As the committee was interested in the relative accuracy of the tests at different thresholds, it was only appropriate to meta-analyse sensitivity and specificity data where multiple studies used the same test (NT-proBNP or BNP) and reported data at the same test threshold. While it was not possible to assess statistical heterogeneity for data that was not meta-analysed, upon viewing the forest plots, the committee agreed that there was clearly a high degree of inconsistency in the results across the thresholds. That is, the expected relationship between sensitivity and specificity and the test threshold was not clearly apparent. This suggested that the study populations or other features of the study design or quality were contributing to differences between test accuracy at different thresholds, rather than these differences necessarily reflecting true threshold-related differences in test accuracy. Sensitivity analyses using just the data assessed as low risk of bias were conducted, to see if this resolved the inconsistency in the results, but the inconsistency between studies remained. Given the committee s ability to establish the most appropriate test thresholds was limited by the thresholds reported by the included studies, the committee decided to contact study authors seeking additional data at the particular thresholds. The committee decided to limit this request to data on NT-proBNP rather than BNP for the multiple reasons: 1. The clinical review demonstrates that NT-proBNP has a greater sensitivity over a range of thresholds compared to BNP. Chronic Heart Failure Diagnosing heart failure NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: 978-1-4731-3093-7 The committee acknowledged the high sensitivity from one study conducted in 1997, but considered that the heart failure population has changed significantly since this study was conducted with a greater proportion of people with HF-PEF, which on a population level tend to have lower NT-proBNP levels than people with HF-REF . Therefore it is highly uncertain as to whether these results represent the diagnostic accuracy for BNP testing in current practice. Whereas, the majority of the high quality NT-proBNP studies are more recent studies and are more likely to be applicable to current practice. Comparing thresholds between BNP and NT-proBNP is inherently difficult as there is no conversion algorithm between them. However, the Zaphiriou study (high quality study assessing both BNP and NT-proBNP) assessed the recommended industry cut-offs for each test. When comparing this data NT-proBNP thresholds have a consistently higher sensitivity than the BNP thresholds. 2. NT-proBNP has a longer stability in blood samples than BNP (days vs 4-6 hours), therefore NT-proBNP is more appropriate for testing in primary care. 3. Sacubitril Valsartan interferes with BNP physiology (TA388). Natriuretic peptides can also be used for monitoring heart failure patients. Therefore, the committee considered it would be more useful to have NT-proBNP as the baseline peptide in case monitoring was needed in a patient with heart failure who is subsequently treated with this drug. The test thresholds at which data was sought were 125pg/mL, 280 pg/mL and 400 pg/mL. The thresholds were selected based on the data already available in the included studies and to minimise the amount of additional data that needed to be collected, while still allowing for assessment of accuracy at key clinically relevant thresholds used in existing NICE guidelines and other international guidance. The results of the requests for additional data meant that meta-analysis of three studies was possible at each of the above thresholds. Unfortunately, despite all three studies being of high quality and enrolling seemingly similar populations, the pooled data was of very low quality due to serious inconsistency and serious imprecision. For this reason, the committee had little confidence in the pooled estimates of sensitivity and specificity. Suspected heart failure and CKD One diagnostic accuracy study was included that evaluated the diagnostic accuracy of BNP at diagnosing heart failure in a population with CKD and respiratory distress. The reference standard used in the study was unclear and may not have fully matched the protocol, but the study was included in the review in the absence of any direct evidence. The evidence was graded very low quality due to very high risk of bias, serious indirectness and serious imprecision. Risk of bias was very high due to it being unclear how participants were selected, unclear whether the reference standard was applied blind to BNP results, and unclear whether any patients were lost to Chronic Heart Failure Diagnosing heart failure NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: 978-1-4731-3093-7 follow up or missing from the analysis. Only the results of the subgroup of patients with CKD stages G3 to G4 were reported in accordance with the protocol. Suspected heart failure and AF No diagnostic accuracy studies meeting the protocol were identified. Six studies in an acute population or setting, and another study with a target condition of major structural heart disease , were identified. After discussion, the committee agreed that these studies should not be included in the review, despite the absence of any direct evidence, as they would not provide reliable evidence in the population of interest. Trade-off between clinical benefits and harms For the reasons outlined above, the committee s discussion of the clinical evidence focussed on NT-proBNP rather than BNP. General suspected heart failure population BNP and NT-proBNP are used as a triage test, with people whose results are above a certain threshold being referred for echocardiography and specialist clinical assessment, following which a definitive diagnosis can be made. The committee noted that the threshold for referral to echocardiography and specialist clinical assessment in the 2010 guideline was 400 pg/mL. The committee agreed that from a clinical perspective, a lower test threshold would mean fewer patients with heart failure would have their diagnoses missed or delayed, avoiding unnecessary hospitalisations and mortality. However, the committee recognised that if the test threshold was set lower than clinically necessary, many people may be unnecessarily referred for echocardiography and specialist clinical assessment. This could cause unnecessary worry for people and their families, as well as delaying diagnosis of an true underlying condition, and having resource and economic implications (discussed below). The committee considered the clinical evidence with the aim to determine which NT-proBNP threshold was most appropriate for identifying patients who should be referred for echocardiography and specialist clinical assessment, focussing on sensitivity of the test. The pooled sensitivity at a threshold of 125pg/mL was 96% (72%-100%), at a threshold of 280pg/mL was 89% (41%-89%), and at a threshold of 400pg/mL was 79% (42%-96%). The committee noted that the pooled evidence was very low quality due to inconsistency between the included studies and consequently very wide confidence intervals around the meta-analysed data. At a threshold of 400pg/mL, the committee also noted that specificity was likely to be much higher (82% (52%-95%)) compared with specificity at the which would reduce any clinical harms of over-referral. The committee discussed possible reasons for the inconsistency between the study results at length, and considered that the differences in sensitivity and specificity were likely to be due to heterogeneity in the study populations. Chronic Heart Failure Diagnosing heart failure NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: 978-1-4731-3093-7 The committee discussed the differences in setting between the studies as there was one Spanish study, one UK study that recruited patients between 2001 and 2003, and one recent UK study. The committee considered that across these settings the population presenting to primary care with signs and symptoms of heart failure could be different. The committee also noted that the proportions of HF-REF and HF-PEF across these studies were very different, supporting the hypothesis that the study populations were not similar. The committee agreed that based on the clinical data alone, it was not possible to establish the threshold that provided the best overall trade-off between benefits and harms. The committee considered that an economic model was necessary to trade-off the benefits of a lower threshold against the potential increases in cost. For that reason, the most clinically and cost- effective threshold was identified as a priority for economic modelling. Suspected heart failure and CKD The committee discussed the evidence in a population of suspected heart failure and CKD. The committee noted that the only evidence available was for BNP at a threshold of 410 pg/mL. No evidence was available for NT- proBNP at any threshold. The committee considered advice from a renal physician co-opted to the committee and the very low quality evidence, and agreed that there was no convincing rationale to have a different test threshold for people with CKD and suspected heart failure. The committee noted that both advancing age and heart failure are associated with a gradual and progressive decline in renal function. In addition, the progression of heart failure and some treatments for heart failure lead to progressive deterioration of renal function. A decline in renal function is associated with increased fluid retention and a rise in the level of the serum natriuretic peptides, including NT-proBNP, even in the absence of heart failure. There is some evidence that the use of higher NT-proBNP thresholds would improve diagnostic accuracy for heart failure in people with significant deterioration of creatinine clearance. Suspected heart failure and AF No evidence was included in a population with suspected heart failure and AF. The committee agreed that in the absence of any evidence, there was no convincing rationale to have a different test threshold for people with AF and suspected heart failure. However the committee noted that atrial fibrillation can raise the level of serum natriuretic peptides, including NT-proBNP, even in the absence of heart failure. This is complicated further in heart failure with preserved ejection fraction, in which 2 echocardiographic diagnostic criteria become unreliable (the left atrial volume and the tissue Doppler imaging assessment of diastolic function). These factors contribute to the complexity of the diagnosis and have a potential impact on the usual thresholds for NT-proBNP in people who have atrial fibrillation. This has been recognised in several ongoing randomised controlled trials of heart failure, Chronic Heart Failure Diagnosing heart failure NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: 978-1-4731-3093-7 which are using higher NT-proBNP thresholds for the diagnosis of heart failure in people with atrial fibrillation. Trade-off between net clinical effects and costs No economic evaluations were identified comparing NT-proBNP thresholds and BNP thresholds. Unit costs of BNP and NT-proBNP were presented to the committee for consideration. As previously discussed in the quality of the clinical evidence section above, the committee agreed that NT-proBNP was a better test than BNP. They were therefore reassured that that the average cost difference between the two tests was only around 4. They discussed that there was some uncertainty in these estimates due to the limited sample size, although there was some overlap in costs where NT-proBNP was less expensive than BNP. The committee also mentioned that the purchase of new equipment for analysing NT-proBNP is not necessary as there are kits available for all main systems. Therefore the committee did not consider that there would be further cost implications beyond those reflected in the costs above. The committee were also aware that NT-proBNP is due to come off patent in the next couple of years and therefore expect the cost of NT-proBNP to decrease. Furthermore, the committee noted that as NT-proBNP overall had a higher sensitivity compared to BNP, there is potential for some offset of the current higher cost of NT-proBNP due to reduced number of false negative results for people being tested with NT-proBNP compared to BNP. A false negative result would either require re-testing, or could result in hospitalisation if an acute episode occurred prior to diagnosis. They therefore considered that taking into consideration the above that NT- proBNP and that the majority of labs now run NT-proBNP, some of them teaching hospitals which receive a high volume of tests, that only recommending NT-proBNP would not have a substantial resource impact for the NHS in England. One economic analysis was identified for this review assessing NT-proBNP thresholds. This study compared the MICE (Male, Infarction, Crepitations, (o)Edema) clinical decision rule using the upper NT-proBNP cut-off, the MICE clinical decision rule using the lower NT-proBNP cut-off, the 2010 NICE guideline recommended strategy (refer straight away for echocardiography if history of previous myocardial infarction (MI), otherwise refer for echocardiography if NT-proBNP>400pg/ml), NT-proBNP threshold of 125pg/ml, echocardiography for all, and do nothing. This analysis found that the 2010 NICE guideline strategy was the most cost effective approach for diagnosing heart failure in patients with suspected heart failure. This analysis was assessed as partially applicable with potentially serious limitations. The committee raised the following limitations of this economic evaluation. Firstly, this analysis used diagnostic accuracy data from the REFER study where the level of NT-proBNP had been used as a criterion in determining whether or not the patient had heart failure. The committee were concerned that this had introduced incorporation bias to the diagnostic accuracy results, Chronic Heart Failure Diagnosing heart failure NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: 978-1-4731-3093-7 potentially biasing the overall results of the model. The committee acknowledged that in practice the level of NT-proBNP is often used as part of the criteria for diagnosing heart failure but agreed that for our purposes in truly identifying the diagnostic accuracy of the test, this data was not considered to be suitable. Secondly, the committee also noted that this analysis did not report any assumptions, costs or QALYs applied to the non-heart failure population in the model. The committee inferred from the results of the model that this population was not directly accounted for, and supposed that the model assumed there was no effect on this population of a differential diagnosis if they enter the diagnostic pathway for heart failure. Thirdly, the committee stated that the definition of MI has changed over time and now includes many scenarios that differ from what was originally meant in the 2010 guideline, and as a result having a history of myocardial infarction (MI) should no longer be a criterion for early echocardiography. Therefore the NICE 2010 guideline diagnostic pathway was no longer considered to be an appropriate strategy to assess. Due to the high clinical and economic importance of this question, an original cost-effectiveness analysis was therefore conducted for this question. The model sought to determine which NT-proBNP threshold is the most cost effective for diagnosing heart failure in patients presenting with signs and symptoms of heart failure. The comparators included were NT-proBNP thresholds of 400pg/ml, 280pg/ml and 125pg/ml, and echocardiography for all. Due to the inconsistency in the pooled results and the very low quality of this data as discussed above, the committee did not consider it appropriate to use the pooled results of these thresholds for the base-case analysis. Therefore the committee decided to choose one diagnostic accuracy study for the base case analysis, and use the other two diagnostic studies to undertake scenario analyses adjusting the population characteristics as appropriate. The committee chose to use the diagnostic accuracy data from the REFER study for the base case analysis; however the accuracy of this data was determined from a reference standard that did not include the level of NT- proBNP in part of the criteria for diagnosing heart failure therefore mitigating the effects of incorporation bias. In contrast to the study identified above, this analysis also incorporated the cost and QALY impact of misdiagnosis for a non-heart failure population. For more information on the model methods and data inputs please see Appendix O. This original analysis found that an NT-proBNP threshold of 400pg/ml is the most cost effective strategy at a threshold of 20,000 per QALY gained (ICER: 5,496 compared to echo all) with a probability of 77% of being the most cost effective at the 20,000 threshold. This result was robust to multiple sensitivity analyses varying key input parameters and structural assumptions. This analysis was assessed as directly applicable with potentially serious Chronic Heart Failure Diagnosing heart failure NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: 978-1-4731-3093-7 limitations. The committee discussed the breakdown of costs and QALYs across the strategies. Contrary to the committees previous statement that sensitivity is the most critical outcome, the model suggests that the specificity of the test is most critical with regards to cost effectiveness. These results demonstrate that the model is being driven by the greater cost reductions and QALY benefits of diagnosing other conditions in the non-heart failure population earlier, rather than the cost reductions and QALY benefits of an earlier diagnosis of heart failure. The committee noted that the QALYs accrued for the heart failure population are very similar across all of the strategies (difference of 0.01 QALYs between the 400pg/ml threshold (lowest QALYs for people with heart failure) and referring all patients for echocardiography (highest QALYs for people with heart failure). The committee was reassured to know that the difference was so small. However, acknowledged that this small difference is likely to be due to the low proportion of people with HF-REF in the model, and hence limited QALY gains from early treatment. Although the REFER study seemed the most appropriate study to choose for the base case analysis as it was the most recent UK study, the committee voiced concern about the very small proportion of HF-REF patients in the study population. The committee considered that this may be due to study selection bias, as patients with severe symptoms, who are thought to be of high risk, are often not recruited into these types of clinical studies due to concern that there would be a delay in their treatment. The committee considered that the patients considered to be of high risk are more likely to have HF-REF than HF-PEF. However, the extent of possible selection bias is unknown. Due to uncertainty around the diagnostic accuracy of the NT-proBNP test, two scenario analyses were undertaken to assess the diagnostic accuracy data from two other studies included in the clinical review (Verdu et al. 2012 and Zaphiriou et al. 2005). When applying the ordinal logistic regression model to the Verdu data to enable the results to be run probabilistically, the mean sensitivity values were not consistent with the reported study values. Therefore the Verdu study was run both probabilistically (using the ordinal logistic regression model data) and deterministically (using the reported study data). The inconsistency in the mean values from the regression model and those reported in the study was thought to be due to the fact that the sensitivity of 280pg/ml and 125pg/ml threshold were both 100%. Ordinal logisitic regression was thought to be the most suitable method to fit a distribution to the diagnostic accuracy data to ensure that the sensitivity and specificity values maintained their order according to the threshold level for each run. Using this method one assumes that the model is predicting values that the data would show if you had a greater sample size. The probabilistic analysis for Verdu supported the results of the base case analysis, showing that 400pg/ml was the most cost effective diagnostic Chronic Heart Failure Diagnosing heart failure NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: 978-1-4731-3093-7 strategy (ICER: 9,842 per QALY gained). The probability of this being the most cost effective strategy at the 20,000 per QALY gained threshold is 62%. The deterministic analysis for Verdu found 280pg/ml to be the most cost-effective diagnostic strategy (ICER: 5,952 per QALY gained). The was considered to be due to the fact that this threshold had both the highest sensitivity and highest specificity of all diagnostic strategies. The other scenario analysis conducted using the data from Zaphiriou found that 280pg/ml was the most cost effective threshold (ICER: 15,088 per QALY gained compared to 125pg/ml). The probability of this being the most cost effective strategy at the 20,000 per QALY gained threshold is 19%. In this analysis the 400pg/ml threshold was dominated (more costly, less effective) by 280pg/ml, although the difference in QALYs between these two strategies was very small (0.003). This result was likely to be driven by the high proportion (76%) of HF-REF in the heart failure population for this study, as those with HF-REF receive a greater QALY benefit of being diagnosed and treated than those with HF-PEF. The results of the scenario analyses were much more uncertain than those of the base case. This was considered to be due to the fact that the sensitivity and specificity values of the NT-proBNP across the thresholds are much closer compared to those in the base case diagnostic accuracy study. The committee also considered that the difference in the probabilistic and deterministic results of the Verdu study highlights the uncertainty in the results. From the results of the economic analyses, the committee agreed to recommend that an NT-proBNP level of 400pg/ml be used to refer a patient for echocardiography when heart failure is suspected in a patient presenting with signs and symptoms of heart failure in primary care. The committee considered the base case analysis to be robust to changes in model assumptions and data inputs. However, they acknowledged the uncertainty that remains for this question due to the inconsistencies in the study populations and diagnostic accuracy data across the studies assessed in the model. However, the results of the scenario analyses using different diagnostic accuracy data from alternative studies were highly uncertain. Therefore, overall the committee agreed that there was currently not enough evidence to support reducing the threshold from 400pg/ml as recommended in the previous guideline. Suspected heart failure and CKD or AF No previously published economic evaluations were identified in these populations. Due to a lack of diagnostic accuracy data for the AF and CKD patients these cohorts were not included in the original economic analysis. However, as mentioned above the committee did not consider there to be a strong rationale to have a different test threshold for people with CKD and suspected heart failure. Chronic Heart Failure Diagnosing heart failure NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: 978-1-4731-3093-7 Other considerations General suspected heart failure population The 2010 guideline considered a wider breadth of evidence than was considered in this review. This review protocol was limited to studies of patients presenting in a primary care or outpatient setting, on the basis that studies of patients in an acute setting now fall within the remit of the acute heart failure guideline. Studies in patients immediately post myocardial infarction (MI) were also excluded on the basis that they also more appropriately fall within the scope of the acute guideline. This review was also limited to patients presenting with signs or symptoms of heart failure, rather than the use of NT-proBNP to screen for heart failure in asymptomatic or high risk populations without signs or symptoms, as the aim of the review was to identify the most relevant evidence to the population of interest. In addition, this review protocol was limited to studies using a reference standard of echocardiography plus clinical assessment for the diagnosis of heart failure. The committee did not consider that echocardiography alone, or reduced ejection fraction on echocardiography, was an appropriate reference standard and studies using that reference standard were excluded from this review. The committee noted that patients can have reduced ejection fraction on echocardiography without having symptomatic heart failure, so echocardiography alone was not a sufficient reference standard. Further, patients with heart failure with preserved ejection fraction in particular could not be diagnosed with echocardiography alone as this diagnosis requires substantial clinical input and judgment. The committee also discussed the 2010 guideline recommendations that provide a different treatment pathway for patients with any previous MI (these patients were referred directly for echocardiography and specialist assessment, without prior natriuretic peptide testing). The committee noted that this was based on the MICE clinical decision rule developed by the Mant 2009 IPD, which included evidence that was outside the scope of this review (for example, it included studies in acute populations, and studies using a wider range of reference standards and target conditions than specified in this protocol). The committee agreed that this distinction between patients who had and had not had any previous MI was not supported by the latest clinical evidence in the population of interest to this review. The committee also noted that the definition of MI had changed over time. The committee agreed that the distinction between patients with and without previous MI should be removed from the diagnostic pathway. NT-proBNP testing should be done in all patients with suspected heart failure regardless of whether or not they have had a previous MI. The committee agreed to remove a recommendation from the 2010 guideline suggesting that a serum natriuretic peptide test should be considered when heart failure is still suspected after transthoracic Doppler 2D echocardiography has shown a preserved left ventricular ejection fraction. The committee recalled that this recommendation was made to inform an individual s prognosis from the NT-proBNP level. However, the Chronic Heart Failure Diagnosing heart failure NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: 978-1-4731-3093-7 committee noted that according to these recommendations, and the removal of the different diagnostic pathway for those with previous MI, all patients should receive an NT-proBNP level and therefore this recommendation was no longer necessary. The committee also reiterated the importance that patients with very high NT-proBNP levels (>2,000pg/ml) receive an echocardiography promptly (within 2 weeks) due to the association of NT-proBNP levels and prognosis. The committee noted that while an NT-proBNP threshold of 400 pg/mL was most cost-effective, some patients with test results below this threshold and even below 125pg/mL went on to be diagnosed with heart failure in the REFER trial. Therefore, it was important that healthcare professionals were aware that even in people with low NT-proBNP results, heart failure cannot definitively be ruled out. The committee noted that NT-proBNP levels were lower in populations of West African/Afro-Caribbeandescent and also in patients with morbid obesity. The committee agreed that in these patients, alternative causes for their symptoms should be reviewed, and if there is still concern that symptoms may be due to heart failure, this should be discussed with a heart failure specialist. The committee considered that the changes to the recommendations would have limited impact on current practice in terms of the diagnostic pathway. However, laboratories that currently only do BNP testing would have to move to NT-proBNP testing and this may have an initial resource impact with regards to implementation. Suspected heart failure and CKD The committee agreed that studies in patients with CKD stage G5 or receiving dialysis were outside the scope of the review. This was on the basis that these patients would already be receiving specialist clinical review and assessment and were not relevant to a diagnostic pathway focussed primarily on patients presenting to primary care with heart failure symptoms. The 2010 CHF guideline CG108 included echocardiography as a second reference standard, the committee discussed the clinical diagnosis of heart failure and agreed that echocardiography alone did not constitute a gold standard for diagnosis and that a definitive diagnosis should be based on the opinion of at least one cardiologist which considered symptoms and objective evidence of cardiac dysfunction (either structural or functional). Due to the lack of evidence regarding the optimal threshold for NT-proBNP in either people with HF and atrial fibrillation or HF and CKD the committee agreed that further research in this area would be beneficial for future updates of this guideline. In addition to this the committee agreed that a large study was needed to Chronic Heart Failure Diagnosing heart failure NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: 978-1-4731-3093-7 provide more certainty with regards to which NT-proBNP threshold (400pg/ml or 125pg/ml) is more clinically and cost effective for the diagnosis of HF in people with suspected HF would also be of benefit for future guideline updates due to the limitations of current diagnostic accuracy studies. The committee agreed that the 400pg/ml and 125pg/ml thresholds would be of most interest as these are the two thresholds used in practice. 400pg/ml is used in the UK, and has previously been used elsewhere until recently. However, the European Society of Cardiology and the American Heart Association has reduced the threshold to 125pg/ml. See section 5.4 of 2010 guideline (Appendix R): BNP2: Natriuretic peptides vs echocardiography. Chronic Heart Failure Diagnosing heart failure NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: 978-1-4731-3093-7 5.4 Recommendations for diagnosing heart failure 5.4.1 Symptoms, signs and investigations 1. Take a careful and detailed history, and perform a clinical examination and tests to confirm the presence of heart failure. [2010] 2. Measure N-terminal pro-B-type natriuretic peptide [NT-proBNP] in people with suspected heart failure. [2018] 3. Because very high levels of NT-proBNP carry a poor prognosis, refer people with suspected heart failure and an NT-proBNP level above 2,000 ng/litre (236 pmol/litre) urgently, to have specialist assessment and transthoracic echocardiography within 4. Refer people with suspected heart failure and an NT-proBNP level between 400 and 2,000 ng/litre (47 to 236 pmol/litre) to have specialist assessment and transthoracic echocardiography within 6 weeks. [2018] 5. Be aware that: an NT-proBNP level less than 400 ng/litre (47 pmol/litre) in an untreated person makes a diagnosis of heart failure less likely the level of serum natriuretic peptide does not differentiate between heart failure with reduced ejection fraction and heart failure with preserved ejection fraction. [2018] 6. Review alternative causes for symptoms of heart failure in people with NT-proBNP levels below 400 ng/litre. If there is still concern that the symptoms might be related to heart failure, discuss with a physician with subspeciality training in heart failure. [2018] 7. Be aware that: obesity, African or African-Caribbean family origin, or treatment with diuretics, angiotensin- converting enzyme(ACE) inhibitors , beta-blockers, angiotensin II receptor blockers (ARBs) or mineralcorticoid receptor antagonist (MRAs) can reduce levels of serum natriuretic peptides. high levels of serum natriuretic peptides can have causes other than heart failure (for example, age over 70 years, left ventricular hypertrophy, ischaemia, tachycardia, right ventricular overload, hypoxaemia [including pulmonary embolism], renal dysfunction [eGFR ], sepsis, chronic obstructive pulmonary disease, diabetes, or cirrhosis of the liver). [2010, amended 2018] 8. Perform transthoracic echocardiography to exclude important valve disease, assess the systolic (and diastolic) function of the (left) ventricle, and detect intracardiac shunts. 9. Transthoracic echocardiography should be performed on high-resolution equipment, by experienced operators trained to the relevant professional standards. Need and demand for these studies should not compromise quality. [2003, amended 2018] 10.Ensure that those reporting echocardiography are experienced in doing so. [2003] Chronic Heart Failure Diagnosing heart failure NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: 978-1-4731-3093-7 11.Consider alternative methods of imaging the heart (for example, radionuclide angiography [multigated acquisition scanning], cardiac MRI or transoesophageal echocardiography) if a poor image is produced by transthoracic echocardiography. [2003, 12.Perform an ECG and consider the following tests to evaluate possible aggravating factors and/or alternative diagnoses: chest X-ray blood tests: renal function profile thyroid function profile liver function profile lipid profile glycosylated haemoglobin (HbA1c) full blood count urinalysis peak flow or spirometry. [2010, amended 2018] 13.Try to exclude other disorders that may present in a similar manner.[2003] 14.When a diagnosis of heart failure has been made, assess severity, aetiology, precipitating factors, type of cardiac dysfunction and correctable causes. [2010] 5.4.2 Heart failure caused by valve disease 15.Refer people with heart failure caused by valve disease for specialist assessment and advice regarding follow-up. [2003] 5.4.3 Reviewing existing diagnoses 16.Review the basis for a historical diagnosis of heart failure, and manage care in accordance with this guideline only if the diagnosis is confirmed. [2003] 17.If the diagnosis of heart failure is still suspected, but confirmation of the underlying cardiac abnormality has not occurred, then the person should have appropriate further Chronic Heart Failure Diagnosing heart failure NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: 978-1-4731-3093-7 5.5 Cardiac Magnetic Resonance Imaging (cMRI) Cardiac magnetic resonance imaging (cMRI) provides accurate and reproducible assessments of the systolic function of the ventricles, and some assessment of diastolic function of the ventricles. It is capable of studying the myocardial perfusion, infiltration and cardiac involvement by oedema, inflammation and scarring. cMRI provides an accurate assessment of the iron content of the myocardium. Using special sequences, cMRI is also capable of assessing ischaemia and scarring without the use of contrast media. cMRI is also capable of assessing valve lesions and shunts as well as measuring cardiac muscle mass and chamber volume. In chronic heart failure, cMRI is currently used in some centres for the assessment of left ventricular ejection fraction, the assessment of myocardial ischaemia, and for the detection and characterisation of myocardial scarring, inflammation or infiltration. There has been a rapid expansion in the number of cardiac magnetic resonance imaging (CMR) tests performed in the UK from 20597 in 2008 to 38485 in 2010 and yet there are no clear recommendations about its use. The role of cMRI in the diagnosis of chronic heart failure, in relation to other imaging techniques is unclear as is its place in the diagnostic pathway for patients with heart failure. This question addressed the clinical efficacy and cost effectiveness of cMRI compared to standard imaging technologies and whether all patients suspected of heart failure should undergo cMRI imaging or should it be used selectively in some patients? 5.5.2 Review question: In people with heart failure what is the clinical and cost effectiveness of cardiac MRI followed by the appropriate patient pathway? For full details see review protocol in Appendix A. Table 26: PICO characteristics of review question Population All people with HF in a community or outpatient setting. Intervention/Co mparators Echocardiography plus routine cardiac MRI Echocardiography plus selective cardiac MRI Echocardiography alone (all interventions will be compared against each other) Outcomes CRITICAL: All-cause mortality (time to event) Health-related quality of life at 12 months (continuous) Unplanned hospitalisation (total number of events (rate ratio)) IMPORTANT: Adverse events related to test (non-specific fibrosis in the presence of renal dysfunction) Reclassification of specific HF aetiology (including ability to classify previous unclassified patients) Change in management HF medication use HF advanced therapy use, including disease specific therapies Repeat testing / additional testing Study design RCTs Chronic Heart Failure Diagnosing heart failure NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: 978-1-4731-3093-7 Systematic reviews of RCTs 5.5.3 Clinical evidence No relevant clinical studies comparing the effectiveness of different cardiac MRI (cMRI) imaging modalities with echocardiography (echo) were identified. 5.5.4 Economic evidence Published literature No relevant health economic studies were identified. See also the health economic study selection flow chart in Appendix D. Unit Costs Table 27: Unit costs of cardiac MRI Description Unit cost Source Cardiac Magnetic Resonance Imaging Scan 264(a) NHS Reference costs 2014/15242 Simple Echocardiogram 84 NHS Reference costs 2014/15242 (a) Weighted average of RD08Z, RD09Z, RD10Z. 5.5.5 Evidence statements Clinical No clinical evidence was identified. Economic No relevant economic evaluations were identified. 5.5.6 Recommendations and link to evidence Recommendations No recommendation Research recommendations What is the optimal imaging technique for the diagnosis of heart failure? Relative values of different outcomes The committee considered the following outcomes to be critical for this review: all-cause mortality, quality of life, and all-cause hospitalisation. Data on all-cause mortality and hospitalisation were considered preferable to data limited to heart-failure related mortality and hospitalisations, primarily for consistency of methodology across the guideline, but also to take into account the potential adverse events associated with cardiac MRI or echocardiography. Adverse events related to the use of gadolinium in cardiac MRI specifically non-specific fibrosis in the presence of renal dysfunction were considered Chronic Heart Failure Diagnosing heart failure NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: 978-1-4731-3093-7 to be important for decision-making. Given the nature of the review, namely to establish whether there was any benefit in using an additional diagnostic test, the committee also specified the following process outcomes as important for decision making: reclassification of specific heart failure aetiology, change in management, change in heart failure medication, advanced therapy use, and the need for repeat or additional testing. Quality of the clinical evidence No clinical evidence was found. Trade-off between clinical benefits and harms As no randomised controlled studies were found that addressed the review question, the committee was not able to make a recommendation on the clinical and cost effectiveness of cardiac MRI in heart failure. The committee decided to make a research recommendation to establish the added value of cardiac MRI (in terms of its clinical and cost effectiveness) in the clinical pathway of heart failure, for the reasons discussed below. Trade-off between net clinical effects and costs No previously published economic evaluations were identified evaluating the cost effectiveness of cardiac MRI (followed by the appropriate patient pathway) in patients with heart failure. The cost of a cardiac MRI and echocardiography was presented to the committee ( 264 and 84 respectively); however, as there was no clinical evidence, the committee could not make a judgement on the cost- effectiveness of cardiac MRI. However, the committee agreed that due to the greater cost of cardiac MRI compared to echocardiography it was important that an assessment of the cost-effectiveness of cardiac MRI was included in the research recommendation. Other considerations The committee considered the use of cardiac MRI in heart failure to be an area of high priority for future research. While cardiac MRI is being increasingly used in heart failure in the UK, there remains large variation in practice across the country, and significant equality issues around access (for example, based on age and geography). There are also significant cost and resource implications. The committee discussed an existing clinical trial that is currently underway ), which will compare outcomes in patients randomised to either routine cardiac MRI or selective (clinically driven) cardiac MRI. The trial is recruiting patients with heart failure and a working clinical diagnosis of non-ischaemic cardiomyopathy and patients with heart failure with preserved ejection fraction. The committee considered that the results of this trial would be very useful in answering the question posed in this review, but noted that it would not answer a number of the questions of interest, namely: the clinical and cost effectiveness of adding cardiac MRI (either routinely or selectively) to echocardiography in all patients with HFREF For those reasons, notwithstanding the trial presently underway, the committee decided to make a research recommendation to establish the added value of cardiac MRI (in terms of its clinical and cost effectiveness) in all patients with heart failure. The committee also discussed the following proposed review question in the guideline scope: What is the role of secondary imaging investigations in Chronic Heart Failure Diagnosing heart failure NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: 978-1-4731-3093-7 diagnosing suspected amyloidosis? The original objective of this question was to see if various imaging techniques (including cardiac MRI and bone scintigraphy using DPD tracing), when used following echocardiography, could identify a particular subset of people with HFPEF caused by amyloidosis. Amyloidosis accounts for around 5-13% of cases with HFPEF. The committee noted that during scoping for the guideline, it was thought that the amyloidosis question would complete the diagnostic picture, sitting alongside general recommendations on cardiac MRI imaging for HF. However, as no evidence was identified for the effectiveness of cardiac MRI in improving outcomes for HF patients, the committee decided that it would not be necessary for the guideline to specifically consider secondary imaging for a relatively narrow subset of patients with HFPEF. The committee noted that future research addressing the research recommendation including the OUTSMART 255 trial should answer the question on whether cardiac MRI in HF patients is clinically and cost- effective. Once this area of uncertainty is resolved for the general HF population, depending on the outcome of that research, it may then be appropriate to consider whether other forms of secondary imaging are effective in specific subpopulations of HF. If cardiac MRI were, in the future, to become a standard first line imaging technique for all HF patients, secondary imaging specific to amyloidosis may not be necessary (or may be used more judiciously in people with suspicious cardiac MRI results). However, until the effectiveness of cardiac MRI is known, the committee agreed that to conduct a review and make guideline recommendations specific to amyloidosis would be premature. Chronic Heart Failure Treating Heart Failure NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: 978-1-4731-3093-7 6 Treating Heart Failure The treatment of heart failure involves management of underlying causes and risk factors, treatment of symptoms and long-term pharmacological and non-pharmacological interventions for specific types of disease. The management of heart failure has evolved with increasing interest in preventative therapies which deal with conditions predisposing to heart failure such as ischaemic herat disease with attedant risk-factors such as smoking and diabetes, and the role of hypertension and obesity in exacerbation of heart failure especially if ejection fraction is preserved. Dietary factors such as salt (sodium intake), fatty acids, cholesterol and carbohydrates are involved in promoting the progression of hypertension, hyperlipidaemia, obesity and diabetes which all have implications for the management of heart failure. The management of these outside heart failure is the subject of separate guidance (see NICE CG 181; PH38) but these recommendations may not apply completely in patients with heart failure . As fluid overload is a common feature of heart failure sodium and fluid restriction has been advised and new evidence is available to be able to review whether this is efficacious. The diagnosis of heart failure has implications for activities of daily life as well as affecting the ability to travel or drive. The presence of oedema and reduced activity found with heart failure prediposes to chest infections and thus this group of patients need to receive advice on vaccination for influenza. The update to the heart failure guideline includes topics where new evidence has emerged since the publication in 2010. A review of new evidence published after 2010 was carried out in order to determine whether any changes to current recommendations where likely to be required. The decision on which topics to include in the update of the guideline was made following consultation of the scope. This section, with the exception of salt and fluid restriction, was not within the scope of the update. For more information on the following aspects of lifestyle please refer to appendix R in the 2003 guideline: vaccinations, sexual activity, air travel, driving For guidance on alcohol and smoking cessation see 6.1.2. 6.1.1 Salt and fluid restriction Information provided to patients with heart failure usually includes advice to restrict salt and fluid intake. Patients often find this difficult to adhere to, and little is known as to whether or not adherence affects their overall condition, and helps prevent episodes of decompensation. There is a concern that advising fluid restriction in the elderly, whose fluid intake is often low, could potentially be harmful. There is currently variation in practice on what advice patients are given by health professionals and consequently confusion and uncertainty among patients about whether salt and fluid restriction is beneficial. Stakeholders identified this as a priority area for the guideline update, and the committee regarded this as an important aspect of patient care and education that required clarification. 6.1.1.2 Review question: What is the clinical and cost effectiveness of salt and/or fluid restriction in people with heart failure? For full details see review protocol in Appendix A. Chronic Heart Failure Treating Heart Failure NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: 978-1-4731-3093-7 Table 28: PICO characteristics of review question Population People diagnosed with heart failure according to the New York Heart Association (NYHA) class system (I-IV), who are being managed as outpatients or in the community. Where possible, results will be stratified based on the serum sodium level of patients at baseline. Interventions / Comparisons Salt and/or fluid restriction programme structured, protocol-driven programme to limit salt and/or fluid to certain levels. Programme may or may not be individualised. General advice to limit salt and/or fluid intake No advice to limit salt and/or fluid intake Interventions compared to each other Outcomes CRITICAL Quality of life at 12 months (Continuous) Unplanned hospitalization (Count rate) IMPORTANT Change in weight at 12 months (Continuous) Change in oedema at 12 months (Continuous) Change in sodium level (Continuous)(in the low baseline sodium strata only) Adverse events - Renal function at 12 months (Dichotomous) Adverse events - Hyperkalaemia at 12 months (Dichotomous) Study design Systematic Review RCT 6.1.1.3 Clinical evidence A search was conducted for randomised control trials looking at the effect of sodium (salt) and/or fluid restriction in people with heart failure being managed in the community. Two studies were included in the review70, 281 these are summarised in Table 29. See also the study selection flow chart in Appendix C, forest plots in Appendix E, study evidence tables in Appendix F, GRADE tables in Appendix H and excluded studies list in Appendix I. Both studies are small, and refer to themselves as pilot studies. One study compared a moderate salt intake (2300mg/day sodium) with low salt intake (1500mg/day sodium) in people with HF and normal serum sodium. A further study compared an education programme with support to maintain fluid restriction at 1.5-2L (intervention) with general support unrelated to the fluid restriction (control) in people with HF who were already in a trial of an intrathoracic impedance monitoring device who had been hospitalised in the last six months. Table 29: Summary of studies included in the review Study Intervention and comparison Population Outcomes Comments Colin- Ramirez (n=19) Salt restriction programme with target of reducing salt to <1500mg/day (n=19) Salt restriction programme with target of reducing salt to <2300mg/day Adults with HFREF or HFPEF on optimally tolerated medical therapy with normal serum sodium Age median 66 Quality of Life (KCCQ) six months Renal failure (Creatinine) six months Actual intake of salt in two groups (median): All results reported using non-parametric summary scores. Significant inequality at Chronic Heart Failure Treating Heart Failure NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: 978-1-4731-3093-7 Study Intervention and comparison Population Outcomes Comments ethnicity baseline. BMI and oedema inadequately reported for extraction. Normal sodium status Pilot study. Reilly Fluid restriction with self-care programme to encourage fluid restriction to 1.5-2L Attention control received same fluid prescription and contacts, but interaction more general Both groups also encouraged to restrict salt to Adults with HF enrolled in a different trial. NYHA class II-IV Had previously been prescribed fluid regimen of Age mean 63 African American EQ5D visual analogue scale (VAS) six months Oedema three months (extracted, but not analysed) Actual fluid intake of two groups: intervention mean 1703, control No baseline sodium levels given. Pilot study. Treating Heart Failure Chronic Heart Failure NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: Table 30: Clinical Evidence summary: Low sodium diet versus moderate sodium diet for heart failure Outcomes No of Participants (studies) Follow up Quality of the evidence (GRADE) Relative effect Anticipated absolute effects Time frame is 6 months Risk with Advice for moderate sodium diet Risk difference with Advice for low sodium diet (95% CI) Quality of Life Kansas City Cardiomyopathy Questionnaire. Scale from: 0 to 100. High is better LOWa,b due to risk of bias The median quality of life in the control groups was The median quality of life in the intervention groups was Renal function Creatinine (umol/L) LOWa,b, due to risk of bias The median renal function in the control groups was The median renal function in the intervention groups was (a) Downgraded by 1 increment if the majority of the evidence was at high risk of bias, and downgraded by 2 increments if the evidence was at very high risk of bias. (b) Imprecision cannot assessed due to reporting of median and inter-quartile range. Table 31: Clinical evidence summary: Fluid restriction programme versus advice on fluid restriction for heart failure Outcomes No of Participant s (studies) Follow up Quality of the evidence (GRADE) Relative effect Anticipated absolute effects Time frame is 6 months Risk with Advice on fluid restriction Risk difference with Programme for fluid restriction (95% CI) Quality of Life EQ5D - visual analogue scale. Scale from: 0 to 100. High is better. VERY LOWa,b,c due to risk of bias, indirectness, imprecision The mean quality of life at 6 months in the control groups was The mean quality of life at 6 months in the intervention groups was (24.96 lower to 7.6 higher) Oedema Congestion score. Scale from: 0 to 5. High is worse. VERY LOWa,c,d due to risk of bias, indirectness, imprecision The mean congestion sore in the control groups was The mean congestion score in the intervention groups was (1.1 lower to 1.24 higher) Treating Heart Failure Chronic Heart Failure NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: (a) Downgraded by 1 increment if the majority of the evidence was at high risk of bias, and downgraded by 2 increments if the majority of the evidence was at very high risk of bias. (b) Downgraded by 1 or 2 increments because the majority of evidence was from an indirect population (people were already enrolled in a intrathoracic impedance monitoring device trial). (c) Downgraded by 1 increment if the confidence interval crossed 1 MID or by 2 increments if the confidence interval crossed both MIDs. (d) Downgraded by 2 increments because the majority of evidence was from an indirect population (people were already enrolled in a intrathoracic impedance monitoring device trial) and was looking at congestion, which includes things other than oedema (the protocol outcome). Chronic Heart Failure Beta-blockers in heart failure and concomitant atrial fibrillation NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: 978-1-4731-3093-7 6.1.1.4 Economic evidence Published literature No relevant health economic studies were identified. See also the health economic study selection flow chart in Appendix D. 6.1.1.5 Evidence statements Clinical Two studies were identified for inclusion within the review. The quality of the evidence ranged from low to very low due to risk of bias, imprecision due to wide confidence intervals surrounding the effect estimate and indirectness of the study population. One study including 38 people with HFREF or HFPEF on optimally tolerated medical therapy with normal serum sodium compared a moderate salt intake (2300mg/day sodium) with low salt intake (1500mg/day sodium). In reality, participants in either arm reduced salt to a relatively similar extent (median difference 63mg/day). The outcome QoL (as measured by the KCCQ) showed a clinically important reduction in quality of life with the low sodium diet. The low sodium diet also showed no clinical effect on renal function. Imprecision could not be assessed for these outcomes as the study reported the results as median and interquartile range. The results of this pilot study were used to inform the larger SODIUM-HF trial, which is currently recruiting The second study which included 25 people, who were already enrolled in a trial of an intrathoracic impedance monitoring device and who had been hospitalised within the previous 6 months, compared an education programme providing support to maintain fluid restriction at 1.5-2L (intervention) with general support unrelated to the fluid restriction (control). The outcome QoL (as measured by the EQ5D VAS) showed a clinically important reduction in quality of life with the fluid restriction programme (associated with wide confidence intervals around the effect estimate). The fluid restriction programme had no clinical effect on the outcome oedema (again associated with wide confidence). Economic No relevant economic evaluations were identified. Chronic Heart Failure Beta-blockers in heart failure and concomitant atrial fibrillation NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: 978-1-4731-3093-7 6.1.1.6 Recommendations and link to evidence Recommendations Do not routinely advise people with heart failure to restrict their sodium or fluid consumption. Ask about salt and fluid consumption and, if needed, advise as follows: restricting fluids for people with dilutional hyponatraemia reducing intake for people with high levels of salt and/or fluid consumption. Continue to review the need to restrict salt or fluid. [2018] Advise people with heart failure to avoid salt substitutes that contain Relative values of different outcomes The committee considered quality of life and unplanned hospitalisation to be the critical outcomes for this review. Data on all-cause hospitalisation were considered preferable to data limited to heart failure (HF) related hospitalisations, as such data take into account the broader unintended consequences of the interventions (for example, an increase in hospitalisations due to adverse events). Change in appetite, weight and oedema, as well as impact on renal function and hyperkalaemia, were considered to be important for decision-making. For patients with low sodium levels at baseline, change in serum sodium level was also considered an important outcome. While serum sodium level is often reported as an outcome in sodium restriction studies, it was not considered clinically relevant for HF patients with normal baseline sodium. Also, while studies often report actual reductions in sodium and/or fluid intake after the delivery of a restriction intervention, again this was not considered to be a key clinically important outcome. Given the nature of the interventions in this review, mortality was not included as an outcome. The committee was more interested in the impact on symptoms and hospitalisation. For the comparison of low sodium diet programme versus moderate sodium diet programme, the only evidence reported in a complete format enabling analysis was on quality of life and renal function. For the comparison of fluid restriction programme versus advice on fluid restriction, the only evidence was on quality of life and oedema. There was no evidence for any comparison on hospitalisation, change in weight, change in sodium level for patients with low baseline sodium, or hyperkalaemia. Quality of the clinical evidence The committee noted the paucity of evidence in this area, which was limited to 2 very small pilot studies looking at different comparisons. Low sodium programme versus moderate sodium programme: The evidence for both quality of life and renal function was graded low quality due to risk of bias (selection bias and performance bias). Imprecision could not be formally assessed due to reporting of the outcomes as median and interquartile range (IQR), but the committee noted the small size of the study. Fluid restriction programme versus general advice on fluid restriction: Chronic Heart Failure Beta-blockers in heart failure and concomitant atrial fibrillation NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: 978-1-4731-3093-7 Recommendations Do not routinely advise people with heart failure to restrict their sodium or fluid consumption. Ask about salt and fluid consumption and, if needed, advise as follows: restricting fluids for people with dilutional hyponatraemia reducing intake for people with high levels of salt and/or fluid consumption. Continue to review the need to restrict salt or fluid. [2018] Advise people with heart failure to avoid salt substitutes that contain The evidence for quality of life was graded very low quality due to risk of bias (selection bias and performance bias), indirectness (indirect population) and imprecision. The evidence for oedema was graded very low quality due to risk of bias (selection bias, performance bias and measurement bias), indirectness (indirect population and outcome) and imprecision. Other comparisons: There was no evidence on any of the following comparisons: Salt restriction programme versus general advice to restrict salt. Salt restriction programme versus no restriction/no advice. Fluid restriction programme versus no restriction/no advice. Trade-off between clinical benefits and harms The committee discussed the evidence for a low sodium programme compared with a moderate sodium programme, which was based on a single small trial. The committee noted that patients median intake of sodium at both baseline and at the end of the study was similar between the 2 groups (at the end of the study, low sodium 1398 mg/day, moderate sodium 1461 mg/day). Notwithstanding the similar reduction in sodium consumption in each group, quality of life in the low sodium group was lower than in the moderate sodium group. This suggested that the restrictive nature of the programme itself, independent of the actual reduction in sodium consumption achieved, had a negative impact on quality of life. There was no clinically important difference in renal function (measured by creatinine) between the low and moderate sodium programmes, which was to be expected given the similarity in the actual sodium levels consumed. The committee also discussed the evidence for a fluid restriction programme compared with general advice to restrict fluid, which again was based on a single small trial. The fluid restriction programme did appear to have a clinically important impact on actual levels of fluid consumed in each group, with the general advice group consuming 300mL more per day on average than the restriction programme group. Quality of life was lower in the restriction programme group than in the general advice group which was agreed to represent a clinically important reduction. The restriction programme did not appear to have any impact on oedema measured via a congestion score , though the committee placed little weight on this scale that has not been validated. In weighing up the possible benefits and harms of salt and fluid restriction, the committee acknowledged the quality of the evidence, which ranged from low to very low, and the uncertainty around the effect estimates. The absence of evidence on most of the outcomes was noted, in particular Chronic Heart Failure Beta-blockers in heart failure and concomitant atrial fibrillation NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: 978-1-4731-3093-7 Recommendations Do not routinely advise people with heart failure to restrict their sodium or fluid consumption. Ask about salt and fluid consumption and, if needed, advise as follows: restricting fluids for people with dilutional hyponatraemia reducing intake for people with high levels of salt and/or fluid consumption. Continue to review the need to restrict salt or fluid. [2018] Advise people with heart failure to avoid salt substitutes that contain hospitalisation, which was stated to be critical for decision making. Although there was only limited evidence and it was uncertain, the committee felt that the the possible negative impact of salt and fluid restriction programmes on patient experience and quality of life should not be ignored. Committee members agreed that the negative impact on quality of life was consistent with their experience in practice, particularly with older, frailer HF patients who often do not drink sufficient fluid, so any advice to restrict fluid further may risk serious dehydration in some patients. In the absence of any evidence of benefit, the committee decided that patients should not be routinely advised to restrict their salt and fluid consumption. The committee discussed whether it would be beneficial to cross-refer to existing healthy eating, cardiovascular risk management or hypertension NICE guidance in the recommendation, but agreed some of this guidance may, in fact, be dangerous to HF patients (for example, the use of sodium substitutes that contain potassium would put HF patients at higher risk of hyperkalaemia). The change in recommendations in standard drug treatments, will result in triple therapy with ACE inhibiter, beta-blocker and MRA becoming more common, and the risks of hyperkalaemia are significant if people are advised to switch from salt to potassium-containing salt substitutes (particularly if their baseline levels of salt intake are high, leading to high level of substitute consumption). A consensus recommendation was made that they should be avoided in the heart failure population, in the hope that this would facilitate communication between patients and professionals on this point. While healthcare professionals should not routinely advise patients to restrict salt or fluid, there may be specific clinical circumstances where restriction is appropriate. For example, both salt and fluid restriction may be beneficial in very severe or advanced heart failure (though should be used very carefully in older patients), and fluid restriction may be beneficial for hyponatremia. 