Graham Powell

Reporting of adverse events in randomised controlled trials of antiepileptic drugs using the CONSORT criteria for reporting harms

PURPOSE To assess the reporting of adverse events (AEs) in randomised controlled trials (RCTs) of antiepileptic drugs (AEDs) using the CONSORT statement for harms 2004, and to determine if reporting has changed since introduction of this standard. PRINCIPAL RESULTS One hundred and fifty two RCTs were included from a search of papers published between 1999 and 2008 inclusive. We identified 23 criteria in the CONSORT statements. The mean number of criteria met per trial was 11.3 (95%CI 10.6-12.0). Commercially funded studies met 12.6 and non-commercially funded met 9.4 (p<0.001). Trials recruiting adults met 12.5 and trials recruiting children met 9.3 (p<0.001). Trials published before 2004 met 11.6 and trials published after 2004 met 11.1 (p=0.53). Commercially funded trials met the majority of criteria more than non-commercially sponsored trials, particularly for definition of AEs (RR 3.15, CI 1.67-5.95) and the use of a validated dictionary of terms (RR 3.46, CI 1.41-8.44). Definitions for AEs (RR 2.32, CI 1.07-5.02) and details of analyses (RR 2.05, CI 1.01-4.15) were reported in adult trials more often than trials in children. MAJOR CONCLUSIONS Reporting of AEs in RCTs of AEDs is poor and has not improved since the publication of the CONSORT guidelines on the reporting of harms. Commercially funded trials were better reported than non-commercially funded trials and trials recruiting adults were better reported than trials recruiting children. These findings have serious implications as poor reporting precludes bias being detected and hinders adequate risk benefit analyses. Journal editors, authors and reviewers should be encouraged to follow current guidance.

Improving the diagnosis of central nervous system infections in adults through introduction of a simple lumbar puncture pack

Background Acute central nervous system (CNS) infections, such as meningitis and encephalitis, are neurological emergencies for which accurate diagnosis and prompt treatment improve the outcome. Analysis of the cerebrospinal fluid (CSF) obtained at lumbar puncture (LP) is pivotal to establishing the diagnosis and guiding management. PCR analysis of the CSF is an important method to identify the pathogen. However, recent studies have demonstrated that many patients have inadequate CSF sample collection and analysis. Aims To increase the proportion of patients having an LP for a suspected CNS infection for whom the appropriate samples are taken. Secondary aims included to increase the proportion of patients for whom a pathogen was identified. Methods The authors developed an LP pack for patients with a suspected CNS infection. They also assessed its impact on diagnosis by comparing practice 6 months before and after its introduction to the medical admissions unit of a large inner city teaching hospital. Results The authors found that the LP pack reduced major errors in CSF sample collection and improved the diagnosis of acute CNS infections; among those patients who had a CSF pleocytosis, the proportion with a viral or bacterial pathogen identified by PCR was increased after introduction of the pack. Discussion This study has demonstrated that the introduction of a simple low-cost LP pack into a busy acute medical setting can improve the diagnosis of CNS infections and, thus, guide treatment. Further work is needed to see if these results are more widely reproducible, and to examine the clinical, health and economic impact on overall management of patients with suspected CNS infections.

Anti-epileptic drug harms: issues for meta-analysis

Objectives Decisions regarding choice and dose of anti-epileptic drug (AED) are driven by considering the potential benefits of reducing seizure frequency against the potential harms of alternative AEDs. Such decisions should be made using the best available evidence, which often requires a quantitative synthesis of data from multiple randomised controlled trials (RCT). However, the systematic review and meta-analysis of harms data is hindered by problems such as inadequate reporting, heterogeneity of harms definitions, and selective reporting bias. Here we will evaluate the quality of reporting of harms data in epilepsy trials, and assess the potential added value of incorporating harms data beyond the clinical indication of epilepsy.

Breakthrough seizures-Further analysis of the Standard versus New Antiepileptic Drugs (SANAD) study

Objectives To develop prognostic models for risk of a breakthrough seizure, risk of seizure recurrence after a breakthrough seizure, and likelihood of achieving 12-month remission following a breakthrough seizure. A breakthrough seizure is one that occurs following at least 12 months remission whilst on treatment. Methods We analysed data from the SANAD study. This long-term randomised trial compared treatments for participants with newly diagnosed epilepsy. Multivariable Cox models investigated how clinical factors affect the probability of each outcome. Best fitting multivariable models were produced with variable reduction by Akaike’s Information Criterion. Risks associated with combinations of risk factors were calculated from each multivariable model. Results Significant factors in the multivariable model for risk of a breakthrough seizure following 12-month remission were number of tonic-clonic seizures by achievement of 12-month remission, time taken to achieve 12-month remission, and neurological insult. Significant factors in the model for risk of seizure recurrence following a breakthrough seizure were total number of drugs attempted to achieve 12-month remission, time to achieve 12-month remission prior to breakthrough seizure, and breakthrough seizure treatment decision. Significant factors in the model for likelihood of achieving 12-month remission after a breakthrough seizure were gender, age at breakthrough seizure, time to achieve 12-month remission prior to breakthrough, and breakthrough seizure treatment decision. Conclusions This is the first analysis to consider risk of a breakthrough seizure and subsequent outcomes. The described models can be used to identify people most likely to have a breakthrough seizure, a seizure recurrence following a breakthrough seizure, and to achieve 12-month remission following a breakthrough seizure. The results suggest that focussing on achieving 12-month remission swiftly represents the best therapeutic aim to reduce the risk of a breakthrough seizure and subsequent negative outcomes. This will aid individual patient risk stratification and the design of future epilepsy trials.

PO240 Using routinely recorded data in a clinical trial

There are a number of clinical and non-clinical administrative datasets that routinely record information on individuals in the UK. Access for secondary uses such as clinical research is permitted when health and social care benefit can be demonstrated. Clinical sources of data are commonly accessed to provide data for retrospective observational and record-linkage studies and provide a valid dataset for this purpose. Routinely recorded data may also present advantages to prospective clinical research such as randomised controlled trials (RCTs). The majority of RCTs incur health service costs as clinicians assess participants, record outcomes and complete Case Report Forms – hence using routinely recorded data may provide an efficient alternative method for data collection in addition to reducing the burden on participants. Furthermore, data from non-clinical routine sources may inform outcomes beyond the standard RCT assessments of clinical efficacy and effectiveness. However, limitations with accuracy of coding, confidentiality, ownership and access have previously been identified as significant barriers. This study has assessed the feasibility of accessing clinical and non-clinical routinely recorded data during a RCT assessing treatments for newly diagnosed epilepsy and will assess the agreement and additional benefits of routinely recorded data compared to data collected using standard prospective methods.

Risk of a seizure recurrence after a breakthrough seizure and the implications for driving: further analysis of the standard versus new antiepileptic drugs (SANAD) randomised controlled trial

Objectives A breakthrough seizure is one occurring after at least 12 months seizure freedom while on treatment. The Driver and Vehicle Licensing Agency (DVLA) allows an individual to return to driving once they have been seizure free for 12 months following a breakthrough seizure. This is based on the assumption that the risk of a further seizure in the next 12 months has dropped <20%. This analysis considers whether the prescribed 1 year off driving following a breakthrough seizure is sufficient for this and stratifies risk according to clinical characteristics. Design, setting, participants, interventions and main outcome measures The multicentre UK-based Standard versus New Antiepileptic Drugs (SANAD) study was a randomised controlled trial assessing standard and new antiepileptic drugs for patients with newly diagnosed epilepsy. For participants aged at least 16 with a breakthrough seizure, data have been analysed to estimate the annual seizure recurrence risk following a period of 6, 9 and 12 months seizure freedom. Regression modelling was used to investigate how antiepileptic drug treatment and a number of clinical factors influence the risk of seizure recurrence. Results At 12 months following a breakthrough seizure, the overall unadjusted risk of a recurrence over the next 12 months is lower than 20%, risk 17% (95% CI 15% to 19%). However, some patient subgroups have been identified which have an annual recurrence risk significantly greater than 20% after an initial 12-month seizure-free period following a breakthrough seizure. Conclusions This reanalysis of SANAD provides estimates of seizure recurrence risks following a breakthrough seizure that will inform policy and guidance about regaining an ordinary driving licence. Further guidance is needed as to how such data should be used. Trial registration number SANAD is registered with the International Standard Randomised Controlled Trial Number Register ISRCTN38354748.

The trials and tribulations of accessing data from routine sources

There are a number of administrative datasets that routinely record information on individuals in the UK. Such routine or ‘Big Data’ sources record specified data variables that are largely limited to those that enable the intended objectives of the data holder. Routine sources include clinical datasets such as Hospital Episode Statistics (HES) and the Clinical Practice Research Datalink (CPRD). In addition, non-health data is recorded by the Department of Work and Pensions (DWP), HM Revenue and Customs (HMRC) and The Driving and Vehicle Licensing Authority (DVLA) in order to meet the specified objectives of each authority. Routine data applied to clinical research is potentially cost and resource-use effective. Clinical sources of data such as HES and CPRD are commonly accessed to provide data for retrospective observational and record-linkage studies and there are many published examples. However, there is limited evidence on the use of routine data in prospective studies, particularly randomised controlled trials (RCTs). This on-going project aims to assess the feasibility, accuracy, reliability and additional benefits of using data from routine sources for patients participating in the Standard and New Antiepileptic Drugs II RCT. Clinical and health economic outcomes will be examined from sources including HES, CPRD, DWP, HMRC and DVLA and assessed in comparison to data obtained from traditional RCT methods. This presentation will narratively summarise the methods of access, application procedures and limitations encountered thus far with accessing individual-level, linked data from the listed routine data sources.

069 Introduction of a simple lumbar puncture pack to a busy medical admissions unit improves diagnosis of central nervous system infections

Background In patients with central nervous system (CNS) infections urgent diagnosis and treatment significantly reduces mortality and neurological morbidity. Cerebrospinal fluid (CSF) analysis, obtained by lumbar puncture (LP), is pivotal to the diagnosis. Recent studies have demonstrated that patients typically do not have the appropriate samples taken. Methods We designed a LP pack including simple clinical guidelines and audited 6 months prior to and after the introduction of this in a busy medical admissions unit. Results The screen identified 177 patients who had an LP; 93 before and 84 after the introduction of the pack; 52 and 41 patients had the LP for a suspected CNS infection respectively. CSF and paired plasma glucose were sent in more patients after the introduction of the LP pack than before [41 (100%) vs 43 (82%), p<0.05 and 41 (100%) vs 24 (46%), p<0.001]. More patients had CSF sent for virological studies [21 (51%) vs 8 (15%), p<0.001] and more had a virus identified [5 (12%) vs 1 (2%), p<0.05]. Additionally, pathogen identification was higher overall (7 (17%) vs 3 (6%) respectively p<0.01]. Discussion The introduction of a simple LP pack in a busy medical admissions unit resulted in significant improvements in CSF investigations and improved diagnostic sensitivity in patients with suspected CNS infection.