Preventive Cardiology 2nd Edition Paul N Durrington BSc MD FRCP FRCPath FMedSci Professor of Medicine University of Manchester, and Honorary Consultant Physician Manchester Royal Infirmary Manchester United Kingdom
The views expressed in this publication are those of the author and not necessarily those of Martin Dunitz Ltd. © 1993, 2001, Paul Durrington First published in the United Kingdom in 1993 by Martin Dunitz Ltd The Livery House, 7–9 Pratt Street, London NW1 0AE Tel: Fax: E-mail: Website:
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Contents
1
Dedication
iv
Acknowledgements
vi
The scale of the problem of coronary heart disease
1
2
Known risk factors for coronary heart disease
4
3
Determination of coronary risk
30
4
Management of the ‘at risk’ individual
40
5
What can be achieved – costs and benefits
70
Suggested further reading
72
Index
76
iii
To my family
iv
‘But there is a disorder of the breast marked with strong and peculiar symptoms, considerable for the kind of danger belonging to it, and not extremely rare, which deserves to be mentioned more at length. The seat of it, and sense of strangling, and anxiety with which it is attended, may make it not improperly be called angina pectoris. They who are afflicted with it are seized while they are walking, (more especially if it be up hill, and soon after eating) with a painful and most disagreeable sensation in the breast, which seems as if it would extinguish life, if it were to increase or continue; but the moment they stand still, all this uneasiness vanishes.’ William Heberden (1768), Medical Transactions of the College of Physicians
‘There is no mystery about why the incidence of vascular disease, like that of bronchial cancer and venereal disease, continues to rise for many decades after pathogenesis is established. Human beings, including physicians and informed laymen, are eager for excuses not to face annoying facts and so they continue to do things which are agreeable but hazardous.’ William Dock (1974), Atherosclerosis. Why do we pretend the pathogenesis is mysterious? Circulation 50: 647–9
v
Acknowledgements
I am grateful to Ms C. Price for expert secretarial assistance.
vi
The scale of the problem of coronary heart disease
1
Coronary heart disease (CHD) kills more than 180,000 people in the UK and 500,000 in the USA every year. This is not, in itself, a reason for prevention, because most of these deaths are in the elderly when other causes of death are prevalent so that preventing one may have very little impact on life-expectancy and may simply change what is written on the death certificate. The real concern is that CHD is also a major cause of premature death (Figure 1). It accounts for 40% of deaths in middle-aged men. Although women are relatively spared before old age, CHD is nonetheless their second commonest cause of premature death after the total deaths due to cancer. In certain age groups, CHD may account for 10 times more deaths than carcinoma of the cervix. Paradoxically, despite this, many countries with well-developed
40 M F Percentage
30
20
10
0 15–24
25–34
35–44
45–54
55–64
65–74
75+
Age
Figure 1
Deaths from CHD at different ages (in years) as a percentage of all deaths. (Data derived from Registrar General of England and Wales.)
1
Preventive Cardiology
programmes for cervical smears have done little about CHD prevention in women. Some 30% of acute medical beds are occupied by patients with CHD in the UK and USA. The cost of lost industrial production and sickness benefit payments due to CHD runs into thousands of millions of dollars. Premature death from CHD is enormously expensive both in human and in economic terms. There have been considerable advances in the medical management of acute myocardial infarction, most notably defibrillation, thrombolytic therapy, coronary angioplasty and aspirin and beta-blocker treatment. Their success does, however, depend on how rapidly they can be delivered, because most deaths from myocardial infarction occur within a few hours (Figure 2). No matter how much effort we expend in trying to get patients into the coronary
100
Still alive (%)
80
60 50 40
F M
20
0 0
Figure 2
2
5
10
15 20 25 30 Hours after onset
35
40
45
50
Length of survival (in hours) after onset of symptoms in those dying in the first year after myocardial infarction. Arrows indicate median survival (3 hours 30 minutes in men and 6 hours 18 minutes in women). (Derived from McNeilly and Pemberton, 1968.)
The scale of the problem of coronary heart disease
care unit rapidly or to deliver coronary care in the community, deaths within the first hour or so continue to be a substantial proportion of the mortality due to myocardial infarction. Overall, acute myocardial infarction carries a mortality of around 30% with women and certain other groups, such as people with diabetes and people from the Indian subcontinent, having an even worse case-fatality. It is particularly important, therefore, to avoid an acute myocardial infarction (or even an episode of acute coronary insufficiency which carries almost as severe a prognosis), if at all possible. About half of all deaths from CHD occur in people already known to have CHD (previous myocardial infarction or angina) or other atherosclerotic disease, such as cerebrovascular or peripheral arterial disease. The prevention of an acute coronary event in them (secondary prevention) thus makes sense not only to postpone death, but to reduce further morbidity. To confine preventive cardiology to secondary prevention, however, is not sensible, because of the high mortality and morbidity associated with first episode of acute myocardial ischaemia. CHD prevention must therefore be undertaken in people who have not yet experienced any coronary symptoms (primary prevention). This involves a strategy to identify particularly high risk individuals from the general population for clinical intervention. There should also be a population strategy to decrease susceptibility to CHD generally. This is because in countries badly affected by CHD, there will be huge numbers of people who are at unacceptably high risk, but who are not currently identified as clinical targets. Coronary prevention need not be more costly than the disease itself and can be effective. The rest of this book is about its practicality.
3
2
Known risk factors for coronary heart disease
The most important risk factors for CHD are: ●
Age
●
Gender
●
Premature menopause
●
Pre-existing CHD (angina, history of myocardial infarction, ECG changes of earlier myocardial infarction) or other atherosclerotic disease (peripheral or cerebral arteriosclerosis)
●
Cigarette smoking
●
Hypertension
●
Diabetes mellitus
●
Acquired dyslipidaemia – raised serum cholesterol, low-density lipoprotein (LDL) cholesterol and/or triglycerides, and/or low highdensity lipoprotein (HDL) cholesterol
●
Genetic dyslipidaemia – familial hypercholesterolaemia etc.
●
Family history of CHD – not attributable to known risk factors
●
Obesity
●
Lack of exercise
●
Social factors (e.g. socio-economic, geographical)
●
Stress and personality
●
Fibrinogen, other coagulation factors and inflammatory markers
Age Advancing age has a striking effect on the likelihood of CHD developing in both men and women (Figure 3). It seems probable that this represents the duration of exposure to CHD risk factors combined with a tendency for some of them to become more severe with age. A decrease in exposure to such risk factors in earlier life is likely to postpone the onset of CHD. Age-related increases in blood pressure and cholesterol are more marked in the obese. Population strategies 4
Known risk factors for coronary heart disease
100 000 M F
CHD deaths (per million)
10 000
1000
100
10
1 25–34 35–44 45–54 55–64 65–74 75–84 Age
Figure 3
85+
Effect of age (in years) on CHD death rate (per million of population). (Data derived from Registrar General of England and Wales.)
aimed at middle-aged populations may eventually decrease CHD rates in the older age groups.
Gender Women have fewer heart attacks than men. This is true at all ages. On average, similar death rates occur in women about 10 years later than in men (Figure 3). In general, risk factors have less impact in women, but this is not the case for women with diabetes or for those having a male pattern of obesity (see Obesity, pages 24–6). It is frequently stated that ‘female protection’ against CHD declines following the menopause. In fact, there is no abrupt change in the CHD rate at the natural menopause; the convergence of the CHD rates in men and women as age advances is related not only to the decrease in oestrogen at the menopause, but also to a decline in the acceleration of CHD deaths in men relative to women from about the time of the male climacteric (see HDL cholesterol, pages 15–9). 5
Preventive Cardiology
Premature menopause Women, whose menopause occurs early – usually as the result of surgery, but also when it is spontaneous or induced by radiation – are at increased risk of CHD. It is important therefore to pay particular attention to the elimination of CHD risk factors in them and to consider oestrogen replacement therapy (see page 62).
Pre-existing CHD People with a history of myocardial infarction, angina or both have already demonstrated their susceptibility to CHD. Thus their high risk is not simply a theoretical possibility as is the case with other high-risk individuals identified by other risk factor combinations. CHD may be discovered for the first time on screening. It is always important to enquire about angina. When CHD is discovered the decision about whether to introduce cholesterol-lowering drugs or how rigorously to treat blood pressure does not require any additional risk assessment. Frequently, however, the discovery does call for further cardiac investigation – particularly in younger patients. Whether or not patients undergo coronary artery bypass surgery after the diagnosis of CHD is made, the treatment of even modest hyperlipidaemia in patients with pre-existing CHD can be associated with an arrest of progression of coronary disease and, in those achieving the lowest levels of LDL cholesterol, with regression of atheromatous lesions. The evidence that treatment of hypertension, diabetes and stopping smoking reduces risk in patients with established CHD is more circumstantial, but nonetheless persuasive.
Other atherosclerotic disease Some 50% of people, who have peripheral or cerebral arteriosclerosis will have an acute myocardial infarction within the next five years. This means that their CHD prognosis is similar to that of myocardial infarction survivors. There is evidence that the treatment of both blood pressure and cholesterol will decrease cerebral infarction risk, but whether either of these influence the outcome of peripheral arterial 6
Known risk factors for coronary heart disease
disease is not known. However, the high CHD risk in patients with cerebrovascular or peripheral arterial disease more than justifies the rigorous treatment of dyslipidaemia and blood pressure in them.
Smoking Cigarette-smoking doubles the likelihood of the development of CHD, more so in those who smoke more than 20 a day. Stopping smoking rapidly decreases CHD risk (Figure 4), even after CHD is clinically evident. Smoking is more common in men than women, but the rate of decline in the habit has been greater in men. Older people seem more successful in giving up smoking than younger ones. Smoking is more prevalent in lower socio-economic classes than among professional or skilled people. Changing to pipe- or cigar-smoking is unlikely to be beneficial.
Hypertension The risk of CHD increases with increasing blood pressure. Both the systolic and diastolic blood pressure are risk factors for CHD (Figure 5).
2.5 Current smoker Non-smoker
Relative risk
2
1.5
1
0.5 0
5
10
15
20+
Years since stopping
Figure 4
Relationship of relative risk of CHD death following cessation of smoking. (Derived from Hammond and Garfinkel 1969.)
7
Preventive Cardiology
2.5
Relative risk
2
1.5
1
0.5
70
Figure 5
80 90 Diastolic BP (mmHg)
100
Relative risk of CHD death in men aged 35–57 years as a function of diastolic blood pressure. (Derived from Kannel et al. 1967.)
This is much less so in societies where the average serum cholesterol is low, such as Japan, although high blood pressure seems universally to be a risk factor for cerebral infarction. Blood pressure is variable and increases, for example, during exercise and when the individual is anxious. It is important therefore that it is measured under standard conditions if it is to be used as a predictor of CHD risk or if its response to therapy is to be reliably monitored. As with cholesterol, it is important to realize the frequency with which different levels of blood pressure occur, if sensible thresholds for intervention are to be set. An initial diastolic blood pressure reading exceeding 90 mmHg occurs in 15% of middle-aged people, and 3–4% will have levels greater than 100 mmHg. Thus, particularly with values of blood pressure which are lower than 160/100 mmHg, an assessment of cardiovascular risk is important in deciding whether to intervene with antihypertensive medication. In the great majority of patients, hypertension, once renal disease has been excluded, is idiopathic. Although dietary salt has claimed much attention as a possible cause over the years and may explain 8
Known risk factors for coronary heart disease
some population differences, of greater quantitative and practical significance are the effects of obesity and alcohol consumption (Figure 6).
Diabetes mellitus The risk of premature CHD is increased two- to three-fold in both insulin-dependent and non-insulin-dependent diabetes. Hyperlipidaemia is common in diabetes, particularly in non-insulin dependent diabetes mellitus (NIDDM). Hypertriglyceridaemia is particularly prevalent in diabetes, but it should also be realized that the CHD risk attributable to cholesterol is much greater in diabetic patients than in similar non-diabetic people, and that there is benefit from lipid-lowering medication at levels of cholesterol that would not warrant treatment in non-diabetic people. Hypertension is also common, and when it occurs in insulin-dependent diabetes mellitus
40
Hypertensive (%)
30
20
10
0 <85 a
Figure 6
85–99 100–114 Weight (kg)
>114
0
0–16 16–35 Alcohol units
≥35
b
Relationship of hypertension in men to (a) body weight (corrected for height) in kg, and (b) alcohol consumption in units/week. (a, Derived from Kannel et al. 1967; b, derived from Arkwright et al. 1982.)
9
Preventive Cardiology
(IDDM), it is often an indicator of nephropathy and is accompanied by proteinuria. The development of even modest proteinuria or persistent microalbuminuria is a particularly adverse sign for CHD risk (Figure 7). The development of this complication should lead to particularly careful management of any associated hyperlipidaemia and hypertension (page 59), as well as to improved glycaemic control. It should also be remembered that coronary prevention measures should be applied to women with diabetes as rigorously as to men (page 19). One reason for the high death rate from CHD in diabetes is that the likelihood of a diabetic patient surviving a myocardial infarction is less than in a non-diabetic. It is important to remember, therefore, that the investigation of newly presenting angina is even more critical in the diabetic patient than in the non-diabetic.
40
Relative risk
30
20
10
0
Figure 7
10
Non diabetics
IDDM without proteinuria
IDDM with proteinuria
Relative risk of cardiovascular death in non-diabetics, IDDM without proteinuria, and IDDM with proteinuria. (Derived from Borch-Johnsen and Kreiner 1987.)
Known risk factors for coronary heart disease
Acquired dyslipidaemia An outline of lipoprotein metabolism is shown in Figure 8.
Cholesterol The serum cholesterol concentration is positively related to the risk of CHD (Figure 9). Although there is no threshold level below which the
Chyomicrons
VLDL
HDL
Figure 8
LDL
Lipoprotein metabolism. Triglyceride-rich lipoproteins from gut (chylomicrons) are broken down in the circulation and removed within a few hours of eating. Triglyceride-rich lipoproteins from liver (very low density lipoprotein; VLDL) are continually present in circulation. Low density lipoprotein (LDL) rich in cholesterol can enter the tissue fluid from the circulation and enter cells requiring cholesterol via their LDL receptors. High density lipoprotein (HDL) from liver and gut assists in the return of excess cholesterol from the tissues to the liver.
11
Preventive Cardiology
18
55 years
CHD risk % over 10 years
16 14 12 10 8 6 35 years 4 2 0 4
Figure 9
5
6 7 8 Serum cholesterol (mmol/l)
9
Percentage of non-diabetic men aged 35 years and 55 years who will develop CHD over the next 10 years as a function of the serum cholesterol (systolic blood pressure assumed to be 135 mmHg and serum HDL cholesterol 1.4 mmol/l) (Derived from Anderson et al 1991).
risk ceases to exist, the curve becomes progressively steeper with increasing cholesterol levels. This means that, for example, the rise in cholesterol from 5 to 6 mmol/l (200–240 mg/dl) produces a much smaller increment in CHD risk than an increase from 9 to 10 mmol/l (350–390 mg/dl). Furthermore, the curve relating cholesterol to CHD risk is much steeper when other risk factors are present (Figure 10). Cholesterol is an interesting risk factor, because, unlike smoking and blood pressure, differences in its concentration can provide an explanation for the widely varying rates of CHD in different parts of the world (Figure 11). These are largely due to national differences in serum cholesterol levels as a consequence of diet: those countries with the lowest levels of cholesterol and CHD consume a greater proportion of dietary energy as carbohydrate rather than fat. In the UK, where cholesterol levels are high compared to most other 12
Known risk factors for coronary heart disease
14
Hg
m 0m
CHD risk % over 10 years
12 10
er.
18
s
Sy
S
8 6
ker.
Smo
4
P lic B
120
Hg
mm
to
Sys
Hg
20 mm
c BP 1
ystoli oker. S
m
Non-s
4
5
6 7 8 Serum cholesterol (mmol/l)
9
Percentage of non-diabetic 35 year old men who will develop CHD over the next 10 years who smoke and have high blood pressure, who smoke and have normal blood pressure and who are nonsmokers with normal blood pressure (serum HDL cholesterol assumed to be 1.4 mmol/l) (Derived from Anderson et al 1991).
600
Finland
Ireland
500 CHD deaths (per 100 000)
BP
k mo
2
Figure 10
ic tol
400 300 200
England New Zealand Australia Hungary USA Canada Israel
England Australia
Denmark
Hungary USA
Sweden
Poland
Belgium
Sweden Israel Former West Germany
Former West Germany Poland
New Zealand
Belgium Switzerland
Switzerland Italy Italy
Yugoslavia
France
France
100 Japan
Japan r = 0.67
r = 0.74
0 5 6 7 Mean serum cholesterol (mmol/l) a
Figure 11
3 4 5 6 Mean serum/HDL cholesterol b
Correlation of deaths due to CHD with (a) mean serum cholesterol and (b) ratio of serum cholesterol to HDL cholesterol (per 100 000 men) in different countries. (Adapted with permission from Simons 1986.)
13
Preventive Cardiology
countries, the daily adult fat intake is almost 100 g. Although differences in the diet of whole populations may have a great influence on the average serum cholesterol, there is tremendous variation in the individual person’s response to diet. Serum cholesterol is determined not simply by the type and quality of fat consumed, but in different individuals is influenced to a varying extent by genetic and acquired factors, such as obesity. Thus one person will show a substantial change in serum cholesterol with dietary modification, whereas another with a similar cholesterol level may show little response. Consequently, a person’s diet is not nearly so strong a risk factor for predicting CHD risk as its end result – his or her serum cholesterol level. In the UK the average serum cholesterol for a middle-aged man is between 6 and 6.5 mmol/l (240–260 mg/dl), whereas in the USA it is almost 1 mmol/l (40 mg/dl) less than this. In women before the menopause it is a little lower and afterwards it is on average higher than in men. Age influences serum cholesterol (Figure 12). Thus the
8 F M 95th percentile
Plasma cholesterol (mmol/l)
7
6 mean 5
5th percentile
4
3
0
Figure 12
14
10
20
30
40 Age
50
60
70
80
Effect of age (in years) on plasma cholesterol levels. (US data. Derived from Rifkind and Segal 1983.)
Known risk factors for coronary heart disease
proportion of the population above a particular level will depend upon the age at which screening is undertaken. Corneal arcus (Figure 13a) and xanthelasmata (Figure 13b) when they occur in young people may indicate the presence of hypercholesterolaemia. Tendon xanthomata (Figure 14) are specific for the genetic disorder, familial hypercholesterolaemia (see pages 21–3).
Low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol Most of the cholesterol in the blood circulation is carried on protein particles called low-density lipoprotein (LDL). It is the LDL which is responsible for the positive relationship between CHD risk and the
a
b
Figure 13
(a) Corneal arcus and (b) xanthelasmata in familial hypercholesterolaemia.
15
Preventive Cardiology
a
b
Figure 14
Tendon xanthomata in familial hypercholesterolaemia.
total amount of cholesterol in plasma. Generally, about one-fifth to one-third (rather more in women than men) of the total cholesterol in plasma is in another lipoprotein called high-density lipoprotein (HDL). This HDL cholesterol is inversely related to CHD risk (Figure 15). LDL is responsible for transporting cholesterol to the tissues and depositing it there, while HDL is involved in the removal of excess cholesterol from the tissues and returning it to the liver (reverse 16
Known risk factors for coronary heart disease
c
Figure 14
cont.
32
M F
CHD risk % over 10 years
28 24 20 16 12
Diabetic
8
Non-diabetic
4 0 0.8
1.0
1.2
1.4
1.6
1.8
2.0
2.4
Serum HDL cholesterol (mmol/l)
Figure 15
Relationship between CHD risk over the next 10 years and serum HDL cholesterol levels on non-diabetic and diabetic men and women aged 55 years (systolic blood pressure assumed to be 150 mmHg and serum cholesterol 6.5 mmol/l). (Derived from Anderson et al 1991.)
17
Preventive Cardiology
cholesterol transport) (Figure 8). In addition to its favourable influence on reverse cholesterol transport, HDL may also protect LDL against modifications to its structure, such as oxidation and glycation, which render it more atherogenic. The HDL cholesterol value is essential in assessing the CHD risk in primary prevention because other CHD risk factors frequently cluster with low HDL values (Figure 16). Unless it is measured, the additional element of risk from a low HDL cholesterol is not accounted for and risk may be underestimated. Without it, the serum cholesterol level, unless grossly elevated, is uninterpretable. The serum concentration of HDL cholesterol is similar in boys and girls until puberty, when it declines rapidly in boys. It remains lower in men throughout life, although it begins to drift upwards in men from their late fifties. In women, in general, serum HDL cholesterol does not decrease at the menopause. In women who develop non-insulin dependent diabetes mellitus (NIDDM) or become insulin-resistant it
Mean serum HDL cholesterol (mmol/l)
2.0 M
1.6 1.4 1.2 1.0 0.8 0.6 0.4 0.2 0
Figure 16
18
F
1.8
0
1
2 Number of risk factors
3
4
Mean serum HDL cholesterol in men and women according to the number of CHD risk factors they have. (Derived from Durrington et al 1999.)
Known risk factors for coronary heart disease
does, however, fall to levels as low as in equivalent men. Serum HDL cholesterol explains much of the difference in CHD risk between men and women and also why women with NIDDM lose the protection against CHD generally present in their sex. Naturally occurring changes in oestrogen in women only partly explain the gender difference in HDL cholesterol levels: the changes in androgen levels in men correlate closely with the difference in HDL between men and women. Androgenization in women with diabetes and insulinresistance states, such as the polycystic ovary syndrome, may account for the low HDL values typically found in these conditions, which are frequently accompanied by an android pattern of obesity rather than the gynaecoid distribution typical of non-diabetic, noninsulin-resistant women. In the prediction of CHD risk the most discriminating method of employing information about the serum cholesterol and HDL cholesterol is to express these as a ratio (see page 37).
Serum triglycerides The serum triglyceride level is related to the risk of CHD, particularly when the cholesterol is also elevated (Figure 17). There has for a long time been controversy about whether triglycerides can contribute to the prediction of CHD risk once other risk factors (serum cholesterol, HDL cholesterol, blood pressure and smoking) have been taken into account. This is largely because triglyceride levels are strongly inversely correlated with HDL cholesterol so that, once this has been included in the assessment of risk, much of the risk associated with triglycerides has already been predicted. Raised triglyceride levels, however, should alert the clinician to the possibility that CHD risk may be higher than suggested by the commonly used methods for risk prediction which do not include triglycerides. It should also be realized that evidence that treating hypertriglyceridaemia can prevent CHD is now strong and that triglycerides must therefore increasingly be viewed as a therapeutic target. One practical problem with the measurement of triglycerides is 19
Preventive Cardiology
15 4 mmol/l
1.5 mmol/l
Relative risk
10
5
5
6
7
8
9
10
Serum cholesterol (mmol/l)
Figure 17
Serum cholesterol concentration as a function of relative risk of CHD death at serum triglyceride levels of 4 mmol/l and 1.5 mmol/l. (Derived from Durrington 1989.)
that, unlike serum cholesterol and HDL cholesterol, they are best measured with the patient fasting. An initial screening for CHD risk in primary prevention can therefore be made on non-fasting blood, measuring only the cholesterol and HDL cholesterol. However, for patients being considered for primary prevention who are at borderline risk for lipid-lowering therapy, raised fasting triglycerides should be sought because this finding would militate in favour of treatment. Before commencing lipid-lowering medication both in primary and in secondary prevention, raised fasting triglyceride levels should always be sought, because this will affect the choice of lipidlowering therapy and whether to employ a combination of lipidlowering drugs. Hypertriglyceridaemia is commonly found in diabetes. Its finding in a patient not previously known to have diabetes should alert the clinician to the possibility that the patient has developed diabetes or, because it may precede the onset of glycaemia of diabetic 20
Known risk factors for coronary heart disease
proportions by several years, to the possibility that the patient may in future become diabetic. The measurement of the fasting triglyceride concentration is also helpful because, together with a knowledge of the serum cholesterol and HDL cholesterol, it allows the LDL cholesterol to be calculated according to the Friedewald formula:
{
}
LDL total serum HDL triglycerides (mmol/l) = – + cholesterol* cholesterol cholesterol 2.2** *All units in mmol/l **5 if units are all mg/dl
Measurement of LDL is recommended in the USA and many other countries as an important step in making the decision to introduce lipid-lowering drug therapy. LDL cholesterol is generally less accurate than the ‘total serum to HDL cholesterol’ ratio in the prediction of CHD risk, and therefore in countries, such as the UK, where only patients at particularly high CHD risk are targeted for drug therapy, LDL cholesterol finds most use in the monitoring of response to therapy.
Genetic dyslipidaemia Familial hypercholesterolaemia Familial hypercholesterolaemia (FH) is easily diagnosed and well understood, and effective treatment is available so that there can be no excuse for omitting to identify patients with FH in a CHD screening programme. FH is a dominantly inherited condition and about one in 500 people in the UK and USA are born with it. Thus it has approximately the same incidence as IDDM. Young men with FH may have heart attacks as early as their twenties and less than half of affected men, if untreated, survive until the age of 60; most male survivors will have had a heart attack or angina by this age. The same applies to 50% of the women with FH, although only 15% will have died by the age of 60. 21
Preventive Cardiology
Adult patients with FH generally have serum cholesterol levels between 9 and 11 mmol/l (350–430 mg/dl). Usually, the triglyceride level is in the normal range, but occasionally it is increased, rarely beyond 4 mmol/l (350 mg/dl). Patients with the condition often have no other CHD risk factors other than an adverse family history. In some, even the family history may be lacking. This is so particularly in the case of a young man who has inherited the condition from his mother, who is not yet old enough to have developed CHD herself. Tendon xanthomata develop in the great majority of adults with FH (Figures 14 a, b and c) from the third decade onwards. Other causes of tendon xanthomata are extremely rare. Corneal arcus (Figure 13a) may also develop at an early age, but this is not invariably the case and is not specific for FH. Xanthelasmata (Figure 13b) may occasionally be spectacular, but the majority of FH patients do not have them. Tendon xanthomata are best discovered by examining the tendons on the dorsum of the hands and the Achilles tendons. The overlying skin is normal in appearance and not yellow. They are hard and may be confused with the bony knuckles if the fingers are not extended during the examination when the xanthomata slide back from the knuckles and can be moved from side to side. The Achilles tendons tend to be irregular and swollen. The cholesterol within them may have set up an inflammatory reaction at some stage in the past and the patient may give a history of Achilles tensynovitis, sometimes recurrent and even leading to orthopaedic referral. FH results from a defect in the LDL receptor (Figure 8) due to a mutation of its gene on chromosome 19. This halves the rate at which LDL cholesterol is removed from the circulation, and it thus accumulates there. Since the condition is entirely genetic, it is present from birth and may be detected in childhood when the other more common, largely nutritional hypercholesterolaemias have not yet developed (Figure 12). Levels of cholesterol of greater than 6.5 mmol/l (260 mg/dl) in the child of a parent with FH are virtually diagnostic. If possible, such children should be identified by the age of 5 years, and the avoidance of obesity and smoking is generally the only treatment 22
Known risk factors for coronary heart disease
given in childhood. It must, however, be recognized that diet alone even in childhood is rarely effective as a means of lowering cholesterol adequately. The use of bile-acid sequestrating agents, such as cholestyramine or colestipol (which are licensed for prescription to children) was once advocated in children. However, this treatment was so unpleasant that it frequently had the effect of alienating children from the clinic by the time they reached their teens. Statin drugs are well-tolerated and frequently effective in FH, but we are less certain of their safety in children. Most centres now begin statin treatment in boys with FH in their late teens. Occasionally statin treatment should be initiated earlier when there is a particularly adverse family history. In women statin treatment is often reserved until their late twenties, although it is important even then that they avoid unplanned pregnancy and stop the treatment when conception is planned. Patients with FH can undoubtedly benefit from coronary artery bypass surgery and cardioprotective drug therapy. FH patients, however, do not generally conform to the stereotype of coronary prone individuals: all too often the urgency of investigating coronary symptoms in young lean, fit-looking people who have FH is not appreciated and tragedy ensues. There are also some families in which hyperlipidaemia runs, whose members seem particularly at risk of premature CHD despite the absence of the clinical features of FH. They often have an increase in both triglycerides and cholesterol and low serum HDL cholesterol. This combination, together with the heightened CHD susceptibility, has been termed ‘familial combined hyperlipidaemia’ (FCH). Often it results from synergism between adverse effects of risk factors such as hyperlipidaemia, hypertension and diabetes or insulin resistance (see page 62) and family history. Although FCH is more loosely defined than FH, it is commoner, affecting between one in 50 and one in 200 people. For the clinician it serves to emphasize the importance of a family history of premature CHD and of the effect of hypertriglyceridaemia in increasing the risk from hypercholesterolaemia. 23
Preventive Cardiology
Family history not attributable to known risk factors It is the everyday experience of doctors and nurses treating young patients with CHD that they frequently are from families in which other relatives have also had heart attacks or developed angina at an early age. Family history can, of course, operate through other known risk factors. Genetic effects can predispose to the development of hyperlipidaemia, hypertension and diabetes; and shared habits, lifestyle and environment can influence, for example, dietary choice, smoking and attitude to exercise. To a large extent, therefore, the influence of family history on CHD risk is embodied in other routinely measured risk factors. However, there does appear to be an effect of adverse family history on CHD over and above this. It has been estimated that the effect of having a male first degree relative who develops CHD or other atherosclerotic disease before the age of 55 years or a female first degree relative with a similar history before the age of 65 years will increase CHD risk by a factor of 1.5 above that calculated using other CHD risk factors (see page 36). This does not mean that this risk cannot be decreased by attention to modifiable risk factors such as smoking, dyslipoproteinaemia and hypertension. The adverse effect of family history often appears to heighten susceptibility to these factors or, in the case of lipids and blood pressure, the extent to which they rise in response to obesity and an unhealthy diet. If genetic factors commonly predisposed to CHD through some other unknown mechanism, one would not expect, for example, to find such low rates of CHD among the inhabitants of countries where serum cholesterol is low, but which rapidly rise when cholesterol levels increase on migration to countries where CHD risk is high. Acquired risk factors change on migration, not the genetic susceptibility. The latter is not expressed unless acquired adverse factors are present.
Obesity Obesity is a risk factor for CHD. The risk comes from the association of obesity with high blood pressure (see page 9), diabetes mellitus 24
Known risk factors for coronary heart disease
(see page 59) and insulin resistance (see page 62) and with its adverse effects on serum lipids (Figure 18). A distinction should be drawn between mild, cosmetic obesity and the more severe degrees which may be associated with more serious hazards to health. Dividing the weight of an individual in Kg by the square of the height in metres, gives an index known as Quetelet’s index (or the body mass index). Values for this exceeding 30 (present in more than 7% of the populations of countries such as the UK and USA) would indicate an unhealthy degree of obesity (Figure 19).* Obesity is a more important risk factor in men than in women. The exception to this is
6.6 Total cholesterol 6.2
Concentration (mmol/l)
5.8 Triglycerides 2.6
2.2
1.8
1.4 HDL cholesterol 1.0 18
Figure 18
22
26 30 Body mass index (kg/m2)
34
Relationship of body mass index to total cholesterol, triglycerides, and HDL cholesterol. (Derived from Thelle et al 1983.)
* For example, a man whose weight is 90 kg and whose height is 1.7 m, has a body mass index of 90 ÷ 1.72 = 31.
25
Preventive Cardiology
in 74
m 1.9 Underweight
Normal
Overweight/ plump
Moderate obesity
Severe obesity
72 1.8 70
Height
68 1.7 66 64
1.6
62 60
1.5
58 40
50
60
70
80
90
100
110
120
130
140
150 kg
100 120 140 160 180 200 220 240 260 280 300 320 Weight
Figure 19
lb
Definitions of body weight in relation to height. (Derived from Garrow 1988.)
the woman who has a more masculine distribution of adipose tissue so that instead of developing adipose buttocks and thighs her abdomen is most affected. She is more likely to have hyperlipidaemia, diabetes/insulin resistance and hypertension. Some people are concerned about weight gain when they stop smoking. Obviously, this is to be avoided, but they can be reassured that the beneficial effect of stopping smoking on cardiovascular risk would generally only be nullified by a weight gain of 2 stones (12 kg).
Lack of exercise There is evidence that people with a physically active job have fewer heart attacks than those with more sedentary occupations. This does not, however, mean that exercise prevents CHD: people pursuing 26
Known risk factors for coronary heart disease
sedentary and physically active lives differ in many other respects. Trials in which exercise has been encouraged as a means of CHD prevention must be viewed with caution. Injudicious exercise in patients with pre-existing CHD is dangerous. Death in the locker room after a game of squash in the middle-aged player is not uncommon and occurs almost invariably in those players with significant coronary atheroma, many of whom had some predisposing factor such as a bad family history or hypertension, and were presumably in the deluded belief that they were doing themselves some good by exercising. Exercise taken wisely, however, does have its good points. It cannot be natural for societies such as ours to take so little exercise as we nowadays do, and this must contribute to the epidemic of obesity. There is no evidence that regular walking or swimming in supervised swimming pools is harmful at any age and jogging (not competitive running) is also probably beneficial to many people, although running 5 miles is probably no more beneficial to health than walking the same distance.
Social factors CHD is still frequently regarded as the disease of the company director. In fact the greatest declines in CHD rates in the UK and USA have occurred in the higher socioeconomic classes. The need to develop strategies that will be effective in the lower socioeconomic groups is frequently overlooked by those who design CHD prevention programmes. People with a low income often have only a very limited ability to change their lifestyle. Obesity and cigarette-smoking are more prevalent in those who are less well-off and who are more likely to believe that diseases are unavoidable. Geography plays a part in CHD too. Migrants from parts of the world where there is little CHD to regions where there are high rates of CHD, increase their risk. For example, the Japanese who went to live in California and Hawaii showed a substantial increase in serum cholesterol, blood pressure and blood glucose and, consequently, in 27
Preventive Cardiology
their CHD risk. Asians originating from the Indian subcontinent generally show an increase in CHD rates to levels even above those of the Western country to which they have migrated. This is largely due to a particularly high prevalence of glucose intolerance and diabetes, affecting some of 20% of them by middle age.
Stress and personality People who have CHD frequently believe themselves to have borne an undue share of the world’s burdens. Stress has long been associated in the layperson’s mind with heart disease and there is no doubt that stressful circumstances make angina more easily provoked. Furthermore, emotional shock or anger may trigger either a rise in blood pressure leading to rupture of a coronary atheromatous plaque or to cardiac dysrhythmia and perhaps to sudden death. Whether, however, stress and personality actually contribute directly to the process by which atheroma develops in the first place is not so certain. Although the suggestion that people with a type A personality are predisposed to CHD has been widely stated, it has not been confirmed. Moreover, if that type of personality is properly channelled, those who have it will do most to reduce their CHD risk factor levels.
Fibrinogen, other coagulation factors and inflammatory markers Myocardial infarction is not generally simply the result of the growth of coronary atheroma, but depends on the rupture of an atheromatous lesion. Cholesterol-rich lesions lacking fibrous tissue which can bind the overlying cap of the lesion to the artery wall are particularly vulnerable. This probably accounts for much of the success of cholesterol-lowering treatment in preventing clinical events. This treatment depletes atheromatous lesions of cholesterol, improving their resistance to rupture. However, other factors such as inflammation of the lesions may also affect the likelihood of rupture; and once rupture has occurred the coagulability of blood will be an important determinant of whether an occlusive clot forms on the torn 28
Known risk factors for coronary heart disease
surface of the lesion. Coagulation factors such as plasma fibrinogen, and markers of inflammation, such as C-reactive protein are thus determinants of the risk of heart attack. At the present time their value in CHD risk screening and intervention is undergoing evaluation.
29
3
Determination of coronary risk
In countries where CHD is prevalent, preventive strategies must aim, on the one hand, to diminish the average level of risk in the general population and, on the other, to target for more intensive intervention those people who already have clinical CHD or are likely to acquire it in the near future. The latter is the ‘high-risk’ or clinical approach for which clinical trial evidence is strong. It is obviously a better option for individuals at high-risk than reliance on population strategies. However, it will not in itself greatly decrease the overall incidence of CHD in countries such as the UK and USA, because in those countries most fatal and non-fatal new CHD cases are in people who are at average levels of CHD risk simply because they are more common than high-risk people (Figure 20). It is important therefore for countries at high CHD risk to have national strategies aimed particularly at stopping smoking, promoting healthy foods and making them readily available, and discouraging sedentary behaviour. This policy should receive the support of healthcare workers, but it is impossible without the political will to regulate by fiscal and legislative means the food and farming industry, the entertainment and leisure industry and the teaching profession and school authorities. The UK has not been notable among the nations making the most progress in this respect. The lack of a consistent public policy for CHD diminishes the effectiveness of non-pharmacological lifestyle interventions by doctors, nurses and dieticians, and increases the pressure for a higher proportion of the population to receive pharmacological intervention – thus to require continuing medical and nursing supervision.
30
Frequency in the general population
Determination of coronary risk
Population at >3% risk 0.25
Figure 20
0.5
1 Annual CHD risk (%)
2
4
The frequency distribution of CHD risk in the middle-aged British population. Because there are many more people whose annual risk is around the average of 1% than at 3%, more new cases of CHD will therefore come from people at only average risk than from those at high risk.
Mutable and immutable risk factors It should be remembered that many factors which allow the identification of an ‘at risk’ individual are not themselves open to modification or alteration. The process of identification is thus distinct from the intervention phase of coronary prevention.
Opportunistic screening versus screening by invitation CHD risk factor screening can be undertaken by a nurse. A questionnaire used in conjunction with the measurement of body weight, height, blood pressure and non-fasting serum cholesterol and HDL cholesterol will identify a large proportion of people who are at increased risk. In general practice some 90% of patients will visit the surgery for some purpose over a period of two years. Thus, if they were asked to spend a few minutes with the screening nurse when 31
Preventive Cardiology
attending for some other purpose, theoretically most of the practice could be screened over the course of a few years. This has the advantage over screening by invitation in that it is less expensive and avoids prior planning. However, many middle-aged men, who are perhaps least likely to attend the surgery, may be missed and some patients attending the surgery are unwell to the point where their serum cholesterol concentration may have decreased. Probably the best approach is not one, but both methods. Thus an opportunistic approach (inviting those unwell to return when they are better), taking advantage of existing clinics (for example, for hypertension or diabetes) and of other screening programmes, such as cervical screening (asking women to bring their husbands then or on some other occasion), can be combined with inviting selected individuals not screened opportunistically in a two-year period. Advertising in the surgery and in local workplaces may also be helpful.
Identifying patients for secondary prevention Existing CHD and other atherosclerotic disease Patients who have survived a myocardial infarction or who have stable or unstable angina have declared themselves to be at high CHD risk, and no further evaluation of their CHD risk is necessary in determining whether they should receive aspirin or treatment for hypercholesterolaemia or high blood pressure. The same is also true of patients with cerebral arteriosclerosis (stroke, transient cerebral ischaemic attacks or significant carotid disease discovered, for example, on ultrasound performed to investigate a carotid bruit) or peripheral arterial disease (intermittent claudication, ischaemic rest pain) who are at similar CHD risk. Patients with clinically overt CHD will also generally require additional medication that has been shown to improve their survival, such as beta-blockers and ACE inhibitors (see pages 65–6).
32
Determination of coronary risk
Identifying patients for primary prevention Who should be screened? Age has such a dominant effect on CHD risk that the younger the age at which screening takes place, the smaller will be the number of people whose risk demands clinical intervention. Screening older people will produce more who can benefit from treatment. Ideally, of course, screening should not be a single shot exercise and should occur on a regular basis, perhaps every five to ten years, at least, from the age of 30. At the present time, however, it is more pragmatic that a start be made in the 35–50 year olds. Efforts should not focus on men even though they are at more risk of CHD than women: to do so is neither feasible nor practical. Men are more likely to attend for screening as the result of pressure from their wives or partners who often are more concerned about diet and health. Furthermore, although less common in men than women, CHD remains one of the major causes of their premature ill health and eventual death. To exclude women is to court disaster. Coronary prevention should be treated as a family matter. The questionnaire used for screening is shown in Table 1.
33
Preventive Cardiology Table 1
Screening questionnaire
Name . . . . . . . . . . . . . . . . . . . . . .
Telephone number . . . . . . . . . .
Sex . . . . . . . . . . . . . . . . . . . . . . .
Age . . . . . . . . . . . . . . . . . . . .
Personal history (previous myocardial infarction/angina of effort/peripheral arterial disease/cerebral arteriosclerosis)* Family history
(angina or heart attack in: mother/sister aged<65 years father/brother aged <55 years)
Smoking
Cigarettes
/day
Other
Diabetes mellitus
Yes/No
Age at menopause
Years
Body weight
kg
Height
cm
Blood pressure
Systolic
mmHg
(treated hypertension Yes/No)
Diastolic
mmHg
Xanthelasmata
Yes/No
Other xanthomata (e.g. tendon)
Yes/No
Corneal arcus in patient aged <50 years
Yes/No
Cholesterol
mmol/l
HDL cholesterol
mmol/l
Date of last tetanus booster Date of last cervical smear *May require further investigation
Assessment of obesity A method of assessing obesity has been given in Figure 19 (page 26).
Blood pressure measurement This should be measured in the sitting position in the right arm, after the patient has rested for five minutes. Patients should be relaxed and sitting comfortably with the arm supported. The correct size cuff must
34
Determination of coronary risk
be used if pressure is not to be overestimated in obesity. Once the cuff has been inflated above the pressure where the brachial artery pulse disappears, the appearance of the first Korotkoff sound (K1) on deflation gives the systolic pressure. Further Korotkoff sounds are auscultated (K4 represents muffled sounds; K5, complete disappearance). K5 should be the chosen end-point for the diastolic pressure. If K5 is difficult due to continuation of sound to zero, then K4 should be measured and recorded. Measurements are taken to the nearest 2 mmHg. In elderly people, in diabetes mellitus and in hypertensive patients on treatment, standing blood pressure should also be measured because of the potential problem of orthostatic hypotension. A diagnosis of hypertension should not be made until blood pressure has been shown to be persistently raised. The blood pressure of almost 50% of people initially categorized as mildly hypertensive is subsequently found on repeated measurement over six months to be in the normal range. The period of observation must, however, depend on severity. Thus in patients with clinically overt CHD or other atherosclerotic disease, more severe hypertension or target organ damage, antihypertensive therapy should be commenced without undue delay.
Lipid measurements In order to assess CHD risk in primary prevention it is essential to measure both serum cholesterol and HDL cholesterol. Both of these measurements can be undertaken on non-fasting samples (see page 20). Omitting HDL cholesterol will lead to overestimation of risk in many healthy women and, conversely, to false reassurance in certain high-risk patients. Fasting is necessary for the measurement of triglycerides, but this is not required for the initial assessment of risk – generally only in borderline cases or to decide on the choice of lipidlowering drug.
35
Preventive Cardiology
Assessment of CHD risk The initial screening can be conveniently undertaken by a nurse or doctor using the questionnaire in Table 1. The information obtained can then be used to make an assessment of CHD, which can be used as a guide to assist clinical judgement in deciding how vigorously to intervene to decrease CHD risk. The best currently available means of assessing CHD risk is to use the charts or computer programme produced jointly by the British Cardiac Society, British Hyperlipidaemia Association, British Hypertension Society and Diabetes UK (Figure 21). These are based on a mathematical equation derived from the results of the Framingham Study, an epidemiological study performed in the USA. Agreement between this and European investigations has been reasonably good at least for men, but it should be remembered that the risk calculated using this method can never be more than a guide. The risk is given as the percentage of people with a particular combination of risk factors who will develop CHD in the next ten years. The risk of stroke is generally about one-quarter of that of CHD. In certain patients the method will undoubtedly give misleading results. Generally, these are patients already known to be at high enough risk for active intervention, namely patients for secondary prevention (see page 32), men and women with familial hypercholesterolaemia (see pages 21–3), proteinuria or other chronic renal disease (see page 10) and women with premature menopause. Methods based on the Framingham equation should also be used with caution in patients with an adverse family history (acute myocardial infarction or angina in male first-degree relative before 55 years of age or a female first-degree relative before 65 years of age) (see page 24) or in patients who have migrated from the Indian subcontinent, because in both these groups CHD risk is likely to be underestimated. As a rule of thumb, in either of these circumstances
36
Determination of coronary risk
multiplying the risk indicated by the charts by 1.5 may give a more reliable estimate. To use the charts, calculate the serum total cholesterol (TC) to HDL cholesterol ratio by dividing TC by HDL cholesterol or simply placing a ruler on the relevant values for TC and HDL on the nomogram in the chart and reading the value where the line joining them crosses the TC:HDL scale. Then find the appropriate chart for a diabetic or non-diabetic, male or female patient of similar age. The point on the chart with the patient’s and TC:HDL cholesterol and systolic blood pressure as co-ordinates is then found. This will be in the green, orange or red zone, which indicate 10 year CHD risks of <15%, 15–30% or >30% respectively. There is also a line in the orange zone to the right of which risk is >20%. This allows patients in the orange zone to be further subdivided into those with CHD risk 15–20% and 20–30% over the next ten years. If the patient is already on antihypertensive or lipid-lowering medication or has only stopped smoking in the last few years, the risk will be higher than in a patient who has habitually run blood pressure and lipid values at their current levels or who has been a life-long nonsmoker. The charts are a guide, but cannot replace clinical judgement.
37
Preventive Cardiology
NO DIABETES CHD risk <15% over next 10 years CHD risk 15–30% over next 10 years CHD risk >30% over next 10 years Serum cholesterol mmol/l 12
CHD risk over next 10 years 15% 20% 30%
HDL cholesterol mmol/l 0 0.5
11 10
SBP = systolic blood pressure mmHg TC : HDL = serum total cholesterol to HDL cholesterol ratio.
7 6
9
14 10 8
1.0 1.5
5
8
4
7
3
6
TC : HDL
2.0 2.5
5 4
MEN AGE NON-SMOKER
AGE NON-SMOKER
SMOKER
35–44 YEARS SMOKER
180
180
180
180
SBP 160
160
SBP 160
160
140
140
140
140
120
120
120
4
6 8 TC : HDL
10
AGE NON-SMOKER
4
6 8 TC : HDL
10
120 4
45–54 YEARS
6 8 TC : HDL
10
AGE NON-SMOKER
SMOKER
4
180
180
SBP 160
160
SBP 160
160
140
140
140
140
120
120
120
10
AGE NON-SMOKER
4
6 8 TC : HDL
10
120 4
55–64 YEARS
6 8 TC : HDL
10
AGE NON-SMOKER
SMOKER
4
180
180
SBP 160
160
SBP 160
160
140
140
140
140
120
120
120
10
AGE NON-SMOKER
4
6 8 TC : HDL
10
120 4
65–74 YEARS
6 8 TC : HDL
10
AGE NON-SMOKER
SMOKER
4
180
180
SBP 160
160
SBP 160
160
140
140
140
140
120
120
120
Figure 21
10
4
6 8 TC : HDL
10
10
SMOKER
180
6 8 TC : HDL
6 8 TC : HDL
65–74 YEARS
180
4
10
SMOKER
180
6 8 TC : HDL
6 8 TC : HDL
55–64 YEARS
180
4
10
SMOKER
180
6 8 TC : HDL
6 8 TC : HDL
45–54 YEARS
180
4
38
WOMEN
35–44 YEARS
120 4
6 8 TC : HDL
10
4
6 8 TC : HDL
CHD risk prediction charts of the British Cardiac Society, British Hyperlipidaemia Association, British Hypertension Society and Diabetes UK. See text for explanation of how to use the charts. (© The University of Manchester)
10
Determination of coronary risk
DIABETES CHD risk <15% over next 10 years CHD risk 15–30% over next 10 years CHD risk >30% over next 10 years Serum cholesterol mmol/l 12
CHD risk over next 10 years 15% 20% 30%
HDL cholesterol mmol/l 0 0.5
11 10
SBP = systolic blood pressure mmHg TC : HDL = serum total cholesterol to HDL cholesterol ratio.
7 6
9
14 10 8
1.0 1.5
5
8
4
7
3
6
TC : HDL
2.0 2.5
5 4
MEN AGE NON-SMOKER
WOMEN
35–44 YEARS
AGE NON-SMOKER
SMOKER
35–44 YEARS SMOKER
180
180
180
180
SBP 160
160
SBP 160
160
140
140
140
140
120
120
120
4
6 8 TC : HDL
10
AGE NON-SMOKER
4
6 8 TC : HDL
10
120 4
45–54 YEARS
6 8 TC : HDL
10
AGE NON-SMOKER
SMOKER
4
SMOKER
180
180
180
SBP 160
160
SBP 160
160
140
140
140
140
120
120
120
6 8 TC : HDL
10
AGE NON-SMOKER
4
6 8 TC : HDL
10
120 4
55–64 YEARS
6 8 TC : HDL
10
AGE NON-SMOKER
SMOKER
4
180
180
SBP 160
160
SBP 160
160
140
140
140
140
120
120
120
10
AGE NON-SMOKER
4
6 8 TC : HDL
10
120 4
65–74 YEARS
6 8 TC : HDL
10
AGE NON-SMOKER
SMOKER
4
180
180
SBP 160
160
SBP 160
160
140
140
140
140
120
120
120
Figure 21
10
4
6 8 TC : HDL
10
10
SMOKER
180
6 8 TC : HDL
6 8 TC : HDL
65–74 YEARS
180
4
10
SMOKER
180
6 8 TC : HDL
6 8 TC : HDL
55–64 YEARS
180
4
10
45–54 YEARS
180
4
6 8 TC : HDL
120 4
6 8 TC : HDL
10
4
6 8 TC : HDL
10
cont.
39
4
Management of the ‘at risk’ individual
●
Stopping smoking
●
Lowering cholesterol
●
Reducing blood pressure
●
Reducing weight
●
Aspirin and cardioprotective drugs
In an individual CHD risk factors may combine together. Some people with multiple risk factors are at high risk even though each of their individual risk factors might, were it occurring in isolation, be no great cause for concern. This is the major reason for adopting a holistic approach to CHD prevention. A blood pressure of 150/90 or a cholesterol of 5.5 mmol/l may be of no clinical significance, for example, in a non-diabetic, but it can be important to treat both in a diabetic patient. A method of assessing CHD, such as that described earlier, may be good for identifying risk, but will give only a poor indication of how far it is possible to reverse that risk. Age, male gender, personal history of vascular disease and family history are all immutable. Glycaemic control in diabetes also does not alter the CHD risk. Stopping smoking and lowering cholesterol and blood pressure have, however, been shown convincingly to reduce CHD risk. The extent to which they do this is discussed in Chapter 5. It is important to realize that the benefit of treatment cannot simply be estimated by recalculating the CHD risk with the patient entered as a non-smoker and with his or her post-treatment lipid and blood pressure levels. It is probably better if one gives patients progress charts to record serial measurement of body weight, blood pressure, cigarette smoking and cholesterol with realistic targets for each of these; it is not helpful to give a patient an absolute risk based substantially on immutable risk factors. 40
Management of the ‘at risk’ individual
Stopping cigarette smoking This must be a primary aim of health promotion. Advice to stop is most successful in the older age group, women in pregnancy and in patients whose health has already suffered some catastrophe, such as a heart attack. Stopping or cutting down on smoking is a highly cost-effective means of decreasing cardiovascular risk, even if it can only be achieved relatively infrequently. Advice to stop smoking is not a ‘once only affair’ and at every visit patients with CHD, hypertension, diabetes, hyperlipidaemia, etc. attending the general practice surgery or hospital clinics should be reminded in no uncertain terms to stop. Smoking can be highly addictive, and psychological treatment or drug therapy to overcome physical dependency should be tried where willpower fails. There is evidence for the efficacy of both nicotine preparations and amfebutamone (bupropion).
Management of hyperlipidaemia Diet Dietary advice should be provided generally for patients with hyperlipidaemia. There is evidence that diet can lower serum cholesterol and triglycerides and reduce CHD risk. Its effects, however, are seldom so great that reliance should be placed upon diet alone in the management of high-risk patients. There are two essential components to the diet. The first is that the obese patient should be advised to lose weight. Simple diet advice is given in Table 2. Even a moderate reduction in obesity is sometimes helpful. All types of hyperlipidaemia in the obese respond to weight reduction. Failure
to
lose
weight
complicates
the
management
of
hyperlipidaemia, hypertension and diabetes. The best way to lose weight is to eat less, particularly less fat. Despite frequent claims to the contrary (by the manufacturers of slimming products), it is not possible to maintain a weight loss of more than about 1 lb/week (0.45 kg/week). Exercise cannot substitute for a reduced energy intake, but it may be critical to maintaining any decrease in body weight achieved by dietary restriction. 41
Preventive Cardiology Table 2
Prevention tastes better than cure*
As part of a healthier lifestyle we should eat less fat. Here are six simple ways to reduce fat in your diet: 1.
Use a low fat spread rather than butter or margarine, and spread it thinly
2.
Try switching from full-cream milk to semi-skimmed milk
3.
Choose low-fat cheese, or cottage cheese in place of full-fat cheese
4.
Eat fish or chicken, but avoid chicken skin as it is fatty
5.
Eat fresh fruit or sandwiches as snacks; choose jacket potatoes rather than chips
6.
Grill rather than fry food, cut off all visible fat and drain off fat during cooking*
*Based on a diet from the Health Education Council
The second important element of diet is to modify fat intake so that saturated fat intake is decreased. Table 3 embodies such advice.
Table 3
A lipid-lowering diet. (The items in italics should also be avoided if you are trying to lose weight.) (Derived from Durrington, 1989.)
MEAT
42
Eat/drink regularly
Eat/drink in moderation
Avoid eating/drinking
Chicken and turkey (without skin) Veal Well-trimmed grilled steak Rabbit, hare, grouse, partridge, pheasant Venison Soya-protein meat substitute
Lean minced beef, boiled and fat skimmed off before draining and frying in permitted oil, to use in chilli, spaghetti sauce, etc.
Ham, beef, pork, lamb, bacon, duck, goose, offal, liver, kidney, tripe, sweetbreads, heart, brain Crackling and skin Sausage Salami Luncheon meat Paté, corned beef Scotch eggs, meat pies and pasties
Management of the ‘at risk’ individual Table 3
cont.
FISH
Eat/drink regularly
Eat/drink in moderation
All fresh, frozen, canned, Shellfish: smoked, soused fish (a) Crustaceans (crabs, Watch tinned fish (olive oil, lobsters, crayfish, sunflower oil, brine, langoustines, shrimps, tomato sauce permitted, prawns, etc.) in modest but not vegetable oil) amounts Oily fish and fish fried in (b) Molluscs (oysters, permitted oils mussels, whelks, winkles, scallops, coquilles, clams, abalone, squid, octopus) a little more generously
Avoid eating/drinking Battered fish Fish roe Taramasalata, caviar Fish paste Potted fish Sweetbreads Fish fried in unsuitable oil or smothered in cheese
NUTS
Eat/drink regularly
Eat/drink in moderation
Avoid eating/drinking
Walnuts Almonds Pecan nuts Chestnuts Hazel (filbert) nuts
Brazil nuts Coconut Peanuts Pistachio nuts Cashew nuts Macadamia nuts (If you are a vegetarian, you may eat more regularly)
43
Preventive Cardiology Table 3
cont.
EGGS AND DAIRY PRODUCE
Eat/drink regularly Skimmed milk Dried skimmed milk Soya milk Low-fat yoghurt Cottage cheese Egg white (meringue) (3 egg yolks per week only)
44
Eat/drink in moderation
Avoid eating/drinking Whole milk, cream, imitation cream, full-fat yoghurt Evaporated or condensed milk Excess eggs Hard cheese, cream cheese or processed cheese (most hard cheeses contain 31–35 g/100 g fat of which two-thirds is saturated fat Edam, gouda, brie, camembert, feta and proprietary low-fat hard cheeses have lower than average fat content Quiche, soufflé, Welsh rarebit, crocque monsieur, cheese pizza, cooked cheese dishes
Management of the ‘at risk’ individual Table 3
cont.
FATS
Eat/drink regularly
Eat/drink in moderation
Avoid eating/drinking
All fats should be limited
Corn oil, sunflower oil, safflower oil, soya oil, olive oil, rapeseed oil, wheatgerm oil, sesame seed oil, poppyseed oil, grapeseed oil Margarine labelled ‘high in polyunsaturates’ or ‘high in linoleic acid’ Ignore ‘low in cholesterol’ (saturated fat should be less than 15 g/100 g) Low-fat spreads
Butter, dripping, suet, lard, margarine, shortening, ghee, cocoa butter, cooking oil, or vegetable oil of unspecified origin Palm oil, coconut oil, peanut oil Peanut butter (especially if hydrogenated)
PREPARED FOODS AND MADE-UP DISHES
Eat/drink regularly
Eat/drink in moderation
Avoid eating/drinking
Home-made is the basic rule Jelly, sorbet
Ice-cream
All bought frozen, tinned or dried or packet prepared meals and dishes, soups and sauces
45
Preventive Cardiology Table 3
cont.
CEREAL FOOD
Eat/drink regularly
Eat/drink in moderation
Wholemeal flour White flour Oatmeal White bread Sugar-coated breakfast Wholegrain bread Wholegrain cereals cereals Porridge White rice Crispbreads Pasta without added egg Wholegrain rice and pasta Muesli without coconut or Popcorn (without butter or fat (consult label) sugar), sweetcorn Water biscuits Homemade cakes, biscuits, pastries and pizzas (no cheese), using permitted oils Chapattis made without fat
Avoid eating/drinking Fancy bread, e.g. croissants, Danish pastries, sponges, choux pastry, and all bought cakes Savoury cheese biscuits, cream crackers, biscuits
FRUIT, VEGETABLES AND SALAD
Eat/drink regularly
Eat/drink in moderation
All fresh, frozen, dried, Chips and roast potatoes bottled or tinned fruit, in permitted oils vegetables and salad, Avocado pears especially peas, beans, lentils, pulses and potatoes (baked or boiled) Olives Ratatouille made with permitted oil
46
Avoid eating/drinking Potato crisps and savoury snacks, chips and roast potatoes cooked in unsuitable oil or fat
Management of the ‘at risk’ individual Table 3
cont.
DRINKS
Eat/drink regularly
Eat/drink in moderation
Avoid eating/drinking
Marmite, Bovril, tea, coffee, mineral water Avoid fruit juice, fizzy drinks and squashes if on a weight-reducing diet unless they are low in calories or sugar
Alcohol-containing drinks Whole milk drinks, (there may be no reason bought soups, creamfor you to be more zealous based liqueurs in this regard than the Malted milk or hot general population unless chocolate drinks – you receive specific advice check fat content even from your doctor) when label says ‘low Beer, sweet sherry, wine fat’ and mixers containing sugar
SWEETS, PRESERVES, JAMS AND SPREADS
Eat/drink regularly
Eat/drink in moderation
Avoid eating/drinking
Chutneys and pickles Sugar-free artificial sweeteners, jam, marmalade, honey
Added sugar (sucrose), fruit sugar (fructose), boiled sweets, fruit, pastilles and jellies, peppermints
Chocolates, chocolate spreads and sweets Toffees, fudge Butterscotch, lemon curd, mincemeat, meat and fish pastes, spreads, coconut bars, etc.
47
Preventive Cardiology Table 3
cont.
SAUCES AND DRESSINGS
Eat/drink regularly
Eat/drink in moderation
Avoid eating/drinking
Herbs, spices, garlic, watercress Lemon and lemon juice Tomato purée and sauce, brown sauce, Tabasco, soy, anchovy, Worcester, tandoori sauces (made with yoghurt) Mint sauce and jelly Redcurrant jelly Vinegar, chutneys and pickles, Cumberland sauce, olive oil Home-made dressings with permitted oils (e.g. French dressing, vinaigrette dressing, etc.) Low-fat yoghurt dressings, sweet-and-sour sauce, Portugaise and Provençale sauce White (béchamel or velouté) sauce made with permitted oils or margarine in place of butter, which may then be converted to a variety of sauces (e.g. parsley, caper, mussel, mustard, curry, wine, mushroom, Véronique, anchovy, etc.)
Sprinkling of Parmesan cheese Bought low-fat or lowcalorie salad dressing
Mayonnaise, ordinary salad cream or other cream dressings and sauces, including hollandaise, tartare, and aïoli Gravy Brandy butter Watch stuffings which may contain unsuitable ingredients
Saturated fats are present in the adipose tissue of warm-blooded animals, for example, in pork, lamb and beef, in dairy products, such as milk, cream, cheese, and in some cooking oils and margarine 48
Management of the ‘at risk’ individual
which are not specifically labelled as being low in saturates. Saturated fats in the diet increase both serum cholesterol and triglycerides: replacing them with carbohydrates (other than simple sugars and syrup), polyunsaturated fats or monounsaturated fats lowers the serum cholesterol and triglycerides. In the non-obese, in whom a dietary energy deficit is not needed, a traditional high saturated fat diet can be replaced by: ●
Increased intake of potatoes, pulses, rice, pasta and fish
●
Use of soya-bean oil, sunflower oil, safflower oil, corn oil, rapeseed oil or olive oil products
●
An increase in other vegetables and fruit in the diet, although it contributes little to energy, enormously increases the variety and appeal of the diet.
Common misunderstandings There is much misunderstanding about diet. Common incorrect beliefs are: ●
Foods labelled low in cholesterol are necessarily healthy (in fact, dietary cholesterol has only a small influence on serum cholesterol compared to that of saturated fat in the diet).
●
Fibre should be taken for its own sake (fibre does not lower serum cholesterol very much, if at all, and its effects on flatulence and wind are unacceptable to most people; undue insistence on increased fibre intake is an obstacle to the success of a lipid-lowering diet).
●
Skimmed milk causes osteoporosis (in fact, it contains more calcium than whole-fat milk).
●
Red meat cannot be eaten (not so: a trimmed, grilled steak has no more fat in it than chicken).
●
Chips cannot be eaten (they can, unless you are trying to lose weight and they are excellent cooked in the recommended oils).
●
Products marked as vegetable oils are acceptable (they are not: they could easily contain palm or coconut oils which are rich in saturates. Stick to the recommended oils and their products). 49
Preventive Cardiology
Alcohol in moderate amounts is not harmful to the heart. However, in the obese it may be a major source of excess energy intake. In hyperlipidaemia, especially when triglycerides are raised, and in hypertension, it may be necessary to monitor a period of abstinence to assess the part it is playing. Excessive alcohol can cause atrial fibrillation, cardiomiopathy or extreme hypertriglyceridaemia, as well as other non-cardiovascular harmful effects. Dietary advice should be given to patients whose cholesterol exceeds 5 mmol/l (200 mg/dl). A diet sheet should always be provided – ideally, with some explanation from a trained nurse. In practical terms, this may be all that can be provided for patients whose 10 year CHD risk is not above 15% (low risk). When the risk is higher, referral to a dietician is advisable so that advice can be tailored to the individual patient’s dietary preferences and misconceptions resolved. If the patient does not do the cooking in the household, then whoever does should also be present on such a visit.
Lipid-lowering drugs Previously held views about what constitutes a raised cholesterol level are in radical need of revision as the results of trials of lipid-lowering drugs show clear benefits in patients with levels as low as 5 mmol/l or even lower (Table 4). Thus failure of the cholesterol level to fall below 5 mmol/l (200 mg/dl) with diet is an indication for the introduction
of
lipid-lowering
medication
in
secondary
prevention. In primary prevention this is also an indication of the patient at high risk of developing CHD. If the CHD risk is high, the threshold cholesterol level at which therapy is initiated should be the same in primary and secondary prevention – namely ≥5 mmol/l.
50
Drug
7.2 6.4 6.9 6.4 4.5 5.4 –
1°
1° 1°
2° 2° 2°
2°
>2.3
2.4 1.8 1.6
– 2.0
1.7
1.5 1.8 1.8 1.6 1.8
–
1.2 0.8 0.9
– 1.2
1.1
1.2 1.1 1.0 0.9 1.0
–
-13% -4% -5%
-9% -10%
-9%
-29% -20% -20% -18% -19%
–
-19% -31% -25%
– -35%
+3%
-10% -12% -14% -12% -13%
–
– +8% +14%
– +10%
+3%
+8% +5% +5% +6% +5%
Outcome Cholesterol Triglycerides HDL-C
-40%
-41% -22% -9%
-20% -34%
-19%
-33% -31% -24% -24% -37%
CHD incidence
4S (Scandinavian Simvastatin Survival Study); WOSCOPS (West of Scotland Coronary Prevention Study); CARE (Cholesterol and Recurrent Events); LIPID (Long-Term Intervention with Pravastatin in Ischaemic Disease); AFCAPS/TexCAPS (Air Force/Texas Coronary Atherosclerosis Prevention Study); LRC (Lipid Research Clinics); WHO (World Health Organization); VAHIT (Veterans Affairs High Density Lipoprotein Intervention Trial); BIP (Bezafibrate Infarction Prevention); – (result not reported)
*+niacin
6.7 7.0 5.4 5.6 5.7
2° 1° 2° 2° 1°
Primary (1°)/ Average lipids at entry (mmol/l) Secondary Cholesterol Triglycerides HDL-C (2°)
Results of lipid-lowering drug trials with clinical end-points in the last 20 years
Statin trials 4S Simvastatin WOSCOPS Pravastatin CARE Pravastatin LIPID Pravastatin AFCAPS/TexCAPS Lovastatin Bile acid sequestrating agent trial LRC Cholestyramine Fibrate trials WHO Clofibrate Helsinki Heart Study Gemfibrozil Stockholm Secondary Prevention Study Clofibrate* VAHIT Gemfibrozil BIP all patients Bezafibrate BIP patients with triglycerides >2.3 mmol/l Bezafibrate
Table 4
Management of the ‘at risk’ individual
51
Preventive Cardiology
There are several lipid-lowering drugs in common use (Table 5). Before starting a lipid-lowering drug it is essential to measure: ●
Fasting cholesterol, triglycerides and, if available, HDL cholesterol (until this stage non-fasting serum and HDL cholesterol can be used in management)
●
Fasting blood glucose
●
Creatinine (or urea) and liver transaminases
●
Urine protein by strip-testing
●
Thyroid function tests, if hypothyroidism is thought possible on clinical grounds.
Table 5
Lipid-lowering drugs in common use
Statins Atorvastatin
10–80 mg daily
Cerivastatin
100–400 µg each evening
Fluvastatin
20–40 mg each evening; 40 mg bd
Pravastatin
10–40 mg each evening
Simvastatin
10–80 mg each evening
Fibrates Bezafibrate mono
400 mg daily
Ciprofibrate
100 mg daily
Fenofibrate
Supralip 160 mg daily; Micro 267 mg daily (67 mg tablets available for patients with renal disease)
Gemfibrozil
600 mg bd
Bile acid sequestrating agents Cholestyramine
2–6 sachets daily in divided doses before meals
Colestipol
Indications for lipid-lowering drugs are shown in Table 6.
52
Management of the ‘at risk’ individual Table 6 ●
Indication for lipid-lowering drugs
Familial hypercholesterolaemia (or other genetic hyperlipidaemia with bad prognosis if untreated)
●
Serum cholesterol ≥5mmol/l + one or more of the following: 1.
Established CHD or other atherosclerotic disease
2.
Proteinuria (or other chronic renal disease)
3.
10-year CHD risk ≥15%*
* Scientific evidence for benefit at this level of risk. Current recommendations in the USA would lead to treatment of some patients at even lower risk, whereas in the UK the National Service Framework, while accepting the evidence for benefit at lower levels of risk, recommends 30% until resources permit! The European recommendation is to treat at 20%.
The most controversial area is the level of CHD risk at which to initiate treatment with a lipid-lowering drug in primary prevention. There seems little point in treating people at a 10 year CHD risk below say 10%. At this level of risk in the first five years of treatment fewer than one person will benefit for every 50 people treated. However, as risk rises, both the number of people who must be treated to prevent a CHD event and the cost of preventing an event decrease. Cost is the main issue determining the level of CHD risk at which lipidlowering therapy is recommended. If cost were not the issue, the scientific evidence of benefit would justify treatment when the 10 year CHD risk was ≥15%. At this level of risk statin treatment would be more cost-effective than most other commonly prescribed medications, including multiple therapy for high blood pressure and for glycaemic control in diabetes. At a CHD risk of 20% over ten years it is clearly cost-effective. This is the level where the Joint European guidelines recommend lipid-lowering drugs. In the USA where the cost of treatment is borne more directly by the patient, lipid-lowering drugs are recommended at lower levels of risk than this. In Britain 30% was proposed in the joint recommendations of the British Cardiac Society, British Hyperlipidaemia Association, British 53
Preventive Cardiology
Hypertension Society and Diabetes UK as the lowest acceptable standard of medical care and it was recommended that the level of risk targeted should be progressively lowered to 15% as resources permit. It should be realized that the cost of treating patients is not simply a reflection of the cost of lipid-lowering drugs. Some groups of patients are much more expensive to treat than others because they require greater expenditure of medical and nursing resources. Diabetic patients are already attending clinics and having their lipid levels monitored. Thus the addition of a lipid-lowering drug to their treatment might reasonably be done at a CHD risk of ≥15%. However, the cost of screening and identifying high-risk patients not currently attending clinics and providing clinical services and drug therapy for them would mean that treatment at a similar level of risk would impose enormous additional expenditure on a socialized health care system, such as that of the UK, the population of which has almost the highest CHD rates in the world. Ironically, lower levels of risk could be targeted more cheaply in countries in which CHD is less common. Nonetheless, current policy in the UK must be viewed as illogical, because it would appear that its citizens are being asked to pay for a health service which is only prepared to devote resources to less common or less important causes of ill health than CHD.
Statins Statin drugs lower serum cholesterol by inhibiting HMG-CoA reductase, the enzyme which is rate-limiting for cholesterol biosynthesis. Statins are effective both in decreasing serum cholesterol substantially and in preventing CHD (Table 4). The principal action of statins is to lower LDL cholesterol. Some statins, such as simvastatin, are now licensed to be used in higher doses than in the clinical trials and new drugs, such as atorvastatin, are more potent. Thus decreases in serum LDL cholesterol of 50% or more can be achieved with statins. They have a more variable effect in decreasing serum triglycerides usually by no more than 20%, and 54
Management of the ‘at risk’ individual
HDL cholesterol increases typically by 5–10%. Although they have the potential to cause myostis or hepatotoxicity, these side-effects have proved rare in clinical practice and in randomized controlled clinical trials. Statin drugs are generally safe to use in patients with renal disease. Stroke too can be prevented by statins, although at present the evidence for this is strongest in patients who already have CHD. The aim of statin treatment should be to reduce serum cholesterol to <5 mmol/l (200 mg/dl) or LDL cholesterol to <3 mmol/l (120 mg/dl). There is some evidence that in secondary prevention the aim should be to achieve yet lower levels of LDL cholesterol, with some authorities recommending that LDL cholesterol levels of <2.5 mmol (100 mg/dl) should be the target. In practice this can be difficult to achieve in patients whose cholesterol levels are initially high, such as those with familial hypercholesterolaemia where starting levels of cholesterol are typically >9 mmol/l (>350 mg/dl). Bile acid sequestrating agents may then be required in addition to statin therapy (see Combination Therapy, pages 56–7). Other drugs which may synergize with statins, such as cholesterol absorption inhibitors, are also under development, and even more potent statins may also be introduced in future. For the present, however, it should be borne in mind that the relationship between serum cholesterol and CHD events is exponential and the decrease in CHD risk in patients with a high initial level will be greater, say, from 10 mmol/l down to 7.5 mmol/l than it will from the additional reduction down to 5 mmol/l, which may not always be achievable. Another group of patients in whom targets for cholesterollowering are difficult to define are those who develop CHD with relatively low cholesterol levels (e.g. 5.5 mmol/l). We know from the clinical trials (Table 4) that they can benefit from statin therapy, but there seems little point in simply lowering their serum cholesterol only to 5 mmol/l. They are presumably more susceptible to the effects of cholesterol and would thus benefit from lower levels still, but how low is desirable? It is generally recommended that the aim of treatment in them should be to reduce cholesterol by at least that achieved in the 55
Preventive Cardiology
trials, namely 25% (equivalent to an LDL cholesterol lowering of 30%). The minimum overall aim of statin treatment should thus be to decrease serum cholesterol to <5 mmol/l (200 mg/dl) or by 25% whichever is the lower level. The equivalent figures for LDL cholesterol lowering would be to <3 mmol/l (120 mg/dl) or by 30%, whichever is the lower level. In patients who present with angina or myocardial infarction, statin treatment should be introduced as soon as it is established that the serum cholesterol is in excess of 5 mmol/l. In patients found to have lower levels it should be appreciated that at the time of an acute event serum cholesterol may be depressed and further measurements should be undertaken not just on a single occasion six weeks after recovery but for longer periods too.
Fibrate drugs These drugs predominantly lower serum triglycerides, usually by around 30%. They also lower serum cholesterol, but to a much smaller extent than statins. In the case of fenofibrate some of this cholesterol-lowering activity is due to a decrease in LDL cholesterol as well as VLDL cholesterol. Fibrate drugs do, however, decrease a subfraction of LDL, which contains little cholesterol and which is thus not appreciated using routine clinical testing. This small, dense LDL may be particularly atherogenic. Serum HDL cholesterol is increased by fibrate drugs slightly more effectively than by statin drugs, usually by 5–15%, and there is evidence that this enhances reverse cholesterol transport. Fibrate drugs are contraindicated in renal disease with the exception of gemfibrozil and fenofibrate, which should be used with caution in reduced dose. They also potentiate coumarin anticoagulants and should only be introduced in patients receiving these drugs with strict anticoagulant suppression. Clofibrate can cause gallstones and is no longer used.
Combination therapy Bile acid sequestrating agents can lower cholesterol effectively, but are not generally tolerated in doses which will achieve a worthwhile 56
Management of the ‘at risk’ individual
reduction when used as monotherapy, because of upper gastrointestinal symptoms and constipation. A dose of two sachets before breakfast may, however, produce a further reduction in cholesterol of 0.5–1.0 mmol/l in patients already receiving full-dose statin treatment. Bile acid sequestrating agents can exacerbate hypertriglyceridaemia. Patients with high cholesterol whose serum triglycerides are ≥10 mmol/l should be referred to a Lipid Clinic, because they may have an increase in fasting chylomicron levels as well as VLDL (type-V hyperlipoproteinaemia), which requires specialist evaluation and does not respond to statins. In patients at high CHD risk with mixed hyperlipidaemia (raised LDL cholesterol and triglyceride <10 mmol/l), when triglyceride levels remain raised despite full-dose statin therapy a fibrate drug may be used in conjunction with a statin. The patient should be carefully monitored for myositis or hepatotoxicity (serum creatine kinase and liver transaminases), but this has proved rare.
Patients with raised triglycerides, but cholesterol <5 mmol/l There is at present no evidence to justify the use of lipid-lowering medication for primary prevention in this type of patient unless they are at particularly high CHD risk. In secondary prevention, however, there is evidence to support the use of fibrate drug therapy.
Management of hypertension Treatment of hypertension decreases the risk of both stroke and CHD. The benefit achieved depends not only on the level of the blood pressure but also, as has been discussed, in the context of cholesterol-lowering with the absolute cardiovascular risk. Thus patients with a relatively minor elevation of blood pressure, but who have multiple additional risk factors, such as diabetes, dyslipidaemia, smoking history or adverse family history, and thus a higher absolute cardiovascular risk, may have a greater likelihood of deriving benefit from antihypertensive medication than those with a higher blood 57
Preventive Cardiology
pressure who lack these other risk factors and are at lower cardiovascular risk. Patients with hypertension should generally receive similar lifestyle and dietary advice to those with dyslipidaemia with additional attention paid to sodium restriction and the avoidance of excess alcohol. For patients with particularly high blood pressure (diastolic pressure ≥100 mmHg) and who have end organ damage (retinopathy, LVH or nephropathy) confirmation of the raised blood pressure does not require a protracted period of observation before commencing antihypertensive treatment. When, however, the blood pressure settles on observation to 160/100 mmHg or lower and in patients whose blood pressure is initially less severe, it is sensible to repeat blood pressure readings over a longer period and to observe the effects of lifestyle and dietary advice. Those whose blood pressure persistently exceeds 160/100 mmHg should then receive antihypertensive medication to reduce blood pressure to <140/<85 mmHg. For those whose blood pressure remains in the range 140/90–159/99 mmHg CHD risk should be estimated using the charts in Figure 21. Those whose ten-year CHD risk is 15% or more should receive antihypertensive medication aiming to decrease blood pressure to <140/<85 mmHg. Others should have their blood pressure and CHD risk reassessed every year or so afterwards to review the decision about drug intervention. Special categories of patient are those with a history of CHD or cerebrovascular disease. In them, antihypertensive medication should be introduced if blood pressure is persistently in excess of 140/85 mmHg. In insulin dependent diabetes, antihypertensive medications should generally be prescribed at a lower blood pressure to achieve levels of <130/<80mmHg in the absence of proteinuria and <125/<75 mmHg if proteinuria is present. Thus the aim of blood pressure treatment is to reduce the levels to <140/<85 mmHg in all patients except IDDM where still lower levels are desirable. 58
Management of the ‘at risk’ individual
Drug therapy for hypertension Diuretic therapy (usually bendrofluazide 2.5 mg daily) is the usual first choice of therapy for hypertension. If this is unsuccessful then a betablocker should be prescribed, unless contraindicated, either alone or in combination with a diuretic. Where possible, control of blood pressure should be achieved through monotherapy with the diuretic being discontinued before commencing the beta-blocker and the combination of a beta-blocker and diuretic only being tried when the beta-blocker has failed. If hypertension persists when fully betablocked or the beta-blocker is not tolerated, treatment with an ACE inhibitor should next be employed, unless contraindicated. This may need to be substituted by an angiotensin II receptor blocker if cough is a problem. ACE inhibitor therapy alone should be tried before using it in combination with a beta-blocker or thiazide. For patients with severe hypertension or in secondary prevention, the clinician may, of course, simply wish to add the additional drugs stepwise with the aim of controlling blood pressure over a shorter period or because the beta-blocker is required in any case for secondary prevention. This is a matter of clinical judgement. However, it should be recognized that, although combination therapy for the management of hypertension is currently widely recommended, complicated treatment regimens do not assist compliance, and there is often no advantage to them over one or two drugs if they achieve the target blood pressure. When combination therapy is necessary advantage should whenever possible be taken of single tablets combining agents: non-compliance is much the commonest cause of failure to control blood pressure. When other antihypertensive agents are inevitable, calcium channel antagonists and alpha-blockers are the most useful with methyldopa, hydralazine still being occasionally valuable in more difficult-to-control hypertension.
Diabetes mellitus As has been stressed previously, patients with diabetes should be a focus of attention in CHD prevention. This was the major reason for 59
Preventive Cardiology
redefining those patients with fasting glucose ≥7 mmol/l as having diabetes, and those whose fasting glucose is in the range 6–6.9 as having
impaired
glucose
tolerance.
The
prevalence
of
hypertriglyceridaemia and hypertension is increased in both NIDDM and IDDM. Hypercholesterolaemia is also common in diabetes in countries where it is common in the general population, whereas in IDDM it occurs with similar frequency to the general population. However, in the context of diabetes hypercholesterolaemia is more risky than in the non-diabetic so that it is important to detect it in both types of diabetes. The currently recommended diabetic diet is the same as that advocated here for the management of hyperlipidaemia. Obviously, simple sugars in the form of refined carbohydrate are to be restricted, but the most important aims of the diabetic diet are the avoidance of obesity and the reduction of dietary fat, particularly saturated fat. Again, it should be remembered that the effects of vegetable fibre in reducing hyperglycaemia are trivial compared to the improvements in glucose tolerance which occur with weight reduction in the obese due to a reduction in dietary fat. Thus the use of unrefined carbohydrate should be encouraged to replace fat calories; however, to promote high-fibre foods without decreasing fat intake is wrong. Advice to lose weight should be regularly reiterated to the obese diabetic. Many patients with NIDDM could become non-diabetic if they would only lose weight. Both hypertriglyceridaemia and hypercholesterolaemia will decrease if glycaemic control is improved. This, together with renewed dietary advice, should be the initial approach to management of hyperlipidaemia in diabetes. For the patient with IDDM this does not inevitably mean an increase in the dose of insulin. Often, improvements can be better achieved by a change in the duration of action of the insulin prescribed and the frequency and timing of its administration to coincide better with meal times and to avoid fear of hypoglycaemia during periods of physical activity. For the NIDDM patient great care must be exercised in the choice of oral 60
Management of the ‘at risk’ individual
hypoglycaemic agent. Many overweight patients obtain little benefit from sulphonylurea drugs, except perhaps initially. Subsequently, their effect in stimulating weight gain causes a further decrease in glucose tolerance. Generally, the overweight patient is best managed initially with a biguanide such as metformin. This drug cannot cause hypoglycaemia, does not produce weight gain and has a modest lipid-lowering effect of its own. It should, of course, not be used in patients who are losing weight as a result of uncontrolled diabetes or who have significant renal impairment. In NIDDM lipid-lowering drugs should be considered when the serum cholesterol exceeds 5 mmol/l and/or serum triglycerides exceed 2.3 mmol/l, if the 10 year CHD risk exceeds 15%. In IDDM there is no reliable means of calculating CHD risk. HDL cholesterol levels are often normal or even high, but HDL does not seem to confer the degree of protection it does in a non-diabetic. It is probably sensible, therefore, to treat cholesterol levels of 5 mmol/l (or LDL cholesterol levels >3.5 mmo/l) in all patients with IDDM aged 20 years or more. An alternative, if it is wished to give priority to patients, say, for lipid-lowering therapy on grounds of risk, is to calculate the risk using the serum cholesterol level in mmol/l in place of the TC:HDL ratio – i.e. replacing HDL cholesterol with a value of 1 mmol/l (40 mg/dl). The initial choice of lipid-lowering agent will depend on whether hypertriglyceridaemia or hypercholesterolaemia is the dominant element, with fibrates being the initial choice in the former and statins in the latter. If the triglyceride levels exceed 10 mmol/l despite attempts to improve glycaemic control, referral to a specialist clinic is indicated. Levels of triglycerides in the range 2.3–10 mmol/l may respond satisfactorily to fibrate therapy, but the patient may be left with cholesterol levels exceeding 5 mmol/l. Treatment with a statin alone may then be tried with the aim of reducing cholesterol levels to <5 mmol/l. If the patient then has persistently high levels of serum triglycerides and is at particularly high CHD risk (for example, already has CHD), then the combination of a statin and a fibrate with adequate supervision can be used. 61
Preventive Cardiology
Hypertension should be scrupulously controlled in both types of diabetes with the aim of maintaining blood pressure levels of <140/<85 mmHg in NIDDM, <130/<80 mmHg in IDDM and <125/<75 mmHg if proteinuria is present.
Insulin-resistance syndrome There are a group of people who are at high risk of CHD who are obese, have an increase in triglycerides and diminished HDL cholesterol levels and who often also have hypertension, episodes of gout and raised cholesterol levels. Although they have not developed hyperglycaemia sufficient to diagnose diabetes (fasting glucose > 7mmol/l), their syndrome is the result of insulin resistance (probably largely caused by obesity). Some of them go on to develop NIDDM and others die of cardiovascular disease before this. Some may already be in the impaired fasting-glucose category (6–6.9 mmol/l). People originating from the Indian subcontinent may be particularly susceptible to this syndrome. It has been variously termed syndrome X (there is another syndrome X – angina with no significant coronary atheroma – so this is confusing), or Reaven’s syndrome. In affected women a male distribution of fat is common (see page 25) and sometimes other features of androgenization such as hirsuties, acne, seborrohea and polycystic ovaries occur. The condition overlaps with familial combined hyperlipidaemia (see page 23), which is a more nebulous entity. A weight-reducing diet is the most important aspect of therapy. If recourse is made to lipid-lowering drugs or to antihypertensive agents, then the same considerations discussed in the management of diabetes apply (see pages 59–62).
Hormone replacement therapy (HRT) Thromboembolism and an increased risk of breast cancer are associated with hormone replacement therapy. There are, however, potential benefits of oestrogens in post-menopausal women since they lower serum LDL cholesterol and raise HDL cholesterol. In observational studies, HRT in the form of conjugated equine 62
Management of the ‘at risk’ individual
oestrogens or synthetic oestrogen metabolised to oestradiol-17β given as HRT in women, following hysterectomy, was associated with a reduced likelihood of death from myocardial infarction compared to women in general. However, women choosing to undergo hysterectomy and receive such treatment are likely to differ in many respects from women in general. Furthermore, for women who have not undergone hysterectomy the situation is more complex since unopposed oestrogen replacement may cause endometrial cancer and to prevent this, progestins are necessary for part of the cycle combined with oestrogen. The effect of a progestin may be to reverse some of the favourable effects of the oestrogen. Without randomized clinical trial evidence in women who have not yet developed CHD, HRT should probably not be prescribed purely for cardio-protection. The first evidence from randomized controlled clinical trials in women with established CHD shows no benefit, but also no harm, in terms of cardiovascular end-points. There thus seems no objection to HRT in women with disabling menopausal symptoms or who have undergone premature menopause as the consequence of primary ovarian failure or secondary to surgery, chemotherapy or radiation. We should, however, still be cautious in hypertension and hypertriglyceridaemia.
Cardioprotective drugs Drug classes which can protect against future coronary events include the following: ●
Aspirin
●
Beta-blockers
●
Statins
●
Fibrates
●
ACE inhibitors
●
Calcium channel blockers
●
Anticoagulants
●
Omega-3 fatty acids 63
Preventive Cardiology
In recent years several classes of drugs have been found to improve survival and to reduce subsequent cardiovascular morbidity in patients presenting with angina or surviving acute myocardial infarction. This subject is reviewed in detail in the companion publication Secondary Prevention Post MI by John McMurray (1997). Some of the drug classes such as beta-blockers, calcium channel blockers and ACE inhibitors are already used in the management of hypertension in patients who do not as yet have clinically evident CHD. The same is also true of statin and fibrate drugs. It is also recommended that the use of aspirin be extended beyond secondary prevention to primary prevention in patients at high CHD risk. Some recent evidence also suggests that ACE inhibitors can prevent the onset of clinical CHD in other high risk groups.
Aspirin The best evidence for the benefit of aspirin treatment is in secondary prevention. The benefit must be balanced against the risk of upper gastrointestinal haemorrhage and dyspepsia. This risk is dose-related and the cardioprotective effect of aspirin is probably achieved with relatively low dosages. Aspirin should therefore generally be prescribed in a dose of 75 mg daily. Aspirin can also be beneficial in primary prevention. However, in patients in whom the likelihood of a CHD event is not high, any benefits may not outweigh the risk of upper gastrointestinal complications. It is difficult to assess the precise level of CHD risk at which there is overall therapeutic benefit. Some authorities have suggested that this may occur when the 10 year CHD risk is as low as 15% (the same level at which treatment of mild hypertension is advocated). Certainly, when the ten-year CHD risk is >30%, aspirin is likely to be beneficial unless there is already a history of upper gastrointestinal disease. Many patients receiving aspirin are also being treated with drugs for dyspepsia. Although common, little is known about this practice. There is evidence that omeprazole or misoprostol can prevent NSAID-associated gastric and duodenal ulcers and that H2-receptor blockers can decrease the 64
Management of the ‘at risk’ individual
likelihood of NSAID-induced duodenal ulceration. The use of antiplatelet drugs other than aspirin may sometimes be justified in secondary prevention when patients are intolerant of aspirin. Also, the possibility that aspirin may ameliorate some of the benefit from ACE inhibitors may herald the more widespread use of alternatives.
Beta-blockers Evidence that beta-adrenoreceptor blocking drugs can prevent further CHD events in secondary prevention is strong. The benefit is clearest with those which decrease resting heart rate, and thus betablockers with intrinsic sympathominetic activity such as oxprenolol and pindolol should be avoided for this purpose. So also should propranolol because the dose of this drug required to achieve betablockade is so highly variable, and many patients who receive it are inadequately beta-blocked because most medical practitioners seem reluctant to titrate the dose sufficiently high. In general, beta-blockers, and drugs such as ACE inhibitors and statins, are widely used in medical practice in doses below those shown to be effective in secondary prevention in clinical trials. The most frequently encountered side-effects with beta-blockade are bronchospasm and exacerbation of heart failure. Heart failure need not be a contraindication to beta-blockade, however, if it is controlled with an ACE inhibitor and a diuretic. The beta-blocker cautiously introduced, albeit in a reduced dose, can still reduce the likelihood of dysrhythmia and further cardiac ischaemic events. For patients intolerant of beta-blockers for reasons such as obstructive airways disease or lack of energy, verapamil may be substituted, but not in patients with heart failure or hypotension.
ACE inhibitors ACE inhibitors are used in severe heart failure to gain symptomatic relief. There is, however, good evidence that in patients with all grades of heart failure ACE inhibitors can extend life expectancy due to a reduced risk of further cardiac events. Similar benefits may also
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Preventive Cardiology
extend to patients with ischaemic heart disease or at high risk of it even
before
left
ventricular
dysfunction
is
evident
on
echocardiography. Clinical guidelines for prescriptions of ACE inhibitors, however, continue to lay stress on confirmation of cardiac failure by echocardiography. The decrease in cardiac events with ACE inhibition is certainly not confined to patients with high blood pressure and remains largely unexplained. Currently ACE inhibitors are not prescribed as frequently as is justified by clinical trial evidence and often are given in inadequate doses. Probably, the most common side-effect of clinical significance due to ACE inhibitors is a persistent cough. It should also not be forgotten that they are a cause of angioneurotic oedema. If given to patients with heart failure requiring high doses of diuretic, the initial dose of an ACE inhibitor may induce severe hypotension. This is most likely if the patient is already hypotensive. The dose of diuretic is generally decreased and a small trial dose of ACE inhibitor given initially. Because the withdrawal of diuretic may precipitate pulmonary oedema, the whole manoeuvre is best carried out in hospital. ACE inhibitors are contraindicated in patients with renal arteriosclerosis, and therefore they should not be prescribed without hospital referral in patients suspected of this diagnosis (because of the presence, say, of peripheral arteriosclerosis) or who have a raised serum creatine. Potassium-sparing diuretic therapy and potassium supplementation should also generally be discontinued in patients receiving ACE inhibitors to avoid hyperkalaemia. The role of the new angiotensin-II receptor antagonists in heart failure is less well established than that of ACE inhibitors, so their present use in heart failure is confined to patients intolerant of ACE inhibition, particularly those who develop a persistent cough. Angiotensin-II receptor antagonists do not cause coughing.
Calcium-channel blockers Although calcium-channel blockers are widely used in clinical practice, evidence that they are cardioprotective as a class is in 66
Management of the ‘at risk’ individual
dispute and indeed some may be harmful. The arguments which surround clinical trial evidence concerning calcium channel antagonists are bewildering and frequently involve subgroup analyses and pooling of data. Single trials have rarely been large enough to answer the important issues which have been raised, and many of the drugs are not in a phase of their development where the substantial investment which would be required for large trials is possible. For the ordinary clinician the conclusion which emerges is that when these drugs are required to obtain symptomatic relief from angina or where other types of drugs have been exhausted for the management of hypertension, the use of calcium-channel antagonists, when not contraindicated, is reasonable. However, we should reconsider their use as first-line agents or simply on prognostic grounds. Calciumchannel blockers are a more heterogeneous group of drugs than, for example, the statins or ACE inhibitors and this makes generalization about their indications and contraindications difficult. Verapamil and diltiazem should be avoided in heart failure or in patients at high risk of developing heart failure. Nifedipine can also exacerbate heart failure, whereas amlodipine and felodipine do not. The latter are therefore preferred for relief of angina when heart failure is present.
Anticoagulants Indications for long-term anticoagulants, such as warfarin, after myocardial infarction include dysrhythmias likely to lead to thromboembolism, such as atrial fibrillation, and significant risk of intraventricular thrombosis because of a large akinetic segment of left ventricular wall or a left ventricular aneurysm.
Omega-3 fatty acids Omega-3 fatty acids (fish oil) can improve prognosis following acute myocardial infarction probably because they decrease sudden deaths due to ventricular dysrhythmia. This is the basis of the recommendation that fatty fish should be eaten at least once each week. In larger doses omega-3 fatty acids can decrease serum
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Preventive Cardiology
triglycerides by almost as much as fibrates. However, fish oil in these doses is not well tolerated. Refined preparations of fish oil in which the active omega-3 fatty acids, eicosapentaenoic and docosahexaenoic acid, are concentrated are being produced and may overcome this problem. Omega-3 fatty acids also reduce blood coagulability, although greater effect may be achieved with even small doses of aspirin.
Coronary artery bypass surgery, angioplasty and stenting Patients presenting with angina or acute myocardial infarction may benefit from coronary angioplasty and stenting, or from coronary artery bypass surgery. Sometimes this will be on symptomatic grounds and sometimes because there may be prognostic benefit. It is extremely difficult to decide without recourse to cardiological investigation whether this is the case for a particular patient. Exercise ECG testing is widely used by non-cardiologists to decide which patients should be referred to cardiologists for further investigation, such as coronary angiography. Certainly, patients with positive tests should be investigated in this way. Exercise testing can, however, be misleading: some patients with positive tests, particularly women, may have coronary spasm often associated with other vasospastic disorders, such as migraine and Raynaud’s disease, and others, whose tests are negative, may have significant coronary artery disease. Younger patients with negative tests despite abnormal resting ECGs or a clear history, and patients who do not achieve their maximum heart rate should be viewed with caution and where any doubt exists referral to a cardiologist should be made.
Exercise Emphasis should not be given to exercise to the exclusion of other CHD prevention measures for which there is better evidence of benefit (see page 26). For those patients who have sustained a myocardial infarction a careful exercise programme (certainly involving walking or 68
Management of the ‘at risk’ individual
swimming in a supervised bath) is often greatly beneficial to their emotional outlook and to restoring their confidence.
Coronary rehabilitation Following acute myocardial infarction or coronary intervention procedures, patients can benefit from cardiac rehabilitation. This should include a staged exercise programme to improve physical performance and build confidence. It is important to detect depressive illness and to view with caution patients who are socially isolated and whose life involves stress. Exercise testing and, if necessary,
echocardiography
and
monitoring
for
cardiac
dysrhythmias should form part of the programme, as should a careful review and treatment of any persisting risk factors, such as smoking, dyslipidaemia and hypertension. Optimization of cardioprotective drugs and dosages and the need for coronary angiography or other investigations should also be undertaken before also ensuring that adequate follow-up arrangements are in place with the patient’s hospital and/or primary care physician.
69
What can be achieved – costs and benefits
5
The clinical trials show that stopping smoking and lowering cholesterol and blood pressure levels reduce cardiovascular risk (see Table 7). The arguments relating to the economic cost of CHD prevention stem largely from a failure to appreciate that many of the trials were conducted in people whose CHD risk was relatively low. Often the participants had only one relatively modest risk factor and frequently were actually at less risk even than the general population. The emphasis in this book, in agreement with that of all current official recommendations, is that clinical intervention should be reserved for people at substantially increased risk either by virtue of a truly high level of cholesterol or blood pressure, or lower levels of these risk factors in combination with established CHD, or with one or more other risk factors for CHD. The cost of screening and intervention is then much cheaper than the enormous cost of CHD (see page 2). Furthermore, the effect of combining treatment of hyperlipidaemia or hypertension with advice to stop smoking produces an even greater benefit with little increase in cost.
Table 7
Reduction in CHD and stroke risk
Risk factor
Smoking
Cholesterol
Blood
intervention
cessation
lowering
pressure lowering
Degree of decrease
Stopped
20–25%
5–10 mmHg
50%
30%
20%
50%
30%
40%
Reduction in CHD morbidity and mortality within five years Reduction in stroke morbidity and mortality within five years
70
What can be achieved – costs and benefits
The approach in this book avoids the prescription of, for example, lipid-lowering drugs to people who will not stand to benefit greatly from them, for this would enormously increase the cost of CHD prevention because it would increase the economic outlay without increasing the number of heart attacks prevented. CHD death rates peaked in the USA, western Europe, Australia and New Zealand at the beginning of the 1980s, and they have since slowly declined, although, of course, remaining at unacceptably high levels. In eastern Europe rates of CHD have continued to increase, but a far greater epidemic in terms of the sheer numbers of people likely to succumb is imminent as the high populations of Asia are exposed to the nutritional change which has been the cause of the disease in the West. Prevention of CHD will thus continue to be one of the greatest challenges to medicine for many years to come.
71
Suggested further reading
Arkwright PD, Beilin LJ, Vandongen R et al. The pressor effect of moderate alcohol consumption in man: a search for mechanisms. Circulation 1982; 66: 1515–19. Anderson KM, Wilson PWF, Odell PM et al. An updated coronary risk profile: a statement for health professionals. Circulation 1991; 83: 356–62. The BIP Study Group. Secondary prevention by raising HDL cholesterol and reducing triglycerides in patients with coronary artery disease. The Bezafibrate Infarction Prevention (BIP) Study. Circulation 2000; 102: 21–7. Borch-Johnsen K, Kreiner S. Proteinuric value as predictor of cardiovascular mortality in insulin dependent diabetes mellitus. Br Med J 1987; 294: 1651–4. British Cardiac Society, British Hyperlipidaemia Association, British Hypertension Society, British Diabetes Association. Joint British recommendations on prevention of coronary heart disease in clinical practice: summary. BMJ 2000; 320: 705–8. Downs GR, Clearfield M, Weiss S et al. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of the AFCAPS/TEXCAPS (Air Force/Texas Coronary Atherosclerosis Prevention Study). JAMA 1998; 279: 1615–22. Durrington PN. Diabetic dyslipidaemia. In: Gill G, MacFarlane I, eds. Clinical Diabetes. Baillieres Clin Endocrinol Metab 1999; 13: 265–78. Durrington PN. Hyperlipidaemia. Diagnosis and management 2nd edn. Oxford: Butterworth Heinemann, 1995. Durrington PN. Rigorous detection and vigorous treatment of familial hypercholesterolaemia. Lancet 2001; 357: 574–5. 72
Suggested further reading
Durrington PN, Illingworth DR. Lipid-lowering drug therapy: more knowledge leads to more problems for composers of guidelines. Curr Opin Lipidol 2000; 11: 345–9. Durrington PN, Prais H. Methods for the prediction of coronary heart disease risk. Heart 2001; 85: 489–90. Durrington PN, Prais H, Bhatnagar D et al. Indications for cholesterollowering medication: comparison of risk-assessment methods. Lancet 1999; 353: 278–81. Fuster V, Ross R, Topol EJ (eds). Atherosclerosis and Coronary Artery Disease. Philadelphia: Lippincott-Raven, 1996. Garrow JS. Obesity and Related Diseases. London: Churchill Livingstone, 1988. Goldstein JL , Hobbs HH , Brown MS. Familial hypercholesterolaemia. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. Metabolic and Molecular Bases of Inherited Disease. 7th edn. New York: McGraw Hill, 1995; 1981–2030. Grundy SM. Dietary therapy of hyperlipidaemia. Baillieres Clin Endocrinol Metabol 1987; 1: 667–8. Hammond EC, Garfinkel L. Coronary heart disease, stroke and aortic aneurysm. Arch Env Health 1969; 19: 167–74. He J, Whetton PK. Selection of initial antihypertensive drug therapy. Lancet 2000; 356: 1942–3. Hebert PR, Gaziano JM, Chan KS, Hennekens CH. Cholesterol lowering with statin drugs, risk of stroke, and total mortality. An overview of randomized trials. JAMA 1997; 278: 313–21. Jorde LB, Williams RR. Relation between family history of coronary artery disease and coronary risk variables. Am J Cardiol 1988; 62: 708–13. Kannel WB, Brand N, Skinner JJ et al. The relationship of obesity to blood pressure and development of hypertension: the Framingham Study. Ann Intern Med 1967; 67: 48–59. McMurray J. Secondary Prevention Post MI. London: Martin Dunitz, 1997.
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McNeilly RH, Pemberton J. Duration of last attack in 998 fatal cases of coronary artery disease and its relation to possible cardiac resuscitation. BMJ 1968; 3: 139–42. Mittleman MA, Maclure M, Tofler GH et al. Triggering of acute myocardial infarction by heavy physical exertion. Protection against triggering by regular exertion. N Engl J Med 1993; 329: 1677–83. National Service Framework. Coronary Heart Disease. London: HMSO, 2000. Petilli D. Hormone replacement therapy and heart disease prevention. Experimentation trumps observation. JAMA 1998; 280: 650–2. Ramsay LE, Williams B, Johnson GDR et al. Guidelines for management of hypertension: report of the third working party of the British Hypertension Society. J Hum Hypertens 1999; 13: 569–92. Report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Arch Intern Med 1988; 148: 36–69. Rifkind BM, Segal P. Lipid Research Clinics Program reference values of hyperlipidaemia and hypolipidaemia. JAMA 1983; 250: 1869–72. Royal College of Physicians Working Party. Obesity. J Roy Coll Phys London 1983; 17: 5–65. Rubins HB, Robins SJ, Collins D et al for the Veterans Affairs HighDensity Lipoprotein Cholesterol Intervention Trial Study Group. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. N Engl J Med 1999; 341: 410–18. Scottish Intercollegiate Guidelines Network (SIGN). Diagnosis and treatment of heart failure due to left ventricular systolic dysfunction. Edinburgh: SIGN 1999 (SIGN publication No 35). Simons LA. Interrelations of lipids and lipoproteins with coronary artery disease mortality in 19 countries. Am J Cardiol 1986; 57: 5G–10G. 74
Suggested further reading
Steinberg D. The cholesterol controversy is over. Why did it take so long? Circulation 1989; 80: 1070–8. Summary of the Second Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults (adult treatment panel). JAMA 1993; 269: 3015–23. Thelle DS, Shaper AG, Whitehead TP et al. Blood lipids in middleaged British men. Br Heart J 1983; 49: 205–13. Wood DA , De Backer G, Faergeman O et al. Prevention of coronary heart disease in clinical practice. Recommendations of the second joint task force of the European Society of Cardiology, European Atherosclerosis Society and European Society of Hypertension. Eur Heart J 1998; 19: 1434–503. Wood
D,
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Poulter
N
et al. Joint
British
recommendations on prevention of coronary heart disease in clinical practice. Heart 1998; 80(Suppl. 2): S1–S29. Yusuf S, Sleight P, Pogue J et al. Effects of an angiotensin-convertingenzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med 342; 145–53.
75
Index
Page numbers in italics refer to figures. ACE inhibitors 59, 65–6 Achilles tenosynovitis 22 age CHD risk and 1, 4–5, 5 HDL cholesterol and 18 screening and 33 serum cholesterol and 14–15, 14 alcohol consumption 50 hypertension and 9, 9, 58 alpha-blockers 59 amfebutamone 41 amlodipine 67 androgens 19 angina cardioprotective drugs 64 CHD risk 6, 32 in diabetes 10 interventional procedures 68 lipid-lowering drugs 56 angioneurotic oedema 66 angioplasty, coronary 68 angiotensin II receptor blockers 59, 66 anticoagulants 56, 67 antihypertensive therapy 57–9 aims 58 benefits 70 choice of drugs 59 combination 59 in diabetes 58, 62 indications 35, 58 risk assessment and 37 antiplatelet drugs 65 Asians 28, 36–7, 62 aspirin 64–5 atherosclerotic disease 6–7, 32 atorvastatin 52, 54 bendrofluazide 59 beta-blockers cardio-protective therapy 65 in hypertension 59 bezafibrate 51, 52 biguanides 61 bile-acid sequestrating agents 52 combination therapy 55, 56–7
76
efficacy 51 in familial hypercholesterolaemia 23 blood pressure CHD risk and 7–8, 8 indicating therapy 58 measurement 34–5 standing 35 targets 58, 62 see also hypertension body mass index 25 bupropion 41 calcium-channel blockers 59, 66–7 carbohydrate, dietary 49, 60 cardioprotective drugs 63–8 carotid disease 32 cereals 46 cerebral arteriosclerosis 6–7, 32, 59 cerivastatin 52 CHD see coronary heart disease children, familial hypercholesterolaemia 22–3 chips 49 cholesterol, serum 11–15 age-related changes 14–15, 14 CHD risk and 11–14, 12, 13 in familial hypercholesterolaemia 22–3 international comparisons 12–14, 13 lipid-lowering drugs and 50, 55–6 measurement 35 in obesity 25 other risk factors and 12, 13 target 55–6 total:HDL cholesterol (TC:HDL) ratio 19, 21, 37, 38 triglycerides and 19, 20 see also hypercholesterolaemia
cholesterol absorption inhibitors 55 cholestyramine 23, 51, 52 chylomicrons 11, 57 cigarette smoking see smoking ciprofibrate 52 clofibrate 51, 56 coagulation factors 28–9 colestipol 23, 52 corneal arcus 15, 15, 22 coronary angioplasty 68 coronary artery bypass surgery 6, 23, 68 coronary artery stenting 68 coronary heart disease (CHD) death rates see mortality rates family history 23, 24, 36 frequency distribution of risk 31 pre-existing see preexisting coronary heart disease rates 1–2 risk assessment see risk assessment risk factors see risk factors coronary rehabilitation 69 costs and benefits, CHD prevention 70–1 CHD 2 lipid-lowering drugs 53–4 cough, ACE inhibitor-induced 66 C-reactive protein 29 dairy produce 44 diabetes mellitus 9–10 antihypertensive therapy 58, 62 CHD risk assessment 39, 61 HDL cholesterol 17, 18–19 hypertriglyceridaemia 9, 20–1, 60, 61 insulin-resistance syndrome and 62 lipid-lowering drugs 54, 61 management 59–62
Index diet common misunderstandings 49 in diabetes 60 in hypertension 58 lipid-lowering 41–50 serum cholesterol and 12–14 weight-reducing 41, 42–8, 62 dietician, referral to 50 diltiazem 67 diuretics 59 dressings 48 drinks 47 dyslipidaemia 11–23 acquired 11–21 genetic 21–3 see also hypercholesterolaemia; hyperlipidaemia; hypertriglyceridaemia eggs 44 exercise 68–9 CHD risk and 26–7 testing 68, 69 weight reduction and 41 familial combined hyperlipidaemia (FCH) 23, 62 familial hypercholesterolaemia (FH) 21–3 lipid-lowering drugs 23, 55 physical signs 15, 15, 16–17, 22 family history, premature CHD 23, 24, 36 fasting, serum triglycerides 20, 35 fats dietary 12–14, 41–50, 60 monounsaturated 49 polyunsaturated 49 saturated 48–9 felodipine 67 fenofibrate 52, 56 fibrates 51, 52, 56 combination therapy 57 in diabetes 61 fibre, dietary 49, 60 fibrinogen, plasma 28–9 fish 43, 67–8 fish oil 67–8 fluvastatin 52 foods ‘low in cholesterol’ 49 prepared 45 see also diet Friedewald formula 21 fruit 46, 49
gemfibrozil 51, 52, 56 gender differences CHD risk 5, 5 HDL cholesterol 18–19 obesity risk 25–6 smoking 7 see also women genetic factors, CHD risk 21–3, 24 glucose, impaired fasting 62 glycaemic control 60–1 H2-receptor blockers 64–5 HDL see high-density lipoprotein heart failure 65–6, 67 high-density lipoprotein (HDL) cholesterol 11, 35 CHD risk 15–19, 17 in diabetes 61 in insulin-resistance syndrome 62 lipid-lowering drug effects 55, 56 in obesity 25 other risk factors and 18, 18 triglycerides and 19 HMG-CoA reductase 54 hormone replacement therapy (HRT) 62–3 hydralazine 59 hypercholesterolaemia in diabetes 60, 61 dietary advice 50 familial see familial hypercholesterolaemia lipid-lowering drugs 50–7 see also cholesterol, serum hyperlipidaemia in diabetes 9 familial combined (FCH) 23, 62 management 41–57 mixed 57 see also dyslipidaemia; hypercholesterolaemia; hypertriglyceridaemia hyperlipoproteinaemia, type-V 57 hypertension 7–9 in diabetes mellitus 9–10, 60 diagnosis 35 management see antihypertensive therapy serum cholesterol and 13 see also blood pressure hypertriglyceridaemia 19–21 in diabetes 9, 20–1, 60, 61
lipid-lowering drugs 54–5, 56, 57 hypotension, drug-induced 66 impaired fasting-glucose 62 inflammatory markers 28–9 insulin-resistance syndrome 62 insulin therapy 60 intermittent claudication 32 ischaemic rest pain 32 jam 47 Japanese migrants 27–8 Korotkoff sounds 35 LDL see low-density lipoprotein lipid-lowering drugs 50–7 aims of treatment 55–6 combination therapy 55, 56–7 cost-effectiveness 53, 70, 71 in diabetes 54, 61 efficacy 51, 70 in familial hypercholesterolaemia 23, 55 indications 50, 53–4 LDL cholesterol and 21, 55, 56 in pre-existing CHD 6, 56 risk assessment 37 serum triglycerides and 20 lipids, serum 35 see also cholesterol, serum; high-density lipoprotein (HDL) cholesterol; lowdensity lipoprotein (LDL) cholesterol; triglycerides, serum lipoprotein metabolism 11 lovastatin 51 low-density lipoprotein (LDL) cholesterol CHD risk 15–19 Friedewald formula 21 lipid-lowering drugs and 21, 54, 56 metabolism 11 low-density lipoprotein (LDL) receptor defects 22 meat 42, 49 menopause 5, 62–3 premature 6 metformin 61 methyldopa 59 microalbuminuria 10 migrants 24, 27–8, 36–7
77
Preventive Cardiology milk 44 skimmed 49 misoprostol 64 mortality rates 1–2, 1 in diabetes 10 myocardial infarction 2–3, 2 trends 71 women 1–2, 1, 5, 5 myocardial infarction 2–3 cardioprotective drugs 64 CHD risk 6, 32 coronary rehabilitation 69 in diabetes 10 exercise after 68–9 interventional procedures 68 lipid-lowering drugs 56 survival rates 2–3, 2 nicotine preparations 41 nifedipine 67 nuts 43 obesity android pattern 19, 26, 62 assessment 25, 26, 34 CHD risk 24–6 in diabetes 60–1 dietary advice 41–50 hypertension and 9, 9 insulin-resistance syndrome 62 lack of exercise and 27 oestrogens CHD risk and 5, 19 replacement therapy 62–3 oils, cooking 45, 49 omega-3 fatty acids 67–8 omeprazole 64 oral hypoglycaemic agents 60–1 oxprenolol 65 peripheral arterial disease 6–7, 32 personality 28 physical activity see exercise pindolol 65 policy, public 30 polycystic ovary syndrome 19 pravastatin 51, 52 pre-existing coronary heart disease 6, 32, 64 antihypertensive therapy 58 lipid-lowering drugs 6, 56 see also angina; myocardial infarction preserves 47
78
prevention high-risk approach 30 population strategies 30 primary 3, 33–7 secondary 3, 32 progestins 63 propranolol 65 proteinuria 10, 58, 62 Quetelet’s index 25 Reaven’s syndrome 62 rehabilitation, coronary 69 renal arteriosclerosis 66 renal disease, lipid-lowering drugs 55, 56 reverse cholesterol transport 16–18 risk assessment 30–7 charts 36–7, 38–9 in diabetes 39, 61 for primary prevention 33–7 for secondary prevention 32 see also screening risk factors 4–29 management 40–69 multiple 40 mutable and immutable 31, 40 screening 31–2 see also specific risk factors salads 46 salt intake, dietary 8–9, 58 sauces 48 screening 33–7 costs and benefits 70 by invitation 31–2 opportunistic 31–2 questionnaire 34 sedentary lifestyle 26–7 simvastatin 51, 52, 54 smoking 7, 27 benefits of cessation 7, 7, 70 cessation 41, 42 CHD risk assessment and 37, 38–9 serum cholesterol and 13 weight gain on cessation 26 social factors, CHD risk 27–8 sodium intake, dietary 8–9, 58 spreads 47 squash 27 statins 52, 54–6 adverse effects 55, 57 combination therapy 55, 56–7
cost-effectiveness 53 in diabetes 61 efficacy 51 in familial hypercholesterolaemia 23, 55 stenting, coronary artery 68 stress 28 stroke 32 prevention 55, 57 risk assessment 36 sulphonylurea drugs 61 sweets 47 swimming 27, 69 syndrome X 62 tendon xanthomata 15, 16–17, 22 thiazide diuretics 59 thyroid function tests 52 transient cerebral ischaemic attacks 32 triglycerides, serum 19–21 in familial hypercholesterolaemia 22 in insulin-resistance syndrome 62 lipid-lowering drugs and 54–5 measurement 19–20, 35 in obesity 25 vegetable oils 49 vegetables 46, 49 verapamil 65, 67 very low-density lipoprotein (VLDL) 11, 57 walking 27, 68–9 warfarin 67 weight, body defining obesity 26 gain, on smoking cessation 26 reduction 41, 42–8, 60, 62 see also obesity women CHD risk 1–2, 1, 5, 5 HDL cholesterol 18–19 hormone replacement therapy 62–3 screening 32, 33 serum cholesterol 14, 14 see also gender differences xanthelasmata 15, 15, 22
