Objective: Funnel plots (plots of effect estimates against sample size) may be useful to detect bias in meta-analyses that were later contradicted by large trials. We examined whether a simple test of asymmetry of funnel plots predicts discordance of results when meta-analyses are compared to large trials, and we assessed the prevalence of bias in published meta-analyses. Design: Medline search to identify pairs consisting of a meta-analysis and a single large trial (concordance of results was assumed if effects were in the same direction and the meta-analytic estimate was within 30% of the trial); analysis of funnel plots from 37 meta-analyses identified from a hand search of four leading general medicine journals 1993-6 and 38 meta-analyses from the second 1996 issue of the Cochrane Database of Systematic Reviews . Main outcome measure: Degree of funnel plot asymmetry as measured by the intercept from regression of standard normal deviates against precision. Results: In the eight pairs of meta-analysis and large trial that were identified (five from cardiovascular medicine, one from diabetic medicine, one from geriatric medicine, one from perinatal medicine) there were four concordant and four discordant pairs. In all cases discordance was due to meta-analyses showing larger effects. Funnel plot asymmetry was present in three out of four discordant pairs but in none of concordant pairs. In 14 (38%) journal meta-analyses and 5 (13%) Cochrane reviews, funnel plot asymmetry indicated that there was bias. Conclusions: A simple analysis of funnel plots provides a useful test for the likely presence of bias in meta-analyses, but as the capacity to detect bias will be limited when meta-analyses are based on a limited number of small trials the results from such analyses should be treated with considerable caution. Key messages Systematic reviews of randomised trials are the best strategy for appraising evidence; however, the findings of some meta-analyses were later contradicted by large trials Funnel plots, plots of the trials9 effect estimates against sample size, are skewed and asymmetrical in the presence of publication bias and other biases Funnel plot asymmetry, measured by regression analysis, predicts discordance of results when meta-analyses are compared with single large trials Funnel plot asymmetry was found in 38% of meta-analyses published in leading general medicine journals and in 13% of reviews from the Cochrane Database of Systematic Reviews Critical examination of systematic reviews for publication and related biases should be considered a routine procedure

/pdf/bias-in-meta-analysis-detected-by-a-simple-graphical-test-5erh428s5c.pdf

Bias in meta-analysis detected by a simple, graphical test

Meta-Analysis in Clinical Trials*

Atherosclerosis is an inflammatory disease. Because high plasma concentrations of cholesterol, in particular those of low-density lipoprotein (LDL) cholesterol, are one of the principal risk factors for atherosclerosis,1 the process of atherogenesis has been considered by many to consist largely of the accumulation of lipids within the artery wall; however, it is much more than that. Despite changes in lifestyle and the use of new pharmacologic approaches to lower plasma cholesterol concentrations,2,3 cardiovascular disease continues to be the principal cause of death in the United States, Europe, and much of Asia.4,5 In fact, the lesions of atherosclerosis represent . . .

https://www.nejm.org/doi/pdf/10.1056/NEJM199901143400207

Atherosclerosis — An Inflammatory Disease

The National High Blood Pressure Education Program presents the complete Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Like its predecessors, the purpose is to provide an evidence-based approach to the prevention and management of hypertension. The key messages of this report are these: in those older than age 50, systolic blood pressure (BP) of greater than 140 mm Hg is a more important cardiovascular disease (CVD) risk factor than diastolic BP; beginning at 115/75 mm Hg, CVD risk doubles for each increment of 20/10 mm Hg; those who are normotensive at 55 years of age will have a 90% lifetime risk of developing hypertension; prehypertensive individuals (systolic BP 120-139 mm Hg or diastolic BP 80-89 mm Hg) require health-promoting lifestyle modifications to prevent the progressive rise in blood pressure and CVD; for uncomplicated hypertension, thiazide diuretic should be used in drug treatment for most, either alone or combined with drugs from other classes; this report delineates specific high-risk conditions that are compelling indications for the use of other antihypertensive drug classes (angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers, beta-blockers, calcium channel blockers); two or more antihypertensive medications will be required to achieve goal BP (<140/90 mm Hg, or <130/80 mm Hg) for patients with diabetes and chronic kidney disease; for patients whose BP is more than 20 mm Hg above the systolic BP goal or more than 10 mm Hg above the diastolic BP goal, initiation of therapy using two agents, one of which usually will be a thiazide diuretic, should be considered; regardless of therapy or care, hypertension will be controlled only if patients are motivated to stay on their treatment plan. Positive experiences, trust in the clinician, and empathy improve patient motivation and satisfaction. This report serves as a guide, and the committee continues to recognize that the responsible physician's judgment remains paramount.

Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure

Context Despite decades of accumulated observational evidence, the balance of risks and benefits for hormone use in healthy postmenopausal women remains uncertain Objective To assess the major health benefits and risks of the most commonly used combined hormone preparation in the United States Design Estrogen plus progestin component of the Women's Health Initiative, a randomized controlled primary prevention trial (planned duration, 85 years) in which 16608 postmenopausal women aged 50-79 years with an intact uterus at baseline were recruited by 40 US clinical centers in 1993-1998 Interventions Participants received conjugated equine estrogens, 0625 mg/d, plus medroxyprogesterone acetate, 25 mg/d, in 1 tablet (n = 8506) or placebo (n = 8102) Main outcomes measures The primary outcome was coronary heart disease (CHD) (nonfatal myocardial infarction and CHD death), with invasive breast cancer as the primary adverse outcome A global index summarizing the balance of risks and benefits included the 2 primary outcomes plus stroke, pulmonary embolism (PE), endometrial cancer, colorectal cancer, hip fracture, and death due to other causes Results On May 31, 2002, after a mean of 52 years of follow-up, the data and safety monitoring board recommended stopping the trial of estrogen plus progestin vs placebo because the test statistic for invasive breast cancer exceeded the stopping boundary for this adverse effect and the global index statistic supported risks exceeding benefits This report includes data on the major clinical outcomes through April 30, 2002 Estimated hazard ratios (HRs) (nominal 95% confidence intervals [CIs]) were as follows: CHD, 129 (102-163) with 286 cases; breast cancer, 126 (100-159) with 290 cases; stroke, 141 (107-185) with 212 cases; PE, 213 (139-325) with 101 cases; colorectal cancer, 063 (043-092) with 112 cases; endometrial cancer, 083 (047-147) with 47 cases; hip fracture, 066 (045-098) with 106 cases; and death due to other causes, 092 (074-114) with 331 cases Corresponding HRs (nominal 95% CIs) for composite outcomes were 122 (109-136) for total cardiovascular disease (arterial and venous disease), 103 (090-117) for total cancer, 076 (069-085) for combined fractures, 098 (082-118) for total mortality, and 115 (103-128) for the global index Absolute excess risks per 10 000 person-years attributable to estrogen plus progestin were 7 more CHD events, 8 more strokes, 8 more PEs, and 8 more invasive breast cancers, while absolute risk reductions per 10 000 person-years were 6 fewer colorectal cancers and 5 fewer hip fractures The absolute excess risk of events included in the global index was 19 per 10 000 person-years Conclusions Overall health risks exceeded benefits from use of combined estrogen plus progestin for an average 52-year follow-up among healthy postmenopausal US women All-cause mortality was not affected during the trial The risk-benefit profile found in this trial is not consistent with the requirements for a viable intervention for primary prevention of chronic diseases, and the results indicate that this regimen should not be initiated or continued for primary prevention of CHD

/pdf/risks-and-benefits-of-estrogen-plus-progestin-in-healthy-4glim99n2t.pdf

Risks and benefits of estrogen plus progestin in healthy postmenopausal women: Principal results from the Women's Health Initiative randomized controlled trial

Background Laboratory, clinical, and epidemiologic studies have recently suggested that regular use of aspirin can reduce colorectal cancer incidence or mortality. However, observational epidemiologic analyses have had limited opportunity to control for confounding bias or to specify aspirin doses used. Purpose Our purpose was to examine the relationship between regular use of low-dose aspirin and incidence of invasive and noninvasive colorectal tumors by utilizing data from the Physicians' Health Study, a randomized, double-blinded, placebo-controlled trial of aspirin and beta carotene. We also attempted to determine whether invasive cancers among aspirin users were associated with rectal bleeding and early stage at diagnosis. Methods The Physicians' Health Study includes 22071 U.S. male physicians. The aspirin arm was terminated in 1988 after a mean follow-up of 5 years. Stage at diagnosis and signs and/or symptoms during presentation were abstracted from medical records. Cox proportional hazards models were used to estimate relative risk (RR), 95% confidence intervals (CIs), and the association between aspirin and bleeding. Differences between aspirin and placebo groups in tumor risk over time were visualized with Kaplan-Meier curves. We assessed the association between aspirin and stage at diagnosis with a Mann-Whitney rank sum statistic for non-parametric comparison of two ordinal distributions. Results The RR of developing colorectal cancer for aspirin compared with placebo was 1.15 (95% CI = 0.80-1.65). For in situ cancers and polyps, the RR was 0.86 (95% CI = 0.68-1.10). There was no significant trend for decreasing RR by year of follow-up for invasive cancers (P = .09) or noninvasive tumors (P = .96). Aspirin and placebo groups did not differ in stage or prevalence of rectal bleeding at diagnosis. Conclusions Regular aspirin use, at a dose adequate for preventing myocardial infarction, was not associated with a substantial reduction in the incidence of colorectal cancer during 5 years of randomized treatment and follow-up. A small decrease in polyps in the aspirin group could not be reliably distinguished from a chance association. Our results suggest that among low-dose aspirin users, (a) colorectal cancer mortality is not likely to be reduced by earlier detection and (b) incidence is not likely to be increased due to aspirin-induced gastrointestinal bleeding. Implications The potential for a benefit from higher doses of aspirin or longer duration of use should be addressed by more detailed observational epidemiologic studies and prevention trials with longer follow-up of randomized participants.

Low-Dose Aspirin and Incidence of Colorectal Tumors in a Randomized Trial

We examined prospectively the relation of nutritional factors with hypertension and blood pressure levels among 41 541 predominantly white US female nurses, aged 38 to 63 years, who comple

/pdf/prospective-study-of-nutritional-factors-blood-pressure-and-2sewt2s6rd.pdf

Prospective Study of Nutritional Factors, Blood Pressure, and Hypertension Among US Women

ARDIOVASCULAR DISEASE (CVD), INCLUDING COROnary heart disease (CHD), stroke, and peripheral vascular disease, is the leading cause of death in the United States and most developed Western countries, and will remain so during the 21st century. 1 In 2004, CVD was listed as the underlying cause of death in 871517 of all 2398000 deaths (36.3%), or 1 of every 2.8 deaths in the United States, with CHD accounting for 52% and stroke for 17%. 2 During the past several decades, CVD mortality has markedly declined in the United States, from more than 50% to approximately 36% as the underlying cause of death. Recent data suggest that the decline is largely due to improved diagnosis and treatment rather than to major successes in primary prevention. In contrast, patients with severe mental illnesses, such as schizophrenia, bipolar disorder, and depression that together affect 5% to 10% of the US population, 3 lose 25 or more years of life expectancy, with the majority of the excess premature deaths due to CVD, not suicide. 4 In this Commentary, we summarize disparities in CVD mortality and prevention efforts comparing the general population and individuals with severe mental illnesses and suggest the urgent need for new paradigms. In the general US population, cigarette consumption has been the leading avoidable cause of all premature deaths, with the amount currently smoked representing a key measure of risk. 5 Smoking rates in the general population have declined from more than 50% in the 1950s to approximately 25% at present. 5 However, among patients with diagnosable mental illness, 50% to 80% are smokers and consume 34% to 44% of all cigarettes in the United States. 6 Although patients with severe mental illness are overrepresentedinstateprogramslikeMedicaid,somestatesdonot cover any form of tobacco-dependence treatment. 7 In addition, only a few states cover all treatments recommended intheUSPreventiveServicesTaskForceguidelinesonsmoking cessation. 7 Moreover, some states that cover tobaccodependence treatment require cost sharing, a serious disincentive for disabled patients with fixed income. 7

https://jamanetwork.com/HttpHandlers/ArticlePdfHandler.ashx?journal=JAMA&articleId=209157&pdfFileName=jco70063_1794_1796.pdf

Severe mental illness and risk of cardiovascular disease.

BACKGROUND\nThe effect of postmenopausal estrogen therapy on the risk of cardiovascular disease remains controversial. Our 1985 report in the Journal, based on four years of follow-up, suggested that estrogen therapy reduced the risk of coronary heart disease, but a report published simultaneously from the Framingham Study suggested that the risk was increased. In addition, studies of the effect of estrogens on stroke have yielded conflicting results.\n\n\nMETHODS\nWe followed 48,470 postmenopausal women, 30 to 63 years old, who were participants in the Nurses' Health Study, and who did not have a history of cancer or cardiovascular disease at base line. During up to 10 years of follow-up (337,854 person-years), we documented 224 strokes, 405 cases of major coronary disease (nonfatal myocardial infarctions or deaths from coronary causes), and 1263 deaths from all causes.\n\n\nRESULTS\nAfter adjustment for age and other risk factors, the overall relative risk of major coronary disease in women currently taking estrogen was 0.56 (95 percent confidence interval, 0.40 to 0.80); the risk was significantly reduced among women with either natural or surgical menopause. We observed no effect of the duration of estrogen use independent of age. The findings were similar in analyses limited to women who had recently visited their physicians (relative risk, 0.45; 95 percent confidence interval, 0.31 to 0.66) and in a low-risk group that excluded women reporting current cigarette smoking, diabetes, hypertension, hypercholesterolemia, or a Quetelet index above the 90th percentile (relative risk, 0.53; 95 percent confidence interval, 0.31 to 0.91). The relative risk for current and former users of estrogen as compared with those who had never used it was 0.89 (95 percent confidence interval, 0.78 to 1.00) for total mortality and 0.72 (95 percent confidence interval, 0.55 to 0.95) for mortality from cardiovascular disease. The relative risk of stroke when current users were compared with those who had never used estrogen was 0.97 (95 percent confidence interval, 0.65 to 1.45), with no marked differences according to type of stroke.\n\n\nCONCLUSIONS\nCurrent estrogen use is associated with a reduction in the incidence of coronary heart disease as well as in mortality from cardiovascular disease, but it is not associated with any change in the risk of stroke.

Postmenopausal Estrogen Therapy and Cardiovascular Disease: Ten-Year Follow-Up From the Nursesʼ Health Study

Background: Early natural menopause has been postulated to increase the risk of cardiovascular disease. Objective: To examine the relation of age at natural menopause with risk of coronary heart disease (CHD) and stroke in the Nurses’ Health Study. Methods: Analysis was restricted to 35 616 naturally postmenopausal women who never used estrogen replacement therapy and with no diagnosed cardiovascular disease at baseline, followed up from 1976 to 1994. Information on menopausal status, age at menopause, and other risk factors was obtained in 1976 and updated every 2 years by mailed questionnaires. Results: During 354 326 person-years of follow-up, we documented 757 incident cases of CHD and 350 incident cases of stroke. After adjusting for age, smoking status, and other cardiovascular risk factors, the relative risks (RRs) across categories of age at natural menopause (,40, 40-44, 45-49, 50-54, and $55 years) were 1.53, 1.42, 1.10, 1.00 (reference), and 0.95, respectively; the RR for each 1-year decrease in age at natural menopause was 1.03 (95% confidence interval, 1.01-1.05). Elevated risk with younger age at menopause was observed among current smokers (RR, 1.04 [95% CI, 1.01-1.07] for each 1-year decrease in age at natural menopause) but not among never smokers (RR, 1.00; 95% CI, 0.96-1.04). Age at natural menopause was not significantly associated with ischemic stroke (RR, 1.01; 95% CI, 0.97-1.04) or hemorrhagic stroke (RR, 1.03; 95% CI, 0.97-1.10). Conclusions: We observed an overall significant association between younger age at menopause and higher risk of CHD among women who experienced natural menopause and never used hormone therapy. This increased risk was observed among current smokers but not among never smokers. The apparent elevated risk of CHD with decreased age at natural menopause among smokers might reflect residual confounding by smoking.

/pdf/age-at-natural-menopause-and-risk-of-cardiovascular-disease-4srvvuo7e5.pdf

Charles H. Hennekens

Papers

Low-Dose Aspirin and Incidence of Colorectal Tumors in a Randomized Trial

Prospective Study of Nutritional Factors, Blood Pressure, and Hypertension Among US Women

Severe mental illness and risk of cardiovascular disease.

Postmenopausal Estrogen Therapy and Cardiovascular Disease: Ten-Year Follow-Up From the Nursesʼ Health Study

Age at natural menopause and risk of cardiovascular disease.