Figure 5: Base-case cost-effectiveness plane showing incremental costs and QALYs of each diagnostic strategy Chronic Heart Failure Diagnosing heart failure The disaggregated costs and QALYs from the probabilistic base case analysis are summarised inTable 17, Table 18 and Table 19 below. Table 17: Breakdown of diagnostic costs Diagnostic strategy Mean cost per patient to diagnose Mean cost of echocardiography and specialist clinical assessment per patient Heart failure COPD Myocaridal ischaemia Echo all 106 309 77 235 Table 18: Breakdown of management costs Diagnostic strategy Heart failure COPD Myocardial ischaemia Echo all 379 651 36 Mean QALYs Mean cost Echo all ICER = 5,496 Chronic Heart Failure Diagnosing heart failure Diagnostic strategy Heart failure COPD Myocardial ischaemia Table 19: Breakdown of QALYs Diagnostic strategy Heart failure population Non-heart failure population Multiple sensitivity analyses were undertaken on the base case analysis including adjusting the proportion of HF-REF patients, extending the time to representation to the GP for false negatives, the prognostic differences for those with NT-proBNP levels above and below 400pg/ml, the composition of other conditions in the non-heart failure population, and the cost of NT-proBNP test. None of these led to a change in the optimal strategy. In addition, two scenario analyses usingalternative diagnostic accuracy study data from Verdu et al. 2012 and Zaphiriou et al. 2005 were undertaken. It was considered important that these were also run probabilistically. However, when applying the ordinal logistic regression to the Verdu study data, the mean specificity values did not match the original study values. This was thought to be due to the fact that both 280pg/ml and 125pg/ml have a sensitivity of 1.00 and don t follow an order as such. Therefore the Verdu study was run both probabilistically (using the ordinal logistic regression model data) and deterministically (using the reported study data).


Therefore the Verdu study was run both probabilistically (using the ordinal logistic regression model data) and deterministically (using the reported study data). The average estimates for the sensitivity and specificity values for Zaphiriou were consistent with the original data and were therefore only run probabilistically.The results of these analyses are presented in detail in Appendix O and summarised below. In the scenario analysis based on Verdu et al. 2012 deterministic analysis, 280pg/ml was found to be the most cost effective NT-proBNP threshold. 280pg/ml dominates 400pg/ml with higher mean QALYs and a lower mean cost, and extendedly dominates 125pg/ml. The incremental cost effectiveness ratio of 280pg/ml compared to echo all is 5,952 per QALY gained. In the scenario analysis based on Verdu et al. 2012 400pg/ml probabilistic anlaysis was found to be the most cost effective NT-proBNP threshold. A threshold of 400pg/ml produces both the highest incremental QALYs and the highest incremental cost versus echo all, and has the highest net monetary benefit at 20,000 per QALY and is therefore the most cost effective diagnostic threshold for referral to echocardiography. The cost-effectiveness ratio of 400pg/ml versus 280pg/ml is 9,842. The probability of 400pg/ml being the most cost effective option at 20,000 per QALY is 62%. In the scenario analysis based on Zaphiriou et al. 2005 280pg/ml was found to be the most cost effective. 280pg/ml dominates (more effective and less costly) 400pg/ml. The cost-effectiveness ratio of 280pg/ml versus 125pg/ml is 15,088. The probability of 280pg/ml being the most cost effective option at 20,000 per QALY is 19%. Chronic Heart Failure Diagnosing heart failure 5.1.5.3.3 Limitations and interpretation This analysis suggests that 400pg/ml is the most cost effective threshold for referring patients presenting to primary care with signs and symptoms of heart failure.


Chronic Heart Failure Diagnosing heart failure 5.1.5.3.3 Limitations and interpretation This analysis suggests that 400pg/ml is the most cost effective threshold for referring patients presenting to primary care with signs and symptoms of heart failure. Many uncertainties in the model structure, and assumptions were explored in sensitivity analyses. The primary limitation of this model is that the diagnostic accuracy data was taken from one diagnostic accuracy study. This was due to the significant inconsistency in the results when a meta- analysis of three studies was undertaken. The committee discussed the diagnostic accuracy studies chosen for the meta-analysis at length to agree on chosing one of the studies for the base case analysis. The committee were aware of the limitations of the diagnostic accuracy study by Taylor et al. 2016 chosen for the base case analysis. Particularly, the committee were concerned about the low proportion of HF-REF in the study, as they would have expected the proportion of HF-REF patients presenting to primary care to be higher. The diagnostic accuracy study by Verdu et al. 2012 was not considered to be appropriate for the base case analysis as it was a Spanish study and not considered to be representative of current UK practice, and therefore generalisable to a UK population. The committee discussed that Zaphiriou was a UK study, however was conducted over ten years ago and again is unlikely to represent the current UK population presenting to primary care. Additionally, the criteria for diagnosing HF-PEF patients on echocardiography were not specifically defined as they are today. The study by Taylor et al. 2016 were recruited from 28 practices across central England between 2011 and 2013. Therefore, this population was considered by the committee to be the most representative of current the population presenting to primary care in current UK practice.


Therefore, this population was considered by the committee to be the most representative of current the population presenting to primary care in current UK practice. The committee raised concern about the low proportion of HF-REF patients identified in this study,. 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. The committee acknowledged that the proportion of HF-REF patients in the heart failure population seems to be gradually declining, but still considered the proportion of HF-REF patients in the study to be low. The committee were concerned that this may bias the model results, as were there more clinical benefit to diagnosing heart failure the greater the benefit of earlier detection and therefore a lower NT-proBNP threshold. This effect was demonstrated in one of the sensitivity analyses (SA3): as the proportion of HF-REF in the model was increased, the cost effectiveness of 400pg/ml decreased although the ICER was still well below the 20,000 threshold. The committee also acknowledged that were there clinically effective treatment for HF-PEF patients, then a lower NT-proBNP threshold is likely to be most cost effective. Due to uncertainty around the diagnostic accuracy of the NT-proBNP test, two scenario analyses were undertaken to assess the diagnostic accuracy data and from two other study populations included in the clinical review.


Due to uncertainty around the diagnostic accuracy of the NT-proBNP test, two scenario analyses were undertaken to assess the diagnostic accuracy data and from two other study populations included in the clinical review. A further limitation of the anlaysis is that 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 Chronic Heart Failure Diagnosing heart failure 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 found 400pg/ml to be the most cost effective NT-proBNP threshold, however when run deterministically using the reported study values 280pg/ml was found to be the most cost-effective threshold. This is likely to be due to the fact that this threshold had both the highest sensitivity and highest specificity. The other scenario analyses (Zaphiriou) found 280pg/ml to be the most cost effective NT-proBNP threshold.


The other scenario analyses (Zaphiriou) found 280pg/ml to be the most cost effective NT-proBNP threshold. The committee considered that the change in result from the Zaphiriou study was due to the high proportion of HF-REF patients in the population, supporting their previous hypothesis that the greater the proportion of heart failure likely to see benefits from treatment the more likely a lower threshold will be more cost effective. Further limitations of the analysis are described in the full model write up in Appendix O. Overall, this original analysis was considered to be directly applicable with potentially serious limitations. 5.1.6 Evidence statements Clinical Plasma BNP Five studies explored the diagnostic test accuracy of plasma BNP for diagnosing chronic heart failure. The quality of the included evidence ranged from high to very low. Evidence was downgraded due to risk of bias and imprecision due to the range of the confidence interval around the point estimate. A number of studies were also downgraded due to indirectness as a result of the study population having a prevalence of CHF much higher than that of a representative sample or due to a lack of information regarding the reference standard used in the study. Two high quality studies (n=206 and n=122) reported a high sensitivity of plasma BNP at the thresholds 30pg/ml and 77pg/ml (95 (89-98) and 97 (83-100) respectively) which met the pre specified threshold of 95% set by the committee for possible recommendation. A further single study (n=200) reported a high specificity of 100 (97-100) at the threshold 400pg/ml. The committee placed an emphasis on specificity for the very high rule in threshold of 400pg/ml of which this study met the specificity threshold.


The committee placed an emphasis on specificity for the very high rule in threshold of 400pg/ml of which this study met the specificity threshold. Very low quality evidence was found for plasma BNP at the threshold of 178pg/ml which reported a poor sensitivity of 47 (33- 62). A further single study of very low quality reported an AUC 0.69. This study did not accurately report the threshold at which this accuracy data was collected. Plasma NT-pro BNP Six studies explored the diagnostic test accuracy of NT-pro BNP for diagnosing chronic heart failure. The quality of the included studies ranged from high to very low. Evidence was downgraded due to risk of bias and imprecision due to the range of the confidence interval around the point estimate. A single study was also downgraded due to indirectness as the study failed to include results for people under 50 years of age as the authors felt as though the prevalence of HF in this group was low. A single high quality study (n=220) reported a high sensitivity of 100 (93-100)% at a number of age specific thresholds (<50 years 50 pg/mL, 50-75 years 75 pg/mL, > 75 years 250 pg/mL). The majority of the evidence for NT-pro BNP was low quality. For women 50 years, a high sensitivity of 100 (90- 100) was observed for a threshold of 67pg/ml which met the sensitivity threshold pre specified by the committee for possible recommendation. For the same group at thresholds of 144pg/ml and 220pg/ml the sensitivities were 94 (80-99) and 91 (76-98) respectively. For men 50 years, high sensitivities of 100 (92-100) and 96 (85-99) were observed at thresholds of 76mg/dl and 93mg/dl respectively. Both of which met the threshold set by the committee.


Both of which met the threshold set by the committee. A further single study of high Chronic Heart Failure Diagnosing heart failure quality (n=206) reported a high sensitivity of 96 (90-99) at a threshold of 166pg/ml which again met the threshold set by the committee. At several thresholds, there was sufficient evidence to pool the diagnostic accuracy data. At the thresholds of 125pg/ml, 280pg/ml and 400pg/ml (3 studies; n=826) the sensitivities were 96 (72-100), 89 (41-99) and 79 (42-96) respectively. For the very high rule in threshold of 2000pg/ml the committee placed an emphasis on specificity. A single high quality study (n=200) reported a specificity of 100 (97-100) at this diagnostic threshold which met the threshold set by the committee for possible recommendation. Economic One cost-utility anlaysis found the most cost effective diagnostic strategy for referring people with signs and symptoms of heart failure for echocardiography is to refer those with a history of myocardial infacrtion straight to echocardiography, and otherwise using an NT-proBNP threshold of 400pg/ml. This was compared to the MICE clinical decision rule (upper and lower thresholds), echo all, NT-proBNP threshold 125pg/ml and do nothing. It was cost effective compared to the do nothing strategy (ICER: 4,400 per QALY gained). This was assessed as diretly applicable with potentially serious limitations. An original cost-utility analysis found that 400pg/ml is the most effective NT-proBNP threshold to use for referring people presenting with signs and symptoms of heart failure for echocardiography compared to 280pg/ml, 125pg/ml and referring all patients straight for echocardiography. It was cost effective compared to referring all patients for echocardiography (ICER: 6,076 per QALY gained). This was assessed as directly applicable with potentially serious limitations.


This was assessed as directly applicable with potentially serious limitations. 5.2 BNP and NT-proBNP in diagnosing heart failure in people with atrial fibrillation 5.2.1 Review question: In people with suspected heart failure who also have atrial fibrillation, what thresholds of N-terminus pro-B-type natriuretic peptide (NT-proBNP) and B-type natriuretic peptide (BNP) are most accurate in identifying heart failure (as indicated by the reference standard)? For full details see review protocol in Appendix A. Table 20: Characteristics of review question Population People with atrial fibrillation and suspected heart failure in a community or outpatient setting. Target condition Heart failure Index test(s) NT-proBNP BNP Reference standard(s) A clinical diagnosis based on the opinion of at least one cardiologist, considering symptoms (potentially with some signs) and objective evidence of cardiac dysfunction (either structural or functional). Statistical measures Diagnostic accuracy of BNP and NT-proBNP: 2x2 tables Specificity Sensitivity PPV/NPV ROC curve or Area under Curve Chronic Heart Failure Diagnosing heart failure Study design Single gate studies (cohort/cross-sectional) 5.2.2 Review question: In people with suspected heart failure who also have atrial fibrillation, what is the clinical and cost effectiveness of N-terminus pro-B-type natriuretic peptide (NT-proBNP) compared to B-type natriuretic peptide (BNP), when each is followed by the appropriate patient pathway, in order to improve patient outcomes? For full details see review protocol in Appendix A. Table 21: PICO characteristics of review question Population People with atrial fibrillation and suspected heart failure in a community or outpatient setting. Index diagnostic test + treatment NT-proBNP assay (at any reported threshold) Treatment/next step in pathway: Echocardiography Comparator index diagnostic tests + treatment BNP assay (at any reported threshold) Treatment/next step in pathway: Echocardiography Outcomes Efficacy outcomes: All-cause mortality Quality of life Unplanned hospitalisation Process outcomes: Number of people receiving echocardiography, i.e.


Index diagnostic test + treatment NT-proBNP assay (at any reported threshold) Treatment/next step in pathway: Echocardiography Comparator index diagnostic tests + treatment BNP assay (at any reported threshold) Treatment/next step in pathway: Echocardiography Outcomes Efficacy outcomes: All-cause mortality Quality of life Unplanned hospitalisation Process outcomes: Number of people receiving echocardiography, i.e., including people who may not have needed it such as those with false positive results Repeat testing / additional testing Secondary accuracy outcomes: Sensitivity / specificity and other test accuracy measures Study design Systematic Review RCT 5.2.3 Clinical evidence A search was conducted for single gate studies assessing the diagnostic test accuracy of BNP or NT- proBNP to identify the presence of heart failure (as indicated by the reference standard) in people with atrial fibrillation and suspected heart failure in a community or outpatient setting. A search was also conducted for diagnostic RCTs comparing outcomes in patients tested with BNP versus NT- proBNP. No studies meeting either review protocol were identified. See also the study selection flow chart in Appendix C and excluded studies list in Appendix I. Chronic Heart Failure Diagnosing heart failure NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: 978-1-4731-3093-7 5.2.4 Economic evidence Published literature No relevant economic evaluations were identified. See also the economic article selection flow diagram in Appendix D. New cost-effectiveness analysis Original economic analysis was planned for this question. However, due to a lack of diagnostic accuracy data for this cohort of patients modelling was not undertaken. 5.2.5 Evidence statements Clinical No clinical evidence was identified for this review question. Economic No relevant economic evaluations were identified.


5.2.5 Evidence statements Clinical No clinical evidence was identified for this review question. Economic No relevant economic evaluations were identified. 5.3 BNP and NT-proBNP in diagnosing heart failure in people with chronic kidney disease 5.3.1 Review question: In people with suspected heart failure who also have chronic kidney disease, what thresholds of N-terminus pro-B-type natriuretic peptide (NT-proBNP) and B- type natriuretic peptide (BNP) are most accurate in identifying heart failure (as indicated by the reference standard)? For full details see review protocol in Appendix A. Table 22: Characteristics of review question Population People with chronic kidney disease (excluding patients on dialysis) and suspected heart failure in a community or outpatient setting. Target condition Heart failure Index test(s) NT-proBNP BNP Reference standard(s) A clinical diagnosis based on the opinion of at least one cardiologist, considering symptoms (potentially with some signs) and objective evidence of cardiac dysfunction (either structural or functional). Statistical measures Diagnostic accuracy of BNP and NT-proBNP: 2x2 tables Specificity Sensitivity PPV/NPV ROC curve or Area under Curve Study design Single gate studies (cohort/cross-sectional) Chronic Heart Failure Diagnosing heart failure NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: 978-1-4731-3093-7 5.3.2 Review question: In people with suspected heart failure who also have chronic kidney disease, what is the clinical and cost effectiveness of N-terminus pro-B-type natriuretic peptide (NT-proBNP) compared to B-type natriuretic peptide (BNP), when each is followed by the appropriate patient pathway, in order to improve patient outcomes? For full details see review protocol in Appendix A. Table 23: PICO characteristics of review question Population People with chronic kidney disease (excluding patients on dialysis) and suspected heart failure in a community or outpatient setting.


Table 23: PICO characteristics of review question Population People with chronic kidney disease (excluding patients on dialysis) and suspected heart failure in a community or outpatient setting. Index diagnostic test + treatment NT-proBNP assay (at any reported threshold) Treatment/next step in pathway: Echocardiography Comparator index diagnostic tests + treatment BNP assay (at any reported threshold) Treatment/next step in pathway: Echocardiography Outcomes Efficacy outcomes: All-cause mortality Quality of life Unplanned hospitalisation Process outcomes: Number of people receiving echocardiography, i.e., including people who may not have needed it such as those with false positive results Repeat testing / additional testing Secondary accuracy outcomes: Sensitivity / specificity and other test accuracy measures Study design Systematic Review RCT 5.3.3 Clinical evidence A search was conducted for single gate studies assessing the diagnostic test accuracy of BNP or NT- proBNP to identify the presence of heart failure (as indicated by the reference standard) in people with chronic kidney disease and suspected heart failure in a community or outpatient setting. A search was also conducted for diagnostic RCTs comparing outcomes in patients tested with BNP versus NT-proBNP. One diagnostic accuracy study was included in the review319, 375 ; it is summarised in Table 24 below. The index test was BNP. The study was downgraded for serious indirectness as the reference standard did not fully match the protocol, but was included in the review in the absence of any direct evidence. Evidence from this study is summarised in the clinical evidence summary in Table 25 below. No diagnostic RCTs meeting the protocol were identified. See also the study selection flow chart in Appendix C, sensitivity/specificity forest plots in Appendix E, study evidence tables in Appendix F and excluded studies list in Appendix I.


See also the study selection flow chart in Appendix C, sensitivity/specificity forest plots in Appendix E, study evidence tables in Appendix F and excluded studies list in Appendix I. Table 24: Summary of studies included in the review Study Population Target condition Index test Reference standard Comments Patients with CKD who visited Heart failure BNP HF diagnosed based on history, radiological findings, and Very high risk of bias Serious indirectness Chronic Heart Failure Diagnosing heart failure NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: 978-1-4731-3093-7 Study Population Target condition Index test Reference standard Comments Nephrology Department with respiratory distress. echocardiographic findings, which included clinical symptoms fulfilling Framingham s criteria, LVEF < 50% on echocardiography, and LV diameter at end-diastole greater than 5.5 cm. No mention of whether or not a cardiologist carried out this assessment. Only the results of the subgroup of patients with CKD 3-4 have been extracted and reported in accordance with the protocol. Diagnosing heart failure Chronic Heart Failure NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: Table 25: Clinical evidence summary: diagnostic test accuracy for index test(s) BNP and NT-proBNP Index Test (Population, Target condition, Threshold) No of studies n Quality Sensitivity % (95% CI) Specificity % (95% CI) Positive Predictive Value (PPV) % Negative Predictive Value (NPV) % AUC Plasma BNP BNP CKD stages 3 &4; HF VERY LOWa,b,c due to very serious risk of bias, serious indirectness, serious imprecision The assessment was conducted with an emphasis on test sensitivity as this was identified by the GC as the primary measure in guiding decision making. The GC set the sensitivity threshold of 95% as an acceptable level to recommend a test. (a) Risk of bias was assessed using the QUADAS-2 checklist.


(a) Risk of bias was assessed using the QUADAS-2 checklist. The evidence was downgraded by 1 increment if the majority of studies were rated at high risk of bias, and downgraded by 2 increments if the majority of studies were rated at very high risk of bias (b) Indirectness was assessed using the QUADAS-2 checklist items referring to applicability. The evidence was downgraded by 1 increment if the majority of studies are seriously indirect, and downgraded by 2 increments if the majority of studies are very seriously indirect (c) Imprecision was assessed according to the range of confidence intervals in the individual study. The evidence was downgraded by 1 increment when there was a 20-40% range of the confidence interval around the point estimate, and downgraded by 2 increments when there was a range of >40% Chronic Heart Failure Diagnosing heart failure NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: 978-1-4731-3093-7 5.3.4 Economic evidence Published literature No relevant economic evaluations were identified. See also the economic article selection flow diagram in Appendix D. New cost-effectiveness analysis Original economic analysis was planned for this question. However, due to a lack of diagnostic accuracy data for this cohort of patients modelling was not undertaken. 5.3.5 Evidence statements Clinical One study was identified which reported the diagnostic test accuracy of BNP for diagnosing HF in people with CKD. The study was rated as very low quality due to risk of bias, imprecision due to the range of the confidence interval around the point estimate and indirectness due a lack of information regarding the reference standard.


The study was rated as very low quality due to risk of bias, imprecision due to the range of the confidence interval around the point estimate and indirectness due a lack of information regarding the reference standard. The study reported a sensitivity and specificity of 81 (67-91) and 90 (80-96) respectively which did not meet the pre specified sensitivity of 95 which was set by the committee as a minimum threshold for possible recommendation. Economic No relevant economic evaluations were identified. 5.3.6 Recommendations and link to evidence Recommendations Measure N-terminal pro-B-type natriuretic peptide [NT-proBNP] in people with suspected heart failure. [2018] 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 2 weeks. [2018] 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] 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] 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 Chronic Heart Failure Diagnosing heart failure NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: 978-1-4731-3093-7 might be related to heart failure, discuss with a physician with a subspeciality interest in heart failure.


ISBN: 978-1-4731-3093-7 might be related to heart failure, discuss with a physician with a subspeciality interest in heart failure. [2018] 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 mineralocorticoid 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 ], sepsis, chronic obstructive pulmonary disease, diabetes, or cirrhosis of the liver). [2010, Research recommendations What is the optimal NT-proBNP threshold for the diagnosis of heart failure in people with atrial fibrillation? What are the optimal NT-proBNP thresholds for diagnosing heart failure in people with IIIb, IV or V chronic kidney disease? What is the optimal threshold for NT-proBNP for the diagnosis of heart failure in people with suspected heart failure: 400 ng/ml or 125 ng/ml? Relative values of different outcomes The investigation into BNP and NT-proBNP in the diagnosis of heart failure was approached by considering both clinical effectiveness and diagnostic accuracy. Within each approach, evidence was sought separately for the general suspected heart failure population, as well as people with atrial fibrillation (AF) and suspected heart failure, and people with chronic kidney disease (CKD) and suspected heart failure. The analysis was broken down into three separate chapters for each population, each of which included two separate review questions. The clinical effectiveness reviews aimed to establish whether using NT- proBNP is more effective than using BNP in terms of improving patient outcomes, in each population. The committee agreed that the critical outcomes were all-cause mortality, quality of life and unplanned hospitalisations.


The committee agreed that the critical outcomes were all-cause mortality, quality of life and unplanned hospitalisations. In addition, a number of process outcomes were considered important, these were number of people receiving echocardiography, i.e., including people who may not have needed it such as those with false positive results, and the need for repeat or additional testing. Test accuracy measures would also be extracted if reported in clinical effectiveness studies. In the reviews focussing on the diagnostic accuracy of NT-proBNP and BNP at different thresholds in each population, sensitivity was considered the most critical outcome. This is because failing to diagnose people who have heart failure may delay the initiation of treatment and increase the risk of unplanned hospitalisations and mortality prior to an eventual diagnosis. A minimum threshold of 95% sensitivity was set for recommending the test. Chronic Heart Failure Diagnosing heart failure NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: 978-1-4731-3093-7 Specificity was also considered important in order to avoid unnecessary referrals for echocardiography and specialist clinical assessment where heart failure was highly unlikely. Other accuracy statistics considered important were positive and negative predictive values and area under the curve (AUC), which provides an overall summary of the test performance. No evidence was identified for any of the clinical effectiveness outcomes for any of the reviews, including the process outcomes. Quality of the clinical evidence No RCTs were identified that compared a diagnostic strategy using NT- proBNP with a diagnostic strategy using BNP to establish the impact on patient outcomes, in any of the patient populations. General suspected heart failure population Eight diagnostic accuracy studies were included that evaluated the diagnostic accuracy of NT-proBNP and/or BNP at diagnosing heart failure in the general suspected heart failure population.


General suspected heart failure population Eight diagnostic accuracy studies were included that evaluated the diagnostic accuracy of NT-proBNP and/or BNP at diagnosing heart failure in the general suspected heart failure population. The quality of the evidence ranged from high to very low. Common issues in in the studies were risk of bias due to unclear participant selection methods, high (or not reported) loss to follow up, extended length of time between BNP test and echo, and poor reporting of accuracy results. Some studies were also downgraded for indirectness of the population, where the prevalence of heart failure was much higher than would be expected in the target population indicating the populations may have been from different settings with a potential variation in the distribution of symptoms and severity. Various test thresholds were reported in the included studies. 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.


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.


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.


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.


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.


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.


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.


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.


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.


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.


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.


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.


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 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.


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.


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 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.


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.


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.


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.


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.


[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.


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.


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.


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.


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.


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.


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.


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.


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.


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.


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.


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.


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.


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.