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1.
Res Synth Methods ; 2020 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-32352639

RESUMO

It is often challenging to present the available evidence in a timely and comprehensible manner. We aimed to visualize the evolution of evidence about antidepressants for depression by conducting cumulative network meta-analyses (NMAs) and to examine whether it could have helped the selection of optimal drugs. We built a Shiny web application that performs and presents cumulative NMAs based on R netmeta. We used a comprehensive dataset of double-blind randomized controlled trials of 21 antidepressants in the acute treatment of major depression. The primary outcomes were efficacy (treatment response) and acceptability (all-cause discontinuation), and treatment effects were summarized via odds ratios. We evaluated the confidence in evidence using the CINeMA (Confidence in Network Meta-Analysis) framework for a series of consecutive NMAs. Users can change several conditions for the analysis, such as the period of synthesis, among the others. We present the league tables and two-dimensional plots that combine efficacy, acceptability and level of confidence in the evidence together, for NMAs conducted in 1990, 1995, 2000, 2005, 2010, and 2016. They reveal that through the past four decades, newly approved drugs often showed initially exaggerated results, which tended to diminish and stabilize after approximately a decade. Over the years, the drugs with relative superiority changed dramatically; but as the evidence network grew larger and better connected, the overall confidence improved. The Shiny app visualizes how evidence evolved over years, emphasizing the need for a careful interpretation of relative effects between drugs, especially for the potentially amplified performance of newly approved drugs.

2.
Lancet Infect Dis ; 2020 May 26.
Artigo em Inglês | MEDLINE | ID: mdl-32470329

RESUMO

BACKGROUND: Antibiotic prophylaxis is frequently continued for 1 day or more after surgery to prevent surgical site infection. Continuing antibiotic prophylaxis after an operation might have no advantage compared with its immediate discontinuation, and it unnecessarily exposes patients to risks associated with antibiotic use. In 2016, WHO recommended discontinuation of antibiotic prophylaxis after surgery. We aimed to update the evidence that formed the basis for that recommendation. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, CINAHL, CENTRAL, and WHO regional medical databases for randomised controlled trials (RCTs) on postoperative antibiotic prophylaxis that were published from Jan 1, 1990, to July 24, 2018. RCTs comparing the effect of postoperative continuation versus discontinuation of antibiotic prophylaxis on the incidence of surgical site infection in patients undergoing any surgical procedure with an indication for antibiotic prophylaxis were eligible. The primary outcome was the effect of postoperative surgical antibiotic prophylaxis continuation versus its immediate discontinuation on the occurrence of surgical site infection, with a prespecified subgroup analysis for studies that did and did not adhere to current best practice standards for surgical antibiotic prophylaxis. We calculated summary relative risks (RRs) with corresponding 95% CIs using a random effects model (DerSimonian and Laird). We evaluated heterogeneity with the χ2 test, I2, and τ2, and visually assesed publication bias with a contour-enhanced funnel plot. This study is registered with PROSPERO, CRD42017060829. FINDINGS: We identified 83 relevant RCTs, of which 52 RCTs with 19 273 participants were included in the primary meta-analysis. The pooled RR of surgical site infection with postoperative continuation of antibiotic prophylaxis versus its immediate discontinuation was 0·89 (95% CI 0·79-1·00), with low heterogeneity in effect size between studies (τ2=0·001, χ2 p=0·46, I2=0·7%). Our prespecified subgroup analysis showed a significant association between the effect estimate and adherence to best practice standards of surgical antibiotic prophylaxis: the RR of surgical site infection was reduced with continued antibiotic prophylaxis after surgery compared with its immediate discontinuation in trials that did not meet best practice standards (0·79 [95% CI 0·67-0·94]) but not in trials that did (1·04 [0·85-1·27]; p=0·048). Whether studies adhered to best practice standards explained all variance in the pooled estimate from the primary meta-analysis. INTERPRETATION: Overall, we identified no conclusive evidence for a benefit of postoperative continuation of antibiotic prophylaxis over its discontinuation. When best practice standards were followed, postoperative continuation of antibiotic prophylaxis did not yield any additional benefit in reducing the incidence of surgical site infection. These findings support WHO recommendations against this practice. FUNDING: None.

3.
PLoS Med ; 17(4): e1003082, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32243458

RESUMO

BACKGROUND: The evaluation of the credibility of results from a meta-analysis has become an important part of the evidence synthesis process. We present a methodological framework to evaluate confidence in the results from network meta-analyses, Confidence in Network Meta-Analysis (CINeMA), when multiple interventions are compared. METHODOLOGY: CINeMA considers 6 domains: (i) within-study bias, (ii) reporting bias, (iii) indirectness, (iv) imprecision, (v) heterogeneity, and (vi) incoherence. Key to judgments 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 contribution matrix can easily be computed using a freely available web application. In evaluating imprecision, heterogeneity, and incoherence, we consider the impact of these components of variability in forming clinical decisions. CONCLUSIONS: Via 3 examples, we show that CINeMA improves transparency and avoids the selective use of evidence when forming judgments, thus limiting subjectivity in the process. CINeMA is easy to apply even in large and complicated networks.

4.
J Clin Epidemiol ; 124: 42-49, 2020 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-32302680

RESUMO

OBJECTIVES: Network meta-analysis (NMA) may produce more precise estimates of treatment effects than pairwise meta-analysis. We examined the relative contribution of network paths of different lengths to estimates of treatment effects. STUDY DESIGN AND SETTING: We analyzed 213 published NMAs. We categorized network shapes according to the presence or absence of at least one closed loop (nonstar or star network) and derived the graph density, radius, and diameter. We identified paths of different lengths and calculated their percentage contribution to each NMA effect estimate, based on their contribution matrix. RESULTS: Among the 213 NMAs included in analyses, 33% of the information came from paths of length 1 (direct evidence), 47% from paths of length 2 (indirect paths with one intermediate treatment) and 20% from paths of length 3. The contribution of paths of different lengths depended on the size of networks, presence of closed loops, and graph radius, density, and diameter. Longer paths contribute more as the number of treatments and loops and the graph radius and diameter increase. CONCLUSION: The contribution of different paths depends on the size and structure of networks, with important implications for assessing the risk of bias and confidence in NMA results.

5.
Lancet ; 395(10228): 986-997, 2020 03 21.
Artigo em Inglês | MEDLINE | ID: mdl-32199486

RESUMO

Fewer than half of new drugs have data on their comparative benefits and harms against existing treatment options at the time of regulatory approval in Europe and the USA. Even when active-comparator trials exist, they might not produce meaningful data to inform decisions in clinical practice and health policy. The uncertainty associated with the paucity of well designed active-comparator trials has been compounded by legal and regulatory changes in Europe and the USA that have created a complex mix of expedited programmes aimed at facilitating faster access to new drugs. Comparative evidence generation is even sparser for medical devices. Some have argued that the current process for regulatory approval needs to generate more evidence that is useful for patients, clinicians, and payers in health-care systems. We propose a set of five key principles relevant to the European Medicines Agency, European medical device regulatory agencies, US Food and Drug Administration, as well as payers, that we believe will provide the necessary incentives for pharmaceutical and device companies to generate comparative data on drugs and devices and assure timely availability of evidence that is useful for decision making. First, labelling should routinely inform patients and clinicians whether comparative data exist on new products. Second, regulators should be more selective in their use of programmes that facilitate drug and device approvals on the basis of incomplete benefit and harm data. Third, regulators should encourage the conduct of randomised trials with active comparators. Fourth, regulators should use prospectively designed network meta-analyses based on existing and future randomised trials. Last, payers should use their policy levers and negotiating power to incentivise the generation of comparative evidence on new and existing drugs and devices, for example, by explicitly considering proven added benefit in pricing and payment decisions.


Assuntos
Aprovação de Equipamentos/normas , Aprovação de Drogas/métodos , Segurança de Equipamentos , Segurança , Biomarcadores Farmacológicos/análise , Tolerância a Medicamentos , Medicina Baseada em Evidências , Humanos , Estados Unidos , United States Food and Drug Administration
6.
BMJ Open ; 10(1): e035073, 2020 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-31959613

RESUMO

INTRODUCTION: There is evidence that different psychosocial interventions could reduce the risk of relapse in schizophrenia, but a comprehensive evidence based on their relative efficacy is lacking. We will conduct a network meta-analysis (NMA), integrating direct and indirect comparisons from randomised controlled trials (RCTs) to rank psychosocial treatments for relapse prevention in schizophrenia according to their efficacy, acceptability and tolerability. METHODS AND ANALYSIS: We will include all RCTs comparing a psychosocial treatment aimed at preventing relapse in patients with schizophrenia with another psychosocial intervention or with a no treatment condition (waiting list, treatment as usual). We will include studies on adult patients with schizophrenia, excluding specific subpopulations (eg, acutely ill patients). Primary outcome will be the number of patients experiencing a relapse. Secondary outcomes will be acceptability (dropout), change in overall, positive, negative and depressive symptoms, quality of life, adherence, functioning and adverse events. Published and unpublished studies will be sought through database searches, trial registries and websites. Study selection and data extraction will be conducted by at least two independent reviewers. We will conduct random-effects NMA to synthesise all evidence for each outcome and obtain a comprehensive ranking of all treatments. NMA will be conducted in R within a frequentist framework. The risk of bias in studies will be evaluated using the Cochrane Risk of Bias tool and the credibility of the evidence will be evaluated using Confidence in Network Meta-Analysis (CINeMA). Subgroup and sensitivity analyses will be conducted to assess the robustness of the findings. ETHICS AND DISSEMINATION: No ethical issues are foreseen. Results from this study will be published in peer-reviewed journals and presented at relevant conferences. PROSPERO REGISTRATION NUMBER: CRD42019147884.

7.
BMJ Open ; 9(11): e033458, 2019 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-31722954

RESUMO

INTRODUCTION: Vasoplegia is common and associated with a poor prognosis in patients with sepsis and septic shock. Vitamin C therapy in combination with vitamin B1 and glucocorticoid, as well as monotherapy in various doses, has been investigated as a treatment for the vasoplegic state in sepsis, through targeting the inflammatory cascade. However, the combination effect and the relative contribution of each drug have not been well evaluated. Furthermore, the best combination between the three agents is currently unknown. We are planning a systematic review (SR) with network meta-analysis (NMA) to compare the different treatments and identify the combination with the most favourable effect on survival. METHODS AND ANALYSIS: We will include all randomised controlled trials comparing any intervention using intravenous vitamin C, vitamin B1 and/or glucocorticoid with another or with placebo in the treatment of sepsis. We are interested in comparing the following active interventions. Very high-dose vitamin C (≥12 g/day), high-dose vitamin C (≥6 g/day), vitamin C (<6 g/day); low-dose glucocorticoid (<400 mg/day of hydrocortisone (or equivalent)), vitamin B1 and combinations of the drugs above. The primary outcome will be all-cause mortality at the longest follow-up within 1 year but 90 days or longer postrandomisation. All relevant studies will be sought through database searches and trial registries. All reference selection and data extraction will be conducted by two independent reviewers. We will conduct a random-effects NMA to synthesise all evidence for each outcome and obtain a comprehensive ranking of all treatments. We will use the surface under the cumulative ranking curve and the mean ranks to rank the various interventions. To differentiate between the effect of combination therapies and the effect of a component, we will employ a component NMA. ETHICS AND DISSEMINATION: This SR does not require ethical approval. We will publish findings from this systematic review in a peer-reviewed scientific journal and present these at scientific conferences. PROSPERO REGISTRATION NUMBER: CRD42018103860.

8.
BMJ Open ; 9(10): e032726, 2019 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-31601607

RESUMO

INTRODUCTION: Individuals with psychosis may access emergency services due to aggression and agitation. When the de-escalation technique fails to achieve tranquillisation, several pharmacological options are available. However, evidence on which intervention to prefer in terms of efficacy and tolerability to achieve resolution of the acute episode (ie, rapid tranquillisation) of aggression and agitation is currently fragmentary. METHODS AND ANALYSIS: We will include all randomised controlled trials comparing drugs or drug combinations or placebo for aggression or agitation episodes in adult individuals with psychosis. We will include individuals with psychosis (eg, schizophrenia and related disorders, bipolar disorder with psychotic symptoms, psychotic depression) but not substance or medication-induced psychosis or psychosis due to another medical condition. Our primary outcomes are the change in aggression or agitation scores within few hours since the administration of the intervention (efficacy outcome) and the proportion of participants who dropped out due to adverse effects (tolerability outcome). We will retrieve relevant studies from the register of studies of the Cochrane Schizophrenia Group. Also, we will run additional searches on CENTRAL, Embase and PubMed to retrieve potentially eligible studies focusing on other psychiatric diagnoses than those in the schizophrenia spectrum. We will conduct a random-effects network meta-analysis (NMA) for primary and secondary outcomes. In case of rare events of dichotomous outcomes, a common-effect Mantel-Haenszel NMA will be used instead. We will use the surface under the cumulative ranking curve and the mean ranks to rank all available treatments. Local and global methods of evaluation of inconsistency will be employed. Quality of evidence contributing to network estimates of the main outcomes will also be assessed with Confidence in Network Meta-Analysis. ETHICS AND DISSEMINATION: This study does not require ethical approval. We will disseminate our findings by publishing results in a peer-reviewed journal. PROSPERO REGISTRATION NUMBER: CRD42019137945.

9.
Stat Med ; 38(27): 5197-5213, 2019 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-31583750

RESUMO

Differences between arm-based (AB) and contrast-based (CB) models for network meta-analysis (NMA) are controversial. We compare the CB model of Lu and Ades (2006), the AB model of Hong et al(2016), and two intermediate models, using hypothetical data and a selected real data set. Differences between models arise primarily from study intercepts being fixed effects in the Lu-Ades model but random effects in the Hong model, and we identify four key difference. (1) If study intercepts are fixed effects then only within-study information is used, but if they are random effects then between-study information is also used and can cause important bias. (2) Models with random study intercepts are suitable for deriving a wider range of estimands, eg, the marginal risk difference, when underlying risk is derived from the NMA data; but underlying risk is usually best derived from external data, and then models with fixed intercepts are equally good. (3) The Hong model allows treatment effects to be related to study intercepts, but the Lu-Ades model does not. (4) The Hong model is valid under a more relaxed missing data assumption, that arms (rather than contrasts) are missing at random, but this does not appear to reduce bias. We also describe an AB model with fixed study intercepts and a CB model with random study intercepts. We conclude that both AB and CB models are suitable for the analysis of NMA data, but using random study intercepts requires a strong rationale such as relating treatment effects to study intercepts.

10.
BMJ Open ; 9(10): e028009, 2019 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-31636110

RESUMO

INTRODUCTION: There are several local treatment methods for cervical intraepithelial neoplasia that remove or ablate a cone-shaped part of the uterine cervix. There is evidence to suggest that these increase the risk of preterm birth (PTB) and that this is higher for techniques that remove larger parts of the cervix, although the data are conflicting. We present a protocol for a systematic review and network meta-analysis (NMA) that will update the evidence and compare all treatments in terms of fertility and pregnancy complications. METHODS AND ANALYSIS: We will search electronic databases (CENTRAL, MEDLINE, EMBASE) from inception till October 2019, in order to identify randomised controlled trials (RCTs) and cohort studies comparing the fertility and pregnancy outcomes among different excisional and ablative treatment techniques and/or to untreated controls. The primary outcome will be PTB (<37 weeks). Secondary outcomes will include severe or extreme PTB, prelabour rupture of membranes, low birth weight (<2500 g), neonatal intensive care unit admission, perinatal mortality, total pregnancy rates, first and second trimester miscarriage. We will search for published and unpublished studies in electronic databases, trial registries and we will hand-search references of published papers. We will assess the risk of bias in RCTs and cohort studies using tools developed by the Cochrane collaboration. Two investigators will independently assess the eligibility, abstract the data and assess the risk of bias of the identified studies. For each outcome, we will perform a meta-analysis for each treatment comparison and an NMA once the transitivity assumption holds, using the OR for dichotomous data. We will use CINeMA (Confidence in Network meta-analysis) to assess the quality of the evidence for the primary outcome. ETHICS AND DISSEMINATION: Ethical approval is not required. Results will be disseminated to academic beneficiaries, medical practitioners, patients and the public. PROSPERO REGISTRATION NUMBER: CRD42018115495.

11.
Biom J ; 2019 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-31661561

RESUMO

One of the key features of network meta-analysis is ranking of interventions according to outcomes of interest. Ranking metrics are prone to misinterpretation because of two limitations associated with the current ranking methods. First, differences in relative treatment effects might not be clinically important and this is not reflected in the ranking metrics. Second, there are no established methods to include several health outcomes in the ranking assessments. To address these two issues, we extended the P-score method to allow for multiple outcomes and modified it to measure the mean extent of certainty that a treatment is better than the competing treatments by a certain amount, for example, the minimum clinical important difference. We suggest to present the tradeoff between beneficial and harmful outcomes allowing stakeholders to consider how much adverse effect they are willing to tolerate for specific gains in efficacy. We used a published network of 212 trials comparing 15 antipsychotics and placebo using a random effects network meta-analysis model, focusing on three outcomes; reduction in symptoms of schizophrenia in a standardized scale, all-cause discontinuation, and weight gain.

12.
Artigo em Inglês | MEDLINE | ID: mdl-31645364

RESUMO

INTRODUCTION: Matching treatment to specific patients is too often a matter of trial and error, while treatment efficacy should be optimised by limiting risks and costs and by incorporating patients' preferences. Factors influencing an individual's drug response in major depressive disorder may include a number of clinical variables (such as previous treatments, severity of illness, concomitant anxiety etc) as well demographics (for instance, age, weight, social support and family history). Our project, funded by the National Institute of Health Research, is aimed at developing and subsequently testing a precision medicine approach to the pharmacological treatment of major depressive disorder in adults, which can be used in everyday clinical settings. METHODS AND ANALYSIS: We will jointly synthesise data from patients with major depressive disorder, obtained from diverse datasets, including randomised trials as well as observational, real-world studies. We will summarise the highest quality and most up-to-date scientific evidence about comparative effectiveness and tolerability (adverse effects) of antidepressants for major depressive disorder, develop and externally validate prediction models to produce stratified treatment recommendations. Results from this analysis will subsequently inform a web-based platform and build a decision support tool combining the stratified recommendations with clinicians and patients' preferences, to adapt the tool, increase its' reliability and tailor treatment indications to the individual-patient level. We will then test whether use of the tool relative to treatment as usual in real-world clinical settings leads to enhanced treatment adherence and response, is acceptable to clinicians and patients, and is economically viable in the UK National Health Service. DISCUSSION: This is a clinically oriented study, coordinated by an international team of experts, with important implications for patients treated in real-world setting. This project will form a test-case that, if effective, will be extended to non-pharmacological treatments (either face-to-face or internet-delivered), to other populations and disorders in psychiatry (for instance, children and adolescents, or schizophrenia and treatment-resistant depression) and to other fields of medicine.

14.
BMJ Open ; 9(8): e028008, 2019 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-31377697

RESUMO

INTRODUCTION: Local treatments for cervical intraepithelial neoplasia (CIN) and microinvasive disease remove or ablate a cone-shaped part of the uterine cervix containing the abnormal cells. A trend toward less radical techniques has raised concerns that this may adversely impact the rates of precancerous and cancerous recurrence. However, there has been no strong evidence to support such claims. We hereby describe a protocol of a systematic review and network meta-analysis that will update the evidence and compare all relevant treatments in terms of efficacy and complications. METHODS AND ANALYSIS: Literature searches in electronic databases (CENTRAL, MEDLINE, EMBASE) or trial registries will identify published and unpublished randomised controlled trials (RCTs) and cohort studies comparing the efficacy and complications among different excisional and ablative techniques. The excisional techniques include cold knife, laser or Fischer cone, large loop or needle excision of the transformation zone and the ablative radical point diathermy, cryotherapy, cold coagulation or laser ablation. The primary outcome will be residual/recurrent disease defined as abnormal histology or cytology of any grade, while secondary outcomes will include treatment failure rates defined as high-grade histology or cytology, histologically confirmed CIN1+ or histologically confirmed CIN2+, human papillomavirus positivity rates, involved margins rates, bleeding and cervical stenosis rates. We will assess the risk of bias in RCTs and observational studies using tools developed by the Cochrane Collaboration. Two authors will independently assess study eligibility, abstract the data and assess the risk of bias. Random-effects meta-analyses and network meta-analyses will be conducted using the OR for dichotomous outcomes and the mean difference for continuous outcomes. The quality of the evidence for the primary outcome will be assessed using the CINeMA (Confidence In Network Meta-Analysis) tool. ETHICS AND DISSEMINATION: Ethical approval is not required. We will disseminate findings to clinicians, policy-makers, patients and the public. PROSPERO REGISTRATION NUMBER: CRD42018115508.

15.
Eur Heart J ; 40(38): 3143-3153, 2019 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-31329852

RESUMO

AIMS : Owing to new evidence from randomized controlled trials (RCTs) in low-risk patients with severe aortic stenosis, we compared the collective safety and efficacy of transcatheter aortic valve implantation (TAVI) vs. surgical aortic valve replacement (SAVR) across the entire spectrum of surgical risk patients. METHODS AND RESULTS : The meta-analysis is registered with PROSPERO (CRD42016037273). We identified RCTs comparing TAVI with SAVR in patients with severe aortic stenosis reporting at different follow-up periods. We extracted trial, patient, intervention, and outcome characteristics following predefined criteria. The primary outcome was all-cause mortality up to 2 years for the main analysis. Seven trials that randomly assigned 8020 participants to TAVI (4014 patients) and SAVR (4006 patients) were included. The combined mean STS score in the TAVI arm was 9.4%, 5.1%, and 2.0% for high-, intermediate-, and low surgical risk trials, respectively. Transcatheter aortic valve implantation was associated with a significant reduction of all-cause mortality compared to SAVR {hazard ratio [HR] 0.88 [95% confidence interval (CI) 0.78-0.99], P = 0.030}; an effect that was consistent across the entire spectrum of surgical risk (P-for-interaction = 0.410) and irrespective of type of transcatheter heart valve (THV) system (P-for-interaction = 0.674). Transcatheter aortic valve implantation resulted in lower risk of strokes [HR 0.81 (95% CI 0.68-0.98), P = 0.028]. Surgical aortic valve replacement was associated with a lower risk of major vascular complications [HR 1.99 (95% CI 1.34-2.93), P = 0.001] and permanent pacemaker implantations [HR 2.27 (95% CI 1.47-3.64), P < 0.001] compared to TAVI. CONCLUSION : Compared with SAVR, TAVI is associated with reduction in all-cause mortality and stroke up to 2 years irrespective of baseline surgical risk and type of THV system.

16.
Lancet ; 394(10202): 939-951, 2019 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-31303314

RESUMO

BACKGROUND: Schizophrenia is one of the most common, burdensome, and costly psychiatric disorders in adults worldwide. Antipsychotic drugs are its treatment of choice, but there is controversy about which agent should be used. We aimed to compare and rank antipsychotics by quantifying information from randomised controlled trials. METHODS: We did a network meta-analysis of placebo-controlled and head-to-head randomised controlled trials and compared 32 antipsychotics. We searched Embase, MEDLINE, PsycINFO, PubMed, BIOSIS, Cochrane Central Register of Controlled Trials (CENTRAL), WHO International Clinical Trials Registry Platform, and ClinicalTrials.gov from database inception to Jan 8, 2019. Two authors independently selected studies and extracted data. We included randomised controlled trials in adults with acute symptoms of schizophrenia or related disorders. We excluded studies in patients with treatment resistance, first episode, predominant negative or depressive symptoms, concomitant medical illnesses, and relapse-prevention studies. Our primary outcome was change in overall symptoms measured with standardised rating scales. We also extracted data for eight efficacy and eight safety outcomes. Differences in the findings of the studies were explored in metaregressions and sensitivity analyses. Effect size measures were standardised mean differences, mean differences, or risk ratios with 95% credible intervals (CrIs). Confidence in the evidence was assessed using CINeMA (Confidence in Network Meta-Analysis). The study protocol is registered with PROSPERO, number CRD42014014919. FINDINGS: We identified 54 417 citations and included 402 studies with data for 53 463 participants. Effect size estimates suggested all antipsychotics reduced overall symptoms more than placebo (although not statistically significant for six drugs), with standardised mean differences ranging from -0·89 (95% CrI -1·08 to -0·71) for clozapine to -0·03 (-0·59 to 0·52) for levomepromazine (40 815 participants). Standardised mean differences compared with placebo for reduction of positive symptoms (31 179 participants) varied from -0·69 (95% CrI -0·86 to -0·52) for amisulpride to -0·17 (-0·31 to -0·04) for brexpiprazole, for negative symptoms (32 015 participants) from -0·62 (-0·84 to -0·39; clozapine) to -0·10 (-0·45 to 0·25; flupentixol), for depressive symptoms (19 683 participants) from -0·90 (-1·36 to -0·44; sulpiride) to 0·04 (-0·39 to 0·47; flupentixol). Risk ratios compared with placebo for all-cause discontinuation (42 672 participants) ranged from 0·52 (0·12 to 0·95; clopenthixol) to 1·15 (0·36 to 1·47; pimozide), for sedation (30 770 participants) from 0·92 (0·17 to 2·03; pimozide) to 10·20 (4·72 to 29·41; zuclopenthixol), for use of antiparkinson medication (24 911 participants) from 0·46 (0·19 to 0·88; clozapine) to 6·14 (4·81 to 6·55; pimozide). Mean differences compared to placebo for weight gain (28 317 participants) ranged from -0·16 kg (-0·73 to 0·40; ziprasidone) to 3·21 kg (2·10 to 4·31; zotepine), for prolactin elevation (21 569 participants) from -77·05 ng/mL (-120·23 to -33·54; clozapine) to 48·51 ng/mL (43·52 to 53·51; paliperidone) and for QTc prolongation (15 467 participants) from -2·21 ms (-4·54 to 0·15; lurasidone) to 23·90 ms (20·56 to 27·33; sertindole). Conclusions for the primary outcome did not substantially change after adjusting for possible effect moderators or in sensitivity analyses (eg, when excluding placebo-controlled studies). The confidence in evidence was often low or very low. INTERPRETATION: There are some efficacy differences between antipsychotics, but most of them are gradual rather than discrete. Differences in side-effects are more marked. These findings will aid clinicians in balancing risks versus benefits of those drugs available in their countries. They should consider the importance of each outcome, the patients' medical problems, and preferences. FUNDING: German Ministry of Education and Research and National Institute for Health Research.


Assuntos
Antipsicóticos/uso terapêutico , Esquizofrenia/tratamento farmacológico , Administração Oral , Antipsicóticos/administração & dosagem , Antipsicóticos/efeitos adversos , Pesquisa Comparativa da Efetividade/métodos , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento
17.
Lancet Psychiatry ; 6(7): 601-609, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31178367

RESUMO

BACKGROUND: Depression is the single largest contributor to non-fatal health loss worldwide. Second-generation antidepressants are the first-line option for pharmacological management of depression. Optimising their use is crucial in reducing the burden of depression; however, debate about their dose dependency and their optimal target dose is ongoing. We have aimed to summarise the currently available best evidence to inform this clinical question. METHODS: We did a systematic review and dose-response meta-analysis of double-blind, randomised controlled trials that examined fixed doses of five selective serotonin reuptake inhibitors (SSRIs; citalopram, escitalopram, fluoxetine, paroxetine, and sertraline), venlafaxine, or mirtazapine in the acute treatment of adults (aged 18 years or older) with major depression, identified from the Cochrane Central Register of Controlled Trials, CINAHL, Embase, LILACS, MEDLINE, PsycINFO, AMED, PSYNDEX, websites of drug licensing agencies and pharmaceutical companies, and trial registries. We imposed no language restrictions, and the search was updated until Jan 8, 2016. Doses of SSRIs were converted to fluoxetine equivalents. Trials of antidepressants for patients with depression and a serious concomitant physical illness were excluded. The main outcomes were efficacy (treatment response defined as 50% or greater reduction in depression severity), tolerability (dropouts due to adverse effects), and acceptability (dropouts for any reasons), all after a median of 8 weeks of treatment (range 4-12 weeks). We used a random-effects, dose-response meta-analysis model with flexible splines for SSRIs, venlafaxine, and mirtazapine. FINDINGS: 28 554 records were identified through our search (24 524 published and 4030 unpublished records). 561 published and 121 unpublished full-text records were assessed for eligibility, and 77 studies were included (19 364 participants; mean age 42·5 years, SD 11·0; 7156 [60·9%] of 11 749 reported were women). For SSRIs (99 treatment groups), the dose-efficacy curve showed a gradual increase up to doses between 20 mg and 40 mg fluoxetine equivalents, and a flat to decreasing trend through the higher licensed doses up to 80 mg fluoxetine equivalents. Dropouts due to adverse effects increased steeply through the examined range. The relationship between the dose and dropouts for any reason indicated optimal acceptability for the SSRIs in the lower licensed range between 20 mg and 40 mg fluoxetine equivalents. Venlafaxine (16 treatment groups) had an initially increasing dose-efficacy relationship up to around 75-150 mg, followed by a more modest increase, whereas for mirtazapine (11 treatment groups) efficacy increased up to a dose of about 30 mg and then decreased. Both venlafaxine and mirtazapine showed optimal acceptability in the lower range of their licensed dose. These results were robust to several sensitivity analyses. INTERPRETATION: For the most commonly used second-generation antidepressants, the lower range of the licensed dose achieves the optimal balance between efficacy, tolerability, and acceptability in the acute treatment of major depression. FUNDING: Japan Society for the Promotion of Science, Swiss National Science Foundation, and National Institute for Health Research.


Assuntos
Transtorno Depressivo Maior/tratamento farmacológico , Mirtazapina/uso terapêutico , Inibidores de Captação de Serotonina/uso terapêutico , Cloridrato de Venlafaxina/uso terapêutico , Relação Dose-Resposta a Droga , Método Duplo-Cego , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Serotoninérgicos/uso terapêutico
18.
Trials ; 20(1): 334, 2019 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-31174597

RESUMO

BACKGROUND: 'Conditional trial design' is a framework for efficiently planning new clinical trials based on a network of relevant existing trials. The framework considers whether new trials are required and how the existing evidence can be used to answer the research question and plan future research. The potential of this approach has not been fully realized. METHODS: We conducted an online survey among trial statisticians, methodologists, and users of evidence synthesis research using referral sampling to capture opinions about the conditional trial design framework and current practices among clinical researchers. The questions included in the survey were related to the decision of whether a meta-analysis answers the research question, the optimal way to synthesize available evidence, which relates to the acceptability of network meta-analysis, and the use of evidence synthesis in the planning of new studies. RESULTS: In total, 76 researchers completed the survey. Two out of three survey participants (65%) were willing to possibly or definitely consider using evidence synthesis to design a future clinical trial and around half of the participants would give priority to such a trial design. The median rating of the frequency of using such a trial design was 0.41 on a scale from 0 (never) to 1 (always). Major barriers to adopting conditional trial design include the current regulatory paradigm and the policies of funding agencies and sponsors. CONCLUSIONS: Participants reported moderate interest in using evidence synthesis methods in the design of future trials. They indicated that a major paradigm shift is required before the use of network meta-analysis is regularly employed in the design of trials.


Assuntos
Ensaios Clínicos como Assunto/métodos , Medicina Baseada em Evidências/métodos , Projetos de Pesquisa , Ensaios Clínicos como Assunto/estatística & dados numéricos , Interpretação Estatística de Dados , Modificador do Efeito Epidemiológico , Europa (Continente) , Medicina Baseada em Evidências/estatística & dados numéricos , Humanos , Modelos Estatísticos , Metanálise em Rede , Projetos de Pesquisa/estatística & dados numéricos , Tamanho da Amostra , Inquéritos e Questionários
19.
Evid Based Ment Health ; 22(2): 61-66, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30996028

RESUMO

INTRODUCTION: We have recently compared all second-generation as well as selected first-generation antidepressants in terms of efficacy and acceptability in the acute treatment of major depression. Here we present a protocol for a network meta-analysis aimed at extending these results, updating the evidence base and comparing all second-generation as well as selected first-generation antidepressants in terms of specific adverse events and tolerability in the acute treatment of major depression in adults. METHODS AND ANALYSIS: We will include all double-blind randomised controlled trials comparing one active drug with another or with placebo in the acute treatment major depression in adults. We will compare the following active agents: agomelatine, amitriptyline, bupropion, citalopram, clomipramine, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, levomilnacipran, milnacipran, mirtazapine, nefazodone, paroxetine, reboxetine, sertraline, trazodone, venlafaxine, vilazodone and vortioxetine. The main outcomes will include the total number of patients experiencing specific adverse events; experiencing serious adverse events; and experiencing at least one adverse event. Published and unpublished studies will be retrieved through relevant database searches, trial registries and websites; reference selection and data extraction will be completed by at least two independent reviewers. For each outcome we will undertake a network meta-analysis to synthesise all evidence. We will use local and global methods to evaluate consistency. We will perform all analyses in R. We will assess the quality of evidence contributing to network estimates with the Confidence in Network Meta-Analysis web application. DISCUSSION: This work will provide an in- depth analysis and an insight into the specific adverse events of individual antidepressants. ETHICS AND DISSEMINATION: This review does not require ethical approval. PROSPERO REGISTRATION NUMBER: CRD42019128141.


Assuntos
Antidepressivos/efeitos adversos , Transtorno Depressivo Maior/tratamento farmacológico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Metanálise em Rede , Ensaios Clínicos Controlados Aleatórios como Assunto , Doença Aguda , Adulto , Protocolos Clínicos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/diagnóstico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Humanos
20.
Stat Med ; 38(16): 2992-3012, 2019 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-30997687

RESUMO

The Mantel-Haenszel (MH) method has been used for decades to synthesize data obtained from studies that compare two interventions with respect to a binary outcome. It has been shown to perform better than the inverse-variance method or Peto's odds ratio when data is sparse. Network meta-analysis (NMA) is increasingly used to compare the safety of medical interventions, synthesizing, eg, data on mortality or serious adverse events. In this setting, sparse data occur often and yet there is to-date, no extension of the MH method for the case of NMA. In this paper, we fill this gap by presenting a MH-NMA method for odds ratios. Similarly to the pairwise MH method, we assume common treatment effects. We implement our approach in R, and we provide freely available easy-to-use routines. We illustrate our approach using data from two previously published networks. We compare our results to those obtained from three other approaches to NMA, namely, NMA with noncentral hypergeometric likelihood, an inverse-variance NMA, and a Bayesian NMA with a binomial likelihood. We also perform simulations to assess the performance of our method and compare it with alternative methods. We conclude that our MH-NMA method offers a reliable approach to the NMA of binary outcomes, especially in the case or sparse data, and when the assumption of methodological and clinical homogeneity is justifiable.

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