Levitiracetam: Initial Epilepsy Therapy in Elderly

Time to treatment withdrawal is longer for initial monotherapy with levitiracetam (LEV) compared to standard antiepileptic drugs (AEDs) in elderly adults with newly diagnosed epilepsy, according to results from the Keppra vs Older Monotherapy in Epilepsy Trial (KOMET) published online in BMC Neurology.¹

“Patients remained in the LEV treatment arm longer than those in the CBZ-CR [controlled release carbamazepine] arm, most likely because of the better tolerability of LEV. While the tolerability of CBZ-CR could have been improved by using a lower starting dose and slower up-titration, the long-term use of CBZ-CR in the elderly population is problematic in light of its enzyme-inducing properties,” wrote first author Bernd Pohlmann-Eden, MD of Dalhousie University (Halifax, Canada), and colleagues.

As an enzyme inducer, carbamazepine can potentially contribute to drug-drug interactions, and have adverse effects on bone health and cardiovascular risk, according to background information in the article.

While the incidence of epilepsy in the elderly is increasing, little evidence exists to guide choice of AED therapy in this population. Elderly individuals often experience age-related physiological changes that can affect drug metabolism, decrease renal excretion, and decrease plasma protein drug binding, all of which can complicate the choice of AED therapy. In addition, elderly individuals often have several medical conditions and require concomitant medication, which can increase the risk for drug-drug interactions.

The study was a post-hoc subgroup analysis of data from KOMET, an unblinded, randomized 52-week, phase IV trial. KOMET took place at 269 centers in 23 European countries and in Australia between February 2005 and October 2007. It was originally designed to compare the effectiveness of monotherapy with LEV to extended release sodium valproate (VPA-ER) or CBZ-CR in adults with newly diagnosed epilepsy. The subgroup analysis included 308 older individuals (mean age 69.6 years) with newly diagnosed epilepsy. Patients were separated into a VPA-ER group or a CBZ-CR group. Within the VPA-ER group, researchers randomized patients to LEV (n = 48) or VPA-ER (n = 53). Within the CBZ-CR group, patients were randomized to LEV (n = 104) or CBZ-CR (n = 103). Preferred first-line therapy was decided at the discretion of the treating physician. Most patients had focal seizures.

Key Results:

• LEV had longer time to treatment withdrawal (primary endpoint):

♦ LEV vs. standard AEDs: HR 0.44 (0.28–0.67)

♦ LEV vs. VPA-ER: 0.46 (0.16–1.33)

♦ LEV vs. CBZ-CR: 0.45 (0.28–0.72)

• LEV had lower 12-month withdrawal rates:

♦ LEV vs. standard AEDs: 20.4 vs. 38.7 %

♦ LEV vs. VPA-ER: 10.4 vs. 23.1 %

♦ LEV vs. CBZ-CR: 25.0 vs. 46.6 %

• Similar time to first seizure for:

♦ LEV vs standard AEDs (HR: 0.92, 95% CI: 0.63–1.35)

♦ LEV vs VPA-ER (HR 0.77, 0.38–1.56)

♦ LEV vs CBZ-CR (HR 1.02, 0.64–1.63)

• Treatment emergent adverse events (AEs) were reported by 76.2, 67.3, and 82.5% of patients given LEV, VPA-ER, and CBZ-CR, respectively

♦ Longer time to treatment withdrawal due to AEs for LEV than for standard AEDs (HR 0.36, 95 % CI 0.20–0.63)

• Serious adverse events: Higher incidence with LEV (18.5%), compared to CBZ-CR (10.7%) and VPA-ER (4.1%)

♦ Similar rate of drug-related adverse events for LEV, CBZ-CR, and VPA-ER (2.0 %, 2.9 %, and 2.0 %, respectively)

Only five randomized controlled trials of AED monotherapy have been done in elderly populations with newly diagnosed epilepsy, according to the authors. They emphasized that the results from the KOMET subgroup analysis agree with those from STEP-ONE, a prospective, randomized double blind trial that compared LEV and lamotrigine (LTG) to CBZ-CR in elderly patients with new onset epilepsy. That study found similar efficacy for monotherapy with LEV or CBZ-CR. In addition, LEV showed better tolerability and better retention rates.²

“The results of this analysis are in agreement with those of the randomized, double-blind STEP-ONE trial and several prospective, observational studies. Consequently, LEV may be considered a suitable option as initial monotherapy for individuals aged 60 years or above with newly diagnosed epilepsy,” they concluded.

However, they emphasized the exploratory nature of these findings, because KOMET was not large enough to do a subgroup analysis by age.

Take-home Points

• KOMET subgroup analysis suggests levitiracetam may be a suitable choice as initial monotherapy in elderly patients with newly diagnosed epilepsy.

• Levitiracetam showed significantly longer time to treatment withdrawal compared to controlled release carbamazepine, and a trend towards longer time to treatment withdrawal compared to extended release valproate.

• Twelve-month withdrawal rates were lower for levitiracetam compared to controlled release carbamazepine and extended release valproate.

• Time to first seizure was similar for all three drugs.

• The longer time to treatment withdrawal for levitiracetam compared to controlled release carbamazepine was most likely related to better tolerability of levitiracetam.

The study was sponsored by UCB Pharma.

One or more authors has received consulting fees, research funding, speaker honoraria from one or more of the following: UCB Pharma, Eisai, Sunovion, SAGE, Sanofi-Aventis, Desitin Pharma, GlaxoSmithKline, Bial, Ever Neuropharma, Medtronics, Takeda, Biogen Idec, Genzyme, FWF Austrian Science Fund, Jubiläumsfond der Österreichischen Nationalbank, Red Bull, and/or Gerot Lannach, Boehringer Ingelheim, ViroPharma, Actavis, Ever Biogen,   

Author Euge Trinka is Chief Executive Officer of Neuroconsult GmbH. Matthias Noack-Rink, Imane Wild, and Konrad J Werhahn are employees of UCB Pharma. Anthony G Marson and Franciscon Ramirez were employees of UCB Pharma when the analysis was conducted.

References:

1. Pohlmann-Eden B, et al. Comparative effectiveness of levetiracetam, valproate and carbamazepine among elderly patients with newly diagnosed epilepsy: subgroup analysis of the randomized, unblinded KOMET study. BMC Neurol. 2016 Aug 23;16(1):149.

2. Werhahn KJ, et al. A randomized, double-blind comparison of antiepileptic drug treatment in the elderly with new-onset focal epilepsy. Epilepsia. 2015 Mar; 56(3):450-459.