosis and management in primary and secondary care. London: NICE.

Netten A, Curtis L and Personal Social Services Research Unit. 2003. Unit costs of health and social care. Kent: Personal Social Services Research Unit.

Ng LL, Loke I, Davies JE, Khunti K, Stone M, Abrams KR, Chin DT and Squire IB. 2003. Identification of previously undiagnosed left ventricular systolic dysfunction: community screening using natriuretic peptides and electrocardiography. Eur J Heart Fail, 5(6), 775-782.

NHS Confederation and British Medical Association. 2003. New GMS contract. London: NHS Confederation and BMA.

Nielsen LS, Svanegaard J, Klitgaard NA and Egeblad H. 2004. N-terminal pro-brain natriuretic peptide for discriminating between cardiac and non-cardiac dyspnoea. Eur J Heart Fail, 6(1), 63-70.

Nielsen OW, Hansen JF, Hilden J, Larsen CT and Svanegaard J. 2000. Risk assessment of left ventricular systolic dysfunction in primary care: cross

97

sectional study evaluating a range of diagnostic tests. BMJ, 320(7229), 220-224.

Nieminen M, Bohm M, Cowie M, Drexler H, Filippatos G, Jondeau G, Hasin Y, Lopez-Sendon J, Mebazaa A, Metra M, Rhodes A and Swedberg K. 2005. Guidelines on the diagnosis and treatment of acute heart failure. Eur Heart J, 26(4), 384-416.

Packer M. 2004. Should b-type natriuretic peptide be measured routinely to guide the diagnosis and management of chronic heart failure? Q J Cardio, 9(2), 153-153.

Pfister R, Scholz M, Wielckens K, Erdmann E and Schneider CA. 2004. Use of NT-proBNP in routine testing and comparison to BNP. Eur J Heart Fail, 6(3), 289-293.

Prasad N, Lindsay M, Srikanthan V, Pell A, Dunn F and Hogg K. 1996. General physicians are as good as cardiologists at interpreting ECGs. BMJ, 312(7031), 639.

Pruszczyk P, Kostrubiec M, Bochowicz A, Styczynski G, Szulc M, Kurzyna M, Fijalkowska A, Kuch-Wocial A, Chlewicka I and Torbicki A. 2003. N-terminal pro-brain natriuretic peptide in patients with acute pulmonary embolism. Eur Respir J, 22(4), 649-653.

Redfield MM, Rodeheffer RJ, Jacobsen SJ, Mahoney DW, Bailey KR and Burnett JC, Jr. 2002. Plasma brain natriuretic peptide concentration: impact of age and gender. J Am Coll Cardiol, 40(5), 976-982.

Remme W, Swedberg K and Task Force for the Diagnosis and Treatment of Chronic Heart Failure ESoC. 2001. Guidelines for the diagnosis and treatment of chronic heart failure. Eur Heart J, 22(17), 1527-1560.

Sadanandan S, Cannon C, Chekuri K, Murphy S, Dibattiste P, Morrow D, de Lemos J, Braunwald E and Gibson C. 2004. Association of elevated b-type natriuretic peptide levels with angiographic findings among patients with unstable angina and non-ST-segment elevation myocardial infarction. J Am Coll Cardiol, 44(3), 564-568.

Sandler D, Steeds R and Hadfield J. 2000. Opening access to echocardiography for general practitioners in North Derbyshire. Brit J Cardiol, 7(2), 94-100.

Scottish Health Purchasing Information Centre. 1998. Heart failure. Edinburgh: SHPIC.

Scottish Intercollegiate Guidelines Network. 1999. Diagnosis and treatment of heart failure due to left ventricular systolic dysfunction. Edinburgh: SIGN.

Seino Y, Ogawa A, Yamashita T, Fukushima M, Ogata K, Fukumoto H and Takano T. 2004. Application of NT-proBNP and BNP measurements in

98

cardiac care: a more discerning marker for the detection and evaluation of heart failure. Eur J Heart Fail, 6(3), 295-300.

Selvais P, Donckier J, Robert A, Laloux O, van Linden F, Ahn S, Ketelslegers J and Rousseau M. 1998. Cardiac natriuretic peptides for diagnosis and risk stratification in heart failure: influences of left ventricular dysfunction and coronary artery disease on cardiac hormonal activation. Eur J Clin Invest, 28(8), 636-642.

Siebenhofer A, Ng L, Berghold A, Hodl R and Pieber T. 2003. Plasma n-terminal pro-brain natriuretic peptide in type 1 diabetic patients with and without diabetic nephropathy. Diabet Med, 20(7), 535-539.

Sim V, Hampton D, Phillips C, Lo SN, Vasishta S, Davies J and Penney M. 2003. The use of brain natriuretic peptide as a screening test for left ventricular systolic dysfunction: cost-effectiveness in relation to open access echocardiography. Fam Pract, 20(5), 570-574.

Smith H, Pickering RM, Struthers A, Simpson I and Mant D. 2000. Biochemical diagnosis of ventricular dysfunction in elderly patients in general practice: observational study. BMJ, 320(7239), 906-908.

Sparrow N, Adlam D, Cowley A and Hampton JR. 2003. The diagnosis of heart failure in general practice: implications for the UK national service framework. Eur J Heart Fail, 5(3), 349-354.

Stewart S, MacIntyre K, Hole D, Capewell S and McMurray J. 2001. More malignant than cancer? Five year survival following a first admission for heart failure. Eur J Heart Fail, 3(3), 315-322.

Stewart S, Jenkins A, Buchan S, McGuire A, Capewell S and McMurray J. 2002. The current cost of heart failure to the national health service in the UK. Eur J Heart Fail, 4(3), 361-371.

Stewart S, MacIntyre K, Capewell S and McMurray J. 2003. Heart failure and the aging population: an increasing burden in the 21st century? Heart, 89(1), 49-53.

Struthers A. Performance of ECG and BNP: Dundee 500 data (Ninewells hospital) [Unpublished].

Talwar S, Squire IB, Davies JE, Barnett DB and Ng LL. 1999. Plasma N-terminal pro-brain natriuretic peptide and the ECG in the assessment of left-ventricular systolic dysfunction in a high risk population. Eur Heart J, 20(23), 1736-1744.

Tang WHW, Girod JP, Lee MJ, Starling RC, Young JB, Van Lente F and Francis GS. 2003. Plasma b-type natriuretic peptide levels in ambulatory patients with established chronic symptomatic systolic heart failure. Circulation, 108(24), 2964-2966.

99

Van Veldhuisen D, Genth-Zotz S, Brouwer J, Boomsma F, Netzer T, Man In 'T, Veld A, Pinto Y, Lie K and Crijns H. 1998. High- versus low-dose ACE inhibition in chronic heart failure: a double-blind placebo-controlled study of imidapril. J Am Coll Cardiol, 32(7), 1811-1818.

Vasan RS, Benjamin EJ, Larson MG, Leip EP, Wang TJ, Wilson PW and Levy D. 2002. Plasma natriuretic peptides for community screening for left ventricular hypertrophy and systolic dysfunction: the Framingham heart study. JAMA, 288(10), 1252-1259.

Villacorta H, Duarte A, Marques DN, Carrano A, Tinoco ME, Dohmann HJF and Ferreira FEG. 2002. The role of B-type natriuretic peptide in the diagnosis of congestive heart failure in patients presenting to an emergency department with dyspnea. Arq Bras Cardiol, 79(6), 564-572.

Wang T, Larson M, Levvy D, Leip E, Benjamin E, Wilson PSP, Omland T and Vasan R. 2002. Impact of age and sex on plasma natriuretic peptide levels in healthy adults. Am J Cardiol, 90(3), 254-258.

Wanless D. 2002. Securing our future health: taking a long-term view: final report. London: HM Treasury.

Weber M, Dill T, Arnold R, Rau M, Muller K, Berkovitsch A, Mitrovic V and Hamm C. 2004. N-terminal b-type natriuretic peptide predicts extent of coronary artery disease and ischemia in patients with stable angina pectoris. Am Heart J, 148(4), 612-620.

Weber T, Auer J and Eber B. 2005. The diagnostic and prognostic value of brain natriuretic peptide and aminoterminal (nt)-pro brain natriuretic peptide. Curr Pharm Des, 11(4), 511-526.

Wright S, Doughty R, Gamble G, Pearl A, Whalley G, Walsh H, Bagg G, Oxenham H, Yandle T, Richards M and Sharpe N. 2003. Plasma-amino-terminal pro-brain natriuretic peptide and accuracy of heart-failure diagnosis in primary care: a randomized, controlled trial. J Am Coll Cardiol, 42(10), 1793-1800.

Wu AHB, Harrison A and Maisel AS. 2004. Reduced readmission rate for alternating diagnoses of heart failure and pulmonary disease after implementation of B-type natriuretic peptide testing. Eur J Heart Fail, 6(3), 309-312.

Yamaguchi H, Yoshida J, Yamamoto K, Sakata Y, Mano T, Akehi N, Hori M, Lim Y, Mishima M and Masuyama T. 2004. Elevation of plasma brain natriuretic peptide is a hallmark of diastolic heart failure independent of ventricular hypertrophy. J Am Coll Cardiol, 43(1), 55-60.

Yamamoto K, Burnett Jr J, Bermudez EA, Jougasaki M, Bailey KR and Redfield MM. 2000. Clinical criteria and biochemical markers for the detection of systolic dysfunction. J Card Fail, 6(3), 194-200.

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Zaphiriou A, Robb S, Murray-Thomas T, Mendez G, Fox K, McDonagh T, Hardman S, Dargie H and Cowie M. The diagnostic accuracy of plasma bnp and NTproBNP in patients referred from primary care with suspected heart failure: results of the UK natriuretic peptide study [Unpublished].

Zile M and Brutsaert D. 2002. New concepts in diastolic dysfunction and diastolic heart failure: diagnosis, prognosis, and measurements of diastolic function. Circulation, 105(11), 1387-1393.

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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 Co-operative)

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

PEER REVIEWERS

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

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.ac.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/rapidhta

• British Columbia Office of Health Technology Assessment (BCOHTA)

http://www.chspr.ubc.ca/cgi-bin/pub?program=bcohta&by=date

• Health Services Utilization and Research Commission, Saskatchewan http://www.saskatoonhealthregion.ca/

• Institute for Clinical and Evaluative Sciences, Ontario http://www.ices.on.ca

• Manitoba Centre for Health Policy, http://www.umanitoba.ca/centres/mchp

• ECRI http://www.ecri.org/

• HSTAT, http://www.ncbi.nlm.nih.gov/books/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/bandolier/

• Ongoing Reviews database

103

http://www.update-software.com/National/

• Medical Research Council – funded research http://fundedresearch.cos.com/MRC/

Clinical Effectiveness: Primary literature

The following sources were searched, via OVID, between February 2004 and June 2004:

• MEDLINE • EMBASE • MEDLINE In Process • CINAHL

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.

Search 1: Diagnostic accuracy 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. diastole/

9. systole/ 10. ((ventric$ or diastol$ or systol$) adj2 (function$ or dysfunction$ or fail$)).tw 11. (lvsd or rvsd or lvd or rvd).tw 12. or/1-11 13. exp natriuretic agents/ 14. (natriuretic$ 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

Search 2: Diagnostic accuracy 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. 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 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/

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

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.

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

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/acad/herg

• Centre for Health Services Research, University of Newcastle http://www.ncl.ac.uk/chsr/research/economics

• SCHARR School of Health and Related Research, Sheffield http://www.shef.ac.uk/uni/academic/R-Z/scharr/

• Health Economics Group, East Anglia http://www.med.uea.ac.uk/research/research_econ/HEG_Intro.htm

• 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/NetEc.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

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

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 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

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

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.

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 Setting Target diagnosis

Diagnostic method

Total number

evaluated for assay

Number assayed

and target

disease

EF cut-off Prospective Manufacturer Mean

age

Cowie (1997) GP referral/open-access echocardiography HF Consensus 106 29 Yes Peninsula NR

Dao (2001) Emergency department HF Consensus 236 97 Yes Biosite 63Lubien (2002) Other LVDD Echo 294 119 NR Yes Biosite 60

Sim (2003) GP referral/open-access echocardiography LVSD Echo 83 26 0.35 Yes Local system 72

Knudsen (2004) Emergency department HF Consensus 155 75 Yes Biosite 76Kruger (2004) Cardiology clinic LVSD Echo 128 66 0.50 Yes Biosite 61Maisel (2002) Emergency department HF Consensus 1,586 744 Yes Biosite 64 Morrison (2002) Emergency department HF Consensus 321 134 Yes Biosite NRDavis (1994) Emergency department HF Consensus 52 32 Yes Local system 74Sparrow (2003) Other LVSD Echo 621 314 0.40 Yes Not described 75

Landray (2000) GP referral/open-access echocardiography LVSD Echo 126 40 NR Yes Shionoria 74

Lainchbury (2003) Emergency department HF Consensus 205 70 Yes Biosite 70

Villacorta (2002) Emergency department HF Single cardiologist 70 36 Yes Biosite 72

Maisel (2001) GP referral/open-access echocardiography LVD Echo 200 95 Yes Biosite 65

Davidson (1996) Other LVSD Nuclear medicine 87 22 0.35 Yes Peninsula 64

Yamamoto (2000) GP referral/open-access echocardiography LVSD Echo 466 51 0.45 Yes Shionoria 65

Logeart (2002) Emergency department HF Consensus 163 115 Yes Biosite 65

Ng (2003) GP referral/open-access echocardiography LVSD Echo 13 17 0.35 Yes Peninsula 63

McDonagh (1998) GP referral/open-access echocardiography LVSD Echo 1,252 37 0.30 Yes Peninsula 51

110

Lead author Setting Target diagnosis

Diagnostic method

Total number

evaluated for assay

Number assayed

and target

disease

EF cut-off Prospective Manufacturer Mean

age

Hutcheon (2002) Other (Day Hospital for elderly) LVSD Echo 299 31 NR Yes Peninsula 79

Misuraca (2002) GP referral/open-access echocardiography HF Consensus 83 45 Yes NR 70

Smith (2000) GP referral/open-access echocardiography LVSD Echo 155 12 NR Yes Peninsula 76

Zaphiriou (unpublished)

GP referral/open-access echocardiography HF Consensus 301 104 Yes Biosite 74

HF = Heart Failure LVDD = Left Ventricular Diastolic Dysfunction LVSD = Left Ventricular Systolic Dysfunction EF = Ejection Fraction NR = Not Reported

111

Table 11 - 2 B-type natriuretic peptide studies – results and comments Lead author Sensitivity Specificity Comments

Cowie (1997) 0.97 0.84 Dao (2001) 0.94 0.94 Lubien (2002) 0.85 0.83 Sim (2003) 0.88 0.60 Knudsen (2004) 0.94 0.45 Kruger (2004) 0.89 0.55 QRS prolongation >0.1 s gives 0.84, 0.63. Maisel (2002) 0.90 0.73 Morrison (2002) 0.94 0.84 Davis (1994) 0.93 0.90 Sparrow (2003) 0.55 0.56 All on loop diuretics already. Not consecutive series of patients Landray (2000) 0.88 0.34 EF cut-off point not specified. Lainchbury (2003) 0.94 0.70 Villacorta (2002) 1.00 0.97 Maisel (2001) 0.92 0.86 52% with dyspnoea. Davidson (1996) 1.00 0.58 Yamamoto (2000) 0.79 0.64 33% symptomatic. Logeart (2002) 0.96 0.31 Ng (2003) 1.00 0.44 McDonagh (1998) 0.76 0.87 Random sample of population rather than symptomatic presenting patients. Hutcheon (2002) 0.97 0.38 Elderly patients examined for various reasons (decreased mobility the most common). Misuraca (2002) 0.93 0.34 Italian study (reported in Italian, English abstract). Smith (2000) 0.92 0.65 Series of elderly patients (not necessarily symptomatic). Zaphiriou (unpublished) 0.79 0. 72

112

Table 11 - 3 All NT-proBNP studies – patient characteristics

Lead author Setting Target diagnosis

Diagnostic method

Total number

evaluated for assay

Number assayed

and target disease

EF cut-off

Prospective Manufacturer Mean age

Jose (2003) Emergency department HF Other 119 73 Yes Biomedica 54

Gustafson (2003) GP referral/ open-access echo LVSD Echo 367 33 0.40 Yes Local system 68.8

Nielsen (2004) GP referral/ open-access echo HF Consensus 146 47 Yes Roche 65

Nielsen (2004) GP referral/ open-access echo HF Consensus 141 34 Yes Roche 65

Bayes-Genis (2004) Emergency department HF Consensus 89 74 0.45 Yes Roche 62

Talwar (1999) Other LVSD Echo 243 96 NR Yes Local system 73

Wright (2003) GP referral/ open-access echo HF Consensus 305 77 Yes Local system 72

Ng (2003) GP referral/ open-access echo LVSD Echo 13 17 0.35 Yes Local system 63

Pfister (2004) Emergency department LVSD Echo 339 24 0.4 Yes Roche

66

McDonagh (2004b) GP referral/ open-access echo HF Other 3,051 94 Yes Roche

56

Bay (2003) Emergency department LVSD Echo 2,193 157 0.40 Yes ELISA (No

detail)

73

Hobbs (2002) GP referral/ open-access echo HF Consensus 591 52 Yes Roche

66 Zaphiriou (unpublished)

GP referral/ open-access echo HF Consensus 302 104 Yes Roche 74

HF = Heart Failure LVSD = Left Ventricular Systolic Dysfunction

113

Table 11 - 4 NT-proBNP studies – results and comments

Lead author Sensitivity Specificity Comments Jose (2003) 0.97 0.89 Framingham criteria for diagnosis-not clear whether >1 assessor. High proportion of heart failure. Gustafson (2003) 0.97 0.46 Nielsen (2004) 0.96 0.67 Males only, grade of dyspnea also recorded. Nielsen (2004) 0.94 0.69 Females only. Bayes-Genis (2004) 0.96 0.60 Talwar (1999) 0.94 0.55 EF cut-off point not specified. Wright (2003) 0.80 0.90 Ng (2003) 1.00 0.46 Pfister (2004) 0.92 0.61 McDonagh (2004b) 0.75 0.79 Epidemiological study, not symptomatic presenting patients. Bay (2003) 0.73 0.82 Hobbs (2002) 1.00 0.70 Random sample – not symptomatic presenting patients. Zaphiriou (unpublished) 0.98 0.35 Symptomatic patients referred from GP.

114

Table 11 - 5 ECG studies – patient characteristics

Lead author Setting Target diagnosis

Diagnostic method

Total number

evaluated for assay

Number assayed

and target disease

EF cut-off Prospective Mean age

Davie (1996) GP referral/open-access echo LVSD Echo 534 96 NR Yes NR

Gillespie (1997) Emergency department LVSD Echo 71 45 NR Yes 73

Nielsen (2000) GP referral/open-access echo LVSD Consensus 126 15 0.45 Yes

71

Hutcheon (2002) Other (Day Hospital for elderly) LVSD Echo 299 31 NR Yes 79

Misuraca (2002) GP referral/open-access echo HF Consensus 83 45 Yes 70

Houghton (1997) GP referral/open-access echo LVSD Echo 200 165 0.4 Yes 65

Ng (2003) GP referral/open-access echo LVSD Echo 1,331 17 0.35 Yes 63

Zaphiriou (unpublished)

GP referral/open-access echo HF Consensus 302 104 Yes 74

Khandekar (1996) GP referral/open-access echo LVSD Echo 137 50 NR NR 65

Sandler (2000) GP referral/open-access echo LVSD Echo 240 71 0.4 No NR

Lindsay (2000) GP referral/open-access echo LVSD Echo 416 97 NR No NR

Struthers (Unpublished)

GP referral/open-access echo HF Single

cardiologist 407 54 Yes NR

Fonseca (2004) GP-based epidemiological study HF Consensus 1,034 539 Yes NR

HF = Heart Failure LVSD = Left Ventricular Systolic Dysfunction NR= Not reported

115

Table 11 - 6 ECG studies – results and comments Lead author Sensitivity Specificity Comments

Davie (1996) 0.94 0.61 Gillespie (1997) 0.98 0.69 Highly-selected group, high prevalence. Nielsen (2000) 0.87 0.56 Hutcheon (2002) 0.97 0.50 Misuraca (2002) 0.93 0.63 Houghton (1997) 0.89 0.46 Cardiologist Houghton (1997) 0.92 0.54 GP number 1 Houghton (1997) 0.90 0.49 GP number 2 Ng (2003) 0.88 0.61 Cardiologist Zaphiriou (unpublished) 0.81 0.60

Khandekar (1996) 0.78 0.20 Machine read

Sandler (2000) 0.73 0.55 Not clear – possibly read by GP. Lindsay (2000) 0.91 0.65 Cardiologist Struthers (Unpublished) 0.95 0.52 Cardiologist

Struthers (Unpublished) 0.94 0.22 Machine

Fonseca (2004) (reported summary results)

0.81 0.51 Cardiologist – not included in analysis – raw data in paper suggests specificity = 35%

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 2,000

laboratory tests

1,000 laboratory

tests

200 point-of-care tests

50 point-of-

care tests

Range of assay costs £15.05– £16.50

£17.75– £18.70 £22.50 £30.00

Laboratory staff £1.00 £1.00 N/A N/A Other test related costs £2.00 £2.00 N/A N/A Additional clinician/nurse time £1.50 £1.50 £7.50 £7.50

Total base case £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.

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Table 11 - 8 Cost of echocardiography Item Costa Source

Capital cost per scan £14 Manufacturer capital costs and 2,140 scans annually (Buckle & Chambers, 2000)

Read costs per scan £52

MTO4 salary + oncosts PSSRU: number of scans 887 (Buckle & Chambers, 2000) + 20% quality assurance

Clinic costs £12 Marginal cost of booking echocardiography

Cardiologist/consultant cost £12 Cardiologist review and assessment

Letter to GP £10 Letter to GP and update electronic and paper records

Letter from GP to patient £2 Patient travel costs for echocardiograph £7 (Netten et al., 2003)

Total costs £109 a All costs rounded to nearest pound.

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 Cost

90% read by MTO4: 10% consultant read £6

Admin to fax to and from surgery £4 Letter from GP to patient £2 Total £12

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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

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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

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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).

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Table 11 - 10 Number of echocardiograms performed during the previous 12 months on patients referred with suspected heart failure by GPs

Number of echocardiograms 200 or

less 201–400

401–600

601–800

801–1,000

Cannot specify or not

given Number of hospitals 3 2 4 3 2 6

11.1.2.2 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)

< 1 1–2 3–4 5–6 7–8 9–10 11-12

Number of hospitals 1 3 1 1 1 4 1

11.1.2.3 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).

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Table 11 - 12 Waiting time for an outpatient clinic appointment (unprioritised)

Waiting time (weeks) < 5 6–10 11–15 16–20 Number of hospitals 1 3 1 1

11.1.2.4 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 2 3

11.1.2.5 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.

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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

≤20% 21–40% 41–60% 61–80% 81–100%

Cannot specify or not

given Number of hospitals 10 3 1 0 2 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).

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12 Glossary

ACE inhibitors Angiotensin-converting enzyme inhibitors. A group of drugs which lower blood pressure and expand blood vessels.

acute coronary syndromes

A collective term for the spectrum of acute coronary disease associated with myocardial ischaemia.

antibodies Special blood proteins produced in response to an antigen.

antigen Any substance that the body regards as foreign or potentially dangerous, against which antibodies are produced.

assay A test to measure the amount of a specific constituent of a solution.

asymptomatic Without symptoms. BNP 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.

cardiologist Specialist doctor who treats patients with heart conditions.

catheterisation Refers to the insertion of a flexible tube into a narrow opening, used to visualise the coronary arteries or to perform angioplasty.

CI 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.

clinical effectiveness

The evaluation of the balance between benefits and risks in a standard clinical setting using outcomes of importance to the patient.

COPD Chronic obstructive pulmonary disease. coronary heart disease

Disease, such as angina, coronary thrombosis or heart attack, caused by the narrowing or blockage of the coronary arteries by atheroma.

cost effectiveness Used in its broadest form, this term encompasses all forms of economic analysis.

cut-off A boundary value for a test variable which distinguishes normal from abnormal results.

decompensated The heart has failed to maintain adequate circulation. DHF Diastolic heart failure. Predominant or isolated

abnormality in diastolic function. diagnosis 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.

diuresis An increase in the secretion of urine by the kidneys. dyspnoea Breathing difficulties.

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ECG Electrocardiogram. A diagnostic test that monitors the electrical activity of the heart.

echocardiography Ultrasound technique used to obtain an image and measurement of the heart.

EF Ejection fraction. A measure of the heart’s capacity to contract and pump blood.

empirical Pertaining to observations and the collection of data. epidemiology The scientific study of the natural history of diseases

and factors associated with diseases. It may involve purely observational studies or interventions in populations.

ESC European Society of Cardiology. false negative A test result which indicates that a patient does not

have the disease of interest, when in fact they do. FDA Food and Drug Administration. GFR Glomerular filtrate rate. gold standard Widely recognised as the best available. GP General practitioner. grey literature 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.

heart failure A condition in which the pumping action of the heart is impaired.

heterogeneous When pertaining to meta-analysis, means that the results of any individual trial are not compatible with those of any of the other trials.

homogeneous When pertaining to meta-analysis, means that the results of any individual trial are compatible with those of any of the other trials.

HTA 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.

incidence The number of new cases of a disease in a year. invasive When pertaining to treatment, involves breaking the

skin, or insertion of an instrument into the body. ischaemic heart disease

Disease of the heart associated with deficient blood supply caused by functional constriction or obstruction within the blood vessels.

left ventricular dysfunction

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.

loop diuretics A class of drugs which act on a particular part of the kidney to cause an increase in urine secretion.

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LVSD Left ventricular systolic dysfunction (see left ventricular dysfunction).

MCN 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 quality-assurance framework describing the standards the service will meet.

meta-regression A method to investigate the results of heterogeneous studies.

morbidity The frequency (incidence and/or prevalence) of a particular disease or group of diseases.

mortality The death rate. myocardial infarction

Damage that occurs to the heart muscle when the oxygen supply is disrupted. This is usually as a result of an occluded coronary artery.

natriuresis An increase in the amount of sodium excreted in urine. nephropathy Disease of the kidney. NHS QIS 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

NHSScotland National Health Service in Scotland. NICE National Institute of Clinical Excellence. NPV Negative predictor value. Percentage of patients with a

negative test who do not have the disease. NT-proBNP N-terminal-pro-BNP. An inactive peptide hormone

produced in the heart. NYHA New York Heart Association. oedema An excess accumulation of fluids in the body. OR 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.

peptides Short chains of amino acids. point-of-care test A diagnostic procedure performed in the vicinity of the

patient. It is also described as ‘near patient test’ and ‘bedside test’.

prevalence The overall proportion of the population who have the disease.

primary care 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

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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.

prognosis An assessment of the expected future course and outcome of a person’s disease.

pulmonary embolism

A blood clot in the lungs.

ROC curve Receiver operating characteristic curve. Used to evaluate the accuracy of any method of predicting different outcomes.

sensitivity The probability that a test result is positive, given that a person has the disease.

sepsis An illness caused by a bacteria infection of the bloodstream.

SIGN Scottish Intercollegiate Guidelines Network. specificity The probability that a test result is negative, given that

a person does not have the disease. syndrome A collection of signs or symptoms. systolic heart failure

The inability to pump an adequate volume of blood and/or to do so only from an abnormally elevated filling pressure.

true positive A test result which correctly indicates that a patient has the disease of interest.

vasodilation Widening of blood vessels.

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