The results of two large British trials that followed epilepsy patients for several years indicate that lamotrigine should be the drug of first choice for people with partial epilepsy and that valproate should be the drug of first choice for people with generalized and unclassifiable epilepsy, investigators reported.
The two Standard and New Antiepileptic Drugs (SANAD) studies were unblinded, randomized, controlled studies conducted in hospital-based outpatient clinics in the United Kingdom.
One study compared the established epilepsy drug carbamazepine with gabapentin, lamotrigine, oxcarbazepine, and topiramate in 1,721 patients with at least two clinically definite, unprovoked epileptic seizures in the previous year. The study included newly diagnosed patients, those who had failed monotherapy and those who had gone into remission but relapsed after treatment was stopped. Their mean age was 38–40 years, and they were followed for up to 6 years, wrote Dr. Anthony G. Marson of the University of Liverpool (England) and his associates.
Patients taking lamotrigine had significantly longer time to treatment failure for any reason (inadequate seizure control or unacceptable adverse events) than did those taking the standard treatment carbamazepine and the newer drugs gabapentin and topiramate, the authors reported. Lamotrigine had an advantage over oxcarbazepine, but it was not significant.
For time elapsed before achieving 12 months of remission, carbamazepine was significantly better than gabapentin. Their analyses suggested there was a nonsignificant advantage for carbamazepine over lamotrigine, topiramate, and oxcarbazepine for this end point. Lamotrigine, they noted, was considered “noninferior” to carbamazepine for 12-month remission from seizures, they added.
“Although there might be circumstances where other drugs are preferred (consideration of teratogenicity, bone health, drug interactions), the better tolerability seen in lamotrigine than carbamazepine, with noninferiority of longer-term efficacy outcomes, lends support to lamotrigine as first-choice treatment for most patients with partial epilepsy,” the authors concluded (Lancet 2007;369:1000–15).
The second SANAD study enrolled 716 patients (mean age 22 years) with generalized onset seizures and seizures that were difficult to classify. Valproate, which the authors said is considered the standard treatment for these patients, was compared with lamotrigine or topiramate for up to 7 years.
Valproate was significantly more effective than topiramate for time to treatment failure, and significantly more effective than lamotrigine for 12-months remission. Based on these results, they concluded that valproate “should remain the first-line treatment for most patients with an idiopathic generalised epilepsy or seizures that are difficult to classify.” But, they added, “there will always be some individual circumstances that would favour the choice of an alternative drug,” such as family planning or drug interactions (Lancet 2007;369:1016–26).
In an accompanying editorial, Dr. Jacqueline French of the department of neurology, University of Pennsylvania, Philadelphia, said that the SANAD studies overcame many of the methodologic problems that have affected studies directly comparing newer antiepileptic drugs such as lamotrigine, topiramate, or levetiracetam with older drugs like carbamazepine or phenytoin. These studies “almost always” conclude that the newer drug is as effective but better tolerated than the older drug, she said (Lancet 2007;369:970–1).
The SANAD studies also are timely because many new drugs have been introduced over the past few decades, she added.
But she said that the question of whether it is possible to identify a drug as the treatment of first choice for patients with epilepsy remained.
Another concern she expressed was that designating a drug as first choice “may reduce the likelihood that a physician will make an effort to match the drug to the patient.” An individualized approach would consider features of a drug that may not be addressed in trials like the SANAD studies, she said, citing as an example lamotrigine's side effect of insomnia, which may not make it the ideal choice for a patient with a sleep disorder.
“Simple is good, but overly simplistic may not provide the optimum benefit to our patients,” Dr. French said.
“It might be wiser to conclude from SANAD that lamotrigine is the drug of first choice in patients with partial seizures, and valproate for patients with generalised or unclassified seizures in the absence of factors that would lead to an alternative choice.”