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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ISBN: Table 62: Angiotensin receptor antagonist (ARB) versus placebo (CKD class 3b-4) Outcomes No of Participants (studies) Follow up Quality of the evidence (GRADE) Relative effect Anticipated absolute effects Risk with Placebo Risk difference with ARB (95% CI) All-cause mortality 2917 VERY LOWa,c due to risk of bias, imprecision (from 32 fewer to 40 more) Combined outcome: cardiovascular mortality or HF admission VERY LOWa,b,c due to risk of bias, indirectness, imprecision (from 86 fewer to 25 more) Morbid event (includes hospitalisation and death) VERY LOWa,b,c due to risk of bias, indirectness, imprecision (from 82 fewer to 0 more) Renal function: change in eGFR 2179 VERY LOWa,c due to risk of bias, imprecision The mean change in eGFR in the control groups was The mean in eGFR in the intervention groups was Renal failure - progression to dialysis 2911 VERY LOWa,c due to risk of bias, imprecision Not estimabled Not estimabled Not estimabled LOWa due to risk of bias (from 29 more to 104 more) 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 due to indirectness, as compound outcome rather than numbers of admissions c 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: Outcomes No of Participants (studies) Follow up Quality of the evidence (GRADE) Relative effect Anticipated absolute effects Risk with Placebo Risk difference with ARB (95% CI) d Unable to calculate as there were zero events in both arms Table 63: ARB high dose versus low dose (CKD class 3a/b) Outcomes No of Participants (studies) Follow up Quality of the evidence (GRADE) Relative effect Anticipated absolute effects Risk with low dose Risk difference with ARB high dose (95% CI) Combined outcome: death or HF hospitalisation 945 VERY LOWa,b due to risk of bias, indirectness (from 53 fewer to 36 more) 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 1 increment due to indirectness as outcome was compound rather than numbers of admissions Table 64: Beta-blocker versus placebo (CKD stages 3-4) Outcomes No of Participants (studies) Follow up Quality of the evidence (GRADE) Relative effect Anticipated absolute effects Risk with Placebo Risk difference with Beta-blocker (95% CI) All-cause mortality - CKD class 3a 1645 LOWb due to risk of bias Estimatea (from 5 fewer to 30 fewer) All-cause mortality - CKD class 3b-4 958 HR 0.55 Estimatea Treating Heart Failure Chronic Heart Failure NICE 2018. 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ISBN: Outcomes No of Participants (studies) Follow up Quality of the evidence (GRADE) Relative effect Anticipated absolute effects Risk with Placebo Risk difference with Beta-blocker (95% CI) LOWb due to risk of bias (from 5 fewer to 60 fewer) All-cause mortality - CKD class 3-4 704 VERY LOWb,c due to risk of bias, imprecision (from 104 fewer to 7 more) Death or hospitalisation - CKD class 3a 669 VERY LOWb,c,e due to risk of bias, indirectness, imprecision Overalld (from 31 fewer to 165 fewer) Death or hospitalisation - CKD class 3b-4 235 VERY LOWb,c,e due to risk of bias, indirectness, imprecision Overalld (from 150 fewer to 18 more) Hospitalisation (time to event) - CKD class 3a 870 VERY LOWb,c due to risk of bias, imprecision (from 84 fewer to 31 more) Hospitalisation (time to event) - CKD class 3b-4 341 VERY LOWb,c due to risk of bias, imprecision (from 67 fewer to 248 fewer) Hospitalisation for cardiovascular disorder - CKD VERY LOWb,c,f due to risk of bias, (from 77 fewer to 56 more) Treating Heart Failure Chronic Heart Failure NICE 2018. 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ISBN: Outcomes No of Participants (studies) Follow up Quality of the evidence (GRADE) Relative effect Anticipated absolute effects Risk with Placebo Risk difference with Beta-blocker (95% CI) indirectness, imprecision HF hospitalisation - CKD class 3a 669 VERY LOWb,c,f due to risk of bias, indirectness, imprecision Overalld (from 5 fewer to 88 fewer) HF hospitalisation - CKD class 3b-4 450 VERY LOWb,c,f due to risk of bias, indirectness, imprecision Overalld (from 101 fewer to 25 more) Renal failure (not defined) 886 LOWb due to risk of bias Not estimableg Not estimabl eg Not estimableg VERY LOWb,c due to risk of bias, imprecision (from 8 fewer to 44 more) VERY LOWb,c due to risk of bias, imprecision Peto Odds (from 0 more to 10 more)i a Control risk taken from MERIT-HF 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 if the confidence interval crossed one MID or by 2 increments if the confidence interval crossed both MIDs d Data insufficient to calculate control risk. Overall risk given e Downgraded by 1 increment due to indirectness as a compound outcome was reported rather than numbers of admissions 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 Beta-blocker (95% CI) f Downgraded by 1 increment due to indirectness as the outcome was reported as a subset of the protocol outcome all-cause hospitalisation g Unable to calculate as zero events in both arms i Absolute risk difference calculated using RevMan software Table 65: Digoxin versus placebo (CKD class 3-5) Outcomes No of Participants (studies) Follow up Quality of the evidence (GRADE) Relative effect Anticipated absolute effects Risk with Placebo Risk difference with Digoxin (95% CI) All-cause mortality - CKD class 3a/b 2939 VERY LOWb,c due to risk of bias, imprecision Overalla (from 46 fewer to 18 more) All-cause mortality - CKD class 4-5 218 VERY LOWb,c due to risk of bias, imprecision Overalla (from 149 fewer to 105 more) Death or Hospitalisation - CKD class 3a/b 2939 VERY LOWa,e due to risk of bias, indirectness Low estimated (from 21 fewer to 75 fewer) Death or Hospitalisation - CKD class 4-5 218 VERY LOWb,c,e due to risk of bias, indirectness, imprecision Low estimated (from 201 fewer to 28 more) a Data not sufficient to calculate control risk. Overall risk for given for participants with eGFR around 45 or below 34 respectively 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 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: Outcomes No of Participants (studies) Follow up Quality of the evidence (GRADE) Relative effect Anticipated absolute effects Risk with Placebo Risk difference with Digoxin (95% CI) d Data not sufficient to calculate control risk. Mortality risk given per group as above (actual risk would be higher as includes hospitalisation) e Downgraded due to indirectness as composite outcome rather than protocol outcome Table 66: Ivabradine versus placebo (CKD class 3a/b) Outcomes No of Participant s (studies) Follow up Quality of the evidence (GRADE) Relative effect Anticipated absolute effects Risk with Placebo Risk difference with Ivabradine (95% CI) Renal function: change in eGFR LOWa due to risk of bias The mean eGFR in control was 53.7 ml/min (SD The mean eGFR in the intervention groups was (2 lower to 2.4 higher) Renal failure 1579 VERY LOWa,b due to risk of bias, imprecision (from 31 fewer to 29 more) VERY LOWa,b due to risk of bias, imprecision (from 24 fewer to 0 more) Bradycardia (symptomatic only) LOWa due to risk of bias (from 7 more to 65 more) 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 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 67: MRA versus placebo (CKD class 3a/b) Outcomes No of Participants (studies) Follow up Quality of the evidence (GRADE) Relative effect Anticipated absolute effects Risk with placebo Risk difference with MRA (95% CI) All-cause mortality (RR) 792 LOWa,b,c due to risk of bias (subgroup), imprecision (from 66 fewer to 6 more) Combined outcome: cardiovascular mortality or HF admission (RR) VERY LOWa,c,d due to risk of bias, indirectness, imprecision (from 45 fewer to 145 fewer) HF hospitalisation (RR) 792 VERY LOWa,c,e due to risk of bias (subgroup), indirectness, imprecision (from 60 fewer to 10 more) Renal function change in eGFR 883 VERY LOWa,c due to risk of bias, imprecision The mean change in eGFR in the control groups was 4.15 ml/min (improvement) The mean change in eGFR in the intervention groups was 2.11 less improvement (4.23 less to 0.01 more) LOWa,f due to risk of bias (from 33 more to 260 more) 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 Reports mortality as relative risk, rather than protocol time to event but not downgraded c Downgraded by 1 increment if the confidence interval crossed one MID or by 2 increments if the confidence interval crossed both MIDs d Downgraded 1 increment for indirectness as reporting compound outcome rather than numbers of hospitalisations e Downgraded 1 increment for indirectness as reporting only proportion having HF hospitalisations, not numbers of all cause hospitalisations f Statistical heterogeneity, but not downgraded as both studies appear to show clinically important difference (harm). Subgroup analysis not done as not appropriate where only two studies. Treating Heart Failure Chronic Heart Failure NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: Chronic Heart Failure Treating Heart Failure NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: 978-1-4731-3093-7 6.2.6.4 Economic evidence Published literature No relevant health economic studies were identified. See also the health economic study selection flow chart in Appendix D. 6.2.6.5 Evidence statements Clinical Twelve studies were identified for inclusion within the review. The majority of the evidence was from subgroup analyses of trials in the general HFREF population. The studies included comparisons of different classes of medicine including angiotensin converting enzyme inhibitors, angiotensin receptor blockers, beta-blockers, digoxin, ivabradine and mineralocorticoid receptor antagonists with placebo in people with chronic kidney disease (specifically at least stage IIIa). Outcomes were analysed by disease severity, where this information was reported by the paper. Evidence was also found comparing high dose ARB with low dose ARB and high dose ACE-inhibitor with low dose ACE- inhibitor. The evidence ranged from low to very low quality with the majority being rated as very low quality. This was based on a number of contributory factors including risk of bias and imprecision due to wide confidence intervals. The studies frequently used a composite outcome of death or hospitalisation, which led to the evidence being downgraded for indirectness. No evidence was identified for the outcomes QoL, arrhythmic events or progression to stage 5 kidney disease/unplanned dialysis. In addition to this no evidence was identified for the interventions of loop diuretics; sacubitril-valsartan; or hydralazine-nitrate versus placebo. Furthermore, no inter or intra class comparisons were identified. ACE inhibitors: For the comparison of ACE inhibitors versus placebo the evidence was rated as very low quality and suggested a clinically important reduction in hospitalisations with ACE inhibitors (n=1036) (associated with wide confidence intervals around the effect estimate). For the outcomes renal function (n=967) and hyperkalemia (n=970) there was no clinical effect of ACE inhibitors. With high dose versus low dose ACE inhibitors all of the outcomes were again rated as very low quality. The outcomes renal dysfunction or hyperkalaemia (associated with wide confidence intervals around the effect estimate) and hypotension/dizziness all suggested a clinically important increase in events with high dose ACE inhibitors (n=988). Mortality did not demonstrate a clear effect with the confidence interval ranging from a decrease and increase in all-cause mortality. ARBs: For the comparison of ARB versus placebo the evidence was rated from low to very low quality. The evidence suggested a clinically important increase in hyperkalemia (n=3065) with ARBs. The composite outcome of CV mortality and HF admission (n=154) suggested a clinically important reduction in events with ARBs. This was also the case for the outcome morbid events which included hospitalisations and death (n=2917). For renal function there was no clinically important effect of ARBs on eGFR (n=2179) and zero events of renal failure or progression to dialysis were reported in a single study (n=2911). For the comparison of high dose ARBs with low dose the evidence was rated as very low quality and suggested a clinically important reduction in HF Chronic Heart Failure Treating Heart Failure NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: 978-1-4731-3093-7 hospitalisations (n=945). Mortality did not demonstrate a clear effect with the confidence interval ranging from a decrease and increase in all-cause mortality. BBs: For the comparison of BBs versus placebo the majority of the evidence was rated as very low quality. The outcome all-cause mortality suggested a clinically important reduction in deaths for CKD class 3a (n=1645) and CKD class 3b-4 (n=958) with BBs. This was also the case for the composite outcome of death or hospitalisation (CKD class 3a (n=669) and hospitalisation alone (CKD class 3a (n=870) and CKD class 3b-4 (n=341)). There was also a clinically important reduction in HF hospitalisations for both CKD class 3a (n=669) and CKD class 3b-4 (n=450) with BBs. For the outcomes bradycardia and hypotension there was no clinical effect of BBs (n=886). Mortality in the CKD class 3-4 (n=704) and CKD class 3b-4 (n=235))did not demonstrate a clear effect with the confidence interval ranging from a decrease and increase in all-cause mortality. Digoxin: For the comparison of digoxin versus placebo the majority of the evidence was rated as very low quality. Mortality in both CKD class 3a-b (n=2939) and CKD class 4-5 (n=218)did not demonstrate a clear effect with the confidence interval ranging from a decrease and increase in all-cause mortality.This was also the case for the composite outcome of death or hospitalisation which again showed a clinically important reduction in events with digoxin. Ivabradine: For the comparison of ivabradine versus placebo the evidence ranged from low to very low quality, and suggested no clinical effect of ivabradine on the outcomes renal function (n=865), renal failure (n=1579), hyperkalaemia (n=1579) and symptomatic bradycardia (n=1579). MRAs: For the comparison of MRA versus placebo the evidence ranged from low to very low quality. HF hospitalisations (n=792) suggested a clinically important reduction with MRAs. This was also the case for the combined outcome of cardiovascular mortality and HF admission (n=912) (associated with wide confidence intervals around the effect estimate). For the outcome hyperkalemia the evidence suggested a clinically important increase with MRAs (n=1675). Mortality (n=792) did not demonstrate a clear effect with the confidence interval ranging from a decrease and increase in all-cause mortality. Economic No relevant economic evaluations were identified. 6.2.6.6 Recommendations and link to evidence Recommendations For people who have heart failure with reduced ejection fraction and chronic kidney disease with an eGFR of 30ml/min/1.73 m2 or above: Offer the treatment outlined in section 6.2.7 and If the person s eGFR is 45ml/min/1.73 m2 or below, consider lower doses and/or slower titration of dose of ACE inhibitors or ARBs, mineralocorticoid receptor antagonists and digoxin. [2018] For people who have heart failure with reduced ejection fraction and chronic kidney disease with an eGFR below 30 ml/min/1.73 m2 , the Chronic Heart Failure Treating Heart Failure NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: 978-1-4731-3093-7 specialist heart failure MDT should consider liaising with a renal physician. Monitor the response to titration of medicines closely in people who have heart failure with reduced ejection fraction and chronic kidney disease, taking into account the increased risk of hyperkalaemia. [2018] Relative values of different outcomes The committee agreed that all-cause mortality, all-cause unplanned hospitalisation and quality of life were the most critical outcomes for determining the efficacy and potential harms of heart failure medications in people with CKD. The committee agreed that the impact of heart failure medication on renal function, and adverse events of the medication (specifically, bradycardia, arrhythmia, hypotension and hyperkalaemia) were also important outcomes. No evidence was found on the effect of any of the medications on quality of life in people with HF and CKD. Quality of the clinical evidence The evidence found was exclusively from subgroup analyses (SGA) of trials in the general HFREF population. None of the subgroups had been pre-specified and stratified, which introduced a risk of bias. Four of the SGAs were published over 10 years after the overall trial was published. The baseline population characteristics of the intervention and control arms within each subgroup were often not published, preventing a proper assessment of the risk of selection bias. The analysis was sometimes given as summary statistics only, without details regarding the numbers in each group, which may also have resulted in bias. These factors combined, along with additional bias issues specific to the individual studies and outcomes, meant that all the evidence found had a high or very high risk of bias. The studies frequently used a composite outcome of death or hospitalisation, which led to the evidence being downgraded for indirectness, as it was not possible to assess the impact on each of these critical outcomes separately. A number of medications had no reported evidence with regards to the population with CKD: loop diuretics; sacubitril-valsartan; and hydralazine- nitrate. The only evidence found on hydralazine-nitrate was the African American Heart Failure Trial327 which was excluded, as the possible CKD subgroup was referred to as having history of chronic renal insufficiency without further definition. Twelve SGAs were considered, 10 of which compared intervention to placebo and 2 that compared different doses of the same drug. There were no intra or inter class comparisons. Most trials considered the intervention on top of existing heart failure drugs (for the era in which the trial took place), except for when Angiotensin II Receptor Blocker (ARB) was considered as an alternative when Angiotensin Converting Enzyme Inhibitors (ACE-I) were not tolerated. Notwithstanding the limitations of the evidence base, the committee agreed that it was important to provide advice for this common subgroup of HFREF patients. Based on the evidence reviewed and the experience of the committee members, consensus was reached on the optimal treatment approach for patients with HFREF and CKD (see discussion below). Trade-off between clinical benefits The committee noted the new HFREF treatment algorithm in this guideline. First-line is double therapy with beta-blocker and ACE-I; or if ACE-I is not Chronic Heart Failure Treating Heart Failure NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: 978-1-4731-3093-7 and harms tolerated, an ARB. If still symptomatic, the addition of a Mineralocorticoid Receptor Antagonist (MRA) ( triple therapy ). Beta-blocker, ACE-I/ARB and MRA combined is referred to as triple therapy . Further medication options after seeking specialist advice, might be sacubitril valsartan (in place of ACEi [or ARB]), digoxin, or ivabradine. For people with CKD stage III and HFREF, the evidence suggested that ACE-I are efficacious and do not result in excess renal complications (such as hyperkalaemia). The committee agreed that ACE-I should be used as part of first-line treatment, as in the general HFREF population. This approach accords with the current practice of regularly prescribing ACE-I in CKD to prevent adverse cardiovascular outcomes. However, people with both CKD and HFREF appear not to get the same increased benefit of a high dose ACEI-I seen in the general HFREF population, perhaps because of additional renal adverse effects related to the drug. The committee agreed that prescribers may wish to carefully consider the utility of titrating to the highest doses in this population, as a lower dose may be just as effective overall, when the potential harms are weighed against the benefits. The high absolute risk of hyperkalaemia was not felt to be a reason to withhold these effective drugs, but should lead to increased attention in monitoring. The evidence also suggested an overall benefit of beta-blockers as first-line treatment alongside ACE-I. This is aligned with practice, with beta-blockers being routinely prescribed in patients with HFREF and established kidney disease. The committee agreed that the evidence on MRA in the CKD/HFREF population also supported the adoption of the general recommendation that it should be prescribed if patients are still symptomatic on beta-blocker plus ACE-I. Just as for the general HFREF population, any further medication (beyond beta-blockers, ACE-I and MRA) for heart failure in people with CKD should be prescribed by, or in liaison with, a heart failure specialist. The committee noted that ARBs for people with CKD showed only limited benefit, based on the evidence reviewed. For digoxin, there was no safety evidence, and the committee expressed concern that the risk of complete heart block and digitalis toxicity may be higher in those with CKD. As digoxin is primarily excreted by the kidneys, safe use of digoxin in people with CKD would include dose titration based on biochemistry and appropriate monitoring, such as the regimen used in the DIG trial 97 . The risk of hyperkalaemia is important in this group. Several studies showed high numbers of additional incidents of hyperkalaemia in the intervention arm. But the risk of hyperkalaemia in this group is not confined to the issue of these particular drugs, as the risk for patients with CKD is high even on placebo. In CKD stage IV, monitoring is already fairly intensive, so any incident hyperkalaemia should be identified and responded to quickly. For people with CKD stage III on heart failure medication, especially on triple therapy, the committee stressed the importance of monitoring of electrolytes and appropriate response to any deterioration. In general, the committee felt the evidence shows the efficacy and safety of specific drugs in this group of patients with renal impairment. Patients with HFREF and CKD stage IIIa or less should be offered standard double or triple therapy, with appropriate modifications to dosing and careful monitoring. The evidence in stage IIIb patients was more limited, and while this group Chronic Heart Failure Treating Heart Failure NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: 978-1-4731-3093-7 would also benefit from standard HFREF therapies, the evidence was not sufficient to support an offer recommendation. Instead, the committee agreed that standard HFREF drugs should be considered in this group. In CKD stage IV, the side effects of all of these medications is likely to be increased. While there is not a substantial evidence base in this population, the committee agreed that standard HFREF treatment recommendations should generally be applied, subject to the consideration of individual risk factors and liaison with renal specialists as appropriate. Trade-off between net clinical effects and costs No previously published economic evaluations were identified specifically for patients with heart failure and chronic kidney disease. Unit costs were not presented to the committee as all of the drugs reviewed are already recommended for all patients with HFREF and have been shown to be cost- effective treatments The committee discussed the cost of monitoring that is required in patients with both HFREF and CKD. The cost of monitoring would primarily involve blood tests to assess serum sodium, potassium, creatinine and eGFR and are therefore likely to be consist of a biochemistry blood test which is a small cost. The committee stressed that close monitoring is even more important in patients with CKD to help prevent hyperkalaemia and possible acute kidney injuries, and therefore the cost of monitoring could be offset by the savings by reducing the potential adverse effects of heart failure treatment on kidney function. The committee stated that close monitoring of patients with HFREF and CKD is common in current practice as these patients are high risk and therefore did not consider that there would be a significant additional resource impact. Based on the balance of the clinical risks and benefits the committee considered that as these drugs are highly cost effective for HF-REF patients and the additional cost of monitoring would be low that these treatments would remain cost effective in patients with HFREF and CKD stages I to IIIb. Other considerations Most patients with heart failure will have some degree of renal impairment. Specialist renal care for people with co-morbid CKD and heart failure is unusual, as renal physicians generally take referrals only after stage IV, unless there are other kidney issues. The committee reported a lack of clarity about using ACE-I, ARB and MRA in patients with CKD where renal function is declining. They discussed that in these circumstances, total cessation of these medications may deprive patients of the beneficial effects on morbidity and mortality. Therefore, modification to the doses of these agents, or even temporary cessation of one or more agents, should be made based on individual patient circumstances, and guidance from renal physicians should be considered where necessary. Due to the lack of evidence identified in this review for those with more severe CKD the committee noted this as an area warranting further research attention. In particular, the committee considered it important to establish the safety and optimal dosing for people with HFREF and more severe CKD (stages IIIb or greater). Chronic Heart Failure Treating Heart Failure NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: 978-1-4731-3093-7 6.2.7 All recommendations for the pharmacological treatment of heart failure 25.Diuretics should be routinely used for the relief of congestive symptoms and fluid retention in people with heart failure, and titrated (up and down) according to need following the initiation of subsequent heart failure therapies. [2003] 26.People who have heart failure with preserved ejection fraction should usually be offered a low to medium dose of loop diuretics (for example, less than 80 mg furosemide per day). People whose heart failure does not respond to this treatment will need further specialist advice. [2003, amended 2018] 6.2.7.2 Calcium-channel blockers 27.Avoid verapamil, diltiazem and short-acting dihydropyridine agents in people who have heart failure with reduced ejection fraction. [2003, amended 2018] 28.Make the decision to prescribe amiodarone in consultation with a specialist. [2003] 29.Review the need to continue the amiodarone prescription at the 6-monthly clinical 30.Offer people taking amiodarone liver and thyroid function tests, and a review of side effects, as part of their routine 6-monthly clinical review. [2003, amended 2018] 31.For people who have heart failure and atrial fibrillation, follow the recommendations on anticoagulation in the NICE guideline on atrial fibrillation. Be aware of the effects of impaired renal and liver function on anticoagulant therapies. [2018] 32.In people with heart failure in sinus rhythm, anticoagulation should be considered for those with a history of thromboembolism, left ventricular aneurysm or intracardiac 6.2.7.5 Contraception and pregnancy In women of childbearing potential who have heart failure, contraception and pregnancy should be discussed. If pregnancy is being considered or occurs, specialist advice should be sought. Subsequently, specialist care should be shared between the cardiologist and 6.2.7.6 ACE inhibitors and beta-blockers 33.Offer an angiotensin-converting enzyme (ACE) inhibitor and a beta-blocker licensed for heart failure to people who have heart failure with reduced ejection fraction. Use clinical judgement when deciding which drug to start first. [2010 ] Chronic Heart Failure Treating Heart Failure NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: 978-1-4731-3093-7 34.Do not offer ACE inhibitor therapy if there is a clinical suspicion of haemodynamically significant valve disease until the valve disease has been assessed by a specialist. [2003] 35.Do not withhold treatment with a beta-blocker solely because of age or the presence of peripheral vascular disease, erectile dysfunction, diabetes, interstitial pulmonary disease or chronic obstructive pulmonary disease. [2010] 6.2.7.6.1 Starting and monitoring ACE inhibitors 36.Start ACE inhibitor therapy at a low dose and titrate upwards at short intervals (for example, every 2 weeks) until the target or maximum tolerated dose is reached. [2010] 37.Measure serum sodium and potassium and assess renal function before and 1 to 2 weeks after starting an ACE inhibitor, and after each dose increment.[2010,amended 2018] 38. Measure blood pressure before and after each dose increment of an ACE inhibitor. Follow the recommendations on measuring blood pressure, including measurement in people with symptoms of postural hypotension, in the NICE guideline on hypertension in 39.Once the target or maximum tolerated dose of an ACE inhibitor is reached, monitor treatment monthly for 3 months and then at least every 6 months, and at any time the person becomes acutely unwell. [2010, amended 2018] 6.2.7.6.2 Starting and monitoring beta-blockers 40.Introduce beta-blockers in a start low, go slow manner. Assess heart rate, and clinical status after each titration. Measure blood pressure before and after each dose increment of a beta-blocker. [2010, amended 2018] 41.Switch people whose condition is stable and who are already taking a beta-blocker for a comorbidity (for example, angina or hypertension), and who develop heart failure with reduced ejection fraction, to a beta-blocker licensed for heart failure. [2010] 6.2.7.7 Alternative treatments if ACE inhibitors are not tolerated 6.2.7.7.1 Angiotensin II receptor antagonists (ARBs) 42.Consider an angiotensin II receptor blocker (ARB) licensed for heart failure as an alternative to an ACE inhibitor for people who have heart failure with reduced ejection fraction and intolerable side effects with ACE inhibitors. [2010] 43.Measure serum sodium and potassium and assess renal function before and after starting an ARB and after each dose increment.[2010, amended 2018] 44.Measure blood pressure after each dose increment of an ARB. Follow the recommendations on measuring blood pressure, including measurement in people with symptoms of postural hypotension, in the NICE guideline on hypertension in adults. Chronic Heart Failure Treating Heart Failure NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: 978-1-4731-3093-7 45.Once the target or maximum tolerated dose of an ARB is reached, monitor treatment monthly for 3 months and then at least every 6 months, and at any time the person becomes acutely unwell. [2010 amended 2018] 6.2.7.7.2 Hydralazine in combination with nitrate 46.If neither ACE inhibitors nor ARBs are tolerated, seek specialist advice and consider hydralazine in combination with nitrate for people who have heart failure with reduced ejection fraction. [2010] 6.2.7.8 Additional treatments if heart failure remains symptomatic or worsens 6.2.7.8.1 Mineralcorticoid receptor antagonists (MRAs) 47.Offer a mineralcorticoid receptor antagonist (MRA) in addition to an angiotensin- converting enzyme inhibitor (ACE) or ARB and beta-blocker, to people who have heart failure with reduced ejection fraction if they continue to have symptoms of heart failure. 48.Measure serum sodium and potassium and assess renal function before and after starting an MRA and after each dose increment. [2018] 49.Measure blood pressure before and after each dose increment of 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. 50.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] 6.2.7.8.2 Specialist treatment Ivabradine 6.2.7.8.3 These recommendations are from Ivabradine for treating chronic heart failure (NICE technology appraisal guidance 267). 51.Ivabradine is recommended as an option for treating chronic heart failure for people: with New York Heart Association (NYHA) class II to IV stable chronic heart failure with systolic dysfunction and who are in sinus rhythm with a heart rate of 75 beats per minute (bpm) or more and who are given ivabradine in combination with standard therapy including beta-blocker therapy, angiotensin-converting enzyme (ACE) inhibitor and aldosterone antagonists, or when beta-blocker therapy is contraindicated or not tolerated and with a left ventricular ejection fraction of 35% or less. [2012] 52.Ivabradine should only be initiated after a stabilisation period of 4 weeks on optimised standard therapy with ACE inhibitors, beta-blockers and aldosterone antagonists. [2012] Chronic Heart Failure Treating Heart Failure NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: 978-1-4731-3093-7 53.Ivabradine should be initiated by a heart failure specialist with access to a multidisciplinary heart failure team. Dose titration and monitoring should be carried out by a heart failure specialist, or in primary care by either a GP with a special interest in heart failure or a heart failure specialist nurse. [2012] Sacubitril valsartan These recommendations are from Sacubitril valsartan for treating symptomatic chronic heart failure with reduced ejection fraction (NICE technology appraisal guidance 388)a . 54.Sacubitril valsartan is recommended as an option for treating symptomatic chronic heart failure with reduced ejection fraction, only in people With New York Heart Association (NYHA) class II to IV symptoms and With a left ventricular ejection fraction of 35% or less and Who are already taking a stable dose of angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor-blockers (ARBS) [2016] 55.Treatment with sacubitril valsartan should be started by a heart failure specialist with access to a multidisciplinary heart failure team. Dose titration and monitoring should be performed by the most appropriate team members as defined in NICE s guideline on chronic heart failure in adults: diagnosis and management. [2016] 56.This guidance is not intended to affect the position of patients whose treatment with sacubitril valsartan was started within the NHS before this guidance was published. Treatment of those patients may continue without change to whatever funding arrangements were in place for them before this guidance was published until they and their NHS clinician consider it appropriate to stop. [2016] Hydralazine in combination with nitrate 57.Seek specialist advice and consider offering hydralazine in combination with nitrate (especially if the person is of African or Caribbean family origin and has moderate to severe heart failure [NYHA class III/IV] with reduced ejection fraction).[2010] Digoxin For recommendations on digoxin for people with atrial fibrillation see the section on rate and rhythm control in the NICE guideline on atrial fibrillation 58.Digoxin is recommended for worsening or severe heart failure with reduced ejection fraction despite first line treatment for heart failureb . Seek specialist advice before 59.Routine monitoring of serum digoxin concentrations is not recommended. A digoxin concentration measured within 8 12 hours of the last dose may be useful to confirm a clinical impression of toxicity or non-adherence[2003] b For recommendations on digoxin for people with atrial fibrillation see the section on rate and rhythm control in the NICE guideline on atrial fibrillation Chronic Heart Failure Treating Heart Failure NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: 978-1-4731-3093-7 60.the serum digoxin concentration should be interpreted in the clinical context as toxicity may occur even when the concentration is within the therapeutic range . [2003] 6.2.7.9 Chronic kidney disease 61.For people who have heart failure with reduced ejection fraction and chronic kidney disease with an eGFR of 30 ml/min/1,73 m2 or above: (estimated glomerular filtration rate) as follows. Offer the treatment outlined in section 6.2.7 and If the person s eGFR is 45 ml/min/1.73 m2 or below, consider lower doses and/or slower titration of dose of ACE inhibitors or ARBs, mineralcorticoid receptor antagonists and 62.For people who have heart failure with reduced ejection fraction and chronic kidney disease with an eGFR below 30 ml/min/1.73 m2, the specialist heart failure MDT should consider liaising with a renal physician [2018] 63.Monitor the response to titration of medicines closely in people who have heart failure with reduced ejection fraction and chronic kidney disease, taking into account the increased risk of hyperkalaemia. [2018] Chronic Heart Failure Treating Heart Failure NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: 978-1-4731-3093-7 6.3 Invasive procedures The update to the heart failure guideline includes topics where new evidence has emerged since the publication in 2010. A review of new evidence published after 2010 was carried out in order to determine whether any changes to current recommendations where likely to be required. The decision on which topics to include in the update of the guideline was made following consultation of the scope. This section with the exception of coronary revascularisation was not within the scope of the update. For more information on the following aspects of invasive procedures such as cardac transplantation please refer to appendix R in the 2003 guideline. 6.3.1 Coronary revascularisation Coronary artery disease (CAD) and heart failure often coexist and a majority of people with heart failure and reduced ejection fraction (HFREF) in the UK will have an ischaemic aetiology149 . Myocardial ischaemia is therefore often an important additional consideration in the management of people with heart failure. Concomitant severe CAD may warrant consideration for revascularisation with coronary artery bypass graft surgery (CABG) or percutaneous coronary intervention (PCI) in view of uncontrolled angina despite medical therapy, evidence of substantial myocardial ischaemia and viability or while undergoing valve intervention. Thus it might appear logical that coronary revascularisation, undertaken either surgically with CABG, or percutaneously with angioplasty, might result in improved outcomes when compared with medical therapy alone. However, the presence of left ventricular systolic dysfunction (LVSD) significantly increases the risk of both surgical and percutaneous revascularisation 373 and, if severe, may contraindicate CABG surgery altogether. Historically, however, there has only been anecdotal evidence of improvement in symptoms or left ventricular function following revascularisation in people with heart failure in the absence of the above special indications. Early randomised studies of coronary artery bypass grafting appeared to support revascularisation, whereby the patients who derived most benefit from surgical intervention were also those patients with impaired LV function, albeit in the context of selective randomisation. However, the landscape of cardiovascular management has changed through the prescription of newer drug therapies, routine acute angioplasty, changes in surgical interventions and the availability of device therapies such as implantable cardioverter defibrillators. It is therefore unclear if people with HFREF and severe CAD should be routinely offered myocardial revascularisation with CABG or PCI. Current practice varies widely depending on local interest and expertise as well as individual patient characteristics. This review was carried out to evaluate the emerging evidence in the field since the previous guidance was published regarding the clinical and cost effectiveness of coronary revascularisation in people with heart failure. 6.3.1.2 Review question: What is the clinical and cost effectiveness of coronary revascularisation with coronary artery bypass grafting or angioplasty in people with heart failure? For full details see review protocol in Appendix A. Table 68: PICO characteristics of review question Population People diagnosed with heart failure with reduced ejection fraction (HFREF). Intervention Coronary artery bypass graft surgery (CABG) CABG + ventricular reconstruction Percutaneous coronary intervention (PCI) Chronic Heart Failure Treating Heart Failure NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: 978-1-4731-3093-7 Comparison Medical management Outcomes CRITICAL All-cause mortality at 30 days (Time to event) All-cause mortality (Time to event) Quality of life at 12 months (Continuous) Unplanned hospitalisation at 12 months (Count rate) IMPORTANT Additional revascularisation events at 24 months (Count rate) Improvement of NYHA class at 12 months (Dichotomous) Improvement in ejection fraction at 12 months (Dichotomous) Adverse events - stroke at 12 months (Dichotomous) Study design Systematic Review RCT 6.3.1.3 Clinical evidence A search was conducted for randomised trials comparing the effectiveness of coronary revascularisation (CABG, CABG + ventricular reconstruction or PCI) with medical management in people with heart failure and reduced ejection fraction. Two studies (reported in 14 publications) were included in the review: HEART65 . These are summarised in Table 69 below. HEART compared an invasive strategy (angiography followed by PCI or CABG at the clinician s discretion) with medical management; STICH compared CABG and medical management. Evidence from these studies is summarised in the clinical evidence summaries below (Table 70 and Table 71). 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. Two studies were included within the 2003 CHF guideline.24, 75 and referred to narratively. These studies have been excluded within the current update as they no longer match the review protocol. For further explanation please see the excluded studies table (appendix I) and the Recommendations and link to evidence. Chronic Heart Failure Treating Heart Failure NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: 978-1-4731-3093-7 Table 69: Summary of studies included in the review Study Intervention and comparison Population Outcomes Comments HEART CABG plus medical therapy n = 30 PCI plus medical therapy n = 15 Medical therapy n = 64 Age, median (IQR): therapy 69 (60 74). %Male: CABG/PCI 94; medical therapy 93. NYHA class, n: I CABG/PCI - 13; medical therapy - II CABG/PCI 28; medical therapy - III/IV CABG/PCI 28; medical therapy 22. All-cause mortality; Dichotomous Quality of life difference between the groups reported only. Quality of life - Minnesota Living With Heart Failure Questionnaire; Mean difference between the groups reported only. Median follow-up of 4.9 years. Only 138 of the planned 800 patients were enrolled because of withdrawal of funding due to slow recruitment and because the larger STICH trial became available. CABG plus medical therapy n = 610 Medical therapy n = 602 Age year, median (IQR): medical therapy 59 (53-67). %Male: CABG 88; medical therapy 88. NYHA class, n: I CABG 65, medical therapy II IV CABG 545; medical therapy 528. All-cause mortality at 30 days and 5 years Quality of life Kansas City Cardiomyopathy Questionnaire. Adjusted mean difference Quality of life state index); Adjusted mean difference Quality of life Adjusted mean difference Quality of life Adjusted mean difference All-cause hospitalisations Median follow-up of 9.8 years. The use of implantable defibrillators was encouraged as part of standard medical therapy. Data was adjusted for patients for repeated assessments of quality of life. 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 Stroke Subsequent procedures CABG Subsequent procedures PCI No. in NYHA Class I Treating Heart Failure Chronic Heart Failure NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: 6.3.1.3.1 CABG versus medical therapy Table 70: Clinical evidence summary: CABG + Medical therapy versus medical therapy Outcomes No of Participants (studies) Follow up Quality of the evidence (GRADE) Relativ e effect CI) Anticipated absolute effects Risk with medical therapy Risk difference with CABG (95% CI) All-cause mortality 1212 MODERATEa due to risk of bias (from 27 fewer to 130 fewer) All-cause mortality at 30 days 1212 MODERATEa due to risk of bias (from 4 more to 70 more) Quality of life - EQ-5D Scale from: 0 to 1. LOWa,b due to risk of bias, imprecision The mean quality of life EQ-5D at 12 months in the control groups was The mean quality of life EQ-5D at 12 months in the intervention groups was Quality of life - EQ5D-VAS Scale from: 0 to 100 MODERATEa due to risk of bias The mean quality of life - EQ5D-VAS in the control groups was The mean quality of life - EQ5D-VAS in the intervention groups was Quality of life KCCQ (quality of life domain) Scale from: 0 to 100. MODERATE a due to risk of bias The mean quality of life - KCCQ at 12 months in the control groups was The mean quality of life - KCCQ at 12 months in the intervention groups was Quality of life - SF-12 (Physical component) MODERATEa due to risk of bias The mean quality of life SF-12 (physical component) at 12 months in the control groups was The mean quality of life SF-12 (physical component) at 12 months 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) Relativ e effect CI) Anticipated absolute effects Risk with medical therapy Risk difference with CABG (95% CI) Quality of life - SF-12 (Mental Component) MODERATEa due to risk of bias The mean quality of life SF-12(mental component) at 12 months in the control groups was The mean quality of life SF-12 (mental component) at 12 months in the intervention groups was All-cause hospitalisations 1212 MODERATEb due to imprecision (from 34 fewer to 141 fewer) Subsequent procedures - CABG 1212 MODERATEa due to risk of bias Peto Odds Ratio (from 138 fewer to 153 fewer) Subsequent procedures - PCI 1212 LOWa,b due to risk of bias, imprecision (from 35 fewer to 8 more) NYHA class I 1212 LOWb,c due to imprecision, indirectness (from 21 more to 140 more) LOWa,b due to risk of (from 16 fewer to 47 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) Relativ e effect CI) Anticipated absolute effects Risk with medical therapy Risk difference with CABG (95% CI) bias, imprecision (a) Downgraded by 1 increment if majority of the evidence was rated high risk of bias, downgraded by 2 increments if majority of the evidence was rated very high risk of bias. (b) Downgraded by 1 increment if the confidence interval crossed one MID, downgraded by 2 increments if the confidence interval crossed both MIDs. (c) Downgraded by 1 increment due to indirectness of the outcome (protocol outcome improvement in NYHA class; extracted outcome no. in NYHA class I). 6.3.1.3.2 Invasive strategy (angiography with intent to revascularise (with CABG or PCI) versus medical therapy Table 71: Clinical evidence summary: Invasive strategy + medical therapy versus medical therapy Outcomes No of Participants (studies) Follow up Quality of the evidence (GRADE) Relative effect Anticipated absolute effects Risk with medical therapy Risk difference with invasive strategy (95% CI) All-cause mortality 136 VERY LOWa,b due to risk of bias, imprecision (from 121 fewer to 224 more) Quality of life - EQ-5D Scale from: 0 to 1. VERY LOWa,b due to risk of bias, imprecision c The mean quality of life EQ-5D at 6 months in the intervention groups was (0.14 lower to 0.10 higher) Quality of life - MLWHF Scale from: 0 to 105. VERY LOWa,b due to risk of bias, imprecision c The mean quality of life - MLWHF at 6 months in the intervention groups was (11.35 lower to 3.55 higher) (a) Downgraded by 1 increment if majority of the evidence was rated high risk of bias, downgraded by 2 increments if majority of the evidence was rated very high risk of bias. (b) Downgraded by 1 increment if the confidence interval crossed one MID, downgraded by 2 increments if the confidence interval crossed both MIDs. (c) Unable to calculate as the study only reported the overall mean difference. Treating Heart Failure Chronic Heart Failure NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: Chronic Heart Failure Treating Heart Failure NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: 978-1-4731-3093-7 6.3.1.4 Economic evidence Published literature No relevant health economic studies were identified. 