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Meta-Analysis
. 2020 Jan 23;1(1):CD005003.
doi: 10.1002/14651858.CD005003.pub3.

Rapid versus slow withdrawal of antiepileptic drugs

Fernando Ayuga Loro  1 , Enrique Gisbert Tijeras  1 , Francesco Brigo  2
Affiliations
Meta-Analysis

Rapid versus slow withdrawal of antiepileptic drugs

Fernando Ayuga Loro et al. Cochrane Database Syst Rev. .

Update in

  • Rapid versus slow withdrawal of antiepileptic drugs.
    Ayuga Loro F, Gisbert Tijeras E, Brigo F. Ayuga Loro F, et al. Cochrane Database Syst Rev. 2022 Jan 10;1(1):CD005003. doi: 10.1002/14651858.CD005003.pub4. Cochrane Database Syst Rev. 2022. PMID: 35005782 Free PMC article.

Abstract
in English, French

Background: The ideal objective of treating a person with epilepsy is to induce remission (free of seizures for some time) using antiepileptic drugs (AEDs) and withdraw the AEDs without causing seizure recurrence. Prolonged usage of AEDs may have long-term adverse effects. Hence, when a person with epilepsy is in remission, it is logical to attempt to discontinue the medication. The timing of withdrawal and the mode of withdrawal arise while contemplating withdrawal of AEDs. This review examines the evidence for the rate of withdrawal of AEDs (whether rapid or slow tapering) and its effect on seizure recurrence. This is an updated version of the original Cochrane Review published in 2006, Issue 2.

Objectives: To quantify risk of seizure recurrence after rapid (tapering period of three months or less) or slow (tapering period of more than three months) discontinuation of antiepileptic drugs in adults and children with epilepsy who are in remission, and to assess which variables modify the risk of seizure recurrence.

Search methods: For the latest update, on 9 April 2019, we searched: Cochrane Register of Studies (CRS Web, which includes the Cochrane Epilepsy Group Specialized Register, CENTRAL, and ClinicalTrials.gov), MEDLINE (Ovid; 8 April 2019), the WHO International Clinical Trials Registry Platform, and SCOPUS. There were no language restrictions.

Selection criteria: Randomized controlled trials that evaluate withdrawal of AEDs in a rapid or slow tapering after varying periods of seizure control in people with epilepsy.

Data collection and analysis: Review authors independently assessed the trials for inclusion and extracted the data. The outcomes assessed included seizure freedom after one, two, or five years of AED withdrawal; time to recurrence of seizure following withdrawal; occurrence of status epilepticus; mortality; morbidity due to seizure, such as injuries, fractures, and aspiration pneumonia; and quality of life (assessed by validated scale).

Main results: In this review update, we have included one new study. The new study randomized 57 children with epilepsy with seizure freedom for at least two years to taper the AED during over one or six months. The study was not blinded and there were no details of randomization. Over the period of 54 months of follow-up, 20/30 participants in the one-month group remained seizure-free compared to 15/27 participants in the six-month group (no evidence of a difference). There was no information on time of seizure recurrence for each group to allow a comparison. One trial had already been included in the previous version of the review; it involved 149 children. There was a non-significant trend toward a lower risk of seizure recurrence after one year of AED withdrawal in participants allocated to slow tapering (risk ratio (RR) 0.76, 95% confidence interval (CI) 0.58 to 1.01; P= 0.06; very low-certainty evidence). At the end of two years, 30 participants were seizure free in the rapid-tapering group and 29 participants in the slow-tapering group (RR 0.87, 95% CI 0.58 to 1.29; P = 0.48; very low-certainty evidence). At the end of five years, 10 participants were seizure free in the rapid-tapering group and six participants in the slow-tapering group (RR 1.40, 95% CI 0.54 to 3.65; P = 0.49; very low-certainty evidence). There were no data for the other outcomes. Due to the methodological heterogeneity and the difference in the duration of tapering we did not perform a quantitative synthesis of these studies.

Authors' conclusions: Since the last version of this review was published, we found one new pediatric study. In view of methodological deficiencies, and small sample size of the two included studies, we cannot draw any reliable conclusions regarding the optimal rate of tapering of AEDs. Using GRADE, we assessed the certainty of the evidence as very low for outcomes for which data were available. We judged both studies to be at high risk of bias. Further studies are needed in adults and children to investigate the optimal rate of withdrawal of AEDs and to study the effects of variables such as seizure types, etiology, mental retardation, electroencephalography abnormalities, presence of neurologic deficits, and other comorbidities on the rate of tapering.

Contexte: L'objectif idéal du traitement d'une personne épileptique est d'induire une rémission (absence de crises pendant un certain temps) en utilisant des médicaments antiépileptiques (MAE) et d’arrêter les MAE sans provoquer de récidive des crises. L'utilisation prolongée des MAE pourrait avoir des effets indésirables à long terme. Par conséquent, lorsqu'une personne épileptique est en rémission, il est logique de tenter d'interrompre la médication. La question du moment et du mode d’arrêt se posent lorsque l'on envisage l’arrêt des MAE. Cette revue examine les données probantes sur le taux d’arrêt des MAE (qu'il s'agisse d'un arrêt rapide ou lent) et son effet sur la récurrence des crises. Ceci est une version mise à jour de la revue Cochrane originale publiée en 2006, numéro 2.

Objectifs: Quantifier le risque de récidive des crises après un arrêt rapide (période de diminution progressive de trois mois ou moins) ou lent (période de diminution progressive de plus de trois mois) des médicaments antiépileptiques chez les adultes et les enfants épileptiques en rémission, et évaluer les variables qui modifient le risque de récidive des crises. STRATÉGIE DE RECHERCHE DOCUMENTAIRE: Pour la dernière mise à jour, le 9 avril 2019, nous avons fait des recherches dans : le registre Cochrane des études cliniques (CRS Web, qui comprend le registre spécialisé du groupe Cochrane sur l’épilepsie, CENTRAL, et ClinicalTrials.gov), MEDLINE (Ovid ; 8 avril 2019), le système d'enregistrement international des essais cliniques (ICTRP) de l’OMS et SCOPUS. Aucune restriction de langue n’a été appliquée. CRITÈRES DE SÉLECTION: Essais contrôlés randomisés qui évaluent l’arrêt des MAE, par une diminution rapide ou lente, après diverses périodes de contrôle des crises chez les personnes épileptiques. RECUEIL ET ANALYSE DES DONNÉES: Les auteurs de l'étude ont, de manière indépendante, évalué les essais pour l'inclusion et ont extrait les données. Les critères de jugement évalués comprenaient l’absence de crise après un, deux ou cinq ans d’arrêt des MAE ; le délai sans récidive de crise après arrêt ; l'apparition d’un état de mal épileptique ; la mortalité ; la morbidité due à la crise, comme les blessures, les fractures et la pneumonie d’aspiration ; et la qualité de vie (évaluée par une échelle validée). RÉSULTATS PRINCIPAUX: Dans cette mise à jour de la revue, nous avons inclus une nouvelle étude. La nouvelle étude a randomisé 57 enfants souffrant d'épilepsie et ne souffrant pas de crises depuis au moins deux ans afin de réduire la prise des MAE pendant au moins un à six mois. L'étude n'a pas été réalisée en aveugle et il n'y a pas eu de détails sur la randomisation. Au cours de la période de suivi de 54 mois, 20/30 participants du groupe un mois sont restés sans crise d'épilepsie, contre 15/27 participants du groupe six mois (pas de preuve de différence). Il n'y avait pas d’information sur le moment de la récidive des crises dans chaque groupe afin de permettre une comparaison. Un essai avait déjà été inclus dans la version précédente de la revue ; il concernait 149 enfants. Nous avons constaté une tendance non‐significative de diminution du risque de récidive des crises après un an d’arrêt des MAE, chez les participants affectés à la diminution lente (rapport de risque (RR) 0,76, intervalle de confiance (IC) à 95% 0,58 à 1,01 ; P= 0,06 ; données probantes de très faible certitude). Au bout de deux ans, 30 participants étaient exempts de crises dans le groupe à diminution rapide et 29 participants dans le groupe à diminution lente (RR 0,87, 95 % IC 0,58 à 1,29 ; P = 0,48 ; données probantes de très faible certitude). Au bout de cinq ans, dix participants étaient exempts de crises d'épilepsie dans le groupe à diminution rapide et six dans le groupe à diminution lente (RR 1,40, IC 95% 0,54 à 3,65 ; P = 0,49 ; données probantes de très faible certitude). Il n'y avait pas de données sur les autres critères de jugement. En raison de l'hétérogénéité méthodologique et de différence dans la durée de la diminution, nous n'avons pas effectué de synthèse quantitative de ces études.

Conclusions des auteurs: Depuis la publication de la dernière version de cette revue, nous avons trouvé une nouvelle étude pédiatrique. Compte tenu des lacunes méthodologiques et de la petite taille de l'échantillon des deux études incluses, nous ne pouvons pas tirer de conclusions fiables concernant le rythme de diminution optimal des MAE. En utilisant GRADE, nous avons évalué la certitude des données probantes comme étant très faible pour les résultats pour lesquels des données étaient disponibles. Nous avons jugé que les deux études présentaient un risque de biais élevé. D'autres études sont nécessaires chez les adultes et les enfants pour étudier le taux d’arrêt optimal des MAE et pour étudier les effets de variables telles que les types de crises, l'étiologie, le retard mental, les anomalies sur l'électroencéphalogramme, la présence de déficits neurologiques et d'autres comorbidités sur le rythme de diminution.

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Conflict of interest statement

FAL: none known. EGT: none known. FB: has acted as a consultant and received travel support from Eisai; he has received payment for lectures from UCB Pharma.

Figures

1
1
Study flow diagram.
2
2
Risk of bias graph: review authors' judgments about each risk of bias item presented as percentages across all included studies.
3
3
Risk of bias summary: review authors' judgments about each risk of bias item for each included study.
See this image and copyright information in PMC

Comment in

References

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