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Summary Background The first episode of schizophrenia is a pivotal phase of this debilitating illness. Which drug to use remains controversial without a summary of all direct or indirect comparisons of drugs. We did a systematic review with pairwise and network meta-analyses of efficacy and tolerability. Methods We searched MEDLINE, Embase, PsycINFO, Cochrane Library, PubMed, Biosis, and ClinicalTrials.gov for randomised controlled trials of antipsychotics for the acute treatment of first-episode schizophrenia, published up to Nov 17, 2016. Our primary outcome was overall change in symptoms. Secondary outcomes were change in positive and negative symptoms, categorical response to treatment, study dropout for any reason and for inefficacy of treatment, use of drugs to treat parkinsonian symptoms, weight gain, sedation, increase in prolactin release, overall functioning, and quality of life. We did the meta-analyses with a random-effects model to calculate standardised mean differences (SMDs) or odds ratios (ORs) with 95% CIs. Findings We identified 19 relevant randomised controlled trials of 12 antipsychotic drugs that involved 2669 participants. 13 of the studies presented data on the primary outcome. For overall reduction of symptoms, amisulpride (SMD −0·37, 95% CI −0·61 to −0·14), olanzapine (−0·25, −0·39 to −0·12), ziprasidone (−0·25, −0·48 to −0·01), and risperidone (−0·14, −0·27 to −0·01) were significantly more efficacious than haloperidol, but the evidence was very low to moderate quality. Amisulpride was superior for reduction of symptoms to quetiapine (SMD −0·25, 95% CI −0·50 to −0·01). Olanzapine was superior to haloperidol and risperidone for reduction of negative symptoms. Several second-generation antipsychotics were superior to haloperidol in terms of all-cause discontinuation. Olanzapine was associated with at least one use of drugs to treat parkinsonian symptoms and quetiapine with less akathisia than haloperidol, aripiprazole, risperidone, and olanzapine, but, again, evidence was very low to low quality. Molindone was superior to risperidone, haloperidol, and olanzapine in terms of weight gain, and superior to risperidone in terms of increase in prolactin release. Interpreation Haloperidol seems to be a suboptimum treatment option for acute treatment of first-episode schizophrenia, but we found little difference between second-generation antipsychotics. The evidence was generally of low quality and the numbers of patients for each drug were small. Thus, the choice of treatment should be guided primarily by side-effects. Funding German Federal Ministry of Education and Research.

When interpreting the relative effects from a network meta-analysis (NMA), researchers are usually aware of the potential limitations that may render the results for some comparisons less useful or meaningless. In the presence of sufficient and appropriate data, some of these limitations (e.g. risk of bias, small-study effects, publication bias) can be taken into account in the statistical analysis. Very often, though, the necessary data for applying these methods are missing and data limitations cannot be formally integrated into ranking. In addition, there are other important characteristics of the treatment comparisons that cannot be addressed within a statistical model but only through qualitative judgements; for example, the relevance of data to the research question, the plausibility of the assumptions, etc. Here, we propose a new measure for treatment ranking called the Probability of Selecting a Treatment to Recommend (POST-R). We suggest that the order of treatments should represent the process of considering treatments for selection in clinical practice and we assign to each treatment a probability of being selected. This process can be considered as a Markov chain model that allows the end-users of NMA to select the most appropriate treatments based not only on the NMA results but also to information external to the NMA. In this way, we obtain rankings that can inform decision-making more efficiently as they represent not only the relative effects but also their potential limitations. We illustrate our approach using a NMA comparing treatments for chronic plaque psoriasis and we provide the Stata commands.

We compared the cumulative network meta-analyses with the recommendations in postmenopausal osteoporosis practice guidelines and actual prescribing practices in the USA. There was no apparent discrepancy between guideline recommendations and drug prescribing rankings, with the exception of vitamin D and calcium, when we used cumulative NMAs as references.To compare the results of cumulative network meta-analyses (NMAs) with the recommendations in postmenopausal osteoporosis practice guidelines and actual prescribing practices in the USA.MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, Web of Science, and Scopus were searched to retrieve randomized controlled trials (RCTs) in July 2017. The Agency for Healthcare Research and Quality's National Guideline Clearinghouse and associated society websites were searched to retrieve guidelines in June 2018. We used the Medical Expenditure Panel Survey (MEPS) to analyze prescription data from 1996 to 2015. Two independent investigators selected eligible RCTs. One investigator selected potential eligible guidelines, which were confirmed by another investigator. Two independent investigators extracted data from included RCTs. One investigator extracted recommendations from guidelines, which were confirmed by another investigator. (Registration: UMIN000031894) RESULTS: We analyzed data from 1995, 2000, 2005, 2010, and 2015. We chose hip fracture as the primary outcome of cumulative NMAs. We included 51 trials, 17 guidelines, and 5099 postmenopausal osteoporosis patients from the MEPS. Bisphosphonate, including alendronate, and combination of vitamin D and calcium (vDCa) were consistently recommendable from an efficacy viewpoint in NMAs and recommended in guidelines. Alendronate was the most prescribed drug (more than 30% over the observation period); however, vDCa was seldom prescribed. The maximum proportion was 5.3% from 2011 to 2015.In postmenopausal osteoporosis, there was no apparent discrepancy between guideline recommendations and drug prescribing rankings, with the exception of vDCa, when we used cumulative NMAs as references.

IntroductionCumulative network meta-analysis (NMA) is a method to provide a global comparison of multiple treatments with real-time update to evidence users. Several studies investigated the ranking of cumulative NMA and the recommendations of practice guidelines. However, to the best of our knowledge, no study has evaluated the cumulative NMA ranking and prescription patterns. Here, we present a protocol for a meta-epidemiological investigation to compare the results of cumulative NMA with the recommendations in postmenopausal osteoporosis practice guidelines and with the actual prescriptions.Method and analysisWe will use the data of primary trials from the upcoming postmenopausal osteoporosis clinical practice guideline of the Endocrine Society. We will conduct cumulative NMA using all eligible trials and generate hierarchy of treatment rankings by using the surface under the cumulative ranking curve. We will search practice guidelines in relevant society websites. Two review authors will extract the practice recommendations. We will use data from the Medical Expenditures Panel Survey, a US representative sample of the non-institutionalised population, to determine the prescription patterns.Ethics and disseminationBecause all data will be retrieved from public databases, institutional review board approval is not required. We will publish our findings in a peer-reviewed journal and present key findings at conferences.Trial registration numberUMIN000031894: Pre-results.

Evaluation of the credibility of results from a meta-analysis has become an intrinsic part of the evidence synthesis process. We present a methodological framework to evaluate Confidence In the results from Network Meta-Analysis (CINeMA) when multiple interventions are compared. CINeMA considers six domains and we outline the methods used to form judgements about within-study bias, across-studies bias, indirectness, imprecision, heterogeneity and incoherence. Key to judgements about within-study bias and indirectness is the percentage contribution matrix, which shows how much information each study contributes to the results from network meta-analysis. The use of contribution matrix allows the semi-automation of the process, implemented in a freely available web application (cinema.ispm.ch). In evaluating imprecision, heterogeneity and inconsistency we consider the impact of these components of variability in forming clinical decisions. Via three examples, we show that CINeMA improves transparency and avoids the selective use of evidence when forming judgements, thus limiting subjectivity in the process. CINeMA is easy to apply even in large and complicated networks, like a network involving 18 different antidepressant drugs.

Hintergrund/Fragestellung: Depressionen sind in der älteren Bevölkerung sehr häufig und führen oft zu einer reduzierten Lebensqualität und im Extremfall zum Tod durch Suizid. Antidepressiva sind die am häufigsten verwendeten Behandlungen. Welches Antidepressiva besonders[zum vollständigen Text gelangen Sie über die oben angegebene URL], EbM und Digitale Transformation in der Medizin; 20. Jahrestagung des Deutschen Netzwerks Evidenzbasierte Medizin

Differences in efficacy between antipsychotics and placebo in schizophrenia trials have decreased over the past decades. Previous studies have tried to identify potential explanatory factors focusing on response to placebo; however, it is still not clear which factors, if any, specifically moderate drug-response, as they may be different from those moderating placebo-response. Therefore, in this meta-regression analysis we explore whether there is an interaction between drug-response and placebo-response in terms of effect size. We systematically searched multiple electronic databases, ClinicalTrials.gov, and the US Food and Drug Administration website for randomized, placebo-controlled trials investigating the efficacy of antipsychotics in patients with acute schizophrenia (last update: October 2016). The main outcome was the change on the Brief Psychiatric Rating Scale or the Positive and Negative Syndrome Scale score from baseline to endpoint after at least 3 weeks of treatment. Multiple patient-, design-, and drug-related potential predictors of response were analyzed by meta-regressions, as predefined in the study protocol. Overall, 167 trials with 28,102 participants were included. Publication year, the number of participants and sites, mean dose, minimum severity threshold as an inclusion criterion, chronicity, industry sponsorship, type of rating scale, diagnostic criteria, and number of medications had a different impact on drug and placebo response. By contrast, baseline severity, duration of wash-out, study duration, and study region affected drug and placebo response in a similar way without a net effect on effect sizes. No other factors had a significant effect on either drug-response or placebo-response. In conclusion, as individual moderators may have different impact on placebo-response and drug-response, it is important to consider also the specific factors influencing drug-response in order to fully understand the difference between antipsychotics and placebo. These results shed further light on the phenomenon of decreasing effect size of antipsychotics for schizophrenia over time and should help design future randomized controlled trials in the field (Prospero registration number CRD42013003342).

The use of the last observation carried forward (LOCF) method for imputing missing outcome data in randomized clinical trials has been much criticized and its shortcomings are well understood. However, only recently have published studies widely started using more appropriate imputation methods. Consequently, meta-analyses often include several studies reporting their results according to LOCF. The results from such meta-analyses are potentially biased and overprecise. We develop methods for estimating summary treatment effects for continuous outcomes in the presence of both missing and LOCF-imputed outcome data. Our target is the treatment effect if complete follow-up was obtained even if some participants drop out from the protocol treatment. We extend a previously developed meta-analysis model, which accounts for the uncertainty due to missing outcome data via an informative missingness parameter. The extended model includes an extra parameter that reflects the level of prior confidence in the appropriateness of the LOCF imputation scheme. Neither parameter can be informed by the data and we resort to expert opinion and sensitivity analysis. We illustrate the methodology using two meta-analyses of pharmacological interventions for depression.

Case-mix heterogeneity across studies complicates meta-analyses. As a result of this, treatments that are equally effective on patient subgroups may appear to have different effectiveness on patient populations with different case mix. It is therefore important that meta-analyses be explicit for what patient population they describe the treatment effect. To achieve this, we develop a new approach for meta-analysis of randomized clinical trials, which use individual patient data (IPD) from all trials to infer the treatment effect for the patient population in a given trial, based on direct standardization using either outcome regression (OCR) or inverse probability weighting (IPW). Accompanying random-effect meta-analysis models are developed. The new approach enables disentangling heterogeneity due to case mix from that due to beyond case-mix reasons., Published on Research Synthesis Methods

Missing outcome data can invalidate the results of randomized trials and their meta-analysis. However, addressing missing data is often a challenging issue because it requires untestable assumptions. The impact of missing outcome data on the meta-analysis summary effect can be explored by assuming a relationship between the outcome in the observed and the missing participants via an informative missingness parameter. The informative missingness parameters cannot be estimated from the observed data, but they can be specified, with associated uncertainty, using evidence external to the meta-analysis, such as expert opinion. The use of informative missingness parameters in pairwise meta-analysis of aggregate data with binary outcomes has been previously implemented in Stata by the metamiss command. In this article, we present the new command metamiss2, which is an extension of metamiss for binary or continuous data in pairwise or network meta-analysis. The command can be used to explore the robustness of results to different assumptions about the missing data via sensitivity analysis.

IntroductionClinical practice guidelines differ in their recommendations on first-line antihypertensive drug classes. No adequately powered randomised controlled trial have assessed all major drug classes against each other, and previous meta-analyses have mainly relied on pairwise meta-analyses for treatment comparisons.Methods and analysisA systematic review and network meta-analysis will be carried out to assess the efficacy and acceptability of all major antihypertensive drug classes. PubMed and CENTRAL were searched on 21 February 2020 to identify randomised controlled trials with at least 1000 person-years of follow-up, assessing any antihypertensive agent against other agents or placebo. All trials fulfilling the inclusion criteria will be assessed for risk of bias using the second version of Cochrane’s risk of bias assessment tool. The study selection process, risk of bias assessment and data extraction are done by two authors in duplicate. Relative risks from individual trials will be combined in pairwise meta-analyses; in the absence of important intransitivity, random-effects network meta-analysis will be performed. The primary outcome for efficacy will be major adverse cardiovascular events, whereas the primary acceptability outcome will be treatment discontinuation for any reason. Additional outcomes include all-cause mortality, cardiovascular mortality, stroke, myocardial infarction, heart failure and acute renal failure. The impact of differences within drug classes will be explored through alternative networks, including analysing thiazide-like and thiazide-type diuretics separately.Ethics and disseminationThis review will only process aggregated study level data and does not require ethical approval. The findings will be published in a peer-reviewed medical journal.PROSPERO registration numberCRD42020205482.

Objective The presence of hydrosalpinx impairs the outcome of in-vitro fertilization embryo transfer (IVF-ET). Surgical methods to either aspirate the fluid or isolate the affected Fallopian tubes have been attempted as a means of improving outcome. The aim of this network meta-analysis was to compare the effectiveness of surgical treatments for hydrosalpinx before IVF-ET. Methods An electronic search of MEDLINE, Scopus, Cochrane Central Register of Controlled Trials (Central) and the US Registry of clinical trials for articles published from inception to July 2015 was performed. Eligibility criteria included randomized controlled trials of women with hydrosalpinx before IVF-ET comparing ultrasound-guided aspiration of the fluid, tubal occlusion, salpingectomy or no intervention. Ongoing pregnancy was the primary outcome and clinical pregnancy, ectopic pregnancy and miscarriage were secondary outcomes. A random-effects network meta-analysis synthesizing direct and indirect evidence from the included trials was carried out. We estimated the relative effect sizes as risk ratios (RRs) and obtained the relative ranking of the interventions using cumulative ranking curves. The quality of evidence according to GRADE guidelines, adapted for network meta-analysis, was assessed. Results Proximal tubal occlusion (RR, 3.22 (95% CI, 1.27–8.14)) and salpingectomy (RR, 2.24 (95% CI, 1.27–3.95)) for treatment of hydrosalpinx were superior to no intervention for ongoing pregnancy. For an outcome of clinical pregnancy, all three interventions appeared to be superior to no intervention. No superiority could be ascertained between the three surgical methods for any of the outcomes. In terms of relative ranking, tubal occlusion was the best surgical treatment followed by salpingectomy for ongoing and clinical pregnancy rates. No significant statistical inconsistency was detected; however, the point estimates for some inconsistency factors and their CIs were relatively large. The small study number and sizes were the main limitations. The quality of evidence was commonly low/very low, especially when aspiration was involved, indicating that the results were not conclusive and should be interpreted with caution. Conclusions Proximal tubal occlusion, salpingectomy and aspiration for treatment of hydrosalpinx scored consistently better than did no intervention for the outcome of IVF-ET. In terms of relative ranking, proximal tubal occlusion appeared to be the most effective intervention, followed by salpingectomy. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

Introduction La mise a disposition de traitements efficaces pour le psoriasis en plaques (Pso) questionne, d’un point de vue ethique, l’utilisation d’un groupe placebo (PBO) dans les essais therapeutiques. Une revue Cochrane et meta-analyse en reseau (MAR) comparant l’efficacite des traitements systemiques du Pso a revele que 69 % des comparaisons impliquaient un groupe PBO dans les essais controles randomises (ECR). L’objectif de cette etude etait d’evaluer la proportion de patients inclus dans le groupe PBO au fil du temps. Materiel et methodes Etaient eligibles tous les ECRs dans le traitement du Pso comparant un biomedicament a un PBO ou a un autre traitement systemique. Le critere de jugement (CJ) principal etait la proportion de patients randomises dans le groupe PBO par an. L’evolution de cette proportion au cours du temps etait testee par une regression lineaire. Un total de 14 reseaux des traitements systemiques du Pso etait construit chaque annee entre 2004 et 2019. Pour chaque reseau, la matrice de contribution des etudes avec groupe PBO dans les estimations des resultats des comparaisons directs et indirectes des MAR etait evaluee (CJ secondaire) a l’aide de l’application web CINeMA (Confidence in Network Meta-Analysis). Les etudes avec PBO etaient divisees selon le desequilibre ou non de la randomisation « 1 : 1 » ou « Resultats Quatre-vingt-un ECR (36 774 patients) ont ete inclus. Nous avons observe une diminution non significative de la proportion de patients randomises dans le groupe PBO au cours du temps entre 2004–2019 (coefficient par an [IC 95 %] = −0,007 [−0,020 a 0,004] ; p = 0,211). La proportion de la contribution des ECRs avec un groupe PBO dans les estimations des resultats des MAR diminuait au cours du temps passant de 100 % de contributions en 2004, 86 % en 2008 a 75 % en 2019. Cependant, la contribution des etudes sans groupe PBO dans les estimations des MAR restait faible (de 0 % en 2004 a 25 % en 2019) ( Figure 2 ). Discussion Notre analyse a montre une diminution non significative dans le temps de la proportion de patients randomises dans le groupe PBO pour l’evaluation des biomedicaments dans le Pso. Cependant, la proportion d’essais sans groupe PBO reste faible. La necessite d’un ECR bien conduit avec groupe PBO pour limiter le risque de conclure a tort a un effet du medicament est requise par les agences du medicament. Cependant, cela n’explique pas une majorite d’etudes versus PBO. Il est necessaire de reconsiderer les futurs designs des ECRs du Pso.

Introduction Le psoriasis est une maladie cutanee inflammatoire. Une revue Cochrane et une meta-analyse (MA) du psoriasis en plaques modere a severe (Pso) a synthetise les resultats des essais controles randomises (ECR) comparant les traitements systemiques (TS) avec le placebo (PBO) (Sbidian et al., 2017). Cette etude a montre une proportion d’evenements indesirables graves (EIG) non significativement differente entre les TS et PBO. Un EIG est un evenement medical entrainant (prolongation) une hospitalisation ou mettant le pronostic vital en jeu. L’objectif etait d’explorer cette absence de difference. Methodes Un protocole a ete publie (PROSPERO, CRD42019124495). Les ECR identifies dans la revue Cochrane ont ete utilises et une mise a jour a ete faite (05/2019). Les criteres d’inclusion etaient : ECR comparant un biologique (BIO) ou apremilast a un PBO dans le Pso. Deux auteurs ont extrait les donnees des revues FDA, clinicaltrials.gov, publications. Le critere de jugement (CJ) principal etait EIG apres exclusion des cas d’aggravation du psoriasis. Les CJ secondaires etaient les evenements d’interets : infections graves, troubles psychiatriques, evenements cardiovasculaires majeurs, cancers. Des MA comparant un traitement au PBO ont ete faites avec RevMan 5.3. Resultats Au total, 49 ECR (23 822 patients) dans lesquels les EIG aggravation du psoriasis etaient renseignes ont ete inclus. Le risque relatif (RR) de survenue des EIG entre les BIO et le PBO n’etait pas significativement different 1,07 (IC95 % : 0,86–1,34). Le RR de survenue des EIG apres l’exclusion des cas d’aggravation du psoriasis devenait significative 1,29 (IC95 % : 1,01–1,64). Les resultats par classe etaient : anti-TNF alpha 1,68 (IC95 % : 1,11–2,54), anti-IL17 1,28 (IC95 % : 0,88–1,85), anti-IL23 0,90 (IC95 % : 0,53–1,52), anti-IL12/23 0,93 (IC95 % : 0,53–1,64), apremilast 0,89 (IC95 % : 0,50–1,58). Il n’y avait pas de difference significative pour les evenements d’interets entre les BIO et le PBO. Conclusion L’exclusion des cas d’aggravation du psoriasis dans les deux bras revele un sur-risque de survenue des EIG dans le groupe BIO. Le PASI eleve (20) a l’inclusion dans ces ECR favoriserait le risque de developper un psoriasis suffisamment severe pour entrer dans la definition d’un EIG, chez les patients non traites. Outre le probleme de masquer une difference de risque pour les EIG, l’utilisation d’un groupe PBO pose une question ethique. Il serait necessaire que les EIG soient rapportes en excluant les aggravations du Pso.

As there is currently no comprehensive evaluation about the efficacy and safety of interventions in elderly patients with major depressive disorder, we did a systematic review and network meta-analysis about all interventions in this population. We searched the specialised register of the Cochrane common mental disorders group, MEDLINE, EMBASE, PsycINFO, CochraneLibrary, ClinicalTrials.gov and the WHO registry until Dec 12, 2017 to identify all randomized controlled trials about the treatment of major depressive disorder in patients over an age of 65. The primary outcome was response defined as reduction of at least 50% on the Hamilton Depression Scale or any other validated depression scale. Secondary outcomes were remission, depressive symptoms, dropouts total, dropouts owing to inefficacy and dropouts due to adverse events, quality of life and social functioning. Additionally, we analysed 116 adverse events. We identified 129 references from 53 RCTs with 9274 participants published from 1990 to 2017. The mean participant age was 73.7 years. In terms of the primary outcome response to treatment the network-meta-analysis showed significant superiority compared to placebo for quetiapine and duloxetine; in addition, agomelatine, imipramine and vortioxetine outperformed placebo in pairwise meta-analyses, and there were also significant superiorities of several antidepressants compared to placebo in secondary efficacy outcomes. Very limited evidence suggests that competitive memory training, geriatric home treatment group and detached mindfulness condition reduce depressive symptoms. Several antidepressants and quetiapine have been shown to be efficacious in elderly patients with major depressive disorder, but due to the comparably few available data, the results are not robust. Differences in the multiple side-effects analysed should also be considered in drug choice. Although there were significant effects for some non-pharmacological treatments, the overall evidence for non-pharmacological treatments in major depressive disorder is insufficient, because it is based on a few trials with usually small sample sizes.

Systematic reviews and meta-analyses of diagnostic test accuracy (DTA)4 studies are becoming increasingly popular in medical literature, with a steep increase in publications after 1990 (1, 2). Although summaries from DTA reviews are largely used by clinicians and policymakers and frequently form the basis of clinical practice guidelines (3), their reporting is usually incomplete (4). In the December 2018 issue of Clinical Chemistry , Salameh and colleagues evaluate the completeness of reporting of such reviews using a sample of 100 DTA reviews published between October 2017 and January 2018 (5). Although some aspects were frequently reported, the reporting of key methodological practices did not meet the standards for high-quality DTA systematic reviews and meta-analyses. Conducting meta-analyses of DTA studies is generally more complex than meta-analyses of intervention studies, and consequently, comprehensive reporting is often more challenging (6–9). The recent development of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)-DTA statement (10), which is an extension of the original PRISMA statement (11), is expected to facilitate the transparent and comprehensive reporting of DTA reviews. PRISMA was initially developed for systematic reviews and meta-analyses of intervention studies and therefore was not adequate for use in the context of DTA reviews. PRISMA-DTA was developed on an evidence-based principle following the best practice for the development of reporting guidelines suggested from the Enhancing the Quality and Transparency Of health Research (EQUATOR) group (12). A multidisciplinary group of 24 experts in diagnostic accuracy research and systematic review methods, journal editors, funders, and end-users of DTA reviews was involved. Having the original PRISMA guidelines as starting point, the group identified items that needed to be added, removed, or modified for the case of DTA …

Missing outcome data can invalidate the results of randomized trials and their meta-analysis. The impact of missing outcome data on the summary effect can be explored by assuming a relationship between the outcome in the observed and the missing participants via an informative missingness parameter (IMP). The use of IMPs in pairwise meta-analysis has been previously implemented in Stata with the metamiss command for the case of binary outcome data. This paper presents the new command metamiss2, which is an extension of metamiss for binary or continuous data in pairwise or network meta-analysis.

Objective: A recent meta-regression had shown that the degree of placebo response, which has increased over the decades, is the major predictor of drug-placebo differences in antipsychotic drug trials in acutely ill patients with schizophrenia. Drug response, however, had remained stable. In the current meta-regression we explored the factors that are associated with placebo-response. Method: We searched multiple electronic databases, ClinicalTrials.gov and the FDA website for randomized, placebo-controlled, antipsychotic drug trials in patients with acute exacerbations of schizophrenia. The outcome was the degree of placebo response measured by the BPRS or PANSS change from baseline to endpoint. 26 patient-, design-, and drug-related potential predictors of placebo response were analyzed by univariable and multivariable meta-regressions. Results: 167 double-blind randomized controlled trials with 28,102 participants were included. The mean PANSS change from baseline was 6.25 (95% CI 4.64,7.85). More recent publication year, larger study sample size, more study sites, use of the PANSS rather than the BPRS scale to measure response, shorter wash-out phases, shorter study duration, lower mean age and shorter duration of illness were associated with larger placebo response in univariable analyses. In a multivariable analysis only the number of study participants and mean participant age had an impact on placebo response. Conclusions: The degree of placebo response is moderated by a number of design and patient-related factors. These explanatory variables of placebo response are only in part identical with those that moderated drug-placebo differences.

Background There is debate in the literature as to whether inclusion of a placebo arm may alter characteristics of antidepressant trials. However, previous research has focused on response rates of various antidepressants on average only, ignoring potential differences among drugs or other aspects of trial findings. Little is known about the impact of a placebo arm on all-cause dropout and dropout due to adverse events. Methods We carried out a systematic review of published and unpublished double-blind randomized controlled trials (RCTs) for the acute treatment of unipolar major depression (update: January 2016). The probability of being allocated to placebo (π) was the exposure of interest, and we examined its influence on responders (efficacy), all-cause dropouts (acceptability) and dropouts due to adverse events (tolerability), while accounting for differences in drugs, trials and patient characteristics in multivariate random effects meta-regression. Results We included 421 studies (68 305 participants) comparing 16 antidepressants or placebo; π ranged from 20% to 50%. Response rate was lower [risk ratio (RR) 0.87; 95% confidence interval (CI) 0.83, 0.92] and all-cause dropout rate higher (RR 1.19; 95% CI 1.08, 1.31) for the same antidepressants in placebo-controlled trials compared with head-to-head trials. The probability of responding decreased by 3% (95% CI 2–5%) for every 10% increase in π, whereas the risk of all-cause dropout increased by 4% (95% CI 1–7%). Tolerability was unaffected by π. Response rate was inversely correlated with dropouts due to any cause (correlation coefficient −0.48; 95% CI −0.58, −0.36) and due to adverse events (−0.34; 95% CI −0.44, −0.23). Conclusions For the same antidepressant, response rate was on average smaller and dropouts higher when placebo was included; however, no association was found with dropouts due to adverse events. Decreased patient expectations, larger dropout rates and use of inappropriate statistical methods to impute missing data may explain this phenomenon. The findings call for caution in the integration of randomized evidence involving placebo arms.

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Hintergrund/Fragestellung: Kinder und Jugendliche mit Schizophrenie stellen eine besonders anfällige Subgruppe dar. Einerseits ist ein frühzeitiger Erkrankungsbeginn häufig mit einer ungünstigeren Prognose verbunden, weshalb eine maximale Wirksamkeit erreicht werden muss. Auf[zum vollständigen Text gelangen Sie über die oben angegebene URL], Brücken bauen – von der Evidenz zum Patientenwohl; 19. Jahrestagung des Deutschen Netzwerks Evidenzbasierte Medizin

More than fifteen years ago, it was noted that the failure rate of antidepressant clinical trials was high, and such negative outcomes were thought to be related to the increasing magnitude of placebo response. However, there is considerable debate regarding this phenomenon and its relationship to outcomes in more recent antidepressant clinical trials. To investigate this, we accessed the US Food and Drug Administration (FDA) reviews for sixteen antidepressants (85 trials, 115 trial arms, 23,109 patients) approved between 1987 and 2013. We calculated the magnitude of placebo and antidepressant responses, antidepressant‐placebo differences, as well as the effect sizes and success rates, and compared these measures over time. Exploratory analysis investigated potential changes in trial design and conduct over time. As expected, the magnitude of placebo response has steadily grown in the past 30 years, increasing since 2000 by 6.4% (r=0.46, p

Pairwise meta-analyses have shown beneficial effects of individual dietary approaches on blood pressure but their comparative effects have not been established. Objective: Therefore we performed a systematic review of different dietary intervention trials and estimated the aggregate blood pressure effects through network meta-analysis including hypertensive and pre-hypertensive patients. Design: PubMed, Cochrane CENTRAL, and Google Scholar were searched until June 2017. The inclusion criteria were defined as follows: i) Randomized trial with a dietary approach; ii) hypertensive and pre-hypertensive adult patients; and iii) minimum intervention period of 12 weeks. In order to determine the pooled effect of each intervention relative to each of the other intervention for both diastolic and systolic blood pressure (SBP and DBP), random effects network meta-analysis was performed. Results: A total of 67 trials comparing 13 dietary approaches (DASH, lowfat, moderate-carbohydrate, high-protein, low-carbohydrate, Mediterranean, Palaeolithic, vegetarian, low-GI/GL, low-sodium, Nordic, Tibetan, and control) enrolling 17,230 participants were included. In the network metaanalysis, the DASH, Mediterranean, low-carbohydrate, Palaeolithic, high-protein, low-glycaemic index, lowsodium, and low-fat dietary approaches were significantly more effective in reducing SBP (¡8.73 to ¡2.32 mmHg) and DBP (¡4.85 to ¡1.27 mmHg) compared to a control diet. According to the SUCRAs, the DASH diet was ranked the most effective dietary approach in reducing SBP (90%) and DBP (91%), followed by the Palaeolithic, and the low-carbohydrate diet (ranked 3rd for SBP) or the Mediterranean diet (ranked 3rd for DBP). For most comparisons, the credibility of evidence was rated very low to moderate, with the exception for the DASH vs. the low-fat dietary approach for which the quality of evidence was rated high. Conclusion: The present network meta-analysis suggests that the DASH dietary approach might be the most effective dietary measure toreduce blood pressure among hypertensive and pre-hypertensive patients based on high quality evidence.

Introduction Une revue Cochrane et meta-analyse (MA) en reseau du psoriasis en plaques modere a severe (Pso) a synthetise les resultats des essais controles randomises (ECR) comparant les traitements systemiques (TS) avec le placebo (PBO). Cette etude a mis en evidence une proportion d’evenements indesirables graves (EIG) non significativement differente entre les TS et PBO. Un EIG est « un evenement indesirable entrainant le deces ou mettant le pronostic vital en jeu ou entrainant une invalidite ou une incapacite significative ou entrainant (prolongeant) une hospitalisation ». L’objectif etait d’explorer cette absence de cette difference. Materiel et methodes Un protocole a ete publie (PROSPERO, CRD42019124495). Les ECR identifies dans la revue Cochrane ont ete utilises et une mise a jour a ete faite (05/2019). Les criteres d’inclusion etaient : ECR comparant un biomedicament (BIO) ou apremilast a un PBO dans le Pso. L’extraction des donnees a ete effectuee par 2 auteurs sur les revues FDA, clinicaltrials.gov, publications. Les criteres de jugement (CJ) principaux etaient les EIG et les EIG apres exclusion des cas d’aggravation du psoriasis. Les CJ secondaires etaient les evenements d’interets : infections graves, troubles psychiatriques, evenements cardiovasculaires majeurs, cancers. Des MA comparant un traitement au PBO ont ete effectuees avec Revman 5,3 (modele a effets fixes). Resultats Un total de 49 ECR (23 822 patients) dans lesquels les EIG aggravation du psoriasis etaient renseignes ont ete inclus. Le risque relatif (RR) de survenue des EIG entre les BIO et le PBO n’etait pas significativement different 1,07 (95 % IC 0,86–1,34). Le RR de survenue des EIG apres l’exclusion des cas d’aggravation du psoriasis devenait significatif 1,29 (95 % IC 1,01–1,64). Les resultats par classe etaient : anti-TNF alpha 1,68 (95 % IC 1,11–2,54), anti-IL17 1,28 (95 % IC 0,88–1,85), anti-IL23 0,90 (95 % IC 0,53–1,52), anti-IL12/23 0,93 (95 % IC 0,53–1,64), apremilast 0,89 (95 % IC 0,50–1,58). Il n’y avait pas de difference significative pour les evenements d’interets entre les BIO et le PBO. Discussion Les revues systematiques/MA dans le Pso ne mettent pas en evidence de difference de risque de survenue des EIG entre les BIO et le PBO. Notre analyse montre que l’exclusion des cas d’aggravation du psoriasis dans les 2 bras revele un sur-risque de survenue des EIG dans le groupe BIO. Il n’y avait pas de sur-risque identifie pour chacun des evenements d’interet pris individuellement. Le PASI eleve (20) a l’inclusion dans ces ECR favoriserait le risque de developper un psoriasis suffisamment severe pour entrer dans la definition d’un EIG, chez les patients non traites. Outre le probleme de masquer une difference de risque pour les EIG, l’utilisation d’un groupe PBO pose une question ethique. Conclusion Il serait necessaire que les EIG soient rapportes egalement en excluant les aggravations de la maladie.

The PRISMA statement is a reporting guideline designed to improve the completeness of reporting of systematic reviews and meta-analyses. Authors have used this guideline worldwide to prepare their reviews for publication. In the past, these reports typically compared 2 treatment alternatives. With the evolution of systematic reviews that compare multiple treatments, some of them only indirectly, authors face novel challenges for conducting and reporting their reviews. This extension of the PRISMA (Preferred Reporting Items for Systematic Reviews and Metaanalyses) statement was developed specifically to improve the reporting of systematic reviews incorporating network meta-analyses.