© 1999 American Heart Association, Inc.
Brief Review |
Coronary Heart Disease: Reducing the Risk
The Scientific Background to Primary and Secondary Prevention of Coronary Heart DiseaseA Worldwide View
From the Institute of Arteriosclerosis Research and Institute of Clinical Chemistry and Laboratory Medicine (G.A., P.C.), University of Münster, Münster, Germany; the Department of Clinical and Experimental Medicine (F.J., M.M.), University of Naples, Naples, Italy; and the University of London (B.L.), London, UK.
Correspondence to Prof Gerd Assmann, International Task Force for Prevention of Coronary Heart Disease, Heerdestraße 9, 48149 Münster, Germany. E-mail chdtask{at}uni-muenster.de
Key Words: atherosclerosis • risk factors • coronary heart disease
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Introduction |
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 Top Introduction Risk Factors for CHDGlobal Risk of CHDManagement of CHD Risk...The Future of Risk...ConclusionsReferences |
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Coronary heart disease (CHD) is the major cause of death in most developed countries and in many developing countries. The clinical complications of CHD lead to substantial disability and are a main source of the rising cost of health care. While CHD incidence is decreasing in western Europe, the United States, and Australia, it is steeply increasing in central and eastern Europe and, to some extent, in Asia and Africa.1 2 3 4 Worldwide, the need for more effective preventive strategies against CHD has become urgent and cannot be postponed. Much has been learned about preventive policies, both at the population and the individual level, in the past decade. The International Task Force for Prevention of CHD has developed an updated document that takes into account the results of the recent, major, lipid-lowering trials of primary and secondary prevention. Clinical and quantitative approaches are provided to assess the global risk of CHD according to classic and newly recognized risk factors and thereby to assign an appropriate level of intervention against risk factors. This targeted strategy maximizes the use of dietary methods and provides clear indications for drug treatment.
The primary importance of improving health-related behavior in the population as a whole is emphasized. In the present document, the undervalued scope for preventive care at the individual clinical level is the major theme; it is based on the selection and management of persons whose level of risk cannot adequately be reduced by presently available population measures.
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Risk Factors for CHD |
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TopIntroductionRisk Factors for CHDGlobal Risk of CHDManagement of CHD Risk...The Future of Risk...ConclusionsReferences |
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Age, sex, and personal and family history of cardiovascular disease are nonmodifiable risk factors for CHD. Hypercholesterolemia, hypertension, and cigarette smoking are the major modifiable risk factors.5 6 7 They powerfully influence risk, are common in populations, and are widely amenable to prevention and treatment. Low HDL cholesterol levels are also regarded as an important risk factor for CHD. Other modifiable determinants of risk should be taken into account in the management of CHD, such as diabetes, obesity, and physical inactivity.8 9 More recently, evidence has accumulated on a possible association of increased triglycerides, lipoprotein(a), and fibrinogen levels with an increased risk of CHD.10 Other variables under current investigation include coagulation factor VIIc, homocysteine,11 12 and plasminogen activator inhibitor-I. A new area of research for candidate risk factors is now directed to polymorphisms and abnormalities in several genes affecting lipoprotein and glucose metabolism and blood pressure regulation, including apolipoprotein E and the enzymes lipoprotein lipase, glucokinase, and angiotensin-converting enzyme (ACE). Inadequate protection of lipoproteins against oxidation is under current investigation as a further risk factor.13
The relationship between nutrition and CHD has now been well
established and is mainly based on epidemiological findings in
populations and nutritional intervention trials.14 15 16 17 18 19 20
Stroke is also an important issue in the population at risk for
CHD.21 Patients with CHD often suffer from stroke and vice
versa. Because stroke and CHD share several risk factors, strategies
aimed at reducing CHD incidence might be expected to also decrease the
incidence of cerebrovascular events. There is increasing evidence that
both antihypertensive treatment and lipid-lowering therapy with
statins, presumably through stabilization of atherosclerotic plaques
with a consequent lower frequency of embolism, reduce the incidence of
stroke. In Western countries, ischemic stroke is much more
common than the hemorrhagic variety (
80% versus 20%).
Nonmodifiable risk factors for ischemic stroke are age, sex,
race, and inherited predisposition. Well-documented modifiable risk
factors are hypertension (the single most important cause of stroke),
diabetes, cardiac disease, cigarette smoking, overweight, elevated
hematocrit, and increased levels of fibrinogen and tissue-type
plasminogen activator
inhibitor.
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Global Risk of CHD |
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Comprehensive assessment of CHD risk is of primary importance. The concept of "global risk" emphasizes the need to include as many as possible of the known independent risk factors in the evaluation of the patient's cardiovascular risk profile, with a view to treating each (but particularly hyperlipidemia and hypertension) in the context of overall risk.22 23 24 Therefore, global risk is important in determining the patient's prognosis, the choice of appropriate therapy, and the target levels for risk factor reduction (ie, serum cholesterol levels to achieve with a given level of risk). In the context of managing elevated plasma lipid levels, this scheme provides for informed decisions regarding how stringent the diet should be, whether a drug should be used and in what dosage, and whether a drug combination is needed. For these purposes, the patient is assigned to the category of average risk or to 1 of 3 levels of increased risk (Table 1
). This may be performed by clinical
judgment or quantitatively by means of the algorithms derived from the
Framingham Study and the PROCAM Study (Prospective
Cardiovascular Münster Study) reported in detail
in the full version of this document.25 26 To illustrate
this concept of global risk estimation, risk calculation in sample
patients in shown in Table 2.
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Management of CHD Risk Factors |
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TopIntroductionRisk Factors for CHDGlobal Risk of CHDManagement of CHD Risk...The Future of Risk...ConclusionsReferences |
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Hyperlipidemia
Hyperlipidemia can be primary or secondary, or both may be present. Primary hyperlipidemias are classified for clinical purposes as (1) hypercholesterolemia (polygenic or familial); (2) combined (mixed) hyperlipidemia; or (3) hypertriglyceridemia.
In cases where hyperlipidemia is secondary to a treatable cause (eg, a side effect of a drug, hypothyroidism, alcohol abuse, or diabetes), this should be dealt with first. Primary hyperlipidemia is treated according to its type and severity, in the context of global risk of CHD. Whenever possible, the physician determines not only total cholesterol but also HDL cholesterol, LDL cholesterol, and triglyceride levels to evaluate the lipid-mediated risk of CHD and to permit a rational choice of drug therapy if required. Diagnosis of hyperlipidemia requires at least 2 consistent analyses.
Hyperlipidemia is managed primarily by conservative
measures (correction of overweight, a lipid-lowering diet, and removal
of underlying causes); drug treatment is instituted only if
conservative measures fail to achieve the lipid target value. The
decision for lipid-lowering drug therapy should be based on trial data
wherever possible. Five major, lipid-lowering trials with
3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors
(statins) have been completed in recent years, and they form the basis
of current recommendations. The results of these trials, the
Scandinavian Simvastatin Survival Study
(4S),27 the West of Scotland Coronary Prevention
Study (WOSCOPS),28 the Cholesterol and
Recurrent Events (CARE) study,29 the Air Force/Texas
Coronary Atherosclerosis Prevention Study
(AFCAPS/TexCAPS),30 and the Lovastatin in the
Prevention of Ischemic Disease (LIPID) study,31
clearly show that lowering LDL cholesterol, the most
atherogenic lipoprotein class, by statin drugs in addition to diet
reduces the incidence of fatal and nonfatal myocardial infarction in
both primary and secondary prevention. Total mortality is also reduced
by LDL cholesterol–lowering treatment, particularly in
individuals with CHD. It should be noted, however, that the numbers
that need to be treated to see an end-point change in such trials
depend on the level of risk in the patients included; in populations at
lower risk, more patients will need to be treated to prevent 1 event
than in populations at high risk, eg, those with established CHD (Table 3). Persons with the highest pretreatment
LDL cholesterol levels achieve greatest benefit from
treatment. Subgroup analyses of these trials have also shown
benefit in various ethnic groups, in both sexes, in all age groups, and
in diabetics. The high incidence of CHD among the elderly
represents a growing problem worldwide. To some extent, doubts
concerning the value of prevention in the elderly may have stemmed from
the belief that once atherosclerosis becomes
established, interventions are unlikely to alter its course. However,
in both the 4S27 and Veterans Administration
studies,31 lowering of LDL cholesterol was as
effective in reducing the risk of cardiovascular events
in the over-60s as in younger participants. Beyond 85 years, high
plasma cholesterol concentrations are associated with
increased life expectancy because undiagnosed cancers and infections
lower cholesterol levels. The effects of
cholesterol-lowering therapy have yet to be assessed in
this age group. A further notable result is the reduction in the
treatment group of the incidence of stroke, a predefined end point in
the LIPID and CARE studies. Side effects were not a serious problem in
any of these trials, and total cancer deaths were not affected by drug
treatment. Furthermore, no trial showed a significant increase in
suicide and violent or accidental death.
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Hypertension
Arterial hypertension is a risk factor for stroke,
CHD, and other cardiovascular diseases.33
Its treatment reduces the incidence of stroke by 40% and of CHD by
14% within 5 years; the benefit occurs in both mild and severe
hypertension and at all ages up to 75 years. The goal for blood
pressure reduction is a systolic pressure of 140 mm Hg or
less and a diastolic pressure of 90 mm Hg or less.
The Hypertension Optimal Treatment (HOT) Study showed that in high-risk
patients with a history of CHD, aggressive antihypertensive therapy is
safe, with no evidence of a U-shaped relationship between attained
diastolic blood pressure and rate of major
cardiovascular events.34 Isolated
systolic hypertension is a cardiovascular risk
factor, especially in the elderly, and should be
treated.35 36 Hypertension tends to coexist with lipid and
thrombogenic risk factors; this clustering is due in part to truncal
obesity and inheritance. Because of the high risk conferred by multiple
risk factors, comprehensive treatment is essential. Nonpharmacological
treatment should be employed in all hypertensives. It may be fully
effective or may lessen the need for drug treatment. Reduction of
overweight and curtailed intake of alcohol are all of proven benefit,
although individual response varies. A decrease in dietary salt to 60
to 100 mmol/d (3.5 to 5.5 g as NaCl) has also been
recommended, although much controversy surrounds this
issue.37 38 Drug treatment commences with monotherapy,
using 1 of the following drugs: thiazide diuretics in low
dosage, ß-blockers (especially if angina is present), ACE
inhibitors, calcium channel blockers, 
-blockers, or
angiotensin II receptor blockers. Although ß-blockers may
cause diabetic patients to be less aware of hypoglycemia and although
both thiazides and ß-blockers may unfavorably alter lipid profiles,
randomized, controlled trials suggest that these agents remain
effective in hypertensive patients with diabetes mellitus. Two or more
drugs are needed in 50% of hypertensives, eg, ACE
inhibitors with a low-dose thiazide or a calcium
antagonist, or a ß-blocker with a calcium
antagonist or a low-dose thiazide. Although
diuretics, ß-blockers, and calcium antagonists
have been shown to reduce morbidity and mortality in systolic
hypertension, this is true for ACE inhibitors only in the
case of hypertensives with heart failure.
Diabetes
Coronary and peripheral atheroscleroses are
major causes of morbidity and mortality in diabetics. Careful diabetic
control is essential. The ideal goal should be to maintain the level of
glycosylated hemoglobin below 7.0%.
To reduce cardiovascular risk in diabetes, meticulous control of blood glucose, correction of obesity by diet and exercise, quitting smoking (of particular importance), correction of abnormal plasma lipids, and blood pressure control are important. In fact, to date, the only treatments that have been shown to reduce mortality in diabetics are statins and blood pressure lowering. Lipid disorders are usually more pronounced in non–insulin-dependent diabetics (type 2) and in glucose-intolerant individuals than in treated insulin-dependent diabetics (type 1) and are improved by glycemic control and correction of overweight. Diet comprises a carbohydrate intake of 55% of calories, emphasizing complex carbohydrates rich in soluble fiber. Total fat intake should be 30% to 35% of daily energy, with reduction of saturated fat to 7% of daily energy. Consumption of monounsaturated fats should be encouraged. Total cholesterol consumption should be restricted to <300 mg/d.
Obesity
The distribution of body fat, and not just its extent, is
important. An excess of truncal and intra-abdominal fat is a risk
factor for CHD and has an adverse influence on lipid levels, blood
pressure, and glucose tolerance. Therefore, central obesity should be
accorded particular attention; this is defined as a waist-to-hip ratio
of >1 in men and >0.85 in women. Life expectancy is greatest at a
body mass index of 18.5 to 25.0. (Body mass index is defined as weight
in kilograms divided by the square of height in meters.) Successful
weight reduction requires the support of the physician, a
calorie-restricted diet, and a suitable exercise program. Although new
drugs are available to treat obesity, their importance in terms of
morbidity and mortality remains to be determined, and the cornerstone
of treatment remains diet and exercise.
Thrombogenic Risk Factors
Thrombogenic factors increase the risk of acute coronary
occlusion and stroke and may play a causal role. Health-related
behavior is important in the management of these factors and includes
smoking cessation, reduction of overweight, a low intake of saturated
fat, and an increased consumption of polyunsaturated fatty acids (
-6
and -3). Weight reduction and some fibrate drugs lower plasma
fibrinogen. Activation of platelets plays a central role in
unstable angina, and antiplatelet drugs can prevent such
activation. The action is maximal immediately after the
ischemic event and lasts 36 months. The effect of
antiplatelet medications is optimal when they are combined with
treatment of the coexistent risk factors, such as cigarette
smoking, hyperlipidemia, and hypertension. The
recommended dosage of acetylsalicylic acid is 75 to
160 mg/d. Ticlopidine can be used as an alternative to
acetylsalicylic acid. Data from a recent, large
trial showed that 75 mg clopidogrel per day may be more effective than
300 mg acetylsalicylic acid per day in reducing the
thrombotic complications of
atherosclerosis.39
Cigarette Smoking
About 30% of cardiovascular deaths are due to
smoking.40 Recent evidence suggests that cigars and pipe
tobacco also confer an increased risk of CHD. Smoking may be an even
more important source of risk in areas with a rising incidence of
cardiovascular disease, such as Asia and eastern and
central Europe, than it is in western Europe and the United States.
Smoking cessation reduces CHD risk and is highly cost-effective. Doctors can contribute to public health education against smoking. Smoking cessation programs include brief individual counseling and extended counseling for the persistent smoker. Nicotine replacement (skin patches with a progressively decreasing dosage) is of value in the motivated patient without CHD but must be supported by a counseling program.
Physical Exercise
Lack of exercise is predictive of high CHD risk, and this
relationship is independent of other risk factors. There is strong
epidemiological evidence that aerobic exercise reduces the risk of CHD.
Individuals who habitually expend 2000 to 3000 kcal/wk in leisure-time
activities have 2 to 3 times fewer coronary events
than do those expending <500 kcal/wk.Those who exercise
regularly have less body fat, a higher HDL cholesterol
level, lower LDL cholesterol and triglyceride
levels, greater insulin sensitivity, and lower blood glucose and blood
pressure. An exercise program should be recommended to all persons with
a sedentary lifestyle, with a clear and detailed prescription to meet
the parallel needs of safety, personal enjoyment, and effectiveness.
Aerobic exercise is obtained by using large-muscle groups to perform a
high number of repetitive movements against relatively low resistance;
brisk walking is an excellent form of aerobic activity. Generally, an
exercise program includes 3 phases. Warming up for 5 to 10 minutes by
stretching and other gentle activity is followed by an endurance or
aerobic phase of 20 minutes or longer, according to fitness level, and
finally a cool-down period of progressively decreasing intensity allows
cardiovascular activity and heat production to
subside gradually. Persons at high CHD risk should exercise under
medical supervision at least initially and should undergo an exercise
ECG test before starting an appropriate program of physical
activity.
Homocysteine
Homocysteine, a sulfur amino acid, is an intermediate product
of the metabolism of methionine and cysteine.
Homocystinuria, a rare homozygous defect, is associated with an up to
10-fold elevation of plasma homocysteine levels, premature
atherosclerosis, and recurrent thromboses. Lesser
degrees of hyperhomocysteinemia are commonly associated with CHD.
However, homocysteine elevation may not be an independent CHD risk
factor, because these levels are related to renal function, smoking,
fibrinogen, and C-reactive protein, which are themselves associated
with an increased incidence of CHD. Moreover, the risk threshold for
homocysteine is unclear and has been reported to lie between 12 and
18 mmol/L. Treatment with folic acid, vitamin
B6, and vitamin B12 lowers
homocysteine levels, but evidence that this treatment reduces the
cardiovascular event rate remains conflicting.
Homocysteine levels should be measured in patients with a history of
premature CHD and/or stroke in the absence of other risk factors.
The Metabolic Syndrome
The metabolic syndrome is a cluster of
metabolic disturbances that strongly predisposes to
the development and progression of atherosclerosis.
Peripheral resistance to insulin seems to be the central
feature of this syndrome, which is characterized by central obesity,
hyperinsulinism, and 1 or more of the following
abnormalities: impaired glucose tolerance, dyslipidemia,
hypertension, hyperuricemia, gout, and fatty liver. The
dyslipidemia of the metabolic syndrome is the
"lipid triad," consisting of high LDL cholesterol and
triglyceride levels and low HDL cholesterol
levels. Treatment is primarily the reduction of body weight through
diet and physical exercise. This may lead to marked improvement or full
correction of the other metabolic disturbances.
There is a steeply increasing incidence of CHD in postmenopausal women. The risk factors that operate in women are similar to those active in men, but women are more vulnerable to smoking and hypertriglyceridemia. Although observational data suggest that estrogen replacement reduces CHD risk, interpretation is limited by possible self-selection in such studies. In a recent controlled trial of hormone replacement therapy with estrogen and progestin in postmenopausal women, no effect on nonfatal myocardial infarction or CHD death was observed.41
The high incidence of CHD in the growing segment of the population aged 60 years and over is of great importance. Although the relative risk conferred by risk factors such as elevated plasma cholesterol in this group is lower than in middle age, the absolute risk is equal or greater. Risk factor intervention may therefore be of considerable value; although controlled-trial data are yet sparse, they tend to support this view. In assessing the need for intervention, both quality of life and life expectancy are taken into account. It should be borne in mind that radical changes in lifestyle become more difficult in the elderly. Also, greater drug use in this age group increases the possibility for drug interactions.
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The Future of Risk Assessment |
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TopIntroductionRisk Factors for CHDGlobal Risk of CHDManagement of CHD Risk...The Future of Risk...ConclusionsReferences |
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It is likely that research currently under way in the areas of genetics, molecular biology, and cardiac physiology will greatly contribute to the assessment of CHD risk in the future. Such issues include (1) genetic polymorphism and abnormalities of genes affecting lipoprotein and glucose metabolism and blood pressure regulation; (2) endothelial function; (3) plaque instability and inflammation; (4) LDL oxidation; and (5) parameters of inflammation (eg, C-reactive protein, Chlamydia pneumoniae, etc).
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Conclusions |
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TopIntroductionRisk Factors for CHDGlobal Risk of CHDManagement of CHD Risk...The Future of Risk...ConclusionsReferences |
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Based on a large body of evidence, prevention of CHD should start with global risk assessment and proceed to suitable treatment of correctable risk factors. If the blood lipid profile is abnormal, this should be corrected. Target levels for LDL cholesterol, according to CHD risk categories, are summarized in Table 4
. Weight control, a qualitatively
satisfactory diet, and suitable aerobic exercise are of paramount
importance. The indications for drug therapy in CHD prevention are
increasingly well defined.
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Footnotes |
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1 Drafting Committee: G. Assmann (Chairman), R. Carmena, P. Cullen, J.-C. Fruchart, B. Lewis, M. Mancini, A. Olsson, R. Paoletti, D. Pometta, and M. Tikkanen.
The full version of this document, which was prepared in cooperation with the International Atherosclerosis Society, has been published in Nutrition, Metabolism and Cardiovascular Disease, volume 8, issue 3, 1998, and is also available on the Task Force Internet home page at http://www.chd-taskforce.com
Received September 28, 1998; accepted November 24, 1998.
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