Coronary artery disease epidemics: not all the same






Christopher Michael REID
MSc, PhD, FCSANZ, FESC
Alice Jane OWEN,PhD
Monash Centre for Cardiovascular Research and Education in Therapeutics
School of Public Health and Preventive Medicine
Monash University
Melbourne, AUSTRALIA
Ben FREEDMAN,OAM,
MBBS, PhD, FRACP, FESC, FACC, FCSANZ
Department of Cardiology
Concord Hospital
Sydney Medical School
University of Sydney
Sydney, AUSTRALIA

Coronary artery disease epidemics: not all the same


by C. M. Reid, A. J. Owen, and
B. Freedman,
Australia



Rapid economic development in low- and middle-income developing economies combined with global aging are 2 major contributors to a potential second-wave epidemic, which will ensure that cardiovascular disease (CVD) remains the number one cause of death and disability around the globe over the foreseeable future. Much has been learned in the second half of the 20th century on underlying risk factors and strategies for cardiovascular disease prevention that may assist countries in Asia, Africa, the Middle East, and Eastern Europe in developing their own effective prevention and management strategies, although a great deal of the problem is economic and related to relative poverty. The reduction seen in CVD death rates in many Western high-income economies over the past decades demonstrates that with effective implementation, much can be done to reduce the individual and community burden. However, major challenges remain in terms of supporting and maintaining a population-based approach by promoting lifestyle-related strategies through public policy and community development, while at the same time effectively allocating limited health care resources to access modern advances in cardiovascular treatments and management at the individual level. Furthermore, there may well be differences in the background risk and presentation of coronary artery disease in this second-wave epidemic due to the accelerated changes in lifestyle and economic development associated with this epidemiological transition occurring in many parts of the world previously having limited exposure to lifestyle-related chronic disease.

Medicographia. 2014;36:11-18 (see French abstract on page 18)



Coronary artery disease (CAD) has been consistently ranked as the number one cause of death and disability in most Western industrialized countries since the mid-1950s. Since reaching a peak in the 1960s and early 1970s, CAD rates have declined considerably, yet CAD remains a major cause of much of the disease burden in these countries. In addition, we are now seeing a second wave epidemic in low-to-middle–income countries where previously communicable disease was the primary cause of mortality in the community. This article will examine the underlying features of these CAD epidemics and identify the major issues that need to be addressed across the globe in order to reduce the impact, from the individual, community, and societal perspectives.

A world in rapid transition

There are striking differences in the prevalence of CAD, as different regions of the world face different stages of the epidemic. The epidemiologic transition model for cardiovascular diseases (CVDs) (Table I)1 describes a series of stages starting from a population profile with a low life expectancy and CVD arising mostly from infectious disease and malnutrition, a pattern commonly seen in low-income/less-developed countries. As economic and public health development improves population nutrition and reduces infectious disease, life expectancy increases and both the pattern and rates of CVD change. In stage 4, commonly seen in high-income countries, life expectancy increases and degenerative CVDs in older age predominate. The varying incidence, prevalence, and mortality rates reflect the different levels of risk factors, other competing causes of death, and availability of resources to combat CVD.


Table I
Table I. Epidemiologic transition for cardiovascular disease.

Abbreviation: CVD, cardiovascular disease.
Modified from reference 1: Yusuf et al. Circulation. 2001;104(22):
2746-2753. © 2001, American Heart Association, Inc.



Historically, the transition from stage 1 through to stage 4 has taken hundreds to thousands of years, but the 20th century has seen an unprecedented rate of development in historically low-income developing countries. Economic globalization has been a fueling factor and the economic development of many low-income developing nations has resulted in a rapid rise in CAD burden due to socioeconomic changes, increase in lifespan, and acquisition of life style related coronary heart disease risk factors.

♦ Global aging
Despite a perception that population aging is an issue only for high-income, well-developed countries, the majority of the world’s population over the age of 60 live in developing nations (Figure 1).2 Between 2000 and 2050, the proportion of the world’s population aged over 60 years will double from around 11% to 22%. The absolute number of people aged 60 years and over is expected to increase from 605 million to 2 billion over the same period. The rate of increase in developing countries is unprecedented. For example, it took more than 100 years for the share of France’s population aged 65 or older to double from 7% to 14%. In contrast, it will take countries like Brazil and China less than 25 years to reach the same growth. Given the increasing risk of CVD with increasing age, even in poor countries, most older people die of diseases such as heart disease, cancer, and diabetes rather than from infectious and parasitic diseases. In addition, older people often have several health problems at the same time, such as diabetes and heart disease.

First-wave cardiovascular epidemic

Following the end of the Second World War in 1945, CAD was relatively stable in the United States, with the age-adjusted death rates accounting for 439 deaths per 100 000 people. This figure remained relatively stable until the 1950s when disease rates began to rise and peaked in 1969 at a rate of 470 deaths/100 000 in the population.3 Approximately 58% of all deaths in the United States in 1968 were of cardiovascular cause, with 37% being due to CAD. Rates of this magnitude were observed in other Western industrialized countries such as Finland, Australia, and the United Kingdom. A number of cross-sectional epidemiological cohort and longitudinal studies identified key clinical and lifestyle-related risk factors such as cigarette smoking, blood cholesterol levels, age, and blood pressure (BP) to be major drivers of risk4-6 and further research continued to improve our understanding of the social determinants of CAD risk.7-10


Figure 1
Figure 1. The changing structure of the world’s population.

The world’s population in aging and, in developed countries, the size of the elderly population has
already surpassed that of the 12-24–year age group.
After reference 2: Rosenberg et al. Global demographic trends. Finance Dev. 2006;43(3).
http://www/imf.org/external/pubs/ft/fandd/2006/09/picture.htm. © 2013, International Monetary
Fund. All rights reserved.



♦ Landmark studies of cardiovascular risk
The Framingham Heart Study, commencing in the 1950s has been one of the key observational studies that has enabled a better understanding of the underlying factors associated with increasing risk of CVD.11 Another important early study of CAD risk factors was the Seven Countries Study, which provided insight into the importance of plasma cholesterol on CAD risk and the influence of cultural and lifestyle factors.12 Studies such as Framingham and the Seven Countries Study provided the impetus for development of the World Health Organization (WHO) MONICA (Multinational MONItoring of trends and determinants in CArdiovascular disease) Project, which made an important contribution to international standardization of cardiovascular mortality, morbidity, and risk-factor measurement.13 Coronary disease in individuals and in populations is significantly related to levels of BP, blood lipoproteins, cigarette smoking, age, family history, diabetes mellitus, obesity, and physical inactivity.14





♦ Strategies for prevention
Understanding the underlying risk factors for CAD paved the way for the development of strategies for disease prevention, which could broadly be divided into 2 approaches: (i) a high risk approach involving identification of those most at risk through medical assessment and risk-factor screening and (ii) a population strategy to encourage shifts in the level of risk factors in the population at large.15 Three key factors emphasized the need for a population-based approach to CAD prevention. Firstly, in two-thirds of cases during this epidemic, the initial manifestation of coronary disease was sudden death and acute myocardial infarction (MI), and over half of all heart attack deaths occurred before the victims reached hospital.16 Although some individuals are in a position to benefit from the advances in emergency hospital care and antithrombotic and antiarrhythmic therapy, the high proportion in whom the catastrophic cardiovascular event occurs without prior warning highlights the importance of population risk-factor reduction as a prevention strategy for sudden cardiac death or MI. This population-based approach is critical both for primary and secondary prevention of CAD. Half of the coronary deaths and MIs will occur in people with known CAD, underscoring the parallel importance of secondary prevention to reduce premature death and MI.


Figure 2
Figure 2. Changing rates of coronary heart disease in the United
States (1950-2008).

Based on data from reference 3: National Heart, Lung, and Blood Institute.
Morbidity and mortality: 2012 Chart Book on Cardiovascular, Lung, and Blood
Diseases. Washington DC: National Institutes of Health; 2012.



Premature mortality attributed to CAD imposes a high social and economic burden on society, and there is evidence to suggest that environmental, social, and behavioral determinants may be a greater contributor to risk than genetic risk factors.17 This has been well demonstrated in studies of migrant populations who tend to adopt the dietary and lifestyle patterns of their new home and also demonstrate the increased risk factors and mortality rates of their new homeland.18,19

♦Turning the tide
The continued monitoring and reporting of CAD mortality has demonstrated the remarkable effect of disease prevention strategies over the past 30 years on these initial high rates. Figure 2 illustrates the percentage change in age-adjusted mortality rates from 1950 to 2008 in the United States.3 The 70% reduction now puts the annual rate at 80 deaths per 100 000 people. This dramatic change and reduction has been seen in a number of countries around the world who were a part of the first CVD epidemic, including Australia, Finland, England, and New Zealand.

While the administrative morbidity and mortality statistics provide the key information on outcomes, they do not provide information on the factors underlying these changes observed over time. Clearly, advances in medical care, including the introduction of mobile intensive care ambulances, the widespread use of lipid-lowering and BP-lowering drugs, the introduction of medical devices, including drug-eluting and bare-metal intracoronary stents, as well as surgical procedures have undoubtedly had a major impact.20 Public health policy in Australia has led the world in relation to cigarette smoking, and has had a major impact as community-wide smoking rates have declined over the past decades in most age groups.21

These health-promotion and health system–wide changes have most likely contributed to the shift in the prevalence of the well-known risk factors for incident cardiovascular events— smoking, BP, and elevated cholesterol. For example, gains made in reducing the burden of CAD in developed countries are well illustrated by the North Karelia Project.22 Rates of heart disease mortality in Finland in the late 1960s were among the highest in the world.22 In 1972, a community-based preventive health program was implemented in the North Karelia region aiming to reduce risk factors for CAD. Over the next 35 years, total cholesterol was reduced by 1.5 mmol/L, diastolic BP was reduced by 8.7 mm Hg, and smoking prevalence was reduced by 15 percentage points. These changes were accompanied by an 80% reduction in CAD mortality in middle-aged men, and it was estimated that three-quarters of the risk reduction could be attributed to improvements in these key risk factors.23 The halving of CVD seen in a number of developed/high-income countries over the past 3 decades has been accompanied by significant developments in pharmaceuticals, clinical guidelines, devices, and surgical intervention for secondary prevention of CAD. However, 50%-75% of the fall in CAD mortality is attributed to population-wide improvements in major risk factors such as smoking, BP, and cholesterol (largely primary prevention), while secondary prevention strategies (including aspirin, thrombolysis, angiotensin-converting enzyme [ACE] inhibitors, statins, coronary artery bypass surgery) explain the remaining 25%-50% of the reduction in mortality.24

Second-wave epidemic

Eastern Europe, Africa, the Middle East, and Asia are the key focal points for the second wave of the CVD epidemic sweeping across the globe (Figure 3).25 From a positive perspective, much of what has been learned from the first-wave epidemic in regard to the underlying risk factors and population strategies for prevention may well be adapted to suit local countries. However, in many developing low-income countries, information systems are lacking on the prevalence and treatment of cardiovascular risk factors in the community. The WHO has developed a risk assessment program (STEPS [STEP wise approach to Surveillance]) that has been adapted and modified to local conditions in order to gain information on the current state of CVD risk factors in these regions.26,27 Mortality statistics and cause of death in particular are also more difficult to quantify in most developing countries, particularly in rural and remote areas around the Asian region. What we can be sure about, however, is that CVD is currently and will continue to be the major cause of death and illness in these developing countries for the foreseeable future.


Figure 3
Figure 3. Second-wave cardiovascular disease epidemic regions across the globe.

After reference 25: World health rankings. World Life Expectancy website.
http://www.worldlifeexpectancy.com/world-health-rankings.



♦ Are all epidemics the same?
The data collected from developing countries support the role of those key underlying risk factors identified during the first wave of the CAD epidemic, and suggest that they remain important targets for prevention in developing countries.27-30 International CVD procedural and management registries are also providing important information on the characteristics of patients presenting for CVD management in developing countries.31 The REACH Registry (REduction of Atherothrombosis for Continued Health) was an observational prospective cohort study of over 67 000 patients from 44 countries around the world, including many economically developing countries in Asia, the Middle East, and Eastern Europe. These data highlighted that across all countries, classic cardiovascular risk factors are consistent and common in patients with coronary disease and are largely undertreated and uncontrolled.31 Most importantly, one-year cardiovascular event rates were highest in Eastern Europe, the Middle East, and Asian countries (with the exception of Japan) with the cardiovascular death rate being almost double that observed in Australia.32 The difference in one-year rates may be related to differences in medical management and risk-factor profiles across the regions. The extent and prevalence of diabetes as a comorbidity in addition to smoking, hypertension, and hyperlipidemia may be of particular relevance to populations facing increasing rates of CVDs. In studies on Malays, Indians, and Chinese undergoing percutaneous coronary intervention in Singapore, diabetes rates were 44%, 48%, and 33%, respectively. This is considerably different to the 24% rate observed in an Australian cohort of patients undergoing similar procedures.33 More importantly, strong ethnic differences in MI event, case-fatality, and coronary mortality rates have been observed among the 3 ethnic groups in Singapore. While Indians had the greatest MI event rates, Malays had the highest case-fatality rates.34 Compared with the Chinese, MI event rates were >2 and >3 times higher, and age-standardized coronary mortality rates were 2.4 and 3.0 times higher for Malays and Indians, respectively. Malays had the highest 3.1-year case-fatality rates, with an adjusted hazard ratio of 1.26 (95% confidence interval, 1.14 to 1.38) compared with the Chinese.34

It is possible that some genetic factors may predispose or protect against acute CAD events. Previous studies have reported that Indians present a varied cardiovascular risk profile, characterized by a high prevalence of insulin resistance, glucose intolerance, central obesity, and diabetes, along with other CAD risk indicators, including the plasminogen activator inhibitor-1, homocysteine, and lipoprotein(a).35 Evidence that this risk pattern is related to genetically determined ethnic factors and that it is directly responsible for the higher risk of CAD events in this ethnic group is lacking. Although it is very likely that ethnic variations in the incidence and, possibly, clinical outcome of acute CAD events exist, the causes for such differences are many and difficult to address fully, given the complex interplay of contributing factors, and at least in the INTERHEART (not an acronym) study, the risk factors associated with MI differed little between many different ethnic groupings and explained most of the variance in MI rate.30,35

CAD prevention strategies

At a population level, the key risk factors for CAD are those shared by most noncommunicable diseases; namely, tobacco use, an unhealthy diet, physical inactivity, and harmful alcohol consumption. For effective CAD prevention, not only are long-term strategies for prevention and reduction of risk factors required, but also ongoing surveillance and monitoring, and provision of early detection and treatment in primary care settings. In many developing/low-to-middle–income countries, hospital-based care dominates national health budgets and a large proportion of people with high cardiovascular risk remain undiagnosed, or may have insufficient access to effective preventive treatment at the primary care level.

Key priorities include provision of the following in primary care/ low-resource health settings: cardiovascular risk assessment and management for prevention of CAD, diabetes management to prevent secondary complications, smoking cessation programs, and equitable access to essential preventive medicines (aspirin, antihypertensive and lipid-lowering drugs, insulin). Similar approaches are also required in secondary prevention. This needs to be supported by public health, regulatory, and educational frameworks to promote reduced tobacco smoking, consumption of a healthy diet, reduced alcohol consumption, and reduced sedentary behavior.

In modeling undertaken to look at the potential impact of key CAD prevention strategies in a high-income–country setting (eg, US population), smoking cessation was the most cost effective intervention for reducing the burden of CAD and was the only strategy for which the savings achieved through reductions in cardiovascular events offset the costs of implementation.36 WHO recommendations for addressing tobacco use include development of national infrastructure for tobacco control (government units, either stand-alone or within health ministries) that is protected from commercial or other vested interests of the tobacco industry; price and tax measures to reduce tobacco consumption; protection from tobacco smoke in enclosed spaces; packaging and labeling of tobacco products; bans on tobacco advertising and sponsorship; educational public health campaigns; and accessible smoking cessation programs.

At a population level, regulatory and educational campaigns to reduce dietary salt and trans-fat intake and price and tax measures to reduce alcohol consumption have also been put forward as strategies to combat CAD risk factors. Elimination/ reduction of industrially produced trans-fats in the US food supply (by use of alternatives to partially hydrogenated oils in cooking), is thought to have the potential to reduce MI and CAD mortality by more than 6%.37

Obesity and physical inactivity are closely related, and are associated with increased risk of developing hypertension, dyslipidemia, and insulin resistance. Interestingly, the CAD risk of those with a high body mass index (BMI) who are physically active/fit appears to be equal to, if not lower than, those with a normal BMI who are physically inactive/unfit,38 suggesting that physical inactivity (and its cardiometabolic sequelae) is a significant contributor to risk. Data from the US Aerobics Center Longitudinal Study suggested that in overweight or obese men, the risk increase for cardiovascular mortality associated with low fitness was of a similar magnitude to the risks imposed by hypertension or high cholesterol levels.39 However, compliance with physical activity prescriptions or recommendations is generally very poor: for every 17 sedentary adults referred by a doctor to a formalized exercise scheme, only 1 would be likely to become moderately active.40 The relatively higher compliance rates and lower costs of BP- and lipid-lowering medications make them an important strategy for risk reduction.

However, the long-term use of recommended preventive cardiovascular drug therapy is inadequate among people at high risk of CVD and this is particularly the case in low- and middle income countries.41 Treatment and adherence gaps are also described in relatively wealthy Organization for Economic Cooperation and Development (OECD) countries with highly developed health care infrastructure and resources.42 In Australia, recent audits of primary health care practices have indicated that combination prescription rates of guideline-indicated BP-lowering drugs, statins, and antiplatelets are as low as 50%43,44 and poor compliance results in lower overall use of these drugs.45

The reasons for low levels of long-term use of preventive medications are multiple and complex.46 Barriers to doctors adopting guideline recommendations can include lack of time, a confusing multiplicity of guidelines, lack of awareness of guidelines, and insufficient resources to implement the recommendations.47-51 Low levels of use of prescribed medications can be associated with taking multiple medicines with complex dosing regimens, inadequate knowledge about such medications, and psychosocial issues.52-54 Patients may also adopt strategies to reduce costs, including not filling prescriptions and delaying or omitting doses.55,56

A strategy based on the use of fixed-dose combination therapy (cardiovascular “polypills”) with generic drug components may help reduce these treatment gaps by reducing cost and complexity of drug regimens and by therapeutic inertia. This may well be a key target for prevention, as Yusuf hypothesized that a polypill combination (aspirin, a β-blocker, a statin, and an ACE inhibitor) could reduce CVD events by 75% in those with vascular disease. Similarly, Wald and Law have proposed that a polypill containing 3 BP-lowering drugs from different classes—aspirin, a statin, and folic acid, each at half doses— for all individuals with established CVD and all those older than 55 years without CVD would safely reduce ischemic heart disease events by 88% and strokes by 80%.57,58

Studies are currently under way around the world in low-income developing countries and high-income countries to test whether this approach will have a significant impact on the second wave of the CVD epidemic across the globe.

Future challenges

Some projections have suggested that gains in reducing the burden of CAD and increasing life expectancy in developed countries over the past few decades may begin to be reversed by the increasing prevalence of obesity and diabetes brought about by unhealthy diets and increasingly sedentary lifestyles.59 As changes to work and technology continue to reduce incidental or occupational physical activity, development of public health strategies to combat physical inactivity presents a major challenge.

CAD also disproportionately affects those in lower socioeconomic groups. A vicious cycle can be created whereby poverty exposes people to behavioral risk factors for CAD, and the onset of disabling or fatal CAD in primary breadwinners can lead families into further poverty. Ensuring timely and affordable access to effective primary prevention remains a challenge in many countries around the globe.


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Keywords: aging; cardiovascular epidemic; coronary artery disease; economic development; lifestyle; population risk-factor reduction; prevention strategies