Systemic treatments for atopic dermatitis (eczema): Systematic review and network meta-analysis of randomized trials.

BACKGROUND: Atopic dermatitis (AD) is an inflammatory skin condition with multiple systemic treatments and uncertainty regarding their comparative impact on AD outcomes. OBJECTIVE: We sought to systematically synthesize the benefits and harms of AD systemic treatments. METHODS: For the 2023 American Academy of Allergy, Asthma & Immunology and American College of Allergy, Asthma, and Immunology Joint Task Force on Practice Parameters AD guidelines, we searched MEDLINE, EMBASE, CENTRAL, Web of Science, and GREAT databases from inception to November 29, 2022, for randomized trials addressing systemic treatments and phototherapy for AD. Paired reviewers independently screened records, extracted data, and assessed risk of bias. Random-effects network meta-analyses addressed AD severity, itch, sleep, AD-related quality of life, flares, and harms. The Grading of Recommendations Assessment, Development and Evaluation approach informed certainty of evidence ratings. This review is registered in the Open Science Framework (https://osf.io/e5sna). RESULTS: The 149 included trials (28,686 patients with moderate-to-severe AD) evaluated 75 interventions. With high-certainty evidence, high-dose upadacitinib was among the most effective for 5 of 6 patient-important outcomes; high-dose abrocitinib and low-dose upadacitinib were among the most effective for 2 outcomes. These Janus kinase inhibitors were among the most harmful in increasing adverse events. With high-certainty evidence, dupilumab, lebrikizumab, and tralokinumab were of intermediate effectiveness and among the safest, modestly increasing conjunctivitis. Low-dose baricitinib was among the least effective. Efficacy and safety of azathioprine, oral corticosteroids, cyclosporine, methotrexate, mycophenolate, phototherapy, and many novel agents are less certain. CONCLUSIONS: Among individuals with moderate-to-severe AD, high-certainty evidence demonstrates that high-dose upadacitinib is among the most effective in addressing multiple patient-important outcomes, but also is among the most harmful. High-dose abrocitinib and low-dose upadacitinib are effective, but also among the most harmful. Dupilumab, lebrikizumab, and tralokinumab are of intermediate effectiveness and have favorable safety.

Method's corner: Allergist's guide to network meta-analysis.

Network meta-analyses (NMAs) simultaneously estimate the effects of multiple possible treatment options for a given clinical presentation. For allergists to benefit optimally from NMAs, they must understand the process and be able to interpret the results. Through a worked example published in Pediatric Allergy and Immunology, we summarize how to identify credible NMAs and interpret them with a focus on recent innovations in the GRADE approach (Grading of Recommendations Assessment, Development, and Evaluation). NMAs build on traditional systematic reviews and meta-analyses that consider only direct paired comparisons by including indirect evidence, thus allowing the simultaneous assessment of the relative effect of all pairs of competing alternatives. Our framework informs clinicians of how to identify credible NMAs and address the certainty of the evidence. Trustworthy NMAs fill a critical gap in providing key inferences using direct and indirect evidence to inform clinical decision making when faced with more than two competing courses of treatment options. This document will help allergists to identify trustworthy NMAs to enhance patient care.

A comparison of parametric propensity score-based methods for causal inference with multiple treatments and a binary outcome.

We consider comparative effectiveness research (CER) from observational data with two or more treatments. In observational studies, the estimation of causal effects is prone to bias due to confounders related to both treatment and outcome. Methods based on propensity scores are routinely used to correct for such confounding biases. A large fraction of propensity score methods in the current literature consider the case of either two treatments or continuous outcome. There has been extensive literature with multiple treatment and binary outcome, but interest often lies in the intersection, for which the literature is still evolving. The contribution of this article is to focus on this intersection and compare across methods, some of which are fairly recent. We describe propensity-based methods when more than two treatments are being compared, and the outcome is binary. We assess the relative performance of these methods through a set of simulation studies. The methods are applied to assess the effect of four common therapies for castration-resistant advanced-stage prostate cancer. The data consist of medical and pharmacy claims from a large national private health insurance network, with the adverse outcome being admission to the emergency room within a short time window of treatment initiation.

Randomization tests for multiarmed randomized clinical trials.

We examine the use of randomization-based inference for analyzing multiarmed randomized clinical trials, including the application of conditional randomization tests to multiple comparisons. The view is taken that the linkage of the statistical test to the experimental design (randomization procedure) should be recognized. A selected collection of randomization procedures generalized to multiarmed treatment allocation is summarized, and generalizations for two randomization procedures that heretofore were designed for only two treatments are developed. We explain the process of computing the randomization test and conditional randomization test via Monte Carlo simulation, developing an efficient algorithm that makes multiple comparisons possible that would not be possible using a standard algorithm, demonstrate the preservation of type I error rate, and explore the relationship of statistical power to the randomization procedure in the presence of a time trend and outliers. We distinguish between the interpretation of the p-value in the randomization test and in the population test and verify that the randomization test can be approximated by the population test on some occasions. Data from two multiarmed clinical trials from the literature are reanalyzed to illustrate the methodology.

Comparative effectiveness of dopamine agonists and monoamine oxidase type-B inhibitors for Parkinson's disease: a multiple treatment comparison meta-analysis.

PURPOSE: To investigate the comparative effectiveness of dopamine agonists and monoamine oxidase type-B (MAO-B) inhibitors available for treatment of Parkinson's disease. METHODS: We performed a systematic literature search identifying randomized controlled trials investigating 4 dopamine agonists (cabergoline, pramipexole, ropinirole, rotigotine) and 3 MAO-B inhibitors (selegiline, rasagiline, safinamide) for Parkinson's disease. We extracted and pooled data from included clinical trials in a joint model allowing both direct and indirect comparison of the seven drugs. We considered dopamine agonists and MAO-B inhibitors given as monotherapy or in combination with levodopa. Selected endpoints were change in the Unified Parkinson's Disease Rating Scale (UPDRS) score, serious adverse events and withdrawals. We estimated the relative effectiveness of each dopamine agonist and MAO-B inhibitor versus comparator drug. RESULTS: Altogether, 79 publications were included in the analysis. We found all the investigated drugs to be effective compared with placebo when given as monotherapy except safinamide. When considering combination treatment, the estimated relative effects of selegiline, pramipexole, ropinirole, rotigotine, cabergoline, rasagiline and safinamide were 2.316 (1.819, 2.951), 2.091 (1.889, 2.317), 2.037 (1.804, 2.294), 1.912 (1.716, 2.129), 1.664 (1.113, 2.418), 1.584 (1.379, 1.820) and 1.179 (1.031, 1.352), respectively, compared with joint placebo and levodopa treatment. CONCLUSIONS: Dopamine agonists were found to be effective as treatment for Parkinson's disease, both when given as monotherapy and in combination with levodopa. Selegiline and rasagiline were also found to be effective for treating Parkinson's disease, and selegiline was the best option in combination with levodopa among all the drugs investigated.

A multiple treatment comparison meta-analysis of monoamine oxidase type B inhibitors for Parkinson's disease.

AIMS: To the best of our knowledge, there are no systematic reviews or meta-analyses that compare rasagiline, selegiline and safinamide. Therefore, we aimed to perform a drug class review comparing all available monoamine oxidase type B (MAO-B) inhibitors in a multiple treatment comparison. METHODS: We performed a systematic literature search to identify randomized controlled trials assessing the efficacy of MAO-B inhibitors in patients with Parkinson's disease. MAO-B inhibitors were evaluated either as monotherapy or in combination with levodopa or dopamine agonists. Endpoints of interest were change in the Unified Parkinson's Disease Rating Scale (UPDRS) score and serious adverse events. We estimated the relative effect of each MAO-B inhibitor versus the comparator drug by creating three networks of direct and indirect comparisons. For each of the networks, we considered a joint model. RESULTS: The systematic literature search and study selection process identified 27 publications eligible for our three network analyses. We found the relative effects of rasagiline, safinamide and selegiline treatment given alone and compared to placebo in a model without explanatory variables to be 1.560 (1.409, 1.734), 1.449 (0.873, 2.413) and 1.532 (1.337, 1.757) respectively. We also found all MAO-B inhibitors to be efficient when given together with levodopa. When ranking the MAO-B inhibitors given in combination with levodopa, selegiline was the most effective and rasagiline was the second best. CONCLUSIONS: All of the included MAO-B inhibitors were effective compared to placebo when given as monotherapy. Combination therapy with MAO-B inhibitors and levodopa showed that all three MAO-B inhibitors were effective compared to placebo, but selegiline was the most effective drug.

Efficacy and safety of drugs for attention deficit hyperactivity disorder in children and adolescents: a network meta-analysis.

The aim of this study is to gather evidence of head-to-head double-blind randomized-controlled trials on the efficacy and safety of available treatments for attention deficit hyperactivity disorder (ADHD) in children and adolescents. A systematic review was conducted by two independent reviewers in ten electronic databases (PROSPERO register CRD42016043239). Methodological quality of included studies was evaluated according to the Jadad scale. Network meta-analyses were performed including double-blinded head-to-head trials comparing active allopathic drugs in patients (0-18 years old) diagnosed with ADHD. The results of efficacy and safety of atomoxetine (ATX), bupropion, buspirone (BSP), dexamphetamine, edivoxetine (EDX), guanfacine (GXR), lisdexamfetamine (LDX), methylphenidate (MPH), mixed amphetamine salts, modafinil, pindolol (PDL), reboxetine (RBX), selegiline, and venlafaxine were analyzed using ADDIS software v.1.16.5. Forty-eight trials were identified (n = 4169 participants), of which 12 were used for efficacy analysis and 33 for safety analysis. On the CGI-I scale, the analysis revealed that MPH was more effective than ATX and GXR. For the safety outcomes, according to drug ranks, LDX was more likely to cause sleep disorders (39%) as well as loss of appetite (65%) and behavior problems such as irritability (60%). BSP (71%) and EDX (44%) caused less appetite decrease. For behavioral effects, PDL was considered safest (50%). For any adverse events, RBX (89%) was the safest alternative. The lack of head-to-head trials properly reporting outcomes of interest limited some comparisons. Network meta-analysis offered a broader overview on the available treatments for ADHD, especially for safety issues, and contributes towards evidence gathering and clinical practice decisions. A core outcome set for ADHD should be designed to guide the conduction and report of clinical trials.

Incorporation of individual-patient data in network meta-analysis for multiple continuous endpoints, with application to diabetes treatment.

Availability of individual patient-level data (IPD) broadens the scope of network meta-analysis (NMA) and enables us to incorporate patient-level information. Although IPD is a potential gold mine in biomedical areas, methodological development has been slow owing to limited access to such data. In this paper, we propose a Bayesian IPD NMA modeling framework for multiple continuous outcomes under both contrast-based and arm-based parameterizations. We incorporate individual covariate-by-treatment interactions to facilitate personalized decision making. Furthermore, we can find subpopulations performing well with a certain drug in terms of predictive outcomes. We also impute missing individual covariates via an MCMC algorithm. We illustrate this approach using diabetes data that include continuous bivariate efficacy outcomes and three baseline covariates and show its practical implications. Finally, we close with a discussion of our results, a review of computational challenges, and a brief description of areas for future research.

Comparative efficacy of triptans for the abortive treatment of migraine: a multiple treatment comparison meta-analysis.

BACKGROUND: Migraine is the most common neurological condition in developed countries. The abortive treatment of migraine attacks is important both for quality of life and costs associated with illness. Triptans, serotonin 5-HT1B/1D receptor agonists, effectively relieve the pain, disability, and associated symptoms of migraine while improving health-related quality of life. Although a number of direct head-to-head triptan comparisons have been made, data for all possible permutations are not available, and unlikely to ever be so, although in clinical practice such information would be useful. OBJECTIVE: We aimed to determine the relative efficacy of all available triptans to abort migraine headache among patients with previous adequate response to migraine treatments. METHODS: We included only double-blinded randomized clinical trials comparing triptans to either placebo or another triptan. Our primary outcomes were pain-free response at two hours and 24-hour sustained pain-free response, and our secondary outcomes were headache response at two hours and 24-hour sustained headache response. We used Bayesian multiple treatment comparison meta-analyses of seven triptans used in adult patients to abort migraine attacks. We applied a random-effects analysis with meta-regression adjusting for dose. Results are reported as odds ratios with 95% credible intervals. RESULTS: We included data from 74 randomized clinical trials. All triptans were significantly superior to placebo for all outcomes, with the exception of naratriptan for 24-hour sustained pain-free response. Eletriptan consistently yielded the highest treatment effect estimates. For the two-hour endpoints, eletriptan was statistically significantly superior to sumatriptan, almotriptan, naratriptan, and frovatriptan for at least one of the two outcomes. Rizatriptan yielded the second highest treatment effects followed by zolmitriptan. For the 24-hour endpoints, eletriptan was statistically significantly superior to sumatriptan, rizatriptan, almotriptan, and naratriptan for at least one of the two outcomes. Frovatriptan data were not available at that endpoint. Further, the probability that eletriptan is the most likely of all triptans to produce a favorable outcome was 68% for pain-free response at two hours, and 54% for 24-hour sustained pain-free response. CONCLUSION: Triptans appear to offer differing treatment effects. In the populations studied eletriptan was most likely to produce pain-free responses that were sustained.

Indirect treatment comparison/network meta-analysis study questionnaire to assess relevance and credibility to inform health care decision making: an ISPOR-AMCP-NPC Good Practice Task Force report.

Despite the great realized or potential value of network meta-analysis of randomized controlled trial evidence to inform health care decision making, many decision makers might not be familiar with these techniques. The Task Force developed a consensus-based 26-item questionnaire to help decision makers assess the relevance and credibility of indirect treatment comparisons and network meta-analysis to help inform health care decision making. The relevance domain of the questionnaire (4 questions) calls for assessments about the applicability of network meta-analysis results to the setting of interest to the decision maker. The remaining 22 questions belong to an overall credibility domain and pertain to assessments about whether the network meta-analysis results provide a valid answer to the question they are designed to answer by examining 1) the used evidence base, 2) analysis methods, 3) reporting quality and transparency, 4) interpretation of findings, and 5) conflicts of interest. The questionnaire aims to help readers of network meta-analysis opine about their confidence in the credibility and applicability of the results of a network meta-analysis, and help make decision makers aware of the subtleties involved in the analysis of networks of randomized trial evidence. It is anticipated that user feedback will permit periodic evaluation and modification of the questionnaire.

Efficacy and acceptability of acute treatments for persistent depressive disorder: a network meta-analysis.

BACKGROUND: We aimed to synthesize the available evidence on the relative efficacy and acceptability of specific treatments for persistent depressive disorder. METHODS: We searched several databases up to January 2013 and included randomized controlled trials that compared acute pharmacological, psychotherapeutic, and combined interventions with each other or placebo. The outcome measures were the proportion of patients who responded to (efficacy) or dropped out from (acceptability) the allocated treatment. Data synthesis was performed with network meta-analysis. RESULTS: A network of 45 trials that tested 28 drugs included data from 5,806 and 5,348 patients concerning efficacy and acceptability, respectively. A second network of 15 trials that tested five psychotherapeutic and five combined interventions included data from 2,657 and 2,719 patients concerning efficacy and acceptability, respectively. Among sufficiently tested treatments, fluoxetine (odds ratio (OR) 2.94), paroxetine (3.79), sertraline (4.47), moclobemide (6.98), imipramine (4.53), ritanserin (2.35), amisulpride (5.63), and acetyl-l-carnitine (5.67) were significantly more effective than placebo. Pairwise comparisons showed advantages of moclobemide (2.38) and amisulpride (1.92) over fluoxetine. Sertraline (0.57) and amisulpride (0.53) showed a lower dropout rate than imipramine. Interpersonal psychotherapy with medication outperformed medication alone in chronic major depression but not in dysthymia. Evidence on cognitive behavioral analysis system of psychotherapy plus medication was partly inconclusive. Interpersonal psychotherapy was less effective than medication (0.48) and cognitive behavioral analysis system of psychotherapy (0.45). Several other treatments were tested in single studies. CONCLUSIONS: Several evidence-based acute pharmacological, psychotherapeutic, and combined treatments for persistent depressive disorder are available with significant differences between them.

Efficient network meta-analysis: a confidence distribution approach.

Network meta-analysis synthesizes several studies of multiple treatment comparisons to simultaneously provide inference for all treatments in the network. It can often strengthen inference on pairwise comparisons by borrowing evidence from other comparisons in the network. Current network meta-analysis approaches are derived from either conventional pairwise meta-analysis or hierarchical Bayesian methods. This paper introduces a new approach for network meta-analysis by combining confidence distributions (CDs). Instead of combining point estimators from individual studies in the conventional approach, the new approach combines CDs which contain richer information than point estimators and thus achieves greater efficiency in its inference. The proposed CD approach can e ciently integrate all studies in the network and provide inference for all treatments even when individual studies contain only comparisons of subsets of the treatments. Through numerical studies with real and simulated data sets, the proposed approach is shown to outperform or at least equal the traditional pairwise meta-analysis and a commonly used Bayesian hierarchical model. Although the Bayesian approach may yield comparable results with a suitably chosen prior, it is highly sensitive to the choice of priors (especially the prior of the between-trial covariance structure), which is often subjective. The CD approach is a general frequentist approach and is prior-free. Moreover, it can always provide a proper inference for all the treatment effects regardless of the between-trial covariance structure.

Methodological review of NMA bias concepts provides groundwork for the development of a list of concepts for potential inclusion in a new risk of bias tool for network meta-analysis (RoB NMA Tool).

INTRODUCTION: Network meta-analyses (NMAs) have gained popularity and grown in number due to their ability to provide estimates of the comparative effectiveness of multiple treatments for the same condition. The aim of this study is to conduct a methodological review to compile a preliminary list of concepts related to bias in NMAs. METHODS AND ANALYSIS: We included papers that present items related to bias, reporting or methodological quality, papers assessing the quality of NMAs, or method papers. We searched MEDLINE, the Cochrane Library and unpublished literature (up to July 2020). We extracted items related to bias in NMAs. An item was excluded if it related to general systematic review quality or bias and was included in currently available tools such as ROBIS or AMSTAR 2. We reworded items, typically structured as questions, into concepts (i.e. general notions). RESULTS: One hundred eighty-one articles were assessed in full text and 58 were included. Of these articles, 12 were tools, checklists or journal standards; 13 were guidance documents for NMAs; 27 were studies related to bias or NMA methods; and 6 were papers assessing the quality of NMAs. These studies yielded 99 items of which the majority related to general systematic review quality and biases and were therefore excluded. The 22 items we included were reworded into concepts specific to bias in NMAs. CONCLUSIONS: A list of 22 concepts was included. This list is not intended to be used to assess biases in NMAs, but to inform the development of items to be included in our tool.

HIGHLIGHTS: • Our research aimed to develop a preliminary list of concepts related to bias with the goal of developing the first tool for assessing the risk of bias in the results and conclusions of a network meta-analysis (NMA).• We followed the methodology proposed by Whiting (2017) and Sanderson (2007) for creating systematically developed lists of quality items, as a first step in the development of a risk of bias tool for network meta-analysis (RoB NMA Tool).• We included items related to biases in NMAs and excluded items that are equally applicable to all systematic reviews as they are covered by other tools (e.g. ROBIS, AMSTAR 2).• Fifty-seven studies were included generating 99 items, which when screened, yielded 22 included items. These items were then reworded into concepts in preparation for a Delphi process for further vetting by external experts.• A limitation of our study is the challenge in retrieving methods studies as methods collections are not regularly updated.

Antioxidant micronutrient supplements for adult critically ill patients: A bayesian multiple treatment comparisons meta-analysis.

BACKGROUND & AIMS: Antioxidant micronutrients (AxMs) have been administered to critically ill adults attempting to counteract the oxidative stress imposed during critical illness. However, results are conflicting and relative effectiveness of AxMs regimens is unknown. We conducted a Bayesian multi-treatment comparison (MTC) meta-analysis to identify the best AxM treatment regimen that will improve clinical outcomes. METHODS: PubMed, EMBASE, Web of Science and Cochrane databases were searched from the inception of databases through August 2020. Randomized controlled trials (RCT) comparing AxMs supplementations with placebo among critically ill adults were included. Two authors assessed trial quality using Cochrane risk of bias tool and assessed certainty of evidence (CoE). A random effect model, non-informative priors Bayesian MTC meta-analysis using gemtc package in R version 3.6.2 was performed. AxMs treatment effect on clinical outcomes (mortality, infection rates, intensive care unit (ICU) and hospital stays and ventilator days) were represented by absolute risk differences (ARD) for dichotomous outcomes and mean differences (MD) for continuous outcomes. Prior to final analysis, we repeated the search through January 2021. RESULTS: 37 RCT (4905 patients) were included with 16 direct comparisons. With respect to mortality, the ARD for "vitamin E" compared with placebo was centred at -0.19 [95%CrI: -0.54,0.16; very low CoE] and was ranked the best treatment for mortality reduction as per surface under the cumulative ranking curve (SUCRA 0.71, 95%CrI: 0.07,1.00). A combination of "selenium, zinc and copper" was ranked the best for lowest ICU stay [-9.40, 95% CrI: -20.0,1.50; low CoE]. A combination of "selenium, zinc, copper and vitamin E" was ranked the best treatment for infection risk reduction [-0.22, 95% CrI: -0.61,0.17; very low CoE]. Ventilator days were least with a combination of "selenium, zinc and manganese" [2.80, 95% CrI: -6.30,0.89; low CoE]. Hospital stay was the lowest using a combination of "selenium, zinc and copper" [-13.00, 95% CrI: -38.00,13.00; very low CoE]. There is substantial uncertainty present in the rankings due to wide and overlapping 95% CrIs of SUCRA scores for the treatments. CONCLUSIONS: Studies on critically ill adult patients have suggested a possible beneficial effects of certain AxM supplementations over and above the recommended dietary allowance. However, evidence does not support their use in clinical practice due to the low confidence in the estimates. Current studies evaluating specific AxMs or their combinations are limited with small sample sizes. REGISTRATION: PROSPERO, CRD42020210199. TAKE-HOME MESSAGE: Evidence suggesting a potential benefit of AxMs use more than recommended doses in critically ill adults is weak, indicating that there is no justification for this practice.

Efficacy, acceptability, and tolerability of antidepressants for sleep quality disturbances in post-traumatic stress disorder: A systematic review and network meta-analysis.

Sleep quality disturbances are a common occurrence in post-traumatic stress disorder (PTSD) and may remain after evidence-based treatment for PTSD has been implemented. If left untreated, sleep disturbance can perpetuate or aggravate the disorder. A systematic review and network meta-analysis (NMA) of randomized controlled trials (RCTs) was conducted comparing efficacy, acceptability, and tolerability among antidepressants for sleep quality improvement in PTSD, using Cochane's RoB2.0 and GRADE approach for NMA. The Cochrane Library, LILACS, PsycINFO, PTSDpubs, and PubMed Central databases were searched from inception to November 29, 2020, leading to the retrieval of 3733 reports. After the selection process, seven RCTs were included in the review (N = 600). We found low certainty of evidence (LCE) that sertraline may improve sleep quality (measured by PSQI) in adult patients with PTSD (MD -0.48, 95% CrI -0.63 to -0.32). Sertraline was as well accepted (RR 1.12, 95% CrI -0.83 to 1.52, very low certainty [VLCE]) and as well tolerated as placebo (RR 0.58, 95% CrI 0.28 to 1.14, LCE). Mirtazapine (MD -3.35, 95% CrI -9.06 to 2.39, LCE), paroxetine (MD -3.13, 95% CrI -7.47 to 1.26, VLCE), nefazodone (MD -0.25, 95% CrI -5.95 to 5.38, VLCE), and bupropion (MD -2.28, 95% CrI -4.75 to 0.21, VLCE) were similar to placebo for improving sleep quality. These antidepressants resulted in little or no benefit for sleep in PTSD. Although the NMA suggested that sertraline may improve sleep in PTSD compared to placebo, due to the low certainty, these estimates are not robust enough to guide clinical decisions.

Concepts and emerging issues of network meta-analysis.

Most diseases have more than two interventions or treatment methods, and the application of network meta-analysis (NMA) studies to compare and evaluate the superiority of each intervention or treatment method is increasing. Understanding the concepts and processes of systematic reviews and meta-analyses is essential to understanding NMA. As with systematic reviews and meta-analyses, NMA involves specifying the topic, searching for and selecting all related studies, and extracting data from the selected studies. To evaluate the effects of each treatment, NMA compares and analyzes three or more interventions or treatment methods using both direct and indirect evidence. There is a possibility of several biases when performing NMA. Therefore, key assumptions like similarity, transitivity, and consistency should be satisfied when performing NMA. Among these key assumptions, consistency can be evaluated and quantified by statistical tests. This review aims to introduce the concepts of NMA, analysis methods, and interpretation and presentation of the results of NMA. It also briefly introduces the emerging issues in NMA, including methods for evaluation of consistency.

Pharmacological treatments for adults with post-traumatic stress disorder: A network meta-analysis of comparative efficacy and acceptability.

BACKGROUND: The purpose of this study was to compare efficacy and acceptability among drug treatments for adults with post-traumatic stress disorder (PTSD) through a systematic review, random-effects pairwise and network meta-analyses. METHODS: Double-blind randomized controlled trials comparing pharmacological interventions for adults with PTSD were searched from database inception through Aug. 28, 2018, on Cochrane (Central), Embase, LILACS, PILOTS, PsycINFO, PubMed, and Web of Science. Clinical trial registries and the websites of pharmaceutical companies were also searched. The GRADE system was used to assess the quality of the evidence. RESULTS: The systematic review included 58 studies comprising 6766 patients randomized to 26 different interventions. Regarding efficacy, topiramate (SMD = -0.57; 95%CrI: -1.07,-0.10), risperidone (SMD = -0.53; 95%CrI: -0.93,-0.15), quetiapine (SMD = -0.59; 95%CrI: -1.06,-0.11), paroxetine (SMD = -0.35; 95%CrI: -0.48,-0.21), venlafaxine (SMD = -0.25; 95%CrI: -0.44,-0.05), fluoxetine (SMD = -0.28; 95%CrI: -0.46,-0.08), and sertraline (SMD = -0.21; 95%CrI: -0.33,-0.09) outperformed placebo. Moreover, phenelzine (RR = 3.39; 95%CrI: 1.43,11.09), lamotrigine (RR = 4.39; 95%CrI: 1.18,26.38), and fluoxetine (RR = 1.28%CrI: 1.01,1.59) outperformed placebo in terms of acceptability. CONCLUSIONS: The NMA supports topiramate, risperidone, quetiapine, paroxetine, venlafaxine, fluoxetine and sertraline as effective pharmacological choices for the treatment of PTSD. Quetiapine and topiramate have the shortcoming of relying on a few small studies, but the clinically meaningful change in symptoms is noteworthy and merits further investigation. Among the pharmacological treatments with evidence of efficacy compared to placebo, fluoxetine achieved a relatively high rank regarding acceptability. To the best of our knowledge, this is the largest contemporary NMA on the subject and the addition of new medications is an important extension of previous meta-analyses, enabling a larger number of drug comparisons.

Application of network meta-analysis in the field of physical activity and health promotion.

Continued advancement in the field of physical activity and health promotion relies heavily on the synthesis of rigorous scientific evidence. As such, systematic reviews and meta-analyses of randomized controlled trials have led to a better understanding of which intervention strategies are superior (i.e., produce the greatest effects) in physical activity-based health behavior change interventions. Indeed, standard meta-analytic approaches have allowed researchers in the field to synthesize relevant experimental evidence using pairwise procedures that produce reliable estimates of the homogeneity, magnitude, and potential biases in the observed effects. However, pairwise meta-analytic procedures are only capable to discerning differences in effects between a select intervention strategy and a select comparison or control condition. In order to maximize the impact of physical activity interventions on health-related outcomes, it is necessary to establish evidence concerning the comparative efficacy of all relevant physical activity intervention strategies. The development of network meta-analysis (NMA)-most commonly used in medical-based clinical trials-has allowed for the quantification of indirect comparisons, even in the absence of direct, head-to-head trials. Thus, it stands to reason that NMA can be applied in physical activity and health promotion research to identify the best intervention strategies. Given that this analysis technique is novel and largely unexplored in the field of physical activity and health promotion, care must be taken in its application to ensure reliable estimates and discernment of the effect sizes among interventions. Therefore, the purpose of this review is to comment on the potential application and importance of NMA in the field of physical activity and health promotion, describe how to properly and effectively apply this technique, and suggest important considerations for its appropriate application in this field. In this paper, overviews of the foundations of NMA and commonly used approaches for conducting NMA are provided, followed by assumptions related to NMA, opportunities and challenges in NMA, and a step-by-step example of developing and conducting an NMA.

Uterotonic drugs to prevent postpartum haemorrhage: a network meta-analysis.

BACKGROUND: Postpartum haemorrhage (PPH) is the leading cause of maternal mortality worldwide. Prophylactic uterotonic drugs can reduce blood loss and are routinely recommended. There are several uterotonic drugs for preventing PPH, but it is still debatable which drug or combination of drugs is the most effective. OBJECTIVES: To identify the most effective and cost-effective uterotonic drug(s) to prevent PPH, and generate a ranking according to their effectiveness and side-effect profile. METHODS: The Cochrane Pregnancy and Childbirth's Trials Register (1 June 2015), ClinicalTrials.gov and the World Health Organization (WHO)'s International Clinical Trials Registry Platform (ICTRP) were searched for unpublished trial reports (30 June 2015). In addition, reference lists of retrieved studies (updated October 2017) were searched for randomised trials evaluating uterotonic drugs for preventing PPH. The study estimated relative effects and rankings for preventing PPH, defined as blood loss of ≥ 500 ml and ≥ 1000 ml. Pairwise meta-analyses and network meta-analysis were performed to determine the relative effects and rankings of all available drugs and combinations thereof [ergometrine, misoprostol (Cytotec®; Pfizer Inc., New York, NY, USA), misoprostol plus oxytocin (Syntocinon®; Novartis International AG, Basel, Switzerland), carbetocin (Pabal®; Ferring Pharmaceuticals, Saint-Prex, Switzerland), ergometrine plus oxytocin (Syntometrine®; Alliance Pharma plc, Chippenham, UK), oxytocin, and a placebo or no treatment]. Primary outcomes were stratified according to the mode of birth, prior risk of PPH, health-care setting, drug dosage, regimen and route of drug administration. Sensitivity analyses were performed according to study quality and funding source, among others. A model-based economic evaluation compared the relative cost-effectiveness separately for vaginal births and caesareans with or without including side effects. RESULTS: From 137 randomised trials and 87,466 women, ergometrine plus oxytocin, carbetocin and misoprostol plus oxytocin were found to reduce the risk of PPH blood loss of ≥ 500 ml compared with the standard drug, oxytocin [ergometrine plus oxytocin: risk ratio (RR) 0.69, 95% confidence interval (CI) 0.57 to 0.83; carbetocin: RR 0.72, 95% CI 0.52 to 1.00; misoprostol plus oxytocin: RR 0.73, 95% CI 0.6 to 0.9]. Each of these three strategies had 100% cumulative probability of being ranked first, second or third most effective. Oxytocin was ranked fourth, with an almost 0% cumulative probability of being ranked in the top three. Similar rankings were noted for the reduction of PPH blood loss of ≥ 1000 ml (ergometrine plus oxytocin: RR 0.77, 95% CI 0.61 to 0.95; carbetocin: RR 0.70, 95% CI 0.38 to 1.28; misoprostol plus oxytocin: RR 0.90, 95% CI 0.72 to 1.14), and most secondary outcomes. Ergometrine plus oxytocin and misoprostol plus oxytocin had the poorest ranking for side effects. Carbetocin had a favourable side-effect profile, which was similar to oxytocin. However, the analysis was restricted to high-quality studies, carbetocin lost its ranking and was comparable to oxytocin. The relative cost-effectiveness of the alternative strategies is inconclusive, and the results are affected by both the uncertainty and inconsistency in the data reported on adverse events. For vaginal delivery, when assuming no adverse events, ergometrine plus oxytocin is less costly and more effective than all strategies except carbetocin. The strategy of carbetocin is both more effective and more costly than all other strategies. When taking adverse events into consideration, all prevention strategies, except oxytocin, are more costly and less effective than carbetocin. For delivery by caesarean section, with and without adverse events, the relative cost-effectiveness is different, again because of the uncertainty in the available data. LIMITATIONS: There was considerable uncertainty in findings within the planned subgroup analyses, and subgroup effects cannot be ruled out. CONCLUSIONS: Ergometrine plus oxytocin, carbetocin and misoprostol plus oxytocin are more effective uterotonic drug strategies for preventing PPH than the current standard, oxytocin. Ergometrine plus oxytocin and misoprostol plus oxytocin cause significant side effects. Carbetocin has a favourable side-effect profile, which was similar to oxytocin. However, most carbetocin trials are small and of poor quality. There is a need for a large high-quality trial comparing carbetocin with oxytocin; such a trial is currently being conducted by the WHO. The relative cost-effectiveness is inconclusive, and results are affected by uncertainty and inconsistency in adverse events data. STUDY REGISTRATION: This study is registered as PROSPERO CRD42015020005; Cochrane Pregnancy and Childbirth Group (substudy) reference number 0871; PROSPERO-Cochrane (substudy) reference number CRD42015026568; and sponsor reference number ERN_13-1414 (University of Birmingham, Birmingham, UK). FUNDING: Funding for this study was provided by the National Institute for Health Research Health Technology Assessment programme in a research award to the University of Birmingham and supported by the UK charity Ammalife (UK-registered charity 1120236). The funders of the study had no role in study design, data collection, data synthesis, interpretation or writing of the report.

Postpartum haemorrhage (PPH) is the most common reason why mothers die in childbirth worldwide. Although most healthy women can cope well with blood loss after birth, some do not, and this can pose a serious risk to their health and even life. To reduce blood loss after birth, the routine administration of a drug to contract the uterus (uterotonic) has become standard practice across the world. This research seeks to identify which is the most effective and cost-effective drug. Different drugs have been used for reducing the occurrence of PPH. They include oxytocin, misoprostol, ergometrine, carbetocin, and combinations of these drugs, each with different effectiveness and side effects. The study synthesised the available evidence to compare all of these drugs and combinations thereof. After putting the results of all available comparisons together in a network, a ranking among them was calculated, and provided robust effectiveness and side-effect profiles for each drug and their associated costs. The study included 137 randomised trials, involving a total of 87,466 women. The results suggested that ergometrine plus oxytocin, carbetocin and misoprostol plus oxytocin are the most effective strategies for preventing PPH and are more effective than the currently recommended drug, oxytocin. Each of these three strategies had almost 100% probability of being ranked first, second or third most effective. Oxytocin was ranked fourth with an almost 0% probability of being ranked in the top three. Ergometrine plus oxytocin and misoprostol plus oxytocin were the worst drug combinations for side effects, with carbetocin having the most favourable side-effect profile. Carbetocin could prevent approximately one further event of PPH out of three in comparison with oxytocin. However, existing carbetocin studies were small and of poor quality. There is need for a large high-quality study comparing carbetocin with the current standard treatment of oxytocin for the prevention of PPH. The cost analyses of the alternative drug strategies remain inconclusive.

A Multiple Treatment Comparison of Eleven Disease-Modifying Drugs Used for Multiple Sclerosis.

BACKGROUND: Several disease-modifying drug therapies are available for the treatment of multiple sclerosis (MS). To ensure the most appropriate MS management, we assessed the effectiveness and cost-effectiveness of the disease-modifying medicines used for MS. METHODS: We conducted a systematic review including 11 disease-modifying drugs used for treatment of adult patients diagnosed with relapsing-remitting MS. We performed a network meta-analysis using both direct and indirect evidence. We examined the endpoints, annual relapse, disability progression, mortality, serious adverse events and withdrawal from the study due to adverse events. Cost-effectiveness was assessed by developing a decision model. The model calculated costs and quality-adjusted life years (QALYs) with different treatment strategies. Uncertainties in the parameter values were explored with a probabilistic sensitivity analysis and several scenario analyses. RESULTS: Alemtuzumab 12 mg was the most effective against annual relapse (high quality evidence). For disability progression, dimethyl fumarate 240 mg and fingolimod 0.5 mg and 1.25 mg were more effective treatment alternatives (high quality evidence). For withdrawal due to adverse events, the conclusion is unclear due to the low quality of the available evidence. Peg-interferon beta-1a was associated with more adverse events (than the other treatments). None of the examined treatments had an effect on overall mortality compared to placebo. The economic analysis indicated that alemtuzumab was more effective in terms of QALYs and less costly than the other treatment alternatives. Discarding alemtuzumab, three treatment alternatives (interferon beta-1b (Extavia), peg-interferon beta-1a and natalizumab) could be considered cost-effective depending on the willingness-to-pay (WTP) threshold. Assuming a WTP below EUR 111,690 per QALY, interferon beta-1b (Extavia) was approximately 36% likely to be the most cost-effective treatment, followed by peg-interferon beta-1a (approximately 34% likely). CONCLUSIONS: Our results showed that alemtuzumab can be considered as more effective and less costly than the other treatment alternatives. There is a substantial potential cost saving if more patients start on the more effective and less costly treatment alternatives.