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

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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

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

The recent publication of a new meta-analysis of 14 randomized trials of antihypertensive drug therapy in the Lancet has heightened the debate regarding the benefits of treatment of hypertension. 1,2 There is little disagreement that pharmacologic therapy results in a decrease in strokes and in stroke deaths, reduction in the occurrence of congestive heart failure, reversal of left ventricular hypertrophy in more patients receiving treatment than on placebo or control, and a reduction in the rate of progression of renal disease in adequately treated hypertensive subjects. 3-7 This article stems from the finding in the new meta-analysis that hypertension treatment results in a significant reduction in coronary heart disease (CHD). Although previous individual trials and overviews have suggested reductions of a similar magnitude, these findings have been dismissed as unimportant because statistical significance was not achieved. 2 This most recent and comprehensive meta-analysis included over 37 000 patients treated for

An overview of the meta-analyses of the hypertension treatment trials.

It is known that cigarette smoking is associated with increased risk of both thrombotic and hemorrhagic stroke among men. To test for such an association among women, we examined the incidence of stroke in relation to cigarette smoking in a prospective cohort study of 118,539 women 30 to 55 years of age and free from coronary heart disease, stroke, and cancer in 1976. During eight years of follow-up (908,447 person-years), we identified 274 strokes, comprising 71 subarachnoid hemorrhages, 26 intracerebral hemorrhages, 122 thromboembolic strokes, and 55 strokes about which information was insufficient to permit classification. The number of cigarettes smoked per day was associated positively with the risk of stroke. Compared with the women who had never smoked, those who smoked 1 to 14 cigarettes per day had an age-adjusted relative risk of 2.2 (95 percent confidence interval, 1.5 to 3.3), whereas those who smoked 25 or more cigarettes per day had a relative risk of 3.7 (95 percent confidence interval, 2.7 to 5.1). For women in this latter group, the relative risk of subarachnoid hemorrhage was 9.8 (95 percent confidence interval, 5.3 to 17.9), as compared with those who had never smoked. Adjustment for the effects of relative weight, hypertension, diabetes, history of high cholesterol, previous use of oral contraceptives, postmenopausal estrogen therapy, and alcohol intake did not appreciably alter the association between cigarette use and incidence of stroke. These prospective data support a strong causal relation between cigarette smoking and stroke among young and middle-aged women.

Cigarette Smoking and Risk of Stroke in Middle-Aged Women

Time trends in hospital mortality and diagnosis of pulmonary embolism.

Age-related macular degeneration (AMD) is the leading cause of irreversible blindness in the United States.1Approximately 25% of people aged 65 years and older have some manifestation of this disease, including large or confluent drusen, retinal pigmentary changes, geographic atrophy, and exudative disease.2Since the elderly make up an increasing proportion of the population, it is estimated that 6.3 million persons will have AMD by the year 2030. This disease, therefore, has important implications for the individual patient as well as the general public. At present, the causes of AMD are unknown and we therefore cannot prevent it. We do not fully understand factors leading to its progression, so early stages cannot be arrested. The only proven method of treatment, laser photocoagulation, is effective for only a small fraction of patients, and vision is often impaired despite treatment.3For these reasons, antioxidant vitamins and minerals represent particularly

Vitamins, minerals, and macular degeneration. Promising but unproven hypotheses.

Background—In several observational studies, patients prescribed calcium channel blockers had higher risks of cardiovascular diseases and mortality than those prescribed other antihypertensive medications. We explored these associations in the Nurses’ Health Study. Methods and Results—A total of 14 617 women who reported hypertension and regular use of diuretics, β-blockers, calcium channel blockers, ACE inhibitors, or a combination in 1988 were included in the analyses. Cardiovascular events and deaths were ascertained through May 1, 1994. We documented 234 cases of myocardial infarction. Calcium channel blocker monodrug users had an age-adjusted relative risk (RR) of myocardial infarction of 2.36 (95% CI, 1.43 to 3.91) compared with those prescribed thiazide diuretics. Women prescribed calcium channel blockers had a higher prevalence of ischemic heart disease. After adjustment for these and other coronary risk factors, the RR was 1.64 (95% CI, 0.97 to 2.77). Comparing the use of any calcium channel bloc...

https://www.ahajournals.org/doi/pdf/10.1161/01.CIR.97.16.1540

Charles H. Hennekens

Papers

An overview of the meta-analyses of the hypertension treatment trials.

Cigarette Smoking and Risk of Stroke in Middle-Aged Women

Time trends in hospital mortality and diagnosis of pulmonary embolism.

Vitamins, minerals, and macular degeneration. Promising but unproven hypotheses.

Prospective Study of Calcium Channel Blocker Use, Cardiovascular Disease, and Total Mortality Among Hypertensive Women The Nurses’ Health Study