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Edaravone for acute stroke: Meta-analyses of data from randomized controlled trials
Abstract and Figures
Aims:
To assess the effectiveness of edaravone for acute stroke including ischemic stroke and intracerebral hemorrhage (ICH).
Methods:
We identified randomized controlled trials with comprehensive searches and performed systematic reviews according to the Cochrane methods of systematical reviews.
Results:
Edaravone can reduce the rate of death or long-term disability significantly for acute ischemic stroke (AIS) (RR = 0.65; 95%CI, 0.48 to 0.89, p = 0.007). However, sensitivity analysis yielded a different result. Edaravone can also improve the short-term neurological impairment of AIS (MD = 7.09; 95%CI, 5.12 to 9.05, p < 0.00001), and ICH (MD = -4.32; 95%CI, -5.35 to -3.29, p < 0.00001).
Conclusions:
Edaravone is beneficial in improving neurological impairment resulting from AIS and ICH. However, currently there is no enough convincing evidence that edaravone reduces death or long-term disability for AIS and ICH.
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... Nevertheless, the aforementioned recommendation was drawn on the unrobust results of previous systematic reviews, suggesting that edaravone could exert slightly promising effects on the neurological deficit improvement of ICH (Yang et al., 2011;Yang et al., 2015). The conclusive effects of edaravone treatment on survival or long-term functional outcomes in patients with ICH remain unclear. ...
... The reported adverse reactions (including kidney impairment, liver impairment, skin irritation, nausea, vomiting, pruritus, and palpitations) may be related to edaravone or other therapeutic agents or procedures. Compared with previous systematic reviews and meta-analyses, our study attempted to explore whether edaravone could reduce mortality or not (Yang et al., 2011;Yang et al., 2015). Consistent with previous studies revealing that edaravone could improve short-term neurological deficits, we confirmed this finding numerically. ...
Background: Edaravone alleviates neurological deficits among patients with intracerebral hemorrhage; however, its effects on mortality and long-term functional outcomes remain unknown.
Objective: To assess clinical outcomes associated with edaravone initiated within 7 days of symptoms onset in intracerebral hemorrhage.
Methods: We systematically searched PubMed, Embase, Cochrane Library, CiNii, China National Knowledge Infrastructure, Chinese VIP information, Wanfang Data, and SinoMed for relevant randomized controlled trials from their inception to 1 May 2021 and conducted a comprehensive systematic review and meta-analysis (PROSPERO registration number: CRD42019147801). All-cause mortality and long-term functional outcomes were taken as the primary outcomes.
Results: A total of 38 randomized controlled trials including 3,454 participants with acute intracerebral hemorrhage were included. The selected articles were of poor quality. Meta-analysis revealed that edaravone could not reduce all-cause mortality [relative risk (RR) = 0.51; 95% confidence interval (CI) (0.11–2.32); p = 0.38]. No studies reported on long-term functional outcomes in those trials. In addition, edaravone alleviated neurological deficits [mean difference (MD) = −5.44; 95% CI (−6.44 to −4.44); p <0.00001], improved the activities of daily living [MD = 8.44; 95% CI (7.65–9.23); p <0.00001], reduced the hematoma volume [MD = −4.71; 95% CI (−5.86 to −3.56); p <0.00001], and increased treatment response [RR = 1.26; 95% CI (1.22–1.31); p <0.00001]. In terms of safety outcome, there was no significant difference between the edaravone group and the control groups [RR = 1.67; 95% CI (0.92 to 3.06); p = 0.09].
Conclusion: Till date, edaravone does not associate with mortality reduction when initiated within 7 days of intracerebral hemorrhage onset. The effect of edaravone on long-term functional outcomes remains unknown due to lack of data. Although edaravone alleviated neurological deficits, improved activities of daily living, and reduced hematoma volume, we cautiously interpreted the results owing to the overall poor quality and high heterogeneity of the included trials. Presently, the results are insufficient to support edaravone as a routine treatment option for acute intracerebral hemorrhage.
... This neuroprotective effect is the reason for its use in patients with ICH [36,41] . Edaravone has been widely used in China and has become a part of the Chinese guidelines for the treatment of acute ICH as a result of its protective nature in preventing neurological impairment and improving prognosis [42][43][44] . ...
Stroke can be mainly categorized into hemorrhagic and ischemic stroke. Intracerebral hemorrhage (ICH) is a subtype of hemorrhagic stroke that is caused due to unconstrained bleeding within the parenchyma of the brain. ICH is one of the major conditions that have a high rate of disease and a high rate of death in a given population. Risk factors for ICH emerged to be age, male gender, hypertension, and intake of alcohol in huge quantities. The frequency of ICH is increased where hypertension is mainly untreated. To improve the prognosis and outcomes of an ICH patient, we need to perform emergent evacuation of blood from the brain parenchyma and prevent edema formation while restricting further neuronal damage due to surgical intervention. Evidence-based guidelines exist for ICH and form the basis for a care framework. The pharmaceutical management of ICH from current literature includes an aggressive reduction in blood pressure, tranexamic acid use, and recombinant activated factor VII administration. In addition, advanced imaging, surgical evacuation of ICH, and minimally invasive surgery techniques for hematoma evacuation could provide great benefits to patients with a large ICH.
... Edaravone is a free radical scavenger, which can play a neuroprotective role by inhibiting endothelial damage and improving cerebral ischemic neuronal damage [13][14][15]. Currently, edaravone has been extensively used in treating acute ischemic stroke (AIS) [16,17]. ...
More and more evidence shows that the pathological mechanism of vascular dementia (VD) is closely related to oxidative stress injury, cell apoptosis, autophagy, inflammatory response, excitatory amino acid toxicity, synaptic plasticity change, calcium overload, and other processes. Edaravone dexborneol (EDB) is a new type of neuroprotective agent that can improve the neurological damage caused by an ischemic stroke. Previous studies showed that EDB has effects on synergistic antioxidants and induces anti-apoptotic responses. However, it remains unclear whether EDB can affect apoptosis and autophagy by activating the PI3K/Akt/mTOR signaling pathway and its impact on the neuroglial cells. In this study, we established the VD model of rats by bilateral carotid artery occlusion to explore the neuroprotective effect of EDB and its mechanism. Morris Water Maze test was applied to assess the cognitive function of rats. H&E and TUNEL staining were applied to observe the cellular structure of the hippocampus. Immunofluorescence labeling was used to observe the proliferation of astrocytes and microglia. ELISA was applied to examine the levels of TNF-α, IL-1β and IL-6, and RT-PCR was applied to examine their mRNA expression levels. Western blotting was applied to examine apoptosis-related proteins (Bax, Bcl-2, Caspase-3), autophagy-related proteins (Beclin-1, P62, LC3B), PI3K/Akt/mTOR signaling pathway proteins and their phosphorylation levels. The results indicated that EDB ameliorates learning and memory in rats subjected to the VD model, alleviates neuroinflammatory response by reducing the proliferation of the neuroglial cell and inhibits apoptosis and autophagy, which may be mediated by the PI3K/Akt/mTOR signaling pathway.
... Edaravone is an effective antioxidant and free radical scavenger, which is mentioned as a neuroprotective agent in the management guidelines for acute ICH in China [190]. Meta-analysis has shown that edaravone can improve short-term neurological function, but convincing evidence that edaravone reduces death or long-term disability for ICH is not enough at the moment [202]. Subcutaneous injection of edaravone in ICH rats could attenuate DNA oxidative markers (apurinic/apyrimidinic abasic sites and 8-hydroxyl-2'-deoxyguanosine variation) to inhibit oxidative injury [203]. ...
Intracerebral hemorrhage (ICH) refers to hemorrhage caused by non-traumatic vascular rupture in the brain parenchyma, which is characterized by acute onset, severe illness, and high mortality and disability. The influx of blood into the brain tissue after cerebrovascular rupture causes severe brain damage, including primary injury caused by persistent hemorrhage and secondary brain injury (SBI) induced by hematoma. The mechanism of brain injury is complicated and is a significant cause of disability after ICH. Therefore, it is essential to understand the mechanism of brain injury after ICH to develop drugs to prevent and treat ICH. Studies have confirmed that many traditional Chinese medicines (TCM) can reduce brain injury by improving neurotoxicity, inflammation, oxidative stress (OS), blood-brain barrier (BBB), apoptosis, and neurological dysfunction after ICH. Starting from the pathophysiological process of brain injury after ICH, this paper summarizes the mechanisms by which TCM improves cerebral injury after ICH and its comparison with conventional western medicine, so as to provide clues and a reference for the clinical application of TCM in the prevention and treatment of hemorrhagic stroke and further research and development of new drugs.
... A systematic review involving 49 animal experiments showed that the functional and cognitive prognosis of edaravone in an animal model of focal cerebral ischemia increased by 30.3% and 25.5%, respectively [13]. A systematic review published by Yang et al. included 18 randomized controlled trials involving 1802 patients, and the results showed that edaravone can significantly reduce the mortality or long-term disability rate of acute ischemic stroke (AIS) [14]. Both of these systematic reviews support the effectiveness of edaravone for acute ischemic stroke. ...
Objective:
To explore the mechanism of edaravone in the treatment of oxidative stress in rats with cerebral infarction based on quantitative proteomics technology.
Method:
The modified Zea Longa intracavitary suture blocking method was utilized to make rat CI model. After modeling, the rat was intragastrically given edaravone for 7 days, once a day. After the 7-day intervention, the total proteins of serum were extracted. After proteomics analysis, the differentially expressed proteins are analyzed by bioinformatics. Then chemoinformatics methods were used to explore the biomolecular network of edaravone intervention in CI.
Result:
The neurological scores and pathological changes of rats were improved after the intervention of edaravone. Proteomics analysis showed that in the model/sham operation group, 90 proteins in comparison group were upregulated, and 26 proteins were downregulated. In the edaravone/model group, 21 proteins were upregulated, and 41 proteins were downregulated. Bioinformatics analysis and chemoinformatics analysis also show that edaravone is related to platelet activation and aggregation, oxidative stress, intercellular adhesion, glycolysis and gluconeogenesis, iron metabolism, hypoxia, inflammatory chemokines, their mediated signal transduction, and so on.
Conclusion:
The therapeutic mechanism of edaravone in the treatment of CI may involve platelet activation and aggregation, oxidative stress, intercellular adhesion, glycolysis and gluconeogenesis, iron metabolism, hypoxia, and so on. This study revealed the serum protein profile of edaravone in the treatment of cerebral infarction rats through serum TMT proteomics and discovered the relevant mechanism of edaravone regulating iron metabolism in cerebral infarction, which provides new ideas for the study of edaravone intervention in cerebral infarction and also provides reference information for future research on the mechanism of edaravone intervention in iron metabolism-related diseases.
... Edaravone has never reached other parts of the world, while in Japan it has been used in daily clinical stroke care since 2001. A number of clinical trials (few showed clinical benefit), meta-analyses (with positive outcomes) [156][157][158][159] and pre-clinical studies have been undertaken (all extensively reviewed elsewhere [160][161][162]), however, the majority were executed in Asian countries. Besides that, despite the described beneficial effect of Edaravone, it was also noted that these results might have been biased [163]. ...
With the introduction of endovascular thrombectomy (EVT), a new era for treatment of acute ischemic stroke (AIS) has arrived. However, despite the much larger recanalization rate as compared to thrombolysis alone, final outcome remains far from ideal. This raises the question if some of the previously tested neuroprotective drugs warrant re-evaluation, since these compounds were all tested in studies where large-vessel recanalization was rarely achieved in the acute phase. This review provides an overview of compounds tested in clinical AIS trials and gives insight into which of these drugs warrant a re-evaluation as an add-on therapy for AIS in the era of EVT. A literature search was performed using the search terms “ischemic stroke brain” in title/abstract, and additional filters. After exclusion of papers using pre-defined selection criteria, a total of 89 trials were eligible for review which reported on 56 unique compounds. Trial compounds were divided into 6 categories based on their perceived mode of action: systemic haemodynamics, excitotoxicity, neuro-inflammation, blood–brain barrier and vasogenic edema, oxidative and nitrosative stress, neurogenesis/-regeneration and -recovery. Main trial outcomes and safety issues are summarized and promising compounds for re-evaluation are highlighted. Looking at group effect, drugs intervening with oxidative and nitrosative stress and neurogenesis/-regeneration and -recovery appear to have a favourable safety profile and show the most promising results regarding efficacy. Finally, possible theories behind individual and group effects are discussed and recommendation for promising treatment strategies are described.
Migraine is a serious central nervous system disease with a high incidence rate. Its pathogenesis is very complex, which brings great difficulties for clinical treatment. Recently, many studies have revealed that mitochondrial dysfunction may play a key role in migraine, which affects the hyperosmotic of Ca ²⁺ , the excessive production of free radicals, the decrease of mitochondrial membrane potential, the imbalance of mPTP opening and closing, and the decrease of oxidative phosphorylation level, which leads to neuronal energy exhaustion and apoptosis, and finally lessens the pain threshold and migraine attack. This article mainly introduces cortical spreading depression, a pathogenesis of migraine, and then damages the related function of mitochondria, which leads to migraine. Oxidative phosphorylation and the tricarboxylic acid cycle are the main ways to provide energy for the body. 95 percent of the energy needed for cell survival is provided by the mitochondrial respiratory chain. At the same time, hypoxia can lead to cell death and migraine. The pathological opening of the mitochondrial permeability transition pore can promote the interaction between pro-apoptotic protein and mitochondrial, destroy the structure of mPTP, and further lead to cell death. The increase of mPTP permeability can promote the accumulation of reactive oxygen species, which leads to a series of changes in the expression of proteins related to energy metabolism. Both Nitric oxide and Calcitonin gene-related peptide are closely related to the attack of migraine. Recent studies have shown that changes in their contents can also affect the energy metabolism of the body, so this paper reviews the above mechanisms and discusses the mechanism of brain energy metabolism of migraine, to provide new strategies for the prevention and treatment of migraine and promote the development of individualized and accurate treatment of migraine.
Purpose
The management of acute stroke is challenging. The aim of this meta-analysis was to determine the efficacy and tolerability of edaravone, with or without thrombolytic therapy, in the treatment of patients with acute ischemic stroke.
Methods
The PubMed, EMBASE, and Cochrane databases were searched for randomized controlled trials (RCTs) and cohort studies. Mean differences (MD), risk ratios (RR), 95% confidence interval (CI), and heterogeneity were calculated.
Findings
Totals of nine RCTs and four cohort studies were included, for a total of 2102 patients. In patients with acute ischemic stroke, edaravone monotherapy was associated with significantly improved Barthel Index of functioning in activities for daily living (MD, 23.95; 95% CI, 18.48 to 29.41; P < 0.001) and neurologic deficit, (as measured using the National Institutes of Health Stroke Scale score) (MD = –3.49; 95% CI, –5.76 to 1.22; P = 0.003), on short-term follow-up. However, edaravone was not associated with an improved rate of death or disability (RR = 0.75; 95% CI, 0.45 to 1.23; P = 0.25) on long-term follow-up.When plus to thrombolytic therapy, edaravone was associated with significant improvements in recanalization rate (RR = 1.71; 95% CI, 1.05 to 2.77; P = 0.03) and neurologic deficit (MD = 3.97; 95% CI, 5.14 to 2.79; P < 0.001), without an increase in the prevalence of bleeding events (RR = 1.11; 95% CI, 0.76 to 1.62; P = 0.59). However, edaravone did not have a significant effect on death or disability (RR = 0.85; 95% CI, 0.69 to 1.04; P = 0.12).
Implications
Based on the findings from the present meta-analysis, edaravone was an effective and well-tolerated neuroprotective agent in these patients with ischemic stroke. With the use of edaravone, activities of daily living and neurologic deficits, along with recanalization rates, were improved on short-term follow-up, but the long-term effects still need confirmation in larger-scale clinical trials.
Introduction
Ischemic stroke is a major cause of death and disability. Despite major advances in reperfusion therapies, most patients don´t benefit from these treatments as the time window for such interventions is limited. Therefore, other treatment options are desirable. Edaravone has been demonstrated in previous studies to reduce neurologic deficits in stroke patients.
Objective
To test the hypothesis that edaravone reduces functional dependence in ischemic stroke patients.
Material and methods
Systematic review and meta-analysis of randomized controlled trials and observational studies comparing edaravone to placebo in adult patients with ischemic stroke. The efficacy outcomes of interest were good and excellent functional outcomes at 90 days, defined as modified Rankin Scale (mRS) scores of 0-2 and 0-1 respectively. The safety outcomes of interest were intracranial hemorrhage and mortality.
Results
19 studies were included. Edaravone treatment was associated with improved chances of 90-day good (OR=1.31, 95%CI 1.06-1.67) and excellent (OR=1.26, 95% CI 1.04-1.54) functional outcomes. Mortality was also lower in edaravone treated patients (OR=0.50, 95% CI 0.45-0.56). There were no differences in terms of intracranial hemorrhage. Most studies were observational and performed in Asian populations, especially Japan. Heterogeneity was high for all outcomes but reduced when analysis was restricted to randomized trials.
Conclusion
Edaravone is a promising treatment for ischemic stroke patients, with a more favorable time window. However, more randomized studies including patient populations outside Asia are required to confirm this hypothesis.
Background:
Acute cerebral infarction threats human health and life safety. The edaravone is a new antioxidant and hydroxyl radical scavenger, which is the novel scavenger for clinical use, mainly for nervous system diseases.
Objective:
The purpose of this study is to observe the clinical treatment effects of edaravone on the degree of improvement of neurological impairment and functional movement impairment in patients with acute cerebral infarction.
Method:
A total of 130 patients admitted to our hospital because of acute cerebral infarction from December 2015 to May 2017 were selected for group analysis. These patients were divided into a control group (n = 65) and a treatment group (n = 65) with a random odd-even method. The control group accepted conventional treatment, while the treatment group received edaravone treatment on top of the conventional treatment of the control group. After treatment, the differences in functional movement, living ability score, neurological score, treatment effect, and adverse reaction of these two groups were tested and compared.
Results:
The total treatment efficiency of conventional treatment in the control group was significantly lower than the combination treatment in the treatment group (P < 0.05). The inter-group differences in the National Institutes of Health Stroke Scale, activities of daily living, and Fugl-Meyer assessment scores after the treatment were significant between these two groups (P < 0.05). The posttreatment effect on the treatment group was superior to that on the control group (P < 0.05). The adverse reaction rate of the treatment group did not significantly vary from that of the control group (P > 0.05).
Conclusion:
Edaravone can significantly improve the degree of neurological impairment during acute cerebral infarction, functional movement, and living quality with a definite effect and high safety. Thus, this drug has a good prospect in clinical treatment.
Objective: To investigate the efficacy of combined intravenous rt-PA and free-radical scavengen (edaravone) on Chinese patients with acute ischemic stroke. Methods: Eighty-nine subjects with ultra-acute ischemic stroke were assigned to the group treated with intravenous rt-PA and another group treated with a combination of intravenous rt-PA and edaravone. The NIH Stroke Scale (NIHSS) and Barthel Index (BI) in 30 days and 90 days after thrombolysis were compared between two groups. Results: There were statistically significant differences between the group of rt-PA thrombolysis and the group of combined with rt-PA and edaravon in the ratio of NIHSS 0-1 of 30 days after therapy (25.0% vs 35.6%, X ² = 8.259, P = 0.041) and 90 days (27.3% vs 40.0%, X ² = 9.158, P = 0.027), as well as in the proportion of BI 95-100 of the same time points (30 days: 20.5% vs 33.3%, X ² = 8.833, P = 0.032; 90 days: 25.0% vs 37.8%, X ² = 8.221, P = 0.042). The rates of hemorrhagic conversion and mortality in two groups were similar. Conclusion: rt-PA combined with free radical scavenger edaravone safely and effectively decreases the loss of neurofunctions and reserves more self-dependence capability in patients with acute ischemic stroke 30 days and 90 days after treatments.
Purpose: To evaluate the clinical efficacy and safety of edaravone in the treatment of acute cerebral haemorrhage (ACH). Methods: This study recruited 120 patients who developed ACH. The patients were divided into control and treatment groups with 60 patients per group. The control group underwent conventional treatment and the treatment group also received intravenous edaravone. The volumes of cerebral edema and cerebral hematoma, high-sensitivity C-reactive protein (hs-CRP) and interleukin-6 (IL-6) levels, and Chinese Stroke Scale (CSS) score before and after treatment were compared between the two groups. Results: The respective cerebral edema volumes of the control and treatment groups decreased from 20.99 ± 12.09 and 21.80 ± 12.01 mL on day 0 to 11.23 ± 6.34 and 12.11 ± 5.98 mL at day 7 and 4.69 ± 4.03 and 4.64 ± 3.9 mL on day 14 (P < 0.05). The respective cerebral hematoma volumes of the control and treatment groups decreased from 18.98 ± 12.04 and 18.97 ± 12.07 mL on day 0 to 12.34 ± 6.57 and 11.89 ± 4.01 mL at day 7 and 9.49 ± 3.95 and 9.52 ± 3.96 mL on day 14. Compared with pre-treatment, hs-CRP and IL-6 levels and CSS score of the two groups decreased significantly following treatment (p < 0.05); the differences in the cerebral edema and hematoma volumes of the two groups on days 7 and 14 were not significant (p > 0.05). The hs-CRP and IL-6 levels and CSS scores of the treatment group decreased appreciably (p < 0.05), while the incidence of adverse reactions in the treatment and control groups was 16.67 and 13.33 %, respectively, but the difference was not significant (p > 0.05). Conclusion: Edaravone shows remarkable clinical efficacy and safety with no obvious adverse reactions in the treatment of ACH. Therefore, its use is recommended. © Pharmacotherapy Group, Faculty of Pharmacy, University of Benin, Benin City, 300001 Nigeria. All rights reserved.
Objective: To assess the clinical effect of edaravone in treatment of patients with acute cerebral infarction (ACI) according to domestic and overseas medical literatures. Methods: We searched the China National Knowledge Infrastructure (CNKI), the China Biological Medicine Data- base (CBMdisc), Pubmed, eBASE (all till Dec. 2008) and the reference lists of related articles. The object of research was confined to the ACI patients and the languages were Chinese and English. Change of nervous functional defect score and improvement rate of nervous function defect were used to evaluate clinical curative effect. The incidence rate of adverse drug reactions was used to evaluate the safety of drug. Two appraisers assessed the quality of studies and data independently. The Rev Man 4.2 software was used for statistical analysis. Results: We identified 169 randomized controlled trials about treating ACI by edaravone complying with the standard and selected 55 randomized control tests by CSS (Chinese stroke scale) Score and clinical effect, which included 2281 cases in treatment group and 2262 cases in control group. To review the document quality using the method of Jadad 7 score, 2 papers got 4 score, 7 papers got 3 score, 16 papers got 2 score and others got 1 score. Among them, 49 papers including 1957 cases in treatment group and 1958 cases in control group were negative control. The clinical effective rate was 61.52% in treatment group and 37.64% in control group [OR = 2.81, 95% CI (2.45-3.21)]. Another 6 papers including 324 cases in treatment group and 304 cases in control group, were cytidine diphosphate choline positive controls. The rates of clinical efficiency were 61.73% in treatment group and 43.75% in control group [OR = 2.16, 95% CI (1.55-3.00)]. Meta-analysis showed that the neurological deficits in treatment group showed significant difference compared with that in control group (P < 0.000 01). The funnel graph was almost symmetrical, but, not funnel plot. Maybe it was related to publication bias analysis, unpublished negative results and low quality of documents. Conclusion: The Meta-analysis results from databases indicated that edaravone injection can provide effective improvements for neurological deficits in ACI and it has instructive meanings to clinical use of edaravone.
Edaravone, a novel free radical scavenger, demonstrates neuroprotective effects by inhibiting vascular endothelial cell injury and ameliorating neuronal damage in ischemic brain models. The present study was undertaken to verify its therapeutic efficacy following acute ischemic stroke. We performed a multicenter, randomized, placebo-controlled, double-blind study on acute ischemic stroke patients commencing within 72 h of onset. Edaravone was infused at a dose of 30 mg, twice a day, for 14 days. At discharge within 3 months or at 3 months after onset, the functional outcome was evaluated using the modified Rankin Scale. Two hundred and fifty-two patients were initially enrolled. Of these, 125 were allocated to the edaravone group and 125 to the placebo group for analysis. Two patients were excluded because of subarachnoid hemorrhage and disseminated intravascular coagulation. A significant improvement in functional outcome was observed in the edaravone group as evaluated by the modified Rankin Scale (p = 0.0382). Edaravone represents a neuroprotective agent which is potentially useful for treating acute ischemic stroke, since it can exert significant effects on functional outcome as compared with placebo. Copyright (C) 2003 S. Karger AG, Basel.
Objective. —To determine if inadequate approaches to randomized controlled trial design and execution are associated with evidence of bias in estimating treatment effects. Design. —An observational study in which we assessed the methodological quality of 250 controlled trials from 33 meta-analyses and then analyzed, using multiple logistic regression models, the associations between those assessments and estimated treatment effects. Data Sources. —Meta-analyses from the Cochrane Pregnancy and Childbirth Database. Main Outcome Measures. —The associations between estimates of treatment effects and inadequate allocation concealment, exclusions after randomization, and lack of double-blinding. Results. —Compared with trials in which authors reported adequately concealed treatment allocation, trials in which concealment was either inadequate or unclear (did not report or incompletely reported a concealment approach) yielded larger estimates of treatment effects ( P P =.01), with odds ratios being exaggerated by 17%. Conclusions. —This study provides empirical evidence that inadequate methodological approaches in controlled trials, particularly those representing poor allocation concealment, are associated with bias. Readers of trial reports should be wary of these pitfalls, and investigators must improve their design, execution, and reporting of trials. ( JAMA . 1995;273:408-412)
The Cochrane Handbook for Systematic Reviews of Interventions (the Handbook) has undergone a substantial update, and Version 5 of the Handbook is now available online at www.cochrane-handbook.org and in RevMan 5. In addition, for the first time, the Handbook will soon be available as a printed volume, published by Wiley-Blackwell. We are anticipating release of this at the Colloquium in Freiburg. Version 5 of the Handbook describes the new methods available in RevMan 5, as well as containing extensive guidance on all aspects of Cochrane review methodology. It has a new structure, with 22 chapters divided into three parts. Part 1, relevant to all reviews, introduces Cochrane reviews, covering their planning and preparation, and their maintenance and updating, and ends with a guide to the contents of a Cochrane protocol and review. Part 2, relevant to all reviews, provides general methodological guidance on preparing reviews, covering question development, eligibility criteria, searching, collecting data, within-study bias (including completion of the Risk of Bias table), analysing data, reporting bias, presenting and interpreting results (including Summary of Findings tables). Part 3 addresses special topics that will be relevant to some, but not all, reviews, including particular considerations in addressing adverse effects, meta-analysis with non-standard study designs and using individual participant data. This part has new chapters on incorporating economic evaluations, non-randomized studies, qualitative research, patient-reported outcomes in reviews, prospective meta-analysis, reviews in health promotion and public health, and the new review type of overviews of reviews.
