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

Finkelstein W, Isselbacher KJ. Cimetidine. N EnglJ_ Med 1978;299:992-6. 2 Harrison AR, Littenberg G, Goldstein L, Kaplowitz N. Pruritus, cimetidine and polycythemia. N EnglJ Med 1979;300:433-4. 3 Zappacosta AR, Hauss D. Cimetidine doesn't help pruritus of uremia. N EnglJ Med 1979;300:1280. 4 Easton P, Galbraith PR. Cimetidine treatment of pruritus in polycythemia vera N EnglJ Med 1978;299:1134. 5 Scott GL, Horton RJ. Pruritus, cimetidine and polycythemia. N Engl J Med 1979;300:434.

https://www.bmj.com/content/bmj/280/6218/939.4.full.pdf

Clearance of bacteriuria on discontinuing oral contraception.

OBJECTIVES Coronary heart disease often presents with ST segment elevation acute myocardial infarction (STEMI). The American College of Cardiology/American Heart Association guidelines stress prompt reperfusion for STEMI. Examining geographic variations in treatment with PPCI (percutaneous primary coronary intervention) and CABG (coronary artery bypass graft) among metropolitan, micropolitan and non-micropolitan rural residents provides a descriptive basis for generating hypotheses concerning place and receipt of guidelines-based treatment. METHODS Using ICD-9 codes for STEMI and excluding beneficiaries with pre-existing MI in claims data, yielded a subset of 18,775 Tennessee Medicare beneficiaries experiencing STEMI from 1996 to 2002. The outcome variable is type of treatment, i.e., in accord (PPCI or CABG present) or not in accord (PPCI or CABG absent) with guidelines. Independent variables include type county residence, hospital volume, race, gender, and age. Analyses include cross-tabulation and logistic regression, estimating separate models by age and type of MI. RESULTS Micropolitan residents with STEMI have the lowest rates for PPCI (18.8%) versus 28.1% percent for metropolitan and 24.2% for non-micropolitan rural residents. CABG follows similar patterns at lower overall rates. Treatment at a heart center with high volume PPCI mediated the relationship between the likelihood of PPCI and place. CONCLUSION The correspondence between metropolitan and rural utilization suggests that access to a full range of treatment options and likelihood of "best practice" care is not dependent on metropolitan residence. This presents the possibility that with some policy changes, e.g., centralization of emergency heart care, the same may ultimately be true for micropolitan residents.

Geographic variations in percutaneous coronary interventions and coronary artery bypass graft surgery among Tennessee elders.

Randomized trials designed a priori to test particular hypotheses provide the most reliable evidence concerning the most plausible small-to-moderate effects of drug therapies or interventions and are a necessary component of a totality of evidence upon which to make rational clinical decisions for individual patients and policy decisions for the health of the general public. As the methodology for the design, conduct and analysis of randomized trials continues to evolve, so do the principles and practical suggestions for their Data and Safety Monitoring Boards (DSMB)s. The implementation of these principles and practical suggestions should enhance the functioning of DSMBs, trial investigators and sponsors, protect the safety of the randomized subjects as well as the independence and integrity of the randomized trials.

https://www.openaccessjournals.com/articles/data-and-safety-monitoring-boards-of-randomized-trials-evolving-principles-and-practical-suggestions.pdf

Data and safety monitoring boards of randomized trials: evolving principles and practical suggestions

Statistics of Coffee Drinking and Myocardial Infarction

The average lifespan of Americans is currently at a record high, having increased 3.8 years overall from 1970 to 1983.1The life expectancy of women, however, is still markedly higher than that of men. At 1983 US death rates, women can expect to live 78.3 years, while the corresponding figure for men is 71 years. The favorable survival experience of women has been due, in part, to their lower rates of lung cancer, the chief cause of cancer deaths, and of coronary heart disease (CHD), the leading cause of all US deaths. In contrast to this encouraging news is the fact that, at present, cigarette smoking is known to be responsible for 85% to 90% of the approximately 120,000 annual lung cancer deaths expected this year in the United States (plus several tens of thousands of other cancer deaths),2as well as perhaps 20% or more of all

Charles H. Hennekens

Papers

Clearance of bacteriuria on discontinuing oral contraception.

Geographic variations in percutaneous coronary interventions and coronary artery bypass graft surgery among Tennessee elders.

Data and safety monitoring boards of randomized trials: evolving principles and practical suggestions

Statistics of Coffee Drinking and Myocardial Infarction

Smoking and coronary heart disease in women.