Comparative Risk of Harm Associated With the Use of Targeted Immunomodulators: A Systematic Review.

OBJECTIVE: To systematically compare the risk of adverse events (AEs) for 13 targeted immunomodulators (TIMs) indicated for ankylosing spondylitis (AS), inflammatory bowel diseases, juvenile idiopathic arthritis, plaque psoriasis, psoriatic arthritis (PsA), or rheumatoid arthritis (RA). METHODS: We searched electronic databases through July 2015 to retrieve randomized controlled trials (RCTs) and observational studies comparing AEs between 2 or more TIMs head-to-head. We reported on the following outcomes: number of AEs, discontinuation due to AEs, serious AEs, mortality, serious infections, tuberculosis, herpes zoster, and malignancies. We qualitatively synthesized the literature and conducted random-effects meta-analyses if 3 or more studies provided data for an outcome. RESULTS: Ten head-to-head RCTs and 51 observational studies were included in this systematic review. A majority of the studies (70%) were conducted in RA patients. Risk of treatment discontinuation due to AEs was higher with infliximab than with adalimumab or etanercept in RA, PsA, and AS. A higher risk for serious infections was noted with infliximab than with abatacept, adalimumab, or etanercept in RA. Risk for treatment discontinuation due to AEs, serious infections, and tuberculosis was lower with etanercept than with adalimumab in RA. Limited evidence suggested no comparative differences in risk for mortality, malignancies, and herpes zoster for adalimumab, etanercept, and infliximab in RA. CONCLUSION: Important differences were noted in the safety profile of TIMs in RA, generally favoring abatacept, adalimumab, and etanercept over infliximab. Head-to-head comparative evidence for other TIMs and non-RA populations was insufficient to draw conclusions for most of the safety outcomes.

Information overload in healthcare: too much of a good thing?

The rapidly growing production of healthcare information - both scientific and popular - increasingly leads to a situation of information overload affecting all actors of the healthcare system and threatening to impede the adoption of evidence-based practice. In preparation for the 2015 Cochrane Colloquium in Vienna, we discuss the issues faced by three major actors of this system: patients, healthcare practitioners, and systematic reviewers. We analyze their situation through the concept of "filter failure", positing that the main problem is not that there is "too much information", but that the traditional means of managing and evaluating information are ill-suited to the realities of the digital age. Some of the major instances of filter failure are inadequate information retrieval systems for point-of-care settings, the problem of identifying all relevant evidence in an exceedingly diverse landscape of information resources, and the very basic lack of health information literacy, concerning not only the general public. Finally, we give an overview of proposed solutions to the problem of information overload. These new or adapted filtering systems include adapting review literature to the specific needs of practitioners or patients, technological improvements to information systems, strengthening the roles of intermediaries, as well as improving health literacy.

Barriers to and facilitators of interventions to counter publication bias: thematic analysis of scholarly articles and stakeholder interviews.

BACKGROUND: When the nature and direction of research results affect their chances of publication, a distortion of the evidence base - termed publication bias - results. Despite considerable recent efforts to implement measures to reduce the non-publication of trials, publication bias is still a major problem in medical research. The objective of our study was to identify barriers to and facilitators of interventions to prevent or reduce publication bias. METHODS: We systematically reviewed the scholarly literature and extracted data from articles. Further, we performed semi-structured interviews with stakeholders. We performed an inductive thematic analysis to identify barriers to and facilitators of interventions to counter publication bias. RESULTS: The systematic review identified 39 articles. Thirty-four of 89 invited interview partners agreed to be interviewed. We clustered interventions into four categories: prospective trial registration, incentives for reporting in peer-reviewed journals or research reports, public availability of individual patient-level data, and peer-review/editorial processes. Barriers we identified included economic and personal interests, lack of financial resources for a global comprehensive trial registry, and different legal systems. Facilitators identified included: raising awareness of the effects of publication bias, providing incentives to make data publically available, and implementing laws to enforce prospective registration and reporting of clinical trial results. CONCLUSIONS: Publication bias is a complex problem that reflects the complex system in which it occurs. The cooperation amongst stakeholders to increase public awareness of the problem, better tailoring of incentives to publish, and ultimately legislative regulations have the greatest potential for reducing publication bias.

A case study of pooled-studies publications indicated potential for both valuable information and bias.

OBJECTIVES: Pooled-studies publications (PSPs) present statistical analyses of multiple randomized controlled trials without a systematic literature search or critical appraisal. We explored the characteristics of PSPs and their potential impact on a systematic review (SR). STUDY DESIGN AND SETTING: We systematically evaluated PSPs excluded from an SR of second-generation antidepressants. We analyzed their basic characteristics, risk of bias, and the effect of new data on review conclusions. RESULTS: We identified 57 PSPs containing a median of five trials (range, 2-11) and 1,233 patients (range, 117-2,919). Ninety-six percent of PSPs were industry funded, and 49% of PSPs contained unpublished data. The median number of citations for PSPs was 29 (range, 0-549). Only 7% planned pooling a priori, and 19% combined trials with identical protocols. Fifty-nine percent of PSPs eligible for general efficacy provided no new data. For some subgroups and accompanying symptoms (e.g., anxiety, insomnia, melancholia, fatigue, sex, and race), more than 30% of PSPs presented entirely new data or data that could alter the strength of the evidence available in the SR. CONCLUSION: In this case study, PSPs provided new information on subgroups and secondary outcomes; however, guidance for reviewers and development of a system to assess their susceptibility to bias are required.

Adjunct ultrasonography for breast cancer screening in women at average risk: a systematic review.

BACKGROUND: Screening with mammography has the ability to detect breast cancer at an early stage but misses some cancers. Supporters of adjunct ultrasonography to the screening regimen argue that it might be a safe and inexpensive approach to reduce the false-negative rates of screening. Critics are concerned that adjunct ultrasonography will also increase the rate of false-positive findings and can lead to unnecessary biopsies and treatments in women at average risk. AIMS: The purpose of this review was to systematically assess the comparative benefits and harms of mammography with adjunct breast ultrasonography and mammography only in breast cancer screening. METHODS: We searched multiple electronic databases and the Cochrane Breast Cancer Group's Specialised Register (from 1995 to February 2012). To detect ongoing or unpublished studies, we searched trial registries and multiple sources of grey literature. Two researchers independently reviewed all abstracts and full-text articles against pre-defined eligibility criteria. We dually rated the risk of bias of studies and the strength of evidence based on established guidance. RESULTS: We did not detect any controlled studies that provide evidence for (or against) the use of adjunct ultrasonography for screening in women at average risk for breast cancer. Extrapolations of results from women at elevated risk for breast cancer indicate that the false-positive rates in women at average risk who were recalled because of positive ultrasonographies will exceed 98%. In women with dense or very dense breast tissue, the evidence regarding the use of adjunct ultrasonography is not conclusive. CONCLUSIONS: No methodologically sound evidence is available justifying the routine use of ultrasonography as an adjunct screening tool in women at average risk for breast cancer. IMPLICATIONS FOR PRACTICE: Clinicians should not use ultrasonography as a screening tool for breast cancer screening on a routine basis. The use should be limited to women with dense breasts for whom the accuracy of mammography is low, or for diagnostic purposes.

Comparative effectiveness of second-generation antidepressants for accompanying anxiety, insomnia, and pain in depressed patients: a systematic review.

BACKGROUND: Patients with major depressive disorder (MDD) often suffer from accompanying symptoms that influence the choice of pharmacotherapy with second-generation antidepressants (SGAs). We conducted a systematic review to determine the comparative effectiveness of citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, desvenlafaxine, duloxetine, venlafaxine, bupropion, mirtazapine, nefazodone, and trazodone, for accompanying anxiety, insomnia, and pain in patients with MDD. METHODS: We conducted searches in multiple databases including MEDLINE®, Embase, the Cochrane Library, International Pharmaceutical Abstracts, and PsycINFO, from 1980 through August 2011 and reviewed reference lists of pertinent articles. We dually reviewed abstracts, full-text articles, and abstracted data. We included randomized, head-to-head trials of SGAs of at least 6 weeks' duration. We grouped SGAs into three classes for the analysis: selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors, and others. We graded the strength of the evidence as high, moderate, low, or very low based on the Grading of Recommendations Assessment, Development and Evaluation (GRADE) Working Group (GRADE) approach. RESULTS: We located 19 head-to-head trials in total: 11 on anxiety, six on insomnia, and four on pain. For the majority of comparisons, the strength of the evidence was moderate or low: evidence is weakened by inconsistency and imprecision. For treating anxiety, insomnia, and pain moderate evidence suggests that the SSRIs do not differ. CONCLUSIONS: Evidence guiding the selection of an SGA based on accompanying symptoms of depression is limited. Very few trials were designed and adequately powered to answer questions about accompanying symptoms; analyses were generally of subgroups in larger MDD trials.