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Whiting P.F.,University of Bristol | Whiting P.F.,Kleijnen Systematic Reviews Ltd | Wolff R.F.,Kleijnen Systematic Reviews Ltd | Deshpande S.,Kleijnen Systematic Reviews Ltd | And 12 more authors.
JAMA - Journal of the American Medical Association | Year: 2015

IMPORTANCE: Cannabis and cannabinoid drugs are widely used to treat disease or alleviate symptoms, but their efficacy for specific indications is not clear. OBJECTIVE: To conduct a systematic review of the benefits and adverse events (AEs) of cannabinoids. DATA SOURCES: Twenty-eight databases from inception to April 2015. STUDY SELECTION: Randomized clinical trials of cannabinoids for the following indications: nausea and vomiting due to chemotherapy, appetite stimulation in HIV/AIDS, chronic pain, spasticity due to multiple sclerosis or paraplegia, depression, anxiety disorder, sleep disorder, psychosis, glaucoma, or Tourette syndrome. DATA EXTRACTION AND SYNTHESIS: Study quality was assessed using the Cochrane risk of bias tool. All review stages were conducted independently by 2 reviewers. Where possible, data were pooled using random-effects meta-analysis. MAIN OUTCOMES AND MEASURES: Patient-relevant/disease-specific outcomes, activities of daily living, quality of life, global impression of change, and AEs. RESULTS: A total of 79 trials (6462 participants) were included; 4 were judged at low risk of bias. Most trials showed improvement in symptoms associated with cannabinoids but these associations did not reach statistical significance in all trials. Compared with placebo, cannabinoids were associated with a greater average number of patients showing a complete nausea and vomiting response (47% vs 20%; odds ratio [OR], 3.82 [95% CI, 1.55-9.42]; 3 trials), reduction in pain (37% vs 31%; OR, 1.41 [95% CI, 0.99-2.00]; 8 trials), a greater average reduction in numerical rating scale pain assessment (on a 0-10-point scale; weighted mean difference [WMD], -0.46 [95% CI, -0.80 to -0.11]; 6 trials), and average reduction in the Ashworth spasticity scale (WMD, -0.36 [95% CI, -0.69 to -0.05]; 7 trials). There was an increased risk of short-term AEs with cannabinoids, including serious AEs. Common AEs included dizziness, dry mouth, nausea, fatigue, somnolence, euphoria, vomiting, disorientation, drowsiness, confusion, loss of balance, and hallucination. CONCLUSIONS AND RELEVANCE: There was moderate-quality evidence to support the use of cannabinoids for the treatment of chronic pain and spasticity. There was low-quality evidence suggesting that cannabinoids were associated with improvements in nausea and vomiting due to chemotherapy, weight gain in HIV infection, sleep disorders, and Tourette syndrome. Cannabinoids were associated with an increased risk of short-term AEs. Copyright 2015 American Medical Association. All rights reserved.


Whiting P.F.,Kleijnen Systematic Reviews Ltd | Whiting P.F.,University of Bristol | Rutjes A.W.S.,University of Bern | Rutjes A.W.S.,University of Chieti Pescara | And 2 more authors.
Journal of Clinical Epidemiology | Year: 2013

Objective To classify the sources of bias and variation and to provide an updated summary of the evidence of the effects of each source of bias and variation. Study Design and Setting We conducted a systematic review of studies of any design with the main objective of addressing bias or variation in the results of diagnostic accuracy studies. We searched MEDLINE, EMBASE, BIOSIS, the Cochrane Methodology Register, and Database of Abstracts of Reviews of Effects (DARE) from 2001 to October 2011. Citation searches based on three key papers were conducted, and studies from our previous review (search to 2001) were eligible. One reviewer extracted data on the study design, objective, sources of bias and/or variation, and results. A second reviewer checked the extraction. Results We summarized the number of studies providing evidence of an effect arising from each source of bias and variation on the estimates of sensitivity, specificity, and overall accuracy. Conclusions We found consistent evidence for the effects of case-control design, observer variability, availability of clinical information, reference standard, partial and differential verification bias, demographic features, and disease prevalence and severity. Effects were generally stronger for sensitivity than for specificity. Evidence for other sources of bias and variation was limited. © 2013 Elsevier Inc. All rights reserved.


Grant
Agency: European Commission | Branch: FP7 | Program: CSA-SA | Phase: HEALTH.2011.4.1-2 | Award Amount: 556.63K | Year: 2011

Full information about completed and ongoing clinical trials is the indispensable base for decision making about medical therapies and diagnostic procedures by patients and doctors. Equally, researchers and research organisations, ethics boards, governments and health system agencies, courts for social justice, pharmaceutical companies and all professional groups of the health care system are dependent on unbiased information. Research projects have consistently shown that for approximately 50% of all launched trials results or reasons for their failure are never published. Not only pharmaceutical industry, but also researchers and their organisations, ethics boards and scientific journals are actively contributing to the general failure to come close to a 100% publication rate. An obvious reason is the complexity of the system as well as the limitation of resources, giving ample space for all stakeholders to avoid appropriate changes and draw attention to deficiencies outside their responsibility. This project is based on the assumption that the existence of broad publication bias with seriously harmful impact has been accepted by all stakeholders and does not require further evidence. The current knowledge on publication bias and its impact will be summarized by systematic reviews of the relevant literature, with emphasis on the situation in the EU. OPEN focuses on the investigation of attitudes and handling of stakeholders involved in the whole knowledge translation process. Surveys, case studies and analyses of policies to reduce publication bias will be conducted to describe the current views and practice of stakeholders who are involved in knowledge translation. These results will be brought together to describe the status quo. Based on those insights recommendations will be derived to reduce publication bias and thus foster the provision of relevant results from clinical trials to citizens and organisations in the EU.


Meissner K.,TU Munich | Meissner K.,Ludwig Maximilians University of Munich | Fassler M.,TU Munich | Fassler M.,University of Zürich | And 7 more authors.
JAMA Internal Medicine | Year: 2013

IMPORTANCE: When analyzing results of randomized clinical trials, the treatment with the greatest specific effect compared with its placebo control is considered to be the most effective one. Although systematic variations of improvements in placebo control groups would have important implications for the interpretation of placebo-controlled trials, the knowledge base on the subject is weak. OBJECTIVE: To investigate whether different types of placebo treatments are associated with different responses using the studies of migraine prophylaxis for this analysis. DESIGN, SETTING, AND PARTICIPANTS: We searched relevant sources through February2012 and contacted the authors to identify randomized clinical trials on the prophylaxis of migraine with an observation period of at least 8 weeks after randomization that compared an experimental treatment with a placebo control group. We calculated pooled random-effects estimates according to the type of placebo for the proportions of treatment response. We performed meta-regression analyses to identify sources of heterogeneity. In a network meta-analysis, direct and indirect comparisons within and across trials were combined. Additional analyses were performed for continuous outcomes. EXPOSURE: Active migraine treatment and the placebo control conditions. MAINOUTCOMES ANDMEASURES: Proportion of treatment responders, defined as having an attack frequency reduction of at least 50%. Other available outcomes in order of preference included a reduction of 50% or greater in migraine days, the number of headache days, or headache score or a significant improvement as assessed by the patients or their physicians. RESULTS: Of the 102 eligible trials, 23 could not be included in the meta-analyses owing to insufficient data. Sham acupuncture (proportion of responders, 0.38 [95% CI, 0.30-0.47]) and sham surgery (0.58 [0.37-0.77]) were associated with a more pronounced reduction of migraine frequency than oral pharmacological placebos (0.22 [0.17-0.28]) and were the only significant predictors of response in placebo groups in multivariable analyses (P =.005 and P =.001, respectively). Network meta-analysis confirmed that more patients reported response in sham acupuncture groups than in oral pharmacological placebo groups (odds ratio, 1.88 [95% CI, 1.30-2.72]). Corresponding analyses for continuous outcomes showed similar findings. CONCLUSIONS AND RELEVANCE: Sham acupuncture and sham surgeryare associated with higher responder ratios than oral pharmacological placebos. Clinicians who treat patients with migraine should be aware that a relevant part of the overall effect they observe in practice might be due to nonspecific effects and that the size of such effects might differ between treatment modalities. © 2013 American Medical Association. All rights reserved.


Harker J.,Kleijnen Systematic Reviews Ltd | Kleijnen J.,Kleijnen Systematic Reviews Ltd | Kleijnen J.,Maastricht University
International Journal of Evidence-Based Healthcare | Year: 2012

Aim Commissioners of Health Technology Assessments require timely reviews to attain efficacious decisions on healthcare and treatments. In recent years, there has been an emergence of 'rapid reviews' within Health Technology Assessments; however, there is no known published guidance or agreed methodology within recognised systematic review or Health Technology Assessment guidelines. In order to answer the research question 'What is a rapid review and is methodology consistent in rapid reviews of Health Technology Assessments?', a study was undertaken in a sample of rapid review Health Technology Assessments from the Health Technology Assessment database within the Cochrane Library and other specialised Health Technology Assessment databases to investigate similarities and/or differences in rapid review methodology utilised. Method In a targeted search to obtain a manageable sample of rapid reviews, the Health Technology Assessment database of The Cochrane Library and six international Health Technology Assessment databases were searched to locate rapid review Health Technology Assessments from 2000 onwards. Each rapid review was examined to investigate the individual methodology used for searching, inclusion screening, quality assessment, data extraction and synthesis. Methods of each rapid review were compared to investigate differences and/or similarities in methodologies used, in comparison with recognised methods for systematic reviews. Results Forty-six full rapid reviews and three extractable summaries of rapid reviews were included. There was a wide diversity of methodology, with some reviews utilising well-established systematic review methods, but many others diversifying in one or more areas, that is searching, inclusion screening, quality assessment, data extraction, synthesis methods, report structure and number of reviewers. There was a significant positive correlation between the number of recommended review methodologies utilised and length of time taken in months. Conclusions Despite the number of rapid reviews published within Health Technology Assessments over recent years, there is no agreed and tested methodology and it is unclear how rapid reviews differ from systematic reviews. In a sample of Health Technology Assessment rapid reviews from 2000 to 2011, there was a wide diversity of methodology utilised in all aspects of rapid reviews. There is scope for wider research in this area to investigate the diversity of methods in more depth during each stage of the rapid review process, so that eventually recommendations could be made for clear and systematic methods for rapid reviews, thus facilitating equity and credibility of this type of important review methodology. © 2012 The Authors. International Journal of Evidence-Based Healthcare © 2012 The Joanna Briggs Institute.


Riemsma R.P.,Kleijnen Systematic Reviews Ltd
The Cochrane database of systematic reviews | Year: 2013

Primary liver tumours and liver metastases from colorectal carcinoma are the two most common malignant tumours to affect the liver. The liver is second only to the lymph nodes as the most common site for metastatic disease. More than half of the patients with metastatic liver disease will die from metastatic complications. Electro-coagulation is the coagulation (clotting) of tissue using a high-frequency electrical current applied locally with a metal instrument or needle with the aim of stopping bleeding. The object of this technique is to destroy the tumour completely, if possible, in a single surgical session. To study the beneficial and harmful effects of electro-coagulation compared with no intervention, to other ablation methods, or systemic treatments in patients with liver metastases. We searched The Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, Science Citation Index Expanded, LILACS, and CINAHL up to December 2012. We included one randomised clinical trial that assessed beneficial and harmful effects of electro-coagulation and its comparators in patients with liver metastases, irrespective of the location of the primary tumour. We extracted relevant information on participant characteristics, interventions, study outcome measures, and data on the outcome measures as well as information on the design and methodology of the trials. Risk of bias of the trials and data extraction was carried out by one author and checked by a second author. We included one randomised clinical trial that compared four groups: electro-coagulation alone, electro-coagulation + dimethyl sulphoxide, electro-coagulation + allopurinol, and control (Salim 1993). The risk of bias in the trial is high. In three groups, patients had their metastases destroyed with diathermy electro-coagulation (current set at No 5) and received: 1) solution of allopurinol by mouth 5 mL 4 x a day or 2) allopurinol by mouth 5 mL (50 mg) 4 x a day or 3) dimethyl sulphoxide by mouth 5 mL (500 mg) 4 x a day. In the control group patients received a solution of allopurinol by mouth 5 mL 4 x a day. The treatment was started in the fifth postoperative day and was continued for five years. Three hundred and six patients who had undergone resection of the sigmoid colon and who had five or more hepatic metastases were included; 75 received electro-coagulation alone (58 were evaluable), 76 received electro-coagulation plus allopurinol (53 were evaluable), 78 received electro-coagulation plus dimethyl sulphoxide (57 were evaluable), and 77 were in the control group (55 evaluable).The authors reported the number of deaths due to disease spread (100% in the control, 98% in electro-coagulation, 87% in electro-coagulation + allopurinol, and 86% in the electro-coagulation + dimethyl sulphoxide groups). There was a significant benefit in favour of the electro-coagulation + allopurinol (risk ratio (RR) 0.87 (95% confidence interval (CI) 0.78 to 0.96)) and electro-coagulation + dimethyl sulphoxide (RR 0.86 (95% CI 0.77 to 0.95)) groups compared to the control group, but no such benefit in the electro-coagulation alone group (RR 0.98 (95% CI 0.95 to 1.02)) compared to the control group. There were no local recurrences, no positive tests for occult blood, and observed pulmonary metastases were always with ultrasonographic evidence of hepatic secondaries and were not significantly different for the experimental groups compared to the control group (electro-coagulation: RR 1.11 (95% CI 0.4 to 3.09)), electro-coagulation + allopurinol (RR 0.86 (95% CI 0.28 to 2.66)), electro-coagulation + dimethyl sulphoxide (RR 0.8 (95% CI 0.26 to 2.48)). None of the adverse events were significantly associated with treatment. On the basis of one randomised trial which did not describe its methodology in sufficient detail to assess risk of bias and quality, excluded 27% of patients after randomisation due to various reasons, and is probably not free from selective outcome reporting bias, there is insufficient evidence to conclude that in patients with colonic cancer liver metastases, electro-coagulation alone brings any significant benefit in terms of survival or recurrence compared with the control. In addition, there is insufficient evidence for the effectiveness of adding allopurinol or dimethyl sulphoxide to electro-coagulation. The probability for selective outcome reporting bias in the trial is high. More randomised trials are needed in order to sufficiently validate electro-coagulation with or without co-interventions.


Riemsma R.P.,Kleijnen Systematic Reviews Ltd
The Cochrane database of systematic reviews | Year: 2013

Primary liver tumours and liver metastases from colorectal carcinoma are the two most common malignant tumours to affect the liver. The liver is second only to the lymph nodes as the most common site for metastatic disease. More than half of the patients with metastatic liver disease will die from metastatic complications. Percutaneous ethanol injection (PEI) causes dehydration and necrosis of tumour cells accompanied by small vessel thrombosis, leading to tumour ischaemia and destruction. To study the beneficial and harmful effects of percutaneous ethanol injection compared with no intervention, other ablation methods, or systemic treatments in patients with liver metastases. We searched the Cochrane Hepato-Biliary Group Controlled Trials Register, Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, Science Citation Index Expanded, LILACS, and CINAHL up to December 2012. We included all randomised clinical trials assessing the beneficial and harmful effects of percutaneous ethanol injection versus no intervention, other ablation methods, or systemic treatments in patients with liver metastases. We extracted the relevant information on participant characteristics, interventions, study outcome measures, and data on the outcome measures for our review, as well as information on the design and methodology of the studies. Quality assessment of the trials fulfilling the inclusion criteria and data extraction from the trials retrieved for final evaluation were done by one author and checked by a second author. One randomised clinical trial was included, comparing transcatheter arterial chemoembolisation (TACE) + percutaneous intratumour ethanol injection (PEI) versus TACE alone. Forty-eight patients with liver metastases were included; 25 received the intervention with PEI and 23 received TACE alone.Mortality data were not reported. The trial reported the survival data after one, two, and three years. In the TACE + PEI group, 92%, 80%, and 64% of the patients survived after 1, 2, and 3 years respectively; in the TACE group, 78.3%, 65.2%, and 47.8% of the patients survived after 1, 2, and 3 years respectively. The hazard ratio was 0.57 (95% CI 0.19 to 1.67). The local recurrence was 16% in the TACE + PEI group and 39.1% in the TACE group, resulting in a relative risk (RR) of 0.41 (95% CI 0.15 to 1.07). Forty-five tumours (66.2%) out of 68 tumours in total shrunk by at least 25% in the TACE + PEI group versus 31 tumours (48.4%) out of 64 tumours in total in the TACE group (RR 2.08; 95% CI 1.03 to 4.2). The authors reported some adverse events, but with very few details. On the basis of one small randomised trial, it can be concluded that addition of PEI to TACE, as compared with TACE alone, in patients with liver metastases seems to bring no clear benefit in terms of survival and local recurrence. The size of the tumour necrosis was larger in the combined treatment group. No intervention-related mortality or major complications were reported. More trials are needed.


Deshpande S.N.,Kleijnen Systematic Reviews Ltd
Health technology assessment (Winchester, England) | Year: 2013

Premature birth is defined as birth of before 37 completed weeks' gestation. Not all pregnant women showing symptoms of preterm labour will go on to deliver before 37 weeks' gestation. Hence, addition of fetal fibronectin (fFN) testing to the diagnostic workup of women with suspected preterm labour may help to identify those women who do not require active management, and thus avoid unnecessary interventions, hospitalisations and associated costs. To assess the clinical effectiveness and cost-effectiveness of rapid fFN testing in predicting preterm birth (PTB) in symptomatic women. Bibliographic databases (including EMBASE, Cochrane Database of Systematic Reviews and Cochrane Central Register of Controlled Trials) were searched from 2000 to September/November 2011. Trial registers were also searched. Systematic review methods followed published guidance; we assessed clinical effectiveness and updated a previous systematic review of test accuracy. Risk of bias was assessed using the Cochrane tool (randomised controlled trials; RCTs) and a modification of QUADAS-2 (diagnostic test accuracy studies; DTAs). Summary risk ratios or weighted mean difference were calculated using random-effects models. Summary sensitivity and specificity used a bivariate summary receiver operating characteristic model. Heterogeneity was investigated using subgroup and sensitivity analyses. Health economic analysis focused on cost consequences. The time horizon was hospital admission for observation. A main structural assumption was that, compared with usual care, fFN testing doesn't increase adverse events or negative pregnancy outcomes. Five RCTs and 15 new DTAs were identified. No RCT reported significant effects of fFN testing on maternal or neonatal outcomes. One study reported a subgroup analysis of women with negative fFN test observed > 6 hours, which showed a reduction in length of hospital stay where results were known to clinicians. Combining data from new studies and the previous systematic review, the pooled estimates of sensitivity and specificity were: 76.7% and 82.7% for delivery within 7-10 days of testing; 69.1% and 84.4% for delivery < 34 weeks' gestation; and 60.8% and 82.3% for delivery < 37 weeks' gestation. Estimates were similar across all subgroups sensitivity analyses. The base-case cost analysis resulted in a cost saving of £23.87 for fFN testing compared with usual care. The fFN testing was cost-neutral at an approximate cost of £45. Probabilistic sensitivity analysis gave an incremental cost (saving) of -£25.59 (97.5% confidence interval -£304.96 to £240.06), indicating substantial uncertainty. Sensitivity analyses indicated that admission rate had the largest impact on results. Fetal fibronectin testing has moderate accuracy for predicting PTB. The main potential role is likely to be reducing health-care resource usage by identifying women not requiring intervention. Evidence from RCTs suggests that fFN does not increase adverse outcomes and may reduce resource use. The base-case analysis showed a modest cost difference in favour of fFN testing, which is largely dependent on whether or not fFN testing reduces hospital admission. Currently, there are no high-quality studies and the existing trials were generally underpowered. Hence, there is a need for high-quality adequately powered trials using appropriate study designs to confirm the findings presented. PROSPERO 2011:CRD42011001468. Available from www.crd.york.ac.uk/PROSPERO/display_record.asp?ID=CRD42011001468. The National Institute for Health Research Health Technology Assessment programme.


Worthy G.,Kleijnen Systematic Reviews Ltd.
Swiss Medical Weekly | Year: 2015

When performing statistical peer review for Swiss Medical Weekly papers there often appear to be common errors or recurring themes regarding the reporting of study designs, statistical analysis methods, results and their interpretation. In order to help authors with choosing and describing the most appropriate analysis methods and reporting their results, we have created a guide to the most common issues and how to avoid them. This guide will follow the recommended structure for original papers as provided in the guidelines for authors (http://blog.smw.ch/what-smw-has-to-offer/guidelines-for-authors/), and provide advice for each section. This paper is intended to provide an overview of statistical methods and tips for writing your paper; it is not a comprehensive review of all statistical methods. Guidance is provided about the choice of statistical methods for different situations and types of data, how to report the methods, present figures and tables, and how to correctly present and interpret the results. © 2015, EMH Swiss Medical Publishers Ltd. All rights reserved.


Riemsma R.P.,Kleijnen Systematic Reviews Ltd
Cochrane database of systematic reviews (Online) | Year: 2012

Primary liver tumours and liver metastases from colorectal carcinoma are the two most common malignant tumours to affect the liver. The liver is second only to the lymph nodes as the most common site for metastatic disease. More than half of the patients with metastatic liver disease will die from metastatic complications. Chemoembolisation is based on the concept that the blood supply to hepatic tumours originates predominantly from the hepatic artery. Therefore, embolisation of the hepatic artery can lead to selective necrosis of the liver tumour while it may leave normal parenchyma virtually unaffected. To study the beneficial and harmful effects of transarterial (chemo)embolisation compared with no intervention or placebo intervention in patients with liver metastases. We searched the Cochrane Hepato-Biliary Group Controlled Trials Register, Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, Science Citation Index Expanded, LILACS, and CINAHL up to November 2011. We included all randomised clinical trials assessing beneficial and harmful effects of transarterial (chemo)embolisation compared with no intervention or placebo intervention in patients with liver metastases, no matter the location of the primary tumour. We extracted relevant information on participant characteristics, interventions, study outcome measures, and data on the outcome measures for our review as well as information on the design and methodology of the studies. Bias risk assessment of the trials, fulfilling the inclusion criteria, and data extraction from the retrieved final evaluation trials were done by one author and checked by a second author. One randomised clinical trial fulfilled the inclusion criteria of the review. Sixty-one patients with colorectal liver metastases were randomised into three intervention groups: 22 received hepatic artery embolisation, 19 received hepatic artery infusion chemotherapy, and 20 were randomised to control, described as "no active therapeutic intervention, although symptomatic treatment was provided whenever necessary". As hepatic artery infusion chemotherapy is not in the scope of this review, we have not included the data from this intervention group. In the remaining two groups that were of interest to the review, 43 of the participants were men and 18 women. Most tumours were synchronous metastases involving up to 75% of the liver and non-resectable. The risk of bias in the trial was judged to be high.Patients were followed-up for a minimum of seven months. Mortality at last follow-up was 86% (19/22) in the hepatic artery embolisation group versus 95% (19/20) in the control group (RR 0.91; 95% CI 0.75 to 1.1), that is, no statistically significant difference was observed. Median survival after trial entry was 7.0 months (range 2 to 44) in the hepatic artery embolisation group and 7.9 months (range 1 to 26) in the control group. Nine out of 22 (41%) in the hepatic artery embolisation group and five out of 20 (25%) in the control group developed evidence of extrahepatic disease (RR 1.64; 95% CI 0.60 to 4.07). Local recurrence was reported for 10 patients in the trial without details about the trial group. Most patients in the embolisation group experienced post-embolic syndrome (82%), and one patient had local haematoma. No other adverse events were reported. The authors did not report if there were any adverse events in the control group. On the basis of one small randomised trial that did not describe sequence generation, allocation concealment or blinding, it can be concluded that in patients with liver metastases no significant survival benefit or benefit on extrahepatic recurrence was found in the embolisation group in comparison with the palliation group. The probability for selective outcome reporting bias in the trial is high. At present, transarterial (chemo)embolisation cannot be recommended outside randomised clinical trials.

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