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) 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. 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) 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. 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) 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.


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.


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.


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.


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.


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. All rights reserved. Subject to Notice of rights.


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. All rights reserved. Subject to Notice of rights. 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).


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.


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.


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).


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.


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.


[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.


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.


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.


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.


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 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.


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.


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.


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.


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).


[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 .


[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.


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.


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.


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.


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.


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.


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.


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.


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) 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).


(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.


ISBN: 978-1-4731-3093-7 6.3.1.4 Economic evidence Published literature No relevant health economic studies were identified. See also the health economic study selection flow chart in Appendix D. Unit costs The unit cost of the revascularisation procedures are shown in Table 72 below. The unit cost of all- cause hospitalisation is also provided in Table 73. Table 72: Cost of revascularisation procedures Procedure Code Average cost Source Coronary Artery Bypass Graft (without ventricular reconstruction) Complex Coronary Artery Bypass Graft (CC score 10+) 17,714 NHS reference costs Percutaneous Coronary Intervention Standard Percutaneous Transluminal Coronary Angioplasty (CC score 8-12+) 4,928 (a) NHS reference costs (a) Weighted cost using the activity reported for each of the included HRG codes. Table 73: Unit costs of all-cause hospitalisation Description Unit cost Source All-cause hospitalisation (non-elective) 2,930 NHS Reference costs 2014/15242 6.3.1.5 Evidence statements Clinical Two studies (reported in 14 publications) were identified for inclusion within the review: The evidence compared both an invasive strategy (angiography followed by PCI or CABG at the clinician s discretion) with medical management and CABG (plus medical management) with medical management alone. The evidence for the outcomes from one study (n=1212) comparing CABG (plus medical management) with medical management alone ranged from moderate to very low. This was due to a risk of bias and imprecision as a result of wide confidence intervals around the effect estimate. A single outcome (NYHA class I) was downgraded due to indirectness of the outcome. The outcome reported was the number of people in NYHA class I at the specified follow-up point of 4.7 years rather than the protocol outcome which was improvement in NYHA class. QoL as measured by the EQ-5D, EQ-5D VAS and KCCQ; all-cause hospitalisation and the need for subsequent procedures (CABG and PCI) showed clinically important benefit from CABG (plus medical management).


QoL as measured by the EQ-5D, EQ-5D VAS and KCCQ; all-cause hospitalisation and the need for subsequent procedures (CABG and PCI) showed clinically important benefit from CABG (plus medical management). The outcomes QoL (SF-12) and stroke showed no clinically important effect of CABG (plus medical management). All-cause mortality at 30 days showed a clinically important harm of CABG (plus medical management), while at the extended follow-up period of 9.8 years there was evidence of a Chronic Heart Failure Treating Heart Failure NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: 978-1-4731-3093-7 clinical benefit of CABG (plus medical management). No evidence was found for the outcome improvement in ejection fraction. The evidence for the outcomes from one study (n=136) comparing an invasive strategy (angiography followed by PCI or CABG at the clinician s discretion) with medical management were all rated as very low. This was due to a risk of bias and imprecision as a result of wide confidence intervals around the effect estimate. Evidence for the outcome all-cause mortality showed a clinically important harm of the invasive strategy (associated with wide confidence intervals around the effect estimate) while evidence for the outcome QoL as measured by the EQ-5D and MLWHF showed no clinically important effect. No evidence was found for improvement in ejection fraction. Economic No relevant economic evaluations were identified. Chronic Heart Failure Treating Heart Failure NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: 978-1-4731-3093-7 6.3.1.6 Recommendations and link to evidence Recommendations Do not routinely offer coronary revascularisation to people who have heart failure with reduced ejection fraction and coronary artery disease.


ISBN: 978-1-4731-3093-7 6.3.1.6 Recommendations and link to evidence Recommendations Do not routinely offer coronary revascularisation to people who have heart failure with reduced ejection fraction and coronary artery disease. [2018] Relative values of different outcomes The committee considered the following outcomes to be critical for this review: all-cause mortality (over study duration), all-cause mortality (at 30 days), quality of life, and all-cause hospitalisation. Data on all-cause mortality and hospitalisation were considered preferable to data limited to heart failure-related mortality and hospitalisations, as such data take into account the broader unintended consequences of the interventions (for example, an increase in mortality or hospitalisations due to adverse events or surgical complications). Improvement in ejection fraction and NYHA class, as well as additional revascularisation events and stroke, were also considered to be important for decision-making. For the comparison of CABG versus medical therapy, there was evidence on all outcomes except for improvement in ejection fraction. For the comparison of an invasive strategy versus medical therapy, there was only evidence for all-cause mortality (over study duration) and quality of life. Quality of the clinical evidence CABG versus medical therapy: The evidence for the outcome of all-cause mortality over the duration of the study was graded low quality due to risk of bias (differential cross-over rates in the intervention and control groups) and imprecision (based on the wide confidence intervals around the relative effect). However, the committee noted that the sensitivity analysis performed by the study authors suggested that the high rate of cross-over might have underestimated the beneficial effect of CABG on mortality, and also noted that the confidence intervals around the absolute effect were reasonably narrow and showed a clinically important benefit.


However, the committee noted that the sensitivity analysis performed by the study authors suggested that the high rate of cross-over might have underestimated the beneficial effect of CABG on mortality, and also noted that the confidence intervals around the absolute effect were reasonably narrow and showed a clinically important benefit. The outcome of all-cause mortality at 30 days was graded moderate quality due to risk of bias (the cross-over rate being higher than the event rate). The evidence for the various quality of life measures were of moderate quality due to risk of bias (attrition). For all-cause hospitalisations, the evidence was graded moderate quality due to imprecision based on the wide confidence intervals around the relative risk estimate, but the committee noted that the confidence intervals around the absolute effect were reasonably narrow and showed a clinically important benefit. The evidence for subsequent CABG procedures was of moderate quality due to risk of bias (attrition), and for both subsequent PCI procedures and stroke was of low quality due to risk of bias (attrition) and imprecision. Finally, the evidence for improvement in NYHA class was graded as low quality due to imprecision and indirectness (the study only reported numbers in class I NYHA at the end of the trial rather than all of those whose NYHA class improved). Invasive strategy versus medical therapy: The evidence for all outcomes was of very low quality. For mortality over the duration of the study, the evidence had very serious imprecision and high risk of bias (unbalanced baseline characteristics between the groups). The quality of life evidence was downgraded for imprecision and risk of bias (lack of blinding). The committee noted that the trial upon which this evidence Chronic Heart Failure Treating Heart Failure NICE 2018. All rights reserved. Subject to Notice of rights.


The committee noted that the trial upon which this evidence Chronic Heart Failure Treating Heart Failure NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: 978-1-4731-3093-7 Recommendations Do not routinely offer coronary revascularisation to people who have heart failure with reduced ejection fraction and coronary artery disease. [2018] was based, HEART,65 enrolled only 138 of the planned 800 patients and was thus underpowered. Other comparisons: There was no other evidence comparing PCI with medical therapy, or CABG plus ventricular reconstruction with medical therapy. Trade-off between clinical benefits and harms The committee discussed the evidence for an invasive strategy (angiography with intent to revascularise (with CABG or PCI)) versus medical therapy. The evidence on mortality suggested a possible clinical harm of an invasive strategy, but the committee was not confident in this evidence due to the very wide confidence intervals around the absolute risk difference (which range from clinically important benefit to clinically important harm) and the risk of bias. An invasive strategy appeared not to have a clinically important impact on quality of life, but again, the committee placed little weight on this evidence due to its very low quality. The committee discussed the evidence for CABG plus medical therapy, compared to medical therapy alone, and noted that CABG led to clinically important reductions in all-cause mortality and all-cause hospitalisations. The committee noted that this clinically important reduction in mortality was only evident at the extended follow-up period of 9.8 years, with 30 day mortality in patients receiving CABG being substantially higher than those receiving medical therapy alone (estimate of 24 more per 1000, ranging from 4 more to 70 more).


The committee noted that this clinically important reduction in mortality was only evident at the extended follow-up period of 9.8 years, with 30 day mortality in patients receiving CABG being substantially higher than those receiving medical therapy alone (estimate of 24 more per 1000, ranging from 4 more to 70 more). CABG was also associated with clinically important improvements in NYHA class and quality of life measured with EQ5D and the Kansas City Cardiomyopathy Questionnaire, though a smaller, not clinically important difference was found using the SF-12. These were notable given the invasive nature of the CABG procedure and the extended recovery period. Randomisation to receive CABG also led to fewer subsequent CABG and PCI procedures compared with patients randomised to medical therapy alone, though for subsequent PCI procedures the evidence was imprecise. For stroke, there appeared to be no clinically important difference between the groups, though the confidence intervals ranged from a clinically important benefit to a clinically important harm and so the committee was not confident in the effect estimate. In weighing up the benefits and harms of revascularisation, the evidence suggested that overall and in the long term, CABG led to improvements in critical outcomes for the people enrolled in the trial, albeit with substantial 30 day mortality. However, the committee had 2 serious concerns about the applicability of the evidence to modern clinical management of heart failure patients in the UK. The committee considered that the evidence for CABG was not generalisable to the majority of heart failure with reduced ejection fraction (HFREF) patients. The committee noted the evidence was based on a single trial ) and that the characteristics of the patients in that trial were not representative of the HFREF population in the UK community.


The committee noted the evidence was based on a single trial ) and that the characteristics of the patients in that trial were not representative of the HFREF population in the UK community. In particular, the committee noted the relatively young average age (60 in the CABG arm and 59 in the medical therapy arm). In contrast, the majority of ischemic HFREF patients in the UK are over 70 years of age, and older Chronic Heart Failure Treating Heart Failure NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: 978-1-4731-3093-7 Recommendations Do not routinely offer coronary revascularisation to people who have heart failure with reduced ejection fraction and coronary artery disease. [2018] patients tend to be frailer and would likely do less well following major surgery such as CABG. 149 After agreeing that CABG should not be routinely offered to typical HFREF patients, the committee discussed whether CABG would be appropriate for patients who present with risk profiles similar to the cohort assessed in STICH(ES). However, the committee was not convinced that the prognostic benefit demonstrated in STICH(ES) would be seen in modern practice. This was primarily because of the relatively small proportion of patients in the trial with Implantable Cardioverter Defibrillators (ICDs), which are now recommended for patients with heart failure and EF 35%.c The committee suggested that a higher rate of ICD usage may have improved the outcomes in the medical therapy arm. For the reasons above, the committee was not convinced that CABG would demonstrate the same beneficial effect in the current UK ischaemic HFREF population, and any possible benefit could be outweighed by an increased risk of serious adverse events during or post-surgery.


For the reasons above, the committee was not convinced that CABG would demonstrate the same beneficial effect in the current UK ischaemic HFREF population, and any possible benefit could be outweighed by an increased risk of serious adverse events during or post-surgery. In light of their concerns about generalisability and applicability of the evidence on CABG to the general HFREF population, the committee decided that CABG should not be routinely offered to patients with HFREF. However, the committee recognised that a proportion of patients with ischemic HFREF may derive substantial benefit from CABG in the long term. In particular, people with more severe coronary artery disease and in whom viability has been established may be more likely to obtain a greater benefit from CABG than the average benefit demonstrated in the STICH(ES) trial although the sub-study looking for an influence of viability on the surgical outcome was unable to confirm this. For HFREF patients with extensive coronary disease, who have a surgical risk profile similar to the patients enrolled in the STICH(ES) trial, clinicians may wish to discuss the evidence on CABG as part of shared decision making regarding treatment options. That this is an area of significant uncertainty should be openly discussed with patients. In any shared-decision making with patients about CABG, a thorough discussion about the potential risks and benefits will be essential to enable informed consent. This discussion should go beyond the immediate post-surgery risks. In particular, clinicians should address any misconception that so long as a patient pulls through the surgery, their heart failure will necessarily be fixed , as some patients will have an excellent symptomatic response and others far less.


In particular, clinicians should address any misconception that so long as a patient pulls through the surgery, their heart failure will necessarily be fixed , as some patients will have an excellent symptomatic response and others far less. It should be emphasised that where benefit accrues from CABG this only occurs after more than 5 years, and that to date it is difficult to identify which individuals will do well. The committee noted that in the UK, PCI is used more commonly than CABG for revascularisation, due to a lower rate of complications and shorter recovery period. However, the committee recognised that in heart failure, there is no RCT evidence on the effectiveness of PCI. A UK study of PCI in patients with HFREF (EF < 30%), extensive coronary disease and viable myocardium (in 30% of dysfunction segments) is currently underway c See TA314 Implantable cardioverter defibrillators and cardiac resynchronisation therapy for arrhythmias and heart failure Chronic Heart Failure Treating Heart Failure NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: 978-1-4731-3093-7 Recommendations Do not routinely offer coronary revascularisation to people who have heart failure with reduced ejection fraction and coronary artery disease. [2018] ). When considering the totality of the evidence for revascularisation, the committee decided that neither CABG nor PCI should be routinely offered to patients with HFREF. This was based on the absence of RCT level evidence supporting the use of PCI in HFREF, and the concerns regarding the applicability of the evidence on CABG in HFREF. Trade-off between net clinical effects and costs No previously published economic evaluations were identified assessing the cost-effectiveness of coronary revascularisation in a heart failure population; therefore the unit costs of CABG and PCI were presented to the committee for consideration of cost effectiveness alongside the clinical evidence.


Trade-off between net clinical effects and costs No previously published economic evaluations were identified assessing the cost-effectiveness of coronary revascularisation in a heart failure population; therefore the unit costs of CABG and PCI were presented to the committee for consideration of cost effectiveness alongside the clinical evidence. The committee discussed that a CABG in people with heart failure would be complex and associated with a prolonged length of stay in both the intensive care unit (ICU) and inpatient ward. The average length of stay reported in the STICH trial was 9 days. Taking these factors into account the committee agreed that the average unit cost for CABG would be at the higher end of the scale in people with heart failure of 17,714 [NHS reference cost HRG ED26A]. The committee also highlighted that additional costs would be incurred prior to a person receiving CABG due to the high cost imaging (perfusion cardiac MRI and/or an invasive angiography) required to determine the location and extent of revascularisation required and the feasibility of the procedure, further increasing costs. As mentioned in the trade-off between clinical benefits and harms section above, the population in the STICH(ES) trial is younger than the typical heart failure population. The committee discussed that there is an increased risk of mortality and complications of surgery with age and therefore agreed that CABG is unlikely to benefit the typical HF-REF population. Due to the high costs of the procedure, as well as the likely incurrence of additional costs of complications, the committee agreed that CABG is highly unlikely to be cost effective in the current UK heart failure population. The committee were uncertain about the cost effectiveness of CABG in a population that reflects those included in the STICH(ES) trial.


The committee were uncertain about the cost effectiveness of CABG in a population that reflects those included in the STICH(ES) trial. The committee discussed that due to the higher uptake of ICDs nowadays, especially in younger patients, the survival benefit of CABG compared to those receiving medical therapy alone found in STICH(ES) could be negated and the average QALY gain could be low. However, the true effect of this is uncertain. The committee agreed that in exceptional cases CABG may be cost effective for a small proportion of people (the committee estimate less than 1%) with ischaemia and with characteristics similar to those in the STICH trial. The committee discussed that CABG should be decided on a case by case basis, resembling current clinical practice, and therefore agreed on a do not routinely offer recommendation. The cost of a PCI is much lower than CABG at 4,928. However, as there was no clinical evidence for PCI alone, the committee could not determine the cost-effectiveness of PCI. The committee were aware that the cost- effectiveness of PCI will be assessed in a health technology assessment alongside the REVIVE trial and therefore did not consider it important to make a research recommendation in this area. Chronic Heart Failure Treating Heart Failure NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: 978-1-4731-3093-7 Recommendations Do not routinely offer coronary revascularisation to people who have heart failure with reduced ejection fraction and coronary artery disease. [2018] Other considerations The committee discussed current practice regarding coronary revascularisation for HFREF in the UK, and the potential impact of their recommendation. In the 2010 guideline, the recommendation was that coronary revascularisation should not be routinely considered. This was based on an evidence review conducted for the 2003 guideline, and the review was not updated in 2010.


This was based on an evidence review conducted for the 2003 guideline, and the review was not updated in 2010. The new recommendation clarifies that coronary revascularisation should not be routinely offered to patients with HFREF without angina, but allows clinicians to use their professional judgement to consider whether coronary revascularisation may be appropriate for each patient on a case by case basis. The committee considered that the new recommendation would be unlikely to have a significant resource impact as they do not consider that it will change current practice. The 2003 CHF guideline made reference to 2 papers narratively regarding this review question. These studies have been excluded within the current review as they were carried out previous to 2001 when new guidance regarding the use of beta-blockers for the management of HF were introduced. The committee agreed that this change in management was likely to have had an effect on treatment strategies overall and therefore only wished to consider studies carried out after 2001. Chronic Heart Failure Treating Heart Failure NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: 978-1-4731-3093-7 6.3.2 Recommendations for invasive procedures 6.3.2.1 Implantable cardioverter defibrillators and cardiac resynchronisation therapy See NICE s technology appraisal guidance on implantable cardioverter defibrillators and cardiac resynchronisation therapy for arrhythmias and heart failure 6.3.2.2 Coronary revascularisation 64.Do not routinely offer coronary revascularisation to people who have heart failure with reduced ejection fraction and coronary artery disease. [2018] 6.3.2.3 Cardiac transplantation 65.Specialist referral for transplantation should be considered for people with severe refractory symptoms or refractory cardiogenic shock [2003] Chronic Heart Failure Rehabilitation in chronic heart failure NICE 2018. All rights reserved. Subject to Notice of rights.


[2018] 6.3.2.3 Cardiac transplantation 65.Specialist referral for transplantation should be considered for people with severe refractory symptoms or refractory cardiogenic shock [2003] Chronic Heart Failure Rehabilitation in chronic heart failure NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: 978-1-4731-3093-7 7 Rehabilitation in chronic heart failure 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. In this section new evidence on home versus centre based cardiac rehabilitation was reviewed. 7.1 Home-based versus centre-based rehabilitation The importance of rehabilitation therapy has been recognised for many years in the management of patients post-myocardial infarction. Many patients with heart failure, especially those with heart failure with reduced ejection fraction (HFREF) have an underlying basis in myocardial iscahemia and previous myocardial events. A number of studies have investigated whether rehabilitation techniques deliver similar benefits in patients with heart failure to those achieved in patients after a myoacrdila infarct. The organisation of heart failure services is evolving to favour home and community-based interventions as opposed to hospital-based provision. There are known inequalities in access to hospital-based rehabilitation services across the UK. This question investigated whether home-based rehabilitation services could deliver similar outcomes to hospital- based rehabilitation services. 7.1.2 Review question: What is the clinical and cost effectiveness of home-based versus centre- based rehabilitation (that includes an exercise element) for people with heart failure (HF)? For full details see review protocol in appendix A.


7.1.2 Review question: What is the clinical and cost effectiveness of home-based versus centre- based rehabilitation (that includes an exercise element) for people with heart failure (HF)? For full details see review protocol in appendix A. Table 74: PICO characteristics of review question Population People diagnosed with HF Intervention Home-based cardiac rehabilitation (CR) service. Programme must be structured, with clear objectives for the participants, and include a monitoring component. Programmes will be included whether they are based solely on exercise or include such as education and/or psychological support other intervention elements (comprehensive cardiac rehabilitation). No minimum duration of intervention. Comparison Centre-based CR service (including community based rehabilitation service and hospital based rehabilitation service). Programme must be structured, with clear objectives for the participants, and include a monitoring component. Programmes will be included whether they are based solely on exercise or include other intervention elements such as education and/or psychological support ( comprehensive CR ). Outcomes CRITICAL All-cause mortality CV mortality Health-related quality of life All cause hospitalisation HF-related hospitalisation IMPORTANT Exercise capacity Chronic Heart Failure Rehabilitation in chronic heart failure NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: 978-1-4731-3093-7 Adverse events (withdrawal from the exercise programme) Adherence (including maintenance of exercise/physical activity) Health service use Study design RCTs (individual or cluster level, including parallel group, cross-over or quasi- randomised designs). 7.1.3 Clinical evidence The following review was conducted by the University of Exeter Medical School Cochrane Cardiac Rehabilitation group as part of a second update to the Cochrane systematic review Home versus centre-based Cardiac Rehabilitation 13 in accordance with NGC methodology. A search was conducted for randomised trials directly comparing home- with centre-based cardiac rehabilitation for people with heart failure. these are summarised in Table 75 below.


A search was conducted for randomised trials directly comparing home- with centre-based cardiac rehabilitation for people with heart failure. these are summarised in Table 75 below. Evidence from these studies is summarised in the clinical evidence summary below in Table 76. 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. All of the studies compared home-based exercise training (which included aerobic circuit training and walking) with centre-based (which included aerobic circuit training, treadmill walking and cycling). Summary of included studies Table 75: Summary of RCTs included in the review Study Intervention and comparison Population Outcomes Comments Cowie (Cowie , Cowie ) Intervention: aerobic circuit (guided by DVD and booklet), 2 weekly phone calls by a physiotherapist; no other treatments reported Frequency: twice per week Duration: 1 hour Intensity: 40-60% heart rate reserve or Borg 12-13, Control: As home but supervised (led by physiotherapist) and hospital-based; no other treatments n = 60 Age (range): 65.8 Gender: 85% male NYHA class II and Mean ejection fraction: NR (systolic dysfunction) Family origin not reported Single centre UK Mortality QoL(MLWHF) Exercise capacity (ISWT) Adherence Maximum duration of follow-up: 2 months The study reported median values only for the outcome QoL (MLWHF), therefore it has not been included in the analysis Daskapan Intervention: Outdoor Walking & n = 29 Mortality Exercise capacity Maximum duration of follow-up: Chronic Heart Failure Rehabilitation in chronic heart failure NICE 2018. All rights reserved. Subject to Notice of rights.


Summary of included studies Table 75: Summary of RCTs included in the review Study Intervention and comparison Population Outcomes Comments Cowie (Cowie , Cowie ) Intervention: aerobic circuit (guided by DVD and booklet), 2 weekly phone calls by a physiotherapist; no other treatments reported Frequency: twice per week Duration: 1 hour Intensity: 40-60% heart rate reserve or Borg 12-13, Control: As home but supervised (led by physiotherapist) and hospital-based; no other treatments n = 60 Age (range): 65.8 Gender: 85% male NYHA class II and Mean ejection fraction: NR (systolic dysfunction) Family origin not reported Single centre UK Mortality QoL(MLWHF) Exercise capacity (ISWT) Adherence Maximum duration of follow-up: 2 months The study reported median values only for the outcome QoL (MLWHF), therefore it has not been included in the analysis Daskapan Intervention: Outdoor Walking & n = 29 Mortality Exercise capacity Maximum duration of follow-up: Chronic Heart Failure Rehabilitation in chronic 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 weekly phone calls provided; no other treatments reported Frequency: 3 sessions per week Duration: 45 minutes Intensity: up to 60% peak heart rate (RPE 12-16) Control: As home but supervised laboratory based (treadmill walking) Age (mean SD): Gender: 73% male NYHA class II and Mean ejection Family origin not reported Single centre Turkey Adherence Data obtained on mortality by personal contact Hwang Intervention: Aerobic and strength training exercises delivered via a synchronous videoconferencing platform across the internet. Participants were provided with additional home exercises to be undertaken three times per week. Educational topics were delivered as electronic slide presentations with a 15 minute interaction period held prior to the exercise session to discuss this.


Educational topics were delivered as electronic slide presentations with a 15 minute interaction period held prior to the exercise session to discuss this. Frequency: 2 sessions per week Duration: 60 minutes Intensity: RPE 9-13 (commencing at very light and progressing to somewhat hard). Exercise prescription was tailored to the participants goal. Control: As home- based Age (mean SD): Gender: 79% male NYHA class II-III: LVEF (mean SD): Family origin: 92% Caucasian Australia Mortality Exercise capacity: o 6 minute walk distance o 10m walk test (comfortable and fast) QoL (EQ-5D) QoL (MLWHFQ) Adherence Maximum duration of follow-up: 24 weeks Chronic Heart Failure Rehabilitation in chronic 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 telerehabilitation but centre-based led by physiotherapists Karapolat Intervention: Walking with pedometer, weekly phone calls provided; breathing and flexibility exercises Frequency: 3 sessions per week Duration: 45-60 minutes Intensity: 60-70% heart rate reserve, level 13-15 on the Borg scale Control: As home but supervised treadmill walking in rehabilitation centre with breathing and flexibility exercises N = 74 Age (mean SD): Intervention: Control: Gender (% male): NYHA class II-III: Mean ejection fraction: Not reported Family origin not reported Single centre Turkey Mortality Exercise capacity Adherence Maximum duration of follow-up: Piotrowicz (Piotrowicz ) Intervention: Continuous walking on level ground and an education programme detailing how to measure HR, BP and body weight; how to evaluate signs and symptoms. All participants received psychological support. The home based group received an EHO 3 device and a mobile phone. Before beginning a training session, participants used the mobile phone to answer symptom based questions.


Before beginning a training session, participants used the mobile phone to answer symptom based questions. A resting ECG was transmitted to the monitoring centre in order to establish that exercise was n = 152 Age (mean): Gender: male Control: 95% male NYHA class II-III: Mean ejection fraction: Home group: Centre group: Family origin not reported Single centre Poland Mortality Exercise capacity Exercise capacity Adherence Maximum duration of follow-up: 2 months Chronic Heart Failure Rehabilitation in chronic 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 safe to continue. sessions per week Duration: 20-45 minutes Intensity: Individually tailored Control: As home but supervised in an outpatient setting, with interval training using a cycle ergonometer Rehabilitation in chronic heart failure Chronic Heart Failure NICE 2018. All rights reserved. Subject to Notice of rights.


sessions per week Duration: 20-45 minutes Intensity: Individually tailored Control: As home but supervised in an outpatient setting, with interval training using a cycle ergonometer Rehabilitation in chronic heart failure Chronic Heart Failure NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: Table 76: Clinical evidence summary: Home-based exercise training versus centre-based exercise training Outcomes No of Participants (studies) Follow up Quality of the evidence (GRADE) Relative effect Anticipated absolute effects Risk with centre-based exercise training Risk difference with home-based exercise training (95% CI) All-cause mortality 335 months VERY LOWa,b due to risk of bias, imprecision Peto odds ratio (from 18 fewer to 82 more) Quality of life - SF-36 Physical component summary (PCS) months LOWa due to risk of bias The mean SF-36 PCS in the centre- based exercise training groups was The mean SF-36 PCS in the home-based exercise training groups was (5.45 lower to 4.33 higher) Quality of life - SF-36 Mental component summary (MCS) months VERY LOWa,b,c due to risk of bias, inconsistency, imprecision The mean SF-36 MCS in the centre- based exercise training groups was The mean SF-36 MCS in the home-based exercise training group was (5.74 lower to 7.18 higher) Quality of life EQ-5D utility HIGH f The mean EQ-5D utility in the home- based exercise training group was (0.16 lower to 0.04 higher) Quality of life - MLWHFQ MODERATEb due to imprecision f The mean MLWHFQ in the home-based exercise training group was (17 lower to 9 higher) Exercise capacity - ISWT 30 VERY LOWa,b due to risk of bias, imprecision The mean exercise capacity - ISWT in the centre-based exercise training groups was The mean exercise capacity - ISWT in the home-based exercise training group was (104.42 lower to 116.22 higher) Exercise capacity - 201 e The mean exercise capacity 6MWT in Rehabilitation in chronic heart failure Chronic Heart Failure NICE 2018.


ISBN: Table 76: Clinical evidence summary: Home-based exercise training versus centre-based exercise training Outcomes No of Participants (studies) Follow up Quality of the evidence (GRADE) Relative effect Anticipated absolute effects Risk with centre-based exercise training Risk difference with home-based exercise training (95% CI) All-cause mortality 335 months VERY LOWa,b due to risk of bias, imprecision Peto odds ratio (from 18 fewer to 82 more) Quality of life - SF-36 Physical component summary (PCS) months LOWa due to risk of bias The mean SF-36 PCS in the centre- based exercise training groups was The mean SF-36 PCS in the home-based exercise training groups was (5.45 lower to 4.33 higher) Quality of life - SF-36 Mental component summary (MCS) months VERY LOWa,b,c due to risk of bias, inconsistency, imprecision The mean SF-36 MCS in the centre- based exercise training groups was The mean SF-36 MCS in the home-based exercise training group was (5.74 lower to 7.18 higher) Quality of life EQ-5D utility HIGH f The mean EQ-5D utility in the home- based exercise training group was (0.16 lower to 0.04 higher) Quality of life - MLWHFQ MODERATEb due to imprecision f The mean MLWHFQ in the home-based exercise training group was (17 lower to 9 higher) Exercise capacity - ISWT 30 VERY LOWa,b due to risk of bias, imprecision The mean exercise capacity - ISWT in the centre-based exercise training groups was The mean exercise capacity - ISWT in the home-based exercise training group was (104.42 lower to 116.22 higher) Exercise capacity - 201 e The mean exercise capacity 6MWT in Rehabilitation in chronic heart failure Chronic Heart Failure NICE 2018. All rights reserved. Subject to Notice of rights.