Cardiovascular Morbidity and Mortality in High‐Risk Populations: Epidemiology and Opportunities for Risk Reduction

Abstract

Despite significant growth in the number of drug classes and individual agents available to combat various cardiovascular (CV) risk factors in clinical practice, the prevalence of these risk factors, including hypertension, diabetes mellitus, and obesity, has remained largely unchanged and in some cases has even increased during the past decade. CV risk factors remain consistently undertreated across the world, despite consensus guidelines issued by national and international health care organizations. Given the earlier onset of obesity and diabetes mellitus in many national populations, beginning from childhood, it is desirable to implement a range of lifestyle and pharmacologic interventions intended to modify CV risk factors while also improving glucose tolerance. Drugs that block the renin‐angiotensin system are associated with reduced incidence of diabetes compared with other antihypertensive agents and should be considered mainstays of therapy for patients with hypertension who are at high risk for diabetes, CV disease, or both.

Cardiovascular (CV) disease remains the number one killer of both men and women in the United States and other western countries. ¹ In recent years, CV disease has become an increasingly important cause of mortality and morbidity in other parts of the world, including China and other Asian countries, where CV mortality is 2‐ to 5‐fold higher than infectious disease mortality. ² Because of this trend, >80% of the global burden of CV disease currently occurs in developing countries rather than developed countries.

Despite significant growth in the number of drug classes and individual agents available to combat various CV risk factors in clinical practice, the prevalence of these risk factors, including hypertension, diabetes mellitus, and obesity, has remained largely unchanged and in some cases has even increased during the past decade. ³ , ⁴ Consequently, about 1 in 8 adults in the United States are currently considered to be at high CV risk, with a >20% chance of developing coronary heart disease (CHD) within the next 10 years. ⁴ This disturbing statistic is due to the combination of an aging population, an increasingly sedentary lifestyle, changing definitions of disease, poor dietary choices, and physicians' underuse of therapy that is shown to be effective in modifying these risk factors.

WHICH PATIENTS ARE CONSIDERED TO BE AT HIGH CV RISK?

Patients With Established CHD

CHD is responsible for 1 of every 5 deaths in the United States. Between 18% and 23% of men and women die within 1 year of having an initial myocardial infarction (MI), whereas 18% to 35% of patients develop recurrent infarction and 7% to 30% suffer from symptomatic heart failure. ¹ Survival after an MI has increased dramatically within the past 2 decades, however. The presence of at least 1 of the 4 most important CV risk factors, which are diabetes mellitus, cigarette smoking, hyperlipidemia, and hypertension, is confirmed in 80% to 90% of patients with symptomatic CHD. ⁵ A recent case‐control study in 52 countries in North America, Europe, Asia, Africa, and the Middle East indicated that, in addition to these risk factors, several other factors contributed significantly to the population‐attributable risk of MI, including psychosocial factors, reduced fruit and vegetable consumption, excessive alcohol intake, and too little physical activity. ⁶ In addition, the populations of South Asian countries (India, Pakistan, Sri Lanka, Bangladesh, and Nepal) are exposed to higher risk‐factor levels at younger ages than those in other countries, which may explain the earlier onset of acute MI in these countries compared with populations from other Asian countries and other parts of the world. ⁷

Patients With CHD Equivalents

Atherosclerosis is a systemic disease, frequently affecting multiple vascular beds. The National Cholesterol Education Program (NCEP) has proposed the term CHD risk equivalents to describe risk factors for individuals whose risk of major coronary events is equivalent to those with established CHD or is >20% in the next 10 years. The NCEP‐defined CHD risk equivalents include the following ⁸ :

Peripheral Arterial Disease (PAD). The prevalence of PAD in the general population is approximately 12%. Most patients with PAD have concomitant atherosclerotic disease in the coronary or carotid circulation. Annual mortality for patients with symptomatic PAD is generally about 5% to 6% per year. Patients with critical limb ischemia, manifested by pain at rest, ischemic ulcer, or gangrene, carry a much higher mortality rate of 25% per year, however. The most common cause of death in patients with PAD is CHD; death rarely is the result of PAD itself. ⁹ , ¹⁰

Abdominal Aortic Aneurysm (AAA). The prevalence of AAA increases with age, from 0% to 5% before age 55 years to 5% to 15% after age 75 years. Patients with AAA demonstrate higher prevalence of hypertension, smoking, MI, heart failure, and lower‐extremity PAD than age‐ and sex‐matched controls. Complications of AAA include rupture, thromboembolism, and compression of the adjacent structures. AAAs gradually increase in size over time, with an average rate between 1 and 4 mm/y; the risk of rupture is approximately 1% per year for aneurysms between 3.5 and 4.9 cm and 5% per year for aneurysms >5 cm. ¹ Therefore, patients with an AAA >5.5 cm or those with rapid aneurysmal expansion should undergo repair to prevent catastrophic complications. ⁹

Cerebrovascular Disease. Prevalence of stroke in the United States is approximately 2.6%. The prevalence of silent cerebral infarction, however, is estimated to be much higher—between 10% and 30%. ¹ In general, mortality of patients after stroke is higher than in patients with symptomatic PAD or recent MI. ¹¹ Stroke accounts for 1 of every 16 deaths in the United States. Although 60% to 70% of deaths occurring during the first 30 days after a stroke are associated with the direct effects of the stroke, >40% of deaths occurring >1 year after a stroke are caused by cardiac diseases. ¹ , ¹² , ¹³

Diabetes Mellitus. The NCEP and most other consensus guidelines consider diabetes a CHD equivalent because the risk of death from CHD among diabetic patients without previous MI is nearly identical to the risk of CHD death among nondiabetic patients with previous MI. ⁸ , ¹⁴ This finding, along with the frequent occurrence of other CV risk factors among patients with diabetes, justifies an intensive preventive strategy for these patients. ⁸ , ¹⁵

Multiple Risk Factors Producing an Aggregate 10‐Year CHD Risk >20%. NCEP adopted the Framingham risk score (FRS) to predict risk of coronary events associated with systolic blood pressure (BP), total cholesterol, high‐density lipoprotein cholesterol, age, and cigarette use. The NCEP has established goals for the primary treatment target (LDL cholesterol) that reflect the degree of risk; therefore, individuals in the highest risk category (10‐year CHD risk >20%) have the most aggressive LDL cholesterol target of <100 mg/dL, along with other intensive risk factor modifications. ⁸ The clinician should keep in mind certain limitations of the FRS risk assessment; although the FRS has been found to reliably predict CHD risk in African Americans and Caucasians, it tends to overestimate risk in patients of Chinese and Hispanic descent. ⁷ , ¹⁶ , ¹⁷

Patients With Other Novel (Emerging) Risk Factors

Despite the utility of the FRS, the algorithm has limited sensitivity in detecting high‐risk individuals among younger adults and women. ¹⁸ , ¹⁹ This limitation has led to the development and increasing incorporation of other strategies to improve CV risk assessment. One promising strategy is the use of inflammatory biomarkers for risk stratification, based on multiple lines of evidence implicating the critical role inflammation plays in the pathogenesis and progression of atherosclerosis. Among markers of systemic inflammation, C‐reactive protein (CRP), an acute‐phase protein produced by the liver upon stimulation by a range of inflammatory cytokines (eg, interleukin [IL]‐6, IL‐1, and tumor necrosis factor‐β), is the strongest independent predictor of MI and CV mortality in an apparently healthy population. ²⁰ , ²¹ Of importance, an analysis from the Women's Health Study showed that CRP measurement provides prognostic information that is independent of that provided by measuring LDL cholesterol level and assessing FRS. ²⁰ For these reasons, the US Centers for Disease Control and Prevention and the American Heart Association recommend measurement of CRP in patients with intermediate risk by global risk assessment (10%–20% risk of CHD per 10 years), at the discretion of the physician, to help guide further evaluation and therapy in the primary prevention of CHD. ²²

Other strategies for CV risk assessment currently under investigation include atherosclerosis imaging using a variety of techniques (eg, coronary calcium by computed tomography, coronary magnetic resonance imaging), abdominal/visceral fat measurement, assessing serum levels of fibrinogen and lipoprotein(a), urinary albumin‐to‐creatinine ratio, and genetic screening. The incremental value of these approaches in identifying individuals at high risk, beyond that provided by traditional risk assessment, remains to be further elucidated and has been questioned. ⁹

MANAGING CHD RISK FACTORS IN HIGH‐RISK PATIENTS

Despite consensus guidelines issued by national and international health care organizations based on data from randomized clinical trials to assist physicians in management of high‐risk patients, CV risk factors remain consistently undertreated across the world. A recent international Reduction of Atherothrombosis for Continued Health (REACH) registry, including more than 67,000 patients with established coronary artery disease, cerebrovascular disease, or PAD, as well as patients with ≥3 risk factors for atherothrombosis, demonstrated that 40% to 70% of these patients have a BP level ≥140/90 mm Hg (Figure). ²³ The regions with the lowest hypertension control rates are Eastern and Western Europe, followed by Australia, the Middle East, and Latin America; however, even in North America and Japan, considered the regions with the highest rates of BP control, only 50% to 60% of high‐risk patients achieved a target BP level of <140/90 mm Hg. In addition, 20% to 70% of these patients continue to have elevated total cholesterol (>200 mg/dL), and 10% to 20% continue to smoke cigarettes. ²³

Figure.

Undertreatment of cardiovascular risk factors in high‐risk populations worldwide. To convert cholesterol to mmol/L, multiply by 0.0259. Reprinted with permission from Bhatt et al. ²³

Similar results have been obtained in studies in patients without established atherosclerotic vascular diseases but with CHD risk equivalents (based on the presence of multiple risk factors or diabetes mellitus). Data from the 1999–2000 dataset from the National Health and Nutrition Examination Survey (NHANES) indicated that only 37% of adults with diabetes achieved the primary treatment goal for hyperglycemia (glycosylated hemoglobin <7%); only 7% achieved simultaneous control of the 3 principal CV risk factors in diabetes, including BP (goal <130/80 mm Hg), total cholesterol (goal <200 mg/dL), and the glycemic target. ²⁴ More recently, data from NHANES 2001–2002 demonstrated that only 29% of patients with combined hypertension and hypercholesterolemia received treatment; overall simultaneous control of hypertension and hypercholesterolemia in these patients was only 9% and was comparable across multiple ethnic groups. ²⁵

REDUCING CV RISK THROUGH RENIN‐ANGIOTENSIN SYSTEM BLOCKADE

Opportunities for reducing the occurrence of CV events in high‐risk individuals include implementing lifestyle interventions along with effective pharmacologic therapy to modify risk factors. Drugs that block the renin‐angiotensin system, such as angiotensin‐converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs), not only lower BP—an important CV risk factor—but also reduce inflammatory proteins such as CRP and serum amyloid A and therefore may provide preventive value beyond BP control. ²⁶ , ²⁷

Numerous clinical trials and meta‐analyses have shown that ACE inhibitors and ARBs are also associated with reduced incidence of diabetes compared with other antihypertensive agents in high‐risk patients. ²⁶ , ²⁸ , ²⁹ , ³⁰ , ³¹ , ³² In the Antihypertensive and Lipid‐Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), which included 33,357 patients aged 55 years or older who were randomized to treatment with chlorthalidone, amlodipine, or lisinopril, incidence of diabetes (fasting serum glucose ≥126 mg/dL [7.0 mmol/L]) at 4 years was 11.6%, 9.8%, and 8.1%, respectively, in patients who did not have diabetes at baseline. There was, however, no difference between groups in the primary outcome of a fatal CHD event or nonfatal MI. ²⁸ A prespecified analysis of data from the Valsartan Antihypertensive Long‐term Use Evaluation (VALUE) trial evaluated the occurrence of new‐onset diabetes in 9995 hypertensive patients treated with valsartan‐based compared with amlodipine‐based regimens. New diabetes was reported in 580 (11.5%) patients taking valsartan and 718 (14.5%) patients taking amlodipine (odds ratio 0.77; 95% confidence interval [CI], 0.69–0.87; P<.0001). ²⁹

Meta‐analyses of clinical trials support these findings. Abuissa and colleagues ³⁰ conducted a meta‐analysis of 12 randomized controlled clinical trials of ACE inhibitors or ARBs to study the efficacy of these medications in prevention of diabetes. ACE inhibitors and ARBs were associated with reductions in the incidence of newly diagnosed diabetes by 27% and 23%, respectively, and by 25% in the pooled analysis. In addition, a recent network meta‐analysis of 22 trials including 143,153 nondiabetic hypertensive patients accounted for both direct and indirect comparisons of the effects of antihypertensive agents on incident diabetes ³¹ ; 3 of these trials included high‐risk patients. The odds ratios for development of new‐onset diabetes were 0.57 (95% CI, 0.46–0.72; P<.0001) for ARBs; 0.67 (95% CI, 0.56–0.80; P<.0001) for ACE inhibitors; 0.75 (95% CI, 0.62–0.90; P=.002) for calcium channel blockers; 0.77 (95% CI, 0.63–0.94; P=.009) for placebo; and 0.90 (95% CI, 0.75–1.09; P=.30) for β‐blockers. Because of their efficacy in preventing diabetes in comparison to other antihypertensive agents, ACE inhibitors and ARBs should be considered a mainstay of therapy in high‐risk patients, particularly those at risk for diabetes.

CONCLUSIONS

The global burden of individuals with symptomatic CV disease and/or at high CV risk is enormous. Important steps to improve the prognosis of high‐risk individuals include increasing public awareness of CV mortality and morbidity associated with various risk factors and implementing lifestyle interventions along with effective pharmacologic therapy to modify these risk factors. Given the earlier onset of obesity and diabetes mellitus in many national populations, beginning from childhood, it is desirable to implement a range of interventions intended to modify CV risk factors while also improving glucose tolerance.

Drugs that block the renin‐angiotensin system, including ACE inhibitors and angiotensin receptor blockers, are associated with reduced incidence of diabetes compared with other antihypertensive agents and should therefore be considered mainstay antihypertensive therapies for individuals at high risk for diabetes and/or CV disease. ²⁶ , ²⁸ , ²⁹ , ³⁰ , ³¹ , ³² In addition, these agents reduce inflammatory proteins such as CRP and serum amyloid A and therefore may provide preventive value beyond BP control. ²⁶ , ²⁷

Disclosure:

Dr Vongpatanasin has no ties with Boehringer Ingelheim Pharmaceuticals, Inc.