Introduction to Global Challenges in Cardiovascular Disease Therapy
Cardiovascular disease (CVD) has become the single greatest cause of death worldwide. In 2004, CVD caused an estimated 17 million deaths and led to 151 million disability-adjusted life-years (DALYs) lost—approximately 30% of all deaths and 14% of all DALYs lost that year. This chapter reviews the variable pattern and burden of CVD, current trends for therapies at the individual level, the diverse challenges for instituting therapeutic medications in low-income countries, and population or public health strategies aimed at the major risk factors for CVD. The cost effectiveness of various interventions to reduce the burden is reviewed in each of the relevant sections.
Burden of Cardiovascular Disease
Examination of regional variations is helpful in understanding global trends in the burden of disease, particularly CVD. Even as age-adjusted rates fall in high-income countries, CVD rates are accelerating worldwide because most low- and middle-income countries are entering the second and third phases of the epidemiologic transition, marked by rising CVD rates. Because 85% of the world’s population lives in low- and middle-income countries, rates in these countries largely drive global rates of CVD, which is the leading cause of death in all developing regions, with the exception of sub-Saharan Africa. However, vast differences in the burden of CVD are seen ( Figure 6-1 ), with CVD death rates as high as 60% in Eastern Europe and as low as 10% in sub-Saharan Africa. These numbers compare with a CVD death rate of 38% in high-income countries.
The World Health Organization (WHO) predicts that by 2030, 33% of all deaths worldwide will be caused by CVD—approximately 24.2 million. CVD tends to strike at an earlier age in developing countries: nearly 80% of deaths in high-income countries occur among those older than 60 years compared with 42% in low- and middle-income countries. In addition, case fatality rates tend to be higher in the lower income countries.
Finally, the economic impact of CVD is enormous. Over the next decade or so, countries such as China, India, and Russia could lose between $200 billion and $550 billion in national income as a result of heart disease, stroke, and diabetes. The costs attributable to nonoptimal levels of blood pressure as mediated through stroke and MI were evaluated for all regions of the world recently. Globally, health care costs of elevated blood pressure were estimated at $370 billion (U.S. dollars) for the year 2001. This amount represented approximately 10% of all global health care expenditures for that year.
In developing countries, a much higher proportion of CVD burden occurs earlier among adults of working age. Under current projections, in developing countries such as South Africa, CVD will strike 40% of adults between the ages of 35 and 64 years compared with 10% in the United States. India and China will have death rates in the same age group that are two and three times that of most developed countries. Given the large populations in these two rapidly growing economies, this trend could have profound economic effects, as workers in their prime succumb to CVD.
Three complementary types of interventions were developed chronologically and can be used to address the global burden of CVD, just as they have been used to address CVD in developed countries. One strategy, referred to as secondary prevention, targets those with acute or established CVD; primary prevention entails risk assessment to target those at high risk as a result of multiple risk factors for intervention before their first CVD event. The third strategy, called primordial prevention, uses mass education or policy interventions directed at the entire population to reduce the overall level of risk. The following sections address these three strategies in the context of efforts to reduce global CVD.
Current Trends and Challenges
Acute Management and Secondary Prevention
Acute Coronary Syndrome
The use of fibrinolytic therapy for acute coronary syndrome (ACS) varies by region. Though this therapy is used more frequently in countries with low gross national income (GNI), the time to initiation of fibrinolysis takes longer than it does in their high-GNI counterparts (4.3 vs. 2.8 hours). In the Global Registry of Acute Coronary Events (GRACE) registry, which included 14 countries in North and South America, Europe, Australia, and New Zealand, streptokinase was the lytic therapy used most often in patients with ST-segment elevation myocardial infarction (STEMI), followed by tissue plasminogen activator and recombinant plasminogen activator. Streptokinase is used most routinely in developing nations because its cost is one tenth that of tissue plasminogen activator.
Fibrinolysis with streptokinase is cost effective in developing nations according to WHO standards. Investigators found that the incremental cost in U.S. dollars per DALY averted was $634 to $734 for aspirin, atenolol, and streptokinase and slightly less than $16,000 for aspirin, atenolol, and tissue plasminogen activator. Secondary analysis further showed that streptokinase given sooner than 6 hours following onset of MI reduces the incremental cost per DALY to less than $440 compared with more than $1300 if given after 6 hours.
As of 2002, the majority of patients with ACS in multiple regions of the world did not undergo any type of revascularization procedure. Rates of percutaneous coronary intervention (PCI) were highest in the United States and were particularly low in Eastern Europe. Unsurprisingly, PCI use was significantly associated with GNI; only 1.3% of STEMI patients in low-GNI countries received PCI compared with 22.7% of STEMI patients in high-GNI countries ( Figure 6-2 ). Reinfarction following fibrinolysis was also much less commonly treated with PCI in non-Western countries, particularly in Russia and Eastern Europe.
Several studies in the past decade have begun to elucidate the use of evidence-based medications for ACS in various parts of the world. The GRACE study found that across the 14 countries included in North and South America, Europe, Australia, and New Zealand, aspirin was used on average in 91% of registered ACS patients. When looked at more closely, however, it was found that countries in Eastern Europe on average used aspirin in only 75% of patients with ACS. A more current study, which stratified countries based on GNI, found that aspirin usage in STEMI patients was actually slightly higher in low-GNI countries compared with high-GNI countries (99.3% vs. 95.4%; P < .0001). Conversely, β-blocker use was lower in low-GNI countries, likely related to higher rates of heart failure. Glycoprotein (GP) IIb/IIIa inhibitors were used as adjunctive therapy to PCI in 39% of patients undergoing PCI in the United States but only in 1% of patients in Eastern Europe and in 4% of patients in Latin America undergoing PCI. The availability of catheterization facilities was associated with an increased use of these agents. However, more up-to-date data on the current trends in GP IIb/IIIa usage globally are lacking.
Angiotensin-converting enzyme (ACE) inhibitors were given to patients with ACS more frequently in Latin America, Eastern Europe, and Asia than in Western countries, presumably because of the higher rates of heart failure in these regions. This finding was supported by Orlandini et al (2006), who confirmed that ACE inhibitors were used more frequently in low-GNI countries. Lipid-lowering agents, as described below, have only recently been added to the WHO Essential Drug List, and therefore data about their use are minimal.
Although it is tempting to ascribe many of the variations in treatment to the high cost of medications and lack of access in developing nations, economics alone cannot explain all of the regional variations seen. For example, Eastern Europe has a high usage rate of ACE inhibitors, which is a relatively expensive medication. However, it has the lowest use of aspirin, which is very inexpensive. Clearly, factors other than cost are contributing to the different prescribing practices seen across the globe.
Data on the number of cardiac surgeries performed internationally and on their outcomes are sparse. In the GRACE study, cardiac artery bypass grafting (CABG) was performed in 4% of patients with STEMI, 10% of those with non-STEMI, and 5% of those with unstable angina, although it is unclear how these percentages differed in developed versus developing countries. Cardiac surgeries are undertaken much less frequently in developing countries compared with their developed counterparts; for example, it was only in 2007 that open-heart surgeries with cardiopulmonary bypass were first performed in Uganda. Groups in some developing nations have decided to evaluate the mortality rate associated with cardiac surgery in their countries, but no global database or systematic method exists by which all countries can collect and submit such data. Such an international database could help identify key areas for improvement and focus efforts by surgeons in developed countries.
It has been estimated that treatment of patients with ischemic heart disease with aspirin, β-blockers, ACE inhibitors, or lipid-lowering drugs can each independently lower the risk of future vascular events by about one fourth; when taken in combination, a reduction in vascular events by two thirds to three fourths can be expected. Multidrug regimens for secondary prevention in low- and middle-income countries are cost effective according to WHO standards, meaning that the intervention would cost less than three times the GNI of these countries.
Despite the clear efficacy of the above medications in the secondary prevention of ischemic heart disease, their use in developing countries is alarmingly low. The WHO study on Prevention of Recurrences of Myocardial Infarction and Stroke (PREMISE), published in 2005, was a cross-sectional survey of 10,000 patients with coronary heart disease and/or cerebrovascular disease in three low-income and seven middle-income countries. It found that in patients with coronary heart disease, 18.8% did not receive aspirin, 51.9% did not receive β-blockers, 60.2% did not receive ACE inhibitors, and 79.2% did not receive statins. Of particular concern is the fact that one tenth of patients with coronary heart disease in the PREMISE study were not on any medications for their heart disease at all. This is in comparison to the European Action on Secondary Prevention by Intervention to Reduce Events (EUROASPIRE II) study, in which 66.4% of patients were on a β-blocker (compared with 48.1% in PREMISE), and 57.7% were on a statin (compared with 20.8% in PREMISE). A similar percentage of patients, however, were on aspirin and ACE inhibitors.
More recently, the Prospective Urban Rural Epidemiology (PURE) study examined the global usage of efficacious medications for secondary prevention of ischemic heart disease. This study was conducted in communities in 17 countries of varying economic status from January 2003 through December 2009. The investigators found that the use of medications—antiplatelet drugs including aspirin, β-blockers, ACE inhibitors or angiotensin receptor blockers (ARBs), and statins—for secondary prevention decreased as country income level decreased ( Figure 6-3 ). Most strikingly, they found that although 11.2% of patients in high-income countries received no medications at all, this percentage increased to 45.1% in upper middle-income countries, 69.3% in lower middle-income countries, and 80.2% in low-income countries. Country-level factors such as economic status influenced the rates of usage more than did individual-level factors such as age, sex, education, smoking status, body mass index (BMI), and hypertension and diabetes status. These estimates are far more grim than those reported in the WHO-PREMISE study and may have to do with the fact that the WHO-PREMISE study included patients who were already accessing hospital-level care and who therefore may have had greater access to medications as well.
Two countries in which the issue of secondary prevention has been more closely studied are India and China, where the prevalence of coronary artery disease (CAD) is very high. A 2009 study of physician prescribing practices at different levels of Indian health care found that among patients with stable known coronary heart disease, aspirin was prescribed in 90.6% of cases, β-blockers in 68.7%, ACE inhibitors or ARBs in 82.5%, statins in 68.8%, and other lipid-lowering drugs were prescribed in 13.5% of patients. Although these rates seem fairly high, only 35.5% of patients were prescribed drugs in all four classes. Interestingly, a trend of decreased use of each of the above agents was evident, and it continued at the primary and secondary levels of health care compared with the tertiary level, indicating a likely slow transition of knowledge in secondary prevention strategies to the community level. This is significant because the majority of patients in India receive their chronic disease care from the primary and secondary levels (12.6% at primary level, 57.2% at secondary level, 30.1% at tertiary level). Gupta et al (2009) confirmed the above finding of low rates of secondary prevention in the primary care setting and further found that women in particular were less likely to receive aspirin or any combination of drugs for secondary prevention than were their male counterparts. In China, the Clinical Pathways for Acute Coronary Syndromes (CPACS) trial was conducted as a prospective study in nearly 3000 patients with suspected ACS. It found that less than 50% of patients were discharged from the hospital on a four-drug regimen of aspirin, β-blocker, ACE inhibitor/ARB, and statin, and the rate of use of these medications was even lower (41%) at 1-year follow-up.
Challenges to Therapeutic Usage
Current State of cardiovascular disease Drug Availability and Affordability in Low- and Middle-Income Countries
A clear barrier to the prevention and treatment of CVD in developing countries is the low availability and affordability of medications. Investigators conducted a survey of 32 medications used to treat chronic diseases such as CVD in three low-income countries—Bangladesh, Malawi, and Nepal—and three low-middle income countries—Brazil, Pakistan, and Sri Lanka. The authors found that the availability of cardiovascular medications was poor in the public sector. For example, hydrochlorothiazide was available in brand or generic form in only 5% of public outlets surveyed in Bangladesh; however, it was available in 85% of private outlets surveyed. Similarly, lovastatin was not available in any public outlets surveyed in Brazil but was present in 75% of private outlets.
Equally as striking is the low level of affordability of these drugs in developing countries. The above study found that a month of combination therapy with the lowest-priced generic version of aspirin, a statin, a β-blocker, and an ACE inhibitor cost 1.5 days’ wages of the lowest level government worker in Sri Lanka; more than 5 days’ wages in Brazil, Nepal, and Pakistan; and more than 18 days’ wages in Malawi ( Figure 6-4 ). Actual affordability is likely worse because many people in developing countries earn less than the lowest paid government worker. Medications in the private sector in the above study were generally more expensive than in the public sector and were reflective of wholesale and retail markups. Specifically, add-on costs to the manufacturer’s price ranged from 18% in Pakistan to more than 90% in countries such as Malawi, where there are no regulatory policies.
A large study of five antihypertensive medications in 36 countries of varying levels of income confirmed the stark reality of the availability and affordability of cardiovascular medicines. Investigators showed that the overall availability of the antihypertensive medicines was poor (mean of 26.3% in the public sector for lowest priced generic, 57.3% in the private sector). Further, the lowest priced generic was in all cases more affordable than the brand product in both the public and private sectors. In fact, buying a brand product cost 4.2 times as much as buying the lowest priced generic.
Role of the World Health Organization Essential Drug List
One of the challenges to improving access is ensuring adequate listing of effective CVD medications on the WHO Essential Drug List (EDL), which is a compilation of medications that the WHO believes are necessary to satisfy the health needs of any population. Since its initial publication in 1977, the list has become a global standard that guides nations in how to allocate health care spending. This is particularly important for developing nations, which spend 25% to 66% of total public and private health spending on pharmaceuticals compared with less than 20% in developed countries. In addition, many international organizations such as the United Nations Children’s Fund (UNICEF), along with nonprofit organizations and supply agencies, base their medicine supply system on the EDL.
Medications are chosen on the basis of disease prevalence, evidence of efficacy and safety, and cost effectiveness. The list is revised every 2 years by the WHO Expert Committee. The addition of a statin in 2007 provides an important case study of how medications can take some time to be added to the EDL. Trials dating back to the mid-1990s had shown that statin therapy leads to improved cardiovascular outcomes in both primary and secondary prevention. In addition, it had been shown by 2003 that statins were cost effective for prevention of CVD in developing countries by WHO standards. However, when the WHO Expert Committee considered statins for inclusion in the EDL in 2005, they concluded that “since no single drug has been shown to be significantly more effective or less expensive than others in the group, none is included in the Model List; the choice of drug for use in patients at highest risk should be decided at the national level.” Subsequently, simvastatin became generic in 2006, leading to a significant reduction in price. Given this new development, two medical students in the United States submitted an application to the Expert Committee in the Fall of 2006, and it was approved in April 2007 for inclusion in the 2007 EDL.
Human Resources Shortages
Although drug access may contribute to the low treatment rates for CVD, one of the most important contributing factors is the shortage of human resources ( Figure 6-5 ). Although attempts have been made to increase education opportunities and train more doctors and nurses, developing countries continue to lose large numbers of trained professionals, as many newly graduated doctors and nurses in developing nations leave to find greater opportunity and better financial compensation in more developed economies. For example, of all the medical graduates produced by the University of Witwatersrand in South Africa in the past 35 years, more than 45%—approximately 2000 physicians—have left the country. In addition, increasing numbers of physicians and nurses seek employment in private industry for better compensation and benefits. To address health care worker shortages in low- and middle-income countries, the WHO has promoted task shifting, which is the process through which tasks are delegated, when appropriate, to less specialized health workers such as nurses. Limited studies have shown that nurses can effectively initiate and manage hypertension treatment.