Vigabatrina versus monoterapia con carbamazepina para la epilepsia
Resumen
Antecedentes
Esta es una actualización de una revisión Cochrane publicada por primera vez en 2012 (Base de datos Cochrane de revisiones sistemáticas 2012, número 1).
La eficacia y la seguridad de la vigabatrina (VGB) como tratamiento complementario para la epilepsia refractaria están bien establecidas. Sin embargo, esta información debe sopesarse con el riesgo de desarrollo de defectos en el campo visual. No se ha examinado sistemáticamente si la monoterapia con VGB es un tratamiento efectivo y seguro, en comparación con la monoterapia con el fármaco antiepiléptico estándar carbamazepina (CBZ) para la epilepsia.
Objetivos
Investigar la eficacia y seguridad de la monoterapia VGB versus CBZ para la epilepsia en niños y adultos.
Métodos de búsqueda
Para la última actualización, se hicieron búsquedas en el Registro Cochrane Central de Ensayos Controlados (Cochrane Central Register of Controlled Trials) (CENTRAL; 2015, número 3 de 4), MEDLINE (1948 hasta julio 2015), EMBASE (1974 hasta julio 2015) y en la Chinese Biomedical Database (CBM) (1979 hasta julio 2015). Se realizaron búsquedas en los registros de ensayos y se contactó al fabricante de VGB, así como a los autores de los estudios incluidos para obtener más información. No se aplicaron restricciones de idioma.
Criterios de selección
Ensayos controlados aleatorizados (ECA) que comparan la monoterapia VGB versus CBZ para la epilepsia.
Obtención y análisis de los datos
Dos autores de la revisión evaluaron de forma independiente la calidad de los ensayos y extrajeron los datos. El resultado principal fue el tiempo hasta el retiro del tratamiento. Los resultados secundarios fueron el tiempo hasta lograr una remisión de seis y 12 meses después de la asignación al azar, el tiempo hasta la primera crisis convulsiva después de la asignación al azar y los eventos adversos. Los resultados se presentaron como cocientes de riesgos instantáneos (CRI) con intervalos de confianza (IC) del 95% (datos de tiempo hasta el evento) o como riesgos relativos (RR) con IC del 95% (eventos adversos).
Resultados principales
Fueron elegibles para su inclusión un total de cinco estudios, que involucraron un total de 734 participantes. Un estudio fue evaluado como de buena calidad y los otros cuatro como de mala calidad. Sin embargo, fue difícil realizar un metaanálisis mediante la extracción de datos agregados para sintetizar los resultados como se había previsto originalmente, principalmente porque no todos los estudios informaron de los mismos resultados que los elegidos para esta revisión. Ninguna diferencia significativa favoreció al VGB o a la CBZ en cuanto al tiempo para la retirada del tratamiento y el tiempo para lograr una remisión de seis meses después de la estabilización de la dosis a partir de la aleatorización, pero los resultados sí mostraron una desventaja para el VGB en cuanto al tiempo para la primera convulsión después de la aleatorización. En comparación con la CBZ, la VGB se asoció con más casos de aumento de peso y menos casos de sarpullido y somnolencia. No hubo diferencias en los defectos del campo visual y los trastornos visuales.
Conclusiones de los autores
Actualmente no hay datos suficientes para considerar el equilibrio entre los riesgos y beneficios del uso de VGB versus monoterapia con CBZ para la epilepsia. Dada la alta prevalencia de defectos del campo visual que se ha informado en una revisión sistemática existente de estudios de observación (Maguire 2010), la monoterapia VGB debe prescribirse con precaución para la epilepsia y no debe considerarse una opción de primera línea. De ser necesario, el campo visual debe ser evaluado con frecuencia. La investigación futura debe centrarse en investigar las razones de los defectos del campo visual y explorar las estrategias potenciales de prevención. Además, los estudios futuros de la monoterapia para la epilepsia deben presentar los resultados de acuerdo a la recomendación de la International League Against Epilepsy (Liga Internacional Contra la Epilepsia) (ILAE), y se debe mejorar su calidad metodológica.
PICO
Resumen en términos sencillos
Vigabatrina versus monoterapia con carbamazepina para la epilepsia
Pregunta de la revisión
Esta revisión es una actualización de una revisión previamente publicada en la Base de Datos Cochrane de Revisiones Sistemáticas (Cochrane Database of Systematic Reviews) (2012, Número 1) titulada "Vigabatrina versus monoterapia con carbamazepina para la epilepsia". Se reviso la evidencia sobre la eficacia y la seguridad de la vigabatrina frente a la carbamazepina (CBZ) cuando se utiliza como monoterapia para la epilepsia. Se encontraron cinco estudios.
Antecedentes
La epilepsia es un trastorno neurológico común que afecta a más de 50 millones de personas en todo el mundo. La eficacia y la seguridad de la vigabatrina como tratamiento complementario de la epilepsia refractaria están bien establecidas. Sin embargo, esta información debe sopesarse con el riesgo de desarrollo de defectos en el campo visual. Se deseaba saber si la monoterapia con vigabatrina es efectiva y segura comparada con el medicamento antiepiléptico estándar carbamazepina como monoterapia para la epilepsia.
Características de los estudios
La evidencia está actualizada hasta julio de 2015. Se encontraron cinco ensayos que evaluaban la monoterapia con vigabatrina o carbamazepina para la epilepsia recién diagnosticada, que reclutaron un total de 734 participantes de entre seis meses y 65 años de edad.
Resultados clave
Los resultados de esta revisión no muestran diferencias significativas entre la vigabatrina y la carbamazepina en cuanto al tiempo transcurrido hasta la retirada del tratamiento y el tiempo para lograr una remisión de seis meses después de la estabilización de la dosis a partir de la asignación al azar, pero revelan algunas desventajas clínicas con la vigabatrina en el tiempo transcurrido hasta la primera convulsión. La vigabatrina presentó más probabilidades de dar lugar a un aumento de peso. Una preocupación de seguridad era la alta prevalencia de defectos en el campo visual, como se informó en una revisión sistemática de los estudios de observación (Maguire 2010).
Calidad de la evidencia
Un estudio fue evaluado como de buena calidad y los otros cuatro como de mala calidad.
Authors' conclusions
Summary of findings
| Vigabatrin (VGB) compared with carbamazepine (CBZ) monotherapy for epilepsy | ||||||
| Patient or population: patients with epilepsy | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | Number of participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| CBZ monotherapy | VGB | |||||
| Time to treatment withdrawal | Patients with epilepsy | HR 0.75 | 446 | ⊕⊕⊝⊝ | No significant decrease in risk of withdrawal with VGB | |
| See comment | See comment | |||||
| Time to achieve 6‐month remission after the first 6 weeks of dose stabilisation from randomisation | Patients with epilepsy | HR 1.18 | 404 | ⊕⊝⊝⊝ | No significant increase in clinical advantage with VGB | |
| See comment | See comment | |||||
| Time to first seizure after randomisation | Patients with epilepsy | HR 1.57 | 404 | ⊕⊕⊝⊝ | Significant increase in clinical disadvantage with VGB | |
| See comment | See comment | |||||
| Adverse events | Patients with epilepsy | RR 5.37 | 54 | ⊕⊝⊝⊝ | Two participants in the VGB group experienced this adverse event | |
| See comment | See comment | |||||
| Medium‐risk population | ||||||
| Not estimable | Not estimable | |||||
| *The basis for assumed risk (e.g. median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence. | ||||||
| aOne study representing 62.5% of participants contributed to this outcome analysis. The remaining 4 studies did not report outcomes chosen for this review. | ||||||
Background
Description of the condition
Epilepsy is a common neurological disorder, affecting more than 50 million people worldwide (Banerjee 2009; De Boer 2008). About 50% to 75% of seizures are well controlled with a single antiepileptic drug (monotherapy) (Vazquez 2004). Standard drugs most commonly used as monotherapy include carbamazepine, valproate and phenytoin. Given that many patients do not achieve seizure freedom with these standard treatments, and that many of those who do achieve seizure freedom do so at the cost of adverse events, it is important to assess the efficacy and tolerability of newer antiepileptic drugs (AEDs).
Description of the intervention
During the past two decades, several newer AEDs have been investigated for epilepsy. Vigabatrin (VGB), a structural analogue of gamma‐aminobutyric acid (GABA), is one of these drugs. Vigabatrin is often administered orally, has been approved by the US Food and Drug Administration to treat refractory complex partial seizures (CPS) and infantile spasms (IS) (Tolman 2009) and is currently available in more than 50 countries (Willmore 2009). A Cochrane systematic review of VGB as an add‐on therapy for people with refractory partial‐onset seizures found that it is effective in reducing seizure frequency, but this fact needs to be weighed against the risk of development of visual field defects (Hemming 2013). Wild 2007 reported a prospective observational study of patients with refractory partial epilepsy; using a multi‐variate model, researchers estimated that 45.1% of patients taking VGB for longer than six months developed a VGB‐associated visual field defect. They also found that the risk of developing a visual field deficit significantly increased with the duration of exposure and the mean dosage taken.
How the intervention might work
Vigabatrin is a relatively new AED that may exert its antiepileptic properties through several mechanisms of action. It can irreversibly inhibit the activity of GABA‐transaminase, resulting in increased levels of GABA, an inhibitory neurotransmitter in the central nervous system (Petroff 1996; Wheless 2007). In animal seizure models, VGB‐induced elevation of GABA levels has been associated with anticonvulsant activity (Gale 1986). Moreover, VGB may stimulate the release of GABA (Willmore 2009).
Why it is important to do this review
This review focused on the use of VGB as monotherapy for people with epilepsy, summarising evidence on efficacy and safety derived from randomised controlled trials (RCTs). This review also cross‐referenced a sister systematic review of observational studies that assessed VGB add‐on treatment and its effects on visual fields (Maguire 2010). This is an update of a Cochrane review first published in 2012.
Objectives
To investigate the efficacy and safety of VGB versus carbamazepine (CBZ) monotherapy for epilepsy in children and adults.
Methods
Criteria for considering studies for this review
Types of studies
Published and unpublished RCTs.
Types of participants
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Male and female patients of all ages with partial‐onset seizures (simple partial, complex partial or secondarily generalising tonic‐clonic seizures) or generalised onset tonic‐clonic seizures.
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Patients treated with monotherapy.
Types of interventions
The experimental group received VGB and the control group was given CBZ as monotherapy.
Types of outcome measures
Primary outcomes
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Time to treatment withdrawal (retention time) for any reason.
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This global effectiveness outcome includes both efficacy and tolerability and is recommended as a primary outcome by the Commission on Antiepileptic Drugs of the International League Against Epilepsy (ILAE) (Commission 1998).
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Secondary outcomes
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Time to achieve six‐month and 12‐month remission after randomisation.
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Time to first seizure after randomisation.
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Numbers of participants who experienced any of the following common and important adverse events: skin rash, weight gain, dizziness, headache, fatigue, drowsiness, insomnia, depression, leucopenia (decrease in the number of white blood cells), visual field defects, visual disturbances, agitation and amnesia.
A systematic review of observational studies (Maguire 2010) assessing the risk of visual field defects was undertaken as part of the review of add‐on VGB for refractory partial‐onset seizures (Hemming 2013). We have presented the results of this review in the Results section and in the Discussion and Authors' conclusions sections of our review of VGB monotherapy.
Search methods for identification of studies
We conducted a systematic search to identify all relevant RCTs and applied no language restrictions.
Electronic searches
This search was run for the original review on 10 October 2011. Subsequent searches were run on 14 November 2013 and 1 July 2015. For the latest update, we searched the following databases.
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The Cochrane Central Register of Controlled Trials (CENTRAL; 2015, Issue 3 of 4), using the strategy outlined in Appendix 1.
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MEDLINE (Ovid, 1948 to 1 July 2015), using the strategy outlined in Appendix 2.
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EMBASE (1974 to 1 July 2015), using the strategy outlined in Appendix 3.
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Chinese BioMedical Database (CBM‐disc) (1980 to 1 July 2015), using the strategy outlined in Appendix 4.
Previously, the Cochrane Epilepsy Group Specialised Register was also searched, but this search is no longer necessary as all Specialised Register records are now included in CENTRAL.
Searching other resources
We searched reference lists of included studies and review articles, as well as relevant journals from recent years. We contacted the pharmaceutical company Hoechst Marion Roussell, which produced VGB, to obtain relevant data, and we searched trial registers for ongoing trials.
Data collection and analysis
Selection of studies
Two review authors (YX, LG) independently reviewed the titles and abstracts of all studies identified during the search. When we had retrieved all potentially relevant papers, each review author independently evaluated the full text of each paper for inclusion. We recorded excluded studies and the reasons for exclusion. Review authors did not disagree at any time regarding the selection of studies for inclusion.
Data extraction and management
We were unable to obtain individual patient data (IPD) from the original investigators. As planned, we performed the analysis based on the published data (Williamson 2002).
Two review authors (YX, LG) independently extracted the following information, using a data extraction form.
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Participants: seizure types, number in each group, age, gender, baseline comparability between groups, presence of neurological signs, date of randomisation, number of seizures before randomisation, electroencephalography (EEG) results.
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Methods: study design, randomisation method, allocation concealment method, stratification factors, blinding methods.
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Interventions: details of VGB or CBZ treatment, such as administration method, dosage and duration.
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Outcomes: primary and secondary outcomes, adverse events.
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Follow‐up: duration of follow‐up, numbers lost to follow‐up, dates of and reasons for treatment withdrawals.
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Other: country and setting, publication year, sources of funding, intention‐to‐treat (ITT) analysis.
Review authors resolved minor disagreements about data extraction by discussion.
Assessment of risk of bias in included studies
Two review authors (YX, LG) independently assessed the methodological quality of the included studies by using the quality checklist recommended by the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). The quality checklist for evaluating risk of bias consists of six specific parameters: (1) sequence generation, (2) allocation concealment, (3) blinding, (4) incomplete outcome data, (5) selective outcome reporting and (6) other bias. For each entry, the judgement ('low risk' of bias, 'high risk' of bias or 'unclear risk' of bias) is followed by a text box that provides a description of study design, conduct or observations that underlie the judgement (Higgins 2011). Assessment of risk of bias resulted in no disagreement between review authors.
Measures of treatment effect
We managed data by applying the ITT principle. For time‐to‐event outcomes, we presented results as hazard ratios (HRs) with 95% confidence intervals (CIs). For dichotomous outcomes (adverse events), we presented results as risk ratios (RRs) with 95% CIs.
Unit of analysis issues
We conducted unit of analysis issues using guidance provided in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).
Dealing with missing data
We contacted the authors of identified studies to obtain further data. We analysed available data when further information was not received after correspondence with study authors.
Assessment of heterogeneity
We evaluated the clinical and methodological heterogeneity of included trials by comparing characteristics of participants, interventions and study designs.
We evaluated statistical heterogeneity among included studies using the Chi2 test and the I2 test. If the I2 statistic was greater than 50% (which indicates substantial heterogeneity (Higgins 2011)), we used a random‐effects model to examine sources of potential clinical and methodological heterogeneity.
Assessment of reporting biases
We could not determine potential publication biases by using funnel plots, as recommended in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011), because too few studies were eligible for inclusion.
Data synthesis
Because of insufficient included studies and lack of uniformity in outcomes reports, we could not perform a meta‐analysis and could describe only some of the results. For adverse events outcomes, as we found no significant statistical heterogeneity among the included studies, we analysed the data using a fixed‐effect model.
Subgroup analysis and investigation of heterogeneity
We intended to undertake the following subgroup analyses.
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Different seizure types (i.e. partial, generalised).
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Different age groups (i.e. children (younger than 17 years of age) and adults).
However, because of the limited data derived from included studies, we could not perform subgroup analyses.
Sensitivity analysis
We intended to perform the following sensitivity analyses.
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Re‐analysis excluding studies without adequate allocation concealment or blinding.
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Re‐analysis using a random‐effects model when a fixed‐effect model was used previously.
However, because of the limited data provided by included studies, we could not perform all of the planned sensitivity analyses.
Results
Description of studies
See Characteristics of included studies and Characteristics of excluded studies.
Results of the search
Through the original search on 10 October 2011, we identified 339 potentially relevant articles (Cochrane Epilepsy Group Specialised Register: 39, CENTRAL: 69, MEDLINE: 55, EMBASE: 136, CBM: 40, pharmaceutical company: 0, trial registers: 0). After reviewing the titles and abstracts, we excluded 314 articles, as they were not relevant or were obvious duplicate publications. Of the remaining 25 articles, we excluded three articles (Edwards 1998; Gobbi 1999; Van Paesschen 1998). Finally, we included in the review five studies (Chadwick 1999; Kalviainen 1995; Sobaniec 2005; Tanganelli 1996; Zamponi 1999) involving 22 articles (see Figure 1). We identified no ongoing trials. We performed an updated search on 1 July 2015 and found no new studies.
Study flow diagram.
Included studies
We included five randomised studies (Chadwick 1999; Kalviainen 1995; Sobaniec 2005; Tanganelli 1996; Zamponi 1999) investigating the efficacy and safety of VGB versus CBZ monotherapy for epilepsy. Some results from the five studies were available as abstracts in conference proceedings before the full texts were published. We contacted study authors to obtain IPD and additional information that may not have been reported in the published articles. Only Dr. David Chadwick (Chadwick 1999) quickly responded to our requests. He told us that the IPD are in the possession of the sponsoring pharmaceutical company Hoechst Marion Roussell (now known as Aventis Pharmaceuticals, Inc.). To date, we have failed to obtain raw data from the company. As planned in the review protocol, we performed the first analysis using only published data (Williamson 2002).
Study design
All five trials were RCTs. In Chadwick 1999, investigators performed double‐blinding and allocation concealment. In Kalviainen 1995, Sobaniec 2005 and Zamponi 1999, researchers used an open control design, meaning that neither investigators nor participants were blinded. All three studies did not mention allocation concealment. Tanganelli 1996 was a response conditional cross‐over study in which only non‐responders were crossed over to phase 2, then to phase 3; therefore, only phase 1 period results were eligible, and blinding and allocation concealment were not mentioned.
Participants
We included five studies involving a total of 734 participants, with 51 to 459 participants reported for each study. All included participants were newly diagnosed with epilepsy. All studies included partial seizures, except Kalviainen 1995, which included both partial and generalised seizures. Participant age ranged from six months to 65 years. Two studies (Chadwick 1999; Kalviainen 1995) included both children and adult participants, two studies (Sobaniec 2005; Zamponi 1999) included only children younger than 17 years of age and Tanganelli 1996 included only adults from 18 to 65 years of age. All studies mentioned baseline seizure frequency over the eight weeks to two years before randomisation, except Zamponi 1999, which reported the number of seizures before randomisation.
Interventions
All five studies compared VGB versus CBZ monotherapy for epilepsy. The dose of VGB in Chadwick 1999 and Kalviainen 1995, both of which included children and adults as participants, was 2.0 g/d or 50 mg/kg/d, with treatment duration of one year. In Sobaniec 2005 and Zamponi 1999, both of which included only children, the dose was between 50 and 60 mg/kg/d, with treatment duration of 24 weeks or two years. In Tanganelli 1996, which included only adults, the dose was 2.5 g/d, with treatment duration of 16 weeks. The dose of CBZ in Chadwick 1999 and Kalviainen 1995 was 600 mg/d or reached a plasma mean level of 35 μmol/L; in Sobaniec 2005 and Zamponi 1999, the dose was between 15 and 20 mg/kg/d; in Tanganelli 1996, it was 1.0 g/d.
Outcomes
Our primary outcome ‐ time to treatment withdrawal ‐ was reported only in Chadwick 1999.
Our secondary outcomes ‐ time to achieve six‐month and 12‐month remission and time to first seizure ‐ were reported only in Chadwick 1999.
All studies reported adverse events; however, in Tanganelli 1996, investigators reported only one adverse event in the CBZ group during the treatment period and provided no details. In Zamponi 1999, because some participants in the VGB or CBZ group were replaced or received other AEDs as add‐on therapy during treatment, real adverse events may be confounded and could not be analysed because IPD were unavailable.
Excluded studies
We excluded three trials for the following reasons: Edwards 1998, a controlled study comparing polytherapy with VGB versus CBZ monotherapy for partial seizures, did not meet our inclusion criteria; Gobbi 1999 was a prospective study that used a non‐RCT design; and Van Paesschen 1998 used magnetic resonance (MR)‐based cerebral T2 relaxation time measurements to compare the neuropathological effects of VGB when compared with CBZ in participants with newly diagnosed epilepsy but provided no clinical outcomes data.
Risk of bias in included studies
See 'Overall results of all risk of bias assessments' as summarised in Figure 2 and Figure 3.
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Allocation
All five studies were reported as randomised. However, only Chadwick 1999 reported the method used to generate allocation sequence (random permuted blocks, stored in sequentially sealed coded envelopes) to ensure adequate allocation concealment. The remaining four studies did not describe the method used to generate allocation sequence and did not mention allocation concealment. We corresponded with the contact authors but were not able to obtain additional information; therefore, it was not possible to determine whether randomisation and allocation concealment were adequate.
Blinding
In Chadwick 1999, all study personnel, participants and outcome assessors were blinded to treatment, and a matched placebo was provided for VGB or CBZ; therefore, we judged that double‐blinding was adequate. Kalviainen 1995, Sobaniec 2005 and Zamponi 1999 used an open control design, which meant that no blinding was adopted in these studies; therefore, we judged double‐blinding as inadequate. The remaining study (Tanganelli 1996) did not mention whether blinding was used; therefore, we judged this as study as having unclear risk of performance bias and detection bias.
Incomplete outcome data
Both Chadwick 1999 and Kalviainen 1995 provided numbers of, and reasons for, withdrawals, which were balanced across groups; we judged these studies to have low risk of incomplete outcome data bias. Tanganelli 1996 reported seven withdrawals due to non‐compliance but provided no details and excluded them from the analysis; therefore, we judged this study to have high risk of bias in this field. Similarly, Zamponi 1999 excluded from the analysis five participants in the CBZ who discontinued treatment because they received other AEDs subsequently as add‐on therapy; we also judged this trial to have high risk of bias in this field. We detected no missing outcome data in Sobaniec 2005; therefore, we judged this trial as having low risk of bias.
Selective reporting
We were not able to confirm whether all prespecified primary or secondary outcomes were reported, as we could not obtain protocols from any of the five included trials. Given that all favourable and unfavourable results were reported in Chadwick 1999 and Kalviainen 1995, we judged both studies to have low risk of selective reporting bias. Both Sobaniec 2005 and Tanganelli 1996 reported only favourable results. In addition, Tanganelli 1996 excluded withdrawals from the final analysis; as a result, we classified Sobaniec 2005 as having unclear risk of bias, and Tanganelli 1996 as having high risk of bias, in this field. We also considered Zamponi 1999 to have high risk of bias in this field because reasons for discontinuation of treatment by participants in the CBZ group were not well addressed.
Other potential sources of bias
Chadwick 1999 was funded by the VGB manufacturer Hoechst Marion Roussell, but because many unfavourable results were reported, conflicts of interest may not exist, and we judged this trial as having low risk of other potential sources of bias. The remaining four studies did not address whether study authors or intervention drugs showed any conflicts of interest; therefore, we judged these studies as having unclear risk of other potential sources of bias.
Effects of interventions
See: Summary of findings for the main comparison VGB compared with CBZ monotherapy for epilepsy
See summary of findings Table for the main comparison.
We included five studies in the final analysis; however, the outcomes chosen for this review were not reported in all studies. As planned in our review protocol, we first performed the analysis according to the reported data.
For analysis of time‐to‐event outcomes, an HR greater than one indicates that an event is more likely to occur with VGB than CBZ; accordingly, for time to treatment withdrawal, or time to first seizure, an HR greater than one indicates a clinical advantage favouring CBZ, and for time to achieve six‐month and 12‐month remission, an HR greater than one indicates a clinical advantage favouring VGB.
Primary outcomes
Time to treatment withdrawal (retention time) for any reason
Only one study involving 459 participants representing 62.5% of participants contributed to this outcome analysis (Chadwick 1999). As a result, we did not perform a meta‐analysis by extracting aggregate data to synthesise results. The reported HR with 95% CI showed no significant differences between VGB and CBZ groups in time to treatment withdrawal, with an adjusted HR of 0.75 (95% CI 0.52 to 1.10) indicating no significant decrease in risk of withdrawal with VGB.
Secondary outcomes
Time to achieve six‐month and 12‐month remission after randomisation
Time to achieve six‐month and 12‐month remission after randomisation was reported only in Chadwick 1999. However, Chadwick 1999 could not be included in this analysis, as the endpoints were time to achieve six‐month remission after the first six weeks of dose stabilisation from randomisation, but not since randomisation. No significant differences between VGB and CBZ groups were noted, and an adjusted HR of 1.18 (95% CI 0.89 to 1.55) indicated no significant increase in clinical advantage with VGB.
Time to first seizure after randomisation
Only one study involving 459 participants contributed to this outcome analysis (Chadwick 1999). Significant differences between VGB and CBZ groups in time to first seizure were noted, with an adjusted HR of 1.57 (95% CI 1.23 to 2.02) indicating a significant increase in clinical disadvantage with VGB.
Adverse events
All five studies reported adverse events, but data from only three studies (Chadwick 1999; Kalviainen 1995; Sobaniec 2005) involving 599 participants and representing 81.6% of participants contributed to this outcome analysis. Data from Tanganelli 1996 and Zamponi 1999 were not available. No significant differences were observed in the total number of participants with adverse events (RR 0.97, 95% CI 0.90 to 1.05) (see Analysis 1.1). The test for homogeneity indicated no significant heterogeneity (I² = 17%); therefore, we applied a fixed‐effect model. When analysed according to individually listed adverse events, VGB was associated with increased rates of weight gain (RR 2.18, 95% CI 1.18 to 4.00) (see Analysis 1.2) and fewer occurrences of skin rash (RR 0.26, 95% CI 0.12 to 0.56) (see Analysis 1.3) and drowsiness (RR 0.76, 95% CI 0.59 to 0.98) (see Analysis 1.4) when compared with CBZ. In addition, no significant differences were noted in the occurrence of headache (RR 0.98, 95% CI 0.69 to 1.40) (see Analysis 1.5), dizziness (RR 0.82, 95% CI 0.54 to 1.26) (see Analysis 1.6), fatigue (RR 0.90, 95% CI 0.63 to 1.29) (see Analysis 1.7), insomnia (RR 2.00, 95% CI 0.93 to 4.31) (see Analysis 1.8), depression (RR 2.22, 95% CI 0.95 to 5.16) (see Analysis 1.9), leucopenia (RR 0.21, 95% CI 0.01 to 4.28) (see Analysis 1.10), visual field defects (RR 5.37, 95% CI 0.27 to 106.88) (see Analysis 1.11), visual disturbances (RR 15.68, 95% CI 0.92 to 266.46) (see Analysis 1.12), agitation (RR 1.24, 95% CI 0.61 to 2.51) (see Analysis 1.13) and amnesia (RR 1.00, 95% CI 0.53 to 1.92) (see Analysis 1.14). We applied a fixed‐effect model. When we replaced the fixed‐effect model with a random‐effects model, we found no significant changes.
We excluded Zamponi 1999 from this outcome analysis because some participants in the VGB or CBZ group had been replaced or had received other AEDs as add‐on therapy during treatment; therefore, real adverse events may be confounded until IPD become available. In this study, in the VGB group, the most frequently reported adverse event was weight gain, which occurred in 10 participants (26.3%); the next most frequent was irritability/excitability, which occurred in six participants (15.8%). In the CBZ group, the most frequent adverse events were skin rash and excessive sedation, each of which occurred in six participants (18.8%). One participant developed skin rash, which was associated with serious leucopenia; however, the white blood cell count returned to a normal level quickly after discontinuation of CBZ. The next most frequently reported adverse event was weight gain, which occurred in only three participants. These results are consistent with outcomes of the combined analysis. We also excluded Tanganelli 1996 from this outcome analysis because only one adverse event was reported in the CBZ group during the first period and no further details were provided.
Maguire 2010 reported a systematic review of 32 observational studies that assessed the prevalence of visual field defects following exposure to VGB for treatment of epilepsy. Review authors indicated that visual field defects occurred in approximately one‐half of adults and one‐third of children, and that increasing age and exposure dose were associated with high risk of this important adverse event.
Discussion
Summary of main results
Vigabatrin has been shown to have some efficacy as adjunctive treatment for refractory epilepsy (Hemming 2013). This systematic review assessed the efficacy and safety of VGB as monotherapy for epilepsy in children and adults. Five studies involving a total of 734 participants were eligible for inclusion. However, it proved difficult to perform a meta‐analysis by extracting aggregate data to synthesise the results as planned, mainly because not all studies reported our chosen outcomes; therefore, we could analyse only available data. For efficacy outcomes, we failed to show significant differences favouring VGB or CBZ for time to treatment withdrawal and time to achieve six‐month remission after dose stabilisation from randomisation. Results did show a disadvantage for VGB on time to first seizure after randomisation when compared with CBZ. For safety outcomes, VGB was associated with more occurrences of weight gain, fewer occurrences of skin rash and drowsiness and no differences in visual field defects and visual disturbances.
It must be noted that most of the review results analysed were based on the largest study (Chadwick 1999). Although we assessed this study to have good methodological quality, it accounted for only 62.5% of the participants included in this review. Results of the remaining four studies, representing 37.5% of participants, were not available for some outcome analyses because of lack of uniformity in reporting of outcomes. Although all four studies assessed were of poor quality, unavailable data may have had a significant impact on the results of this review. In Sobaniec 2005, Tanganelli 1996 and Zamponi 1999, study authors revealed no significant differences in efficacies between VGB and CBZ when using different outcome measurements. In Kalviainen 1995, study authors indicated that more participants taking VGB discontinued treatment and fewer were seizure free, but adverse events were fewer than with CBZ. We are not able to combine these trials for analysis until additional data are made available for an update of this review.
Another point to note is that all reported adverse events were short‐term, and the most important adverse event of VGB ‐ visual field defects ‐ was reported rarely in any of the five studies, especially in the largest study, Chadwick 1999. Although study authors have clarified that the study was initiated before first reports described visual field defects in participants exposed to VGB, it is understandable that RCTs have reported fewer safety concerns. Randomised controlled trials often include small numbers of participants and short‐term follow‐up, and they can provide sufficient statistical power for testing efficacy outcomes but not for identifying harms; this would decrease the external validity of safety concerns (Yazici 2008). Another important factor is that VGB‐associated visual field defects are often asymptomatic, and this would greatly decrease reporting rates. As a result, it is not surprising that in this review, only two studies reported small numbers of participants who experienced visual field defects or visual disturbances and did not show significant differences between treatments. To better understand the safety of a drug, observational studies with large number of participants are more suitable than RCTs for detecting unexpected adverse events. A systematic review of 32 observational studies (Maguire 2010) assessing risk of visual field defects has been undertaken as part of the review of add‐on VGB for refractory partial‐onset seizures (Hemming 2013). Results have indicated that visual field defects occurred in approximately one‐half of adults and one‐third of children exposed to VGB for treatment of epilepsy. Review authors also found that increasing age and exposure dose were associated with higher risk of this important adverse event (Maguire 2010).
Overall completeness and applicability of evidence
It is difficult to give any recommendations for clinical practice of VGB monotherapy in treating epilepsy. In this review, most results were based on the largest study. We were not able to use aggregate data to synthesise results from the remaining four studies, which did not report the outcomes chosen for this review. Additionally, not all outcomes, subgroup analyses or sensitivity analyses could be performed as planned because included studies were few.
Quality of the evidence
The small number and poor quality of included studies and unavailable data make the results of this review unconvincing. Only one study (Chadwick 1999) was assessed as having good quality; investigators used a double‐blinding design and adequate methods of randomisation and allocation concealment. We assessed the remaining four trials (Kalviainen 1995; Sobaniec 2005; Tanganelli 1996; Zamponi 1999) as having poor quality; three of them (Kalviainen 1995; Sobaniec 2005; Zamponi 1999) used an open control design, which meant that no blinding was adopted; the other study (Tanganelli 1996) did not mention blinding. In addition, all four studies reported no details of the randomisation method used, and did not provide clear information on allocation concealment. Absence of blinding and unclear methods of randomisation and allocation concealment contribute to high risk of selection, performance and detection bias, which may lead to an overestimation of intervention effects (Boutron 2004; Shulz 1995). In spite of poor methodological quality and lack of uniformity in reported outcomes, of the four studies assessed as having poor quality (Kalviainen 1995; Sobaniec 2005; Tanganelli 1996; Zamponi 1999), two contributed to the analysis of adverse events (Kalviainen 1995; Sobaniec 2005).
Other concerns included statistical power and clinical heterogeneity of included studies. Only Chadwick 1999 reported a sample size calculation and performed an ITT analysis; the other four studies (Kalviainen 1995; Sobaniec 2005; Tanganelli 1996; Zamponi 1999) carried out no sample size calculations and did not report ITT analysis. All four studies recruited relatively small numbers of participants, which may have led to inadequate statistical power; obviously neither Tanganelli 1996 nor Zamponi 1999 performed an ITT analysis because some participants were excluded from the final analysis. Clinical heterogeneity was another important concern; first, age of participants ranged from six months to 65 years, one study recruited only adults and some studies included only children; second, the reported dose and duration of VGB varied substantially among studies.
Potential biases in the review process
Potential biases from trials
Although we undertook an extensive and comprehensive search to limit bias in the review process, we could not confirm whether other studies with negative findings were not identified because trials with negative findings remain unpublished more often than trials with positive findings (Hopewell 2009). In addition, upon contacting study authors, we did not receive all additional information required.
Potential biases from review authors
Review authors introduced into the review process no potential biases. In preparing this review, two review authors independently read and screened trials retrieved for inclusion and independently extracted data and assessed the quality of included trials to minimise potential biases. The authors of this review have reported no conflicts of interest related to the review.
Agreements and disagreements with other studies or reviews
No systematic reviews have explored the efficacy and safety of vigabatrin versus carbamazepine as monotherapy for epilepsy.
Study flow diagram.
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Comparison 1 Vigabatrin versus carbamazepine (adverse events), Outcome 1 Total number of participants with adverse events.
Comparison 1 Vigabatrin versus carbamazepine (adverse events), Outcome 2 Weight gain.
Comparison 1 Vigabatrin versus carbamazepine (adverse events), Outcome 3 Skin rash.
Comparison 1 Vigabatrin versus carbamazepine (adverse events), Outcome 4 Drowsiness.
Comparison 1 Vigabatrin versus carbamazepine (adverse events), Outcome 5 Headache.
Comparison 1 Vigabatrin versus carbamazepine (adverse events), Outcome 6 Dizziness.
Comparison 1 Vigabatrin versus carbamazepine (adverse events), Outcome 7 Fatigue.
Comparison 1 Vigabatrin versus carbamazepine (adverse events), Outcome 8 Insomnia.
Comparison 1 Vigabatrin versus carbamazepine (adverse events), Outcome 9 Depression.
Comparison 1 Vigabatrin versus carbamazepine (adverse events), Outcome 10 Leucopenia.
Comparison 1 Vigabatrin versus carbamazepine (adverse events), Outcome 11 Visual field defects.
Comparison 1 Vigabatrin versus carbamazepine (adverse events), Outcome 12 Visual disturbances.
Comparison 1 Vigabatrin versus carbamazepine (adverse events), Outcome 13 Agitation.
Comparison 1 Vigabatrin versus carbamazepine (adverse events), Outcome 14 Amnesia.
| Vigabatrin (VGB) compared with carbamazepine (CBZ) monotherapy for epilepsy | ||||||
| Patient or population: patients with epilepsy | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | Number of participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| CBZ monotherapy | VGB | |||||
| Time to treatment withdrawal | Patients with epilepsy | HR 0.75 | 446 | ⊕⊕⊝⊝ | No significant decrease in risk of withdrawal with VGB | |
| See comment | See comment | |||||
| Time to achieve 6‐month remission after the first 6 weeks of dose stabilisation from randomisation | Patients with epilepsy | HR 1.18 | 404 | ⊕⊝⊝⊝ | No significant increase in clinical advantage with VGB | |
| See comment | See comment | |||||
| Time to first seizure after randomisation | Patients with epilepsy | HR 1.57 | 404 | ⊕⊕⊝⊝ | Significant increase in clinical disadvantage with VGB | |
| See comment | See comment | |||||
| Adverse events | Patients with epilepsy | RR 5.37 | 54 | ⊕⊝⊝⊝ | Two participants in the VGB group experienced this adverse event | |
| See comment | See comment | |||||
| Medium‐risk population | ||||||
| Not estimable | Not estimable | |||||
| *The basis for assumed risk (e.g. median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence. | ||||||
| aOne study representing 62.5% of participants contributed to this outcome analysis. The remaining 4 studies did not report outcomes chosen for this review. | ||||||
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Total number of participants with adverse events Show forest plot | 3 | 599 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.97 [0.90, 1.05] |
| 2 Weight gain Show forest plot | 2 | 511 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.18 [1.18, 4.00] |
| 3 Skin rash Show forest plot | 2 | 545 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.26 [0.12, 0.56] |
| 4 Drowsiness Show forest plot | 2 | 545 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.76 [0.59, 0.98] |
| 5 Headache Show forest plot | 2 | 545 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.98 [0.69, 1.40] |
| 6 Dizziness Show forest plot | 3 | 599 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.82 [0.54, 1.26] |
| 7 Fatigue Show forest plot | 1 | 457 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.90 [0.63, 1.29] |
| 8 Insomnia Show forest plot | 3 | 599 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.00 [0.93, 4.31] |
| 9 Depression Show forest plot | 2 | 545 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.22 [0.95, 5.16] |
| 10 Leucopenia Show forest plot | 1 | 54 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.21 [0.01, 4.28] |
| 11 Visual field defects Show forest plot | 1 | 54 | Risk Ratio (M‐H, Fixed, 95% CI) | 5.37 [0.27, 106.88] |
| 12 Visual disturbances Show forest plot | 1 | 88 | Risk Ratio (M‐H, Fixed, 95% CI) | 15.68 [0.92, 266.46] |
| 13 Agitation Show forest plot | 1 | 457 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.24 [0.61, 2.51] |
| 14 Amnesia Show forest plot | 1 | 457 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.00 [0.53, 1.92] |
