BRECKENRIDGE, COLO. – Lamotrigine and gabapentin are the newly crowned, evidence-based first-line treatments for new-onset epilepsy arising in the elderly, according to the findings of a major new Veterans Affairs trial.
Both drugs significantly outperformed carbamazepine in VA Cooperative Study 428, a multicenter randomized double-blind clinical trial involving 593 veterans with new-onset seizures after age 60.
Lamotrigine showed a consistent trend for more favorable outcome measures compared with gabapentin, although many of these differences did not achieve statistical significance.
Both newer drugs significantly outperformed carbamazepine, Mark C. Spitz, M.D., reported at a conference on epilepsy syndromes sponsored by the University of Texas at San Antonio.
The study's primary end point was retention in the trial on the assigned drug after 12 months. The rates were 58% for patients randomized to lamotrigine, 49% for gabapentin, and 37% for carbamazepine.
The drugs were roughly equally effective at controlling seizures. Rather, the difference in outcome was due to disparities in tolerability.
Despite the fact that older veterans are a notoriously uncomplaining group that tends to stick with a problematic assigned treatment well beyond the point when others would bail out, more than 27% of the carbamazepine group dropped out of the trial due to intolerable side effects, compared with 17% on gabapentin and 10% on lamotrigine, noted Dr. Spitz, professor of neurology at the University of Colorado, Denver.
Target doses in the study were 150 mg/day of lamotrigine, 1,500 mg/day of gabapentin, and 600 mg/day of carbamazepine. Physicians were permitted to deviate from the standard titration schedules based upon a patient's signs and symptoms in a way that mirrored common clinical practice. This was done in 30% of cases.
There was a nonsignificant trend for less neurologic toxicities with the newer drugs. The significant differences in systemic toxicity involved weight gain and loss, water retention, and hypersensitivity-type skin rashes.
Skin rash occurred in 10% of patients on carbamazepine, 5% on gabapentin, and–to the great surprise of Dr. Spitz and the other investigators–in a mere 2.7% of lamotrigine-treated patients.
Three percent of carbamazepine-treated patients experienced skin rash requiring hospitalization, compared with none of the gabapentin group and 0.5% on lamotrigine. The sole death in the trial occurred in a patient on carbamazepine who developed Stevens-Johnson syndrome with multiorgan failure.
Because lamotrigine carries a black box warning about serious rashes including Stevens-Johnson syndrome, its titration schedule was more protracted than were those of the other agents. Patients started with 25 mg at bedtime for 2 weeks, then 25 mg b.i.d. for 2 weeks, followed by 50 mg b.i.d. for 2 weeks, and then 75 mg b.i.d.
The trial was designed a decade ago, at a time when investigators viewed carbamazepine as the best-proven antiepileptic drug for the elderly. The goal was to learn whether the then-new gabapentin and lamotrigine were clinically advantageous.
Today, phenytoin is the agent most often prescribed for epilepsy in the elderly. Indeed, a recent VA system-wide study showed 80% of veterans with epilepsy diagnoses are on phenytoin, a finding Dr. Spitz finds disconcerting because of the drug's narrow therapeutic range, complex pharmacokinetics, associated accelerated bone loss, and reduced hepatic clearance in the elderly.
The primary results of VA Study 428 will soon be published. The trial–one of the largest ever to focus on new-onset epilepsy in the elderly–includes numerous secondary end points expected to provide follow-up analyses for years to come.
The study has already provided data serving to debunk widespread misconceptions regarding the nature of seizure disorders arising in older people.