, 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 5.1.4 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 suspected of heart failure in a community or outpatient setting. A search was also conducted for diagnostic RCTs comparing outcomes in people tested with BNP versus NT-proBNP. The search dates were limited to studies published from 2009 onwards, as this review was an update of a review within CG108 (the 2010 CHF guideline). The 2010 update included Mant 2009212 . Mant Chronic Heart Failure Diagnosing heart failure NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: 978-1-4731-3093-7 conducted a meta-analysis of studies investigating the accuracy of BNP and/or NT-proBNP in diagnosing heart failure in a range of settings and populations, and using a range of reference standards. Only those studies from Mant 2009212 that matched the current protocol were included in this review. which used echocardiography as the reference standard, these papers have been excluded within the current update as the committee agreed that echocardiography was not an appropriate reference standard for the diagnosis of heart failure. In total, 8 diagnostic accuracy studies were included in the review79,173,243,245,330, 359,379,380 these are summarised in Table 11 below. Evidence from these studies is summarised in the clinical evidence summary. 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. No diagnostic RCTs meeting the protocol were identified. Table 11: Summary of studies included in the review Study Population Target condition Index test Reference standard Comments People with suspected heart failure Age range: 24- Gender (M:F): UK Heart failure BNP ESC criteria, assessed by panel of three cardiologists People with suspected heart failure Age (mean Gender (M:F): The Netherlands Heart failure BNP NT-proBNP ESC criteria and Heart Failure Society of America assessed by panel of cardiologist, pulmonologist and a GP. Full diagnostic accuracy results not reported. People complaining of dyspnoea of at Heart failure NT-proBNP ESC criteria Results stratified by age and sex. High risk of bias 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 least 2 weeks duration. Not all participants were suspected to have heart failure, and a small number already had a clinical diagnosis of heart failure. Age (median; Gender (M:F): Denmark Serious indirectness people completed the study) People presenting with dyspnoea, or oedema and a working diagnosis of heart failure Age (median; Gender (M:F): Ireland Heart failure BNP Clinical assessment and objective evidence based on echocardiography, assessed by a single cardiologist Very high risk of bias Serious indirectness People with symptoms suggestive of heart failure Age (mean Heart failure NT-proBNP ESC criteria, assessed by a panel of three cardiology specialists 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 Gender (M:F): UK People with suspected heart failure Age (mean Gender (M:F): Spain Heart failure NT-proBNP ESC criteria, assessed by a single cardiologist People with suspected heart failure based on new symptoms Age (median; Gender (M:F): UK Heart failure BNP NT-proBNP ESC criteria, assessed by a single cardiologist People with suspected heart failure based on symptoms and clinical examination Age (mean Gender (M:F): Heart failure BNP NT-proBNP Presence of HF symptoms/signs and either: (a) an EF < 50%, according to the ESC criteria or (b) elevated LV filling pressure. Assessed by one of seven cardiologists. Full diagnostic accuracy results not reported. 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 Switzerland Diagnosing heart failure Chronic Heart Failure NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: Table 12: Clinical evidence summary: diagnostic test accuracy for index test(s) BNP and NT-proBNP Index Test (Threshold) No of studies n Quality Sensitivity % Specificity % Positive Predictive Value (PPV) % Negative Predictive Value (NPV) % AUC Plasma BNP BNP - 100 pg/mL 2e Axsym Centaur BNP - 178 pg/mL 1 105 VERY LOWa,c,d due to serious risk of bias, serious indirectness, serious imprecision BNP - 400 pg/mL 1e Axsym Centaur [Threshold data not accurately reported] due to serious risk of bias, serious indirectness - - - - 0.69 Plasma NT-proBNP NT-pro BNP Age specific thresholds NT-pro BNP Women 50 years due to serious risk of bias, serious indirectness Diagnosing heart failure Chronic Heart Failure NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: Index Test (Threshold) No of studies n Quality Sensitivity % Specificity % Positive Predictive Value (PPV) % Negative Predictive Value (NPV) % AUC NT-pro BNP Men 50 years due to serious risk of bias, serious indirectness NT-pro BNP Men 50 years due to serious risk of bias, serious indirectness NT-pro BNP due to serious inconsistency, serious imprecision Pooledf: Pooledf: NT-pro BNP Women 50 years due to serious risk of bias, serious indirectness NT-pro BNP Men 50 years due to serious risk of bias, serious indirectness NT-pro BNP NT-pro BNP Women 50 years due to serious risk of bias, serious indirectness, serious imprecision NT-pro BNP due to serious inconsistency, very serious imprecision Pooledf: Pooledf: Diagnosing heart failure Chronic Heart Failure NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: Index Test (Threshold) No of studies n Quality Sensitivity % Specificity % Positive Predictive Value (PPV) % Negative Predictive Value (NPV) % AUC NT-pro BNP g VERY LOWb,d due to serious inconsistency, very serious imprecision Pooledf: Pooledf: NT-pro BNP [Threshold data not accurately reported] due to serious risk of bias, serious indirectness - - 0.74 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 (except for the very high rule in thresholds of 400 ng/mL BNP and 2000 ng/mL NT-proBNP where specificity was the emphasis). 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. 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) Inconsistency was assessed by inspection of the sensitivity/specificity plots. Particular attention was placed on the sensitivity threshold(s) set by the GC as an acceptable level to recommend a test. The evidence was: downgraded by 1 increment if the individual study values varied across 2 areas, where values of individual studies are above/below 50%, or above/below the acceptable threshold 95%. downgraded by 2 increments if the individual study values varied across 3 areas, where values of individual studies are above/below 50%, and above/below the acceptable threshold 95%. (c) 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. (d) Imprecision was assessed based on inspection of the confidence region for sensitivity in the diagnostic meta-analysis. 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%. (e) One study reported the results of two BNP tests at this threshold: Axsym & Centaur (reported in that order in the table above). (f) Pooled sensitivity/specificity from diagnostic meta-analysis. (g) Three studies (n= 826) included in pooled analysis (one study only reported NPV and AUC and could not be pooled). Chronic Heart Failure Diagnosing heart failure NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: 978-1-4731-3093-7 5.1.5 Economic evidence 5.1.5.1 Published literature No economic evaluations were identified comparing NT-proBNP thresholds and BNP thresholds. One relevant economic evaluation was identified and included in this review. This is summarised in the health economic profile below (Table 13) and the health economic tables in Appendix G. See also the economic article selection flow diagram in Appendix D. Diagnosing heart failure Chronic Heart Failure NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: Table 13: Health economic evidence profile Study Applicabilit y Limitations Other comments Costs (c) Effects (QALYs) (c) Incrementa l cost (d) Incrementa l effects (d) Cost- effectiveness (d) Uncertainty Monahan [UK] Directly applicable(a ) Potentially serious limitations (b) Cost-utility analysis (health outcome: QALYs) Decision tree used to categorise patients according to diagnostic Population: Primary care patients aged 55years or over presenting to GP with symptoms suggestive of HF recruited across 28 central England practices in the UK. Interventions: 1. MICE clinical decision rule, upper cut-off 2. MICE clinical decision rule, lower cut-off guideline recommended strategy 4. Echo all sensitivity analysis showed that the probability that Intervention 3 is the optimal strategy at 99.9%. remains the most cost effective strategy in a number of scenario analyses. However, when proportion of HF-REF is the most cost effective strategy. When proportion of HF-REF is 100% became the most cost effective strategy. effects) is higher than for 2 vs 3) Diagnosing heart failure Chronic Heart Failure NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: Study Applicabilit y Limitations Other comments Costs (c) Effects (QALYs) (c) Incrementa l cost (d) Incrementa l effects (d) Cost- effectiveness (d) Uncertainty 6. Do nothing Lifetime horizon Abbreviations: ICER: incremental cost-effectiveness ratio; MICE: Male, Infarction, Crepitations, Edema; QALY: quality-adjusted life years; RCT: randomised controlled trial (a) Recent UK study from a NHS and PSS perspective. (b) The analysis used diagnostic accuracy data where the level of NT-proBNP was used as a criterion in determining whether or not the patient had heart failure, therefore introducing incorporation bias to the diagnostic accuracy results. The committee were concerned that the hospitalisation rates applied in the model were overestimated compared to current clinical practice. The model does not report the outcomes for those who do not have heart failure and no assumptions have been reported for this population (c) Incremental cost/QALYs compared to do nothing (intervention 6) (d) Incremental cost/QALYs/cost effectiveness ratio compared to next most effect treatment option that is not ruled out by dominance or extended dominance. An option is ruled out by dominance when another option has higher QALYs and lower costs. An option is ruled out by extended dominance when it has a higher ICER than the next, more effective, option and so this option can never be the most cost effective. ICERs reported rounded to the nearest 100. Chronic Heart Failure Diagnosing heart failure 5.1.5.2 Unit costs The unit costs of BNP and NT-proBNP are provided below to aid committee discussion. Test costs were sought from a range of hospital trusts. Three sites provided unit cost information for BNP, and five sites provided unit cost information for NTproBNP. The average of these are reported below. Table 14: Cost of natriuretic peptide tests Test Unit cost 5.1.5.3 New cost-effectiveness analysis The committee identified this area as a priority for original economic analysis. The committee sought to determine whether natriuretic peptide testing is cost-effective and if so what the most cost- effective diagnostic threshold should to refer for echocardiography and specialist clinical assessment. In recent years the European Society of Cardiology (ESC) has lowered their recommended natriuretic peptide thresholds from 100pg/ml for BNP and 400pg/ml for NT-proBNP to 35pg/ml (BNP) and 125pg/ml respectively, due to concern that previously recommended thresholds were too high. The committee also raised concerns that the threshold recommended in the 2010 Chronic Heart Failure (CHF) guideline (which was in line with the previous ESC thresholds) may be too high, resulting in some patients with heart failure receiving a delayed diagnosis and either re-presenting to primary care at a later date with worsening symptoms or presenting to hospital due to a decompensation. Lowering the threshold could also allow for earlier diagnosis and a better prognosis of these patients. However, the committee also noted that lowering the threshold may greatly increase cost to the NHS due to the greater number of referrals for echocardiography and specialist clinical assessment, many of which are unlikely to lead to a diagnosis of heart failure and therefore the diagnosis of other possible underlying conditions could be delayed. Therefore, original cost-effectiveness modelling was undertaken for this question. A summary is included here. Evidence statements summarising the results of the analysis can be found below. The full analysis can be found in Appendix O. A cost-utility analysis was undertaken to determine the most cost effective threshold level of natriuretic peptide for referral from primary care for echocardiography and specialist clinical assessment. A decision tree with an attached Markov model was used to estimate lifetime quality- adjusted life years (QALYs) and costs from a current UK NHS and personal social services perspective. The analysis was conducted in accordance with the NICE reference case unless otherwise stated including discounting at 3.5% for costs and QALYs. The population entering the model are those presenting to primary care with signs and symptoms of heart failure, including breathlessness, fatigue or ankle swelling and upon clinical examination the general practitioner (GP) suspects that the patient has heart failure. The NICE 2010 Chronic Heart Failure guideline (CG108) recommendations state that patients with a previous history of myocardial infarction (MI) should be referred for echocardiography without a natriuretic peptide test. However, the committee decided that this was no longer appropriate as the definition of MI has changed over time and now includes many scenarios that differ from what was included in the Mant et al. 2009 HTA which formed the basis of the recommendation in the 2010 guideline212 . People who first Chronic Heart Failure Diagnosing heart failure present to an acute emergency setting were excluded as this population is covered by the Acute Heart Failure guideline (CG187). The committee decided to exclude BNP testing from this analysis for the multiple reasons. The most important factor is that the clinical review demonstrates that NT-proBNP has a greater sensitivity over a range of thresholds compared to BNP. The committee emphasised the clinical importance of sensitivity over specificity as the test is used as a rule out for heart failure. Secondly, on a practical level and since the test will be requested mainly by primary care and be sent to the laboratories with inherent delay in transport, NT-proBNP has a longer stability in blood samples than BNP (days versus 4-6 hours), therefore NT-proBNP is more appropriate for testing in primary care. Thirdly, although it is unlikely at this stage for a patient not diagnosed with heart failure to be on Sacubitril Valsartan which interferes with BNP physiology (TA388), natriuretic peptides can also be used for monitoring heart failure patients, therefore 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 new drug. The following NT-proBNP thresholds were chosen as comparators: 400pg/ml 2010 NICE recommended threshold and previous 2012 ESC threshold 125pg/ml 2016 ESC threshold 280pg/ml the optimal threshold found in one study included in clinical review359 , and also lies close to the middle of the other 2 thresholds. As a reference, a diagnostic strategy was also included where no NT-proBNP test is undertaken and all patients with suspected heart failure are referred for echocardiography plus specialist clinical assessment. The model is structured in 2 parts: A decision tree is used to calculate the proportion of the population that fall into one of a number of cohorts according to their underlying condition and test result. The decision tree calculates the proportion of patients who will receive a false negative (FN), false positive (FP), true negative (TN), or true positive (TP) NT-proBNP test result according to the sensitivity, specificity and prevalence data. Patients with a positive test result (levels above the chosen threshold) are then referred for echocardiography and specialist clinical assessment to determine if they have heart failure or not. A Markov model then evaluates patients health and cost outcomes according to their cohort once the initial NT-proBNP test result is determined accounting for waiting times for diagnostic tests. For more detailed explanation of the model structure, please refer to the technical report in Appendix O. A number of assumptions were made when developing the model. The key assumptions are outlined below but are also discussed in more detail in Appendix O: Echocardiography plus specialist clinical assessment is 100% accurate. False negative patients are subsequently correctly diagnosed through 1 of 2 possible channels: A patient is hospitalised due their undiagnosed heart failure and are diagnosed during admission A patient re-presents to their GP within 6 months where the NT-proBNP test is repeated. The committee considered that after this we could assume that their NT- proBNP levels would be over 400pg/ml and therefore the patient would be referred for an echocardiogram and specialist clinical assessment and be correctly diagnosed. Chronic Heart Failure Diagnosing heart failure There is no mortality or morbidity benefit of treatment for HF-PEF patients. Heart failure for those with a NT-proBNP level < 400pg/ml will be less severe compared to those above the threshold and therefore mortality and hospitalisation rates will be lower than those reported in the literature. The cost and disutility consequences of missing these patients is therefore likely to be lower than for those with higher NT-proBNP levels. An individual s NT-proBNP level does not affect the rate of hospitalisation or mortality for other (non-HF) conditions. In heart failure patients with NT-proBNP levels <400pg/ml (treated or untreated) a hospitalisation causes their NT-proBNP levels to permanently be raised over 400pg/ml due to a worsening in their heart failure. Untreated heart failure patients (both HF-REF and HF-PEF) progress to having NT-proBNP levels >400pg/ml after 6 months if they have not already progressed due to hospitalisation. As HF-PEF patients are considered as untreated, all HF-PEF patients therefore progress to higher severity 6 months after first presentation. Treated low severity HF-REF patients who do not experience a hospitalisation progress to having NT-proBNP levels >400pg/ml 5 years after first presentation. The most common alternative diagnoses if a patient does not have heart failure are COPD, myocardial ischaemia, and obesity. The committee considered that the percentage of patients with these conditions would be 35% and 15%, and 50%, respectively. Patients do not have multiple-morbidities. Model inputs were based on clinical evidence identified in the systematic review undertaken for the guideline, supplemented by additional data sources as required. These are described in full in the technical report in Appendix O. All model inputs and assumptions were validated by the guideline committee. Sensitivity analyses were also undertaken in areas of uncertainty to see how robust the model results are. The base-case results are presented below. For a full write up of the model results and sensitivity analyses see Appendix O. In the base-case analysis 400pg/ml was found to be the most cost effective NT-proBNP threshold. Results are summarised below in Table 15 with regards to costs, QALYs and cost-effectiveness (net monetary benefit, and probability of cost effective at 20,000 per QALY threshold), and Table 16 with regards to ranking of the strategies. 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 probability of 400pg/ml being the most cost effective option at 20,000 per QALY is 77%. Table 15: Base case analysis results (probabilistic analysis) Diagnostic strategy Mean per patient NMB at threshold Probability most CE option at 20,000 per QALY Costs QALYs Chronic Heart Failure Diagnosing heart failure Diagnostic strategy Mean per patient NMB at threshold Probability most CE option at 20,000 per QALY Costs QALYs Abbreviations: CE = cost effective; QALYS: quality adjusted life years;.NMB: net monetary benefit. Table 16: Base case analysis ranking results Diagnostic strategy Probability Probability Probability Probability The mean costs and QALYs from the probabilistic analysis have also been presented graphically on the cost-effectiveness plane in Figure 5. The cost-effectiveness ratio of 400pg/ml versus echo all is 5,496. 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). 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. 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. 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. 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 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. 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. 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. 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., 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. 5.3 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. 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. 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. 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 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. [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. 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. 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. Sensitivity analyses using just the data assessed as low risk of bias were conducted, to see if this resolved the inconsistency in the results, but the inconsistency between studies remained. Given the committee s ability to establish the most appropriate test thresholds was limited by the thresholds reported by the included studies, the committee decided to contact study authors seeking additional data at the particular thresholds. The committee decided to limit this request to data on NT-proBNP rather than BNP for the multiple reasons: 1. The clinical review demonstrates that NT-proBNP has a greater sensitivity over a range of thresholds compared to BNP. Chronic Heart Failure Diagnosing heart failure NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: 978-1-4731-3093-7 The committee acknowledged the high sensitivity from one study conducted in 1997, but considered that the heart failure population has changed significantly since this study was conducted with a greater proportion of people with HF-PEF, which on a population level tend to have lower NT-proBNP levels than people with HF-REF . Therefore it is highly uncertain as to whether these results represent the diagnostic accuracy for BNP testing in current practice. Whereas, the majority of the high quality NT-proBNP studies are more recent studies and are more likely to be applicable to current practice. Comparing thresholds between BNP and NT-proBNP is inherently difficult as there is no conversion algorithm between them. However, the Zaphiriou study (high quality study assessing both BNP and NT-proBNP) assessed the recommended industry cut-offs for each test. When comparing this data NT-proBNP thresholds have a consistently higher sensitivity than the BNP thresholds. 2. NT-proBNP has a longer stability in blood samples than BNP (days vs 4-6 hours), therefore NT-proBNP is more appropriate for testing in primary care. 3. Sacubitril Valsartan interferes with BNP physiology (TA388). Natriuretic peptides can also be used for monitoring heart failure patients. Therefore, the committee considered it would be more useful to have NT-proBNP as the baseline peptide in case monitoring was needed in a patient with heart failure who is subsequently treated with this drug. The test thresholds at which data was sought were 125pg/mL, 280 pg/mL and 400 pg/mL. The thresholds were selected based on the data already available in the included studies and to minimise the amount of additional data that needed to be collected, while still allowing for assessment of accuracy at key clinically relevant thresholds used in existing NICE guidelines and other international guidance. The results of the requests for additional data meant that meta-analysis of three studies was possible at each of the above thresholds. Unfortunately, despite all three studies being of high quality and enrolling seemingly similar populations, the pooled data was of very low quality due to serious inconsistency and serious imprecision. For this reason, the committee had little confidence in the pooled estimates of sensitivity and specificity. Suspected heart failure and CKD One diagnostic accuracy study was included that evaluated the diagnostic accuracy of BNP at diagnosing heart failure in a population with CKD and respiratory distress. The reference standard used in the study was unclear and may not have fully matched the protocol, but the study was included in the review in the absence of any direct evidence. The evidence was graded very low quality due to very high risk of bias, serious indirectness and serious imprecision. Risk of bias was very high due to it being unclear how participants were selected, unclear whether the reference standard was applied blind to BNP results, and unclear whether any patients were lost to Chronic Heart Failure Diagnosing heart failure NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: 978-1-4731-3093-7 follow up or missing from the analysis. Only the results of the subgroup of patients with CKD stages G3 to G4 were reported in accordance with the protocol. Suspected heart failure and AF No diagnostic accuracy studies meeting the protocol were identified. Six studies in an acute population or setting, and another study with a target condition of major structural heart disease , were identified. After discussion, the committee agreed that these studies should not be included in the review, despite the absence of any direct evidence, as they would not provide reliable evidence in the population of interest. Trade-off between clinical benefits and harms For the reasons outlined above, the committee s discussion of the clinical evidence focussed on NT-proBNP rather than BNP. General suspected heart failure population BNP and NT-proBNP are used as a triage test, with people whose results are above a certain threshold being referred for echocardiography and specialist clinical assessment, following which a definitive diagnosis can be made. The committee noted that the threshold for referral to echocardiography and specialist clinical assessment in the 2010 guideline was 400 pg/mL. The committee agreed that from a clinical perspective, a lower test threshold would mean fewer patients with heart failure would have their diagnoses missed or delayed, avoiding unnecessary hospitalisations and mortality. However, the committee recognised that if the test threshold was set lower than clinically necessary, many people may be unnecessarily referred for echocardiography and specialist clinical assessment. This could cause unnecessary worry for people and their families, as well as delaying diagnosis of an true underlying condition, and having resource and economic implications (discussed below). The committee considered the clinical evidence with the aim to determine which NT-proBNP threshold was most appropriate for identifying patients who should be referred for echocardiography and specialist clinical assessment, focussing on sensitivity of the test. The pooled sensitivity at a threshold of 125pg/mL was 96% (72%-100%), at a threshold of 280pg/mL was 89% (41%-89%), and at a threshold of 400pg/mL was 79% (42%-96%). The committee noted that the pooled evidence was very low quality due to inconsistency between the included studies and consequently very wide confidence intervals around the meta-analysed data. At a threshold of 400pg/mL, the committee also noted that specificity was likely to be much higher (82% (52%-95%)) compared with specificity at the which would reduce any clinical harms of over-referral. The committee discussed possible reasons for the inconsistency between the study results at length, and considered that the differences in sensitivity and specificity were likely to be due to heterogeneity in the study populations. Chronic Heart Failure Diagnosing heart failure NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: 978-1-4731-3093-7 The committee discussed the differences in setting between the studies as there was one Spanish study, one UK study that recruited patients between 2001 and 2003, and one recent UK study. The committee considered that across these settings the population presenting to primary care with signs and symptoms of heart failure could be different. The committee also noted that the proportions of HF-REF and HF-PEF across these studies were very different, supporting the hypothesis that the study populations were not similar. The committee agreed that based on the clinical data alone, it was not possible to establish the threshold that provided the best overall trade-off between benefits and harms. The committee considered that an economic model was necessary to trade-off the benefits of a lower threshold against the potential increases in cost. For that reason, the most clinically and cost- effective threshold was identified as a priority for economic modelling. Suspected heart failure and CKD The committee discussed the evidence in a population of suspected heart failure and CKD. The committee noted that the only evidence available was for BNP at a threshold of 410 pg/mL. No evidence was available for NT- proBNP at any threshold. The committee considered advice from a renal physician co-opted to the committee and the very low quality evidence, and agreed that there was no convincing rationale to have a different test threshold for people with CKD and suspected heart failure. The committee noted that both advancing age and heart failure are associated with a gradual and progressive decline in renal function. In addition, the progression of heart failure and some treatments for heart failure lead to progressive deterioration of renal function. A decline in renal function is associated with increased fluid retention and a rise in the level of the serum natriuretic peptides, including NT-proBNP, even in the absence of heart failure. There is some evidence that the use of higher NT-proBNP thresholds would improve diagnostic accuracy for heart failure in people with significant deterioration of creatinine clearance. Suspected heart failure and AF No evidence was included in a population with suspected heart failure and AF. The committee agreed that in the absence of any evidence, there was no convincing rationale to have a different test threshold for people with AF and suspected heart failure. However the committee noted that atrial fibrillation can raise the level of serum natriuretic peptides, including NT-proBNP, even in the absence of heart failure. This is complicated further in heart failure with preserved ejection fraction, in which 2 echocardiographic diagnostic criteria become unreliable (the left atrial volume and the tissue Doppler imaging assessment of diastolic function). These factors contribute to the complexity of the diagnosis and have a potential impact on the usual thresholds for NT-proBNP in people who have atrial fibrillation. This has been recognised in several ongoing randomised controlled trials of heart failure, Chronic Heart Failure Diagnosing heart failure NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: 978-1-4731-3093-7 which are using higher NT-proBNP thresholds for the diagnosis of heart failure in people with atrial fibrillation. Trade-off between net clinical effects and costs No economic evaluations were identified comparing NT-proBNP thresholds and BNP thresholds. Unit costs of BNP and NT-proBNP were presented to the committee for consideration. As previously discussed in the quality of the clinical evidence section above, the committee agreed that NT-proBNP was a better test than BNP. They were therefore reassured that that the average cost difference between the two tests was only around 4. They discussed that there was some uncertainty in these estimates due to the limited sample size, although there was some overlap in costs where NT-proBNP was less expensive than BNP. The committee also mentioned that the purchase of new equipment for analysing NT-proBNP is not necessary as there are kits available for all main systems. Therefore the committee did not consider that there would be further cost implications beyond those reflected in the costs above. The committee were also aware that NT-proBNP is due to come off patent in the next couple of years and therefore expect the cost of NT-proBNP to decrease. Furthermore, the committee noted that as NT-proBNP overall had a higher sensitivity compared to BNP, there is potential for some offset of the current higher cost of NT-proBNP due to reduced number of false negative results for people being tested with NT-proBNP compared to BNP. A false negative result would either require re-testing, or could result in hospitalisation if an acute episode occurred prior to diagnosis. They therefore considered that taking into consideration the above that NT- proBNP and that the majority of labs now run NT-proBNP, some of them teaching hospitals which receive a high volume of tests, that only recommending NT-proBNP would not have a substantial resource impact for the NHS in England. One economic analysis was identified for this review assessing NT-proBNP thresholds. 