Adjusting for bias in unblinded randomized controlled trials

It may not always be possible to blind participants of a randomized controlled trial for treatment allocation. As a result, estimators of the actual treatment effect may be biased. In this paper, we will extend a novel method, originally introduced in genetic research, for instrumental variable meta-analysis, adjusting for bias due to unblinding of trial participants. Using simulation studies, this novel method, “Egger Correction for non-Adherence”, is introduced and compared to the performance of the “intention-to-treat,” “as-treated,” and conventional “instrumental variable” estimators. Scenarios considered (time-varying) non-adherence, confounding, and between-study heterogeneity. The effect of treatment on a binary endpoint was quantified by means of a risk difference. In all scenarios with unblinded treatment allocation, the Egger Correction for non-Adherence method was the least biased estimator. However, unless the variation in adherence was relatively large, precision was lacking, and power did not surpass 0.50. As a comparison, in a meta-analysis of blinded randomized controlled trials, power of the conventional IV estimator was 1.00 versus at most 0.14 for the Egger Correction for non-Adherence estimator. Due to this lack of precision and power, we suggest to use this method mainly as a sensitivity analysis.

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Incidence of Adverse Psychiatric Events During Treatment of Inflammatory Bowel Disease With Biologic Therapies: A Systematic Review

Crohn's & Colitis 360 ◽

10.1093/crocol/otz053 ◽

2019 ◽

Vol 2 (1) ◽

Author(s):

Avni Jain ◽

Ruth Ann Marrie ◽

Leigh Anne Shafer ◽

Lesley A Graff ◽

Scott B Patten ◽

...

Keyword(s):

Systematic Review ◽

Randomized Controlled Trials ◽

Fixed Effects ◽

Biologic Therapy ◽

Meta Analysis ◽

Risk Difference ◽

Controlled Trials ◽

Randomized Controlled ◽

Inflammatory Bowel ◽

Biologic Medication

Abstract We conducted a systematic review and a fixed-effects meta-analysis to determine whether incident adverse psychiatric events (APE) including depression, anxiety, psychosis, or suicide were associated with biologic therapy in IBD. Six randomized controlled trials and a cohort study met criteria, reporting an incidence of APE in 4,882 patients. The risk difference per 100 person-months of any APE with a biologic medication was 0.01 (95% confidence interval = 0.00–0.02). There was insufficient evidence available in randomized controlled trials to conclude that biologic therapy in IBD is associated with an increased incidence of APE.

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Role of preoperative intravenous iron therapy to correct anemia before major surgery: a systematic review and meta-analysis

Systematic Reviews ◽

10.1186/s13643-021-01579-8 ◽

2021 ◽

Vol 10 (1) ◽

Author(s):

Abdelsalam M. Elhenawy ◽

Steven R. Meyer ◽

Sean M. Bagshaw ◽

Roderick G. MacArthur ◽

Linda J. Carroll

Keyword(s):

Randomized Controlled Trials ◽

Iron Supplementation ◽

Controlled Trial ◽

Meta Analysis ◽

Intravenous Iron ◽

Major Surgery ◽

Controlled Trials ◽

Blood Transfusions ◽

Randomized Controlled ◽

Iv Iron

Abstract Background Preoperative anemia is a common comorbidity that often necessitates allogeneic blood transfusion (ABT). As there is a risk associated with blood transfusions, preoperative intravenous iron (IV) has been proposed to increase the hemoglobin to reduce perioperative transfusion; however, randomized controlled trials (RCT) investigating this efficacy for IV iron are small, limited, and inconclusive. Consequently, a meta-analysis that pools these studies may provide new and clinically useful information. Methods/design Databases of MEDLINE, EMBASE, EBM Reviews; Cochrane-controlled trial registry; Scopus; registries of health technology assessment and clinical trials; Web of Science; ProQuest Dissertations and Theses; Clinicaltrials.gov; and Conference Proceedings Citation Index-Science (CPCI-S) were searched. Also, we screened all the retrieved reference lists. Selection criteria Titles and abstracts were screened for relevance (i.e., relevant, irrelevant, or potentially relevant). Then, we screened full texts of those citations identified as potentially applicable. Results Our search found 3195 citations and ten RCTs (1039 participants) that met our inclusion criteria. Preoperative IV iron supplementation significantly decreases ABT by 16% (risk ratio (RR): 0.84, 95% confidence interval [CI]: 0.71, 0.99, p = 0.04). In addition, preoperatively, hemoglobin levels increased after receiving IV iron (mean difference [MD] between the study groups: 7.15 g/L, 95% CI: 2.26, 12.04 g/L, p = 0.004) and at follow-up > 4 weeks postoperatively (MD: 6.46 g/L, 95% CI: 3.10, 9.81, p = 0.0002). Iron injection was not associated with increased incidence of non-serious or serious adverse effects across groups (RR: 1.13, 95% CI: 0.78, 1.65, p = 0.52) and (RR: 0.96, 95% CI: 0.44, 2.10, p = 0.92) respectively. Conclusions With moderate certainty, due to the high risk of bias in some studies in one or two domains, we found intravenous iron supplementation is associated with a significant decrease in the blood transfusions rate, and modest hemoglobin concentrations rise when injected pre-surgery compared with placebo or oral iron supplementation. However, further full-scale randomized controlled trials with robust methodology are required. In particular, the safety, quality of life, and cost-effectiveness of different intravenous iron preparations require further evaluation.

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A Systematic Review and Meta-Analysis of Immune-Related Adverse Events of Anti-PD-1 Drugs in Randomized Controlled Trials

Technology in Cancer Research & Treatment ◽

10.1177/1533033820967454 ◽

2020 ◽

Vol 19 ◽

pp. 153303382096745

Author(s):

Yukun Wang ◽

Dejiu Kong ◽

Chaokun Wang ◽

Jing Chen ◽

Jing Li ◽

...

Keyword(s):

Randomized Controlled Trial ◽

Adverse Events ◽

Randomized Controlled Trials ◽

Controlled Trial ◽

Meta Analysis ◽

Control Group ◽

Controlled Trials ◽

Cochrane Central Register ◽

Targeted Drugs ◽

Randomized Controlled

Objective: We aimed to evaluate immune-related adverse events occurring in clinical trials of anti-programmed cell death 1 (PD-1) drugs, compared with control treatments, including chemotherapy, targeted drugs, or placebo. Further we compared the occurrence of immune -related events in patients treated with different anti-PD-1 drugs. Data Sources: Randomized controlled trial (RCT) data were sourced from PubMed, Embase, and the Cochrane Central Register of Controlled Trials combined with https://clinicaltrials.gov . Methods: Randomized controlled trial of anti-PD-1 drugs compared with control treatments published between January 1, 1970 and March 1,2019, were searched and data on trial patient characteristics, and adverse events extracted, reviewed, and subjected to meta-analysis. Results: Eighteen Randomized controlled trials were included in our study. The Randomized controlled trials compared nivolumab (n = 12), pembrolizumab (n = 6), with chemotherapy (n = 13), targeted drugs (n = 2), or placebo (n = 3). Compared with the control group, the risk of any immune-related adverse events in patients treated with anti-PD-1 drugs was increased (RR, 2.65; 95% confidence interval, 1.84–3.83; P < 0.00001). Of the immune-related adverse events, the risk rates of pneumonitis (risk ratio, 2.10; 95% CI, 0.85-5.18), colitis (2.96;1.62-5.38), hypophysitis(4.79;1.54-14.89), hypothyroidism(7.87;5.36-11.57), hyperthyroidism (7.03;4.35-11.34), rash (1.58;0.98-2.54), pruritus (2.28; 1.38-3.76), and hepatitis (9.31;2.18-39.85) were increased by anti-PD-1 drugs. Further, the risk of immune-related adverse events was similar for patients treated with pembrolizumab and nivolumab ( P = 0.14). Conclusions: In addition to previously reported organ-specific immune-related adverse events, we found that the risk of hyperthyroidism was also increased, in anit-PD-1-treated patients, relative to control treatments. The risk of total immune-related adverse events, was similar for pembrolizumab and nivolumab.

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Effect of reductions in amyloid levels on cognitive change in randomized trials: instrumental variable meta-analysis

BMJ ◽

10.1136/bmj.n156 ◽

2021 ◽

pp. n156 ◽

Cited By ~ 1

Author(s):

Sarah F Ackley ◽

Scott C Zimmerman ◽

Willa D Brenowitz ◽

Eric J Tchetgen Tchetgen ◽

Audra L Gold ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Randomized Controlled Trials ◽

Instrumental Variable ◽

Meta Analysis ◽

Standardized Uptake Value ◽

Cognitive Change ◽

Cognitive Test ◽

Controlled Trials ◽

Randomized Controlled

Abstract Objective To evaluate trials of drugs that target amyloid to determine whether reductions in amyloid levels are likely to improve cognition. Design Instrumental variable meta-analysis. Setting 14 randomized controlled trials of drugs for the prevention or treatment of Alzheimer’s disease that targeted an amyloid mechanism, identified from ClinicalTrials.gov. Population Adults enrolled in randomized controlled trials of amyloid targeting drugs. Inclusion criteria for trials vary, but typically include adults aged 50 years or older with a diagnosis of mild cognitive impairment or Alzheimer’s disease, and amyloid positivity at baseline. Main outcome measures Analyses included trials for which information could be obtained on both change in brain amyloid levels measured with amyloid positron emission tomography and change in at least one cognitive test score reported for each randomization arm. Results Pooled results from the 14 randomized controlled trials were more precise than estimates from any single trial. The pooled estimate for the effect of reducing amyloid levels by 0.1 standardized uptake value ratio units was an improvement in the mini-mental state examination score of 0.03 (95% confidence interval −0.06 to 0.1) points. This study provides a web application that allows for the re-estimation of the results when new data become available and illustrates the magnitude of the new evidence that would be necessary to achieve a pooled estimate supporting the benefit of reducing amyloid levels. Conclusions Pooled evidence from available trials reporting both reduction in amyloid levels and change in cognition suggests that amyloid reduction strategies do not substantially improve cognition.

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The Effects of Exclusively Resistance Training-Based Supervised Programs in People with Depression: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

International Journal of Environmental Research and Public Health ◽

10.3390/ijerph17186715 ◽

2020 ◽

Vol 17 (18) ◽

pp. 6715

Author(s):

Lara Carneiro ◽

José Afonso ◽

Rodrigo Ramirez-Campillo ◽

Eugenia Murawska-Ciałowciz ◽

Adilson Marques ◽

...

Keyword(s):

Depressive Symptoms ◽

Resistance Training ◽

Randomized Controlled Trials ◽

Controlled Trial ◽

Meta Analysis ◽

Cochrane Library ◽

Controlled Trials ◽

Positive Effects ◽

Randomized Controlled ◽

Moderate Effect Size

The purpose of this study was to systematically review the effects of supervised resistance training (RT) programs in people diagnosed with depression or depressive symptoms. The following databases were used to search and retrieve the articles: Cochrane Library, EBSCO, PEDro, PubMed, Scopus and Web of Science. The search was conducted in late June 2020. Search protocol required the title to contain the words depression or depressive or dysthymia. Furthermore, the title, abstract or keywords had to contain the words or expressions: “randomized controlled trial”; and “strength training” or “resistance training” or “resisted training” or “weight training”. The screening provided 136 results. After the removal of duplicates, 70 records remained. Further screening of titles and abstracts resulted in the elimination of 57 papers. Therefore, 13 records were eligible for further scrutiny. Of the 13 records, nine were excluded, and the final sample consisted of four articles. Results were highly heterogeneous, with half of the studies showing positive effects of resistance training and half showing no effects. In two of the four combinations, the meta-analysis revealed significant benefits of RT in improving depressive symptoms (p ≤ 0.05). However, considering significant differences with moderate (Effect Size = 0.62) and small (ES = 0.53) effects, the heterogeneity was above 50%, thus suggesting a substantial level. To draw meaningful conclusions, future well-designed randomized controlled trials (RCTs) are needed that focus on understudied RT as a treatment for depression.

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Pre-operative iron allows correction of anaemia before abdominal surgery: A systematic review and meta-analysis of randomized controlled trials

British Journal of Surgery ◽

10.1093/bjs/znab202.011 ◽

2021 ◽

Vol 108 (Supplement_4) ◽

Author(s):

J Meyer ◽

R Cirocchi ◽

S Di Saverio ◽

F Ris ◽

J Wheeler ◽

...

Keyword(s):

Blood Transfusion ◽

Abdominal Surgery ◽

Randomized Controlled Trials ◽

Meta Analysis ◽

Haemoglobin Concentration ◽

Poor Quality ◽

Risk Difference ◽

Major Abdominal Surgery ◽

Controlled Trials ◽

Randomized Controlled

Abstract Objective Professional surgical societies recommend the identification and treatment of pre-operative anaemia in patients scheduled for abdominal surgery. However, the evidence supporting this recommendation has been of poor quality until the recent release of several randomized controlled trials (RCT) addressing the question. Our aim was to determine if pre-operative iron allows correction of haemoglobin concentration and decreased incidence of peri-operative blood transfusion in patients undergoing major abdominal surgery. Methods MEDLINE, Embase and CENTRAL were searched for RCTs written in English and assessing the effect of pre-operative iron on the incidence of peri-operative allogeneic blood transfusion in patients undergoing major abdominal surgery. Pooled relative risk (RR), risk difference (RD) and mean difference (MD) were obtained using models with random effects. Heterogeneity was assessed using the Q-test and quantified using the I2 value. Results Four RCTs were retained for analysis out of 285 eligible articles. MD in haemoglobin concentration between patients with pre-operative iron and patients without pre-operative iron was of 0.81 g/dl (3 RCTs, 95% CI: 0.30 to 1.33, I2: 60%, p = 0.002). Pre-operative iron did not lead to reduction in the incidence of peri-operative blood transfusion in terms of RD (4 RCTs, RD: -0.13, 95% CI: -0.27 to 0.01, I2: 65%, p = 0.07) or RR (4 RCTs, RR: 0.57, 95% CI: 0.30 to 1.09, I2: 64%, p = 0.09). Conclusion Pre-operative iron significantly increases haemoglobin concentration by 0.81 g/dl before abdominal surgery but does not reduce the need for peri-operative blood transfusion. Important heterogeneity exists between existing RCTs in terms of populations and interventions. Future trials should target patients suffering from iron-deficiency anaemia and assess the effect of intervention on anaemia-related complications.

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