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Christian Gluud - One of the best experts on this subject based on the ideXlab platform.
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Assessing imprecision in Cochrane systematic reviews: a comparison of GRADE and Trial Sequential Analysis
Systematic reviews, 2018Co-Authors: Greta Castellini, Christian Gluud, Matteo Bruschettini, Silvia Gianola, Lorenzo MojaAbstract:The evaluation of imprecision is a key dimension of the grading of the confidence in the estimate. Grading of Recommendations Assessment, Development and Evaluation (GRADE) gives recommendations on how to downgrade evidence for imprecision, but authors vary in their use. Trial Sequential Analysis (TSA) has been advocated for a more reliable assessment of imprecision. We aimed to evaluate reporting of and adherence to GRADE and to compare the assessment of imprecision of intervention effects assessed by GRADE and TSA in Cochrane systematic reviews. In this cross-sectional study, we included 100 Cochrane reviews irrespective of type of intervention with a key dichotomous outcome meta-analyzed and assessed by GRADE. The methods and results sections of each review were assessed for adequacy of imprecision evaluation. We re-analyzed imprecision following the GRADE Handbook and the TSA Manual. Overall, only 13.0% of reviews stated the criteria they applied to assess imprecision. The most common dimensions were the 95% width of the confidence intervals and the optimal information size. Review authors downgraded 48.0% of key outcomes due to imprecision. When imprecision was re-analyzed following the GRADE Handbook, 64% of outcomes were downgraded. Agreement between review authors’ assessment and assessment by the authors of this study was moderate (kappa 0.43, 95% confidence interval [CI] 0.23 to 0.58). TSA downgraded 69.0% outcomes due to imprecision. Agreement between review authors’ GRADE assessment and TSA, irrespective of downgrading levels, was moderate (kappa 0.43, 95% CI 0.21 to 0.57). Agreement between our GRADE assessment following the Handbook and TSA was substantial (kappa 0.66, 95% CI 0.49 to 0.79). In a sample of Cochrane reviews, methods for assessing imprecision were rarely reported. GRADE according to Handbook guidelines and TSA led to more severe judgment of imprecision rather than GRADE adopted by reviews’ authors. Cochrane initiatives to improve adherence to GRADE Handbook are warranted. TSA may transparently assist in such development.
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trial Sequential Analysis in systematic reviews with meta Analysis
BMC Medical Research Methodology, 2017Co-Authors: Jorn Wetterslev, Janus Christian Jakobsen, Christian GluudAbstract:Most meta-analyses in systematic reviews, including Cochrane ones, do not have sufficient statistical power to detect or refute even large intervention effects. This is why a meta-Analysis ought to be regarded as an interim Analysis on its way towards a required information size. The results of the meta-analyses should relate the total number of randomised participants to the estimated required meta-analytic information size accounting for statistical diversity. When the number of participants and the corresponding number of trials in a meta-Analysis are insufficient, the use of the traditional 95% confidence interval or the 5% statistical significance threshold will lead to too many false positive conclusions (type I errors) and too many false negative conclusions (type II errors). We developed a methodology for interpreting meta-Analysis results, using generally accepted, valid evidence on how to adjust thresholds for significance in randomised clinical trials when the required sample size has not been reached. The Lan-DeMets trial Sequential monitoring boundaries in Trial Sequential Analysis offer adjusted confidence intervals and restricted thresholds for statistical significance when the diversity-adjusted required information size and the corresponding number of required trials for the meta-Analysis have not been reached. Trial Sequential Analysis provides a frequentistic approach to control both type I and type II errors. We define the required information size and the corresponding number of required trials in a meta-Analysis and the diversity (D2) measure of heterogeneity. We explain the reasons for using Trial Sequential Analysis of meta-Analysis when the actual information size fails to reach the required information size. We present examples drawn from traditional meta-analyses using unadjusted naive 95% confidence intervals and 5% thresholds for statistical significance. Spurious conclusions in systematic reviews with traditional meta-analyses can be reduced using Trial Sequential Analysis. Several empirical studies have demonstrated that the Trial Sequential Analysis provides better control of type I errors and of type II errors than the traditional naive meta-Analysis. Trial Sequential Analysis represents Analysis of meta-analytic data, with transparent assumptions, and better control of type I and type II errors than the traditional meta-Analysis using naive unadjusted confidence intervals.
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constraint induced movement therapy trial Sequential Analysis applied to cochrane collaboration systematic review results
Trials, 2014Co-Authors: Greta Castellini, Christian Gluud, Silvia Gianola, Rita Banzi, Davide Corbetta, Roberto Gatti, Valeria Sirtori, Lorenzo MojaAbstract:Background Trial Sequential Analysis (TSA) may establish when firm evidence about the efficacy of interventions is reached in a cumulative meta-Analysis, combining a required information size with adjusted thresholds for conservative statistical significance. Our aim was to demonstrate TSA results on randomized controlled trials (RCTs) included in a Cochrane systematic review on the effectiveness of constraint-induced movement therapy (CIMT) for stroke patients.
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sulfonylurea versus metformin monotherapy in patients with type 2 diabetes a cochrane systematic review and meta Analysis of randomized clinical trials and trial Sequential Analysis
CMAJ Open, 2014Co-Authors: Bianca Hemmingsen, Jeppe Schroll, Jorn Wetterslev, Christian Gluud, A Vaag, David P Sonne, L H Lundstrom, Thomas AlmdalAbstract:BACKGROUND Guidelines recommend metformin as the first-line oral treatment for type 2 diabetes. We conducted a systematic review to assess whether the use of second- and third-generation sulfonylurea agents is associated with benefits and harms in terms of patient-important outcomes compared with metformin. METHODS We searched several electronic databases and other sources for randomized clinical trials published to August 2011. We included trials that compared sulfonylurea versus metformin monotherapy among patients 18 years or older with type 2 diabetes and that had an intervention period of at least 24 weeks. We assessed risk of bias and extracted data related to interventions and outcomes. The risk of random errors was assessed by trial Sequential Analysis. RESULTS We included 14 trials (4560 participants). All trials were judged to be at high risk of bias. Data on patient-important outcomes were sparse. Compared with metformin, sulfonylurea did not significantly affect all-cause mortality (relative risk [RR] 0.98, 95% confidence interval [CI] 0.61 to 1.58) or cardiovascular mortality (RR 1.47, 95% CI 0.54 to 4.01). Sulfonylurea significantly decreased the risk of nonfatal macrovascular outcomes (RR 0.67, 95% CI 0.48 to 0.93). However, the definition of this outcome varied among trials, and trial Sequential Analysis showed that more trials are needed before reliable conclusions can be drawn. No differences between sulfonylurea and metformin were found for change in fasting blood glucose level or glycosylated hemoglobin concentration in the random-effects model. Sulfonylurea resulted in greater weight gain compared with metformin, a finding confirmed in the trial Sequential Analysis. Significantly more patients in the sulfonylurea arm than in the metformin arm had mild hypoglycemia (RR 2.95, 95% CI 2.13 to 4.07) and severe hypoglycemia (RR 5.64, 95% CI 1.22 to 26.00). INTERPRETATION Some evidence suggests that, compared with metformin, second- and third-generation sulfonylureas may not affect all-cause or cardiovascular mortality but may decrease the risk of nonfatal macrovascular outcomes among patients with type 2 diabetes. They may also increase the risk of hypoglycemia. In general, the available data were too few and inconsistent to provide firm evidence concerning patient-important outcomes in relation to the benefits and harms of sulfonylurea versus metformin monotherapy.
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intensive glycaemic control for patients with type 2 diabetes systematic review with meta Analysis and trial Sequential Analysis of randomised clinical trials
BMJ, 2011Co-Authors: Bianca Hemmingsen, Christian Gluud, A Vaag, Thomas Almdal, Soren S Lund, Christina Hemmingsen, Jorn WetterslevAbstract:Objective To assess the effect of targeting intensive glycaemic control versus conventional glycaemic control on all cause mortality and cardiovascular mortality, non-fatal myocardial infarction, microvascular complications, and severe hypoglycaemia in patients with type 2 diabetes. myocardial infarction may be reduced (relative risk 0.85, 0.76 to 0.95; P=0.004; 28 111 participants, 8 trials), but this finding was not confirmed in trial Sequential Analysis. Intensive glycaemic control showed a reduction of the relative risks for the composite microvascular outcome (0.88, 0.79 to 0.97; P=0.01; 25 600 participants, 3 trials) and retinopathy (0.80, 0.67 to 0.94; P=0.009; 10 793 participants, 7 trials), but trial Sequential analyses showed that sufficient evidence had not yet been reached. The estimate of an effect on the risk of nephropathy (relative risk 0.83, 0.64 to 1.06; 27 769 participants, 8 trials) was not statistically significant. The risk of severe hypoglycaemia was significantly increased when intensive glycaemic control was targeted (relative risk 2.39, 1.71 to 3.34; 27 844 participants, 9 trials); trial Sequential Analysis supported a 30% increased relative risk of severe hypoglycaemia.
Jorn Wetterslev - One of the best experts on this subject based on the ideXlab platform.
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eversion technique versus conventional endarterectomy with patch angioplasty in carotid surgery protocol for a systematic review with meta analyses and trial Sequential Analysis of randomised clinical trials
BMJ Open, 2020Co-Authors: Martijn S Marsman, Jorn Wetterslev, Abdelkarime Kh Jahrome, Frans L Moll, Frederik Keus, P W H E Vriens, Ronald L A W Bleys, G G KoningAbstract:Introduction Traditional carotid endarterectomy is considered to be the standard technique for prevention of a new stroke in patients with a symptomatic carotid stenosis. Use of patch angioplasty to restore the arterial wall after longitudinal endarterectomy is, to date, not unequivocally proven to be superior to eversion technique. A systematic review is needed for evaluation of benefits and harms of the eversion technique versus the traditional endarterectomy with patch angioplasty in patients with symptomatic carotid stenosis. Methods and outcomes The review will be conducted according to this protocol following the recommendations of the ‘Cochrane Handbook for Systematic Reviews’ and reported according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses. Randomised clinical trials comparing eversion technique versus endarterectomy with patch angioplasty in patients with a symptomatic stenosis of the internal carotid artery will be included. Primary outcomes are all-cause mortality rate, health-related quality of life and serious adverse events. Secondary outcomes are 30-day stroke and mortality rate, symptomatic arterial restenosis or occlusion and non-serious adverse events. The databases Cochrane Central Register of Controlled Trials, PubMed/MEDLINE and EMBASE will be searched (November 2019). We will primarily base our conclusions on meta-analyses of trials with overall low-risk of bias. We will use trial Sequential Analysis to assist the evaluation of imprecision in Grading of Recommendations, Assessment, Development and Evaluation. However, if pooled point estimates of all trials are similar to pooled point estimates of trials with overall low risk of bias and there is lack of a statistical significant interaction between estimates from trials with overall high risk of bias and trials with overall low risk of bias we will consider the trial Sequential Analysis adjusted precision of the estimate achieved in all trials as the result of our meta-analyses. Ethics and dissemination The proposed systematic review will collect and analyse data from published studies, therefore, ethical approval is not required. The results of the review will be disseminated by publication in a peer-review journal and submitted for presentation at conferences. PROSPERO registration number CRD42019119361.
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trial Sequential Analysis in systematic reviews with meta Analysis
BMC Medical Research Methodology, 2017Co-Authors: Jorn Wetterslev, Janus Christian Jakobsen, Christian GluudAbstract:Most meta-analyses in systematic reviews, including Cochrane ones, do not have sufficient statistical power to detect or refute even large intervention effects. This is why a meta-Analysis ought to be regarded as an interim Analysis on its way towards a required information size. The results of the meta-analyses should relate the total number of randomised participants to the estimated required meta-analytic information size accounting for statistical diversity. When the number of participants and the corresponding number of trials in a meta-Analysis are insufficient, the use of the traditional 95% confidence interval or the 5% statistical significance threshold will lead to too many false positive conclusions (type I errors) and too many false negative conclusions (type II errors). We developed a methodology for interpreting meta-Analysis results, using generally accepted, valid evidence on how to adjust thresholds for significance in randomised clinical trials when the required sample size has not been reached. The Lan-DeMets trial Sequential monitoring boundaries in Trial Sequential Analysis offer adjusted confidence intervals and restricted thresholds for statistical significance when the diversity-adjusted required information size and the corresponding number of required trials for the meta-Analysis have not been reached. Trial Sequential Analysis provides a frequentistic approach to control both type I and type II errors. We define the required information size and the corresponding number of required trials in a meta-Analysis and the diversity (D2) measure of heterogeneity. We explain the reasons for using Trial Sequential Analysis of meta-Analysis when the actual information size fails to reach the required information size. We present examples drawn from traditional meta-analyses using unadjusted naive 95% confidence intervals and 5% thresholds for statistical significance. Spurious conclusions in systematic reviews with traditional meta-analyses can be reduced using Trial Sequential Analysis. Several empirical studies have demonstrated that the Trial Sequential Analysis provides better control of type I errors and of type II errors than the traditional naive meta-Analysis. Trial Sequential Analysis represents Analysis of meta-analytic data, with transparent assumptions, and better control of type I and type II errors than the traditional meta-Analysis using naive unadjusted confidence intervals.
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sulfonylurea versus metformin monotherapy in patients with type 2 diabetes a cochrane systematic review and meta Analysis of randomized clinical trials and trial Sequential Analysis
CMAJ Open, 2014Co-Authors: Bianca Hemmingsen, Jeppe Schroll, Jorn Wetterslev, Christian Gluud, A Vaag, David P Sonne, L H Lundstrom, Thomas AlmdalAbstract:BACKGROUND Guidelines recommend metformin as the first-line oral treatment for type 2 diabetes. We conducted a systematic review to assess whether the use of second- and third-generation sulfonylurea agents is associated with benefits and harms in terms of patient-important outcomes compared with metformin. METHODS We searched several electronic databases and other sources for randomized clinical trials published to August 2011. We included trials that compared sulfonylurea versus metformin monotherapy among patients 18 years or older with type 2 diabetes and that had an intervention period of at least 24 weeks. We assessed risk of bias and extracted data related to interventions and outcomes. The risk of random errors was assessed by trial Sequential Analysis. RESULTS We included 14 trials (4560 participants). All trials were judged to be at high risk of bias. Data on patient-important outcomes were sparse. Compared with metformin, sulfonylurea did not significantly affect all-cause mortality (relative risk [RR] 0.98, 95% confidence interval [CI] 0.61 to 1.58) or cardiovascular mortality (RR 1.47, 95% CI 0.54 to 4.01). Sulfonylurea significantly decreased the risk of nonfatal macrovascular outcomes (RR 0.67, 95% CI 0.48 to 0.93). However, the definition of this outcome varied among trials, and trial Sequential Analysis showed that more trials are needed before reliable conclusions can be drawn. No differences between sulfonylurea and metformin were found for change in fasting blood glucose level or glycosylated hemoglobin concentration in the random-effects model. Sulfonylurea resulted in greater weight gain compared with metformin, a finding confirmed in the trial Sequential Analysis. Significantly more patients in the sulfonylurea arm than in the metformin arm had mild hypoglycemia (RR 2.95, 95% CI 2.13 to 4.07) and severe hypoglycemia (RR 5.64, 95% CI 1.22 to 26.00). INTERPRETATION Some evidence suggests that, compared with metformin, second- and third-generation sulfonylureas may not affect all-cause or cardiovascular mortality but may decrease the risk of nonfatal macrovascular outcomes among patients with type 2 diabetes. They may also increase the risk of hypoglycemia. In general, the available data were too few and inconsistent to provide firm evidence concerning patient-important outcomes in relation to the benefits and harms of sulfonylurea versus metformin monotherapy.
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intensive glycaemic control for patients with type 2 diabetes systematic review with meta Analysis and trial Sequential Analysis of randomised clinical trials
BMJ, 2011Co-Authors: Bianca Hemmingsen, Christian Gluud, A Vaag, Thomas Almdal, Soren S Lund, Christina Hemmingsen, Jorn WetterslevAbstract:Objective To assess the effect of targeting intensive glycaemic control versus conventional glycaemic control on all cause mortality and cardiovascular mortality, non-fatal myocardial infarction, microvascular complications, and severe hypoglycaemia in patients with type 2 diabetes. myocardial infarction may be reduced (relative risk 0.85, 0.76 to 0.95; P=0.004; 28 111 participants, 8 trials), but this finding was not confirmed in trial Sequential Analysis. Intensive glycaemic control showed a reduction of the relative risks for the composite microvascular outcome (0.88, 0.79 to 0.97; P=0.01; 25 600 participants, 3 trials) and retinopathy (0.80, 0.67 to 0.94; P=0.009; 10 793 participants, 7 trials), but trial Sequential analyses showed that sufficient evidence had not yet been reached. The estimate of an effect on the risk of nephropathy (relative risk 0.83, 0.64 to 1.06; 27 769 participants, 8 trials) was not statistically significant. The risk of severe hypoglycaemia was significantly increased when intensive glycaemic control was targeted (relative risk 2.39, 1.71 to 3.34; 27 844 participants, 9 trials); trial Sequential Analysis supported a 30% increased relative risk of severe hypoglycaemia.
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hypothermia after cardiac arrest should be further evaluated a systematic review of randomised trials with meta Analysis and trial Sequential Analysis
International Journal of Cardiology, 2011Co-Authors: Niklas Nielsen, Christian Gluud, Hans Friberg, Johan Herlitz, Jorn WetterslevAbstract:BACKGROUND: Guidelines recommend mild induced hypothermia (MIH) to reduce mortality and neurological impairment after out-of-hospital cardiac arrest. Our objective was to systematically evaluate the evidence for MIH taking into consideration the risks of systematic and random error and to GRADE the evidence. METHODS: Systematic review with meta-Analysis and trial Sequential Analysis of randomised trials evaluating MIH after cardiac arrest in adults. We searched CENTRAL, MEDLINE, and EMBASE databases until May 2009. Retrieved trials were evaluated with Cochrane methodology. Meta-analytic estimates were calculated with random- and fixed-effects models and random errors were evaluated with trial Sequential Analysis (TSA). RESULTS: Five randomised trials (478 patients) were included. All trials had substantial risk of bias. The relative risk (RR) for death was 0.84 (95% confidence interval (CI) 0.70 to 1.01) and for poor neurological outcome 0.78 (95% CI 0.64 to 0.95). For the two trials with least risk of bias the RR for death was 0.92 (95% CI 0.56 to 1.51) and for poor neurological outcome 0.92 (95% confidence interval 0.56 to 1.50). TSA indicated lack of firm evidence for a beneficial effect. The substantial risk of bias and concerns with directness rated down the quality of the evidence to low. CONCLUSIONS: Evidence regarding MIH after out-of-hospital cardiac arrest is still inconclusive and associated with non-negligible risks of systematic and random errors. Using GRADE-methodology, we conclude that the quality of evidence is low. Our findings demonstrate that clinical equipoise exists and that large well-designed randomised trials with low risk of bias are needed.
Jorn Wetterslev - One of the best experts on this subject based on the ideXlab platform.
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lower vs higher fluid volumes during initial management of sepsis a systematic review with meta Analysis and trial Sequential Analysis
Chest, 2020Co-Authors: Tine Sylvest Meyhoff, Morten Hylander Moller, Peter Buhl Hjortrup, Maria Cronhjort, Anders Perner, Jorn WetterslevAbstract:Objective IV fluids are recommended during the initial management of sepsis, but the quality of evidence is low, and clinical equipoise exists. We aimed to assess patient-important benefits and harms of lower vs higher fluid volumes in adult patients with sepsis. Methods We conducted a systematic review with meta-Analysis and trial Sequential Analysis (TSA) of randomized clinical trials of IV fluid volume separation in adult patients with sepsis. We adhered to our published protocol; the Cochrane handbook; the Preferred Reporting Items for Systematic Reviews and Meta-Analyses; and the Grading of Recommendations Assessment, Development and Evaluation statements. The primary outcomes were all-cause mortality, serious adverse events (SAEs), and quality of life. Results We included nine trials (n = 637); all were published after 2015 and had an overall high risk of bias. We found no statistically significant difference between lower vs higher fluid volumes in all-cause mortality (relative risk [RR], 0.87; 95% CI, 0.69-1.10; I2 = 0%; TSA-adjusted CI, 0.34-2.22) or SAEs (RR, 0.91; 95% CI, 0.78-1.05; I2 = 0%; TSA-adjusted CI, 0.68-1.21). No trials reported on quality of life. We did not find differences in the secondary or exploratory outcomes. The quality of evidence was very low across all outcomes. Conclusions In this systematic review, we found very low quantity and quality of evidence supporting the decision on the volumes of IV fluid therapy in adults with sepsis. Trial Registry ClinicalTrials.gov ; No.: NCT03668236 ; URL: www.clinicaltrials.gov ;
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plexus anesthesia versus general anesthesia in patients for carotid endarterectomy with patch angioplasty protocol for a systematic review with meta analyses and trial Sequential Analysis of randomized clinical trials
International Journal of Surgery Protocols, 2020Co-Authors: Martijn S Marsman, Frans L Moll, Frederik Keus, P W H E Vriens, Jorn Wetterslev, D Van Aalst, F G Van Rooij, J M M Heyligers, Kh A Jahrome, G G KoningAbstract:Introduction: Traditional carotid endarterectomy is considered to be the standard technique for prevention of a new stroke in patients with a symptomatic carotid stenosis. Use of plexus anesthesia or general anesthesia in traditional carotid endarterectomy is, to date, not unequivocally proven to be superior to one other. A systematic review is needed for evaluation of benefits and harms to determine which technique, plexus anesthesia or general anesthesia is more effective for traditional carotid endarterectomy in patients with symptomatic carotid stenosis. Methods and outcomes: The review will be conducted according to this protocol following the recommendations of the ‘Cochrane Handbook for Systematic Reviews’ and reported according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses. Randomized Clinical Trials comparing plexus anesthesia versus general anesthesia in traditional carotid endarterectomy will be included. Primary outcomes will be postoperative death and/ or stroke ( We will primarily base our conclusions on meta-analyses of trials with overall low risk of bias. We will use Trial Sequential Analysis to assist the evaluation of imprecision in Grading of Recommendations Assessment, Development and Evaluation. However, if pooled point-estimates of all trials are similar to pooled point-estimates of trials with overall low risk of bias and there is lack of a statistical significant interaction between estimates from trials with overall high risk of bias and trials with overall low risk of bias we will consider the Trial Sequential Analysis adjusted confidence interval precision of the estimate achieved in all trials as the result of our meta-analyses. Ethics and dissemination: The proposed systematic review will collect and analyze secondary data from already performed studies therefore ethical approval is not required. The results of the systematic review will be disseminated by publication in a peer-review journal and submitted for presentation at relevant conferences.
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does ondansetron modify sympathectomy due to subarachnoid anesthesia meta Analysis meta regression and trial Sequential Analysis
Anesthesiology, 2016Co-Authors: Abdullah Sulieman Terkawi, Jorn Wetterslev, Dimitris Mavridis, Pamela Flood, Rayan S Terkawi, Aref Bin A Abdulhak, Megan S Nunemaker, Mohamed TiouririneAbstract:BACKGROUND Disagreement among many underpowered studies has led to an equivocal understanding of the efficacy of the 5-HT3 antagonist ondansetron in preventing the consequences of sympathectomy after subarachnoid anesthesia. The authors assessed the efficacy of ondansetron with respect to the overall quality and statistical power of the meta-analyses. METHODS The authors used a standard and a newer method of meta-Analysis, trial Sequential Analysis (TSA), to estimate adjusted CIs based on how much information has been accrued. They also used random-effects meta-analyses techniques, small trial bias assessment, selection models, sensitivity analyses, and the Grading of Recommendations on Assessment, Development, and Evaluation system. These results from the aforementioned techniques were compared, and importance of consideration of these factors was discussed. RESULTS Fourteen randomized placebo-controlled trials (1,045 subjects) were identified and analyzed. By using conventional meta-analyses, the authors determined that ondansetron was associated with reduction in the incidence of hypotension (relative risk = 0.62 [95% CI, 0.46 to 0.83], P = 0.001; TSA-adjusted CI, 0.34 to 1.12; I = 60%, P = 0.002) and bradycardia (relative risk = 0.44 [95% CI, 0.26 to 0.73], P = 0.001; TSA-adjusted CI, 0.05 to 3.85; I = 0%, P = 0.84). However, the authors found indications of bias among these trials. TSAs demonstrated that the meta-Analysis lacked adequate information size and did not achieve statistical significance when adjusted for sparse data and repetitive testing. The Grading of Recommendations on Assessment, Development, and Evaluation system showed that the results had low to very low quality of evidence. CONCLUSIONS The analyses fail to confirm evidence that ondansetron reduces the incidence of hypotension and bradycardia after subarachnoid anesthesia due to the risk of bias and information sizes less than the required. As results from meta-Analysis are given significant weight, it is important to carefully evaluate the quality of the evidence that is input.
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inhaled nitric oxide for acute respiratory distress syndrome and acute lung injury in adults and children a systematic review with meta Analysis and trial Sequential Analysis
Anesthesia & Analgesia, 2011Co-Authors: Arash Afshari, Jesper Brok, A M Moller, Jorn WetterslevAbstract:Acute hypoxemic respiratory failure, defined as acute lung injury and acute respiratory distress syndrome, are critical conditions associated with frequent mortality and morbidity in all ages. Inhaled nitric oxide (iNO) has been used to improve oxygenation, but its role remains controversial. We performed a systematic review with meta-Analysis and trial Sequential Analysis of randomized clinical trials (RCTs). We searched CENTRAL, Medline, Embase, International Web of Science, LILACS, the Chinese Biomedical Literature Database, and CINHAL (up to January 31, 2010). Additionally, we hand-searched reference lists, contacted authors and experts, and searched registers of ongoing trials. Two reviewers independently selected all parallel group RCTs comparing iNO with placebo or no intervention and extracted data related to study methods, interventions, outcomes, bias risk, and adverse events. All trials, irrespective of blinding or language status were included. Retrieved trials were evaluated with Cochrane methodology. Disagreements were resolved by discussion. Our primary outcome measure was all-cause mortality. We performed subgroup and sensitivity analyses to assess the effect of iNO in adults and children and on various clinical and physiological outcomes. We assessed the risk of bias through assessment of trial methodological components. We assessed the risk of random error by applying trial Sequential Analysis.
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trial Sequential Analysis reveals insufficient information size and potentially false positive results in many meta analyses
Journal of Clinical Epidemiology, 2008Co-Authors: Jesper Brok, Christian Gluud, Kristian Thorlund, Jorn WetterslevAbstract:Abstract Objectives To evaluate meta-analyses with trial Sequential Analysis (TSA). TSA adjusts for random error risk and provides the required number of participants (information size) in a meta-Analysis. Meta-analyses not reaching information size are analyzed with trial Sequential monitoring boundaries analogous to interim monitoring boundaries in a single trial. Study Design and Setting We applied TSA on meta-analyses performed in Cochrane Neonatal reviews. We calculated information sizes and monitoring boundaries with three different anticipated intervention effects of 30% relative risk reduction (TSA 30% ), 15% (TSA 15% ), or a risk reduction suggested by low-bias risk trials of the meta-Analysis corrected for heterogeneity (TSA LBHIS ). Results A total of 174 meta-analyses were eligible; 79 out of 174 (45%) meta-analyses were statistically significant ( P 30% showed firm evidence in 61%. TSA 15% and TSA LBHIS found firm evidence in 33% and 73%, respectively. The remaining significant meta-analyses had potentially spurious evidence of effect. In the 95 statistically nonsignificant ( P ≥0.05) meta-analyses, TSA 30% showed absence of evidence in 80% (insufficient information size). TSA 15% and TSA LBHIS found that 95% and 91% had absence of evidence. The remaining nonsignificant meta-analyses had evidence of lack of effect. Conclusion TSA reveals insufficient information size and potentially false positive results in many meta-analyses.
Rolf Rossaint - One of the best experts on this subject based on the ideXlab platform.
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ephedrine versus phenylephrine as a vasopressor for spinal anaesthesia induced hypotension in parturients undergoing high risk caesarean section meta Analysis meta regression and trial Sequential Analysis
International Journal of Obstetric Anesthesia, 2019Co-Authors: M Heesen, Rolf Rossaint, K Rijs, N Hilber, W Ngan D Kee, C D Van Der Marel, Markus KlimekAbstract:Abstract Background Phenylephrine is the preferred vasopressor for the prevention and treatment of spinal anaesthesia-induced hypotension during caesarean section, because studies on low-risk elective patients found it to have a less detrimental effect on umbilical artery pH compared with ephedrine. However, limited data exist from high-risk parturients and parturients with uteroplacental insufficiency. Methods We systematically searched for randomised, controlled, double-blinded trials of these two vasopressors in high-risk caesarean sections. We applied conventional meta-Analysis, trial Sequential Analysis, computing the required information size that would exclude type I and II errors, contour-enhanced funnel plot testing for publication bias, meta-regression to assess the dose–response relationship, and the Grading of Recommendations Assessment, Development, and Evaluation system (GRADE). The incidence of fetal acidosis (umbilical arterial pH Results Eight trials (712 patients) with low risk of bias were identified. Pooling six studies of patients with preeclampsia and other reasons for fetal compromise, as well as subgroup Analysis of the preeclampsia studies, revealed no significant differences in the incidence of fetal acidosis. Trial Sequential Analysis showed that the required information size was not reached. The funnel plot was not suggestive of publication bias. Meta-regression showed no dose-response relationship. The GRADE score was moderate quality. Conclusions Despite several studies and a large number of patients there was insufficient evidence to make a recommendation for choice of vasopressor in high-risk caesarean section. Trials with adequate power to detect differences in the incidence of fetal acidosis between ephedrine and phenylephrine are required to provide evidence-based guidance.
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efficacy of perioperative dexmedetomidine on postoperative delirium systematic review and meta Analysis with trial Sequential Analysis of randomised controlled trials
BJA: British Journal of Anaesthesia, 2018Co-Authors: X Duan, Robert D Sanders, M Coburn, Rolf Rossaint, Julia Van Waesberghe, Ana KowarkAbstract:Abstract Background The influence of dexmedetomidine on postoperative delirium (POD) in adult surgical patients remains controversial. We aimed to analyse whether dexmedetomidine use could decrease POD incidence in this population and its relation to timing of dexmedetomidine administration and patient age. Methods We used random-effects modelled meta-Analysis, trial Sequential Analysis, and followed Cochrane methodology with Grading of Recommendations Assessment, Development, and Evaluation (GRADE). PubMed and Cochrane library were searched up to July 2017 for randomised controlled trials that analysed POD incidence of adult surgical patients (age ≥18 yr) after dexmedetomidine administration. Results Eighteen studies (comprising 3309 patients) were included. There was decreased risk of POD with dexmedetomidine use for the entire adult surgical population [odds ratio (OR) 0.35; 95% confidence interval (CI) 0.24–0.51)], with firm evidence from trial Sequential Analysis. Pre-specified subgroup analyses confirmed this result with firm evidence for cardiac and non-cardiac surgical patients, (OR 0.41; 95% CI 0.26–0.63) and (OR 0.33; 95% CI 0.18–0.59), respectively. We also found firm evidence for reduction of POD if dexmedetomidine is administered during the postoperative period (OR 0.30; 95% CI 0.21–0.44), in patients aged Conclusion Dexmedetomidine can reduce POD incidence for adult cardiac and non-cardiac surgical patients. The optimal dose and timing of dexmedetomidine and influence on other outcomes or particular patient populations with risk factors warrants further studies. Clinical trial registration PROSPERO: CRD42017072380.
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co administration of dexamethasone with peripheral nerve block intravenous vs perineural application systematic review meta Analysis meta regression and trial Sequential Analysis
BJA: British Journal of Anaesthesia, 2017Co-Authors: M Heesen, Rolf Rossaint, Markus Klimek, G Imberger, Sanne E Hoeks, Sebastian StraubeAbstract:Abstract Background I.V. and perineural dexamethasone have both been found to prolong loco-regional analgesia compared with controls without dexamethasone. It is unclear whether perineural administration offers advantages when compared with i.v. dexamethasone. Methods A systematic literature search was performed to identify randomized controlled double-blind trials that compared i.v. with perineural dexamethasone in patients undergoing surgery. Using the random effects model, risk ratio (for binary variables), weighted mean difference (for continuous variables) and 95% confidence intervals were calculated. We applied trial Sequential Analysis to assess the risks of type I and II error, meta-regression for the study of the doseresponsive relationship, and the Grading of Recommendations Assessment, Development, and Evaluation system. Results We identified 10 randomized controlled double-blind trials (783 patients). When using conventional meta-Analysis of nine low risk of bias trials, we found a statistically significantly longer duration of analgesia, our primary outcome with perineural dexamethasone (241 min, 95%CI, 87, 394 min). When trial Sequential Analysis was applied, this result was confirmed. Meta-regression did not show a dose-response relationship. Despite the precision in the results, using the Grading of Recommendations Assessment, Development, and Evaluation system (GRADE), we assessed the quality of the evidence for our primary outcome as low. Conclusions There is evidence that perineural dexamethasone prolongs the duration of analgesia compared with i.v. dexamethasone. Using GRADE, this evidence is low quality.
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effects of epidural volume extension by saline injection on the efficacy and safety of intrathecal local anaesthetics systematic review with meta Analysis meta regression and trial Sequential Analysis
Anaesthesia, 2017Co-Authors: M Heesen, Rolf Rossaint, Markus Klimek, Sandra Weibel, Lidia R Arends, Peter KrankeAbstract:Epidural volume extension, a modification of combined spinal-epidural anaesthesia, involves the epidural injection of saline in order to increase the spread of drugs given intrathecally. Results from individual studies have so far been contradictory and we aimed to gather the available evidence for this technique. We performed a systematic literature search for randomised, controlled trials comparing epidural volume extension after spinal injection with a control group without epidural injection in patients undergoing surgery. Conventional meta-analyses, trial Sequential analyses and meta-regression were performed, with the Grading of Recommendations on Assessment, Development and Evaluation (GRADE) approach used to express reliability of outcome estimates. We included 15 studies with 1177 participants. Meta-analyses for the primary outcomes, such as maximum sensory height (6 studies, 274 participants, mean difference (MD) (95%CI) -0.59 (-1.24 to 0.07) dermatomes, low-quality evidence) and hypotension (10 studies, 683 participants, risk ratio (95%CI) 0.84 (0.66-1.07), low-quality evidence), did not differ significantly between the two treatment arms, but trial Sequential Analysis suggested insufficient evidence to be certain of these findings. Meta-regression suggested a volume-dependent effect, with higher volumes causing a higher spread of intrathecal drugs and a higher incidence of hypotension. A sub-group Analysis indicated a pronounced effect on motor block recovery time when a lower anaesthetic dose plus epidural volume extension was compared with a higher anaesthetic dose without epidural volume extension, the MD (95%CI) being -66.75 (-76.0 to -57.5) min, with trial Sequential Analysis suggesting the evidence was sufficient to draw this conclusion. In trials using the same anaesthetic mixture in the epidural volume extension and the control groups, motor block recovery time did not differ between groups, with a MD (95%CI) of -1.06 (-5.48 to 3.36) min, although trial Sequential Analysis suggested insufficient evidence. In summary, there is not enough evidence to draw definite conclusions on the effect of epidural volume extension. The quality of the current evidence is low for both efficacy (maximum sensory height) and safety (hypotension). However, there may be a significantly shorter motor block recovery time when different anaesthetic mixtures are used in epidural volume extension and control groups; this warrants further investigation.
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effects of epidural volume extension by saline injection on the efficacy and safety of intrathecal local anaesthetics systematic review with meta Analysis meta regression and trial Sequential Analysis
Anaesthesia, 2017Co-Authors: M Heesen, Rolf Rossaint, Markus Klimek, Sandra Weibel, Lidia R Arends, Peter KrankeAbstract:Epidural volume extension, a modification of combined spinal-epidural anaesthesia, involves the epidural injection of saline in order to increase the spread of drugs given intrathecally. Results from individual studies have so far been contradictory and we aimed to gather the available evidence for this technique. We performed a systematic literature search for randomised, controlled trials comparing epidural volume extension after spinal injection with a control group without epidural injection in patients undergoing surgery. Conventional meta-analyses, trial Sequential analyses and meta-regression were performed, with the Grading of Recommendations on Assessment, Development and Evaluation (GRADE) approach used to express reliability of outcome estimates. We included 15 studies with 1177 participants. Meta-analyses for the primary outcomes, such as maximum sensory height (6 studies, 274 participants, mean difference (MD) (95%CI) -0.59 (-1.24 to 0.07) dermatomes, low-quality evidence) and hypotension (10 studies, 683 participants, risk ratio (95%CI) 0.84 (0.66-1.07), low-quality evidence), did not differ significantly between the two treatment arms, but trial Sequential Analysis suggested insufficient evidence to be certain of these findings. Meta-regression suggested a volume-dependent effect, with higher volumes causing a higher spread of intrathecal drugs and a higher incidence of hypotension. A sub-group Analysis indicated a pronounced effect on motor block recovery time when a lower anaesthetic dose plus epidural volume extension was compared with a higher anaesthetic dose without epidural volume extension, the MD (95%CI) being -66.75 (-76.0 to -57.5) min, with trial Sequential Analysis suggesting the evidence was sufficient to draw this conclusion. In trials using the same anaesthetic mixture in the epidural volume extension and the control groups, motor block recovery time did not differ between groups, with a MD (95%CI) of -1.06 (-5.48 to 3.36) min, although trial Sequential Analysis suggested insufficient evidence. In summary, there is not enough evidence to draw definite conclusions on the effect of epidural volume extension. The quality of the current evidence is low for both efficacy (maximum sensory height) and safety (hypotension). However, there may be a significantly shorter motor block recovery time when different anaesthetic mixtures are used in epidural volume extension and control groups; this warrants further investigation.
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efficacy and safety of intravenous lidocaine for postoperative analgesia and recovery after surgery a systematic review with trial Sequential Analysis
BJA: British Journal of Anaesthesia, 2016Co-Authors: Stephanie Weibel, Arash Afshari, Johanna Jokinen, Nathan L Pace, Alexander Schnabel, Markus W Hollmann, Klaus Hahnenkamp, L H J Eberhart, Daniel M Poepping, Peter KrankeAbstract:Abstract Background Improvement of postoperative pain and other perioperative outcomes remain a significant challenge and a matter of debate among perioperative clinicians. This systematic review aims to evaluate the effects of perioperative i.v. lidocaine infusion on postoperative pain and recovery in patients undergoing various surgical procedures. Methods CENTRAL, MEDLINE, EMBASE, and CINAHL databases and ClinicalTrials.gov, and congress proceedings were searched for randomized controlled trials until May 2014, that compared patients who did or did not receive continuous perioperative i.v. lidocaine infusion. Results Forty-five trials (2802 participants) were included. Meta-Analysis suggested that lidocaine reduced postoperative pain (visual analogue scale, 0 to 10 cm) at 1–4 h (MD −0.84, 95% CI −1.10 to −0.59) and at 24 h (MD −0.34, 95% CI −0.57 to −0.11) after surgery, but not at 48 h (MD −0.22, 95% CI −0.47 to 0.03). Subgroup Analysis and trial Sequential Analysis suggested pain reduction for patients undergoing laparoscopic abdominal surgery or open abdominal surgery, but not for patients undergoing other surgeries. There was limited evidence of positive effects of lidocaine on postoperative gastrointestinal recovery, opioid requirements, postoperative nausea and vomiting, and length of hospital stay. There were limited data available on the effect of systemic lidocaine on adverse effects or surgical complications. Quality of evidence was limited as a result of inconsistency (heterogeneity) and indirectness (small studies). Conclusions There is limited evidence suggesting that i.v. lidocaine may be a useful adjuvant during general anaesthesia because of its beneficial impact on several outcomes after surgery.
