Angina and its treatment

There have been many attempts to reduce the mortality from coronary artery disease (CAD) in the community by addressing the risk factors in the general population. Greater appreciation of the importance of CAD and increased understanding of risk factors are leading to improvements in the prevention and management of this disorder by hospital doctors, primary healthcare physicians and other groups. Some preventive measures, such as advice on diet, exercise and smoking cessation can be directed towards the whole population. Those with known risk factors, such as hypertension and hypercholesterolaemia, require specific treatment regimens and those who already have the disease, i.e. post infarct and angina patients, need particular attention. This review is concerned and directed specifically towards the management of patients with angina. CAD is the leading cause of death world-wide, accounting for 6·26 million deaths in 1990 (1). In countries with a high or relatively high incidence of coronary heart disease, the prevalence of angina may be as much as 30 000–40 000 per million total population (2). The severity of anginal symptoms has an impact on a person's quality of life. This may limit everyday activities and in some cases lead to early retirement. Even patients with stable angina experience more stressful events, have more sleep disturbance (nightmares, tiredness at work) and psychosomatic symptoms than their healthy counterparts. Patients suffering from angina have a similar psychosocial risk profile to patients who have experienced an acute myocardial infarction (MI) (3), and are also at increased risk of sudden death (4). Greater emphasis on prevention could reduce this high mortality rate. However, despite these facts, there is good evidence to suggest that the condition of angina is under-diagnosed and suboptimally treated. There is tremendous scope for improving the way this disorder is managed and part of this will involve greater collaboration between doctors, pharmacists and patients. (CAD)Angina Pectoris is defined as a ‘chest discomfort due to myocardial ischaemia associated with coronary artery disease’ (2). Typically, a patient with angina complains of central chest pain, usually described as heavy, gripping, or constricting, which is brought on by exertion or stress and is relieved by rest and glyceryl trinitrate (GTN). The pain may spread down the left arm, sometimes down both arms and may also spread up the neck to the jaw. The pain experienced often frightens the person involved, resulting in marked anxiety. Patients may even feel they are about to die. There are variations of the above description, but any adult with chest pain, which appears to be related to increased heart rate or heart work may have angina. CAD may be considered as a spectrum of disorders caused by atherosclerosis, the gradual narrowing and eventual occlusion of the coronary arteries resulting in stenosis. Atherosclerosis is the result of a complex interaction between blood elements, disturbed blood flow and vessel wall abnormality (5). The degree of stenosis is an important factor; a coronary artery must be narrowed by at least 50–70% in luminal diameter before coronary blood flow is inadequate to meet the metabolic demands of the heart during increased exercise or stress (2). The mechanism responsible for the sudden conversion of a stable atherosclerotic plaque to an unstable and life-threatening condition is usually plaque disruption with superimposed thrombosis. Plaque disruption is more dependent on plaque composition and vulnerability than on the degree of stenosis (5). The loss of blood supply to the heart muscle can:• make it unable to increase its work in response to demands made during exercise or stress• lead to progressive muscle dysfunction that causes heart failure• cause death of some of the heart muscle (infarction), which may present as a typical heart attack (MI, coronary thrombosis). Equally often the patient is not aware of having ‘an attack’ (which is observed on an electrocardiogram – ECG) and this situation is described as a silent infarct• disrupt the normal electrical conducting system in the heart, which produces ventricular fibrillation (VF), the major cause of sudden death. Precise figures for the morbidity and mortality of CAD vary from country to country and depend on definitions and data collection methods. However, it is generally accepted that CAD is the most common cause of death in the developed countries of the world and is responsible for at least 25% of all deaths. One-fifth of all these deaths are sudden and can be the first and only clinical event resulting from the underlying CAD (4). The beneficial effect of advances in hospital treatment, such as thrombolysis, has dramatically reduced in-hospital mortality for MI, e.g. mortality for patients < 55-year-old being only 3% (6). Unfortunately, two-thirds of all patients with CAD still die before reaching hospital. Studying CAD events in three health districts in England and Wales during 1994–5, Norris et al. (6) showed that a high proportion (74%) of fatal events occurred outside hospital (91% of fatalities at age < 55 and 70% at age 65–74 years). It follows from the above that every effort must be made to decrease outside hospital death from CAD by offering better primary and secondary prevention, increasing public awareness of the symptoms of a heart attack and last, but not least, improving response times by the ambulance service. Taking a careful history and, if necessary, seeking supporting evidence from specific investigations is essential for making a diagnosis of angina. Physical examination of the patient may not reveal any diagnostic signs, however, there may be evidence of key risk factors for the development of CAD or of existing vascular disease. Thus, there may be evidence that the patient:• smokes• has or has had hypertension• has peripheral vascular disease• already has evidence of heart failure. In a patient with angina it is obviously desirable to address and correct any reversible risk factor which would be expected to cause the progression of CAD (Fig. 1, Table 1) (7). Actions to reverse coronary risk factors. Smoking is the most important modifiable coronary risk factor and should receive the most attention. Recently, a large prospective study conducted in China showed that smoking is already causing ≈750 000 deaths a year and it is predicted that this will rise to 3 million per year by the time the young smokers reach middle and old age (8). The study also showed that smoking caused more deaths in men than women (13% vs. 3%, respectively), as the proportion of young women who smoke is small. The adverse effect of smoking on the risk of myocardial infarction is greater in female than male smokers (9). Tobacco constituents exerting an antioestrogenic effect may explain this difference. Women smokers are relatively deficient in oestrogen, tend to have an early menopause and are more likely to develop osteoporosis. Recently, the Edinburgh Artery Study confirmed the relationship between smoking and cardiovascular risk factors in the development of peripheral artery disease (PAD) and CAD, both considered sequelae of atherothrombosis (10). Lack of exercise is a contributing factor to CAD. For patients with established CAD it may be difficult to increase their levels of exercise without causing pain. Nevertheless, they should be encouraged to take as much exercise as they reasonably can and should be actively discouraged from being too sedentary, which is likely to have an adverse effect (11). In 1996, the United States National Institute of Health convened a consensus development conference on physical activity and cardiovascular health and unanimously reached the conclusion that ‘moderate levels of regular physical activity confer significant health benefits’. They suggest that all children and adults should gradually build up to 30 min of activity of moderate intensity on most, preferably all, days of the week (12). Being overweight is also an important contributor to the development of CAD. It is important to take into account the weight history of a patient since being overweight in middle age is a risk factor for CAD in late life (13). The presence of high plasma concentrations of low-density lipoproteins (LDL), in particular smaller, denser atherogenic LDL, is central to the causation of CAD. Thus, a large calorie intake and a high proportion of saturated fats in the diet are bad. Saturated fatty acids are the major preventable cause of raised plasma concentrations of total cholesterol and LDL. ReplaceÍment of saturated fatty acids with other major nutrients (carbohydrates, polyunsaturated fatty acids, or monounsaturated fatty acids) produces a fall in cholesterol levels (14). An observational study performed in a cohort of vegetarians and other health conscious people, followed up for an average of 17 years, showed that daily consumption of fresh fruit was associated with a significant reduction in mortality from CAD (24%), cerebrovascular disease (32%) and all causes of death combined (21%) (15). The impact of fruit and vegetables may be in part related to their antioxidant content, a subject discussed in the next section. High-dose combination of antioxidant nutrients (alpha-tocopherol (800 i.u. vitamin E), vitamin C (1000 mg) and beta-carotene (24 mg)) can reduce the susceptibility of LDL to oxidation in-patients with CAD (16). Antioxidants also act to prevent or delay the development of CAD by inhibiting monocyte adhesion and platelet activation, offering protection against the cytotoxic effect of oxidized LDL, and preserving endothelium-derived nitric oxide activity (17). A randomised controlled trial, the Cambridge Heart Antioxidant Study (CHAOS), assessed the effects of vitamin E (a–tocopherol – 400 or 800 i.u.) on the risk of cardiovascular death and nonfatal MI in patients with clinically and angiographically proven coronary atherosclerosis. This trial showed that vitamin E reduced the risk of nonfatal myocardial infarction by 77%. Beneficial effects were apparent within one year of treatment (18). A recent study in patients receiving thrombolytic therapy for acute MI assessed markers of antioxidant defence (vitamin E and total antioxidant capacity) and oxidative damage (lipid hydroperoxides). This study demonstrated that streptokinase-initiated reperfusion of ischaemic myocardium is associated with a dramatic fall in antioxidant defences in the first 30 min of treatment, which was associated with a corresponding rise in free radical damage (19). This supports the potential role of antioxidants in the prevention and treatment of CAD and further research is required to determine their future clinical importance. A recent review indicates how antioxidants may achieve these beneficial effects and also presents some evidence that pharmacological preparations are available in forms capable of producing measurable changes in serum antioxidant defence (20). Some disorders undoubtedly increase the risk of dying from coronary heart disease and merit specific attention, these are: High blood pressure predisposes to CAD and to strokes (cerebrovascular disease). However, whereas successful blood pressure (BP) control reduces the risk of having a stroke, the impact on CAD has been much less impressive (21). The reasons for this are matters for debate and speculation, but include the suggestions that the treatment• has not lowered BP adequately• has lowered BP too much• has been started too late• has involved the use of drugs which are not ‘cardioprotective’ There is considerable evidence that beta-blockers are more likely to have a beneficial effect. This is based on their impact on the underlying disease and clinical trial data (26, 27). Patients with hypertension and angina should be considered for treatment with a beta-blocker, as there is more evidence that these drugs are cardioÍprotective, and they have been shown to be effective in both these disorders. Until very recently the role of cholesterol has often been referred to as the ‘lipid hypothesis’. Both primary and secondary prevention trials with lipid lowering agents have now proven the role of cholesterol as a central cause for CAD. The West of Scotland Study (WOSCOPS), the first long-term primary prevention trial using a statin (pravastatin), reduced total cholesterol concentration by 20%, LDL by 26% and triglycerides by 12% and showed a reduction of 28% in deaths due to coronary heart diseases (28). Therefore, WOSCOPS clearly showed benefit from reducing hyperÍcholesterolaemia in men at high risk for CAD. The Scandinavian Simvastatin Survival Study Group (4S), the first secondary prevention trial, assessed the impact of simvastatin in post-MI and angina patients with a raised plasma cholesterol (5·5–8·0 mmol/l). It demonstrated that compared with placebo-treated patients, simvastatin produced a 30% reduction in the relative risk of death from all causes and a 42% risk reduction in deaths from CAD. The reduction in risk of major CAD events was the same in patients with previous MI or angina only and there was no gender difference up to the age of 70 years (29). To evaluate the impact of lipid lowering therapy with pravastatin in post-MI patients with relatively normal plasma cholesterol concentrations (3·6–5·4 mmol/l) the Cholesterol and Recurrent Events (CARE) Study was performed. This study showed a significant reduction in CAD mortality (20%) and in the incidence of CAD (24%) in the pravastatin treated group compared with placebo. In addition, the need for coronary surgery or angioplasty was reduced by 27% (30). More recently, the Long-term Intervention with Pravastatin in Ischaemic Disease (LIPID) study, the third and largest of the secondary prevention trials, reported its results. It was a randomised trial which showed that pravastatin reduced CAD mortality (24%) and overall mortality (22%) in patients with a history of MI or unstable angina with a broad range of cholesterol levels (31). The LIPID Study also showed a reduction in the incidence of strokes (19%). Evidence from these trials has now made the treatment of hypercholesterolaemia with statins of paramount importance in the management of CAD. Statins, as inhibitors of the enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, reduce the availability of cholesterol and upregulate LDL receptors, leading to accelerated removal of LDL from the circulation. They are the most powerful and consistent means available of lowering plasma cholesterol and have few adverse effects (31, 32). Patients with angina should be treated similarly to post-MI patients as they have clinical evidence of CAD and are likely to benefit from cholesterol reduction, even if their cholesterol is not raised, as demonstrated in the CARE study (30). This would only apply to those whose life expectancy is not already reduced due to coexisting disorders such as cancer, dementia or serious chest disorders. Occlusion of a narrowed coronary artery may occur because a clot forms at the affected site. This may be prevented by administering anticoagulants (to reduce clotting factors in the blood) or by giving aspirin (to reduce platelet aggregation) (33). Anticoagulation therapy is difficult, requires regular monitoring and its benefits in angina are not proven. Once endothelial integrity has been breached there follows a cascade of events that ultimately will create the necessary conditions for the development of thromboembolism. The importance of treating (potential) thromboembolism associated with CAD should not be underestimated. The Thrombosis Prevention Trial, a randomised trial of low-intensity oral anticoagulation with warfarin and low-dose aspirin (75 mg/day) showed that combined treatment with warfarin and aspirin is more effective in the reduction of CAD than either agent on its own (34). This trial demonstrated that five CAD events could be avoided by treating men with combined warfarin and aspirin for one or three using warfarin and three using aspirin The use of warfarin therapy has a serious risk of and for this careful monitoring is essential The use of aspirin is for all patients who have established CAD, there are specific such as in a of is associated with the least risk of and it is more the Study showed that of a of aspirin (75 mg/day) with treatment reduced the risk of acute myocardial infarction without the risk of patients with CAD are to die from the most serious attempts to reduce the in patients by drugs that the and have because they have increased mortality the not the use of in all patients with the reduction in death risk supports the use of in patients for therapy is In the reduced the incidence of or death of acute MI with or ventricular It is important to that the reduction in the rate of patients was only in those patients who were also Thus, the benefit of appears to be to that of therapy by means of increasing and electrical in the heart, reduces the risk of and sudden death (26, Thus, the evidence available not suggest that patients should have an as part of the management of their angina. However, the of beta-blockers could be considered as an for their the women are at increasing risk of CAD. It is not therapy is or it is the of who is at risk associated with increased less better diet, more that to take There has been some that may decrease the incidence of CAD and increase the incidence of of the and However, recent of clinical trials data has that therapy not prevent cardiovascular events the Heart and Study a trial for secondary prevention of coronary heart disease in women showed that during an average of years not reduce the overall rate of CAD more women in the group experienced events and disease Thus, there is no evidence that women should be receiving for the prevention of CAD and it should be avoided if there is a history of The risk of a women or dying of as to but one should in that age a much more increase in mortality from heart disease than from Thus, a age should on Patients with a history are more to develop CAD. Patients with angina have CAD and a history will not to the of their However, if the angina is or if there is a history of CAD, their children are at increased risk and should be advice against smoking and have their blood pressure and plasma cholesterol concentrations The in the treatment of angina is to reduce myocardial consumption increase myocardial In to achieve three of drugs can be Table the and of these groups. increase coronary blood cause of coronary arteries and reduce platelet adhesion and The most are and have considerable as agents because they are to use and work However, or high plasma concentration to the development of may be to for a that this at the are daily with less than between the and can also be to any patients those with left ventricular the heart rate and reduce myocardial and decrease heart work and myocardial They also blood flow myocardial blood by reducing the of the ventricular that coronary artery that the There is good evidence that drugs are better and that drugs are the drugs for which there is more evidence that they are and reduce sudden death Patients on or about to beta-blockers need to be aware of the between the potential benefits and which may be on controlled preparations despite the trials have not reduced CAD mortality agents can be in – and are the most They act by of vascular – and act on muscle and conducting as present the evidence that and are to beta-blockers for secondary prevention in patients with good left ventricular An increasing of patients with angina are by coronary However, a on the and the for would be in this for of should be considered as part of the at all may be considered to be the relatively young and those with a response to those with pain or a quality of life This for myocardial has been the effective coronary artery surgery for It the affected of the coronary artery and with a the is but or left are because of a long-term (2). In of patients is effective in symptoms and reducing the risk of death for up to years the trials have compared treatment with but of these is the scope of this review was in and the of performed has the of (2). is an effective treatment for cases of stable angina are a to the of in the coronary artery and the vessel by a at the of the (2). on risk factors, more and treatment of those with angina and greater to surgery for those who would benefit are Patients with angina have coronary artery disease and they will benefit from an management directed towards their coronary risk factors and their This will to their quality of life and such management will important as the population