Cholesterol reduction and death from noncoronary causes: evidence from randomised controlled trials*

An overview of randomised trials of cholesterol reduction (26 trials, 50,000 patients, net cholesterol reduction ?10%) provides clear evidence of a reduction in the incidence of coronary heart disease (CHD) after just a few years of treatment. Overall, the observed reduction in CHD death (9%± 3) was only half as large as the reduction in non-fatal myocardial infarction (19%±4), although both were statistically significant (2p <0.005). In these trials, 60% of all deaths were from CHD, and since treatment reduced these by about 9%, the expected reduction in total deaths was about 5–6%. This expected reduction falls within the 95% confidence interval of the observed effect of cholesterol reduction on total mortality in these trials. There were small excesses of deaths from cancer and deaths from trauma among patients allocated active treatment. However, in no single trial, nor in the trials collectively, were these increases individually statistically significant. Furthermore, the increases did not appear to be specific to any one agent nor were the increases consistent between trials of the same agent. These observations suggest that the small excesses of noncoronary deaths observed in the cholesterol reduction trials may have occurred by chance. Evidence from ongoing longer-term studies of treatments producing larger cholesterol reductions will be useful in further delineating the effects, if any, of such treatments on non-coronary mortality.     

Cholesterol, coronary heart disease and stroke: a review of published evidence from observational studies and randomized controlled trials

In observational epidemiologic studies, lower blood cholesterol is associated with a reduced risk from coronary heart disease (CHD) throughout the normal range of cholesterol values observed in most Western populations. There is a continuous positive relationship between CHD risk and blood cholesterol down to at least 3 to 4 mmol/l, with no threshold below which a lower cholesterol is not associated with a lower risk. Observational studies suggest that a prolonged difference in total cholesterol of about 1 mmol/l is associated with one-third less CHD deaths in middle age. Evidence from large-scale cholesterol lowering trials in patients at high-risk of CHD have demonstrated that much of the epidemiologically predicted difference in CHD risk associated with differences in cholesterol was achieved within a few years of treatment. Moreover, these trials have demonstrated that such therapy was not associated with increased non-CHD mortality. Total cholesterol is transported in blood as low-density lipoprotein cholesterol or LDL cholesterol (about 70%) and as high density lipoprotein cholesterol or HDL cholesterol (about 30%). Since these two cholesterol fractions have opposing effects on vascular risk, a 1 mmol/l reduction in LDL cholesterol is likely to be associated with 40 to 50% lower CHD risk. The size of the absolute reduction in CHD produced by lowering total and LDL cholesterol is determined by an individual's overall risk rather than their initial cholesterol level. Consequently, the benefits of drug treatment to lower LDL cholesterol are greater in those at higher absolute risk of CHD rather than at high cholesterol levels. Dietary saturated fat is the chief determinant of total and LDL cholesterol levels. Replacing 60% of the intake of saturated fat by other fats and reducing the intake of dietary cholesterol could reduce blood total cholesterol levels by about 0.8 mmol/l (that is by 10 to 15%), with four fifths of this reduction being in LDL cholesterol.     

Can change in high-density lipoprotein cholesterol levels reduce cardiovascular risk?

Background

The cardiovascular risk reduction observed in many trials of lipid-lowering agents is greater than expected on the basis of observed low-density lipoprotein cholesterol (LDL-C) level reductions. Our objective was to explore the degree to which high-density lipoprotein cholesterol (HDL-C) level changes explain cardiovascular risk reduction.

Methods

A systematic review identified trials of lipid-lowering agents reporting changes in HDL-C and LDL-C levels and the incidence of coronary heart disease (CHD). The observed relative risk reduction (RRR) in CHD morbidity and mortality rates was calculated. The expected RRR, given the treatment effect on total cholesterol level, was calculated for each trial with logistic regression coefficients from observational studies. The difference between observed and expected RRR was plotted against the change in HDL-C level, and a least-squares regression line was calculated.

Results

Fifty-one trials were identified. Nineteen statin trials addressed the association of HDL-C with CHD. Limited numbers of trials of other therapies precluded additional analyses. Among statin trials, therapy reduced total cholesterol levels as much as 32% and LDL-C levels as much as 45%. HDL-C level increases were <10%. Treatment effect on HDL-C levels was not a significant linear predictor of the difference in observed and expected CHD mortality rates, although we observed a trend in this direction (P = .08). Similarly, HDL-C effect was not a significant linear predictor of the difference between observed and expected RRRs for CHD morbidity (P = .20).

Conclusions

Although a linear trend toward greater risk reduction was observed with greater effects on HDL-C, differences were not statistically significant. The narrow range of HDL-C level increases in the statin trials likely reduced our ability to detect a beneficial HDL-C effect, if present.     

Mortality reductions in patients receiving exercise-based cardiac rehabilitation: how much can be attributed to cardiovascular risk factor improvements?

BACKGROUND: It is unclear how much of the reduction in cardiac mortality in coronary heart disease (CHD) patients with exercise training is the result of direct effects on the heart and coronary vasculature, or to indirect effects, via primary risk factors. OBJECTIVE: The aim of this article was to quantify the cardiac mortality benefits of exercise-based rehabilitation attributable to risk factor reductions versus the direct effects on the heart and vasculature. METHODS: The IMPACT coronary heart disease model was used to examine the reduction in cardiac mortality attributable to changes in risk factors from a meta-analysis of cardiac rehabilitation randomized, controlled trials. Patients were receiving rehabilitation following an acute myocardial infarction, angina pectoris or revascularization. Outcomes considered were primary risk factors (total cholesterol, systolic blood pressure and smoking behaviour) and cardiac mortality. RESULTS: Nineteen exercise-only cardiac rehabilitation trials (including 2984 patients) were identified. Across these trials, exercise training reduced pooled cardiac mortality by 28% (relative risk, 0.72, 95% confidence interval 0.55-0.95), with 30 fewer deaths than in the control group. Applying the CHD model, approximately 17 (58%) of these 30 fewer deaths were attributable to reductions in major cardiovascular risk factors: 7.1 deaths (minimum estimate 6.2, maximum estimate 9.5) attributable to an 18% reduction in smoking prevalence; 5.9 deaths (minimum -0.6, maximum 12.6) to a 0.11 mmol/l reduction in cholesterol, and 4.4 deaths (-1.0 minimum, 6.7 maximum) to a 2.0 mmHg reduction in systolic blood pressure. CONCLUSIONS: Approximately half of the 28% reduction in cardiac mortality achieved with exercise-based cardiac rehabilitation may be attributed to reductions in major risk factors, particularly smoking.     

An analysis of randomized trials evaluating the effect of cholesterol reduction on total mortality and coronary heart disease incidence

The primary aim of this study was to estimate the relation between cholesterol reduction and total mortality and coronary heart disease (CHD) incidence. Secondarily, the clinical issues of whether the efficacy of cholesterol lowering is dependent on the treatment modality, presence of CHD at baseline, or the simultaneous introduction of other interventions was explored. All randomized clinical intervention trials of cholesterol reduction were used in an overview analysis of total mortality rate and CHD incidence; analysis was performed with weighted linear regression. The trials include those that used primary and secondary intervention, diet and drugs, and single or multifactor design. Nineteen trials were analyzed for total mortality, and of the 19, 16 were analyzed for CHD incidence rate. Net difference in cholesterol change between study groups was used as the independent variable, and the three previously mentioned dichotomous design characteristics were used as additional independent variables. For every 1% reduction in cholesterol, an estimated 2.5% reduction in CHD incidence is indicated (95% CL: 1.1, 3.9). With regard to CHD drug trials tended toward better efficiency in cholesterol lowering than did dietary trials. With regard to total mortality, this efficiency was higher in secondary than in primary preventive trials. The efficiency was also somewhat dependent on the baseline cholesterol level. This study shows that cholesterol reduction is effective in lowering CHD incidence, but cholesterol reduction must be at least 8-9% to be effective in lowering total mortality.     

Contribution of modern cardiovascular treatment and risk factor changes to the decline in coronary heart disease mortality in Scotland between 1975 and 1994

OBJECTIVE: To estimate the fall in coronary heart disease (CHD) mortality in Scotland attributable to medical and surgical treatments, and risk factor changes, between 1975 and 1994. DESIGN: A cohort model combining effectiveness data from meta-analyses with information on treatment uptake in all patient categories in Scotland. SETTING AND PATIENTS: The whole Scottish population of 5.1 million, including all patients with recognised CHD. INTERVENTIONS: All cardiological, medical, and surgical treatments, and all risk factor changes between 1975 and 1994. Data were obtained from epidemiological surveys, routine National Health Service sources, and local audits. MAIN OUTCOME MEASURES: Deaths from CHD in 1975 and 1994. RESULTS: There were 15 234 deaths from CHD in 1994, 6205 fewer deaths than expected if there had been no decline from 1975 mortality rates. In 1994, the total number of deaths prevented or postponed by all treatments and risk factor reductions was estimated at 6747 (minimum 4790, maximum 10 695). Forty per cent of this benefit was attributed to treatments (initial treatments for acute myocardial infarction 10%, treatments for hypertension 9%, for secondary prevention 8%, for heart failure 8%, aspirin for angina 2%, coronary artery bypass grafting surgery 2%, and angioplasty 0.1%). Fifty one per cent of the reduction in deaths was attributed to measurable risk factor reductions (smoking 36%, cholesterol 6%, secular fall in blood pressure 6%, and changes in deprivation 3%). Other, unquantified factors apparently accounted for the remaining 9%. These proportions remained relatively consistent across a wide range of assumptions and estimates in a sensitivity analysis. CONCLUSIONS: Medical treatments and risk factor changes apparently prevented or postponed about 6750 coronary deaths in Scotland in 1994. Modest gains from individual treatments produced a large cumulative survival benefit. Reductions in major risk factors explained about half the fall in coronary mortality, emphasising the importance and future potential of prevention strategies.     

Pleiotropic effects of statins: benefit beyond cholesterol reduction? A meta-regression analysis.

OBJECTIVES: This study sought to determine whether statins reduce coronary heart disease (CHD) risk more than other interventions that also primarily lower low-density lipoprotein cholesterol (LDL-C). BACKGROUND: Statins have anti-inflammatory, immunomodulatory, antithrombotic, vascular, and other non-LDL-C-lowering effects. It is unclear whether these pleiotropic effects contribute to cardiovascular risk reduction beyond that expected from LDL-C reduction alone. METHODS: Trials published in English language journals were retrieved by searching Medline (1966 to October 2004), bibliographies, and the author's reference files. Randomized, placebo-controlled trials of interventions to primarily lower LDL-C of three or more years' duration in which clinical disease or death were primary outcomes were used. Information on sample size, treatment type and duration, participant characteristics at baseline, reduction in lipids, and outcome was independently abstracted by two authors (J.R. and N.M.) using a standardized protocol. Data from 5 diet, 3 bile acid sequestrant, 1 surgery, and 10 statin trials, with 81,859 participants, were included in the CHD meta-regression analysis. RESULTS: The regression lines for non-statin and statin trials were similar and consistent with a one-to-one relationship between LDL-C lowering and CHD and stroke reduction over five years of treatment. CONCLUSIONS: The pleiotropic effects of statins do not seem to contribute an additional cardiovascular risk reduction benefit beyond that expected from the degree of LDL-C lowering observed in other trials that primarily lowered LDL-C.     

Sex and time differences in the associations of non-high-density lipoprotein cholesterol versus other lipid and lipoprotein factors in the prediction of cardiovascular death (The Rancho Bernardo Study)

Non-high-density lipoprotein (HDL) cholesterol (total cholesterol [TC] minus HDL cholesterol) has been suggested as the preferred lipid fraction to predict cardiovascular disease. We compared the ability of lipids, lipoproteins, the ratio of total to HDL cholesterol (TC/HDL), and non-HDL cholesterol to predict fatal coronary heart disease (CHD) and cardiovascular disease in 1,386 women and 1,094 men (mean age 69 years). After 10 years, there were more deaths in men (n = 310) than women (n = 268), but the proportions of deaths attributed to CHD (23% and 25%, respectively) and cardiovascular disease (48% and 47%) were similar. In men, age-adjusted values for non-HDL cholesterol, TC/HDL ratio, and triglycerides each predicted a significantly increased risk of CHD and cardiovascular disease; none of these associations was independent of pack-years of smoking, systolic blood pressure, fasting plasma glucose, body mass index, and physical activity. In women, age-adjusted non-HDL cholesterol levels did not predict CHD or cardiovascular disease events before or after adjusting for these covariates and for estrogen replacement therapy. In women, only the ratio of TC to HDL cholesterol predicted CHD and cardiovascular disease deaths independent of estrogen use and other risk factors. Observed associations were sensitive to time, being evident in women at 3 and 5 years, and lost thereafter, but not apparent before 10 years in men. Thus, non-HDL cholesterol is not superior to individual lipids, lipoproteins, or their ratios in the prediction of cardiovascular death in older adults.     

Projected coronary heart disease risk benefit with ezetimibe

Low density lipoprotein (LDL) cholesterol and total cholesterol (TC) are the primary clinical parameters of interest for any cholesterol intervention. Clinicians are interested in how the reduction of these lipid parameters as well as increases in high density lipoprotein (HDL) relate to changes in coronary heart disease (CHD) risk. The objective of this analysis was to estimate the additional CHD risk reduction that could potentially be provided by co-administration of ezetimibe with statin therapy. Data from four double-blind placebo controlled clinical trials were used to predict the level of CHD risk reduction that might be achieved by co-administration of ezetimibe with statin therapy when compared to those receiving statin as monotherapy. Patients without a previous history of CHD were included in the analysis. Projected CHD risk reduction was calculated as percent change in projected CHD risk from baseline to 12 weeks based on observed lipid levels at those time points. For all the studies combined greater reductions in percent change in 5-year CHD risk were observed for patients receiving ezetimibe and statin as co-therapy, 53.4%, when compared to those receiving statin alone, 39.7%. Co-administration of ezetimibe with statin therapy provides an additional 13.7% reduction in predicted 5-year CHD risk when compared to statin monotherapy. Reductions in 5-year CHD risk for each of the statin studies ranged from 16.1% for lovastatin to 9.8% for atorvastatin. Co-administration of ezetimibe with statins could significantly reduce CHD events in patients with primary hypercholesterolemia.     

低心血管病危险人群死亡的相对危险及期望寿命

目的：探讨低心血病危险与冠心病、脑卒中、恶性肿瘤死亡及总死亡的关系,以及对平均期望寿命的影响。方法：1982－1985年在我国不同地区的10组人群（年龄35－59岁）共3万余人中进行心血管病危险因素调查,并随访至2000年底,登记并核实其全部残因情况。结果：24900人中（男性12497人,女性12403人）,7．7％的男性,28．9％的女性基线心血管病危险因素处于低危险水平,在其后平均15．2年的随访过程中,总死亡、冠心病死亡（女性）、脑卒中死亡明显低于其他人群,男性和女性平均期望寿命分别延长2．6年和4．0年。结论：低心血管危险人群,不仅心血管病死亡减少,且总病死率降低,平均期望寿命延长。     

Does lowering serum cholesterol levels lower coronary heart disease risk?

Many lines of evidence converge toward the conclusion that low-density lipoprotein cholesterol (LDLC) is indeed a causal factor in the genesis of CHD. These range from animal studies, pathology studies, inborn errors of metabolism, clinical observations, and the existence of plausible biologic mechanisms, to the vast body of epidemiologic evidence. Observations of the association of LDLC with CHD hold between different populations, in the same population at different times, and to studies of individuals within populations. Finally, the clinical trials of cholesterol lowering, together with regression studies in animals and angiographic studies in humans, provide compelling evidence that the progress of atherosclerosis can be halted and the clinical sequelae can be reduced. The newly available results from more recent intervention studies have reinforced the validity of this conclusion. The intervention studies reduced the CHD incidence rate by approximately 2% for every 1% reduction in total cholesterol (TC) even though the studies were of relatively short duration (typically 5 years). More prolonged exposure to lower TC levels can be expected to yield even greater ultimate benefit. The benefit is most clearcut for men at highest risk. The combined data indicate that both fatal and nonfatal CHD can be reduced. More data on the extremes of age, on subjects with moderate elevations of TC, and on women would be valuable, but it is reasonable to proceed with advice to the general population aimed at reducing average cholesterol levels, and also to identify and treat those at high risk. There is good reason to expect that these measures will further reduce MI events and in all likelihood also MI deaths. Whether they will also reduce overall mortality is at present a moot point; however, a reduction in the burden of nonfatal MI would in itself be a very desirable objective.     

Is there a role for the glycemic index in coronary heart disease prevention or treatment?

The clinical application of the glycemic index (GI) to the prevention and treatment of chronic diseases is controversial. No evidence exists for the implementation of low-GI diets for a reduction in coronary heart disease (CHD) mortality, events, or morbidity. Observational studies report conflicting evidence on the role of low-GI diets in CHD and risk factors for CHD. Randomized clinical trials report a small reduction in total cholesterol (-6.6 mg/dL) from low-GI diets compared with high-GI diets, but no reduction in other risk factors, such as low-density lipoprotein or high-density lipoprotein cholesterol, triglycerides, fasting glucose, insulin, or body weight. Currently, the research suggests a minimal role for the implementation of low-GI diets in the prevention or treatment of CHD.     

Serum cholesterol, blood pressure, cigarette smoking, and death from coronary heart disease. Overall findings and differences by age for 316,099 white men. Multiple Risk Factor Intervention Trial Research Group.

To assess the combined influence of blood pressure (BP), serum cholesterol level, and cigarette smoking on death from coronary heart disease (CHD) and to describe how these associations vary with age, data on those factors and on mortality for 316,099 men screened for the Multiple Risk Factor Intervention Trial (MRFIT) were examined. Vital status of participants has been determined after an average follow-up of 12 years; 6327 deaths from CHD have been identified. Strong graded relationships between serum cholesterol levels above 4.65 mmol/L (180 mg/dL), systolic BP above 110 mm Hg, and diastolic BP above 70 mm Hg and mortality due to CHD were evident. Smokers with serum cholesterol and systolic BP levels in the highest quintiles had CHD death rates that were approximately 20 times greater than nonsmoking men with systolic BP and cholesterol levels in the lowest quintile. Systolic and diastolic BP, serum cholesterol level, and cigarettes per day were significant predictors of death due to CHD in all age groups. Systolic BP was a stronger predictor than diastolic BP. These results, together with the findings of clinical trials, offer strong support for intensified preventive efforts in all age groups.     

The lipid hypothesis in the etiopathogenesis of ischemic heart disease: confirmations and doubts resulting from primary prevention trials

Sufficient evidence exists today pointing to the relationship between high levels of plasma cholesterol and coronary atherosclerosis. Up to now, however, the last criterion for validating the aetiopathogenetic relationship between dyslipidemia and CHD, i.e., the demonstration that reduction of plasma cholesterol reduced the formation or progression of the plaque and the incidence of its fatal or non-fatal cardiac and vascular complications, has been lacking. For more than two decades, numerous trials have had this aim in mind but until very recently results have not been substantiated owing to various deficiencies in the method. Before publication of the NHLBI Task Force of Atherosclerosis, eleven major randomised clinical studies based on hypolipidemia interventions were completed. The three studies involving dietetic interventions were considered non-conclusive overall because of the lack of a double-blind factor and of other important epidemiological criteria. Of three pharmacological trials only two involved studies of primary prevention carried out on a population of hypercholesterolaemics. These produced partial results on certain cardiac end-points but not on total deaths and at times not even on deaths from CHD. Multifactorial studies, finally, were even less demonstrative. Taken together, however, the trials based on hypolipidemia interventions point to interesting though not definitive evidence of a reduction in blood cholesterol levels to reduce the incidence and mortality from CHD. According to the NHLBI, many of these studies lacked important features that were codified and suggested for later studies.(ABSTRACT TRUNCATED AT 250 WORDS)     

中国冠心病二级预防研究

目的判定在与西方人群相比血清胆固醇水平相对较低的中国冠心病患中,通过血脂康调整血脂能否降低各种冠心病相关事件的危险性,并判定对各种原因死亡的影响。方法本研究为多中心、随机、双盲、安慰剂对照的长期随访临床试验,研究时间从1996年5月至2003年12月,在中国19个省市自治区的65家临床协作医疗中心,对4870例血清总胆固醇水平在4．40～6．47mmol／L(170～250mg/d1)之间、年龄在18～75岁,有明确心肌梗死史的中国冠心病患进行了平均4年的随访观察,以比较血脂康胶囊0．6g,2次／d与安慰剂的作用。主要终点为冠心病事件,包括非致死性心肌梗死及冠心病死亡,次要目标为能否减少非心血管病事件如肿瘤、脑卒中、自杀、经皮冠状动脉介入术(PCI)和(或)冠状动脉旁路移植术(CABG)需求以及总死亡。结果主要终点在血脂康治疗组的发生率为5．72％,安慰剂对照组为10．41％,治疗组相对危险降低45．1％(P=0．0000),其中冠心病死亡治疗组为3．19％,对照组为5．49％,治疗组相对危险降低31．0％(P=0．0048),非致死性心肌梗死治疗组为1．93％,对照组为4．92％,治疗组相对危险降低60．8％(P=0．0000)。次要终点(脑卒中、肿瘤、PCL／CABG的需求)的发生率治疗组为69．2例次／1000人,对照组为100．4例次／1000人,治疗组相对危险降低31．1％(P=0．0004),其中PCI和(或)CABG的需求,治疗组为30．1例次／1000人,对照组为45．1例次／1000人,治疗组相对危险降低33．3％(P=0．0097)。各种原因的死亡在治疗组为5．19％,对照组为7．74％,治疗组相对危险降低33．0％(P=0．0003),其中肿瘤死亡在治疗组降低54．7％(P=0．0138)。在临床不良反应和实验室指标异常方面,治疗组和对照组之间差异无统计学意义。结论与安慰剂比较,血脂康胶囊治疗能显降低冠心病患非致死性心肌梗死及冠心病死亡的发生率。能显减少对PCI和(或)CABG的需求,能显减少肿瘤死亡和各种原因的总死亡。表明中国冠心病患服用血脂康胶囊调整血脂可获得明显益处。     

Blood pressure and coronary heart disease: a review of the evidence

Overviews of randomized controlled trials and prospective observational studies provide the most reliable data on the association between blood pressure and coronary heart disease (CHD). The totality of evidence indicates a strong association between blood pressure and CHD, which is continuous down to levels of at least 115 mm Hg systolic. Overall, for those 60 to 69 years of age, a 10 mm Hg lower systolic blood pressure is associated with about one-fifth lower risk of a CHD event. The size and shape of this association is consistent across regions, for males and females, and for fatal events as well as nonfatal myocardial infarction. Trials comparing active treatment to placebo or no treatment have demonstrated that the benefits of blood pressure lowering with different classes of drugs (e.g., diuretics, beta-blockers, ACE inhibitors, calcium antagonists) are broadly similar, with approximately one-fifth reduction in CHD. ACE inhibitors achieve this with relatively modest blood pressure reductions, but the size of the reduction for calcium antagonists remains uncertain and appears somewhat less than expected from the blood pressure reduction. Trials confirm the expectation from cohort studies of benefits increasing with the amount of blood pressure lowering, and benefit accruing among those with average or even below average blood pressure. Observational data suggest that the proportional association is attenuated with age, but attenuation is less evident in trial data. However, in both cohort studies and clinical trials, CHD risk differences associated with a given blood pressure difference increase with age. The important points to emerge from this review are, first, that the relative benefits of blood pressure lowering for CHD prevention are likely to be consistent across a range of different populations. Second, there is likely to be considerable benefit with blood pressure lowering below "traditional" hypertension thresholds, especially in those with high absolute risk. Third, initiating and maintaining the maximum tolerated blood pressure reduction is a more important issue than choice of initial agent. Finally, and most importantly, the large majority of people have suboptimal blood pressure (e.g., systolic > 115 mm Hg) and so initiatives to lower blood pressure population-wide are an essential adjunct to targeted treatment programs.     

The relationship of age, blood pressure, serum cholesterol and smoking habits with the risk of typical and atypical coronary heart disease death in the European cohorts of the Seven Countries Study

OBJECTIVE: To explore whether "typical" coronary heart disease (CHD) such as fatal myocardial infarction and sudden death relate to major cardiovascular risk factors in the same way as the "atypical" CHD, such as fatal heart failure and chronic arrhythmias. DESIGN AND SETTING: Ten cohorts (6633 cardiovascular disease-free men, aged 40-59) in five European countries were examined, age and three major risk factors were measured (systolic blood pressure, serum cholesterol, and smoking habits) and 35-year mortality data were collected. Proportional hazard models were solved with typical and atypical CHD deaths treated separately. RESULTS: Death rates from typical and atypical CHD were inversely related among the five countries. Mean age at death was significantly higher for atypical than typical (75.8 versus 71.6 years; p < 0.001). In the multivariate analysis conducted on pools of 5 countries (adjusted for countries), the relationship of risk factors with typical CHD was direct and significant for age (hazard ratio-HR-for 5 years of age 1.44 (95% CI 1.36-1.52)), systolic blood pressure (HR for 20 mm Hg, 1.39 (95% CI 1.32-1.47)), serum cholesterol (HR for 1 mmol/l of 1.22 (95% CI 1.16-1.27)) and smoking habits (HR smokers versus non-smokers of 1.39 (95% CI 1.24-1.57)). For atypical CHD, age had a larger HR of 2.27 (95% CI 2.05-2.52), systolic blood pressure had a smaller HR of 1.28 (95% CI 1.16-1.41), serum cholesterol had an inverse non-significant HR of 0.90 (0.58-1.58) and smoking habits had a larger HR of 1.54 (95% CI 1.26-1.89). CONCLUSIONS: Age and serum cholesterol were differently related with typical and atypical CHD deaths, suggesting different etiologies for these coronary diseases.     

Review of lipid-lowering clinical trials in relation to observational epidemiologic studies

A review of the experimental clinical trials and observational cohort evidence relating serum cholesterol level and its reduction to risks of coronary heart disease (CHD) discloses strong similarities among the quantitative and qualitative relationships found in these studies. Not only are the risk functions similar, but the percent reduction observed is the same as that predicted from the population experience and is proportional to the degree of cholesterol lowering. Furthermore, the risk function is continuous from the highest to the lowest serum cholesterol levels studied. These findings confirm the lipid hypothesis and indicate that lowering serum cholesterol reduces CHD risk. The understanding and control of CHD requires a dual approach: (1) identification and treatment of high-risk individuals, and (2) modification of environmental and behavioral determinants to achieve more favorable distributions of serum cholesterol in populations.     

Treatment and prevention of coronary heart disease by lowering serum cholesterol levels; from the pioneer work of C.D. de Langen to the third "Dutch Consensus on Cholesterol".

In the beginning of this century a possible relation was observed between cholesterol-rich foods, blood cholesterol levels and atherosclerosis by "pioneers" in this field as Anitschkow and De Langen. In the second half of this century a definite link was established between serum cholesterol levels and development of coronary heart disease (CHD). In angiographic studies it has recently been shown that a decrease in total cholesterol as well as in low-density lipoprotein cholesterol level results in a retardation of the progression of vascular disease. Furthermore, clinical event intervention trials demonstrated that therapy with cholesterol synthesis inhibitors reduces not only cardiovascular and total mortality, but also other manifestations of CHD. These recent results prompted to revise, for the second time, the Dutch consensus text for lipid lowering therapy, with the following conclusions. Hypercholesterolaemia is treated with a low-saturated fat diet and normalisation of weight. For individuals, this might result in a reduction of the risk for myocardial infarction or death and for the population in a decrease of the mean serum cholesterol concentration and a reduction of the incidence of CHD. The indication for drug therapy is founded on the expected effectiveness to reduce the incidence of (new manifestations of) CHD, which is related to the level of the absolute risk of vascular disease. Treatment with cholesterol synthesis inhibitors must be considered in (a) patients with familial hypercholesterolaemia; (b) all patients with a history of myocardial infarction or other symptomatic vascular disease with a total cholesterol concentration above 5.0 mmol/l and a life expectancy of at least five years; (c) persons without known vascular disease with a combination of diabetes mellitus, hypertension, hypercholesterolaemia, cigarette smoking and high risk for development of CHD, rising from 25% per 10 years at the age of 40 years to 35-40% per 10 years at the age of 70 years, with a life expectancy of at least five years. If these guidelines are followed, the calculated cost-effectiveness is about Dfl. 40,000 per life year gained or less. The consensus committee judges this reasonable in comparison with other therapeutic interventions in the Netherlands. Thus by now, with regard to lipids and atherosclerosis, the definite link has been established between observational medicine and an effective treatment modality which is applicable in daily practise.