International Journal of Environmental Research and Public Health Review Effectiveness and Cost-Effectiveness of Case Management in Advanced Heart Failure Patients Attended in Primary Care: A Systematic Review and Meta-Analysis Caterina Checa 1,2,3, *, Carlos Canelo-Aybar 4 , Stefanie Suclupe 5 , David Ginesta-López 3 , Anna Berenguera 1,2 , Xavier Castells 1,6 , Carlos Brotons 7 and Margarita Posso 6 1 Doctoral Program in Methodology of Biomedical Research, Public Health in Department of Pediatrics, Obstetrics and Gynecology, Preventive Medicine and Public Health, Universitat Autònoma de Barcelona (UAB), 08193 Bellaterra, Spain 2 Fundació Institut Universitari per a la Recerca a l’Atenció Primària de Salut Jordi Gol i Gurina (IDIAPJGol), 08007 Barcelona, Spain 3 Primary Healthcare Centre Dreta de l’Eixample, 08013 Barcelona, Spain 4 Iberoamerican Cochrane Centre, Department of Clinical Epidemiology and Public Health, Biomedical Research Institute Sant Pau (IIB Sant Pau), Sant Antonio María Claret 167, 08025 Barcelona, Spain 5 Department of Clinical Epidemiology and Public Health, de la Santa Creu i Sant Pau (IIB Sant Pau) University Hospital, 08041 Barcelona, Spain 6 Department of Epidemiology and Evaluation, IMIM (Hospital del Mar Medical Research Institute), 08003 Barcelona, Spain 7 Biomedical Research Institute (IBB Sant Pau), Sardenya Primary Health Care Center, 08025 Barcelona, Spain * Correspondence: caterina.checa@uab.cat Citation: Checa, C.; Canelo-Aybar, C.; Suclupe, S.; Ginesta-López, D.; Abstract: Aims: Nurse-led case management (CM) may improve quality of life (QoL) for ad- Berenguera, A.; Castells, X.; Brotons, vanced heart failure (HF) patients. No systematic review (SR), however, has summarized its C.; Posso, M. Effectiveness and effectiveness/cost-effectiveness. We aimed to evaluate the effect of such programs in primary Cost-Effectiveness of Case care settings in advanced HF patients. We examined and summarized evidence on QoL, mortality, Management in Advanced Heart hospitalization, self-care, and cost-effectiveness. Methods and results: The MEDLINE, CINAHL, Failure Patients Attended in Primary Embase, Clinical Trials, WHO, Registry of International Clinical Trials, and Central Cochrane were Care: A Systematic Review and searched up to March 2022. The Consensus Health Economic Criteria instrument to assess risk- Meta-Analysis. Int. J. Environ. Res. of-bias in economic evaluations, Cochrane risk-of-bias 2 for clinical trials, and an adaptation of Public Health 2022, 19, 13823. https:// Robins-I for quasi-experimental and cohort studies were employed. Results from nurse-led CM doi.org/10.3390/ijerph192113823 programs did not reduce mortality (RR 0.78, 95% CI 0.53 to 1.15; participants = 1345; studies = 6; Academic Editor: Jayasree (Joy) I2 = 47%). They decreased HF hospitalizations (HR 0.79, 95% CI 0.68 to 0.91; participants = 1989; Basu studies = 8; I2 = 0%) and all-cause ones (HR 0.73, 95% CI 0.60 to 0.89; participants = 1012; studies = 5; Received: 25 September 2022 I2 = 36%). QoL improved in medium-term follow-up (SMD 0.18, 95% CI 0.05 to 0.32; participants = Accepted: 21 October 2022 1228; studies = 8; I2 = 28%), and self-care was not statistically significant improved (SMD 0.66, 95% Published: 24 October 2022 CI −0.84 to 2.17; participants = 450; studies = 3; I2 = 97%). A wide variety of costs ranging from USD 4975 to EUR 27,538 was observed. The intervention was cost-effective at ≤EUR 60,000/QALY. Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in Conclusions: Nurse-led CM reduces all-cause hospital admissions and HF hospitalizations but not published maps and institutional affil- all-cause mortality. QoL improved at medium-term follow-up. Such programs could be cost-effective iations. in high-income countries. Keywords: case management; advanced heart failure; cost-effectiveness; meta-analyses; mortality; quality of life; hospital admissions; self-care Copyright: © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and 1. Introduction conditions of the Creative Commons Attribution (CC BY) license (https:// Heart failure (HF) occurs when blood flow is insufficient to meet tissue metabolic creativecommons.org/licenses/by/ needs [1]. Advanced HF (stage D according to America Guidelines) is defined by the 4.0/). Int. J. Environ. Res. Public Health 2022, 19, 13823. https://doi.org/10.3390/ijerph192113823 https://www.mdpi.com/journal/ijerph Int. J. Environ. Res. Public Health 2022, 19, 13823 2 of 22 presence of symptoms at minimal effort/rest, or hypoperfusion, despite optimal treat- ment [2,3]. The New York Heart Association (NYHA) also provides a broadly used method of classifying HF severity; advanced HF corresponds to classes III to IV [4]. In 2017, data from the European Heart Failure Registry reported 8.1% and 28.1% for 12-month mortality and hospitalization, respectively, with NYHA III and IV representing a strong predictor of mortality [5]. Advanced HF involves multiple hospital admissions and increased costs for both acute and stable phases [2]. An economic study performed in an HF population in the United States estimated a lifetime cost of USD 126,819 per patient representing around 1–2% of the healthcare budget [6]. Furthermore, quality of life (QoL) is also affected. A systematic review indicated moderate/poor QoL, particularly in elderly and female populations [7], and a greater deterioration in those with advanced HF [8]. One strategy is the nurse-led case management (CM) model, which is a collaborative process of assessment, planning, facilitation, care coordination, evaluation, and advocacy for options and services to meet an individual’s and family’s comprehensive health needs through communication and available resources to promote patient safety, quality of care, and cost-effective outcomes [9,10]. Implemented in community settings, it has achieved improvements in HF-related outcomes and QoL. A 2019 Cochrane systematic review summarized the evidence of all types of CM models for HF patients in all stages. It suggested they be effective in reducing hospitalizations and all-cause mortality [11]. Nevertheless, the effectiveness of CM in advanced HF-related outcomes is controver- sial. Rogers et al. reported that an interdisciplinary intervention could improve QoL [12] whilst another study reported it did not ameliorate hospitalizations/mortality [13]. To date, no systematic review has summarized the effect of nurse-led CM models on an advanced HF population. We aimed therefore to evaluate the effect of such programs in primary care settings for advanced HF patients and their effect on QoL, mortality, hospitalization, costs, and cost-effectiveness outcomes. 2. Methods 2.1. Study Inclusion Criteria 2.1.1. Types of Design Prospective studies with control groups as randomized controlled trials, quasi-experimental, and cohort studies. 2.1.2. Types of Participants Patients ≥18 years with advanced HF, III/IV NYHA classification, stage D of the American College of Cardiology Foundation/American Heart Association (ACCF/AHA), or under palliative care. 2.1.3. Types of Interventions Inclusion criteria: • Studies where the nurse-led CM model effect was measured. • Community interventions including those commencing in hospital. Exclusion criteria: • Nurse-led CM interventions developed only in hospitals. • Cardiac rehabilitation programs, unless providing elements of nurse-led CM. • Community interventions from specialized HF clinics directed by cardiologists. • Only one educational session, without follow-up phone calls/patient interaction. Int. J. Environ. Res. Public Health 2022, 19, 13823 3 of 22 2.1.4. Type of Comparator/Control Studies comparing the intervention with usual care or another nurse-led CM program within primary/community care. 2.1.5. Outcomes Primary Outcome Nurse-led CM program effects on mortality in primary care settings on advanced HF patients. Secondary Outcomes Results regarding QoL, hospitalization, adherence to treatment, undesirable effects, costs, and cost-effectiveness. Types of Outcome Measures • QoL measured by EuroQol-5D, SF-8, SF-36, and the Kansas City Cardiomyopathy Questionnaire (KCCQ) scales, etc. • All-cause and HF mortality. • Number of HF hospitalizations or for any other cause during follow-up. • Self-care measured by the Appraisal of Self-care Agency (ASA) Scale, European Heart Failure Self-care Behavior Scale, and Self-care of Heart Failure Index. • Costs associated with health resources. • Cost per QALY (quality-adjusted life year), cost per year of life gained. Outcomes were measured by follow-up time when available (<6 months, 6–12 months, >12 months), age, and type of consultations (home visits/telemedicine). 2.2. Search Methods 2.2.1. Electronic Searches Searches were performed with MEDLINE, CINAHL, Embase, Clinical Trials, WHO, Registry of International Clinical Trials, and Central Cochrane. The World Health Orga- nization’s International Clinical Trials Registry (ICTRP) platform (http://apps.who.int/ trialsearch/, accessed on 24 March 2022), and the ISRCT registry (https://www.isrctn.com/, accessed on 24 March 2022) were used. One hundred ongoing studies were identified by the USA ClinicalTrials.gov registry (https://ClinicalTrials.gov/, accessed on 24 March 2022), however, there were no partial results published and they were excluded. The database was EndNote χ2 software. Publications were included up to March 2022 (See Appendix A). 2.2.2. Other Resources A manual inspection of the references in previous systematic reviews of HF patient nurse-led CM models was conducted. Gray literature was reviewed, and experts consulted. 2.3. Data Collection and Analysis 2.3.1. Study Selection Initial screening of titles/abstracts was performed by a reviewer. A random sample of 20% of the retrieved references was evaluated by a second reviewer in order to guarantee the quality of the process. Two reviewers then independently assessed eligibility of the 405 studies based on full-text reading. In case of discrepancy, there were consensus sessions. The Rayyan program [14] was employed throughout. A PRISMA flow chart depicts the study selection (Figure 1). For excluded studies at the full-text level, see Supplementary Material Table S1. Int. J. Environ. Res. Public Health 2022, 19, 13823 4 of 22 Figure 1. Study flow chart of studies evaluating clinical efficacy. 2.3.2. Data Extraction/Management Data included author/s, publication year, design, sample and intervention characteris- tics, and outcomes. Funding information was from economic studies. Data extraction was performed in duplicate. 2.3.3. Risk-of-Bias Assessment The Cochrane risk-of-bias 2 tool (RoB2) [15] was employed for clinical trials and the Risk-of-Bias in Non-randomized Studies of Interventions (Robins-I) [16] for cohort studies. The Robins-I was adapted for quasi-experimental studies (Supplementary Material Table S2). Disease decline over time was assumed as a confounder and penalized if the participants were overstable/decompensated during follow-up. In the risk of bias due to intervention classification, intervention/inclusion criteria were either clearly predefined or not. The Consensus Health Economic Criteria (CHEC) list was employed for economic evaluations [17]. All studies were peer-reviewed, and in the case of any discrepancies, consensus was reached. In studies that measured more than one outcome, these were assessed separately in the outcome domains of the tools. 2.3.4. Intervention Characteristics Interventions were classified as basic or intensive and determined according to staff availability and issue management during follow-up. Table 1 depicts the intervention and characteristics. Subgroup analyses were carried out by age ranges (>85 years, 65–85 years, <65 years) and time to follow-up (<6 months, 6–12 months, and >12 months). Population characteris- tics and outcome measurement instruments were evaluated. Int. J. Environ. Res. Public Health 2022, 19, 13823 5 of 22 Table 1. Characteristics and summary of results of the included studies for the evaluation of case management in advanced heart failure patients. Studies Evaluating Clinical Efficacy Study Design Mean Age (Standard Intervention Maximum Gender (% Women) Author, Year (Number of Deviation) Characteristics Follow-Up Outcome Case Management vs. Population Control Country Subjects Case Management vs. and Main Time Measures Control Included) Control Component * (Days) Patients from community or Intensive Aiken, 2006 [18] hospitalized with chronic RCT (N = 129) 68 (14) vs. 70 (13) β 58 vs. 70 intervention b,f Usual care 270 Quality of life USA heart failure in NYHA Home visits III or IV Intensive Treatment Bondmass, 2007 RCT 62.1 (13.9) vs. 62.8 Patients hospitalized with NHV: Nurse 63.3 vs. 60.4 intervention c,f 90 adherence, [19] USA (N = 186) (12.4) HF in NYHA III or IV home visits Telemedicine quality of life Patients in the community RCT Total: 71.0 (11.9) vs. diagnosed with HF >18 Total: (N = 382) Total: 42 vs. 40 71.9 (10.5) years and being treated by Intensive Boyne, 2012 [20] Subgroup NYHA Subgroup in NYHA Hospitalizations Subgroup in NYHA an HF nurse and a intervention a,c,e Usual Care 365 Netherlands III: 153 III and IV: not for HF III and IV: not cardiologist in an HF clinic Telemedicine Subgroup NYHA reported reported Subgroup analysis in IV: 10 NYHA III and IV All-cause hos- Brännström, Patients in the community Intensive RCT 81.9 (7.2) vs. 76.6 pitalizations, 2014 [21] 27.8 vs. 30.6 diagnosed with HF in intervention b,f Usual Care 180 (N = 72) (10.2) quality of life, Sweden NYHA III or IV Home visits self-efficacy Total: 74 (11) vs. Total: 43 vs. 39 Patients hospitalized Comin-Colet, 75 (11) Intensive RCT Subgroup in NYHA with HF Hospitalizations 2016 [22] Subgroup in NYHA intervention c,d,f HF program 180 (N = 178) III and IV: not Subgroup analysis in for HF Spain III and IV: not Telemedicine reported NYHA III and IV reported Int. J. Environ. Res. Public Health 2022, 19, 13823 6 of 22 Table 1. Cont. Studies Evaluating Clinical Efficacy Study Design Mean Age (Standard Intervention Maximum Gender (% Women) Author, Year (Number of Deviation) Characteristics Follow-Up Outcome Case Management vs. Population Control Country Subjects Case Management vs. and Main Time Measures Control Included) Control Component * (Days) All-cause Intensive mortality, hos- De la Porte, 2007 Patients in the community RCT intervention a,f,g pitalizations [23] 70 (10) vs. 71 (10) 34 vs. 21 or hospitalized with NYHA Usual Care 365 (N = 340) Clinical for HF, Netherlands III or IV consultations self-care, and quality of life Quasi- experimental Delaney, 2010 Patients with a primary Intensive Hospitalizations studio with [24] Overall: 79.04 (11.8) π 58.3 vs. 58.3 diagnosis of HF in NYHA intervention b,c Usual care 90 for HF, quality control without USA III or IV Telemedicine of life randomization (N = 24) All-cause Basic intervention mortality, hos- Ekman, 1998 [25] RCT Patients hospitalized with a,f,g (office hours) pitalizations Overall: 80.3 (6.8) π 42 π Usual care 180 Sweden (N = 158) HF in NYHA III or IV Clinical for HF, consultations all-cause hospi- talizations Patients in the community Quasi- Basic All-cause Fonarow, 1997 diagnosed with HF in experimental intervention a,f 180 pre and mortality, hos- [26] 52.6 (10) 19 NYHA III or IV and Usual care pre-post Clinical 180 post pitalizations USA potential candidates for (N = 214) consultations for HF transplantation Patients in the community RCT Total: 64.8 (13.9) vs. Total: 27.4 vs. 31.1 GESICA, 2005 diagnosed with HF and Basic Total: (N = 1518) 65.2 (12.7) Subgroup in NYHA From 180 to Hospitalizations [27] >18 years intervention f Usual Care Subgroup NYHA Subgroup: not III and IV: not 365 for HF Argentina Subgroup analysis in Phone calls III or IV: (N = 750) reported reported NYHA III and IV Int. J. Environ. Res. Public Health 2022, 19, 13823 7 of 22 Table 1. Cont. Studies Evaluating Clinical Efficacy Study Design Mean Age (Standard Intervention Maximum Gender (% Women) Author, Year (Number of Deviation) Characteristics Follow-Up Outcome Case Management vs. Population Control Country Subjects Case Management vs. and Main Time Measures Control Included) Control Component * (Days) All-cause mortality, Intensive hospitalizations Goldberg, 2003 RCT 57.9 (15.7) vs. 60.2 Patients hospitalized with 30.4 vs. 34.5 intervention c Usual Care 180 for HF, all cause [28] USA (N = 280) (14.9) HF in NYHA III or IV Telemedicine hospitalizations and quality of life Basic Quasi- All-cause Holst, 2001 [29] Patients with NYHA intervention a experimental 54 (13) 16.6 Usual care 180 hospitalizations, Australia III or IV Clinic (N = 42) quality of life consultations Hospitalizations Jaarsma, 1999 Basic for HF, All-cause Patients hospitalized for [30] RCT (N = 179) 73 (9) vs. 73 (9) 44 vs. 41 intervention b,g Usual care 270 hospitalizations, HF with NYHA III or IV Netherlands Home visits treatment adherence Jaarsma, 2000 Patients admitted in Basic Self-care, quality [31] RCT (N = 132) 72 (9) vs. 72 (10) 45 vs. 36 cardiology unit for HF intervention a,b,f,g Usual care 270 of life Netherlands with NYHA III or IV Home visits All-cause Up to cardiac Basic mortality, Lynga, 2012 [13] RCT 73.7 (9.9) vs. 73.5 Patients hospitalized for hospitaliza- 24.1 vs. 26.1 intervention a,c,g Usual Care hospitalizations Sweden (N = 319) (10.4) HF with NYHA III or IV tion or 365 Telemedicine for HF, all-cause days hospitalizations Int. J. Environ. Res. Public Health 2022, 19, 13823 8 of 22 Table 1. Cont. Studies Evaluating Clinical Efficacy Study Design Mean Age (Standard Maximum Gender (% Women) Intervention Author, Year (Number of Deviation) Follow-Up Outcome Case Management vs. Population Characteristics and Control Country Subjects Case Management vs. Time Measures Control Main Component * Included) Control (Days) Intensive Man, 2018 [32] Patients hospitalized for RCT (N = 84) 78.3 (16.8) vs. 78.4 (10) 56.1 vs. 39 intervention b,f Usual care 90 Quality of life China HF with NYHA III or IV Home visits Basic McDonald, 2001 Hospitalizations Patients hospitalized with intervention a,f,g [33] RCT (N = 70) 69.9 (11.3) vs. 67.9 (12) 14.3 vs. 18.6 Usual care 30 for HF, all-cause HF and NYHA III or IV Clinical Ireland mortality consultations Median (interquartile Patients admitted to range) Total: 50.2 vs. 50.5 hospital for Total: 73 (62–84) vs. 74 Intensive Ong, 2016 [34] RCT Subgroup in NYHA decompensated HF and All-cause (63–82) intervention c,f,g Usual care 180 USA (N = 1437) III and IV: not >50 years old hospitalizations Subgroup in NYHA Telemedicine reported Subgroup analysis in III and IV: not NYHA III and IV reported All-cause Patients hospitalized for mortality, Intensive Rogers, 2017 [12] RCT 71.9 (12.4) vs. 69.8 HF or within 2 weeks of hospitalizations 44 vs. 50.7 intervention b Usual Care 180 USA (N = 150) (13.4) discharge and dyspnea at for HF, all-cause Not clearly reported rest or minimal exertion hospitalizations, quality of life Schellinger, 2011 Patients with a primary or Basic intervention a Cohort study ∞ ∞ All-cause [35] 75.63 vs. 73.84 52 vs. 48.4 secondary HF diagnosis Clinical Usual care 60 (N = 1894) hospitalizations USA in community setting consultations Int. J. Environ. Res. Public Health 2022, 19, 13823 9 of 22 Table 1. Cont. Studies Evaluating Clinical Efficacy Study Design Mean Age (Standard Maximum Gender (% Women) Intervention Author, Year (Number of Deviation) Follow-Up Outcome Case Management vs. Population Characteristics and Control Country Subjects Case Management vs. Time Measures Control Main Component * Included) Control (Days) Quasi- experimental Shah, 1998 [36] Patients hospitalized Basic intervention f,g All-cause hos- (N = 27) 62 (range 42–81) 0 Usual care 365 USA for HF Phone calls pitalizations Subgroup NYHA III and IV (N = 17) All-cause Basic intervention a Smith, 2014 [37] RCT 62.6 (14.1) vs. 62.1 Patients hospitalized with mortality, hos- 44 vs. 34 Clinical Usual Care 365 USA (N = 198) (12.5) HF in NYHA III or IV pitalizations consultations for HF Vavouranakis, Quasi- Patients in the community Basic All-cause hos- 2003 [38] experimental 65.4 (6.7) 12.1 with HF and NYHA III or intervention b,f,g Usual care 365 pitalizations, Greece (N = 33) IV Home visits quality of life Two placebo calls from Intensive All-cause hos- Yuet, 2016 [39] RCT 78.3 (16.8) vs. 78.4 Patients hospitalized with assistant 55.1 vs. 39 intervention b,f 90 pitalizations, China (N = 84) (10.0) HF in NYHA III or IV unrelated to Home visits quality of life clinical issues Basic Zamanzadeh, Patients diagnosed with Self-care RCT 65.82 (9.87) vs. 61.63 intervention a,f,g 2013 [40] 42.1 vs. 52.5 HF in NYHA III or IV and Usual Care 90 (treatment (N = 78) (12.47) Clinical Iran an ejection fraction <40% adherence) consultations RCT: randomized control trial. HF: heart failure. NYHA: New York Heart Association. * This classification was based on the number of contacts made with the patients, staff availability, and the extent to which they addressed the issues during follow-up. The main component of each intervention was also described: a —clinical consultations, b —home visits, c —remote vital sign monitoring, d —videophone, e —messaging, f —scheduled telephone calls, g —telephone availability of staff (unscheduled). ∞ There is no exact information about the “no program” group but it seems to be similar to the uncompleted follow-up. π Case management vs. control not reported. β Population with advanced chronic diseases. Advanced HF disease not reported. Int. J. Environ. Res. Public Health 2022, 19, 13823 10 of 22 2.3.5. Data Synthesis and Registry The analysis was an intention-to-treat approach, and all participants were included to reduce the potential selection bias. Outcome data were evaluated at <6 months, 6–12 months, and >12 months follow-up when available. Mortality/hospitalization were meta-analyzed using Review Manager (RevMan, ver- sion 5.3.5., Cochrane Collaboration, Oxford, UK) and STATA software (v.14.0, STATA Corp, College Station, TX, USA). Pooled relative risk ratios (RRs) and standard mean differences (SMDs) for binary and continuous outcomes were evaluated with the random effect model approach. When means and standard deviations (SDs), or changes of means and SDs from baseline were not reported, they were calculated using standard errors (SE), confidence intervals (CI), or the correlation coefficient. Magnitude of heterogeneity was assessed using Higgins’s I2 statistics and interpreted according to the Cochrane Handbook (0–40%: low, 30–60%: moderate, 50–90%: substantial, 75–100%: considerable). Meta-analysis forest plots for consistency were inspected, given that I2 statistics might be artificially inflated when effect estimates from primary studies were very precise [41]. For all meta-analyses with at least 10 included studies, the publication bias was assessed by a visual inspection of Begg’s funnel plot and statistically, using Egger’s test for small study effects (funnel plot asymmetry). Systematic Reviews of Economic Evaluations guides were followed to analyzed costs and the cost-effectiveness of primary studies [42]. The study was registered in the International Prospective Register of Systematic Reviews (PROSPERO) and published with ID number CRD42020160810. 3. Results 3.1. Selection of Primary Studies From 5944 records from four databases, 2129 studies remained. We then reviewed 405 full-text articles: 14 were selected for synthesis. We also reviewed all primary studies obtained from 55 systematic reviews identified in the title/abstract screening and selected 16. In total, 30 studies were included in the evidence synthesis. Of these 30, 25 described the benefits/risks of a nurse-led CM model, and 5 were economic evaluations (Figure 1). 3.2. Study Characteristics 3.2.1. Evidence of Effects (Benefits and Risks) The 25 included studies were published between 1997 and 2016 (Table 1). The majority (17) were from the US and European countries. Most were randomized controlled trials, except for five quasi-experimental studies and one prospective cohort. Populations were mainly men >60 years. The identification was performed primarily at the hospital or community level. In 22 of the 25 included studies, the comparator was usual care. Most studies had a follow-up of more than six months, with a maximum of one year. Twelve intensive and thirteen basic programs compared their effect with usual care. The intensity classification was based on the number of contacts made with the patients, staff availability, and to what extent they addressed the issues in the follow-up visits. Telemedicine and home-visit interventions were mainly intensive programs whereas others (clinical consultations, phone calls) were basic. 3.2.2. Cost-Effectiveness Studies Five economic evaluations were identified. Three were cost-effectiveness studies, and two cost-benefit analyses. All had been performed in high-income countries, four in European ones and another in the US (Table 2). Int. J. Environ. Res. Public Health 2022, 19, 13823 11 of 22 Table 2. Characteristics and summary of results of the included studies for the economic evaluation of case management in advanced heart failure patients. Studies Evaluating the Economic Evidence for Nurse Case Management Risk of Bias Author, Study Design, Intervention Time Horizon, Difference in Cost Population Control Difference in Outcome ICER (CHEC) Year Country Characteristics * Perspective (Year Value) Score) Patients admitted to Reference SC: USD 3979 Intensive hospital with 90 days, (2003) USA Dollars USD −759 due to reduction Gregory, Cost-benefit, intervention: 2, USD +237 not considered cost primary SC healthcare Intensive vs. SC: USD in hospitalization costs per 11.5/19 2006 [43] USA 6, 7 (24 h saving diagnosis of HF perspective 996 additional cost per patient availability) in NYHA III or patient IV Patients admitted to Basic Reference SC: no cost 3 months, EUR −43,955 due to Ledwidge, Cost-benefit, hospital with a intervention: 1, Basic vs. SC: EUR 113 Net saving EUR −379.75 per SC healthcare reduction in hospitalization 12/19 2003 [44] Ireland diagnosis of HF 6, 7 (working (1999) additional cost per patient perspective costs per patient in hours) patient NYHA IV Reference QALY SC: EUR 10,692 per QALY LY LY (cost/LY) (cost/QALY) patient (2009) Patients Basic Basic vs. SC: EUR 1101 admitted to intervention: 1, 7 Basic vs. SC: Basic vs. SC: Basic vs. SC: Basic vs. SC: Cost- 18 months, additional cost per Postmus, hospital with (working hours) 0.014 0.042 EUR 77,335 EUR 25,923 effectiveness, healthcare patient (2009) 2011 [45] primary Intensive SC 14/19 Sweden diagnosis of HF intervention: 1, perspective Intensive vs: SC: EUR Intensive vs. Intensive vs. Intensive vs. Intensive vs. in NYHA III or 2, 6, 7 (24 h 1770 additional cost per SC: EUR SC: EUR SC: 0.029 SC: 0.057 IV availability) patient (2009) 59,289 30,933 Intensive vs. basic: EUR Intensive vs. Intensive vs. Intensive vs. Intensive vs. 669 additional cost per basic: EUR basic: basic: 0.015 basic: 0.014 patient (2009) 42,839 EUR 45,219 Int. J. Environ. Res. Public Health 2022, 19, 13823 12 of 22 Table 2. Cont. Studies Evaluating the Economic Evidence for Nurse Case Management Risk of Bias Author, Study Design, Intervention Time Horizon, Difference in Cost Population Control Difference in Outcome ICER (CHEC) Year Country Characteristics * Perspective (Year Value) Score) Reference QALY SC: EUR 15,407 per QALY LY LY (cost/LY) (cost/QALY) Basic patient (2015) intervention Patients > 70 Basic vs. SC: EUR 7042 (nurse telephone Basic vs. SC: Basic vs. SC: Basic vs. SC: Basic vs. SC: Cost- years admitted Lifetime (20 additional cost per effectiveness support): 1, 6, 7 0.75 0.96 EUR 9398 EUR 7364 Grustam, to hospital with years), health patient (2015) (working hours) SC 16/19 2018 [46] Markov model, a diagnosis of system Netherlands Intensive Intensive vs. SC: EUR Intensive vs. Intensive vs. HF in perspective Intensive vs. Intensive vs. intervention 12,131 additional cost per SC: EUR SC: EUR NYHA IV SC: 0.86 SC: 1.14 (home patient (2015) 14,027 10,644 telemonitoring): 3 Intensive vs. basic: EUR Intensive vs. Intensive vs. Intensive vs. Intensive vs. 5090 additional cost per basic: EUR basic: EUR basic: 0.12 basic: 0.18 patient (2015) 44,040 27,733 Patients Reference SC: EUR 5727 diagnosed with Cost- 6 months, per patient (2012) Sahlen, 2016 HF in NYHA III Intensive effectiveness, SC healthcare Intensive vs. SC: EUR 0.25 QALY Dominant 13/19 [47] or IV and intervention: 2, 6 Sweden perspective −1649 saving cost per attended in the patient community * Intervention characteristics; 1 —clinical consultations, 2 —home visits, 3 —remote vital signs monitoring, 4 —videophone, 5 —messaging, 6 —scheduled telephone calls, 7 —telephone availability of staff (unscheduled). ICER: incremental cost-effectiveness ratio. QALY: quality-adjusted life years. LY: life year. CHEC: consensus on health economics criteria checklist. SC: standard care. HF: heart failure. NYHA: New York Heart Association. Int. J. Environ. Res. Public Health 2022, 19, 13823 13 of 22 3.3. Quality of Included Studies 3.3.1. Randomized Control Trials The RoB2 Cochrane [15] tool was used to evaluate the risk of bias (Supplementary Material Table S3). Most studies presented issues with random sequence generation; however, baseline group characteristics did not suggest a randomization concern. To evaluate the risk of bias of the reported results, all study original protocols were examined to compare the planned statistical analysis with the final result. In nine studies, the protocol was missing and thus referred to as a lack of information with some concerns. Most studies with protocol (8 out of 10) were assessed as a low risk of bias. Hospitaliza- tion/mortality was considered a low risk of bias. QoL and self-care outcomes presented some concerns as the interventions were not blinded, and the questionnaires were generally self-reported (Supplementary Material Table S3). 3.3.2. Nonrandomized Trials The risk of bias in the quasi-experimental and cohort studies was assessed with the ROBINS-I tool (16) (Supplementary Material Table S4). Only one cohort study was identified (Schellinger 2011 [35]). Studies were classified as having a high risk of bias when patients were too stable/decompensated during follow-up. If no control group was present, the progression of advanced HF was considered to play a role in the intervention effectiveness. Since nonrandomized control trials had lower levels of evidence than randomized ones, they were not included in the meta-analysis, although descriptively reported. 3.3.3. Economic Evaluations The CHEC tool [17] was used to assess the economic evaluations (Table 2). All studies had a clear research question, with a well-defined population. The economic evaluations were considered as social ones, since they included costs related to patient care beyond hospital admissions. The quality of such studies was therefore downgraded. Intervention cost-effectiveness was taken to be >6 months although three of the five studies had a shorter follow-up time. Only one study declared its source of funding (Sahlen et al. [47]). Overall, three economic evaluations had a moderate/low risk of bias, and two were high risk. 3.4. Evidence of Effects 3.4.1. All-Cause Mortality Six studies reported all-cause mortality and indicated no improvement (RR 0.78, 95% CI 0.53 to 1.15; participants = 1345; studies = 6; I2 = 47%, low risk of bias). The follow-up was 12 months in three studies and 6 months in the others. To avoid one death, 32.15 patients were required (Figure 2). The forest plot did not suggest a marked heterogeneity, nor did the subgroup analysis by length of follow-up indicate differences amongst subgroups (p = 0.34). There were, however, some differences in the type of CM (p = 0.07). Telemedicine was more effective than home visits (RR 0.47, 95% CI 0.27 to 0.83; participants = 2686 in two studies I2 0%, low risk of bias) with 6 and 12 months of follow-up (Goldberg 2003 [28] and Lynga 2012 [13], respectively) (Supplementary Material Figure S1). Int. J. Environ. Res. Public Health 2022, 19, 13823 14 of 22 Figure 2. Cont. Int. J. Environ. Res. Public Health 2022, 19, 13823 15 of 22 Figure 2. Metanalysis for all-cause mortality, hospitalizations for heart failure, all-cause hospitaliza- tions, quality of life, and self-care. CM: nurse-led case management. 3.4.2. Mortality for Heart Failure None of the studies reported deaths due to HF. 3.4.3. Hospitalizations for Heart Failure Eight studies described HF hospitalizations and results showed CM as effective in avoiding them (HR 0.79, 95% CI 0.68 to 0.91; participants = 1989; studies = 8; I2 = 0%, low risk of bias). Five studies lacked full information, and two were not randomized controlled trials, and thus excluded. Nevertheless, the results showed that CM was beneficial for advanced HF (Supplementary Material Table S5). 3.4.4. All-Cause Hospitalizations Five studies reported hospitalizations for all causes and demonstrated CM as protec- tive for this outcome (HR 0.73, 95% CI 0.60 to 0.89; participants = 1012; studies = 5; I2 = 36%, low risk of bias). The subgroup analysis by age, time to follow-up, and CM type did not suggest any differences among groups (p = NA, p = 0.05 and p = 0.40, respectively) (Supplementary Material Figure S1). Seven studies were excluded since four were not randomized controlled trials and three lacked information. Nevertheless, results indicated the benefits of nurse-led CM (Supplementary Material Table S5). 3.4.5. Quality of Life Eight studies reported QoL and indicated a beneficial effect (SMD 0.18, 95% CI 0.05 to 0.32; participants = 1228; studies = 8; I2 = 28%, moderate risk of bias) (Figure 2). Subgroup differences in follow-up showed that the beneficial effect started at 6 months but was lost at 12 months (p = 0.02). In addition, testing for subgroup differences in the Int. J. Environ. Res. Public Health 2022, 19, 13823 16 of 22 type of nurse-led CM suggested an improvement in home visits rather than telemedicine or other means (p = 0.02) (Supplementary Material Figure S1). 3.4.6. Self-Care Three studies reported self-care and indicated a statistically nonsignificant benefi- cial effect. The heterogeneity among studies was high (SMD 0.66, 95% CI −0.84 to 2.17; participants = 450; studies = 3; I2 = 97%, moderate risk-of-bias). 3.5. Costs and Cost-Effectiveness of Nurse-Led CM 3.5.1. Cost of the Intervention Except for one study (Sahlen et al. [47]), all reported that investment in a new in- tervention was greater than in usual care. Cost varied according to intensity, year of implementation, and country. Related costs were mainly linked to healthcare professionals and telemedicine devices in those studies proposing remote data transfer (Table 2). 3.5.2. Cost-Effectiveness (Cost per QALY) Three studies reported results in the incremental cost-effectiveness ratio (ICER) per QALY of the intervention compared with usual care. They also presented the lowest risk of bias and the largest time horizon (Postmus et al., Grustam et al. and Sahlen et al. [45–47]). They reported that intensive interventions, compared with basic ones/usual care, obtained larger benefits in terms of QALY and LY in NYHA III/IV patients. Regarding the ICER per QALY, ICERs of EUR 59,289 and EUR 14,027, respectively, were observed when comparing intensive versus usual care. Figures were below EUR 60,000/QALY. 3.5.3. Cost-Benefit Studies Studies reported savings due to fewer hospital admissions. The net benefit was mainly determined by the price of the intervention. 4. Discussion This systematic review summarized the quality of evidence regarding the effectiveness/ cost-effectiveness of nurse-led CM programs in advanced HF populations. We included 30 studies, 25 reported effectiveness (19 randomized controlled trials, 5 quasi-experimental, and 1 cohort), and 5 economic evaluations. Only meta-analyzed studies with a low risk of bias, or with the lowest risk of bias available, were analyzed. Nonrandomized trials or studies lacking data were excluded. The latter were presented as narrative results and showed the same direction of effectiveness. Our results were nonsignificant to indicate that nurse-led CM intervention reduced all-cause mortality. Interventions with telemedicine were the most effective. No study reported mortality due to HF. Regarding HF hospitalizations, we found eight low-risk-of-bias randomized controlled trials. Five additional studies were narratively summarized. Nurse-led CM, telemedicine, and home visits were effective in preventing HF and all-cause hospitalizations. Eight studies reported an improvement in QoL at 6 months which did not extend at 12 months. Three studies suggested that patients in the program had better self-care, although this was not statistically significant and the intervention costs among studies ranged from USD 4975 (2003-year value) to EUR 27,538 (2015-year value). The most recent similar review (Takeda) explored different CM interventions for all- stage HF patients. Whilst our results concurred, they were not statistically significant, in contrast to other authors [11,48,49]; the fact that our population was at the final stage of the disease may have played a role. In a similar manner to Bashi et al. [50], we found that patients with lower mortality were those who received telemedicine. Such results are, however, controversial as Flod- gren et al. described no differences with usual care [51]. Reasons for this may include sociocultural differences, and in this sense, further research is required. Int. J. Environ. Res. Public Health 2022, 19, 13823 17 of 22 We observed that the nurse-led CM interventions reduced the risk of hospitalizations. This is a relevant finding since hospitalizations for advanced HF are common [52] and avoiding hospitalization can also reduce mortality [53]. In agreement with Rice et al. [54], QoL improved with the intervention. We found, however, that in our population this was at 6 months after the intervention and only lasted up to 12 months. Nevertheless, due to the advanced stage of the disease, we believe any gain, or even maintenance, in the QoL of patients with advanced HF to be relevant. QoL did not improve in the telemedicine group, concurring with Bauce et al. [55]. Personal contact with healthcare professionals can produce a certain emotional proximity which may have a positive impact on QoL and should be further evaluated. Nurse-led CM interventions could also improve self-care [56]. Nevertheless, our findings were not statistically significant, and there was considerable heterogeneity among studies. The intervention effect was lost with time as patients lost motivation. Factors favoring long-term self-care should be further explored as they have an impact on the reduction of hospital admissions [57]. Nurse-led CM could be cost-effective, a finding that concurs with Rice et al. [54], probably due to the savings from fewer hospitalizations. In terms of QALYs, Fergenbaum et al. concluded that a home-based intervention improved the QALY by 0.11 and reduced costs [58]. In our review, all the studies that reported QALYs described improvements above the figure described by Fergenbaum except for the Postmus study. Advanced HF patients require more resources to improve their QALY thus increasing incremental cost. Nurse-led CM was not found to be particularly cost-effective, nevertheless, a threshold of EUR 60,000/QALY may be considered affordable for high-income countries. Further studies should consider differentiating advanced HF from the general HF population, since this subgroup has different needs. Limitations • The limitations of this systematic review are mostly derived from those of the primary included studies. We found seven, five, and four studies corresponding to all-cause hospitalizations, HF hospitalizations, and QoL, respectively, with concerns of a high risk of bias leading to their exclusion from the pooled analysis. We did, however, narratively summarize these data and found similar results in most cases. • Nurse-led CM interventions may have varying characteristics according to their set- tings which could result in heterogeneity. For clarification, we created a descriptive table with all the characteristics of each intervention. • The CM overall effect can be affected over time. We observed a short-term beneficial effect that was depleted on the medium/long term. We therefore carried out the meta-analysis with different follow-up time groups to analyze this factor. 5. Conclusions Nurse-led CM can reduce all-cause hospital admissions and HF hospitalizations but not all-cause mortality. QoL improved in medium-term follow-up, and better self- care/survival was reported, although it was not statistically significant. The intervention could be cost-effective for less than EUR 60,000/QALY. More intensive nurse-led case management studies are needed to determine the cost-effectiveness of the program. Supplementary Materials: The following supporting information can be downloaded at: https: //www.mdpi.com/article/10.3390/ijerph192113823/s1, Figure S1: Meta-analysis of subgroups according follow-up time, type of nurse-led case management delivered and age Table S1: Excluded articles at full text level; Table S2: ROBINS-I adaptation; Table S3: Assessment of Risk of bias (RoB) in Randomized controlled trial studies; Table S4: Assessment of Risk of bias with adaptation ROBINS-I tool in non-Randomized controlled trial studies; Table S5: Descriptive tables of studies with incomplete outcome data. Int. J. Environ. Res. Public Health 2022, 19, 13823 18 of 22 Author Contributions: Conceptualization, C.C. and M.P.; methodology, M.P., X.C. and C.C.; software, C.C.; validation, S.S., D.G.-L., A.B., X.C., C.B. and M.P.; formal analysis, C.C.-A., C.C. and M.P.; investigation, C.C., C.C.-A., S.S., D.G.-L., A.B., X.C., C.B. and M.P.; resources, C.C., C.C.-A., S.S., D.G.-L. and A.B.; data curation, C.C.-A.; writing—original draft preparation, C.C., M.P. and D.G.-L.; writing—review and editing, C.C., C.C.-A., S.S., D.G.-L., A.B., X.C., C.B. and M.P.; visualization C.C., C.C.-A., S.S., D.G.-L., A.B., X.C., C.B. and M.P.; supervision, M.P.; project administration, C.C. and M.P.; funding acquisition, C.C. All authors have read and agreed to the published version of the manuscript. Funding: This study was developed with the support of the Departament de Salut de la Generalitat de Catalunya, in the call corresponding to 2018 for the granting of subsidies from the Pla Estratègic de Recerca i Innovació en Salut (PERIS) 2019–2021, modality of “Grants for the intensification of the research activity of health professionals without specialized health training”, with the file code SLT008/18/00130. Webpage: http://salutweb.gencat.cat/ca/inici/, accessed on 20 October 2022. Acknowledgments: We would like to thank Lorea Galnares Cordero, for her work in the strategy and search of primary studies for this review in the databases. Secondly, we thank Stephanie Lonsdale Anning for her review of the written English of this paper. This systematic review is part of the work of the Doctoral Program in Methodology of Biomedical Research and Public Health at the Department of Pediatrics, Obstetrics, and Gynecology, Preventive Medicine, and Public Health, Universitat Autònoma de Barcelona (UAB) in which the researcher, Caterina Checa, is studying. Conflicts of Interest: The authors have declared that no competing interests exist. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Appendix A Electronic Database Strategy Medline, Via Pubmed Heart Failure #1 Search “Heart Failure”[Mesh] #2 Search “Heart Arrest”[Mesh] #3 Search “Shock, Cardiogenic”[Mesh] Search (heart[Title/Abstract] OR cardi *[Title/Abstract] OR myocard *[Title/Abstract]) AND #4 (failur *[Title/Abstract] OR decompensat *[Title/Abstract] OR insufficien *[Title/Abstract] OR incompet *[Title/Abstract] OR arrest[Title/Abstract] OR shock[Title/Abstract]) #5 Search #1 OR #2 OR #3 OR #4 344766 Nurses #6 Search “Nurses”[Mesh] #7 Search “Nurses, Community Health”[Mesh] #8 Search “Nursing”[Mesh] #9 Search “Primary Nursing”[Mesh] #10 Search “Nursing Care”[Mesh] #11 Search “Primary Care Nursing”[Mesh] #12 Search “Practice Patterns, Nurses”[Mesh] #13 Search nurs *[Title/Abstract] #14 Search “Patient Care Team”[Mesh] Search (multidisciplinar *[Title/Abstract] OR multi-disciplinar *[Title/Abstract] OR #15 interdisciplinar *[Title/Abstract]) OR ((care[Title/Abstract] OR healthcare[Title/Abstract] OR “health care”)[Title/Abstract] AND (team[Title/Abstract] OR teams[Title/Abstract])) #16 Search #6 OR #7 OR #8 OR #9 OR #10 OR #11 OR #12 OR #13 OR #14 OR #15 754499 Int. J. Environ. Res. Public Health 2022, 19, 13823 19 of 22 Case Management #17 Search “Patient Care Management”[Mesh] #18 Search “Patient Care Planning”[Mesh] #19 Search “Case Management”[Mesh] #20 Search “Case Managers”[Mesh] #21 Search “Disease Management”[Mesh] #22 Search manag *[Title/Abstract] #23 Search #17 OR #18 OR #19 OR #20 OR #21 OR 1893972 Primary Care #24 Search “Primary Health Care”[Mesh] #25 Search “General Practice”[Mesh] #26 Search “Family Practice”[Mesh] #27 Search “Community Medicine”[Mesh] #28 Search “Community Health Services”[Mesh] #29 Search “Community Health Nursing”[Mesh] #30 Search “Home Care Services”[Mesh] #31 Search “Home Health Nursing”[Mesh] #32 Search “Community Health Planning”[Mesh] #33 Search “Community Health Centers”[Mesh] #34 Search “Ambulatory Care”[Mesh] #35 Search “Ambulatory Care Facilities”[Mesh] Search (primary[Title/Abstract]) AND (care[Title/Abstract] OR healthcare[Title/Abstract] OR #36 “health care”[Title/Abstract]) Search ((general[Title/Abstract] OR family[Title/Abstract])) AND (practic *[Title/Abstract] OR #37 medicine[Title/Abstract]) Search (community[Title/Abstract]) AND (medicine[Title/Abstract] OR care[Title/Abstract] #38 OR healthcare[Title/Abstract] OR service[Title/Abstract] OR services[Title/Abstract] OR health[Title/Abstract]) #39 Search ((ambulatory[Title/Abstract] OR outpatient[Title/Abstract])) AND care[Title/Abstract] Search ((community[Title/Abstract] OR neighbo*[Title/Abstract] OR outpatient[Title/Abstract] OR walk-in[Title/Abstract] OR “walk in”[Title/Abstract])) AND #40 (center[Title/Abstract] OR centers[Title/Abstract] OR centre[Title/Abstract] OR centres[Title/Abstract] OR clinic[Title/Abstract] OR clinics[Title/Abstract]) #41 Search (home[Title/Abstract]) AND (care[Title/Abstract] OR health[Title/Abstract]) Search #24 OR #25 OR #26 OR #27 OR #28 OR #29 OR #30 OR #31 OR #32 OR #33 OR #34 OR #42 #35 OR #36 OR #37 OR #38 OR #39 OR #40 OR #41 1133580 TOTAL #43 Search #5 AND #16 AND #23 AND #42 2055 References 1. 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