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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.
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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).