Are low cholesterol values associated with excess mortality?

The relation between cholesterol concentration and mortality was studied prospectively over 17 years in 630 New Zealand Maoris aged 25-74. The dead or alive state of each person was determined in 1981. The causes of death were divided into three categories: cancer, cardiovascular disease, and "other." Using univariate and both linear and non-linear multivariate methods of analysis for survivorship data, significant inverse relations with serum cholesterol were found for total mortality in women, for mortality from cancer in men and women, and for other causes of mortality in both men and women. The inverse and non-linear association with total mortality in women remained significant when deaths in the first five years of follow up were excluded. This suggests that the association was not explained by undetected illness causing low cholesterol concentrations at the time of initial examination.     

Non-fasting serum triglyceride concentration and mortality from coronary heart disease and any cause in middle aged Norwegian women.

OBJECTIVE--To study the association between non-fasting serum triglyceride concentrations and mortality in women from coronary and cardiovascular disease and all causes. DESIGN--Follow up by ambulatory teams of men and women who underwent cardiovascular screening for a mean of 14.6 years. SETTING--National health screening service in Norway. SUBJECTS--25,058 men and 24,535 women aged 35-49 years. MAIN OUTCOME MEASURE--Predictive value of non-fasting serum triglyceride concentrations. RESULTS--At initial screening total serum cholesterol concentration, serum triglyceride concentration, blood pressure, height, and weight were measured, and self reported information about smoking habits, physical activity, and time since last meal were recorded. During subsequent follow up 108 women died from coronary heart disease, 238 from cardiovascular diseases, and 931 from all causes. In women mortality increased steadily with increasing triglyceride concentration for all three causes of death. With the proportional hazards model and adjustment for age, systolic blood pressure, total cholesterol concentration, time since last meal, and number of cigarettes a day the relative risk between triglyceride concentration > or = 3.5 mmol/l and < 1.5 mmol/l was 4.7 (95% confidence interval 2.5 to 8.9) for deaths from coronary heart disease, 3.0 (1.9 to 4.8) for deaths from cardiovascular disease, 2.3 (1.8 to 2.9) for total deaths in all women. CONCLUSIONS--A raised non-fasting concentration of triglycerides is an independent risk factor for mortality from coronary heart disease, cardiovascular disease, and any cause mortality among middle aged Norwegian women in contrast to what is seen in men.     

Lowering cholesterol concentrations and mortality: a quantitative review of primary prevention trials.

OBJECTIVE--To determine the effects of lowering cholesterol concentrations on total and cause specific mortality in randomised primary prevention trials. DESIGN--Qualitative (meta-analytic) evaluation of total mortality from coronary heart disease, cancer, and causes not related to illness in six primary prevention trials of cholesterol reduction (mean duration of treatment 4.8 years). PATIENTS--24,847 Male participants; mean age 47.5 years. MAIN OUTCOME MEASURES--Total and cause specific mortalities. RESULTS--Follow up periods totalled 119,000 person years, during which 1147 deaths occurred. Mortality from coronary heart disease tended to be lower in men receiving interventions to reduce cholesterol concentrations compared with mortality in control subjects (p = 0.06), although total mortality was not affected by treatment. No consistent relation was found between reduction of cholesterol concentrations and mortality from cancer, but there was a significant increase in deaths not related to illness (deaths from accidents, suicide, or violence) in groups receiving treatment to lower cholesterol concentrations relative to controls (p = 0.004). When drug trials were analysed separately the treatment was found to reduce mortality from coronary heart disease significantly (p = 0.04). CONCLUSIONS--The association between reduction of cholesterol concentrations and deaths not related to illness warrants further investigation. Additionally, the failure of cholesterol lowering to affect overall survival justifies a more cautious appraisal of the probable benefits of reducing cholesterol concentrations in the general population.     

Assessing possible hazards of reducing serum cholesterol.

OBJECTIVE--To assess whether low serum cholesterol concentration increases mortality from any cause. DESIGN--Systematic review of published data on mortality from causes other than ischaemic heart disease derived from the 10 largest cohort studies, two international studies, and 28 randomised trials, supplemented by unpublished data on causes of death obtained when necessary. MAIN OUTCOME MEASURES--Excess cause specific mortality associated with low or lowered serum cholesterol concentration. RESULTS--The only cause of death attributable to low serum cholesterol concentration was haemorrhagic stroke. The excess risk was associated only with concentrations below about 5 mmol/l (relative risk 1.9, 95% confidence interval 1.4 to 2.5), affecting about 6% of people in Western populations. For noncirculatory causes of death there was a pronounced difference between cohort studies of employed men, likely to be healthy at recruitment, and cohort studies of subjects in community settings, necessarily including some with existing disease. The employed cohorts showed no excess mortality. The community cohorts showed associations between low cholesterol concentration and lung cancer, haemopoietic cancers, suicide, chronic bronchitis, and chronic liver and bowel disease; these were most satisfactorily explained by early disease or by factors that cause the disease lowering serum cholesterol concentration (depression causes suicide and lowers cholesterol concentration, for example). In the randomised trials nine deaths (from a total of 687 deaths not due to ischaemic heart disease in treated subjects) were attributed to known adverse effects of the specific treatments, but otherwise there was no evidence of an increased mortality from any cause arising from reduction in cholesterol concentration. CONCLUSIONS--There is no evidence that low or reduced serum cholesterol concentration increases mortality from any cause other than haemorrhagic stroke. This risk affects only those people with a very low concentration and even in these will be outweighed by the benefits from the low risk of ischaemic heart disease.     

Does plasma cholesterol concentration predict mortality from coronary heart disease in elderly people? 18 year follow up in Whitehall study.

OBJECTIVE--To explore the extent to which the relation between plasma cholesterol concentration and risk of death from coronary heart disease in men persists into old age. DESIGN--18 year follow up of male Whitehall civil servants. Plasma cholesterol concentrations and other risk factors were determined at first examination in 1967-9 when they were aged 40-69. Death of men up to 31 January 1987 was recorded. SUBJECTS--18,296 male civil servants, 4155 of whom died during follow up. MAIN OUTCOME MEASURES--Cause and age of death. Cholesterol concentration in 1967-9 and number of years elapsed between testing and death. RESULTS--1676 men died of coronary heart disease. The mean cholesterol concentration in these men was 0.32 mmol/l higher than that in all other men (95% confidence interval 0.26 to 0.37 mmol/l). This difference in cholesterol concentrations fell 0.15 mmol/l with every 10 years'' increase in age at screening. The risk of raised cholesterol concentration fell with age at death. Compared with other men cholesterol concentration in those who died of coronary heart disease was 0.44 mmol/l higher in those who died aged less than 60 and 0.26 mmol/l higher in those aged 60-79 (p = 0.03). For a given age at death the longer the gap between cholesterol measurement and death the more predictive the cholesterol concentration, both for coronary heart disease and all cause mortality (trend test p = 0.06 and 0.03 respectively). CONCLUSION--Reducing plasma cholesterol concentrations in middle age may influence the risk of death from coronary heart disease in old age.     

Plasma cholesterol concentration and death from coronary heart disease: 10 year results of the Whitehall study.

Ten year mortality from coronary heart disease in 17,718 middle aged men was related to their initial plasma cholesterol concentrations. The relative risk of death from coronary heart disease declined with age, but the absolute excess risk did not. The risk gradient was continuous over the whole range of cholesterol concentrations, the lowest mortality being among men with concentrations below the lowest decile. It seems that, as with blood pressure, the average cholesterol concentration in the blood pressure, the average cholesterol concentration in the population is too high: lowest concentrations are prognostically the best. A quarter of all deaths from coronary heart disease related to cholesterol occurred among men with concentrations above the top decile, but 55% occurred among men with concentrations in the middle three fifths of the distribution; this figure of 55% could be reduced only by a policy aimed at lowering concentrations in the whole population.     

Relation of low diastolic blood pressure to coronary heart disease death in presence of myocardial infarction: the Framingham Study.

OBJECTIVE--To examine the hypothesis that a J curve relation between blood pressure and death from coronary heart disease is confined to high risk subjects with myocardial infarction. DESIGN--Cohort longitudinal epidemiological study with biennial examinations since 1950. SETTING--Framingham, Massachusetts, USA. SUBJECTS--5209 subjects in the Framingham study cohort followed up by a person examination approach. MAIN OUTCOME MEASURES--Coronary heart disease deaths and non-cardiovascular disease deaths in men and women with or without myocardial infarction relative to blood pressure. RESULTS--Among subjects without myocardial infarction non-cardiovascular disease deaths were twice to three times as common as coronary heart disease deaths. Furthermore, there was no significant relation between non-cardiovascular disease death and diastolic or systolic blood pressure. Also coronary heart disease deaths were linearly related to diastolic and systolic blood pressures. Among high risk patients (that is, people with myocardial infarction but free of congestive heart failure) death from coronary heart disease was more common than non-cardiovascular disease death. There was a significant U shaped relation between coronary heart disease death and diastolic blood pressure. Although there was an apparent U shaped relation between coronary heart disease death and systolic blood pressure, it did not attain statistical significance when controlling for age and change in systolic blood pressure from the pre-myocardial infarction level. None of the above conclusions changed when adjustments were made for risk factors such as serum cholesterol concentration, antihypertensive treatment, and left ventricular function. The U shaped relation between diastolic blood pressure and high risk subjects existed for both those given antihypertensive treatment and those not. CONCLUSIONS--These data suggest that an age and sex independent U curve relation exists for diastolic blood pressure and coronary heart disease deaths in patients with myocardial infarction but not for low risk subjects without myocardial infarction. The relation seems to be independent of left ventricular function and antihypertensive treatment.     

Cholesterol and mortality in New Zealand Maoris.

The relation between serum cholesterol concentration and mortality was studied prospectively over 11 years in 630 New Zealand Maoris aged 25-74. Serum cholesterol concentration was measured at initial examination in 1962-3 in 94% of the subjects and whether each was dead or alive was determined in 1974. The causes of death were divided into three categories: cancer, cardiovascular disease, and "other." The Mantel-Haenszel method of analysis of survivorship data showed a significant inverse relation between serum cholesterol concentration and overall mortality in men (x 2/2 = 11.6; p = 0.003) and women (x 2/2 = 7.6; p = 0.02) with odds ratios of 2.3 and 1.9 respectively. Similar significant inverse relations were found for cancer and "other" causes of death. These relations remained significant when baseline age, systolic blood pressure, and the Quetelt index were controlled in Cox''s proportional hazards regression model. The results of this study provide evidence for a potentially deleterious effect of low serum cholesterol concentration. Hence, further research is needed before indiscriminate efforts are made to lower serum cholesterol concentrations in New Zealand Maoris.     

Raised serum urate concentration as risk factor for premature mortality in middle aged men: relation to death from cancer.

Low serum cholesterol concentrations are associated with deaths from cancer. This association was found in a prospective study of middle aged men in Malmö and consideration of possible explanations for the lowering of serum cholesterol prompted an analysis of serum urate in relation to deaths from cancer. A total of 127 of the 7725 participants in the Malmö study had died since screening. A weakly positive but significant correlation between raised serum urate concentration and total mortality was found. This correlation was wholly explained by neoplastic deaths (p less than 0.01), while there were no associations with alcohol related deaths or with deaths from coronary heart disease. When the deaths from cancer were classified as "early" or "late"--that is, occurring less than or more than 2.5 years after the screening--the correlation between raised urate concentrations and cancer mortality was confined to the "early" deaths (p less than 0.001). Further studies are needed to substantiate the relation between raised serum urate concentrations and fatal neoplasia. Nevertheless, these findings weigh against recent suggestions that uric acid has an antioxidant protective effect against cancer.     

Total and high density lipoprotein cholesterol in the serum and risk of mortality: evidence of a threshold effect.

The association of serum total and high density lipoprotein cholesterol values with 15 year mortality was examined in a cohort of 10 059 Israeli male civil servants and municipal employees aged 40 and above. In 618 of 1664 deaths in the cohort (37%) coronary heart disease was documented as the cause of death. Risk of mortality was analysed by quintiles. Neither total mortality nor coronary heart disease mortality rose with serum cholesterol concentrations up to 5.6 mmol/1 (216 mg/100 ml), representing 60% of the sample. Rates rose appreciably only in the highest quintile (cholesterol concentration greater than 6.2 mmol/1; greater than 241 mg/100 ml). High density lipoprotein cholesterol was similarly, although inversely, associated with total mortality when expressed as a percentage of total cholesterol. The inverse association of high density lipoprotein cholesterol with coronary heart disease mortality was, in contrast, continuous. These data support the hypothesis that over most of the range of cholesterol values coronary mortality risk and total mortality risk are nearly independent of total cholesterol and most probably independent of low density lipoprotein cholesterol values. In multivariate analysis a low concentration of high density lipoprotein cholesterol appeared to be more predictive of mortality than a high concentration of total cholesterol. The latter was very weakly related to mortality from all causes after multivariate adjustment. It is concluded that the findings of this and other major epidemiological studies support the notion of a "threshold effect." Success in reducing mortality through the pharmacological reduction of serum cholesterol in hypercholesterolaemic patients does not warrant a similar approach in people with average or slightly above average values. These findings appear to provide support for a "high risk strategy" in reducing the risk of coronary heart disease.     

Coronary heart disease and mortality in middle aged men from different occupational classes in Sweden.

In the Gothenburg primary prevention study 7083 middle aged men were classified into five categories by occupational state. A retrospective analysis of the data showed that low occupational class was associated with slight increases in smoking rates, systolic blood pressure, serum cholesterol concentration, body mass index, and heart rate. Alcohol abuse was strongly associated with low occupational class. After a mean of 11.8 years'' follow up the incidence of coronary heart disease was found to be strongly and inversely related to occupational class. For death from coronary heart disease this association fell just below significance when other risk factors were taken into account, but the inverse association between non-fatal myocardial infarction and occupational class persisted even in multivariate analysis. A weak but independent inverse relation was found between occupational class and fatal cancer. Mortality from all causes in the lowest occupational class was 12% compared with 6% in the highest class, and this difference could only partly be explained by other factors. After 10 years a sub-sample of the men were examined again. Risk factors had decreased in all occupational classes, but the changes in risk were not associated with occupational class. Social class, defined by occupation, in Sweden is clearly related to the incidence of coronary heart disease.     

Serum high density lipoprotein cholesterol,alcohol, and coronary mortality in male smokers.

OBJECTIVE--To determine whether the increase in mortality from coronary heart disease with high concentration (> 1.75 mmol/l) of high density lipoprotein cholesterol could be due to alcohol intake. DESIGN--Cohort study. SETTING--Placebo group of the alpha tocopherol, beta carotene cancer prevention (ATBC) study of south western population in Finland. PARTICIPANTS--7052 male smokers aged 50-69 years enrolled to the ATBC study in the 1980s. MAIN OUTCOME MEASURES--The relative and absolute rates adjusted for risk factors for clinically or pathologically verified deaths from coronary heart disease for different concentrations of high density lipoprotein cholesterol with and without stratification for alcohol intake. Similar rates were also calculated for different alcohol consumption groups. RESULTS--During the average follow up period of 6.7 years 258 men died from verified coronary heart disease. Coronary death rate steadily decreased with increasing concentration of high density lipoprotein cholesterol until a high concentration. An increase in the rate was observed above 1.75 mmol/l. This increase occurred among those who reported alcohol intake. Mortality was associated with alcohol intake in a J shaped dose response, and those who reported consuming more than five drinks a day (heavy drinkers) had the highest death rate. Mortality was higher in heavy drinkers than in non-drinkers or light or moderate drinkers in all high density lipoprotein categories from 0.91 mmol/l upward. CONCLUSIONS--Mortality from coronary heart disease increases at concentrations of high density lipoprotein cholesterol over 1.75 mmol/l. The mortality was highest among heavy drinkers, but an increase was found among light drinkers also.     

Impact of cardiovascular risk factors on coronary heart disease and mortality among middle aged diabetic men: a general population study.

OBJECTIVE--To investigate the effect of cardiovascular risk factors on coronary heart disease and all cause mortality in middle aged diabetic men. DESIGN--Prospective population study based on data collected from second screening (from 1974 to 1977) in the multifactor primary prevention trial and follow up until March 1983. SETTING--Gothenburg, Sweden. SUBJECTS--6897 Men aged 51 to 59, of whom 232 were self reported diabetics and 6665 were non-diabetic; none had a history of myocardial infarction. MAIN OUTCOME MEASURES--Incidences of coronary heart disease and mortality from all causes. RESULTS--Diabetic men with a serum cholesterol concentration greater than 7.3 mmol/l had a significantly higher incidence of coronary heart disease during follow up than those with a concentration less than or equal to 5.5 mmol/l (28.3% v 5.4%; p = 0.020); corresponding figures for non-diabetic men were 9.4% and 2.4% respectively. In multivariate logistic regression analyses serum cholesterol concentration and smoking habit were independent predictors of coronary heart disease (odds ratio serum cholesterol concentration 6.1 (95% confidence interval 2.1 to 17.6) current smoking 2.9 (1.1 to 7.5)) and of all cause mortality (3.2 (1.3 to 7.9), 3.0 (1.4 to 6.7) respectively) in diabetic men whereas systolic blood pressure, body mass index, family history, marital state, and alcohol abuse were not. Low occupational class was an independent predictor of mortality (2.4 (1.01 to 5.5)), but not of coronary heart disease, in diabetic men. CONCLUSIONS--Middle aged diabetic men with hypercholesterolaemia are at very high risk of developing coronary heart disease and of dying prematurely. Lowering serum cholesterol concentration in such subjects seems to be warranted.     

High serum insulin-like growth factor binding protein-1 is associated with increased cardiovascular mortality in elderly men.

Insulin-like growth factor binding protein-1 (IGFBP-1) has been implicated in the development of cardiovascular disease, but it is not known whether IGFBP-1 is related to cardiovascular mortality. We examined the relation of circulating IGFBP-1 to death from coronary heart disease, cardiovascular disease, and all causes in a cohort study consisting of 622 men aged 65 - 84 years, at baseline in 1984. Fasting serum IGFBP-1 and other risk factors were measured in 1984 and 1989. Cardiovascular events for those who died between 1984 and 1995 were analyzed, and cardiovascular diagnoses were coded centrally according to standardized procedures. Of the 622 men, 358 died between 1984 and 1995; 160 deaths were due to cardiovascular causes, 113 of which were coronary deaths. High fasting serum IGFBP-1 concentration (> 75 percentile) in 1984 was associated with increased five-year total mortality (OR 2.05, 95 % CI 1.41 - 2.99; p < 0.0002), cardiovascular mortality (OR 2.20, 95 % CI 1.37 - 3.50; p < 0.0009) and coronary heart disease mortality (OR 2.29, 95 % CI 1.35 - 3.88; p < 0.002). After adjustment for age, high serum IGFBP-1 concentrations still carried an increased risk of total mortality due to (OR 1.73, 95 % CI 1.16 - 2.59; p < 0.007), cardiovascular (OR 1.91 95 % CI 1.18 - 3.09; p < 0.008) and coronary heart disease (OR 2.02. 95 % CI 1.18 - 3.47; p < 0.01). In conclusion, high fasting serum IGFBP-1 is related to increased five-year total and cardiovascular mortality in elderly men.     

How can we best prolong life? Benefits of coronary risk factor reduction in non-diabetic and diabetic subjects.

OBJECTIVE--To compare the theoretical benefits of different approaches to reduce risk factors for coronary heart disease in subjects at risk. DESIGN--The results of findings from meta-analyses of intervention studies on cause specific mortality and of observational studies on smokers and ex-smokers were applied to observational data on 10 year cause specific mortality derived from the multiple risk factor intervention trial. Lifetable analyses were used to estimate gains in life expectancy. SUBJECTS--Diabetic and non-diabetic men initially 35-57 years of age. MAIN OUTCOME MEASURES--10 year mortality from coronary heart disease, 10 year total mortality, man years of intervention to prevent one death and one death from coronary heart disease, gain in life expectancy, and drug costs per year of additional life in diabetic and non-diabetic men of 45. RESULTS--In non-diabetic men a 10 year mortality from coronary heart disease of 14.4 per 1000 would be reduced by a mean of 0.58, 0.82, 2.64, and 2.74 per 1000 by antihypertensive treatment, lowering cholesterol concentration, taking aspirin, and stopping smoking respectively; a 10 year total mortality of 44.1 per 1000 would fall by a mean of 1.06, 5.16, and 8.65 per 1000 with antihypertensive and aspirin treatment and stopping smoking respectively and increased by a mean of 0.07 per 1000 with the lowering of cholesterol concentration. In diabetic men the reductions in mortality from coronary heart disease would be between three and five times greater, and total mortality would show mean reductions of 5.81, 0.56, 16.17, and 20.84 per 1000 respectively, with all interventions of significant benefit except the lowering of cholesterol concentration. Between 2400 and 3800 man years of pharmacological intervention were calculated as being necessary to prevent one death from coronary heart disease in a non-diabetic man, and between 800 and 1200 man years in a diabetic man. The loss of life expectancy associated with smoking and hypertension is greater than that accruing from hypercholesterolaemia, but stopping smoking would prolong life by a mean of around four years in a 45 year old non-diabetic man and three years in a diabetic man, whereas aspirin and antihypertensive treatment would provide approximately one year of additional life expectancy in both categories. CONCLUSIONS--Studies to date have shown little impact of drugs that lower cholesterol concentration and blood pressure on either coronary heart disease or total mortality. Although new treatments for hypercholesterolaemia and hypertension might help prevent coronary heart disease, other approaches to reduce the burden of premature death are required.     

Survival in treated hypertension: follow up study after two decades

Objective: To compare survival and cause specific mortality in hypertensive men with non-hypertensive men derived from the same random population, and to study mortality and morbidity from cardiovascular diseases in the hypertensive men in relation to effects on cardiovascular risk factors during 22-23 years of follow up. Design: Prospective, population based observational study. Subjects and methods: 686 hypertensive men aged 47-55 at screening compared with 6810 non-hypertensive men. The hypertensive men were having stepped care treatment with either β adrenergic blocking drugs, thiazide diuretics, or combination treatment. Mortality, morbidity, and adverse effects were registered at yearly examinations and from death certificates. Main outcome measures: All cause mortality and cause specific mortality. Results: Treated hypertensive men had significantly impaired probability of total survival as well as survival from coronary heart disease and stroke. All cause mortality as well as coronary heart disease and stroke mortality were very similar in hypertensive men and normotensive men during the first decade, but increased steadily thereafter despite continuous good blood pressure control. Smoking, signs of target organ damage, and high serum cholesterol levels, but not blood pressure at screening, were significantly related to the incidence of coronary heart disease during follow up. In time dependent Cox’s regression analysis, the incidence of coronary heart disease was significantly related only to serum cholesterol concentrations in the study. Cancer mortality was almost similar in treated hypertensive men (61/686, 8.9%) and non-hypertensive men (732/6810, 10.8%). Conclusion: Treated hypertensive men had impaired survival and increased mortality from cardiovascular disease compared with non-hypertensive men of similar age. These differences were observed during the second decade of follow up. During an observation period of 22-23 years—about 15 000 patient years—hypertensive men receiving diuretics and β blockers had no increased risk of cancer or non-cardiovascular disease.

Key messages

• Hypertension is a prevalent (10-20%) and important risk factor for cardiovascular disease.
• In controlled trials over 3-5 years drug treatment for hypertension prevents these complications, but little is known about long term prognosis
• During 20-22 years treated hypertensive men had a significantly increased mortality, especially from coronary heart disease, compared with non-hypertensive men from the same population
• The high incidence of myocardial infarction was related to organ damage, smoking, and cholesterol at the time of entry to the study, and to achieved serum cholesterol concentrations during follow up
• The poor prognosis for mortality from coronary heart disease is dependent upon strict monitoring of serum cholesterol concentrations

     

Serum cholesterol concentration and mortality from accidents,suicide, and other violent causes.

OBJECTIVE--To study the association of mortality from accidents, suicides, and other violent deaths with serum cholesterol concentration. DESIGN--Baseline measurements in two randomly chosen independent cohorts were carried out in 1972 and 1977. Mortality was monitored over 10-15 years through the national death registry. SETTING--Eastern Finland. SUBJECTS--The two cohorts comprised men (n = 10,898) and women (n = 11,534) born between 1913 and 1947. There were 193 deaths due to accidents, suicides, and violence among men and 43 among women. MAIN OUTCOME MEASURE--Mortality from accidents, suicides, and other violent deaths was used as the end point. Deaths from these causes were pooled together in the analyses. RESULTS--Serum cholesterol concentration was not associated with mortality from accidents, suicides, and other violent deaths in the univariate analyses or in the proportional hazards regression analyses including smoking, systolic blood pressure, alcohol drinking, and education. In both genders smoking was more prevalent among those who died from accidents, suicides, and other violent causes than from other causes. Frequent use of alcohol increased mortality from these causes. CONCLUSION--The risk of accidents, suicides, and other violent deaths was not related to serum cholesterol concentration, whereas such deaths were more prevalent in smokers and alcohol drinkers.     

Alcohol and mortality from all causes

A large number of prospective studies have observed an inverse relationship between a moderate intake of alcohol and coronary heart disease morbidity and mortality. Concerning death from all-causes, results are not unanimous. Alcohol intake was associated with a protection of all-cause mortality in England and USA physicians and the large study of the American Cancer Society. None of these studies separated the effects of different alcoholic beverages. In our prospective studies in France on 35 000 middle-aged men, we observed that only wine at moderate intake, was associated with a protective effect on all-cause mortality. The reason was that in addition to the known effect on cardiovascular diseases, a very moderate intake of wine, protected also from cancer and other causes as confirmed by Gronbaek in Denmark. Our recent results also indicate that the protective effect of a moderate intake of wine on all-cause mortality is observed at all levels of blood pressure and serum cholesterol.     

Cholesterol lowering and mortality: the importance of considering initial level of risk.

OBJECTIVE--To investigate the level of risk of death from coronary heart disease above which cholesterol lowering treatment produces net benefits. DESIGN--Meta-analysis of results of randomised controlled trials of cholesterol lowering treatments. METHODS--Published and unpublished data from all identified randomised controlled trials of cholesterol lowering treatments with six months or more follow up and with at least one death were included in the meta-analysis. The analyses were stratified by the rate of death from coronary heart disease in the control arms of the trials. MAIN OUTCOME MEASURES--Death from all causes, from coronary heart disease, and from causes other than coronary heart disease. RESULTS--In the pooled analysis, net benefit in terms of total mortality from cholesterol lowering was seen only for trials including patients at very high initial risk of coronary heart disease (odds ratio 0.74; 95% confidence interval 0.60 to 0.92). In a medium risk group no net effect was seen, and in the low risk group there were adverse treatment effects (1.22; 1.06 to 1.42). In a weighted regression analysis a significant (p < 0.001) trend of increasing benefit with increasing initial risk of coronary heart disease was shown. Raised mortality from causes other than coronary heart disease was seen in trials of drug treatment (1.21; 1.05 to 1.39) but not in the trials of non-drug treatments (1.02; 0.88 to 1.19). Cumulative meta-analysis showed that these results seem to have been stable as new trials appeared. CONCLUSION--Currently evaluated cholesterol lowering drugs seem to produce mortality benefits in only a small proportion of patients at very high risk of death from coronary heart disease. Population cholesterol screening could waste resources and even result in net harm in substantial groups of patients. Overall risk of coronary heart disease should be the main focus of clinical guidelines, and a cautious approach to the use of cholesterol lowering drugs should be advocated. Future trials should aim to clarify the level of risk above which treatment is of net benefit.     

Systematic underestimation of association between serum cholesterol concentration and ischaemic heart disease in observational studies: data from the BUPA study.

OBJECTIVE--To estimate the size of the association between serum concentration of low density lipoprotein cholesterol and mortality from ischaemic heart disease. DESIGN--Prospective study of total serum cholesterol concentration and mortality from ischaemic heart disease in 21,515 men (538 deaths) and study of total cholesterol concentration measured on two occasions an average of three years apart in 5696 men in whom low density lipoprotein cholesterol concentration was also measured on the second occasion. SUBJECTS--Men who attended the medical centre of the British United Provident Association (BUPA) in London between 1975 and 1982. MAIN OUTCOME MEASURE--The difference in mortality from ischaemic heart disease for a 0.6 mmol/l difference in concentration of low density lipoprotein cholesterol after adjustment for, firstly, regression dilution bias, which arises from the random fluctuation of serum cholesterol concentration in people over time, and, secondly, the surrogate dilution effect, which arises because differences in total cholesterol concentration between people reflect smaller differences in low density lipoprotein cholesterol concentration. RESULTS--The observed difference in mortality from ischaemic heart disease associated with a difference of 0.6 mmol/l in total serum cholesterol concentration was 17% but increased to 24% after correction for the regression dilution bias and to 27% (95% confidence interval 21% to 33%) after adjustment for both sources of underestimation, which provides an estimate of the difference in mortality for a true difference of 0.6 mmol/l in low density lipoprotein cholesterol concentration. The association was greater at younger ages. The estimated decrease in mortality from all causes was 6% before and 10% (1% to 17%) after adjustment for the two sources of underestimation. There was no excess mortality from any cause associated with low cholesterol concentration. CONCLUSIONS--The association between serum cholesterol concentration and ischaemic heart disease is materially stronger than directly inferred from prospective studies. This has important implications for the health benefit of achieving low cholesterol concentrations.