Antiepileptic Drug Efficacy may not Be So Great

AEDs are the mainstay of the treatment of epilepsy. A large number of new drugs have become available in the last two decades. These newer agents generally offer a better adverse effect profile and fewer drug-drug interactions compared with the older drugs. Efficacy, however, may not be much better.

In a recently published manuscript, Beyenburg et al seek to do so. They did a detailed literature search, and identified blinded trials of patients with refractory epilepsy. They then calculated 50% responder rates and seizure freedom rates (both of which are well accepted measures in epilepsy trials) and adjusted for placebo data. Subgroup and heterogeneity analyses, and an analysis of efficacy v. publication date were also performed.

They found 317 papers, of which 55 (17%) constituted the final data set for their analysis. Of these, 46 were trials including only adults. Data for a total of 11,106 patients were analyzed. 35% of patients on active treatment showed a 50% response, v. 15% of placebo patients, yielding a 21% risk differential between active and placebo treatments. Seizure freedom rates were 8.2% for active treatment patients v. 2.1% for placebo. This resulted in a weighted risk differential of 6%. They posit a publication bias (in favor of drug response) in the adult trials, but not the trials of children with epilepsy.

The authors conclude that efficacy in the trials they analyzed was disappointingly small. They also wonder about the degree to which data from short term trials can be generalized to longer term treatment. Finally, they note that, since they had no "head to head" trials to analyze, they cannot comment on relative AED efficacy.

I have some thoughts about this analysis. First, the patients recruited for such trials have often been on many AEDs in the past without acceptable efficacy. A subset of such patients probably won't respond well to any AED. Second, the trials analyzed were adjunctive trials. Often, antiepileptic drug efficacy is better when the agent is used as monotherapy. Third, as the authors note, heterogeneity of trial design is probably a major factor in their rather disappointing results. Finally, the 50% responder rate, while the "gold standard" of efficacy per the FDA, is not of much clinical relevance to most patients. The acceptable number of seizures for most people with epilepsy is zero.

Thus, it is clear that patients who don't respond well to the first few AEDs frequently don't gain much with trials of additional agents. Achieving seizure freedom is rare. Our current crop of drugs is not ideal for such patients.

Antiepileptic drugs (AEDs) are the mainstay of the treatment of epilepsy. A large number of new drugs have become available in the last two decades. These newer agents generally offer a better adverse effect profile and fewer drug-drug interactions compared with the older drugs. Efficacy, however, may not be much better. There are a number of ways of analyzing efficacy, but most published data to date do not take placebo response into account. Placebo response is often an effect of significant size, and varies a good deal from trial to trial. Thus, it is hard to compare drug efficacy in trials without accounting for placebo effect.