Reliable evidence from placebo-controlled, randomized, clinical trials for menopausal hormone therapy's influence on incidence and deaths from breast cancer.

In an invited editorial, Dr Shapiro proposes that vaginal bleeding leading to unblinding and subsequent detection bias explains the breast cancer increase seen with estrogen plus progestin in the Women's Health Initiative (WHI) clinical trial (1) . In the context of a uniform detection program of protocol-mandated annual mammography and breast examinations, such a proposal is medically implausible. Dr Shapiro suggests detection bias would identify a larger number of 'slowly growing tumors that would otherwise remain clinically silent'. The findings of more advanced cancers with increased deaths from breast cancer in the estrogen plus progestin group refute this conjecture. During early post-intervention phases of both WHI hormone therapy trials, when breast cancer detection bias is asserted by Dr Shapiro because participants had been informed of randomization assignment, breast cancer incidence rates were lower (rather than higher) than during intervention. Thus, Dr Shapiro's claims are directly refuted by findings from the WHI randomized clinical trials. Health-care providers should be aware that randomized clinical trial evidence supports estrogen plus progestin increasing breast cancer incidence and deaths from breast cancer. In contrast, among women with prior hysterectomy, randomized clinical trial evidence supports estrogen alone reducing breast cancer incidence and deaths from breast cancer.

Health risks and benefits from calcium and vitamin D supplementation: Women's Health Initiative clinical trial and cohort study.

SUMMARY: The Women's Health Initiative (WHI) double-blind, placebo-controlled clinical trial randomly assigned 36,282 postmenopausal women in the U.S. to 1,000 mg elemental calcium carbonate plus 400 IU of vitamin D(3) daily or placebo, with average intervention period of 7.0 years. The trial was designed to test whether calcium plus vitamin D supplementation in a population in which the use of these supplements was widespread would reduce hip fracture, and secondarily, total fracture and colorectal cancer. INTRODUCTION: This study further examines the health benefits and risks of calcium and vitamin D supplementation using WHI data, with emphasis on fractures, cardiovascular disease, cancer, and total mortality. METHODS: WHI calcium and vitamin D randomized clinical trial (CT) data through the end of the intervention period were further analyzed with emphasis on treatment effects in relation to duration of supplementation, and these data were contrasted and combined with corresponding data from the WHI prospective observational study (OS). RESULTS: Among women not taking personal calcium or vitamin D supplements at baseline, the hazard ratio [HR] for hip fracture occurrence in the CT following 5 or more years of calcium and vitamin D supplementation versus placebo was 0.62 (95 % confidence interval (CI), 0.38-1.00). In combined analyses of CT and OS data, the corresponding HR was 0.65 (95 % CI, 0.44-0.98). Supplementation effects were not apparent on the risks of myocardial infarction, coronary heart disease, total heart disease, stroke, overall cardiovascular disease, colorectal cancer, or total mortality, while evidence for a reduction in breast cancer risk and total invasive cancer risk among calcium plus vitamin D users was only suggestive. CONCLUSION: Though based primarily on a subset analysis, long-term use of calcium and vitamin D appears to confer a reduction that may be substantial in the risk of hip fracture among postmenopausal women. Other health benefits and risks of supplementation at doses considered, including an elevation in urinary tract stone formation, appear to be modest and approximately balanced.

Hormone replacement therapy and cardiovascular disease.

A large amount of research continues to be conducted on the mechanisms of hormone replacement therapy (HRT) effects, and the first of the large clinical trials published its results during the past year. In addition to the well known effects on LDL-cholesterol, HDL-cholesterol, and triglycerides, recent studies confirmed that estrogen with or without a progestin lowers lipoprotein (a) concentrations in women (but not in men). In men, estrogen appears to have a similar effect on other lipids and lipoproteins and on plasminogen activator inhibitor-1 as in women. A comparison of estrogen with simvastatin indicated that simvastatin is better at lowering LDL-cholesterol while estrogen is better at raising HDL-cholesterol; when given in combination the additional effects were modest. Estrogen and simvastatin had similar beneficial effects on endothelial function. The estrogen effect on endothelial function may be blocked by medroxyprogesterone, but the data are inconsistent. These studies of intermediate outcomes were put in perspective by the results of a landmark secondary prevention trial of coronary heart disease (CHD). This randomized placebo-controlled trial (Heart and Estrogen/Progestin Replacement Study) of conjugated equine estrogens plus medroxyprogesterone failed to show the anticipated reduction in CHD, and at the same time the threefold increase in venous thromboembolism confirmed that HRT is procoagulant. Therefore, it is still not known whether HRT is a viable option for the prevention of CHD. The preliminary data on selective estrogen receptor modulators are not overly promising, but a definitive trial to test whether raloxifene will reduce CHD is ongoing.

Twelve-year results of the Coronary Risk Factor Study (CORIS).

BACKGROUND: After 4 years a coronary heart disease risk factor intervention programme produced equally large and significantly reduced risk profiles in two intervention towns compared with a control town. Intervention effects through community participation were assessed after cessation of the active intervention programme. The impact of secular trends was assessed in the control town and in two previously unstudied towns. METHODS: Cross-sectional surveys were done in a random sample of 1620 participants aged 15-64 years in the three original towns 12 years after the initial quasi-experimental study. Two years later 327 subjects, aged 35-44 years, were studied in the original control town and in two non-intervention towns. Risk factor knowledge, smoking and medical histories were determined by questionnaire. Blood pressure, anthropometry and blood lipids were recorded. Data were compared across towns, and with previous surveys. RESULTS: At 12 years the low intensity intervention town maintained a significantly better risk factor profile than the control town, while the high intensity intervention town now matched the control town. No differences in risk factor profiles were found between the control town and the two new towns. Deaths from coronary heart disease and strokes showed a downward trend in the study area. CONCLUSIONS: Outcome suggests large ongoing secular trends during the study could have overtaken the intervention effects in the high intensity town, but not in the low intensity intervention town, which showed an advantage over the control town. These results support the effectiveness of media-based, long term health promotion strategies to reduce cardiovascular disease risk profiles.

Lipid-lowering interventions in angiographic trials.

This analysis examines the pooled data from all 14 published randomized angiographic trials (with 16 treatment arms) by type of cholesterol-lowering intervention evaluated, and for all the trials combined. All interventions reduced low density lipoprotein (LDL) cholesterol levels (average reduction, 26%), whereas the effects on high density lipoprotein (HDL) cholesterol and triglycerides varied by type of intervention. Meta-analyses of the angiographic outcomes indicated that treatment reduced the odds for disease progression by 49%, increased the odds for no change by 33%, and increased the odds for regression by 219%. Cardiovascular events were reduced by 47%. Thus, lipid reduction is effective for modifying the angiographic outcome and for reducing the incidence of coronary artery disease events. All types of intervention (lifestyle, drugs, or surgery) had overall favorable effects on angiographic and clinical outcomes. There was no class effect for the statin group of drugs. Surgery (partial ileal bypass) had the most favorable angiographic outcome, possibly because of a longer duration of therapy. Trials with higher baseline LDL levels tended to have more favorable angiographic outcomes. Analyses of in-trial levels of LDL were confounded by baseline levels, and analyses of change in LDL levels in the treatment groups were confounded by not including zero change (i.e., no treatment). It is hypothesized that lowering LDL levels by 30 mg/dl (0.8 mmol/liter) is sufficient on average to modify the angiographic outcome, with modest gains from further reductions in LDL levels.

Cholesterol reduction yields clinical benefit. A new look at old data.

BACKGROUND: There has been a continuing debate about the overall benefit of cholesterol lowering. We performed a novel meta-analysis of all randomized trials of more than 2 years' duration (n = 35 trials) to describe how coronary-heart-disease (CHD), non-CHD, and total mortality are related to cholesterol lowering and to type of intervention. METHODS AND RESULTS: The analytic approach was designed to separate the effects of cholesterol lowering itself from the other effects of the different types of intervention used. For every 10 percentage points of cholesterol lowering, CHD mortality was reduced by 13% (P < .002) and total mortality by 10% (P < .03). Cholesterol lowering had no effect on non-CHD mortality. Certain types of intervention had specific effects independent of cholesterol lowering. Fibrates (clofibrates, 7 trials; gemfibrozil, 2 trials) increased non-CHD mortality by about 30% (P < .01) and total mortality by about 17% (P < .02). Hormones (estrogen, 2 trials; dextrothyroxin, 2 trials) increased CHD mortality in men by about 27% (P < .04), non-CHD mortality by about 55% (P < .03), and total mortality by about 33% (P < .01). No specific effects independent of cholesterol lowering were found due to diet (n = 11) or other interventions (resins, 5; niacin, 3; statins, 2; partial ileal bypass, 1). CONCLUSIONS: The results suggest that cholesterol lowering itself is beneficial but that specific adverse effects of fibrates and hormones increase the risk of CHD (hormones only), non-CHD, and total mortality.

The evolution of the Women's Health Initiative: perspectives from the NIH.

The Women's Health Initiative (WHI) addresses some of the major health concerns of postmenopausal women. It is designed to test whether long-term preventive measures will decrease the incidence of cardiovascular disease, certain cancers, and fractures, and it seeks to find better predictors of future health and disease in older women. This report traces the evolution of the clinical trial and observational study (CT/OS) components of WHI from early planning in the 1980s to the current status of the WHI CT/OS as an integrated, ongoing clinical study. Particular attention is directed to the antecedent planning meetings and feasibility studies that formed the underpinnings of the WHI. The issues of hormone replacement therapy and of the optimal diet for postmenopausal women were investigated for almost a decade prior to WHI. However, no studies of sufficient size and duration to confidently test the value and risks of these approaches were initiated because of the cost and insufficient political commitment. The initiation of WHI in 1991 represents the confluence of scientific need and capability with the social priorities to improve the health and welfare of women.

Community-based intervention: the Coronary Risk Factor Study (CORIS).

The Coronary Risk Factor Study (CORIS) examined the feasibility and effectiveness of a multifactorial community intervention programme to reduce coronary heart disease (CHD) risk factor levels. Three Afrikaner communities were surveyed before and after a 4-year intervention in two of the communities, the third serving as a control (C). Intervention was primarily by small mass media (low-intensity intervention, LII) or by small mass media plus interpersonal intervention to high-risk individuals (high-intensity intervention, HII). After allowing for change in C, significant net reductions in blood pressure, smoking, and risk score were obtained in LII and HII alike. Though the total cholesterol (TC) fell by 10-12%, there was no net reduction in favour of the intervention communities. However, LII and HII resulted in significant increases in high-density lipoprotein cholesterol (HDL-C) levels and HDL-C/TC ratios in comparison to C. Overall, the LII community fared almost as well as the HII community, and high-risk individuals did not show a greater change in risk factors than others. We conclude that community-based intervention works, and that in these particular communities a media-based health education programme was more cost-effective than one which adds a greater degree of interpersonal intervention.

Changes in smoking during a community-based cardiovascular disease intervention programme. The Coronary Risk Factor Study.

A prospective anti-smoking clinical trial was conducted as part of a coronary risk factor intervention study in three rural South African communities in the south-western Cape over a period of 4 years. The aim of this part of the study was to reduce smoking rates in two of the communities through application of high- and low-intensity intervention. The effect was evaluated by examining the net change in smoking habits, which was defined as the residual change in the intervention areas after allowing for change in the reference area. This paper presents the analyses of the estimated effect of the programme on the cohort aged 15-64 years at baseline who participated in the two surveys (4,087 subjects). The intervention programme among men in the high-intensity intervention area resulted in a reduction of 8.4% in smoking rates and 13.0% in the amount smoked per day. Among women in this area there was a reduction of 30.6% in smoking rates and 20.5% in amount smoked. Smoking and the amount smoked per day also decreased in the low-intensity intervention area, but less so than in the high-intensity intervention area. Smoking quit rates were strongly associated with initial smoking levels, with light smokers being significantly more successful quitters than heavy smokers. This study has proved that a community-based intervention programme can effectively reduce smoking.

Relation of family history and reversible risk factors to coronary heart disease prevalence in an Afrikaner community.

In a cross-sectional study of an Afrikaner community (n = 2,722 men and n = 3,173 women aged 25-64 years), family history of coronary heart disease (CHD) was associated with an adverse risk factor profile and with prevalent CHD. Men with myocardial infarction (MI) and a family history of CHD had higher total minus high density lipoprotein cholesterol (TC-HDLC) levels than men with MI but no CHD family history. In preliminary multiple regression analyses, family history of CHD appeared to exert its effect partly independently of known risk factors and partly dependently through age, TC minus HDLC, and HDLC. Even though their association with MI was weakened after entering family history into the models, the reversible risk factors (particularly TC minus HDLC, HDLC, and uric acid levels) continued to contribute to CHD. For MI in men, there was an interaction between family history of CHD and TC minus HDLC, to the extent that raised TC minus HDLC levels were adverse only in the presence of a positive CHD family history. The findings suggest coinheritance of high blood cholesterol and increased susceptibility to CHD. If confirmed in prospective studies, the interaction between family history and TC minus HDLC will have implications for cholesterol screening and management.

Choice of coronary heart disease risk factor variables in a cross-sectional study of white South Africans.

This report explores the possibility of redefining risk factors so as to improve their observed associations with prevalent coronary heart disease (CHD). A large cross-sectional community study of 5,895 white males and females aged 25-64 years yielded 240 cases of confirmed angina pectoris and 361 of confirmed myocardial infarction. Odds ratios for CHD end-points by level of risk factors when risk factors were expressed in the conventional manner (e.g. total cholesterol, systolic and diastolic blood pressure or current smoking) were often low and not statistically significant. Redefinition of risk factor variables in a manner that improved their specificity or compensated to some extent for the decreased risk factor exposure as a result of a CHD event (e.g. stopping smoking after a myocardial infarct) improved the strength of association. In this study, the most useful cholesterol variable was total cholesterol minus high-density lipoprotein cholesterol; for blood pressure the most useful variable was a blood pressure of 160/95 mmHg or above and/or being on anti-hypertensive treatment; and for smoking the most useful variable was the total duration of smoking (previous and current). Strong associations with CHD end-points were also found for conventionally expressed serum uric acid, diabetes prevalence (females) and family history of CHD. The study suggests that appropriate redefinition of risk factor variables and CHD end-points in cross-sectional studies yields associations similar in strength and direction to those found in prospective studies.

Relationship between high density lipoprotein subfractions and coronary risk factors in a rural white population.

The relationship of serum high density lipoprotein cholesterol (HDL-C) levels and of the HDL2-C and HDL3-C subfractions to several factors associated with coronary risk was examined in a cross-sectional study, which included 655 men and 731 women ages 20 to 64 years. Participants with coronary heart disease (CHD) had lower levels of HDL-C, HDL2-C, and HDL3-C; however, only HDL-C in women was significant. Maleness, body mass index, triglyceride levels, tobacco use, and carbohydrate intake (in men) were significantly inversely related to total HDL-C, while alcohol intake was significantly positively related to HDL-C. The associations were stronger for HDL2-C than for HDL3-C, except that alcohol intake in men was more strongly related to HDL3-C. The findings of this study suggest that several factors that influence CHD risk do so in part through modifying HDL2-C levels.

The coexistence of major coronary heart disease risk factors in the coloured population of the Cape Peninsula (CRISIC study).

A cross-sectional study of risk factors for coronary heart disease in a random sample of 976 people from a South African coloured population revealed this group to be at great risk. The prevalences of individual and of coexisting reversible risk factors--hypercholesterolaemia, hypertension and smoking--were highest in the older subjects, who use medical services more often. One or more of the three risk factors was present in 80% of men aged 45 years or over. Smoking was the most common single risk factor for both sexes, and almost 30% of women aged 45 years or over were hypertensive. Hypertension and smoking was the most common combination for males and hypertension and hypercholesterolaemia the most common for females. Medical personnel could identify and treat these very-high-risk patients if they were to screen for all the risk factors after identifying any one risk factor. Younger people at risk and particularly younger men, who rarely utilise health services, should be reached at their workplace for early identification of risk factors.

Health actions and disease patterns related to coronary heart disease in the coloured population of the Cape Peninsula.

The health-related behaviour of the Cape Peninsula coloured population, which has been shown to have an adverse coronary heart disease (CHD) risk factor profile, is reported. Private medical services were used most often by participants: 54.1% and 51.6% of males and females respectively had made use of these services during the preceding year. Only 17.9% and 21.8% of males and females respectively had attended day hospitals during the year. Blood pressures were measured in 43.8% and 57.1% of male and female participants respectively during the year preceding the study. The results indicated the need for the measurement of blood pressure to determine the true prevalence of hypertension, since patient reporting of the condition was inaccurate. Attempts to give up smoking had been made by 44.4% of male and 47.1% of female smokers. About 75% of the participants were found to have hypercholesterolaemia, yet their knowledge of the prudent diet was poor and few reported appropriate dietary modifications to protect against CHD. Frequent reporting of hypercholesterolaemia, hypertension and constipation by the study population highlights the need for dietary education. Mortality rates (MRs) for CHD and cerebrovascular disease (CVD) for the coloured and the white populations were compared. In all age groups white males had higher MRs for CHD than coloured males, while coloured females older than 34 years had higher rates than their white counterparts. The coloured population had MRs for CVD that were higher than those of whites.

Socio-economic status, risk factors and coronary heart disease. The CORIS baseline study.

The relationship of socio-economic status (SES) indicators and coronary risk factors (RFs) with coronary heart disease (CHD) prevalence was examined in 5 620 subjects aged 20-60 years who participated in the Coronary Risk Factor (CORIS) baseline study. Education and income (with some exceptions in males) were strongly and inversely related to hypercholesterolaemia, low high-density lipoprotein cholesterol, hypertension, smoking, overweight and prevalence of angina pectoris. In contrast, type A behaviour was positively associated with higher income and education. Females showed stronger SES-RF relationships than males. Town-dwelling females were more likely to be smokers, and had a higher prevalence of angina pectoris and myocardial infarction. The lowest overall prevalence of RFs, angina pectoris and myocardial infarction was found in the professional and managerial categories for both males and females. The SES indicators had little or no independent effect on CHD prevalence in multivariate logistic analyses after inclusion of the standard RFs. We conclude that these indicators relate to RFs, and through them to CHD.

Hypercholesterolaemia in a rural white population and its relationship with other coronary risk factors.

The risk factor and dietary associations of hypercholesterolaemia were analysed. Twenty per cent of the 6,332 respondents aged 20-64 years in the Coronary Risk Factor Study (CORIS) were considered hypercholesterolaemic (i.e. above the 80th percentile). In this sample only 13.4% of men and 6.7% of women were on treatment, and only 32.7% and 37.1% respectively had 'desirable' high-density lipoprotein cholesterol levels. Hypercholesterolaemia was significantly associated with a personal or family history of coronary heart disease, hypertension, smoking, obesity and hyperuricaemia. Analysis of the dietary intakes of a 15% subsample of the total population revealed no significant differences between high- and low-risk subjects in intake of dietary fats and cholesterol. However, high-risk subjects consumed significantly more animal protein and significantly less dietary fibre than those with a low cholesterol level. These findings reflect a subpopulation at high risk of coronary heart disease. Their risk can be reduced to some extent by population strategies towards healthier lifestyles; ultimately the high-risk individuals have to be identified and appropriately treated.