Comparative efficacy and tolerability of anti-epileptic drugs for refractory focal epilepsy: systematic review and network meta-analysis reveals the need for long term comparator trials.

AIMS: To evaluate the comparative efficacy (50% reduction in seizure frequency) and tolerability (premature withdrawal due to adverse events) of anti-epileptic drugs (AEDs) for refractory epilepsy. METHODS: We searched Cochrane Central Register of Controlled Trials (Cochrane Library 2009, issue 2) including Epilepsy Group's specialized register, MEDLINE (1950 to March 2009), EMBASE (1980 to March 2009), and Current Contents Connect (1998 to March 2009) to conduct a systematic review of published studies, developed a treatment network and undertook a network meta-analysis. RESULTS: Forty-three eligible trials with 6346 patients and 12 interventions, including placebo, contributed to the analysis. Only three direct drug comparator trials were identified, the remaining 40 trials being placebo-controlled. Conventional random-effects meta-analysis indicated all drugs were superior in efficacy to placebo (overall odds ratio (OR] 3.78, 95% CI 3.14, 4.55) but did not permit firm distinction between drugs on the basis of the efficacy or tolerability. A Bayesian network meta-analysis prioritized oxcarbazepine, topiramate and pregabalin on the basis of short term efficacy. However, sodium valproate, levetiracetam, gabapentin and vigabatrin were prioritized on the basis of short-term efficacy and tolerability, with the caveat that vigabatrin is recognized as being associated with serious visual disturbance with chronic use. CONCLUSION: Of the wide range of AEDs licensed for the treatment of refractory epilepsy, sodium valproate, levetiracetam and gabapentin demonstrated the best balance of efficacy and tolerability. Until regulators mandate greater use of active comparator trials with longer term follow-up, network meta-analysis provides the only available means to quantify these clinically important parameters.

Clopidogrel and interaction with proton pump inhibitors: comparison between cohort and within person study designs.

OBJECTIVE: To measure the association between use of proton pump inhibitors and a range of harmful outcomes in patients using clopidogrel and aspirin. DESIGN: Observational cohort study and self controlled case series. SETTING: United Kingdom General Practice Research Database with linked data from the Myocardial Ischaemia National Audit Project (MINAP) and the Office for National Statistics (the cardiovascular disease research using linked bespoke studies and electronic records (CALIBER) collaboration) POPULATION: 24,471 patients receiving clopidogrel and aspirin. MAIN OUTCOME MEASURES: The primary outcome was death or incident myocardial infarction. Secondary outcomes were death, incident myocardial infarction, vascular death, and non-vascular death. Comparisons were made between proton pump inhibitor use and non-use. RESULTS: Of the 24,471 patients prescribed clopidogrel and aspirin, 12,439 (50%) were also prescribed a proton pump inhibitor at some time during the study. Death or incident myocardial infarction occurred in 1419 (11%) patients while they were receiving a proton pump inhibitor compared with 1341 (8%) who were not receiving a proton pump inhibitor. In multivariate analysis, the hazard ratio for the association between proton pump inhibitor use and death or incident myocardial infarction was 1.37 (95% confidence interval 1.27 to 1.48). Comparable results were seen for secondary outcomes and with other 2C19 inhibitors and with non-2C19 inhibitors. With the self controlled case series design to remove the effect of differences between people, there was no association between proton pump inhibitor use and myocardial infarction, with a rate ratio of 0.75 (0.55 to 1.01). Similarly, with the self controlled case series there was no association with myocardial infarction for other 2C19 inhibitors/non-inhibitors. CONCLUSION: The lack of a specific association and the discrepancy between findings of the analyses between and within people suggests that the interaction between proton pump inhibitors and clopidogrel is clinically unimportant.