MO256THE TREATMENT EFFECT OF RAS BLOCKADE ON PROTEINURIA IN IGA NEPHROPATHY PATIENTS AS A SURROGATE FOR RENAL EVENTS AND DECLINE IN EGFR: AN ANALYSIS OF RANDOMIZED CONTROLLED TRIALS

Abstract Background and Aims Renin-Angiotensin System Blockade (RASB) is the cornerstone of standard-of-care in IgA nephropathy. Randomized controlled trials (RCTs) have shown the treatment benefit of RASB therapy on proteinuria and risk of renal failure. The objective of this study was to describe the relationships between the treatment effect of RASB on proteinuria and (i) risk of renal events, and (ii) decline in eGFR, as an endpoint proximal to renal failure. To this aim, trial level (TL) and simple weighted linear regression (SWR) analyses were conducted on RCTs identified through a systematic literature review, with RASB as the active intervention. Methods A systematic literature review of available peer-reviewed literature from 1990 to 2020 was performed applying the following inclusion criteria: RCT in patients with biopsy-proven IgAN, investigating the effects of RASB as an intervention, sample size >25, measurement of proteinuria at baseline and at >3 months. At least 1 renal event (defined as ≥50% decline in eGFR, CKD Stage 5, dialysis or transplantation) was required for the renal event analysis and similarly, at least 12 months follow-up was required for the decline in eGFR analysis. For the relationship between proteinuria and risk of renal events, 4 studies including 5 comparisons were identified, while 9 studies including 10 comparisons were identified for the analysis of proteinuria vs eGFR decline. Proteinuria change from baseline was calculated from the value closest to 6 months. If annualized change in eGFR was reported, these data were used, otherwise annualized change in eGFR was calculated per year of follow-up. Methods as described by Burzykoski & Buyse (2006) and Joffe & Greene (2008) were used for TL meta-regression analyses; the resulting meta-regression line was displayed with an 80% credible interval band (CB). Given the assumptions made in this analysis, a SWR analysis was also performed; to compensate for potential underestimation of error associated with the regression line, a 99.9% CB was applied in the SWR analysis. Results For RASB treatment effects on renal events, a statistical association was found with treatment effects on proteinuria with a TL slope estimate = 15.30 95% CI (0.57, 38.79), R2 = 0.88 95% CI (0.22, 1.00); using the lower CI of 0.75 for the estimated slope, a 30% treatment effect on proteinuria would be expected to result in at least a 25% reduction in the risk of renal events. As individual subject level data were not available, the correlation between errors on treatment effects for proteinuria and treatment effects for renal events were unknown, resulting in a wide CB on the meta-regression line and a wide CI for the slope estimate. The SWR approach is not hampered by lack of subject level data and gave a slope estimate of 3.5 95% CI (2.1, 5.0) with R2 = 0.97, such that a 30% treatment effect on proteinuria would be expected to result in at least a 64% reduction in the risk of renal events. For treatment effects on annualized eGFR versus effects on proteinuria, the TL slope estimate was -5.1 95% CI (-30.2, 35.0), R2 = 0.89 95% CI (0.15, 1.00); the corresponding SWR slope estimate was -7.6, 95% CI (-12.3, -2.8) with R2 = 0.71. A 30% treatment effect on proteinuria would be expected to result in a 2.6 mL/min (TL analysis) to 3.9 mL/min slower decline (SWR analysis) in annualized eGFR. Conclusion In patients with IgAN, associations were seen between treatment effects of RASB on proteinuria and on the clinically relevant endpoints of renal events and annualized change in eGFR. Consistent with TL analyses of RCTs across a variety of mechanisms of actions, these data, specific to RASB, contribute to the growing evidence base supporting the use of proteinuria as a valid surrogate endpoint in IgAN.

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Blinding, sham, and treatment effects in randomized controlled trials for back pain in 2000–2019: A review and meta-analytic approach

Clinical Trials ◽

10.1177/1740774520984870 ◽

2021 ◽

pp. 174077452098487

Author(s):

Brian Freed ◽

Brian Williams ◽

Xiaolu Situ ◽

Victoria Landsman ◽

Jeehyoung Kim ◽

...

Keyword(s):

Back Pain ◽

Active Treatment ◽

Treatment Effect ◽

Effect Size ◽

Treatment Effects ◽

Effect Sizes ◽

Controlled Trials ◽

Sham Treatment ◽

Randomized Controlled ◽

Random Guess

Background: Blinding aims to minimize biases from what participants and investigators know or believe. Randomized controlled trials, despite being the gold standard to evaluate treatment effect, do not generally assess the success of blinding. We investigated the extent of blinding in back pain trials and the associations between participant guesses and treatment effects. Methods: We did a review with PubMed/OvidMedline, 2000–2019. Eligibility criteria were back pain trials with data available on treatment effect and participants’ guess of treatment. For blinding, blinding index was used as chance-corrected measure of excessive correct guess (0 for random guess). For treatment effects, within- or between-arm effect sizes were used. Analyses of investigators’ guess/blinding or by treatment modality were performed exploratorily. Results: Forty trials (3899 participants) were included. Active and sham treatment groups had mean blinding index of 0.26 (95% confidence interval: 0.12, 0.41) and 0.01 (−0.11, 0.14), respectively, meaning 26% of participants in active treatment believed they received active treatment, whereas only 1% in sham believed they received sham treatment, beyond chance, that is, random guess. A greater belief of receiving active treatment was associated with a larger within-arm effect size in both arms, and ideal blinding (namely, “random guess,” and “wishful thinking” that signifies both groups believing they received active treatment) showed smaller effect sizes, with correlation of effect size and summary blinding indexes of 0.35 ( p = 0.028) for between-arm comparison. We observed uniformly large sham treatment effects for all modalities, and larger correlation for investigator’s (un)blinding, 0.53 ( p = 0.046). Conclusion: Participants in active treatments in back pain trials guessed treatment identity more correctly, while those in sham treatments tended to display successful blinding. Excessive correct guesses (that could reflect weaker blinding and/or noticeable effects) by participants and investigators demonstrated larger effect sizes. Blinding and sham treatment effects on back pain need due consideration in individual trials and meta-analyses.

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Exercise therapy for sarcopenia in rheumatoid arthritis: A meta-analysis and meta-regression of randomized controlled trials

Clinical Rehabilitation ◽

10.1177/02692155211035539 ◽

2021 ◽

pp. 026921552110355

Author(s):

Chun-De Liao ◽

Hung-Chou Chen ◽

Shih-Wei Huang ◽

Tsan-Hon Liou

Keyword(s):

Rheumatoid Arthritis ◽

Randomized Controlled Trials ◽

Muscle Mass ◽

Exercise Therapy ◽

Treatment Effects ◽

Meta Analysis ◽

Controlled Trials ◽

Regression Analyses ◽

Randomized Controlled ◽

Meta Regression

Objective: Rheumatoid arthritis and age are associated with high sarcopenia risk. Exercise is an effective treatment for preventing muscle mass loss in older adult populations. It remains unclear whether exercise affects muscle mass in people with rheumatoid arthritis. Thus, this meta-analysis investigated the effect of exercise on muscle mass gain in patients with rheumatoid arthritis. Data sources: PubMed, EMBASE, the Cochrane Library, the Physiotherapy Evidence Database (PEDro), the China Knowledge Resource Integrated Database, and Google Scholar were systematically searched until June 2021. Methods: The present study was conducted according to the guidelines recommended by the Preferred Reporting Items for Systematic Reviews and Meta-Analysis. Randomized controlled trials (RCTs) that reported the effects of exercise on muscle mass for rheumatoid arthritis were identified. The included RCTs were subject to meta-analysis and risk of bias assessment. Subgroup and random-effects meta-regression analyses were performed to identify any heterogeneity ( I2) of treatment effects across studies. Results: We included nine RCTs with a median PEDro score of 6/10 (range: 4/10–8/10). The weighted mean effect size for muscle mass was 0.77 (95% CI: 0.30–1.24; P = 0.001; I2 = 77%). Meta-regression analyses indicated that the disease duration significantly explained variance of treatment effects across studies (β = −0.006, R2 = 69.7%, P = 0.005). Conclusions: Exercise therapy effectively increased muscle mass in patients with rheumatoid arthritis. Treatment effects may be attenuated in those who have had rheumatoid arthritis for a relatively long time.

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Treatment outcomes for anorexia nervosa: a systematic review and meta-analysis of randomized controlled trials

Psychological Medicine ◽

10.1017/s0033291718002088 ◽

2018 ◽

Vol 49 (4) ◽

pp. 535-544 ◽

Cited By ~ 40

Author(s):

Stuart B. Murray ◽

Daniel S. Quintana ◽

Katharine L. Loeb ◽

Scott Griffiths ◽

Daniel Le Grange

Keyword(s):

Anorexia Nervosa ◽

Treatment Effect ◽

Psychological Symptoms ◽

Risk Of Bias ◽

Controlled Trials ◽

Significant Treatment Effect ◽

Significant Treatment ◽

Randomized Controlled ◽

Meta Analyses

AbstractBackgroundTo determine the impact of specialized treatments, relative to comparator treatments, upon the weight and psychological symptoms of anorexia nervosa (AN) at end-of-treatment (EOT) and follow-up.MethodsRandomized controlled trials (RCTs) between January 1980 and December 2017 that reported the effects of at least two treatments on AN were screened. Weight and psychological symptoms were analyzed separately for each study. PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines were followed, and studies were assessed using the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) criteria and Cochrane risk of bias tool.ResultsWe identified 35 eligible RCTs, comprising data from 2524 patients. Meta-analyses revealed a significant treatment effect on weight outcomes at EOT [g= 0.16, 95% CI (0.05–0.28),p= 0.006], but not at follow-up [g= 0.11, 95% CI (−0.04 to 0.27),p= 0.15]. There was no significant treatment effect on psychological outcomes at either EOT [g= −0.03, 95% CI (−0.14 to 0.08),p= 0.63], or follow-up [g= −0.001, 95% CI (−0.11 to 0.11),p= 0.98]. There was no strong evidence of publication bias or significant moderator effects for illness duration, mean age, year of publication, comparator group category, or risk of bias (allpvalues > 0.05).ConclusionsCurrent specialized treatments are more adept than comparator interventions at imparting change in weight-based AN symptoms at EOT, but not at follow-up. Specialized treatments confer no advantage over comparator interventions in terms of psychological symptoms. Future precision treatment efforts require a specific focus on the psychological symptoms of AN.

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The Effect of Partly Missing Covariates on Statistical Power in Randomized Controlled Trials With Discrete-Time Survival Endpoints

Methodology ◽

10.1027/1614-2241/a000121 ◽

2017 ◽

Vol 13 (2) ◽

pp. 41-60

Author(s):

Shahab Jolani ◽

Maryam Safarkhani

Keyword(s):

Randomized Controlled Trials ◽

Discrete Time ◽

Treatment Effect ◽

Survival Data ◽

Controlled Trials ◽

Missing Covariates ◽

Indicator Method ◽

Imputation Methods ◽

Randomized Controlled ◽

Baseline Covariates

Abstract. In randomized controlled trials (RCTs), a common strategy to increase power to detect a treatment effect is adjustment for baseline covariates. However, adjustment with partly missing covariates, where complete cases are only used, is inefficient. We consider different alternatives in trials with discrete-time survival data, where subjects are measured in discrete-time intervals while they may experience an event at any point in time. The results of a Monte Carlo simulation study, as well as a case study of randomized trials in smokers with attention deficit hyperactivity disorder (ADHD), indicated that single and multiple imputation methods outperform the other methods and increase precision in estimating the treatment effect. Missing indicator method, which uses a dummy variable in the statistical model to indicate whether the value for that variable is missing and sets the same value to all missing values, is comparable to imputation methods. Nevertheless, the power level to detect the treatment effect based on missing indicator method is marginally lower than the imputation methods, particularly when the missingness depends on the outcome. In conclusion, it appears that imputation of partly missing (baseline) covariates should be preferred in the analysis of discrete-time survival data.

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Faculty Opinions recommendation of Between-centre differences and treatment effects in randomized controlled trials: a case study in traumatic brain injury.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.13360103.14730254 ◽

2011 ◽

Author(s):

Nicole Gabler

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Randomized Controlled Trials ◽

Treatment Effects ◽

Controlled Trials ◽

Randomized Controlled

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Time to onset of cannabidiol (CBD) treatment effect in Lennox–Gastaut syndrome: Analysis from two randomized controlled trials

Epilepsia ◽

10.1111/epi.16878 ◽

2021 ◽

Author(s):

Michael Privitera ◽

Hari Bhathal ◽

Matthew Wong ◽

J. Helen Cross ◽

Elaine Wirrell ◽

...

Keyword(s):

Randomized Controlled Trials ◽

Treatment Effect ◽

Controlled Trials ◽

Randomized Controlled ◽

Time To Onset ◽

Syndrome Analysis

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Time to onset of cannabidiol treatment effects in Dravet syndrome: Analysis from two randomized controlled trials

Epilepsia ◽

10.1111/epi.16974 ◽

2021 ◽

Author(s):

Jennifer Madan Cohen ◽

Daniel Checketts ◽

Eduardo Dunayevich ◽

Boudewijn Gunning ◽

Ann Hyslop ◽

...

Keyword(s):

Randomized Controlled Trials ◽

Treatment Effects ◽

Dravet Syndrome ◽

Controlled Trials ◽

Randomized Controlled ◽

Time To Onset ◽

Syndrome Analysis

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Conservative oxygen therapy for critically ill patients: a meta-analysis of randomized controlled trials

Journal of Intensive Care ◽

10.1186/s40560-021-00563-7 ◽

2021 ◽

Vol 9 (1) ◽

Author(s):

Xiao-Li Chen ◽

Bei-Lei Zhang ◽

Chang Meng ◽

Hui-Bin Huang ◽

Bin Du

Keyword(s):

Sensitivity Analysis ◽

Randomized Controlled Trials ◽

Critically Ill Patients ◽

Oxygen Therapy ◽

Primary Outcome ◽

Meta Analysis ◽

Controlled Trials ◽

Icu Patients ◽

Randomized Controlled

Abstract Objective Conservative oxygen strategy is recommended in acute illness while its benefit in ICU patients remains controversial. Therefore, we sought to conduct a systematic review and meta-analysis to examine such oxygen strategies’ effect and safety in ICU patients. Methods We searched PubMed, Embase, and the Cochrane database from inception to Feb 15, 2021. Randomized controlled trials (RCTs) that compared a conservative oxygen strategy to a conventional strategy in critically ill patients were included. Results were expressed as mean difference (MD) and risk ratio (RR) with a 95% confidence interval (CI). The primary outcome was the longest follow-up mortality. Heterogeneity, sensitivity analysis, and publication bias were also investigated to test the robustness of the primary outcome. Results We included seven trials with a total of 5265 patients. In general, the conventional group had significantly higher SpO2 or PaO2 than that in the conservative group. No statistically significant differences were found in the longest follow-up mortality (RR, 1.03; 95% CI, 0.97–1.10; I2=18%; P=0.34) between the two oxygen strategies when pooling studies enrolling subjects with various degrees of hypoxemia. Further sensitivity analysis showed that ICU patients with mild-to-moderate hypoxemia (PaO2/FiO2 >100 mmHg) had significantly lower mortality (RR, 1.24; 95% CI, 1.05–1.46; I2=0%; P=0.01) when receiving conservative oxygen therapy. These findings were also confirmed in other study periods. Additional, secondary outcomes of the duration of mechanical ventilation, the length of stay in the ICU and hospital, change in sequential organ failure assessment score, and adverse events were comparable between the two strategies. Conclusions Our findings indicate that conservative oxygen therapy strategy did not improve the prognosis of the overall ICU patients. The subgroup of ICU patients with mild to moderate hypoxemia might obtain prognosis benefit from such a strategy without affecting other critical clinical results.

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Inverted internal limiting membrane flap technique versus internal limiting membrane peeling for large macular holes: A meta-analysis of randomized controlled trials

Ophthalmic Research ◽

10.1159/000515283 ◽

2021 ◽

Author(s):

Ji-Guo Yu ◽

Jing Wang ◽

Yi Xiang

Keyword(s):

Randomized Controlled Trials ◽

Meta Analysis ◽

Internal Limiting Membrane ◽

Controlled Trials ◽

Ilm Peeling ◽

Closure Rate ◽

Flap Technique ◽

Randomized Controlled ◽

Macular Holes

Background: Vitrectomy with internal limiting membrane (ILM) peeling is an effective surgical procedure for the treatment of macular holes (MHs). However, there is a possibility of poor postoperative anatomical closure with conventional ILM peeling for MHs larger than 400 μm. Therefore, a novel inverted ILM flap technique was developed for such cases. Objectives: This meta-analysis study was performed to evaluate and compare the anatomical and visual outcomes of the inverted ILM flap technique and ILM peeling in large MHs. Methods: The Cochrane Library, PubMed, and Embase databases were searched to identify randomized controlled trials (RCTs). The trial eligibility and risk of bias were assessed according to Cochrane review methods. The primary outcome measures included MH closure rate and postoperative visual acuity (VA). Subgroup analysis of postoperative VA based on follow-up time was also conducted. Pooled odds ratios (ORs), weighted mean difference (WMD), and 95% confidence intervals (CIs) were calculated. Statistical analysis was performed using RevMan 5.3 software. Results: Five RCTs with a total of 155 eyes in the inverted ILM flap group and 161 eyes in the ILM peeling group were included in this meta-analysis. Statistical meta-analysis revealed that the overall MH closure rate in the inverted ILM flap group was significantly higher than that in the ILM peeling group (OR, 3.10; 95% CI, 1.25 to 7.66; P = 0.01). The postoperative VA was significantly better in the inverted ILM flap group than ILM peeling group (WMD, -0.14; 95% CI, -0.21 to -0.07; P = 0.0002). The subgroup meta-analysis indicated that the postoperative VA was significantly better in the inverted ILM flap group than ILM peeling group (WMD, -0.17; 95% CI, -0.26 to -0.08; P = 0.0004) at the 3-month follow-up. However, no significant difference was observed between the two groups at the 6-month follow-up (WMD, -0.09; 95% CI, -0.20 to 0.02; P = 0.10). Conclusions: Vitrectomy with inverted ILM flap technique showed a higher anatomical closure rate as well as visual gain—although only in the short-term as no difference in visual recovery was found at the 6-month follow-up—than did ILM peeling in large MHs. The inverted ILM flap technique should be considered as a preferred and routine procedure for the treatment of patients with MHs larger than 400 µm.

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