Monotherapy in Newly Diagnosed Epilepsy: Levetiracetam Versus Standard Anticonvulsants

Commentary

KOMET: An Unblinded, Randomised, Two Parallel-Group, Stratified Trial Comparing the Effectiveness of Levetiracetam With Controlled-Release Carbamazepine and Extended-Release Sodium Valproate as Monotherapy in Patients With Newly Diagnosed Epilepsy.

Trinka, E, Marson, AG, Van Paesschen W, Kalviainen R, Marovac J, Duncan B, Buyle S, Hallstrom Y, Hon P, Muscas GC, Newton M, Meencke HJ, Smith PE, Pohlmann-Eden B. J Neurol Neurosurg Psychiatry 2013;84:1138–1147.H.

OBJECTIVE: To compare the effectiveness of levetiracetam (LEV) with extended-release sodium valproate (VPA-ER) and controlled-release carbamazepine (CBZ-CR) as monotherapy in patients with newly diagnosed epilepsy. METHODS: This unblinded, randomised, 52-week superiority trial (NCT00175903) recruited patients (>/=16 years of age) with >/=2 unprovoked seizures in the previous 2 years and >/=1 in the previous 6 months. The physician chose VPA or CBZ as preferred standard treatment; each patient was randomised to standard treatment or LEV. The primary outcome was time to treatment withdrawal (LEV vs standard antiepileptic drugs (AEDs)). Analyses also compared LEV with VPA-ER, and LEV with CBZ-CR. FINDINGS: 1688 patients (mean age 41 years; 44% female) were randomised to LEV (n=841) or standard AEDs (n=847). Time to treatment withdrawal was not significantly different between LEV and standard AEDs: HR (95% CI) 0.90 (0.74 to 1.08). Time to treatment withdrawal (HR (95% CI)) was 1.02 (0.74 to 1.41) for LEV/VPA-ER and 0.84 (0.66 to 1.07) for LEV/CBZ-CR. Time to first seizure (HR, 95% CI) was significantly longer for standard AEDs, 1.20 (1.03 to 1.39), being 1.19 (0.93 to 1.54) for LEV/VPA-ER and 1.20 (0.99 to 1.46) for LEV/CBZ-CR. Estimated 12-month seizure freedom rates from randomisation: 58.7% LEV versus 64.5% VPA-ER; 50.5% LEV versus 56.7% CBZ-CR. Similar proportions of patients within each stratum reported at least one adverse event: 66.1% LEV versus 62.0% VPA-ER; 73.4% LEV versus 72.5% CBZ-CR. CONCLUSIONS: LEV monotherapy was not superior to standard AEDs for the global outcome, namely time to treatment withdrawal, in patients with newly diagnosed focal or generalised seizures.

The choice of initial antiseizure medication (ASM) in newly diagnosed patients with epilepsy is of utmost importance. This choice is made based on the seizure type, patient comorbidities, concomitant medications and possible interactions, safety in pregnancy and lactation, and adverse event profile. A proper choice may improve compliance and minimize the time before driving and resumption of other baseline activities. Randomized, double-blinded, placebo-controlled trials are the gold standard for studying the efficacy and tolerability of ASM. However, they have short duration and are conducted in settings that do not resemble actual clinical practice.

Levetiracetam (LEV) is a new generation ASM whose use has increased tremendously over the past several years by epileptologists as well as neurologists, emergency physicians, neurointensivists, and neurosurgeons, owing to its ease of use, linear pharmacokinetics, and lack of interactions with other drugs (1). LEV was compared with controlled-release carbamazepine (CBZ-CR) in a prospective study in patients with partial or generalized seizures in a setting that mimicked clinical practice (2). The authors reported similar efficacy, with 73% of patients randomized to LEV and 72.8% of those randomized to CBZ-CR in achieving seizure freedom at the last evaluated dose in a per protocol analysis. Another trial, the Standard and New Antiepileptic Drugs (SANAD) trial, also mimicked routine clinical practice and was unblinded for up to 6 years (3). In that trial 1721 patients considered appropriate candidates for CBZ treatment were randomized to CBZ versus other newer generation ASMs, excluding LEV, and the authors concluded that lamotrigine was better than CBZ regarding time to treatment failure.

The current study, Keppra Versus Older Monotherapy in Epilepsy Trial (KOMET), resembles the SANAD trial in design, but the aim was to study LEV versus older generation medications (4). This multicenter, unblinded, randomized, 52-week, controlled superiority trial was carried out in 269 centers in Europe and Australia. The authors divided newly diagnosed patients with epilepsy into two arms, one in which valproic acid (VPA) was considered the best-recommended treatment, and the other in which CBZ was considered best. They then randomized the first arm into the extended-release formulation of valproic acid (VPA-ER) versus LEV, and the other into CBZ-CR versus LEV. The controlled-release formulation of the standard ASM was chosen because of better reported tolerability (5, 6). The decision whether VPA or CBZ was considered standard initial treatment was made by the clinician, and did not require neuroimaging or EEG. The target doses of each medication (LEV 1000 mg/d, VPA-ER 1000 mg/d, and CBZ-CR 600 mg/d) were reached in 2 weeks, and further titration depended on the clinical situation with maximum doses of each medication set a priori: LEV 3000 mg/d, VPA-ER 2000 mg/d, and CBZ-CR 1600 mg/d). The primary outcome measure was time to withdrawal from treatment with the aim of comparing LEV with the other two standard ASMs, and the primary analysis was by intention-to-treat.

Randomization occurred in 1698 patients and the intention-to-treat analysis included 1688 patients with similar demographics and epilepsy characteristics between the LEV and the standard ASM treatments. Similar proportions in the LEV and the standard ASM groups were still taking the randomized treatment at 12 months (1266 patients, 75%, total). Median daily doses, including the titration period, were 987 mg/d for both LEV and VPA-ER, and 588 mg/d for CBZ-CR. The time to treatment withdrawal was not statistically significantly different between LEV and standard ASMs, with a trend for longer such time with LEV. However, the time to first seizure, a secondary outcome measure, was longer in the standard ASM arm than with LEV (1.20, 95% CI 1.03–1.39).

Subanalyses concluded similar time to treatment withdrawal for LEV and VPA-ER, as well as for LEV and CBZ-CR, with no statistically significant difference between patients who had focal seizures only and those who had generalized seizures only. Although not statistically significant, time to first seizure slightly favored VPA-ER and CBZ-CR over LEV. In one subanalysis, estimated seizure-freedom rates at 1 year were lower (58.7%) for LEV compared with VPA-ER (64.5%), and in the other, these rates were also lower for LEV (50.5%) compared with CBZ-CR (56.7%). There were no differences in the quality of life or adverse events between LEV and standard ASMs.

Lack of confirmation of seizures types by EEG or neuroimaging before assigning a patient to either arm of the study is not a significant limitation in the KOMET trial since it is consistent with actual clinical practice, as often an ASM is prescribed prior to obtaining imaging or EEG studies. Whereas CBZ may not be appropriate for idiopathic generalized epilepsies, both LEV and VPA can be considered broad-spectrum ASMs, and their similarity to treatment withdrawal was seen in the stratum where 70% of patients had generalized seizures. Similarly, the unblinded treatment and lack of standardization of best treatment option that takes into consideration co-morbidities and other factors are in line with routine clinical practice.

We need more such studies that directly inform clinical practice, and for durations that are longer than one year. Although in the United States, for example, LEV is not approved as a first-line ASM, it is often used as first-line in both outpatient and inpatient settings. For many clinicians, it is considered an important addition to our armamentarium owing to its favorable pharmacokinetic profile, as mentioned above, efficacy in focal and generalized epilepsies, and tolerable adverse event profile. In addition, accumulating evidence of the safety of LEV in pregnancy (7) further increases its utility in clinical practice. Indeed, the study at hand confirms its usefulness as first-line therapy.

The rate of treatment retention (75%), a rough composite of both efficacy and tolerability, in this trial is consistent with figures from other studies. Similarly, the seizure-freedom rates are also consistent with previous studies. It is classic teaching in epilepsy now that initial antiseizure treatment can achieve seizure freedom in two-thirds of newly diagnosed patients (8). Interestingly, this rate remains fixed even after the plethora of newer generation ASMs, including ones with novel mechanisms of action (9). This underlines questions about mechanisms of pharmacoresistance, highlights the need for early surgical evaluations, and calls for more research in the area of neuromodulation.