Brian Hutton

Meta-analysis: intravenous immunoglobulin in critically ill adult patients with sepsis.

Context Effects of polyclonal intravenous immunoglobulin therapy (IVIG) on the mortality rate of critically ill patients with sepsis are unclear. Contribution This meta-analysis of 20 randomized trials that studied 2621 critically ill adult patients with sepsis found that treatment with polyclonal IVIG decreased the risk for death more than placebo or no intervention (risk ratio, 0.74 [95% CI, 0.62 to 0.89]). Survival benefits seemed most prominent with higher doses and prolonged administration of IVIG and in more severely ill patients. Cautions Because most trials had methodological limitations and were performed before modern intensive care management strategies, the authors recommend that a large trial be performed to confirm the findings. The Editors Severe infections are a leading cause of death in the intensive care unit (ICU), with a mortality rate ranging from 20% for sepsis to 50% for septic shock (1, 2). During the past 25 years, researchers have focused on controlling the overwhelming inflammatory response after bacterial invasion. Before the publication of the Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) trial, which evaluated activated protein C (3), few immune or coagulation modulators that improved survival had been found. Physicians use intravenous immunoglobulin (IVIG), a fractionated blood product, for treating a variety of health conditions. On the basis of the concept of modulation of the inflammatory cascade during sepsis, IVIG may be a useful adjuvant treatment. Its exact mechanism of action when used to treat sepsis remains unknown, but it exceeds a direct antigenantibody reaction (4). Recent consensus guidelines do not recommend the widespread use of IVIG in patients with severe sepsis or septic shock (5, 6). Instead, IVIG use is suggested as a therapy in group A streptococcal toxic shock syndrome (7). Despite these recommendations, 15% of the off-label use of IVIG in the United States is to treat a broad range of infectious diseases (8). Two meta-analyses that evaluated the effect of polyclonal IVIG on death in patients with sepsis produced conflicting results. In a systematic review (9) published in the Cochrane Library and favoring IVIG, researchers pooled results from 6 studies of adults. A large, unpublished trial was not considered to be eligible for that review (10). Conversely, in a recent meta-analysis not favoring IVIG, researchers pooled results from many studies and included adult and neonatal populations, which differ in acquired humoral immunity (11). Thus, some concerns preclude definitive conclusion of their results on the effect of polyclonal IVIG in the adult population. We performed this systematic review to determine the survival benefit of polyclonal IVIG in critically ill adult patients with sepsis, severe sepsis, or septic shock. Methods Search Strategy We developed a systematic search strategy that we applied to MEDLINE (1966 to May 2006) and the Cochrane Central Register of Controlled Trials (May 2006 edition) to identify randomized, controlled trials that evaluated IVIG as a mode of therapy, regardless of the clinical field associated with studies. The strategy combined the text terms ivig, igiv, intravenous immune globulin, intravenous immunoglobulin, gammagard, vigam, gamimmune, flebogamma, sandoglobulin, iveegam, pentaglobin, intraglobin, endoglobulin, and gammaglobulin by using the Dickersin filter for randomized, controlled trials (12). The bibliographies of all identified meta-analyses and trials were also reviewed to identify relevant reports. Two authors independently reviewed citations retrieved from the electronic search to identify potentially relevant trials for this review. When a unanimous decision could not be reached, a third party was consulted. Study Selection To be eligible, studies had to be randomized, controlled trials comparing IVIG therapy with placebo or no intervention in critically ill adult patients with sepsis. We considered trials to be conducted in adults if most patients were 18 years of age or older. Sepsis was defined according to the American College of Chest Physicians (ACCP)Society of Critical Care Medicine (SCCM) guidelines (13) or was extrapolated to these criteria if not provided. The primary outcome measure was death, and the secondary outcomes were length of stay in the ICU and days of mechanical ventilation. We did not restrict study eligibility to language or type of publication. Data Abstraction We developed a standardized data abstraction form that included the country of study origin, methods of therapy compared, dosage and duration of treatment, the number of patients randomly assigned to each treatment group, length of follow-up, patient demographic characteristics, all pertinent outcome information, and adverse events and withdrawals within each treatment group. We consulted a translator for each relevant reference that was published in a foreign language. If data abstractors were unclear on any information of interest in an included study, we contacted study authors for them to clarify the methods or provide additional data as needed. Figure 1. Study flow diagram. IVIG = intravenous immunoglobulin. Data Synthesis We used random-effects models to synthesize data from included studies according to the DerSimonianLaird method, as suggested when between-study heterogeneity is suspected (14). For circumstances in which pooling of trials was inappropriate, we provide a qualitative discussion of the findings. We analyzed discrete and continuous data by using Review Manager, version 4.2.7 (RevMan, The Cochrane Collaboration, Oxford, United Kingdom). We expressed dichotomous data measures of effect, such as death, as risk ratios with 95% CIs. A risk ratio less than 1.0 suggested a reduced risk for death for patients in the IVIG group compared with those in the control group. A risk ratio greater than 1.0 suggested an increased risk for death for patients in the IVIG group compared with those in the control group. For continuous data, we expressed measures of effect, such as length of stay in the ICU or days of mechanical ventilation, as weighted mean differences with 95% CIs. We performed statistical tests for heterogeneity (a P value< 0.10 indicated statistical significance) and investigated I2 measures of consistency across trials (15). We tried to discover and explain the primary sources of the heterogeneity. We hypothesized that methodological differences, differences in diagnosis and severity of disease, differences in the treatment regimen, or simply chance would explain heterogeneity. Thus, we performed a series of sensitivity analyses based on study characteristics (high methodological quality, published and peer-reviewed trials, double-blind studies, diagnosis and severity, dose regimen, duration of therapy, timing of administration, and period of publication) to further explore heterogeneity and evaluate the robustness of our findings. For independent subgroups of trials, we assessed interaction by using a mixed-effects model. We used the Jadad scale to assess some variables of trial methods (16). This scale provides scoring for randomization (0 to 2 points), double-blinding (0 to 2 points), and withdrawals (1 point), with scores ranging from 0 to 5. We used available peer-reviewed, published information and information from authors to assess studies for methodological quality studies. However, we considered only peer-reviewed, published trials that obtained a Jadad score of 5 to be of high methodological quality. Role of the Funding Source The Ontario Ministry of Health and Long-Term Care, Ontario, Canada, provided funding for the study. The funding source had no role in the design, conduct, or analysis of the study or in the decision to submit the manuscript for publication. Dr. Turgeon had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Results Search Results We identified 4096 citations of randomized, controlled trials of IVIG (3300 from MEDLINE and 796 from the Cochrane Central Register of Controlled Trials) (Figure 1) by using the systematic literature search. We deemed 33 citations to be potentially eligible. We excluded 13 studies for the following reasons: design other than a randomized, controlled trial (n= 5); duplicate publication (n= 4); inadequate randomization procedure (n= 2); use of monoclonal IVIG (n= 1); and study on prophylactic use of IVIG (n= 1). Twenty trials of 2621 patients met inclusion criteria for our review (Figure 1 and Table 1). Table 1. Baseline Characteristics of Patients, Minimal Inclusion Criteria, and Intravenous Immunoglobulin Regimen Study Characteristics Among the selected trials, 15 were published in English (10, 17, 19, 22, 23, 2529, 3236), 3 in German (18, 20, 24), 1 in Turkish (30), and 1 in Japanese (31). Eighteen trials were conducted in Europe (10, 1719, 2124, 2630, 3236), 1 in North America (25), and 1 in Asia (31). Seventeen of the selected trials were published as articles (17, 18, 2132, 3436), 1 as an abstract (10), 1 as an abstract and a book chapter (20, 21), and 1 as a letter (33) (Table 2). All trials published as articles were peer-reviewed but only 7 were blinded (10, 25, 26, 29, 30, 34, 35) (Table 2). Nine studies were multicenter studies (10, 21, 26, 28, 29, 31, 3436), including 2 large trials (10, 31). Two trials enrolled a total of 4 patients younger than 18 years of age (23, 32); in 3 other trials, the age restriction was 15 years of age or older (26, 29) and 14 years of age or older (19). In 1 trial (19), 17% of included patients did not meet inclusion criteria, and in another trial (31), 20% of patients had severe infections instead of sepsis. One trial (29) included data from a previous trial (26) that we removed and analyzed separately because of different inclusion criteria. Table 2. Characteristics of the Methodolo

Does analysis using “last observation carried forward” introduce bias in dementia research?

If there were a prize for the most inappropriate analytical technique in dementia research, “last observation carried forward” would be the runaway winner. As a society, we have spent millions of dollars on drug research in the hope of improving the care of the estimated 24.3 million people who

The quality of reporting methods and results in network meta-analyses: an overview of reviews and suggestions for improvement.

Introduction Some have suggested the quality of reporting of network meta-analyses (a technique used to synthesize information to compare multiple interventions) is sub-optimal. We sought to review information addressing this claim. Objective To conduct an overview of existing evaluations of quality of reporting in network meta-analyses and indirect treatment comparisons, and to compile a list of topics which may require detailed reporting guidance to enhance future reporting quality. Methods An electronic search of Medline and the Cochrane Registry of methodologic studies (January 2004–August 2013) was performed by an information specialist. Studies describing findings from quality of reporting assessments were sought. Screening of abstracts and full texts was performed by two team members. Descriptors related to all aspects of reporting a network meta-analysis were summarized. Results We included eight reports exploring the quality of reporting of network meta-analyses. From past reviews, authors found several aspects of network meta-analyses were inadequately reported, including primary information about literature searching, study selection, and risk of bias evaluations; statement of the underlying assumptions for network meta-analysis, as well as efforts to verify their validity; details of statistical models used for analyses (including information for both Bayesian and Frequentist approaches); completeness of reporting of findings; and approaches for summarizing probability measures as additional important considerations. Conclusions While few studies were identified, several deficiencies in the current reporting of network meta-analyses were observed. These findings reinforce the need to develop reporting guidance for network meta-analyses. Findings from this review will be used to guide next steps in the development of reporting guidance for network meta-analysis in the format of an extension of the PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analysis) Statement.

Network meta‑analysis for comparing treatment effects of multiple interventions: an introduction

AbstractnSystematic reviews and meta-analyses of randomized trials have long been important synthesis tools for guiding evidence-based medicine. More recently, network meta-analyses, an extension of traditional meta-analyses enabling the comparison of multiple interventions, use new statistical methods to incorporate clinical evidence from both direct and indirect treatment comparisons in a network of treatments and associated trials. There is a need to provide education to ensure that core methodological considerations underlying network meta-analyses are well understood by readers and researchers to maximize their ability to appropriately interpret findings and appraise validity. Network meta-analyses are highly informative for assessing the comparative effects of multiple competing interventions in clinical practice and are a valuable tool for health technology assessment and comparative effectiveness research.

Safety, effectiveness, and cost effectiveness of long acting versus intermediate acting insulin for patients with type 1 diabetes: systematic review and network meta-analysis

Objective To examine the safety, effectiveness, and cost effectiveness of long acting insulin for type 1 diabetes. Design Systematic review and network meta-analysis. Data sources Medline, Cochrane Central Register of Controlled Trials, Embase, and grey literature were searched through January 2013. Study selection Randomized controlled trials or non-randomized studies of long acting (glargine, detemir) and intermediate acting (neutral protamine Hagedorn (NPH), lente) insulin for adults with type 1 diabetes were included. Results 39 studies (27 randomized controlled trials including 7496 patients) were included after screening of 6501 titles/abstracts and 190 full text articles. Glargine once daily, detemir once daily, and detemir once/twice daily significantly reduced hemoglobin A1c compared with NPH once daily in network meta-analysis (26 randomized controlled trials, mean difference −0.39%, 95% confidence interval −0.59% to −0.19%; −0.26%, −0.48% to −0.03%; and −0.36%, −0.65% to −0.08%; respectively). Differences in network meta-analysis were observed between long acting and intermediate acting insulin for severe hypoglycemia (16 randomized controlled trials; detemir once/twice daily versus NPH once/twice daily: odds ratio 0.62, 95% confidence interval 0.42 to 0.91) and weight gain (13 randomized controlled trials; detemir once daily versus NPH once/twice daily: mean difference 4.04 kg, 3.06 to 5.02 kg; detemir once/twice daily versus NPH once daily: −5.51 kg, −6.56 to −4.46 kg; glargine once daily versus NPH once daily: −5.14 kg, −6.07 to −4.21). Compared with NPH, detemir was less costly and more effective in 3/14 cost effectiveness analyses and glargine was less costly and more effective in 2/8 cost effectiveness analyses. The remaining cost effectiveness analyses found that detemir and glargine were more costly but more effective than NPH. Glargine was not cost effective compared with detemir in 2/2 cost effectiveness analyses. Conclusions Long acting insulin analogs are probably superior to intermediate acting insulin analogs, although the difference is small for hemoglobin A1c. Patients and their physicians should tailor their choice of insulin according to preference, cost, and accessibility. Systematic review registration PROSPERO CRD42013003610.

Network meta-analysis incorporating randomized controlled trials and non-randomized comparative cohort studies for assessing the safety and effectiveness of medical treatments: challenges and opportunities

Network meta-analysis is increasingly used to allow comparison of multiple treatment alternatives simultaneously, some of which may not have been compared directly in primary research studies. The majority of network meta-analyses published to date have incorporated data from randomized controlled trials (RCTs) only; however, inclusion of non-randomized studies may sometimes be considered. Non-randomized studies can complement RCTs or address some of their limitations, such as short follow-up time, small sample size, highly selected population, high cost, and ethical restrictions. In this paper, we discuss the challenges and opportunities of incorporating both RCTs and non-randomized comparative cohort studies into network meta-analysis for assessing the safety and effectiveness of medical treatments. Non-randomized studies with inadequate control of biases such as confounding may threaten the validity of the entire network meta-analysis. Therefore, identification and inclusion of non-randomized studies must balance their strengths with their limitations. Inclusion of both RCTs and non-randomized studies in network meta-analysis will likely increase in the future due to the growing need to assess multiple treatments simultaneously, the availability of higher quality non-randomized data and more valid methods, and the increased use of progressive licensing and product listing agreements requiring collection of data over the life cycle of medical products. Inappropriate inclusion of non-randomized studies could perpetuate the biases that are unknown, unmeasured, or uncontrolled. However, thoughtful integration of randomized and non-randomized studies may offer opportunities to provide more timely, comprehensive, and generalizable evidence about the comparative safety and effectiveness of medical treatments.

Safety and effectiveness of dipeptidyl peptidase-4 inhibitors versus intermediate-acting insulin or placebo for patients with type 2 diabetes failing two oral antihyperglycaemic agents: a systematic review and network meta-analysis

Objective To evaluate the effectiveness and safety of dipeptidyl peptidase-4 (DPP-4) inhibitors versus intermediate-acting insulin for adults with type 2 diabetes mellitus (T2DM) and poor glycaemic control despite treatment with two oral agents. Setting Studies were multicentre and multinational. Participants Ten studies including 2967 patients with T2DM. Interventions Studies that examined DPP-4 inhibitors compared with each other, intermediate-acting insulin, no treatment or placebo in patients with T2DM. Primary and secondary outcome measures Primary outcome was glycosylated haemoglobin (HbA1c). Secondary outcomes were healthcare utilisation, body weight, fractures, quality of life, microvascular complications, macrovascular complications, all-cause mortality, harms, cost and cost-effectiveness. Results 10 randomised clinical trials with 2967 patients were included after screening 5831 titles and abstracts, and 180 full-text articles. DPP-4 inhibitors significantly reduced HbA1c versus placebo in network meta-analysis (NMA; mean difference (MD) −0.62%, 95% CI −0.93% to −0.33%) and meta-analysis (MD −0.61%, 95% CI −0.81% to −0.41%), respectively. Significant differences in HbA1c were not observed for neutral protamine Hagedorn (NPH) insulin versus placebo and DPP-4 inhibitors versus NPH insulin in NMA. In meta-analysis, no significant differences were observed between DPP-4 inhibitors and placebo for severe hypoglycaemia, weight gain, cardiovascular disease, overall harms, treatment-related harms and mortality, although patients receiving DPP-4 inhibitors experienced less infections (relative risk 0.72, 95% CI 0.57 to 0.91). Conclusions DPP-4 inhibitors were superior to placebo in reducing HbA1c levels in adults with T2DM taking at least two oral agents. Compared with placebo, no safety signals were detected with DPP-4 inhibitors and there was a reduced risk of infection. There was no significant difference in HbA1c observed between NPH and placebo or NPH and DPP-4 inhibitors. Trial registration number PROSPERO # CRD42013003624.

The pharmacological and non-pharmacological treatment of attention deficit hyperactivity disorder in children and adolescents: A systematic review with network meta-analyses of randomised trials.

Background Attention deficit hyperactivity disorder (ADHD) is one of the most commonly diagnosed psychiatric disorders in childhood. A wide variety of treatments have been used for the management of ADHD. We aimed to compare the efficacy and safety of pharmacological, psychological and complementary and alternative medicine interventions for the treatment of ADHD in children and adolescents. Methods and findings We performed a systematic review with network meta-analyses. Randomised controlled trials (≥ 3 weeks follow-up) were identified from published and unpublished sources through searches in PubMed and the Cochrane Library (up to April 7, 2016). Interventions of interest were pharmacological (stimulants, non-stimulants, antidepressants, antipsychotics, and other unlicensed drugs), psychological (behavioural, cognitive training and neurofeedback) and complementary and alternative medicine (dietary therapy, fatty acids, amino acids, minerals, herbal therapy, homeopathy, and physical activity). The primary outcomes were efficacy (treatment response) and acceptability (all-cause discontinuation). Secondary outcomes included discontinuation due to adverse events (tolerability), as well as serious adverse events and specific adverse events. Random-effects Bayesian network meta-analyses were conducted to obtain estimates as odds ratios (ORs) with 95% credibility intervals. We analysed interventions by class and individually. 190 randomised trials (52 different interventions grouped in 32 therapeutic classes) that enrolled 26114 participants with ADHD were included in complex networks. At the class level, behavioural therapy (alone or in combination with stimulants), stimulants, and non-stimulant seemed significantly more efficacious than placebo. Behavioural therapy in combination with stimulants seemed superior to stimulants or non-stimulants. Stimulants seemed superior to behavioural therapy, cognitive training and non-stimulants. Behavioural therapy, stimulants and their combination showed the best profile of acceptability. Stimulants and non-stimulants seemed well tolerated. Among medications, methylphenidate, amphetamine, atomoxetine, guanfacine and clonidine seemed significantly more efficacious than placebo. Methylphenidate and amphetamine seemed more efficacious than atomoxetine and guanfacine. Methylphenidate and clonidine seemed better accepted than placebo and atomoxetine. Most of the efficacious pharmacological treatments were associated with harms (anorexia, weight loss and insomnia), but an increased risk of serious adverse events was not observed. There is lack of evidence for cognitive training, neurofeedback, antidepressants, antipsychotics, dietary therapy, fatty acids, and other complementary and alternative medicine. Overall findings were limited by the clinical and methodological heterogeneity, small sample sizes of trials, short-term follow-up, and the absence of high-quality evidence; consequently, results should be interpreted with caution. Conclusions Clinical differences may exist between the pharmacological and non-pharmacological treatment used for the management of ADHD. Uncertainties about therapies and the balance between benefits, costs and potential harms should be considered before starting treatment. There is an urgent need for high-quality randomised trials of the multiple treatments for ADHD in children and adolescents. PROSPERO, number CRD42014015008.

Stop this waste of people, animals and money

Our evidence disputes this view. We spent 12 months rigorously characterizing nearly 2,000 biomedical articles from more than 200 journals thought likely to be predatory. More than half of the corresponding authors hailed from highand upper-middle-income countries as defined by the World Bank. Of the 17% of sampled articles that reported a funding source, the most frequently named funder was the US National Institutes of Health (NIH). The United States produced more articles in our sample than all other countries save India. Harvard University (with 9 articles) in Cambridge, Massachusetts, and the University of Texas (with Predatory journals are easy to please. They seem to accept papers with little regard for quality, at a fraction of the cost charged by mainstream openaccess journals. These supposedly scholarly publishing entities are murky operations, making money by collecting fees while failing to deliver on their claims of being open access and failing to provide services such as peer review and archiving. Despite abundant evidence that the bar is low, not much is known about who publishes in this shady realm, and what the papers are like. Common wisdom assumes that the hazard of predatory publishing is restricted mainly to the developing world. In one famous sting, a journalist for Science sent a purposely flawed paper to 140 presumed predatory titles (and to a roughly equal number of other open-access titles), pretending to be a biologist based in African capital cities. At least two earlier, smaller surveys found that most authors were in India or elsewhere in Asia. A campaign to warn scholars about predatory journals has concentrated its efforts in Africa, China, India, the Middle East and Russia. Frequent, aggressive solicitations from predatory publishers are generally considered merely a nuisance for scientists from rich countries, not a threat to scholarly integrity. Stop this waste of people, animals and money

Cardiovascular and Renal Outcomes of Renin–Angiotensin System Blockade in Adult Patients with Diabetes Mellitus: A Systematic Review with Network Meta-Analyses

Background Medications aimed at inhibiting the renin–angiotensin system (RAS) have been used extensively for preventing cardiovascular and renal complications in patients with diabetes, but data that compare their clinical effectiveness are limited. We aimed to compare the effects of classes of RAS blockers on cardiovascular and renal outcomes in adults with diabetes. Methods and Findings Eligible trials were identified by electronic searches in PubMed/MEDLINE and the Cochrane Database of Systematic Reviews (1 January 2004 to 17 July 2014). Interventions of interest were angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and direct renin (DR) inhibitors. The primary endpoints were cardiovascular mortality, myocardial infarction, and stroke—singly and as a composite endpoint, major cardiovascular outcome—and end-stage renal disease [ESRD], doubling of serum creatinine, and all-cause mortality—singly and as a composite endpoint, progression of renal disease. Secondary endpoints were angina pectoris and hospitalization for heart failure. In all, 71 trials (103,120 participants), with a total of 14 different regimens, were pooled using network meta-analyses. When compared with ACE inhibitor, no other RAS blocker used in monotherapy and/or combination was associated with a significant reduction in major cardiovascular outcomes: ARB (odds ratio [OR] 1.02; 95% credible interval [CrI] 0.90–1.18), ACE inhibitor plus ARB (0.97; 95% CrI 0.79–1.19), DR inhibitor plus ACE inhibitor (1.32; 95% CrI 0.96–1.81), and DR inhibitor plus ARB (1.00; 95% CrI 0.73–1.38). For the risk of progression of renal disease, no significant differences were detected between ACE inhibitor and each of the remaining therapies: ARB (OR 1.10; 95% CrI 0.90–1.40), ACE inhibitor plus ARB (0.97; 95% CrI 0.72–1.29), DR inhibitor plus ACE inhibitor (0.99; 95% CrI 0.65–1.57), and DR inhibitor plus ARB (1.18; 95% CrI 0.78–1.84). No significant differences were showed between ACE inhibitors and ARBs with respect to all-cause mortality, cardiovascular mortality, myocardial infarction, stroke, angina pectoris, hospitalization for heart failure, ESRD, or doubling serum creatinine. Findings were limited by the clinical and methodological heterogeneity of the included studies. Potential inconsistency was identified in network meta-analyses of stroke and angina pectoris, limiting the conclusiveness of findings for these single endpoints. Conclusions In adults with diabetes, comparisons of different RAS blockers showed similar effects of ACE inhibitors and ARBs on major cardiovascular and renal outcomes. Compared with monotherapies, the combination of an ACE inhibitor and an ARB failed to provide significant benefits on major outcomes. Clinicians should discuss the balance between benefits, costs, and potential harms with individual diabetes patients before starting treatment. Review registration PROSPERO CRD42014014404