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.

Cognitive function and retinal and ischemic brain changes: the Women's Health Initiative.

OBJECTIVE: To examine the association between retinopathy and cognitive decline or brain lesions and volumes in older women. METHODS: This study included 511 women aged 65 and older who were simultaneously enrolled in the Women's Health Initiative Memory Study and the Sight Examination Study. In this analysis, we examined the link between retinopathy, assessed using fundus photography (2000-2002), cognitive performance over time assessed by the modified Mini-Mental State Examination (3MSE) (1996-2007), and white matter hyperintensities and lacunar infarcts in the basal ganglia. RESULTS: Presence of retinopathy was associated with poorer 3MSE scores (mean difference = 1.01, SE: 0.43) (p = 0.019) over a 10-year follow-up period and greater ischemic volumes in the total brain (47% larger, p = 0.04) and the parietal lobe (68% larger, p = 0.01) but not with measures of regional brain atrophy. CONCLUSIONS: The correspondence we found between retinopathy and cognitive impairment, along with larger ischemic lesion volumes, strengthens existing evidence that retinopathy as a marker of small vessel disease is a risk factor for cerebrovascular disease that may influence cognitive performance and related brain changes. Retinopathy may be useful as a clinical tool if it can be shown to be an early marker related to neurologic outcomes.

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.

Cholesterol reduction yields clinical benefit: impact of statin trials.

BACKGROUND: We determined the effect of incorporating the results of eight recently published trials of Hmg CoA reductase inhibitors ("statins") on the conclusions from our previously published meta-analysis regarding the clinical benefit of cholesterol lowering. METHODS AND RESULTS: We used the same analytic approach as in our previous investigation, separating the specific effects of cholesterol lowering from the effects attributable to the different types of intervention studied. The reductions in coronary heart disease (CHD) and total mortality risk observed for the statins fell near the predictions from our earlier meta-analysis. Including the statin trial findings into the calculations led to a prediction that for every 10 percentage points of cholesterol lowering, CHD mortality risk would be reduced by 15% (P<.001), and total mortality risk would be reduced by 11% (P<.001), as opposed to the values of 13% and 10%, respectively, reported previously. Cholesterol lowering in general and by the statins in particular does not increase non-CHD mortality risk. CONCLUSIONS: Adding the results from the statin trials confirmed our original conclusion that lowering cholesterol is clinically beneficial. The relationships (slope) between cholesterol lowering and reduction in CHD and total mortality risk became stronger, and the standard error of the estimated slopes decreased by about half. Use of statins does not increase non-CHD mortality risk. The effect of the statins on CHD and total mortality risk can be explained by their lipid-lowering ability and appears to be directly proportional to the degree to which they lower lipids.

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.

Apolipoprotein B levels and related factors in a rural white South African community--the CORIS study. Coronary Risk Factor Study.

OBJECTIVE: In a survey of the Coronary Risk Factor Study (CORIS), apolipoprotein B (apoB) levels were determined to ascertain their impact on coronary heart disease (CHD) risk. Other CHD risk factors associated with apoB were also identified. DESIGN: Cross-sectional analytical study, which included CHD risk factor and dietary questionnaires, electrocardiography, anthropometric and blood pressure measurements, and a blood sample for a lipid profile. SETTING AND PARTICIPANTS: The three districts of Riversdale, Robertson and Swellendam in the south-western Cape; a 25% random sample of 1,528 white respondents aged 15-68 years. RESULTS: Men tended to have higher mean apoB levels than women. Classification of CHD risk by apoB levels and total cholesterol (TC) levels did not correspond, as only 61% of men and 58.5% of women were classified in the same risk categories. Respondents in the highest apoB risk category reported a medical history of hypercholesterolaemia and hypertension more frequently than those in lower categories. There was a significant increase from the low to the high apoB risk category of TC, low-density lipoprotein (LDL) cholesterol, triglyceride levels, body mass index and percentage body fat. Using stepwise multiple regression, 84.9% of the variation in apoB of men and 85.8% in apoB of women were accounted for by significantly associated variables. CONCLUSION: Although apoB may be a better predictor of CHD than TC or LDL cholesterol concentrations, its easy approximation with the formula (TC-HDLC)/2 + 20, high cost, measurement variability and an approach in management similar to that for raised TC discourage its routine use in the screening of patients for CHD.

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.