CORAL GABLES, FLA—Which antiepileptic drug (AED) is the best to treat the more than 300,000 elderly with epilepsy? Commenting on the results of the latest VA Cooperative Study, lead investigator R. Eugene Ramsay, MD, Professor of Neurology and Psychiatry, and Director of the International Center for Epilepsy at the University of Miami School of Medicine, said, “With this new evidence we have to strongly consider a major shift in our treatment paradigm in the older patient with seizures, away from carbamazepine to new drugs which have better side-effect profiles or pharmacokinetics. We now have evidence for gabapentin and lamotrigine. Carbamazepine no longer has the position it had as the drug of choice because it is not as well tolerated.”

THREE POPULAR AEDs GO HEAD TO HEAD

Dr. Ramsay led investigators at 18 centers to enroll 593 patients 60 or older (mean age, 72.3) in a 12-month, double-blind, parallel study that compared the effectiveness of lamotrigine (150 mg/day), gabapentin (1,500 mg/day), and carbamazepine (600 mg/day) in elderly patients with new-onset partial seizures. Approximately 200 patients participated in each study arm. The most common etiologies for seizure disorders were cerebral infarction (32%), unknown (24.7%), cerebral arteriosclerosis (14.7%), and head trauma (6.8%).

The titration rate of carbamazepine was 200 mg/day for two weeks, then 400 mg/day for two weeks, then 600 mg/day. The titration rate for lamotrigine was 25 mg/day for two weeks, 50 mg/day for two weeks, 100 mg/day for one week, then 150 mg/day. Gabapentin was the most rapidly titrated: 300 mg/day every three days until the target dosage of 1,500 mg/day was reached. Dosages could be modified to improve seizure control or ameliorate adverse events.

Dr. Ramsay explained, “We set up this study to simulate clinical practice. If, as we were titrating up, patients experienced side effects, we could titrate them down one increment, and then go back up. But if they continued to experience side effects, they were dropped from the study.”

The primary outcome measure was retention in the study, a combination of seizure control and tolerability. Retention was greatest for lamotrigine (57.9%), followed by gabapentin (49.2%), and carbamazepine (36.6%). Both lamotrigine and gabapentin retention rates were statistically superior to carbamazepine. However, there was no significant statistical difference in retention rates between lamotrigine and gabapentin.

Two hundred forty patients (40.4%) completed the study at 12 months. Of these, 53.2% were seizure-free. Seizure-free rates were the highest for lamotrigine (46.4%), followed by gabapentin (41.2%) and carbamazepine (39.4%). “If someone can tolerate a drug and tolerate it well, the seizures can be controlled by any of the three drugs. But if you really want to maximize your chances of tolerating the drug and being seizure-free, you take the drug that is best tolerated,” Dr. Ramsay observed.

“The most common reason for people not continuing in the study was adverse events due to the AEDs. Only 2% to 3% of patients dropped out due to failure to be controlled by the study drug. Only 2% were lost to follow-up. Twelve percent were voluntary withdrawals, and 39 patients died. These were people in their 70s and 80s who died of heart attacks and strokes.”

Dropouts due to adverse events were most likely to occur in the patients on carbamazepine (27.3%), followed by gabapentin (17.4%) and lamotrigine (10%), he said. The incidence of cognitive impairment was similar among the three drugs: carbamazepine (32.4%), gabapentin (29.4%), and lamotrigine (23%).

Weight gain also occurred with all three of the drugs; gabapentin (67.8%), carbamazepine (51.5%), and lamotrigine (47.5%). Dr. Ramsay attributed these relatively high numbers to the fact that patients were carefully weighed at each visit and followed for 12 months. All three drugs could also cause weight loss, although lamotrigine was the closest to being “weight neutral,” with nearly as many patients losing as gaining weight.

Dr. Ramsay acknowledged that one of the limitations of the study is that it did not include all of the new drugs. He added, “I think levetiracetam, oxcarbazepine, topiramate, and zonisamide also need to have formal testing to see where they reside in the treatment of the older patient.”

NEWER DRUGS FOR OLDER PATIENTS

In terms of recommendations for treatment of elderly patients with AEDs, Dr. Ramsay advised, “We have to now consider that the older drugs that have been considered the drugs of choice, such as carbamazepine, may be replaced by the new drugs, such as gabapentin and lamotrigine. If someone is significantly overweight, then gabapentin is not the first choice. However, if someone is on a lot of other medications, then gabapentin may be the drug of choice because it has no known drug interactions.”

Although gabapentin could be much more rapidly titrated than lamotrigine, reaching target dose levels in 15 days compared to six weeks, Dr. Ramsay observed that this apparent advantage of gabapentin did not seem to significantly influence the results in the elderly patients in his team’s study. “We cannot consider slow titration a problem because we lost so few people for lack of seizure control,” he said.

NR

—Andrew N. Wilner, MD

Suggested Reading
Leppik IE, Birnbaum A. Epilepsy in the elderly. Semin Neurol. 2002;22:309-320.
Ramsay RE, Pryor F. Epilepsy in the elderly. Neurology. 2000;55(5 suppl 1):S9-S14.

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