JACC gol. 27, No. 5 PASTERNAK ET AL. · JACC gol. 27, No. 5 PASTERNAK ET AL. 979 April...

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difference is usually called attributable risk. For coronary heart disease risk factors, the absolute attributable risk increases often markedly with age, whereas the relative risk may, in fact, decrease. For example, the relative risk of stroke due to hypertension is smaller in the elderly than in middle age, but among 100 treated patients, older patients will receive more absolute benefits from treatment than middle-aged adults. Nonetheless, for common and serious diseases, such as heart disease and stroke, a small alteration in relative risk will have an important clinical and public health impact.

The strength of one risk factor in the presence of another may be greater than the sum of the strengths of the individual factors. For example, women of childbearing age who use oral contraceptives have about twice the risk of myocardial infarction than nonusers. In addition, women of childbearing age who smoke have about 13 times the risk of myocardial infarction than nonsmokers. However, women of childbearing age who both use the pill and smoke have about 40 times the risk of myocardial infarction compared to those who do neither. Finally, given the risk and prevalence of oral contraceptives and cigarette smoking in the U.S. population, oral contraceptives accounts for almost 400 deaths each year, whereas cigarette smoking accounts for 400,000 deaths each year.

Points to remember:. 1. In assessing a risk factor, one can reasonably conclude

the presence or absence of a valid statistical association, having considered the possible roles of chance, bias and confounding as alternative explanations.

2. In making a judgment about a cause and effect relationship, one must consider not simply the results of a single study, but the totality of the evidence from all studies. Furthermore, criteria that increase belief in causality include strength of association, temporal sequence, dose-response, consistency, biologic plausibility and specificity.

3. Risk can be measured in relative or absolute terms. Whereas high relative risks increase the likelihood of a cause/

effect relationship, high absolute attributable risks identify the public health consequences and value of treatment.

F u r t h e r R e a d i n g s

Books 1. Friedman LM, Furbcrg CD, DeMets DL. Fundamentals of Clinical Trials.

3rd ed. St. Louis: Mosby-Year Book, 1995. 2. Friedman GD. Primer of Epidemiology. 2nd ed. New York: McGraw-Hill

Book Company, 1980. 3. Hennekens CH, Buring JE. Epidemiology in Medicine. Boston: Little Brown

and Company, 1987. 4. Hulley SB, Cummings SR. Designing Clinical Research. An Epidemiologic

Approach. Baltimore: Williams & Wilkins, 1988.

Journal Articles 5. Guyatt GH, Sackett DL, Cook DJ. Users' guides to the medical literature: II.

How to use an article about therapy or prevention: A. Are the results of the study valid? JAMA 1993;270:2598-601.

6. Guyatt GH, Sackett DL, Cook DJ. Users' guides to the medical literature: II. How to use an article about therapy or prevention: B. What were the results and will they help me in caring for my patients? JAMA 1994;271:59-63.

7. Hayward RSA, Wilson MC, Tunis SR, Bass EB, Guyatt G. Users' guides to the medical literature: VIII. How to use clinical practice guidelines: A. Are the recommendations valid? JAMA 1995;274:570-4.

8. Jaeschke R, Guyatt G, Sackett DL. Users' guides to the medical literature: III. How to use an article about a diagnostic test: A. Are the results of the study valid? JAMA 1994;271:389-91.

9. Jaeschke R, Guyatt GH, Sackett DL. Users' guides to the medical literature: III. How to use an article about a diagnostic test: B. What are the results and will they help me in caring for my patients? JAMA 1994;271:703-7.

10. Laupacis A, Wells G, Richardson S, Tugwell PT. Users' guides to the medical literature: V. How to use an article about prognosis. JAMA 1994;272:234-7.

11. Levine M, Walter S, Lee H, Haines T, Holbrook A, Moyer V. Users' guides to the medical literature: IV. How to use an article about harm. JAMA 1994;271:1615-9.

12. Oxman AD, Cook D J, Guyatt GH. Users' guides to the medical literature: VI. How to use an overview. JAMA 1994;273:1610-3.

13. Oxman AD, Saekett DL, Guyatt GH. Users' guides to the medical literature: I. How to get started. JAMA 1993;270:2093-5.

14. Richardson WS, Detsky AS. Users' guides to the medical literature: VII. How to use a clinical decision analysis. A. Are the results of the study valid? JAMA 1995;273:1292-5.

15. Richardson WS, Detsky AS. Users' guides to the medical literature: VII. How to use a clinical decision analysis: B. What are the results and will they help me in caring for my patients. JAMA 1995;273:1610-3.

Task Force 3. Spectrum of Risk Factors for Coronary Heart Disease

R I C H A R D C. PASTERNAK, MD, FACC, CHAIR, SCOTT M. G R U N D Y , MD, PHD,

D A N I E L LEVY, MD, FACC, P A U L D. THOMPSON, MD, FACC

Understanding the concept of risk and risk factors is central to the evaluation of the hazard for coronary disease events and essential for appropriate clinical decision making with respect to the management of specific factors associated with coronary

disease risk. The notion of risk is not new, but the idea that specific factors serve as markers of the level of risk has arisen relatively recently, largely as a result of population-based studies such as the Framingham Heart Study. Critical to our

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understanding is the sometimes tenuous relationship between risk factors and causality. The importance of a risk factor rests on three fundamental relations: 1) the biologic connection between the factor and the atherosclerotic process (see Task Force 1); 2) the statistical strength of its association with future cardiovascular disease events, often termed its "relative risk" (see Task Force 2); and 3) the extent to which changes in the factor have been shown to influence the future clinical course. Such changes can be observed, as with age, or produced with an intervention, as with low density lipoprotein (LDL) cholesterol.

Risk Factor Categories Risk factors have been categorized by several properties,

including modifiable versus nonmodifiable, life-style versus biochemical/physiologic, continuous versus dichotomous, individual versus population, causal versus associative, chronic versus acute and others.

For the present purpose, namely, matching management intensity with cardiovascular risk, we propose a scheme divided into categories of descending levels of evidence to support direct management. That is, we propose to begin with those risk factors for which the most conclusive evidence exists and whose management favorably affects outcome, and we end with. those factors for which there are no direct management opportunities or for which modification would be unlikely to affect the course of disease (the presence of such factors may, however, lead to more intense management of other risk factors). By focusing on management priorities, categorized by evidence of treatment efficacy, we recognize that for the purposes of this Bethesda Conference, causality is of secondary importance. Therefore, for example, diabetes falls into category II because, despite our knowledge of its causal role in atherosclerosis, the benefit of treatment in lowering vascular risk is less well established. Conversely, thrombogenic factors fall into category I because of abundant evidence supporting the benefit of treatment and the magnitude of this treatment effect even though identification of a specific prothrombotic factor is often lacking.

Proposed risk factor categories: I. Risk factors for which interventions have been proved to

reduce the incidence of coronary artery disease events. II. Risk factors for which interventions are likely, based on

our current pathophysiologic understanding and on epidemiologic and clinical trial evidence, to reduce the incidence of coronary artery disease events.

III. Risk factors clearly associated with an increase in coronary artery disease risk, and which, if modified, might lower the incidence of coronary artery disease events.

IV. Risk factors associated with increased risk but which cannot be modified or whose modification would be unlikely to change the incidence of coronary disease events.

For more than 50 years, research has suggested that diet is a, if not the, major environmental cause of coronary atherosclerosis. Within populations, a diet high in saturated fat,

cholesterol and calorie content is widely recognized to exacer- bate many of the traditional risk factors, including dyslipidemia, obesity and diabetes. Dietary sodium is important in hypertensive patients. More recently, intake of foods high in antioxidants, folate, vitamins B 6 and B12 and soluble fiber have been suggested to lower coronary artery disease risk. Con- sumption of different unsaturated fatty acids (e.g., transfatty acids, marine oils) also affects risk. Because dietary modification is of importance throughout the course of evaluation and management of many of the major risk factors, an imprudent "diet" itself has not been included in the list of risk factors as categorized below. Rather, diet is seen to interact with many different risk factors at many different levels. Were diet to be included as a single factor, it would qualify for category I status.

Category I: Risk Factors for Which Interventions Have Been Proved to Reduce the Incidence of Coronary Artery Disease Events Cigarette smoking. The evidence that cigarette smoking

increases the risk for cardiovascular disease is based on observational studies, is overwhelming and is considered proved by the Task Force (1). The cardiovascular risk of smoking was appreciated as early as the middle of this century (2). The Surgeon General's report in 1964 established this epidemiologic relationship (3), and the 1989 Surgeon General's report presented definitive data from observational case-control and cohort studies that showed that smoking increased cardiovascular mortality by 50% and essentially doubled the incidence of cardiovascular disease (4). Importantly, a linear relation exists between cardiovascular risk and cigarettes consumed (5), with relative risks approaching 5.5 for fatal cardiovascular events among heavy smokers compared with nonsmokers (6). Smok- ing accelerates the atherogenic process in both a duration- and dose-dependent fashion. In one study of women, cigarette smoking accounted for half of all coronary disease deaths (7). An average smoker dies 3 years earlier than a nonsmoker, and a person known to be at "high risk" for coronary disease dies 10 to 15 years earlier if he or she smokes (8,9). Smoking amplifies the effect of other risk factors, thereby accelerating atherosclerosis and influencing the production of acute cardiovascular events (10). Dietary factors, hyperlipidemia and hypertension markedly increase the effect of cigarette smoking on coronary artery disease mortality and morbidity. In particular, events related to thrombus formation, plaque instability and arrhythmias are all influenced by cigarette smoking.

Clinical data accumulated over the past 20 years strongly suggest that smoking cessation reduces the risk of cardiovascular events (11). Prospective cohort studies show that the risk of myocardial infarction declines more rapidly than overall death from cardiovascular disease, with the greatest propor- tion of risk reduction occurring in the first several months after cessation. A number of studies have demonstrated that patients who continue to smoke after acute myocardial infarction

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have an increase in the risk of death and reinfarction. The increase in risk of death has ranged from 22% to 47%. Paradoxically, many studies of acute mortality with myocardial infarction have found better survival in smokers than in nonsmokers. These results seem to emanate from the younger age of smokers when they have an acute event, coupled with their lesser underlying atherosclerosis at the time of the acute event. Smoking has been clearly implicated in bypass graft atherosclerosis and thrombosis. Continued smoking after bypass grafting is associated with a twofold increase in the relative risk of death and an increase in nonfatal myocardial infarction and angina.

Environmental exposure to second-hand smoke also poses considerable risk. It is estimated that passive smoking causes almost 40,000 heart disease deaths yearly in the United States. This exposure is the third leading cause of preventable death in this country (12). A degree of "conditioning" may compensate for some of the effects of chronic smoking among regular smokers, but this is less active among those with passive exposure to smoke. Paradoxically, it is possible that the risk of passive smoking may actually be even greater in individuals not preconditioned by habitual smoke exposure (12).

Low density lipoprotein cholesterol. Total blood cholesterol is conclusively linked to the development of coronary artery disease events, with a continuous and graded risk down to a total cholesterol <180 mg/dl (13,14). Most of this risk is explained by the LDL cholesterol concentration. Therefore, this document focuses on LDL cholesterol rather than total cholesterol. The evidence linking LDL cholesterol and coronary artery disease is derived from extensive epidemiologic, laboratory and clinical trial data. Low density lipoprotein is the lipoprotein most strongly associated with risk for coronary heart disease in epidemiologic studies. In general, these studies indicate a 2% to 3% difference in risk for coronary heart disease per 1% difference in LDL cholesterol level (15). In population studies, LDL cholesterol parallels changes in total cholesterol, whereas in individual subjects the relationship is not always tight. Thus, there is a need for measurement of LDL cholesterol levels in high risk patients. In the United States, the National Cholesterol Education Program (NCEP) Adult Treatment Panel II has stratified the risk of LDL levels as follows: LDL cholesterol ->160 mg/dl is "high risk LDL cholesterol"; 130 to 159 mg/dl is "borderline high risk LDL cholesterol"; and <130 mg/dl is a "desirable LDL cholesterol" (15). The LDL cholesterol increases with age and is also increased by weight gain and diets high in saturated fat and cholesterol. Genetic factors further contribute to the variation in LDL cholesterol levels in the general population. Levels of LDL may be increased in chronic hypothyroidism, the ne- phrotic syndrome, certain liver diseases, estrogen deficiency and dysglobulinemia. Certain constellations of lipids appear to increase overall risk synergistically. Elevated LDL cholesterol, elevated triglycerides and low high density lipoprotein (HDL) cholesterol levels constitute a particularly adverse risk profile, as reported in the Helsinki Heart Study (16) and the Prospec- tive Cardiovascular MOnster (PROCAM) study (17).

Table 1. Classification of Blood Pressure for Adults 18 Years and Older*

SBP DBP Category (ram Hg) (mm Hg)

Normal <130 <85 High normal 130-139 85-89 Hypertensiont

Stage 1 (mild) 140-159 90-99 Stage 2 (moderate) 160-179 100-109 Stage 3 (severe) 180-209 110-119 Stage 4 (very severe) ->210 ->120

*When systolic (SBP) and diastolic blood pressures (DBP) fall into different categories, the higher category should be selected to classify the subject's blood pressure status, tBased on the average of two or more readings taken at each of two or more visits after initial screening. Reprinted with permission from the National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland. The Fifth Report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure. Arch Intern Med. 1993;153:154-83.

Several recent reports indicate that therapeutic lowering of LDL cholesterol levels is highly effective in secondary prevention. Angiographic studies show that reduction of LDL levels can delay progression of coronary atherosclerosis and in some cases, promote regression of lesions. However, of even greater importance, these trials demonstrate that LDL lowering produces a striking reduction in acute coronary events (unstable angina pectoris and acute myocardial infarction). These beneficial outcomes have now been observed in a meta-analysis of earlier secondary prevention trials (18), in angiographic trials (19) and in the recently reported Scandinavian Simvastatin Survival Study (20). In the latter study, LDL lowering induced by an HMG-CoA reductase inhibitor reduced coronary mortality by 42% and total mortality by 30%. Thus, studies of several types have demonstrated the benefit of LDL lowering in secondary prevention, probably by reducing the risk for plaque rupture.

Clinical trials also demonstrate benefit from LDL lowering in primary prevention, as indicated by the recent West of Scotland Study (21). However, the number of infarctions and deaths are less dramatic than for secondary prevention because patients are not at the same high risk as those with established coronary artery disease. Nonetheless, even in primary prevention trials, the data indicate that a 1-mg/dl lowering of LDL cholesterol levels results in an approximate 1% to 2% reduction in relative risk for coronary artery disease.

Hypertension, Although "cut points" for classification of abnormally elevated levels of blood pressure (Table 1) have been established, data from numerous studies indicate a continuous relationship between systolic and diastolic arterial pressure and cardiovascular risk (22,23). Evidence of target organ involvement at relatively modest levels of hypertension has recently led to a reclassification from the traditional "mild-moderate-severe" to four specific "stages" of hypertension (24). Both the level of blood pressure and markers of end-organ damage are used clinically in the estimation of

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hypertension severity. Specifically, left ventricular hypertrophy (as discussed later), retinopathy and decreased renal function, all of which occur as a consequence of hypertension, are themselves independent markers of cardiovascular risk. Thus, like diabetes mellitus, hypertension is both a risk factor and a "disease."

Nearly 50 million adult Americans, roughly 30% of U.S. adults, have hypertension. It is more prevalent in African- Americans and increases with age. In populations with coronary artery disease, the incidence of hypertension is as much as three times higher in African-Americans than in other ethnic groups (25,26). Hypertension also appears to be more severe in blacks, who have a fivefold higher incidence of severe hypertension (diastolic blood pressure ->115 mm Hg) than whites. Epidemiologically, the risk of hypertension has often been difficult to evaluate independent of its strong association with other risk factors, including physical inactivity, obesity, alcohol and sodium consumption and psychological issues. A meta- analysis by MacMahon and colleagues (27) of nine prospective, observational studies involving over 400,000 participants showed a strongly positive relationship between both systolic and diastolic blood pressure and coronary heart disease; the relationship was linear, without a threshold effect, and showed a relative risk that approached 3.0 at the highest pressures. The presence of such additional factors appears to be both partially causal for hypertension (e.g., weight gain predisposes to elevations in blood pressure) and additive (physical inactivity and hypertension together confer much higher cardiovascular risk than either alone). The mechanism whereby hypertension increases coronary events results from both the direct vascular injury caused by increases in blood pressure and from its effects on the myocardium, including increased wall stress and myocardial oxygen demand.

There is considerable evidence that reducing blood pressure decreases the development of cardiovascular disease events, including coronary artery disease, stroke and heart failure. The reduction in coronary artery disease events in these studies has often been less than that expected from the magnitude of blood pressure reduction. This observation should neither diminish acceptance of the causal role of hypertension in the production of coronary artery disease events or in the importance of its treatment; but it has called attention to both the potentially proatherogenic effects of certain antihypertensive treatments (such as the unfavorable lipid effects of thiazides) and to the possible consequences of excessive blood pressure lowering once severely stenotic coronary or peripheral vascular disease is established.

Left ventricular hypertrophy. Left ventricular hypertrophy is the response of the heart to chronic pressure or volume overload, or both. Its prevalence and incidence are higher with increasing levels of blood pressure (28). For over a quarter of a century, epiderniologic studies have implicated left ventricular hypertrophy as a risk factor for the development of cardiovascular disease, including myocardial infarction, congestive heart failure and sudden death (29,30). Earlier studies documenting the haz- ards associated with left ventricular hypertrophy were based on its

detection on the electrocardiogram (ECG). Echocardiography now provides an autopsy validated, noninvasive method for quantifying left ventricular mass. The use of echocardiography in epidemiologic studies has resulted in an increased appreci- ation of the role of left ventricular hypertrophy as a precursor of coronary artery disease (31). Its association with increased risk has been described in hospital- and clinic-based studies (32-34) and in population studies (31,35,36).

There is a growing body of evidence in hypertensive patients that regression of left ventricular hypertrophy can occur in response to pharmacologic and nonpharmacologic (37,38) antihypertensive treatment. Recent data suggest that regression of left ventricular hypertrophy can reduce the cardiovascular disease burden associated with this condition. A report from the Framingham Heart Study found that subjects who demonstrated ECG evidence of regression of left ventricular hypertrophy were at substantially reduced risk for a cardiovascular event (39) compared to subjects who did not. There are no large-scale echocardiographic studies documenting the prognostic implications of regression of left ventricular hypertrophy, and no intervention trials targeting regression of left ventricular hypertrophy, rather than blood pressure control, have prospectively demonstrated a benefit of regression of left ventricular hypertrophy. Such studies have been planned and are needed to definitively establish the direct benefits of regression of left ventricular hypertrophy.

Thrombogenic factors. Coronary thrombosis is present in most cases of acute myocardial infarction. Aspirin has been documented to reduce both primary and secondary coronary heart disease events, demonstrating that reduction of "thrombogenic" risk improves outcome (40). A number of prothrombotic factors have been identified and can be quantified (41). Some factors can be changed by pharmacologic and behavioral treatments. However, the treatment of any single variable has not been shown to lower coronary, disease risk. Thrombogenic factors are included in this category because antithrombotic treatment itself has been established to lower risk. Thus, in the case of thrombogenic factors, we know that treatment affects risk, but often we do not know which specific abnormalities are being treated.

The importance of thrombogenic factors is further suggested by observations that only one-third of acute myocardial infarctions can be accounted for by other risk factors, such as elevated lipid levels, smoking and hypertension (42). Further- more, a wide variety of clinical conditions known to affect coagulability are accompanied by increased risk of vascular thrombosis. In some cases, these conditions are associated with the production of specific prothrombotic substances, such as antiphospholipid antibody in systemic lupus erythematosus and homocysteine in homozygous homocystinuria. Deficien- cies of serum coagulation inhibitors (e.g., antithrombin III, protein C and protein S) have also been shown to predict thrombotic events, although this has been shown more conclusively for venous as opposed to arterial disease. Treatment of these specific abnormalities generally lowers the risk for thrombotic vascular events.


The production of a coronary thrombus is stimulated by both local factors leading to plaque disruption and hemostasis, and by an imbalance between factors favoring clot formation and those favoring clot lysis. This balance varies in a circadian fashion, with diurnal variation in the incidence of myocardial infarction, stroke, sudden death and silent ischemia (43). The complexity of the clotting cascade and the endogenous throm- bolytic systems makes it clear that a variety of individual factors could be responsible for the enhancement of a thrombotic state. In general, large observational epidemiologic studies have identified constellations of thrombotic factors (see later) associated with an increased risk for coronary artery disease events (44,45). However, it remains uncertain how much the elevated levels of prothrombotic factors are markers of underlying vascular disease rather than primary abnormalities themselves. As with other factors, there appears to be a strong interactive effect when other major risk factors are present as well. Increased cholesterol, in particular, enhances the risk for coronary artery disease events among patients with abnormal hemostatic factors (46).

Except in the presence of a rare specific disease, such as protein C deficiency, there are no cost-effective tests or measures of the prothrombotic state. Thus, in the case of this risk factor, treatment of thrombogenic risk is generally undertaken without identification of the individual factor responsible. Although much attention has been directed at identifying specific thrombogenic abnormalities, direct specific treatment has not yet been shown to alter risk, as discussed later.

Elevated plasma fibrinogen levels predict coronary artery disease risk in prospective observational studies (47). The increase in risk related to fibrinogen is continuous and graded (48). Patients in the upper tertile of fibrinogen distribution have more than a twofold increase in risk for coronary events compared with the lower tertile. In the presence of total cholesterol or LDL cholesterol elevations, high fibrinogen levels increase coronary heart disease risk more than sixfold (46). Low fibrinogen levels appear to offer protection, even in the presence of high total cholesterol levels (49). The predictive power of an elevated fibrinogen level appears to be independent of other risk factors. However, elevated triglycerides, smoking and physical inactivity all are associated with increased fibrinogen levels. Exercise and smoking cessation appear to favorably alter fibrinogen levels, as do fibric acid- derivative drugs. Reducing fibrinogen levels could lower risk by improving plasma viscosity and myocardial oxygen delivery and by diminishing the risk of thrombosis (41). Anticoagulant or antiplatelet therapy may reduce the effect of an elevated fibrinogen level by blocking its impact on the coagulation system, even though these agents do not lower the level of fibrinogen itself.

Several studies support a positive relationship between platelet aggregability and vascular disease, a finding consistent with the known role of platelets in thrombosis and coronary artery disease events (41). Measures of platelet hyperaggrega- bility, including the presence of spontaneous platelet aggregation (50) and increased platelet aggregability induced by

conventional stimuli (51), increase risk in both cohort and cross-sectional studies. Although the benefit of aspirin therapy in primary and secondary prevention has been clearly established, this has not yet been etiologically linked to the reversal of specific platelet abnormalities.

Factor VII is a procoagulatory, vitamin K-dependent protein. High levels of Factor VII coagulant (VIIc) activity are associated with increased coronary artery disease risk in prospective observational studies (45). The level of Factor VIIc is influenced by dietary saturated fat intake and by estrogen use (52). Support for the role of Factor VII is also provided by evidence that it is rapidly affected by oral anticoagulants, which have been shown to lower the risk of myocardial infarction in prospective randomized trials (53).

Other hemostatic factors of possibly causal importance include plasminogen activator inhibitor-1 antigen, tissue-type plasminogen activator (t-PA) antigen, yon Willebrand factor, C-reactive protein, protein C and antithrombin III levels (41,54). It is probable that anticoagulants affect several of these factors, partially explaining their influence on decreasing coronary artery disease risk.

Category II. Risk Factors for Which Interventions Are Likely to Lower Coronary

Artery Disease Events Diabetes mellitus. The relationship between diabetes and

athcrosclerotic risk is complex. Strong epidemiologic and clinical evidence indicates that diabetes mellitus is a major risk factor for coronary artery disease. This is true for both insulin-dependent diabetes mellitus (IDDM) and non-insulin- dependent diabetes mellitus (NIDDM). Atherosclerosis accounts for 80% of all diabetic mortality (55-57). Coronary artery disease alone is responsible for 75% of total atherosclerotic deaths; the remainder results from an admixture of stroke and peripheral vascular disease. Coronary mortality is increased threefold to tenfold in patients with Type I IDDM compared with that in age-matched nondiabetic control subjects. In patients with Type II NIDDM, coronary mortality is increased 200% in male and 400% in female patients. The National Cholesterol Education Program estimates that 25% of all heart attacks in the United States occur in patients with diabetes (58,59).

Because the metabolic abnormalities among different types of diabetic patients and different individual diabetic subjects vary considerably, it is difficult to match the "intensity" of this risk factor with its level of risk. For example, NIDDM, despite lesser degrees of hyperglycemia, may induce greater cardiovascular risk than IDDM (10). Other factors accompanying NIDDM (e.g., insulin resistance, hyperinsulinemia and dyslipidemia) may contribute to the increase in coronary disease risk associated with this form of diabetes. In addition, knowledge that patients with IDDM are at heightened risk for coronary artery disease suggests a pathogenetic role for hyperglycemia as well. Support for this role comes from the observation that,

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among patients with IDDM, better metabolic control appears to lower vascular risk, whereas this has not been clearly shown for NIDDM (60,61).

Some studies suggest that premenopausal women with diabetes have an absolute risk similar to that of men of the same age; if so, the protection against coronary disease af- forded by the premenopausal state may be reduced (62,63). Other studies, however, are not in agreement with this claim, and thus, diabetic women may still enjoy some protection against coronary artery disease (59,64).

Regardless of the underlying metabolic abnormalities, the National Diabetes Data Group (65) defines diabetes as a fasting blood sugar greater than 140 mg/dl. This abnormality is present in approximately 10% of adult Americans (66). In clinical practice, routine oral glucose tolerance testing is less often performed than in the past, whereas measurement of glycohemoglobin concentrations is often employed instead as an assessment of long-term (6 to 8 weeks) glucose control and as a marker of the diabetic state.

Difficulty in understanding the relative risk due to diabetes is most likely due to at least two general factors: 1) the extent to which other metabolic and vascular abnormalities are present, especially those which also independently increase coronary artery disease risk (e.g., lipids and blood pressure), and 2) the extent to which the diabetic disorder is due to inadequate insulin secretion versus inadequate insulin action (i.e., insulin resistance). For example, in IDDM the presence of renal complications, as measured by proteinuria, appears to lead to blood pressure and lipid changes, which in turn increase coronary artery disease risk (67). Other factors in the diabetic patient that increase coronary artery disease risk include increased triglyceride and low HDL cholesterol levels, increased insulin concentrations, central adiposity and hypertension.

Diabetes remains a risk factor for poor outcome in patients with established coronary artery disease, even after angiographic and other clinical characteristics are considered. In the long-term follow-up data from the Coronary Artery Surgery Study (CASS), patients with diabetes had a 57% increase in risk of death after controlling for other known risk factors. After acute myocardial infarction, patients with diabetes have a higher risk of death and other complications. Diabetes has been consistently identified as a risk factor for poor long-term outcome after bypass surgery. In particular, the risk increases after the acute recovery from the operation. The Diabetes Control and Complications Trial (60) convincingly demonstrated that improved glucose control prevents the microvascular complications of IDDM; a reduction in macrovascular complications was probable as well. The role of glucose control in NIDDM is untested.

Physical inactivity. Physical inactivity has recently become a major target of preventive medicine in the United States (68). Approximately 12% of all mortality in the United States may be related to lack of regular physical activity, and physical inactivity is associated with at least a twofold increase in risk for coronary artery disease events (69). It is difficult to measure

physical activity, and consequently, it is difficult to quantify the relationship between the amount of exercise and coronary heart disease risk. Nevertheless, over 50 studies have established that physical activity, either on the job or during leisure time, reduces the risk of coronary artery disease events, particularly in men (70-72). The overall reduction in coronary artery disease events persists despite a small transient increase in the risk of myocardial infarction or sudden death that occurs during physical activity (73,74). Reduction in risk appears greatest between nonactive and moderately active individuals. Less benefit occurs with increases from moderate to extreme amounts of total energy expenditure (69,71,75), Although any activity appears to be of benefit, those activities of higher intensity (->7 kcal/min), such as brisk walking or heavy garden- ing, appear to be more protective (42,76,77).

Exercise probably exerts its beneficial effect through a variety of direct and indirect mechanisms (78). Physical training improves the myocardial supply/demand relationship, lowers triglycerides and raises HDL cholesterol, lowers blood pressure, decreases platelet aggregation and improves other clotting factors. Furthermore, a lower rate of sudden death among those who exercise regularly is consistent with some animal studies suggesting improved myocardial electrical sta- bility. Studies of exercise in both animals (79) and humans (80) with established coronary atherosclerosis demonstrate slowing of atherosclerotic progression, and in some circumstances, actual reversal of the process occurs.

Although no single trial of physical activity in patients with coronary artery disease has had sufficient power to convincingly demonstrate a risk reduction, intermediate end points (e.g., HDL cholesterol and blood pressure) (70) are regularly improved, and several meta-analyses of randomized trials support a powerful (20% to 30%) reduction in coronary disease deaths with regular aerobic exercise (81,82). Interest- ingly, no reduction in nonfatal myocardial infarctions seems to o c c u r .

High density lipoprotein cholesterol. There is a strong inverse epidemiologic association between HDL cholesterol and coronary artery disease risk. This relationship is main- tained over a wide range of HDL levels, and it is estimated that for every 1-mg/dl decrease in HDL cholesterol, the relative risk for coronary disease events increases by 2% to 3% (83). The relationship appears to be equally strong in men and women and among asymptomatic individuals as well as patients with established coronary disease. Some, but not all, genetic deficiencies of HDL or apolipoprotein A-I, the main apolipoprotein in HDL, are associated with premature atherosclerosis, and high HDL levels have been associated with longevity in some studies.

High density lipoprotein cholesterol levels are strongly influenced by family history and by certain life-style factors that in themselves are also risk factors (including cigarette smoking, obesity and physical inactivity). Frequently, but not invariably, low HDL levels are accompanied by high levels of triglycerides due to the close metabolic relationship involv-

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ing cholesterol ester transfer between HDL particles and triglyceride-rich lipoproteins.

Because many lipid-active agents and life-style changes affect multiple lipids simultaneously, it has been difficult to demonstrate that increasing HDL cholesterol independently lowers coronary heart disease risk. No completed trial has been able to address the efficacy of raising HDL cholesterol alone; several are under way. The observation in the Helsinki Heart Study that the reduction in coronary artery disease with gemfibrozil exceeded that expected from the LDL changes alone has been interpreted to indicate a therapeutic benefit from increasing HDL (16). However, there is no consensus on this interpretation of the Helsinki Heart Study results. The Adult Treatment Panel II has identified an HDL cholesterol <35 mg/dl as "low" and considers the presence of high HDL cholesterol a "negative" risk factor (15).

Obesity. There is a linear relationship between body mass and mortality (84). Twenty percent of Americans between 25 and 34 years of age are classified as obese, and approximately 10% of the population becomes obese with each succeeding decade up to the age of 55 (85).

Obesity is associated with other risk factors, including hypertension, glucose intolerance, and decreased HDL and increased triglyceride concentrations. Much of the increased coronary artery disease risk associated with obesity is mediated by these associations. Visceral or central abdominal obesity, which can be quantified by the waist to hip ratios, is a common form of moderate obesity associated with a particular pattern of insulin resistance and hypertension. This pattern has been shown to markedly increase coronary disease risk (86). It appears that the desirable waist to hip ratio is <0.9 for men and 0.8 for middle-aged women (87,88). No study has specifically examined the effect of weight loss or the type of weight loss on coronary artery disease events. Obesity is included as a class II risk factor because of the probability that weight reduction will beneficially alter other important risk factors, often markedly so.

Postmenopausal status. Although coronary artery disease presents about a decade later in women compared with men, cardiovascular disease is nevertheless the leading cause of death among U.S. women. The observation that the protection conferred upon women appears to be lost after natural menopause, and that coronary disease risk clearly increases after surgical menopause, supports the concept that endogenous estrogen protects women against vascular injury (89,90).

Evidence of the beneficial effects of postmenopausal estrogen replacement are derived almost entirely from observational studies. Case-control and cohort studies suggest that estrogen replacement results in a 50% reduction in the risk of developing coronary disease (91,92) and an even greater risk reduction for subsequent coronary events among women with established coronary artery disease (93). Exogenous estrogen favorably affects both HDL and LDL cholesterol, although it modestly elevates serum triglycerides. When lipid levels are factored into a multivariate analysis, the protective effect of exogenous estrogen appears to diminish by about half, suggest-

ing that nonlipid factors, including probable direct effects of estrogen on the vessel wall, may produce some of estrogen's benefit (89). However, these data are observational, and women on postmenopausal hormone therapy may be particularly conscientious about their health and employ other risk- reducing behaviors not accounted for by observational studies. Accordingly, proof of the protective effect of postmenopausal hormone replacement therapy awaits prospective clinical trials, including the Women's Health Initiative. These results will not be available for the next decade.

Category III. Risk Factors Clearly Associated With an Increase in Coronary Artery Disease

Risk, Which, If Modified, Might Lower the Incidence of Coronary Artery Disease Events

Psychosocial factors. As specific risk factors become more difficult to objectively quantify or to reverse with specific interventions, proof that their treatment lowers risk becomes increasingly difficult to demonstrate, regardless of the importance of the factor itself. Thus, demonstration that improve- ment in psychosocial factors lowers coronary heart disease risk has been elusive. A variety of psychosocial factors are associated with increased coronary heart disease risk. Best charac- terized is the so-called type A personality (94,95). However, years of study of type A behavior itself, and efforts to change that behavior, have not convincingly demonstrated that it changes coronary artery disease risk. Psychological stress and particularly the traits of depression and hostility are emerging as factors that reproducibly associate with an increase in coronary artery disease risk (96-98). Social factors that contribute to the relative isolation of individuals (such as lower educational level, economic insecurity and absence of family members or social contacts) are also related to increased coronary artery disease risk in observational studies (99,100).

The mechanism by which psychological and social issues may influence coronary artery disease can be divided into two general categories: 1) direct mechanisms exerting their influence through neuroendocrine effects, particularly by changes in brain catecholamine and serotonin levels and the brain's responsiveness; 2) indirect mechanisms influencing the patient's adherence to preventive recommendations and compli- ance with therapeutic strategies. Recent data suggest that the two mechanisms may be linked. For example, it has been shown that serotonin-active drugs in selected (e.g., depressed) patients may enhance smoking cessation (101).

The presence of major depression after acute myocardial infarction increases 6-month mortality more than and independent of such clinical factors as heart failure and extent of coronary disease (96,98). Hostility appears to have a particularly powerful influence on coronary artery disease outcome compared to other psychosocial factors (97,102). Patients without a "confidant" (spouse or other) have a threefold increase in 6-month mortality after acute myocardial infarction (99). Chronic stress, such as that produced by situations with


"high demand and low control" (103), doubles the risk of developing a myocardial infarction, even after controlling for other risk factors. Acute psychological stress may also increase risk of coronary artery disease events (104).

Interventions to improve psychosocial traits can improve adherence to medical regimens and enhance an individual's psychological state. Control of other risk factors can thereby be favorably influenced as well. Data from small prospective trials and from a meta-analysis of intervention trials also suggest that mortality and the frequency of recurrent events can be reduced (105,106).

Triglyeerides. The relationship between serum triglyceride and coronary artery disease has been difficult to elucidate and remains controversial. Triglyceride levels uniformly predict coronary heart disease in univariate analyses but often lose their predictive power when other risk factors, particularly HDL cholesterol, are added in a multivariate analysis. Some have suggested that HDL cholesterol and triglycerides should not be considered separately and that the combination of low HDL cholesterol and high triglycerides together is responsible for the marked increase in coronary artery disease risk when abnormalities of either alone are analyzed (107). When increased triglyceride levels are associated with increases in very LDL particles, high concentrations of "small, dense" LDL or high apolipoprotein B, the risk for coronary artery disease events is increased (108-110).

This issue has become more complex with recognition of two important nonlipid associations of high triglyceride levels: 1) Abnormalities of various clotting factors are also associated with hypertriglyceridemia (111). 2) In the syndrome that is variously known as syndrome X or familial dyslipidemic hypertension, high triglyceride levels, low HDL cholesterol, insulin resistance, abdominal adiposity and hypertension coexist and are metabolically linked (112). Patients with this constellation are relatively common, comprising an estimated 12% of all hypertensive patients (113,114), and are noted to have a markedly increased risk of coronary artery disease events.

Weight loss, dietary changes, including caloric restriction and a decrease in alcohol consumption, smoking cessation and physical activity all decrease triglyceride levels. However, it cannot be currently determined whether any reduction in risk resulting from these changes is due to the triglyceride lowering itself. Several lipid-lowering studies have suggested that the greatest reduction in coronary artery disease mortality and events occurs with LDL cholesterol lowering in patients with elevated triglyceride levels (16,115). Thus, detection and reduction of an elevated triglyceride level appears to be most important in patients at highest risk, particularly those with other risk factors, including an elevated LDL cholesterol and a decreased HDL cholesterol.

A 1992 Consensus Development Conference defined 200 to 400 mg/dl as "borderline high triglyceride," 400 to 1,000 mg/dl as "high triglyceride" and >1,000 mg/dl as "very high triglyceride" (116). Based on these definitions, the Adult Treatment Panel II has suggested a treatment algorithm for the atherosclerosis-prone individual with elevated triglyceride levels (15).

Lipoprotein(a). Lipoprotein(a) [Lp(a)] is a lipoprotein particle consisting of an LDL molecule in which the major apoprotein of LDL, apo B100, is linked to an additional large protein designated apo(a) (117). Although Lp(a) was identified and linked to coronary artery disease over 30 years ago, recent attention derives from both further epidemiologic evidence of this risk association and from recognition that apo(a) has structural homology with plasminogen, making Lp(a) a potential inhibitor of fibrinolysis (117,118).

Lipoprotein(a) levels are not normally distributed. They are markedly skewed to the lower end of the range, and some individuals have virtually undetectable levels. Levels within populations vary 1,000-fold (119) and are independent of other lipid levels. Lipoprotein(a) levels are largely genetically determined through autosomal dominant inheritance (117). Among patients with premature coronary artery disease, 15% to 20% have elevated Lp(a) levels, making Lp(a) the most common inherited lipoprotein disorder associated with premature coronary disease (120). Lipoprotein(a) levels increase slightly with age, are higher in blacks than in whites and tend to be higher in women (121,122). Lipoprotein(a) levels increase by about 8% in women after menopause (121). Diet does not appear to affect Lp(a) levels; however, both anabolic steroids and estro- gens reduce Lp(a), although the effect is highly variable (117,118,123). Among conventional lipid agents, only niacin lowers Lp(a) levels (117).

The evidence that Lp(a) is a risk factor for coronary artery disease events is based largely on retrospective observational studies (117,118). These findings, combined with laboratory investigations demonstrating a variety of proatherogenic effects for Lp(a), have led to widespread interest in Lp(a) as an important risk factor (124). Large prospective study data are, however, controversial. Recently one study failed to demonstrate an association between Lp(a) and risk of myocardial infarction among men (119), whereas another supported the association between Lp(a) and coronary disease events (125). No prospective interventional trial information is available to confirm the importance of Lp(a) in coronary disease. Further- more, issues of sample handling, risk in different populations and the relative importance of different Lp(a) isoforms will need to be addressed before the role of Lp(a) in coronary artery disease risk can be resolved.

Homocysteine. Catabolism of the amino acid homocysteine is largely dependent on the enzyme cystathionine B-synthase, the complete absence of which leads to the childhood disease homocysteinuria and early mortality due in part to advanced arterial lesions (126). Heterozygosity for the enzyme produces elevated homocysteine levels in adulthood (126). Homocys- teine levels can also be increased by deficiencies of vitamins B 6 and B12 or folate (127,128). Increased homocysteine levels are associated with increased risk of both coronary artery disease and peripheral arterial disease (126,129). Of patients identified with elevated homocysteine levels, approximately two thirds appear to be associated with low levels of these vitamins (127). While prevalence information regarding increased homocysteine levels is complex and incomplete, data from the elderly


cohort of the Framingham Heart Study population suggest that over 20% of this population has elevated homocysteine levels (127). Homocysteine-induced vascular damage may occur as a consequence of the amino acid's procoagulant activities or by direct injury of vascular endothelium (126). From both mech- anistic and epidemiologic points of view, bomocysteine appears to be unrelated to other cardiovascular risk factors.

The prevalence of hyperhomocysteinemia among patients with vascular disease varies from approximately 25% to 45%, depending on the age group studied (129). The risk of premature occlusive vascular disease is 30 times greater for those with elevated levels than for normal control subjects (129). An elevated homocysteine level is associated with a 3.4-fold increase in 5-year myocardial infarction risk in a prospective study of participants in the Physician's Health Study (130). Because vitamin B6, vitamin B12 or folate supplements can reverse moderately elevated blood levels of homocysteine, prospective clinical trials have been proposed (131).

Oxidative stress. Extensive laboratory data indicate that the oxidative modification of LDL cholesterol, particularly in the vessel wall, accelerates the atherogenic process (132,133). Oxidized LDL cholesterol may facilitate atherosclerotic disease by recruiting monocyte macrophages, stimulating auto- antibodies, stimulating LDL uptake by macrophages and increasing vascular tone and coagulability. Antioxidants, both in vivo and in vitro, can increase LDL resistance to oxidation and are associated with lower coronary artery disease risk in epidemiologic studies. Reports of antioxidant vitamin consumption as part of a regular diet have suggested that those diets high in vitamin C, vitamin E and beta-carotene are protective against coronary heart disease in both men and women (134-136). Many other dietary and nondietary factors may reduce LDL oxidation, including selenium, estrogen, flavonoids, magnesium and monounsaturated fat. Iron, copper, zinc and saturated fats all are likely to increase oxidative potential.

Prospective observational studies suggest a powerful effect of antioxidant vitamin supplement consumption, particularly vitamin E, but results are inconsistent and may depend on baseline consumption of foods with antioxidant potential or on the presence of other oxidative stresses such as smoking (137,138). Although several small prospective interventional trials in animals and humans have suggested a benefit of vitamin supplements, the only large prospective randomized trial--the Finnish Alpha-Tocopherol Beta-Carotene Cancer Prevention Study--failed to lower coronary artery disease risk among middle-aged male smokers (139). Thus, although en- hanced dietary intake of foods with antioxidant potential is likely to be of benefit, the value of vitamin supplementation continues to be unresolved. Several prospective trial results are due in the near future (140).

Alcoholic beverage consumption. Individuals reporting moderate amounts of alcohol intake (approximately one to three drinks daily) have a 40% to 50% reduction in coronary artery disease risk compared with individuals who are abstinent (141-143). Excessive consumption of alcohol is associated with

increased coronary disease risk (144), possibly resulting from misclassification of alcoholic cardiomyopathy as coronary heart disease or from alcohol's ability to produce hypertension and to increase cardiac arrhythmias (145). In addition, excessive early alcohol intake can produce many other medical problems that can outweigh its beneficial effects on coronary artery disease risk.

An alcohol-induced increase in HDL cholesterol accounts for approximately half of the reduction in myocardial infarctions associated with moderate alcohol intake. Alcohol appears predominantly to reduce the incidence of myocardial infarction and sudden cardiac death and has less effect on the incidence of angina pectoris (143). This suggests that alcohol's reduction in risk may be mediated by effects on vascular reactivity (146) or on hemostatic factors (147,148), thereby reducing acute events rather than reducing coronary atherosclerosis progression. This concept is supported by limited autopsy data indicating that alcohol has little effect on coronary atherosclerosis among moderate drinkers (143) and by several angiographic studies documenting fewer coronary oc- clusions among moderate drinkers (149).

It has been suggested that the reduction in coronary disease risk associated with alcoholic beverages is due to the effect of alcohol alone. Several studies demonstrate similar reductions in risk for beer, wine and hard liquor (143,150), whereas wine alone accounts for most of the reduction in risk in some studies (151,152), and beer may actually increase risk in others (152). Among populations with high cholesterol and saturated fat intake, wine consumption is more strongly related to reduced risk than total alcohol consumption, and wine intake might explain some of the decreased rate of coronary heart disease among the French despite their high saturated fat intake (151). Both red wine and grape juice inhibit platelet activity in vivo (147), lending credence to the idea that some derivative of red grapes is beneficial. Such observations raise the possibility that the alcohol-containing beverage itself may also influence coronary artery disease risk.

Category IV. Risk Factors Associated With Increased Risk but Which Cannot Be

Modified or Whose Modification Would Be Unlikely to Change the Incidence of

Coronary Disease Events Although age, gender and family history are not modifiable,

it is likely that all these factors exert their influence on coronary artery disease risk, at least in part through other risk factors noted previously. In Western populations, coronary artery disease risk increases nearly linearly with age and is greater in men compared to women until approximately age 75, when the prevalence is nearly equal. Below 55 years of age, the incidence of coronary heart disease among men is three to four times that among women; after 55 years, the rate of increase with age in men declines and that in women continues to increase, so that incidence rates in men and women become

JACC VoL 27, No. 5 PASTERNAK ET AL. 987 April 1996:964-1047 TASK FORCE 3

similar in older persons (153). The gender differential is greatly attenuated in nonwhite populations and in populations with low coronary heart disease rates (154). In patients with known coronary artery disease, age is one of the most powerful predictive factors for death, although its relationship to nonfatal events has been less thoroughly evaluated. In the post- myocardial infarction setting, older patients are at higher subsequent risk of death than younger patients, and the effect of age predominates over other risk factors.

Because coronary artery disease clusters in families, a family history of premature coronary heart disease is a risk factor. The National Cholesterol Education Program (NCEP) lists the family history of premature coronary heart disease high on their list of recognized risk factors (15). With increasing numbers of elderly patients, the high prevalence of coronary heart disease and increasing levels of therapeutic intervention in older patients, it is important to define "premature" in relation to the development of coronary heart disease. Although age is a continuous variable, cut points are useful; and for this purpose, the NCEP defines a family history of premature coronary heart disease as a definite myocardial infarction or sudden death before 55 years of age in a father or other male first-degree relative, or before 65 years of age in a mother or other female first-degree relative.

Over a decade and a half ago, Hopkins and Williams (155) surveyed 246 "suggested coronary risk factors" from the literature. A similar survey undertaken today would most likely add dozens more. If the only criteria for identification of a "risk factor" is recognition of an association with coronary heart disease, then the total number of such factors would be enormous. Many factors cited in such reviews are often the source of much media and lay attention, including markers such as the ear lobe crease, premature baldness and height, to name a few. Although recognition of such factors may help to predict future coronary events, their modification is not likely to influence the course of an individual's vascular disease, and thus, for the purposes of the task of matching level of risk with level of management, they need not be considered further.

Summary In matching management intensity with cardiovascular risk,

we proposed a scheme of categories of descending levels of evidence to support the benefit of direct management. That is, we began with those risk factors for which the most conclusive evidence exists and whose management favorably affects outcomes, and we ended with those factors for which management opportunities are minimal or absent or for which modification would not or could not alter the course of the disease. The proposed risk factor categories are as follows:

I. Risk factors for which interventions have proved to reduce the incidence of coronary artery disease events (cigarette smoking, LDL cholesterol, hypertension, thrombogenic factors).

II. Risk factors for which interventions are likely, based on our current pathophysiologic understanding and on epidemi-

ologic and clinical trial evidence, to reduce the incidence of coronary artery disease events (diabetes, physical inactivity, HDL cholesterol, obesity, postmenopausal status).

III. Risk factors clearly associated with an increase in coronary artery disease risk and which, if modified, might lower the incidence of coronary artery disease events (psychosocial factors, triglycerides, Lp(a), homocysteine, oxidative stress, alcohol consumption).

IV. Risk factors associated with increased risk but which cannot be modified or whose modification would be unlikely to change the incidence of coronary disease events (age, gender, family history and many others).

Dietary modification is important throughout the course of evaluation and management of many of the major risk factors. Therefore, "diet" has not been included in the list of risk factors as categorized in this task force. Rather, we recognize that diet interacts with different risk factors at many different levels. If diet were to be included, it would qualify for category I status.

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