Currently, the double-blind placebo-controlled studies are the "gold standard" for assessing the efficacy and tolerability of antiepileptic drugs (AD). Nevertheless, these studies are not devoid of a number of shortcomings and the main one is the limited duration of the study compared with the long-term, in many cases, lifelong epilepsy course. It is known that a drug previously effective may be replaced by another because of the development of tolerance to it or the appearance of intolerable or unacceptable side effects. Decrease in the effectiveness of AD can be associated with the evolution of the disease itself, for example, medial temporal epilepsy, but even so, doctors usually increase the dose of AD, replace the drug with another, add one more.
An indicator that allows to evaluate the success of long-term application of a AD is the level of retention on the drug (% of patients who continue treatment after a certain period of time, usually 6 or 12 months from the beginning of the study). Retention rate is an integrated indicator reflecting, on the one hand, its tolerance, on the other - the development of tolerance to it. Our review reflects the results of long-term (6 months or more) studies on both traditional (valproate, carbamazepine) and new (lamotrigine, topiramate, levetiracetam, oxcarbazepine) AD. Valproate and carbamazepine. Valproate (valproate salt) (Depakin® and carbamazepine (Tegretol®, Finplexin®) are traditional ADs and are considered the "gold standard" for the treatment of epilepsy. Both drugs have been used to treat epilepsy since the 60s of the 20th century. Valproate - A broad-spectrum drug, carbamazepine is used mainly for symptomatic and presumably focal epilepsies, it is contraindicated in most idiopathic generalized epilepsies, and phenytoin is added in the United States with carbamazepine and valproate. oshedshie years been a number of studies on the efficacy and tolerability of these drugs.
A study conducted by M. Kuncikova et al. showed high efficacy and good tolerability of sodium valproate in the treatment of partial epilepsy in children and adults. Remission rate reached 84% in children and 73% of adults, while noting the high level of retention on the drug (90% after 6 months of treatment). Only 2% of patients discontinued the study because of side effects. A multicentre study comparing the efficacy of sodium valproate and carbamazepine (EPITEG group) in the treatment of adults and children was conducted in the UK.
In the EPITEG study on adults, patients with newly diagnosed epilepsy with primary generalized, partial or secondary generalized seizures were included. Patients were divided into groups: those receiving valproate sodium (200 mg twice, n = 149) and taking carbamazepine (100 mg twice, n = 151). If necessary, the dose was increased either until the seizures ceased, or until toxic effects appeared.
Valproate sodium and carbamazepine showed similar efficacy, but after 6 months in the valproate-treated group there remained significantly more patients than in the other (90% vs. 75%, p = 0.001). Cancellation because of side effects was more often performed with carbamazepine than valproate (15% versus 5% in the first 6 months of therapy). By the end of the three-year follow-up period, more than 70% of the patients studied either stayed on the prescribed therapy or stopped taking the drug after long-term remission. In general, the study showed a good tolerability of traditional AD in the treatment of epilepsy in adults.
In the EPITEG study on the use of PED in pediatric practice, 260 children with newly diagnosed primary generalized or partial epilepsy who underwent two or more generalized tonic-clonic or partial seizures in the previous 6 months were included. The children were divided into two groups: one took sodium valproate (n = 130), the other received carbamazepine (n = 130). Both were observed outpatiently for 3 years. If necessary, the dose of AD increased or until the cessation of attacks, or before the manifestation of toxic effects. Both drugs showed equivalent efficacy, side effects were insignificant and rarely required cancellation.
Comparative efficacy of monotherapy with phenobarbital, phenytoin, carbamazepine and sodium valproate in newly diagnosed epilepsy in children was studied by M. de Silva and co-authors. In an open randomized trial, 167 children aged 3 to 16 years old, who had undergone at least two partial or generalized tonic-clonic seizures, were included. Children were divided into groups according to the prescribed drug - one of the four ADs. The study protocol was close to the usual clinical practice. Efficacy was assessed by time until the first attack after the start of therapy and the time to achieve an annual remission. The results of the use of all four drugs were favorable. During 3 years of follow-up, annual remission was achieved in 73% of children. Between the drugs, there were no significant differences in efficacy. The highest level of manifestations of side effects requiring withdrawal of treatment was noted with phenobarbital (6 of the first 10 patients in the group receiving this drug), and in the following, phenobarbital was not prescribed. Among the remaining three ADs, phenytoin (9%) was more often abolished than carbamazepine or valproate (4% each).
A similar comparative study was conducted by A.J. Heller and co-authors in newly diagnosed epilepsy in adults. 243 patients aged 16 years and over who had undergone at least two partial or generalized tonic-clonic seizures were allocated to groups to receive phenobarbital, phenytoin, carbamazepine and sodium valproate. 75% of patients achieved annual remission during a three-year follow-up period. The drugs demonstrated equivalent efficacy, but differed in portability. The withdrawal of therapy due to side effects was necessary in a total of 10% of patients, while in the group of patients taking phenobarbital, this proportion was 22%, taking phenytoin, carbamazepine and valproate - 3, 11 and 5%, respectively. The authors believe that when choosing a drug, one should evaluate the level of toxicity and cost.
New anticonvulsants: lamotrigine (Lamictal®), levetiracetam (Keppra®), topiramate (Topamax®), refer to broad-spectrum drugs. Occarbazepine (Trileptal®) and gabapentin (Neurontin®) are indicated for the treatment of symptomatic and supposedly symptomatic focal epilepsy. Despite the fact that, according to some data, the new ADs are similar in efficiency to traditional ones, but are better tolerated, the results of the studies and clinical practice show that they differ markedly both in effectiveness and in the level of retention on the drug. Thus, gabapentin appeared to be a drug with low antiepileptic activity and was registered for the treatment of neuropathic pain; Lamotrigine combines relatively low efficacy with good tolerability; Topiramate high efficiency is combined with a relatively low level of retention.
A number of studies have been carried out to evaluate the efficacy and tolerability of new AD: open prospective and retrospective studies of new drugs, comparative studies, meta-analyzes (reviews based on the mathematical treatment of double-blind placebo-controlled studies compared to AD). In the study of H. P. Bootsma and co-authors, devoted to the study of the efficacy of topiramate, the retention rate on the drug was 53% in a year, 45% at 2 years, 38% at 3 years and 30% at 4 years after the administration of the drug. Thus, after 4 years 70% of patients stopped taking topiramate, in 65% of cases it was associated with side effects of the drug.
A study of the efficacy and tolerability of levetiracetam in children and adolescents with refractory epilepsy was conducted by S. von Stuelpnagel and co-authors . The study included 129 patients with an average age of 10.6 years, with severe epilepsy, often with mental retardation. Patients received levetiracetam at an average dose of 39.8 mg / kg per day (6-70 mg / kg). The treatment yielded results in 35 patients (27.1%), of which 5 had seizures. The level of retention on the drug among patients with successful treatment after 3 years was 22.5%.
A retrospective multicenter study of the efficacy, tolerability, and assessment of retention in levetiracetam was carried out by D. Peake and co-authors. The study included 200 children from 0.3 to 19 years with refractory epilepsy. The dose of levetiracetam ranged from 8 to 100 mg / kg per day (average 39 mg / kg). The drug was well tolerated. The level of retention on the drug 1 year after the start of the study was 49%. At 2, 6 and 12 months, seizures decreased by more than 50% in 60, 40 and 32%, respectively, including the absence of seizures, respectively, in 14, 14 and 5% of patients. The authors evaluate the levels of efficacy of therapy and retention on the drug in this group of children with resistant epilepsy as good.
In a British study, R. J. Simister et al. compared retention rates to several new ADs in adult patients with chronic epilepsy and mental retardation. Two years after the start of treatment, the retention rate was 85% for oxcarbazepine, 57% for lamotrigine, 56% for levetiracetam and 45% for topiramate. For tiagabine and gabapentin, this level was 24 and 15%, respectively. The highest incidence of side effects was recorded with topiramate (60%), the least - levetiracetam (16%).
S. Chung et al. studied retention rates in five new ADs: levetiracetam, lamotrigine, oxcarbamazepine, topiramate, and zonisamide. The evaluation was carried out at 4, 12, 24, 52 and 104 weeks. A total of 828 AD assignments were analyzed. The retention rate was highest for lamotrigine (74.1%), followed by zonisamide (60.2%), oxcarbazepine (58.8%), levetiracetam (53.6%), and topiramate (44.2%). The abolition of drugs was most often associated with inefficiency (29.5%) and sedative side effects (20.5%). As a rule, the drug was canceled in the first 6 months of therapy. Some causes of withdrawal were specific for specific AD: behavioral disorders and excitability in the use of levetiracetam; Rash in connection with taking carbamazepine and lamotrigine; Oxcarbazepine caused hyponatraemia; Topiramate and zonisamide were canceled because of kidney stones.
Meta-analysis allows for an indirect comparison of the efficacy and tolerability of drugs. The results of one of the meta-analyzes are shown in the figure. The response rate (on the vertical axis) reflects the effectiveness of the drug (the higher, the more effective), the level of withdrawal (horizontally) - tolerability (the closer to zero, the less often the drug is canceled). For most new ADs, except levetiracetam, there is a regularity: the more effective the drug, the lower the level of confinement.