Comparative effectiveness of anti-seizure medications in emulated trials using medical informatics

Anti-seizure medications (ASMs) are often prescribed using a trial-and-error approach with a similar sequence for many patients. Comparative effectiveness data beyond the first ASM prescription are limited. Artificial intelligence can automatically extract information from electronic health records (EHRs) and augment clinical trials. We conducted a retrospective cohort comparative effectiveness study of currently available ASMs using emulated clinical trials through a causal inference- and informatics-based framework. We extracted data from EHRs using natural language processing algorithms to collect epilepsy covariates and seizure outcomes. We compared ASMs using weighted Kaplan-Meier analyses and log-rank tests with Bonferroni corrections. We compared ASMs across seizure freedom over 2 years of follow-up, and drug retention rate over 5 years of follow-up. Emulated trials included 1596 patients (8379 patient-years) for seizure freedom as outcome and 2945 patients (14 238 patient-years) for retention as outcome. For all epilepsy types, among first-line ASMs, levetiracetam and lamotrigine were superior to oxcarbazepine for seizure freedom (P < 0.001), and levetiracetam was superior to lamotrigine and oxcarbazepine for retention (P < 0.001); among second-line ASMs, lacosamide had the best retention (P < 0.001) but lower seizure freedom rate than topiramate (P = 0.032); among third-line ASMs, cenobamate had longer retention than brivaracetam, but lower seizure freedom rate than clobazam and brivaracetam (P < 0.001). For focal epilepsies, first-line ASMs achieved similar rates of seizure freedom, but levetiracetam remained superior to lamotrigine and oxcarbazepine for retention (P < 0.001); among second-line ASMs, topiramate and lacosamide were both superior to zonisamide for seizure freedom (P < 0.001), while lacosamide remained superior to topiramate and zonisamide for retention (P < 0.002); among third-line ASMs, cenobamate, brivaracetam and clobazam achieved similar retention and seizure freedom. For generalized and unclassified epilepsies, first-line ASMs achieved similar seizure freedom, but levetiracetam remained superior to lamotrigine and oxcarbazepine for retention (P < 0.02); topiramate had the best seizure freedom among second-line ASMs (P < 0.001), while lacosamide again had better retention than zonisamide (P < 0.006); there were insufficient patients included in third-line ASM trials for this subgroup. In conclusion, emulated clinical trials provide a useful framework for studying the comparative effectiveness of anti-seizure medications using real-world observational data. Our findings of differences in seizure freedom and retention between ASMs help to generate hypotheses that should be tested in future prospective, randomized comparative effectiveness trials.