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
0 114
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 aged2.3 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
