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Title: Harms of antiepileptic drugs : issues in reporting and systematic reviews
Author: Shukralla, A. A.
ISNI:       0000 0004 7428 6443
Awarding Body: University of Liverpool
Current Institution: University of Liverpool
Date of Award: 2018
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Aims In this thesis, we shall discus the reporting of harms in randomised controlled trials using the CONSORT statement for harms 2004. To determine if reporting has changed since the introduction of this standard. To evaluate the effects of lacosamide when used as an add-on for drug resistant epilepsy in a systematic review and use it as a model to test hypothesis if harms. Develop new tools and methodologies in analysing harms in systematic reviews and to test of harms across indications can be used for antiepileptic drugs in systematic reviews Methods Statistical analyses were conducted using SPSS version 17, RevMan version 5.0 and Comprehensive Meta-analysis version 3.0 to analyses data. Continuous variables were compared with means using the Student t-tests analyses of variance (ANOVA). Proportion data were compared using relative risks. These were calculated using either and random or fixed effects models where appropriate. Heterogeneity was explored using statistical tests of heterogeneity and meta-regression. One hundred and fifty two RCTs published between 1999 and 2008 were included for analysis. Three epilepsy RCTs published between 2007 and 2010 were include for systematic reviews of lacosamide and an additional four neuropathy trials were included. One hundred and six randomised controlled trials of antiepileptic drugs were included to analyses harms across indications. Results 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. Three lacosamide trials were included in systematic reviews. The overall risk ratio for a 50% or greater reduction in seizure frequency for all doses of lacosamide compared to placebo was 1.70 (CI 1.38 to 2.10). The overall risk ratio for seizure freedom for all doses of lacosamide compared to placebo was 2.50 (CI 0.85 to 7.34). The overall risk ratio for treatment withdrawal for all doses of lacosamide compared to placebo was 1.88 (CI 1.40 to 2.52). Adverse effects, which were significantly associated with lacosamide, were abnormal coordination, blurred vision, diplopia, dizziness, fatigue, nausea and vomiting. Four lacosamide trials of neuropathy were selected and harms data form these were incorporated to data from epilepsy trials. The following harms outcomes: Any adverse events, dizziness, fatigue, headache, nasophryngitis, nausea, somnolence, tremor, vertigo, vision blurred, vomiting and withdraws due to adverse events were meta-analyzed. Only tremor (I2 of 0-64%) and nasophryngitis (I2 of 27-64%) showed significant heterogeneity in statistical tests. only outcome that changed effect size to yield a significant result when neuropathy trials were combined was fatigue. For the 400mg dose of lacosamide, the summary measures were 2.0 (95% CI of 1.0 to 4.03) and this changed to 1.98 (95% CI of 1.11 to 3.52) when neuropathy trials were combined. Therefore, harms across indications could be used for lacosamide. To test the hypothesis if harms across indications such as headache and neuropathy trials of other antiseptic drugs, meta-regression was used to further explore heterogeneity. Only lacosamide and lamotrigine could have harms across indications summated in systematic reviews but not for pregabalin and gabapentin due to significant heterogeneity, which could be explained by dose effects. Conclusion 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. Lacosamide is effective in treating partial epilepsy versus placebo for the 200mg, 400mg and 600mg doses. Harms from neuropathy trials can be used to improve harms reporting in systematic reviews of lacosamide. Harms across indications could also be used for lamotrigine but not for pregabalin and gabapentin. Novel methods need to be developed for incorporating observational studies in systemic reviews. Clinicians and Journal Editors need to have a greater awareness of poor harms reporting in RCTs and this needs to be more transparent.
Supervisor: Marson, Anthony ; Tudur Smith, Catrin Sponsor: Not available
Qualification Name: Thesis (M.D.) Qualification Level: Doctoral