STUDY DESIGN. Aims. Keywords Chronic heart failure Left ventricular systolic dysfunction Disease management

Transcription

1 European Journal of Heart Failure (2011) 13, doi: /eurjhf/hfr048 STUDY DESIGN The WHICH? trial: rationale and design of a pragmatic randomized, multicentre comparison of home- vs. clinic-based management of chronic heart failure patients Simon Stewart 1 *, Melinda J. Carrington 1, Thomas Marwick 2, Patricia M. Davidson 3, Peter Macdonald 4, John Horowitz 5, Henry Krum 6, Phillip J. Newton 7, Christopher Reid 6, and Paul A. Scuffham 8, on behalf of the Which Heart failure Intervention is most Cost-effective & consumer friendly in reducing Hospital care (WHICH?) trial Investigators 1 Department of Preventative Health, Baker IDI Heart and Diabetes Institute, Melbourne, Australia; 2 Cardiovascular Imaging Research Unit (CIRCUS), School of Medicine, The University of Queensland, Princess Alexandra Hospital, Brisbane, Australia; 3 The Centre for Cardiovascular and Chronic Care, Curtin Health Innovative Research Institute, University of Technology/Curtin University, St Vincent s and Mater Health, Sydney, Australia; 4 St Vincent s Hospital and Victor Chang Cardiac Research Institute, Sydney, Australia; 5 The Queen Elizabeth Hospital and University of Adelaide, Adelaide, Australia; 6 Monash Centre of Cardiovascular Research and Education in therapeutics, School of Public Health & Preventive Medicine, Monash University, Melbourne, Victoria, Australia; 7 The Centre for Cardiovascular and Chronic Care, Curtin Health Innovative Research Institute, University of Technology/Curtin University, St Vincent s and Mater Health, Sydney, Australia; and 8 Department of Health Economics, Centre for Applied Health Economics, School of Medicine, Griffith University, Logan, Australia Received 6 December 2010; revised 28 February 2011; accepted 14 March 2011; online publish-ahead-of-print 26 May 2011 See page 823 for the editorial comment on this article (doi: /eurjhf/hfr076) Aims To describe the rationale and design of the Which Heart failure Intervention is most Cost-effective & consumer friendly in reducing Hospital care (WHICH?) trial.... Methods WHICH? is a pragmatic, multicentre, randomized controlled trial that seeks to determine if multidisciplinary management of chronic heart failure (CHF) patients post-acute hospitalization delivered in a patient s own home is superior to care delivered via a specialist CHF outpatient clinic. The composite primary endpoint is all-cause, unplanned recurrent hospitalization or death during months of follow-up. Of 688 eligible patients, 280 patients (73% male and 66% principal diagnosis of CHF) with a mean age of years have been randomized to home- (n ¼ 143) or clinic-based (n ¼ 137) post-discharge management. This will provide 80% power (two-sided alpha of 0.05) to detect a 15% absolute difference in both the primary end-point and rate of all-cause hospital stay. Preliminary data suggest that the two groups are well matched in nearly all baseline socio-economic and clinical parameters. The majority of patients have significant co-morbidity, including hypertension (63%), coronary artery disease (55%), and atrial fibrillation (53%) with an accordingly high Charlson Index of Comorbidity Score ( ).... Perspective Despite its relatively small size, the WHICH? trial is well placed to examine the relative impact of two of the most commonly applied forms of face-to-face management designed to reduce recurrent hospitalization and prolong survival in CHF patients Keywords Chronic heart failure Left ventricular systolic dysfunction Disease management * Corresponding author. Tel: , Fax: , simon.stewart@bakeridi.edu.au Published on behalf of the European Society of Cardiology. All rights reserved. & The Author For permissions please journals.permissions@oup.com.

2 910 S. Stewart et al. Introduction In response to the growing burden associated with chronic heart failure (CHF), in particular costly hospital admissions and poor survival in affected individuals, 1 CHF management programmes (CHF-MPs) now form part of the gold-standard management of the syndrome. 2 Yet, debate on the best approach to CHF management continues. 3 These predominantly multidisciplinary programmes target recently hospitalized patients in an effort to optimise the longer-term management of CHF, including postacute discharge care within the community. 4 Following the publication of seminal randomized trials undertaken in the mid-to-late 1990s, 5 9 meta-analyses have confirmed the benefits of CHF-MPs in reducing re-admission rates, improving quality of life, reducing costs, and prolonging survival relative to usual care. 4 However, translation into practice is often imperfect due to selective application of key components integral to effective CHF management. 10 Moreover, there is an increasing awareness of the need to undertake rigorous trials testing the efficacy of nonpharmacological interventions but within a framework of pragmatism which recognizes that the real world is often far removed from the strict confines of clinical trials. 3 The updated CONsolidating Standards Of Reporting Trials (CONSORT) guidelines for pragmatic trials, which have direct relevance to health care practice, represent a key indicator of the importance of such trials. 11 In the historical development of CHF-MPs, two major forms of face-to-face management have been found to have the greatest impact on health outcomes relative to usual care. 3,11 The first of these is multidisciplinary care provided via a specialist CHF clinic (usually located in a tertiary referral hospital) as originally applied by Cline et al. 6 and later by Stromberg et al. 12 An alternative model is multidisciplinary care predominantly applied in the community and involving a comprehensive home visit, as applied by Stewart et al. 8,9 and Blue et al. 5 A combination of these two potentially divergent approaches has produced positive health outcomes. 7 Notwithstanding increasing interest in remote management techniques in CHF, 13,14 which contradict the positive results of a recent Cochrane Review, 15 many health care services tend to adopt either a clinic- or home-based approach. 10 Nevertheless, from a consumer and cost-benefit perspective, there may well be important differences between clinic- and home-based management, particularly in relation to addressing treatment adherence. Certainly, the strength of evidence in favour of a homebased strategy was slightly stronger in a contemporary meta-analysis of the evidence 4 and there are theoretical benefits from seeing patients in their own environment. Previously, patient access to a specialist outpatient clinic has been shown to be an impediment in recruiting for a randomized controlled trial of CHF management, 16 but the characteristics of affected patients and the complexity of CHF management has undoubtedly changed. We believed, therefore, that a head-to-head trial of these two distinct forms of management was timely and appropriate. Consistent with the recently reported COACH (Coordinating Study Evaluating Outcomes of Advising and Counseling in Heart Failure) study 17 that directly compared usual management via a cardiologist with a moderate-to-intensive CHF-MP in limiting recurrent hospitalization, the WHICH? trial investigators are currently undertaking a head-to-head comparison of the efficacy of a home- vs. clinic-based intervention in CHF using a pragmatic, multicentre, randomized controlled study design. Study design Study hypothesis The Which Heart failure Intervention is most Cost-effective & consumer friendly in reducing Hospital care (WHICH?) trial recruited hospitalized patients with a confirmed diagnosis of CHF (including those with preserved and impaired left ventricular dysfunction). Specifically, the study is testing the hypothesis that compared to an equivalent clinic-based programme of management, a nurse-led, post-discharge, multidisciplinary MP for CHF patients involving post-discharge home visits, will be superior in reducing the composite primary end-point of unplanned (all-cause) re-admission or death during months of follow-up by an absolute margin of 15%. It is further hypothesized that a home-based approach will also (cost-effectively) reduce the rate of unplanned hospital stay (all-cause) by a minimum of 15% relative to clinic-based management during study follow-up. Study design As shown in Figure 1, the WHICH? trial is a multicentre, randomized controlled study that is registered with the Australian New Zealand Clinical Trials Registry (Number ). It conforms to principles outlined in the Declaration of Helsinki and to the CONSORT guidelines for a pragmatic study comparing the efficacy of two non-pharmacological health interventions. 11 The trial has been approved by the Human Research Ethics Committee of the Princess Alexandra Hospital, Brisbane; St Vincent s Hospital, Sydney; and the Queen Elizabeth Hospital, Adelaide, Australia. All subjects provided written informed consent to participate during the index hospitalization. Study end-points The primary end-point of the WHICH? trial is a composite of allcause, recurrent unplanned hospitalization (as opposed to a planned/elective hospital admission) or all-cause mortality during months of follow-up. These composite events will also be examined separately as: (i) a proportion of affected individuals and, with respect to the duration of event-free survival, survival and, (ii) in the case of hospitalization, rate of hospitalization and related stay (per patient per month of follow-up). All end-points are reviewed and adjudicated by an independent and blinded endpoint committee with main comparisons to be reported on an intention-to-treat basis. Secondary end-points include: rate of CHF-related hospitalization, generic (SF ) and CHF-specific (Minnesota Living With Heart Failure Questionnaire 19 ) changes in quality of life from baseline, and uptake of gold-standard therapy [including prescribed doses of angiotensin-converting enzyme (ACE) inhibitors and beta blockers] at 6, 12, and 18 months. One of the most critical components of this study is an economic analysis. Cost per quality-adjusted life year averted will be assessed using data from the EQ-5D 20,21 and according to

3 The WHICH? trial 911 Figure 1 Which Heart failure Intervention is most Cost-effective & consumer friendly in reducing Hospital care (WHICH?) trial study schema. gold-standard methods 22 to determine if there are potential cost advantages in applying one approach over the other. This is especially important if superiority of the approach is not initially established on the basis of the primary end-point, but there are differences in the pattern of recurrent hospital stay between groups. Health care costs will therefore be independently monitored during study follow-up (by P.S. s group). These include: (i) the cost of applying the study intervention; (ii) community-based health care costs; (iii) prescribed pharmacotherapy and; (iv) inpatient/outpatient hospital activity. All costs will be standardized

4 912 S. Stewart et al. (adjusting for inflation) to the last full financial year of the study. Another key component of evaluation is consumer choice. This will be assessed in a number of ways including: (i) the rate of patient recruitment relative to eligibility (potentially indicating a reluctance to allow chance to determine how they would be subsequently managed); (ii) the proportion of patients who withdrew when informed of the group allocation and; (iii) a detailed study of the patients and their carer s perceptions and preferences concerning their CHF management. Patient cohort and selection criteria All patients admitted to three tertiary referral hospitals in South Australia (The Queen Elizabeth Hospital, Adelaide), New South Wales (St Vincent s Hospital, Sydney), and Queensland (The Princess Alexandra Hospital, Brisbane), Australia, were screened for study eligibility. Study recruitment was completed on 1 April 2010 allowing for censoring of all study end-points on 31st March Patients aged 18 years who were discharged home were eligible to participate if they had a diagnosis of CHF, with persistent moderate-to-severe symptoms [New York Heart Association (NYHA) class II-III], as confirmed by a cardiologist and consistent with Australian guidelines 23 and a history of at least one admission for acute heart failure. In the presence of preserved systolic function (left ventricular ejection.45%), diastolic dysfunction was defined and staged in accordance with recent guidelines from the European Association of Echocardiography and American Society of Echocardiography. 24 Patients were excluded if they lived outside a 30 km radius of the participating hospital, had a terminal condition (other than CHF) that was likely to result in death or hospitalization within 12 months, were non-english speaking and/or unable to give fully informed consent (e.g. due to significant cognitive impairment). Study group allocation Block randomization was applied for each study site, with patients stratified according to the presence or absence ( preserved CHF) of left ventricular systolic dysfunction defined as a left ventricular ejection fraction (LVEF) 45%. Study recruitment Figure 2 shows the flow of patient recruitment resulting in the 280 eligible patients who consented to participate in this study. Research teams at each hospital reviewed inpatient lists and case records to identify potentially eligible patients, with the majority being recruited from cardiology and general medical units. As suggested by these data, a significant proportion of the overall total of 723 eligible patients (34%) were reluctant to enter the trial after being informed of what participation entailed and/or withdrew their initial consent to participate when their group intervention was allocated. Refusal to participate was supplemented by a component of physician preference to direct patients towards one form of intervention over the other (formally reported in 3.6% of eligible cases). As also shown in Figure 2, a similar proportion of patients were randomized to the home- (n ¼ 143) or clinic-based (n ¼ 137) post-discharge management. Baseline profiling All participating patients were initially subject to comprehensive socio-demographic and clinical profiling using a combination of self-report and review of patient records. This included mandatory data pertaining to the patient s cardiac history, function, and CHF-related treatment. Cognitive function was measured by the Montreal Cognitive Assessment tool 25 and cognitive impairment defined by a score of Depressive symptoms were initially assessed by the Arroll screening tool, 27 followed by the CES-D scale 28 if patient s provided positive responses to the Arroll questionnaire. Clinically, glomerular filtration rate was calculated using the Cockcroft2Gault formula (e-gfr) and impaired kidney function determined by a value,60 ml/min/1.73 m Preliminary data suggest that the two study groups are well matched in nearly all baseline socio-economic and clinical parameters. The majority of patients have significant co-morbidity, including hypertension (63%), coronary artery disease (55%), and atrial fibrillation (53%) with a correspondingly high Charlson Index of Comorbidity Score ( ). Principles of WHICH? trial interventions Each of the participating sites had pre-existing CHF-MPs applying a combination of home- and clinic-based, multidisciplinary intervention. Each site modified their programmes accordingly to accommodate both forms of management for the WHICH? study. Consistent with expert guidelines for the application of CHF-MPs, 2 regardless of the vehicle for delivery, the following key components of management are being applied in both groups: (i) pre-discharge planning; (ii) formal pathways to improve communication within the health care team; (iii) optimization of gold-standard pharmacological therapy (including up-titration of doses to evidence-based levels); (iv) application of non-pharmacological strategies including access to formal/informal exercise programmes, monitoring weight and adjusting dietary intake; (v) patient (and caregiver) education; (vi) promotion of self-care; (vii) increased surveillance for impending crises. In order to apply the above and improve subsequent health outcomes (particularly reduced risk of recurrent hospitalization and/ or premature death), these components are being applied in different settings with one arm applying the intervention from a hospital perspective and the other from a community perspective. Those patients randomized to the clinic-based intervention are predominantly managed via a dedicated specialist heart failure clinic at their tertiary hospital and co-ordinated by an experienced CHF nurse. A fundamental rule for delineating the type of intervention applied in patients assigned to this group is the absence of any home visits by their specialist team. In contrast, those allocated to home-based intervention were initially subject to a comprehensive home visit at 7 14 days posthospitalization by a different CHF nurse. A subsequent report was then sent to their local general practitioner (GP) and cardiologist outlining key findings and recommendations, including the need

5 The WHICH? trial 913 Figure 2 CONSORT flow chart of patient recruitment and group randomization in the Which Heart failure Intervention is most Cost-effective & consumer friendly in reducing Hospital care (WHICH?) trial. for community pharmacist review. As per usual post-discharge care, patients allocated to home-based intervention (HBI) are not prevented from attending their tertiary care hospital for routine outpatient management, but are not permitted to attend the specialist CHF clinic. The study nurse follows up all recommendations with the patient s GP and pharmacist where appropriate. All patients are subject to a combination of face-to-face and/or telephone contacts depending on a standardized assessment of clinical stability, additional risk factors for adverse health outcomes (e.g. treatment non-adherence and/or poor self-care behaviours), and adequacy of pharmacological and non-pharmacological management relative to current guidelines. 30,31 The pharmacological management of those with preserved systolic function, while recognizing limited evidence for definitive treatment, is based on contemporary Australian guidelines (updated in 2010). 23 Further, each patient has access to advice from their respective CHF nurse when required. Standardized chronic heart failure management As part of the WHICH? trial, the CHF teams at each of the three study hospitals aim to provide the following components of patient management (regardless of group allocation).

6 914 S. Stewart et al. In-hospital management All patients are reviewed by the CHF nurse and the following tasks/actions performed: Initial assessment W Presenting symptoms W Baseline observations and results Echocardiogram/angiogram/chest X-ray W Medical history Cardiac and co-morbidities W Risk factor history W Weight and body mass index calculated W Diet history W Activity and exercise history W Sleep apnoea status/management W Social and emotional well-being W Immunisation history W Community services Education W National Heart Foundation of Australia patient booklet (Living with heart failure) W Weight diary W Action plan Planned care W Decision regarding exercise programme/clinic/telephone or home visits made according to group allocation W Referral to other services as needed W Communication with GP regarding Admission to hospital and outcomes Intervention/s from CHF service and plan of care (clinic or home) Ongoing assessment/treatment required Further management required (immunisations) Further investigations required (sleep apnoea/anaemia/ renal function) Post-discharge management Full physical assessment W Lying and standing blood pressure W Pulse W Respirations W Jugular venous pressure W Heart sounds W Chest auscultation W Peripheral oedema/circulation Symptom assessment W NYHA severity of shortness of breath W Orthopnoea/paroxysmal nocturnal dyspnoea W Appetite/evidence of cachexia or malnutrition Compliance with CHF monitoring and self management W Weight record viewed/discussed W Fluid intake assessed (alcohol intake) W Diet W Medications Ongoing HF self management education Follow up any investigations Assess W Pattern of attendance at GP/cardiologist W Emotional status W Activity levels W Self-care behaviours (dependent/independent) W Sleep apnoea W Immunisation status W Health-related quality of life (overall and CHF-specific) Plan future care W Titrate medication as needed in consultation with GP/cardiologist/cardiology registrar W Organise further tests as needed pathology/chest X-ray/ updated echocardiography in consultation with GP/cardiologist/cardiology registrar W Referral to allied health care professionals as needed (see below) W Referral for community services as needed W Communication with GP Allied health staff referral as needed: W Physiotherapist for exercise assessment/musculoskeletal problems/functional assessment prescription of home exercise programme W Occupational therapist for energy conservation/cognition and memory issues/home assessment W Dietician review for weight gain/loss, fluid and salt restrictions W Social work for financial/social issues and assistance W Pharmacist for clinic review or community-based review (see below) Specific components of home-based intervention Assessment of the physical surrounds of the patient s home environment Counselling of family members and significant others present in the home Detailed assessment of the patient s social support and coping skills Review of the patient s access to past and present medications Review the patient s food supply (i.e. evidence of processed and fresh food) and cooking facilities Identification of key equipment (i.e. weigh scales and touchpad telephone) Close liaison with the patient s GP to ensure reviews and recommendations are received and appropriately acted upon Organize community pharmacist home medication review as indicated: W Comprehensive medication history W Education regarding compliance and aids W Clinical medication review W Medication counselling W Advice for nursing and medical staff for related medication issues Specific components of clinic-based intervention Liaison with attending cardiologist/cardiology registrar Liaison with clinic pharmacist following their review:

7 The WHICH? trial 915 o Comprehensive medication history o Education regarding compliance and aids o Clinical medication review o Medication counselling o Advice for nursing and medical staff for related medication issues Study power and statistical analyses This study was initially designed to directly compare the cost effectiveness of clinic- and home-based CHF management and provide sufficient study power to compare outcomes at each site using data from an Australian cohort of CHF patients. 31 However, due to the slower-than-expected rate of study recruitment (see Figure 1 and commentary on consumer/health professional preferences) and the rate of outcomes reported by the COACH Study Investigators, 17 the study was redesigned in consultation with a bio-statistician to evaluate composite event-free survival across the three sites. By late 2010, cumulative event rates suggested that 90 deaths (30% of the study cohort) and at least 300 unplanned admissions would occur by the end of the follow-up period. Based on 1:1 randomization and 80% power (two-sided alpha of 0.05), a minimum of 128 patients in each group (256 in total) would be sufficient to detect a 15% absolute difference (nominally expected to occur in 60% of patients exposed to HBI during a minimum months of follow-up) in the primary end-point. An increased target of 145 patients in each group was established (290 patients) to provide 80% power to detect a 15% variation in the rate of all-cause hospital stay (nominal rate of days per patient per month). We have previously demonstrated that this component of health care activity is not only the largest contributor to CHF-related costs, 32 but most critical in determining which form of CHF-MP should be applied. 33 The study will also provide sufficient power to determine independent correlates (Cox Proportional Hazards Models) of event-free survival, including the mode of management (home- vs. clinic-based), participating centre, gender, left ventricular function and co-morbidity. It is important to note that if we were to adequately test a non-inferiority hypothesis at a pre-specified non-inferiority margin of 10% (based on same effect size and study power), a total of 1336 patients would have been required. Discussion WHICH? is a pragmatic trial that aims to delineate between two of the most popular and applied methods of CHF management, home- vs. clinic-based care, to provide the best health outcomes. In doing so, it is designed to explore the cost dynamics of providing gold-standard management in different settings relative to potential health care gains and investigate consumer preferences around CHF management, the latter representing a prospectively planned component of the overall programme of research. Although recent attention has firmly focused on the role of remote monitoring techniques, including telephone support and/or telemonitoring following demonstrable benefits with this kind of approach, 15 it remains clear that in-person approaches will remain central to CHF management. 34 This seems particularly true given the recent completion of two large but negative trials of remote CHF management emanating from the USA 13 and Europe. 14 As such, it is prudent to use the type of taxonomy proposed by Krumholz et al. 35 to examine the variable components within different approaches to applying CHF-MPs. Despite recent calls to revisit the evidence in favour of CHF-MPs, 3,36 it would be imprudent and potentially reckless to readily abandon the lessons learned from a series seminal trials that first appeared in the mid-1990s. Recent, largely negative reviews, have selectively failed to cite these trials and the summative evidence to portray a weak evidence base. However, it is worth emphasizing that a series of pioneering, appropriately powered randomized trials (typically involving hundreds rather than thousands of patients) 5 9 transformed the contemporary management of CHF to an enhanced level of care usually reserved for those participating in clinical trials and this has been accompanied by improved CHF-related outcomes in countries like Sweden where they have been widely applied. 1 It is therefore important that we seek to better understand how CHF-MPs improve health outcomes and refine our approach to implementing them to ensure that we apply the most cost-effective components. Given the development of CHF-MPs along two fundamentally different (in terms of location) but similar (in terms of principles of management) streams that continue to inform the contemporary services, 10 we chose to test the hypothesis that one of these approaches is superior to the other with respect to recurrent hospitalization and death (in essence event-free survival). Whether we will demonstrate any clear difference between the two forms of CHF-MP is yet to be determined. As indicated, we initially considered undertaking a sufficiently powered non-inferiority trial but we have insufficient numbers to do so at a clinically relevant threshold. However, at the time of designing the study, it was ascertained that there was sufficient evidence to favour a homebased approach over a clinic-based approach with respect to both health outcomes (with more robust risk reductions relating to all-cause hospitalization and death relative to usual care reported for HBIs 4 ) and potential cost benefits (in respect to reduced frequency of hospital stay) to undertake a superiority trial. It is important to note that our difficulty in recruiting for this study, because of entrenched preferences from a consumer and health professional perspective for each approach, is significant in itself. Given that women with CHF are generally older than their male counterparts, 1 this may well explain the unusual profile for a CHF-MP in our cohort, with a predominance of men and mean age of 71 years. Anecdotal evidence suggests that some patients prefer being visited at home (particularly if they are frail and have difficulty attending a hospital clinic). At the same time, other patients undoubtedly prefer the idea of leaving their house, associating with other patients and seeing a range of health care workers at their local hospital. Such entrenched positions and wishes underscore rather than undermine the potential value of this trial in determining if it really matters if CHF management is applied via a homeor clinic-based approach. These accepted limitations may have resulted in a potentially biased patient cohort. Whatever the result of WHICH?, it will be important for those delivering a CHF-MP to carefully examine the evidence this trial delivers, particularly those clinicians who are influenced by personal

8 916 S. Stewart et al. preferences in their delivery of CHF management. Ultimately, as the literature evolves, we may conclude that a hybrid approach, as applied by Rich et al. in their seminal trial of a CHF-MP, 7 is most cost effective in improving health outcomes. In conclusion, the WHICH? trial is a pragmatic head-to-head study of home- vs. clinicbased management of hospitalized patients with CHF. The results of this important study, like that of the recently reported COACH Study, 17 will further inform debate on how best to deliver CHF management to predominantly old and frail patients at risk of recurrent hospitalization and premature death. Acknowledgements The authors gratefully acknowledge the cardiac research nurses for patient recruitment, home and clinic visits and data collection. The data management team and project co-ordinator, Ms Alicia Calderone, are sincerely thanked along with Ms Geraldine Lee for her assistance in setting up the trial. Express thanks to Dr Yih Kai Chan for his assistance with data analyses. Funding The WHICH? study is funded by the National Health and Medical Research Council of Australia (Number ) and individual investigators (S.S., M.C., C.R., and P.S.) are supported by the National Health and Medical Research Council of Australia. Conflict of interest: none declared References 1. Stewart S, Ekman I, Ekman T, Oden A, Rosengren A. Population impact of heart failure and the most common forms of cancer: a study of hospital cases in Sweden (1988 to 2004). Circ Cardiovasc Qual Outcomes 2010;3: National Heart Foundation of Australia. Multidisciplinary care for people with chronic heart failure. Principles and recommendations for best practice, 2010, Canberra, Australia. 3. Clark AM, Thompson DR. What heart failure programme works best? Wrong question, wrong assumptions. Eur J Heart Fail 2010;12: McAlister FA, Stewart S, Ferrua S, McMurray JJ. Multidisciplinary strategies for the management of heart failure patients at high risk for admission: a systematic review of randomized trials. J Am Coll Cardiol 2004;44: Blue L, Lang E, McMurray JJ, Davie AP, McDonagh TA, Murdoch DR, Petrie MC, Connolly E, Norrie J, Round CE, Ford I, Morrison CE. Randomised controlled trial of specialist nurse intervention in heart failure. BMJ 2001;323: Cline CM, Israelsson BY, Willenheimer RB, Broms K, Erhardt LR. Cost-effective management programme for heart failure reduces hospitalisation. Heart 1998; 80: Rich MW, Beckham V, Wittenberg C, Leven CL, Freedland KE, Carney RM. A multidisciplinary intervention to prevent the readmission of elderly patients with congestive heart failure. N Engl J Med 1995;333: Stewart S, Marley JE, Horowitz JD. Effects of a multidisciplinary, home-based intervention on unplanned readmissions and survival among patients with chronic congestive heart failure: A randomised controlled study. Lancet 1999; 354: Stewart S, Pearson S, Horowitz JD. Effects of a home-based intervention among patients with congestive heart failure discharged from acute hospital care. Arch Intern Med 1998;158: Driscoll A, Worrall-Carter L, Hare DL, Davidson PM, Riegel B, Tonkin A, Stewart S. Evidence-based chronic heart failure management programs: reality or myth? Qual Saf Health Care 2009;18: Zwarenstein M, Treweek S, Gagnier JJ, Altman DG, Tunis S, Haynes B, Oxman AD, Moher D. Improving the reporting of pragmatic trials: an extension of the CONSORT statement. BMJ 2008;337:a Stromberg A, Martensson J, Fridlund B, Levin LA, Karlsson JE, Dahlstrom U. Nurse-led heart failure clinics improve survival and self-care behaviour in patients with heart failure: results from a prospective, randomised trial. Eur Heart J 2003; 24: Chaudhry SI, Mattera JA, Curtis JP, Spertus JA, Herrin J, Lin Z, Phillips CO, Hodshon BV, Cooper LS, Krumholz HM. Telemonitoring in patients with heart failure. N Engl J Med 2010;363: Koehler F, Winkler S, Schieber M, Sechtem U, Stangl K, Bohm M, Boll H, Kim SS, Koehler K, Lucke S, Honold M, Heinze P, Schweizer T, Braecklein M, Kirwan BA, Gelbrich G, Anker SD. Telemedical Interventional Monitoring in Heart Failure (TIM-HF), a randomized, controlled intervention trial investigating the impact of telemedicine on mortality in ambulatory patients with heart failure: study design. Eur J Heart Fail 2010;12: Inglis SC, Clark RA, McAlister FA, Ball J, Lewinter C, Cullington D, Stewart S, Cleland JG. Structured telephone support or telemonitoring programmes for patients with chronic heart failure. Cochrane Database Syst Rev 2010;8:CD Ekman I, Andersson B, Ehnfors M, Matejka G, Persson B, Fagerberg B. Feasibility of a nurse-monitored, outpatient-care programme for elderly patients with moderate-to-severe, chronic heart failure. Eur Heart J 1998;19: Jaarsma T, van der Wal MH, Lesman-Leegte I, Luttik ML, Hogenhuis J, Veeger NJ, Sanderman R, Hoes AW, van Gilst WH, Lok DJ, Dunselman PH, Tijssen JG, Hillege HL, van Veldhuisen DJ. Effect of moderate or intensive disease management program on outcome in patients with heart failure: Coordinating Study Evaluating Outcomes of Advising and Counseling in Heart Failure (COACH). Arch Intern Med 2008;168: Brazier JE, Roberts J. The estimation of a preference-based measure of health from the SF-12. Med Care 2004;42: Rector TS, Kubo SH, Cohn JN. Validity of the Minnesota Living with Heart Failure questionnaire as a measure of therapeutic response to enalapril or placebo. Am J Cardiol 1993;71: Brooks R. EuroQol: the current state of play. Health Policy 1996;37: Dolan P, Gudex C, Kind P, Williams A. The time trade-off method: results from a general population study. Health Econ 1996;5: Gold MR, Siegel JE, Russell LB, Weinstein MC. Cost-effectiveness in Health and Medicine. Oxford: Oxford University Press; Krum H, Jelinek MV, Stewart S, Sindone A, Atherton JJ, Hawkes AL. Guidelines for the prevention, detection and management of people with chronic heart failure in Australia Med J Aust 2006;185: Nagueh SF, Appleton CP, Gillebert TC, Marino PN, Oh JK, Smiseth OA, Waggoner AD, Flachskampf FA, Pellikka PA, Evangelista A. Recommendations for the evaluation of left ventricular diastolic function by echocardiography. J Am Soc Echocardiogr 2009;22: Nasreddine ZS, Phillips NA, Bedirian V, Charbonneau S, Whitehead V, Collin I, Cummings JL, Chertkow H. The Montreal Cognitive Assessment, MoCA: a brief screening tool for mild cognitive impairment. J Am Geriatr Soc 2005;53: McLennan SN, Mathias JL, Brennan LC, Russell ME, Stewart S. Cognitive impairment predicts functional capacity in dementia-free patients with cardiovascular disease. J Cardiovasc Nurs 2010;25: Arroll B, Khin N, Kerse N. Screening for depression in primary care with two verbally asked questions: cross sectional study. BMJ 2003;327: Radloff LS. The CES-D Scale: a self-report depression scale for research in the general population. Appl Psychol Meas 1977;1: Kidney Health Australia. Chronic Kidney Disease (CKD) Management in General Practice. Melbourne: Kidney Health Australia; Chan YK, Stewart S, Calderone A, Scuffham P, Goldstein S, Carrington MJ. Exploring the potential to remain Heart : initial findings of a multicentre, randomised study of nurse-led, home-based intervention in a hybrid health care system. Int J Cardiol. Published online ahead of print 16 December PMID: Carrington MJ, Stewart S, on behalf of the NIL-CHF Investigators. Bridging the gap in heart failure prevention: rationale and design of the Nurse-led intervention for Less Chronic Heart Failure (NIL-CHF) Study. Eur J Heart Fail 2010;12: Stewart S, Jenkins A, Buchan S, McGuire A, Capewell S, McMurray JJ. The current cost of heart failure to the National Health Service in the UK. Eur J Heart Fail 2002;4: Stewart S, Blue L, Walker A, Morrison C, McMurray JJ. An economic analysis of specialist heart failure nurse management in the UK; can we afford not to implement it? Eur Heart J 2002;23: Sochalski J, Jaarsma T, Krumholz HM, Laramee A, McMurray JJ, Naylor MD, Rich MW, Riegel B, Stewart S. What works in chronic care management: the case of heart failure. Health Aff (Millwood) 2009;28: Krumholz HM, Currie PM, Riegel B, Phillips CO, Peterson ED, Smith R, Yancy CW, Faxon DP. A taxonomy for disease management: a scientific statement from the American Heart Association Disease Management Taxonomy Writing Group. Circulation 2006;114: Clark AM, Savard LA, Thompson DR. What is the strength of evidence for heart failure disease-management programs? J Am Coll Cardiol 2009;54: