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

Terman, Samuel W.; Wang, Chang; Wang, Lu; Braun, Kees P.J.; Otte, Willem M.; Slinger, Geertruida; Kerr, Wesley T.; Lossius, Morten I.; Bonnett, Laura; Burke, James F.; Marson, Anthony G

doi:10.1111/epi.17273

Cited by 7 publications

(10 citation statements)

References 41 publications

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“…The difference in seizure recurrence between patients who continued and discontinued ASM is not significant, whilst neuropsychological tests showed a significant improvement in several domains after withdrawal. The Medical Research Council study included 1013 pediatric and adult patients on polytherapy [42][43][44]. After two years, the rate of recurrent seizures was significantly higher after ASM withdrawal (41% vs 22%).…”

Section: Epilepsymentioning

confidence: 99%

The sense of stopping migraine prophylaxis

et al. 2023

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Introduction Migraine prophylactic therapy has changed over recent years with the development and approval of monoclonal antibodies (mAbs) targeting the calcitonin gene-related peptide (CGRP) pathway. As new therapies emerged, leading headache societies have been providing guidelines on the initiation and escalation of such therapies. However, there is a lack of robust evidence looking at the duration of successful prophylaxis and the effects of therapy discontinuation. In this narrative review we explore both the biological and clinical rationale for prophylactic therapy discontinuation to provide a basis for clinical decision-making. Methods Three different literature search strategies were conducted for this narrative review. These include i) stopping rules in comorbidities of migraine in which overlapping preventives are prescribed, notably depression and epilepsy; ii) stopping rules of oral treatment and botox; iii) stopping rules of antibodies targeting the CGRP (receptor). Keywords were utilized in the following databases: Embase, Medline ALL, Web of Science Core collection, Cochran Central Register of Controlled Trials, and Google Scholar. Discussion Reasons to guide decision-making in stopping prophylactic migraine therapies include adverse events, efficacy failure, drug holiday following long-term administration, and patient-specific reasons. Certain guidelines contain both positive and negative stopping rules. Following withdrawal of migraine prophylaxis, migraine burden may return to pre-treatment level, remain unchanged, or lie somewhere in-between. The current suggestion to discontinue CGRP(-receptor) targeted mAbs after 6 to 12 months is based on expert opinion, as opposed to robust scientific evidence. Current guidelines advise the clinician to assess the success of CGRP(-receptor) targeted mAbs after three months. Based on excellent tolerability data and the absence of scientific data, we propose if no other reasons apply, to stop the use of mAbs when the number of migraine days decreases to four or fewer migraine days per month. There is a higher likelihood of developing side effects with oral migraine preventatives, and so we suggest stopping these drugs according to the national guidelines if they are well tolerated. Conclusion Translational and basic studies are warranted to investigate the long-term effects of a preventive drug after its discontinuation, starting from what is known about the biology of migraine. In addition, observational studies and, eventually, clinical trials focusing on the effect of discontinuation of migraine prophylactic therapies, are essential to substantiate evidence-based recommendations on stopping rules for both oral preventives and CGRP(-receptor) targeted therapies in migraine. Graphical Abstract

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Section: Epilepsymentioning

confidence: 99%

The sense of stopping migraine prophylaxis

et al. 2023

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“…First, intention to discontinue (eg, being randomized, or deciding at a clinic visit) is not identical to actually discontinuing and thus our findings could understate the influence of discontinuation. However, we previously demonstrated that the effect of nonadherence to randomized arm in MRC was trivial, 16 and adherence to randomized arms was nearly perfect in Lossius data. 11 Second, each interaction must be interpreted in the setting of included confounders and modeling assumptions, it is not possible to test for all possible higher-order effects or interactions, and no dataset in existence has measured all possibly relevant variables.…”

Section: Our Work Has Limitationsmentioning

confidence: 94%

“… Medical Research Council (MRC) RCT 10 : Adults and children with epilepsy who were at least 2 years seizure free were randomized to discontinue (decrementing doses every ~4 weeks until off) versus continue ASMs, across 40 centers in the United Kingdom. Five percent of the withdrawal group did not withdraw and 35% of the continuation group did not continue, but this resulted in negligible bias 16 The Akershus RCT (Lossius et al 11 …”

Section: Methodsmentioning

confidence: 99%

“…We produced average cumulative seizure incidence curves for discontinuation versus continuation with a time‐to‐event discrete logistic regression model (with a cubic term for time) via the cumulative product method akin to Kaplan‐Meier curve methodology (multiplying each months seizure‐free probability times the previous months value) 18,19 . This enabled us to avoid the proportional hazards assumption, which was violated in MRC 16 . We standardized over confounders listed in Table S1.…”

Section: Methodsmentioning

confidence: 99%

“…Our prior work produced the first-ever dose-response curves regarding ASM discontinuation to explore how seizure risk changes across partial dose reductions. 16 Fourth, each dataset has limitations. For example, while clinical trials are not confounded, patients enrolled in clinical trials may not exactly represent its intended source population due to the nature of recruitment and structured observation, and the Lossius et al trial enrolled an unusually low-risk population.…”

Section: Our Work Has Limitationsmentioning

confidence: 99%

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Variation in seizure risk increases from antiseizure medication withdrawal among patients with well‐controlled epilepsy: A pooled analysis

Terman,

Slinger,

Koek

et al. 2023

Epilepsia Open

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ObjectiveGuidelines suggest considering antiseizure medication (ASM) discontinuation in seizure‐free patients with epilepsy. Past work has poorly explored how discontinuation effects vary between patients. We evaluated (1) what factors modify the influence of discontinuation on seizure risk; and (2) the range of seizure risk increase due to discontinuation across low‐ versus high‐risk patients.MethodsWe pooled three datasets including seizure‐free patients who did and did not discontinue ASMs. We conducted time‐to‐first‐seizure analyses. First, we evaluated what individual patient factors modified the relative effect of ASM discontinuation on seizure risk via interaction terms. Then, we assessed the distribution of 2‐year risk increase as predicted by our adjusted logistic regressions.ResultsWe included 1626 patients, of whom 678 (42%) planned to discontinue all ASMs. The mean predicted 2‐year seizure risk was 43% [95% confidence interval (CI) 39%–46%] for discontinuation versus 21% (95% CI 19%–24%) for continuation. The mean 2‐year absolute seizure risk increase was 21% (95% CI 18%–26%). No individual interaction term was significant after correcting for multiple comparisons. The median [interquartile range (IQR)] risk increase across patients was 19% (IQR 14%–24%; range 7%–37%). Results were unchanged when restricting analyses to only the two RCTs.SignificanceNo single patient factor significantly modified the influence of discontinuation on seizure risk, although we captured how absolute risk increases change for patients that are at low versus high risk. Patients should likely continue ASMs if even a 7% 2‐year increase in the chance of any more seizures would be too much and should likely discontinue ASMs if even a 37% risk increase would be too little. In between these extremes, individualized risk calculation and a careful understanding of patient preferences are critical. Future work will further develop a two‐armed individualized seizure risk calculator and contextualize seizure risk thresholds below which to consider discontinuation.Plain Language SummaryUnderstanding how much antiseizure medications (ASMs) decrease seizure risk is an important part of determining which patients with epilepsy should be treated, especially for patients who have not had a seizure in a while. We found that there was a wide range in the amount that ASM discontinuation increases seizure risk—between 7% and 37%. We found that no single patient factor modified that amount. Understanding what a patient's seizure risk might be if they discontinued versus continued ASM treatment is critical to making informed decisions about whether the benefit of treatment outweighs the downsides.

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