Evaluating Mortality with Erythropoietic Stimulating Agents (ESAs) in the Nephrology Setting: The Distinction between Evaluating Trials That Measure Survival as a Primary or Secondary Efficacy Endpoint Versus a Safety Endpoint.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 962-962
Author(s):  
Sara E. Barnato ◽  
Charles L. Bennett ◽  
Kathleen Elverman ◽  
Dennis P. West ◽  
Mark Courtney
Keyword(s):  
Clinical Trials ◽  
Relative Risk ◽  
Randomized Trials ◽  
Randomized Clinical Trials ◽  
Outcome Measure ◽  
Meta Analysis ◽  
Safety Measure ◽  
Significant Safety ◽  
Randomized Controlled ◽  
Efficacy Outcome

Abstract Background: At ASCO 2007, we reported increased mortality risks when ESAs are administered to anemic cancer patients who are receiving chemotherapy when target hemoglobin levels are beyond the correction of anemia. In February 2007, a meta-analysis of nine randomized clinical trials with 5,143 patients published in the Lancet [vol 369; 381–88] identified a statistically significant risk of all cause mortality (relative risk (RR) of 1.17, 95% confidence interval (CI) 1.01, 1.35) when anemic patients with chronic kidney disease received ESAs targeted to higher hemoglobin concentrations (120–150 g/L). A recent report from the RADAR (Research against Adverse Drug Reactions) group raises concern that survival analyses might differ depending on whether survival was evaluated as a measure of efficacy versus a measure of safety. Herein, we re-analyze the data by evaluating randomized clinical trials according to whether or not survival was prospectively included as a primary or secondary efficacy outcome. Methods: Risks of death in randomized controlled clinical trials included in the Lancet meta-analysis were evaluated. We classified those studies based on their mortality outcomes, either as an efficacy outcome or as a safety outcome. Effect estimates for RR and 95% CI were derived from Stata (version 9.1, College Station, TX), calculated with random-effects models and pooled by use of the Dersimonian and Laird method. Results: In studies where survival was measured as an efficacy endpoint, the relative risk of mortality with ESAs targeted to higher hemoglobin levels was 1.27 (1.08, 1.49), a number greater than the relative risk reported in the Lancet meta-analysis. Conclusions: Randomized controlled trials should be included in meta-analyses that evaluate harms only if the relevant safety measure is prospectively included as a primary or secondary efficacy outcome measure in the study protocol. When survival was included as part of the efficacy analysis, a statistically significant safety signal was present. Randomized trials that included harms as a measure of safety did not present a statistically significant safety signal. Including randomized trials that include harms as a safety measure introduce noise and can mask safety signals. Studies: Events: RR (95% CI) Survival included as a primary or secondary efficacy outcome measure: High vs Low Hb Target: Besarab 1998 (n=1233) 183/618 vs 150/615 1.21 (1.01, 1.46) Gouva 2004 (n=88) 4/43 vs 3/45 1.40 (0.33, 5.87) Drueke 2006 (n=602) 31/300 vs 21/302 1.49 (0.87, 2.53) Singh 2006 (n=1432) 52/715 vs 36/717 1.45 (0.96, 2.19) Subtotal (n=3355) 270/1676 vs 210/1679 1.27 (1.08, 1.49) Survival included only as a safety measure: High vs Low Hb Target: Foley 2000 (n=146) 4/73 vs 3/73 1.33 (0.31, 5.75) Furuland 2003 (n=416) 29/216 vs 27/200 0.99 (0.61, 1.62) Roger 2005 (n=154) 0/75 vs 0/79 not estimable Levin 2005 (n=152) 1/74 vs 3/78 0.35 (0.04, 3.30) Parfrey 2005 (n=696) 12/396 vs 20/300 0.45 (0.23, 0.92) Rossert 2006 (n=390) 1/195 vs 6/195 0.17 (0.02, 1.37) Subtotal (n=1954) 47/1029 vs 59/925 0.67 (0.37, 1.19)

scholarly journals Comparing The Efficacy of Anti-Infectious Drugs For The Treatment of Mild To Severe COVID-19 Patients: A Protocol For A Systematic Review And Network Meta-Analysis of Randomized Clinical Trials.

2021 ◽  
Author(s):  
Dejene Tolossa Debela ◽  
Kidist Digamo Heraro ◽  
Abebaw Fekadu ◽  
Merga Belina ◽  
Tsegahun Manyazewal
Keyword(s):  
Systematic Review ◽  
Clinical Trials ◽  
English Language ◽  
Randomized Clinical Trials ◽  
Meta Analysis ◽  
Antiviral Drug ◽  
Standard Of Care ◽  
Randomized Controlled ◽  
Primary Endpoints ◽  
Independent Review

Abstract Background: COVID-19 is a viral infection spreading at a great speed and has quickly caused an extensive burden to individuals, families, countries, and the world. No intervention has yet been proven highly effective for the treatment of COVID-19. Different drugs were being evaluated and reported through randomized clinical trials, and more are currently under trial. This review aimed to compare the efficacy of anti-infectious drugs with a comparator of the standard of care or placebo in patients with COVID-19.Methods: Two independent review authors will extract data and assess a risk of bias using RoB2. Randomized controlled trials (RCT) that evaluate single and/or combined antiviral drugs recommended by WHO latest guideline for the treatment of COVID-19 will be included. We will search for Pub Med, the Cochrane Center for Clinical Trial database (CENTRAL), clinicaltrials.gov, etc. databases for articles published in the English language between December 2019 to April 2021. We will follow the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P) involving Network Meta-analysis guidelines to design and report of the results. The primary endpoints will be time to clinical recovery and time to RNA negativity. The certainty of evidence will be evaluated using the GRADE extension of NMA. Data analysis will be performed using the frequentist NMA approach with the netmeta package implemented in R.Discussion: This review will reveal the best antiviral drug treatment for covid-19 and show the hierarchy of those drugs.Systematic review registration: The protocol was registered on PROSPERO with ID number CRD42021230919

scholarly journals Randomized Controlled Trials of Early Ambulatory Hydroxychloroquine in the Prevention of COVID-19 Infection, Hospitalization, and Death: Meta-Analysis

2020 ◽  
Author(s):  
Joseph A. Ladapo ◽  
John E. McKinnon ◽  
Peter A. McCullough ◽  
Harvey Risch
Keyword(s):  
Systematic Review ◽  
Clinical Trials ◽  
Side Effects ◽  
Fixed Effects ◽  
Randomized Clinical Trials ◽  
Meta Analysis ◽  
Controlled Trials ◽  
Cochrane Central Register ◽  
Randomized Controlled ◽  
Exposure Prophylaxis

Objective--To determine if hydroxychloroquine (HCQ) reduces the incidence of new illness, hospitalization or death among outpatients at risk for or infected with SARS-CoV-2 (COVID-19). Design--Systematic review and meta-analysis of randomized clinical trials. Data sources--Search of MEDLINE, EMBASE, PubMed, medRxiv, PROSPERO, and the Cochrane Central Register of Controlled Trials. Also review of reference lists from recent meta-analyses. Study selection--Randomized clinical trials in which participants were treated with HCQ or placebo/standard-of-care for pre-exposure prophylaxis, post-exposure prophylaxis, or outpatient therapy for COVID-19. Methods--Two investigators independently extracted data on trial design and outcomes. Medication side effects and adverse reactions were also assessed. The primary outcome was COVID-19 hospitalization or death. When unavailable, new COVID-19 infection was used. We calculated random effects meta-analysis according to the method of DerSimonian and Laird. Heterogeneity between the studies was evaluated by calculation of Cochran Q and I2 parameters. An Egger funnel plot was drawn to investigate publication bias. We also calculated the fixed effects meta-analysis summary of the five studies. All calculations were done in Excel, and results were considered to be statistically significant at a two-sided threshold of P=.05. Results--Five randomized controlled clinical trials enrolling 5,577 patients were included. HCQ was associated with a 24% reduction in COVID-19 infection, hospitalization or death, P=.025 (RR, 0.76 [95% CI, 0.59 to 0.97]). No serious adverse cardiac events were reported. The most common side effects were gastrointestinal. Conclusion--Hydroxychloroquine use in outpatients reduces the incidence of the composite outcome of COVID-19 infection, hospitalization, and death. Serious adverse events were not reported and cardiac arrhythmia was rare. Systematic review registration--This review was not registered.

Efficacy and Tolerability of Prostaglandin-Timolol Fixed Combinations: A Meta-Analysis of Randomized Clinical Trials

2011 ◽  
Vol 22 (1) ◽  
pp. 5-18 ◽  
Author(s):  
Florent Aptel ◽  
Michel Cucherat ◽  
Philippe Denis
Keyword(s):  
Clinical Trials ◽  
Intraocular Pressure ◽  
Relative Risk ◽  
Randomized Clinical Trials ◽  
Meta Analysis ◽  
Conjunctival Hyperemia ◽  
Time Points ◽  
Curve Change ◽  
The Mean ◽  
The Individual

Purpose To evaluate the intraocular pressure (IOP)-lowering effects and tolerability of the 3 prostaglandin-timolol fixed combinations (PG-timolol FCs). Methods Clinical trials comparing directly the PG-timolol FCs or comparing the PG-timolol FCs to their individual components were thoroughly searched. The main outcome measures were efficacy assessed by IOP (taken at 9 AM, noon, 4 PM, and over the mean diurnal curve) change at 3 months (or after 1 to 6 months of treatment if no data were available at month 3) from baseline and tolerability assessed by the incidence of conjunctival hyperemia. Results Twenty trials were identified (n=4684 patients). Intraocular pressure reduction was usually greater with the 3 PG-timolol FCs than the individual PG (mean difference [MD] 0.00 mmHg to 2.59 mmHg; p>0.1 to p<0.001). The incidence of hyperemia was significantly less with latanoprost- and bimatoprost-timolol FCs than with the individual PG (relative risk = 0.66 and 0.61; p=0.05 and p<0.001). From direct comparisons, IOP reduction was significantly greatest with bimatoprost-timolol FC, at 9 AM, 4 PM, and over the mean diurnal curve compared to latanoprost-timolol FC (MD = 0.90 mmHg to 1.48 mmHg; p<0.001) and at all time points compared to travoprost-timolol FC (MD = 0.66 mmHg to 0.90 mmHg; p<0.001). The incidence of hyperemia was not significantly less with latanoprost-timolol FC than with bimatoprost-timolol FC (relative risk = 1.32; p>0.1). Conclusions The 3 PG-timolol FCs provide a greater IOP reduction and lower incidence of hyperemia than the 3 PGs alone. The direct comparisons suggest a greater efficacy of the bimatoprost-timolol FC compared with latanoprost- and travoprost-timolol FCs.

scholarly journals Effectiveness of Educational Intervention on Influenza Vaccine Uptake: A Meta-Analysis of Randomized Controlled Trials

2020 ◽  
Author(s):  
Xiaoju ZHOU ◽  
Xuequn ZHAO ◽  
Jun LIU ◽  
Wenjie YANG
Keyword(s):  
Clinical Trials ◽  
Influenza Vaccine ◽  
Publication Bias ◽  
Uptake Rate ◽  
Randomized Clinical Trials ◽  
Meta Analysis ◽  
Intervention Group ◽  
Vaccine Uptake ◽  
Controlled Trials ◽  
Randomized Controlled

Background: This study aimed to explore effective education method to improve influenza vaccine uptake rate. Methods: Meta-analysis of Randomized Clinical Trials was conducted in this study including subgroup analysis and publication bias test. Electronic databases comprised PubMed, EBSCO, Elsevier, Springer, Wiley, and Cochrane were searched for studies published up to Oct 8, 2019. Results: Influenza vaccination was significantly different in massages or letters intervention group (OR=1.30, 95%CI: 1.05-1.61). No heterogeneity and publication bias existed in this meta-analysis (I 2=43.60%, P=0.131, Pbegg =0.754, Pegger=0.051). Conclusion: Education by messages and letters was effective according to this study. Education messages could be more efficacy combined with easer vaccine access.

Lipid-Lowering Therapy and Hemorrhagic Stroke Risk: Comparative Meta-Analysis of Statins and PCSK9 Inhibitors

Stroke ◽  
2021 ◽  
Author(s):  
Borja E. Sanz-Cuesta ◽  
Jeffrey L. Saver
Keyword(s):  
Clinical Trials ◽  
Ischemic Stroke ◽  
Relative Risk ◽  
Transient Ischemic Attack ◽  
Hemorrhagic Stroke ◽  
Randomized Clinical Trials ◽  
Meta Analysis ◽  
Lipid Lowering ◽  
Medication Dose ◽  
Ischemic Attack

Background and Purpose: Statins were shown to increase hemorrhagic stroke (HS) in patients with a first cerebrovascular event in 2006 (SPARCL), likely due to off-target antithrombotic effects, but continued to sometimes be used in patients with elevated HS risk due to absence of alternative medications. Recently, the PCSK9Is (proprotein convertase subtilisin kexin 9 inhibitors) have become available as a potent lipid-lowering class with potentially less hemorrhagic propensity. Methods: We performed a systematic comparative meta-analysis assessing HS rates across all completed statin and PCSK9I randomized clinical trials with treatment >3 months, following PRISMA guidelines. In addition to HS rates across all trials, causal relation was probed by evaluating for dose-response relationships by medication (low versus high medication dose/potency) and by presence and type of preceding brain vascular events at inception (none versus ischemic stroke/transient ischemic attack versus HS). Results: The systematic review identified 36 statin randomized clinical trials (204 918 patients) and 5 PCSK9I randomized clinical trials (76 140 patients). Across all patient types and all medication doses/potencies, statins were associated with increased HS: relative risk 1.15, P =0.04; PCSK9Is were not ( P =0.77). In the medication dose/potency analysis, higher dose/potency statins (7 trials, 62 204 patients) were associated with magnified HS risk: relative risk, 1.53; P =0.002; higher dose/potency PCSK9Is (1 trial, 27 564 patients) were not ( P =0.99). In the type of index brain vascular injury analysis for statins (5 trials, 9772 patients), prior ischemic stroke/transient ischemic attack was associated with a magnified risk of HS: relative risk, 1.43; P =0.04; and index intracerebral hemorrhage was associated with an extremely high effect estimate of risk of recurrent HS: hazard ratio, 4.06. For PCSK9Is, prior ischemic stroke/transient ischemic attack (1 trial, 5337 patients) was not associated with increased HS risk ( P =0.97). Conclusions: Statins increase the risk of HS in a medication dose- and type of index brain vascular injury-dependent manner; PCSK9Is do not increase HS risk. PCSK9Is may be a preferred lipid-lowering medication class in patients with elevated HS risk, including patients with prior HS.

scholarly journals Glucagon-Like Peptide-1 Receptor Agonists and Cardiovascular Events: A Meta-Analysis of Randomized Clinical Trials

2011 ◽  
Vol 2011 ◽  
pp. 1-10 ◽  
Author(s):  
Matteo Monami ◽  
Francesco Cremasco ◽  
Caterina Lamanna ◽  
Claudia Colombi ◽  
Carla Maria Desideri ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Cardiovascular Events ◽  
Randomized Trials ◽  
Randomized Clinical Trials ◽  
Meta Analysis ◽  
Diabetic Patients ◽  
Cardiovascular Safety ◽  
Type 2 Diabetic Patients ◽  
Receptor Agonists

Objective. Data from randomized clinical trials with metabolic outcomes can be used to address concerns about potential issues of cardiovascular safety for newer drugs for type 2 diabetes. This meta-analysis was designed to assess cardiovascular safety of GLP-1 receptor agonists.Design and Methods. MEDLINE, Embase, and Cochrane databases were searched for randomized trials of GLP-1 receptor agonists (versus placebo or other comparators) with a duration ≥12 weeks, performed in type 2 diabetic patients. Mantel-Haenszel odds ratio with 95% confidence interval (MH-OR) was calculated for major cardiovascular events (MACE), on an intention-to-treat basis, excluding trials with zero events.Results. Out of 36 trials, 20 reported at least one MACE. The MH-OR for all GLP-1 receptor agonists was 0.74 (0.50–1.08),P=.12(0.85 (0.50–1.45),P=.55, and 0.69 (0.40–1.22),P=.20, for exenatide and liraglutide, resp.). Corresponding figures for placebo-controlled and active comparator studies were 0.46 (0.25–0.83),P=.009, and 1.05 (0.63–1.76),P=.84, respectively.Conclusions. To date, results of randomized trials do not suggest any detrimental effect of GLP-1 receptor agonists on cardiovascular events. Specifically designed longer-term trials are needed to verify the possibility of a beneficial effect.

scholarly journals Hydroxychloroquine plus standard care compared with the standard care alone in COVID-19: a meta-analysis of randomized controlled trials

2020 ◽  
Author(s):  
Bahman Amani ◽  
Ahmad Khanijahani ◽  
Behnam Amani
Keyword(s):  
Clinical Trials ◽  
Randomized Controlled Trials ◽  
Standard Care ◽  
Randomized Clinical Trials ◽  
Meta Analysis ◽  
Cochrane Library ◽  
Controlled Trials ◽  
Efficacy And Safety ◽  
Randomized Controlled ◽  
Significant Difference

AbstractBackground & ObjectiveThe efficacy and safety of Hydroxychloroquine (HCQ) in treating coronavirus disease COVID-19 pandemic is disputed. This study aimed to examine the efficacy and safety of HCQ plus the standard of care in COVID-19 patients.MethodsPubMed, The Cochrane Library, Embase, and web of sciences were searched up to June 1, 2020. The references list of the key studies was reviewed for additional relevant resources. Clinical studies registry databases were searched for identifying potential clinical trials. The quality of the included studies was evaluated using the Cochrane Collaboration’s tool. Meta-analysis was performed using RevMan software (version 5.3).ResultsThree randomized controlled trials with total number of 242 patients were identified eligible for meta-analysis. No significant differences were observed between HCQ and standard care in terms of viral clearance (Risk ratio [RR] = 1.03; 95% confidence interval [CI] = 0.91, 1.16; P = 0.68), disease progression (RR = 0.92; 95% CI = 0.10, 0.81; P = 0.94), Chest CT (RR = 1.40; 95% CI = 1.03, 1.91; P = 0.03). There is a significant difference between HCQ and standard care for adverse events (RR = 2.88; 95% CI = 1.50, 5.54; P = 0.002).ConclusionAlthough the current meta-analysis failed to confirm the efficacy and safety of HCQ in the treatment of COVID-19 patients, further rigorous randomized clinical trials are necessary to evaluate conclusively the efficacy and safety of HCQ against COVID-19.

scholarly journals Meta-analysis of randomized trials of ivermectin to treat SARS-CoV-2 infection

2021 ◽  
Author(s):  
Andrew Hill ◽  
Anna Garratt ◽  
Jacob Levi ◽  
Jonathan Falconer ◽  
Leah Ellis ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Randomized Trials ◽  
Randomized Clinical Trials ◽  
Meta Analysis ◽  
Severe Infection ◽  
Viral Clearance ◽  
Reactive Protein ◽  
Wide Range ◽  
High Concentrations

Abstract Ivermectin is an antiparasitic drug being investigated for repurposing against SARS-CoV-2. Ivermectin showed in-vitro activity against SARS-COV-2 at high concentrations. This meta-analysis investigated ivermectin in 24 randomized clinical trials (3328 patients) identified through systematic searches of PUBMED, EMBASE, MedRxiv and trial registries. Ivermectin was associated with reduced inflammatory markers (C-Reactive Protein, d-dimer and ferritin) and faster viral clearance by PCR. Viral clearance was treatment dose- and duration-dependent. In 11 randomized trials of moderate/severe infection, there was a 56% reduction in mortality (Relative Risk 0.44 [95%CI 0.25-0.77]; p=0.004; 35/1064 (3%) deaths on ivermectin; 93/1063 (9%) deaths in controls) with favorable clinical recovery and reduced hospitalization. Many studies included were not peer reviewed and a wide range of doses were evaluated. Currently, WHO recommends the use of ivermectin only inside clinical trials. A network of large clinical trials is in progress to validate the results seen to date.

scholarly journals Hydroxychloroquine Efficacy for the Treatment of Patients with COVID-19: A Systematic Review and Meta-Analysis

2020 ◽  
Author(s):  
Nayara Izabel Viana ◽  
Ruan Pimenta ◽  
Guilherme Lopes Gonçalves ◽  
Thaynara Faria Gomes ◽  
Vanessa Ribeiro Guimarães ◽  
...  
Keyword(s):  
Systematic Review ◽  
Clinical Trials ◽  
Randomized Clinical Trials ◽  
Standard Treatment ◽  
Meta Analysis ◽  
Antiviral Treatment ◽  
Public Health Emergency ◽  
Quality Information ◽  
Transmission Rates ◽  
Randomized Controlled

Abstract Background and Purpose: COVID-19 (Coronavirus Disease - 2019) represents a public health emergency because of the elevated transmission rates and associated mortality. There is an urgent need to limit the spread of the virus and to develop an effective antiviral treatment for the patients harboring such disease. This meta-analysis aimed to evaluate the results of the existing randomized clinical trials assessing the use of Hydroxychloroquine (HCQ) to treat COVID-19.Methods: A systematic review was performed on PubMed and Google Scholar according to the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) recommendations. Information from randomized controlled trials (RCT) was retrieved and included in a meta-analysis.Results: Among 214 studies that were found, 3 were included for in the meta‐ analysis. Patients treated with HCQ had a faster clearance of virus or pneumonia improvement than those that received standard treatment (OR = 7.08, 95% CI 2.79 to 4.12; P = 0.001). Only minor side effects were reported.Conclusions: Although this meta-analysis has found favorable evidence for the use of HCQ in the treatment of COVID-19, the literature does not yet present well-designed clinical studies that demonstrate the effectiveness of this medication. We believe that clinical trials coordinated by standardized guidelines, with complete and quality information, must be carried out worldwide and are urgently needed.

Comparison of Percentage of Syllables Stuttered With Parent-Reported Severity Ratings as a Primary Outcome Measure in Clinical Trials of Early Stuttering Treatment

2018 ◽  
Vol 61 (4) ◽  
pp. 811-819 ◽  
Author(s):  
Mark Onslow ◽  
Mark Jones ◽  
Sue O'Brian ◽  
Ann Packman ◽  
Ross Menzies ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Randomized Trials ◽  
Primary Outcome ◽  
Outcome Measure ◽  
Primary Outcome Measure ◽  
Analysis Of Covariance ◽  
Data Sets ◽  
Randomized Controlled ◽  
Absolute Agreement

Purpose This report investigates whether parent-reported stuttering severity ratings (SRs) provide similar estimates of effect size as percentage of syllables stuttered (%SS) for randomized trials of early stuttering treatment with preschool children. Method Data sets from 3 randomized controlled trials of an early stuttering intervention were selected for analyses. Analyses included median changes and 95% confidence intervals per treatment group, Bland–Altman plots, analysis of covariance, and Spearman rho correlations. Results Both SRs and %SS showed large effect sizes from pretreatment to follow-up, although correlations between the 2 measures were moderate at best. Absolute agreement between the 2 measures improved as percentage reduction of stuttering frequency and severity increased, probably due to innate measurement limitations for participants with low baseline severity. Analysis of covariance for the 3 trials showed consistent results. Conclusion There is no statistical reason to favor %SS over parent-reported stuttering SRs as primary outcomes for clinical trials of early stuttering treatment. However, there are logistical reasons to favor parent-reported stuttering SRs. We conclude that parent-reported rating of the child's typical stuttering severity for the week or month prior to each assessment is a justifiable alternative to %SS as a primary outcome measure in clinical trials of early stuttering treatment.

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