Cognitive effects of lamotrigine compared with topiramate in patients with epilepsy
Blum D, Meador K, Biton V, Fakhoury T, Shneker B, Chung S, et al.;
Commented by , 26 Oct 2006
Background
Adverse cognitive effects are an important concern with antiepileptic drugs (AEDs) (ref. 1, ref. 2). Data suggest that lamotrigine is less likely to cause cognitive dysfunction than topiramate (ref. 3, ref. 4, ref. 5, ref. 6, ref. 7) but well controlled head-to-head comparisons of these drugs in patients with epilepsy have not been performed.
Aim
To compare the effects of lamotrigine and topiramate on cognitive function during adjunctive therapy in adults with refractory partial epilepsy.
Methods
- 193 patients with partial seizures (maximum 8 per month) with or without secondary generalization were randomized to receive double-blind lamotrigine or topiramate in addition to pre-existing treatment with up to two AEDs, one of which had to be phenytoin or carbamazepine
- treatment included 8-week titration to a target dose of 500 mg/day for lamotrigine and 300 mg/day for topiramate, followed by 8 week maintenance at fixed dosages
- primary endpoint was change (end of maintenance vs baseline) in a combined analysis of several standardized measures of cognition.
Results
- cognitive performance at study end (sum of the ranks of changes for all cognitive tests) was better for lamotrigine than for topiramate (415 vs 315, p<0.001). For the Controlled Oral Association Task and the Symbol Digit Modalities tests, treatment effects exceeded the minimum clinically important difference
- premature withdrawals for adverse events occurred in 21% of the patients on lamotrigine and 25% of those on topiramate. Premature withdrawals due to cognition-related adverse events occurred more commonly with topiramate than with lamotrigine (6% vs 0%)
- seizure-free rates were higher with topiramate than with lamotrigine, both during titration (60% vs 42%, p = 0.019) and during maintenance (57% vs 41%, p = 0.054).
Professor Perucca's comments
In terms of ability to control for confounders and rigorous testing, this is the best study ever performed on the comparative cognitive effects of lamotrigine and topiramate. It confirms that, under the conditions of the study, topiramate adversely impacts on cognitive function to a greater extent than lamotrigine.
The findings are neither new nor unexpected. Lamotrigine is known to have a rather favorable cognitive profile, (ref. 8), whereas topiramate has been frequently associated with cognitive dysfunction (ref. 2, ref. 3, ref. 9, ref. 10), a problem that can be minimized (ref. 11, ref. 12) but not avoided completely (ref. 13) by slow titration and use at low dosages.
As remarked in an accompanying editorial (ref. 14), "when a trial is sponsored by industry, subtle biases in its design may be invisible to all but the experienced". Although it is relatively common in industry-driven trials to have dosing biases in favour of the sponsor’s product (ref. 15, ref. 16), in this particular case titration rates and target doses probably did not discriminate greatly against topiramate.
However, use of forced titration and fixed target dosages, while justifiable in a regulatory trial, deviates from sound clinical practice (ref. 15): in this respect, the results of the study do not reflect optimal use of the study drugs, which should allow flexible dose adjustment based on efficacy and tolerability. This might have placed topiramate at special disadvantage: in fact, topiramate tolerability can be improved by reducing dose of comedication (ref. 12), which was not permitted in this study.
Choice of endpoints is another area that requires scrutiny for potential biases. In this trial, the primary outcome was an adverse effect (an unusual choice in trial methodology), and one of a type, which was expected to favour the sponsor’s product. When using an AED in refractory epilepsy, it is questionable to disregard seizure control as a primary or co-primary endpoint.
In this study, sample size and duration of treatment were insufficient to assess seizure frequency changes in a highly meaningful way, and seizures were only assessed retrospectively without seizure diaries (a questionable choice). In spite of this, there was a clear and statistically significant trend for topiramate to produce better seizure control.
This raises the issue of how tolerability would have compared if the two drugs had been used at similarly efficacious doses. To be fair, other aspects in the study design were not in favour of lamotrigine: for example, there is evidence that lamotrigine efficacy is better in patients receiving valproate (ref. 17, ref. 18), which was not an accepted comedication in this study.
In conclusion, this study supports existing evidence that lamotrigine has a better cognitive profile than topiramate, but does not answer important questions such as:
- relative cognitive effects of the two drugs at optimally adjusted dosages
- characteristics of patients vulnerable to adverse cognitive effects
- applicability of the findings to patients with more severe epilepsy and more frequent seizures (in whom potential cognitive improvement resulting from suppression of epileptic activity could theoretically compensate to a greater extent for the direct adverse effects of treatment)
- influence of type of comedication on outcome
- impact of adverse drug effects and seizure frequency changes on quality of life
- comparative tolerability during use as monotherapy.
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