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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/
JACC gol. 27, No. 5
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effect relationship, high absolute attributable risks identify the
public health consequences and value of treatment.
Further Readings
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. P A S T E R N A K , 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. T H O M P S O N , 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,
P A S T E R N A K ET AL.
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cholesterol and calorie content is widely recognized to exacerbate 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. Consumption 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). Smoking 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 proportion 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 nephrotic 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 Prospective Cardiovascular MOnster (PROCAM) study (17).
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Table 1. Classification of Blood Pressure for Adults 18 Years
and Older*
Category
Normal
High normal
Hypertensiont
Stage 1 (mild)
Stage 2 (moderate)
Stage 3 (severe)
Stage 4 (very severe)
SBP
(ram Hg)
DBP
(mm Hg)
<130
130-139
<85
85-89
140-159
160-179
180-209
->210
90-99
100-109
110-119
->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 AfricanAmericans 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 metaanalysis 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 hazards associated with left ventricular hypertrophy were based on its
P A S T E R N A K ET AL.
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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 appreciation 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). Furthermore, 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. Deficiencies 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.
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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 thrombolytic 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 acidderivative 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 hyperaggregability, including the presence of spontaneous platelet aggregation (50) and increased platelet aggregability induced by
JACC Vol. 27, No. 5
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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-insulindependent 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 afforded 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
PASTERNAK ET AL.
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983
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 gardening, 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 stability. 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). Interestingly, no reduction in nonfatal myocardial infarctions seems to
occur.
High density lipoprotein cholesterol. There is a strong
inverse epidemiologic association between HDL cholesterol
and coronary artery disease risk. This relationship is maintained 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-
984
PASTERNAK ET AL.
TASK F O R C E 3
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.
Postmenopausalstatus. 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-
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April 1996:964-1047
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 riskreducing 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
Psychosocialfactors. 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 improvement 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 characterized 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 compliance 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
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April 1996:964-1047
"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).
PASTERNAK ET AL.
TASK FORCE 3
985
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 estrogens 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. Furthermore, 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). Homocysteine levels can also be increased by deficiencies of vitamins B6
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
986
PASTERNAK ET AL.
TASK FORCE 3
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 mechanistic 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 autoantibodies, 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 enhanced 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
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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 occlusions 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
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PASTERNAK ET AL.
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 postmyocardial 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-
987
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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