Q J Med 2000; 93: 567-574
© 2000 Association of Physicians
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Identifying patients at risk for coronary heart disease: implications from trials of lipid-lowering drug therapy
From the Departments of Medicine and 1 Biochemistry, Dumfries and Galloway Royal Infirmary, Dumfries, UK
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Summary |
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 Top Summary IntroductionPlasma lipids and CHD...Lipid lowering and CHD...Therapy options and...Other drug measures for...Nutritional supplementsRecommendationsWhat remains to be...References |
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Abnormal lipid levels contribute significantly to the risk of coronary heart disease (CHD), which is increased further in the presence of other risk factors. The association between elevated low-density lipoprotein (LDL) cholesterol and CHD risk is well established, and large primary and secondary prevention studies of HMG-CoA reductase inhibitors (statins) have shown conclusively that lowering LDL cholesterol levels reduces CHD events and total mortality. Regardless of the intervention used (diet, surgery, drugs), reduction of plasma cholesterol has consistently produced a reduction in cardiovascular risk. Absolute benefit is greatest in those who are at highest risk initially, and trial results suggest that the lower the LDL cholesterol level achieved, at least down to LDL of 3.0 mmol/l, then the lower is the CHD event risk. Epidemiological data also point to the negative impact of other lipids on CHD risk. Low levels of high-density lipoprotein (HDL) and high levels of triglycerides (particularly in conjunction with an LDL/HDL ratio >5) are particularly strong risk factors for CHD. Thus, although prevention trials to date have primarily assessed the impact of LDL lowering on CHD events, the initial assessment of CHD risk should consider a more detailed atherogenic profile including HDL and triglyceride levels. A general approach to preventing cardiovascular disease should include strategies to reduce the overall CHD risk by lifestyle modification and management of modifiable risk factors such as smoking, hypertension and diabetes. Based on data from recent prevention studies, and because they are the most potent lipid-lowering agents available for lowering LDL cholesterol, statins have appropriately become the drug of choice for most patients with hyperlipidaemia who require drug therapy.
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Introduction |
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TopSummaryIntroductionPlasma lipids and CHD...Lipid lowering and CHD...Therapy options and...Other drug measures for...Nutritional supplementsRecommendationsWhat remains to be...References |
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Coronary heart disease (CHD) remains a serious public health problem, accounting for 150 000 deaths annually in the UK: approximately 1 in 4 deaths in men and 1 in 5 deaths in women.1 It is also the most common cause of premature death in the UK: 28% of premature deaths in men and 17% of premature deaths in women are from CHD. Although often thought of as a male disease, CHD is the number one killer of women, causing more deaths annually than breast cancer.1
It is well established that a Western lifestyle—a high-fat, high-calorie diet, physical inactivity and tobacco smoking—plays an important role in the cause and risk of CHD. The biochemical or physiological consequences of this lifestyle include elevated blood pressure, elevated plasma total cholesterol, low plasma high-density lipoprotein (HDL) cholesterol, elevated plasma triglyceride, diabetes, obesity and thrombogenic factors.2 The contribution of these modifiable risk factors to the risk of developing a future coronary event, is considerable, particularly in combination with non-modifiable personal characteristics such as age, male sex and family history of early-onset CHD.
Chief among the modifiable risk factors are abnormal serum lipoprotein concentrations. Accordingly, treatment guidelines advocate aggressive lipid-lowering therapy in patients at highest absolute risk (i.e. generally those with multiple risk factors, with established atherosclerosis, and/or with diabetes) for future coronary events.2–8 This article will review the impact of abnormal serum lipoprotein concentrations on CHD risk, and consider recent evidence from primary and secondary coronary prevention studies on treatment of patients with hyperlipidaemia. The currently available options for lipid lowering will also be discussed.
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Plasma lipids and CHD risk |
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TopSummaryIntroductionPlasma lipids and CHD...Lipid lowering and CHD...Therapy options and...Other drug measures for...Nutritional supplementsRecommendationsWhat remains to be...References |
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LDL cholesterol
The association between plasma total cholesterol (or LDL cholesterol) and CHD risk is well established. Results from a 12-year follow-up of 316 099 men screened for the Multiple Risk Factor Intervention Trial (MRFIT) showed a strong graded relationship between serum cholesterol levels and CHD mortality, with death rates ranging from 7.7 per 10 000 person-years for men with serum cholesterol levels of 3.6 to 4.1 mmol/l, to 54.5 per 10 000 person-years for men with serum cholesterol levels above 8.3 mmol/l.9 Rates of CHD deaths for the three categories of serum cholesterol levels below 4.7 mmol/l were similar (range 7.7–8.9), suggesting a risk gradient above this level. The level of CHD risk and the predictive power of serum cholesterol is significantly modified by the presence of non-lipid risk factors, especially smoking, hypertension and diabetes. For example, a 12-year follow-up of MRFIT subjects showed that the absolute risk of death was at least three times higher for diabetics than for non-diabetics, and that this relationship was amplified by serum cholesterol (Figure 1
).10 Thus, epidemiological evidence supports the view that LDL cholesterol is important in atherosclerosis development.
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Other plasma lipids
A strong inverse relationship between plasma HDL cholesterol levels and CHD risk has been shown in both sexes.11 Compared with women with HDL cholesterol levels in the highest quartile (>1.7 mmol/l), Framingham women with HDL cholesterol levels in the lowest quartile (<1.2 mmol/l) had a nearly six-fold excess risk of myocardial infarction. Among men in the Helsinki Heart Study, an LDL/HDL cholesterol ratio >5 was the strongest predictor of cardiac events.12 Elevated serum triglyceride levels are also associated with an increased risk of CHD in univariate analysis; however, this relationship is not as strong, or disappears when statistical adjustment is made for the effects of other risk factors, HDL cholesterol in particular.13
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Lipid lowering and CHD risk reduction |
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TopSummaryIntroductionPlasma lipids and CHD...Lipid lowering and CHD...Therapy options and...Other drug measures for...Nutritional supplementsRecommendationsWhat remains to be...References |
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The Scandinavian Simvastatin Survival Study (4S), a high-risk secondary prevention study, was the first study to demonstrate unequivocally a reduction in all-cause mortality with lipid-lowering therapy.14 The Cholesterol And Recurrent Events (CARE) trial15 and the Longterm Intervention with Pravastatin in Ischaemic Disease (LIPID) Study16 reported similar results in patients with established CHD and average cholesterol levels. The West of Scotland Coronary Prevention Study (WOSCOPS) was the first to show net benefits with a statin in primary prevention.17 The Airforce Coronary Atherosclerosis Prevention Study (AFCAPS) has subsequently confirmed that the benefits of lipid-lowering therapy with statins extend to individuals previously regarded as being at relatively low risk for a coronary event.18 It has been estimated from these trials that CHD risk is reduced by 15% for each 10% reduction in plasma LDL cholesterol,19 or by 25% for a 1 mmol/l reduction in plasma total cholesterol20 (Table 1
, Figure 2). Follow-up studies have shown benefit for important subgroups within these trials including women,21,22 the elderly21,23 and patients with diabetes.24–26 A meta-analysis of statin trials suggests, in addition, that treatment with HMG-CoA reductase inhibitors prevents stroke in middle aged subjects.27
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There remains some controversy as to whether there is an LDL cholesterol threshold below which no further clinical benefit will be observed. Post hoc analyses from WOSCOPS suggest that in the primary prevention of CHD, patients who start with an LDL cholesterol of 5.0 mmol/l experience no further benefit when this is reduced below 3.7 mmol/l.28 Analyses of the relation between baseline LDL and outcome in the secondary prevention trials, CARE and LIPID, also suggest a law of diminishing returns: i.e. progressively less benefit at lower initial levels of LDL. Benefits were less when baseline LDL was below 3.2 mmol/l in CARE17 and below 3.5 mmol/l in LIPID18 (Figure 3
). No such threshold was seen in 4S29 but this may simply be because the lowest quartile of risk in 4S included patients with LDL up to 4.4 mmol/l.30 The design of 4S probably precludes an analysis of initial LDL and outcome in a low LDL subset therefore. These findings are exactly as predicted from prospective observational data which show progressively less CHD risk at lower levels of cholesterol.9
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A recent and welcome development has been the demonstration that gemfibrozil, a fibrate, may also reduce the risk of recurrent events in patients with established vascular disease who have normal cholesterol, normal triglycerides and low HDL.31 Until the publication of the Veteran's Affairs High-density lipoprotein cholesterol Intervention Trial (VA-HIT), the evidence that the benefits of fibrates outweighed the risks of using this class of drugs rested with one primary prevention trial, the Helsinki Heart Study.32 The implication of VA-HIT is that MI patients who do not fulfil the criteria for treatment with a statin, might now be offered treatment with gemfibrozil.
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Therapy options and considerations |
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TopSummaryIntroductionPlasma lipids and CHD...Lipid lowering and CHD...Therapy options and...Other drug measures for...Nutritional supplementsRecommendationsWhat remains to be...References |
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The most recent UK,3–7 European2 and US8 guidelines emphasize intensive treatment (usually pharmacological) for patients at highest risk of developing coronary disease, recommendations that are supported by the results from large primary and secondary coronary prevention studies discussed above. Management of patients with hyperlipidaemia should always be part of a general approach to preventing cardiovascular disease and should include strategies to reduce CHD risk imposed by other modifiable risk factors. Dietary and lifestyle changes are an integral part of risk management; however, in reality, many patients are not able to achieve desirable LDL cholesterol targets with dietalone,33 which means that those at high CHD risk will require pharmacological intervention.
Statins are the most potent agents for reducing LDL cholesterol levels. Results from the large prevention studies have confirmed that they are well tolerated, with rates of adverse events similar in both statin and placebo groups, and no increased risk of non-CHD mortality with active treatment. Drug choice should be made on the balance of trial evidence, safety and cost effectiveness, also by the initial level of cholesterol and thus the expected degree of cholesterol lowering required to reach target level in patients with severe hypercholesterolaemia.34
Bile acid sequestrants (resins) and nicotinic acid (niacin) also lower LDL cholesterol; whereas the effects of fibrates on LDL cholesterol can be variable35 (Table 2). Resins are unpalatable and may also increase triglycerides.35 Niacin has historically been associated with poor patient compliance due to flushing and gastrointestinal disturbances; however a new extended release niacin formulation appears to minimize these adverse effects, and thus may improve patient compliance with this agent.36
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Fibrates are most likely to be effective in patients with elevated triglycerides and low HDL, a group in whom the evidence of benefit from statins is less strong. Despite the encouraging results from VA-HIT, however, there remain concerns about the potential for fibrates to increase non CHD mortality, as preliminary results from the Bezafibrate Infarction Prevention (BIP) study, presented at the 20th Congress of the European Society of Cardiology, showed no significant overall benefit.
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Other drug measures for preventing CHD |
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TopSummaryIntroductionPlasma lipids and CHD...Lipid lowering and CHD...Therapy options and...Other drug measures for...Nutritional supplementsRecommendationsWhat remains to be...References |
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Low dose aspirin 75 mg per day should be considered for all men and women with established vascular disease, and also in primary prevention for those at high risk.3 Treatment of hypertension is recommended according to national guidelines.3,37,38 Fish oil supplements in capsule form have been shown to reduce cardiovascular death rates by 30% in the GISSI-Prevenzione study of MI survivors,39 while the results of the Heart Outcomes Prevention Evaluation (HOPE) study indicate that ACE inhibition using ramipril can substantially reduce morbidity and mortality among high risk patients with evidence of vascular disease, or diabetes plus one other risk factor, even in the absence of heart failure or a known low ejection fraction.40 The first randomized trial of HRT in post-menopausal women with CHD did not reduce the overall rate of CHD events.41 HRT should not however be withheld from women who have other indications for its use. Somewhat disappointingly, the use of anti-oxidant drugs, particularly vitamin E and beta carotene, may actually be harmful.42
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Nutritional supplements |
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TopSummaryIntroductionPlasma lipids and CHD...Lipid lowering and CHD...Therapy options and...Other drug measures for...Nutritional supplementsRecommendationsWhat remains to be...References |
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Phytosterols are a group of compounds present in various plants and plant products e.g. some vegetables and fruits. One of the phytosterols, sitostanol, has been incorporated into the Benecol food product range which is now widely available in the UK. Phytosterols reduce total cholesterol by 10% and LDL cholesterol by 13%.43 There is no evidence yet that they reduce cardiovascular disease, as trials have involved only relatively small numbers of subjects and have been of fairly short duration. Moreover, the Department of Health have advised against the use of Benecol products in pregnant and lactating women and young children on the grounds that lowering serum cholesterol in these individuals may be inappropriate.44 Another nutritional supplement under investigation at present is folic acid. Folic acid reduces homocysteine levels, the latter being widely investigated as a potential new risk factor for cardiovascular disease. The effect of homocysteine reduction on cardiovascular events is currently being investigated in randomized controlled trials.45
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Recommendations |
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TopSummaryIntroductionPlasma lipids and CHD...Lipid lowering and CHD...Therapy options and...Other drug measures for...Nutritional supplementsRecommendationsWhat remains to be...References |
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Serum total cholesterol alone is a poor predictor of CHD risk which is much increased when other risk factors are present. Because well-established risk factors such as smoking, serum cholesterol, hypertension and diabetes act together to produce a heightened level of risk, the importance of rigorous sustained intervention in individuals with multiple risk factors for CHD cannot be overstated. Clinical and epidemiological data also point to considering the atherogenic profile of the individual by using serum total cholesterol, HDL cholesterol and triglyceride levels in the initial patient assessment.
The benefits of lipid-lowering have been demonstrated in both high- and low-risk patient groups. There is little disagreement that patients up to the age of 75 years with established vascular disease should be offered treatment with a statin if their serum total cholesterol is greater than 5 mmol/l.3–7 Some type of primary prevention is warranted in all patients at risk for CHD, particularly dietary and lifestyle modifications in the younger patients since these strategies will likely be most effective when patients incorporate them into their lives at a relatively young age. Pharmacotherapy may be necessary in older patients, particularly those with other risk factors in whom lifestyle interventions are unsuccessful. Based on available trial evidence, treatment goals for serum total cholesterol and LDL cholesterol are less than 5.0 mmol/l and 3.0 mmol/l, respectively, in patients at sufficiently high risk to justify drug treatment.3–7
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What remains to be done? |
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TopSummaryIntroductionPlasma lipids and CHD...Lipid lowering and CHD...Therapy options and...Other drug measures for...Nutritional supplementsRecommendationsWhat remains to be...References |
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There remains a need to develop more sophisticated means of identifying patients at risk in primary prevention. Some progress has already been made. The development of risk scoring methods such as the Sheffield Table,46 New Zealand Guidelines47 and Joint British Chart3 mean that it is no longer necessary to estimate CHD risk simply by counting risk factors. Based on the Framingham risk function, these three risk scores represent a major advance in risk assessment. An analysis of the utility of these three risk scores in a clinical setting suggests that the Joint British Chart may be the most suitable for use in primary care.48 The new European guidelines2 are also based on Framingham data but do not include HDL cholesterol as a risk factor, and so are considered a less useful tool for targeting therapy in primary prevention. The current minimum Joint British recommendation is that individuals without overt vascular disease whose estimated CHD risk remains >3% per year by one of these risk methods despite a 3–6 month trial of diet and lifestyle, and whose serum total cholesterol is >5 mmol/l, should be offered drug treatment with a statin. The ultimate aim is that individuals with CHD risk >1.5% per year should also receive statins when economic considerations allow (perhaps as soon as 2003 when simvastatin comes off patent in the UK).
All guidelines on treatment of lipids in primary prevention of coronary disease emphasize that risk will be underestimated in certain groups of patients: those with familial hypercholesterolaemia or a strong family history of premature coronary disease, patients with electrocardiographic LVH, type 1 diabetics and type 2 diabetics with nephropathy, British Asians, and patients who have only recently stopped smoking or started antihypertensive therapy. Moreover, for individuals whose CHD risk is borderline for drug treatment by one of the risk assessment methods described, there is an additional need for better discriminators of CHD risk in order to more precisely target therapies. The measurement of CRP,49 carotid intima media thickness,50 lipoprotein (a),51 LDL particle size,52 and homocysteine,53 while not yet incorporated into existing risk scores, may further refine the process of risk assessment in selected cases. Nonetheless, and until more definitive answers are available, current evidence supports UK,3–7 European2 and US8 guidelines which emphasize serum total and LDL cholesterol targets for lipid-lowering treatment.
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Notes |
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Address correspondence to Dr C.G. Isles, Department of Medicine, Dumfries and Galloway Royal Infirmary, Dumfries DG1 4AP. e-mail: C.Isles{at}dgri.scot.nhs.uk
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References |
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TopSummaryIntroductionPlasma lipids and CHD...Lipid lowering and CHD...Therapy options and...Other drug measures for...Nutritional supplementsRecommendationsWhat remains to be...References |
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