Caballero B. (ed.) Encyclopaedia of Food Science, Food Technology and Nutrition. Ten-Volume Set

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Hypotheses Tested by Dietary

Intervention Trials

0019 It would be a mistake to summarize the present

situation on dietary trials in CHD, as results are

constantly accumulating and the picture is changing.

Rather, intervention trials in a few areas will be

described briefly, largely in order to illustrate meth-

odological aspects.

Dietary Fat Reduction

0020 Undoubtedly, the relationship of saturated fat to fat

reduction has been more investigated in the preven-

tion of CHD than any other potential prophylactic.

The early trials focused largely on the reduction of

total fat in the diet; interest then focused on the P:S

ratio (the ratio of polyunsaturated to saturated fats)

and on monounsaturated fats. Almost all metaana-

lyses or overviews of dietary RCTs have failed to

detect any significant reduction in mortality from

dietary changes aimed at reducing cholesterol, though

several overviews have reported a significant reduc-

tion of around 20% in the incidence of nonfatal

myocardial infarctions. (See Cholesterol: Role of

Cholesterol in Heart Disease; Fats: Requirements.)

0021 An issue worth noting because of its wider rele-

vance to the drawing of conclusions from trials is

the degree to which successful trials are cited in pref-

erence to negative trials. A report of an overview of

22 RCTs in which the effect of a reduction in dietary

fat intake had been examined went on to examine

how often these trials had been cited in the general

literature. It was found that the few trials in which a

reduction in CHD had been observed had been cited

six times more frequently than the trials which had

failed to find such an effect. This positive bias in the

reporting of trials is serious bias in any overview of

the literature, whether this is based upon a formal

metaanalysis, or simply an impression gained from

reading the literature.

0022 The relevance of cholesterol level to vascular dis-

ease has been very considerably reinforced by the

results of recent RCTs of statin drugs. These drugs

substantially reduce cholesterol level, and at the same

time are associated with a reduction in vascular dis-

ease incidence and mortality. The reduction in disease

appears however to commence virtually immediately,

and this has led to the suggestion that some of the

benefit from these drugs may arise because of effects

that have been described on platelet function, on

hemostasis and on immunological mechanisms.

0023 Within the area of lipids and vascular disease, one

trial stands out. This tested the effect of the so-called

‘Mediterranean diet,’ a dietary pattern modeled on

the dietary pattern in Crete and other Mediterranean

communities. The initial finding was a 70% reduction

in all-cause mortality together with comparable reduc-

tions in nonfatal events, and these results have been

sustained in a 4-year follow-up, reported in 1999. The

diet advised in this trial was rich in fruit and vegetables,

but the group responsible for the study considered

that its most important feature was its richness in

a-linolenic acid. In the trial this last was achieved by

distributing a special margarine containing rapeseed

oil to half the subjects. At present only one RCT of a

Mediterranean type of diet has been reported. Clearly

there is an urgent need for further trials.

Fatty Fish

0024The hypothesis that fatty fish, fish oil, or eicosapen-

taenoic acid might reduce the risk of CHD emerged

from surveys of Inuit in Greenland in the 1930s.

Later, historical studies showed that changes in fish

consumption during World War II had been accom-

panied in The Netherlands and in Norway by de-

creases in heart disease mortality. Laboratory and

animal studies then examined the effects of fish oil

on various risk factors and certain mechanisms

involved in CHD. This was the background to the

setting-up of a major RCT of fish and mortality. A

total of 2033 men were randomized factorially to

three interventions, one of which was the consump-

tion of fatty fish on at least 2 days each week. The

consumption of fish was associated with a reduction

in mortality of about 30% and a saving of lives of

about 36 per 1000 men advised. Because these esti-

mates of benefit are derived from the results of a

single trial they carry a considerable uncertainty. Fur-

ther trials are required, followed, hopefully, by a

metaanalysis. It is notable, however, that this trial

gave no evidence that nonfatal infarctions were re-

duced by the fish consumption. Indeed, there were

rather more nonfatal infarctions in the men advised

(4.8%) than in the other men (3.2%). It is therefore

possible that the effect of fish is to reduce the risk of

death after infarction rather than to reduce the

incidence of infarction. Evidence consistent with

this hypothesis comes from studies of the electrical

stability of the myocardium in animals, following

experimentally induced infarction.

Fruit and Vegetables

0025It is believed that the oxidation of lipids is an im-

portant step in the development of atherosclerosis.

Oxidized low-density lipoprotein cholesterol is

potentially highly atherogenic, while antioxidants

prevent its oxidation and reduce the risk of other

oxidative damage, thus retarding the development

of atherosclerosis. There is therefore growing interest

in the protective effect of both supplements of the

1666 CORONARY HEART DISEASE/Intervention Studies

antioxidant vitamin supplements, including vitamins

E, C, and b-carotene, and in fruit and vegetables

which carry these and other antioxidants.

0026 Numerous observational studies based on commu-

nities and on individuals give supporting evidence of

benefit. In fact, the evidence is virtually totally consist-

ent that subjects and groups with high consumptions of

fruit and/or vegetables have a reduced incidence of

both digestive cancers and of CHD. Despite their con-

sistency, however, these observations are seriously open

to confounding by related social and other dietary

factors. Hence there is no substitute for RCTs.

0027 A number of RCTs have been conducted to test the

effects of supplements of vitamins E, C, and/or

b-carotene. A recent overview of these has concluded

that ‘there is no clear indication for the use of these

supplements . . . and the suggestion of potential harm

associated with b-carotene in two clinical trials

(indicates) that b-carotene in the form of additional

vitamin supplements should be avoided.’

0028 On the other hand, RCTs of fruit and vegetables

necessitate increasing consumption of these foods by

half the subjects studied, and even in a so-called

secondary preventive trial the dietary increase has

to be either large or prolonged, or both. This makes

such trials very difficult. The diets of older subjects

tend to be relatively fixed, and it is exceedingly

difficult to persuade subjects – even patients who

have already had a clinical CHD event – to increase

their consumption of any food item. In our experience

this is especially true for fruit and vegetables. (See

Antioxidants: Natural Antioxidants.)

Dietary Fiber

0029 For a very long time there has been interest in dietary

fiber. At first this focused upon ‘roughage,’ or un-

absorbed dietary material, and measures such as

fecal bulk and bowel transit time were commonly

used. Interest then focused on cereal fiber, the diseases

of possible relevance being bowel cancer and CHD.

Numerous observational studies have been reported,

but one of the uncertainties in all of these is the effect

of confounding factors. In fact, confounding is a

major source of possible confusion in all dietary stud-

ies that are dependent upon observation. The diet of

an individual is determined by a host of factors, in-

cluding lifestyle, education, social standing and

income level, educational and psychological factors.

Furthermore, the consumption of any one food or

diet factor is interrelated with a host of other foods,

and cannot realistically be considered in isolation.

For example, an increase in the consumption of

wholemeal bread will probably lead to an increase

in spreading fats; an increase in fish consumption will

probably be balanced by a reduction in meat. It will be

almost impossible to take account of all these con-

founding and interrelated factors in a study of disease

incidence in relation to a single food item or nutrient.

The final elucidation of relationships between diet and

disease must therefore be ultimately dependent upon

intervention studies, in which control over confound-

ing is achieved by randomization, and different levels

of dietary intake are achieved experimentally.

0030There has been only one RCT of dietary fiber and

CHD. This was conducted by Burr and his colleagues

in south Wales. Advice was given to 1017 men who

had already had a myocardial infarct. This led to a

mean intake of cereal fiber of 19 g per day, compared

with 9 g in 1016 controls given no advice about fiber.

After 2 years there was no significant difference in the

deaths in those given the advice about fiber (12.1%)

compared to those not so advised (9.9%).

0031Interest in fiber has however shifted again, and

attention is now being focused on soluble fiber.

This, too, is confounded and interrelated with numer-

ous other food items and nondietary items and its

importance will only be sorted out by RCTs.

Interpretation of the Results of RCTs

Relative and Absolute Risk Reduction

0032There are two important aspects of trials that should

be understood. First, the results of a controlled trial

can be expressed as ‘relative’ protection, or the ‘rela-

tive’ reduction in the outcome events, or they can be

expressed in terms of the ‘absolute’ effect of the inter-

vention. This can be very easily illustrated.

0033In the Diet and Reinfarction Trial (DART) 1015

post-myocardial infarction patients were given

advice to eat fatty fish on at least 2 days per week. A

group of 1018 other patients, selected at random, were

given no such advice. During the next 2 years 127

(12.5%) of the men advised to take fish had a CHD

event, while 149 (14.6%) given no such advice had an

event. The difference between these incident figures

implies a relative reduction in the risk of an event of

30%. On the other hand, the absolute reduction was

2% over the 2 years or one IHD event was prevented

per year in every 100 patients advised to eat fatty fish.

0034Both these figures are correct, but each expresses

rather different concepts. Thus the relative reduction,

or relative benefit, is the proportionate extent to

which the risk is reduced in a group in which there

has been an intervention, compared to a control group

with no such intervention. The absolute reduction, or

absolute benefit, is the number of events prevented.

Another way of expressing this last is the number

needed to treat (NNT) to prevent one disease event.

Clearly, for fatty fish, this is 100 patients for 1 year.

CORONARY HEART DISEASE/Intervention Studies 1667

0035 While figures of absolute benefit may at first sight

appear disappointing, they carry a wealth of infor-

mation. Thus, in the above example, one can say that,

of every 100 patients advised to eat fatty fish, a CHD

event will be prevented in one or two each year, but

about six will still die from CHD each year. About 92

will derive no benefit because, judging from the

experience of the subjects in the control group, they

would have survived anyway. No worry! They will

have enjoyed the fatty fish and will probably have

saved money on meat!

0036 Intervention with drugs has much the same protect-

ive effect (for example, antihypertensives achieve a

relative reduction in CHD event of about 25%, that

is, closely similar to the 30% achieved by fish con-

sumption in DART). However the patients who are

given drugs, and who would have survived anyway,

will have been exposed to the undesirable side-effects

of the drugs, and their therapy will have generated

considerable costs. None of this is meant to imply

that dietary intervention is a substitute for medica-

tion. Raised CHD risk factors should be treated ap-

propriately, but considerations should also be given

to dietary intervention. These are not in competition.

Overviews or Metaanalyses

0038 In the nature of things, certainty is unobtainable and

even the largest and most carefully conducted RCT

can, by chance, give a wrong answer. Firm conclu-

sions should only be based on evidence drawn from a

number of trials. The play of chance can never be

ruled out, whatever the level of statistical signifi-

cance, and consistency in a number of studies is likely

to be a better guide to truth than the results of any

single study. Further to this, the results of any single

trial cannot be extrapolated to the general population

with certainty. Conclusions from a trial are limited

by issues such as the selection of patients tested, the

diagnostic criteria used, the way the intervention was

achieved, and the possibility that the intervention

may have affected other factors of relevance to the

disease. Together, these uncertainties can make it in-

appropriate and perhaps misleading to generalize the

results from any one study to patients in general and

make them the basis of clinical recommendations.

0045 Hence the importance of overviews of studies, or

metaanalyses of data from a number of different

studies. This approach is particularly appropriate

with RCTs, but it is important that data from every

relevant RCT are included.

0039 In fact, even the most meticulous search of the

literature followed by a formal overview of all the

evidence from relevant RCTs still leaves uncertainties.

There is publication bias, and reports which report an

effect are generally more likely to be accepted by a

journal than those which show no effect. But then this

limitation affects judgments based simply on cumula-

tive reading of the literature, however carefully done.

Nevertheless, the approach in research that is likely to

get closest to the truth is clearly drawing conclusions

from all the available acceptable evidence. Cochrane,

an epidemiologist, saw this and he commented in a

Rock Carling lecture, later published as Effectiveness

and Efficiency: ‘It is surely a great criticism of our

profession that we have not organised a critical sum-

mary, by speciality or sub-speciality, adapted period-

ically, of all relevant clinical trials.’

The Cochrane Collaboration

0040This urging by Cochrane led to the setting-up of

the Cochrane Centre in Oxford, and then to the

Cochrane Collaboration, a worldwide effort coordin-

ated in 11 Cochrane Centres. The collaboration aims

to identify every RCT ever done in medical care, to

group these by clinical objective, and make them

readily available as databases. These then constitute

the basis for statistical overviews, or metaanalyses,

which draw on all the acceptable trial evidence

relevant to each clinical procedure.

Final Considerations

0041RCTs of dietary factors are immensely difficult and

before one is mounted consideration should be given

to a number of general considerations relevant to

intervention in cardiovascular disease. In summary,

there are unlikely to be any easy answers!

0042First, compliance with a dietary intervention is

likely to be poor. Trials of the effect of dietary advice

on cholesterol levels have generally shown very little

effect, and to some extent – and probably a very large

extent – this is because of the difficulties most people

find in making a significant, let alone a large, reduc-

tion in dietary saturated fats. Likewise, attempts to

increase the intake of dietary fiber or fruit and vege-

table intake have achieved relatively little change.

Results such as these have far-reaching implications

for the acceptability of prophylactic strategies in

symptomless subjects, or in the general population.

0043Second, effectiveness is likely to be low. Geoffrey

Rose defined a paradox – population preventive strat-

egies, even those with large overall potential benefit,

are likely to confer little benefit on the individual –

and he went on to describe the overall benefit/risk

balance in strategies involving the general population

as ‘worrisome.’ An overview by Davey-Smith and

Ebrahim of nine major population-based RCTs

of the effect of advice on diet, smoking, and blood

1668 CORONARY HEART DISEASE/Intervention Studies

pressure led to the conclusion: ‘The pooled effect of

intervention on multiple risk-factors is insignificant.’

0044 Third, the costs of intervention are likely to be

high. The cost of an intervention strategy that really

matters is not the cost of the change of diet, the cost

of nutritional supplements of medication in a single

subject. Rather, the cost that matters is that of

treating a sufficient number of subjects, for a suffi-

cient time to save one life, or prevent one disease

event. While this approach has been well developed

with drug therapy, the most relevant costs of a dietary

intervention are those that arise from the need for

subjects to accept a change in their diet, and for

most of us, a possible small change in the long-term

risk of a disease is far from the front of our minds

when preparing a meal.

See also: Antioxidants: Natural Antioxidants; Role of

Antioxidant Nutrients in Defense Systems; Cholesterol:

Role of Cholesterol in Heart Disease; Epidemiology;

Fats: Requirements

Further Reading

Alderson M (1983) An Introduction to Epidemiology, 2nd

edn. London: Macmillan.

Bradford-Hill A (1971) Principles of Medical Statistics, 9th

edn. London: Lancet.

Burr ML (1983) Epidemiology for nutritionists. 3. The

design of studies. Human Nutrition: Applied Nutrition

37A: 339–347.

Burr ML, Fehily AM, Gilbert JF et al. (1989) Effects of

changes in fat, fish, and fibre intakes on death and

myocardial reinfarction: Diet and Reinfarction Trial

(DART). Lancet ii: 757–761.

Cochrane AL (1971) Effectiveness and Efficiency: Random

Reflections on Health Services. London: Royal Society

of Medicine Press.

Davey-Smith G and Ebrahim S (1996) Health Promotion in

Older People for the Prevention of Coronary Disease and

Stroke. Health Promotion Effectiveness Review: Sum-

mary Bulletin 1. London: Health Education Authority.

Margetts BM and Nelson M (1977) Design Concepts in

Nutritional Epidemiology, 2nd edn. Oxford: OUP.

Muldoon MF, Manuck SB and Matthews KA (1990)

Lowering cholesterol concentrations and mortality: a

quantitative review of primary prevention trials. British

Medical Journal 301: 309–313.

Peto R, Pike MC, Armitage P et al. (1976) Design and

analysis of randomized clinical trials requiring pro-

longed observation of each patient. I. Introduction and

design. II. Analysis and examples. British Journal of

Cancer 34: 585–612; 35: 1–39.

Pocock SJ (1983) Clinical Trials: A Practical Approach.

New York: Wiley.

Ravenov U (1992) Cholesterol lowering trials in coronary

heart disease: frequency of citation and outcome. British

Medical Journal 305: 15.

Prevention

F G Huffman and S Nath, Florida International

University, Miami, FL, USA

Background

0001There has been a steady decline of coronary heart

disease (CHD)-related mortality in most industrialized

nations over the past few years. Despite this fact, CHD

remains the leading cause of morbidity and mortality in

adults of middle years and older (after age 65), leading

to a loss of productivity and substantial healthcare

costs in the industrialized countries. The World Health

Organization estimates that by the year 2010, CHD

would be the leading cause of death in the developing

countries as well. Therefore, prevention (both primary

and secondary) of CHD is extremely important from a

public health point of view.

0002The preceding section in this chapter highlights the

etiology of CHD that includes both modifiable and

nonmodifiable risk factors. Among all CHD risk

factors, cigarette smoking, unhealthy diet, overweight

or obesity, physical inactivity, high blood lipids (high

total cholesterol and elevated low-density lipoprotein

cholesterol), high blood pressure or hypertension, and

high blood glucose (also metabolic syndrome) are

preventable or manageable. Several prophylactic

therapies and screening of high-risk individuals also

offer potential benefits for the prevention of CHD

(Table 1).

0003Primary prevention of CHD is generally defined as

the modification of risk factors or prevention of the

development of these risk factors, with the aim of

delaying or preventing a first coronary event (angina

pectoris, myocardial infarction, or sudden death),

offers the greatest opportunity for reducing the burden

of CHD from a personal, economical, and global

aspect. The prime objective of primary prevention is

to reduce both short-term (< 10 years) and long-term

(> 10 years) risk. However, secondary prevention in-

cludes therapy or measures to minimize recurrent cor-

onary event (angina pectoris, history of myocardial

infarction, history of bypass graft or angioplasty) and

decrease mortality and morbidity in patients with es-

tablished CHD, which is not cost-effective in most

cases. The potential benefits of primary prevention

exceed those of secondary prevention, since 30%

of patients with first myocardial infarction survive

less than 3 months. The first CHD event may progress

to prolong permanent morbidity. Both primary and

secondary preventions share many common character-

istics (Figure 1). Therefore, the elements of both

CORONARY HEART DISEASE/Prevention 1669

primary and secondary preventions are addressed

simultaneously. Combining both primary and second-

ary prevention, the overall objective of CHD preven-

tion is to reduce the risk of initial or subsequent CHD

events, thereby reducing premature CHD-related mor-

bidity and mortality, and prolonging survival.

Primary and Secondary Preventive

Measures for CHD

Smoking

0004 Cigarette smoking is a convincing risk factor for

CHD, and cessation of smoking (including all forms

of tobacco) rapidly and significantly decreases the

risk for the development of CHD and CHD-related

mortality in a very cost-effective way. Smoking

cessation is a complex, multifactorial, and difficult

process. Simple brief counseling with a clear, firm,

positive, encouraging, and sympathetic attitude is

the first step in the management of smoking cessation.

Persistent smokers may require extended counsel-

ing, more than one session preferably, by a skilled

counselor or psychologist. Nicotine chewing gum or

transdermal nicotine replacement patches with a

progressively decreasing dosage can be helpful for

heavily addictive persons as an adjunct to counseling.

0005 Family support is very important in smoking cessa-

tion. Encouragement from a family or spouse is of

great help. ‘Smoke-free’ environments at home, res-

taurants, work sites, public transport vehicles, and

other public premises can greatly improve the atmos-

phere for smoking cessation attempts by smokers.

Diet

0006Diet is an important determinant for the development

of CHD by affecting the obesity, blood pressure, and

blood lipids. Therefore, it is crucial to maintain a

‘healthy diet,’ which constitutes (1) consumption of

six or more servings of whole-grain products with

25 g of fiber, especially soluble fiber; (2) consump-

tion of at least five servings of fruits and vegetables

(> 400 g per day); (3) limiting consumption of satur-

ated fat < 10% (preferably < 7%) of total daily cal-

ories, and cholesterol < 300 mg per day (preferably

< 200 mg per day); (4) consumption of polyunsatur-

ated fatty acids up to 10% of total daily calories; (5)

limiting salt intake to 6 g per day, the equivalent of

100 mmol of sodium per day; and (6) limiting alcohol

consumption to one or two standard drinks for men

per day and not more than one drink for women (a

pregnant woman should not drink) per day to prevent

or delay the development of CHD risk.

Overweight and Obesity

0007Patients who are overweight (body mass index

(BMI ¼kg m

2

) > 25 kg m

2

) or obese (BMI > 30 kg

2

), or with excess truncal or abdominal fat (waist

circumference > 102 cm in men and > 88 cm in

women), are at increased risk for CHD, because of

the adverse effects of fat on blood lipid levels, blood

tbl0001 Table 1 Prevention of coronary heart disease

Lifestylemodification Goals

Smoking cessation Encourage patient to stop smoking completely

Healthy diet 25 g of fiber, >400 g of fruits and vegetables; <30% fat, <10% saturated fat, poly- and monounsaturated

fat 10% each, <300 mg of cholesterol of daily calories; salt intake 6 g or less per day

Weight control Maintain a healthy BMI (18.9–24.9)

Physical activity 30–60 min aerobic activity four to six times a week

Risk factors Goal Recommendeddrugs

Blood lipid Statins

LDL cholesterol <130 mg dl

1

Total cholesterol <200 mg dl

1

Blood pressure Low-dose thiazide

Systolic 130–139 mmHg Diuretics

Diastolic 85–89 mmHg b-blockers

ACE inhibitors

Calcium antagonist

Prophylactic therapy Purpose

Aspirin (75–325 mg

per day)

For secondary prevention and maybe for primary prevention

ACE inhibitors For secondary prevention

Statins For both primary and secondary prevention

Folic acid For primary prevention

BMI, body mass index; LDL, low-density lipoprotein; ACE, angiotensin-converting enzyme.

1670 CORONARY HEART DISEASE/Prevention

pressure, and glucose tolerance. Prospective epidemi-

ological studies have shown a J-shaped association

between BMI and all-cause mortality among Western

populations. High-risk populations require profes-

sional advice on weight reduction.

0008 Successful weight reduction is not easy to manage,

often requiring long-term professional support and

encouragement, good motivation of the person, a cal-

orie-restricted lipid-lowering diet, and a suitable phys-

ical activity program. Realistic weight-reduction goals

should be based on short-term results and agreed be-

tween the physician and the patient. It is recommended

that a weight reduction of 0.5–1 kg per week is a

suitable rate until the target weight goal is achieved.

The National Heart, Lung, and Blood Institute, USA

has recommended that a person with BMI 27–35

should decrease their caloric intake by 300–500 kcal

per day, and a person with BMI > 35 should decrease

their caloric intake by 500–1000 kcal per day from

their diet to achieve a 10% weight loss in 6 months.

0009 There has been considerable concern about the

usage of drugs and their possible side-effects for

weight reduction. For example, sibutramine, a sym-

pathomimetic, reduces food intake but may cause

hypertension and tachycardia. Lipase inhibitor orli-

stat (Xenical) has significant effect on weight reduc-

tion but may cause severe gastrointestinal symptoms.

Weight loss is usually observed within 2 weeks of

initiation of therapy. However, researchers agree that

a reduction in caloric intake combined with regular

physical activity may be the most effective and safe

method in reducing excess body fat.

Physical Activity

0010 Prospective epidemiological studies have documented

that sedentary lifestyle is a strong predictor of CHD

risk, irrespective of other risk factors. Therefore, a

regular, suitable exercise program is recommended

for a sedentary person, since it has favorable effects

on body weight, blood pressure, blood lipids, insulin

sensitivity, and glucose tolerance. Epidemiological

studies have demonstrated strong evidence that aer-

obic exercise reduces the risk of CHD. Brisk walking,

jogging, cycling, mowing, swimming, aerobic dancing,

skipping, and other recreational sports that require

movement are good examples of aerobic exercise.

0011It is now recommended that everyone must perform

at least 30–60 min of physical exercise four to six times

a week. Generally, an exercise program includes a 5–

10-min warm-up by stretching and other gentle activ-

ity followed by 20–30 min endurance or aerobic

phase, and finally 5–10 min of a cool-down phase.

Physical exercise prescription (intensity and duration)

for patients with clinically established CHD must be

based on comprehensive clinical evaluation and

results of exercise testing. The Second Joint Task

Force of European and other Societies on Coronary

Prevention recommends that the intensity and dur-

ation of activity should initially be set low and grad-

ually increased according to the limits imposed by

exercise-induced symptoms. Patients recovering from

myocardial infarction and other cardiac events should

also be given advice about a suitable, gradually in-

creasing exercise program. In these patients, exercise

programs must be supervised, and ECG monitoring

should be used in the early stages.

Blood Lipids

0012CHD risk is best evaluated by measuring plasma

concentrations of total cholesterol, low-density

lipoprotein (LDL) cholesterol, and high-density lipo-

protein (HDL) cholesterol. Results from animal

experiments, epidemiological, and other studies con-

sistently demonstrate an independent, strong,

Prevention of Coronary Heart Disease

Prophylactic medications

(aspirin, β blockers,

statins, ACE inhibitors)

Secondary Prevention

Prophylactic medications

(aspirin, statins, folic

acid)

Screening for family

history

Primary Prevention

Modifiable Risk Factors

Smoking

Atherogenic diet

Overweight/obesity

Physical inactivity

Blood lipids

Metabolic syndrome

Type 2 diabetes

High blood pressure

fig0001 Figure 1 Shared preventable measures in primary and secondary prevention of coronary heart disease. ACE, angiotensin-

converting enzyme.

CORONARY HEART DISEASE/Prevention 1671

positive, and graded relationship between high total

cholesterol and elevated LDL cholesterol and the risk

of CHD development. Recently, several clinical trials

consistently showed that LDL-lowering therapy re-

duces the total mortality, CHD-related mortality,

major coronary events, and coronary artery proced-

ures in persons with established CHD and persons

with CHD risk equivalent (i.e., diabetes). Based on

the results of prospective epidemiological and clinical

trials with both angiographic and clinical end points,

an LDL cholesterol level of < 100 mg dl

1

is set as the

goal of therapy in secondary prevention. Two basic

components of LDL-lowering therapy are ‘thera-

peutic life changes’ (Table 2) and drug therapy.

0013 Therapeutic Life Changes (TLC) The Third Report

of the National Cholesterol Education Program

(NCEP) Expert Panel, USA, 2001, recommends

a multifactoral life style approach that includes:

(1) reduction of saturated fat intakes (< 7% of total

calories) and cholesterol (< 200 mg per day), (2) con-

sumption of plant sterols (2 g per day) and soluble

fiber (10–25 g per day), (3) weight reduction, and (4)

increased physical activity.

0014 Drug Therapy In order to attain the goal of LDL

cholesterol levels of < 100 mg dl

1

, many persons

with CHD and CHD risk equivalents will need LDL

cholesterol-lowering drug therapy in addition to

TLC. Low-density lipoprotein cholesterol should be

measured on admission or within 24 h in order to

decide the need for drug treatment. Currently, four

major classes of drugs are widely used to lower LDL

cholesterol effectively: hepatic hydroxymethylglu-

taryl coenzyme A (HMG CoA) reductase inhibitors

(statins), bile acid-binding resins, fibric acid deriva-

tives, and nicotinic acid. Recently, many compre-

hensive clinical trials with statins have robustly

documented that this class of drugs is the most effect-

ive in lowering LDL cholesterol from angiographical

and clinical end points. Statins also have a better

safety profile compared with other classes of drugs.

Therefore, at present, the statins are the first line of

drugs used to lower total and LDL cholesterol levels.

In some special conditions, like familial hypercholes-

terolemia, a combination of drugs (statin and resin or

statin, resin, nicotinic acid) may be used.

Blood Pressure

0015 A large number of epidemiological studies have demon-

strated that elevated arterial blood pressure is a risk

factor for CHD. The goal for blood pressure reduction

is to maintain systolic blood pressure (SBP) < 140 mmHg

and diastolic blood pressure (DBP) < 90 mmHg. The

goal can be achieved by nonpharmacological treatment

(lifestyle modification) alone or in combination with

pharmacological therapy.

0016Lifestyle modifications Several randomized clinical

trials have evaluated the effectiveness of lifestyle inter-

ventions on managing mildly elevated blood pressure

in a cost-effective way. The essential features of life-

style modifications are to: (1) maintain a healthy

weight or reduction of excess body weight based on

BMI; (2) achieve a moderate level of physical fitness

by 30–45 min of aerobic physical activity in most days

of the week; (3) reduce salt (sodium) intake moder-

ately (100 mmol per day) and not to exceed total salt

intake of 6 g per day (however, results from the meta-

analysis of randomized clinical trials presently do not

recommend a restriction of salt intake for the normo-

tensive population); (4) increase the intakes of potas-

sium (60–90 mmol per day) preferably from fruits and

vegetables; and (5) limit alcohol consumption to no

more than two standard drinks for men and one for

women per day. Table 3 demonstrates the elements of

lifestyle modification or nonpharmacological treat-

ment for elevated blood pressure.

0017Pharmacological treatment Several large-scale,

multicenter, randomized, controlled trials have cred-

ibly demonstrated that antihypertensive medications

lower CHD-related morbidity and mortality and

all-cause mortality. The decision to commence

pharmacological treatment relies on the degree of

blood pressure elevation, presence of target organ

damage (e.g., heart disease, nephropathy, peripheral

arterial disease, and retinopathy), presence of clinical

cardiovascular disease and other risk factors, or

conditions such as diabetes. A general agreement,

however, is that an individual with a ‘high normal

BP’ (130–139/85–89 mmHg) and with target organ

disease and/or diabetes should be treated with

tbl0002Table 2 Components of therapeutic life changes

Weight reduction Balance energy intake and

expenditure to maintain a healthy

weight (BMI 18.5–24.9)

Increased physical activity 30–60 min aerobic exercise most

days of the week

Healthy diet

Saturated fat <7% of total calories

Polyunsaturated fat 10% of total calories

Monounsaturated fat 20% of total calories

Total fat 25–35% of total calories

Carbohydrate 50–60% of total calories

Fiber 20–30 g per day

Protein *15% of total calories

Cholesterol <200 mg per day

Adapted from the Third Report of the National Cholesterol Education

Program (NCEP), USA, 2001.

BMI, body mass index.

1672 CORONARY HEART DISEASE/Prevention

antihypertensive medication after a trial of lifestyle

modification. Drug treatment begins with monother-

apy, low doses followed by slow titration to achieve

24-h control with once-daily medication depending

on the patient’s age, needs, and response, as well as

economic condition. The most commonly used anti-

hypertensive agents: thiazide diuretics in low dosage,

b-blockers (especially if angina is present), angioten-

sin-converting enzymes (ACE) inhibitors, calcium an-

tagonists, a-blockers, and angiotensin II receptor

blockers. Most experts prefer low-dose thiazide diur-

etics or b-blockers as a first line of antihypertensive

agents, unless contraindicated. Other preferred

choices for initial therapy are: b-blockers for hyper-

tensives with uncomplicated myocardial infarction;

ACE inhibitors for individuals with CHD and

decreased ejection fraction, with left ventricular func-

tion, diabetes with proteinuria; and thiazide,

b-blockers, or calcium antagonist (calcium channel

blocker) for isolated systolic hypertension. Isolated

systolic hypertension is a CHD risk factor, especially

for the elderly, and should be managed properly.

0018 The antihypertensive agents are not free of adverse

effects. However, the use of combinations of low

doses of two agents from different classes have been

shown to potentiate the effect of other agents without

incurring any adverse effects.

Blood Glucose

0019 Data from large numbers of epidemiological and (in-

cluding the Framingham Study) pathological studies

document hyperglycemia as an independent risk

factor for CHD. Persons with both type 1 and type 2

diabetes and diabetic women are at increased risk for

developing CHD than nondiabetics and diabetic men,

respectively. The underlying mechanisms for this

remain to be answered. In addition to hyperglycemia,

diabetics frequently have other classical risk factors

for CHD – hypertension, lack of physical activity, low

levels of HDL cholesterol, and hypertriglyceridemia–

that intensify the risk of developing CHD events.

0020 The effects of glycemic control among diabetics and

alteration in CHD risk have not been appraised con-

clusively. Results from randomized controlled trials

show that prudent insulin therapy retards the occur-

rence of microvascular events and a nonsignificant

reduction of macrovascular events in patients with

type 1 diabetes. To date, no clinical or epidemiological

evidence of the role of blood glucose control in

reducing CHD events significantly in patients with

type 2 diabetes has been documented. However,

there is general agreement that control of blood

glucose (hemoglobin A

< 7.0%) among type 2 dia-

betics may minimize CHD complications. In order to

achieve an acceptable level of hemoglobin A

, type 2

diabetics often need professional dietary advice (redu-

cing total calorie and fat intake), reduction of over-

weight or obesity (5–9 kg irrespective of starting

weight), and increased level of physical activity as a

first line of management. Frequent aerobic exercise (at

least 30 min most days of the week) also facilitates

blood glucose control and weight control. Oral hypo-

glycemic agents come as a second line of therapy when

a desirable hemoglobin A

cannot be achieved with

lifestyle modification alone.

0021Control of blood glucose also maintains normal

plasma lipid levels in patients with type 1 diabetes

without nephropathy. Diabetic dyslipidemia (ele-

vated triglycerides, low HDL cholesterol), which is

more pronounced among type 2 diabetics, may be

corrected by normalizing blood glucose using oral

hypoglycemic agents. The primary goal of LDL chol-

esterol < 100 mg dl

1

can be achieved by moderate

caloric restriction (250–500 cal less than the average

daily intake), 30% fat, < 7% saturated fat, and

< 300 mg of cholesterol per day. Cholesterol-lowering

therapy is recommended if dietary modification fails.

The primary goal for blood pressure in diabetics is to

maintain blood pressure < 130/85 mmHg. Moderate

weight loss has also been shown to reduce dyslipid-

emia and hypertension among diabetics. Smoking

cessation is obligatory. Guidelines to reduce CHD

for diabetics are shown in Table 4.

Metabolic Syndrome

0022There is mounting recognition that many persons

have a collection of multiple major risk factors and

tbl0003 Table 3 Lifestyle modifications for high blood pressure

Lose weight if overweight or obese

Increase aerobic physical activity 30–45 min for most days of the

week

Stop smoking completely

Limit sodium intake to 6 g or less per day

Maintain adequate intake of dietary potassium

Limit alcohol intake to one or two drinks per day

tbl0004Table 4 Guidelines to reduce coronary heart disease in

patients with diabetes mellitus

Risk factors Recommendations

Smoking Complete cessation

Physical activity At least 30 min three or four times per

week

Weight reduction 5–9 kg irrespective of starting weight

Hemoglobin A

Target: <7%

Fasting blood glucose Target: 80–120 mg dl

1

LDL cholesterol Target: <100 mg dl

1

Calorie restriction 250–500 kcal less than average daily

intake

Blood pressure Target: <130/85 mmHg

CORONARY HEART DISEASE/Prevention 1673

emerging risk factors for CHD; a cluster of these

conditions is known as a metabolic syndrome charac-

terized by abdominal obesity, ‘lipid triad’ (elevated

serum triglycerides, low HDL cholesterol, and high

LDL cholesterol) hypertension, insulin resistance,

and other thrombogenic risk factors. Primary preven-

tion is mainly focused on reducing body weight

through diet and by increasing physical activity. Diet-

ary modification and physical activity also effectively

normalize dyslipidemia.

Prophylactic Therapies

0023 To prevent the aforementioned classical risk factors

and other thrombogenic factors that play pivotal roles

in the CHD events, a great deal of emphasis is placed

using several prophylactic drug therapies. Likewise,

increased consumption of polyunsaturated fatty acids

(o-3 and o-6) may be used as antithrombic agents.

0024 Aspirin Compelling evidence from randomized

studies insinuates that a low dose of aspirin or acetyl-

salicylic acid (between 75 and 325 mg) daily may

considerably reduce subsequent myocardial infarction

and all-cause mortality among patients with postmyo-

cardial infarction. With regard to primary prevention,

the use of aspirin and the balance between benefits and

hazards is not lucid. However, a recent meta-analysis

has suggested that aspirin may be used as a primary

prevention agent but requires formal accurate estima-

tion of absolute CHD event risk. A maintenance dose

of 75 mg of aspirin is recommended as a secondary

prevention for all postmyocardial infarctive patients if

not contraindicated.

0025 b-blockers Results from the meta-analysis indicate

that b-blockers substantially decrease all-cause mor-

tality in patients following myocardial infarction.

Therefore, like aspirin therapy, b-blockers should be

reckoned for patients following myocardial infarc-

tion if not contraindicated.

0026 ACE inhibitors ACE inhibitors significantly reduce

all-cause mortality and the risk of progression of

heart failure among patients following myocardial

infarction and with chronic left ventricular systolic

dysfunction.

0027 Statins Although TLC is considered as the basis of

prevention to lower the high total cholesterol and

elevated LDL cholesterol, recently, several trials with

statins have documented unambiguously that statins

may be used as a method for primary prevention with-

out any substantial side-effects. Recent pharmaco-

economic analyses indicate that statin therapy may

be highly cost-effective in secondary prevention and

moderately so in primary prevention. However, the

cost-effectiveness of statins as a primary prevention

needs to be evaluated from a global perspective.

0028Estrogen Abundant observational studies strongly

and consistently attest that postmenopausal estrogen

replacement therapy (ERT) may protect against

CHD. However, recent, multicenter, randomized,

placebo-controlled secondary prevention trials have

negated this finding and documented that ERT may

increase the risk of venous thromboembolism in post-

menopausal women with CHD. Therefore, ERT is

not recommended for secondary prevention of CHD

for the postmenopausal women. The use of ERT may

be effective as a primary prevention of CHD. None

the less, ERT may be appropriate for postmenopausal

women to continue when they are already receiving

this treatment.

0029Folic acid A high level of total plasma homocysteine

(> 15 mmol l

1

) is considered as a notable risk factor

for CHD based on epidemiological studies. High

levels of homocysteine may be acquired, because of

a deficiency of folic acid, or congenital, because

of genetic mutation of a thermolabile variant of the

methylenetetrahydrofolate reductase gene. Supple-

mentation with folic acid (0.5–5.0 mg) reliably and

effectively reverses the hyperhomocysteinemia.

Screening

0030First-degree relatives (parents, siblings, and descend-

ants and other close relatives) of the patient suspected

of having familial hypercholesterolemia, or other in-

herited genetic lipid disorder, or individual with pre-

mature CHD (men < 55 years and women < 65 years)

should be regularly screened for risk factors as they

are at increased risk for CHD.

Conclusion

0031Prevention of coronary heart disease is a global public

health challenge. Given the unique and wide array of

the determinants of health (access to quality health-

care, health policies and interventions, physical and

social environments, and individual behavior and

biology) in the different geographic areas of the

world, the orderliness of preventive care for CHD

will vary from one country to another. Therefore, it

would not be pragmatic to define the aforementioned

CHD prevention as a sole model; rather, the universal

standards of prevention should be ensued and exer-

cised. The implementation of these recommendations

and emerging scientific knowledge in view of CHD

prevention should be incorporated in a person’s life-

style as well as in a healthcare provider’s professional

care. In the near future, the Human Genome Project

1674 CORONARY HEART DISEASE/Prevention

will also be able to explicate the genetic factors that

predispose to CHD.

See also: Coronary Heart Disease: Etiology and Risk

Factor; Dietary Requirements of Adults; Exercise:

Metabolic Requirements; Fats: Digestion, Absorption,

and Transport; Glucose: Maintenance of Blood Glucose

Level; Obesity: Etiology and Diagnosis; Slimming:

Metabolic Conseqences of Slimming Diets and Weight

Maintenance; Smoking, Diet, and Health