CC BY-NC-ND
0Accepted Manuscript
JOURNAL OF Is. CARDIAC ^^ FAILURE
i»HFSA
Title: Understanding the Epidemiology of Heart Failure to Improve Management Practices: an Asia-Pacific Perspective
Author: Jeyamalar Rajadurai, Hung-Fat Tse, Chao-Hung Wang, Ning-I Yang,
Jingmin Zhou, David Sim
PII: S1071-9164(17)30026-X
DOI: http://dx.doi.org/doi: 10.1016/j.cardfail.2017.01.004
Reference: YJCAF 3916
To appear in: Journal of Cardiac Failure
Received date: 6-7-2016
Revised date: 13-12-2016
Accepted date: 18-1-2017
Please cite this article as: Jeyamalar Rajadurai, Hung-Fat Tse, Chao-Hung Wang, Ning-I Yang, Jingmin Zhou, David Sim, Understanding the Epidemiology of Heart Failure to Improve Management Practices: an Asia-Pacific Perspective, Journal of Cardiac Failure (2017), http://dx.doi.org/doi: 10.1016/j.cardfail.2017.01.004.
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Understanding the epidemiology of heart failure to improve management practices: an Asia-Pacific perspective
Running title: Epidemiology of HF in Asia-Pacific
Authors: Jeyamalar Rajadurai, MBBS,a • Hung-Fat Tse, MBBS, MD, PhD,b • Chao-Hung Wang, MD, PhD,c, Ning-I Yang, MBChB,c • Jingmin Zhou, MD,d • David Sim, MBBSe a Department of Cardiology, Subang Jaya Medical Centre, Subang Jaya, Malaysia b Department of Medicine, University of Hong Kong, Queen Mary Hospital, Hong Kong, Peoples' Republic of China
c Heart Failure Research Center, Division of Cardiology, Department of Internal Medicine, Chang Gung Memorial Hospital, Keelung; Chang Gung University College of Medicine, Taoyuan, Taiwan. d Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China
e Department of Cardiology, National Heart Centre Singapore, Singapore
Corresponding author
Dr Jeyamalar Rajadurai
Department of Cardiology, Subang Jaya Medical Centre, Subang Jaya, Malaysia
Tel: +60 3 5639 1212
Fax: +60 3 5639 1209
email: rjeyacardio@gmail.com
Acknowledgements
The authors were assisted in the preparation of the manuscript by Derek Lavery and Sharon Smalley (CircleScience, an Ashfield company, part of UDG Healthcare plc), funded by Novartis Pharma AG, Basel, Switzerland. Keywords
Asia-Pacific; heart failure; epidemiology; management
Word count (excluding highlights, abstract, references and tables): 4768
Highlights
• Reliable data on the epidemiology of heart failure (HF) is lacking in Asia-Pacific
• Compared to the West, patients are younger with more severe signs/symptoms of HF
• Patients receive lower-than-recommended levels of pharmacological treatment
• Patients in the region are underrepresented in clinical studies
• Robust epidemiological data from regional studies will improve future management Abstract (196/200 words)
Heart failure (HF) is a major global healthcare problem with an estimated prevalence of approximately 26 million. In Asia-Pacific regions, HF is associated with a significant socio-economic burden and high rates of hospital admission. Epidemiological data that could help to improve management approaches to address this burden in Asia-Pacific regions are limited, but suggests patients with HF in Asia-Pacific are younger and have more severe signs and symptoms of HF than those of Western countries. However, local guidelines are based largely on the European Society of Cardiology and American College of Cardiology Foundation/American Heart Association guidelines, which draw their evidence from studies where Western patients form the major demographic and patients from the Asia-Pacific region are under-represented. Furthermore, regional differences in treatment practices likely impact on patient outcomes. In the following review, we examine epidemiological data from existing regional registries which indicate that these patients represent a distinct sub-population of patients with HF. In addition, we highlight that patients with HF are under-treated in the region despite the existence of local guidelines. Finally, we provide suggestions on how data can be enriched throughout the region, which may positively impact upon local guidelines and improve management practices.
Introduction
Heart failure (HF) has an estimated global prevalence of approximately 26 million, is a leading cause
of morbidity and mortality, and therefore, a global healthcare problem. In Asia-Pacific regions, HF is associated with a significant socio-economic burden, representing a major cause of hospital admissions and readmissions, loss of work and productivity, and death.3-6 In Western countries, extensive information is available on the epidemiology and management of HF due to the established
7 12 13 14
disease-specific registries " and clinical guidelines. In contrast, reliable data on disease prevalence and incidence of HF in Asia-Pacific regions are lacking and it is likely that region-wide differences in treatment practices impact upon patient outcomes. An accurate account of HF in this region is critical and has the potential to influence clinical management, which may improve patient outcomes over the short and longer term.
In this narrative review, current understanding of the epidemiology of HF in Asia-Pacific regions is discussed (supported by data from local disease registries and regional clinical trials), to characterize how patients from these regions may differ from Western countries. We review current clinical management practices and local guidelines throughout the region, highlighting ways in which regional data and management practices can be enhanced in order to improve patient outcomes.
Search strategy
We searched PubMed for English language articles reporting on the epidemiological data and current management practices of adults with HF in Asia-Pacific regions published between January 2000 and August 2016 using the following search criteria: Asia/Asia Pacific, heart failure/chronic heart failure/acute heart failure (including heart failure with reduced or preserved ejection fraction). The search results were first evaluated by title and/or abstract for relevant publications, particularly registry, observational and controlled studies. Full articles were reviewed for those citations identified for inclusion in the manuscript, the majority of which were published after 2010. We also examined the official websites of national HF societies to identify local HF guidelines.
The epidemiology of HF in Asia-Pacific regions
Prevalence of HF
Approximately 5.7 million (2.2%) adults aged >20 years in the United States of America (USA) have HF.15 In contrast to Western countries, there are large gaps in information relating to HF in Asia.16 According to the America Heart Association (AHA), current estimates of the prevalence of HF in this
region ranges from 1.26% to 6.7%. Looking specifically at individual countries and areas within Asia, the enormity of the problem becomes clear. For example, in China alone, approximately 4.2 million people have HF, while in India prevalence estimates vary widely between 1.3 and 23 million, and in
17—19
Southeast Asia, 9 million people are estimated to have HF. Additionally, based on the incidence
of de novo HF in the USA (10 out of 1000 people aged >65 years, per year), it has been predicted
that more than 0.37 million Japanese individuals aged >65 years will develop new-onset HF in 2025. With the ageing population and the rising prevalence of various cardiovascular risk factors, such as hypertension and diabetes, it is evident that a significant number of people will continue to develop HF
16 21 23
every year in the region. ' - Data available from the few regional studies indicate a prevalence of HF among hospitalized patients of 3.4-6.7 %,20, 24 and in common with evidence from Western populations, studies suggest that hospitalization for HF is increasing in the region.25,26 Further detail by type of HF is required to characterize the region-specific burden of disease. The following overview provides a summary of the current epidemiological data of acutely decompensated HF (ADHF) and chronic HF (HF with reduced ejection fraction [HFrEF] and HF with preserved ejection fraction [HFpEF]) in Asia-Pacific.
Acutely decompensated HF
Patients with ADHF commonly present in the emergency setting and require urgent management. Admission to hospital for ADHF is a powerful predictor of readmission and post-discharge death in patients with chronic HF.27, 28 Therefore, identification and appropriate management of these patients is crucial for improving outcomes.
Despite an increase in the prevalence of ADHF, there are still limited data on its epidemiology, treatment and prognosis in the Asia-Pacific region. As shown in Table 1, regional data are available from the Acute Decompensated Heart Failure Registry-International Asia-Pacific (ADHERE-AP),29 the Thai Acute Decompensated Heart Failure Registry (Thai-ADHERE),30 the Acute
Decompensated Heart Failure Syndromes (ATTEND) registry, the Korean Acute Heart Failure
(KorAHF) registry and the Taiwan Society of Cardiology - Heart Failure with reduced Ejection
Fraction (TSOC-HFrEF) registry which can be compared with data from the USA (Acute Decompensated Heart Failure National Registry [ADHERE]),9 Europe (EuroHeart Failure Survey II [EHFS II])34 and the United Kingdom National Heart Failure Audit (UKNHFA).35
Overall, patients from Asia-Pacific were similar to Western populations, but with some notable differences. With the exception of patients enrolled in the ATTEND registry (mean age 73 years), the mean ages of patients with ADHF in Asia-Pacific (64-69 years) are lower than that of Western registries (69-78 years), including the Get With The Guidelines-HF registry conducted in the USA (2005-2014; N=117,761).36 A known history of HF was reported in similar proportions of patients across the registries (50-75 o/o),9,29,30,32,34,35 aside from ATTEND and TSOC-HFrEF (36 % and 40 %,
respectively). Overall, in both Asian and Western registries, a history of ischemic heart disease was relatively common, although some variation was observed (31-58%; Table 1).9, 29-35 However, incidence of valvular heart disease was lower in regional registries compared with the EHFS II study (Table 1).9, 29-35 Intra-regional variation in co-morbidity rates could help explain these differences.
Despite some differences in patient characteristics, the burden of in-hospital morbidity/mortality in Asia-Pacific is similar to Western registries. With the exception of Japanese patients (where median hospital length of stay was 21 days), hospital stay was similar in Asia-Pacific registries compared with ADHERE, EHFS II and UKNHFA (median length of stay 6-8 days vs 49 days, respectively).9, 29-35 The range in length of hospital stay may be a result of differences between national health insurance systems, hospital location (e.g. metropolitan vs. rural), and hospital teaching/academic status.37, 38 In-hospital mortality in the Asia-Pacific registries was also generally comparable to those in western registries, despite more patients requiring mechanical ventilation in the Asia-Pacific region (Table 1).
Data from the ASCEND-HF trial (Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure) trial, covering five geographical regions including North America, Western Europe and Asia-Pacific, are consistent with registry findings; for example, patients from Asia Pacific were younger (62 years) compared with those from North America (67 years) and Europe
(74 years), and hypertension was the most common comorbidity irrespective of region studied. Moreover, median length of hospital stay was 5 days for patients in Asia Pacific and in North America, but was slightly greater in Western Europe (8 days).
Chronic HF
Table 2 summarizes the baseline clinical characteristics of patients enrolled in chronic HF registries across Asia-Pacific,16, 40-45 compared with patients enrolled in registries in the USA (ADHERE)9 and
Europe (EHFS II / UKNHFA).3435 In general, patients were younger than those in Western countries, as shown in the recent Asian Sudden Cardiac Death in Heart Failure (ASIAN-HF) and INTERnational Congestive Heart Failure (INTER-CHF) registry studies where mean age was 60 years.16, 45 The majority of patients with HF in Asia-Pacific were male and aside from three studies that recruited only patients with a left ventricular ejection fraction (LVEF) <40 %,16, 42, 43 the prevalence of HFrEF was 3759 % (Table 2). Furthermore, patients with HF in regional registries were predominately New York Heart Association (NYHA) class II/III.16, 40-45
Ischemic heart disease was the major cause of HF in Asia-Pacific populations (27-48 %), not too dissimilar to that observed in Western populations (40-58 %).9, 16, 34, 35, 40-42, 45 Despite some inconsistencies, comorbidities, such as hypertension and diabetes were highly prevalent in Asian patients with HF (Table 2).16, 41-45 Notably, some registry populations (HEARTS, Dubai) were highly heterogeneous, containing sub-populations from other regions and ethnic
groups.
A number of global HF trials have examined geographic variations in clinical profile, management and post-discharge outcomes.46, 47 Similar to the registry data, notable differences were recorded in the Prospective Comparison of Angiotensin Receptor Neprilysin Inhibitor with Angiotensin-Converting Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) trial for patient age (58 years in Asia Pacific and 65-68 years in US/western Europe); furthermore, evidence-based therapies were most frequently used in Western regions.47 Of note, this study found that the risk of death was greater in Asia Pacific compared with North America.
A focus on HFpEF
13, 14
Despite clear guidance on the definition, diagnosis and treatment of HFrEF versus HFpEF there is limited epidemiological data on HFpEF in Asia-Pacific populations. The majority of data are accessible through chronic HF registries, predominately in Japanese populations (e.g. Chronic Heart Failure Analysis and Registry in the Tohoku District [CHART] studies). In these studies, the prevalence of HFpEF ranged from 50-70 % of the total HF population,48-50 higher than that reported in
multi-ethnic studies in Singapore (38.3 %) and the INTER-CHF study of 5,813 patients from Africa, Asia, the Middle East and South America (26 % of the total population and 41 % of 2661 Asian
participants). Further, the prevalence of HFpEF in Japan is higher than in Western registries (5169 % vs 36 %-47 %, respectively),49, 52-54 and continues to increase(46 % vs 63 % in CHART-1 [2000-2005] and CHART-2 [2006-2010], respectively),41 which is in contrast to the modest increase
in prevalence recorded in the Framingham studies (33 % in 2000 vs 39 % in 2010). The underlying reasons for the difference in rates are unclear at present; however lifestyle factors are likely to have a
major impact on disease prevalence (both HFpEF and HF in general).
Large-scale studies including the Japanese Cardiac Registry of Heart Failure in Cardiology (JCARE-CARD) have demonstrated that compared with patients with HFrEF, Japanese patients with an LVEF >50 % are significantly older, more likely to be female with higher systolic blood pressure (SBP), and lower heart rate (HR).48, 50 Patients with HFpEF were also more likely to have a history of hypertension, renal failure, anemia and atrial fibrillation compared with patients with HFrEF, in which hyperlipidemia, sustained ventricular tachycardia or ventricular fibrillation, and prior coronary revascularization were more common.48 These data are supported by observations from the
multi-ethnic study in Singapore and in a population-based study conducted in northeast China. In this latter study of 2230 patients, the prevalence of HFpEF was greater in women than men (4.9 % vs 1.8 %, respectively; p < 0.01) and increased with age in both sexes; furthermore, while men with HFpEF had a higher prevalence of hypertension, obesity and history of heart disease, women with
HFpEF tended to have hypertension, history of stroke, hyperuricemia and reduced renal function.
Several studies have reported that all-cause mortality in Japanese patients with HFpEF is not significantly different to that in patients with HFrEF (ranging from ~20-25 % in both populations).41, 48,
In contrast, Yap et al. reported a lower 2-year all-cause mortality rate in patients with HFpEF compared with patients with HFrEF in a broad spectrum of Asian ethnicities (27 % vs 37 %,
respectively). Encouragingly, data from the CHART-2 study suggest that the 3-year incidence rates
of all-cause and cardiovascular (CV) death of patients with both HFrEF and HFpEF are improving.
Current HF diagnostic and treatment patterns in Asia-Pacific
Our review of the epidemiological data for HF has revealed considerable inter- and intra-regional variations which include differences in the underlying causes of HF and the prevalence of comorbidities within the region, the age of patients hospitalized for HF and length of hospital stay between Asia-Pacific and Western countries. Possible explanations include genetic and disease modifying factors (e.g. risk factors for CV disease and comorbidities) but also contrasting approaches to management.58, 59 In the Asia-Pacific region overall, the diagnosis of HF is usually made on clinical grounds. In the ADHERE-AP registry, measurement of natriuretic peptide levels was performed in few patients hospitalized for ADHF; brain natriuretic peptide (BNP) was assessed in 7.8 % and N-terminal
pro B-type natriuretic peptide (NT-proBNP) was assessed in 8.5 % of cases, respectively. Use of echocardiography was higher; left ventricular (LV) function was assessed in approximately half of
patients. In contrast, echocardiography was performed in 94.5 % of patients in the TSOC-HFrEF registry and NT-proBNP, BNP and troponin levels determined in 22.7 %, 32.4 % and 64.4 % of cases,
correspondingly, while, in the Korean HF (KorHF) registry, 76.6 % and 79.8 % of patients hospitalized for ADHF were assessed for natriuretic peptide levels or LV function, respectively, to support a clinical diagnosis.42 In patients with stable HF in the outpatient setting, assessment of LV function is considerably lower. In Australian primary care clinics, echocardiography was performed in approximately 22 % and 64 % of outpatients with a suspected or known diagnosis of HF, respectively.60
The use of intravenous (IV) diuretics to relieve volume overload in patients admitted to hospital with ADHF in the Asia-Pacific registries was common (63-96 %), similar to the ADHERE and EHFS II registries (87 % and 84 %, respectively) (Table 1). Administration of IV nitrates and use of inotropic agents in the region was higher than reported in ADHERE, but comparable to EHFS II registries (Table 1) and more patients required mechanical ventilation (8-20 %, compared with 3-5 % in the Western registries). This suggests that patients admitted to hospital with ADHF in Asia-Pacific regions may present with more clinically severe conditions.
Despite evidence that adherence to pharmacological treatment guidelines results in improved clinical outcomes,61, 62 the reported use of pharmacotherapy is generally lower in Asia-Pacific countries compared with patients with HF enrolled in Western registries (Tables 1 and 2). There were fewer patients discharged on evidence-based HF treatment in the Asia-Pacific registries. The use of renin angiotensin aldosterone system (RAAS) inhibitors ranged from 51-75 % in the region, lower than that reported in ADHERE (83 %), EHFS II (80 %) and the UKNHFA (91%) (Table 2).9, 16, 34, 35, 4042, 44, 45 p-blocker use varied widely in Asia-Pacific registries (Table 2), although recent data from ASIAN-HF (79%) and INTER-CHF (61%) were more comparable to Western studies (61-86 %) (Table 2).9, 16, 34, 35, 40-45 Of interest, higher proportions of patients with HFrEF (90 %) and HFpEF (83 %) enrolled in the Swedish HF Registry (2005-2012; N=41,976), received p-blockers,63 compared
with other European studies, despite limited evidence of the benefit of p-blockers in HFpEF.
The use of aldosterone antagonists ranged widely throughout the region. Low use (19 %) was reported in the Japanese CHART-1 study, which was comparable to the 16 % of patients prescribed aldosterone antagonists before hospital admission in the Get With The Guidelines-HF registry in the USA (2005-2014; N=117,761);36 in other studies, reported use ranged from 27-53 %, which was comparable to other Western registries (33-59 %).9, 16, 34, 35, 40-42, 44, 45 High use of aldosterone antagonists (75 %) was reported in the Chinese Chronic HF with reduced ejection fraction (CHF-REF) study.43 Of note, the aldosterone antagonist spironolactone was primarily used, as eplerenone is not approved for use in many countries in the region.
A relatively higher proportion of patients (48-58 %) were prescribed digitalis in China and Japan (according to CHART-1, CHF-REF and the large registry conducted in China by Yu et al.),40,41,43 compared with other Asia-Pacific countries (7-28 %).41,44,45 The role of digitalis in the treatment of HF
is less certain, and use is less common in the USA and Europe, with 19-38 % of patients reported to receive digitalis in the ADHERE, Get With The Guidelines-HF, EHFS II and UKNHFA registries.9,34-
In general, prescription of diuretics (mainly loop diuretics) was similar between patients with HF in Asia-Pacific (56-91 %), and in the USA and Europe (65-98 %; Table 2). Device use (defibrillator, pacemaker, or cardiac resynchronization therapy) was low in the region (2-6 %) which was consistent with EHFS II (1-3 %),34 but lower than that reported in more recent studies in Europe (use ranging
from 5-18 %) and America (5.1-5.4 %).64, 65 By contrast, device use was considerably greater in the ASIAN-HF registry (14.3 %).16
Recent data from a multi-ethnic Asian population indicated that patients with HFpEF were less likely to receive angiotensin-receptor-blockers/angiotensin-converting-enzyme inhibitors (ARBs/ACEIs) (60 % vs 74 %), diuretics (78 % vs 87 %), MRAs (8 % vs 22 %), p-blockers (50 % vs 65 %) and statins (61 % vs 72 %) than patients with HFrEF (all p < 0.001).51 This was supported by Takada et al. who reported that Japanese patients with a LVEF >50 % were less likely to receive RAAS inhibitors (70 % vs 80 %, p < 0.001), loop diuretics (31 % vs 57 %, p < 0.001), aldosterone antagonists (14 % vs 34 %, p < 0.001) and p-blockers (40 % vs 65 %, p < 0.001) than patients with a
LVEF <50 %. The use of statins was consistent in both populations in this study.
Finally, treatment patterns across the Asia-Pacific region vary not only by country but also by setting. In general, patients with HF managed by cardiologists in hospitals compared with those managed by General Practitioners (GPs) in primary care were more likely to be treated at target doses of RAAS inhibitors and p-blockers (Table 3).66-70
Progress towards improvements in data quality and management practices in Asia-Pacific
Epidemiological data from the Asia-Pacific region is relatively limited compared with data from Western populations, despite the existence of some registries. However, our review of the epidemiological and treatment data available for the region underlines the need to improve the quality of data collected on patients as well as management practices, to reduce inequalities within and between countries.
Regional studies
Available registry data indicates that patients with HF from Asia-Pacific represent a distinct population compared with their Western counterparts (Tables 1 and 2). Clinical trials provide the means to further capture and understand baseline characteristics of patient populations, across different countries and regions. While trial inclusion and exclusion criteria may limit the generalizability to some extent, such information would provide insights that could lead to improvements in local management practices. However, it is widely recognized that patients from Asia-Pacific countries are underrepresented in
global HF clinical trials.
Enrolment of Asian patients ranged from 1-27 % in recent landmark trials such as Metoprolol Randomized Intervention Trial in congestive Heart Failure (MERIT-HF), Systolic Heart Failure Treatment with the If Inhibitor Ivabradine Trial (SHIFT), Randomized Aldactone Evaluation Study (RALES), Eplerenone in Mild Patients Hospitalization And Survival study in Heart Failure (EMPHASIS-HF), PARADIGM-HF, Heart Failure Endpoint Evaluation of Angiotensin II Antagonist Losartan (HEEAL), Aliskiren Trial on Acute Heart Failure Outcomes (ASTRONAUT) and ASCEND-HF where white patients predominated.39,46,47,72 Other large HF trials, including Studies of Left Ventricular Dysfunction Treatment (SOLVD-T) and Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM)-Added, have not included any Asian patients.59, 72
There is an urgent need for increased representation of patients from Asia and the Pacific in
future clinical trials and international registries. However, important progress is being made in this respect as evidenced by the initial patient characteristics data from the ASIAN-HF registry of 5,276 patients with HFrEF from 11 countries (China, Hong Kong, India, Indonesia, Japan, Malaysia, Philippines, Republic of Korea, Singapore, Taiwan and Thailand).16 Implementation of diagnostic tools
in the region, specifically echocardiography, which was shown to be underperformed on patients in
ADHERE-AP compared with data from Western registries, is being examined. Furthermore, ASIAN-HF will explore the controversy over sudden cardiac death and use of implantable devices in the region. According to Western data, sudden cardiac death accounts for ~50 % of deaths in patients with HF,74 however some studies have suggested a lower incidence in Asian patients and recent trials have provided inconclusive data on the benefit of implantable devices.75-78 It is anticipated that data from ASIAN-HF will address the ambiguity surrounding sudden cardiac death and device use in the
region allowing physicians to make informed decisions on treatment intervention.
Regionally specific data will also be generated as part of the Asian Network for Translational Research and Cardiovascular Trials (ATTRaCT) initiative which will investigate the underlying CV disease pathophysiology of HF in Asia with the aim of identifying target diagnostic tools and therapies. Further regional trials of note include the Singapore Heart Failure Outcomes and Phenotypes (SHOP) and Prospective Evaluation of Outcome in Patients with Heart Failure with Preserved Left Ventricular Ejection Fraction (PEOPLE) studies. These are the first studies determining the epidemiology, outcomes and inter-ethnic differences in patients with HFpEF in Singapore (n = 1,250) and New Zealand (n = 1,073), respectively.79
Data of relevance for the region will also be generated by the International Registry to Assess Medical Practice with Longitudinal Observation for Treatment of Heart Failure (REPORT-HF), a global, prospective, observational study that will characterize patient outcomes following an index hospitalization for HF.80 It is anticipated that approximately 20,000 patients with new onset HF will be enrolled in >300 sites in 40 countries with a follow-up period of 3 years.
The studies discussed above will significantly enhance epidemiological data in the region, however, fundamental improvements to the number of Asian-Pacific patients represented in global trials including clinical and observational studies are essential to fully understand future regional trends and the overall disease burden. Dedicated regional clinical trials, designed specifically to
account for patient characteristics and clinical practices may also be warranted. One such example is the ongoing RELAXin in Acute Heart Failure in Asia (RELAX-AHF-ASIA) trial, which has been designed to account for specific management pathways for acute HF in the region.81
Several barriers to patient enrolment currently exist, including (i) poor awareness of HF and knowledge of the clinical trial process; (ii) reluctance to participate due to cultural/social beliefs; and
(iii) poor access to hospitals/medical centers (particularly for rural/remote patients). Strategies to improve patient education would be effective in tackling the first two barriers; the third barrier would most likely require intervention by organizations with the medical sphere to improve local infrastructure.
In parallel, improvements to study centers throughout the region will be required to support increased numbers of enrolled patients. These include (i) enhanced medical and administrative resources in local academic centers (e.g. availability of diagnostic tools and trained support staff); (ii) increased number of participating centers in global trials; (iii) improved recognition of centers currently participating in global trials; and (iv) closer relationships between academic establishments and pharmaceutical organizations (effectively demonstrated by The Agency for Science, Technology and Research and The National University Heart Centre, Singapore).79 A coordinated effort on behalf of physicians, academic establishments, pharmaceutical companies and local government will be required to successfully accomplish these goals.
Differences between regional guidelines and ESC or ACCF/AHA guidelines
Many countries in the Asia-Pacific region have published practical guidelines on the diagnosis and treatment of HF to drive improvements in management practices.82-89 These guidelines are based mainly on evidence derived from clinical trials conducted in Europe and the USA and as a result,
82 83 85 86 88 90
guidelines published by Asia-Pacific countries are somewhat overlapping. , , , -
While regional guidelines are largely consistent with ESC and ACCF/AHA guidelines in terms of pharmacological therapy, varying emphases are placed on wider management aspects. The Japanese Circulation Society (JCS) guidelines (published in 2013), along with a simple set of guidelines for chronic HF, emphasize the importance of determining targets in the treatment and management of patients.89
In China, the guidelines (published in 2014) emphasize the usefulness of BNP and NT-proBNP in the diagnosis and evaluation of patients with HF and the importance of optimizing standard medical therapy for 3-6 months before the implantation of a cardiac resynchronization device, the recommendation of which has been updated to include patients with NYHA class II HF and a left-branch bundle block pattern QRS width >150 ms. Australian guidelines published in 2011 highlight
evidence to support non-pharmacological management (e.g. benefits of regular physical activity) alongside pharmacological management of patients with HF.90
Malaysian guidelines (published in 2014) provide similar recommendations to those for China, but in addition address HF in patients who are pregnant, as well as infants and children, patient groups rarely mentioned in other guidelines.85 The need for a multidisciplinary approach to the management of patients with HF is also highlighted. Furthermore, in Singapore, HF guidelines published in 2004 provide recommendations not only for healthcare professionals on diagnostic approaches, pharmacological, and surgical therapy (including mechanical devices),87 but have also published detailed guidelines for clinical pharmacists88 with information on therapy initiation, titration and how to monitor, prevent, and manage possible side effects.
Finally, the Taiwan Society of Cardiology guidelines (published in 2012) recognize that social and ethno-cultural differences between Chinese and Western populations may confound the management of Chinese patients with HF.85 For instance, recommendations regarding the use of warfarin suggest that the maintenance dose proposed in Western guidelines may not be suitable for Taiwanese patients with HF as a result of inter-individual and inter-ethnic differences.85 This should also be considered by other Asian countries. However, while detailed recommendations for cardiac rehabilitation and palliative care are provided, recommendations are not accompanied by classifications and levels of evidence to guide clinical decision making, as in the ESC and ACCF/AHA guidelines.
Multidisciplinary disease management programs
A key feature of current ESC and ACCF/AHA guidelines is a focus on multidisciplinary
disease management programs, , which have been shown to reduce hospitalization, improve quality of life and prolong survival,91-95 yet are mentioned in few regional guidelines.85,86,88-90
In Asia-Pacific, preliminary evidence suggests that multidisciplinary disease management programs are effective in reducing all-cause mortality and HF-related re-hospitalizations in high-density populations with nationalized healthcare and easy access to cardiologists.70 Additionally, there are a number of hospital-based HF clinics that currently offer various outreach services (e.g. home visits and telephone support). The use of telephone support and telemetry provides the opportunity to advise patients with symptoms to seek immediate help allowing for earlier intervention, which may
reduce or prevent hospital admissions and all-cause mortality.96 However there are very few specialized clinics in the community, resulting in limited access to specialists and additional resources which are more easily accessible in hospitals. Home visits or home-based HF clinics have been shown to reduce recurrent hospital stay and are associated with significantly less total healthcare expenditure per quality-adjusted life years compared with community based intervention.97
Limitations
This is a narrative review of currently published data, including observational registry studies, controlled trials and treatment guidelines. As is typical with such publications, discussions include historical data and are somewhat limited to methodological flaws introduced in the reviewed studies. Moreover, there is a potential for bias resulting from lack of a clear systematic methodology. However, in the current paper, the majority of articles included were published after 2010, and of particular note, comparison of key findings (Tables 1 and 2) are based on registry data from heterogeneous sources. A systematic review could have provided a more reliable and accurate picture of heart failure in Asia Pacific compared with Western regions and may have identified common methodological weaknesses and errors in the reviewed data. Nevertheless, given the heterogeneous nature of the studies discussed, a narrative approach is considered to be of most value.
Summary and conclusions
HF is a global healthcare problem and a leading cause of morbidity and mortality in Asia-Pacific, and
has recently been described as a 'pandemic'. Analysis of recent clinical trials and disease registries highlight several regional trends: (i) patients with HF in Asia-Pacific are younger and present with more severe signs and symptoms of HF than those of Western countries; (ii) ischemic cardiomyopathy, valvular heart disease, hypertension, and diabetes are common etiological and co-morbid factors and these will have a greater impact on healthcare systems in the future; (iii) patients receive lower-than-recommended levels of treatment despite the existence of local clinical guidelines; and (iv) intra-regional variation exists. While current ongoing observational studies, including ASIAN-HF, which has recently highlighted the significant heterogeneity among Asian patients with HFrEF,16 will address the lack of regional epidemiological data and positively influence local clinical guidelines, a significant effort will be required to address the under-representation of Asian-Pacific patients in
global trials. Further resources are needed to better characterize patients, drive improvements in local clinical practice and inform local guidelines in order to improve the outlook for patients in the region.
Funding
The writing/editorial support was funded by Novartis Pharma AG, Basel, Switzerland. Disclosures
Jeyamalar Rajadurai, Hung-Fat Tse, Chao-Hung Wang, Ning-I Yang and Jingmin Zhou declare that they have no conflict of interest. David Sim has received speaker honoraria from Novartis.
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Table 1. Baseline characteristics and clinical treatment of patients with acute decompensated heart failure enrolled in regional registries
ATTEND31 EHFS II34 /
Study ADHERE-AP29 Thai-ADHERE30 KorAHF32 TSOC-HFrEF33 ADHERE9 UKNHFA35
Geography (timeframe) 8 countries in Asia-Pacific (2006-8) Thailand (2006-7) Japan (2007-12) Republic of Korea (2011-12) Taiwan (2013-14) USA (2001-4) Europe / UK (2004-5) / (201415)
Patients, n 10,171 1612a 4842 2066 1509 159,168 3580 / 56,915 cases (N=41,461)
Mean age, years 66 64 73 ^ 69 64 72 70 / 78
Male, % 57 50 58 55 72 48 61 / 55
Mean LVEF, % NR NR NR 40 28 38 38 / NR
LVEF <40 %, % 53 40 53 56 100 51 66D / NR
Known HF history 64 67 36 50 40 76 63 / NR
NYHA I/II/III/IV, NR NR/15/16/70 <2/16/38/44 NR/NR/41/41c NRA2/NRa/NRa NR NR / NR/19/45/37
Etiology, %
Ischemic heart disease 50 47 31 38 44 58 54 / 51e & 40f
Valvular heart disease NR 19 19 13 8 NR 34 / 23e & 33f
Hypertensive NR 12 18 6 5 NR 11 / NR
Cardiomyopathy NR 14 13 15 33s NR 19 / NR
Comorbidities, %
Hypertension 64 65 69 59 35 74 63 / 52e & 61f
Dyslipidemia NR 51 37 NR 20n NR NR / NR
Diabetes 44
mellitus 45 47 34 36 NR 33 / 33e & 33f
Chronic kidney 22' 19J NR 14J 32 30J 17J / NR
disease
Atrial fibrillation 24 24 40K 27 26 31 39K /21e & 22f
COPD NR 81 10m 11m 11' 31' 19 / 17e & 19f
Previous stroke or TIA 13 12 14 15 9 NR 13 / NR
In-hospital management, %
IV diuretics 85 96 76 72 63 87 84 / NR
IV nitrates 14 22 35 40 NR 9 38 / NR
IV inotropic agents 15 23 19 32 37 8 30n / NR
Mechanical ventilation/intub ation 9 20 8 14 13 3 5 / NR
Discharge medication, %
RAAS inhibitors 63 48 70-75o 65 62 83 80p / 91e
ß-blockers 41 25 67 44 60 80 61 / 86e
Aldosterone antagonists 31 17 40-50° 40 49 33 48 / 52e
Diuretics NR 73 80-85° NR 82 87 90 / 98e
Digitalis 34q 26q 10-15° NR 26 38q 31 / 23eq
Calcium channel blockers NR NR 25-30° NR NR NR 15 / NR
Statins NR NR 30-35° NR NR NR 42 / NR
ICD 1.6 3r 3.4 1.4s 1.0s NR 1.2s / NR
CRT 4.2 3r 2.3 1.3s 1.0s NR 2.7s / NR
Outcomes, %
Median length of hospital stay,
6 8 21 8 8 4 9 / 9
In-hospital mortality, % 5 6 6 6 2 4 7 / 9.6
Footnotes
a 2041 admissions; b LVEF <45 %; c reported as severity of dyspnea; d 88% of patients had severe HF (NYHA class III or IV); e heart failure reduced ejection fraction; f heart failure preserved ejection fraction; g dilated cardiomyopathy; h atherogenic dyslipidemia; 1 chronic renal insufficiency (>177 |imol/L/>2.0 mg/dL or on dialysis; j chronic renal failure/insufficiency; k atrial fibrillation or atrial flutter; ' COPD or asthma; m chronic respiratory disease; n IV positive inotropes were administered as follows: dopamine (11 %); dobutamine (10 %); levosimendan (4 %); noradrenaline (3 %) and adrenaline (2 %); o data has been approximated; p angiotensin converting enzyme inhibitor or angiotensin receptor blocker; q digoxin; r CRT or ICD; s during hospitalization. Abbreviations
ADHERE, acute decompensated heart failure national registry; ADHERE-AP, acute decompensated heart failure registry-international Asia-Pacific; ARIC, Atherosclerosis Risk in Communities Study Community Surveillance; ATTEND, acute decompensated heart failure syndromes registry; COPD, chronic obstructive pulmonary disease; CRT, cardiac resynchronization therapy; EHFS II, EuroHeart failure survey II; HF, heart failure; ICD, implantable cardioverter defibrillator; IV, intra-venous; KorAHF, Korean acute heart failure registry; LVEF, left ventricular ejection fraction; NR, not reported; NYHA, New York Heart Association; RAAS, renin angiotensin aldosterone system; Thai-ADHERE, Thai acute decompensated heart failure registry; TIA, transient ischemic attack; TSOC-HFrEF, Taiwan Society of Cardiology - Heart Failure with reduced Ejection Fraction registry; UKNHFA, United Kingdom National Heart Failure Audit
Table 2. Baseline characteristics and clinical treatment of patients enrolled in regional chronic heart failure registries
Study ASIAN-HF16 Yu et al.40 CHART- 141 KorHF42 CHF-REF43 CHART- 241 HEARTS44 INTER-CHFa45 ADHERE9 EHFS II34/ UKNHFA35
Geography (timeframe) 11 countries in Asia (2012-15) China (2000-10) Japan (2000-4) Republic of Korea (2004-9) China (2005-9) Japan (2006-10) Dubai (2011-12) 4 countries in Asia (2012-14) USA (2001-4) Europe / UK (2004-5) / (2014-15)
Patients, n 5276 12,450 1006 1527 2154 3676 504 2661 159,168 3580 / 56,915 cases (N=41,461)
Mean age, years 60 62 69 69 64 70 63 60 72 70 / 78
Male, % 78 58 64 56 79 66 65 59 48 61 / 55
Mean LVEF, % 28 (median) NR 50 29 37 56 NR NR 38 38 / NR
LVEF <40 %, % 100 NR 54b 100 100 b t- 3 54 59c 51 66d / NR
Known HF history 64.1e NR NR 31 NR NR 82 28e 76 63 / NR
NYHA I/II/III/IV, % 13/52/29/6 <1/23/50/ 27 NR/78/21/ 1 NR/NR/60/ 60f 0/41/34/25 NR/86/14/ 1 NR 13/45/29/ 13 NR NR / NR/19/45/ 37
Etiology, %
Ischemic heart disease 47 28 27 40 NR 48 NR 48 58 54 /51g& 40h
Valvular heart disease NR 18 NR 13 NR NR NR 13 NR 34 / 23g & 33h
Hypertensive NR 32 NR NR NR NR NR 14 NR 11 / NR
Cardiomyopat hy NR 27 33 22 NR 18 NR 10 NR 19 / NR
Comorbidities, %
Hypertension 52 NR 46 42 57 87 72 59 74 63 / 52s & 61h
Dyslipidemia NR NR 16 NR 24 78 23 26 NR NR / NR
Diabetes mellitus 40 NR 19 31 17 35 66 28 NR 33 / 33s & 33h
Chronic kidney disease NR NR NR 7' NR NR NR 7 30' 17' / NR
Atrial fibrillation 18 NR 42 21j 16 42 21 NR 31 39j / 21s & 22h
COPD 8k NR NR 3 23 NR 171 NR 311 19 / 17s & 19h
Previous stroke or TIA 6 NR NR 8 5 NR 13 10 NR 13 / NR
Medication, %
RAAS inhibitors 75 51 69 68 66 73 73 68 55m 80 / 91s
ß-blockers 79 44 29 41 68 51 81 61 58 61 / 86s
Aldosterone antagonists 59 53 19 38 75 27 49 44 16 48 / 52s
Diuretics 82 69 77 NR 74 56 91 62 65 90 / 98s
Digitalis NR 48 49 NR 58n 25 7 28 19n 31 / 23sn
Calcium channel blockers NR NR 29 NR 46 38 15 NR 11 15 / NR
Statins NR NR NR NR 43 36 67 NR 47 42 / NR
ICD 14° NR 1.6° NR 2.2° 2.8° NR NR 5.4p 1.2p / NR
CRT 14° NR 1.6° NR 5.8 2.8n NR NR NR 2.7p / NR
Footnotes
INTER-CHF was conducted in 16 countries across Africa, Asia, Middle East and South America (only data for Asia are presented in the table); LVEF <50 %; c 41% of patients had preserved ejection fraction (defined as LVEF >50%); d LVEF <45 %; e previous hospitalization for HF (in past year for INTER-CHF); f reported as 60 % (NYHA class III-IV); g heart failure reduced ejection fraction; h heart failure preserved ejection fraction; 1 chronic renal insufficiency; j atrial fibrillation or atrial flutter; k chronic respiratory disease; ' COPD or asthma; m Total calculated percentage of patients treated with angiotensin-converting-enzyme inhibitors, angiotensin receptor blockers and renin inhibitors; n digoxin; o CRT-D or ICD; p during hospitalization Abbreviations
ADHERE, acute decompensated heart failure national registry; ADHERE-AP, acute decompensated heart failure registry-international Asia-Pacific; ASIAN-HF, Asian Sudden Cardiac Death in Heart Failure; ATTEND, acute decompensated heart failure syndromes registry; CHART, Chronic Heart Failure Analysis and Registry in the Tohoku District; CHF-REF, Chinese Chronic HF with reduced ejection fraction; COPD, chronic obstructive pulmonary disease; CRT, cardiac resynchronization therapy; EHFS II, EuroHeart failure survey II; HEARTS, Heart Function Assessment Registry Trial in Saudi Arabia; HF, heart failure; ICD, implantable cardioverter defibrillator; INTER-CHF, INTERnational Congestive Heart Failure; IV, intra-venous; KorHF, Korean heart failure registry; LVEF, left ventricular ejection fraction; NR, not reported; NYHA, New York Heart Association; Thai-ADHERE, Thai acute decompensated heart failure registry; RAAS, renin angiotensin aldosterone system, TIA, transient ischemic attack; UKNHFA, United Kingdom National Heart Failure Audit
Table 3. Regional management of patients with heart failure in primary care versus at a specialized unit
JCARE-GENERAL JCARE-GENERAL
Study Krum et al.200166 GP-HF67 Hospital-HF67 Yao et al.201168 Ho et al.201469 Mao et al. 201470
Geography Australia Japan Japan Australia Australia Taiwan
(timeframe) (1998) (2004-5) (2004-5) (2006-11) (2006-11) (2010-12)
Study design Prospective multicenter Prospective multicenter Prospective multicenter Retrospective analysis of medical records at single center Retrospective analysis of medical records at a single center Prospective single center
Population Outpatients with known or suspected HF presenting to a primary care physician Outpatients with stable HF managed by primary care physicians in general practice Outpatients with stable HF managed by cardiologists in hospital Patients hospitalized for HF Patients with documented HF attending a multidisciplinary clinic in tertiary hospital Patients with documented HF attending a multidisciplinary clinic in tertiary hospital
Patients, n 2,905 1,405 1,280 667 255 349
Mean age, years NR 77 71 76 81 60
Male, % NR 38 55 53 47 70
Assessment of LV function, % 64 (known HF); 22 (suspected HF) NR NR 36 NR 100
LVEF <40 %, % NR NR NR 50a 43b 66c
Medication, %
RAAS inhibitors 59d 51 69 58 97 92
ß-blockers 12 18 38 35 93 77
Aldosterone antagonists 8 NR NR 12 NR NR
Diuretics 63 58 66 72 NR NR
Digitalis 31e 41 45 19c NR NR
Calcium channel blockers 10 41 33 11 NR NR
Statins NR NR NR 22 NR NR
Footnotes
a LVEF <45 %; b Systolic HF; c Mao CT, Liu MH, Hsu KH, Fu TC, Wang JS, Huang YY, et al. Unpublished data; d ACEI; e digoxin Abbreviations
ACEI, angiotensin-converting-enzyme inhibitor; HF, heart failure; JCARE-GENERAL, Japanese cardiac registry of heart failure in general practice; LV, left ventricular; LVEF, left ventricular ejection fraction; NR, not reported; RAAS, renin angiotensin aldosterone system
