Asian Cardiovasc Thorac Ann 1998;6:245-249
© 1998 Asia Publishing EXchange Pte Ltd
Medical Therapy for Coronary Artery Disease: Primary and Secondary Prevention
Krishnankutty Sudhir, MBBS, PhD
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Baker Medical Research Institute and Alfred Hospital Prahran, Melbourne, VIC, Australia
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For reprint information contact: Krishnankutty Sudhir, MBBS, PhD Alfred and Baker Medical Unit Alfred Hospital 3rd Floor Philip Block, Commercial Road Prahran, Melbourne, VIC 3181, Australia Tel: 61 3 9276 3320 Fax: 61 3 9276 3488 Email:krishna.sudhir{at}baker.edu.au
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ABSTRACT
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This review examines the various approaches to primary prevention and some aspects of secondary prevention of coronary artery disease. The role of aspirin, beta blockers, exercise, diets, fish intake, vitamin E, and folic acid are discussed. The potential role of chlamydia in atherosclerosis, the protective effect of alcohol consumption, and the benefits of female sex hormones are also examined. An update on lipid-lowering therapy and a summary of recent major clinical trials establishing the use of 3-hydroxy-3-methyglutaryl coenzyme A reductase inhibitors in primary and secondary prevention of coronary artery disease are provided.
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INTRODUCTION
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Coronary artery disease (CAD) continues to be a major cause of morbidity and mortality in Western societies. Approximately two out of every three incidents of myocardial infarction (MI) occur without warning and of note, one third of first MIs are fatal; 20% of patients die out of hospital and 13% die within the first 24 to 48 hours of hospitalization. These data emphasize the need for better strategies of primary prevention to significantly impact on the incidence and mortality of CAD. This review examines the various medical approaches available for both primary and secondary prevention.
Over the last few years, it has become evident that acute coronary syndromes such as unstable angina and MI are often precipitated by lesions that appear angiographically as mild degrees of stenosis. Falk and colleagues1 showed that 68% of all MIs were caused by angiographic stenoses of less than 50%, 18% of MIs were caused by lesions between 50% and 70%, while only a minority (14%) of MIs were caused by a greater than 70% stenosis. Milder stenoses that are clinically vulnerable appear to be lipid-laden with thin fibrous caps, making them prone to rupture. By contrast, the more stable lesions with more severe stenoses appear to have smaller lipid cores and an abundance of fibrous tissue, rendering them physically less prone to rupture. The cause or causes of plaque rupture are unclear but may be related to altered shear stresses at the site of fissuring. However, it is of interest that inflammatory cells (T lymphocytes and macrophages) have been identified at the shoulder of the plaque where it meets the normal vessel wall. It is likely that proteolytic enzymes produced by these inflammatory cells cause fissuring of the fibrous cap leading to localized thrombosis, thus precipitating acute coronary syndrome.2 Therefore, prevention of this syndrome might involve one or more of the following strategies: inhibition of thrombosis; stabilization of plaque, possibly by strengthening the fibrous cap; and inhibition of inflammation within the plaque.
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ASPIRIN
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The Physicians' Health Study3 demonstrated a 44% reduction in the incidence of MI in US physicians randomly assigned to aspirin therapy (325 mg per day) over a 5-year period. While the mechanism of action of aspirin in this situation has always been assumed to be inhibition of platelet thrombosis, a recent study suggested that its antiinflammatory properties might contribute to its cardiovascular benefits.4 Baseline levels of C-reactive protein in the Physicians' Health Study were found to be predictive of both the subsequent risk of MI as well as the beneficial effects of aspirin. Patients in the highest quartile of baseline C-reactive protein levels were found to derive the greatest benefit from aspirin and subjects in the lowest quartile appeared to derive no benefit. These open data suggest the possibility that antiinflammatory properties of aspirin are important in its role in cardiovascular prophylaxis.
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BETA BLOCKERS
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The role of beta blockers in secondary prevention iswell established with evidence of a decrease in mortality associated with their use following MI.5 In primary prevention in hypertensive patients, most studies such as the Medical Research Council trial, the International Prospective Primary Prevention Study in Hypertension, and the Heart Attack Primary Prevention in Hypertension study were unable to find a more beneficial effect of beta blockers compared to thiazide diuretics.6 However, in one study, the Metoprolol Atherosclerosis Prevention in Hypertensives study, a lower total mortality was observed in the metoprolol-treated group compared to the diuretic-treated group.7
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EXERCISE, DIETS, AND FISH INTAKE
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Regular exercise appears to decrease the risk of MI. In a prospective study in which subjects were stratified on the basis of leisure-time physical activity, the relative risk of MI in the third of subjects with the highest level of physical activity (more than 2.2 hours per week) was 0.31, 95% confidence interval (CI) 0.12 to 0.85,p = 0.02, compared to the third with the lowest level of exercise (p = 0.04 for linear trend over all three groups).8 Exercise regimens are often combined with diets and there is evidence in patients with coronary artery disease thata low-fat vegetarian diet, smoking cessation, stress management, and moderate exercise induces regression of coronary atherosclerosis.9 Modest levels of fish intake also appear to be protective. A recent study suggested that at an average fish consumption of 35 g daily or more compared with none, the relative risks of death from coronary heart disease and from sudden and non-sudden myocardial infarction were 0.62 (0.4 to 0.94) and 0.56 (0.33 to 0.93) respectively, with a graded relationship between the relative risks and the strata of fish consumption.10 These findings were accounted for by the relationship of fish consumption to non-sudden death from MI (relative risk, 0.33; 95% CI, 0.12 to 0.19; p = 0.007).
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VITAMIN E AND FOLIC ACID
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Several experimental studies have suggested that Vitamin E favorably influences the course of coronary artery disease. Benefits of Vitamin E were prospectively assessed in the Cambridge Heart Antioxidant Study that demonstrated a significantly reduced risk of the primary trial endpoint of cardiovascular death and nonfatal MI (relative risk, 0.53; 95% CI, 0.34 to 0.83; p = 0.005).11 The beneficial effects on this composite endpoint were due to a significant reduction in the risk of nonfatal MI (14 versus 41; relative risk, 0.23; 95% CI, 0.11 to 0.47; p = 0.005). However, there were no significant excess of cardiovascular death in the alpha tocopherol group(27 versus 23; relative risk, 1.18; 95% CI, 0.62 to 2.27; p = 0.61). Further prospective studies in larger cohorts are required to resolve the issue of the effects of antioxidants on cardiovascular deaths.
In the recent past, homocystinemia has received considerable attention as a novel risk factor for coronary artery disease. A strong graded relationship was found between plasma homocysteine levels and overall mortality. Over a 4-year follow-up, 3.8% of patients with homocysteine levels below 9 µmol·L–1 died, compared to 24.7% of those with homocysteine levels of 15 µmol·L–1 or higher.12 Another study determined that a 5 µmol·L–1 total homocysteine increment elevates CAD risk by as much as a cholesterol increase of 0.5 µmol·L–1 (20 mg·dL–1). Increased folic acid intake (approximately 200 µg per day) reduces total homocysteine levels by approximately 4 µmol·L–1.13 However, at the present time, prospective studies examining the efficacy of such therapy in cardiovascular prophylaxis are needed.
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ANTI-CHLAMYDIA PROPHYLAXIS
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Several infectious agents have been reported to be associated with atherosclerotic plaque. Chlamydia pneumoniae has been detected in coronary atherosclerotic tissue and elevated levels of antibodies to chlamydia as well as chlamydial lipopolysaccharide group antigen have been demonstrated in patients with coronary artery disease.14,15 Use of the antibiotic azithromycin in male survivors of MI showed that an increased Chlamydia pneumoniae antibody titer might be a predictor for further adverse cardiovascular events in post-MI patients. Taking a short course of azithromycin may lower this risk and the potential of action against chlamydia as a factor in coronary disease prevention requires further study.
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ALCOHOL CONSUMPTION
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A negative association has been reported between alcohol consumption and the risk of MI. Particularly strong evidence is the reported inverse association between wine ethanol and CAD.17 The beneficial effect of regular alcohol consumption was assumed to be via an elevation of high-density lipoprotein cholesterol but a recent report suggested that red wine (and grape juice) exerts an antiplatelet effect in dogs.18 Because red wine and grape juice (but not white wine) were effective in inhibiting platelet thrombosis, it was inferred that there were beneficial compounds in red wine and grape juice that are either absent or present in a lower concentration in white wine, such as fungicides, tannins, anthocyanins, and phenolic flavonoids (including flavonols and flavones). However, in the Northern California Kaiser study on the effect of consumption of red wine, white wine, liquor, and beer on the risk of hospitalization for coronary artery disease, it was concluded that ethanol consumption was protective against CAD and that there were minor additional benefits of beer and wine but not especially of red wine.19
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FEMALE SEX HORMONES
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In postmenopausal women, numerous studies have suggested beneficial effects of estrogen supplementation with a large majority showing a significant (mean, 50%) reduction in the incidence of cardiovascular disease in women taking hormone replacement therapy. However, all of these were observational studies of estrogen use rather than randomized prospective controlled trials. Several ongoing prospective studies are designed to determine the effects of hormone supplementationon angiographic evidence of coronary artery disease, cardiovascular events, and mortality. One of these, the Women's Health Initiative sponsored by the National Institutes of Health, will examine the role of hormonal therapy in primary prevention of CAD.20 The results of these trials must be awaited to determine the precise beneficial effects of hormone replacement therapy, free from bias and confounding factors that are inherent in observational studies (see addendum).
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LIPID-LOWERING THERAPY
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Several studies during the past two decades have examined the issue of whether lipid lowering by diet, surgery, or pharmacotherapy could induce regression of atherosclerosis. Most of these studies showed minimal degrees of regression of coronary atheroma but surprisingly, they revealed significant degrees of reduction of clinical events. Among the 3-hydroxy-3-methyglutaryl coenzyme A reductase inhibitors (statins), pravastatin was observed to significantly reduce clinical events in the Pravastatin Limitation of Atherosclerosis in the Coronary Arteries I study and the Regression Growth Evaluation Statin Study.21,22 However, many of these studies were not designed to address the issue of a reduction in clinical events or mortality and it was not until the mid 1990s that it was shown conclusively that statin therapy reduced cardiovascular events and mortality in the setting of both primary and secondary prevention. In the context of secondary prevention, the Scandinavian Simvastatin Survival Study23 showed that in hypercholesterolemic patients with a history of MI, 5 years of treatment with simvastatin resulted in a 30% decrease in total mortality, largely due to a 44% reduction in coronary mortality. In the more recent Cholesterol and Recurrent Events (CARE) trial24, some of the observations of the Scandinavian Simvastatin Survival Study were extended; even patients with normal cholesterol levels who had experiencedMI had a 24% reduction in risk (95% CI, 9% to 36%; p = 0.003) of the combined endpoint of fatal and nonfatal MI.
In the Lipid Research Clinics Coronary Primary Prevention Trial,25 the hypothesis tested was that lowering plasma cholesterol in middle-aged men with primary hyper-cholesterolemia who are otherwise healthy leads to a reduction in coronary heart disease as manifested bya reduction in confirmed MI over a 7-year follow-up.The treatment group received a moderate cholesterol-lowering diet plus cholestyramine. Treatment resultedin a 19% reduction in confirmed myocardial infarction (p < 0.05). In the Helsinki Heart Study,26 the effect of gemfibrozil was examined in asymptomatic middle-aged men with primary dyslipidemia. The cumulative rate of cardiac endpoints at 5 years was reduced by 34% (95% CI, 8.2% to 52.6%; p < 0.02). The Asymptomatic Carotid Artery Progression Study27 tested the effect of lovastatin on early-stage carotid atherosclerosis in asymptomatic men and women. The incidence of major cardiovascular events in patients on lovastatin (in combination with warfarin) was 5 compared to 14 in the control group (p < 0.05).
However, the first study to firmly demonstrate thebenefit in primary prevention of statin therapy alone was the West of Scotland Coronary Prevention Study (WOSCOPS)28 that showed pravastatin therapy for primary prevention was effective in reducing the incidence of MI and death from cardiovascular causes. Scottish men (n = 6595) between the ages of 45 and 64 years with hypercholesterolemia and no history of MI were randomly assigned to receive pravastatin (40 mg daily) or a placebo over a 5-year period. There were 248 coronary events in the placebo group and 174 in the pravastatin group giving a relative reduction of 31% (95% CI, 17% to 43%; p < 0.001). There were similar reductions in confirmed nonfatal MI (31% reduction, p < 0.001), death from coronary heart disease (confirmed cases alone: 28% reduction, p = 0.13; confirmed plus suspected cases: 33% reduction, p = 0.042), and death from all cardiovascular causes (32% reduction, p = 0.033). There was no excess of deaths from noncardiovascular causes in the pravastatin group. A 22% reduction in the risk of death from any cause was observed in the pravastatin group (95% CI, 0% to 40%; p = 0.051). The authors concluded that pravastatin therapy reduced the incidence of MI and death from cardiovascular causes in hypercholesterolemic men with no history of MI.
The Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS)29 was another primary prevention study that examined the effects of lovastatin on the incidence of acute major coronary events (sudden cardiac death, fatal and nonfatal MI, and unstableangina) in 5608 men and 997 women with average cholesterol levels and relatively low high-density lipo-protein cholesterol levels. Lovastatin induced a 36% reduction (p < 0.001) in the primary endpoint (the first major coronary event) and significant reductions in the incidence of fatal and nonfatal cardiovascular events (reduction 24%, p = 0.006), unstable angina (reduction 34%, p = 0.017), fatal and nonfatal MI (reduction 35%, p = 0.014), and the need for revascularization (reduction 33%, p = 0.004). There were no significant reductions in total or cardiovascular mortality. AFCAPS/TexCAPS extended the findings of WOSCOPS by demonstrating the beneficial effect of a statin in primary prevention in a cohort of men and women with average cholesterol levels.
At the 70th Annual Sessions of the American Heart Association held in Orlando, Florida, November 1997, preliminary results from the Long-term Intervention with Pravastatin in Ischaemic Disease (LIPID)30 study were presented. LIPID was a secondary prevention study that examined the effects of pravastatin in patients with previous MI or unstable angina and with average cholesterol levels. The LIPID study demonstrated that pravastatin induced significant reductions in total mortality (reduction, 23%; p = 0.000002), coronary mortality (reduction, 24%; p = 0.0004), total stroke (reduction, 20%; p = 0.022), cardiovascular mortality (reduction, 24%; p = 0.0002), fatal and nonfatal MI (reduction, 29%; p < 0.00001) and the requirement for coronary artery bypass grafting (reduction, 24%; p = 0.0001). This extended the findings of the CARE report by showing the benefit of statin therapy in secondary prevention in a large cohort of men and women, in patients less than 55 years of age, and in those with a history of unstable angina.
In summary, aspirin, exercise, vitamin E, moderate alcohol consumption, and hormonal therapy in women appear to be useful strategies for prevention of CAD.In addition, the recently documented role of 3-hydroxy-3-methyglutaryl coenzyme A reductase inhibitors inboth primary prevention (pravastatin in WOSCOPS and lovastatin in AFCAPS/TexCAPS) and secondary prevention (pravastatin in the CARE and LIPID studies) suggests that moderate lipid-lowering also has substantial clinical benefits.
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ADDENDUM
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In the recently published Heart and Estrogen/Progestin Replacement Study (HERS), the effect of hormonal therapy on the risk for CHD events in postmenopausal women with established coronary disease was examined in 2763 women. Subjects were randomized to 0.625 mg of conjugated equine estrogens plus 2.5 mg of medroxy-progesterone acetate in 1 tablet daily or a placebo; follow-up averaged 4.1 years. Overall, there were no significant differences between groups in the primary outcome or in any of the secondary cardiovascular outcomes: 172 women in the hormone group and 176 women in the placebo group had MI or CHD death (relative hazard, 0.99; 95% CI, 0.80–1.22). The lack of an overall effect occurred despite a net 11% lower low-density lipoprotein cholesterol level and 10% higher high-density lipoprotein cholesterol level in the hormone group (each p < 001). There were, however, more CHD events in the hormone group than in the placebo group in year 1 and fewer in years 4 and 5. More women in the hormone group than in the placebo group experienced venous thromboembolic events and gallbladder disease. Based on the finding of no overall cardiovascular benefit and a pattern of early increase in risk of CHD events, the authors recommended against starting this treatment for the purpose of secondary prevention of CHD but stated that it could be appropriate for women already receiving this treatment to continue.
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ABSTRACT
INTRODUCTION
