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. Therefore it was decided not to make a clinical recommendation on the use of MRAs in this population pending further evidence. Trade-off between net clinical effects and costs No previously published economic evaluations were identified for chronic heart failure patients with preserved ejection fraction and therefore unit costs were presented to the committee for consideration. This included annual drug costs: spironolactone (25mg: 18, 50mg: 41) and eplerenone with a specialist nurse ( 45.50) and blood tests ( 3), and the costs of all cause hospitalisation ( 2,930) and acute kidney injury ( 2,337). The committee noted that there could be potential cost savings from a reduced number of all cause hospitalisations for those treated with MRAs; however, as mentioned above, the clinical evidence for this outcome is uncertain. The committee also noted the greater number of acute kidney injury (AKI) events occurring in those treated with MRAs and agreed that the high cost of AKI would likely outweigh any potential cost savings from 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 reduced hospitalisation. Due to the uncertainty on the clinical benefit of MRAs in this population, and the lack of published economic evaluations, the committee could not make a clear judgement on the cost-effectiveness of MRAs for those with chronic heart failure with preserved ejection fraction and therefore did not make a recommendation. Other considerations The majority of the evidence in this review was from the TOPCAT trial265 a large, high quality study comparing spironolactone with placebo in patients with heart failure with preserved ejection fraction. The main report of this study was published in 2014, but the committee was aware of the subsequent post-hoc analyses of this study investigating regional variation in the results259 . The post-hoc analyses noted a substantial (~4 fold) difference in the primary composite outcome (time to cardiovascular death, aborted cardiac arrest, or hospitalisation for heart failure), as well as substantial differences in baseline characteristics, between patients randomised from Russia and Georgia compared with patients from the United States, Canada, Brazil and Argentina (the Americas). In the Americas, a substantial and clinically important reduction in the primary composite outcome was seen in patients with a phenotype more typical of HFPEF as defined in the UK. A similar difference was found across the other clinical outcomes recorded. In the post-hoc analysis, the study authors examined the baseline characteristics and responses to treatment in each region, and speculated that the clinical diagnostic criteria for heart failure with preserved ejection fraction were not uniformly interpreted or applied. It noted that the death rate of the cohort from Russia/Georgia was more reflective of the general population than of patients with heart failure. The authors concluded that 2 distinctly different populations were enrolled in the 2 regions. The authors acknowledged that the overall neutral finding of TOPCAT would generally be considered the most reliable result of the trial, and that their post-hoc analysis should not be considered definitive. However, they concluded that the findings from the post-hoc analysis may be informative to those currently faced with clinical decisions for patients with heart failure with preserved ejection fraction with anticipated risk profiles similar to those enrolled in the Americas . The committee discussed the findings of the post-hoc analysis and agreed that, while interesting, it was not sufficient to support any recommendation to use MRAs in this population. Post-hoc subgroup analyses, while useful in hypothesis generation, are generally at high risk of bias and should always be interpreted with great caution. The previous guideline for chronic heart failure (CG108) included 8 studies which are referenced in the clinical review. These studies have all been excluded within this review as they no longer meet the review protocol. The committee discussed the current protocol for this review question and agreed that the previously included studies, which had a population of people with heart failure post myocardial infarction, were not appropriate for consideration within the review as these people represented a 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 significantly different population. In addition to this the committee agreed that the minimum duration of follow-up for included studies should be 6 months to ensure an accurate clinical effect can be established. In addition to this the committee agreed that cross-over studies should be excluded to ensure that potential carryover effects are not confounding the outcome. The committee noted that a prospective randomised registry-based trial in HFPEF was due to start recruiting (Spironolactone Initiation Registry Randomized Interventional Trial in Heart Failure With Preserved Ejection Fraction (SPIRRIT) that would help answer the questions in this field. Chronic Heart Failure Treating Heart Failure NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: 978-1-4731-3093-7 6.2.4 Mineralocorticoid Receptor Antagonists in HFREF The renin-angiotensin system and its products play a key role in the pathogenesis of heart failure. The final product of this pathway is the neurohormone aldosterone is involved in cardiac fibrosis, sodium retention and other pathways leading to deterioration in heart failure. Mineralocorticoid receptor antagonists (MRA) block the action of aldosterone leading to a potent diuretic effect and may also inhibit aldosterone-stimulated fibrosis in the myocardium. The two licensed MRAs are spironolactone and eplerenone. Studies published since the last update of this guideline in 2010 have investigated whether MRA therapy would result in clinical benefits in the general population of patients with heart failure with reduced ejection fraction (HFREF) as opposed to those post-acute myocardial infarction or with highly symptomatic disease. Nonetheless, MRAs like other drugs affecting the renin-angiotensin- aldosterone pathway (including ACE-Is and ARBs) have the potential to induce adverse events including electrolyte disturbances (particularly hyperkaleaemia) and worsening renal dysfunction resulting in increased morbidity and hospitalisations. Concerns about their adverse effects and uncertainty about their benefits have reduced the uptake of these medications in clinical practice. The aim was to review the evidence for the clinical and cost-effectiveness of MRAs in people with HFREF. 6.2.4.2 Review question: What is the clinical and cost effectiveness of adding a mineralocorticoid receptor antagonist to existing standard first line treatment in people with heart failure with reduced ejection fraction? For full details see review protocol in Appendix L. Table 46: PICO characteristics of review question Population People diagnosed with heart failure with reduced ejection fraction (HFREF). 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 Chronic Heart Failure Treating Heart Failure NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: 978-1-4731-3093-7 6.2.4.3 Clinical evidence A search was conducted for randomised controlled trials comparing the effectiveness of mineralocorticoid receptor antagonists with placebo in in people with heart failure with reduced ejection fraction (HFREF) on current standard first line treatment. Four studies (reported in 13 papers) were included in the review: Eplerenone in Mild Patients Hospitalization and Survival Study , EMPHASIS-HF in Japanese patients (J- , Randomized Aldactone Evaluation Study (RALES)268, 350, 351 and Udelson 2010345 . These are summarised in Table 47 below. Three of the included studies compared eplerenone with placebo and one study compared spironolactone with placebo. Evidence from these studies is summarised in the clinical evidence summary below (Table 48). 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. The majority of patients in the RALES study268, 350, 351 were not taking beta-blockers as background medication, as the study was conducted prior to beta-blockers being mainstream first line treatment. Because of this, any evidence of a beneficial effect of adding MRAs to first line therapy from this study would likely be overestimated. The evidence has therefore been downgraded for indirectness for the efficacy outcomes where the RALES study makes up the majority of the evidence have been excluded within the current 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 47: Summary of studies included in the review Study Intervention and comparison Population Outcomes Comments EMPHASIS- HF Zannad Intervention: Eplerenone (up to 50 mg / day) Comparison: Placebo People aged 55 years with NYHA class II heart failure and LVEF 30% (or 35% if also QRS duration treatment with ACEI, ARB or both and a BB (unless contraindicated) at the recommended maximum dose. 87% on BB, 93% on ACEI and/or ARB. Patients were within 6 months of hospitalisation for CV reason (or high levels of BNP/NTpro-BNP). Mortality Hospitalisation Adverse events (renal function, hyperkalaemia, hypotension, gynaecomastia/br east pain) Mild heart failure population. Trial was stopped prematurely according to pre-specified rules after a median follow- up period of 21 months. J-EMPHASIS- HF Intervention: Eplerenone (up to 50 People aged 55 Mortality Hospitalisation EMPHASIS-HF trial in a Japanese population. Chronic Heart Failure Treating Heart Failure NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: 978-1-4731-3093-7 Study Intervention and comparison Population Outcomes Comments Tsutsui mg / day) Comparison: Placebo years with NYHA class II heart failure or higher, and LVEF 30% (or 35% if also QRS duration treatment with ACE inhibitor, ARB, - blocker, or diuretic. Patients were within 6 months of hospitalisation for CV reason (or high levels of BNP/NTpro-BNP). Adverse events (renal impairment, hyperkalaemia, hypotension, gynaecomastia) Higher incidence of diabetes, angina pectoris and coronary artery bypass grafting in the placebo group. Maximum of 4 yrs intervention plus 1 year follow-up. RALES Intervention: Spironolactone (up to 50 mg / day) Control: Placebo People with NYHA class IV heart failure in previous six months (class III or IV at time of enrolment) and LVEF 35%, treatment with ACEI, loop diuretic and (in most cases) digoxin. on ACEI. Mortality Hospitalisation (for cardiac causes) Change in NYHA class Adverse events (renal function, gynaecomastia, hyperkalaemia) Severe heart failure population. Most patients not on beta-blockers. Trial was stopped early based on the interim results and the advice of the data and safety monitoring board . Trial had a mean follow-up period of 24 months. Trial included in 2010 guideline. Udelson Intervention: Eplerenone (50 mg / day) Control: Placebo People aged 21 years with NYHA class II or III health failure and LVEF with ACEI and/or ARB and BB (unless documented intolerance). ACEI and/or ARB. NYHA class Adverse events (hyperkalaemia, renal function, hypotension) Moderate severity heart failure population. Quality of life (Kansas City) results not extracted as only reported narratively (p value). Treating Heart Failure Chronic Heart Failure NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: Table 48: Clinical evidence summary: Mineralocorticoid receptor antagonists versus placebo for heart failure with reduced 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 4621 VERY LOWa, b, c due to inconsistency, indirectness, imprecision (from 57 fewer to 0 more) All-cause hospitalisation 4400 VERY LOWa, b,j due to indirectness, imprecision, inconsistency Rate Ratio 397 events per 1000 person- yearsd 83 fewer events per 1000 person years (from 52 fewer to 115 fewer) Hospitalisation for any cause (dichotomous) VERY LOWb,e due to risk of bias, imprecision (from 221 fewer to 11 more) Change in NYHA class - Improved 1456 VERY LOWa,b,e due to risk of bias, indirectness, imprecision (from 33 more to 152 more) 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) Hyperkalaemia variousg LOWe, h due to risk of bias, inconsistency (from 12 more to 145 more) Renal function (change in creatinine (umol / L) - continuous) MODERATEe due to risk of bias The mean renal function (change in creatinine (umol / l) - continuous) in the control groups was The mean renal function (change in creatinine (umol / l) - continuous) in the intervention groups was Renal function (change in eGFR (ml/min/173m^2) - continuous) MODERATEe due to risk of bias The mean renal function (change in eGFR continuous) in the control groups was The mean renal function (change in eGFR (ml/min/173m^2) - continuous) in the intervention groups was Renal function (creatinine increased - dichotomous) VERY LOWb, e due to risk of bias, imprecision (from 19 fewer to 190 more) Renal function (30% reduction in eGFR MODERATEe due to risk of bias (from 58 more to 157 more) Renal impairment (not defined) 221 VERY LOWb,e due to risk of bias, imprecision (from 75 fewer to 36 more) 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) Renal failure (not defined) VERY LOWb,e due to risk of bias, imprecision (from 12 fewer to 13 more) Gynaecomastia - Spironolactone 1217 MODERATEe due to risk of bias (from 31 more to 177 more) Gynaecomastia (or other breast disorders) - Eplerenone VERY LOWb,e due to risk of bias, imprecision Peto odds ratio (from 3 fewer to 3 more) LOWb,e due to risk of bias, imprecision (from 6 fewer to 29 more) (a) Downgraded by one increment as the majority of the evidence included an indirect population (not on beta-blockers). (b) Downgraded by 1 increment if the confidence interval crossed one MID or by 2 increments if the confidence interval crossed both MIDs. (c) Downgraded by 1 increment because: Heterogeneity, I2=63%, unexplained by subgroup analysis. (d) Control group risk based on risk reported in EMPHASIS, as that population were on current first line treatment including beta-blockers. (e) 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. (f) Control group risk based on risk reported in EMPHASIS, as it carries the vast majority of the weight in the meta-analysis. (g) EMPHASIS - serum potassium > 5.5 mmol/L. RALES serum potassium 5.5 mmol/L. Udelson 2010 - no definition. Tsutsui 2017 no definition. (h) Downgraded by 1 or 2 increments because: Heterogeneity, I2=79%, p=0.002, unexplained by subgroup analysis. (i) Peto odds ratio due to zero events in one trial.j Downgraded by 1 increment because: Heterogeneity, I2=59%, unexplained by subgroup analysis. Chronic Heart Failure Treating Heart Failure NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: 978-1-4731-3093-7 6.2.4.4 Economic evidence Published literature No economic evaluations were identified in the 2003 guideline (CG5). Two studies were included in the 2010 guideline update (CG108): one Irish cost-effectiveness study assessing the addition of spironolactone to optimal medical treatment based on the RALES trial for patients with severe heart failure (NYHA class III-IV) and LVSD,334 which is included in this review and is summarised in the health economic profile below (Table 49) and the health economic evidence table in Appendix G; and one UK cost-effectiveness study assessing the addition of eplerenone to optimal medical treatment based on the EPHESUS trial for patients with heart failure and LVSD, post-acute myocardial which has been excluded from this review as this population is no longer included in the scope of this guideline. This population is now covered in the Acute Heart Failure guideline (CG187). Five additional health economic studies were identified with the relevant comparison from the update searches. One study is included in this review, and is summarised in the health economic evidence profile below (Table 49) and the health economic evidence tables in Appendix G. 194 The other studies were selectively excluded due to the availability of more applicable evidence. 2, 3,21,332 These are listed in Appendix I, with reasons for exclusion given. See also the health economic study selection flow chart in Appendix D. Treating Heart Failure Chronic Heart Failure NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: Table 49: Health economic evidence profile: Mineralocorticoid receptor antagonists versus placebo for heart failure with reduced ejection fraction Study Applicability Limitations Other comments Incremental cost Incremental effects Cost- effectiveness Uncertainty (UK) Directly applicable(a) Potentially serious limitations(b) Discrete event simulation model using EMPHASIS-HF RCT trial data. Two comparators: 1. Standard therapy (ACEi and BB) 2. Eplerenone (starting dose of 25mg daily increased to 50mg daily after 4 weeks) in addition to standard therapy. Trial follow-up: 4 years Lifetime time horizon modelled QALY gained Eplerenone remained cost- effective after undertaking both deterministic and probabilistic sensitivity analysis. Two scenario analyses using EMPHASIS-HF data with no extrapolation and another using only a 2 year time horizon generated ICERs of 20,730 and 20,101 per QALY gained, respectively. In all other scenario analyses eplerenone remained cost-effective. Partially applicable(c) Potentially serious limitations(d) Cost effectiveness analysis reporting cost per life year gained Two comparators: 1. Optimal medical management (might include diuretics, ACEi, digoxin, BB, or a combination of these) 2. Spironolactone added to optimal medical management Time horizon: 10 years NR NR 291/ LY gained(e) Two-way sensitivity analysis variation of probabilities of death One-way sensitivity analysis additional outpatient visits required to initiate medication for One-way sensitivity analysis cost of hospitalisation varied ( 663; spironolactone cohort dominates (it is more effective and less costly than) the placebo cohort. Treating Heart Failure Chronic Heart Failure NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: Abbreviations: ACEi = Angiotensin-converting enzyme inhibitor; BB = Beta-blockers; CHF = chronic heart failure; ICER: incremental cost-effectiveness ratio; LYG =life year Gained; NYHA = New York Heart Association Classification; QALY: quality-adjusted life years; RALES = Randomised Aldactone Evaluation Study; RCT: randomised controlled trial. (a) UK NHS perspective, however HRQoL is not reported directly from patients the trial analysis is based upon. (b) The analysis is based on estimates of relative treatment effect and resource use from a single study, so does not reflect all available evidence in this area. There is cross-over between the trial arms. Utility values are not reported directly from patients of the EMPHASIS-HF trial. Potential bias due to the sponsor of the study. (c) Analysis developed from an Irish perspective, a healthcare system reasonably comparable to the UK NHS; Population assessed limits the generalisation of results. There is also some uncertainty regarding the applicability of resource use and costs from the Irish NHS in 2003 to current NHS setting. (d) Outcomes were not reported as QALYs; Incremental cost and incremental effect were not reported. (e) Using the utility score proposed by Mant 2009212 of 0.65 for patients with heart failure, we estimated the threshold in cost per LYG equivalent to the 20,000 per QALY gained, proposed by NICE, to be 13,000 per LYG. Chronic Heart Failure Treating Heart Failure NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: 978-1-4731-3093-7 6.2.4.5 Evidence statements Clinical Four studies (reported in 13 publications), comparing MRAs with placebo in people with heart failure with reduced ejection fraction on current standard first line treatment, were identified for inclusion within the review. Three of the studies compared eplerenone with placebo and one study compared spironolactone with placebo. The quality of the evidence ranged from moderate 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 and indirectness of the reported outcomes. Moderate quality evidence was found for the outcomes renal function as measured by a 30% reduction in eGFR from baseline (n=1663) and gynaecomastia as a result of spironolactone use (n=1217), and low quality evidence was found for the outcome hyperkalaemia (n=4786), all of which showed a clinically important harm with the use of MRAs. Moderate quality evidence was also found for the outcomes renal function as measured by change in creatinine (n=2729) and renal function as measured by change in eGFR (n=2737), both of which showed no clinically important effect with the use of MRAs. The outcomes all-cause mortality (n=4621), hospitalisation for any cause (dichotomous) (n=221) and all-cause hospitalisation (n=4400) were rated as very low quality for the first two and low quality for the latter, and showed a clinically important reduction in deaths with the use of MRAs (associated with wide confidence intervals around the effect estimate). The outcome change in NYHA class (n=1456) was rated very low quality and also showed a clinically important benefit with MRA use. Three of these outcomes (all-cause mortality, all-cause hospitalisation and Change in NYHA class Improved) were downgraded for indirectness due to the fact that the majority of people included were not taking beta-blockers as concomitant medication. As a result of this, it is likely that any evidence of a beneficial effect of adding MRAs to first line therapy may have been overestimated for these outcomes. Yet, the outcome hospitalisation for any cause (dichotomous) showed the same effect in a different population albeit with a much smaller sample size (n=221) (associated with wide confidence intervals around the effect estimate). The outcome renal impairment (not defined) (n=221) was of very low quality and showed a clinical benefit of MRA. The remaining outcomes, renal function as measured by increased creatinine (n=226), renal failure (n=2729), gynaecomastia (n=2950) and hypotension (n=3176) were all rated as low or very low quality and showed no clinical effect with MRAs. Economic One cost-utility analysis found that eplerenone in addition to standard therapy is cost effective compared to standard therapy alone for those with heart failure with reduced ejection fraction (ICER: 3,520). This analysis was assessed as partially applicable with potentially serious limitations. One cost-effectiveness analysis found that spironolactone in addition to optimal medical management is more costly and more effective than optimal medical management alone. This was assessed as partially applicable with potentially serious limitations. 6.2.4.6 Recommendations and link to evidence Recommendations Offer a mineralcorticoid receptor antagonist (MRA), in addition to an angiotensin-converting enzyme (ACE) inhibitor (or ARB) and beta-blocker, to people who have heart failure with reduced ejection fraction if they continue to have symptoms of heart failure. [2018] Measure serum sodium and potassium and assess renal function before Chronic Heart Failure Treating Heart Failure NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: 978-1-4731-3093-7 and after starting an MRA and after each dose increment.[2018] Measure blood pressure before and after each dose increment of an MRA. Follow the recommendations on measuring blood pressure, including measurement in people with symptoms of postural hypotension, in the NICE guideline on hypertension in adults. [2018] Once the target, or maximum tolerated, dose of an MRA is reached, monitor treatment monthly for 3 months and then at least every 6 months, and at any time the person becomes acutely unwell. [2018] 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 such data take 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 quality of life. The evidence for eplerenone and spironolactone was analysed together for all outcomes except for gynaecomastia, where the 2 interventions were analysed separately due to gynaecomastia being a common adverse effect of spironolactone but an uncommon effect of eplerenone. Quality of the clinical evidence The evidence for the critical outcomes of all-cause mortality, all-cause hospitalisation and hospitalisation for any cause (dichotomous) was graded low to very low quality due to indirectness (the majority of the evidence was from a population not on beta-blockers), imprecision (based on the confidence intervals around the relative effect) and inconsistency (due to heterogeneity in the case of all-cause mortality caused by a study with a small sample size). However, the committee noted that for all-cause mortality and all-cause hospitalisation, the confidence intervals around the absolute effect were reasonably narrow and the committee was confident that in each case that there was a clinically important effect. The quality of the evidence for the important outcomes ranged from moderate to very low. For the adverse event of hyperkalaemia, the quality of the evidence was low, due to inconsistency and risk of bias which likely underestimated the incidence of hyperkalaemia (as the incidence of hyperkalaemia of 7 % was far exceeded by the rate of drug discontinuation of 17%). For deterioration in renal function, the quality of the evidence varied, with the majority of the evidence being of moderate quality, again due to risk of bias. The quality of the evidence for gynaecomastia was moderate for spironolactone due to risk of bias which likely underestimated the incidence of the event, and very low for eplerenone due to risk of bias and imprecision (though regarding the latter, the committee noted that there was no serious imprecision in the confidence intervals around the estimated absolute effect). The quality of the evidence for hypotension was low due to risk of bias and imprecision. The quality of evidence for change in NYHA class was very low due to risk of bias, indirectness and imprecision, and so it did not weigh heavily in decision making. Chronic Heart Failure Treating Heart Failure NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: 978-1-4731-3093-7 Trade-off between clinical benefits and harms The use of mineralocorticoid receptor antagonists (MRAs) led to a clinically important reduction in mortality and hospitalisations, and possibly an improvement in NYHA class. However, MRAs also led to a clinically important increase in the number of patients experiencing hyperkalaemia. There was also some evidence of worsening renal function and an increase in hypotension in patients using MRAs, though this evidence was mixed and mostly suggested a difference of insufficient magnitude to be clinically important. The use of spironolactone was associated with a clinically important increase in gynaecomastia. This was not the case for eplerenone, where the very low quality evidence suggested that there was no clinically important difference. The committee agreed that there was likely to be no clinically important difference between the eplerenone and placebo group. Overall, the beneficial effects of MRAs on mortality and hospitalisation outweighed the risk of hyperkalaemia and the possible impact on renal function. The committee acknowledged that the quality of the evidence on the risk of hyperkalaemia and renal function impairment was affected by the risk of bias, which may have led to an underestimation of the actual risk of hyperkalaemia/renal impairment in this population (as there was a proportion of participants who discontinued the study drug but remained in the study, and due to the strict inclusion criteria). The potential underestimation of these risks is confirmed by the results of other studies, which suggest a higher rate of these adverse events in patients using MRAs . However, these risks can be managed by starting patients on appropriate doses, measuring patients potassium levels and renal function at baseline and monitoring those levels regularly, and appropriate dose adjustment (see NICE Acute Kidney Injury guideline CG169). Patients with chronic renal impairment and hence the lowest eGFR appear to be those who have the most to gain in terms of mortality benefit. There is, however, a small cohort of patients who may experience a clinically significant deterioration in renal function and this highlights the need for baseline measurement and meticulous monitoring and follow-up by someone with specific expertise in managing heart failure and acute kidney injury. The committee acknowledged the evidence of an increased risk of gynaecomastia in patients taking spironolactone, but noted that the majority of patients did not experience this adverse event. Clinicians should consider switching to eplerenone in patients who experience gynaecomastia while taking spironolactone. Switching should be considered as part of shared decision making, as the value placed on avoiding gynaecomastia varies from patient to patient. Overall, the clinically important reduction in all-cause mortality and hospitalisation supported a recommendation to offer MRAs to all people with HFREF who remain symptomatic despite treatment with beta-blockers and ACE inhibitors. The committee also recommended baseline measurement and regular monitoring of patients renal function and potassium levels, as well as drug interactions, and that clinicians seek specialist advice in the case of deterioration (rather than automatically discontinuing the MRA). The committee discussed the intervals at which patients taking MRAs should Chronic Heart Failure Treating Heart Failure NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: 978-1-4731-3093-7 be monitored and agreed that this should take place before starting an MRA, 1-2 weeks after commencing the medicine and after each dose increment. Once a person had reached their target or highest tolerated dose they should be monitored monthly for 3 months to ensure no adverse effects. After this, the committee agreed that 6 monthly monitoring was sufficient or when a person became acutely unwell. The importance of measuring blood pressure after each dose increment was also stressed by the committee as postural hypotension was a common cause of hospital admission in the elderly. For further explanation of the monitoring recommendations please see section 4.3.8 of the methodology section of the guideline and appendix D. Trade-off between net clinical effects and costs Two relevant economic analyses were identified that compared the additional use of mineralcorticoid receptor antagonists to optimal medical management. One UK economic evaluation assessed the addition of eplerenone to optimal medical management based on the EMPHASIS-HF trial included in the clinical review. This analysis found that the addition of eplerenone to optimal medical management was more effective and more costly than optimal medical management alone, with an ICER of 3,520 per QALY gained and was therefore considered to be cost effective. The committee noted that at the time of this analysis the cost of eplerenone was around 42, however, as this drug has recently come off patent its price has significantly decreased. Therefore, the ICER will now be much lower. One Irish economic evaluation assessed the addition of spironolactone to optimal medical management based on the RALES RCT included in the clinical review. This analysis was reviewed in the previous 2010 guideline update. This analysis found that the addition of spironolactone to optimal medical management was more effective and more costly than optimal medical management alone, with an additional cost of 291 per life year gained. The main limitation of this analysis is that it does not incorporate quality of life and could therefore not be assessed using the NICE cost per QALY threshold. However, in the 2010 guideline an equivalent threshold of 13,000 per life year gained was calculated based on a utility value of 0.65, as reported in a health technology assessment by Mant et al. 2009. The committee agreed to also adopt this threshold, and the addition of MRAs to optimal medical management was considered to be cost effective. The committee noted that costs are likely to have risen since this was last reported in the previous guideline, but agreed that this would not change the overall conclusion of the result. The committee noted the higher risk of renal dysfunction for people taking MRAs. Renal dysfunction was not included in the Irish study, but was included in the UK study model. The committee considered that the associated cost in the UK economic analysis may have been underestimated due to the definitions adopted to report renal dysfunction in the EMPHASIS- HF trial, and believed that a significant proportion of these patients are likely to have had acute kidney injury (AKI) which incurs a higher cost than that adopted in the economic analysis. However, due to the negative effects that MRAs have on renal function the committee decided to recommend that blood monitoring should be undertaken during uptitration in the first 3 months, and then 6 monthly thereafter. This frequency of monitoring was previously suggested in the 2010 CHF guideline (CG108) Appendix D practical notes . Uptitration monitoring was a requirement of the EMPHASIS- Chronic Heart Failure Treating Heart Failure NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: 978-1-4731-3093-7 HF clinical trial and therefore these costs were incorporated in the UK study. This consisted of 2 sets of blood tests and 2 hospital appointments with a consultant, and further monitoring costs were assumed to be the same as standard care. Although the committee recommend a couple more blood tests than were undertaken in the trial, this additional cost would be minor. In the Irish study, 1 extra outpatient visit for monitoring in the MRA arm compared to the standard care arm was assumed. The study also reports that even if 4 additional outpatient visits were assumed that spironolactone is still highly cost-effective. Taking this into consideration the committee agreed that MRAs would still remain highly cost-effective and therefore should be offered to chronic heart failure patients with reduced ejection who remain symptomatic on current first line therapy. Other considerations The committee considered that the introduction and continuation of MRAs, as with all pharmaceuticals in heart failure, should be part of shared decision making, and noted that this was already reflected in recommendation [85] in the communication section of the chronic heart failure guidance. A lay committee member raised the issue of polypharmacy and whether, if a person s heart function improves significantly, one or more of medications could be discontinued. The clinical committee members acknowledged the understandable desire of patients to not take more medications than required and the burden of polypharmacy. There are no large-scale trials addressing this question so evidence in this regard is lacking. Healthcare professionals should ensure that patients are on appropriate polypharmacy while taking into account that the reduction or removal of particular medications, even in controlled heart failure, has empirically been noted to lead to deterioration of heart function and risk of arrhythmia. The decision to discontinue therapies should therefore be made on an individual patient basis, as part of shared decision with the patient as part of the wider multi- disciplinary team, with full discussion of potential risks and benefits and taking into account patient side-effects and symptoms. The committee discussed current practice regarding the prescribing of MRAs, and the potential impact of their recommendation. In the 2010 guideline, MRAs can be considered as one of several second line treatment options, after specialist advice. The new recommendation is stronger than the previous recommendation on the use of MRAs ( offer rather than consider ) and the suggestion to seek specialist advice prior to introduction has been removed. This is due to the strengthening of the evidence base and the recognition of local variation in heart failure multidisciplinary teams. Further, it is in line with the recommendations in the Acute Heart Failure guideline (CG187), from which many patients are likely to transition to chronic management. In formulating the new recommendation, the committee discussed the patient population to whom the recommendation should apply. RALES required an entry ejection fraction (EF) of 35%, and EMPHASIS 30%. The committee agreed that this was critical to the studies designs to ensure that the correct population was being studied, but that there is some variation about the measurement of ejection fraction. Accordingly MRAs should be offered to all people with HFREF, as the evidence indicated a beneficial effect across the disease severity spectrum and is likely to remain cost effective. The committee considered whether MRAs should be offered to all people Chronic Heart Failure Treating Heart Failure NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: 978-1-4731-3093-7 with HFREF who remain symptomatic on after the optimisation of beta- blocker and ACEi dose titration. The committee did not consider that the evidence supported the initiation of triple therapy immediately following diagnosis of HFREF, as the patient populations included in the review were all symptomatic on existing first line treatment. Furthermore, taking the technology appraisals into consideration, sacubitril valsartan and ivabradine recommendations were added as possible specialist treatments. The committee recognised that the strengthening of the recommendation to offer MRAs for this population could have a significant resource impact for the NHS due to increased prescribing volume. However, there was good economic evidence suggesting that the addition of MRAs for patients with heart failure with reduced ejection fraction in the community is cost- effective. Although spironolactone is currently cheaper than eplerenone the committee decided not to specify which drug should be prescribed and agreed that this should be the decision of the prescribing clinician while taking into account the pharmacological differences of the 2 medicines, as there has been no head to head comparison trial of the 2 drugs. The previous guideline for chronic heart failure (CG108) included 8 studies which are referenced in the clinical review. Seven of these studies have been excluded within the current review as they no longer meet the review protocol. The committee discussed the protocol for this review question and agreed that the previously included studies which had a population of people with heart failure post myocardial infarction were not appropriate for consideration within the review as these people represented a significantly different population. In addition to this the committee agreed that the minimum duration of follow-up for included studies should be 6 months and have a minimum sample size of 100 to ensure an accurate clinical effect can be established. In addition to this, the committee agreed that cross-over studies should be excluded to ensure that potential carryover effects are not confounding the outcome. Chronic Heart Failure Treating Heart Failure NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: 978-1-4731-3093-7 6.2.5 Iron supplementation for iron deficiency in heart failure Iron deficiency (both with or without overt anaemia) commonly occurs in heart failure affecting between and a third and half176 of patients, and appears to be related to disease severity176 as well as being an independent predictor of mortality. Iron deficiency in heart failure has been an area of intense research since the last guideline update. One of the postulated mechanisms for iron deficiency in the context of heart failure is malabsorption and therefore the mode of delivery of iron supplementation (oral versus intravenous) has also been an area of investigation. There are currently no specific quality standards addressing this area. 6.2.5.2 Review question: What is the clinical and cost effectiveness of iron supplementation in people with chronic heart failure and iron deficiency? For full details see review protocol in Appendix A. Table 50: PICO characteristics of review question Population People with heart failure who also have iron deficiency (whether or not they are anaemic), are on optimal heart failure medical therapy and are in a community or outpatient setting Interventions Intravenous iron Oral iron Comparisons Each other Placebo Outcomes CRITICAL: Mortality Quality of life Unplanned hospitalisation IMPORTANT: Improvement in exercise tolerance Change in haemoglobin in anaemic patients Withdrawal due to adverse events/tolerability Adverse events (hypertension, anaphylaxis/hypersensitivity, stroke, gastrointestinal) Study design Systematic review of RCTs RCT 6.2.5.3 Clinical evidence A search was conducted for randomised trials investigating the effectiveness of intravenous (IV) or oral iron supplementation, compared with each other or placebo, for patients with heart failure (HF) who also have iron deficiency (ID). and , and IRONOUT HF200 ; these are summarised in Table 51 below. Four trials compared IV iron with placebo; of which 1 trial also included an oral iron arm. A further single study compared oral iron with placebo. Two of the trials were in patients with anaemia; the other 3 trials included both anaemic and non-anaemic patients. Evidence from these studies is summarised in the clinical evidence summaries below (Table 52 toTable 54). 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. Chronic Heart Failure Treating Heart Failure NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: 978-1-4731-3093-7 Table 51: Summary of studies included in the review Study Intervention and comparison Population Outcomes Comments CONFIRM- HF trial: Ponikowski Intervention: Two injections (at baseline and week 6) of IV iron (ferric carboxymaltose) each equivalent to 500 or 1000 mg of iron, depending on weight and Hb. Maintenance injections of 500 mg iron at weeks 12, 24 and 36 if ID still present. Control: Matching placebo (saline solution) N = 304 Stable ambulatory HF patients with ID NYHA class II or III LVEF 45% Elevated NPs Hb <15 g/dL at screening visit Study duration: Mortality Quality of life KCCQ) Hospitalisation Exercise tolerance Discontinuation due to adverse events Drug related vascular disorders Drug related gastrointestinal disorders FAIR-HF trial: Anker (Anker , Comin-colet , Filippatos , Gutzwiller , Ponikowski ) Intervention: Weekly injections of IV iron (ferric carboxymaltose) equivalent to 200 mg iron, until week 8 or week 12, depending on required iron-repletion dose. Maintenance injections every four weeks until week 24. Control: Matching placebo (saline solution) N = 461 Ambulatory HF patients with ID NYHA class II or III LVEF 40% (class II) or 45% (class III) Hb at screening between 95 - Study duration: Mortality Quality of life VAS, KCCQ) Hospitalisation Exercise tolerance Stroke Gastrointestinal disorders IRON-HF trial: Beck- da-silva (Beck-da- ) Intervention 1: Weekly infusions of IV iron (iron sucrose) equivalent to 200mg iron for 5 weeks, plus oral placebo Intervention 2: Oral iron (ferrous sulphate) 200 mg three times / day for 8 weeks, plus IV placebo (saline) Control: Placebo of both IV and oral preparations N = 23 HF outpatients with ID HF diagnosis 3 months NHYA class II-IV LVEF < 40% Hb 12g/dL and Study duration: Mortality Improvement in NYHA class (surrogate for quality of life) Study terminated due to poor recruitment IRONOUT HF trial: Lewis Intervention: Oral iron. oral iron polysaccharide 150 mg twice daily for 16 weeks Control: Matching placebo Stable HFREF outpatients with ID Mortality Permanent study drug discontinuation Adverse events Serious adverse Study reported several outcomes (peak walk test distance and Chronic Heart Failure Treating Heart Failure NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: 978-1-4731-3093-7 Study Intervention and comparison Population Outcomes Comments NYHA class II-IV LVEF 40% Hb between 9 and 15 g/dL (men) or 9 and (women) Study duration: events Change in peak Change in 6 minute walk test distance Change in KCCQ clinical summary score KCCQ) as median and IQR Toblli (Toblli ) Intervention: Weekly infusions of IV iron (iron sucrose) equivalent to 200 mg iron for 5 weeks Control: Matching placebo (saline solution) N = 60 HF outpatients with ID, anaemia and CKD NYHA class II-IV LVEF 35% creatinine ml/min Hb <12.5 g/dl for men and <11.5 g/dl for women Mortality Quality of life (MLWHFQ) HF hospitalisations Exercise tolerance Change in haemoglobin Abdominal pain Nausea Systolic blood pressure patients recruited and analysis published. patients recruited subsequently and second analysis published on full dataset. Study duration: Treating Heart Failure Chronic Heart Failure NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: Table 52: Clinical evidence summary: IV iron 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 Intravenous iron (95% CI) months VERY LOWa,b due to risk of bias, imprecision (from 31 fewer to 34 more) Quality of life EQ5D. Scale from: 0 to 1. HIGH The mean change in quality of life in the control groups was The mean quality of life in the intervention groups was Quality of life EQ5D VAS. Scale from: 0 to 100. months LOWa, b due to risk of bias, imprecision The mean change in quality of life in the control groups was The mean quality of life in the intervention groups was Quality of life KCCQ. Scale from: 0 to 100. months LOWa, b due to risk of bias, imprecision The mean change in quality of life in the control groups was The mean quality of life in the intervention groups was Quality of life MLWHFQ . Scale from: 0 to 105. HIGH The mean quality of life in the control groups was The mean quality of life in the intervention groups was 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 Intravenous iron (95% CI) Improvement in NYHA class Data on improvement in NYHA has only been extracted where quality of life data is not reported in a trial. VERY LOWa, b, c due to risk of bias, indirectness, imprecision (from 144 fewer to 1000 more) Hospitalisation due to HF 40 LOWa,c due to risk of bias, indirectness Peto Odds (from 450 fewer to 50 more) Hospitalisation all cause 760 months LOWa, b due to risk of bias, imprecision Rate Ratio Moderated (from 57 fewer to 191 fewer) Exercise tolerance months MODERATE b due to imprecision The mean exercise tolerance in the control groups was The mean exercise tolerance in the intervention groups was Haemoglobin in anaemic patients (anaemia defined as <12.5g/dL for men and <11.5g/dL for women) HIGH The mean haemoglobin in anaemic patients in the control groups was The mean haemoglobin in anaemic patients in the intervention groups was 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 Intravenous iron (95% CI) Discontinuation: adverse events 304 VERY LOWa, b due to risk of bias, imprecision (from 78 fewer to 52 more) Ischaemic stroke 459 VERY LOWa, b due to risk of bias, imprecision Peto Odds (from 10 fewer to 20 more) Drug related vascular disorders (not defined) VERY LOWa, b, c due to risk of bias, indirectness, imprecision Peto Odds (from 20 fewer to 20 more) Gastrointestinal disorders (not defined) LOWa, b due to risk of bias, imprecision (from 2 fewer to 173 more) Drug related gastrointestinal disorders (not defined) VERY LOWa, b due to risk of bias, imprecision Peto Odds (from 10 fewer to 40 more) 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 Intravenous iron (95% CI) LOWb due to imprecision (from 31 fewer to 471 more) Abdominal pain 60 LOWb due to imprecision Peto Odds (from 120 fewer to 50 more) Systolic blood pressure 60 MODERATEb due to imprecision The mean systolic blood pressure in the control groups was The mean systolic blood pressure in the intervention groups was (1.95 lower to 4.55 higher) (a) 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 increment if the confidence interval crossed 1 MID or by 2 increments if the confidence interval crossed both MID. (c) Downgraded by 1 increment as the outcome is indirect. (d) Mean control group rate per 100 patient-years. 