Expanding the global borders of heart failure: the SHOP and PEOPLE studies

This editorial refers to ‘Mortality associated with heart failure with preserved vs. reduced ejection fraction in a prospective international multi-ethnic cohort study’†, by C.S.P. Lam et al., on page 1770. Heart failure (HF) represents a growing global epidemic affecting ∼26 million patients worldwide1 and is associated with economic costs in excess of US$100 billion.2 , 3 The global burden of HF is projected to rise over the next decade given the ageing population and longitudinal improvements in guideline-directed medical therapies, survival after acute myocardial infarction, management of co-morbidities, and global processes of care. However, these population estimates have largely been described within the context of registries and epidemiological surveys confined to select regions, namely North America and Europe. Few epidemiological data have emerged from South America, Africa, the Middle East, and Asia-Oceanic regions (Take home figure), and data that do exist are subject to important limitations. Surveillance in these regions is often limited to the inpatient setting, is of variable quality and completeness, and often lacks imaging/biomarker correlates and long-term clinical outcome data. Select completed or active global epidemiological studies of heart failure encompassing >500 000 patients across >75 countries. ADHERE = Acute Decompensated Heart Failure National Registry; ADHERE-AP = Acute Decompensated Heart Failure National Registry International–Asia Pacific; ASIAN-HF = Asian Sudden Cardiac Death in Heart Failure; ATTEND = Acute Decompensated Heart Failure Syndromes; EHFS = European Heart Failure Survey; ESC‐HF = European Society of Cardiology‐Heart Failure; G-CHF = Global Congestive Heart Failure; GWTG‐HF = Get With The Guidelines‐Heart Failure; INTER-CHF = International Congestive Heart Failure Study; OPTIMIZE‐HF = Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients With Heart Failure; PEOPLE = Prospective Evaluation of Outcome in Patients With Heart Failure With Preserved Left Ventricular Ejection Fraction; REPORT-HF = International Registry to assess medical Practice with Longitudinal Observation for Treatment of Heart Failure; SHOP = Singapore Heart Failure Outcomes and Phenotypes; THESUS‐HF = The Sub‐Saharan Africa Survey of Heart Failure. There is a substantial need for more complete epidemiological data capture across global regions. First, there is a greater population at risk in low- and middle-income countries and it is uncertain whether medical and device interventions are readily generalizable to this broader population. Secondly, clinical trials in HF have undergone major shifts in the distribution of primary enrolling sites from North America to Asia, Eastern Europe, and other regions of the world over the last two decades.4 Greater depth in understanding background HF rates, practice patterns, and clinical outcomes may guide site selection, clinical trial planning, and power estimates. Thirdly, there is important inter- and intraregion variation in background aetiological factors, co-morbid conditions, access to and costs of care, and overall standard of living that may drive risk and progression of HF, and potentially influence responses to investigational therapies.5 Similarly, knowledge and health attitudes towards HF may vary considerably across regions. Finally, increased sampling of global cohorts with established HF diagnoses may provide better estimates of the relative distribution of HF with reduced, mid-range, and preserved ejection fraction (EF).6 In this issue of the European Heart Journal, Lam et al.7 present in-depth data from 2039 unselected patients across the EF spectrum from the SHOP (Singapore Heart Failure Outcomes and Phenotypes) and PEOPLE (Prospective Evaluation of Outcome in Patients With Heart Failure With Preserved Left Ventricular Ejection Fraction) studies. SHOP and PEOPLE represent prospective, dual-nation, epidemiological investigations with parallel designs and similar eligibility criteria. Patients were identified across 10 centres in Singapore and New Zealand after clinical diagnoses of HF were established (by European Society of Cardiology criteria) during or soon after hospitalization. Enrolled subjects had routine biomarker assessment and echocardiography performed, and were followed for up to 2 years for clinical outcomes (all-cause death and hospitalization for HF). In Singapore, the distribution of HF with preserved, mid-range, and reduced EF was 22, 11, and 67%, respectively, while corresponding enrolled subsets in New Zealand were 35, 14, and 51%, respectively. Consistent with previous epidemiological reports, patients with HF with preserved EF tended to be older, women, and with greater prevalence of systemic hypertension and atrial fibrillation than other EF groups. At 2-year planned follow-up, patients with HF with preserved EF faced a lower risk of clinical events compared with other EF groups, but this risk was attenuated after accounting for baseline variation in N-terminal pro-brain natriuretic peptide (NT-proBNP) levels. NT-proBNP remained an independent predictor of clinical outcomes, regardless of baseline EF. The SHOP and PEOPLE investigators have accomplished what few global studies have—they systematically captured biomarker, echocardiographic, and follow-up clinical outcome data in a diverse group of HF patients. Several findings are noteworthy: patients in these cohorts presented at younger ages (mean age 65 years) compared with other US and European hospitalized HF registries (mean age ∼70–75 years).1 Data from ADHERE (Acute Decompensated Heart Failure Registry) International-Asia Pacific from >10 000 patients hospitalized for HF between 2006 and 2008 showed a similar average age (mean age 66 years), ranging widely from 53 years in the Philippines to 77 years in Australia, Hong Kong, and Taiwan.8 This marked variation in age of presentation may be substantially influenced by country-specific phase of development and local health resources. The more contemporary ASIAN-HF (Asian Sudden Cardiac Death in Heart Failure) registry enrolled a similarly young cohort (mean age 60) and highlighted significant variation in patient characteristics by ethnicity and regional income level.9 Evolving risk factor patterns in Western epidemiological studies of HF have shown gradual reductions in prevalent HF with reduced EF and improvement in its associated clinical prognosis.10 Younger age of the enrolled cohorts in SHOP and PEOPLE may explain the distribution in EF-based phenotypes, with relative under-representation of patients with HF with preserved EF. Indeed, when enrolment is restricted to older, purely hospitalized cohorts, higher proportions of HF with preserved EF are observed and long-term event rates are uniformly elevated across the EF spectrum. In nearly 40 000 older patients (median age 80 years) hospitalized for HF in the GWTG-HF (Get With The Guidelines®-Heart Failure) registry linked to Medicare data, equal proportions (46%) had reduced and preserved EF, and 5-year mortality was ∼75% regardless of baseline EF range.11 Greater non-cardiac co-morbidity burden in older patients with HF with preserved EF may contribute disproportionately to adverse prognosis compared with patients in lower EF ranges.12 These data from SHOP and PEOPLE also serve to validate NT-proBNP as a marker of risk in this multi-ethnic cohort. Natriuretic peptides are subject to variation by ventricular wall thickness, race, body mass index, renal function, and other factors. NT-proBNP levels were consistently lower in HF with preserved EF compared with lower EF ranges in both Singapore and New Zealand. After accounting for variation in NT-proBNP, adjusted risk of 2-year clinical events was similar across EF-based groups. As other recent studies have shown,13 patients with clinical diagnoses of HF with an EF in a range that has been deemed ‘mid-range’ appear to have overall risk trajectories similar to those with higher EF. HF with mid-range EF in SHOP and PEOPLE accounted for 10–15% of patients with intermediate demographic, biomarker, and echocardiographic profiles. Risk of 2-year mortality appears similar to that of HF with preserved EF. SHOP and PEOPLE fill important gaps in our understanding of HF epidemiology in the Asia-Oceanic region. Future studies will need to continue to navigate challenges in mapping global HF epidemiology. Investigators will need to sample rural communities adequately (beyond immediate surveillance of academic centres). Based on resource availability, cause-specific events identified in epidemiological studies should be fully ascertained and adjudicated. ASIAN-HF is one such registry that is evaluating the burden and risk factors of sudden death in Asian patients with HF.9 Finally, global integrated studies will need to be conducted broadly across regions in a standardized fashion to facilitate comparability. INTER-CHF (INTERnational Congestive Heart Failure Study)14 is a completed multinational cohort study of 5813 HF patients from 16 low- and middle-income countries, two-thirds of whom were identified via outpatient clinics. More recently, the G-CHF (Global Congestive Heart Failure; ClinicalTrials.gov Identifier: NCT03078166) prospective global registry was launched, with anticipated enrolment of 25 000 patients with prevalent HF encompassing 200 sites across 33 countries. The ongoing ascertainment of high-quality, rich data from previously unmapped regions is the first step to developing effective strategies to lessen the global impact of HF. Conflict of interest: M.V. is supported by the NHLBI T32 post-doctoral training grant (T32HL007604). S.D.S. has received research grants from Alnylam, Amgen, AstraZeneca, Bellerophon, Celladon, Gilead, GlaxoSmithKline, Ionis Pharmaceutics, Lone Star Heart, Mesoblast, MyoKardia, NIH/NHLBI, Novartis, Sanofi Pasteur, and Theracos, and has consulted for Alnylam, Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, Corvia, Gilead, GlaxoSmithKline, Ironwood, Merck, Novartis, Pfizer, Takeda, and Theracos.