Executive Summary

Over the last century, life expectancy at birth has, for most populations, increased by more than 25 years. The epidemiologic transition, described more than 20 years ago, is key to understanding this global improvement in health and planning for future improvements (Omran, 1971). The transition recognizes, primarily because of the aging population worldwide, that the spectrum of disease in developing countries is changing from one of communicable diseases and perinatal and nutritional disorders to one of predominantly noncommunicable disease, most notably cardiovascular disease (CVD). This is the term used by the scientific community to embrace not just conditions of the heart (coronary artery disease; valvular, muscular, and congenital disease), but also hypertension and conditions involving the cerebral, carotid, and peripheral circulation. This report addresses the research needed to improve understanding of the scope of this challenge, the various risk factors involved, and ways of preventing and treating these diseases that will be both feasible and affordable for the developing world.

CVD has been identified as the primary noncommunicable health problem throughout the developing world. This is so for a number of reasons. The contribution of CVD to the burden of disease is increasing, all socioeconomic groups are vulnerable, and CVD inflicts major economic and human costs. Of the 52 million deaths reported worldwide in 1990, 15 million are attributable to CVD. CVD accounts for almost 10 percent of the global burden of disease measured by a combination of death and disability, and this is expected to increase to nearly 15 percent by the year 2020. By the mid-1990s, CVD most likely became the developing world's leading cause of death. It is not surprising, therefore, that a recent report of the Ad Hoc Committee on Health and Research refers to CVD as an ''emerging epidemic" (Ad Hoc Committee, 1996). On a global scale, the two principal forms of CVD are ischemic heart disease and cerebrovascular dis-



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Executive Summary Over the last century, life expectancy at birth has, for most populations, increased by more than 25 years. The epidemiologic transition, described more than 20 years ago, is key to understanding this global improvement in health and planning for future improvements (Omran, 1971). The transition recognizes, primarily because of the aging population worldwide, that the spectrum of disease in developing countries is changing from one of communicable diseases and perinatal and nutritional disorders to one of predominantly noncommunicable disease, most notably cardiovascular disease (CVD). This is the term used by the scientific community to embrace not just conditions of the heart (coronary artery disease; valvular, muscular, and congenital disease), but also hypertension and conditions involving the cerebral, carotid, and peripheral circulation. This report addresses the research needed to improve understanding of the scope of this challenge, the various risk factors involved, and ways of preventing and treating these diseases that will be both feasible and affordable for the developing world. CVD has been identified as the primary noncommunicable health problem throughout the developing world. This is so for a number of reasons. The contribution of CVD to the burden of disease is increasing, all socioeconomic groups are vulnerable, and CVD inflicts major economic and human costs. Of the 52 million deaths reported worldwide in 1990, 15 million are attributable to CVD. CVD accounts for almost 10 percent of the global burden of disease measured by a combination of death and disability, and this is expected to increase to nearly 15 percent by the year 2020. By the mid-1990s, CVD most likely became the developing world's leading cause of death. It is not surprising, therefore, that a recent report of the Ad Hoc Committee on Health and Research refers to CVD as an ''emerging epidemic" (Ad Hoc Committee, 1996). On a global scale, the two principal forms of CVD are ischemic heart disease and cerebrovascular dis-

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ease (stroke), which together account for two-thirds of the CVD burden; the projected increase in total CVD burden is largely attributable to these conditions. Data on the economic cost of CVD in developing countries are limited, but in the United States, the direct and indirect costs of CVD are already 3 percent of the gross national product. In developing countries, CVD is more likely to attack adults in their productive middle years than it is in developed countries. This has a profound and adverse impact on households, families, and society. What explanation can be offered for the global epidemic of CVD and the expectation that it will worsen in the future? The world population is expanding by 80 million people per year. Because of declining mortality and fertility rates, this increase is most notable among the middle- and older-age groups that are likely to develop CVD. Economic development has brought higher incomes that are allowing the adoption of a Western life-style, which may include a diet high in fat, sugar, and salt; increased tobacco use; and less physical activity. These behavioral changes have been accelerated by rapid migration of large populations to the major cities of developing countries. Interactions among risk factors can increase the incidence of CVD. The impact of adopting a Western life-style can be severe when more than one behavior change predisposes to CVD. Given the enormous potential for applying research and technological advances to prevention and treatment of CVD, there is hope that the epidemic can be controlled. The following observations suggest that premature death can be avoided and the quality of life improved in middle and later years: dramatic declines in CVD mortality in Western countries; geographic variations in CVD mortality; and established associations of adult mortality with modifiable risk factors, such as tobacco use and obesity. Reducing the prevalence of CVD risk factors has been shown to decrease mortality and disability in middle-aged and older persons and to lead to a better quality of life. Risk factor prevention programs and low-cost case management are feasible, cost-effective ways of reducing CVD mortality and disability. In most developing countries, however, implementation of these approaches and programs is hampered by the lack of awareness of cost-effective CVD control options and the concern that investment in CVD will detract from efforts to control communicable diseases and improve perinatal and nutritional disorders. It is important, therefore, to develop a dialogue based on informed understanding of the growing threat that CVD poses to developing countries and of the need for research and development (R&D) to provide effective, affordable, and widely applicable responses to this threat.

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This Institute of Medicine (IOM) report provides a basis for the dialogue. It offers recommendations on opportunities and priorities for R&D to reduce the CVD burden in developing countries, as well as the institutional arrangements needed to achieve these goals. The IOM committee approached its assessment of the scope of the problem by following the five-step sequence proposed in the Ad Hoc Committee's report: (1) determine the size of the CVD burden, (2) identify the reasons for the CVD burden, (3) evaluate the adequacy of the current knowledge base, (4) evaluate the promise of R&D efforts, and (5) assess the adequacy of the current level of effort. This rationale is described further in Appendix A. RECOMMENDATIONS The committee used the following four criteria to establish priorities for R&D investment to control CVD in developing countries: Investments should have a large-scale impact on populations, regardless of gender, socioeconomic status, or geographic location. Incremental implementation of investments may be necessary in many countries. Investments in one country should involve methods and processes (but not necessarily results) that are broadly transferable to other low- and middle-income countries. Investments should yield results within a time frame of 5 to 10 years, although evaluation of the results over a longer term may be desirable. Investments should focus on measurable data with collection that follows established methodologies in epidemiology, health policy, economics, and social behavior. Using these criteria, the committee prepared recommendations for R&D investment in six broad areas for the control of CVD: Determine the magnitude of the CVD burden in developing countries. Develop targeted, effective primordial and primary prevention strategies using case-control studies. Reduce tobacco use. Detect and treat high blood pressure. Initiate pilot studies to evaluate essential vascular packages of effective, low-cost drugs. Develop and assess algorithms of affordable clinical care for CVD. To support the first six recommendations, the committee then recognized broader needs with two additional recommendations: Build the capacity to conduct R&D activities.

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Develop institutional mechanisms that facilitate CVD prevention and control. Determine the Magnitude of the CVD Burden in Developing Countries Recommendation 1. Create standardized surveys using networks such as the MONICA (World Health Organization Multinational Monitoring of Trends and Determinants in Cardiovascular Disease) model (including selected sentinel sites) to monitor levels and trends of clinical events and cardiovascular risk factors. The major goal of these surveys is to describe the prevalence and distribution of clinical events and of conventional risk factors associated with CVD by age, sex, and ethnicity in representative samples of the population. Thus, the surveys should involve moderately large sample sizes (several tens of thousands or hundreds of thousands of people) and simple, focused data collection activities. Like vital registration, cross-sectional surveys of this type require a valid sampling frame. Ideally, data from local cross-sectional studies should be linked to local estimates of the magnitude of various risk factors, which would be drawn from case-control or prospective studies. Survey data could also be linked to local mortality data. The recommended surveys should be repeated at regular intervals to assess trends in the levels and distribution of CVD risk factors. If the surveys are appropriately designed to allow repeated observations of many individuals and to take successive independent samples, they can also be used to quantify the strength of association between a CVD risk factor with eventual development of disease. However, patient follow-up in many developing country populations is difficult because of a lack of vital registration systems, high population mobility, and variable access to medical care. Thus, it may be easier in such populations to classify mortality status rather than attempt to record nonfatal events associated with CVD. Recommendation 2. Expand national and regional systems for vital registration. There are several ways to obtain essential vital registration information. The essential information is a record of all deaths in the population, classified by age and sex. Priority assistance should be given to countries that currently lack a system to obtain this basic information. Appropriate sampling frames should be built into each system to allow identification of geographic, ethnic, and rural and urban differences in CVD mortality and morbidity.

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In developing countries, most vital registries are government funded and lack a research component. Where registration systems are currently inadequate improved systems must be developed. One possibility is the capture—recapture method for deriving better estimates of total deaths. Recommendation 3. Improve the accuracy and completeness of cause-of-death statistics. Cause-of-death studies, which provide information on the underlying reasons for death, currently exist only in developed countries and, to a lesser extent, in Latin America. Determination of cause-specific mortality in most developing countries could be strengthened through the use of community-based random samples, sentinel sites, surveillance systems modeled after those used in the MONICA model, and verbal autopsy techniques (i.e., techniques that involve questioning relatives in person or by phone about the circumstances surrounding a death, especially for CVD-related deaths). Thus, priority areas for research support are establishing and evaluating sentinel registration sites, and validating and using verbal autopsy techniques. Recommendation 4. Develop better estimates of disability. Most developing countries lack reliable estimates of the level of disability caused by CVD or other diseases. Further, the estimates that are available are not standardized across populations. Focused pilot studies could generate appropriate estimates with standard, validated measures of quality-of-life. Develop Targeted, Effective Primordial and Primary Prevention Strategies Using Case-Control Studies Recommendation 5. Determine the contributions to morbidity and mortality of established and new risk factors for CVD, and assess their interactions with case-control studies. Case-control studies of disease incidence can identify the strength of association between a risk factor and CVD. They may also uncover new risk factors. Although prospective studies are more robust methodologically because exposure to the risk factor demonstrably precedes disease, retrospective case-control studies can usually generate needed data more quickly and at lower cost. Ideally, the occurrence of first myocardial infarctions should be studied to avoid survival bias and postmorbid modification of risk factors. Key conditions that might be studied using case-control methods include acute myocardial infarction, acute stroke, transient ischemic attacks, congestive heart failure, and peripheral vascular disease. Estab-

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lished risk factors for CVD include hypertension, tobacco use, dietary intakes high in fat, salt, and sugar, and inadequate exercise. Reduce Tobacco Use Recommendation 6. Research on tobacco control in developing countries should (1) estimate the prevalence of regular tobacco use in population samples; (2) monitor tobacco consumption trends in vulnerable groups such as children, adolescents, and women; (3) evaluate the cost-effectiveness of community-based interventions that promote abstinence from tobacco; (4) evaluate the cost-effectiveness of tobacco cessation programs aimed at changing the behavior of current smokers; and (5) estimate the economic impact of tobacco control on developing countries that grow and manufacture tobacco or tobacco products for domestic or foreign markets in order to encourage the change to alternative crops and manufacturing. Current levels of risk factors, most notably tobacco usage, will determine future age-specific mortality and morbidity rates. The numbers of global deaths and of disability-adjusted life years (DALYs) that result from tobacco use are expected to increase to about 8.3 million and 124 million, respectively, by 2020, with more than 70 percent of these occurring in developing countries. These trends amount to a doubling of the percentage of current deaths due to tobacco use worldwide and a tripling of current DALYs lost. Thus, decreasing tobacco use would reduce both the substantial burden of CVD-associated disease projected for developing countries and the significant burden of other tobacco-related diseases, including certain cancers and chronic obstructive pulmonary disease. Detect and Treat High Blood Pressure Recommendation 7. Research on the control of hypertension in developing country populations should be undertaken to (1) estimate the distribution of high blood pressure and the prevalence of hypertension in populations; (2) evaluate the cost-effectiveness of community-based, life-style-linked interventions (salt intake, increase exercise, improve stress management) aimed at decreasing the incidence of high blood pressure; (3) assess the cost-effectiveness of programs to detect and treat hypertension by improving awareness, treatment initiation and adherence, and level of control; and (4) evaluate the effectiveness of low-cost combination drug therapies developed by countries such as China.

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High blood pressure is a major contributor to both coronary heart disease and stroke. Even small decreases in the incidence of high blood pressure could have a profound effect on lowering CVD rates. Hypertension control programs are an ideal first step for CVD prevention and control for a number of reasons: (1) hypertension is a risk factor for both coronary heart disease and stroke; (2) such programs have a "clinical" appeal to both care providers and the community; (3) the results are easily measurable; (4) the impact on hypertension awareness, treatment status, and level of control can be measured in a relatively short time (i.e., five years); (5) such programs create a natural coalition among various categories of health care providers (nurses, multipurpose health workers, general practitioners, internists, cardiologists, nephrologists, neurologists, obstetricians, ophthalmologists, nutritionists, stress therapists, and exercise program managers) who play an important role in the detection or management of hypertension and its sequelae; and (6) the concept of "comprehensive cardiovascular reduction" as part of hypertension management makes it possible to incorporate strategies aimed at modifying other CVD risk factors, such as tobacco use, high blood lipid levels, diabetes, and obesity. Initiate Pilot Studies to Evaluate Essential Vascular Packages of Effective, Low-Cost Drugs Recommendation 8. Evaluate the responses of different ethnic populations to cardiovascular drugs and interventions, and determine whether any different responses have implications for drug treatment. Recommendation 9. Expand the participation of developing country research institutions in multicenter, collaborative clinical trials of essential vascular packages (EVPs) and other affordable, widely applicable interventions. Evidence from randomized trials indicates that several of the clinical treatments now available can provide cost-effective care for patients with established CVD. Aspirin, beta-blockers, angiotensin-converting enzyme inhibitors, and cholesterol-lowering statin drugs reduce the probability of death and subsequent nonfatal major vascular events in patients with established ischemic heart disease. However, to have a sustained impact in developing countries, these drugs will have to be inexpensive and widely accessible. Although cholesterol-lowering drugs such as statins are currently expensive compared to aspirin or beta-blockers, their costs may decrease in the next five years when their patents expire. These drugs could then become key components of an EVP, or combination of drugs, that would be used to treat patients with CVD. The committee believes strongly that large numbers of people in developing countries could

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benefit from such an EVP. Because its delivery would rely on patients presenting themselves for treatment and would not involve screening costs, the EVP could be highly cost-effective. Packaging EVPs into single, once-a-day formulations, as is done for multidrug treatment of tuberculosis, could substantially improve compliance. The goals for the EVP should be (1) to use low-cost, generic versions of drugs; (2) to achieve near-universal access to these proven interventions; and (3) to price the packages so they are affordable for developing country clinics and patients. The acceptability, use, and effectiveness of the EVP will have to be assessed, along with other parameters that measure diffusion into practice (discussed under Recommendation 10). Such testing could be in the form of randomized trials assessing delivery of the package versus standard clinical care. If acceptable, the EVP should then be included both in a publicly financed, universally available essential package of clinical services and in treatment lists covered by health insurance. Efforts to educate physicians and to increase patient awareness about the value of such packages should also be supported. Goals (2) and (3) could be addressed by pricing the reimbursements for treatment to the lowest-cost basis of the EVP. Develop and Assess Algorithms of Affordable Clinical Care for CVD Recommendation 10. Research should be undertaken to develop algorithms for affordable diagnosis and management of hypertension, dyslipidemia, diabetes, acute myocardial infarction, angina, stroke, transient ischemic attacks, congestive heart failure, peripheral vascular disease, post-myocardial infarction rehabilitation and risk management, and poststroke rehabilitation and risk management. The development of algorithms for CVD care could improve the awareness and utilization of effective treatments. To be maximally effective, the algorithms should be adapted to address different cultural needs and should be widely applicable and usable by both physicians and nonphysicians and for different levels of care. Each algorithm should define clinical diagnostic or presumptive criteria, along with the steps for administering and evaluating simple medical treatments. The acceptability and use of each algorithm should be measured, appropriate marketing developed for both the public and private sectors, and cooperation obtained from the pharmaceutical industry. The algorithms should be developed and implemented according to local needs and cultural norms. Further, the results of using an algorithm for CVD care should be monitored and the impact on disease outcome evaluated.

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Build the Capacity to Conduct R&D Activities Recommendation 11. Building regional capacity for R&D requires establishing or expanding: (1) training programs in cardiovascular epidemiology, clinical research methodology, health policy research, and health economics; (2) institutional capacity for undertaking integrated research relevant to CVD control; and (3) collaboration through twin-center programs and regional research networks. The capacity to conduct research at regional and local levels must be strengthened before efforts to control CVD can be effective in developing countries. Therefore, the level and intensity of training in public health and preventive medicine have to be substantially increased throughout the developing world, not just for highly educated health professionals but, more important, for health workers at all levels. Only a small fraction of the necessary training capacity can be achieved through existing programs and methods; further, even the current capacity cannot be maintained without vigorous continuing education programs. For the recommendations in this report to be implemented productively in developing countries, a major international commitment must be made for the development of training programs and the use of current technologies. These are needed to improve the effectiveness of efforts and investments in CVD control. Develop Institutional Mechanisms for Facilitating CVD Prevention and Control Recommendation 12. The committee recommends establishing a Steering Committee for CVD R&D under the aegis of the Global Forum for Health Research. The functions of this committee would include, but not be limited to, the following: (1) establishing a program of competitive grant awards in priority areas of CVD research, modeled after the United Nations Development Programme—World Bank—World Health Organization Special Programme for Research and Training in Tropical Diseases; (2) establishing a global network on CVD health policy; and (3) promoting exchanges of CVD scientists from industry, academia, and the ministries of developing and developed countries. It has become increasingly important to consider the organizational arrangements that will facilitate CVD prevention and control around the world. The ultimate goal is to establish an R&D capability that will be effective and sustainable. The committee's recommendation for creating a Steering Committee for Cardiovascular R&D stresses flexibility in priority setting, competitive grant

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making, and global networking and partnering. These characteristics are hallmarks of the Special Programme for Research and Training in Tropical Diseases and led to its selection as the model for the proposed steering committee. The control of communicable, childhood, and maternal diseases worldwide has benefited from several decades of major international efforts. Such large-scale efforts are lacking for CVD. Yet the evidence that premature death can be avoided and quality of life improved in later years includes dramatic declines in CVD mortality in Western countries, geographic variation in CVD mortality, and established associations of adult mortality with modifiable risk factors, such as tobacco use and obesity. Reducing the prevalence of these risk factors has been shown to decrease mortality in both middle-aged and older persons and to lead to less disability and a better quality of life in later years. Programs for risk factor prevention and low-cost case management of CVD offer feasible, cost-effective ways to reduce CVD mortality and disability in developing countries. They should yield high payoffs in health status and in economic productivity.