Giving an Older Patient Newer Drugs

Commentary

A Randomized, Double-Blind Comparison of Antiepileptic Drug Treatment in the Elderly With New-Onset Focal Epilepsy.

Werhahn KJ, Trinka E, Dobesberger J, Unterberger I, Baum P, Deckert-Schmitz M, Kniess T, Schmitz B, Bernedo V, Ruckes C, Ehrlich A, Krämer G. Epilepsia 2015;56(3):450–459.

OBJECTIVE: To compare the effectiveness of controlled-released carbamazepine (CR-CBZ) to levetiracetam (LEV) and to lamotrigine (LTG) in elderly patients with newly diagnosed focal epilepsy. METHODS: Randomized, double-blind, parallel-group trial conducted between January 2007 and August 2011, in 47 ambulatory or hospital sites in Germany, Austria, or Switzerland. Eligible participants were aged ≥60, had new-onset epilepsy, had no acute illness as the cause of their seizures, and had no contraindication to the drugs in the trial. Patients were randomized 1:1:1 to CR-CBZ, LTG, or LEV. Doses were up-titrated for 6 weeks and could be maintained or adjusted depending on seizure relapse or tolerability over an additional period of 52 weeks. Primary outcome was the retention to treatment at week 58; secondary measures related to seizure and adverse event frequency. RESULTS: Of 361 randomized patients, 359 were included (CR-CBZ n = 121, LTG n = 117, LEV n = 122) in the modified intent-to-treat population (mean age [range] 71.4 [60–95] years). At week 58, the retention rate for LEV was significantly higher than for CR-CBZ (61.5% vs. 45.8%, p = 0.02), and similar to LTG (55.6%). Seizure freedom rates at weeks 30 and 58 were not different across the groups. Twice as many patients receiving CR-CBZ discontinued due to adverse events or death compared to those in the LEV group (32.2% vs. 17.2%; odds ratio 2.28, 95% confidence interval [CI] 1.25–4.19, p = 0.007), whereas discontinuation was intermediate for LTG (26.3%). Median daily doses of completers (n = 195) were CR-CBZ 380.0 mg/day (333.0–384.0), LTG 95 mg/day (94.0–97.0), and LEV 950 mg/day (940.0–985.0). SIGNIFICANCE: In the initial monotherapy of focal epilepsy in the elderly, 1-year retention to LEV was higher compared to CR-CBZ due to better tolerability. Retention of LTG was intermediate and close to LEV, but did not differ significantly from either comparators.

It is often observed that children are not just small adults. They are physiologically different in many ways, including in drug metabolism and susceptibility to idiosyncratic side effects of drugs. At the other end of the life span, similar observations can be made regarding how older adults differ from their younger adult counterparts. These differences at each end of the age spectrum are especially pertinent to the treatment of epilepsy, which has a bimodal distribution of incidence, with peaks in the young and old. The largest and fastest growing peak is in older adults, with one estimate suggesting that half of all epilepsy may be in adults over age 60 by the year 2020 (1).

As the pace of new antiepileptic drug (AED) development accelerated in the 1990s, new algorithms for selecting AEDs had to be developed on the basis of relatively few comparative AED trials. A few of these trials focused on determining the optimal choice of AED for older patients. In 1999, Brodie and colleagues reported findings in 150 older adults with new-onset epilepsy who were randomized to treatment with immediate release carbamazepine (CBZ-IR)—the de facto standard for treatment of partial seizures at the time—or lamotrigine (LTG) (2). The primary outcome measure was retention on the randomly selected AED over the 24-week study. The findings were striking—the CBZ-treated subjects were more than twice as likely to come off of therapy, and the greater attrition in the CBZ group was nearly all accounted for by poorer tolerability. The importance of tolerability was emphasized by the larger US Department of Veterans Affairs (VA) cooperative study of epilepsy in the elderly, which compared CBZ-IR, LTG, and also gabapentin (GBP) using a similar survival analysis (3). Although efficacy did not greatly vary among the AEDs studied, there were significant differences in tolerability, again with more dropouts because of adverse effects in the CBZ-IR group than the others.

As the use of controlled-release CBZ (CBZ-CR) preparations became more common, many argued that the correct comparison with newer AEDs should be with the better-tolerated CBZ-CR. In 2007, Saetre and colleagues reported findings in 185 adults aged 65 years or older who were randomized to treatment with CBZ-CR or LTG and followed over 40 weeks (4). In this study, the primary measure, retention on AED over the course of the study, did not differ between the two drugs. Similarly, time to withdrawal and proportion of seizure-free patients were similar. Still, there was a signal that tolerability was important: nearly twice as many CBZ-CR subjects discontinued the drug because of adverse effects, a finding that was not statistically significant in this sample.

With time, more AEDs entered the market and came into common use as monotherapy for focal seizures. In 2010, Arif and coworkers reported findings from a nonrandomized, retrospective study of 10 AEDs in a population of 417 older adults with epilepsy (5). They reported that LTG and levetiracetam (LEV) had the highest retention rates among all of the AEDs studied. LTG had the highest seizure-free rates for a 12-month period, followed by LEV. The study design was highly prone to bias but suggested that other AEDs were worthy of study in the elderly.

Indeed, work led by Cramer and Leppik in 2003 suggested a favorable tolerability profile of LEV in elderly subjects involved in studies of epilepsy, psychiatric, and cognitive disorders (6). In these studies, few differences were seen between the adverse event profile of LEV in younger and older adults. A small retrospective study (7) and a larger observational study (8) of LEV use in older patients with epilepsy also reported favorable findings and suggested that a larger randomized study of LEV in this population was warranted. Small studies of LEV in older adults with poststroke epilepsy (9) or epilepsy and Alzheimer disease (10) suggested good tolerability and efficacy. Finally, Brodie and colleagues, in a randomized study of LEV and CBZ-CR in nonelderly subjects, found similar seizure-free rates and lower (but nonsignificant) rates of discontinuation with LEV (11). This begged the question of how LEV might perform relative to “standard therapy” in older adults with epilepsy.

It is precisely this question that is addressed by Werhahn and colleagues in their study of new-onset focal epilepsy in people aged 60 and over. In addition to age, two comments about the patient population should be made. First, they used an inclusive definition of epilepsy that comprised patients with a single seizure but epileptiform findings on EEG or lesion(s) on imaging; in fact, these subjects made up well over one-third of the study population. This is in line with the current International League Against Epilepsy (ILAE) definition of epilepsy but differs from previous studies of this type. Second, all subjects in this European study were Caucasian.

The study was a 58-week randomized, double-blind, active comparator study. Subjects were randomized in equal proportions to CBZ-CR, LTG, or LEV, titrated to target doses over 6 weeks, and then followed for a year. The equivalence of the target doses (CBZ-CR, 400 mg/d; LTG, 100 mg/d; and LEV, 1,000 mg/d) can be endlessly debated, but the study design allowed flexible dosing after initial titration to mimic clinical practice. Of interest, although these target doses might seem relatively low, the median daily doses in patients who completed the trial arrived at by flexible dosing was lower than the target for all drugs (CBZ-CR, 380 mg; LTG, 95 mg; and LEV, 950 mg). The primary outcome measure was retention on drug at 58 weeks, and a number of secondary outcomes including seizure-free rates, time to first seizure or first adverse event, and preplanned subgroup analyses were included. The study was designed to detect a 20% difference in retention between LEV and CBZ-CR with 85% power.

Retention at the end of the study was highest for LEV, intermediate for LTG, and lowest for CBZ-CR, but only the LEV to CBZ-CR difference was statistically significant. Seizure-free rates, as a measure of efficacy, did not differ among the groups, nor did time to first seizure or time to first adverse event. Rates of adverse events were high in all groups and not significantly different, but more were judged to be drug related in the CBZ-CR group, and discontinuation because of adverse events and serious adverse events was significantly higher in the CBZ-CR group. More subjects in the CBZ-CR group had elevated liver transaminases, and three were hospitalized with drug-induced hepatotoxicity.

In sum, the present study builds on prior work and provides solid support for LEV to be included in the group of AEDs that are favored for the treatment of older adults with epilepsy, perhaps simply confirming the current practice of many providers. It again emphasizes the point that tolerability is paramount, and efficacy, while important, less often determines AED choice in the elderly.