Global Perspective on Acute Coronary Syndrome: A Burden on the Young and Poor

Abstract

Ischemic heart disease (IHD) is the greatest single cause of mortality and loss of disability-adjusted life years (DALYs) worldwide, and a substantial portion of this burden falls on low- and middle-income countries (LMICs). Deaths from IHD and acute coronary syndrome (ACS) occur, on average, at younger ages in LMICs than in high-income countries, often at economically productive ages, and likewise frequently affect the poor within LMICs. While data regarding ACS in LMICs are limited, there is a growing literature in this area and the research gaps are being steadily filled. In high-income countries, decades of investigation into the risk factors for ACS and development of behavioral programs, medications, interventional procedures, and guidelines have provided us with the tools to prevent and treat events. Although similar tools can be, and in fact have been, implemented in many LMICs, challenges remain in the development and implementation of cardiovascular health promotion activities across the entire life course, as well as in access to treatment for ACS and IHD. Intersectoral policy initiatives and global coordination are critical elements of ACS and IHD control strategies. Addressing the hurdles and scaling successful health promotion, clinical and policy efforts in LMICs are necessary in order to adequately address the global burden of ACS and IHD.

Introduction

Ischemic heart disease (IHD) is the greatest single cause of mortality and loss of disability-adjusted life years (DALYs) worldwide, accounting for roughly seven million deaths and 129 million DALYs annually.^1,2 Cardiovascular disease exerts a significant economic toll, accounting for one-third of a projected $47 trillion in economic losses to non-communicable diseases (NCDs) over the next 20 years.³ While high-income countries (HICs) continue to deal with significant IHD mortality, nearly two-thirds of all IHD DALYs and over half of deaths occur in LMICs. Many of these countries have experienced transformational economic growth and lifestyle changes over the past several decades that have increased the prevalence of IHD risk factors and rates of mortality.^4-8 Understanding this change, how it compares with past experience in HICs, and available measures to stem the global tide of IHD mortality make up the research and action frontier regarding acute coronary syndrome (ACS) and IHD in LMICs.

The epidemiologic transition provides a useful framework for understanding the rise of IHD in LMICs (Figure 1).^9,10 The epidemiologic transition posits that populations initially start with low life expectancies with mortality primarily driven by infections, under-nutrition, and illness and injury related to childbirth and early childhood (“age of pestilence and famine”). As sanitation and agriculture improve, these causes of death gradually recede (“age of receding pandemics”) until NCDs, particularly IHD and cancers, dominate the causes of death (“age of degenerative and man-made diseases”). Still later, as cancers and IHD become preventable or controllable, the burden of these diseases shift to older ages (“age of delayed degenerative diseases”).¹¹ A “fifth stage” has also been proposed, in light of recent adverse trends in physical activity and diet—an age of “obesity and inactivity”.¹²

Figure 1.

The epidemiologic transition in the United States, which was already well underway by 1900. From: JAMA. 1999;281(1):61-66.²⁰⁵

Rapid urbanization, mechanization of transport, and increasingly sedentary jobs in LMICs have led to an acceleration and overlap between the stages of the epidemiologic transition.^13-16 While infections, under-nutrition, and maternal/child mortality are still important, they are no longer dominant causes of death in many LMICs: IHD is now one of the top five causes of death in all regions of the world except sub-Saharan Africa. Even in sub-Saharan Africa, cardiovascular disease is the leading cause of death among individuals over age 30.¹⁷ Overall, the numbers of deaths and DALYs attributable to IHD have risen since 1990.^18,19 This acceleration in the rise of NCDs without a similar reduction of infectious disease burden, has led to a challenging “double burden of disease” in many countries.^13,20,21 In addition, the age-standardized mortality rates from IHD are higher in many LMICs than in HICs, thus indicating more individuals are dying at a younger age from IHD in LMICs (Figure 2).¹⁹ While much of the IHD burden in LMICs is occurring as those regions and individuals enter higher economic strata, there remains a substantial health and economic burden on the poorer segments of LMIC societies resulting from IHD and related NCDs.^22-24 In addition, given population growth in LMICs, the absolute numbers of individuals with premature IHD is substantial even as global, age-standardized IHD mortality rates have declined.^18,19

Figure 2.

Mortality rates from IHD per 100,000 in 2010 by country, ages 15-49, males (top) and females (bottom). Data from 2012 Global Burden of Disease.²⁰⁶

There has also been a dramatic rise in several IHD risk factors. Obesity and overweight prevalence has been increasing in many LMICs,^6,25-27 more than tripling between 1975 and 1997 among children in Brazil from 4.1% to 13.9%.²⁵ The age-standardized prevalence of obesity and overweight increased from 30.8% in 1980 to 46.4% in 2008, with half of the increase occurring after 2000.²⁷ Globally, mean body mass index has been increasing in nearly every region of the world (Figure 3). Other biological risk factors have demonstrated geographic and temporal variability. Comprehensive analyses of systolic blood pressure have revealed increases in sub-Saharan Africa and South/Southeast Asia, relatively little change in Latin America, and substantial decreases in HICs (Figure 4).⁴ In contrast, mean serum cholesterol levels have tended to decline in several regions of the world, although at varying rates⁵: while HICs and the former Soviet Union have experienced notable declines, South Asia has seen much more modest declines, while Latin America and the Middle East did not change and levels actually rose in East Asia (Figure 5).

Figure 3.

Age-standardized mean body-mass index (BMI) by sex and region. Green: high-income countries, Black: East Asia/Pacific, Red: Eastern Europe/Central Asia, Dark Blue: Latin America/Caribbean, Light Blue: Middle East/North Africa, Purple: South Asia, Yellow: Sub-Saharan Africa.

Figure 4.

Age-standardized mean systolic blood pressure (SBP) by sex and region. Color coding as in Figure 3.

Figure 5.

Age-standardized mean total cholesterol by sex and region. Color coding as in Figure 3.

Underpinning the rises in biological risk factors have been rises in behavioral risk factors. Though recent reports suggest that global smoking prevalence has declined since 1980, the total number of smokers has increased to nearly one billion people in 2012²⁸ and remains common in many LMICs²⁹ despite some notable successes.^30-32 There is also significant geographic variability in smoking rates, with certain areas (Russia, Eastern Europe, Central Asia, China, Southeast Asia, North Africa, and parts of South America) characterized by high age-standardized prevalence of daily smoking (Figure 6). Consumption of other unhealthy products, such as sugary beverages, processed foods, and alcohol have increased.³³ Likewise, large numbers of adults around the world have low levels of physical activity; although there are significant regional variations, several LMICs have physical inactivity levels that rival those of HICs (Figure 7).³⁴ From the most recent Global Burden of Disease estimates, the top 10 risk factors contributing to mortality and DALYs in LMICs were all behavioral or biological risks for NCDs (Figure 8).³⁵

Figure 6.

Age-standardized prevalence of smoking as percent of population, males (top), females (bottom). From JAMA. 2014;311(2):183-192.²⁸

Figure 7.

Age-adjusted percent of adults who are physically inactive, males (A) and females (B). From Lancet 2012, 380(9838):247-257.³⁴

Figure 8.

Percentage of total deaths (top) and DALYs (bottom) in LMICs for males (left) and females (right) of all ages attributable to different categories of risk factors. Data from 2012 Global Burden of Disease.²⁰⁶

In this review, we aim to describe the global perspective regarding ACS. However, given the limited, though growing, body of data regarding ACS outside of HICs, we use IHD as a surrogate for ACS when data for ACS are not available. Thus, we examine in detail the trends of IHD burden in HICs, compare and contrast the recent experience in LMICs, discuss the history of ACS treatment and prevention in HICs, and outline steps for addressing ACS in LMICs.

Rise and Fall of IHD Mortality in HICs

Current HICs struggled with growing rates of ACS and associated mortality during the mid-twentieth century.^36-38 However, HICs have experienced significant declines mortality rates from all cardiovascular conditions since the 1960s.^39-41 Both treatment and prevention have contributed to the observed reductions in IHD mortality in HICs (Table 1).^42-44 Treatment includes improved care for ACS, as well as chronic medical management of IHD. Preventive efforts include both behavioral and pharmacological initiatives.

Table 1.

Declines in coronary heart disease mortality in selected high- and middle-income countries, with attributable portions due to risk factor changes (prevention) and treatment.

Region	Years	Age Range	Initial CHD Mortality Rate+	Final CHD Mortality Rate+	Percent Change	Percent Attributable to Prevention	Percent Attributable to Treatment
England & Wales207	1981-2000	25-84	Males: ~530	Males: ~250	-53	58	42
			Females: ~180	Females: ~90	-50
Finland208	1982-1997	35-64	Males: 420	Males: 150	-64.3	53-72	23
			Females: 70	Females: 20	-71
Ireland209	1985-2000	25-84	8681*	4918#	-47	48.1	43.6
Italy210	1980-2000	25-84	Males: 267.1	Males: 141.3	-47.1	55	40
			Females: 161.3	Females: 78.8	-51.1
Auckland, New Zealand211	1982-1993	All Ages	2366*	1808#	-23.6	54	46
Scotland212	1975-1994		21438*	15234#	-28.9	51	40
Sweden213	1986-2002	25-84	Males: 544.1	Males: 253.4	-53.4	55	36
			Females: 291.5	Females: 140.0	-52.0
USA214	1980-2000	25-84	Males: 542.9	Males: 266.8	-50.9	44	47
			Females: 263.3	Females: 134.4	-49.0

⁺Rates given per 100,000 population

^*Expected number of deaths in final year with age-specific rates of initial year

^#Observed number of deaths in final year

CHD = coronary heart disease

Advances in the acute management of ACS include many celebrated achievements in intensive care-related and interventional approaches to cardiovascular medicine: the creation of the coronary care unit⁴⁵; the introduction of streptokinase⁴⁶ and later thrombolytic drugs;⁴⁷ and the development of coronary artery catheterization, balloon angioplasty,⁴⁸ and surgical revascularization.^41,49 These advances made it possible, rather than to simply observe the natural history of ACS complications, to intervene and attempt to modify the natural course of illness. Use of emergency medical systems, initially established for trauma care and to transport patients with suspected ACS, has also helped reduce the time between symptom onset and intervention, despite underutilization by many individuals who have acute events.^50-52 These interventions have changed acute management from passivity and impotence to activity and intervention, with the potential to avert premature death and disability.

Further success in IHD treatment is reflected in the multi-dimensional approach to medical management of IHD and secondary prevention of further events. This foundation of optimal medical therapy includes a combination of medications that is started acutely and maintained post-ACS: aspirin, beta blockers, angiotensin-converting enzyme (ACE) inhibitors, or angiotensin receptor blockers, and statins. The evidence for their use has been established over several decades, including the ISIS series of trials for beta blockers,⁵³ aspirin (alongside streptokinase),⁵⁴ and ACE inhibitors.⁵⁵ Longer-term evidence for these medications has been built up in meta-analyses of numerous trials.^56-59 Evidence for statins began to emerge with low-dose therapies in the 4S and CARE trials,^60,61 while later trials showed the increased benefits of more intensive lipid-lowering.^62-64

Improvements in primordial and primary prevention were driven first by an understanding of the underlying risks of cardiovascular disease, particularly through the Framingham Heart Study^65,66 and the Seven Countries Study.⁶⁷ These and related studies⁶⁸ helped define the roles of tobacco use, blood pressure, and cholesterol as risk factors for IHD, challenging beliefs about the benign nature of some risk factors and making what had seemed an inevitable consequence of aging become something that could potentially be prevented.^69,70

Building on the evidence of risk, intervention studies changed the practice of prevention. Pharmacological intervention was pioneered by the VA Cooperative Studies,⁷¹ showing reductions in morbidity and mortality in individuals treated for hypertension. For cholesterol, the Lipid Research Clinics trial provided early evidence that cholesterol reduction using medication could reduce incidence of IHD.⁷² Likewise, dietary and behavior change were first validated with the Oslo Study Group trial,⁷³ while the North Karelia Project and later the Five Community Study provided evidence of the effects of public health approaches.^74,75 The modern-day guidelines for cholesterol, blood pressure, and lifestyle modification are the result of decades-long efforts to accommodate the latest evidence from rigorous clinical trials into best practice recommendations.^76-80 These efforts, in combination with regulatory initiatives to ban trans fats^81,82 and global tobacco control,⁸³ have made substantial impact, with corresponding decreases in blood pressure, lipid levels, and tobacco use over time.^84-88

However, there are still major gaps in the midst of these overall improvements, and also concerning trends with respect to overweight, obesity, and diabetes. Body mass index has increased worldwide virtually without exception.⁶ Within the United States, the past decade has seen a rise in the prevalence of obesity among adult men as well as women belonging to racial or ethnic minorities.⁸⁹ There have also been declines in physical activity and increases in caloric intake.^90,91 In terms of overall cardiovascular health, less than 1% of adults in the United States were found to have “ideal cardiovascular health”, with high prevalence noted for poor diet (>90%) and high body-mass index (>50%).⁹² Projections of these trends suggest that, without intervention, poor health behaviors will continue to be highly prevalent with increases in diabetes prevalence and subsequent cardiovascular complications.⁹³

ACS and IHD Burden in LMICs

In some respects, the ACS and IHD situation in LMICs today is more similar to that of HICs in decades past. In particular, the burden of ACS is not solely on the rich nor on the elderly, but also on the poor and working-age⁹⁴. According to the most recent Global Burden of Disease study, the median age of death from IHD among males was a decade younger in LMICs than in HICs in 2010 (Figure 9). This may be due to earlier onset of ACS and IHD, as well as shorter survival after ACS. The available results from the OASIS-1 and -2 registries⁹⁵ and epidemiologic studies in India^96-98 suggest that earlier age for first ACS in LMICs is a major contributing factor. Registry data from many other LMICs also support the assertion that ACS often occur at younger ages than in HICs:^99-109 Strikingly, a registry from the United Arab Emirates reported a mean age of 50.8 years.¹¹⁰ Earlier age for first ACS is likely due to earlier acquisition of adverse health behaviors and IHD risk factors^{10,97,111,112} in the current context of economic development and globalization. One notable exception to this overall trend is the experience of an ACS registry in Thailand.^113,114

Figure 9.

Age distribution of male (top) and female (bottom) IHD (ischemic heart disease) deaths in 2010 among countries classified as high-income versus low- and middle-income. Data from 2012 Global Burden of Disease.¹

The treatment and outcomes of ACS in LMICs are variable but often suboptimal (Table 2).¹¹⁵ Observational studies do suggest that, to a large extent, the in-hospital treatment of ACS in LMICs includes the use of aspirin, ACE inhibitors, and beta blockers.^{95,98,116-118} The ACCESS Study, a prospective observational registry of patients hospitalized for ACS between 2007 and 2008 in 19 LMICs, found that aspirin and lipid-lowering therapies were each given to more than 90% of patients, while uptake of beta-blockers and ACE inhibitors were at 78% and 68%, respectively.¹¹⁶ However, comparison of countries participating in the OASIS registries found lower use of heparin in LMICs than in HICs, while the ACCESS investigators found that only 39% of patients presenting with ST-elevation myocardial infarction received fibrinolysis. In addition, there also exist substantive within-country differences in the management of ACS, as is the case in India.¹¹⁵

Table 2.

Summary of published literature regarding acute coronary syndrome in low- and middle-income countries.

Study	Region	Study Design	N	Mean Age	In-Hospital					Discharge				F/U	%Morality
					ASA	ACE-I/ARB	Statin	BB	Reperfusion	ASA	ACE-I/ARB	Statin	BB
ACCEPT (106)	Brazil	Registry	2,485	63	0.97	0.68	0.91	0.80	0.88*	NR	NR	NR	NR	30-Day	1.6
ACCESS (116)	Algeria, Argentina, Brazil, Colombia, Dominican Republic, Ecuador, Egypt, Guatemala, Iran, Jordan, Kuwait, Lebanon, Mexico, Morocco, Saudi Arabia, South Africa, Tunisia, United Arab Emirates, Venezuela	Registry	12,068	59.2	0.93	0.78	0.94	0.78	0.28	0.90	0.75	0.89	0.76	12 months	7.3
Aga Khan University Hospital, Nairobi (101)	Nairobi, Kenya	Registry	111	64	NR	NR	NR	NR	0.38	NR	NR	NR	NR	In-Hospital	8.1
Brazilian Registry of Acute Coronary Syndromes (RBSCA) (100)	Brazil	Registry	2,693	63	0.95	0.70	0.77	0.77	0.643	NR	NR	NR	NR	In-Hospital	5.5
BRIDGE-ACS (177)◆)	Brazil	Randomized Trial	548	62	0.958	NR	0.729	NR	NR	0.928	0.761	0.86	0.817	30-Day	8.4
CRACE (108)	China	Registry	1,301	63	0.98	0.82	0.74	0.98	0.64	NR	NR	NR	NR	In-Hospital	4
CREATE (130)	India	Registry	20,937	58	0.979**	0.568	0.52	0.59	0.104	NR	NR	NR	NR	30-Day	6.7
DEMAT (118)	India	Registry	1,565	58	0.96	NR	0.93	0.79	0.67	0.94	0.66	0.88	0.79	30-Day	2.1
Euro Heart Survey 2009 AMI Snapshot (107) ♓	Armenia, Bosnia-Herzegovinia, Bulgaria, Croatia, Czech Republic, Georgia, Hungary, Kazakhstan, Kosovo, Macedonia, Moldova, Poland, Romania, Russian Federation, Serbia and Montenegro, Slovakia, Slovenia, Ukraine	Cross-Sectional Survey	1,329	64	0.96	0.86	0.92	0.84	0.62	0.92	0.85	0.92	0.84	In-Hospital	9
Gulf RACE-2 (109)	Bahrain, Saudi Arabiam Qatar, Oman, United Arab Emirates, Yemen	Registry	7,930	57	0.98	0.76	0.95	0.74	0.18	0.93	0.78	0.91	0.79	12 months	12
Kerala ACS Registry (98)	Kerala, India	Registry	25,748	60	0.93	0.28	0.70	0.66	0.33	0.76	0.26	0.70	0.63	In-Hospital	3.9
OASIS-2 (95)	Bangladesh, China, India, Lithuania, Russia, Maldives, Slovenia, Ukraine	Registry	4,615	60.7	0.95	NR	NR	0.67	NR	NR	NR	NR	NR	24 months	9.5
PURE (119,120) ❖	Argentina, Bangladesh, Brazil, Canada, Chile, China, Colombia, India, Iran, Malaysia, Poland, Pakistan, South Africa, Sweden, Turkey, United Arab Emirates, Zimbabwe	Prospective Cohort	153,966	57	NA	NA	NA	NA	NA	0.21	0.16	0.09	0.17	NR	NR
RENASICA II (99)	Mexico	Registry	8,600	62	0.88	0.71	0.14	0.51	0.51	NR	NR	NR	NR	30-Day	10
TACSR (113)	Thailand	Registry	9,373	NR	0.95	0.63	0.80	0.62	0.37	NR	NR	NR	NR	In-Hospital	12.6
TRACS (114)	Thailand	Registry	2,007	64	0.99	0.71	0.94	0.62	0.48	NR	NR	NR	NR	12-Months	17.7
UAE-ACS Registry (110)	United Arab Emirates	Registry	1,842	51	0.95	0.70	0.93	0.81	0.814***	0.92	0.68	0.90	0.82	In-Hospital	1.7
WHO-PREMISE (121)	Brazil, Egypt, India, Indonesia, Iran, Pakistan, Russia, Sri Lanka, Tunisia, Turkey	Cross-Sectional Survey	10,000	59	NA	NA	NA	NA	NA	0.821	0.398	0.298	0.481	NA	NA
WHO-SAGE (128)	China, Ghana, India, Mexico, Russia, South Africa	Prospective Cohort	47,443	44	NA	NA	NA	NA	NA	NR	NR	NR	NR	NR	NR

^◆BRIDGE-ACS (177) data from control arm only.

^♓Euro Heart Study data from Central and Eastern regions only

^❖PURE study ages for CHD only, proportions for CHD in LMICs only.

^*STEMI patients only;

PCI + CABG;

^**Any antiplatelet agents;

Fibrinolytics & CABG & deferred PCI;

^***STEMI with LBBB patients only

NA = not applicable; NT = not reported

Further, continuation of these medications following discharge is poor: investigators from the PURE study found that among individuals with previous cardiovascular events, nearly 70% of those in lower-middle-income countries and 80% of those in low-income countries were on no medication for secondary prevention.¹¹⁹ They also found lower uptake of lifestyle changes following cardiovascular events in LMICs than in HICs, with 75% of individuals in HICs quitting smoking versus 42% in lower-middle- and 38% in low-income countries.¹²⁰ Likewise, the WHO PREMISE survey of coronary artery disease patients in LMICs found that while aspirin was in widespread use and that over 75% of respondents were aware of behavioral risk factors for cardiovascular disease, a majority engaged in less than 30 minutes of physical activity weekly and less than a third were taking statins.¹²¹ Administrative data among IHD patients from Andhra Pradesh were similarly discouraging, with only 15.6% receiving aspirin and 6.0% on cholesterol-lowering medications.¹⁰⁵ Evidence for the quality of clinical outcomes is conflicting. The OASIS registries found comparable mortality rates across participating countries after age-adjustment. By contrast, a review of randomized trials of ST-elevation myocardial infarction treatments found that trial sites in LMICs had higher mortality rates than their counterparts in HICs, which the authors explained by increased numbers of high-risk patients.¹²² Further clarification of the quality of ACS outcomes in LMICs is needed.

In addition, the impact of ACS and IHD on household livelihood is substantial in LMICs. As noted above, in LMICs these events occur at younger ages, often during peak economic productivity. Households experience a double burden both from the great expense of treating ACS and from the loss of income of the affected individual. In general, NCD expenditures increased as a proportion of out-of-pocket health care costs in India from 1995 to 2004, and were found to have greater odds of carrying catastrophic health expenditure than did communicable diseases among hospitalized patients.¹²³ Additional work confirms that individuals with NCDs have higher health expenditures than individuals with communicable diseases^24,124 and that households with an individual with an NCD are more likely to face catastrophic health expenditures.^124,125 In a multi-country survey of individuals hospitalized for cardiovascular conditions, more than half of the hospitalized individuals reported catastrophic health expenditures or distress financing.²³ Survival with disability, such as diminished exercise capacity that may arise from heart failure related to IHD, may further burden households’ stretched finances. Testimonies from individuals living with NCDs are notable for their desire not to be a burden on their families.¹²⁶

The socio-economic gradient of ACS in LMICs is also quite striking. Even in low-income countries, these are diseases that inflict a large burden on the poor. For instance, in South Africa, poorer districts of Cape Town had higher rates of mortality from NCDs than did wealthier districts.¹²⁷ In the SAGE surveys of health in six middle-income countries, hypertension prevalence was high, between 30% and 36%, across all income strata.¹²⁸ A survey of 1600 rural villages in India found higher prevalence of tobacco and alcohol use and lower intake of fruits and vegetables among poorer respondents.¹²⁹ Likewise, more than 70% of individuals with suspected myocardial infarction in the Indian CREATE registry were classified as “poor” or “lower middle income”.¹³⁰ Further, higher socio-economic status was found to be protective against risk of myocardial infarction in India.¹³¹ While there are likely geographic variations—the poor of sub-Saharan Africa face considerable burden from infectious and nutritional diseases—it is clear that the poor in LMICs do indeed experience a substantial burden of ACS and IHD.

Stemming the Tide: Cardiovascular Health Promotion Throughout the Life Course

Despite the challenges of addressing ACS in LMICs, the time is now to implement interventions aimed at cardiovascular health promotion throughout the life course.^132,133 Health promotion activities directed at all ages, access to essential medicines,¹³⁴ improved quality of health care services to manage risk factors and treat acute events, and intersectoral policy initiatives¹³⁵ can, in combination, prevent millions of premature deaths in the coming decades. A wide array of interventions are cost-effective and scalable in LMICs¹³⁶, and an analysis by the World Health Organization (WHO) of intervention packages for specific risk factors suggests that implementation can be done at very low cost per-person.¹³⁷

There is increasing evidence that IHD risk factors have their origins in early childhood.^138-143 Health promotion interventions targeted at young children may have beneficial impacts both on short-term health behaviors, as well as long-term risk factors.^144-149 Effective school-based interventions are those that include the family, and that center on realistic intermediate objectives such as changes in attitude, knowledge, dietary patterns or levels of physical activity, as early control measures that improve cardiovascular health.¹⁵⁰ Critical to the success of these interventions is community engagement, cultural relevance and appropriateness, optimization of the school environment, and involvement of the family.^151-153 Programs that have been implemented successfully in LMICs^144,145 can be reproduced in other low-resource settings.^154,155

Addressing dietary risk factors can be cost-effective. An analysis of salt-reduction measures estimated conservatively that a 15% reduction in salt intake could save 2.4 million lives over 10 years at a cost of $0.50 per person,¹⁵⁶ in line with other findings suggesting that salt reduction at processing stages of food production can be cost-effective.¹⁵⁷ Likewise, reductions in saturated and trans-fats by controlling use in food processing can be cost-effective, estimated at $40 per DALY in Latin America when focusing on trans-fats.^136,157 By focusing on processing sources, these interventions are readily scalable, costing less than $0.01 per person.¹³⁷

Physical activity remains a challenge to evaluate; however, the WHO estimates that a public awareness campaign could be implemented at $0.038 per person. One major challenge to physical activity has been urbanization, which has produced mechanized transportation environments that discourage physical activity.¹⁵⁸ However, there are clear interventions for addressing lifestyle and the built environment,¹⁵⁹ and WHO guidelines on physical activity provide a clear way forward.¹⁶⁰ Efforts in Brazil and Colombia to improve physical activity in cities are one example of success in this area,¹⁶¹ although there is substantial room to improve policies promoting healthy diets and physical activity.¹⁶²

Effective interventions are also well known to reduce tobacco use, many of which are provisions of the Framework Convention on Tobacco Control: restrictions on advertising, packaging, marketing to minors, use in public spaces, and taxes.⁸³ Extensive analysis has suggested that these interventions produce robust results, with particularly strong response to taxation in developing countries.¹⁶³ Further, these are highly cost-effective, from $3-$42 for a 33% tax rate on tobacco to $55-$761per DALY in LMICs for nicotine replacement therapy.¹⁶⁴ The WHO’s “best buys” for global health estimate that a package of interventions including taxation, packaging and advertising restrictions, counter-advertising, and use restrictions could be implemented for approximately $0.11 per person.¹³⁷ However, there have been several challenges to ratification and implementation of the Framework Convention.¹⁶⁵ One major challenge has been the push for voluntary, nation-level approaches rather than a coordinated global treaty.^166-170 After passage of the Framework Convention, it has been documented that the tobacco industry has attempted to undermine this treaty by subverting its provisions,^171-173 has pursued lawsuits against signatories that have implemented treaty provisions,¹⁷⁴ and has been noted by the WHO as actively preventing implementation of treaty provisions that aim to keep the tobacco industry out of public health policy-making.¹⁷⁵ Robust and transparent governance is necessary to overcome these challenges.¹⁷⁶

Treatment of ACS and IHD

Approaches to treatment can be divided into two categories: interventions for acute events and interventions for primary and secondary prevention. According to the Disease Control Priorities Project,¹⁷ streptokinase was the most cost-effective reperfusion therapy at cost $634-$734 per DALY. This strategy, however, became more expensive per DALY saved as time to treatment increased. Alteplase and coronary artery bypass surgery were both over $10,000 per DALY. The use of aspirin, beta blockers, and ACE inhibitors was found to be cost-effective, and in some circumstances cost-saving. To date, there remains a dearth of research on the cost-effectiveness of reperfusion therapies in LMICs.¹³⁶ In-hospital use of other evidence-based management, such as anticoagulation, antiplatelet medications, and statins, can be improved with the implementation of systems-level approaches such as reminder, checklists, case management, and educational materials.¹⁷⁷

For primary and secondary prevention, a multidrug regimen consisting of a beta-blocker or calcium channel-blocker, an ACE-inhibitor, aspirin, and a statin was found to be cost-effective.¹⁷⁸ On the basis of the need for a multidrug regimen for pharmacotherapy, efforts have been made at creating a polypill that brings together these various medications and makes adherence simpler.^179-182 A meta-analysis of trials found that, compared to placebo, a polypill did reduce blood pressure and serum lipids.¹⁸³ The polypill strategy is generally thought to be associated with improved adherence related to fewer number of pills to be consumed on a daily basis. However, the data regarding adherence of a cardiovascular polypill are mixed. The meta-analysis concluded that the polypill strategy had lower rates of adherence, with 20% of polypill recipients discontinuing use versus 14% of those on placebo or monotherapy, although the trials included were highly heterogenous.¹⁸³ On the other hand, the more recent UMPIRE study found much higher rates of adherence for those receiving a polypill versus usual care.¹⁸⁴ If the challenges in developing a polypill are overcome, it is possible that this, too, will be a cost-effective and essential tool for prevention.^185,186

Medication access remains a significant challenge in LMICs.^187,188 Data from India indicate that poor patients are less likely to receive evidence-based in-hospital treatments such as revascularization, thrombolytics, and lipid-lowering drugs.¹³⁰ Surveys of medication use suggest low levels of uptake of therapy for primary and secondary prevention of IHD.^119,121 Affordability is an important reason as to why uptake is so low: IHD medication may cost more than an individual’s daily income.^24,136 As these medications must be taken daily for many years, cost is a primary concern in ensuring that the majority of those in need have the ability to access appropriate care. Innovative strategies to optimize the health care workforce to manage IHD and ACS,¹⁸⁹ as well as to improve access to essential medicines,¹³⁴ are required.

Integrated Health Service Delivery, Intersectoral Policy, and Global Coordination

Health care delivery systems in LMICs would benefit from a comprehensive approach that integrates services related to NCDs and communicable diseases such as HIV.¹⁹⁰ Beyond the above-described interventions for specifically ACS and IHD, overall cardiovascular care in LMICs would benefit from strengthening health systems, improving quality of care, optimizing human resources for health, establishing secure supply chains of drugs and technology, and promoting equitable access to care. Instead of vertical, disease-specific programs, a “diagonal” approach in which cardiovascular-related health care delivery is integrated into a comprehensive approach to health systems strengthening will likely yield superior results^191-195. In order to maximize the effectiveness of health sector-specific interventions, they should be implemented in the context of broader population-level policy changes and community-level programs.

Thus, the remaining intervention necessary – perhaps underlying all of the above interventions – is comprehensive intersectoral policy dedicated to NCDs in general.^135,196,197 The roots of IHD risk are not contained solely within the health sector, and the entire spectrum of stakeholders are required to commit to policies and programs that will create the conditions that improve cardiovascular health. This would include, at a minimum, representation from the health, education, infrastructure, transportation, urban planning, trade, and finance sectors. In addition, productive partnerships among government, private sector, and civil society are possible and required.

Finally, although the large global burden of NCDs is well-established, funding from donors does not match this reality. In 2010, although NCDs collectively accounted for 49.8% of DALY burden of disease, they received only 2.3% of development assistance for health.¹⁹⁸ Within the WHO’s own budget, only 12% was allocated to NCDs for the 2006-2007 fiscal year, out of line with disease burden.¹⁹⁹ Analysis of spending by donors broadly, including private philanthropies such as the Gates Foundation, showed a similarly skewed allocation, with HIV/AIDS accounting for the largest portion of health spending, far in excess of its DALY-measured burden compared to NCDs and to other communicable diseases.²⁰⁰ Another study reported spending of $0.78 per DALY for NCDs versus $23.90 per DALY for HIV, TB, and malaria.²⁰¹ While funding for NCDs has increased over the past decade,^198,201 allocation of funding that is more in-line with actual disease burden may aid the achievement of an array of global health goals,. The prospects for improving this balance of funding are challenging and require greater participation among aid recipient countries and alignment of UN institutions around NCD goals.²⁰² At the country level, health insurance and payment systems ideally should ensure equitable access to both in-hospital treatment of ACS as well as long-term outpatient access to medications and rehabilitative services.²⁰³ In addition, public-private partnerships and other innovative financing mechanisms will be required.

Conclusion

Similar to the situation in HICs decades ago, LMICs today are well into a transition toward increasing morbidity and mortality from ACS and IHD. However, there are features that distinguish the patterns of ACS in LMICs from HICs. First, the death toll falls more heavily upon younger, productive ages in LMICs than in HICs, with mortality rates among adults aged 15-49 in some LMICs nearly double that in HICs. Second, the rate of the epidemiologic transition to increased burden from IHD has happened more rapidly in LMICs today than in HICs in the past. In addition, ACS and IHD are not diseases confined to the privileged classes; rather, there is a significant burden that also falls hard upon the lower-income strata in LMICs, who often are unable to afford the costs of medical therapy for primary or secondary prevention of IHD, let alone the expensive treatments for ACS that have helped make acute events more survivable in HICs. Together, these help explain the substantial economic burden that is anticipated from ACS and IHD if no action is taken.

Despite the immense burden, the global community is aided by new knowledge and discoveries made during the past half century. We continue to evolve more efficient and efficacious treatment strategies for ACS, ranging from rapid transport of patients to hospitals via emergency medical systems, to timely reperfusion, through to long-term cardiac rehabilitation, optimal medical therapy and risk factor control. We understand what the underlying risk factors for ACS are and how to prevent them through cardiovascular health promotion activities throughout the life course, appropriate therapeutic strategies, and intersectoral policy. The scientific challenge is primarily in translating this existing knowledge to new settings. In addition, the growing body of ACS literature from LMICs highlights the importance of local, national, and regional registries as important sources of information about current practices and inspiration for improvement and change.^115,204

The critical task is implementation: the tools that we have need to be materialized. This involves engaging in health promotion activities in early childhood, ensuring access to essential medicines to treat and prevent ACS, developing resource- and context-specific clinical guidelines, implementing laws and regulations to protect the public’s health from harmful products, planning the growth of cities to promote healthy behavior, and support from donor countries and international organizations to match the scale of the global burden of ACS, IHD, and other NCDs. We are well-equipped to confront this challenge so long as our will meets it.

Abbreviations and Acronyms

ACE

angiotensin-converting enzyme

ACS

acute coronary syndrome

DALY

disability-adjusted life year

HICs

high-income countries

IHD

ischemic heart disease

LMICs

low- and middle-income countries

NCDs

non-communicable diseases

WHO

World Health Organization