Drug Choices for Different Seizures Get Clarification

LIVERPOOL, England, March 23 -- Lamotrigine (Lamictal) should be the drug of choice for patients with partial-onset epileptic seizures while valproate (Depacon) heads the list for generalized and unclassifiable seizures, two major studies have found.

Despite the lack of comparative evidence, especially for longer seizure control, newer antiepileptic drugs are increasingly prescribed, said Anthony Marson, M.D., of the University of Liverpool, and colleagues in the March 24 issue of the Lancet.

To examine seizure control, tolerability, quality of life, and economic outcomes, the researchers undertook two unblinded randomized controlled studies, called the Standard and New Antiepileptic Drugs (SANAD) trials.

For partial onset epilepsy, the researchers recruited 1,721 patients from British hospital-based outpatient clinics. The patients were randomly assigned to carbamazepine, an established first-line epilepsy drug for partial onset seizures, or gabapentin (Neurontin), lamotrigine, oxcarbazepine (Trileptal), and topiramate (Topamax).

Fewer patients were randomized to the more recently approved oxcarbazepine, they noted.

Patients were to be seen for follow-up at three months, six months, one year and at successive yearly intervals from the date of randomization.

Overall, the investigators found that for patients with partial onset seizures requiring monotherapy, lamotrigine was significantly better at delaying time to treatment failure than the carbamazepine, and the newer drugs, gabapentin and topiramate.

For time to 12-month remission from seizures, lamotrigine was found non-inferior to carbamazepine, they reported.

The results were:

• For time to treatment failure, lamotrigine was significantly more effective than carbamazepine (hazard ratio 0.78), gabapentin (HR 0.65), and topiramate (HR 0.64), and had a non-significant advantage compared with oxcarbazepine (HR 1.15).
• For time to 12-month remission, carbamazepine was significantly better than gabapentin (HR 0.75), and estimates suggested a non-significant advantage for carbamazepine against lamotrigine (HR 0.91), topiramate (HR 0.86), and oxcarbazepine (HR 0.92).
• In an analysis, at two and four years, the difference (95% CI) in the proportion achieving a 12-month remission (lamotrigine-carbamazepine) was zero (CI -8 to 7) and five (-3 to 12), suggesting non-inferiority of lamotrigine compared with carbamazepine.

Lamotrigine is a cost-effective alternative for patients diagnosed with partial onset seizures, given the differences in treatment failure, the authors wrote. For example, 21% of treatment failures for carbamazepine were related to rash, versus 14% for lamotrigine.

The differences are clinically important, the researchers said, with 12% and 8% fewer patients having treatment failure on lamotrigine than carbamazepine at one and two years after randomization.

Although age itself did not affect outcomes, there was no evidence of an interaction between age and drug treatment groups, indicating that individual drug results are applicable throughout life, the researchers said.

The economic analysis lent support to lamotrigine over preferred to carbamazepine in terms of both cost per seizure avoided and cost per quality of life gained, the researchers said.

"We see no reasons to prefer gabapentin or topiramate to the standard drug carbamazepine, except where there might be individual mitigating factors, the researchers said.

As for oxcarbazepine, the investigators wrote that it might be the most cost-effective of the drugs assessed, but in the absence of firm conclusions about its clinical effectiveness, further outcomes are needed before the drug can be accepted or rejected as first-line treatment.

Since SANAD was designed, three further new antiepileptic drugs have been licensed in the Britain, the researchers wrote, and the same questions would apply to them. However, for partial epilepsies, they must be compared with lamotrigine and possibly oxcarbazepine, rather than carbamazepine, the authors concluded.

The other part of SANAD recruited 716 patients and compared valproate (Depacon)--the standard treatment for patients with generalized onset seizures and unclassified seizures-with the newer drugs lamotrigine and topiramate.

Valproate, they concluded, is better tolerated than topiramate and more efficacious than lamotrigine. The drug was significantly more effective than topiramate for treatment failure, and more effective than lamotrigine for 12-month remission.

Valproate should remain the drug of choice for many of these patients, they said, whereas lamotrigine should be generally avoided because of its inferior efficacy, and topiramate because of inferior tolerability.

However, Dr. Marson and colleagues said, there are individual circumstances, such as drug interactions and family planning, that would favor the choice of another drug.

The study was not designed or powered to examine pregnancy outcomes, something of a concern when valproate is used for women of child-bearing age, the researchers said.

Unfortunately, they added, evidence for the safety of topiramate during pregnancy remains sparse, so that there would be difficulty deciding on treatment for women with idiopathic generalized epilepsy during their child-bearing years.

In this study, patients were randomly assigned to valproate, lamotrigine, or topiramate from January 1999 to August 2004 and were followed to mid-January 2006. The findings were::

• For time to treatment failure, valporate was significantly better than topiramate (hazard ratio 1.57), but there was no significant difference between valproate and lamotrigine (HR 1.25).
• For patients with idiopathic generalized epilepsy, valproate was significantly better than both lamotrigine (HR 1.55) and topiramate (HR 1.89).
• For the time to 12-month remission, valproate was significantly better than lamotrigine overall (HR 0.76), and for the subgroup with idiopathic generalized epilepsy (HR 0.68).
• However, there was no significant difference between valproate and topiramate in either the analysis overall or for the subgroup with idiopathic generalized epilepsy.

The researchers noted that although lamotrigine was the poorest option for seizure control in this part of SANAD, it was the overall preferred option in other part. Results from SANAD, they said, could be interpreted as indicating that lamotrigine should not be regarded as a broad-spectrum antiepileptic, but as a first-line treatment reserved for partial onset seizures and localization-related epilepsy syndromes.

Repeating the caution raised for SANAD's study of drugs for partial onset epilepsy, the researchers noted that two further drugs for generalized epilepsies have been licensed in the United Kingdom, so that these drugs must now be tested against valproate in similar populations.

SANAD, the investigators concluded, has shown that "we have a robust method to answer these questions."

In an accompanying editorial, Jacqueline French, M.D, of the University of Pennsylvania in Philadelphia, wrote that "simple is good, but overly simplistic may not provide the optimum benefit to our patients."

Physicians overwhelmed by the number of antiepileptics will welcome these results, she said. However, she cautioned that a compelling concern of designating one drug as first choice is that physicians may not make an effort to match the drug to the patient, concerns not necessarily addressed in trials such as SANAD.

For example, lamotrigine can cause insomnia and may be a problem during a woman's child-bearing years. Valproate, in addition to pregnancy hazards, has been associated with a higher likelihood of weight gain, while alterations in liver-function tests and platelet counts and would not be a wise choice for patients with bleeding risks.

Therefore, she said, it would be wiser to conclude that lamotrigine is the drug of first choice in patients with partial seizures and valproate would head the list for those with generalized or unclassified seizure--in the absence of factors that would lead to an alternative choice.

Dr. Marson reported receiving fees and reimbursement for attending conferences from Jannsen Cilag, GlaxoSmithKline, Novartis, Pfizer, and Sanofi-Synthelabo, and research funding from Pfizer.

Dr. French reported compensation for consulting and lectures from Johnson & Johnson, Medpointe, UCB, Abbott, Pfizer, UCB Pharma, Cephalon, GlaxoSmithKline, and Esai.