"Real World " Experiences with AED Therapy

SAN DIEGO—Most of the second-generation antiepileptic drugs (AEDs), with the exception of gabapentin, provide similar efficacy in real-world clinical settings, according to a retrospective review of AED use at Penn State, Milton S. Hershey Medical Center. According to Paul H. McCabe, MD, and colleagues, this finding is important because it is unlikely that a large, randomized, comparative study of these agents will ever be performed, and clinical trials do not always reflect conditions in community-based clinical practices.

REAL-WORLD DATA

Dr. McCabe and coworkers reviewed the charts of patients treated at the medical center with second-generation AEDs between January 1, 1993 and June 30, 2005. Included were 94 patients treated with gabapentin, 299 treated with levetiracetam, 498 treated with lamotrigine, 146 treated with oxcarbazepine, 222 treated with topiramate, and 180 treated with zonisamide. Many patients were exposed to more than one of these agents, so results were reported according to patient exposures for each drug rather than by number of patients. Dr. McCabe presented the findings at the 60th Annual Meeting of the American Epilepsy Society.

Seizure-free rates and rates of treatment discontinuation due to adverse events were generally comparable for all agents studied except gabapentin, which was less effective and had higher rates of discontinuation due to lack of efficacy. Lamotrigine was associated with the highest seizure-free rate (30.7%) and the lowest rate of discontinuation for adverse events (6.43%). The most common side effects leading to discontinuation were mood/behavior effects of levetiracetam and zonisamide, rash with lamotrigine, balance and vision disturbances for oxcarbazepine, and cognitive effects of topiramate. Dr. McCabe emphasized that his data reflect “the incidence of side effects in the ‘real world’ of treating epilepsy, as opposed to very strict guidelines that must be followed in controlled trials.”

However, in an interview with Neurology Reviews, Dr. McCabe cautioned against making too much of the minor differences between most of these agents. He pointed out that the prior number of AED exposures were not equal across all groups. “For example, topiramate appears to have a lower overall rate of seizure-freedom, but [that group of patients] had one of the highest numbers of prior AEDs tried (4.2) compared to several of the others, and a higher mean duration of seizures,” he explained. As another example, he said, “Zonisamide had a relatively high seizure-free rate, but there was a large percentage of patients with primary generalized seizures compared with the other AEDs.” Although zonisamide is not FDA approved for this use, Dr. McCabe believes there is good evidence to support this off-label use.

On average, patients had prior exposure to 3.15 to 4.57 AEDs. Investigators commented, “Even when used late, the newer agents still can produce seizure-freedom in a significant number of patients.” When used as a fifth agent or even later, newer agents produced seizure-free rates as follows: 18.6% for lamotrigine, 14.8% for topiramate, 14% for levetiracetam, 9.62% for zonisamide, 7.89% for oxcarbazepine, and 2.12% for gabapentin. Dr. McCabe told Neurology Reviews that the number of concomitant AEDs may be a factor, as well as the particular AEDs used. “For example, roughly 50% to 60% of patients who became seizure-free when lamotrigine was used as the fifth AED or later were also on valproic acid. This is a known successful combination.” Nonetheless, based on these findings, Dr. McCabe said that his institution is now more likely to favor use of lamotrigine, topiramate, or levetiracetam for patients who already failed three or more drugs.

The study also revealed that patients who became seizure-free generally did so at lower doses. Compared with patients who had a 50% decrease in seizure-rates or those who had no change, patients who became seizure-free did so at doses typically 60% to 80% lower. Dr. McCabe explained, “With the newer AEDs, we have more room to increase doses before having significant side effects compared with the older AEDs. Therefore, many epileptologists have been pushing the doses until we reach toxicity or seizure-freedom. This can sometimes add six months to a year.” Based on his findings, he suggested that “if no response is seen with a ‘reasonable’ dose of an AED, it is time to change to another drug rather than continuing to increase the dose because there are no side effects.” However, he cited one exception, saying that it is reasonable to pursue dose escalation for patients who show improvement with each dose increase, in the absence of adverse events. “We do have outliers on very high doses of each of the newer AEDs. This is different from patients showing no response or very little response at all.” He also cautioned, “I do not want people to have the impression that you should try all drugs before considering surgery.Certain patient groups have a much better response to surgery and should be referred at an early time.” Patients who would be candidates for surgery would include those with temporal lobe epilepsy, especially those with evidence of mesial temporal sclerosis, he said.

A FEW LIMITATIONS

This study is limited primarily by its retrospective nature and the fact that it reflects a tertiary referral population consisting largely of patients refractory to the first AED(s) used by patients’ referring physicians. However, Dr. McCabe commented, “One may argue that our study was not a prospective study, but the data were collected in a ‘prospective’ manner over the years that we followed these patients, and there was little variability in documenting seizures and side effects since the staff at our center had very little change since the introduction of the newer AEDs.” He noted that the study did not review use of the newer AEDs in special populations such as pregnancy, the elderly, or patients with hepatic dysfunction.

Dr. McCabe noted, “Good efficacy can be seen with the newer drugs, even after patients have failed to become seizure-free with the older AEDs.” In his opinion, the newer drugs offer advantages over older AEDs because efficacy is comparable. The newer drugs are better tolerated and have fewer drug interactions. He pointed out that treatment selection must often be based not only on the efficacy/safety of the drug but also on individual patient characteristics. Finally, Dr. McCabe concluded that his research provides information regarding the incidence of adverse events and rates of seizure response for readers to consider as a reference.

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