The outcome data reported by each study was not meta-analysed due to the significant degree of variation in the methods of obtaining this information across studies. The committee also noted that the subjective nature of the adherence data, when self-reported by people in a home- based exercise programme, meant that it was potentially less reliable. The majority of trials poorly reported details of sequence generation, concealment of the random allocation sequence and blinding of outcome assessment; contributing to the overall high risk of bias in the body of evidence for all outcomes. Losses to follow-up, which varied widely across studies, also contributed to the risk of bias for some outcomes. Trade-off between clinical benefits and harms There was no consistent evidence of a clinically important difference in exercise capacity between home-based and centre-based rehabilitation when quantified via the ISWT, 6MWT, VO2 max and 10 metre walk test (fast). A similar result was seen for quality of life, with no consistent evidence of a clinically important difference between home and centre-based rehabilitation. This was also the case for adherence, with no consistent clinical benefit being observed. The committee noted that this evidence was more challenging to interpret as variation in the way this data was reported across studies prohibited the meta-analysis of these results. In addition to this the committee noted that self-reported adherence by participants enrolled in a home-based exercise programme were likely to be less reliable due to the subjective nature of the reporting. Similarly, no clinically important difference in mortality was seen between the groups, although this estimate was seriously imprecise, with confidence intervals ranging from a clinically important reduction to a clinically important increase in deaths in the home-based groups. Based on the clinical evidence reviewed, the committee agreed that home- and centre-based forms of cardiac rehabilitation seem to be similarly effective for patients with heart failure. The committee noted that the body of evidence was small (5 trials of 335 patients) and the majority of outcomes were at high risk of bias. The patient populations included in the trials were also much younger than the typical heart failure patients Chronic Heart Failure Rehabilitation in chronic heart failure NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: 978-1-4731-3093-7 in the UK. However, the committee agreed that this was common in rehabilitation trials and wasn t specific to home versus centre-based trials. The committee acknowledged that the findings of this review which suggested that no clear difference could be demonstrated between home- and centre-based programmes. The committee also noted that findings in younger populations might also not translate to more typical older patient populations. The committee was also conscious that the critical outcome of hospitalisation was not reported by any of the included studies. The evidence on patient completion suggested a clinically important increase in completion rates in the home-based groups compared to the centre-based groups. For some patients, the burden of travelling to a centre for rehabilitation and/or dislike of exercising in a group setting may be a substantial barrier to participation in centre-based programmes. For these patients, home-based rehabilitation may be a more attractive and achievable option. Similarly, a patient representative expressed his view that the main concern of many younger patients with heart failure is to learn and understand their limits with professional supervision, to enable them to then exercise safely and comfortably alone. The committee expressed its concern about the continuing low uptake of rehabilitation since the previous guideline52 and agreed that there may be inequalities in the ability to access rehabilitation, especially for older, frailer patients with heart failure. The committee agreed that the delivery of home-based rehabilitation may increase access and uptake, which is a major priority in the management of heart failure. The committee considered that even a modest increase had the potential to result in a marked improvement in patient outcomes at the population level. The committee also discussed the potential downsides of a home-based programme, including: the loss of face-to-face support and encouragement from health professionals and peers, especially compared with a group programme; increased feeling of isolation for some patients; the potential for reduced adherence among some patients, and for patients to experience technological and comprehension barriers to full participation, which may not be picked up in patient self-reports. On balance, the committee agreed that choice of participating in a more traditional and supervised centre-based programme or a home-based programme should ideally reflect the preference of the individual patient. The committee therefore decided to maintain the current recommendation to offer cardiac rehabilitation to heart failure patients, but removed the limitations on the mode of delivery. The committee agreed that the setting and format of the programme should facilitate the person s ability to access the programme. The committee noted that several comprehensive, evidence-based, home-delivered cardiac rehabilitation programmes are currently available. These programmes typically involve an overarching self-help manual outlining the programme, and include an exercise training element (such as open air walking or indoor exercises using a DVD), as well as educational (for example, medications, symptom monitoring and help-seeking) and psychological (for example, managing stress and anxiety) components. The programmes are overseen by a trained healthcare professional who patients can contact for further advice. The specific home-based programmes in the included studies were as follows: three studies were based on outdoor walking training, with the addition of flexibility and breathing exercises (1 study), and the addition of telephone conversations with a psychologist (1 study); one study was based on a DVD of functional aerobic exercises interspersed with active recovery. Chronic Heart Failure Rehabilitation in chronic heart failure NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: 978-1-4731-3093-7 All home-based programmes in the included studies were accompanied by tele- monitoring and written information, and some programmes included the use of heart rate monitors and pedometers. One programme utilised remote monitoring equipment (an EHO 6 device enabling the recording and transmission of an ECG via a mobile phone). The committee discussed how a home-based programme would be delivered and how professional support would be accessed in the NHS context. The committee did not expect a home-based programme would involve regular face-to-face contact with health professionals and agreed the use of expensive equipment would not be required. The committee agreed that, regardless of the programme delivery format or setting, all patients should be assessed by a trained healthcare professional prior to commencement, in order to: ensure that the person can safely participate in exercise-based cardiac rehabilitation; tailor an appropriate programme for the patient. In addition, professional support should be available to patients throughout both centre and home-based programmes and patients should be advised on how to access that support. Trade-off between net clinical effects and costs One relevant economic evaluation was identified and included in this review that compared home-based rehabilitation to hospital-based rehabilitation for people with heart failure. This was a 5 year follow-up comparative costing of patients who participated in a trial by Cowie et al. 2011 included in the clinical review. The study found home-based rehabilitation to be more costly compared to hospital-based rehabilitation. When discussing this paper, the committee considered that the estimated intervention cost of home-based rehabilitation would be lower in current practice. In the study, the cost of DVD production to deliver the home-based intervention was divided by the number of patients in the study arm (n=15) to give the average cost per patient. In practice with a much larger population size, the committee considered that home-based rehabilitation would be less costly than hospital-based rehabilitation as the fixed cost of producing a DVD would be divided over a greater number of patients, and the marginal cost of providing each additional DVD would be minimal. The estimated intervention cost of hospital-based rehabilitation is unlikely to differ in current practice. The committee also noted that the admission costs were higher in the home-based rehabilitation group in this study. However, the committee considered this to be highly uncertain due to the small sample size of the study, and therefore did not put much weight on this finding. Although there was no clinical evidence for hospitalisations, the committee considered that home-based rehabilitation would have similar hospitalisation rates as hospital-based rehabilitation, and therefore admission costs would not differ greatly between the 2 interventions. The committee were concerned with the small sample size of this study (n=30), that there was a large age difference of patients in each arm, and that no health outcomes were reported, and therefore this study was assessed as partially applicable with very serious limitations. Due to the limited quality of economic evidence, the committee considered the current cost of hospital-based rehabilitation. According to NHS reference costs the cost of Rehabilitation for Acute Myocardial Infarction or Other Cardiac Disorders (VC38Z) is 238. The committee also mentioned that these patients are likely to require transport, further increasing the cost of this intervention. The other interventions for home-based rehabilitation programmes identified in the clinical review consisted of outdoor walking and weekly telephone calls to healthcare staff. The committee considered that this would require limited NHS resource if such Chronic Heart Failure Rehabilitation in chronic heart failure NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: 978-1-4731-3093-7 programmes were implemented. Overall, the committee did not consider that home-based rehabilitation would be more costly than hospital/community rehabilitation as health professionals are not required to visit patients in their homes, and in some instances could be less costly. The lack of uptake of rehabilitation since the previous guideline has meant that the cost savings previously predicted due to reductions in hospitalisations have not come to fruition. Although there is no clinical evidence for hospitalisations the committee considered that home-based rehabilitation would have the same effect in reducing hospitalisations as hospital or centre based rehabilitation. Therefore the cost savings of rehabilitation are more likely to be met if home based rehabilitation is made available to aid in increasing the uptake of rehabilitation. The committee mentioned that in some areas hospital/centre-based rehabilitation is not available due to the significant up-front cost required to initiate the service. The committee agreed that initiating home-based rehabilitation programmes is unlikely to incur as high a cost, particularly if existing cardiac rehabilitation programmes are already in place, and considered that this recommendation would aid in reducing barriers to access. Due to the considerations above, the committee decided that home-based rehabilitation should be available for heart failure patients to increase uptake of rehabilitation and facilitate the previously predicted cost-savings. Other considerations The committee noted that access to cardiac rehabilitation for heart failure patients is currently highly variable and uptake nationally remains low. The committee s recommendation should address some of the underlying issues by improving access, equity, participation and adherence. The CHF Quality standard (QS9 2016, statement number 7) identified the need for choice of venues and measures such as providing transport when offering rehabilitation programmes to ensure equality of access for all the heart failure population. This update has added to the 2010 recommendations on rehabilitation while recognising the importance of programmes including a psychological and educational component and that the programme may be incorporated within an existing cardiac rehabilitation programme. The committee also noted the recommendations in the Patient experience in adult NHS services guideline that advocates an individualised approach to healthcare services tailored to patient needs and circumstances. All patients in the trials had HF with reduced ejection fraction (HFREF). However, as the 2010 recommendation to offer cardiac rehabilitation applied to all patients with heart failure, the committee saw no reason to limit the updated recommendation following this evidence review. Chronic Heart Failure Monitoring NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: 978-1-4731-3093-7 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 includes monitoring using repeated biomarker measurement or imaging, and telemonitoring and self monitoring. Other topics were not within the scope of the update. For more information refer to Appendix R, the 2003 guideline: 1. Clinical review. For more information please refer to Section 8.1 of the 2003 Guideline 22 . 2. Therapeutic drug monitoring of serum digoxin concentrations. For more information please refer to Section 8.4 of the 2003 Guideline 22 8.1 Monitoring using repeated biomarker measurement or imaging for management of chronic heart failure Clinicians treating patients with HF use a combination of symptoms (e.g degree of breathlessness) and examination findings (e.g. heart rate, blood pressure) to make decisions about treatment changes. Biomarkers are substances measurable in the blood stream which can be used to diagnose and monitor disease. Natriuretic peptides are released from the myocardium in response to fluid overload. The two main natriuretic peptides used in clinical practice are amino-terminal pro-B-type natriuretic peptide (NT-proBNP) and B-type natriuretic peptide (BNP). The measurement of natriuretic peptides is recommended for the diagnosis of HF but their role in the on-going management (i.e monitoring of heart failure) remains a topic of active research and there is uncertainty about the optimum diagnostic thresholds for natriuretic peptides. Troponin is released in response to myocardial injury and is important in the diagnosis of myocardial infarction but it s role in HF is unclear. Co-existing conditions such as chronic kidney disease (CKD) and atrial fibrillation (AF) can affect the level of biomarkers in the bloodstream and this may influence their utility in diagnosis and monitoring of heart failure. Similarly imaging techniques for HF such as cardiac MRI and echocardiography which can be used to assess the structure and functional status of the heart could be used for similar purposes. A number of evidence-based treatments for heart failure reduce hospital admissions and increase survival, particularly for patients with heart failure with reduced ejection fraction (HFREF). Typically these trials use fixed doses and thus their recommendations apply to the average population rather than any particular individual. Objective tests such as measurement of biomarkers and imaging could potentially also be used to inform management decisions and optimise treatment for individuals. The aim of this review was to examine the clinical and cost-effectiveness of biomarker measurement or imaging in the management of patients with HF. Chronic Heart Failure Monitoring NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: 978-1-4731-3093-7 8.1.2 Review question: What is the clinical and cost effectiveness of biomarker-based monitoring, monitoring with cardiac MRI, and monitoring with repeated echocardiography in people with heart failure? For full details see review protocol in Appendix A. Table 78: PICO characteristics of review question Population People diagnosed with heart failure in a community or outpatient setting. Age under 75 years Aged 75 years and over Interventions Biomarker monitoring: serial (protocol-driven) measurements of circulating biomarker concentration: NT-proBNP (alone) BNP (alone) Troponin (alone) Combination of 2 biomarkers Combination of all 3 biomarkers Imaging monitoring: serial (protocol-driven) cardiac MRI Imaging monitoring: serial (protocol-driven) echocardiography Comparisons Each other Usual care: Clinical monitoring (protocol-driven) Usual care: Clinical monitoring (not protocol-driven) Outcomes CRITICAL Mortality (Time to event) Quality of life at 12 months (Continuous) Unplanned hospitalisation (all-cause) (Count rate) IMPORTANT Adverse events - hypotension (Dichotomous) Adverse events - hyperkalaemia (Dichotomous) Adverse events - renal function (Continuous) Adverse events - bradycardia (Dichotomous) Adverse events - arrhythmic events (Dichotomous) Study design Systematic reviews of RCTs RCTs 8.1.3 Clinical evidence A search was conducted for randomised trials and systematic reviews of randomised trials comparing the effectiveness of monitoring with repeated biomarker measurement (BNP, NT-proBNP or troponin) or repeated cardiac imaging (echocardiography or cardiac MRI), compared to usual care without repeated measurement or imaging. were included in the review, as well as three systematic reviews (4 providing additional information on some of the primary studies these are summarised in Table 79 and Table 80 below. See also the study selection flow chart in Chronic Heart Failure Monitoring NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: 978-1-4731-3093-7 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 14 studies involved repeated BNP or NT-proBNP (together called NP) biomarker testing. No relevant studies comparing usual care with troponin or combinations of different biomarkers were identified. No relevant studies comparing usual care with routine cardiac imaging were identified. The majority of the trials only included patients with HFREF as this is where the evidence base is for most of the treatments for HF.Treatment algorithms varied in the NP monitoring arm, some treated to an absolute NP target; others set a personal target based on percentage drop of NP levels; others did not aim to reduce NP levels, but used serial measurements to detect increases thought to represent deterioration and acted accordingly. The comparator arm involved treatment guided by protocol driven clinical monitoring in thirteen of fourteen studies. The comparator arm of one study and a third arm of two studies appeared to comprise of usual care that did not have a formal protocol for guiding treatment (described hereafter as no protocol ). The results are presented separately for the clinical monitoring and no protocol comparison arms because it was felt that any form of guided treatment was likely to have an effect on outcomes. The NP guided and clinically guided treatment arms were based in a specialist clinic in thirteen out of fourteen studies. The exception took place in primary care under general practitioners who had received training on how to use the monitoring protocols. One of the no protocol arms took place in a specialist clinic, and two were in primary care with no extra training. Study details and results were taken from the first available source in the following hierarchy. The choice of source was based on utilising the advantages of individual patient data analysis while being able to present results for each study separately, stratified by age, wherever possible: individual patient-level data (IPD) from the meta-analysis in an NIHR funded HTA (Pufulete ) aggregate data from the same meta-analysis (Pufulete 2017273 ) based on the Troughton IPD meta-analysis IPD data from analysis of the Troughton 2014 meta-analysis55, 338 aggregate data from a Cochrane meta-analysis (McLellan 2016219 ) individual study reports A single study was included in the 2010 update (CG108) of this question30 . This paper has been excluded in the current review as it no longer matches the protocol. For further explanation please see the Recommendations and link to evidence. Table 79: Summary of systematic reviews included in the review Study Intervention and comparison (in HF clinic unless stated otherwise) Population Primary studies included McLellan, Cochrane systematic review NP guided therapy versus Usual care (review refers to as Health plan alone) Range of intervention times: 1- Anguita 2010, BATTLESCARRED, Berger 2010, Christchurch pilot, NorthStar, OPTIMA, PRIMA, PROTECT, Shochat 2012, SIGNAL- HF, STARS-BNP, TIME-CHF, UPSTEP Pufulete NIHR HTA NP guided therapy versus Usual care (review refers to as Symptom-guided therapy ) Stratified by age or over) analysis As IPD: Anguita 2010, NorthStar, Shochat Chronic Heart Failure Monitoring NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: 978-1-4731-3093-7 Study Intervention and comparison (in HF clinic unless stated otherwise) Population Primary studies included Range of intervention times: 3- available As aggregate data: BATTLESCARRED, Berger 2010, Christchurch pilot, PRIMA, PROTECT, Shochat 2012, SIGNAL- HF, STARS-BNP, TIME-CHF Troughton (Brunner-la ) Troughton review NP-guided therapy versus Usual care (review refers to as Clinically-guided therapy ) Range of intervention times: 3- Subgroups for age, and others including CKD As IPD: BATTLESCARRED, Berger 2010 (labelled Vienna ), Christchurch pilot, PRIMA, PROTECT, SIGNAL-HF, TIME-CHF, UPSTEP NP: natriuretic peptides including BNP and NT-proBNP Table 80: Summary of primary studies included in the review Study Intervention and comparison (in HF clinic unless stated otherwise) Population Outcomes Comments NP monitoring: Therapy increased to target (BNP level < Clinical monitoring: Therapy intensified to reach target (congestion score and months Age mean: 69(10) Recently hospitalised and NYHA II/III HTA IPD: Mortality by age All-cause admission by age Recruited on discharge BATTLESCARRE D trial: Lainchbury (Lainchbury ) NP monitoring: Therapy increased to achieve clinical and NP target (congestion score<2 Clinical monitoring: Therapy increased to meet target months No protocol: Discharged to primary care Age > 18 mean: Recently hospitalised HF- admission Elevated NP (NT- proBNP > 50 pmol/L) HTA aggregate: Mortality by age Troughton IPD: HF admission Study papers: Quality of life renal function, no monitoring arm Recruited from hospital Chronic Heart Failure Monitoring NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: 978-1-4731-3093-7 Study Intervention and comparison (in HF clinic unless stated otherwise) Population Outcomes Comments (Adlbrecht ) NP monitoring: Therapy intensified to meet or maintain target (NT-proBNP <2200pg/l), Clinical monitoring: Therapy intensified at clinician s discretion according to clinical assessment No protocol: Discharged to primary care Age mean: 71(12) Recently hospitalised with NYHA class III/IV and cardiothoracic ratio > 0.5 or LVEF HTA aggregate: Mortality by age Troughton IPD: HF admission Study papers: No monitoring arm Recruited from hospital Christchurch pilot Troughton NP monitoring: Treatment intensified to reach target (NT- Clinical monitoring: Therapy increased to reach target months Age mean: 70(10) LVEF < 40%, NYHA class II-IV Treatment with at least ACEi and loop diuretic HTA aggregate: Mortality by age Study papers: All-cause admission Hypotension Renal function Recruited in hospital or HF clinic GUIDE-IT trial: NP monitoring: titrate HF therapy to target an NT-proBNP level of < 1000 pg/mL, 12-24 months Clinical monitoring: Therapy intensified at clinician discretion according to clinical assessment based on 2013 AHA/ACC guideline, 12-24 months Age median (IQR): NP monitoring: 62 LVEF < 40%, history of HF event within the prior 12 months and an NT- proBNP level of more than 2000 pg/mL or BNP of more than 400 pg/mL within the prior 30 days All-cause mortality HF hospitalisations (count rate) Symptomatic hypotension Symptomatic bradycardia Hyperkalaemia Worsening renal function Recruited at 45 sites in the US and Canada The study was premature ly discontinu ed due to lack of efficacy (based on statistical significanc e) of evidence for the biomarker- guided treatment group compared Chronic Heart Failure Monitoring NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: 978-1-4731-3093-7 Study Intervention and comparison (in HF clinic unless stated otherwise) Population Outcomes Comments with clinical monitoring Northstar trial: NP monitoring: Further investigation and treatment if months Clinical monitoring: Therapy intensified at clinician discretion according to clinical assessment, 30 months Age 18 years, LVEF 45 % Elevated NP (NT- ml) despite education on CHF and optimal ACE/ARB and BB therapy HTA IPD: Mortality by age all-cause admission by age Recruited from HF clinics OPTIMA trial: NP monitoring: Therapy intensified according to clinical status and serial BNP levels, 2 years Clinical monitoring: Therapy was intensified according to clinical status, 2 years Age limits 18-90, Recently hospitalised, NYHA III/IV and HTA: None Study papers: Mortality by age all-cause admission by age No informatio n on recruitmen t PRIMA trial: NP monitoring: therapy increased to reach or maintain target (NT-proBNP at the lowest level recorded at discharge or two weeks following), 24 months Clinical monitoring: Therapy increased at clinician s discretion according to clinical assessment, 24 months Age mean: 72(12) Recently hospitalised HF- admission, mainly NYHA III, Elevated NPs (NT- proBNP levels at admission 1700 pg/mL) that respond to treatment (decrease 10% at discharge) HTA aggregate: Mortality by age Troughton IPD: HF admission Recruited from hospital PROTECT trial: (Weiner , Mallick , Ibrahim , Bhardwaj , Bhardwaj )) NP monitoring: Therapy intensified to reach target (NT- months Clinical monitoring: Therapy intensified at clinician discretion according to clinical assessment, 6-12 months Age 21 years, NYHA class II-IV, LVEF 40%, destabilisation in (attended hospital or clinic for worsening HF) HTA: Nil Troughton IPD: HF hospitalisation Study papers: Quality of life Hypotension Recruited Chronic Heart Failure Monitoring NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: 978-1-4731-3093-7 Study Intervention and comparison (in HF clinic unless stated otherwise) Population Outcomes Comments n=76 renal failure atrial fibrillation ventricular arrhythmia NP monitoring: Therapy increased if NT-proBNP No protocol: No treatment algorithm reported, 11 months Age mean: 73(8) NYHA I/II/III/IV HTA IPD: Mortality by age all-cause admission by age Recruited SIGNAL-HF trial: NP monitoring (in primary care): Treatment increased to achieve target (NT-proBNP reduction of 50% from baseline), 9 months Clinical monitoring (in primary care): Therapy increased at clinician s discretion according to clinical assessment, 9 months Age mean: 78(7) NYHA class II-IV, LVEF < 50%, stable in primary care Elevated NPs (NT- proBNP levels males > 800, females > 1000 ng/L) HTA aggregate: Mortality by age Troughton IPD: HF admission Study papers: Quality of life Recruited from primary STARS-BNP trial: Jourdain NP monitoring: Therapy intensified to reach target Clinical monitoring: Therapy intensified at clinician discretion according to clinical assessment, 15 months Age > 18 years NYHA class II/III, LVEF < 45% No admission or change of medication in last month, optimal medical treatment with diuretics, ACEi/ARB and BB HTA aggregate: Mortality by age Troughton IPD: HF admission Study papers: Renal function Recruited from clinics TIME-CHF trial: (Pfisterer , Brunner-la , Sanders-van , Sanders-van , Kaufmann ) NP monitoring: Therapy intensified to reach BNP target n=251 with rEF, 59 with pEF Clinical monitoring: Therapy intensified to reach target (NYHA II), 18 months n=248 with rEF, 64 with pEF Age 60 years, mean: NYHA class II with current therapy, HF admission in the last year, elevated NPs (NT- proBNP of 400pg/mL if < pg/mL if 75y) HTA aggregate: Mortality by age all-cause admission by age Study papers: Quality of life Hypotension Bradycardia renal failure hyperkalaemia Recruited from multiple centres in Switzerlan d and Germany Chronic Heart Failure Monitoring NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: 978-1-4731-3093-7 Study Intervention and comparison (in HF clinic unless stated otherwise) Population Outcomes Comments Stratified by LVEF status UPSTEP trial: Karlstrom (Karlstrom , Karlstrom ) NP monitoring: Therapy increased towards guideline- target doses to reach BNP Clinical monitoring: Therapy intensified at clinician s discretion according to clinical assessment Age > 18 years, LVEF < 40%, NYHA class II-IV, worsening HF (requiring hospitalisation and/or IV support) Elevated BNP those aged < 75 years and > 300 ng/L for those aged > 75 years) despite standard treatment with ACEi/ARB and BB HTA IPD: All-cause admission by age Study papers: Quality of life Recruited ACEi/ARB: Angiotensin converting enzyme inhibitor and/or Aldosterone receptor blocker, BB: Beta-blocker, IV: Intravenous therapy, NP: natriuretic peptides including BNP and NT-proBNP Monitoring Chronic Heart Failure NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: Table 81: Clinical evidence summary: NP monitoring versus clinical monitoring Outcomes No of Participants (studies) Follow up Quality of the evidence (GRADE) Relative effect Anticipated absolute effects Risk with Clinical monitoring Risk difference with NP monitoring (95% CI) Mortality (HR) - Age <75 years 1234 LOWb,c,g due to risk of bias, imprecision Estimatea (from 103 fewer to 0 more) Mortality (HR) - Age 75 and over LOWb,c,g due to risk of bias, imprecision Estimatea (from 56 fewer to 200 more) Mortality (RR) - All ages 946 LOWb,c due to risk of bias, imprecision (from 50 fewer to 26 more) All-cause hospitalisation (HR) - Age <75 years MODERATEc due to imprecision Estimatee (from 4 fewer to 152 fewer) All-cause hospitalisation (HR) - Age 75 and over MODERATEc due to imprecision Estimatee (from 64 fewer to 83 more) All-cause hospitalisation (RR) - All ages LOWb,c due to risk of bias, imprecision (from 180 fewer to 66 more) All-cause hospitalisation (Rate Ratio) - All ages VERY LOWb,c due to risk of bias, imprecision Rate Ratio 694 events per 1000 person- years 181 fewer events per 1000 person years (from 417 fewer to 257 more) HF hospitalisation (HR) - All ages VERY LOWb,c,d due to risk of bias, Estimatef (from 2 fewer to 87 fewer) Monitoring 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 Clinical monitoring Risk difference with NP monitoring (95% CI) indirectness, imprecision HF hospitalisation (RR) - All ages VERY LOWb,c,d due to risk of bias, indirectness, imprecision (from 395 fewer to 15 more) HF hospitalisation (Rate Ratio) All ages VERY LOWb,c,d due to risk of bias, indirectness, imprecision Rate ratio 618 events per 1000 person years 161 more events per 1000 person years (from 49 more to 297 more) Quality of life MLWHFQ final 462 MODERATEb due to risk of bias The mean quality of life (MLWHFQ) in the control groups was The mean quality of life(MLWHFQ) in the intervention groups was (2.23 lower to 5.02 higher) Quality of life - KCCQ change 250 LOWb due to risk of bias The mean quality of life (KCCQ) in the control groups was The mean quality of life (KCCQ)in the intervention groups was (7.19 lower to 1.99 higher) Quality of life SF36 physical final VERY LOW b,i due to risk of bias, inconsistency The mean quality of life (SF36 physical) in the control groups was The mean quality of life (SF36 physical) in the intervention groups was (5.13 lower to 4.47 higher) Quality of life SF36 mental final MODERATEb due to risk of bias The mean quality of life (SF36 mental) in the control groups was The mean quality of life (SF36 mental) in the intervention groups was (1.9 lower to 2.02 higher) Renal function - All ages eGFR, creatinine clearance MODERATEb The mean eGFR in the control group was The mean eGFR in the intervention groups was 0.76 ml/min lower Monitoring 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 Clinical monitoring Risk difference with NP monitoring (95% CI) and creatinine level 6-12 months due to risk of bias 51ml/min (3.8 lower to 2.09 higher)h VERY LOWb,c due to risk of bias, imprecision (from 57 fewer to 83 more) Acute Kidney Injury - Age <75 years LOWc due to imprecision (from 82 fewer to 181 more) Acute Kidney Injury - Age 75 and over LOWc due to imprecision (from 125 fewer to 79 more) Acute Kidney Injury - All ages 151 VERY LOWb,c due to risk of bias, imprecision (from 28 fewer to 187 more) Worsening renal function All ages LOWb,c due to imprecision (from 4 fewer to 60 more) Hyperkalaemia - Age <75 years VERY LOWb,c due to risk of bias, imprecision (from 47 fewer to 194 more) Hyperkalaemia - Age 75 and over VERY LOWb,c due to risk of bias, imprecision (from 82 fewer to 120 more) Hyperkalaemia All ages 894 VERY LOWb,c due to risk of bias, imprecision (from 4 fewer to 53 more) Hypotension - Age <75 years 210 VERY LOWb,c due to risk of bias, imprecision (from 52 fewer to 246 more) Monitoring 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 Clinical monitoring Risk difference with NP monitoring (95% CI) Hypotension - Age 75 and over VERY LOWb,c due to risk of bias, imprecision (from 51 more to 341 more) Hypotension - All ages 1114 LOWb due to risk of bias Peto odds (from 4 more to 65 more) Bradycardia - Age <75 years 210 LOWc due to imprecision (from 27 fewer to 200 more) Bradycardia - Age 75 and over 289 VERY LOWb,c due to risk of bias, imprecision (from 42 fewer to 141 more) Symptomatic bradycardia All ages MODERATEb due to risk of bias - j j Significant Ventricular Arrhythmia - All ages VERY LOWb,c due to risk of bias, imprecision (from 25 fewer to 249 more) New Atrial Fibrillation - All ages LOWc due to imprecision (from 61 fewer to 64 more) a The age-specific control risk was calculated from TIME-CHF and BATTLESCARRED 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 Downgraded by 1 increment because due to indirectness of the outcome e The age-specific control risk was taken from TIME-CHF Monitoring 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 Clinical monitoring Risk difference with NP monitoring (95% CI) f The control rate refers to the overall control risk in the Troughton meta-analysis (11 studies) g Heterogeneity could not be formally assessed due to use of pooled data, which comprised seven of the nine included studies for the outcome. The paper reporting the pooled data did not report any statistics related to heterogeneity h Scores estimated using a standardised mean difference of -0.04 (-0.2 to 0.11) i Downgraded by 2 increment as point estimates were inconsistent with little overlap of confidence intervals, not enough studies to perform sub-group analysis, I2 j Unable to estimate as zero events in both arms of the trial Table 82: Clinical evidence summary: NP monitoring v no monitoring protocol Outcomes No of Participants (studies) Follow up Quality of the evidence (GRADE) Relative effect Anticipated absolute effects Risk with No monitoring (primary or secondary care) Risk difference with NP monitoring Mortality (HR) - Age <75 years 70 LOWb due to risk of bias Estimatea (from 37 fewer to 309 fewer) Mortality (HR) - Age 75 and over 50 VERY LOWb,c due to risk of bias, imprecision Estimatea (from 207 fewer to 584 more) Mortality (RR) - Age <75 years 122 MODERATEc due to imprecision (from 234 fewer to 0 more) Mortality (RR) - Age 75 and over 121 MODERATEc due to imprecision (from 28 fewer to 414 more) Mortality (RR) - All ages 182 HIGH (from 43 fewer to 253 fewer) Monitoring 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 No monitoring (primary or secondary care) Risk difference with NP monitoring All-cause hospitalisation (HR) - Age <75 years VERY LOWb,c due to risk of bias, imprecision Estimated (from 215 fewer to 224 more) All-cause hospitalisation (HR) - Age 75 and over VERY LOWb,c due to risk of bias, imprecision Estimated (from 77 fewer to 284 more) HF hospitalisation (RR) - Age <75 years 122 VERY LOWc,e due to indirectness, imprecision (from 183 fewer to 133 more) HF hospitalisation (RR) - Age 75 and over 121 LOWc,e due to indirectness, imprecision (from 43 fewer to 382 more) HF hospitalisation (RR) - All ages 182 MODERATEe due to indirectness (from 202 fewer to 416 fewer) a Age-specific control rate taken from BATTLESCARRED usual care group 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 Age-specific control rate taken from TIME-CHF clinically guided group (no usual care control available) e Downgraded by one increment because the outcome was an indirect indicator of the protocol outcome Chronic Heart Failure Monitoring NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: 978-1-4731-3093-7 8.1.4 Economic evidence Published literature No economic evaluations were identified in the 2003 guideline (CG5). One previously published economic evaluation was included in the 2010 guideline update (CG108) which assessed NP guided monitoring to usual care based on a clinical trial by Troughton et al. 2000339 . However, a US Medicare perspective was taken and therefore this study has been excluded from this review in line with the protocol. An original economic analysis was conducted for this question in the 2010 guideline. An update of this analysis with the addition of new clinical evidence has been included in this review.191 A further two health economic evaluations were identified with the relevant comparison and have been included in this review.223 These are summarised in the health economic evidence profile below (Table 83) and the health economic evidence tables in Appendix G. See also the health economic study selection flow chart in Appendix D. Monitoring Chronic Heart Failure NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: Table 83: Health economic evidence profile: NP guided therapy versus usual care Study Applicability Limitations Other comments Costs Effects Inc. cost Inc. effects Cost- effectiveness Uncertainty Laram e [UK] Directly applicable(a) Minor Limitations (b) Cost-utility analysis, Monte Carlo simulation model Comparators: 1. Usual care in the community 2. Specialist clinical assessment natriuretic peptide monitoring Lifetime horizon modelled Population split into multiple sub-groups: o Patients with CHF and LVSD 1. n/a 1. n/a - - - - QALY gained o Patients with CHF and LVSD aged <75 years 1. n/a 1. n/a - - - - 2. NR 2. NR Baseline Probability cost- 3. NR 3. NR NR NR 2,871 per QALY gained o Patients with CHF and LVSD aged 75 years 1. n/a 1. n/a - - 2. NR 2. NR Baseline Probability cost- 3. NR 3. NR NR NR 5,392 per QALY gained Monitoring Chronic Heart Failure NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: Study Applicability Limitations Other comments Costs Effects Inc. cost Inc. effects Cost- effectiveness Uncertainty o Patients with CHF of any cause QALY gained Probability cost- QALY gained Probability cost- o Patients with CHF of any cause aged 1. NR 1. NR Baseline - 2. NR 2. NR NR NR Extendedly dominated - 3. NR 3. NR NR NR 2,517 per QALY gained Probability cost-effective o Patients with CHF of any cause aged 1. NR 1. NR Baseline Probability cost- 2. NR 2. NR NR NR 11,508 per QALY gained 3. NR 3. NR NR NR Dominated. - Moertl [Austria] Partially applicable(c) Potentially Serious Limitations (d) Cost-utility analysis, Markov model Comparators: 1. Usual care in community 2. Nurse-led MDT 3. NT-proBNP guided intensive management 20 year time horizon effective) - effective) - threshold): NR Monitoring Chronic Heart Failure NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: Study Applicability Limitations Other comments Costs Effects Inc. cost Inc. effects Cost- effectiveness Uncertainty modelled Pufulete (Mohiud ) [UK] Directly applicable(e) Minor Limitations (f) Cost-utility analysis, Markov model Comparators: clinically-guided therapy 2. Specialist-led BNP- guided therapy Lifetime horizon modelled Population split into multiple sub-groups: o All HF patients aged - - 2-1: QALY gained Probability cost- o HF-REF patients aged <75 years - - 2-1: QALY gained Probability cost- threshold): NR o HF-PEF patients aged <75 years - - 2-1: QALY gained Probability cost- o All HF patients 75 years - - 2-1: saves (less costly, more effective) Probability cost- threshold): NR o HF-REF patients 75 years - - 2-1: QALY gained Probability cost- Abbreviations: BNP: brain natriuretic peptide; CHF: chronic heart failure; ICER: incremental cost-effectiveness ratio; HF; heart failure; LVSD; left ventricular systolic dysfunction; MDT: multidisciplinary team; QALY: quality-adjusted life years; RCT: randomised controlled trial Monitoring Chronic Heart Failure NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: (a) Preference weights of EQ-5D scores were based on subjects region of origin, not necessarily UK tariff (31% US, 52% Western Europe, 14% Latin America). Disease progression not captured in the model. (b) Austrian payer perspective. EQ-5D not used to capture quality of life - utility scores converted from MLWHF questionnaire using previously published algorithm. Costs and effects discounted at 5%. (c) Cost of GP visits and drug costs were not collected and not included in the analysis of the clinical trial phase. (d) None (e) Disease progression not captured in the model. Chronic Heart Failure Monitoring NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: 978-1-4731-3093-7 8.1.5 Evidence statements Clinical Seventeen studies, comparing repeated biomarker measurement (BNP or NT-proBNP) with usual care (either protocol driven or not protocol driven and without repeated measurement) in people with heart failure were identified for inclusion within the review. The quality of the evidence ranged from moderate to very low. Evidence was downgraded for a number of reasons including risk of bias, imprecision due to wide confidence intervals surrounding the effect estimate, indirectness of the reported outcomes, and inconsistency due to heterogeneity in the effect estimates reported by the studies. Outcomes were stratified by age (<75 years and 75 years) where the study had reported this. NP monitoring versus clinical monitoring All ages: Moderate quality evidence was found for the outcomes QoL as measured by the MLWHFQ (n=462) and the SF-36 mental component summary (n=418) both of which suggested no clinical effect of NP monitoring. Further moderate quality evidence was found for the outcome renal function as measured by eGFR, creatinine clearance and creatinine level (n=654) which also suggested no clinical effect of NP monitoring. Low quality evidence was found for the outcomes mortality (n=946) and hospitalisations (RR)(n=220), there was a reduction in hosptilisations suggesting a clinical benefit of NP monitoring (associated with wide confidence intervals around the effect estimate). Mortality did not demonstrate a clear effect with the confidence interval ranging from a decrease and increase in all-cause mortality. Low quality evidence was also found for the outcomes QoL as measured by the KCCQ (n=250), worsening renal function (n=849), hypotension (n=1114) and atrial fibrillation (n=151) all of which showed no clinical effect of NP monitoring. Very low quality evidence was found for the outcome hospitalisations reported as rate ratio (n=69) which suggested a clinically important decrease with NP monitoring. Further very low quality evidence was found for the outcome HF hospitalisation. When reported as a hazard ratio (n=1515) and risk ratio (n=52) the outcome showed a clinically important reduction with NP monitoring monitoring (associated with wide confidence intervals around the effect estimate). When reported as a rate ratio (n=894) the evidence suggested a clinically important increase in the number of HF hospitalisations with NP monitoring. For the outcomes creatinine rise >30% (n=220), acute kidney injury (n=151), hyperkalaemia (n=894), and significant ventricular arrhythmia (n=151) there was no suggestion of a clinically important effect on these outcomes. Age <75 years: Moderate quality evidence was found for the outcome hospitalisation (n=572) which suggested a clinically important reduction with NP monitoring. Low quality evidence was found for the outcomes mortality (n=1234) which suggested a clinically important reduction in deaths with NP monitoring. Further low quality evidence was found for the outcomes acute kidney injury (n=210) and bradycardia (n=210) both of which suggested no clinical effect of NP monitoring. Very low quality evidence was found for the outcome hyperkalaemia (n=210) which suggested no clinical effect of NP monitoring, and hypotension (n=210) which suggested a clinical harm with NP monitoring. Age 75 years: Moderate to very low quality evidence was found for the outcomes hospitalisations (n=598), mortality (n=1254), hyperkalaemia (n=289) and hypotension (n=289) . Hospitalisations and hyperkalaemia suggested a clinically important increase with NP monitoring (all associated with wide Chronic Heart Failure Monitoring NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: 978-1-4731-3093-7 confidence intervals around the effect estimate). For the outcomes acute kidney injury and bradycardia (n=289) low to very low quality evidence was found which suggested no clinical effect of NP monitoring. Mortality did not demonstrate a clear effect with the confidence interval ranging from a decrease and increase in all-cause mortality. NP monitoring versus no monitoring protocol All ages: High quality evidence was found for the outcome mortality (n=182), and moderate quality evidence for HF hospitalisations (n=182) both of which suggested a clinically important reduction in deaths with NP monitoring. Age <75 years: Moderate to very low quality evidence was found for the outcome mortality reported as a hazard ratio (n=70) and a risk ratio (n=122) both of which suggested a clinically important reduction in the number of deaths with NP monitoring. Very low quality evidence was found for the outcomes all- cause hospitalisation (n=50) and HF hospitalisation (n=122). For the outcome all-cause hospitalisation there was a clinically important increase with NP monitoring. However for HF hospitalisations the evidence suggested a clinically important reduction with NP monitoring. Age 75 years: Moderate to very low quality evidence was found for the outcomes mortality reported as a hazard ratio (n=50) and a risk ratio (n=121) both of which did not demonstrate a clear effect with the confidence interval ranging from a decrease and increase in all-cause mortality.Very low quality evidence was also found for the outcomes all-cause hospitalisation (n=70) and HF hospitalisation (n=121) both of which suggested a clinically important increase with NP monitoring No relevant studies comparing usual care with troponin or combinations of different biomarkers were identified. No relevant studies comparing usual care with routine cardiac imaging were identified. Economic One cost utility analysis found that: o in patients with CHF and LVSD specialist natriuretic peptide monitoring was cost effective compared to specialist clinical assessment (ICER: 3,304 per QALY gained). in patients under the age of 75 with CHF and LVSD specialist natriuretic peptide monitoring was cost effective compared to specialist clinical assessment (ICER: 2,871 per QALY gained). in patients over the age of 75 with CHF and LVSD specialist natriuretic peptide monitoring was cost effective compared to specialist clinical assessment (ICER: 5,392 per QALY gained). o in patients with CHF of any cause specialist natriuretic peptide monitoring was cost effective compared to specialist clinical assessment and usual care in the community (ICER: 14,694 per QALY gained compared to specialist clinical assessment). in patients under the age of 75 with CHF of any cause specialist natriuretic peptide monitoring was cost effective compared to specialist clinical assessment and usual care in the community (ICER: 2,517 per QALY gained compared to usual care in the community). Specialist clinical assessment was extendedly dominated. Chronic Heart Failure Monitoring NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: 978-1-4731-3093-7 in patients over the age of 75 with CHF of any cause specialist clinical assessment was cost effective compared to specialist natriuretic peptide monitoring and usual care in the community (ICER: 11,508 per QALY gained compared to usual care in the community). Specialist natriuretic peptide monitoring was dominated by specialist clinical assessment. This analysis was assessed as directly applicable with minor limitations. One cost-utility analysis found that NT-proBNP guided intensive management was dominant (more effective and less costly) compared to nurse-led MDT management and usual care in the community. This was assessed as partially applicable with potentially serious limitations. One cost-utility analysis found that: o in heart failure patients (any cause) under the age of 75 specialist-led BNP guided therapy was cost effective (ICER: 10,057 per QALY gained) compared to specialist-led clinically-guided therapy; o in heart failure patients (any cause) over the age of 75 specialist-led BNP guided therapy dominated (less costly, more effective) specialist-led clinically-guided therapy; o in HF-REF patients under the age of 75 specialist-led BNP guided therapy was cost effective (ICER: 9,840 per QALY gained) compared to specialist-led clinically-guided therapy; o in HF-REF patients over the age of 75 specialist-led BNP guided therapy was cost effective (ICER: 8,123 per QALY gained) compared to specialist-led clinically-guided therapy; o in HF-PEF patients under the age of 75 specialist-led BNP guided therapy was cost effective (ICER: 9,066 per QALY gained) compared to specialist-led clinically-guided therapy. This was assessed as directly applicable with minor limitations. 8.2 Monitoring using repeated biomarker measurement or imaging for management of chronic heart failure in people who also have chronic kidney disease Biomarkers are substances measurable in the blood stream which can be used to diagnose and monitor disease. Chronic kidney disease (CKD) develops when damage to the kidney results in reduced function. The extent of this damage can be approximated by blood tests to estimate glomerular filtration rate (GFR) from the kinetics of a stable excreted substance e.g. creatinine and a urine test to detect renal leakage of protein- usually albumin. The management of CKD is covered by NICE guideline CG182. Natriuretic peptides and troponin are raised in patients with HF and could potentially be used to guide treatment. However renal function can affect the level of biomarkers in the blood principally by affecting their clearance and this effect could influence their interpretation of biomarker results by clinicians. Imaging with echocardiography or cardiac MRI could be an alternative method of monitoring. The aim of this section of the review is to examine the clinical and cost-effectiveness of biomarker measurement or imaging in the management of heart failure in patients with CKD. 8.2.2 Review question: What is the clinical and cost effectiveness of biomarker-based monitoring, monitoring with cardiac MRI, and monitoring with repeated echocardiography in people with heart failure who also have CKD? For full details see review protocol in Appendix A. Chronic Heart Failure Monitoring NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: 978-1-4731-3093-7 Table 84: PICO characteristics of review question Population People diagnosed with heart failure in a community or outpatient setting who also have chronic kidney disease Aged under 75 years Aged 75 and over. Interventions Biomarker monitoring: serial (protocol-driven) measurements of circulating biomarker concentration: NT-proBNP (alone) BNP (alone) Troponin (alone) Combination of 2 biomarkers Combination of all 3 biomarkers Imaging monitoring: serial (protocol-driven) cardiac MRI Imaging monitoring: serial (protocol-driven) echocardiography Comparisons Each other Usual care: Clinical monitoring (protocol-driven) Usual care: Clinical monitoring (not protocol-driven) Outcomes CRITICAL Mortality (Time to event) Quality of life at 12 months (Continuous) Unplanned hospitalisation (all-cause) (Count rate) IMPORTANT Adverse events - hypotension (Dichotomous) Adverse events - hyperkalaemia (Dichotomous) Adverse events - renal function (Continuous) Adverse events - bradycardia (Dichotomous) Adverse events - arrhythmic events (Dichotomous) Study design Systematic reviews of RCTs RCTs 8.2.3 Clinical evidence A search was conducted for randomised trials and systematic reviews of randomised trials comparing the effectiveness of monitoring with repeated biomarker measurement (BNP, NT-proBNP or troponin) or repeated cardiac imaging (echocardiography or cardiac MRI), compared to usual care without repeated measurement or imaging, that had a population or subgroup with chronic kidney disease. Subgroup analyses in one primary study 114 and one systematic review 55, 338 , including an individual patient data meta-analysis of seven studies, were included in the review. These are summarised in Table 85 and Table 86, and the clinical evidence is summarised in Table 87. See also the study selection flow chart in Appendix C, forest plots in Appendix E, study evidence tables in Appendix F, GRADE tables in Appendix H and excluded studies list in Appendix I. Chronic Heart Failure Monitoring NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: 978-1-4731-3093-7 All of the studies involved repeated BNP or NT-proBNP (together called NP) biomarker testing. Treatment algorithms varied, with some treating to an absolute target, others aiming for a personal target best on percentage drop of levels. These were compared against clinical monitoring in the other study arm. No relevant studies comparing usual care with routine cardiac imaging, troponin, or combinations of different biomarkers were identified. Table 85: Summary of systematic review included in the review Study Intervention and comparison (in HF clinic unless stated otherwise) Population Included data Troughton (Brunner-la ) Troughton IPD NP-guided therapy vs Clinically-guided therapy (3-24 months) Stratified by LVEF status. Age mean (SD): Studies included in IPD: BATTLESCARRED, Berger 2010, Christchurch pilot, PRIMA, PROTECT, SIGNAL-HF, TIME- CHF*, UPSTEP *the HFpEF arm of TIME-CHF is included in Brunner La Rocca, but not the original meta-analysis ACEi/ARB: Angiotensin converting enzyme inhibitor and/or Aldosterone receptor blocker, BB: Beta-blocker, IV: Intravenous therapy, NP: natriuretic peptides including BNP and NT-proBNP Table 86: Summary of primary studies included in the review Study Intervention and comparison (in HF clinic unless stated otherwise) Population Outcomes Comments BATTLESCARRE D trial: Lainchbury (Lainchbury ) NP monitoring: Therapy increased to achieve clinical and NP target (congestion score<2 Clinical monitoring: Therapy increased to meet target months No protocol: Discharged to primary care Age > 18 mean: HF-admission Elevated NP (NT- proBNP > 50 pmol/L) Troughton IPD: Mortality Recruited from hospital Chronic Heart Failure Monitoring NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: 978-1-4731-3093-7 Study Intervention and comparison (in HF clinic unless stated otherwise) Population Outcomes Comments (Adlbrecht ) NP monitoring: Therapy intensified to meet or maintain target (NT-proBNP <2200pg/l), Clinical monitoring: Therapy intensified at clinician s discretion according to clinical assessment No protocol: Discharged to primary care Age mean: 71(12) Recently hospitalised with NYHA class III/IV and cardiothoracic ratio > 0.5 or LVEF Troughton IPD: Mortality Recruited from hospital Christchurch pilot Troughton NP monitoring: Treatment intensified to reach target (NT- Clinical monitoring: Therapy increased to reach target (Framingham score <2) Age mean: 70(10) LVEF < 40%, NYHA class II-IV Treatment with at least ACEi and loop diuretic Troughton IPD: Mortality Recruited in hospital or HF clinic PRIMA trial: NP monitoring: therapy increased to reach or maintain target (NT-proBNP at the lowest level recorded at discharge or two weeks following), 24 months Clinical monitoring: Therapy increased at clinician s discretion according to clinical assessment, 24 months Age mean: 72(12) Recent HF- admission, mainly NYHA III, Elevated NPs (NT- proBNP levels at admission 1700 pg/mL) that respond to treatment (decrease 10% at discharge) Troughton IPD: Mortality Primary paper: Admissions (as days in hospital) Recruited from hospital PROTECT trial: (Weiner , Mallick , Ibrahim , Bhardwaj ) NP monitoring: Therapy intensified to reach target (NT- months Clinical monitoring: Therapy intensified at clinician discretion according to clinical assessment, 6-12 months Age 21 years, NYHA class II-IV, LVEF 40%, destabilisation in (attended hospital or clinic for worsening HF) Troughton IPD: Mortality Recruited Chronic Heart Failure Monitoring NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: 978-1-4731-3093-7 Study Intervention and comparison (in HF clinic unless stated otherwise) Population Outcomes Comments SIGNAL-HF trial: NP monitoring (in primary care): Treatment increased to achieve target (NT-proBNP reduction of 50% from baseline), 9 months Clinical monitoring (in primary care): Therapy increased at clinician s discretion according to clinical assessment, 9 months Age mean: 78(7) NYHA class II-IV, LVEF < 50%, stable in primary care Elevated NPs (NT- proBNP levels males > 800, females > 1000 ng/L) Troughton IPD: Mortality Recruited from primary TIME-CHF trial: (Pfisterer , Brunner-la , Sanders-van , Sanders-van , Kaufmann ) NP monitoring: Therapy intensified to reach BNP target n=251 with rEF, 59 with pEF Clinically monitoring: Therapy intensified to reach target (NYHA II), 18 months n=248 with rEF, 64 with pEF Age 60 years, NYHA class II with current therapy, HF admission in the last year, elevated NPs (NT- proBNP of 400pg/mL if < pg/mL if 75y) Stratified by LVEF status Troughton IPD: Mortality* Recruited from multiple centres in Switzerlan d and Germany ACEi/ARB: Angiotensin converting enzyme inhibitor and/or Aldosterone receptor blocker, BB: Beta-blocker, IV: Intravenous therapy, NP: natriuretic peptides including BNP and NT-proBNP Monitoring Chronic Heart Failure NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: Table 87: Clinical evidence summary: NP monitoring versus clinical monitoring in people who also have chronic kidney disease Outcomes No of Participant s (studies) Follow up Quality of the evidence (GRADE) Relativ e effect CI) Anticipated absolute effects Risk with Clinical monitoring Risk difference with NP monitoring All-cause mortality 1147 months VERY LOW b,c,e due to risk of bias, imprecision, inconsistency Approximatea (from 105 fewer to 172 more) All-cause hospitalisation (days in hospital) VERY LOWb,c,d due to risk of bias, imprecision, indirectness The mean all-cause hospitalisation (days in hospital) in the control group was 6.54 days in hospital The mean all-cause hospitalisation (days in hospital) in the intervention groups was (2.81 lower to 3.57 higher) a Control group risk not available, approximated from risk for both arms combined, will under-estimate effect 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 Downgraded by 1 increment for indirectness as proxy for the protocol outcome of rate ratio of all-cause admissions e Downgraded by 1 increment as point estimates were inconsistent, not enough studies to perform subgroup analysis, I2 Chronic Heart Failure Monitoring NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: 978-1-4731-3093-7 8.2.4 Economic evidence Published literature No previously published economic evidence was identified for this question in the review. See also the health economic study selection flow chart in Appendix D. 8.2.5 Evidence statements Clinical Subgroup analyses in one primary study and one systematic review (which included an IPD meta- analysis of seven studies) were identified for inclusion within the review. All of the included studies compared repeated biomarker measurement (BNP or NT-proBNP) with clinical monitoring in people with HF who also have CKD. The quality of the evidence was very low as a result of risk of bias, imprecision due to wide confidence intervals surrounding the effect estimate, indirectness of the outcome and inconsistency due to heterogeneity in the results reported by individual studies. Mortality did not demonstrate a clear effect with the confidence interval ranging from a decrease and increase in all-cause mortality.The outcome all-cause hospitalisations (as measured by days in hospital) suggested no clinical effect of NP monitoring. Economic No economic evaluations were identified. 8.3 Monitoring using repeated biomarker measurement or imaging for management of chronic heart failure in people who also have atrial fibrillation Atrial fibrillation (AF) is an abnormal heart rhythm affecting 2-3% of the adult population but is more common in patients with HF. Patients may be aware of palpitations, fatigue or breathlessness although many are asymptomatic. AF may be detected on examination, with an irregular pulse, and confirmed by ECG. The treatment of AF includes rate and rhythm control as well as anticoagulation to reduce the stroke risk. The management of AF is covered by NICE guideline CG180. Biomarkers are substances measurable in the blood stream which can be used to diagnose and monitor disease. Natriuretic peptides are released from the myocardium in response to fluid overload. The two main natriuretic peptides used in clinical practice are amino-terminal pro-B-type natriuretic peptide (NT-proBNP) and B-type natriuretic peptide (BNP). Troponin is released in response to myocardial injury. Natriuretic peptides and troponin are raised in patients with HF and could potentially be used to guide treatment however AF can affect the level of these biomarkers by affecting their physiology of their secretion into the blood and also potentially affect their clearance thus affecting the ability of clinicians to interpret their results. Imaging with echocardiography or cardiac MRI could be an alternative method of monitoring. Chronic Heart Failure Monitoring NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: 978-1-4731-3093-7 The aim of this section of the review is to examine the clinical and cost-effectiveness of biomarker measurement or imaging in the management of heart failure in patients with AF. 8.3.2 Review question: What is the clinical and cost effectiveness of biomarker-based monitoring, monitoring with cardiac MRI, and monitoring with repeated echocardiography in people with heart failure who also have atrial fibrillation? For full details see review protocol in Appendix A. Table 88: PICO characteristics of review question Population People diagnosed with heart failure in a community or outpatient setting who also have atrial fibrillation Aged under 75 years Aged 75 and over. 