Transitivity, coherence, and reliability of network meta-analyses comparing proximal humerus fracture treatments: a meta-epidemiological study.

BACKGROUND: Network meta-analyses can be valuable for decision-makers in guiding clinical practice. However, for network meta-analysis results to be reliable, the assumptions of both transitivity and coherence must be met, and the methodology should adhere to current best practices. We aimed to assess whether network meta-analyses of randomized controlled trials (RCTs) comparing interventions for proximal humerus fractures provide reliable estimates of intervention effects. METHODS: We searched PubMed, EMBASE, The Cochrane Library, and Web of Science for network meta-analyses comparing interventions for proximal humerus fractures. We critically assessed the methodology regarding the development of a protocol, search strategy, trial inclusion, outcome extraction, and the methods used to conduct the network meta-analyses. We assessed the transitivity and coherence of the network graphs for the Constant score (CS), Disabilities of the Arm, Shoulder, and Hand score (DASH), and additional surgery. Transitivity was assessed by comparing probable effect modifiers (age, gender, fracture morphology, and comorbidities) across intervention comparisons. Coherence was assessed using Separating Indirect from Direct Evidence (SIDE) (Separating Indirect from Direct Evidence) and the design-by-treatment interaction test. We used CINeMA (Confidence in Network Meta-analyses) to assess the confidence in the results. RESULTS: None of the three included network meta-analyses had a publicly available protocol or data-analysis plan, and they all had methodological flaws that could threaten the validity of their results. Although we did not detect incoherence for most comparisons, the transitivity assumption was violated for CS, DASH, and additional surgery in all three network meta-analyses. Additionally, the confidence in the results was 'very low' primarily due to within-study bias, reporting bias, intransitivity, imprecision, and heterogeneity. CONCLUSIONS: Current network meta-analyses of RCTs comparing interventions for proximal humerus fractures do not provide reliable estimates of intervention effects. We advise caution in using these network meta-analyses to guide clinical practice. To improve the utility of network meta-analyses to guide clinical practice, journal editors should require that network meta-analyses are done according to a predefined analysis plan in a publicly available protocol and that both coherence and transitivity have been adequately assessed and reported.

Impact of active placebo controls on estimated drug effects in randomised trials: a systematic review of trials with both active placebo and standard placebo.

BACKGROUND: An estimated 60% of pharmacological randomised trials use placebo control interventions to blind (i.e. mask) participants. However, standard placebos do not control for perceptible non-therapeutic effects (i.e. side effects) of the experimental drug, which may unblind participants. Trials rarely use active placebo controls, which contain pharmacological compounds designed to mimic the non-therapeutic experimental drug effects in order to reduce the risk of unblinding. A relevant improvement in the estimated effects of active placebo compared with standard placebo would imply that trials with standard placebo may overestimate experimental drug effects. OBJECTIVES: We aimed to estimate the difference in drug effects when an experimental drug is compared with an active placebo versus a standard placebo control intervention, and to explore causes for heterogeneity. In the context of a randomised trial, this difference in drug effects can be estimated by directly comparing the effect difference between the active placebo and standard placebo intervention. SEARCH METHODS: We searched PubMed, CENTRAL, Embase, two other databases, and two trial registries up to October 2020. We also searched reference lists and citations and contacted trial authors. SELECTION CRITERIA: We included randomised trials that compared an active placebo versus a standard placebo intervention. We considered trials both with and without a matching experimental drug arm. DATA COLLECTION AND ANALYSIS: We extracted data, assessed risk of bias, scored active placebos for adequacy and risk of unintended therapeutic effect, and categorised active placebos as unpleasant, neutral, or pleasant. We requested individual participant data from the authors of four cross-over trials published after 1990 and one unpublished trial registered after 1990. Our primary inverse-variance, random-effects meta-analysis used standardised mean differences (SMDs) of active versus standard placebo for participant-reported outcomes at earliest post-treatment assessment. A negative SMD favoured the active placebo. We stratified analyses by trial type (clinical or preclinical) and supplemented with sensitivity and subgroup analyses and meta-regression. In secondary analyses, we investigated observer-reported outcomes, harms, attrition, and co-intervention outcomes. MAIN RESULTS: We included 21 trials (1462 participants). We obtained individual participant data from four trials. Our primary analysis of participant-reported outcomes at earliest post-treatment assessment resulted in a pooled SMD of -0.08 (95% confidence interval (CI) -0.20 to 0.04; I2 = 31%; 14 trials), with no clear difference between clinical and preclinical trials. Individual participant data contributed 43% of the weight of this analysis. Two of seven sensitivity analyses found more pronounced and statistically significant differences; for example, in the five trials with low overall risk of bias, the pooled SMD was -0.24 (95% CI -0.34 to -0.13). The pooled SMD of observer-reported outcomes was similar to the primary analysis. The pooled odds ratio (OR) for harms was 3.08 (95% CI 1.56 to 6.07), and for attrition, 1.22 (95% CI 0.74 to 2.03). Co-intervention data were limited. Meta-regression found no statistically significant association with adequacy of the active placebo or risk of unintended therapeutic effect. AUTHORS' CONCLUSIONS: We did not find a statistically significant difference between active and standard placebo control interventions in our primary analysis, but the result was imprecise and the CI compatible with a difference ranging from important to irrelevant. Furthermore, the result was not robust, because two sensitivity analyses produced a more pronounced and statistically significant difference. We suggest that trialists and users of information from trials carefully consider the type of placebo control intervention in trials with high risk of unblinding, such as those with pronounced non-therapeutic effects and participant-reported outcomes.

Interleukin-6 blocking agents for treating COVID-19: a living systematic review.

BACKGROUND: It has been reported that people with COVID-19 and pre-existing autoantibodies against type I interferons are likely to develop an inflammatory cytokine storm responsible for severe respiratory symptoms. Since interleukin 6 (IL-6) is one of the cytokines released during this inflammatory process, IL-6 blocking agents have been used for treating people with severe COVID-19. OBJECTIVES: To update the evidence on the effectiveness and safety of IL-6 blocking agents compared to standard care alone or to a placebo for people with COVID-19. SEARCH METHODS: We searched the World Health Organization (WHO) International Clinical Trials Registry Platform, the Living OVerview of Evidence (L·OVE) platform, and the Cochrane COVID-19 Study Register to identify studies on 7 June 2022. SELECTION CRITERIA: We included randomized controlled trials (RCTs) evaluating IL-6 blocking agents compared to standard care alone or to placebo for people with COVID-19, regardless of disease severity. DATA COLLECTION AND ANALYSIS: Pairs of researchers independently conducted study selection, extracted data and assessed risk of bias. We assessed the certainty of evidence using the GRADE approach for all critical and important outcomes. In this update we amended our protocol to update the methods used for grading evidence by establishing minimal important differences for the critical outcomes. MAIN RESULTS: This update includes 22 additional trials, for a total of 32 trials including 12,160 randomized participants all hospitalized for COVID-19 disease. We identified a further 17 registered RCTs evaluating IL-6 blocking agents without results available as of 7 June 2022.  The mean age range varied from 56 to 75 years; 66.2% (8051/12,160) of enrolled participants were men. One-third (11/32) of included trials were placebo-controlled. Twenty-two were published in peer-reviewed journals, three were reported as preprints, two trials had results posted only on registries, and results from five trials were retrieved from another meta-analysis. Eight were funded by pharmaceutical companies.  Twenty-six included studies were multicenter trials; four were multinational and 22 took place in single countries. Recruitment of participants occurred between February 2020 and June 2021, with a mean enrollment duration of 21 weeks (range 1 to 54 weeks). Nineteen trials (60%) had a follow-up of 60 days or more. Disease severity ranged from mild to critical disease. The proportion of participants who were intubated at study inclusion also varied from 5% to 95%. Only six trials reported vaccination status; there were no vaccinated participants included in these trials, and 17 trials were conducted before vaccination was rolled out. We assessed a total of six treatments, each compared to placebo or standard care. Twenty trials assessed tocilizumab, nine assessed sarilumab, and two assessed clazakizumab. Only one trial was included for each of the other IL-6 blocking agents (siltuximab, olokizumab, and levilimab). Two trials assessed more than one treatment. Efficacy and safety of tocilizumab and sarilumab compared to standard care or placebo for treating COVID-19 At day (D) 28, tocilizumab and sarilumab probably result in little or no increase in clinical improvement (tocilizumab: risk ratio (RR) 1.05, 95% confidence interval (CI) 1.00 to 1.11; 15 RCTs, 6116 participants; moderate-certainty evidence; sarilumab: RR 0.99, 95% CI 0.94 to 1.05; 7 RCTs, 2425 participants; moderate-certainty evidence). For clinical improvement at ≥ D60, the certainty of evidence is very low for both tocilizumab (RR 1.10, 95% CI 0.81 to 1.48; 1 RCT, 97 participants; very low-certainty evidence) and sarilumab (RR 1.22, 95% CI 0.91 to 1.63; 2 RCTs, 239 participants; very low-certainty evidence). The effect of tocilizumab on the proportion of participants with a WHO Clinical Progression Score (WHO-CPS) of level 7 or above remains uncertain at D28 (RR 0.90, 95% CI 0.72 to 1.12; 13 RCTs, 2117 participants; low-certainty evidence) and that for sarilumab very uncertain (RR 1.10, 95% CI 0.90 to 1.33; 5 RCTs, 886 participants; very low-certainty evidence). Tocilizumab reduces all cause-mortality at D28 compared to standard care/placebo (RR 0.88, 95% CI 0.81 to 0.94; 18 RCTs, 7428 participants; high-certainty evidence). The evidence about the effect of sarilumab on this outcome is very uncertain (RR 1.06, 95% CI 0.86 to 1.30; 9 RCTs, 3305 participants; very low-certainty evidence). The evidence is uncertain for all cause-mortality at ≥ D60 for tocilizumab (RR 0.91, 95% CI 0.80 to 1.04; 9 RCTs, 2775 participants; low-certainty evidence) and very uncertain for sarilumab (RR 0.95, 95% CI 0.84 to 1.07; 6 RCTs, 3379 participants; very low-certainty evidence). Tocilizumab probably results in little to no difference in the risk of adverse events (RR 1.03, 95% CI 0.95 to 1.12; 9 RCTs, 1811 participants; moderate-certainty evidence). The evidence about adverse events for sarilumab is uncertain (RR 1.12, 95% CI 0.97 to 1.28; 4 RCT, 860 participants; low-certainty evidence).  The evidence about serious adverse events is very uncertain for tocilizumab (RR 0.93, 95% CI 0.81 to 1.07; 16 RCTs; 2974 participants; very low-certainty evidence) and uncertain for sarilumab (RR 1.09, 95% CI 0.97 to 1.21; 6 RCTs; 2936 participants; low-certainty evidence). Efficacy and safety of clazakizumab, olokizumab, siltuximab and levilimab compared to standard care or placebo for treating COVID-19 The evidence about the effects of clazakizumab, olokizumab, siltuximab, and levilimab comes from only one or two studies for each blocking agent, and is uncertain or very uncertain. AUTHORS' CONCLUSIONS: In hospitalized people with COVID-19, results show a beneficial effect of tocilizumab on all-cause mortality in the short term and probably little or no difference in the risk of adverse events compared to standard care alone or placebo. Nevertheless, both tocilizumab and sarilumab probably result in little or no increase in clinical improvement at D28. Evidence for an effect of sarilumab and the other IL-6 blocking agents on critical outcomes is uncertain or very uncertain. Most of the trials included in our review were done before the waves of different variants of concern and before vaccination was rolled out on a large scale. An additional 17 RCTs of IL-6 blocking agents are currently registered with no results yet reported. The number of pending studies and the number of participants planned is low. Consequently, we will not publish further updates of this review.

Control interventions in randomised trials among people with mental health disorders.

BACKGROUND: Control interventions in randomised trials provide a frame of reference for the experimental interventions and enable estimations of causality. In the case of randomised trials assessing patients with mental health disorders, many different control interventions are used, and the choice of control intervention may have considerable impact on the estimated effects of the treatments being evaluated. OBJECTIVES: To assess the benefits and harms of typical control interventions in randomised trials with patients with mental health disorders. The difference in effects between control interventions translates directly to the impact a control group has on the estimated effect of an experimental intervention. We aimed primarily to assess the difference in effects between (i) wait-list versus no-treatment, (ii) usual care versus wait-list or no-treatment, and (iii) placebo interventions (all placebo interventions combined or psychological, pharmacological, and physical placebos individually) versus wait-list or no-treatment. Wait-list patients are offered the experimental intervention by the researchers after the trial has been finalised if it offers more benefits than harms, while no-treatment participants are not offered the experimental intervention by the researchers. SEARCH METHODS: In March 2018, we searched MEDLINE, PsycInfo, Embase, CENTRAL, and seven other databases and six trials registers. SELECTION CRITERIA: We included randomised trials assessing patients with a mental health disorder that compared wait-list, usual care, or placebo interventions with wait-list or no-treatment . DATA COLLECTION AND ANALYSIS: Titles, abstracts, and full texts were reviewed for eligibility. Review authors independently extracted data and assessed risk of bias using Cochrane's risk of bias tool. GRADE was used to assess the quality of the evidence. We contacted researchers working in the field to ask for data from additional published and unpublished trials. A pre-planned decision hierarchy was used to select one benefit and one harm outcome from each trial. For the assessment of benefits, we summarised continuous data as standardised mean differences (SMDs) and dichotomous data as risk ratios (RRs). We used risk differences (RDs) for the assessment of adverse events. We used random-effects models for all statistical analyses. We used subgroup analysis to explore potential causes for heterogeneity (e.g. type of placebo) and sensitivity analyses to explore the robustness of the primary analyses (e.g. fixed-effect model). MAIN RESULTS: We included 96 randomised trials (4200 participants), ranging from 8 to 393 participants in each trial. 83 trials (3614 participants) provided usable data. The trials included 15 different mental health disorders, the most common being anxiety (25 trials), depression (16 trials), and sleep-wake disorders (11 trials). All 96 trials were assessed as high risk of bias partly because of the inability to blind participants and personnel in trials with two control interventions. The quality of evidence was rated low to very low, mostly due to risk of bias, imprecision in estimates, and heterogeneity. Only one trial compared wait-list versus no-treatment directly but the authors were not able to provide us with any usable data on the comparison. Five trials compared usual care versus wait-list or no-treatment and found a SMD -0.33 (95% CI -0.83 to 0.16, I² = 86%, 523 participants) on benefits. The difference between all placebo interventions combined versus wait-list or no-treatment was SMD -0.37 (95% CI -0.49 to -0.25, I² = 41%, 65 trials, 2446 participants) on benefits. There was evidence of some asymmetry in the funnel plot (Egger's test P value of 0.087). Almost all the trials were small. Subgroup analysis found a moderate effect in favour of psychological placebos SMD -0.49 (95% CI -0.64 to -0.30; I² = 53%, 39 trials, 1656 participants). The effect of pharmacological placebos versus wait-list or no-treatment on benefits was SMD -0.14 (95% CI -0.39 to 0.11, 9 trials, 279 participants) and the effect of physical placebos was SMD -0.21 (95% CI -0.35 to -0.08, I² = 0%, 17 trials, 896 participants). We found large variations in effect sizes in the psychological and pharmacological placebo comparisons. For specific mental health disorders, we found significant differences in favour of all placebos for sleep-wake disorders, major depressive disorder, and anxiety disorders, but the analyses were imprecise due to sparse data. We found no significant differences in harms for any of the comparisons but the analyses suffered from sparse data. When using a fixed-effect model in a sensitivity analysis on the comparison for usual care versus wait-list and no-treatment, the results were significant with an SMD of -0.46 (95 % CI -0.64 to -0.28). We reported an alternative risk of bias model where we excluded the blinding domains seeing how issues with blinding may be seen as part of the review investigation itself. However, this did not markedly change the overall risk of bias profile as most of the trials still included one or more unclear bias domains. AUTHORS' CONCLUSIONS: We found marked variations in effects between placebo versus no-treatment and wait-list and between subtypes of placebo with the same comparisons. Almost all the trials were small with considerable methodological and clinical variability in factors such as mental health population, contents of the included control interventions, and outcome domains. All trials were assessed as high risk of bias and the evidence quality was low to very low. When researchers decide to use placebos or usual care control interventions in trials with people with mental health disorders it will often lead to lower estimated effects of the experimental intervention than when using wait-list or no-treatment controls. The choice of a control intervention therefore has considerable impact on how effective a mental health treatment appears to be. Methodological guideline development is needed to reach a consensus on future standards for the design and reporting of control interventions in mental health intervention research.

Interleukin-1 blocking agents for treating COVID-19.

BACKGROUND: Interleukin-1 (IL-1) blocking agents have been used for treating severe coronavirus disease 2019 (COVID-19), on the premise that their immunomodulatory effect might be beneficial in people with COVID-19. OBJECTIVES: To assess the effects of IL-1 blocking agents compared with standard care alone or with placebo on effectiveness and safety outcomes in people with COVID-19. We will update this assessment regularly. SEARCH METHODS: We searched the Cochrane COVID-19 Study Register and the COVID-19 L-OVE Platform (search date 5 November 2021). These sources are maintained through regular searches of MEDLINE, Embase, CENTRAL, trial registers and other sources. We also checked the World Health Organization International Clinical Trials Registry Platform, regulatory agency websites, Retraction Watch (search date 3 November 2021). SELECTION CRITERIA: We included randomised controlled trials (RCTs) evaluating IL-1 blocking agents compared with standard care alone or with placebo for people with COVID-19, regardless of disease severity. DATA COLLECTION AND ANALYSIS: We followed Cochrane methodology. The protocol was amended to reduce the number of outcomes considered. Two researchers independently screened and extracted data and assessed the risk of bias with the Cochrane Risk of Bias 2 tool. We rated the certainty of evidence using the GRADE approach for the critical outcomes of clinical improvement (Day 28; ≥ D60); WHO Clinical Progression Score of level 7 or above (i.e. the proportion of participants with mechanical ventilation +/- additional organ support OR death) (D28; ≥ D60); all-cause mortality (D28; ≥ D60); incidence of any adverse events; and incidence of serious adverse events. MAIN RESULTS: We identified four RCTs of anakinra (three published in peer-reviewed journals, one reported as a preprint) and two RCTs of canakinumab (published in peer-reviewed journals). All trials were multicentre (2 to 133 centres). Two trials stopped early (one due to futility and one as the trigger for inferiority was met). The median/mean age range varied from 58 to 68 years; the proportion of men varied from 58% to 77%. All participants were hospitalised; 67% to 100% were on oxygen at baseline but not intubated; between 0% and 33% were intubated at baseline. We identified a further 16 registered trials with no results available, of which 15 assessed anakinra (four completed, four terminated, five ongoing, three not recruiting) and one (completed) trial assessed canakinumab. Effectiveness of anakinra for people with COVID-19 Anakinra probably results in little or no increase in clinical improvement at D28 (risk ratio (RR) 1.08, 95% confidence interval (CI) 0.97 to 1.20; 3 RCTs, 837 participants; absolute effect: 59 more per 1000 (from 22 fewer to 147 more); moderate-certainty evidence. The evidence is uncertain about an effect of anakinra on 1) the proportion of participants with a WHO Clinical Progression Score of level 7 or above at D28 (RR 0.67, 95% CI 0.36 to 1.22; 2 RCTs, 722 participants; absolute effect: 55 fewer per 1000 (from 107 fewer to 37 more); low-certainty evidence) and ≥ D60 (RR 0.54, 95% CI 0.30 to 0.96; 1 RCT, 606 participants; absolute effect: 47 fewer per 1000 (from 72 fewer to 4 fewer) low-certainty evidence); and 2) all-cause mortality at D28 (RR 0.69, 95% CI 0.34 to 1.39; 2 RCTs, 722 participants; absolute effect: 32 fewer per 1000 (from 68 fewer to 40 more); low-certainty evidence).  The evidence is very uncertain about an effect of anakinra on 1) the proportion of participants with clinical improvement at ≥ D60 (RR 0.93, 95% CI 0.78 to 1.12; 1 RCT, 115 participants; absolute effect: 59 fewer per 1000 (from 186 fewer to 102 more); very low-certainty evidence); and 2) all-cause mortality at ≥ D60 (RR 1.03, 95% CI 0.68 to 1.56; 4 RCTs, 1633 participants; absolute effect: 8 more per 1000 (from 84 fewer to 147 more); very low-certainty evidence). Safety of anakinra for people with COVID-19 Anakinra probably results in little or no increase in adverse events (RR 1.02, 95% CI 0.94 to 1.11; 2 RCTs, 722 participants; absolute effect: 14 more per 1000 (from 43 fewer to 78 more); moderate-certainty evidence).  The evidence is uncertain regarding an effect of anakinra on serious adverse events (RR 0.95, 95% CI 0.58 to 1.56; 2 RCTs, 722 participants; absolute effect: 12 fewer per 1000 (from 104 fewer to 138 more); low-certainty evidence). Effectiveness of canakinumab for people with COVID-19 Canakinumab probably results in little or no increase in clinical improvement at D28 (RR 1.05, 95% CI 0.96 to 1.14; 2 RCTs, 499 participants; absolute effect: 42 more per 1000 (from 33 fewer to 116 more); moderate-certainty evidence).  The evidence of an effect of canakinumab is uncertain on 1) the proportion of participants with a WHO Clinical Progression Score of level 7 or above at D28 (RR 0.72, 95% CI 0.44 to 1.20; 2 RCTs, 499 participants; absolute effect: 35 fewer per 1000 (from 69 fewer to 25 more); low-certainty evidence); and 2) all-cause mortality at D28 (RR:0.75; 95% CI 0.39 to 1.42); 2 RCTs, 499 participants; absolute effect: 20 fewer per 1000 (from 48 fewer to 33 more); low-certainty evidence).  The evidence is very uncertain about an effect of canakinumab on all-cause mortality at ≥ D60 (RR 0.55, 95% CI 0.16 to 1.91; 1 RCT, 45 participants; absolute effect: 112 fewer per 1000 (from 210 fewer to 227 more); very low-certainty evidence). Safety of canakinumab for people with COVID-19 Canakinumab probably results in little or no increase in adverse events (RR 1.02; 95% CI 0.86 to 1.21; 1 RCT, 454 participants; absolute effect: 11 more per 1000 (from 74 fewer to 111 more); moderate-certainty evidence). The evidence of an effect of canakinumab on serious adverse events is uncertain (RR 0.80, 95% CI 0.57 to 1.13; 2 RCTs, 499 participants; absolute effect: 44 fewer per 1000 (from 94 fewer to 28 more); low-certainty evidence). AUTHORS' CONCLUSIONS: Overall, we did not find evidence for an important beneficial effect of IL-1 blocking agents. The evidence is uncertain or very uncertain for several outcomes. Sixteen trials of anakinra and canakinumab with no results are currently registered, of which four are completed, and four terminated. The findings of this review are updated on the COVID-NMA platform (covid-nma.com).

Efficacy and safety of COVID-19 vaccines.

BACKGROUND: Different forms of vaccines have been developed to prevent the SARS-CoV-2 virus and subsequent COVID-19 disease. Several are in widespread use globally.  OBJECTIVES: To assess the efficacy and safety of COVID-19 vaccines (as a full primary vaccination series or a booster dose) against SARS-CoV-2. SEARCH METHODS: We searched the Cochrane COVID-19 Study Register and the COVID-19 L·OVE platform (last search date 5 November 2021). We also searched the WHO International Clinical Trials Registry Platform, regulatory agency websites, and Retraction Watch. SELECTION CRITERIA: We included randomized controlled trials (RCTs) comparing COVID-19 vaccines to placebo, no vaccine, other active vaccines, or other vaccine schedules. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. We used GRADE to assess the certainty of evidence for all except immunogenicity outcomes.  We synthesized data for each vaccine separately and presented summary effect estimates with 95% confidence intervals (CIs).  MAIN RESULTS: We included and analyzed 41 RCTs assessing 12 different vaccines, including homologous and heterologous vaccine schedules and the effect of booster doses. Thirty-two RCTs were multicentre and five were multinational. The sample sizes of RCTs were 60 to 44,325 participants. Participants were aged: 18 years or older in 36 RCTs; 12 years or older in one RCT; 12 to 17 years in two RCTs; and three to 17 years in two RCTs. Twenty-nine RCTs provided results for individuals aged over 60 years, and three RCTs included immunocompromized patients. No trials included pregnant women. Sixteen RCTs had two-month follow-up or less, 20 RCTs had two to six months, and five RCTs had greater than six to 12 months or less. Eighteen reports were based on preplanned interim analyses. Overall risk of bias was low for all outcomes in eight RCTs, while 33 had concerns for at least one outcome. We identified 343 registered RCTs with results not yet available.  This abstract reports results for the critical outcomes of confirmed symptomatic COVID-19, severe and critical COVID-19, and serious adverse events only for the 10 WHO-approved vaccines. For remaining outcomes and vaccines, see main text. The evidence for mortality was generally sparse and of low or very low certainty for all WHO-approved vaccines, except AD26.COV2.S (Janssen), which probably reduces the risk of all-cause mortality (risk ratio (RR) 0.25, 95% CI 0.09 to 0.67; 1 RCT, 43,783 participants; high-certainty evidence). Confirmed symptomatic COVID-19 High-certainty evidence found that BNT162b2 (BioNtech/Fosun Pharma/Pfizer), mRNA-1273 (ModernaTx), ChAdOx1 (Oxford/AstraZeneca), Ad26.COV2.S, BBIBP-CorV (Sinopharm-Beijing), and BBV152 (Bharat Biotect) reduce the incidence of symptomatic COVID-19 compared to placebo (vaccine efficacy (VE): BNT162b2: 97.84%, 95% CI 44.25% to 99.92%; 2 RCTs, 44,077 participants; mRNA-1273: 93.20%, 95% CI 91.06% to 94.83%; 2 RCTs, 31,632 participants; ChAdOx1: 70.23%, 95% CI 62.10% to 76.62%; 2 RCTs, 43,390 participants; Ad26.COV2.S: 66.90%, 95% CI 59.10% to 73.40%; 1 RCT, 39,058 participants; BBIBP-CorV: 78.10%, 95% CI 64.80% to 86.30%; 1 RCT, 25,463 participants; BBV152: 77.80%, 95% CI 65.20% to 86.40%; 1 RCT, 16,973 participants). Moderate-certainty evidence found that NVX-CoV2373 (Novavax) probably reduces the incidence of symptomatic COVID-19 compared to placebo (VE 82.91%, 95% CI 50.49% to 94.10%; 3 RCTs, 42,175 participants). There is low-certainty evidence for CoronaVac (Sinovac) for this outcome (VE 69.81%, 95% CI 12.27% to 89.61%; 2 RCTs, 19,852 participants). Severe or critical COVID-19 High-certainty evidence found that BNT162b2, mRNA-1273, Ad26.COV2.S, and BBV152 result in a large reduction in incidence of severe or critical disease due to COVID-19 compared to placebo (VE: BNT162b2: 95.70%, 95% CI 73.90% to 99.90%; 1 RCT, 46,077 participants; mRNA-1273: 98.20%, 95% CI 92.80% to 99.60%; 1 RCT, 28,451 participants; AD26.COV2.S: 76.30%, 95% CI 57.90% to 87.50%; 1 RCT, 39,058 participants; BBV152: 93.40%, 95% CI 57.10% to 99.80%; 1 RCT, 16,976 participants). Moderate-certainty evidence found that NVX-CoV2373 probably reduces the incidence of severe or critical COVID-19 (VE 100.00%, 95% CI 86.99% to 100.00%; 1 RCT, 25,452 participants). Two trials reported high efficacy of CoronaVac for severe or critical disease with wide CIs, but these results could not be pooled. Serious adverse events (SAEs) mRNA-1273, ChAdOx1 (Oxford-AstraZeneca)/SII-ChAdOx1 (Serum Institute of India), Ad26.COV2.S, and BBV152 probably result in little or no difference in SAEs compared to placebo (RR: mRNA-1273: 0.92, 95% CI 0.78 to 1.08; 2 RCTs, 34,072 participants; ChAdOx1/SII-ChAdOx1: 0.88, 95% CI 0.72 to 1.07; 7 RCTs, 58,182 participants; Ad26.COV2.S: 0.92, 95% CI 0.69 to 1.22; 1 RCT, 43,783 participants); BBV152: 0.65, 95% CI 0.43 to 0.97; 1 RCT, 25,928 participants). In each of these, the likely absolute difference in effects was fewer than 5/1000 participants. Evidence for SAEs is uncertain for BNT162b2, CoronaVac, BBIBP-CorV, and NVX-CoV2373 compared to placebo (RR: BNT162b2: 1.30, 95% CI 0.55 to 3.07; 2 RCTs, 46,107 participants; CoronaVac: 0.97, 95% CI 0.62 to 1.51; 4 RCTs, 23,139 participants; BBIBP-CorV: 0.76, 95% CI 0.54 to 1.06; 1 RCT, 26,924 participants; NVX-CoV2373: 0.92, 95% CI 0.74 to 1.14; 4 RCTs, 38,802 participants). For the evaluation of heterologous schedules, booster doses, and efficacy against variants of concern, see main text of review. AUTHORS' CONCLUSIONS: Compared to placebo, most vaccines reduce, or likely reduce, the proportion of participants with confirmed symptomatic COVID-19, and for some, there is high-certainty evidence that they reduce severe or critical disease. There is probably little or no difference between most vaccines and placebo for serious adverse events. Over 300 registered RCTs are evaluating the efficacy of COVID-19 vaccines, and this review is updated regularly on the COVID-NMA platform (covid-nma.com). Implications for practice Due to the trial exclusions, these results cannot be generalized to pregnant women, individuals with a history of SARS-CoV-2 infection, or immunocompromized people. Most trials had a short follow-up and were conducted before the emergence of variants of concern. Implications for research Future research should evaluate the long-term effect of vaccines, compare different vaccines and vaccine schedules, assess vaccine efficacy and safety in specific populations, and include outcomes such as preventing long COVID-19. Ongoing evaluation of vaccine efficacy and effectiveness against emerging variants of concern is also vital.

[The PRISMA 2020 statement: an updated guideline for reporting systematic reviewsDeclaración PRISMA 2020: una guía actualizada para la publicación de revisiones sistemáticas]. / A declaração PRISMA 2020: diretriz atualizada para relatar revisões sistemáticas.

The Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) statement, published in 2009, was designed to help systematic reviewers transparently report why the review was done, what the authors did, and what they found. Over the past decade, advances in systematic review methodology and terminology have necessitated an update to the guideline. The PRISMA 2020 statement replaces the 2009 statement and includes new reporting guidance that reflects advances in methods to identify, select, appraise, and synthesise studies. The structure and presentation of the items have been modified to facilitate implementation. In this article, we present the PRISMA 2020 27-item checklist, an expanded checklist that details reporting recommendations for each item, the PRISMA 2020 abstract checklist, and the revised flow diagrams for original and updated reviews.

La declaración PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses), publicada en 2009, se diseñó para ayudar a los autores de revisiones sistemáticas a documentar de manera transparente el porqué de la revisión, qué hicieron los autores y qué encontraron. Durante la última década, ha habido muchos avances en la metodología y terminología de las revisiones sistemáticas, lo que ha requerido una actualización de esta guía. La declaración PRISMA 2020 sustituye a la declaración de 2009 e incluye una nueva guía de presentación de las publicaciones que refleja los avances en los métodos para identificar, seleccionar, evaluar y sintetizar estudios. La estructura y la presentación de los ítems ha sido modificada para facilitar su implementación. En este artículo, presentamos la lista de verificación PRISMA 2020 con 27 ítems, y una lista de verificación ampliada que detalla las recomendaciones en la publicación de cada ítem, la lista de verificación del resumen estructurado PRISMA 2020 y el diagrama de flujo revisado para revisiones sistemáticas.

The PRISMA 2020 statement: An updated guideline for reporting systematic reviews.

Matthew Page and co-authors describe PRISMA 2020, an updated reporting guideline for systematic reviews and meta-analyses.

Antibiotics for secondary prevention of coronary heart disease.

BACKGROUND: Coronary heart disease is the leading cause of mortality worldwide with approximately 7.4 million deaths each year. People with established coronary heart disease have a high risk of subsequent cardiovascular events including myocardial infarction, stroke, and cardiovascular death. Antibiotics might prevent such outcomes due to their antibacterial, antiinflammatory, and antioxidative effects. However, a randomised clinical trial and several observational studies have suggested that antibiotics may increase the risk of cardiovascular events and mortality. Furthermore, several non-Cochrane Reviews, that are now outdated, have assessed the effects of antibiotics for coronary heart disease and have shown conflicting results. No previous systematic review using Cochrane methodology has assessed the effects of antibiotics for coronary heart disease. OBJECTIVES: We assessed the benefits and harms of antibiotics compared with placebo or no intervention for the secondary prevention of coronary heart disease. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, LILACS, SCI-EXPANDED, and BIOSIS in December 2019 in order to identify relevant trials. Additionally, we searched TRIP, Google Scholar, and nine trial registries in December 2019. We also contacted 11 pharmaceutical companies and searched the reference lists of included trials, previous systematic reviews, and other types of reviews. SELECTION CRITERIA: Randomised clinical trials assessing the effects of antibiotics versus placebo or no intervention for secondary prevention of coronary heart disease in adult participants (≥18 years). Trials were included irrespective of setting, blinding, publication status, publication year, language, and reporting of our outcomes. DATA COLLECTION AND ANALYSIS: Three review authors independently extracted data. Our primary outcomes were all-cause mortality, serious adverse event according to the International Conference on Harmonization - Good Clinical Practice (ICH-GCP), and quality of life. Our secondary outcomes were cardiovascular mortality, myocardial infarction, stroke, and sudden cardiac death. Our primary time point of interest was at maximum follow-up. Additionally, we extracted outcome data at 24±6 months follow-up. We assessed the risks of systematic errors using Cochrane 'Rosk of bias' tool. We calculated risk ratios (RRs) with 95% confidence intervals (CIs) for dichotomous outcomes. We calculated absolute risk reduction (ARR) or increase (ARI) and number needed to treat for an additional beneficial outcome (NNTB) or for an additional harmful outcome (NNTH) if the outcome result showed a beneficial or harmful effect, respectively. The certainty of the body of evidence was assessed by GRADE. MAIN RESULTS: We included 38 trials randomising a total of 26,638 participants (mean age 61.6 years), with 23/38 trials reporting data on 26,078 participants that could be meta-analysed. Three trials were at low risk of bias and the 35 remaining trials were at high risk of bias. Trials assessing the effects of macrolides (28 trials; 22,059 participants) and quinolones (two trials; 4162 participants) contributed with the vast majority of the data. Meta-analyses at maximum follow-up showed that antibiotics versus placebo or no intervention seemed to increase the risk of all-cause mortality (RR 1.06; 95% CI 0.99 to 1.13; P = 0.07; I2 = 0%; ARI 0.48%; NNTH 208; 25,774 participants; 20 trials; high certainty of evidence), stroke (RR 1.14; 95% CI 1.00 to 1.29; P = 0.04; I2 = 0%; ARI 0.73%; NNTH 138; 14,774 participants; 9 trials; high certainty of evidence), and probably also cardiovascular mortality (RR 1.11; 95% CI 0.98 to 1.25; P = 0.11; I2= 0%; 4674 participants; 2 trials; moderate certainty of evidence). Little to no difference was observed when assessing the risk of myocardial infarction (RR 0.95; 95% CI 0.88 to 1.03; P = 0.23; I2 = 0%; 25,523 participants; 17 trials; high certainty of evidence). No evidence of a difference was observed when assessing sudden cardiac death (RR 1.08; 95% CI 0.90 to 1.31; P = 0.41; I2 = 0%; 4520 participants; 2 trials; moderate certainty of evidence). Meta-analyses at 24±6 months follow-up showed that antibiotics versus placebo or no intervention increased the risk of all-cause mortality (RR 1.25; 95% CI 1.06 to 1.48; P = 0.007; I2 = 0%; ARI 1.26%; NNTH 79 (95% CI 335 to 42); 9517 participants; 6 trials; high certainty of evidence), cardiovascular mortality (RR 1.50; 95% CI 1.17 to 1.91; P = 0.001; I2 = 0%; ARI 1.12%; NNTH 89 (95% CI 261 to 49); 9044 participants; 5 trials; high certainty of evidence), and probably also sudden cardiac death (RR 1.77; 95% CI 1.28 to 2.44; P = 0.0005; I2 = 0%; ARI 1.9%; NNTH 53 (95% CI 145 to 28); 4520 participants; 2 trials; moderate certainty of evidence). No evidence of a difference was observed when assessing the risk of myocardial infarction (RR 0.95; 95% CI 0.82 to 1.11; P = 0.53; I2 = 43%; 9457 participants; 5 trials; moderate certainty of evidence) and stroke (RR 1.17; 95% CI 0.90 to 1.52; P = 0.24; I2 = 0%; 9457 participants; 5 trials; high certainty of evidence). Meta-analyses of trials at low risk of bias differed from the overall analyses when assessing cardiovascular mortality at maximum follow-up. For all other outcomes, meta-analyses of trials at low risk of bias did not differ from the overall analyses. None of the trials specifically assessed serious adverse event according to ICH-GCP. No data were found on quality of life. AUTHORS' CONCLUSIONS: Our present review indicates that antibiotics (macrolides or quinolones) for secondary prevention of coronary heart disease seem harmful when assessing the risk of all-cause mortality, cardiovascular mortality, and stroke at maximum follow-up and all-cause mortality, cardiovascular mortality, and sudden cardiac death at 24±6 months follow-up. Current evidence does, therefore, not support the clinical use of macrolides and quinolones for the secondary prevention of coronary heart disease. Future trials on the safety of macrolides or quinolones for the secondary prevention in patients with coronary heart disease do not seem ethical. In general, randomised clinical trials assessing the effects of antibiotics, especially macrolides and quinolones, need longer follow-up so that late-occurring adverse events can also be assessed.

Interleukin-6 blocking agents for treating COVID-19: a living systematic review.

BACKGROUND: Interleukin 6 (IL-6) blocking agents have been used for treating severe coronavirus disease 2019 (COVID-19). Their immunosuppressive effect might be valuable in patients with COVID-19 characterised by substantial immune system dysfunction by controlling inflammation and promoting disease tolerance. OBJECTIVES: To assess the effect of IL-6 blocking agents compared to standard care alone or with placebo on efficacy and safety outcomes in COVID-19. We will update this assessment regularly. SEARCH METHODS: We searched the World Health Organization (WHO) International Clinical Trials Registry Platform (up to 11 February 2021) and the L-OVE platform, and Cochrane COVID-19 Study Register to identify trials up to 26 February 2021. SELECTION CRITERIA: We included randomised controlled trials (RCTs) evaluating IL-6 blocking agents compared with standard care alone or with placebo for people with COVID-19, regardless of disease severity. DATA COLLECTION AND ANALYSIS: We followed standard Cochrane methodology. The protocol was amended to reduce the number of outcomes considered. Two review authors independently collected data and assessed the risk of bias with the Cochrane Risk of Bias 2 tool. We rated the certainty of evidence with the GRADE approach for the critical outcomes such as clinical improvement (defined as hospital discharge or improvement on the scale used by trialists to evaluate clinical progression or recovery) (day (D) 28 / ≥ D60); WHO Clinical Progression Score of level 7 or above (i.e. the proportion of participants with mechanical ventilation +/- additional organ support OR death) (D28 / ≥ D60); all-cause mortality (D28 / ≥ D60); incidence of any adverse events; and incidence of serious adverse events. MAIN RESULTS: We identified 10 RCTs with available data including one platform trial comparing tocilizumab and sarilumab with standard of care. These trials evaluated tocilizumab (nine RCTs including two platform trials; seven were reported as peer-reviewed articles, two as preprints; 6428 randomised participants); and two sarilumab (one platform trial reported as peer reviewed article, one reported as preprint, 880 randomised participants). All trials included were multicentre trials. They were conducted in Brazil, China, France, Italy, UK, USA, and four were multi-country trials. The mean age range of participants ranged from 56 to 65 years; 4572 (66.3%) of trial participants were male. Disease severity ranged from mild to critical disease. The reported proportion of participants on oxygen at baseline but not intubated varied from 56% to 100% where reported. Five trials reported the inclusion of intubated patients at baseline. We identified a further 20 registered RCTs of tocilizumab compared to placebo/standard care (five completed without available results, five terminated without available results, eight ongoing, two not recruiting); 11 RCTs of sarilumab (two completed without results, three terminated without available results, six ongoing); six RCTs of clazakisumab (five ongoing, one not recruiting); two RCTs of olokizumab (one completed, one not recruiting); one of siltuximab (ongoing) and one RCT of levilimab (completed without available results). Of note, three were cancelled (2 tocilizumab, 1 clazakisumab). One multiple-arm RCT evaluated both tocilizumab and sarilumab compared to standard of care, one three-arm RCT evaluated tocilizumab and siltuximab compared to standard of care and consequently they appear in each respective comparison. Tocilizumab versus standard care alone or with placebo a. Effectiveness of tocilizumab for patients with COVID-19 Tocilizumab probably results in little or no increase in the outcome of clinical improvement at D28 (RR 1.06, 95% CI 1.00 to 1.13; I2 = 40.9%; 7 RCTs, 5585 participants; absolute effect: 31 more with clinical improvement per 1000 (from 0 fewer to 67 more); moderate-certainty evidence). However, we cannot exclude that some subgroups of patients could benefit from the treatment. We did not obtain data for longer-term follow-up (≥ D60). The effect of tocilizumab on the proportion of participants with a WHO Clinical Progression Score of level of 7 or above is uncertain at D28 (RR 0.99, 95% CI 0.56 to 1.74; I2 = 64.4%; 3 RCTs, 712 participants; low-certainty evidence). We did not obtain data for longer-term follow-up (≥ D60). Tocilizumab reduces all-cause mortality at D28 compared to standard care alone or placebo (RR 0.89, 95% CI 0.82 to 0.97; I2 = 0.0%; 8 RCTs, 6363 participants; absolute effect: 32 fewer deaths per 1000 (from 52 fewer to 9 fewer); high-certainty evidence). The evidence suggests uncertainty around the effect on mortality at ≥ D60 (RR 0.86, 95% CI 0.53 to 1.40; I2 = 0.0%; 2 RCTs, 519 participants; low-certainty evidence). b. Safety of tocilizumab for patients with COVID-19 The evidence is very uncertain about the effect of tocilizumab on adverse events (RR 1.23, 95% CI 0.87 to 1.72; I2 = 86.4%; 7 RCTs, 1534 participants; very low-certainty evidence). Nevertheless, tocilizumab probably results in slightly fewer serious adverse events than standard care alone or placebo (RR 0.89, 95% CI 0.75 to 1.06; I2 = 0.0%; 8 RCTs, 2312 participants; moderate-certainty evidence). Sarilumab versus standard care alone or with placebo The evidence is uncertain about the effect of sarilumab on all-cause mortality at D28 (RR 0.77, 95% CI 0.43 to 1.36; 2 RCTs, 880 participants; low certainty), on all-cause mortality at ≥ D60 (RR 1.00, 95% CI 0.50 to 2.0; 1 RCT, 420 participants; low certainty), and serious adverse events (RR 1.17, 95% CI 0.77 to 1.77; 2 RCTs, 880 participants; low certainty). It is unlikely that sarilumab results in an important increase of adverse events (RR 1.05, 95% CI 0.88 to 1.25; 1 RCT, 420 participants; moderate certainty). However, an increase cannot be excluded No data were available for other critical outcomes. AUTHORS' CONCLUSIONS: On average, tocilizumab reduces all-cause mortality at D28 compared to standard care alone or placebo and probably results in slightly fewer serious adverse events than standard care alone or placebo. Nevertheless, tocilizumab probably results in little or no increase in the outcome clinical improvement (defined as hospital discharge or improvement measured by trialist-defined scales) at D28. The impact of tocilizumab on other outcomes is uncertain or very uncertain. With the data available, we were not able to explore heterogeneity. Individual patient data meta-analyses are needed to be able to identify which patients are more likely to benefit from this treatment. Evidence for an effect of sarilumab is uncertain and evidence for other anti-IL6 agents is unavailable. Thirty-nine RCTs of IL-6 blocking agents with no results are currently registered, of which nine are completed and seven trials were terminated with no results available. The findings of this review will be updated as new data are made available on the COVID-NMA platform (covid-nma.com).

Guidelines for Reporting Trial Protocols and Completed Trials Modified Due to the COVID-19 Pandemic and Other Extenuating Circumstances: The CONSERVE 2021 Statement.

Importance: Extenuating circumstances can trigger unplanned changes to randomized trials and introduce methodological, ethical, feasibility, and analytical challenges that can potentially compromise the validity of findings. Numerous randomized trials have required changes in response to the COVID-19 pandemic, but guidance for reporting such modifications is incomplete. Objective: As a joint extension for the CONSORT and SPIRIT reporting guidelines, CONSERVE (CONSORT and SPIRIT Extension for RCTs Revised in Extenuating Circumstances) aims to improve reporting of trial protocols and completed trials that undergo important modifications in response to extenuating circumstances. Evidence: A panel of 37 international trial investigators, patient representatives, methodologists and statisticians, ethicists, funders, regulators, and journal editors convened to develop the guideline. The panel developed CONSERVE following an accelerated, iterative process between June 2020 and February 2021 involving (1) a rapid literature review of multiple databases (OVID Medline, OVID EMBASE, and EBSCO CINAHL) and gray literature sources from 2003 to March 2021; (2) consensus-based panelist meetings using a modified Delphi process and surveys; and (3) a global survey of trial stakeholders. Findings: The rapid review yielded 41 673 citations, of which 38 titles were relevant, including emerging guidance from regulatory and funding agencies for managing the effects of the COVID-19 pandemic on trials. However, no generalizable guidance for all circumstances in which trials and trial protocols might face unanticipated modifications were identified. The CONSERVE panel used these findings to develop a consensus reporting guidelines following 4 rounds of meetings and surveys. Responses were received from 198 professionals from 34 countries, of whom 90% (n = 178) indicated that they understood the concept definitions and 85.4% (n = 169) indicated that they understood and could use the implementation tool. Feedback from survey respondents was used to finalize the guideline and confirm that the guideline's core concepts were applicable and had utility for the trial community. CONSERVE incorporates an implementation tool and checklists tailored to trial reports and trial protocols for which extenuating circumstances have resulted in important modifications to the intended study procedures. The checklists include 4 sections capturing extenuating circumstances, important modifications, responsible parties, and interim data analyses. Conclusions and Relevance: CONSERVE offers an extension to CONSORT and SPIRIT that could improve the transparency, quality, and completeness of reporting important modifications to trials in extenuating circumstances such as COVID-19.

European Society Paediatric Gastroenterology, Hepatology and Nutrition Guidelines for Diagnosing Coeliac Disease 2020.

OBJECTIVES: The ESPGHAN 2012 coeliac disease (CD) diagnostic guidelines aimed to guide physicians in accurately diagnosing CD and permit omission of duodenal biopsies in selected cases. Here, an updated and expanded evidence-based guideline is presented. METHODS: Literature databases and other sources of information were searched for studies that could inform on 10 formulated questions on symptoms, serology, HLA genetics, and histopathology. Eligible articles were assessed using QUADAS2. GRADE provided a basis for statements and recommendations. RESULTS: Various symptoms are suggested for case finding, with limited contribution to diagnostic accuracy. If CD is suspected, measurement of total serum IgA and IgA-antibodies against transglutaminase 2 (TGA-IgA) is superior to other combinations. We recommend against deamidated gliadin peptide antibodies (DGP-IgG/IgA) for initial testing. Only if total IgA is low/undetectable, an IgG-based test is indicated. Patients with positive results should be referred to a paediatric gastroenterologist/specialist. If TGA-IgA is ≥10 times the upper limit of normal (10× ULN) and the family agrees, the no-biopsy diagnosis may be applied, provided endomysial antibodies (EMA-IgA) will test positive in a second blood sample. HLA DQ2-/DQ8 determination and symptoms are not obligatory criteria. In children with positive TGA-IgA <10× ULN at least 4 biopsies from the distal duodenum and at least 1 from the bulb should be taken. Discordant results between TGA-IgA and histopathology may require re-evaluation of biopsies. Patients with no/mild histological changes (Marsh 0/I) but confirmed autoimmunity (TGA-IgA/EMA-IgA+) should be followed closely. CONCLUSIONS: CD diagnosis can be accurately established with or without duodenal biopsies if given recommendations are followed.

Conflicts of interest in clinical guidelines, advisory committee reports, opinion pieces, and narrative reviews: associations with recommendations.

BACKGROUND: Treatment and diagnostic recommendations are often made in clinical guidelines, reports from advisory committee meetings, opinion pieces such as editorials, and narrative reviews. Quite often, the authors or members of advisory committees have industry ties or particular specialty interests which may impact on which interventions are recommended. Similarly, clinical guidelines and narrative reviews may be funded by industry sources resulting in conflicts of interest. OBJECTIVES: To investigate to what degree financial and non-financial conflicts of interest are associated with favourable recommendations in clinical guidelines, advisory committee reports, opinion pieces, and narrative reviews. SEARCH METHODS: We searched PubMed, Embase, and the Cochrane Methodology Register for studies published up to February 2020. We also searched reference lists of included studies, Web of Science for studies citing the included studies, and grey literature sources. SELECTION CRITERIA: We included studies comparing the association between conflicts of interest and favourable recommendations of drugs or devices (e.g. recommending a particular drug) in clinical guidelines, advisory committee reports, opinion pieces, or narrative reviews. DATA COLLECTION AND ANALYSIS: Two review authors independently included studies, extracted data, and assessed risk of bias. When a meta-analysis was considered meaningful to synthesise our findings, we used random-effects models to estimate risk ratios (RRs) with 95% confidence intervals (CIs), with RR > 1 indicating that documents (e.g. clinical guidelines) with conflicts of interest more often had favourable recommendations. We analysed associations for financial and non-financial conflicts of interest separately, and analysed the four types of documents both separately (pre-planned analyses) and combined (post hoc analysis). MAIN RESULTS: We included 21 studies analysing 106 clinical guidelines, 1809 advisory committee reports, 340 opinion pieces, and 497 narrative reviews. We received unpublished data from 11 studies; eight full data sets and three summary data sets. Fifteen studies had a risk of confounding, as they compared documents that may differ in other aspects than conflicts of interest (e.g. documents on different drugs used for different populations). The associations between financial conflicts of interest and favourable recommendations were: clinical guidelines, RR: 1.26, 95% CI: 0.93 to 1.69 (four studies of 86 clinical guidelines); advisory committee reports, RR: 1.20, 95% CI: 0.99 to 1.45 (four studies of 629 advisory committee reports); opinion pieces, RR: 2.62, 95% CI: 0.91 to 7.55 (four studies of 284 opinion pieces); and narrative reviews, RR: 1.20, 95% CI: 0.97 to 1.49 (four studies of 457 narrative reviews). An analysis combining all four document types supported these findings (RR: 1.26, 95% CI: 1.09 to 1.44). One study investigating specialty interests found that the association between including radiologist guideline authors and recommending routine breast cancer screening was RR: 2.10, 95% CI: 0.92 to 4.77 (12 clinical guidelines). AUTHORS' CONCLUSIONS: We interpret our findings to indicate that financial conflicts of interest are associated with favourable recommendations of drugs and devices in clinical guidelines, advisory committee reports, opinion pieces, and narrative reviews. However, we also stress risk of confounding in the included studies and the statistical imprecision of individual analyses of each document type. It is not certain whether non-financial conflicts of interest impact on recommendations.

Postponement of Death by Statin Use: a Systematic Review and Meta-analysis of Randomized Clinical Trials.

BACKGROUND: The average postponement of the outcome (gain in time to event) has been proposed as a measure to convey the effect of preventive medications. Among its advantages over number needed to treat and relative risk reduction is a better intuitive understanding among lay persons. OBJECTIVES: To develop a novel approach for modeling outcome postponement achieved within a trial's duration, based on published trial data and to present a formalized meta-analysis of modeled outcome postponement for all-cause mortality in statin trials. METHODS: The outcome postponement was modeled on the basis of the hazard ratio or relative risk, the mortality rate in the placebo group and the trial's duration. Outcome postponement was subjected to a meta-analysis. We also estimated the average outcome postponement as the area between Kaplan-Meier curves. Statin trials were identified through a systematic review. RESULTS: The median modeled outcome postponement was 10.0 days (interquartile range, 2.9-19.5 days). Meta-analysis of 16 trials provided a summary estimate of outcome postponement for all-cause mortality of 12.6 days, with a 95% postponement interval (PI) of 7.1-18.0. For primary, secondary, and mixed prevention trials, respectively, outcome postponements were 10.2 days (PI, 4.0-16.3), 17.4 days (PI, 6.0-28.8), and 8.5 days (PI, 1.9-15.0). CONCLUSIONS: The modeled outcome postponement is amenable to meta-analysis and may be a useful approach for presenting the benefits of preventive interventions. Statin treatment results in a small increase of average survival within the duration of a trial. SYSTEMATIC REVIEW REGISTRATION: The systematic review was registered in PROSPERO [CRD42016037507] .

Financial conflicts of interest in systematic reviews: associations with results, conclusions, and methodological quality.

BACKGROUND: Financial conflicts of interest in systematic reviews (e.g. funding by drug or device companies or authors' collaboration with such companies) may impact on how the reviews are conducted and reported. OBJECTIVES: To investigate the degree to which financial conflicts of interest related to drug and device companies are associated with results, conclusions, and methodological quality of systematic reviews. SEARCH METHODS: We searched PubMed, Embase, and the Cochrane Methodology Register for studies published up to November 2016. We also read reference lists of included studies, searched grey literature sources, and Web of Science for studies citing the included studies. SELECTION CRITERIA: Eligible studies were studies that compared systematic reviews with and without financial conflicts of interest in order to investigate differences in results (estimated treatment effect and frequency of statistically favourable results), frequency of favourable conclusions, or measures of methodological quality of the review (e.g. as evaluated on the Oxman and Guyatt index). DATA COLLECTION AND ANALYSIS: Two review authors independently determined the eligibility of studies, extracted data, and assessed risk of bias. We synthesised the results of each study relevant to each of our outcomes. For meta-analyses, we used Mantel-Haenszel random-effects models to estimate risk ratios (RR) with 95% confidence intervals (CIs), with RR > 1 indicating that systematic reviews with financial conflicts of interest more frequently had statistically favourable results or favourable conclusions, and had lower methodological quality. When a quantitative synthesis was considered not meaningful, results from individual studies were summarised qualitatively. MAIN RESULTS: Ten studies with a total of 995 systematic reviews of drug studies and 15 systematic reviews of device studies were included. We assessed two studies as low risk of bias and eight as high risk, primarily because of risk of confounding. The estimated treatment effect was not statistically significantly different for systematic reviews with and without financial conflicts of interest (Z-score: 0.46, P value: 0.64; based on one study of 14 systematic reviews which had a matched design, comparing otherwise similar systematic reviews). We found no statistically significant difference in frequency of statistically favourable results for systematic reviews with and without financial conflicts of interest (RR: 0.84, 95% CI: 0.62 to 1.14; based on one study of 124 systematic reviews). An analysis adjusting for confounding due to methodological quality (i.e. score on the Oxman and Guyatt index) provided a similar result. Systematic reviews with financial conflicts of interest more often had favourable conclusions compared with systematic reviews without (RR: 1.98, 95% CI: 1.26 to 3.11; based on seven studies of 411 systematic reviews). Similar results were found in two studies with a matched design, which therefore had a reduced risk of confounding. Systematic reviews with financial conflicts of interest tended to have lower methodological quality compared with systematic reviews without financial conflicts of interest (RR for 11 dimensions of methodological quality spanned from 1.00 to 1.83). Similar results were found in analyses based on two studies with matched designs. AUTHORS' CONCLUSIONS: Systematic reviews with financial conflicts of interest more often have favourable conclusions and tend to have lower methodological quality than systematic reviews without financial conflicts of interest. However, it is uncertain whether financial conflicts of interest are associated with the results of systematic reviews. We suggest that patients, clinicians, developers of clinical guidelines, and planners of further research could primarily use systematic reviews without financial conflicts of interest. If only systematic reviews with financial conflicts of interest are available, we suggest that users read the review conclusions with skepticism, critically appraise the methods applied, and interpret the review results with caution.

Pain relief that matters to patients: systematic review of empirical studies assessing the minimum clinically important difference in acute pain.

BACKGROUND: The minimum clinically important difference (MCID) is used to interpret the clinical relevance of results reported by trials and meta-analyses as well as to plan sample sizes in new studies. However, there is a lack of consensus about the size of MCID in acute pain, which is a core symptom affecting patients across many clinical conditions. METHODS: We identified and systematically reviewed empirical studies of MCID in acute pain. We searched PubMed, EMBASE and Cochrane Library, and included prospective studies determining MCID using a patient-reported anchor and a one-dimensional pain scale (e.g. 100 mm visual analogue scale). We summarised results and explored reasons for heterogeneity applying meta-regression, subgroup analyses and individual patient data meta-analyses. RESULTS: We included 37 studies (8479 patients). Thirty-five studies used a mean change approach, i.e. MCID was assessed as the mean difference in pain score among patients who reported a minimum degree of improvement, while seven studies used a threshold approach, i.e. MCID was assessed as the threshold in pain reduction associated with the best accuracy (sensitivity and specificity) for identifying improved patients. Meta-analyses found considerable heterogeneity between studies (absolute MCID: I2 = 93%, relative MCID: I2 = 75%) and results were therefore presented qualitatively, while analyses focused on exploring reasons for heterogeneity. The reported absolute MCID values ranged widely from 8 to 40 mm (standardised to a 100 mm scale) and the relative MCID values from 13% to 85%. From analyses of individual patient data (seven studies, 918 patients), we found baseline pain strongly associated with absolute, but not relative, MCID as patients with higher baseline pain needed larger pain reduction to perceive relief. Subgroup analyses showed that the definition of improved patients (one or several categories improvement or meaningful change) and the design of studies (single or multiple measurements) also influenced MCID values. CONCLUSIONS: The MCID in acute pain varied greatly between studies and was influenced by baseline pain, definitions of improved patients and study design. MCID is context-specific and potentially misguiding if determined, applied or interpreted inappropriately. Explicit and conscientious reflections on the choice of a reference value are required when using MCID to classify research results as clinically important or trivial.

The matching quality of experimental and control interventions in blinded pharmacological randomised clinical trials: a methodological systematic review.

BACKGROUND: Blinding is a pivotal method to avoid bias in randomised clinical trials. In blinded drug trials, experimental and control interventions are often designed to be matched, i.e. to appear indistinguishable. It is unknown how often matching procedures are inadequate, so we decided to systematically identify and analyse studies of matching quality in drug trials. Our primary objective was to assess the proportion of studies that concluded that the matching was inadequate; our secondary objective was to describe mechanisms for inadequate matching. METHODS: Systematic review. We searched PubMed, Google Scholar and Web of Science Citation Index for studies that assessed whether supposedly indistinguishable interventions (experimental and control) in randomized clinical drug trials could be distinguished based on physical properties (e.g. appearance or smell). Two persons decided on study eligibility and extracted data independently. Our primary analysis was based on the conclusions of each study. In supportive analyses, we defined a low and a high threshold for inadequate matching. We summarised results qualitatively. RESULTS: We included studies of 36 trials, of which 28 (78%) were published before 1977. The studies differed considerably with regard to design, methodology and analysis. Sixteen of the 36 studies (44%) concluded inadequate matching. When we adapted high or low thresholds for inadequate matching, the number of trials with inadequate matching was reduced to 12 (33%) or increased to 26 (72%). Inadequate matching was concluded in 7 of 22 trials (32%) based on a defined cohort of trials. Inadequate matching was concluded in 9 of 14 trials (64%) which were not based on a trial cohort, and therefore at a higher risk of publication bias. The proportion of inadequate matching did not seem to depend on publication year. Typical mechanisms of inadequate matching were differences in taste or colour. CONCLUSION: We identified matching quality studies of 36 randomized clinical drug trials. Sixteen of the 36 studies (44%) concluded inadequate matching. Few studies of matching quality in contemporary trials have been published, but show similar results as found for older trials. Inadequate matching in drug trials may be more prevalent than commonly believed.

Mechanisms and direction of allocation bias in randomised clinical trials.

BACKGROUND: Selective allocation of patients into the compared groups of a randomised trial may cause allocation bias, but the mechanisms behind the bias and its directionality are incompletely understood. We therefore analysed the mechanisms and directionality of allocation bias in randomised clinical trials. METHODS: Two systematic reviews and a theoretical analysis. We conducted one systematic review of empirical studies of motives/methods for deciphering patient allocation sequences; and another review of methods publications commenting on allocation bias. We theoretically analysed the mechanisms of allocation bias and hypothesised which main factors predicts its direction. RESULTS: Three empirical studies addressed motives/methods for deciphering allocation sequences. Main motives included ensuring best care for patients and ensuring best outcome for the trial. Main methods included various manipulations with randomisation envelopes. Out of 57 methods publications 11 (19 %) mentioned explicitly that allocation bias can go in either direction. We hypothesised that the direction of allocation bias is mainly decided by the interaction between the patient allocators' motives and treatment preference. CONCLUSION: Inadequate allocation concealment may exaggerate treatment effects in some trials while underestimate effects in others. Our hypothesis provides a theoretical overview of the main factors responsible for the direction of allocation bias.

Comparison of central adjudication of outcomes and onsite outcome assessment on treatment effect estimates.

BACKGROUND: Assessment of events by adjudication committees (ACs) is recommended in multicentre randomised controlled trials (RCTs). However, its usefulness has been questioned. OBJECTIVES: The aim of this systematic review was to compare 1) treatment effect estimates of subjective clinical events assessed by onsite assessors versus by AC, and 2) treatment effect estimates according to the blinding status of the onsite assessor as well as the process used to select events to adjudicate. SEARCH METHODS: We searched Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, EMBASE, PsycINFO, CINAHL and Google Scholar (25 August 2015 as the last updated search date), using a combination of terms to retrieve RCTs with commonly used terms to describe ACs. SELECTION CRITERIA: We included all reports of RCTs and the published RCTs included in reviews and meta-analyses that reported the same subjective outcome event assessed by both an onsite assessor and an AC. DATA COLLECTION AND ANALYSIS: We extracted the odds ratio (OR) from onsite assessment and the corresponding OR from AC assessment and calculated the ratio of the odds ratios (ROR). A ratio of odds ratios < 1 indicated that onsite assessors generated larger effect estimates in favour of the experimental treatment than ACs. MAIN RESULTS: Data from 47 RCTs (275,078 patients) were used in the meta-analysis. We excluded 11 RCTs because of incomplete outcome data to calculate the OR for onsite and AC assessments. On average, there was no difference in treatment effect estimates from onsite assessors and AC (combined ROR: 1.00, 95% confidence interval (CI) 0.97 to 1.04; I(2) = 0%, 47 RCTs). The combined ROR was 1.00 (95% CI 0.96 to 1.04; I(2) = 0%, 35 RCTs) when onsite assessors were blinded; 0.76 (95% CI 0.48 to 1.12, I(2) = 0%, two RCTs) when AC assessed events identified independently from unblinded onsite assessors; and 1.11 (95% CI 0.96 to 1.27, I(2) = 0%, 10 RCTs) when AC assessed events identified by unblinded onsite assessors. However, there was a statistically significant interaction between these subgroups (P = 0.03) AUTHORS' CONCLUSIONS: On average, treatment effect estimates for subjective outcome events assessed by onsite assessors did not differ from those assessed by ACs. Results of subgroup analysis showed an interaction according to the blinded status of onsite assessors and the process used to submit data to AC. These results suggest that the use of ACs might be most important when onsite assessors are not blinded and the risk of misclassification is high. Furthermore, research is needed to explore the impact of the different procedures used to select events to adjudicate.