Search

Background: In this network meta-analysis, we compared the effectiveness and reproductive morbidity associated with various treatment methods for cervical intraepithelial neoplasia (CIN). Methods: We searched electronic databases (MEDLINE, Embase, CENTRAL) from inception until 9 March 2022 for randomised and non-randomised studies reporting on oncological and reproductive outcomes after excisional or ablative CIN treatments. The primary outcomes were any treatment failure (defined as any abnormal histology or cytology) and preterm birth (

Network meta-analysis has been used to answer a range of clinical questions about the preferred intervention for a given condition. Although the effectiveness and safety of pharmacological agents depend on the dose administered, network meta-analysis applications typically ignore the role that drugs dosage plays in the results. This leads to more heterogeneity in the network. In this paper, we present a suite of network meta-analysis models that incorporate the dose–effect relationship using restricted cubic splines. We extend existing models into a dose–effect network meta-regression to account for study-level covariates and for groups of agents in a class-effect dose–effect network meta-analysis model. We apply our models to a network of aggregate data about the efficacy of 21 antidepressants and placebo for depression. We find that all antidepressants are more efficacious than placebo after a certain dose. Also, we identify the dose level at which each antidepressant's effect exceeds that of placebo and estimate the dose beyond which the effect of antidepressants no longer increases. When covariates were introduced to the model, we find that studies with small sample size tend to exaggerate antidepressants efficacy for several of the drugs. Our dose–effect network meta-analysis model with restricted cubic splines provides a flexible approach to modelling the dose–effect relationship in multiple interventions. Decision-makers can use our model to inform treatment choice.

Dose-response models express the effect of different dose or exposure levels on a specific outcome. In meta-analysis, where aggregated-level data is available, dose-response evidence is synthesized using either one-stage or two-stage models in a frequentist setting. We propose a hierarchical dose-response model implemented in a Bayesian framework. We develop our model assuming normal or binomial likelihood and accounting for exposures grouped in clusters. To allow maximum flexibility, the dose-response association is modelled using restricted cubic splines. We implement these models in R using JAGS and we compare our approach to the one-stage dose-response meta-analysis model in a simulation study. We found that the Bayesian dose-response model with binomial likelihood has lower bias than the Bayesian model with normal likelihood and the frequentist one-stage model when studies have small sample size. When the true underlying shape is log-log or half-sigmoid, the performance of all models depends on choosing an appropriate location for the knots. In all other examined situations, all models perform very well and give practically identical results. We also reanalyze the data from 60 randomized controlled trials (15,984 participants) examining the efficacy (response) of various doses of serotonin-specific reuptake inhibitor (SSRI) antidepressant drugs. All models suggest that the dose-response curve increases between zero dose and 30-40 mg of fluoxetine-equivalent dose, and thereafter shows small decline. We draw the same conclusion when we take into account the fact that five different antidepressants have been studied in the included trials. We show that implementation of the hierarchical model in Bayesian framework has similar performance to, but overcomes some of the limitations of the frequentist approach and offers maximum flexibility to accommodate features of the data. TH and GS are funded by the European Union’s Horizon 2020 research and innovation programme under grant agreement No 825162. ME was supported by special project funding (grant 17481) from the Swiss National Science Foundation.

BACKGROUND: Many psychosocial and psychological interventions are used in patients with schizophrenia, but their comparative efficacy in the prevention of relapse is not known. We aimed to evaluate the efficacy, acceptability, and tolerability of psychosocial and psychological interventions for relapse prevention in schizophrenia. METHODS: To conduct this systematic review and network meta-analysis we searched for published and unpublished randomised controlled trials that investigated psychosocial or psychological interventions aimed at preventing relapse in patients with schizophrenia. We searched EMBASE, MEDLINE, PsycINFO, BIOSIS, Cochrane Library, WHO International Clinical Trials Registry Platform, and ClinicalTrials.gov up to Jan 20, 2020, and searched PubMed up to April 14, 2020. We included open and masked studies done in adults with schizophrenia or related disorders. We excluded studies in which all patients were acutely ill, had a concomitant medical or psychiatric disorder, or were prodromal or "at risk of psychosis". Study selection and data extraction were done by two reviewers independently based on published and unpublished reports, and by contacting study authors. Data were extracted about efficacy, tolerability, and acceptability of the interventions; potential effect moderators; and study quality and characteristics. The primary outcome was relapse measured with operationalised criteria or psychiatric hospital admissions. We did random-effects network meta-analysis to calculate odds ratios (ORs) or standardised mean differences (SMDs) with 95% CIs. The study protocol was registered with PROSPERO, CRD42019147884. FINDINGS: We identified 27 765 studies through the database search and 330 through references of previous reviews and studies. We screened 28 000 records after duplicates were removed. 24 406 records were excluded by title and abstract screening and 3594 full-text articles were assessed for eligibility. 3350 articles were then excluded for a variety of reasons, and 244 full-text articles corresponding to 85 studies were included in the qualitative synthesis. Of these, 72 studies with 10 364 participants (3939 females and 5716 males with sex indicated) were included in the network meta-analysis. The randomised controlled trials included compared 20 psychological interventions given mainly as add-on to antipsychotics. Ethnicity data were not available. Family interventions (OR 0·35, 95% CI 0·24-0·52), relapse prevention programmes (OR 0·33, 0·14-0·79), cognitive behavioural therapy (OR 0·45, 0·27-0·75), family psychoeducation (OR 0·56, 0·39-0·82), integrated interventions (OR 0·62, 0·44-0·87), and patient psychoeducation (OR 0·63, 0·42-0·94) reduced relapse more than treatment as usual at 1 year. The confidence in the estimates ranged from moderate to very low. We found no indication of publication bias. INTERPRETATION: We found robust benefits in reducing the risk of relapse for family interventions, family psychoeducation, and cognitive behavioral therapy. These treatments should be the first psychosocial interventions to be considered in the long-term treatment for patients with schizophrenia. FUNDING: German Ministry for Education and Research.

BACKGROUND Decision makers often need to assess the real-world effectiveness of new drugs prelaunch, when phase II/III randomized controlled trials (RCTs) but no other data are available. OBJECTIVE To develop a method to predict drug effectiveness prelaunch and to apply it in a case study in rheumatoid arthritis (RA). METHODS The approach 1) identifies a market-approved treatment ( S) currently used in a target population similar to that of the new drug ( N); 2) quantifies the impact of treatment, prognostic factors, and effect modifiers on clinical outcome; 3) determines the characteristics of patients likely to receive N in routine care; and 4) predicts treatment outcome in simulated patients with these characteristics. Sources of evidence include expert opinion, RCTs, and observational studies. The framework relies on generalized linear models. RESULTS The case study assessed the effectiveness of tocilizumab (TCZ), a biologic disease-modifying antirheumatic drug (DMARD), combined with conventional DMARDs, compared to conventional DMARDs alone. Rituximab (RTX) combined with conventional DMARDs was identified as treatment S. Individual participant data from 2 RCTs and 2 national registries were analyzed. The model predicted the 6-month changes in the Disease Activity Score 28 (DAS28) accurately: the mean change was -2.101 (standard deviation [SD] = 1.494) in the simulated patients receiving TCZ and conventional DMARDs compared to -1.873 (SD = 1.220) in retrospectively assessed observational data. It was -0.792 (SD = 1.499) in registry patients treated with conventional DMARDs. CONCLUSION The approach performed well in the RA case study, but further work is required to better define its strengths and limitations.

Objectives: To synthesize the evidence from randomized controlled trials concerning systemic treatment regimens for patients with cancer of unknown primary site (CUP). Data sources: PubMed and the Cochrane Library Central Registry of Controlled Trials. Review methods: We retrieved all randomized controlled trials comparing at least two arms of different systemic treatment regimens or a systemic regimen to no treatment in patients with CUP, excluding data on favorable subset CUP, whenever these could be separated. Treatments were categorized according to whether they involved platinum, taxane, both, or neither; non-platinum/non-taxane regimens were also categorized in monotherapy and combination regimens. We extracted or estimated the logarithm of the hazard ratio and its variance for death for each randomized comparison. Multiple-treatments meta-analysis with a hierarchical Bayesian model obtained summary hazard ratios with 95% credibility intervals. Results: Ten articles were eligible for the meta-analysis. No trials compared systemic treatment to best supportive care and all arms referred to chemotherapy regimens. Overall 683 subjects were randomly assigned and eight randomized comparisons were used for the multiple-treatments meta-analysis of survival (543 patients). Multiple-treatments meta-analysis showed no significant benefit for any treatment group over others, with wide credibility intervals. Point estimates of hazard ratios favored platinum, taxane, or both (hazard ratios 0.69, 0.66, and 0.81, respectively, as compared with monotherapy with an agent other than platinum or taxane). Conclusion: No type of chemotherapy has been solidly proven to prolong survival in patients with CUP. Regimens using either platinum or taxanes or both need further testing. © 2009 Elsevier Ltd. All rights reserved. 35 7 570 573

Background Different therapeutic strategies are available for the treatment of people with relapsing-remitting multiple sclerosis (RRMS), including immunomodulators, immunosuppressants and biologics. Although there is consensus that these therapies reduce the frequency of relapses, their relative benefit in delaying new relapses or disability worsening remains unclear due to the limited number of direct comparison trials. Objectives To compare the benefit and acceptability of interferon beta-1b, interferon beta-1a (Avonex, Rebif), glatiramer acetate, natalizumab, mitoxantrone, fingolimod, teriflunomide, dimethyl fumarate, alemtuzumab, pegylated interferon beta-1a, daclizumab, laquinimod, azathioprine and immunoglobulins for the treatment of people with RRMS and to provide a ranking of these treatments according to their benefit and acceptability, defined as the proportion of participants who withdrew due to any adverse event. Search methods We searched the Cochrane Multiple Sclerosis and Rare Diseases of the CNS Group Trials Register, which contains trials from CENTRAL (2014, Issue 9), MEDLINE (1966 to 2014), EMBASE (1974 to 2014), CINAHL (1981 to 2014), LILACS (1982 to 2014), clinicaltrials.gov and the WHO trials registry, and US Food and Drug Administration (FDA) reports. We ran the most recent search in September 2014. Selection criteria Randomised controlled trials (RCTs) that studied one or more of the 15 treatments as monotherapy, compared to placebo or to another active agent, for use in adults with RRMS. Data collection and analysis Two authors independently identified studies from the search results and performed data extraction. We performed data synthesis by pairwise meta-analysis and network meta-analysis. We assessed the quality of the body of evidence for outcomes within the network meta-analysis according to GRADE, as very low, low, moderate or high. Main results We included 39 studies in this review, in which 25,113 participants were randomised. The majority of the included trials were short-term studies, with a median duration of 24 months. Twenty-four (60%) were placebo-controlled and 15 (40%) were head-to-head studies.Network meta-analysis showed that, in terms of a protective effect against the recurrence of relapses in RRMS during the first 24 months of treatment, alemtuzumab, mitoxantrone, natalizumab, and fingolimod outperformed other drugs. The most effective drug was alemtuzumab (risk ratio (RR) versus placebo 0.46, 95% confidence interval (CI) 0.38 to 0.55; surface under the cumulative ranking curve (SUCRA) 96%; moderate quality evidence), followed by mitoxantrone (RR 0.47, 95% CI 0.27 to 0.81; SUCRA 92%; very low quality evidence), natalizumab (RR 0.56, 95% CI 0.47 to 0.66; SUCRA 88%; high quality evidence), and fingolimod (RR 0.72, 95% CI 0.64 to 0.81; SUCRA 71%; moderate quality evidence).Disability worsening was based on a surrogate marker, defined as irreversible worsening confirmed at three-month follow-up, measured during the first 24 months in the majority of included studies. Both direct and indirect comparisons revealed that the most effective treatments were mitoxantrone (RR versus placebo 0.20, 95% CI 0.05 to 0.84; SUCRA 96%; low quality evidence), alemtuzumab (RR 0.35, 95% CI 0.26 to 0.48; SUCRA 94%; low quality evidence), and natalizumab (RR 0.64, 95% CI 0.49 to 0.85; SUCRA 74%; moderate quality evidence).Almost all of the agents included in this review were associated with a higher proportion of participants who withdrew due to any adverse event compared to placebo. Based on the network meta-analysis methodology, the corresponding RR estimates versus placebo over the first 24 months of follow-up were: mitoxantrone 9.92 (95% CI 0.54 to 168.84), fingolimod 1.69 (95% CI 1.32 to 2.17), natalizumab 1.53 (95% CI 0.93 to 2.53), and alemtuzumab 0.72 (95% CI 0.32 to 1.61).Information on serious adverse events (SAEs) was scanty, characterised by heterogeneous results and based on a very low number of events observed during the short-term duration of the trials included in this review. Authors' conclusions Conservative interpretation of these results is warranted, since most of the included treatments have been evaluated in few trials. The GRADE approach recommends providing implications for practice based on moderate to high quality evidence. Our review shows that alemtuzumab, natalizumab, and fingolimod are the best choices for preventing clinical relapses in people with RRMS, but this evidence is limited to the first 24 months of follow-up. For the prevention of disability worsening in the short term (24 months), only natalizumab shows a beneficial effect on the basis of moderate quality evidence (all of the other estimates were based on low to very low quality evidence). Currently, therefore, insufficient evidence is available to evaluate treatments for the prevention of irreversible disability worsening.There are two additional major concerns that have to be considered. First, the benefit of all of these treatments beyond two years is uncertain and this is a relevant issue for a disease with a duration of 30 to 40 years. Second, short-term trials provide scanty and poorly reported safety data and do not provide useful evidence in order to obtain a reliable risk profile of treatments. In order to provide long-term information on the safety of the treatments included in this review, it will be necessary also to evaluate non-randomised studies and post-marketing reports released from the regulatory agencies. Finally, more than 70% of the studies included in this review were sponsored by pharmaceutical companies and this may have influenced the results.There are three needs that the research agenda should address. First, randomised trials of direct comparisons between active agents would be useful, avoiding further placebo-controlled studies. Second, follow-up of the original trial cohorts should be mandatory. Third, more studies are needed to assess the medium and long-term benefit and safety of immunotherapies and the comparative safety of different agents.

A multivariate meta-analysis of two or more correlated outcomes is expected to improve precision compared with a series of independent, univariate meta-analyses especially when there are studies reporting some but not all outcomes. Multivariate meta-analysis requires estimates of the within-study correlations, which are seldom available. Existing methods for analysing multiple outcomes simultaneously are limited to pairwise treatment comparisons. We propose a model for a joint, simultaneous synthesis of multiple dichotomous outcomes in a network of interventions and introduce a simple way to elicit expert opinion for the within-study correlations by utilizing a set of conditional probability parameters. We implement our multiple-outcomes network meta-analysis model within a Bayesian framework, which allows incorporation of expert information. As an example, we analyse two correlated dichotomous outcomes, response to the treatment and dropout rate, in a network of pharmacological interventions for acute mania. The produced estimates have narrower confidence intervals compared with the simple network meta-analysis. We conclude that the proposed model and the suggested prior elicitation method for correlations constitute a useful framework for performing network meta-analysis for multiple outcomes. © 2014 John Wiley and Sons, Ltd.

BACKGROUND: Mortality from upper gastrointestinal bleeding in patients with liver disease is high. Recombinant human activated factor VII (rHuFVIIa) has been suggested for patients with liver disease and upper gastrointestinal bleeding. OBJECTIVES: To assess the beneficial and harmful effects of rHuFVIIa in patients with liver disease and upper gastrointestinal bleeding. SEARCH METHODS: We searched the Cochrane Hepato-Biliary Group Controlled Trials Register (December 2011), the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library (Issue 4, 2011), MEDLINE (1948 to December 2011), EMBASE (1980 to December 2011), Science Citation Index Expanded (1900 to December 2011), and LILACS (December 2011). We sought additional randomised trials from the reference lists of the trials and reviews identified through the electronic searches. SELECTION CRITERIA: Randomised clinical trials. DATA COLLECTION AND ANALYSIS: Outcome data from randomised clinical trials were extracted and were presented using random-effects model meta-analyses. Data on the risk of bias in the included trials were also extracted. MAIN RESULTS: We included two trials with 493 randomised participants with various Child-Pugh scores. The trials had a low risk of bias. The rHuFVIIa administration did not reduce the risk of mortality within five days (21/288 (7.3%) versus 15/205 (7.3%); risk ratio (RR) 0.88, 95% confidence interval (CI) 0.48 to 1.64, I(2) = 49%) and within 42 days (5/286 (1.7%) versus 36/205 (17.6%); RR 1.01, 95% CI 0.55 to 1.87, I(2) = 55%) when compared with placebo. Trial sequential analysis demonstrated that there is sufficient evidence to exclude that rHuFVIIa decreases mortality by 80%, but there is insufficient evidence to exclude smaller effects. The rHuFVIIa did not increase the risk of adverse events by number of patients (218/297 (74%) and 164/210 (78%); RR 0.94, 95% CI 0.84 to 1.04, I(2) = 1%), serious adverse events by adverse events reported (164/590 (28%) versus 123/443 (28%); RR 0.91, 95% CI 0.75 to 1.11, I(2) = 0%), and thromboembolic adverse events (16/297 (5.4%) versus 14/210 (6.7%); RR 0.80, 95% CI 0.40 to 1.60, I(2) = 0%) when compared with placebo. AUTHORS' CONCLUSIONS: We found no evidence to support or reject the administration of rHuFVIIa for patients with liver disease and upper gastrointestinal bleeding. Further adequately powered randomised clinical trials are needed in order to evaluate the proper role of rHuFVIIa for treating upper gastrointestinal bleeding in patients with liver disease. Although the results are based on trials with low risk of bias, the heterogeneity and the small sample size result in rather large confidence intervals that cannot exclude the possibility that the intervention has some beneficial or harmful effect. Further trials with alow risk of bias are required to make more confident conclusions about the effects of the intervention. Cochrane Database Syst Rev

OBJECTIVE: To assess whether there are preferences and avoidances for specific comparisons in a clinical trials agenda. STUDY DESIGN AND SETTING: We tested for homophily (preference to compare agents against others in the same class) and co-occurrence (preference or avoidance of specific head-to-head comparisons) in the randomized trials agenda of antifungal agents. We searched MEDLINE and Cochrane Library databases for English language randomized trials evaluating systemic antifungals against Candida or Aspergillus in adults. We extracted data on compared regimens, sample size, publication year, indication (treatment/prophylaxis), and underlying disease. RESULTS: One hundred forty-four trials (74 treatments, 70 prophylaxes) were found (n=27,497 patients). Among polyene and azole groups, agents were compared within the same class more often than across classes (homophily test P

OBJECTIVE: To present some simple graphical and quantitative ways to assist interpretation and improve presentation of results from multiple-treatment meta-analysis (MTM). STUDY DESIGN AND SETTING: We reanalyze a published network of trials comparing various antiplatelet interventions regarding the incidence of serious vascular events using Bayesian approaches for random effects MTM, and we explore the advantages and drawbacks of various traditional and new forms of quantitative displays and graphical presentations of results. RESULTS: We present the results under various forms, conventionally based on the mean of the distribution of the effect sizes; based on predictions; based on ranking probabilities; and finally, based on probabilities to be within an acceptable range from a reference. We show how to obtain and present results on ranking of all treatments and how to appraise the overall ranks. CONCLUSIONS: Bayesian methodology offers a multitude of ways to present results from MTM models, as it enables a natural and easy estimation of all measures based on probabilities, ranks, or predictions. J Clin Epidemiol