Levetiracetam monotherapy, controlled-release carbamazepine monotherapy, and lamotrigine monotherapy have similar efficacy among elderly adults with new-onset focal epilepsy, according to research published in the March issue of Epilepsia. Levetiracetam has superior tolerability in this population, however, compared with controlled-release carbamazepine. Lamotrigine’s tolerability may be between those of levetiracetam and carbamazepine.
“This randomized-controlled trial provides evidence supporting the use of levetiracetam as first-line treatment for elderly patients with new-onset focal epilepsy and points to the value of lamotrigine as an alternative [to levetiracetam],” said Konrad J. Werhahn, MD, Professor of Neurology at the University Medical Center of the Johannes Gutenberg University in Mainz, Germany.
Half of all newly occurring epileptic seizures are expected to occur in patients age 60 and older in 2020. Few trials have evaluated treatment options for these patients, however. Observational data suggesting that levetiracetam may be effective in this population prompted Dr. Werhahn and colleagues to conduct a comparative trial.
A Yearlong Maintenance Period
Between March 2007 and August 2011, the investigators randomized 361 patients to controlled-release carbamazepine, lamotrigine, or levetiracetam. Eligible participants were age 60 or older and had new-onset focal epilepsy. The researchers excluded patients with symptomatic seizures occurring less than two weeks after the onset of acute cerebral insults and patients previously treated with valproate within four weeks of screening.
During a six-week period, doses were titrated to initial target amounts of 400 mg/day of carbamazepine, 100 mg/day of lamotrigine, or 1,000 mg/day of levetiracetam. The investigators selected these doses based on previous studies in the elderly. A 52-week maintenance period followed the titration period. Dose adjustments were allowed during the maintenance period to address concerns about tolerability and seizure control. Patients were withdrawn if they did not tolerate doses within this range or if they had recurrent seizures despite receiving the maximum dose.
The trial’s primary outcome measure was the retention rate at week 58, as measured from day 1 of treatment. Secondary outcome measures included seizure-freedom rates at weeks 30 and 58, time to first seizure, and time to first drug-related adverse event.
Adverse Events Occurred Earlier With Carbamazepine
The retention rate at week 58 was 45.8% for carbamazepine, 55.6% for lamotrigine, and 61.5% for levetiracetam. Retention rates were significantly different for all groups. Logistic regression analysis suggested that the number of concomitant diseases influenced retention at week 58.
The researchers found no significant differences in rates of seizure freedom at week 30 or at week 58. The rate of seizure freedom at week 58 was 33.3% for carbamazepine, 38.5% for lamotrigine, and 42.6% for levetiracetam. The time to first seizure after randomization or after titration was similar between treatment arms.
The incidence of reported adverse events was similar between treatment groups. Most adverse events were of mild to moderate severity. The most common adverse events were dizziness, fatigue, and headache. Adverse events occurred earlier with carbamazepine than with the other drugs. Also, more discontinuations due to adverse events occurred in the carbamazepine group than in the other groups.
“To our knowledge, the present trial is the first prospective comparison of levetiracetam with the optimal and most widely used formulation (controlled-release) of carbamazepine in this population,” said Dr. Werhahn, who receives compensation for activities with UCB Pharma. “Average doses of the drugs during the trial were all lower than the predefined target doses (most notably for carbamazepine), and also lower than those recommended in the individual product labels. This [datum] supports the recommendation that initial dosing of epilepsy medication for elderly patients should be lower, with a slower titration schedule than that used in younger adults, to reduce the risk of tolerability issues.
Although the study was not powered for the inclusion of the lamotrigine arm, “clear differences were evident in the tolerability profiles of these drugs during the trial, suggesting that the differences in retention rates at week 58 were driven primarily by the drugs’ tolerability profiles, rather than their efficacy,” Dr. Werhahn concluded.