[Show abstract][Hide abstract] ABSTRACT: To develop prognostic models for time to 12-month remission and time to treatment failure after initiating antiepileptic drug monotherapy for generalised and unclassified epilepsy.
We analysed data from the Standard and New Antiepileptic Drug (arm B) study, a randomised trial that compared initiating treatment with lamotrigine, topiramate and valproate in patients diagnosed with generalised or unclassified epilepsy. Multivariable regression modelling was used to investigate how clinical factors affect the probability of achieving 12-month remission and treatment failure.
Significant factors in the multivariable model for time to 12-month remission were having a relative with epilepsy, neurological insult, total number of tonic-clonic seizures before randomisation, seizure type and treatment. Significant factors in the multivariable model for time to treatment failure were treatment history (antiepileptic drug treatment prior to randomisation), EEG result, seizure type and treatment.
The models described within this paper can be used to identify patients most likely to achieve 12-month remission and most likely to have treatment failure, aiding individual patient risk stratification and the design and analysis of future epilepsy trials.
Journal of neurology, neurosurgery, and psychiatry 11/2013;
[Show abstract][Hide abstract] ABSTRACT: To determine the standard of reporting of harms-related data, in randomised controlled trials (RCTs) according to the Consolidated Standards of Reporting Trials (CONSORT) statement extension for harms.
The Cochrane library, Ovid MEDLINE, Scopus and ISI Web of Knowledge were searched for relevant literature.
We included publications of studies that used the CONSORT harms extension to assess the reporting of harms in RCTs.
We identified 7 studies which included between 10 and 205 RCTs. The clinical areas of the 7 studies were: hypertension (1), urology (1), epilepsy (1), complimentary medicine (2) and two not restricted to a clinical topic. Quality of the 7 studies was assessed by a risk of bias tool and was found to be variable. Adherence to the CONSORT harms criteria reported in the 7 studies was inadequate and variable across the items in the checklist. Adverse events are poorly defined, with 6 studies failing to exceed 50% adherence to the items in the checklist.
Readers of RCT publications need to be able to balance the trade-offs between benefits and harms of interventions. This systematic review suggests that this is compromised due to poor reporting of harms which is evident across a range of clinical areas. Improvements in quality could be achieved by wider adoption of the CONSORT harms criteria by journals reporting RCTs.
[Show abstract][Hide abstract] ABSTRACT: Outcome reporting bias (ORB) in randomised trials has been identified as a threat to the validity of systematic reviews. Previous work highlighting this problem is limited to considering a single primary review outcome. The aim of this study was to assess ORB across all efficacy outcomes in the Cochrane systematic reviews of cystic fibrosis.
Systematic reviews of interventions for cystic fibrosis published on the Cochrane Library by the Cochrane Cystic Fibrosis and Genetic Disorders Group before 2010 were assessed for discrepancies in outcomes between review protocol and full review. ORB in eligible trials was also assessed for all efficacy review outcomes. Two authors independently classified each outcome using a nine-point classification system developed by the Outcome Reporting Bias In Trials study. These classifications were used to inform the assessment of the risk of bias for selective outcome reporting for each trial.
-46 Cochrane cystic fibrosis systematic reviews were included. The median number of primary outcomes, number of trials and participants per trial in the reviews were 3 (IQR 2, 3), 4 (IQR 2, 8) and 21 (IQR 14, 41), respectively. 18 reviews (39%, 18/46) had a discrepancy in outcomes between protocol and full review. 37 reviews were eligible to be included in the ORB assessment. When considering review primary outcomes and all review outcomes, ORB was suspected in at least one trial in 86% and 100%, respectively.
Assessment of ORB within a systematic review of a single primary outcome underestimates the risk of ORB in comparison to the assessment of multiple primary and secondary outcomes. ORB in trials is highly prevalent within systematic reviews of cystic fibrosis when assessed across all outcomes. This could be reduced by the development of a core outcome set for trials and systematic reviews in cystic fibrosis.
[Show abstract][Hide abstract] ABSTRACT: Many randomised trials in surgery suffer from recruitment rates that lag behind projected targets. We aim to identify perceived barriers to recruitment among these pioneering trials in the field of head and neck cancer surgery.
Recruiting centres to all three trials (Selective Elective Neck Dissection (SEND), Positron Emission Tomography (PET)-Neck and Hyperbaric Oxygen in the Prevention of Osteoradionecrosis (HOPON)) were contacted by email by the chief investigators. Responders were asked to complete a web-based survey in order to identify the barriers to recruitment in their centre and grade each by severity.
Secondary care: 44 head and neck oncology regional referral centres.
Analysis was based on 85 responses evenly distributed between the three trials.
The most commonly identified perceived barriers to recruitment (more than 50% of responders identified the item as a barrier in all the three trials) in the order of frequency were: patients consent refusal because of expressed treatment preference, patients consent refusal owing to aversion to randomisation, excess complexity/amount of information provided to patients and lack of time in clinic to accommodate research. The most severely rated of these problems was consent refusal because of the expressed treatment preference and lack of time in the clinic.
Our findings confirm others' work in surgery that the most significant barrier to trial recruitment in head and neck cancer surgery is the patient's preference for one arm of the trial. It may be that additional training for those taking consent may be helpful in this regard. It is also important to adequately resource busy surgical clinics to support clinical trial recruitment.
[Show abstract][Hide abstract] ABSTRACT: This is an updated version of the original Cochrane review published in The Cochrane Library 2001, Issue 4.Worldwide, particularly in the developing world, phenytoin and phenobarbitone are commonly used antiepileptic drugs, primarily because they are inexpensive. The aim of this review is to summarise data from existing trials comparing phenytoin and phenobarbitone.
To review the best evidence comparing phenobarbitone and phenytoin when used as monotherapy in participants with partial onset seizures or generalised tonic-clonic seizures with or without other generalised seizure types.
We searched the Cochrane Epilepsy Group trials register (31 May 2012), the Cochrane Central Register of Controlled Trials (CENTRAL Issue 5 of 12, The Cochrane Library 2012) and MEDLINE (1946 to May week 4, 2012). We hand-searched relevant journals, contacted pharmaceutical companies, original trial investigators and experts in the field.
Randomised controlled trials in children or adults with partial onset seizures or generalised onset tonic-clonic seizures with a comparison of phenobarbitone monotherapy with phenytoin monotherapy.
This was an individual participant data (IPD) review. Outcomes were time to (a) treatment withdrawal (b) 12-month remission (c) six-month remission and (d) first seizure post randomisation. Cox proportional hazards regression models were used to obtain study-specific estimates of hazard ratios (HRs) with 95% confidence intervals (CIs) with the generic inverse variance method used to obtain the overall pooled estimate of HRs and 95% CIs.
Data have been obtained for four of eight studies meeting the inclusion criteria, amounting to 599 individuals, or approximately 63% of the potential data.The main overall results (pooled HR, 95% CI) were (a) time to treatment withdrawal 1.62 (1.23 to 2.14); (b) time to 12-month remission 0.90 (0.69 to 1.18) (c) time to six-month remission 0.92 (0.73 to 1.16) and (d) time to first seizure 0.85 (0.68 to 1.05). These results indicate a statistically significant clinical advantage for phenytoin in terms of treatment withdrawal. However, this result may have been confounded by several factors including substantial statistical heterogeneity between studies and lack of blinding in two studies.
The results of this review show that phenobarbitone was significantly more likely to be withdrawn than phenytoin. Given that no significant differences for seizure outcomes were found, the higher withdrawal rate with phenobarbitone may be due to adverse effects. Several factors may have confounded the results of this review.
Cochrane database of systematic reviews (Online) 01/2013; 1:CD002217.
[Show abstract][Hide abstract] ABSTRACT: Aim: Although several genetic and nongenetic factors are associated with warfarin dose, approximately 40% of variability remains unexplained. An as yet unexplored factor is medication adherence. Here, we investigate the influence of adherence on response to warfarin and on pharmacogenetic analyses of association. Patients & methods: A total of 311 patients starting warfarin were followed-up prospectively, and adherence was measured at 1, 8 and 26 weeks. The association between adherence and warfarin response was tested, and the additional proportion of variability in response explained by adherence was assessed. Results: Significant associations were found between adherence and achievement of stable dose and time taken to achieve it, with nonadherers taking longer. Adjusting for adherence increased the proportion of explained variability in treatment response by up to 8%. Conclusion: Given the significant contribution of adherence to drug response, we recommend that consideration is given to the value of assessing adherence when designing future pharmacogenetic studies of warfarin and other drugs. Original submitted 19 July 2012; Revision submitted 26 November 2012.
[Show abstract][Hide abstract] ABSTRACT: Source data verification (SDV) is a resource intensive method of quality assurance frequently used in clinical trials. There is no empirical evidence to suggest that SDV would impact on comparative treatment effect results from a clinical trial.
Data discrepancies and comparative treatment effects obtained following 100% SDV were compared to those based on data without SDV. Overall survival (OS) and Progression-free survival (PFS) were compared using Kaplan-Meier curves, log-rank tests and Cox models. Tumour response classifications and comparative treatment Odds Ratios (ORs) for the outcome objective response rate, and number of Serious Adverse Events (SAEs) were compared. OS estimates based on SDV data were compared against estimates obtained from centrally monitored data.
Data discrepancies were identified between different monitoring procedures for the majority of variables examined, with some variation in discrepancy rates. There were no systematic patterns to discrepancies and their impact was negligible on OS, the primary outcome of the trial (HR (95% CI): 1.18(0.99 to 1.41), p = 0.064 with 100% SDV; 1.18(0.99 to 1.42), p = 0.068 without SDV; 1.18(0.99 to 1.40), p = 0.073 with central monitoring). Results were similar for PFS. More extreme discrepancies were found for the subjective outcome overall objective response (OR (95% CI): 1.67(1.04 to 2.68), p = 0.03 with 100% SDV; 2.45(1.49 to 4.04), p = 0.0003 without any SDV) which was mostly due to differing CT scans.
Quality assurance methods used in clinical trials should be informed by empirical evidence. In this empirical comparison, SDV was expensive and identified random errors that made little impact on results and clinical conclusions of the trial. Central monitoring using an external data source was a more efficient approach for the primary outcome of OS. For the subjective outcome objective response, an independent blinded review committee and tracking system to monitor missing scan data could be more efficient than SDV.
[Show abstract][Hide abstract] ABSTRACT: Warfarin is a highly effective anticoagulant however its effectiveness relies on maintaining INR in therapeutic range. Finding the correct dose is difficult due to large inter-individual variability. Two genes, CYP2C9 and VKORC1, have been associated with this variability, leading to genotype-guided dosing tables in warfarin labeling. Nonetheless, it remains unclear how genotypic information should be used in practice. Navigating the literature to determine how genotype will influence warfarin response in a particular patient is difficult, due to significant variation in patient ethnicity, outcomes investigated, study design, and methodological rigor. Our systematic review was conducted to enable fair and accurate interpretation of which variants affect which outcomes, in which patients, and to what extent.
A comprehensive search strategy was applied and 117 studies included. Primary outcomes were stable dose, time to stable dose and bleeding events. Methodological quality was assessed using criteria of Jorgensen and Williamson and data synthesized in meta-analyses using advanced methods. Pooled effect estimates were significant in most ethnic groups for CYP2C9*3 and stable dose (mutant types requiring between 1.1(0.7-1.5) and 2.3 (1.6-3.0)mg/day). Effect estimates were also significant for VKORC1 and stable dose for most ethnicities, although direction differed between asians and non-asians (mutant types requiring between 0.8(0.4-1.3) and 1.5(1.1-1.8)mg/day more in asians and between 1.5(0.7-2.2) and 3.1(2.7-3.6)mg/day less in non-asians). Several studies were excluded due to inadequate data reporting. Assessing study quality highlighted significant variability in methodological rigor. Notably, there was significant evidence of selective reporting, of outcomes and analysis approaches.
Genetic associations with warfarin response vary between ethnicities. In order to achieve unbiased estimates in different populations, a high level of methodological rigor must be maintained and studies should report sufficient data to enable inclusion in meta-analyses. We propose minimum reporting requirements, suggest methodological guidelines and provide recommendations for reducing the risk of selective reporting.
PLoS ONE 08/2012; 7(8):e44064.
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