1. Introduction

The assessment of patients with suspected heart valve disease begins with a comprehensive clinical assessment, comprising history taking and systematic physical examination including cardiac auscultation to detect murmurs and associated changes in the normal heart sounds. This initial clinical assessment can be performed in primary care, in hospital settings outside cardiology or within cardiology, it can increase or decrease the suspicion of existence of heart valve disease and it can provide indications of heart valve disease severity. However, the firm diagnosis of existence and of severity of heart valve disease is made with cardiac imaging, primarily with echocardiography.

There is access to echocardiography as a result of a referral from primary care or from hospital settings outside or within cardiology. However, if cardiac auscultation is reassuring, echocardiography may be unnecessary. The capacity for echocardiography is not unlimited and unnecessary assessments would both inconvenience the individual assessed and delay the essential assessment of another individual. Consequently, it is important to identify the symptoms and signs that indicate referral for echocardiography.

The clinical pathway comprising referral for echocardiography and subsequent assessment of the result to decide if referral to a specialist is needed, may introduce delay in the care of patients with severe symptoms due to potentially severe heart valve disease. Consequently, it is important to identify the symptoms and signs that indicate direct referral to a specialist to avoid delay. Specialist clinics offer one stop echocardiography or echocardiography prior to the clinic appointment, as such shortening the clinical pathway.

2. Signs and symptoms indicating echocardiography referral

2.1. In adults with suspected heart valve disease what symptoms and signs indicate referral (for example from primary care) for echocardiography?

2.1.1. Summary of the protocol

For full details see the review protocol in Appendix A.

Table 1

PICO characteristics of review question.

2.1.2. Methods and process

This evidence review was developed using the methods and process described in Developing NICE guidelines: the manual. Methods specific to this review question are described in the review protocol in appendix A and the methods document.

Declarations of interest were recorded according to NICE’s conflicts of interest policy.

2.1.3. Diagnostic evidence

2.1.3.1. Included studies

A search was conducted for cross-sectional and prospective and retrospective cohort studies assessing the diagnostic test accuracy of murmur with or without other signs or symptoms (heart sounds and/or symptoms) to identify whether the condition is present (as indicated by the reference standard) in people under investigation for condition heart valve disease.

Diagnostic association studies that report data on the association between murmur with or without other signs or symptoms (heart sounds and/or symptoms) and diagnosis of heart valve disease were also considered for all populations and tests because the available diagnostic accuracy evidence was either mostly indirect or limited to small samples.

Thirty studies with diagnostic accuracy data or data that could be used to calculate diagnostic accuracy data were included in the review;^{5, 11, 16–19, 21–23, 27, 29, 34, 51, 72, 86, 97, 103, 109, 113, 117, 121, 132, 137, 139, 143, 163, 171, 174, 175, 230} these are summarised in Table 2 below. All of the studies reported cross-sectional diagnostic data. Evidence from these studies is summarised in the clinical evidence summary below in Tables 3–16.

Most of the studies investigated the accuracy of murmur alone for the diagnosis of heart valve disease, with the definition of the murmur and person conducting auscultation differing between studies. However, two studies^{23, 174} looked at murmur plus symptoms, three studies^174,19,132 assessed murmur plus an absent or reduced second heart sound, and one study¹⁷⁴ looked at murmur plus abnormal ECG.

The assessment of the evidence quality was conducted with emphasis on test sensitivity, as this was identified by the committee as the primary measure in guiding decision-making as the priority would be to avoid missing cases (false negatives) and not sending them for further testing as a result. The committee set clinical decision thresholds as sensitivity = 0.60.

Reference standards

Of the 30 studies included in the review, 25 used the preferred reference standard of echocardiography. However, a further 5 studies were included that used cardiac catheterisation as the method of confirming valve disease, as this was the preferred method confirming valve disease before echocardiography was available. This more invasive procedure was used in older studies, and these results were analysed separately to data using echocardiography as the reference standard.

Populations

Studies that involved screening for heart valve disease and murmurs in presumably healthy populations where there could be no reason for a suspicion of heart valve disease were excluded, for example, where screening was performed for everyone who experienced a hip fracture or in populations that were said to be healthy. However, studies where there was not necessarily a suspicion of heart valve disease but had some indication for either attendance at hospital or primary care, echocardiography or were experiencing cardiac symptoms were included, as there was limited evidence where the populations were defined as specifically being suspected of having heart valve disease.

Studies where the presence of a murmur was required for a participant to be included in a study were also included, despite the fact that this would mean all were already known to be index test positive before enrolment. Limited diagnostic accuracy data can be obtained from these studies, but it was agreed to include these given that murmur would be one of the main reasons for suspicion of heart valve disease and these studies could still provide information on the proportion of those with the murmur that actually had reference standard confirmed valve disease, in the form of the positive predictive ratio. The limitations of these studies were highlighted.

For further details of the review methods see section 2.1.6 Summary of the diagnostic evidence.

See also the study selection flow chart in Appendix C, and sensitivity and specificity forest plots in Appendix E, and study evidence tables in Appendix D.

2.1.3.2. Excluded studies

See the excluded studies list in Appendix I.

2.1.4. Summary of studies included in the diagnostic evidence

Table 2

Summary of studies included in the evidence review.

See Appendix D for full evidence.

2.1.5. Summary of the diagnostic evidence

The assessment of the evidence quality was conducted with emphasis on test sensitivity as this was identified by the committee as the primary measure in guiding decision-making. The committee set a clinical decision threshold of 0.6 for sensitivity.

The populations, target conditions and index tests used across the included studies were considered to be very broad and wide-ranging, and therefore no studies were pooled into a diagnostic meta-analysis. Sensitivity and specificity for each individual study is given below, separated into broad categories based on the population and also by whether the reference standard was echocardiography or cardiac catheterisation.

For studies where all of those included had to be positive for murmur with/without another characteristic (which was used as an index test in our review), sensitivity and specificity, as well as other measures, could not be calculated, and positive predictive values are instead presented.

Note that although all included studies detected heart valve disease as the target condition, the type of heart valve disease that was included in the studies varied. For example, some studies aimed to diagnose and report any type of valve disease (including aortic stenosis, aortic regurgitation, mitral stenosis, mitral regurgitation and tricuspid regurgitation), while others focused specifically on one or two types of valve disease, such as aortic stenosis or mitral stenosis and mitral regurgitation, or any type of regurgitation but not stenosis (i.e. aortic regurgitation, mitral regurgitation and tricuspid regurgitation). Where possible, results have been calculated for ‘any valve disease’; however, in many cases results are reported separately for each type of valve disease as it was not possible to determine how many may have had more than one type of valve disease at the same time to calculate diagnostic accuracy results for overall heart valve disease in each study.

Reference standard – echocardiography

Table 3

Clinical evidence summary: murmur for heart valve disease in various settings in populations with various indications for assessment.

Table 4

Clinical evidence summary: murmur for heart valve disease in populations with MVP that has already been diagnosed by echocardiography.

Table 5

Clinical evidence summary: murmur for heart valve disease in a population with mitral annular calcium observed by echocardiography.

Table 6

Clinical evidence summary: murmur for heart valve disease (all with murmur to be included).

Table 7

Clinical evidence summary: murmur + dyspnoea for heart valve disease in acute medical patients admitted to geriatric ward of hospital.

Table 8

Clinical evidence summary: murmur + angina for heart valve disease in acute medical patients admitted to geriatric ward of hospital.

Table 9

Clinical evidence summary: murmur + other indication (dyspnoea, peripheral oedema or other) for heart valve disease in patients with suspected heart failure of heart valve disease).

Table 10

Clinical evidence summary: systolic murmur + absent/reduced second heart sound for heart valve disease.

Table 11

Clinical evidence summary: non-flow murmur for heart valve disease in pregnant women.

Table 12

Clinical evidence summary: murmur in pregnant women for heart valve disease (all with murmur to be included).

Table 13

Clinical evidence summary: murmur + abnormal ECG (left ventricular hypertrophy) for heart valve disease in acute medical patients admitted to geriatric ward of hospital.

Table 14

Clinical evidence summary: murmur + abnormal ECG (atrial fibrillation) for heart valve disease in acute medical patients admitted to geriatric ward of hospital.

Reference standard – cardiac catheterisation

Table 15

Clinical evidence summary: murmur for heart valve disease in various settings in populations with various indications for assessment.

Table 16

Clinical evidence summary: systolic murmur for heart valve disease (all with murmur to be included).

2.1.6. Economic evidence

2.1.6.1. Included studies

No health economic studies were included.

2.1.6.2. Excluded studies

No relevant health economic studies were excluded due to assessment of limited applicability or methodological limitations.

See also the health economic study selection flow chart in Appendix F.

2.1.7. Summary of included economic evidence

None

2.1.8. Economic model

This area was not prioritised for new cost-effectiveness analysis.

2.1.9. Unit costs

Relevant unit costs are provided below to aid consideration of cost effectiveness.

Table 17

UK cost of echocardiogram.

3. Signs and symptoms indicating referral to a specialist

3.1. In adults with suspected heart valve disease, what symptoms and signs indicate direct referral (for example from primary care) to a specialist?

3.1.1. Summary of the protocol

For full details see the review protocol in Appendix A.

Table 18

PICO characteristics of review question.

3.1.2. Methods and process

This evidence review was developed using the methods and process described in Developing NICE guidelines: the manual. Methods specific to this review question are described in the review protocol in appendix A and the methods document.

Declarations of interest were recorded according to NICE’s conflicts of interest policy.

3.1.3. Diagnostic evidence

3.1.3.1. Included studies

A search was conducted for cross-sectional and prospective and retrospective cohort studies assessing the diagnostic test accuracy of murmur with or without other signs or symptoms (heart sounds and/or symptoms) to identify whether the condition is present (as indicated by the reference standard) in people under investigation for condition severe heart valve disease.

Diagnostic association studies that report data on the association between murmur with or without other signs or symptoms (heart sounds and/or symptoms) and diagnosis of severe heart valve disease were also considered for all populations and tests because the available diagnostic accuracy evidence was either mostly indirect or limited to small samples.

Nineteen studies with diagnostic accuracy data or data that could be used to calculate diagnostic accuracy data were included in the review;^{3, 5, 16–19, 51, 63, 89, 109, 117, 121, 131, 132, 134, 163, 171, 174, 191} these are summarised in Table 19 below. All of the studies reported cross-sectional diagnostic data. Most of the studies investigated the accuracy of murmur alone for the diagnosis of severe heart valve disease, with the definition of the murmur and person conducting auscultation differing between studies. However, two studies^{174, 191} looked at murmur plus symptoms, three studies^{3, 132, 174} assessed murmur plus an absent or reduced second heart sound, and one study¹⁷⁴ looked at murmur plus abnormal ECG.

One of these studies¹⁹ also provided diagnostic association data for a particular index test (murmur + diminished aortic closure sound) for the diagnosis of moderate or severe aortic stenosis.

Evidence from these studies is summarised in the clinical evidence summary below in Tables 20–32 below.

The assessment of the evidence quality was conducted with emphasis on test sensitivity, as this was identified by the committee as the primary measure in guiding decision-making as the priority would be to avoid missing cases (false negatives) and not sending them for further testing as a result. The committee set clinical decision thresholds as sensitivity = 0.60.

Reference standards

Only studies that had used echocardiography as a reference standard for confirming valve disease were included in this review as the older method of confirming valve disease (cardiac catheterisation) is not as good at assessing the severity of heart valve disease as the current gold standard of echocardiography is, and this review focuses on the diagnosis of severe heart valve disease, which may differ between cardiac catheterisation and echocardiography.

Populations

Studies that involved screening for heart valve disease and murmurs in presumably healthy populations where there could be no reason for a suspicion of heart valve disease were excluded, for example, where screening was performed for everyone who experienced a hip fracture or in populations that were said to be healthy. However, studies where there was not necessarily a suspicion of heart valve disease but had some indication for either attendance at hospital or primary care, echocardiography or were experiencing cardiac symptoms were included as indirect evidence, as there was limited evidence where the populations were defined as specifically being suspected of having heart valve disease. This were analysed separately to populations with suspected heart valve disease.

Studies where the presence of a murmur was required for a participant to be included in a study were also included, despite the fact that this would mean all were already known to be index test positive before enrolment. Limited diagnostic accuracy data can be obtained from these studies, but it was agreed to include these as indirect evidence given that murmur would be one of the main reasons for suspicion of heart valve disease and these studies could still provide information on the proportion of those with the murmur that actually had reference standard confirmed valve disease, in the form of the positive predictive ratio. The limitations of these studies were highlighted and they were analysed separately to other studies.

For further details of the review methods see section 3.1.6 Summary of the diagnostic evidence.

See also the study selection flow chart in Appendix C, sensitivity and specificity forest plots in Appendix E, and study evidence tables in Appendix D.

3.1.3.2. Excluded studies

See the excluded studies list in Appendix I.

3.1.4. Summary of studies included in the diagnostic evidence

Table 19

Summary of studies included in the evidence review.

See Appendix D for full evidence tables.

3.1.5. Summary of the diagnostic evidence

The populations, target conditions and index tests used across the included studies were considered to be very broad and wide-ranging, and therefore no studies were pooled into a diagnostic meta-analysis. Sensitivity and specificity for each individual study is given below, separated into broad categories based on the population.

For studies where all of those included had to be positive for murmur with/without another characteristic (which was used as an index test in our review), sensitivity and specificity, as well as other measures, could not be calculated, and positive predictive values are instead presented.

Note that although all included studies detected heart valve disease as the target condition, the type of heart valve disease that was included in the studies varied. For example, some studies aimed to diagnose and report any type of valve disease (including aortic stenosis, aortic regurgitation, mitral stenosis, mitral regurgitation and tricuspid regurgitation), while others focused specifically on one or two types of valve disease, such as aortic stenosis or mitral stenosis and mitral regurgitation, or any type of regurgitation but not stenosis (i.e. aortic regurgitation, mitral regurgitation and tricuspid regurgitation). Where possible, results have been calculated for ‘any valve disease’; however, in many cases results are reported separately for each type of valve disease as it was not possible to determine how many may have had more than one type of valve disease at the same time to calculate diagnostic accuracy results for overall heart valve disease in each study.

The assessment of the evidence quality was conducted with emphasis on test sensitivity as this was identified by the committee as the primary measure in guiding decision-making. The committee set a clinical decision threshold of 0.6 for sensitivity.

Table 20

Clinical evidence summary: murmur for moderate or severe heart valve disease in various settings in populations with various indications for assessment.

Table 21

Clinical evidence summary: murmur for moderate or severe heart valve disease in populations with MVP that has already been diagnosed by echocardiography.

Table 22

Clinical evidence summary: murmur for moderate or severe heart valve disease in a population with mitral annular calcium observed by echocardiography.

Table 23

Clinical evidence summary: murmur for heart valve disease (all had a murmur to be included in the study).

Table 24

Clinical evidence summary: murmur in pregnant women for heart valve disease (all with murmur to be included).

Table 25

Clinical evidence summary: murmur + syncope for significant heart valve disease in acute medical patients admitted to geriatric ward of hospital.

Table 26

Clinical evidence summary: murmur + dyspnoea for significant heart valve disease in acute medical patients admitted to geriatric ward of hospital.

Table 27

Clinical evidence summary: murmur + angina for significant heart valve disease in acute medical patients admitted to geriatric ward of hospital.

Table 28

Clinical evidence summary: systolic murmur + syncope on exertion with/without chest pain for heart valve disease (all had this combination to be included in the subgroup).

Table 29

Clinical evidence summary: systolic murmur +absent/reduced second heart sound for heart valve disease.

Table 30

Clinical evidence summary: murmur + abnormal ECG (left ventricular hypertrophy) for heart valve disease in acute medical patients admitted to geriatric ward of hospital.

Table 31

Clinical evidence summary: murmur + abnormal ECG (atrial fibrillation) for heart valve disease in acute medical patients admitted to geriatric ward of hospital.

Table 32

Clinical evidence summary: Systolic murmur + diminished aortic closure sound vs. systolic murmur without diminished aortic closure sound – association with a diagnosis of moderate or severe AS.

3.1.6. Economic evidence

3.1.6.1. Included studies

No health economic studies were included.

3.1.6.2. Excluded studies

No relevant health economic studies were excluded due to assessment of limited applicability or methodological limitations.

See also the health economic study selection flow chart in Appendix F.

3.1.7. Summary of included economic evidence

None

3.1.8. Economic model

This area was not prioritised for new cost-effectiveness analysis.

3.1.9. Unit costs

Table 33

UK appointment costs.

4. The committee’s discussion of the evidence

5. Women of child-bearing age and pregnancy

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Appendices

Final

Evidence reviews underpinning recommendations 1.1.1 to 1.1.5 and 1.1.8 to 1.1.11 in the NICE guideline

These evidence reviews were developed by the National Guideline Centre, hosted by the Royal College of Physicians

Disclaimer: The recommendations in this guideline represent the view of NICE, arrived at after careful consideration of the evidence available. When exercising their judgement, professionals are expected to take this guideline fully into account, alongside the individual needs, preferences and values of their patients or service users. The recommendations in this guideline are not mandatory and the guideline does not override the responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or their carer or guardian.

Local commissioners and/or providers have a responsibility to enable the guideline to be applied when individual health professionals and their patients or service users wish to use it. They should do so in the context of local and national priorities for funding and developing services, and in light of their duties to have due regard to the need to eliminate unlawful discrimination, to advance equality of opportunity and to reduce health inequalities. Nothing in this guideline should be interpreted in a way that would be inconsistent with compliance with those duties.

NICE guidelines cover health and care in England. Decisions on how they apply in other UK countries are made by ministers in the Welsh Government, Scottish Government, and Northern Ireland Executive. All NICE guidance is subject to regular review and may be updated or withdrawn.