To quantify the effect of estrogen replacement therapy on breast cancer risk, we combined dose-response slopes of the relative risk of breast cancer against the duration of estrogen use across 16 studies. Using this summary dose-response slope, we calculated the proportional increase in risk of breast cancer for each year of estrogen use. For women who experienced any type of menopause, risk did not appear to increase until after at least 5 years of estrogen use. After 15 years of estrogen use, we found a 30% increase in the risk of breast cancer (relative risk, 1.3; 95% confidence interval [CI], 1.2 to 1.6). The increase in risk was largely due to results of studies that included premenopausal women or women using estradiol (with or without progestin), studies for which the estimated relative risk was 2.2 (CI, 1.4 to 3.4) after 15 years. Among women with a family history of breast cancer, those who had ever used estrogen replacement had a significantly higher risk (3.4; CI, 2.0 to 6.0) than those who had not (1.5; CI, 1.2 to 1.7).

We critically appraised the medical literature to evaluate whether there is a point beyond which blood pressure reduction in hypertensive subjects is no longer beneficial and possibly even deleterious. Thirteen studies that stratified cardiovascular outcomes by level of achieved blood pressure in treated hypertensive subjects who had been followed up for at least 1 year were critiqued by four independent reviewers. Data addressing population, protocol, and methodological characteristics were evaluated. Studies did not show a consistent J-shaped relationship between treated blood pressure and stroke, but they did demonstrate a consistent J-shaped relationship for cardiac events and diastolic blood pressure. The beneficial therapeutic threshold point was 85 mm Hg. We conclude that low treated diastolic blood pressure levels, ie, below 85 mm Hg, are associated with increased risk of cardiac events.

Evidence of the potential impact of intravenous thrombolytic therapy on short-term revascularization rates among patients with acute myocardial infarction was sought. Because nonrandomized comparisons with conventional treatment would be subject to various confounders, a meta-analysis of randomized controlled trials was performed. Seven trials were included, applying standard doses of either tissue plasminogen activator or streptokinase without an aggressive revascularization protocol. Follow-up ranged from 14 to 30 days. The revascularization rates among treated patients in all trials were lower than in the conservative arm of the Thrombolysis in Myocardial Infarction Phase II trial, which established the current procedural benchmarks for postthrombolysis management. However, the aggregate volume of bypass surgery and angioplasty in patients treated with tissue plasminogen activator was more than double that of controls (odds ratio, 2.25; 95% confidence interval, 1.31 to 3.94), with a smaller but still significant increase for streptokinase-treated patients (odds ratio, 1.66; 95% confidence interval, 1.08 to 2.59). Combining all trials, the increase in mechanical revascularization was 80% (95% confidence interval, 33% to 144%). Thus, for patterns of practice currently accepted in North America, intravenous thrombolysis for myocardial infarction leads to a significant short-term increase in clinical and angiographic indications for revascularization as compared with conventional treatment.

We performed a meta-analysis of 25 randomized control trials that compared endoscopic hemostasis with standard therapy for bleeding peptic ulcer. For recurrent or continued bleeding, the mean rate in control patients was 0.39, and the pooled rate difference, or reduction due to therapy, was 0.27 +/- 0.15 (95% confidence interval) (69% relative reduction). For emergency surgery, the mean rate in control patients was 0.26, and the pooled rate difference was 0.16 +/- 0.05 (62% relative reduction). Most important, for overall mortality, the mean rate in control patients was 0.10, and the pooled rate difference was 0.03 +/- 0.02 (30% relative reduction). The effects were greatest in patients with spurting or visible blood vessels and equivocal when the ulcer showed only signs of recent bleeding. We conclude that endoscopic hemostasis is clearly effective but that data were insufficient for direct comparisons between modalities. Randomized control trials to compare the different modes of endoscopic therapy should continue.

We identified 24 modern studies of childhood exposures to lead in relation to IQ. From this population, 12 that employed multiple regression analysis with IQ as the dependent variable and lead as the main effect and that controlled for nonlead covariates were selected for a quantitative, integrated review or meta-analysis. The studies were grouped according to type of tissue analyzed for lead. There were 7 blood and 5 tooth lead studies. Within each group, we obtained joint P values by two different methods and average effect sizes as measured by the partial correlation coefficients. We also investigated the sensitivity of the results to any single study. The sample sizes ranged from 75 to 724. The sign of the regression coefficient for lead was negative in 11 of 12 studies. The negative partial r's for lead ranged from -.27 to -.003. The power to find an effect was limited, below 0.6 in 7 of 12 studies. The joint P values for the blood lead studies were less than .0001 for both methods of analysis (95% confidence interval for group partial r, -.15 +/- .05), while for the tooth lead studies they were .0005 and .004, respectively (95% confidence interval for group partial r, -.08 +/- .05). The hypothesis that lead impairs children's IQ at low dose is strongly supported by this quantitative review. The effect is robust to the impact of any single study.

To evaluate the comparative efficacy and cost-effectiveness of various antihypertensive medications in persons aged 35 through 64 years with diastolic blood pressure of 95 mm Hg or greater and no known coronary heart disease, we used the Coronary Heart Disease Policy Model, which is a computer simulation of overall mortality as well as the mortality, morbidity, and cost of coronary heart disease in the US population. From the pooled literature, we estimated the antihypertensive and total cholesterol effects of various antihypertensive regimens. For 20 years of simulated therapy from 1990 through 2010, the cost per year of life saved was projected to be $10,900 for propranolol hydrochloride; $16,400 for hydrochlorothiazide; $31,600 for nifedipine; $61,900 for prazosin hydrochloride; and $72,100 for captopril. Doubling the cholesterol effects of the agents under study did not significantly change their effectiveness because, in general, lowering diastolic blood pressure by 1 mm Hg was equivalent to lowering the cholesterol level by 6%. Although any projection requires multiple estimates, each of which may be open to debate, propranolol appears to be the preferred initial option under most of a variety of alternative assumptions.