Objective To ascertain the current burden of adverse drug reactions (ADRs) through a prospective analysis of all admissions to hospital. Design Prospective observational study. Setting Two large general hospitals in Merseyside, England. Participants 18 820 patients aged > 16 years admitted over six months and assessed for cause of admission. Main outcome measures Prevalence of admissions due to an ADR, length of stay, avoidability, and outcome. Results There were 1225 admissions related to an ADR, giving a prevalence of 6.5%, with the ADR directly leading to the admission in 80% of cases. The median bed stay was eight days, accounting for 4% of the hospital bed capacity. The projected annual cost of such admissions to the NHS is £466m (€706m, $847m). The overall fatality was 0.15%. Most reactions were either definitely or possibly avoidable. Drugs most commonly implicated in causing these admissions included low dose aspirin, diuretics, warfarin, and non-steroidal anti-inflammatory drugs other than aspirin, the most common reaction being gastrointestinal bleeding. Conclusion The burden of ADRs on the NHS is high, accounting for considerable morbidity, mortality, and extra costs. Although many of the implicated drugs have proved benefit, measures need to be put into place to reduce the burden of ADRs and thereby further improve the benefit:harm ratio of the drugs.

https://www.bmj.com/content/bmj/329/7456/15.full.pdf

Adverse drug reactions as cause of admission to hospital: prospective analysis of 18 820 patients

Angina/Non-ST-Elevation Myocardial Infarction : ACC/AHA 2007 Guidelines for the Management of Patients With Unstable ISSN: 1524-4539 Copyright © 2007 American Heart Association. All rights reserved. Print ISSN: 0009-7322. Online 72514 Circulation is published by the American Heart Association. 7272 Greenville Avenue, Dallas, TX doi: 10.1161/CIRCULATIONAHA.107.18194

https://cdr.lib.unc.edu/downloads/vd66w2108

ACC/AHA 2007 Guidelines for the Management of Patients With Unstable Angina/Non-ST-Elevation Myocardial Infarction. A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients With Unstable Angina/Non-ST-Elevation Myocardial Infarction)...

Background Anemia, a common complication of chronic kidney disease, usually develops as a consequence of erythropoietin deficiency. Recombinant human erythropoietin (epoetin alfa) is indicated for the correction of anemia associated with this condition. However, the optimal level of hemoglobin correction is not defined. Methods In this open-label trial, we studied 1432 patients with chronic kidney disease, 715 of whom were randomly assigned to receive a dose of epoetin alfa targeted to achieve a hemoglobin level of 13.5 g per deciliter and 717 of whom were assigned to receive a dose targeted to achieve a level of 11.3 g per deciliter. The median study duration was 16 months. The primary end point was a composite of death, myocardial infarction, hospitalization for congestive heart failure (without renal replacement therapy), and stroke. Results A total of 222 composite events occurred: 125 events in the high-hemoglobin group, as compared with 97 events in the low-hemoglobin group (hazard ratio, 1.34; 95% confidence interval, 1.03 to 1.74; P = 0.03). There were 65 deaths (29.3%), 101 hospitalizations for congestive heart failure (45.5%), 25 myocardial infarctions (11.3%), and 23 strokes (10.4%). Seven patients (3.2%) were hospitalized for congestive heart failure and myocardial infarction combined, and one patient (0.5%) died after having a stroke. Improvements in the quality of life were similar in the two groups. More patients in the high-hemoglobin group had at least one serious adverse event. Conclusions The use of a target hemoglobin level of 13.5 g per deciliter (as compared with 11.3 g per deciliter) was associated with increased risk and no incremental improvement in the quality of life. (ClinicalTrials.gov number, NCT00211120.)

https://www.nejm.org/doi/pdf/10.1056/NEJMoa065485

Correction of Anemia with Epoetin Alfa in Chronic Kidney Disease

The mismatch negativity (MMN) in basic research of central auditory processing: a review.

http://hwmaint.circ.ahajournals.org/cgi/reprint/110/9/e82.pdf

ACC/AHA Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction

To establish the evidence base for the diagnosis of sleep apnea (SA) in adult patients, a systematic review of the literature from 1980 through November 1, 1997 was performed. Diagnostic studies were included if they reported results of any test to establish or support a diagnosis of SA, in comparison to a diagnosis from a full polysomnogram (PSG). Test results were meta-analyzed using fixed effects models and summary receiver operating characteristic curves (ROCs) to examine consistency of tests within and between diagnostics vs. the "gold standard" of PSG. From a total of 937 studies, 249 fit the broad eligibility criteria for inclusion in the clinical trial database and its data were extracted from these reports; useable data for statistical analyses were reported in 71 studies (7,572 patients). The sensitivity and specificity of partial channel and partial time PSGs appeared most promising as replacements for full PSG in patients suspected of obstructive SA. Clinical prediction rules (multivariate models) were also promising. Studies of portable sleep monitors, radiologic or morphologic features, and focused questionnaires were too heterogeneous to be meta-analyzed. In general, the diversity of study designs and objectives were very high and the methodological rigor of these studies as assessments of diagnostic tests was very low. Thus, we are still not in a position to recommend standardization of diagnostic methodology for sleep apnea. Instead, our recommendations for future research include standardization of terms and diagnostic criteria, and consistently reported statistics to enhance the utility of this literature.

/pdf/systematic-review-and-meta-analysis-of-the-literature-3p6m2pokbl.pdf

Systematic Review and Meta-analysis of the Literature Regarding the Diagnosis of Sleep Apnea

Purpose
Uncertain short- and long-term cancer risks with anti-TNF therapies is a concern, and led to a recent black box warning This meta-analysis, requested by the European Medicines Agency, aimed at better assessing short-term risks by using meta-analytic techniques based on individual patient data from all corporate-sponsored randomized controlled trials (RCTs) of adalimumab, etanercept, and infliximab

Methods
All 74 RCTs of TNF inhibitors of at least 4 weeks duration were provided to independent investigators, including case narratives for events occurring between trial start until 30 days after planned end of treatment and indicating a possible cancer Relative risks were estimated using Bayesian piecewise exponential models

Results
One hundred thirty (084%) of 15 418 individuals randomized to anti-TNF therapy were diagnosed with cancer, compared to 48 (064%) of 7486 individuals randomized to comparators The relative risks associated with all anti-TNF were 099 (95%CI 061–168) for cancers excluding non-melanoma skin cancer (NMSC), and 202 (95%CI 111–395) for NMSC There were indications of differences in the relative risks for the three anti-TNF drugs, but also of differences across the cancer rates in the three comparator arms for adalimumab, etanercept, and infliximab

Conclusions
Despite a reassuring overall short-term risk, we could neither refute nor verify that individual anti-TNF therapies affect the short-term clinical emergence of cancer Despite representing the best available evidence, statistical precision, and differences in baseline cancer risk and reporting detail between trials of adilumumab, etanercept, and infliximab hampered distinction of drug-specific from trial effects, illustrating the challenges in safety-assessments using RCT meta-analyses Long-term risk assessment requires observational studies Copyright © 2010 John Wiley & Sons, Ltd

Cancer risk with tumor necrosis factor alpha (TNF) inhibitors: meta‐analysis of randomized controlled trials of adalimumab, etanercept, and infliximab using patient level data

Objective To determine the risk of cardiovascular events and death in patients receiving statin treatment for cholesterol regulation. Methods Systematic review and meta-analysis of all randomized controlled trials that were published as of April 15, 1997. Primary or secondary prevention trials or regression trials were eligible. Main Outcome Measures All-cause mortality, fatal myocardial infarction (MI) or stroke, nonfatal MI or stroke, angina, and withdrawal from the studies. Both random- and fixed-effects models were run for the outcomes of interests, and results are expressed as odds ratios (ORs). Sensitivity analyses tested the impact of the study type and duration, statin treatment type, and control arm event rates. Intent-to-treat denominators were used whenever they were available, and the number needed to treat was calculated when appropriate. Results Seventeen studies (21,303 patients) were included (2 secondary prevention studies, 5 mixed primary-secondary prevention population studies, and 10 regression trials). Treatment groups included lovastatin (t=5), pravastatin (t=10), and simvastatin (t=3). For all-cause mortality, the OR was 0.76 (95% confidence interval [CI], 0.67-0.86) in favor of receiving statin treatment; for fatal MI, the OR was 0.61 (95% CI, 0.48-0.78); for nonfatal MI, the OR was 0.69 (0.54-0.88); for fatal stroke, the OR was 0.77 (95% CI, 0.57-1.04); for nonfatal stroke, the OR was 0.69 (95% CI, 0.54-0.88); and for angina, the OR was 0.70 (95% CI, 0.65-0.76). Conclusions Patients who received statin treatment demonstrated a 20% to 30% reduction in death and major cardiovascular events compared with patients who received placebo. This advantage was generally present across study types and statin treatment types and for patients with less severe dyslipidemias. The benefit in clinical outcomes was noticeable as early as 1 year.

https://jamanetwork.com/journals/jamainternalmedicine/articlepdf/1105635/ioi81023.pdf

Clinical outcomes in statin treatment trials: a meta-analysis.

Bisphosphonate drugs for treating osteoporosis are excreted by the kidney. However, many of the major trials on efficacy and safety of the bisphophonates for treating osteoporosis excluded patients with significant renal compromise. Since both osteoporosis and renal insufficiency become more prevalent with age, it seems prudent for physicians to be aware of the prevalence of renal dysfunction in patients with osteoporosis who are candidates for treatment with bisphosphonates. Data on 13,831 men and women aged 20+ from the Third National Health and Nutrition Examination Survey, 1988-1994 (NHANES III) were used to study the occurrence of compromise in renal clearance function in men and women with osteopenia and osteoporosis. To estimate creatinine clearance (CCr), a measure of renal function, serum creatinine (sCr), weight and age were inserted into the Cockcoft-Gault (C-G) formula. The World Health Organization gender specific bone mineral density (BMD) cut-offs were used to define the populations with osteopenia and osteoporosis. For women ages 20-80+ with osteoporosis, the percent prevalence (95% CI) for mild to moderate compromise of CCr </=60 ml/min is estimated to be 85% (79%, 91%) and for severe renal compromise of CCr <35 ml/min to be 24% (19%, 29%). In women with osteoporosis and severe compromise, the age specific prevalence is negligible through ages 50-59 and then rises steeply to 54% (46%, 62%) for ages 80+. Similarly, in women with osteopenia and severe renal compromise, the age specific prevalence is also negligible through ages 50-59 and then rises to 37% (28%, 45%) for ages 80+. Lower prevalence estimates hold for men with about 11% of men with osteoporosis having severe renal compromise as compared to 24% for women. These data suggest that there is a substantial prevalence of candidates for treatment of osteoporosis and osteopenia who have significant renal compromise but for whom there is a dearth of clinical trial data on the impact of treatment.

Relationship between age, renal function and bone mineral density in the US population

This systematic review and meta-analysis were undertaken to determine whether reduction mammaplasty improves measurable outcomes in women with breast hypertrophy. A systematic review of the literature in 5 languages from 1985 until March 1999 was performed, and data were compared for meta-analysis. Eligible studies were both experimental and observational and involved women with preoperative physical and/or psychosocial signs and symptoms who underwent reduction mammaplasty for breast hypertrophy. Outcomes assessed were postoperative physical signs and symptoms such as shoulder pain, shoulder (bra strap) grooving, and quality-of-life domains, such as physical and psychological functioning, and were expressed primarily as risk differences (RDs). Twenty-nine studies of 4173 patients met all eligibility criteria. Reduction mammaplasty was associated with a statistically significant improvement in physical signs and symptoms involving shoulder pain (RD, 0.71 [95% confidence interval (CI), 0.62-0.80]); shoulder grooving (RD, 0.69 [95% CI, 0.60-0.78]); upper/lower back pain (RD, 0.59 [95% CI, 0.48-0.70]); neck pain (RD, 0.50 [95% CI, 0.37-0.64]); intertrigo (RD, 0.44 [95% CI, 0.34-0.54]); breast pain (RD, 0.36 [95% CI, 0.17-0.55]); headache (RD, 0.28 [95% CI, 0.11-0.46]); and pain/numbness in the hands (RD, 0.11 [95% CI, 0.04-0.18]). The quality-of-life parameter of physical functioning was also statistically significant (RD, 0.58 [95% CI, 0.44-0.71]), while psychological functioning was not significant (RD, 0.46 [95% CI, 0.00-1.00]). The evidence suggests that women undergoing reduction mammaplasty for breast hypertrophy have significant postoperative improvement in preoperative signs and symptoms, quality of life, or both.

Susan D. Ross

Papers

Systematic Review and Meta-analysis of the Literature Regarding the Diagnosis of Sleep Apnea

Cancer risk with tumor necrosis factor alpha (TNF) inhibitors: meta‐analysis of randomized controlled trials of adalimumab, etanercept, and infliximab using patient level data

Clinical outcomes in statin treatment trials: a meta-analysis.

Relationship between age, renal function and bone mineral density in the US population

Clinical outcomes in reduction mammaplasty: a systematic review and meta-analysis of published studies.