Humanistic burden and economic impact of heart failure – a systematic review of the literature

Background: Heart failure (HF) is increasing in prevalence worldwide. This systematic review was conducted to inform understanding of its humanistic and economic burden. Methods: Electronic databases (Embase, MEDLINE®, and Cochrane Library) were searched in May 2017. Data were extracted from studies reporting health-related quality of life (HRQoL) in 200 patients or more (published 2007–2017), or costs and resource use in 100 patients or more (published 2012–2017). Relevant HRQoL studies were those that used the 12- or 36-item Short-Form Health Surveys, EuroQol Group 5-dimensions measure of health status, Minnesota Living with Heart Failure Questionnaire or Kansas City Cardiomyopathy Questionnaire. Results: In total, 124 studies were identified: 54 for HRQoL and 71 for costs and resource use (Europe: 25/15; North America: 24/50; rest of world/multinational: 5/6). Overall, individuals with HF reported worse HRQoL than the general population and patients with other chronic diseases. Some evidence identified supports a correlation between increasing disease severity and worse HRQoL. Patients with HF incurred higher costs and resource use than the general population and patients with other chronic conditions. Inpatient care and hospitalizations were identified as major cost drivers in HF. Conclusions: Our findings indicate that patients with HF experience worse HRQoL and incur higher costs than individuals without HF or patients with other chronic diseases. Early treatment of HF and careful disease management to slow progression and to limit the requirement for hospital admission are likely to reduce both the humanistic burden and economic impact of HF.


Introduction
Heart failure (HF) is estimated to affect more than 23 million people worldwide 1 and is increasing in prevalence 2 . Causes of HF include those of cardiac aetiology in addition to chronic diseases such as diabetes mellitus (DM) and chronic kidney disease (CKD) 3 ; HF has been reported as the most common cardiovascular complication of DM 4 . The growing prevalence of HF can be attributed both to the increasing median age of populations worldwide and to the increasing prevalence of cardiovascular disease, obesity, and DM 1,4 . Early treatment of DM could have a significant impact in preventing the development of HF in a proportion of patients, limiting both the humanistic burden, which we consider for the purposes of this review as the effect of HF on the health-related quality of life (HRQoL) of the individuals affected 5 , and the economic impact of the disease.
HF is chronic and progressive in nature, and can be classified into New York Heart Association (NYHA) classes I-IV based on physical limitation and objective assessment of the presence of cardiovascular disease 6 or according to percentage ejection fraction 7 . The pathophysiology of HF with reduced ejection fraction (HFrEF) differs from that of HF with preserved ejection fraction (HFpEF), with a higher prevalence of non-cardiac morbidities (including DM and hypertension) in patients with HFpEF than in those with HFrEF. Given the differences in aetiology and progression of these diseases 7 , the economic burden of HFrEF and HRpEF may vary [8][9][10] . The signs and symptoms of HF include breathlessness, swelling, fatigue, and fluid retention, which can lead to reduced mobility and impaired daily physical functioning 11 . Patients may also face psychological problems, such as depression or anxiety, as well as social concerns, especially regarding isolation 12 . The impact of HF symptoms upon multiple aspects of patients' lives means that the condition can cause a significant reduction in HRQoL 13 . Impaired HRQoL in patients with HF compared with those with chronic disease or healthy individuals is well documented 14 , and directly surveying the patient's daily wellbeing is key to understanding the impact of disease on their daily life 14,15 . Both HF-specific and generic HRQoL instruments can be used to measure the effects of HF on patients' daily lives and well-being 16 .
Most patients with HF require routine management of their disease 13 . Treatment typically comprises daily medication as well as periodic visits to primary care providers; however, the most economically costly aspect of the disease is admission to hospital and subsequent inpatient care 17 . This is often required owing to worsening of symptoms. The acute nature of these occurrences, along with the risk of infection, can mean that patients with HF may be admitted to hospital as an emergency case 18 , incurring high costs 19 . Patients are typically treated in the intensive care unit, with clinical stabilization and symptom improvement as the primary focus following admission 18 . Once a patient's condition has stabilized, they are likely to be transferred to the ward, and a multidisciplinary approach employed to aid disease management 18 . Treatment optimization and the management of both cardiovascular and noncardiovascular comorbidities play a significant role in preventing further hospitalizations, because hospitalization with HF is associated with high rates of readmission 18 . Outside hospital, many patients with HF receive care in a primary setting or may receive informal care and support in the home, imposing a wider societal cost 20 .
This systematic review (SR) was conducted to inform understanding of the humanistic burden and economic impact of HF by identifying relevant evidence on HRQoL, costs, and medical resource use in patients with HF. Introduction -Defined humanistic burden as used in the context of this publication -Included introductory text on the difference between heart failure with reduced ejection fraction and heart failure with preserved ejection fraction.
-Introduced the fact that patients with heart failure experience worse health-related quality of life than those with other chronic disease Methods -Clarified that the systematic review that informs this manuscript was not prospectively registered with the National Institute for Health Research International Prospective Register of Systematic Reviews (PROSPERO); however, the protocol is available from the corresponding author Discussion -Clarified the intention of this review was to provide an overview of the humanistic and economic impact of heart failure that supplements the published literature Defined humanistic burden as used in the context of this publication Introduced discussion on the limited treatment options available to patients with heart failure with preserved ejection fraction Conclusions -Clarified that our findings suggest that both humanistic and economic burden is increased in patients with heart failure compared with patients without heart failure, rather than those with other chronic diseases as there were not sufficient data identified to support this statement -Discussed the challenges of quantifying the detriment experienced by patients with heart failure from a broad evidence base and provided an overarching assessment of the literature and European congresses, American Heart Association Scientific Sessions, European Society of Cardiology (ESC) Congress, World Congress of Cardiology and Cardiovascular Health, American College of Cardiology Annual Scientific Session, and ESC Heart Failure. The search strings used to identify evidence are listed in Table 1. This review was not prospectively registered with the National Institute for Health Research International Prospective Register of Systematic Reviews (PROSPERO), but the protocol is available on request from the corresponding author.
Citation screening and full text review Abstracts and titles identified were screened by an independent reviewer to determine whether they met the PICOS (patient, interventions, comparisons, outcomes, and study design) eligibility criteria (Table 2), in accordance with 2009 Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines 21 . All publications that met the entry criteria for the review were obtained as full articles and reassessed against the review criteria. Owing to the large number of citations meeting the predefined inclusion criteria,   Table 2.

Data extraction
For each publication, information was extracted into a dataextraction table. For each study, NYHA classification, age, and comorbidities including CKD and DM were recorded.

Search results
In the initial searches, 11 622 papers were identified, of which 2186 were removed as duplicates, and 9436 papers were included for electronic screening. Electronic screening identified 8166 papers that did not meet the inclusion criteria. In total, 124 papers were identified for inclusion following full paper review: 54 papers reporting HRQoL and 71 papers reporting costs and resource use (including one reference that reported data for both outcomes). A PRISMA flow diagram is shown in Figure 1. The studies identified were grouped according to the key data presented, as shown in Figure 2.   HRQoL by HF severity Studies from Sweden 25 , Australia 26 , and the USA 27,28 assessed HRQoL by NYHA HF class and reported a greater humanistic burden with more severe disease ( Figure 4). Based on  the evidence identified, there was a reduction in HRQoL between NYHA HF classes I and II 25,27,28 and classes II and III 25-28 , and between classes III and IV 25-28 , assessed using the Minnesota Living with Heart Failure Questionnaire (MLHFQ) and the Kansas City Cardiomyopathy Questionnaire (KCCQ), both of which are cardiac-specific instruments. One study also reported decreasing SF-36 PCS and MCS scores with increasing NYHA HF class 25 . For SF-12 scores, there was a greater reduction between NYHA classes I and II, and smaller reductions between more severe NYHA classes ( Figure 4). A consistent decrease in utilities between classes II and III (-0.042) and classes III and IV (-0.041), measured using the 5-level EQ-5D (EQ-5D-5L) was also reported by a single study alongside a decline in MLHFQ scores (Figure 4) 26 .
Two further studies, both conducted in the USA, reported a negative correlation between HRQoL and increasing HF severity. A study of patients with HF living in a rural location reported a negative association between NYHA HF class and MLHFQ score, but did not report results by separate NYHA classes 29 . Another study investigated HRQoL in a subgroup of patients with HF as a comorbidity, from a population with CKD in a subanalysis of the Hemodialysis Study, a randomized controlled trial of patients undergoing haemodialysis. Reductions in both mental and physical HRQoL were reported with increasing HF severity (categories ranging from 'absent' to 'severe'). Scores in the role-limiting (physical), bodily pain, general health, vitality, social functioning, and mental health domains, as well as overall PCS scores, decreased with increasing HF severity 30 .
Few longitudinal studies reporting HRQoL in HF were identified. Of the studies that were purely observational, two reported a decrease in HRQoL over time, whereas the remaining three reported an improvement in HRQoL across the study period. A UK cohort study investigating HRQoL in patients with HF relative to those with other chronic diseases reported generic and disease-specific HRQoL scores at baseline and 1 year. Patients with HF were the only group to report a reduction in HRQoL over the follow-up period, with significantly lower EQ-5D VAS scores indicating worse HRQoL at 1 year 24 . A US study reported HRQoL over a follow-up of up to 6.6 years, adjusting for the effect of time on disease deterioration 30 . PCS scores decreased over time, along with scores for six of the eight SF-36 domains; MCS scores and scores for the role-limiting (mental) domain did not decrease over time 30 .
A study in the Netherlands, however, reported that patients with a higher level of education experienced a statistically significant improvement in the role-limiting (emotional) domain of the SF-36 across an 18-month longitudinal study (p=0.015). No significant difference was found in the remaining SF-36 domains 31 . Patients in a Canadian study in whom HF was diagnosed following an emergency department (ED) visit reported increases in physical HRQoL scores over a 12-month period (SF-12 PCS score: 1.6-3.4; KCCQ-physical limitation score: 5.6-9.4) 32 . An analysis modelled health trajectories over 12 months defined by patients' KCCQ scores over time using data from the Patient-Centered Disease Management for Heart Failure trial. Patients with a poor or moderate health status trajectory experienced improvements in KCCQ scores between baseline and 3 months followed by a stabilization in scores up to 12 months, whereas those who had a trajectory of 'marked improvement' reported an increase in HRQoL over the whole 12-month period 33 .
In a number of the longitudinal studies identified, healthcare professionals provided support to patients over the follow-up period, which was considered likely to impact HRQoL. These studies are summarized in Extended data: Supplemental Table 1 34 . Studies in Norway 35 and in Spain 36 reported a statistically significant improvement in MLHFQ scores between baseline and 6 or 12 months, respectively, for patients monitored over the study period. In the Spanish study, patients continued to experience an increase in HRQoL over 5 years 36 . An improvement in MLHFQ scores over 12 months following enrolment into an HF clinic was also reported by patients in a Canadian study 37 .

HRQoL in patients with HF by ejection fraction status
Few studies comparing HRQoL in patients with HFpEF and those with HFrEF were identified. In a study conducted in Germany, patients with HFpEF reported better physical functioning, measured using the SF-36, than patients with HFrEF 38 . A study conducted in the USA reported that patients with HFpEF experienced no greater impact on HRQoL than those with HFrEF as disease severity increased. However, patients with HFpEF, with KCCQ scores in the lowest quartile, had a higher risk of mortality or hospitalization as well as lower rates of event-free survival than those who had scores in the highest quartile 27 .

HRQoL in patients with HF and comorbidities
Comorbidities in patients with HF were typically associated with reductions in HRQoL (Extended data: Supplemental Table 1 34 ). In studies conducted in Spain and the USA, respectively, patients with HF and iron deficiency 39 or pain 40 reported higher overall and physical summary MLHFQ scores, representative of worse HRQoL, than those without these comorbidities. However, a further study in the USA found that although patients with anaemia reported worse baseline KCCQ scores than those without, deterioration in HRQoL over a 3-month period was similar in both populations 28 . Patients in a study in the Netherlands who experienced difficulties with sexual activity reported worse HRQoL than those without difficulties 41 . In a US study, excessive daytime sleepiness and cognitive impairment were associated with comparatively lower HRQoL 42 . In a second US study, patients who had comparatively lower haemoglobin levels at baseline reported worse KCCQ and MLHFQ scores than those with higher haemoglobin levels 43 .
Patients in Australia, the UK, Ireland, the USA, and Norway who had ischaemic heart disease with ischaemic HF, angina, or a myocardial infarction as a comorbidity reported PCS scores that were lower than expected for the general population (more than one SD below the standardized mean of the general US population), whereas MCS scores were within one SD of the mean 44 . Two further studies, one in Italy 69 and the other multinational 70 , found that KCCQ score was a predictor of mortality, and a study in the USA reported a negative association between MLHFQ score and cardiac event-free survival 71 . Physical and depressive symptoms, in addition to spiritual well-being and comorbidity count, were negatively correlated with HF-specific health status (partially determined by KCCQ score) in patients in the USA 72 . An Australian study examined the contribution of MLHFQ and EQ-5D scores to composite scoring systems in HF trials 73 .

Impact of sociodemographic status on HRQoL in patients with HF
In several studies, patient ethnicity and sex were shown to impact HRQoL (Extended data: Supplemental  85 . A breakdown of constituent costs in this study is shown in Figure 5. Another study compared allowed monthly Medicare costs and resource use for patients with HF and all individuals who made Medicare claims (fee-for-service population). Per-patient allowed monthly costs for HF were 3.2 times higher than those incurred by the average fee-forservice patient (US$3395 vs US$1045) 95 . Patients with HF also had comparatively higher rates of inpatient admission, 30-day readmission, and use of skilled nursing facilities, meaning that higher costs were incurred for all of these resources, compared with the Medicare fee-for-service population.
Additional evidence indicated that HF is associated with increased resource use. A study of patients who were admitted to hospital for trauma and subsequently discharged found that the presence of HF was associated with a 71% increased risk of Three studies compared the costs associated with HF and those for other chronic diseases. One study showed that similar total annual costs were associated with HF and obesity (US$1642 and US$1908, respectively); however, these conditions were considerably more costly than hypertension, which was associated with costs of US$431 per annum 99 . A second study reported that total annual costs were nearly twofold higher for HF than for DM, partly owing to higher inpatient and outpatient costs 87 . Finally, a study reporting disease-specific costs showed that HF incurred higher annual medical and pharmacy costs than asthma, coronary artery disease, COPD, DM, hyperlipidaemia, and hypertension 82 .

Costs for HF as a comorbidity
Three studies showed that HF is associated with additional costs in patients with DM. A UK study estimated that annual inpatient care costs for a typical 60-year-old man with type 2 DM are more than six times higher in the presence of HF than if HF does not occur (£3191 for HF vs £459 for no HF) 100 . The occurrence of HF in a patient with DM was also estimated to result in 84% higher non-inpatient costs.  associated with an additional US$490 and US$640, respectively (p<0.001).

Costs by HF ejection fraction status
Two Swedish studies collected data on the total annual direct costs associated with HFrEF 106 and HFpEF 107 . These studies, however, were not conducted simultaneously or designed to compare costs by ejection fraction, so limited inference should be drawn from across-study comparisons. HFrEF was associated with slightly higher annual costs than HFpEF (€12 447 vs €11 344), as a result of higher costs associated with inpatient care, hospitalizations, and medication. Annual outpatient clinic costs were approximately 43% higher for HFpEF than for HFrEF (€1561 vs €1094).
Two US studies compared resource use between patients with HFrEF and those with HFpEF. One study found no significant difference between the two groups in terms of 30-day hospital readmission rate. However, patients with HFrEF had a significantly greater length of stay (LoS) in hospital than patients with HFpEF (HFrEF: 10.9 days; HFpEF: 8.5 days; p=0.027) 96 . In a second study, there were no significant differences between groups in terms of adjusted 30-day readmission rates, annual hospitalization rate, LoS, or pharmaceutical dispenses. Although the absolute differences between cohorts were small, HFpEF was associated with significantly more outpatient visits (HFpEF: 21.5; HFrEF: 20.1; p<0.002) and ED visits (HFpEF: 3.24; HFrEF: 2.94; p<0.002) annually than HFrEF, as well as a significantly higher rate of readmission within 1 year (HFpEF: 58%; HFrEF: 55%; p=0.010) 108 .
Costs for inpatient care and hospitalization in patients with HF Inpatient care and hospitalization were identified as major cost drivers in HF and were reported as the single largest contributor to costs in multiple studies across different geographies. There was relatively wide variation across studies in the percentage of costs contributed by inpatient care, which can be accounted for by differences between populations and disparities in the types of costs included in each study.
In total, five European studies presented inpatient care or hospitalization as a percentage of total or direct costs: one each from Germany 77 and Italy 81 and three from Sweden 78,106,107 . Inpatient care or hospitalization contributed 69-87% of total costs in these studies (Extended data: Supplemental Several other studies reported inpatient or hospitalization costs (Extended data: Supplemental Table 2 90 ). Seven studies, two from the UK 100,113 and five from the USA 19,114-117 , collected data on overall inpatient/hospitalization costs associated with HF; however, these were not reported as a percentage of total costs. Additionally, five US studies reported the costs associated with a single hospitalization [118][119][120][121][122] , and one reported the cost of an 'acute HF hospital episode' as US$10 775 123 .

Hospitalization and readmission rates for patients with HF
Patients' risk of hospitalization for HF or readmission within 1 year is likely to be influenced by factors such as disease severity, and consequently a wide range of rates were reported across the studies identified. There was a larger evidence base for all-cause 30-day readmission rates; these studies indicated that between 15% and 30% of patients hospitalized for HF are likely to be readmitted within a month after discharge from hospital.  145 , and the association between heart rate and medical costs in patients with HF 146 , respectively.

Discussion
Given the breadth of the evidence identified and the differences in methodology, health technologies and countries in which studies were conducted, we provide an overview of the humanistic and economic impact of HF, intended to supplement the published literature.

Key findings -HRQoL
The evidence identified in this SR illustrates that HF is associated with a substantial humanistic burden. For the purposes of this review, we consider humanistic burden to represent the impact of HF on the individual affected, as indicated by patient-reported outcomes. Patients with HF experience worse HRQoL than both individuals without HF and patients with other chronic diseases, and the burden of HF is greater for patients with more severe disease than for those at earlier stages. Poor mental health, comorbidities, and hospitalization are likely to be associated with worse HRQoL in patients with HF, whereas appropriate disease intervention can help to bring about improvements in HRQoL. This is supported by evidence that HRQoL decreases over time in the absence of disease management, but for patients who were provided support, HRQoL increased over time. Taken together with evidence indicating the positive impact of disease management and self-care, and structured support, this indicates possible ways of improving HRQoL for patients with HF.
Key findings -costs and resource use The majority of the economic studies identified in this SR were conducted in the USA, with a smaller evidence base in Europe and relatively few studies from the rest of the world. HF is associated with considerable healthcare costs, and patients with HF incur higher costs and greater resource use, including inpatient, outpatient, and informal care, than individuals without HF or with other chronic diseases. The occurrence of HF as a comorbidity is also associated with extra costs. There is evidence to indicate that costs rise with increasing severity of HF, although this is based on only one study. The results of studies reporting costs and resource use by ejection fraction were mixed and did not provide sufficient evidence to conclude whether HFrEF or HFpEF incurs higher costs. As the diagnosis of HF has previously hinged on EF, with therapy development focused on reduced EF, limited evidence may be available on the treatment of HFpEF 147 . Patients with HF are at a relatively high risk of hospitalization or readmission; accordingly, inpatient care and hospitalizations were identified as key cost drivers.
Several studies suggested that improved disease management, with the aim of reducing the number of inpatient cases and reducing patients' risk of hospital readmission, could be a way to limit the economic impact of HF. Specific strategies discussed included use of case-management programmes, identification of risk factors for readmission, and optimization of medication, for example by improving adherence.

Evidence gaps
This SR identified a broad range of studies; consequently, this review has focused on key areas of interest that best illustrate the impact of HF. Some studies have been presented in less detail, either because they did not discuss these key themes or because the data reported were not readily comparable with the rest of the evidence base, owing to differences in study population, setting, or time frame.
Although a large number of studies were identified, some gaps in the evidence base were apparent. In studies comparing patients with HF and individuals with other chronic conditions, disease severity in the individual patient populations was not specified, nor was the impact of treatment interventions over the period of the study. This is particularly relevant when comparing different diseases, for which the effect of treatment upon HRQoL may vary considerably. Further studies on HRQoL in patients with HF, particularly those assessing the incremental effects of the disease over time or with increasing severity, would be valuable as part of an overall approach to identify means of improving patients' well-being.
A relatively small number of studies that assessed the economic impact of HF included detailed clinical information.
The majority of studies in this SR, particularly those from the USA, which was the country with the largest evidence base, identified patients with HF in administrative claims databases using International Classification of Diseases diagnosis codes. This meant that factors such as comorbidities, HF severity by NYHA classification, and disease history were not known for all patient populations. These factors can have a large impact on disease outcomes and associated costs; therefore, some of the variation between the costs reported in different studies is likely to be attributable to factors that are not recorded. Economic studies in which patients' medical records are available might therefore be valuable to obtain more granular data on cost drivers in HF. In addition, there is little published information on the indirect costs associated with HF, with very few studies reporting data on informal care for patients with HF; thus, the wider societal impact of the disease is not immediately apparent in the literature.

Limitations
The design and scope of this SR meant that it is possible that not all relevant evidence was identified. Restrictions were applied to the evidence identified in the initial searches, by patient numbers, HRQoL instrument, and type of study. In particular, the restriction to economic studies including at least 100 patients and humanistic studies including at least 200 patients may have skewed the SR toward studies using patient registries and administrative claims data. Therefore, any studies with smaller sample sizes that included detailed clinical data for patients would not have been examined within the scope of the review. A formal assessment of the studies included was not carried out as part of the review process. This would typically include evaluation of each study's inclusion criteria, measurement methods, analytic methods, and risk of bias 148 . Although all evidence discussed here is of value to address our research question, such an assessment might have highlighted any studies that were of particularly high or low quality, and helped to explain any major differences between the trends reported in different studies.

Conclusions
Our findings indicate that both the humanistic and economic burden is increased in patients with HF compared with individuals without HF. Quantification of the detriment experienced by patients with HF is challenging owing to the heterogeneity of the study population and methodology employed as well as inherent differences between health systems and costs in different countries. However, there is overarching evidence to suggest that the burden of disease increases as disease worsens. Inpatient care and hospitalization costs were identified as key economic drivers.
It appears that slowing or preventing HF progression is likely to improve patients' overall well-being, a healthcare aim that is particularly important given the substantial and increasing humanistic burden experienced by patients with HF. Reduction in patients' hospitalization rates, and limiting the overall requirement for inpatient care, is the healthcare goal that would have the greatest impact on the economic burden of HF. The evidence that we have identified suggests that early treatment of HF to prevent or to delay disease progression, as well as careful disease management to avoid or lessen the need for hospital admission, is likely to lessen the humanistic burden and economic impact of HF.

Data availability
Underlying data All data underlying the results are available as part of the article (included under extended data), and no additional source data are required to support our results.
Extended data figshare: Supplemental content 1 -Supplemental The systematic review protocol is available on request by contacting the corresponding author.

Open Peer Review
other published reviews We have amended the conclusions to include the challenges of drawing specific conclusions from such wide-reaching studies and provided some overarching conclusions; however, given the disparate nature of the evidence base, care should be taken in drawing definitive conclusions ○ quantifying the impact of heart failure on the patient using patient-reported outcomes. With regard to the conclusions drawn, we identified some evidence that compared HRQoL in patients with HF and those with chronic disease; however, we agree that this was not sufficient to support our conclusions and we amended them as you suggest We have also clarified that the wide range of outcomes and healthcare costs identified in our review limits the ability to draw to a clear conclusion from the evidence presented The benefits of publishing with F1000Research: Your article is published within days, with no editorial bias • You can publish traditional articles, null/negative results, case reports, data notes and more • The peer review process is transparent and collaborative • Your article is indexed in PubMed after passing peer review • Dedicated customer support at every stage • For pre-submission enquiries, contact research@f1000.com