(b) Imprecision cannot assessed due to reporting of median and inter-quartile range. Table 31: Clinical evidence summary: Fluid restriction programme versus advice on fluid restriction for heart failure Outcomes No of Participant s (studies) Follow up Quality of the evidence (GRADE) Relative effect Anticipated absolute effects Time frame is 6 months Risk with Advice on fluid restriction Risk difference with Programme for fluid restriction (95% CI) Quality of Life EQ5D - visual analogue scale. Scale from: 0 to 100. High is better. VERY LOWa,b,c due to risk of bias, indirectness, imprecision The mean quality of life at 6 months in the control groups was The mean quality of life at 6 months in the intervention groups was (24.96 lower to 7.6 higher) Oedema Congestion score. Scale from: 0 to 5. High is worse. VERY LOWa,c,d due to risk of bias, indirectness, imprecision The mean congestion sore in the control groups was The mean congestion score in the intervention groups was (1.1 lower to 1.24 higher) Treating Heart Failure Chronic Heart Failure NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: (a) Downgraded by 1 increment if the majority of the evidence was at high risk of bias, and downgraded by 2 increments if the majority of the evidence was at very high risk of bias. (b) Downgraded by 1 or 2 increments because the majority of evidence was from an indirect population (people were already enrolled in a intrathoracic impedance monitoring device trial). (c) Downgraded by 1 increment if the confidence interval crossed 1 MID or by 2 increments if the confidence interval crossed both MIDs. (d) Downgraded by 2 increments because the majority of evidence was from an indirect population (people were already enrolled in a intrathoracic impedance monitoring device trial) and was looking at congestion, which includes things other than oedema (the protocol outcome). Chronic Heart Failure Beta-blockers in heart failure and concomitant atrial fibrillation NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: 978-1-4731-3093-7 6.1.1.4 Economic evidence Published literature No relevant health economic studies were identified. See also the health economic study selection flow chart in Appendix D. 6.1.1.5 Evidence statements Clinical Two studies were identified for inclusion within the review. The quality of the evidence ranged from low to very low due to risk of bias, imprecision due to wide confidence intervals surrounding the effect estimate and indirectness of the study population. One study including 38 people with HFREF or HFPEF on optimally tolerated medical therapy with normal serum sodium compared a moderate salt intake (2300mg/day sodium) with low salt intake (1500mg/day sodium). In reality, participants in either arm reduced salt to a relatively similar extent (median difference 63mg/day). The outcome QoL (as measured by the KCCQ) showed a clinically important reduction in quality of life with the low sodium diet. The low sodium diet also showed no clinical effect on renal function. Imprecision could not be assessed for these outcomes as the study reported the results as median and interquartile range. The results of this pilot study were used to inform the larger SODIUM-HF trial, which is currently recruiting The second study which included 25 people, who were already enrolled in a trial of an intrathoracic impedance monitoring device and who had been hospitalised within the previous 6 months, compared an education programme providing support to maintain fluid restriction at 1.5-2L (intervention) with general support unrelated to the fluid restriction (control). The outcome QoL (as measured by the EQ5D VAS) showed a clinically important reduction in quality of life with the fluid restriction programme (associated with wide confidence intervals around the effect estimate). The fluid restriction programme had no clinical effect on the outcome oedema (again associated with wide confidence). Economic No relevant economic evaluations were identified. Chronic Heart Failure Beta-blockers in heart failure and concomitant atrial fibrillation NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: 978-1-4731-3093-7 6.1.1.6 Recommendations and link to evidence Recommendations Do not routinely advise people with heart failure to restrict their sodium or fluid consumption. Ask about salt and fluid consumption and, if needed, advise as follows: restricting fluids for people with dilutional hyponatraemia reducing intake for people with high levels of salt and/or fluid consumption. Continue to review the need to restrict salt or fluid. [2018] Advise people with heart failure to avoid salt substitutes that contain Relative values of different outcomes The committee considered quality of life and unplanned hospitalisation to be the critical outcomes for this review. Data on all-cause hospitalisation were considered preferable to data limited to heart failure (HF) related hospitalisations, as such data take into account the broader unintended consequences of the interventions (for example, an increase in hospitalisations due to adverse events). Change in appetite, weight and oedema, as well as impact on renal function and hyperkalaemia, were considered to be important for decision-making. For patients with low sodium levels at baseline, change in serum sodium level was also considered an important outcome. While serum sodium level is often reported as an outcome in sodium restriction studies, it was not considered clinically relevant for HF patients with normal baseline sodium. Also, while studies often report actual reductions in sodium and/or fluid intake after the delivery of a restriction intervention, again this was not considered to be a key clinically important outcome. Given the nature of the interventions in this review, mortality was not included as an outcome. The committee was more interested in the impact on symptoms and hospitalisation. For the comparison of low sodium diet programme versus moderate sodium diet programme, the only evidence reported in a complete format enabling analysis was on quality of life and renal function. For the comparison of fluid restriction programme versus advice on fluid restriction, the only evidence was on quality of life and oedema. There was no evidence for any comparison on hospitalisation, change in weight, change in sodium level for patients with low baseline sodium, or hyperkalaemia. Quality of the clinical evidence The committee noted the paucity of evidence in this area, which was limited to 2 very small pilot studies looking at different comparisons. Low sodium programme versus moderate sodium programme: The evidence for both quality of life and renal function was graded low quality due to risk of bias (selection bias and performance bias). Imprecision could not be formally assessed due to reporting of the outcomes as median and interquartile range (IQR), but the committee noted the small size of the study. Fluid restriction programme versus general advice on fluid restriction: Chronic Heart Failure Beta-blockers in heart failure and concomitant atrial fibrillation NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: 978-1-4731-3093-7 Recommendations Do not routinely advise people with heart failure to restrict their sodium or fluid consumption. Ask about salt and fluid consumption and, if needed, advise as follows: restricting fluids for people with dilutional hyponatraemia reducing intake for people with high levels of salt and/or fluid consumption. Continue to review the need to restrict salt or fluid. [2018] Advise people with heart failure to avoid salt substitutes that contain The evidence for quality of life was graded very low quality due to risk of bias (selection bias and performance bias), indirectness (indirect population) and imprecision. The evidence for oedema was graded very low quality due to risk of bias (selection bias, performance bias and measurement bias), indirectness (indirect population and outcome) and imprecision. Other comparisons: There was no evidence on any of the following comparisons: Salt restriction programme versus general advice to restrict salt. Salt restriction programme versus no restriction/no advice. Fluid restriction programme versus no restriction/no advice. Trade-off between clinical benefits and harms The committee discussed the evidence for a low sodium programme compared with a moderate sodium programme, which was based on a single small trial. The committee noted that patients median intake of sodium at both baseline and at the end of the study was similar between the 2 groups (at the end of the study, low sodium 1398 mg/day, moderate sodium 1461 mg/day). Notwithstanding the similar reduction in sodium consumption in each group, quality of life in the low sodium group was lower than in the moderate sodium group. This suggested that the restrictive nature of the programme itself, independent of the actual reduction in sodium consumption achieved, had a negative impact on quality of life. There was no clinically important difference in renal function (measured by creatinine) between the low and moderate sodium programmes, which was to be expected given the similarity in the actual sodium levels consumed. The committee also discussed the evidence for a fluid restriction programme compared with general advice to restrict fluid, which again was based on a single small trial. The fluid restriction programme did appear to have a clinically important impact on actual levels of fluid consumed in each group, with the general advice group consuming 300mL more per day on average than the restriction programme group. Quality of life was lower in the restriction programme group than in the general advice group which was agreed to represent a clinically important reduction. The restriction programme did not appear to have any impact on oedema measured via a congestion score , though the committee placed little weight on this scale that has not been validated. In weighing up the possible benefits and harms of salt and fluid restriction, the committee acknowledged the quality of the evidence, which ranged from low to very low, and the uncertainty around the effect estimates. The absence of evidence on most of the outcomes was noted, in particular Chronic Heart Failure Beta-blockers in heart failure and concomitant atrial fibrillation NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: 978-1-4731-3093-7 Recommendations Do not routinely advise people with heart failure to restrict their sodium or fluid consumption. Ask about salt and fluid consumption and, if needed, advise as follows: restricting fluids for people with dilutional hyponatraemia reducing intake for people with high levels of salt and/or fluid consumption. Continue to review the need to restrict salt or fluid. [2018] Advise people with heart failure to avoid salt substitutes that contain hospitalisation, which was stated to be critical for decision making. Although there was only limited evidence and it was uncertain, the committee felt that the the possible negative impact of salt and fluid restriction programmes on patient experience and quality of life should not be ignored. Committee members agreed that the negative impact on quality of life was consistent with their experience in practice, particularly with older, frailer HF patients who often do not drink sufficient fluid, so any advice to restrict fluid further may risk serious dehydration in some patients. In the absence of any evidence of benefit, the committee decided that patients should not be routinely advised to restrict their salt and fluid consumption. The committee discussed whether it would be beneficial to cross-refer to existing healthy eating, cardiovascular risk management or hypertension NICE guidance in the recommendation, but agreed some of this guidance may, in fact, be dangerous to HF patients (for example, the use of sodium substitutes that contain potassium would put HF patients at higher risk of hyperkalaemia). The change in recommendations in standard drug treatments, will result in triple therapy with ACE inhibiter, beta-blocker and MRA becoming more common, and the risks of hyperkalaemia are significant if people are advised to switch from salt to potassium-containing salt substitutes (particularly if their baseline levels of salt intake are high, leading to high level of substitute consumption). A consensus recommendation was made that they should be avoided in the heart failure population, in the hope that this would facilitate communication between patients and professionals on this point. While healthcare professionals should not routinely advise patients to restrict salt or fluid, there may be specific clinical circumstances where restriction is appropriate. For example, both salt and fluid restriction may be beneficial in very severe or advanced heart failure (though should be used very carefully in older patients), and fluid restriction may be beneficial for hyponatremia. In addition, for patients consuming large quantities of sodium or fluid, reduction to normal levels of consumption may be beneficial (especially for hypertensive patients consuming a large amount of salt). Healthcare professionals should ask their patients about their levels of salt and fluid consumption in order to provide appropriate advice, and this should not be open-ended, but there should be opportunities to review whether the strategy was effective for the individual. The committee recognised the uncertainty in the evidence and the possibility Chronic Heart Failure Beta-blockers in heart failure and concomitant atrial fibrillation NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: 978-1-4731-3093-7 Recommendations Do not routinely advise people with heart failure to restrict their sodium or fluid consumption. Ask about salt and fluid consumption and, if needed, advise as follows: restricting fluids for people with dilutional hyponatraemia reducing intake for people with high levels of salt and/or fluid consumption. Continue to review the need to restrict salt or fluid. [2018] Advise people with heart failure to avoid salt substitutes that contain that future research may conclude that salt and/or fluid restriction is beneficial. In particular, the large RCT currently underway comparing a low sodium diet versus usual care (general advice to limit salt) (SODIUM-HF346 ). Given the importance of this issue to patients, the potential for significant negative impact on quality of life, and the absence of any randomised evidence of benefit, a do not routinely offer recommendation was made, acknowledging that this review will be updated in the future if new evidence arises to change the recommendation. The need for further trials of fluid restriction was considered either of advice about restriction, or based on actual restriction values While some further guidance on overall efficacy would clarify the population benefit, further research would be difficult to carry out, and would not change the conclusion that advice should be given on an individual basis according to intake and fluid balance in the individual. Trade-off between net clinical effects and costs No previously published economic evaluations were identified assessing the cost effectiveness of salt and/or fluid restriction programmes in people with heart failure. As described in the trade of between clinical benefits and harms above, the committee considered that the harms of salt and fluid restriction, particularly in terms of quality of life, outweighed the benefits in most circumstances, and therefore decided that salt and fluid restriction should not be routinely offered. Current practice is highly variable, but many health professionals do advise people with heart failure to restrict their salt and fluid intake. The committee therefore considered that implementing a do not routinely offer recommendation might improve quality of life for current heart failure patients and could also be cost saving due to reduced appointment time as most people will no longer require information and advice on how to restrict their intake of salt and fluid. Other considerations The committee are aware of a recently published large observational study104 (with propensity matching on plausible confounders) on the impact of dietary sodium restriction on heart failure outcomes. The study included patients in an unrelated trial, categorising them into sodium restricted and unrestricted groups based on their sodium intake prior to death or hospitalisation. This study found that sodium restriction was associated with a statistically significant and clinically important increase in the risk of death or HF hospitalisation, and was not associated with improved quality of life, physical functioning, 6-min walk distance, or symptoms. The study concluded that in symptomatic patients with chronic HF, sodium restriction may have a detrimental impact on outcome . While a randomised trial is needed to definitely address the role of sodium restriction in heart failure, the Chronic Heart Failure Beta-blockers in heart failure and concomitant atrial fibrillation NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: 978-1-4731-3093-7 Recommendations Do not routinely advise people with heart failure to restrict their sodium or fluid consumption. Ask about salt and fluid consumption and, if needed, advise as follows: restricting fluids for people with dilutional hyponatraemia reducing intake for people with high levels of salt and/or fluid consumption. Continue to review the need to restrict salt or fluid. [2018] Advise people with heart failure to avoid salt substitutes that contain committee considered that this non-randomised evidence provided further support for its recommendation to not routinely offer sodium restriction until such randomised evidence is available. Current practice regarding salt and fluid restriction is highly variable, with some healthcare professionals advising patients to restrict intake and others not. The lay members indicated that salt and fluid restriction is the subject of much discussion in patient groups. Given it is one of a limited number of opportunities for self-management in HF, some patients may feel that it enables them to exercise some personal control over the course of what is an unpredictable and serious long term condition. However, the variation in practice and advice has led to confusion and uncertainty among patients about whether salt and fluid restriction is necessary or beneficial. The recommendation to not routinely advise salt and fluid restriction should operate to reduce variation in practice across the country, and ensure that any discussions between patients and healthcare professionals start from a consistent position. Where patients are currently attempting to restrict salt and/or fluid without specific clinical circumstances for doing so, healthcare professionals should discuss the uncertainty in the evidence with those patients as part of shared decision making. Patients may have been asked to restrict fluid intake during acute episodes, and not given information on when this is no longer indicated. The decision on whether to continue to restrict salt and/or fluid should take into account patient preferences. 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 6.1.2 Recommendations on lifestyle 6.1.2.1 Smoking and alcohol See NICE s guidance on smoking and tobacco and alcohol. 6.1.2.2 Salt and fluid restrictions 18.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] 19.Advise people with heart failure to avoid salt substitutes that contain potassium. [2018] 20.Offer people with heart failure an annual vaccination against influenza. [2003] 21.Offer people with heart failure vaccination against pneumococcal disease (only required 6.1.2.4 Contraception and pregnancy 22.In women of childbearing potential who have heart failure, contraception and pregnancy should be discussed. If pregnancy is being considered or occurs, specialist advice should be sought. Subsequently, specialist care should be shared between the cardiologist and 6.1.2.5 Air travel 23.Air travel will be possible for the majority of people with heart failure, depending on their clinical condition at the time of travel. [2003] 24.Large Goods Vehicle and Passenger Carrying Vehicle licence: physicians should be up to date with the latest Driver and Vehicle Licensing Agency guidelines. Check the website for regular updates [2003] 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 6.2 Pharmacological treatment 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 drugs to include in the update of the guideline was made following consultation of the scope. Drugs reviewed in the update included: Mineralocorticoid receptor antagonists Beta-blockers in people with with CHF and atrial fibrillation Treating heart failure in people with chronic kidney disease Iron supplementation As a consequence of updating the mineralocorticoid evidence, and the need to incorporate new NICE technology appraisal guidance for sacubitril valsartan and ivabradine within the treatment pathway, the initiation and sequencing of pharmacological therapies was considered and revised by the guideline committee. The following agents were not considered in the update. For more information: Refer to Appendix R, the 2010 Guideline: Angiotensin converting enzyme inhibitors (ACEI) Beta-blockers Hydralazine and nitrate combination Angiotensin-II receptor antagonists Refer to Appendix R, the 2003 Guideline Amiodarone Anticoagulants Inotropic agents Calcium channel blockers Diuretics Digoxin 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 6.2.2 Beta-blockers in people with heart failure and atrial fibrillation Since the early 1990s, there have been several randomised controlled trials which clearly demonstrated that beta-blockers can significantly reduce the morbidity and mortality of patients with HFREF. Beta-blockers have been recommended in NICE heart failure guidance since 2003.The prescription of beta-blockers in heart failure has become more common as recorded in successive large observational studies such as those from the UK National Heart Failure audit. This development has been associated with a progressive decline in the reported mortality of patients with HFREF over the past 10 years or so. However, in 2014 a high-profile individual patient data meta-analysis was published, which examined the role of beta-blockers in a specific sub-population of HREF patients who also have atrial fibrillation (AF). This paper failed to demonstrate the same mortality benefit of beta-blockers as had previously been seen in the overall HFREF population. Therefore it became important to review the guidance for the use of beta-blockers in this sub-population of patients. 6.2.2.2 Review question: What is the clinical and cost effectiveness of beta-blockers in the management of chronic heart failure in people with heart failure with reduced ejection fraction (HFREF) and atrial fibrillation? For full details see review protocol in Appendix A. Table 32: PICO characteristics of review question Population People diagnosed with HFREF with concomitant atrial fibrillation. Intervention(s) Beta-blockers: bisoprolol (up to 10mg once daily) carvedilol (up to 50mg twice daily) nebivolol (licensed in stable mild to moderate heart failure in people over 70 years) (up to 10mg once daily) metoprolol CR/XL(up to 200 mg once daily) In addition to usual care in CHF. Comparison(s) Placebo In addition to usual care in CHF. Outcomes CRITICAL All-cause mortality Health-related quality of life Unplanned hospitalisation IMPORTANT Other adverse events (stroke, bradycardia, hypotension) Improvement of NYHA class Study design Systematic reviews of RCTs RCTs 6.2.2.3 Clinical evidence A search was conducted for randomised trials comparing the effectiveness of beta-blockers versus placebo in addition to usual care in people with chronic heart failure and atrial fibrillation. One study 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 was included in the review;181 it is summarised in Table 33 below. 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. is an individual patient data (IPD) meta-analysis which compiled subgroup data from 10 major beta-blocker mortality trials. The meta-analysis included 4 studies comparing carvedilol and placebo; 2 studies comparing metoprolol and placebo; 2 studies comparing bisoprolol and placebo; 1 study comparing nebivolol and placebo; and 1 study comparing bucindolol and placebo. The committee discussed the studies included within the IPD and agreed that: Bucindolol is not licensed for any indication in the UK (it does not have marketing authorisation), nor is it currently used in practice for HF-REF. This is due to a lack of trial data suggesting prognostic benefit of bucindolol in patients with HF-REF, with respect to all-cause mortality. In addition to this Bucindolol demonstrates pharmacogenetic differences in different ethnicities. Based on this, the committee concluded that results of trials using this beta-blocker should be excluded. Although the form of metoprolol (metroprolol succinate) used in MERIT-HF349 is not available in the UK, an alternative form metoprolol tartrate is available and licensed for use in clinical practice (though it is not licensed for heart failure). The committee agreed that the 2 forms were likely to have a similar overall effect despite difference in pharmacokinetic properties (metoprolol succinate is longer acting and more bioavailable than tartrate). Overall, the committee agreed that studies using this beta-blocker were still considered relevant and should be included. For the outcome all-cause mortality, the IPD presented the results of the individual trials separately. This allowed us to exclude the BEST trial36 , which used bucindolol, from our meta-analysis. For the other reported outcomes (heart-failure related hospitalisation and non-fatal stroke), only an overall summary statistic was reported in the IPD. For this reason, we contacted the study authors and obtained the overall effect estimates for these outcomes with the BEST trial excluded from the analysis (this was a pre-specified sensitivity analysis conducted by the authors that was not reported in the main paper). The data presented and analysed in this review therefore excludes the BEST trial. Data could not be obtained for the studies CORPENICUS251 (unable to obtain full text paper) and (no extractable data). However data for these 2 studies was included in the IPD meta- analysis as published by Kotecha181 . Table 33: Summary of studies included in the review Study Intervention and comparison Population Outcomes Comments Kotecha Beta blockers (n = Bucindolol; bisoprolol; carvedilol; metoprolol; and, nebivolol Placebo (n = 1543) Matching placebo was reported in 4 included trials: ANZ; BEST; CIBIS I; and, SENIORS. Age, median years (IQR): 69 (61 74). % Female: beta-blocker: LVEF, median (IQR): 0.33). All-cause mortality (time- to-event) First heart- failure-related hospital admission (time- to-event) Non-fatal stroke (time-to-event) All outcomes reported at 3.3 years Studies included in the IPD: - ANZ - BEST - CAPRICORN - CIBIS I - CIBIS II - CORPENICUS - MDC - MERIT-HF - US-HF - SENIORS Pre-defined sensitivity analysis excluding the results of the BEST trial (bucindolol vs placebo) 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 Study Intervention and comparison Population Outcomes Comments NYHA III: beta-blocker: Only unconfounded head-to-head trials with recruitment of more than 300 people and a planned follow-up of more than 6 months were eligible for inclusion in the IPD. was conducted by the authors of this IPD. These results were obtained directly from the authors and have been extracted in this review. Table 34: Summary of studies included in the Kotecha 2014 IPD* Study Intervention and comparison Inclusion criteria Exclusion criteria Bollano ANZ Carvedilol (n=207) Placebo (n=208) Chronic stable heart failure due to ischaemic heart disease (defined as a documented history of myocardial infarction, typical angina, an exercise electrocardiogram positive for ischaemia, or angiographic evidence of coronary disease) LVEF by radionuclide ventriculography of less current NYHA class II or III, or previous class II-IV current NYHA class IV heart rate below 50 bpm; sick sinus syndrome; second degree or third- degree heart block; blood pressure below 90 mmHg systolic or above 160/100 mm Hg; treadmill exercise duration less than 2 min or more than 18 min (modified Naughton protocol); coronary event or procedure (myocardial infarction, unstable angina, coronary- artery bypass surgery, or coronary angioplasty) within the previous 4 weeks; primary myocardial or valvular disease; current treatment with a - blocker, -agonist, or verapamil; insulin-dependent diabetes mellitus; chronic obstructive airways disease; hepatic disease (serum 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 Study Intervention and comparison Inclusion criteria Exclusion criteria aminotransferase above three times normal); renal impairment (serum creatinine >250 mol/L); or any other life-threatening non-cardiac disease. , Lechat CIBIS II Bisoprolol (n=1327) Placebo (n=1320) Ambulatory aged 18 80 years LVEF, measured within 6 weeks of randomisation, of 35% or less NYHA class III and IV diagnosis of chronic heart failure, made at least 3 months previously , with clinical stability during the preceding 6 weeks for heart failure or 3 months for acute myocardial infarction or unstable angina. Cardiovascular therapy had to have been unchanged in the 2 weeks before randomisation treatment with ACEI (if tolerated); use of digoxin was optional uncontrolled hypertension, myocardial infarction or unstable angina pectoris in the previous 3 months, percutaneous transluminal coronary angioplasty or coronary artery bypass graft in the previous 6 months previous or scheduled heart transplant, atrioventricular block greater than first degree without a chronically implanted pacemaker, resting heart rate of less than 60 bpm, systolic blood pressure at rest of less than 100 mm Hg, renal failure (serum creatinine 300 mol/L), reversible obstructive lung disease pre-exisintg or planned therapy with - adrenoreceptor blockers Dargie CAPRICORN Carvedilol (n = 975) placebo (n=984) centres People aged 18 years or older stable, definite myocardial infarction occurring 3 21 days before randomization LVEF 40% by two- dimensional echocardiography or by radionuclide or contrast ventriculography, or wall- motion-score index of 1.3 or less; receipt of concurrent treatment with ACEI for at least 48 hours and stable dose for more than 24 h unless there was intolerance of ACEI people with heart failure appropriately treated with diuretics and ACEI during the acute phase, Unstable angina, hypotension (systolic blood pressure <90 mm Hg), uncontrolled hypertension, bradycardia (heart rate <60 bpm), and unstable insulin-dependent diabetes mellitus People with a continuing need for -blockers for any indication other than heart failure were excluded, as were those requiring ongoing therapy with inhaled 2- agonists or steroids. People who continue to require intravenous diuretics or inotropes, or those with uncontrolled heart failure Domanski Bisoprolol (n = 320) Aged between 18 and 75 years heart failure due to hypertrophic or restrictive 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 Study Intervention and comparison Inclusion criteria Exclusion criteria CIBIS I Placebo (n=321) chronic heart failure with or without sinus rhythm, and dyspnea or fatigue corresponding to NYHA class III or IV people had to be ambulatory and not awaiting cardiac transplantation mandatory background medication was diuretic and vasodilator therapy. LVEF < 40% (isotopic or angiographic performed within 4 weeks before randomization) aetiology of heart failure was defined as (1) idiopathic dilated cardiomyopathy when no known cause of cardiomyopathy could be found, (2) ischaemia when typical history of coronary artery disease, history of myocardial infarction, or presence of significant (70%) coronary artery stenoses had been hypertension when history of established hypertension or antihypertensive therapy was present, and (4)valvular heart disease; people with primary valvular disease (that had to be surgically repaired for at least 6 months) and people with nonischaemic dilated cardiomyopathy associated with a significant mitral valve insufficiency clinical stability, defined as the absence of any episode of heart failure decompensation during the 6 week period before entry into the trial and the absence of major modification of heart failure therapy in the previous 3 weeks. cardiomyopathy with predominant left ventricular diastolic dysfunction, heart failure secondary to mitral or aortic valve disease that was not surgically repaired or had been surgically repaired for less than 6 months, patient with coronary heart disease awaiting bypass surgery or a recent history of myocardial infarction (less than 3 months) people already on a heart transplantation waiting list nonambulatory patient with disabling permanent dyspnea at rest insulin-dependant diabetes asthma renal insufficiency (serum creatinine >300 mol/L) hypothyroidism or hyperthyroidism people whose life expectancy was shortened by a severe illness such as malignant disease resting heart rate <65 bpm or systolic blood pressure < 100 mm Hg or >160 mm Hg immediately before randomization. Flather Nebivolol (n=1067) Aged 70 years new drug therapy for heart 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 Study Intervention and comparison Inclusion criteria Exclusion criteria , Mulder SENIORS Placebo (n=1061) clinical history of chronic heart failure with at least one of the following features: documented hospital admission within the previous 12 months with a discharge diagnosis of congestive heart failure or documented LVEF 35% within the previous 6 months failure in the 6 weeks prior to randomization a change in cardiovascular drug therapy in the 2 weeks prior to randomization heart failure due primarily to uncorrected valvular heart disease contraindication or previous intolerance to beta-blockers (e.g. heart rate < 60 bpm or systolic blood pressure <90 mm Hg) current use of beta-blockers significant hepatic or renal dysfunction cerebrovascular accidents within the previous 3 months being on a waiting list for percutaneous coronary intervention or cardiac surgery or other major medical conditions that may have reduced survival during the period of the study , Joglar US-HF Carvedilol (n=696) Placebo (n=398) Multicentre with varying treatment protocols. Symptomatic heart failure for at least three months ejection fraction 35%, despite at least two months of treatment with diuretics and an ACE (if tolerated) A major cardiovascular event or a major surgical procedure within three months of entry into the study; uncorrected, primary valvular disease; active myocarditis; sustained ventricular tachycardia or advanced heart block not controlled by antiarrhythmic intervention or a pacemaker; systolic blood pressure of more than 160 or less than 85 mm Hg or diastolic blood pressure of more than 100 mm Hg; a heart rate of less than 68 beats per minute; clinically important hepatic or renal disease; or any condition other than heart failure that could limit exercise or survival. people receiving calcium- channel blockers, - or - adrenergic agonists or class IC 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 Study Intervention and comparison Inclusion criteria Exclusion criteria or III antiarrhythmic agents were not enrolled. people already receiving - blockers Waagstein MDC Metoprolol Placebo (n=189) Symptomatic dilated cardiomyopathy and ejection fraction below aged 16-75 years people were required to have achieved a state of compensated heart failure by means of conventional heart failure treatment, which could include digitalis, diuretics, ACEI and nitrates. Systolic BP of 90 mm Hg and heart rate of 45 bpm treatment with -blockers , calcium channel blockers, inotropic agents (except digitalis), or high doses of tricyclic antidepressant drugs significant coronary artery disease shown by angiography ( > 50% obstruction of a major epicardial vessel) clinical or histological signs of ongoing myocarditis, other life threatening diseases chronic obstructive lung disease requiring 2-agonists excessive alcohol consumption (> 700 g per week) *Data could not be directly extracted for: CORPENICUS251 which could not be accessed and MERIT- . Treating Heart Failure Chronic Heart Failure NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: Table 35: Clinical evidence summary: beta-blocker versus placebo Outcomes No of Participants (studies) Follow up Quality of the evidence (GRADE) Relative effect Anticipated absolute effects Risk with placebo Risk difference with beta-blockers (95% CI) All-cause mortality 2666 MODERATEb due to imprecision (from 22 fewer to 32 more) First heart-failure related hospital admission MODERATEa due to indirectness (from 32 fewer to 16 more) Fatal and non-fatal stroke at 3.3 years LOWb due to imprecision c c (a) Downgraded by 1 increment due to indirectness of the outcome which only reported first heart-failure related hospital admission rather than all-cause. (b) Downgraded by 1 increment if the confidence interval crossed one MID or by 2 increments if the confidence interval crossed both. (c) Not estimable as only the summary statistic was reported by Kotecha 2014181 and no additional information regarding the event rates were available from the original papers. (d) Control group risk was calculated as a median from the data included within the original CIBIS-II349 , SENIORS 230 publications, as this could not be attained from the IPD. Chronic Heart Failure Treating Heart Failure NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: 978-1-4731-3093-7 6.2.2.4 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 In the absence of any economic analysis, unit costs for beta-blockers are presented in Table 36. Additional costs are likely to be incurred in the first year of beta-blocker initiation due to up-titration. These costs are presented in Table 37. The cost of heart failure hospitalisation and first year after stroke are also presented in Table 38 and Table 39 below. Table 36: UK unit costs of Beta-blockers Drug mg/unit Units/day Units/pack Cost/pack ( ) Cost/unit ( ) Cost/year ( ) Sources: NHS Drug Tariff, May 2016240 ; BNF May 2016161 Table 37: Additional first year costs for up-titration Description Unit cost Source Notes Community nurse specialist appointment 10-15 minute appointment occurring every 2 weeks until maximum tolerated dose achieved. Electrocardiogram 52.13 (a) NHS Reference Undertaken in first appointment, and may be repeated at later appointments if necessary. (a) Cost to direct access diagnostic services. Table 38: Cost of heart failure hospitalisation Description Unit cost Source Notes Chronic Heart Failure Treating Heart Failure NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: 978-1-4731-3093-7 Description Unit cost Source Notes Non-elective admission for Heart Failure or Shock 2,768 NHS Reference Cost weighted according to units of activity for each CC group. First year NHS costs of stroke were calculated from the Sentinel National Audit Programme: cost and cost-effectiveness analysis (unpublished report to NHS England), May 2016181 . Costs in the audit were reported by age, sex and type of stroke (ischaemic or haemorrhagic). Using the average age and percentage of females reported in Kotecha et al. 2014181 and an assumption that 80% of cases were ischaemic stroke, and 20% haemorrhagic stroke (committee consensus) the weighted costs are presented below. Table 39: First year costs of stroke Initial NIHSS Weighted average cost per patient (a)(b) (a) Assuming mean age = 69 costs are reported for the age group 65-74 years181 and assuming 19% female population 181 . (b) Assuming 80% ischaemic stroke, 20% haemorrhagic stroke (committee consensus). 6.2.2.5 Evidence statements Clinical One study was identified for inclusion within the review. The study consisted of an IPD meta-analysis which included data from 9 trials. The trials compared the effectiveness of beta-blockers with placebo in addition to usual care in people with chronic heart failure and atrial fibrillation. The meta- analysis included 4 studies comparing carvedilol and placebo; 2 studies comparing metoprolol and placebo; 2 studies comparing bisoprolol and placebo and 1 study comparing nebivolol and placebo. All-cause mortality (9 studies; n=2666) was rated as moderate quality evidence, no clear effect was shown with the confidence interval ranging from a decrease and increase in all-cause mortality. First heart-failure related admission was rated as moderate quality evidence (due to the indirectness of the outcome which did not report all-cause admissions as per the protocol) and showed no clinically important effect of beta-blockers (1 study; n=2616). Fatal and non-fatal stroke (1 study; n=2616) was rated as low quality evidence due to imprecision (as the confidence intervals surrounding the point estimate were wide). An absolute effect for this outcome could not be calculated as only the summary statistic was reported by the authors of the study with no report of event rates. No evidence was identified for the outcomes quality of life or improvement in NYHA class. Economic No relevant economic evaluations were identified. 6.2.2.6 Recommendations and link to evidence Recommendations No recommendation. Research recommendation What is the clinical and cost-effectiveness of beta blockers in patients with heart failure with reduced ejection fraction who are in atrial fibrillation? Chronic Heart Failure Treating Heart Failure NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: 978-1-4731-3093-7 Relative values of different outcomes The committee considered the following outcomes as critical for this review: all-cause mortality, quality of life and all-cause hospitalisation. Data on all- cause mortality and all-cause hospitalisation were considered preferable to data limited to heart-failure related mortality and hospitalisations, as such data take into account the broader unintended consequences of the interventions (for example, an increase in mortality or hospitalisations due to adverse events). The committee agreed that cardiovascular mortality and heart failure related hospital admissions would be considered if the all-cause data was not available. The following outcomes were considered important: improvement of NYHA class and adverse events (stroke, bradycardia and hypotension). Overall, the committee considered that all-cause mortality was the most essential of the critical outcomes for decision making. No evidence was found for the following outcomes: quality of life, improvement of NYHA class, bradycardia and hypotension. Quality of the clinical evidence The only included study was an individual patient data meta-analysis (IPD). The quality of the evidence ranged from high to low quality across the outcomes. The committee agreed that all-cause mortality was the most essential of the critical outcomes. The quality of the evidence for this outcome was moderate due to imprecision of the confidence interval around the point estimate. For heart-failure related hospital admission the evidence was rated as moderate quality due to the indirectness of the outcome. This was due to the fact that this outcome would not capture those hospitalisations that may relate to the intervention but are not considered heart failure related . For the adverse outcome of stroke, the quality of the evidence was rated as low due to wide confidence intervals surrounding the point estimate. Prior to commencing the review, the committee noted that only bisoprolol, carvedilol, and nebivolol were licensed for use in heart failure in the UK. Trade-off between clinical benefits and harms Evidence was found on the following outcomes: all-cause mortality, unplanned hospitalisation and stroke. The committee considered that all-cause mortality was the most essential of the critical outcomes for decision making and the discussion of the committee focussed on this outcome. In patients with HF-REF and atrial fibrillation, the meta-analysis showed a small increase in the number of deaths in the beta-blocker group, however, the committee were not confident in the evidence due to the wide confidence intervals around the absolute effect estimate, which ranged from a clinically important harm to a clinically important benefit of beta-blockers. Similarly, the data suggest a slight increase in the risk of stroke, but the committee was not confident in the effect estimate due to the very serious imprecision. Therefore, the committee was not confident that the evidence actually showed harm in those prescribed beta-blockers. The evidence did not show any clinically important reduction in the number of heart-failure hospitalisations in people taking beta-blockers. The committee also noted the indirectness of this outcome: the data does not take into account the broader unintended consequences of the intervention Chronic Heart Failure Treating Heart Failure NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: 978-1-4731-3093-7 such as adverse events leading to hospitalisation (for example, bradycardia). The committee noted that the uncertainty in the evidence is likely to be due to the fact that the analysis was a retrospective sub-group analysis. Due to this uncertainty the committee did not consider that they could make a recommendation for the use of beta-blockers in those with heart failure with reduced ejection fraction and atrial fibrillation. Therefore, the committee agreed to make a research recommendation for a prospective RCT to be undertaken to determine whether or not beta-blockers should be given to patients with HF-REF and AF. Trade-off between net clinical effects and costs No relevant economic studies were identified from the published literature. Unit costs of beta-blockers, the costs for heart-failure related hospitalisation and stroke were therefore presented to the committee for consideration of cost-effectiveness. The committee noted the high cost of low dose (2.5mg) Nebivolol, however, this beta-blocker is not commonly prescribed. If used, it is often a higher dosage that is split to gain the required dose; therefore this high cost is not always incurred. The committee discussed and agreed that an up-titration appointment would likely occur every 2 weeks and would most likely be in a community setting with a specialist nurse. The committee agreed a conservative appointment time of 30 minutes. The committee agreed to the chosen HRG codes for heart failure hospitalisation, and decided that a weighted average of these codes based on activity would be the most suitable as an average cost of heart failure hospitalisation. The committee stated that stroke events in patients with chronic heart failure and AF are likely to be of greater severity and therefore of higher cost. Given that the committee found that the clinical evidence for the use of beta-blockers compared with placebo for all outcomes was highly uncertain, the committee could not determine cost-effectiveness with any certainty, and therefore agreed to incorporate this in the research recommendation. Other considerations The committee decided only to review the evidence in the HF-REF and AF population, and not the HF-PEF and AF population, because there is no prognostic evidence for use of beta-blockers in HF-PEF. The committee were aware of the recent IPD published by Kotecha180 which looked at the effect of baseline heart rate on mortality in a subgroup of people with AF treated with beta-blockers. The committee agreed that the previously reported IPD data by Kotecha181 and the resulting data obtained directly from the trial authors was more appropriate for inclusion within the review as these summary statistics did not include the BEST trial of bucindolol versus placebo which is not licensed for any indication in the UK. Chronic Heart Failure Treating Heart Failure NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: 978-1-4731-3093-7 6.2.3 Mineralocorticoid Receptor Antagonists in HFPEF Heart failure with preserved ejection fraction (HFpEF) is associated with myocardial stiffness and reduced ventricular filling. The mechanism for this is incompletely understood but cell hypertrophy and interstitial fibrosis can be found in myocardial biopsies of patients with HFpEF. A number of drugs affecting parts of the renin-angiotensin pathway have been developed and shown to be effective in the treatment of heart failure with reduced ejection fraction (HFREF). Many have also been investigated in HFpEF but have not shown similar benefits so currently none of these drugs are recommended for treatment of patients with HFpEF. The mineralocorticoid aldosterone, the neurohormone produced as the final product of the renin-angiotensin system is known to promote myocyte hypertrophy and fibrosis. Inhibition through mineralocorticoid receptor antagonism has been hypothesised to counteract the underlying pathological process causing HFpEF. Spironolactone and eplerenone are mineralocorticoid receptors antagonists (MRAs) licensed for treatment of people with HFREF. New studies have investigated the role of MRAs in patients with HFpEF. The aim of this review was to examine the clinical and cost-effectiveness of MRAs in people with HFpEF. 6.2.3.2 Review question: What is the clinical and cost effectiveness of mineralocorticoid receptor antagonists in people with heart failure with preserved ejection fraction? For full details see review protocol in Appendix A. Table 40: PICO characteristics of review question Population People diagnosed with heart failure with preserved ejection fraction (HFPEF). Interventions Mineralocorticoid receptor antagonist: Spironolactone (up to 50mg/day) Eplerenone (up to 50mg/day) Comparison Placebo Outcomes CRITICAL All-cause mortality Quality of life Unplanned hospitalisation IMPORTANT Improvement of NYHA class Adverse events - Renal function Adverse events Gynaecomastia Adverse events Hypotension Adverse events - Hyperkalaemia Study design Systematic Review RCT 6.2.3.3 Clinical evidence A search was conducted for randomised controlled trials comparing the effectiveness of mineralocorticoid receptor antagonists with placebo in people with heart failure with preserved ejection fraction (HFPEF) on current standard first line treatment. Two studies (reported in 11 publications) were included in the review: Treatment Of Preserved Cardiac function heart failure with Chronic Heart Failure Treating Heart Failure NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: 978-1-4731-3093-7 and Aldosterone Receptor Blockade in Diastolic Heart Failure (Aldo-DHF).108, 109 . These are summarised in Table 41 below. 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. These studies have all been excluded within this review, because they no longer meet the review protocol. For further explanation please refer to the excluded clinical studies table (appendix I) and the Recommendations and link to evidence Table 41: Summary of studies included in the review Study Intervention and comparison Population Outcomes Comments Aldo-DHF Edelmann Intervention: Spironolactone (25 mg / day) Comparison: Placebo People aged 50 years with chronic NYHA class II or III heart failure, preserved LVEF 50%, and evidence of diastolic dysfunction/atrial fibrillation. 72% on BB, 77% on ACEI or ARB. Mortality Quality of life (SF- Functioning, Minnesota Living with Heart Failure Questionnaire) Hospitalisation Adverse events (gynaecomastia, hyperkalaemia, renal function) NYHA class Length of follow up: 1 year. SF-36 global self- assessment, Patient Health Questionnaire depression scale, and Hospital Anxiety and Depression Scale were also reported in study but have not been extracted as validated quality of life measures were also reported. TOPCAT Intervention: Spironolactone (15 45 mg / day) Comparison: Placebo People aged 50 years with symptomatic heart failure and LVEF 45%. 78% on BB, 84% on ACEI or ARB. Mortality Quality of life Kansas City Cardiomyopathy Questionnaire) Hospitalisation Adverse events (gynaecomastia, hyperkalaemia, renal function) Length of follow up: 3.3 years. McMaster Overall Treatment Evaluation instrument was also used to assess quality of life but was not been extracted as validated quality of life measures were also reported. Treating Heart Failure Chronic Heart Failure NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: Table 42: Clinical evidence summary: Mineralocorticoid receptor antagonists versus placebo for heart failure with preserved ejection fraction Outcomes No of Participants (studies) Follow up Quality of the evidence (GRADE) Relative effect Anticipated absolute effects Risk with Placebo Risk difference with Mineralocorticoid receptor antagonist (95% CI) All-cause mortality (time to event) 3445 MODERATEa due to imprecision (from 34 fewer to 12 more) All-cause mortality (dichotomous) 400 VERY LOWa, c due to risk of bias, imprecision Peto Odds Quality of life (Kansas City) Kansas City Cardiomyopathy Questionnaire. Scale from: 0 to 100. LOWc due to risk of bias b The mean quality of life (kansas city) in the intervention groups was Quality of life (EQ-VAS) EQ-VASi . Scale from: 0 to 100. time unclearj LOWc due to risk of bias b The mean quality of life (eq-vas) in the intervention group was (0.27 lower to 1.21 higher) Quality of life (MLWHF). Scale from: 0 to 105. MODERATEc due to risk of bias The mean quality of life (minnesota) in the control groups was The mean quality of life (minnesota) in the intervention groups was (3.54 lower to 3.54 higher) Quality of life (SF-36 Physical Functioning) SF-36 Physical Functioning scale MODERATEc due to risk of bias The mean quality of life (sf-36 physical functioning) in the control groups was The mean quality of life (sf-36 physical functioning) in the intervention groups was (6.61 lower to 2.61 higher) Treating Heart Failure Chronic Heart Failure NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: Outcomes No of Participants (studies) Follow up Quality of the evidence (GRADE) Relative effect Anticipated absolute effects Risk with Placebo Risk difference with Mineralocorticoid receptor antagonist (95% CI) All-cause hospitalisation (count rate) 3445 HIGH Rate Ratio 200 events per 1000 person- years 12 fewer events per 1000 person- years (from 26 fewer to 4 more) All-cause hospitalisation (dichotomous) 408 MODERATEa due to imprecision (from 32 fewer to 159 more) Participants with NYHA class I status 400 VERY LOWa,c,e due to risk of bias, indirectness, imprecision (from 40 fewer to 39 more) Hyperkalaemia serum potassium > or 5.5mm/L MODERATEc due to risk of bias (from 59 more to 119 more) Worsening renal function variousd MODERATEc due to risk of bias (from 39 more to 120 more) Gynaecomastia variousf LOWc,e due to risk of bias, indirectness Peto Odds (from 8 more to 32 more) (a) Downgraded by 1 increment if the confidence interval crossed one MID or by 2 increments if the confidence interval crossed both MIDs. Treating Heart Failure Chronic Heart Failure NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: (b) Unable to calculate as the control group risk was not reported. (c) 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 . (d) TOPCAT used serum creatinine level 2 times the baseline value and above the upper limit of the normal range; ALDO-DHF used eGFR < 30mL/min/1.73m2, or eGFR decrease > 15mL/min/1.73m2 versus baseline. (e) Downgraded by 1 increment because the study had indirect outcomes. (f) TOPCAT: Breast tenderness or enlargement leading to study drug discontinuation; ALDO-DHF: "Gynaecomastia" (not defined) (g) Unable to calculate as there were zero events in the control arm. (h) Not the full EQ-5D, just the VAS component. (i) Time outcome reported unclear. Study states that impacts of therapy on changes in [the scores] over time were examined using a repeated-measure analysis of covariance (using all follow-up time points (4, 12, 24, 36, 48 and 60 months)) . Chronic Heart Failure Treating Heart Failure NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: 978-1-4731-3093-7 6.2.3.4 Economic evidence Published literature No relevant health economic studies were identified. Unit costs In the absence of any economic analysis, unit costs are presented in Table 43 below for consideration of cost effectiveness. Additional costs are likely to be incurred in the first year of initiation due to up- titration. These costs are presented in Table 44. Table 43: Unit costs of Mineralcorticoid receptor antagonists Drug Mg/unit Units/day Units/pack Cost/pack ( ) Cost/unit ( ) Cost/year ( ) Source: NHS Drug Tariff, May 201793, 239, 240 , Table 44: Unit costs of up-titration Description Unit cost Source Nurse specialist appointment in community setting (a) 91 per hour of client contact Phlebotomy (b) 3 NHS Reference costs 2014/15242 (a) 30 minute appointment occurring every 4 weeks until maximum tolerated dose achieved. (b) Direct access service (community). In addition, the unit costs of all cause hospitalisation and acute kidney injury are presented in Table 45 below. The GC agreed that the cost of acute kidney injury treatment would be typical for a chronic heart failure population experiencing hyperkalaemia or worsening renal function. Table 45: Unit costs of clinical outcomes Description Code Unit cost Source All-cause hospitalisation (non-elective) - 2,930 NHS Reference costs Acute kidney injury (with and without interventions) LA07H-P 2,337(a) NHS Reference costs (a) Weighted using the activity reported for each of the included HRG codes. 6.2.3.5 Evidence statements Clinical Two studies (reported in 11 publications), comparing MRAs with placebo in people with heart failure with preserved ejection fraction on current standard first line treatment, were identified for inclusion within the review. Both studies compared spironolactone with placebo. The quality of the evidence ranged from high to very low. Evidence was downgraded due to a number of contributory factors including risk of bias, imprecision due to wide confidence intervals surrounding the effect estimate Chronic Heart Failure Treating Heart Failure NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: 978-1-4731-3093-7 and indirectness of the reported outcomes. All-cause mortality (n=3445) was rated as moderate quality with the confidence interval ranging from a decrease and increase in all-cause mortality hHigh quality evidence was found for all-cause hospitalisation (count rate) (n=3445), and showed a clinically important reduction with MRAs (associated with wide confidence intervals around the effect estimate). Moderate quality evidence was found for the outcomes QoL as measured by the MLWHF (n=400) and SF-36 physical functioning component (n=400), all-cause hospitalisation (dichotomous) (n=408), hyperkalaemia (n=3845) and worsening renal function (n=3845). For both the moderate quality QoL outcomes there was no clinical effect of MRAs. For the remaining moderate quality outcomes there was a clinically important increase in hospitalisations (associated with wide confidence intervals around the effect estimate), hyperkalaemia and worsening renal function with MRAs. The remaining outcomes were all rated as low or very low quality. These included all-cause mortality (dichotomous), QoL as measured by the KCCQ and EQ5D-VAS, number of participants with NYHA class I status and gynaecomastia. All of these outcomes showed no clinical effect of MRAs. Economic No relevant economic evaluations were identified. 6.2.3.6 Recommendations and link to evidence Research recommendation No recommendation 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, as all-cause takes into account the broader unintended consequences of the interventions (for example, an increase in mortality or hospitalisations due to adverse events). Improvement of NYHA class and specified adverse events (hyperkalaemia, renal function, hypotension, and gynaecomastia) were also considered to be important for decision-making. Evidence was identified for all outcomes except for hypotension. Quality of the clinical evidence The evidence for the critical outcome of all-cause mortality (measured as time to event) was moderate quality, though the confidence intervals around the absolute effect were imprecise, ranging from 34 fewer deaths to 12 more deaths per 1000 individuals. Time to event data could not be extracted from the smaller included study, so dichotomous data was extracted instead, which was very low quality due to risk of bias and very serious imprecision (no events occurred in the placebo arm and only one event in the intervention arm). The evidence for the critical outcome of quality of life ranged from moderate to low quality due to risk of bias stemming from the reporting of the data. The evidence on all-cause hospitalisation (measured as a count rate number of events) was high quality, while the evidence from the second smaller study was reported as number of participants with events and was moderate quality due to imprecision. The evidence was of moderate quality for the important outcomes of hyperkalaemia and worsening renal function (due to risk of bias caused by likely underestimation of the frequency of events) and was of low quality for Chronic Heart Failure Treating Heart Failure NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: 978-1-4731-3093-7 Research recommendation No recommendation gynaecomastia (due to risk of bias and indirectness again due to likely underestimation of the incidence of events). Evidence quality was very low for improvement in NYHA class (due to risk of bias, indirectness and imprecision), meaning that the committee placed little weight on this outcome in their decision making. Trade-off between clinical benefits and harms There was moderate quality evidence estimating 13 fewer deaths per 1000 patients and high quality evidence estimating12 fewer hospitalisations per 1000 patients per year in people taking mineralocorticoid receptor antagonists (MRAs). The committee noted that although the confidence intervals were mostly indicating beneft there was also indication of increased mortality and hospitalisation There was also moderate quality evidence (from a smaller study that did not report number of events) that suggested an increase in the number of patients hospitalised for any cause in the intervention group compared to the placebo group, though this evidence was imprecise. Based on the body of evidence, the committee concluded that it was unclear whether MRAs have a clinical benefit, a clinical harm, or no effect on mortality and hospitalisation in this population. The committee discussed the clinically important harm of MRAs on renal function (estimate of 77 more patients experiencing worsening renal function per 1000 in the intervention group) and hyperkalaemia (estimate of 87 more per 1000). They also noted the increased risk of gynaecomastia in patients taking spironolactone (estimate of 17 more per 1000), and that all of these effect estimates were subject to a high risk of bias likely to underestimate the effect. The committee also acknowledged that the use of MRAs had no clinically important impact on quality of life or NYHA class. The committee was aware that post hoc analyses of the principle trial (TOPCAT) suggested a considerable degree of heterogeneity within the population recruited and that MRAs might habe differential effcts in the different groups. Due to the uncertainties around any possible benefit of MRAs on mortality and hospitalisations in this population, a lack of alternative treatments and the clinically important risk of deteriorating renal function and hyperkalaemia, the committee was uncertain about the affect of MRAs in HFPEF but aware they were used in clinical practice. 