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. Table 53: Clinical evidence summary: oral 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 Oral iron (95% CI) VERY LOWa, b,e due to risk of bias, imprecision, Peto Odds ratio Moderate (from 13 fewer to 128 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 Oral iron (95% CI) inconsistency 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 Moderate (from 27 fewer to 1000 more) Permanent study drug discontinuation LOW b due to imprecision (from 78 fewer to 107 more) Adverse events (not described) 225 VERY LOWa, b, c due to risk of bias, indirectness, imprecision (from 146 fewer to 99 more) Serious adverse events (not described) VERY LOWa, b, c due to risk of bias, indirectness, imprecision (from 44 fewer to 136 more) Change in peak VO2 ml/kg/min 225 LOW a,d due to risk of bias - The median change in peak VO2 in the placebo group was ml/kg/min The median change in peak VO2 in the oral iron group was Change in 6-minute walk test distance (m) LOWa,d due to risk of bias - The median walk test distance in The median 6 minute walk test distance in the oral iron group 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 Oral iron (95% CI) the placebo group was Change in KCCQ clinical summary score (Higher score indicates better outcome) LOW a,d due to risk of bias - The median KCCQ in the placebo group was The median KCCQ clinical summary score in the oral iron group was (a) Downgraded by 1 increment if the majority of the evidence was at high risk of bias, and downgraded by 2 increments if the 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 MIDs . (c) Downgraded by 1 increment as the outcome is indirect. (d) Unable to assess imprecision as study reported the results as median and IQR. (e) Downgraded by 1 increment due to heterogeneity, I2 =51%. Table 54: Clinical evidence summary: IV iron versus oral iron Outcomes No of Participants (studies) Follow up Quality of the evidence (GRADE) Relative effect Anticipated absolute effects Risk with Oral iron Risk difference with Intravenous iron (95% CI) VERY LOWa, b due to risk of bias, imprecision Peto Odds Ratio (from 100 fewer to 500 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 Oral iron 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 137 fewer to 797 fewer) (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 MIDs. (c) Downgraded by 1 increment as the outcome is indirect. Chronic Heart Failure Treating Heart Failure NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: 978-1-4731-3093-7 6.2.5.4 Economic evidence Published literature One health economic study was identified with the relevant comparison and has been included in . This is summarised in the health economic evidence profile below (Table 55) and the health economic evidence table in Appendix G. Four economic studies relating to this review question were identified but were selectively excluded due to the availability of more applicable evidence73 . 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 55: Health economic evidence profile: IV iron versus placebo Study Applicability Limitations Other comments Incremental cost Incremental effects Cost- effectiveness Uncertainty Gutzwiller Directly applicable (a) Potentially serious limitations (b) Within-trial analysis of FAIR- . Comparators: 1. No iron treatment 2. Iron repletion with ferric carboxymaltose IV bolus injection 24 week follow-up QALY gained Probability Intervention 2 cost- effective ( 20K/30K threshold): Univariate and probabilistic sensitivity analysis undertaken. Frequency and duration of hospitalisation, QALY difference, and cost of hospital day were the most influential parameters. None of the parameters tested resulted in an ICER above 20,000 per QALY gained. Abbreviations: ICER: incremental cost-effectiveness ratio; QALY: quality-adjusted life years; RCT: randomised controlled trial (a) The FAIR-HF trial did not include British participants, but was mostly performed in European countries with a predominantly Caucasian population. This is unlikely to change the conclusions of cost-effectiveness. (b) Short time horizon may not capture full costs and effects of the intervention. Lack of detailed medical resource use data. Within-trial analysis and so does not reflect full body of available evidence for all comparators; FAIR-HF is one of 4 studies comparing IV iron to no iron treatment. Chronic Heart Failure Treating Heart Failure NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: 978-1-4731-3093-7 Unit costs Relevant unit costs of oral and intravenous iron are provided below to aid consideration of cost effectiveness. Oral iron The cost of oral iron therapy was taken from the Drug Tariff, May 2016240 with the number of tablets prescribed estimated from the Prescription Cost Analysis, July 2016.143 Table 56 below, shows a weighted average of the 2 most commonly prescribed tablets. Table 56: Cost of oral iron therapy Drug Tablets Cost per tablet ( ) Tablets per day Cost per month ( ) Weighted average 5.70 Intravenous iron These costs were updated from the NICE clinical guideline entitled Anaemia management in people with chronic kidney disease (AMCKD) (NG8). In the AMCKD guideline, cost was estimated based on: drug cost, staff time, clinical space, administrator time, and transport. Detail regarding the sources and assumptions used for costing are outlined below. Staff time was estimated by the committee members and the infusion time dependent on drug SPCs. Observation (30 minutes) is required for all regimens. It was assumed that a nurse would observe 2 patients concurrently. The cost of a band 6 nurse at a rate of 51 per hour was applied80 . The following costs were taken from a published cost analysis for pre-dialysis patients conducted at Kings College Hospital, London368 : Clinic space - 5 per patient-hour Clerical staff - 3.28 per visit Transporting a patient to hospital (assumed 10% patients will require this) - 45 for return visit Disposables were assumed to cost 5 per visit (including cannula, needles, syringes, dressing, IV giving set and sodium chloride solution). The unit costs of intravenous iron were estimated based on the doses reported in the trials included in the clinical review. These are summarised below and more detail is available in Table 57: FAIR-HF: min. dose (11x200mg) = 831, max. dose (15 x 200mg) = 1,133 CONFIRM-HF: min (1x500mg/vial) = 131, max. dose (7x500mg/vial) = 916* IRON-HF: 5x200mg = 374 * please note that the cost of 1000mg vial has fallen and is now less costly than two 500mg vials. Therefore this cost may be slightly over-estimated if an initial dose of 1000mg was given rather than 500mg. All maintenance doses in the trial were 500mg. Treating Heart Failure Chronic Heart Failure NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: Table 57: Cost of IV iron therapy Regimen Drug cost ( ) Nurse time per infusion, minutes Nurse cost ( ) (b) Other ( ) Total ( ) Tria l Drug Iron mg/ vial Vials /visit No. visits Cost/ vial (a) Total drug cost Preparation Infusio n Observatio n Cost per visit Total cost Consumable s Transport Admin time and clinic space FAIR-HF Ferric Carboxy- maltose Ferric Carboxy- maltose CONFIRM-HF Ferric Carboxy- maltose Ferric Carboxy- maltose IRON-HF Iron Sucrose (infusion ) (a) BNF, May 2016161 Chronic Heart Failure Treating Heart Failure NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: 978-1-4731-3093-7 6.2.5.5 Evidence statements Clinical Five studies were identified for inclusion within the review. Four trials compared IV iron with placebo; 1 of which 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. The evidence ranged from high to very low quality. Evidence was downgraded for a number of reasons including risk of bias, imprecision due to wide confidence intervals surrounding the effect estimate and indirectness of the reported outcome. For the comparison of IV iron with placebo a number of the outcomes were rated as high quality evidence . These included QoL (as measured by the EQ5D scale (n=459) and MLWHFQ (n=40)) and the haemoglobin level in people with anaemia (n=60). These outcomes all showed a clinically important symptomatic benefit of IV iron. Moderate quality evidence was found for the outcomes exercise tolerance (n=688) and systolic blood pressure (n=60) both of which suggested no clinical effect of IV iron. The remaining outcomes were all rated as low or very low quality evidence. Of these outcomes, , QoL (as measured by both the EQ5D VAS (n=679) and KCCQ scales (n=678)), hospitalisation (due to both HF (n=40) and all-cause (n=760)) all showed a clinically important benefit of IV iron (associated with wide confidence intervals around the effect estimate). The outcome ischaemic stroke (n=459) was also rated as very low quality evidence and suggested a clinical harm of IV iron, this was associated with wide confidence intervals around the effect estimate. The remaining outcomes which included mortality,improvement in NHYA class (data on improvement in NYHA has only been extracted where quality of life data is not reported in a trial), discontinuation due to adverse events, drug related vascular disorders, gastrointestinal disorders, nausea and abdominal pain failed to identify any clear clinical effect of IV iron. For the comparison of oral iron with placebo, very low quality evidence was found for the outcomes mortality (n=238, 2 studies), improvement in NYHA class (n=13, study), adverse events (n=225, 1 study) and serious adverse events (n=225, 1 study). The evidence showed a clinically important increase in mortality and clinically important improvement in NHYA class with oral iron (both associated with wide confidence intervals around the effect estimate). Data on improvement in NYHA has only been extracted where quality of life data is not reported in a trial.The evidence for both adverse events and serious adverse events suggested no clinical effect of oral iron. This was also the case for permanent study drug discontinuation which was rated as low quality. The evidence for change in peak VO2, 6 minute walk test distance and KCCQ clinical summary score were reported by the study as median and IQR. Therefore, imprecision could not be assessed. The comparison of IV iron with oral iron included the same outcomes (mortality and change in NYHA class) which were also rated as very low quality evidence (n=17 for both). Change in NYHA (data on improvement in NYHA has only been extracted where quality of life data is not reported in a trial), showed a clinical harm of IV iron when compared to oral iron (associated with wide confidence intervals around the effect estimate). Mortality did not demonstrate a clear effect with the confidence interval ranging from a decrease and increase in all-cause mortality. Economic One cost-utility analysis found that iron supplementation was cost-effective compared to no iron treatment for patients with heart failure and iron deficiency (ICER = 3,997 cost per QALY). This was assessed as directly applicable with potentially serious limitations. Chronic Heart Failure Treating Heart Failure NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: 978-1-4731-3093-7 6.2.5.6 Recommendations and link to evidence Recommendation No recommendation Relative values of different outcomes The committee agreed that all-cause mortality, quality of life and unplanned hospitalisation were the most critical outcomes for decision making. The committee agreed that the impact of iron on improvement in exercise tolerance, change in haemoglobin in anaemic patients, withdrawal due to adverse events/tolerability and adverse events (including hypertension, anaphylaxis/hypersensitivity, stroke and gastrointestinal issues) were also important outcomes. The committee discussed the outcome change in haemoglobin and agreed that it was only relevant to capture this information in people who had low baseline haemoglobin levels (people with anaemia) as increasing haemoglobin levels in these people was likely to have a beneficial clinical effect. Conversely in people with normal haemoglobin levels, increasing this was less likely to have a clinical effect. The incidence of anaphylaxis/hypersensitivity was not reported in any of the included trials. Quality of the clinical evidence Four studies were identified that included an IV iron arm versus placebo; 2 small trials and 2 larger multi-centre trials. One of these studies also included an oral iron arm in addition to a further single study which looked at just oral iron versus placebo. IV iron versus placebo: For mortality, the evidence was rated very low quality due to risk of bias and imprecision. In addition to this the evidence for all-cause hospitalisation was graded as low quality for the same reasons. However, the committee noted that the confidence intervals around the absolute effect were reasonably narrow for this outcome, suggesting that the committee could have greater confidence in the result. Another study reported heart failure related hospitalisations (rather than all-cause); this outcome was downgraded for indirectness as the outcome may not have captured all of the potential hospitalisations relating to the intervention. The committee noted that quality of life measures reported by the studies, both general (EQ5D and EQ5D-VAS) and disease-specific scales (KCCQ and MLWHFQ), ranged from high quality to low quality. One study did not report quality of life, but reported change in NYHA class. This outcome was downgraded for indirectness as the committee agreed that the outcome would give some idea of overall improvement in the severity of HF symptoms. For the important outcomes, the quality of the evidence ranged from high to moderate. The outcome exercise tolerance, as measured by the 6-minute walk test, was rated as moderate quality due to imprecision and haemoglobin change in anaemic patients was rated as high quality. The committee noted that evidence regarding discontinuation and adverse events were graded as low and very low quality, often due to missing data Chronic Heart Failure Treating Heart Failure NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: 978-1-4731-3093-7 and imprecision. However, they were reassured that discontinuation and gastrointestinal disorder rates appeared low. Oral iron versus placebo: For mortality the evidence was rated as very low quality due to risk of bias, imprecision and inconsistency. The committee discussed the inconsistency of the results and noted that the single study showing a negative effect of oral iron was the larger of the 2 studies and weighted more heavily in the meta- analysis. The outcome improvement in NYHA class was also rated as very low quality due to risk of bias, indirectness (as this was interpreted as a surrogate for QoL as it implies an improvement in symptoms) and imprecision. The confidence intervals surrounding the effect estimate were wide which reduced the committee s ability to be confident in the results. The committee noted that evidence regarding discontinuation and adverse events and serious adverse events were graded as low and very low quality, often due to risk of bias and imprecision. Both of the adverse event outcomes were also downgraded for indirectness due to the lack of description regarding what these events consisted of, making it difficult for the committee to interpret this evidence. The committee agreed that discontinuation and adverse event rates with oral iron appeared low (difference against placebo was less than 50 per 1000 for all 3 outcomes). No evidence was identified for anaphylaxis or hypersensitivity. The evidence for peak VO2, 6 minute walk test distance and KCCQ clinical summary score were reported by the study as median and IQR. Therefore imprecision could not be assessed. It was noted that the populations in the included trials was not representative of the general HF population, being in general younger and having fewer comorbidities. The committee was unsure how the benefit seen in the trials would translate in the general HF population. It was also discussed whether the trials had been long enough to encompass the possible risks and benefits. In addition, the committee noted that the trials had only included people with reduced ejection fraction, so there was a lack of evidence in people with iron deficiency and HFPEF. Trade-off between clinical benefits and harms IV iron IV iron for people with HFREF and iron deficiency appeared to have a clinically important benefit on quality of life and haemoglobin levels (in people with anaemia). However, the impact on mortality was unclear. The committee noted that while the point estimate showed a clinically important reduction in deaths, the confidence intervals around the absolute effect were wide, reducing their confidence in the effect estimate. The effect estimate suggested a clinically important reduction in hospitalisations also (130 fewer hospitalisations per 1000 people); the committee agreed that this appeared to represent a marked decrease. There was no clinical effect shown on exercise tolerance. In terms of adverse effects, there was no evidence of potential gastro- intestinal disturbance (difference against placebo was less than 50 per 1000 for discontinuation). The committee also agreed that the impact on systolic Chronic Heart Failure Treating Heart Failure NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: 978-1-4731-3093-7 blood pressure was not clinically significant. The committee was concerned by the apparent excess of ischaemic stroke in the IV iron arm, but noted that this was from only 2 occurrences in 1 study. On the basis of these findings the committee was uncertain that the benefits of IV iron had been completely demonstrated. Although there was some high (and low quality) evidence on quality of life, the committee agreed that this was not enough to support a recommendation when taking into account the uncertainty of the evidence on the other outcomes. The GC noted quality of life was a secondary endpoint in the trials and hospitalisations are the main outcome the study was powered for. The committee decided that making a recommendation in this area was premature given the variation seen in outcomes and differences in administration protocols between current studies and preferred UK practice.They were aware of continuing studies in the field including Intravenous Iron Treatment in Patients With Heart Failure and Iron Deficiency (IRONMAN), Intravenous Iron in Patients With Systolic Heart Failure and Iron Deficiency to Improve Morbidity & Mortality (FAIR- HF2), and Randomized Placebo-controlled Trial of FCM as Treatment for Heart Failure With Iron Deficiency (HEART-FID). The latter two trials are using ferric carboxymaltose (FCM), however all IV formulations would be relevant and could be considered together unlike oral preparations where varaiations in bioavailability may be more of an issue. Because of the potential to cause toxicity using iron therapy, there needs to be good evidence that a patient is iron deficient prior to being given IV iron. A small percentage of patients with HF have iron overload as the cause of their HF. There was also concern that because iron deficiency can be a symptom of other disorders, particularly gastro-intestinal tract cancer, there was the risk of missing other causes if the iron was replaced without further investigation. The committee heard testimony from the co-optee renal physician who regularly oversees IV infusion on an outpatient basis for patients with anaemia and/or renal disease and regularly cares for people with heart failure. He reported that using a dosage regimen similar to CONFIRM-HF was generally well tolerated. It was suggested, however, that the population currently given IV iron, like the population included in the clinical trials, may not be reflective of the population treated for HF in practice, and that tolerability may be worse in typical patients with HF who are on average older and have more comorbidities. No evidence was found indicating whether repeat administration will always be necessary, nor the frequency of any such repeat administration. However, the co-optee confirmed that the experience from the chronic kidney disease (CKD) community is that they actively recall patients to repeat iron infusion, as reflected in the CKD and anaemia guidelines, and there is no expectation that patients would stop needing iron supplementation. It was felt this was also likely to be the case for people with HF and iron deficiency. Oral iron Oral iron for people with HFREF and iron deficiency appeared to show a clinically important increase in mortality. In terms of adverse events, there was no evidence of a clinically important effect. Oral iron appeared to show a clinically important improvement in NYHA class, which may be suggestive Chronic Heart Failure Treating Heart Failure NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: 978-1-4731-3093-7 of an overall improvement in the severity of CHF symptoms in these patients. However, the width of the confidence intervals reduced the committee s ability to interpret this result. Oral iron showed a marginal increase in peak VO2 max and a relative decrease in distance walked in the 6-minute walk test. However, these results were reported as median and interquartile range and therefore could not be assessed for imprecision. Similar to IV iron the committee agreed that due to the potential to cause toxicity using iron therapy, there needs to be good evidence that a patient is iron deficient prior to being given oral iron. In addition, the committee agreed that the cause of iron deficiency should be fully investigated to ensure that other causes could be elucidated before starting replacement therapy. The committee also noted that patient compliance with oral iron tended to be poor in clinical practice due to unpleasant gastrointestinal side effects. Overall, the committee agreed that there did not appear to be a benefit of oral iron in people with HFREF and iron deficiency and therefore decided not to make a recommendation regarding oral iron. Trade-off between net clinical effects and costs No previously published economic evaluations were identified that considered oral iron supplementation compared to no supplementation or IV iron supplementation compared to oral iron supplementation in people with HF and iron deficiency. One relevant economic evaluation was included in this review that considered IV iron supplementation compared to no iron supplementation for people with HF and iron deficiency. This was based on the FAIR-HF trial included in the clinical review. This economic evaluation found that IV iron supplementation increased costs and improved health (increased QALYs) compared with no iron supplementation with an incremental cost- effectiveness ratio of 3,977 per QALY gained. The probability that IV iron is cost effective at the 20,000 per QALY threshold was around 99%. The analysis only reflected the effectiveness evidence from 1 RCT of 4 included in the clinical review and was assessed as directly applicable with potentially serious limitations. The committee were concerned that the time horizon of this economic evaluation is short and therefore does not capture the longer term costs and effects of treatment. The trial with the longest follow-up included in the clinical review was CONFIRM-HF, which had a 12 month follow up. This trial implemented different dosing regimes of 500mg or 1000mg of iron given per visit compared to 200mg per visit as in the other included trials. Unit costs of IV iron were presented to the committee for consideration of the costs and cost effectiveness associated with different dosing regimes. The mean total dose in CONFIRM-HF trial was 1500mg over 1 year. The unit cost per milligram of iron is the same between the 100mg and 500mg vial sizes; however, the 500mg dosing regime (as in CONFIRM-HF) requires significantly fewer visits than the 200mg dosing regime and is therefore less costly. The committee also noted that such a regime is likely to be more acceptable to people due to the fewer number of visits. It was noted that this dosing regime is similar to current clinical practice in the NHS for people receiving IV iron therapy (for example, anaemic patients with CKD). The committee therefore considered the cost effectiveness of IV iron supplementation based on the clinical evidence of CONFIRM-HF with a different dosing regime and longer follow-up. The committee noted that all- Chronic Heart Failure Treating Heart Failure NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: 978-1-4731-3093-7 cause hospitalisation event rates in CONFIRM-HF were similar to those of FAIR-HF. CONFIRM-HF did not report the EQ-5D index, only the EQ-5D VAS which suggested that there was a benefit in quality of life. Comparing the EQ- 5D VAS and Kansas City Cardiomyopathy Questionnaire (KCCQ) scores from FAIR-HF and CONFIRM-HF the clinical review shows that there was a smaller quality of life gain in CONFIRM-HF than that found in FAIR-HF. The committee considered that the overall cost will be lower in CONFIRM-HF than FAIR-HF due to the reduced intervention cost and similar reduced hospitalisation rate to that of FAIR-HF and therefore considered that IV iron therapy administered according to the CONFIRM-HF dosing regime and over a 12 month period is likely to be cost-effective. Due to the lack of evidence on the effectiveness of IV iron after 12 months and whether to continue or stop supplementation, the committee were still concerned that 12 months was not a sufficient follow-up period to capture all costs and effects of iron supplementation. The unit costs of oral iron were also presented to the committee for consideration. The committee noted that although oral iron is much cheaper, as mentioned above, the clinical evidence suggests that there is no clinical benefit. In addition, the committee also discussed that there are also compliance issues in clinical practice and therefore there is not likely to be any benefit of oral iron to people with HF. The high cost of IV iron supplementation and the large population of people with HF requiring treatment would mean a positive recommendation for IV iron supplementation would have a large cost impact for the NHS. Considering this, the committee agreed that overall both the clinical and cost-effectiveness evidence was currently too uncertain to recommend that patients with iron deficiency should be treated with IV iron supplementation. The committee stated that trials currently underway should help to strengthen both the clinical and economic evidence to aid recommendations for IV iron supplementation in the future. Other considerations Iron deficiency is a common comorbidity with HF. It has been estimated that up to 30 to 50% of patients with NYHA class II-IV heart failure have iron deficiency, and that the prognosis for these patients is worse than for patients without iron deficiency. 176 Therefore any recommendations will have implications for a large number of people covered by this guideline. The studies of IV iron included those with and without low haemoglobin and this review did not distinguish between them, as it was the committee s intention to make recommendations that covered both anaemic and non-anaemic patients with iron deficiency. There are guidelines on treating iron deficiency anaemia in the general population, which recommend a trial of oral iron. However, the evidence included within this review does not suggest a clinical benefit of oral iron for people with HFREF and iron deficiency alone. The committee considered a number of points about the potential impacts of making a recommendation for the treatment of iron-deficiency in people with HF. Testing for iron deficiency; treating with oral iron; regimens of IV iron replacement (from provider and patient perspective); and ongoing clinical trials. The committee considered whether the potential benefits from iron replacement in people with iron-deficiency (with and without anaemia) was such that there should be a recommendation to test all people with HF for Chronic Heart Failure Treating Heart Failure NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: 978-1-4731-3093-7 iron-deficiency. There was consensus that iron studies were already done for everyone known to have anaemia (estimated at around 10% HF population), and that people with HF in a specialist clinic would generally also get iron studies, but that this left a large number who would currently not be tested. If any treatment recommendation were made, it would be important to raise awareness of iron-deficiency in HF amongst non-specialists in order to ensure equity of access to treatment. However, since this review has not looked at the effectiveness of testing for iron deficiency, the committee could only consider a recommendation that all people with HF be tested if there was robust evidence of both clinical and cost effectiveness of treating identified iron deficiency, particularly in those without anaemia. Since this was lacking, the committee felt that no such recommendations could be made, but felt that this could change in the future. It was discussed that despite general consensus that oral iron was largely ineffective and poorly tolerated, patients were sometimes offered oral iron in clinical practice, often by their GP. This clinical opinion was confirmed by the results from the IRONOUT-HF study which showed that oral iron did not have a clinical benefit in people with HFREF and iron deficiency. The committee considered the different regimens of IV iron in various trials and in the real-life situation. Practice tends to be moving from multiple long infusions to shorter injections to replace iron more quickly. The patient representatives expressed a preference for large infusion if this completely replaced their iron more quickly, as they felt this would quickly improve their quality of life. There was consensus that we should be moving towards a separate pathway for iron deficiency in HF, in a manner similar to the pathway for anaemia in CKD, and that this was likely to include IV iron. However, the committee considered that a general recommendation at this time would be a change in practice with an impact from both testing and treatment, without high quality evidence that this would be beneficial. It was felt that when further evidence was published in the future, this should be revisited. The committee was aware of the currently active IRONMAN trial (https://clinicaltrials.gov/ct2/show/NCT02642562), funded by the British Heart Foundation, that will look at longer time points. It was commented that this will be useful to find out whether the effect is simply on symptoms due to replacing iron, or whether it has an effect on HF pathophysiology (a feasible mechanism was offered involving myocyte iron use). It should also provide long term data on clinical effectiveness. The committee noted that the trials had only included people with reduced ejection fraction. It was decided that it would not be possible to generalise the evidence in these trials to people with HFPEF, as the patholophysiology differs, and therefore the balance of benefits and harms may be different. The committee were aware of a clinical trial which was currently active and included people with HFpEF. The FAIR-HFpEF trial (https://clinicaltrials.gov/ct2/show/NCT03074591) will look at the outcomes exercise capacity, QoL, NYHA functional class, mortality and HF related hospitalisations in people with heart failure with preserved ejection fraction and iron deficiency with and without anaemia randomised to either IV iron or placebo. Based on this, the committee decided not to recommend further research in the area. Chronic Heart Failure Treating Heart Failure NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: 978-1-4731-3093-7 6.2.6 Pharmacological treatment for heart failure in people with heart failure and chronic kidney disease Chronic kidney disease (CKD), defined by a reduction in glomerular filtration rate (eGFR) to <60 and/or persistent albuminuria, is a common and important comorbidity in people with heart failure that confers significant additional risks of mortality, hospitalisation and adverse drug reactions. People with severe CKD (eGFR<30 ml/min/1.73 m2 ) have largely been excluded from key randomised controlled trials of heart failure pharmacotherapies, and the evidence base for such therapies in this important subgroup has therefore been lacking and clinical practice inconsistent The presence of even mild or moderate CKD (eGFR 31-59 ml/min/1.73 m2 ) can limit the ability to introduce and/or adequately up-titrate heart failure medications, many of which are potentially nephrotoxic and often reduced or discontinued in people with worsening renal function or acute kidney injury complicating intercurrent illness or concomitant drug therapy. People with CKD are also more prone to develop adverse effects related to their heart failure medication including hyperkalaemia and hypotension as well as worsening renal function, which is often mild but may be significant in the long term and contribute to deteriorating renal function and worsening heart failure prognosis As a result, there may be significant underutilisation of evidence-based pharmacotherapies in people with heart failure who also have CKD, particularly those with HFREF, who may be denied potentially life-saving disease-modifying medication. When considering the update of this guideline this topic was highlighted as an important area to review to establish if pharmacological interventions recommended for the general heart failure population were associated with similar clinical benefits, risks and cost effectiveness in people with heart failure who also have CKD. 6.2.6.2 Review question: What is the clinical and cost effectiveness of pharmacological interventions for heart failure in people with heart failure who also have chronic kidney disease? For full details see review protocol in Appendix A. Table 58: PICO characteristics of review question Population Adults with heart failure and chronic kidney disease (at least stage 3A / eGFR <60 mL/min), who are not on dialysis. Interventions / Comparisons Angiotensin Converting Enzyme (ACE) inhibitor Angiotensin Receptor Antagonist / Blocker (ARB) Beta-Adrenergic Antagonia / Blocker (Beta-blocker) Mineralocorticoid Receptor Antagonist (MRA) Digoxin Diuretics loop and loop-related Ivabradine and Sacubitril-Valsartan Hydralazine-Nitrate Compared against each other (class versus class and within class comparisons), against the same drug at a different dose, or against placebo. Outcomes CRITICAL All-cause mortality Quality of life Unplanned hospitalization IMPORTANT Chronic Heart Failure Treating Heart Failure NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: 978-1-4731-3093-7 Renal function Adverse events - Bradycardia Adverse events - Arrhythmic events Adverse events - Progression to stage five kidney disease / unplanned dialysis Adverse events - Hypotension Adverse events - Hyperkalaemia Study design Systematic Review RCT 6.2.6.3 Clinical evidence A search was conducted for randomised trials comparing the effectiveness of medications for long- term treatment of heart failure (HF) in patients with both HF and chronic kidney disease of stage 3 or all of which were sub-group analyses of randomised controlled trials of HF medication in the wider HF population. Trials of medication versus placebo were identified in the following drug . In addition, there was a dose comparison for ACE inhibitors289 . No evidence was found regarding the use of loop diuretics, sacubitril-valsartan or hydralazine/nitrate in people with HF and CKD. The critical outcomes of mortality and hospitalisation were frequently reported, but no studies reporting quality of life or change in NYHA class were identified. The included studies are summarised in Table 59 below. Evidence from these studies is summarised in the clinical evidence summary below(Table 60 to 65). 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. Table 59: Summary of studies included in the review Study Intervention and comparison Population Outcomes Comments ATLAS trial, Ryden (Massie Cleland ) Angiotensin converting enzyme (ACE) inhibitors. per day Angiotensin converting enzyme (ACE) inhibitors. Lisinopril 2.5-5mg per day Duration 4y average (median 46 months). N=988 patients with CKD Post-hoc subgroup analysis of multicentre trial HF: NYHA class III or IV (or class II if admission for acute decompensation of heart failure in last 6 months) with ejection fraction 30%, who had received diuretics for at least 60 days CKD subgroup: Creatinine between 1.5 and 2.5 mg/dl, which equates to eGFR , therefore mostly stage Mortality Hospitalisation Hyperkalaemia 94. 31% of patients in trial had CKD stage Subgroup status: Ejection fraction: All reduced NYHA class: Mixed (mainly III) Industry funded 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 CHARM- Overall trial: (Pfeffer ) Angiotensin receptor antagonists. Candesartan up to 32mg (as tolerated) Placebo average (range 2-4y). N=154 patients with CKD Subgroup analysis, pre- specified but not stratified HF: symptomatic HF (NYHA II-IV) for at least four weeks CKD subgroup: Creatinine between 2 and 3 mg/dl, equating approximately to GFR , stage 3b-4 Hospitalisation Hyperkalaemia Analysis of pooled results of three trials (looking at ARBs in different HF populations). 2% of patients in trials had CKD stage 3b+ Subgroup status: Ejection fraction: Mixed NYHA class: Mixed (II-IV) Industry funded HEAAL trial: Konstam Angiotensin receptor antagonists. Losartan 150mg per day Angiotensin receptor antagonists. Losartan Duration median 4.7y N=945 patients with CKD Pre-specified subgroup analysis of multicentre study. HF: NYHA class II-IV, intolerant to ACE- inhibitors CKD subgroup: eGFR Hospitalisation Recruitment dates not reported. 20% of patients in trial had Subgroup status: Ejection fraction: All reduced NYHA class: Mixed, most class II Funded by industry SOLVD-treat trial: Bowling (Bohm ; SOLVD investigators ) Angiotensin converting enzyme (ACE) inhibitors. Enalapril 2.5 to Placebo Duration Mean 41 months N=1036 patients with CKD Post-hoc subgroup analysis of older trialb HF: LVEF <35% who were not currently receiving ACEIs CKD subgroup: Mortality Hospitalisation Renal function Hyperkalaemia Recruited 1986-89. 40% of patients in trial had CKD (10% Subgroup status: Ejection fraction: All reduced NYHA class: mixed Original study funded by industry, but this analysis was not VAL-HeFT trial: Anand (Lesogor ; Cohn ) Angiotensin receptor antagonists/blockers (ARB) Valsartan, target dose 160mg twice a day with creatinine and blood Post-hoc analysis of multicentre trial. HF: Stable, symptomatic HF, LVSD Mortality Hospitalisation Renal function Renal failure Hyperkalaemia Recruitment dates NK. 58% of patients in trial had CKD stage Subgroup status: Ejection fraction: All 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 pressure monitoring Placebo with creatinine and blood pressure monitoring Duration 2y average (mean 23 months, range 0-38 months) on echo. On HF medication. CKD subgroup: subdivided by those with and without proteinuria) mostly stage 3, some early 4. reduced NYHA class: Mixed Funded by industry CIBIS-II trial: Castagno ) Intervention 1: Beta- blockers (BB). Bisoprolol dose increased progressively to 10mg daily according to tolerance. Placebo. average (mean) N = 1119 patients with CKD Subgroup analysis of older trialb HF: LVEF 35% or less. Symptoms corresponding to class III or IV of the New York Heart Association (NYHA). Stability during the preceding 6 weeks. Cardiovascular therapy including a diuretic and ACE inhibitor. CKD subgroup: Two strata eGFR 45-59, stage eGFR ~20a Mortality Hospitalisation Recruitment dates not reported. 43% of patients in trial had Subgroup status: Ejection fraction: All reduced NYHA class: Class III or IV Industry funded MERIT-HF trial: Ghali (MERIT-HF group ) Intervention 1: Beta- blockers (BB). Metoprolol CR/XL. target dose of 200mg daily. Placebo. Duration 1 year N=1469 patients with CKD Post-hoc subgroup analysis of older trialb HF: aged 40-80 y, HF class II-IV, ejection fraction <40% taking ACE-I unless not tolerated and diuretics. CKD subgroup: Two strata eGFR 45 to 60, eGFR <45, class Mortality Hospitalisation 98. 37% of patients in trial had CKD (12% Subgroup status: Ejection fraction: All reduced NYHA class: Mixed Funded by industry 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 SENIORS trial: Cohen- (Flather ) Intervention 1: Beta- blockers (BB). Nebivolol initial target of 10mg once daily Placebo. Duration mean 21 (SD 9) months. N=704 patients with CKD Post-hoc subgroup analysis of multicentre trial of elderly patients HF: Aged 70 years or over. Documented heart failure of any severity, plus either: LVEF of <35% in last 6 months; or hospitalisation for decompensated HF in the previous year CKD subgroup: Tertile of study population with the poorest renal function, eGFR ~20a - Mortality Hospitalisation Renal function Bradycardia Hypotension 02. Divided into tertiles (33%) of renal function. Subgroups: Ejection fraction: Mixed NYHA class: Mixed Funded by industry EMPHASIS- HF trial: Eschalier (Zannad ) Mineralocorticoid receptor antagonists (MRA). Eplerenone 50mg once daily, with potassium monitoring Placebo, with potassium monitoring Duration ave 2y (median 21 months, range 0-60 months). N=912 patients with CKD Pre-specified subgroup analysis of multicentre trial. HF: NYHA functional class II symptoms, age 30-35% with QRS duration of >130 msec on electrocardiography), admission for cardiovascular reason within last six months (or BNP 250 pg/ml). Existing tx with ACE-I and/or ARB, and a B- blocker (unless contraindicated). CKD subgroup: eGFR Hospitalisation Renal function Hyperkalaemia Recruited 2006-10. 33% of patients in trial had CKD stage Subgroup status: Ejection fraction: All reduced NYHA class: All patients class II Funded by industry RALES trial: Vardeny (Pitt , Vardeny ) Mineralocorticoid receptor antagonists (MRA). Spironolactone dose N=792 patients with CKD Post-hoc subgroup analysis of older trialb Mortality Hospitalisation Hyperkalaemia Recruited 1995-96. 48% of patients in trial had CKD class 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 per day according to response Placebo HF: HF for at least 6 weeks, NYHA class III- IV and had been NYHA IV at some point in the previous 6 months, were being treated with an ACE inhibitor (if tolerated) and a loop diuretic, LVEF CKD subgroup: Subgroup status: Ejection fraction: All reduced NYHA class: Class III or IV Funded by industry SHIFT trial: Voors (Swedberg ) Ivabradine to a target dose of 7 5 mg twice daily according to heart rate Placebo according to heart rate Duration Median 23 months. N=1579 patients with CKD Pre-specified subgroup of multicentre trial HF: Adults in sinus rhythm 70 bpm. Stable symptomatic heart failure, admission for HF within the previous year, and an LVEF of CKD subgroup: Renal function Bradycardia Hyperkalaemia 10. 26% of patients in trial had CKD stage Subgroup status: Ejection fraction: All reduced NYHA class: Mixed Funded by industry DIG trial: Shlipak (DIG ) Digoxin. An algorithm based on age, gender, weight and creatinine levels determined doses of digoxin. Placebo Duration mean 3 years N=3157 patients with CKD Subgroup analysis of multicentre North American trial HF: Stable heart failure and left ventricular ejection fraction <45% and were in sinus rhythm CKD subgroup: Two strata eGFR 30-59, stage eGFR ~20a Mortality Hospitalisation Recruited 1991-93. 46% of patients in trial had CKD (3% Subgroup status: Ejection fraction: All reduced NYHA class: Mixed Chronic Heart Failure Treating Heart Failure NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: 978-1-4731-3093-7 (a) GFR approximated using creatinine level (umol/l) and average participant demographics using the abbreviated MDRD equation: 186 x (Creat / 88.4)-1.154 x (mean age)-0.203 x (0.742 x (proportion female%)) (b) Ten or more years elapsed between the publication of the main trial results and the publication of the reported sub- group analysis Treating Heart Failure Chronic Heart Failure NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: Table 60: Clinical evidence summary: ACE-inhibitor versus Placebo (CKD stages 3-4) Outcomes No of Participant s (studies) Follow up Quality of the evidence (GRADE) Relative effect Anticipated absolute effects Risk with Placebo Risk difference with ACE-inhibitor All-cause mortality - CKD stages 3-4 1036 VERY LOWa,b due to risk of bias, imprecision (from 86 fewer to 18 more) All-cause mortality - CKD stage 3b and 4 only VERY LOW a,b due to risk of bias, imprecision (from 158 fewer to 21 more) All-cause hospitalisation 1036 VERY LOW a,b due to risk of bias, imprecision (from 101 fewer to 20 more) Renal function (change in serum creatinine umol/l) LOWa due to risk of bias The mean change in serum creatinine (umol/l) in the control groups was The mean change in serum creatinine (umol/l) in the intervention groups was VERY LOW a,b due to risk of bias, imprecision (from 5 fewer to 42 more) a Downgraded by 2 increments if the majority of the evidence was at very high risk of biasb 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. 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ISBN: Table 61: ACE-inhibitor high dose versus low dose (CKD stages 3b-4) Outcomes No of Participants (studies) Follow up Quality of the evidence (GRADE) Relative effect Anticipated absolute effects Risk with low dose Risk difference with ACE-inhibitor high dose (CKD All-cause mortality 988 VERY LOWb,c due to risk of bias, indirectness Overall riska (from 52 fewer to 69 more) Mortality or Hospitalisation 988 VERY LOWb,c,d due to risk of bias, indirectness Overall riska (from 33 fewer to 36 more) Renal dysfunction or hyperkalaemia 988 VERY LOWb,c,d,e due to risk of bias, indirectness, imprecision (from 22 more to 159 more) VERY LOWb,c,d due to risk of bias, indirectness (from 66 more to 211 more) a Data insufficient to calculate control group, overall risk for CKD group given b 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 c Downgraded by 1 increment because the majority of evidence was from an indirect population (defined CKD in terms of creatinine, not eGFR) d Downgraded by 1 increment because the outcome was compound, and could not extract protocol outcome e 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. 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