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Heart Failure Care in Low- and Middle-Income Countries: A Systematic Review and Meta-Analysis

  • Thomas Callender,

    Affiliation: The George Institute for Global Health, University of Oxford, Oxford, United Kingdom

  • Mark Woodward,

    Affiliations: The George Institute for Global Health, University of Oxford, Oxford, United Kingdom, The George Institute for Global Health, University of Sydney, Sydney, Australia

  • Gregory Roth,

    Affiliation: Institute for Health Metrics and Evaluation, University of Washington, Seattle, Washington, United States of America

  • Farshad Farzadfar,

    Affiliations: Non-Communicable Diseases Research Centre, Tehran University of Medical Sciences, Tehran, Iran, Endocrinology and Metabolism Research Centre, Tehran University of Medical Sciences, Tehran, Iran

  • Jean-Christophe Lemarie,

    Affiliation: Effi-Stat, Paris, France

  • Stéphanie Gicquel,

    Affiliation: Effi-Stat, Paris, France

  • John Atherton,

    Affiliation: Department of Cardiology, Royal Brisbane and Women's Children Hospital and University of Queensland School of Medicine, Brisbane, Australia

  • Shadi Rahimzadeh,

    Affiliations: Non-Communicable Diseases Research Centre, Tehran University of Medical Sciences, Tehran, Iran, Department of Epidemiology, Shahid Beheshti University of Medical Sciences, Tehran, Iran

  • Mehdi Ghaziani,

    Affiliations: Non-Communicable Diseases Research Centre, Tehran University of Medical Sciences, Tehran, Iran, Endocrinology and Metabolism Research Centre, Tehran University of Medical Sciences, Tehran, Iran

  • Maaz Shaikh,

    Affiliations: The George Institute for Global Health, University of Oxford, Oxford, United Kingdom, The George Institute for Global Health, Hyderabad, India

  • Derrick Bennett,

    Affiliation: Clinical Trials Service Unit, University of Oxford, Oxford, United Kingdom

  • Anushka Patel,

    Affiliation: The George Institute for Global Health, University of Sydney, Sydney, Australia

  • Carolyn S. P. Lam,

    Affiliation: National University of Singapore, Singapore

  • Karen Sliwa,

    Affiliation: Hatter Institute for Cardiovascular Research in Africa, University of Cape Town, Cape Town, South Africa

  • Antonio Barretto,

    Affiliation: Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil

  • Bambang Budi Siswanto,

    Affiliation: National Cardiovascular Centre University Indonesia, Jakarta, Indonesia

  • Alejandro Diaz,

    Affiliation: Universidad Nacional del Centro de la Provincia de Buenos Aires, Buenos Aires, Argentina

  • Daniel Herpin,

    Affiliation: Centre Hospitalier Universitaire de Poitiers, Poitiers Cedex, France

  • Henry Krum,

    Affiliation: Centre of Cardiovascular Research & Education in Therapeutics, Monash University, Melbourne, Australia

  • Thomas Eliasz,

    Affiliation: The George Institute for Global Health, University of Oxford, Oxford, United Kingdom

  • Anna Forbes,

    Affiliation: The George Institute for Global Health, University of Oxford, Oxford, United Kingdom

  • Alastair Kiszely,

    Affiliation: The George Institute for Global Health, University of Oxford, Oxford, United Kingdom

  • Rajit Khosla,

    Affiliation: The George Institute for Global Health, University of Oxford, Oxford, United Kingdom

  • Tatjana Petrinic,

    Affiliation: Bodleian Healthcare Libraries, University of Oxford, Oxford, United Kingdom

  • Devarsetty Praveen,

    Affiliations: The George Institute for Global Health, University of Sydney, Sydney, Australia, The George Institute for Global Health, Hyderabad, India

  • Roohi Shrivastava,

    Affiliation: The George Institute for Global Health, University of Oxford, Oxford, United Kingdom

  • Du Xin,

    Affiliation: The George Institute for Global Health, Peking University, Beijing, China

  • Stephen MacMahon,

    Affiliations: The George Institute for Global Health, University of Oxford, Oxford, United Kingdom, The George Institute for Global Health, University of Sydney, Sydney, Australia

  • John McMurray,

    Affiliation: University of Glasgow, Glasgow, United Kingdom

  •  [ ... ],
  • Kazem Rahimi

    kazem.rahimi@georgeinstitute.ox.ac.uk

    Affiliation: The George Institute for Global Health, University of Oxford, Oxford, United Kingdom

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Heart Failure Care in Low- and Middle-Income Countries: A Systematic Review and Meta-Analysis

  • Thomas Callender, 
  • Mark Woodward, 
  • Gregory Roth, 
  • Farshad Farzadfar, 
  • Jean-Christophe Lemarie, 
  • Stéphanie Gicquel, 
  • John Atherton, 
  • Shadi Rahimzadeh, 
  • Mehdi Ghaziani, 
  • Maaz Shaikh
PLOS
x

Abstract

Background

Heart failure places a significant burden on patients and health systems in high-income countries. However, information about its burden in low- and middle-income countries (LMICs) is scant. We thus set out to review both published and unpublished information on the presentation, causes, management, and outcomes of heart failure in LMICs.

Methods and Findings

Medline, Embase, Global Health Database, and World Health Organization regional databases were searched for studies from LMICs published between 1 January 1995 and 30 March 2014. Additional unpublished data were requested from investigators and international heart failure experts. We identified 42 studies that provided relevant information on acute hospital care (25 LMICs; 232,550 patients) and 11 studies on the management of chronic heart failure in primary care or outpatient settings (14 LMICs; 5,358 patients). The mean age of patients studied ranged from 42 y in Cameroon and Ghana to 75 y in Argentina, and mean age in studies largely correlated with the human development index of the country in which they were conducted (r = 0.71, p<0.001). Overall, ischaemic heart disease was the main reported cause of heart failure in all regions except Africa and the Americas, where hypertension was predominant. Taking both those managed acutely in hospital and those in non-acute outpatient or community settings together, 57% (95% confidence interval [CI]: 49%–64%) of patients were treated with angiotensin-converting enzyme inhibitors, 34% (95% CI: 28%–41%) with beta-blockers, and 32% (95% CI: 25%–39%) with mineralocorticoid receptor antagonists. Mean inpatient stay was 10 d, ranging from 3 d in India to 23 d in China. Acute heart failure accounted for 2.2% (range: 0.3%–7.7%) of total hospital admissions, and mean in-hospital mortality was 8% (95% CI: 6%–10%). There was substantial variation between studies (p<0.001 across all variables), and most data were from urban tertiary referral centres. Only one population-based study assessing incidence and/or prevalence of heart failure was identified.

Conclusions

The presentation, underlying causes, management, and outcomes of heart failure vary substantially across LMICs. On average, the use of evidence-based medications tends to be suboptimal. Better strategies for heart failure surveillance and management in LMICs are needed.

Please see later in the article for the Editors' Summary

Editors' Summary

Background

A healthy heart pumps about 23,000 liters of blood around the body every day. This blood delivers oxygen and nutrients to the rest of the body and carries carbon dioxide and waste products away from the tissues and organs. A healthy heart is therefore essential for life. Unfortunately, many people (particularly elderly people) develop heart failure, a life-threatening condition in which the heart no longer pumps enough blood to meet all the body's needs because it has become too weak or too stiff to work properly. Heart failure can affect the left, right, or both sides of the heart, and it can develop slowly (chronic heart failure) or quickly (acute heart failure). Its symptoms include swelling (edema) of the feet, ankles, and legs, tiredness, and shortness of breath. Heart failure, which is most commonly caused by coronary heart disease (blockage with fatty deposits of the blood vessels that supply the heart) or high blood pressure (hypertension), cannot be cured. However, lifestyle changes (for example, losing weight and avoiding salty food) and various medications can control heart failure and improve the quality of life of patients.

Why Was This Study Done?

In high-income countries (HICs), heart failure is a common condition that typically consumes 1%–2% of healthcare resources. Experts believe that heart failure may soon become a major public health issue in low- and middle-income countries (LMICs) because fewer people are dying of infectious diseases in these countries than in the past. LMICs need to plan for this eventuality, but little is known about the current burden of heart failure in LMICs. Here, the researchers undertake a systematic review and meta-analysis of published and unpublished information on the presentation, causes, management, and outcomes of heart failure in LMICs. A systematic review uses predefined criteria to identify all the research on a given topic; a meta-analysis uses statistical approaches to combine the results of several studies.

What Did the Researchers Do and Find?

The researchers identified 49 published studies and four unpublished databases that provided information on nearly 240,000 hospitalizations for acute and chronic heart failure in 31 LMICs. Across these LMICs, the average age of patients admitted to hospital for heart failure was 63 years, more than ten years younger than the average admission age in HICs. Differences in mean age at presentation, which ranged from 42 years in Cameroon and Ghana to 75 years in Argentina, largely correlated with the human development index (a measure of national well-being) of individual LMICs. Notably, acute heart failure accounted for 2.2% of all hospital admissions in the LMICs for which data were available. Hypertension was the main cause of heart failure in Africa and the Americas, whereas ischemic heart disease was the main cause in all other regions. More than two-thirds of patients were prescribed diuretics for heart failure, whereas only 57% of patients were treated with angiotensin-converting enzyme inhibitors, only 34% were treated with beta-blockers, and only 32% were treated with mineralocorticoid receptor antagonists, the three treatments currently recommended in guidelines for managing heart failure. Finally, on average, patients admitted to hospital for heart failure in LMICs spent ten days in hospital, and 8.3% of them died in hospital (compared to 6.7% and 4% of similar patients across Europe and the US, respectively).

What Do These Findings Mean?

These findings show that the presentation, causes, management, and outcomes of heart failure vary substantially across LMICs. Importantly, however, these findings reveal that heart failure is already a major burden in LMICs and that the use of recommended medications for heart failure is currently suboptimal in these countries. Because the studies included in this systematic review and meta-analysis set out to answer different research questions and used different methods to diagnose heart failure, the estimates of the burden of heart failure in LMICs provided here may not be completely accurate. Moreover, because the data were derived mainly from urban tertiary referral hospitals, these findings may not reflect the broader picture of heart failure in the community in LMICs. However, although additional studies are needed to completely assess the burden of heart failure in LMICs, the present findings nevertheless highlight the need to implement better strategies for the management of heart failure in LMICs.

Additional Information

Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001699.

  • This study is further discussed in a PLOS Medicine Perspective by Druin Burch
  • The US National Heart, Lung, and Blood Institute provides information for patients about heart failure
  • The UK National Health Service Choices website provides information about all aspects of heart failure
  • The American Heart Association, a not-for-profit organization, also provides detailed information about heart failure for patients and their carers
  • The British Heart Foundation, a not-for-profit organization, provides additional information about heart failure, including a personal story about heart failure; further personal stories about heart failure are provided by the not-for-profit organization Healthtalkonline
  • Heart Failure Matters provides practical information about heart failure for patients, families, and caregivers in several languages; its website includes an animated journey through heart failure and several personal stories about the condition
  • MedlinePlus provides links to further resources about heart failure (in English and Spanish)

Introduction

In high-income countries (HICs), heart failure is a well-recognized public health problem representing a significant burden for patients and healthcare systems [1],[2]. For example, in the UK and US, heart failure is one of the leading causes of hospitalisation, and despite recent advances, outcomes remain poor [3][6]. Of those hospitalised for heart failure in the UK, about 10% will die during admission [6]. In the US, between 20% and 27% of those who survive to discharge will be re-admitted within 30 d [7], whilst 5-y mortality rates range between 40% and 65% amongst the US, UK, Netherlands, and Sweden [2][4],[8],[9]. The costs associated with heart failure care are also substantial. In many HICs, heart failure typically consumes 1%–2% of healthcare resources [2], mainly because of repeated admissions to hospitals and prolonged inpatient stays.

With demographic changes and the epidemiological transition to non-communicable diseases [10],[11], heart failure is expected to become a major public health issue in low- and middle-income countries (LMICs). Yet systematic evidence for its current burden to patients and health services is limited [1],[2],[12]. In fact, the last review of the burden of heart failure in LMICs, conducted over ten years ago, found no population studies and concluded that published data on heart failure epidemiology were almost entirely absent from most populations across the world [12]. As a result, many of our assumptions regarding the current burden of this condition worldwide are based on extrapolations from studies conducted in HICs, which may not be appropriate [1],[2].

Therefore, we sought to conduct a systematic review of both published and unpublished data regarding the patterns of heart failure presentation, management, and outcomes in LMICs.

Methods

This systematic review was designed and undertaken according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [13]. A study protocol describing the methodology has been published previously [14]. In brief, we searched Medline, Embase, Global Health Database, and WHO regional databases for articles published between 1 January 1995 and 30 March 2014 with the subject terms “heart failure” or “cardiomyopathies” or any related terms AND “incidence”, “prevalence”, “cause*”, “etiology”, “aetiology”, “epidemiolog*”, “burden”, “management”, “treatment”, “prevent*”, “population based”, “community”, “trends”, “survey”, “surveillance”, “mortality”, “morbidity”, “fatalit*”, or “attack rate”. Relevant studies from LMICs on the epidemiology, diagnosis, management, and outcomes of heart failure were included. There were no language restrictions. We also scrutinised the reference lists of study reports and review articles, and inquired among our collaborators and international heart failure experts about any additional databases or studies of which they may be aware. We further searched the Institute for Health Metrics and Evaluation's Global Health Data Exchange as well as the websites of regional and country-specific societies of cardiology to identify further datasets.

Figure 1 summarises the retrieval and selection process for studies and relevant databases. After removing duplicate reports, two reviewers independently screened all titles and abstracts for their potential eligibility and extracted data using a pre-designed form. Studies were eligible for inclusion if they reported on heart failure patients from LMICs as defined by the World Bank [15]. Studies must have reported on at least 100 cases and contained relevant information on demographic characteristics, prevalence, case fatality, underlying aetiology, or management of patients with heart failure. Studies confined to subgroups of patients with heart failure (for example, those that included only dilated cardiomyopathy or heart failure as a complication of acute myocardial infarction) were excluded, as were studies that clearly did not include a representative sample of patients from the setting chosen (for example, studies that selected people referred to an echocardiography department, or studies that excluded adult populations) [14]. Investigators of multinational studies that had not reported findings by country were contacted for country-specific data.

Quality Assessment

In order to capture a comprehensive overview of heart failure in LMICs, a wide range of studies, each with differing objectives and designs, were included. Studies meeting the minimum quality requirement, as specified below, for inclusion were analysed for both methodological limitations and reporting quality, using items from the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines [16] (Tables 16). Specifically, the sample size of each study, the location and type of healthcare facility, diagnostic methods used, and patient selection criteria were documented. In addition, we assessed each study's specific methodological strengths and weaknesses as well as likely external validity.

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Table 3. Characteristics of Eastern Mediterranean region studies and databases included.

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Table 5. Characteristics of South East Asia region studies and databases included.

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Table 6. Characteristics of Western Pacific region studies and databases included.

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Statistical Analysis

Study-specific data on percentages are presented as forest plots with exact binomial 95% confidence intervals (CIs). These percentages were pooled, by World Health Organization region (Table 7) and across regions, using the random effects method of DerSimonian and Laird [17]. Heterogeneity between studies was quantified by the I2 statistic and tested using Cochran's Q test. Means were rarely reported with an estimate of variability, and, consequently, we weighted individual means by study size in pooled analyses, and present the pooled mean and the range of means.

Patients presenting acutely to hospitals may differ in many respects from those that are seen in clinics for chronic management. When pooling the data we therefore indicate the setting of each study in all forest plots. Studies from community primary care or outpatient clinics were designated as non-acute, and studies from inpatient populations, acute. Studies reporting both inpatient and outpatient data were included in the non-acute category. Additional subgroup analyses were performed by level of country income and by study time period. For income level analyses, studies were divided into low-income, low-middle-income, and upper-middle-income groups according to World Bank [15] country classification at the final year of the recruitment period of the study. The relationship between a study's mean age at admission for heart failure and the human development index (HDI) [18] for the country involved was estimated with linear regression analysis; the HDI was taken for the closest year to the final year of patient recruitment for the studies representing each country. The HDI is a composite measure of development produced by the United Nations Development Programme that incorporates life expectancy, education, and gross national income per capita [18]. Random effects meta-regression was performed to investigate study year as an explanation for the between-study heterogeneity in causes of heart failure, management, and in-hospital mortality. Corresponding bubble plots were drawn, with the size of each bubble inversely proportional to the estimated variance in the respective study.

Statistical analyses were done using R version 3.0.2 and Stata version 11.2.

Results

Geographic Distribution and Study Description

Overall, 49 published studies [19][67] and four unpublished datasets ([68][70]; S. Rahimzadeh, F. Farzadfar F, M. Ghaziani, unpublished data) were included; their geographical distribution is presented in Figure 2, and key study characteristics, divided by WHO region, are summarised in Tables 16. We obtained unpublished country datasets from the Acute Decompensated Heart Failure Registry (ADHERE)–International [68] regarding Malaysia and the Philippines, as well as the Identification of Patients with Heart Failure and Preserved Systolic Function (I PREFER) registry [70] including Iran, Lebanon, Egypt, Tunisia, Algeria, Chile, Colombia, and Mexico. Additional unpublished data were contributed from Iran (S. Rahimzadeh, F. Farzadfar F, and M. Ghaziani, unpublished data) and India [69].

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Figure 2. Geographic distribution of studies on heart failure in lowand middle-income countries.

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Most studies were based in a single hospital, although 21 datasets documented multi-centre studies in Algeria [70], Argentina [21],[43],[44], Brazil [40],[45], Chile [41],[70], Colombia [70], China [55],[57],[62], Egypt [70], Indonesia [20], India [69], Iran (S. Rahimzadeh, F. Farzadfar F, and M. Ghaziani, unpublished data; [70]), Lebanon [70], Thailand [52], Malaysia [68], Mexico [70], Philippines [68], Romania [50], Tunisia [70], Turkey [49],[63],[64], and a further nine countries in sub-Saharan Africa [35]. Four studies involved both inpatient and outpatient data [22],[24],[26],[36], six studies referred solely to patients seen at outpatient clinics [27],[39],[61],[66],[67],[70], three studies described heart failure in primary care settings [62][64], and the remainder reported solely on inpatient populations. One study was a population-based assessment of the prevalence of heart failure in Turkey [63].

Case Identification and Ascertainment

The studies together included 237,908 episodes of heart failure hospitalisation. The median number of cases across all studies was 386 (range: 100–194,098). Diagnosis of heart failure was established according to the Framingham criteria [71] in 12 studies [21],[22],[24],[28][31],[42],[48],[55],[62],[70]. European Society of Cardiology guidelines were used in eight studies [25][27],[41],[50],[54],[60],[61], the Boston criteria [72] in three studies [39],[40],[47], and the American Heart Association guidelines in two studies [49],[53], and the diagnosis was left to the investigator's or examining physician's discretion in 26 studies ([19],[20],[23],[32][38],[43][46],[51],[52],[56][58],[64],[65],[67][69]; S. Rahimzadeh, F. Farzadfar F, and M. Ghaziani, unpublished data). One study diagnosed all cases of heart failure solely using echocardiography [59]. Information on the use of additional investigative tools, including echocardiography, chest radiography, and electrocardiography, was provided in 28 studies [19][21],[24][26],[28],[31],[35],[39],[41][43],[46],[48][50],[51],[54],[56],[57],[59],[61],[63],[64],[66],[70],[73]. Of these, 14 studies performed echocardiography on all patients [19],[24][26],[28],[35],[46],[48],[53],[54],[59],[61],[63],[66]. The mean left ventricular ejection fraction (LVEF) was documented in 18 studies, reporting data from Algeria [70], Egypt [70], Tunisia [70], Cameroon [24], Ethiopia [35], Sudan [35], Mozambique [35], Kenya [35], Uganda [35], Senegal [35], South Africa [25], Nigeria [26],[28], Brazil [19],[39],[42],[46],[66], Chile [41],[70], Colombia [70], Mexico [70], Romania [50], Serbia [61], Turkey [49], Iran [70], Lebanon [70], Indonesia [20], Thailand [52], and China [53]. Across all studies, mean LVEF was 40% (range: 27%–57%) (Table 8). Hospitalised patients had a mean LVEF of 38% (27%–57%), with a corresponding figure of 48% (29%–55%) in non-acute settings.

Demographic Characteristics

The demographic characteristics of patients and outcomes by region are shown in Table 8. The corresponding data by country are shown in Table 9. Men made up 58% (95% CI: 54%–62%) of study participants (Figure 3). The mean age of patients for each region ranged from just over 52 y (range: 42–64) in Africa to 70 y (range: 53–77) in the Americas, and when combined across all regions was 63 y (range: 42–77). The mean age of patients on admission rose with the country income level. In low-income countries, the corresponding figure was 50 y (range: 42–58), rising to 60 y (range: 50–74) in low-middle-income countries, and reaching 70 y (range: 54–77) in upper-middle-income countries. Mean age also correlated with the HDI across countries (r = 0.71, p<0.001) (Figure 4).

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Figure 4. Correlation of age and human development index, by country.

r = 0.71, p<0.001. The HDI is a measure produced by the United Nations Development Programme that incorporates gross national income per capita, life expectancy, and time spent in education. It serves as a single statistic that provides a comparable measure of development across nations. HF, heart failure.

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Causes of Heart Failure

Although most studies made a clear distinction between aetiologies and co-morbidities, the categories reported were highly variable, and multiple causes were often attributed to individual cases of heart failure. Across all LMICs, non-communicable diseases, and in particular ischaemic heart disease (IHD) and hypertension, are the leading causes of heart failure (Table 10). However, there is heterogeneity between the regions. IHD is the most commonly reported cause of heart failure in all regions except Africa and the Americas (Figures 5 and 6). In the Americas hypertension and IHD are responsible for a similar percentage of documented cases, at 31% (95% CI: 19%–43%, I2 99%, p for heterogeneity <0.001) and 33% (95% CI: 27%–38%, I2 96%, p<0.001), respectively. In Africa, 8% (95% CI: 5%–11%, I2 98%, p<0.001) of heart failure is due to IHD, with hypertension the dominant cause, responsible for 46% (95% CI: 36%–55%, I2 98%, p<0.001) of cases. Cardiomyopathies cause 24% (95% CI: 20%–29%, I2 99%, p<0.001) of heart failure cases across LMICs taken together (Figure 7). Idiopathic, hypertrophic, and restrictive cardiomyopathies are reported across all countries; however, other specific types of cardiomyopathies showed substantial regional variation. Peri-partum and HIV-associated cardiomyopathies were reported only in Africa. By contrast, Chagas cardiomyopathy remains a Latin American phenomenon [21],[43]. Valvular heart disease is responsible for 18% (95% CI: 15%–22%, I2 98%, p<0.001) of cases of heart failure across LMICs (Figure 8).

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Figure 5. Aetiology of heart failure: ischaemic heart disease by region.

Percentage of heart failure cases with a documented cause of IHD.

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Figure 6. Aetiology of heart failure: hypertension by region.

Percentage of heart failure cases with a documented cause of hypertension.

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Figure 7. Aetiology of heart failure: cardiomyopathies by region.

Percentage of heart failure cases with a documented cause of cardiomyopathy.

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Figure 8. Aetiology of heart failure: valvular heart disease by region.

Percentage of heart failure cases with a documented cause of valvular heart disease.

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Management of Heart Failure

Amongst all studies, the management of heart failure varies considerably between regions and within regions, as well as between studies from the same country (Table 11). The most commonly prescribed treatments are loop and/or thiazide diuretics, prescribed for 69% (95% CI: 60%–78%, I2 100%, p<0.001) of individuals in LMICs worldwide (Figure 9). Angiotensin-converting enzyme inhibitors (ACEIs) are used in 57% (95% CI: 49%–64%, I2 100%, p<0.001) of cases, beta-blockers in 34% (95% CI: 28%–41%, I2 100%, p<0.001), and mineralocorticoid receptor antagonists in 32% (95% CI: 25%–39%, I2 100%, p<0.001) (Figures 1012).

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Figure 9. Diuretic use by region.

Loop and/or thiazide diuretics. ∧Rahimzadeh S, Farzadfar F, Ghaziani M (2013) Iranian hospital data project (unpublished data).

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Figure 10. Angiotensin-converting enzyme inhibitor use by region.

∧Rahimzadeh S, Farzadfar F, Ghaziani M (2013) Iranian hospital data project (unpublished data).

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Figure 11. Beta-blocker use by region.

∧Rahimzadeh S, Farzadfar F, Ghaziani M (2013) Iranian hospital data project (unpublished data).

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Figure 12. Mineralocorticoid receptor antagonist use by region.

∧Rahimzadeh S, Farzadfar F, Ghaziani M (2013) Iranian hospital data project (unpublished data).

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Outcomes

Across LMICs, patients admitted with heart failure remained in hospital for a mean of 10 d (Table 8). The mean hospital stay ranged from 3 d in India to 23 d amongst studies from China. Wide differences were observed amongst Argentinian and Brazilian studies. In Argentina, length of stay varied between studies from 5 d to 25 d, with an overall mean of 7 d. In Brazil, the range was between 9 and 25 d, with an overall mean of 10 d (see Table 9 for individual study data).

In-hospital mortality was 8% (95% CI: 6%–10%, I2 99%, p<0.001) (Figure 13) across the 23 studies that reported this measure ([20],[21],[23],[29],[31],[33][35],[40],[41],[43][46],[48],[50],[52],[56][58],[68][69]; S. Rahimzadeh, F. Farzadfar F, and M. Ghaziani, unpublished data), with no significant association with the country-level length of stay. Four studies reported longer-term outcome data, showing comparable mortality rates post-discharge: THESUS-HF, a multi-centre study of heart failure across nine countries of sub-Saharan Africa, found that mortality from heart failure was 4.2% in hospital and 17.8% at 6 mo after hospital discharge [35]. In Brazil, Barretto and colleagues reported a mortality rate of 8.8% in hospital and 25.8% at 1 y [19], whilst in Pakistan, after almost a year of follow-up, a similar mortality rate of 27.5% was recorded [47]. Of the Brazilian cohort studied by de Campos Lopes and colleagues, 44% were alive at 21 mo of follow-up [42].

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Figure 13. In-hospital mortality rates by region.

∧Rahimzadeh S, Farzadfar F, Ghaziani M (2013) Iranian hospital data project (unpublished data).

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Data relating to heart failure as a proportion of total hospital admissions were available for five countries. Across these countries, heart failure accounted for 2.2% (range: 0.3%–7.7%) of total admissions. Brazil was the only LMIC with nationwide registry data compiled for all patients with heart failure treated by its public health system [74]. Here, heart failure was responsible for 2.2% of total hospitalisations across the country [74]. In India, heart failure accounted for only 0.37% of cases from a sample of 1,551,410 hospitalisations, as derived from billing data in Andhra Pradesh [69]. Out of a representative sample of 38,926 hospital admissions in Iran, 0.3% were identified as having heart failure as the primary cause of admission (S. Rahimzadeh, F. Farzadfar F, and M. Ghaziani, unpublished data). By contrast, 5.8% of total hospital admissions in Cameroon were due to heart failure [24],[29], and 7.7% in Argentina [23].

In sub-Saharan Africa, the total number of cardiovascular admissions was reported, rather than total hospital admissions. In Nigeria, heart failure accounted for 31% of cardiovascular cases presenting to hospital [27], with corresponding figures of 38% in Senegal [38] and 47% in Soweto, South Africa [75].

Population-level data regarding the prevalence of heart failure were available in only one study, from Turkey [63]. Here an absolute prevalence of 2.9% for heart failure was found across the sample [63].

Effect of Time on Heterogeneity of Outcomes

Meta-regression was performed to investigate the potential effect of the time period in which each study was undertaken on between-study heterogeneity in the causes, management, and outcomes of heart failure.

A statistically significant effect was observed between the study time period and hypertension as a cause of heart failure, which rose by 2.5% per year (95% CI: 1.4%–3.6%, p<0.001) between 1990 and the late 2000s (Figure 14). There was no evidence to suggest that study time period had a significant effect on the other main causes of heart failure (IHD: 0.05%, 95% CI: −1.4% to 1.5%, p<0.95; cardiomyopathies: 0.65%, 95% CI: −0.3% to 1.6%, p<0.19; valvular heart disease: −0.04%, 95% CI: −0.7% to 0.6%, p<0.89) (Figures 1517).

The reported utilization rates for medical treatments of heart failure did not differ significantly over time, with the exception of beta-blockers, which showed an increase of 2.8% per year (95% CI: 1.5%–4.1%, p<0.001) (Figure 18). Corresponding figures were −0.4% per year (95% CI: −1.8% to 0.98%, p = 0.56) for ACEI use and 0.67% (95% CI: −0.9% to 2.2%, p = 0.38) for mineralocorticoid receptor antagonist use, with loop and/or thiazide diuretic use changing by −0.49% per year (95% CI: −1.9% to 0.9%, p = 0.49) (Figures 1921).

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Figure 19. Meta-regression of angiotensin-converting enzyme inhibitor use against study period.

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Figure 20. Meta-regression of mineralocorticoid receptor antagonist use against study period.

http://dx.doi.org/10.1371/journal.pmed.1001699.g020

There was also some evidence to suggest in-hospital mortality rate declined by 0.28% per year between 1990 and 2010 (95% CI: −0.54% to −0.012%, p = 0.042) (Figure 22).

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Figure 22. Meta-regression of in-hospital mortality rates against study period.

http://dx.doi.org/10.1371/journal.pmed.1001699.g022

Discussion

Our study presents, to our knowledge, the most comprehensive review to date and the first pooled analysis of the burden of heart failure in LMICs worldwide, collating data on over 230,000 episodes from 31 countries, with representation from all world regions. We found that heart failure is already a major burden to populations and health services in LMICs, where it makes up an average of 2.2% of hospital admissions, affecting more men than women. Reflecting the broad range of countries included and their differing levels of socio-economic development, there are wide variations in patient characteristics and the causes of heart failure and its management. Nonetheless, noticeable similarities can be discerned both between the included LMICs themselves and between these LMICs and HICs.

Across all LMICs from which data were available, the mean age of patients was 63 y, which is over a decade younger than in studies from HICs [76],[77]. The observed differences in age between the countries correlated strongly with the differences in HDI across them. Alongside this is the graded rise in the mean age of patients from represented low-income, low-middle-income, and upper-middle-income countries, from 50 y in the former to 60 y and 70 y, respectively. Thus, the age of presentation in upper-middle-income countries comes close to that in HICs (70 y in the EuroHeart Failure Survey II across 30 countries in Europe [76] and 72 y in ADHERE in the US [77]).

Substantial inter-regional variation is present in the causes ascribed to individual cases of heart failure. Heart failure is a syndrome made up of a constellation of signs and symptoms, with additional features present on further investigation. Given that a number of its aetiological underpinnings are often potential co-morbidities, disentangling one from the other is fraught with challenges, particularly in low-resource environments without recourse to a broad range of investigative tools [31]. Although 80% of studies from the Americas, Western Pacific, and Europe reporting aetiologies for heart failure documented the use of additional investigative tools, only 50% of studies from Africa did so. Nevertheless, our results are broadly consistent with the patterns of risk factors reported by Khatibzadeh and colleagues in their recent review of the worldwide risk factors for heart failure [78], as well as those of the Global Burden of Disease Study [10]. It is of note that preventable non-communicable diseases, in particular IHD and hypertension, are responsible for the large majority of cases worldwide.

Current guidelines worldwide stress the importance of ACEIs, beta-blockers, and mineralocorticoid receptor antagonists in the management of heart failure with reduced LVEF, with loop/thiazide diuretics given for symptom relief. Across the 29 studies from which management data were available, few studies reported the LVEF of patients, and fewer still separated data by LVEF. Overall mean LVEF was 40%: 38% amongst inpatients and 48% amongst those in non-acute settings. Consequently, it is not possible to make strong conclusions about the adherence of practice to evidence-based practices worldwide, but it is evident that management diverges considerably between regions and remains suboptimal on average. Data from the EuroHeart Failure Survey II of 30 high-income European countries also demonstrated poor medical management [76]. In this study, the mean LVEF of patients was 38%, and just over one-third of patients had a LVEF>45% [76]. Here, 71% of individuals were prescribed ACEIs, 48% a mineralocorticoid receptor antagonist, and 61% a beta-blocker at discharge [76]. The corresponding figures across our dataset are 57%, 32%, and 34%, respectively.

Across represented LMICs, patients admitted with heart failure had a poorer immediate prognosis than those in many HICs. However, as is the case for HICs, the estimates from LMICs varied substantially, although we found the difference between the two outlying regions in terms of prognosis, the Americas and South East Asia, was not statistically significant (p = 0.27). On average, the in-hospital mortality rate was 8.3% in LMICs, compared to 6.7% in the EuroHeart Failure II Survey [76] and 4% in ADHERE in the US [77]. Such differences, and the wide heterogeneity both within LMICs and between LMICs and HICs, may be due to different thresholds for hospitalisation or differences in patient characteristics, treatment strategies, or hospital characteristics. Reports of outcomes after hospital discharge were available from some studies, and these were more comparable to estimates from HICs [4],[6],[19],[42],[47].

Remarkable regional variation exists in the incidence of heart failure admissions to hospital. Of particular note is the low rate of reported admissions for heart failure in India and Iran. Unpublished data from India, based on the hospital billing codes assigned to patients from a sample of just under 1,551,410 admissions, showed an incidence of 0.37% [69]. Similarly, 0.3% of all hospital admissions were attributed to heart failure in a registry of over 80,000 hospitalisations across a number of hospitals in Iran (S. Rahimzadeh, F. Farzadfar F, and M. Ghaziani, unpublished data). These figures are an order of magnitude smaller than what is reported in HICs. There are several possible reasons for this observation. For example, it may be that in these countries, hospitals are still largely used for procedure-related activities, as opposed to pure medical management. In such a setting, treatment of medical conditions, such as heart failure, is much more likely to take place in the outpatient setting, for which data from India and Iran are lacking. Overall, the population-level incidence and prevalence of heart failure, despite its significance and dominance amongst cardiovascular diseases presenting to hospitals worldwide, remains largely unknown. Similarly, few data regarding the direct and indirect costs of heart failure are available in LMICs, information that is vital in understanding and measuring the value of different health service configurations and novel interventions.

This review collates data over a time period of almost 20 y, which may be one explanation for the degree of heterogeneity in results between studies. However, when study period was analysed using meta-regression against the causes, management, and outcomes of heart failure, only three statistically significant effects were found. These included a rising percentage of patients in whom hypertension was reported as a contributing cause of heart failure, an increasing trend in the reported prescription of beta-blockers over time, and a substantial decline in in-hospital death rates (see Figures 14, 18, and 22). Although these associations are plausible and—in case of beta-blocker use and mortality rates—encouraging, they should be interpreted cautiously because of the potential for confounding.

Limitations

The data included are derived from a heterogeneous group of studies that set out with differing research goals. Variation in the methodologies used, particularly in methods of standardising the diagnosis and assessment of heart failure, may impact on some of the findings. These factors likely explain the high estimates of between-study variation that we found. Such variation may lead to underestimation of the true prevalence of heart failure, as well as inaccuracies in the causes ascribed to cases of heart failure. Our study includes individuals from three groups: those with their first presentation with acute heart failure, those with acute decompensation of chronic heart failure, and those with stable chronic heart failure seen in the outpatient clinic setting. Differences between healthcare systems may mean that the characteristics of patients seen in various settings may differ between countries, whilst adherence to gold-standard management may be more common amongst those with stable chronic heart failure seen in outpatient settings staffed by cardiologists than amongst those with acute heart failure treated in hospitals staffed by general internal physicians. In analysing these patients we have focussed on the evidence-based medical management methods common to all three groups. Combining data from 1995 to 2014, this study summarises management techniques over an almost 20-y period, an approach that may underestimate adherence to current management standards. However, when evaluated with meta-regression, the heterogeneity in a management variable was rarely found to be explained by changes over time. Another limitation of our study is that our data are derived from studies conducted for the most part in urban tertiary referral centres, which may not reflect the broader picture of heart failure in other hospitals and the community. Finally, despite the large number of studies included, information from some regions and for some outcomes was limited. In countries where few data are available, these results may not be truly reflective of the population and should therefore be interpreted as only a guide to the true prevalence, causes, and management of heart failure.

Conclusion

This review shows that heart failure places a considerable burden on health systems in LMICs, and affects a wide demographic profile of patients in these countries. Non-communicable diseases dominate the causes of heart failure across LMICs, although infectious valvular diseases and cardiomyopathies continue to impose a significant burden. Together, this suggests a double burden of communicable and non-communicable diseases for countries in the midst of epidemiological transition. In addition, we have identified high in-hospital mortality and wide variation and significant suboptimal use of pharmacological therapies. Further population-level studies, with clear case and outcome definitions, are needed for a more accurate assessment of heart failure in LMICs.

Supporting Information

Protocol S1.

Study protocol: systematic review of the burden of heart failure in low- and middle-income countries.

doi:10.1371/journal.pmed.1001699.s001

(PDF)

Checklist S1.

PRISMA 2009 checklist.

doi:10.1371/journal.pmed.1001699.s002

(DOC)

Author Contributions

Analyzed the data: TC KR MW. Wrote the first draft of the manuscript: TC KR. Contributed to the writing of the manuscript: TC KR MW GR JM FF. ICMJE criteria for authorship read and met: TC MW GR FF JM KR JCL SG JA SR MG SM MS DB AP CSPL KS AB BBS AD DH HK TE AF AK RK TP DP RS DX. Agree with manuscript results and conclusions: TC MW GR FF JM KR JCL SG JA SR MG SM MS DB AP CSPL KS AB BBS AD DH HK TE AF AK RK TP DP RS DX. Designed the study: KR DB. Provided input on study design: DX AP SM. Designed the search strategy, and contributed to abstract reviews and data extraction plans: TE AF AK RK TP DP RS. Completed data extraction and coordinated the collection of unpublished data: KR TC. Provided input on writing of the manuscript and analyzing of the data: MW GR FF JM. Contributed significantly to reviewing the manuscript: JA HK KS DB AP CSPL. Contributed data: JCL SG SR MG FF MS JA BBS AB AD DH. TC had full access to all the data in the study and he takes responsibility for the integrity of the data and the accuracy of the data analysis.

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