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Keywords:

  • Refractory epilepsy;
  • Antiepileptic drugs;
  • Seizure-freedom;
  • 50% seizure reduction;
  • Responder rate;
  • Enzyme induction;
  • Nonenzyme-inducing AEDs

Summary

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Disclosures
  7. References
  8. Appendix

Purpose:  Given serious concerns over the adverse effects of enzyme induction, modern nonenzyme-inducing antiepileptic drugs (AEDs) may be preferable, provided they have similar efficacy as enzyme-inducing AEDs. This is currently unclear.

Methods:  Therefore, we performed a meta-analysis of the evidence to determine the placebo-corrected efficacy of adjunctive treatment with modern nonenzyme-inducing AEDs versus modern enzyme-inducing AEDs that are on the market for refractory focal epilepsy.

Key Findings:  Of 322 potentially eligible articles reviewed in full text, 129 (40%) fulfilled eligibility criteria. After excluding 92 publications, 37 studies dealing with a total of 9,860 patients with refractory focal epilepsy form the basis for the evidence. The overall weighted pooled-risk ratio (RR) in favor of enzyme-inducing AEDs over placebo was 2.37 (95% confidence interval [CI] 1.77–3.18, p < 0.001) for at least 50% seizure reduction and 4.45 (2.26–8.76, p < 0.001) for seizure freedom. The corresponding weighted pooled RR in favor of nonenzyme-inducing AEDs over placebo was 2.28 (95% CI 2.03–2.57, p < 0.001) for at least 50% seizure reduction and 3.23 (95% CI 2.23–4.67, p < 0.001) for seizure freedom. In a meta-regression analysis in the same sample with at least 50% seizure reduction as outcome, the ratio of RRs for enzyme-inducing AEDs (eight studies) versus nonenzyme-inducing AEDs (29 studies) was 1.01 (95% CI 0.77–1.34, p = 0.92)). Similarly, the ratio of RRs for a seizure-free outcome for enzyme-inducing AEDs (six studies) versus nonenzyme-inducing AEDs (19 studies) was 1.38 (95% CI 0.60–3.16, p = 0.43).

Significance:  Although the presence of moderate heterogeneity may reduce the validity of the results and limit generalizations from the findings, we conclude that the efficacy of adjunctive treatment with modern nonenzyme-inducing AEDs is similar to that of enzyme-inducing AEDs. Given the negative consequences of enzyme induction, our data suggest that nonenzyme-inducing AEDs may be useful alternatives to enzyme-inducing AEDs for treatment of refractory focal epilepsy.

There is emerging evidence on the negative aspects of enzyme-inducing antiepileptic drugs (AEDs). These drugs stimulate the de novo synthesis of monooxygenase and conjugating enzymes, thereby reducing the duration and intensity of action of a wide range of lipid soluble drugs, including anticoagulants, cytotoxics, analgesics, antiretrovirals, statins, antihypertensive agents, oral contraceptives, cardiac antiarrhythmics, immunosuppressants and, of course, other AEDs (Nebert & Russell, 2002; Perucca, 2005). Enzyme induction will decrease the efficacy of many of these agents, thereby resulting in treatment failure. Potential problems can include a higher risk of reduced tumor control in patients with cancer (Vecht et al., 2003), lower survival in B-lineage leukemia (Relling et al., 2000), breakthrough pain, progressive AIDS, transplant rejection, uncontrolled hypertension, and unwanted pregnancy (Mintzer, 2010). In addition, there is mounting evidence that induction of endogenous metabolic pathways contributes to a growing incidence of osteoporosis, sexual dysfunction, and ischemic heart disease in persons with epilepsy (Pack, 2008; Mintzer et al., 2009). Lastly, withdrawal of enzyme-inducing AEDs will increase the concentration of induced drugs, bringing with it substantial risk of toxicity if their doses are not concomitantly reduced (Perucca & Tomson, 2011). Although more evidence is needed, modern nonenzyme-inducing AEDs may be preferable provided they have efficacy similar to that of enzyme-inducing AEDs (Mintzer & Mattson, 2009). This is currently unclear. Therefore, we performed a meta-analysis of the evidence to determine the placebo-corrected efficacy of adjunctive treatment with modern nonenzyme-inducing AEDs versus modern enzyme-inducing AEDs on the market for refractory focal epilepsy.

Methods

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Disclosures
  7. References
  8. Appendix

Data sources

A medical librarian performed a comprehensive literature search of the Pubmed, Medline, Embase, Index Medicus, and Cochrane databases (Search strategy in Appendix 1). Literature searches were restricted to full-length articles published in English up to May 2011.

Study selection and classification

Two reviewers independently applied the following study inclusion criteria: reports of 20 or more patients with refractory focal epilepsy of any age undergoing adjunctive treatment with modern AEDs that are currently on the market for treatment of refractory epilepsy. The studies had to fulfill the following four criteria: (1) double-blind or include a double-blind placebo-controlled study phase, (2) provide a quantitative report of seizure freedom or 50% seizure reduction for adjunctive AED and placebo, (3) include a description of the type of epilepsy, and (4) refer to the number of patients undergoing each intervention. We further subclassified studies into those of enzyme-inducing and nonenzyme-inducing AEDs. The exclusion criteria and the yield of the literature search, which forms the evidence base for the review, are presented in the results section.

Data gathering

Two reviewers independently abstracted all data, resolving disagreements through discussion. We accepted outcome definition as used by authors in each study. These usually referred to seizure outcome in terms of seizure freedom, 50% seizure reduction, or both, versus baseline.

Definitions

In the absence of a uniformly accepted definition at the time when the studies were performed, epilepsy was defined as refractory in this study when one or, mostly, several AEDs had failed to control seizures prior to entry in the double-blind trial included for analysis. The following modern AEDs entering the European market since the launch of vigabatrin were classified as nonenzyme inducers: gabapentin, lacosamide, levetiracetam, lamotrigine, pregabalin, retigabine, rufinamide, tiagabine, vigabatrin, and zonisamide. The following modern AEDs were classified as enzyme inducers: eslicarbazepine, oxcarbazepine, and topiramate (>200 mg/day).

Data analysis

For comparison of seizure-free outcome, as defined by the authors, between AED versus placebo groups, we produced summary estimates for the studies with the relative risk (RR) with 95% confidence intervals (CIs), with values >1 favoring AEDs (Beyenburg et al., 2010). We aggregated the RRs in a forest plot. In a similar analysis, we determined the overall placebo-corrected pooled RR in favor of adjunctive AED treatment for 50% responder rate. For both outcomes, we present stratified analyses for nonenzyme-inducing AEDs and enzyme-inducing AEDs.

The number of studies in the various analyses varies because not all studies provided data on both seizure freedom and 50% seizure reduction. The meta-analyses were performed using random-effects models, aggregating studies with a weighting equal to the inverse of the variance of the estimate for the study. Random-effects models were chosen because of heterogeneity between studies and because we wanted to generalize beyond the studies in our sample (Hedges & Vevea, 1998). The weights are not shown on the forest plots. We assessed interstudy variability (heterogeneity) by describing I2, that is, the percentage of total variation across studies that is due to heterogeneity rather than chance (Higgins et al., 2003). Percentages of 25%, 50%, and 75% have been suggested to indicate low, medium, and high heterogeneity (Higgins et al., 2003). In addition, we present the results of a test for heterogeneity using the Q statistic of DerSimonian & Laird (1986).

Publication bias was assessed with a funnel plot showing the standard error of the logarithm of the risk ratio versus the risk ratios (Egger et al., 1997).

In a meta-regression analysis, we assessed whether some of the heterogeneity in treatment effects could be explained by differences between nonenzyme-inducing AEDs and enzyme-inducing AEDs, using a random-effects maximum likelihood approach (Thompson & Higgins, 2002). In our data, three studies with topiramate were included—all of them using daily doses >200 mg and hence were categorized as enzyme inducers in the analyses. Because of the possible misclassification of topiramate, we have conducted a supplementary analysis without the studies on topiramate. We used the Metan, Metareg, Metafunnel, and Heterogi procedures with Stata version 10.1 for analyses (Stata Corp., College Station, TX, U.S.A.)

Results

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Disclosures
  7. References
  8. Appendix

Evidence base

The literature search yielded 322 potentially eligible articles reviewed in full text; 129 (40%) fulfilled eligibility criteria, and after excluding 92 publications, 37 publications (11%) constituted the data set for this analysis (Fig. 1).

image

Figure 1.   Evidence base. *Reasons for exclusion: Single-blind studies or dose-escalation studies in the same patients with different lengths of study periods (N = 2); monotherapy studies (N = 8); <20 study completers (N = 10); pooled-data from other studies, reviews, and meta-analyses (N = 28); studies on generalized epilepsy (N = 7); studies on felbamate (N = 3), which is not recommended for the treatment of focal seizures (Elger et al., 2011), AED dose levels above or below the dose recommendations of the labeled product (N = 13); and studies of agents not marketed (N = 23). More than one reason may apply.

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Study population and trial design

We identified a total of 9,860 patients with refractory epilepsy taking either AEDs (n = 6,408) or placebo (n = 3,452) in 37 randomized controlled trials (Table 1). All studies reported seizure outcome in groups undergoing adjunctive treatment with modern nonenzyme-inducing AEDs or enzyme-inducing AEDs versus placebo (Table 1).

Table 1.   Efficacy analysis of studies
AuthorDrug studiedEfficacy analysisAdditional detailed reports on seizure- free rates
  1. PP, per protocol set population; RP, randomized patient population; ITT, intention to treat; MITT, modified ITT; iITT, inferential ITT; C, completers; PEAP, primary efficacy analysis population; EEP, efficacy evaluable population; =, same result; AEDs: ESL, eslicarbazepine; GBP, gabapentin; LCM, lacosamide; LEV, levetiracetam; LTG, lamotrigine; OXC, oxcarbazepine; PGB, pregabalin; RTG, retigabine; RUF, rufinamide; TPM, topiramate; VGB, vigabatrin; ZNS, zonisamide. an = 50, “evaluable” n = 44.

Enzyme-inducers   
 Ben-Menachem et al. (1996)TPMITT 
 Korean Study (1999)TPMITTYes
 Barcs et al. (2000)OXCITT, C =Yes
 Glauser et al. (2000)OXCITTYes
 Yen et al. (2000)TPMITT 
 Elger et al. (2007)ESLITTYes
 Gil-Nagel et al. (2009)ESLITTYes
 Ben-Menachem et al. (2010)ESLITT, PPYes
Nonenzyme inducers   
 Anhut et al. (1994)GBPRP 
 Messenheimer et al. (1994)LTGITT, C = 
 French et al. (1996)VGBITTYes
 Kälviäinen et al. (1998)TGBITTYes
 Appleton et al. (1999)GBPMITT 
 Duchowny et al. (1999)LTGITT 
 Ben-Menachem & Falter (2000)LEVITTYes
 Betts et al. (2000)LEViITTYes
 Cereghino et al. (2000)LEVITTYes
 Shorvon et al. (2000)LEViITTYes
 Faught et al. (2001)ZNSITTYes
 Pålhagen et al. (2001)RUFITTa 
 Boon et al. (2002)LEViITTYes
 French et al. (2003)PGBITT 
 Arroyo et al. (2004)PGBITTYes
 Sackellares et al. (2004)ZNSITT 
 Beydoun et al. (2005)PGBITTYes
 Brodie et al. (2005)ZNSITT, PEAP, EEPYes
 Elger et al. (2005)PGBITTYes
 Glauser et al. (2006)LEVITTYes
 Tsai et al. (2006)LEVITTYes
 Yamauchi et al. (2006)GBPPP 
 Ben-Menachem et al. (2007)LCMITT 
 Naritoku et al. (2007)LTGITTYes
 Porter et al. (2007)RTGITT 
 Halász et al. (2009)LCMITTYes
 Brodie et al. (2010)RTGITTYes
 Chung et al. (2010)LCMITTYes
 French et al. (2011)RTGITTYes

Seizure reduction in studies of adjunctive nonenzyme-inducing AEDs versus placebo

In a total of 29 studies, overall 1,810 of 5,060 (35.8%, range 14.3–45.8%) adults and children with refractory epilepsy showed a 50% seizure reduction with adjunctive nonenzyme-inducing AED treatment compared to 428 of 2,781 (15.4%, range 4.5–25.8%) controls receiving adjunctive placebo, giving a weighted pooled RR of 2.28 (95% CI 2.03–2.57, z = 13.58, p < 0.001) for 50% seizure reduction of adjunctive AED treatment versus placebo (Fig. 2), that is, in favor of nonenzyme-inducing AEDs. Assessment of heterogeneity showed moderate heterogeneity with I2 of 29.6% (95% CI 0.0–55.4) and Q statistic 39.8 (p = 0.07).

image

Figure 2.   Forest plot of risk ratios in the included trials for showing at least a 50% reduction in seizures with adjunctive AED treatment compared with placebo. The trials are pooled in strata according to class of drug, as enzyme-inducing AEDs (eight studies) or nonenzyme-inducing AEDs (29 studies), in a meta-analysis using a random-effects model. Seizure reduction was used as defined by study authors. The black marker and the horizontal lines show the RRs and 95% CIs for each trial. The size of the shaded square is proportional to the weight of the study (% weight) in the pooled estimated RR. The diamond represents the pooled RR and 95% CI. I2 is a measure of heterogeneity between the studies. Events, treatment = number of patients reaching the defined endpoint and the total number treated with AEDs. Events, control = number of patients reaching the defined endpoint and the total number on placebo treatment.

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Seizure reduction in studies of adjunctive enzyme-inducing AEDs versus placebo

In a total of eight studies, overall 525 of 1,348 (39.5%, range 31.4–50.6%) adults and children with refractory epilepsy showed a 50% seizure reduction with adjunctive enzyme-inducing AED treatment compared to 110 of 671 (16.4%, range 0–27.7%) controls receiving adjunctive placebo, giving a weighted pooled RR of 2.37 (95% CI 1.77–3.18, z = 5.81, p < 0.001) for 50% seizure reduction of adjunctive AED treatment versus placebo (Fig. 2), that is, in favor of enzyme-inducing AEDs. Assessment of heterogeneity showed moderate heterogeneity with I2 of 52.7% (95% CI 0.0–78.7) and Q statistic 14.79 (p = 0.039).

Seizure freedom in studies of adjunctive nonenzyme-inducing AEDs versus placebo

Overall in 19 studies, 211 of 3,305 (6.4%, range 2.0–20.8%) adults and children with refractory epilepsy were seizure free compared to 30 of 1,920 (1.6%, 0–8.2%) controls receiving adjunctive placebo, giving a weighted pooled RR of 3.23 (95% CI 2.23–4.67, z = 6.24, p < 0.001) in favor of nonenzyme-inducing AEDs (Fig. 3). Assessment of heterogeneity showed low heterogeneity with I2 of 0.0% (95% CI 0.0–48.9) and Q statistic 12.00 (p = 0.85).

image

Figure 3.   Forest plot of risk ratios in the included trials for being seizure-free with adjunctive AED treatment compared with placebo. Seizure freedom was used as defined by study authors. The trials are pooled in strata according to class of drug, as enzyme-inducing AEDs (six studies) or nonenzyme-inducing AEDs (19 studies), in a meta-analysis using a random-effects model. The black marker and the horizontal lines show the RRs and 95% CIs for each trial. The size of the shaded square is proportional to the weight of the study (% weight) in the pooled estimated RR. The diamond represents the pooled RR and 95% CI. I2 is a measure of heterogeneity between the studies. Events, treatment = number of patients reaching the defined endpoint and the total number treated with AED. Events, control = number of patients reaching the defined endpoint and the total number on placebo treatment.

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Seizure freedom in studies of adjunctive enzyme-inducing AEDs versus placebo

Overall in six studies, 116 of 1,297 (8.9%, range 3.7–24.0%) adults and children with refractory epilepsy were seizure free compared to 9 of 620 (1.5%, range 0.6–8.5%) controls receiving adjunctive placebo, giving a weighted pooled RR of 4.45 (95% CI 2.26–8.76, z = 4.32, p < 0.001) in favor of enzyme-inducing AEDs (Fig. 3). Assessment of heterogeneity showed low heterogeneity with I2 of 0.0% (95% CI 0.0–74.6) and Q statistic 3.91 (p = 0.56).

In a meta-regression analysis in the same sample with at least 50% seizure reduction as outcome, the ratio of RRs for enzyme-inducing AEDs (eight studies) versus nonenzyme-inducing AEDs (29 studies) was 1.01 (95% CI 0.77–1.34, p = 0.92). Similarly, the ratio of RRs for a seizure-free outcome for enzyme-inducing AEDs (six studies) versus nonenzyme-inducing AEDs (20 studies) was 1.38 (95% CI 0.60–3.16). After also accounting for heterogeneity due to era of publication, before 2001 versus 2001 and later, the results of the meta-regression analyses were essentially unchanged (Table 2).

Table 2.   Meta-regression analysis, multivariate
 Ratio of risk ratios95% CIp-Value
  1. EI-AEDs, enzyme-inducing AEDs; NEI-AEDs, nonenzyme inducing AEDs.

50% seizure reduction (37 studies)   
 EI-AEDs versus NEI-AEDs0.970.73–1.290.825
 Time of publication (2001 and later versus before 2001)0.850.67–1.090.200
Seizure freedom (25 studies)   
 EI-AEDs versus NEI-AEDs1.250.55–2.850.586
 Time of publication (2001 and later versus before 2001)0.510.22–1.200.116

When excluding topiramate in the analysis, for enzyme inducers the pooled RRs for 50% seizure reduction were 2.07 (95% CI 1.59–2.69, p < 0.001, five pooled studies) and for seizure freedom 4.24 (95% CI 2.07–8.68, p < 0.001, five pooled studies). This did not affect the analysis of the nonenzyme-inducer group. In the corresponding meta-regression analysis without topiramate the ratio of RRs of 50% seizure reduction for enzyme-inducing AEDs versus nonenzyme-inducing AEDs was 0.91 (95% CI 0.68–1.21, p = 0.50), and for seizure freedom 1.31 (95% CI 0.55–3.15, p = 0.53).

We did not find sufficient data to explore other potential factors such as intention to treat versus not, specific drugs, duration of epilepsy, or number of past AEDs prior to randomization as sources of heterogeneity in meta-regression analysis, or to present meaningful stratified analyses for highest dose studied versus all available doses, or adults versus children.

The funnel plots were asymmetrical, suggesting that there may be a publication bias in the sample, as more studies with small numbers of participants (or large standard errors of the logRR) would be expected (Fig. 4).

image

Figure 4.   Analysis of publication bias with a plot of the standard error of the natural logarithm of the risk ratios (se[logRR]) versus the risk ratios (funnel plot). The vertical line represents the pooled estimate of the meta-analysis. The dotted lines define a region within which 95% of points might lie in the absence of both heterogeneity and publication bias (pseudo 95% confidence interval [CI]). Studies included in the meta-analysis of at least 50% seizure reduction (n = 37, upper panel), and seizure-freedom (n = 25, lower panel).

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Discussion

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Disclosures
  7. References
  8. Appendix

Our analysis of the placebo-corrected efficacy of adjunctive treatment with modern enzyme-inducing AEDs and nonenzyme-inducing AEDs in a total of 9,860 patients with refractory focal epilepsy had the following main results. The overall weighted pooled risk ratio in favor of enzyme-inducing AEDs over placebo was similar to the corresponding weighted pooled risk ratio for nonenzyme-inducing AEDs over placebo. This includes both at least 50% seizure reduction and seizure-freedom in the total sample of adults and children. In addition, both classes of drugs clearly showed efficacy by reducing seizures. In a meta-regression analysis, comparing the pooled risk ratios for the efficacy of the two classes of drugs versus placebo, we found no evidence of superiority of the enzyme-inducing AEDs compared with nonenzyme-inducing AEDs.

The study was based on available studies according to the inclusion criteria and may have had insufficient power to detect a difference. The meta-regression analysis of 50% seizure reduction comprised 37 studies and resulted in a ratio of the risk ratios close to 1, suggesting that a finding of no difference is plausible. In contrast, the similar analysis of seizure freedom (ratio of risk ratios 1.38) comprised 25 studies. Possibly the lack of statistical significance here may be related to the smaller sample size and hence be a power issue.

Although the presence of low to moderate heterogeneity may reduce the validity of the results and limit generalizations from the findings (see limitations), we conclude that the efficacy of adjunctive treatment with modern nonenzyme-inducing AEDs is similar to that of enzyme-inducing AEDs. Given the emerging evidence on serious adverse consequences of enzyme induction, our data suggest that nonenzyme-inducing AEDs may be useful alternatives to enzyme-inducing AEDs for refractory epilepsy.

Our result that adjunctive treatment with modern nonenzyme-inducing versus enzyme-inducing AEDs has similar efficacy, needs to be seen in a clinical context. Our study could not and did not intend to examine the risk–benefit balance of switching from enzyme-inducing AEDs to nonenzyme-inducing AEDs in refractory epilepsy. Although improved therapeutic efficiency with better tolerability has been reported in patients with epilepsy who switching from a traditional enzyme-inducing AED to lamotrigine, oxcarbazepine, or topiramate monotherapy or combination therapy (Kuzniecky & Mortati, 2005; Lim et al., 2009), no class I evidence exists for the seizure outcome of switching from enzyme-inducing AEDs to nonenzyme-inducing AEDs. Clearly, further firm evidence is needed to assess the safety and risk–benefit balance of switching to nonenzyme-inducing AEDs in refractory epilepsy.

Our large meta-analysis on seizure outcome following adjunctive treatment with modern nonenzyme-inducing AEDs has its limitations. We analyzed seizure-free outcome as shown in the publication, usually with a last observation carried forward replacement for missing values, which may provide inflated efficacy data as compared to completer analysis (Gazzola et al., 2007). Moreover, the trials considered in our meta-analysis did not have a patient group receiving no treatment. Therefore, the outcome seen in the placebo group includes a number of effects, including the placebo effect, the psychological Hawthorne effect, the regression to the mean, and changes in the natural history of the epilepsy (Sillanpää & Schmidt, 2006) and other, less well-defined variables possibly affecting the placebo response (Rheims et al., 2008, 2011; Guekht et al., 2010).

We found low-moderate heterogeneity within studies in terms of outcome measures used to determine seizure freedom and 50% seizure reduction. Such inconsistency in the results can be caused by differences between the studies in study design factors, such as funding, design, publication status, publication year, study outcome, and length of follow-up, or diversity in patient characteristics, such as mean age, epilepsy duration, number and pharmacologic profile of concomitant AEDs, dosage of the drugs, and mean baseline seizure frequency (Maguire et al., 2008). Another inherent limitation is incomplete data reporting of published trials. Although most studies were truly on an intention-to-treat basis, we could not determine in all studies whether they are intention to treat or not (or some of them may be for one outcome, but not the other). Some studies did not clearly report how many patients were randomized. Often, dropouts were not properly accounted for. Sometimes only percentages were reported for the outcomes and had to be converted to number of patients, or had to be estimated by looking at a graph. Therefore, heterogeneity may reduce the validity of the results and limit generalizations from the findings. We explored the heterogeneity using stratified analyses, used a random-effects meta-analysis, and also performed a meta-regression analysis incorporating study-level covariates. We could not perform a formal assessment or a ranking of the quality of the studies. Finally, there may have been a publication bias, as possibly some of the small studies with small effect sizes for adjunctive AEDs versus placebo may not have been published. However, other potential causes of asymmetry in funnel plots need to be considered, such as true heterogeneity between studies, selection based on methodologic quality, English language bias (the preferential publication of negative findings in languages other than English), or choice of effect measure (Egger et al., 1997).

In addition, our study could not address the important issue of how the efficacy of modern nonenzyme-inducing AEDs compares with that of older AEDs or no treatment. Other important and possibly favorable features of modern nonenzyme-inducing AEDs such as safety, tolerability, and, in particular, ease of use and absence of drug interactions could not be examined. Furthermore, robust evidence is needed from well-controlled comparative trials that treatment with nonenzyme-inducing AEDs improves survival and is not associated with higher toxicity in patients receiving cytotoxic treatment. Such evidence is needed, as one study counter intuitively showed higher survival following cytotoxic therapy in patients with glioblastoma taking enzyme-inducing AEDs (Jaeckle et al., 2009). Finally, given the absence of double-blind placebo-controlled comparative trials for adjunctive treatment, we could not compare directly the efficacy among individual modern AEDs. Despite these limitations, our data present the best available evidence for placebo-corrected efficacy of adjunctive treatment with modern enzyme-inducing versus nonenzyme-inducing AEDs and are informative on the efficacy of modern enzyme-inducing and nonenzyme-inducing AEDs for treating patients with drug-resistant partial epilepsy.

The main implications of our results are as follows. The emerging disadvantages of enzyme-inducing AEDs, as outlined in the introduction, which, however, need robust confirmation by further evidence, and the similar efficacy of modern nonenzyme-inducing AEDs, as shown in our study, suggest that nonenzyme-inducing AEDs may be a useful alternative to enzyme-inducing AEDs without having to fear lower efficacy of nonenzyme-inducing AEDs. Starting adjunctive treatment of refractory focal epilepsy with modern nonenzyme-inducing AEDs has become a feasible treatment option, when possible, after careful consideration of the overall risk–benefit balance for the individual patient. Although more evidence is needed, our result may have important implications for the general health of people with refractory epilepsy and may encourage some physicians to prefer nonenzyme-inducing AEDs over the use of enzyme-inducing AEDs in routine clinical practice. Finally, it is reassuring that modern nonenzyme-inducing AEDs have similar efficacy as enzyme-inducing AEDs; however, the efficacy of modern AEDs in general is disappointingly small, and new avenues for developing more effective AEDs are needed (Löscher & Schmidt, 2011).

Disclosures

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Disclosures
  7. References
  8. Appendix

SB has received hospitality and honoraria/advisory board membership from Merck Serono, Eisai, and UCB Pharma in the last 5 years. KS has received hospitality and honoraria from GlaxoSmithKline in the last 5 years. DS has received hospitality and honoraria/advisory board membership from UCB Pharma, Sun Pharma, and Johnson & Johnson in the last 5 years. We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

References

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Disclosures
  7. References
  8. Appendix

Appendix

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Disclosures
  7. References
  8. Appendix

Appendix: Literature Search Strategy

1. First step

“Epilepsy” [MeSH] OR (“epilepsy” [TW] AND “anticonvulsants” [TW]).

2. Second step

“Incidence” [MESH] OR “Follow-Up Studies” [MESH] OR “Prognosis” [MeSH:NOEXP] OR “prognos*” [TW] OR “predict*” [TW] OR “course” [TW] OR “outcome” [TW] OR “Survival Analysis” [MH:NOEXP].

3. Third step

“randomized controlled trial” [PTYP] OR “random*” [TW] OR (“double”[TW] AND “blind*” [TW]) OR “placebo” [TW] OR “drug therapy” [SH] OR “anticonvulsants” [SH] OR “antiepileptic drugs “ [SH] OR “therapeutic use” [SH:NOEXP] OR “cohort studies” [MESH] OR “risk” [MESH] OR (“odds” [TW] AND “ratio*” [TW]) OR (“relative” [TW] AND “risk” [TW]) OR “case control*” [TW] OR “case-control studies” [MESH].

4. Limits

–2011, Human, Journal article.