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

On September 2, 2022, the US Food and Drug Administration (FDA) issued emergency use authorizations and the Centers for Disease Control and Prevention immediately endorsed use of new boosters created to combat the most recent and highly prevalent omicron variants of coronavirus disease 2019 (COVID-19), namely BA.4 and BA.5.1,2 Fortunately, these most recent and most highly prevalent variants, while more communicable, are less lethal. Health care providers should be aware that more widespread vaccinations with these boosters now can avoid the specter of future and more lethal variants becoming realities. 

http://www.amjmed.com/article/S0002934322007264/pdf

Newest Guidance and Evidence for Health Care Providers: COVID-19 and Other Vaccines

Risk factors for coronary artery disease were present to a greater degree in children of men who had experienced premature myocardial infarction when compared to children of unaffected male parents. Levels' of cholesterol and body weight, as well as family history of premature CAD, differed significantly between the groups of children. The chance of identifying a chiM with hyperlipidemia was three times greater if the father had premature CAD. Data regarding familial aggregation of risk factors for CAD are reviewed and their significance discussed.

Risk factors for coronary artery children of affected families disease in

https://ajph.aphapublications.org/doi/pdf/10.2105/AJPH.2009.170795

IncreasedBlack-WhiteDisparitiesinMortalityAfter theIntroductionofLifesavingInnovations:APossible ConsequenceofUSFederalLaws

Antithrombotic and thrombolytic therapies confer clear net benefits in the treatment of acute myocardial infarction. Antithrombotic therapy with aspirin yields conclusive reductions in vascular mortality as well as reinfarction and stroke, and should be administered to all patients with suspected acute myocardial infarction. There is presently no clear evidence of net benefits from adding either delayed subcutaneous or immediate intravenous heparin to an antithrombotic regimen of aspirin. Direct thrombin inhibitors have theoretical advantages over heparin as antithrombotic agents, but further data are needed from large-scale randomized trials to determine whether these agents confer net benefits when given in conjunction with aspirin. Thrombolytic therapy yields clear reductions in mortality and should be considered for all patients with suspected acute myocardial infarction presenting within 12 h of symptom onset. The differences in the efficacy, safety or ease of administration of the various thrombolytic agents are small compared with the substantial benefits that would result from the wider use and earlier administration of any of the available agents. More widespread use of antithrombotic and thrombolytic therapies for acute myocardial infarction could prevent tens of thousands of premature deaths annually in the USA alone, and hundreds of thousands worldwide.

Antithrombotic and thrombolytic therapies for acute myocardial infarction.

In Reply. —Our article on the TOHP Phase I results elicited contrasting reactions regarding the lack of an effect of stress management on blood pressure. Dr David appears not to be surprised by the outcome, and speculates that we were intervening too late in the natural history, after the effects of chronic stress become self-sustaining. Unfortunately, the mechanisms that mediate stress-related elevations of blood pressure are poorly understood, and the role of episodic, stress-related elevations of blood pressure (cardiovascular reactivity) in the development of sustained hypertension remains unresolved. 1 Also, this interpretation is somewhat at variance with results of a meta-analysis that suggested a benefit for diastolic blood pressure in already hypertensive individuals. 2 David's prediction about lack of an effect of the TOHP intervention on catecholamine and cortisol excretion is borne out by preliminary analyses, although whether this represents swamping of chronic effects by acute stresses is unclear. Dr

Charles H. Hennekens

Papers

Newest Guidance and Evidence for Health Care Providers: COVID-19 and Other Vaccines

Risk factors for coronary artery children of affected families disease in

IncreasedBlack-WhiteDisparitiesinMortalityAfter theIntroductionofLifesavingInnovations:APossible ConsequenceofUSFederalLaws

Antithrombotic and thrombolytic therapies for acute myocardial infarction.

Distress Over the Noneffect of Stress-Reply