Reappraisal of the Medical Research Council Antiepileptic Drug Withdrawal Study: contamination-adjusted and dose-response re-analysis

Abstract

Objective: The 1991 Medical Research Council (MRC) Study compared seizure relapse for seizure-free patients randomized to withdraw vs continue of antiseizure medications (ASMs). We re-analyzed this trial to account for crossover between arms using contamination-adjusted intention to treat (CA ITT) methods, to explore dose-response curves, and to validate predictions against external data. ITT assesses the effect of being randomized to withdraw, as-treated analysis assesses the confounded effect of withdrawing, but CA ITT assesses the unconfounded effect of actually withdrawing. Methods: CA ITT involves two stages. First, we used randomized arm to predict whether patients withdrew their ASM (logistic) or total daily ASM dose (linear). Second, we used those values to predict seizure occurrence (logistic). Results: The trial randomized 503 patients to withdraw and 501 patients to continue ASMs. We found that 316 of 376 patients (88%) who were randomized to withdraw decreased their dose at every pre-seizure visit, compared with 35 of 424 (8%) who were randomized to continue (p <.01). Adjusted odds ratios of a 2-year seizure for those who withdrew vs those who did not was 1.3 (95% confidence interval [CI] 0.9–1.9) in the as-treated analysis, 2.5 (95% CI 1.9–3.4) comparing those randomized to withdraw vs continue for ITT, and 3.1 (95% CI 2.1–4.5) for CA ITT. Probabilities (withdrawal vs continue) were 28% vs 24% (as-treated), 40% vs 22% (ITT), and 43% vs 21% (CA ITT). Differences between ITT and CA ITT were greater when varying the predictor (reaching zero ASMs) or outcome (1-year seizures). As-treated dose-response curves demonstrated little to no effects, but larger effects in CA ITT analysis. MRC data overpredicted risk in Lossius data, with moderate discrimination (areas under the curve ~0.70). Significance: CA ITT results (the effect of actually withdrawing ASMs on seizures) were slightly greater than ITT effects (the effect of recommend withdrawing ASMs on seizures). How these findings affect clinical practice must be individualized.