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 December 22, 2021, the US Food and Drug Administration (FDA) granted an Emergency Use Authorization (EUA) for the first oral antiviral, a pill containing 2 protease inhibitors, nirmatrelvir and ritonavir (Paxlovid, Pfizer), for the early treatment of coronavirus disease 2019 (COVID-19).1FDA News Release. Coronavirus (COVID-19) update: FDA authorizes first oral antiviral for treatment of COVID-19.https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-authorizes-first-oral-antiviral-treatment-covid-19. Accessed February 2, 2022.Google Scholar This drug was approved for adults 18 years of age and older with acute COVID-19 as well as having a prespecified risk factor for progression to severe disease or 60 years of age or older regardless of chronic medical conditions. The pivotal trial enrolled high-risk newly infected patients who had neither received a COVID-19 vaccine nor had been previously infected. The prespecified primary outcome was hospitalization due to COVID-19 or death from any cause during 28 days of follow-up. Among 2085 randomized subjects, the primary outcome occurred in 0.8% of 1039 who received the active drug (1 death) and 7.8% of 1046 given placebo (10 deaths), a highly significant 88% reduction.1FDA News Release. Coronavirus (COVID-19) update: FDA authorizes first oral antiviral for treatment of COVID-19.https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-authorizes-first-oral-antiviral-treatment-covid-19. Accessed February 2, 2022.Google Scholar The following day, the FDA issued another EUA for a novel viral RNA polymerase inhibitor, molnupiravir (Merck/Ridgeback Biotherapeutics). In January 2022, advisers to the FDA debated the benefits and risks. First, the benefit is far lower than for nirmatrelvir and ritonavir, and second, risks include the possibility of mutations that might make the virus more dangerous or transmissible.2The COVID-19 Treatment Guidelines Panel. Statement on therapies for high-risk, nonhospitalized patients with mild to moderate COVID-19. Available at:https://www.covid19treatmentguidelines.nih.gov/therapies/statement-on-therapies-for-high-risk-nonhospitalized-patients/. Accessed February 2, 2022.Google Scholar In a randomized trial in 1408 randomized subjects, the primary outcome occurred in 6.8% among 709 assigned to molnupriavir and 9.7% of 699 given a placebo, a significant but, much lower, 30% reduction. The advisory committee was split on molnupriavir, with a 13-10 vote approving the drug.3FDA News Release. Coronavirus (COVID-19) update: FDA authorizes additional oral antiviral for treatment of COVID-19 in certain adults. Available at:https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-authorizes-first-oral-antiviral-treatment-covid-19. Accessed February 2, 2022.Google Scholar We express optimism to health providers regarding the potentially large clinical and public health impacts of their judicious prescription of the new oral antiviral drugs to prevent progression of early COVID-19 in high-risk patients, as well as their wider use of vaccines to prevent severe and fatal COVID-19 infections. With respect to early preemptive antiviral therapy, the new oral antiviral drugs are projected to cost approximately $500 and can be taken at home.1FDA News Release. Coronavirus (COVID-19) update: FDA authorizes first oral antiviral for treatment of COVID-19.https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-authorizes-first-oral-antiviral-treatment-covid-19. Accessed February 2, 2022.Google Scholar,3FDA News Release. Coronavirus (COVID-19) update: FDA authorizes additional oral antiviral for treatment of COVID-19 in certain adults. Available at:https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-authorizes-first-oral-antiviral-treatment-covid-19. Accessed February 2, 2022.Google Scholar To preserve antiviral efficacy for as long as possible, these drugs must be prescribed judiciously by health care providers. This implies that the oral antiviral drug should be prescribed to patients with symptoms of COVID-19 within 5 days as well as proof of a positive standardized diagnostic test. These drugs should not be prescribed for either worried uninfected patients or immunized infected patients at low risk of progression to severe disease. Health care providers should be aware that their unrestricted widespread prescription and prolonged use will likely accelerate the emergence and rapid spread of variants highly resistant to these promising drugs, as occurred with amantadine and rimantadine for influenza4Centers for Disease Control and Prevention (CDC). Influenza antiviral drug resistance. Available at: https://www.cdc.gov/flu/treatment/antiviralresistance.htm. Accessed February 2, 2022.Google Scholar and following the introduction and widespread single-drug use of zidovudine (AZT) for HIV infection.5Wainberg MA Brenner BG Turner D Changing patterns in the selection of viral mutations among patients receiving nucleoside and nucleotide drug combinations directed against human immunodeficiency virus type 1 reverse transcriptase.Antimicrob Agents Chemother. 2005; 49: 1671-1678https://doi.org/10.1128/AAC.49.5.1671-1678.2005Crossref PubMed Scopus (22) Google Scholar In regard to the enormous importance of vaccination for prevention, on December 27, 2021, unvaccinated patients had 10 times the risk of becoming infected and 20 times the risk of death from COVID-19, compared with the fully vaccinated who had also received a booster. This implies that the risk of death from COVID-19 among patients receiving 2 doses and a booster is no higher than that from influenza. Moreover, the unvaccinated had 5 times the risk of becoming infected and 14 times the risk of death from COVID-19, compared with those who were vaccinated but had not received a booster.6Centers for Disease Control and Prevention. COVID data tracker. Cases and deaths by vaccination status. Available at: https://covid.cdc.gov/covid-data-tracker/#datatracker-home. Accessed February 2, 2022.Google Scholar In the United States, fortunately, health care providers are the most trusted professionals by the general public, especially for reliable information about COVID-19.7Hamel L, Kirzinger A, Muñana C, et al. KFF COVID-19 Vaccine Monitor December 2020. Kaiser Family Foundation. Available at:https://www.kff.org/coronavirus-covid-19/report/kff-covid-19-vaccine-monitor-december-2020/. Accessed February 2, 2022.Google Scholar Health care providers already have and will continue to play a crucial role in reducing preventable morbidity and mortality from COVID-19. Today, their powerful advocacy of more widespread vaccinations is crucial to the primary prevention of COVID-19. In addition, they are now able to add to their armamentarium against COVID-19 their judicious prescription of the new antiviral drugs for high-risk, newly infected patients as soon as possible following their diagnosis, or within 5 days of the onset of symptoms.1FDA News Release. Coronavirus (COVID-19) update: FDA authorizes first oral antiviral for treatment of COVID-19.https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-authorizes-first-oral-antiviral-treatment-covid-19. Accessed February 2, 2022.Google Scholar In the prescription of oral antivirals, health care providers will need to inform their patients and monitor their side effects, which include renal, hepatic, and adverse interactions with other widely prescribed and used drugs.1FDA News Release. Coronavirus (COVID-19) update: FDA authorizes first oral antiviral for treatment of COVID-19.https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-authorizes-first-oral-antiviral-treatment-covid-19. Accessed February 2, 2022.Google Scholar Access will be an issue for several months, but it is encouraging that the US government has already bought 10 million courses of treatment from Pfizer for $5 billion.1FDA News Release. Coronavirus (COVID-19) update: FDA authorizes first oral antiviral for treatment of COVID-19.https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-authorizes-first-oral-antiviral-treatment-covid-19. Accessed February 2, 2022.Google Scholar As of February 1, 2022, the omicron variant accounts for >99%% of all US cases. Omicron was, not surprisingly, first detected in South Africa and the United Kingdom, a tribute to their robust genomic surveillance of COVID-19. Notably, the United Kingdom leads the world in genomic surveillance and South Africa is in the top 10, whereas the U.S. is ranked 43rd. It is clear that omicron is far more transmissible but also less virulent than the delta variant. The United States needs to conduct far greater genomic surveillance to detect emerging variants as early as possible, especially variants that are even more resistant to the first-generation vaccines and that might be more virulent to more effectively target preventive efforts, particularly new adaptive vaccines.8Robishaw JD Alter SM Solano JJ et al.Genomic surveillance to combat COVID-19: challenges and opportunities.Lancet-Microbe. 2021; 2: e481-e484Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar In summary, health care providers must remain cognizant that achieving much higher vaccination rates is essential to prevent, mitigate, and control the US epidemic and the worldwide pandemic and to stem the continued ravaging of health care systems around the world. Failure to greatly reduce the incidence of active COVID-19 in the United States and worldwide will predictably accelerate the emergence and spread of vaccine-resistant and more virulent strains associated with greater transmissibility, giving life to the specter of global deaths from COVID-19 surpassing the number of deaths from the great influenza pandemic of 1918, which has already occurred in the United States, and complete devastation of health care systems and collapse of national economies. Health providers and political leaders must unite to urgently address “vaccine misinformation” and eliminate “vaccine hesitancy,” which are fueling the current epidemic of COVID-19 in the United States, primarily among the unvaccinated.9Loomba S de Figueiredo A Piatek SJ, et al.Measuring the impact of COVID-19 vaccine misinformation on vaccination intent in the UK and USA.Nat Hum Behav. 2021; 5: 337-348https://doi.org/10.1038/s41562-021-01056-1Crossref PubMed Scopus (345) Google Scholar We dedicate this manuscript to the memory of our valued mentor, colleague, and dear friend, Donald B. Louria, MD (1928-2001). 

http://www.amjmed.com/article/S0002934322001954/pdf

Cautious Optimism and Considerations for Health Providers and Patients: Oral Antiviral for Early Treatment of High-Risk Patients and Vaccines for Prevention of COVID-19

Dr Wagner notes the paucity of secondary prevention data and virtual lack of primary prevention data concerning cholesterol lowering with statin drugs in women. While awaiting the accumulation of direct data from trials, 1 we believe the overall results rather than sex-specific subgroup analyses provide the most reliable estimates of treatment effects. 2 Further, in the large-scale secondary prevention trials, there do not appear to be qualitative differences in treatment effects between men and women. Thus, it would be unusual to find qualitative differences between men and women in cardiovascular disease benefits in the ongoing primary prevention trials.

Cholesterol Lowering With Statin Drugs: Evidence in Women-Reply

Myocardial infarction: acute and chronic aspirin use

In Reply —Ms Karns and Ms Cullison erroneously suggest that we failed to consider an important point—the possibility of biased selection into the study of only the healthiest women This is incorrect, because only about 10% of the approximately 400 000 participants in the Women's Health Study are also participating in the Women's Health Study randomized trial of aspirin and vitamin E and signed a consent to avoid taking aspirin or other platelet-active drugs for the duration of the trial They correctly suggest that the observed 24% increase may be an underestimate, but fail to consider that an overestimate is also plausible 1 Specifically, among women with breast implants, physicians may be more likely to diagnose and participants may be more likely to report connective-tissue diseases Dr Romano raises the issue of the importance of considering atypical connective-tissue diseases such as fibromyalgia, an issue that had not been hypothesized when the Mayo Clinic

Charles H. Hennekens

Papers

Cautious Optimism and Considerations for Health Providers and Patients: Oral Antiviral for Early Treatment of High-Risk Patients and Vaccines for Prevention of COVID-19

Cholesterol Lowering With Statin Drugs: Evidence in Women-Reply

Myocardial infarction: acute and chronic aspirin use

Breast Implants and Connective-Tissue Disease-Reply

The Crucial and Urgent Role of Family Physicians in Increasing COVID-19 Vaccinations