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Epilepsia. 2018 Nov;59(11):2118-2124. doi: 10.1111/epi.14565. Epub 2018 Sep 24.

Response to treatment schedules after the first antiepileptic drug failed.

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Department of Neurology, West China Hospital, Sichuan University, Chengdu, China.
Department of Geriatrics, Affiliated Hospital of Qingdao University, Qingdao, Shandong, China.
Regenerative Medical Research Center, West China Hospital, Sichuan University, Chengdu, China.
Department of Biostatistics, School of Public Health, Yale University, New Haven, Connecticut.
Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, UK.



After the failure of the first antiepileptic drug (AED) at doses > 50% defined daily dose (DDD), there are three options for patients with epilepsy: combination therapy, alternative therapy, and increased dosage of the first AED. However, present studies have not provided evidence for which option is best. Therefore, we conducted this retrospective observational cohort study to compare the effects of three treatment schedules.


Patients diagnosed with newly diagnosed epilepsy at the epilepsy clinic of West China Hospital between August 2006 and February 2016 were evaluated for eligibility for this study. Patients who failed to respond to the first AED at doses > 50% DDD were included, and divided into three cohorts: increased dosage, combination therapy, and alternative therapy. Cumulative incidence curves for time to seizure freedom were compared for different cohorts by Gray test. Competing risk regression was conducted to evaluate the association of clinical predictors with seizure freedom.


Altogether, 502 patients (277 male, 55.2%) were included for further analysis, and the median duration of follow-up was 32 months (range = 8-127). The probability of seizure freedom was significantly higher in patients receiving combination therapy (n = 323) compared to the alternative therapy cohort (n = 76, P < 0.001) and increased dosage cohort (n = 103, P = 0.025). Competing risk regression analysis showed that combination therapy significantly increased the probability of seizure freedom (hazard ratio [HR] = 2.423, 95% confidence interval [CI] = 1.529-3.841, P < 0.001). In addition, male sex and generalized seizure were significantly associated with increased probability of seizure freedom (male sex: HR = 1.440, 95% CI = 1.106-1.880, P = 0.007; generalized seizure: HR = 1.543, 95% CI = 1.176-2.020, P = 0.002).


Combination therapy may increase the probability of seizure freedom for patients with first AED failure due to lack of efficacy.


alternative therapy; combination therapy; dose; treatment failure

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