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Real-life experience with brivaracetam in 101 patients with difficult-to-treat epilepsy—A monocenter survey
Seizure 48 (2017) 11–14
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Seizure journal homepage: www.elsevier.com/locate/yseiz
Real-life experience with brivaracetam in 101 patients with difficult-to -treat epilepsy—A monocenter survey Bernhard J. Steinhoff* , Matthias Bacher, Iancu Bucurenciu, Barbara Hillenbrand, Tassanai Intravooth, Reinhold Kornmeier, Christoph Kurth, Jakob Stockinger, Anke M. Staack Kork Epilepsy Center, Kehl-Kork, Germany
A R T I C L E I N F O
A B S T R A C T
Article history: Received 27 January 2017 Received in revised form 27 February 2017 Accepted 17 March 2017 Available online xxx
Purpose: To assess the efficiency of brivaracetam under real-world conditions in a tertiary referral epilepsy center. Methods: We consecutively collected patients treated at our center with brivaracetam (BRV). After a minimum observation period of six months we retrospectively analyzed the efficiency of BRV. Results: Data of 101 patients (mean age 42 years, range 18–81 years, 54 females,) were analyzed. The median number of antiepileptic drugs (AEDs) used prior to BRV was 10 (range 2–18). The initial dose of BRV was at least 50 mg per day, the mean maintenance dose at cut-off was 168.6 mg (median 200 mg, range 50–400 mg). Efficacy data were assessed for the last three months or at the time of the last observation carried forward if BRV had been discontinued prematurely. Responder rate was 27.8% (n = 28) with 7% seizure-free patients. Adverse events (AEs) occurred in 37 patients (37%). Most frequent AEs were dizziness (16%) and somnolence (11%). Psychiatric adverse events comprised irritability, aggression, depression and psychosis in single cases. Retention rate after six months was 51.5%. Main reason for discontinuation was a lack of efficacy. In 43 cases LEV and BRV were switched. The switch was performed abruptly without complications. In 26 cases (60%) BRV was discontinued and re-switched to LEV within weeks, mainly due to a lack of better efficacy. After the switch from LEV to BRV we even saw an aggravation both of seizure frequency and severity in 5 cases. Retention rate in patients who had not been on LEV was 57%. Conclusion: In our hands BRV appeared to be well tolerated and easy to handle. The retention rate was influenced by patients who were switched from LEV and re-switched because BRV was not more efficient. Switching from and re-switching to LEV was easy. © 2017 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.
Keywords: Brivaracetam Antiepileptic drugs Epilepsy Real world experience
1. Introduction Like levetiracetam (LEV), brivaracetam (BRV) is a ligand of the synaptic vesicle protein SV2A. This mechanism is thought to be the principle one [1,2]. BRV was recently approved for the adjunctive treatment of adults and adolescents 16 years with partial seizures with and without secondary generalization in the European Union and the
* Corresponding author at: Epilepsiezentrum Kork, Landstraße 1, 77694 KehlKork, Germany. E-mail address: [email protected] (B.J. Steinhoff).
United States [1]. It was introduced to the market in Germany in February of 2016. The Kork Epilepsy Center is one the largest traditional epilepsy centers in Germany offering 122 in-patient beds and more than 6.000 out-patient appointments per year. As a consequence, many of our patients suffer from difficult-to-treat epilepsy syndromes with ongoing seizures in spite of numerous previous therapeutic strategies [3,4]. As soon as a new antiepileptic drug (AED) is marketed many of those patients who have been urgently waiting or a new treatment option will be treated with such a new AED within a relatively short period of time [3]. This report comprises patients who were treated with BRV from the time of launch in February of 2016 on. After a minimum observation time of six months, i.e., in November of 2016, we
http://dx.doi.org/10.1016/j.seizure.2017.03.010 1059-1311/© 2017 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.
12
B.J. Steinhoff et al. / Seizure 48 (2017) 11–14
made a cut-off and retrospectively analyzed efficacy and tolerability of BRV. 2. Patients and methods From February of 2016 on we consecutively collected data from adult out- and inpatients of the Kork Epilepsy Center who were treated with BRV. Data comprised age, etiology, classification of epileptic seizures and syndromes, baseline AED medication and seizure frequency according to patient’s diary or inpatient observation by our staff. BRV was always started according to a bid regimen with 25 mg bid, 50 mg bid or 100 mg bid, respectively. Patients on levetiracetam (LEV) were switched abruptly to BRV according to a ratio as follows: 1000 mg LEV were replaced by 50 mg BRV, 2000 mg LEV by 100 mg BRV and 3000 mg LEV by 200 mg BRV. BRV was increased, decreased or stopped according to the clinical course. We stopped recruiting in May of 2016. Patients were consecutively followed and contacted monthly. In case of any question, adverse event, or any other clinically relevant problem, patients had the opportunity to contact us by telephone, fax or e mail at any time. In an emergency case admission to the hospital was possible. Efficacy data comprised the seizure count and the assessment of seizure type on the basis of the patient’s reports and diaries. All patients used seizure diaries. During their hospital stays seizures were classified and documented by the staff. The seizure frequency was evaluated for the last three months prior to the individual cutoff and compared to a retrospective baseline of three months prior to the initiation of adjunctive BRV. If patients had discontinued prematurely this observation period was shortened accordingly. Patients who discontinued BRV due to tolerability reasons within one month were counted as non-responders concerning seizure frequency. Tolerability and adverse events were updated at least monthly. Patients were asked for any adverse events they observed. In addition a list of potential adverse events like dizziness, fatigue, somnolence, ataxia, dysarthia, blurred vision, diplopia, irritability, aggression, depression and psychotic symptoms was covered during the interview. Cut-off for the data analysis presented here was in November of 2016, so that the minimum observation period was 6 months (if patients had been started with BRV in May). Adverse events were assessed at the time of the last observation both in patients who were still on BRV in November of 2016 and in patients who had discontinued the drug in the meantime. Retention was documented monthly. 3. Results We included 101 patients. Mean age was 42 years with a range between 18 and 81 years. Fifty-four patients (53%) were female. Etiology was distributed as follows: Structural causes were apparent in 71%; the etiology was unclear in 27%. In one case each a genetic cause with a mutation in the SCN1A gene and elevated anti-GAD antibodies were evident. In all patients partialonset seizures occurred, three of them had only generalized tonicclonic seizures with presumably partial onset. The remaining 98 patients (97%) had partial-onset seizures with and without secondary generalization. Secondary generalized tonic-clonic seizures (GTCS) were apparent in 86 cases (85%); the seizures of the remaining 15 patients did not tend to generalize. The median number of antiepileptic drugs (AEDs) used prior to BRV was 10 (range 2–18). When BRV was initiated, three patients were on a monotherapy with LEV and switched to an off-label monotherapy with BRV. The remaining 98 patients got BRV as adjunctive AED. Their baseline treatment consisted of one AED in 35%, of two AEDs in 46%, of three AEDs in 16%, and of 4 AEDs in 4%.
In patients on baseline monotherapy the most commonly used AED was lamotrigine (LTG). The new AEDs that were introduced to Germany most recently and that are still available are lacosamide (LCM) eslicarbazepine acetate (ESL) and perampanel (PER). These belonged to the baseline medication in 18, 10 and 10%, respectively and were even used in off-label monotherapy occasionally (LCM: n = 6, ESL: n = 4, PER: n = 1). In 43% LEV and BRV were switched. The switch was performed abruptly and did not cause problems. The initial dose of BRV was at least 50 mg per day, the mean maintenance dose at cut-off was 168.6 mg (median 200 mg, range 50–400 mg). Considering efficacy 27.8% (n = 28) was responders with a seizure reduction by at least 50% per month over the last three months. Seven of these patients (7% of all) were completely seizure-free. All seizure-free patients were on a baseline monotherapy or on a combination of 2 AEDs. The number of previously used AEDs was lower than in the whole patient group (median = 6, range 2–8). Mean BRV dose in the seizure-free patients was 135.8 mg and thus lower than in the whole patient group. Among the 89 patients with GTCs including 3 patients with GTCS only 10 were seizure-free under BRV (11.2%). Fourteen patients took doses beyond the recommended maximum 200 mg per day according to the labeling. In five of them, additional response was seen. However, in 2 of these 5 responders we had to decrease the dose of 250 mg and 300 mg, respectively, again due to dizziness. Adverse events (AEs) occurred in 37 patients (37%). Most frequent AEs were dizziness (16%) and somnolence (11%). Psychiatric advents were assessed by personal examination and comprised irritability, aggression, depression and psychosis in single cases. We observed no hematological, cardiovascular or dermatological complications. In several cases carbamazepine epoxide was markedly elevated under the influence of BRV which led to dizziness which resolved after reduction of carbamazepine. In another case a severe hyponatremia of 123 mmol/l occurred with BRV and ESL only after the introduction of BRV which resolved after the discontinuation of BRV due to a lack of efficacy. Table 1 summarizes the adverse events. Retention rate after six months was 51.5% (n = 52). The main reason for discontinuation was a lack of efficacy (30.6%) according to the patient’s opinion. In no case did patients wish to discontinue BRV due to a lack of efficacy if they observed a reduction of seizure frequency of at least 50%. Adverse events were the only reason for discontinuation in 3 cases only. Two patients complained about dizziness, one of each about additional ataxia and somnolence, respectively. The third patient discontinued due to marked somnolence and irritability. In the remaining cases both lack of efficacy and tolerability issues led to the discontinuation of BRV. In 26 cases (60%) BRV was discontinued and re-switched to LEV resulting in a retention rate of 40%, mainly since the efficacy of adjunctive BRV was not clearly superior. Tolerability was the reason for a switch in 6 patients only. Three of them benefitted because of less irritability (n = 2) or somnolence (n = 1). After the Table 1 Adverse events. Adverse event
%
N
Dizziness Somnolence Ataxia Increase of seizure frequency/severity Irritability Depression Psychosis Headache Nausea
15.8 9.9 5.0 5.0 4.0 2.0 2.0 1.0 1.0
16 10 5 5 4 2 2 1 1
B.J. Steinhoff et al. / Seizure 48 (2017) 11–14
switch from LEV to BRV we saw an aggravation both of seizure frequency and severity with an increase or a new onset of SGTC in 5 cases. An increase of the frequency of GTCS was seen in one other patient. Retention rate in patients who had not been on LEV was 57%. 4. Discussion With every new AED we hope to considerably reduce the number of patients who still experience ongoing seizure in spite of numerous therapeutic options, including various previous AEDs and sometimes even neurostimulation or epilepsy surgery. The marketing of a new AED requires that efficacy and safety were shown convincingly in randomized placebo-controlled trials. In two phase II and four phase III trials adjunctive BRV was tested in patients with difficult-to-treat and still active epilepsies with partial-onset seizures [5–11]. This led to the labeling for adjunctive treatment of patients with partial-onset seizures from the age of 16 years on with a daily dose recommendation between 50 mg and 200 mg [1]. Still, since most patients with drug-resistant epilepsies are missed by pivotal AED trials [4] we have no good evidence for the practical value of a new AED prior to its use in the real world. The patient population in our survey certainly represented a severely intractable group. The median number of previous AEDs was 10, and many of them were still on the latest AEDs that had been introduced prior to BRV. In our hands the responder rate was 27.8%. In a very similar setting we observed a responder rate of 45.9% with adjunctive PER [3] and of 48.6% with PER and 28.6% with LCM, respectively [12]. The rate of seizure freedom with BRV in our study was 7% and thus also in the range of LCM (4.3%) and below the results we achieved with PER at our center (13.5% and 14.3%, respectively) [3,12]. The ultimate goal of any antiepileptic therapy is freedom from seizures. Although a rate of 7% seizure-free patients may be rather disappointing at first glance, one has to consider that the probability of achieving this in our group of patients is certainly much lower than in newly-onset epilepsies [13]. Still, seizure freedom rates were only 2.5%, 5.1% and 4.0% with adjunctive BRV doses of 50 mg, 100 mg, and 200 mg, respectively according to the pooled data of the pivotal trials [11] and this comparably low in patients with hitherto intractable epilepsies. The group of seizurefree patients with adjunctive BRV represented a probably slightly less drug-resistant population than the whole group, because the history of previous AEDs was less extensive. Still, the median was 6 previous AEDs and thus high enough to suggest a markedly reduced probability of achieving freedom of seizures [13]. Eleven percent of the patients with GTCS were free of these seizures during the observation period under treatment with BRV. However, one has to consider that the frequency of GTCS is not too high in many patients so that in some of these patients the freedom of GTCS might have resulted from the spontaneous course rather than from BRV. Longer observation periods are necessary to address the efficacy in patients with GTCS appropriately. Tolerability of BRV was very good. If we compare our results with the survey we conducted with LCM and PER in an identical setting, a rate of 36% AEs is remarkable in this group of patients with a sometimes considerable drug load. AE rates were 54% and 73%, respectively, for PER and 45.7% for adjunctive LCM [3,12]. The distribution of AEs was similar to the results of the phase II and III trials [5–11]. Considering the mode of action of BRV it is somewhat surprising that dizziness is one of the most common AE: It is very rarely seen with LEV and was not necessarily predictable because BRV is supposed to act even more potently and selectively at the SV2A binding site compared to LEV [14]. The differing AE profile may be due to the differing interaction with the SV2A protein that was recently reported [15]. Although psychiatric adverse events
13
were rare, they still occured both in patients who were switched to BRV from LEV and in patients where BRV was added. The interaction between BRV and carbamazepine that leads to an increase of carbamazepine epoxide [16] may be clinically relevant since toxic symptoms such as dizziness may occur. If patients are switched from LEV to BRV, the possibility of seizure aggravation should be considered which happened in 5 cases (11.6% of all switched patients). The previous seizure situation was re-established in them when they were back to LEV. Retention rate is a parameter that usually nicely reflects the efficiency of a new AED because both efficacy and tolerability have an impact on the probability of staying on an adjunctive AED or of discontinuing it. However, due to new legislation aimed at regulating the German drug market which is effective from 2011 on, there was the fear that one year after launch the BRV might be withdrawn from the German market, after the Federal Joint Committee (Gemeinsamer Bundesausschuss, G-BA), the highest decision-making body of the joint self-government of physicians, dentists, hospitals and health insurance funds in Germany, had ruled that no evidence of an additional benefit of BRV over comparative therapies had been provided. This had happened previously with retigabine and perampanel. The profile of BRV that allows the very rapid initiation of a maintenance dose [1,2,5–11] and the sudden and complete switch from LEV and a re-switch if necessary encouraged us in many cases to introduce BRV but also to judge it more critically than previous adjunctive new AEDs. According to our experiences with perampanel there is only a realistic chance of achieving reimbursement via International drug supply after a withdrawal from the German market if a marked benefit could be demonstrated. Therefore we certainly discontinued BRV more closely in line with an apparent influence on the retention rate. Real-world data such as that in this paper certainly have methodological limitations. The protocol is not standardized. At least in out-patients, efficacy and tolerability data are highly influenced by the quality of self-reporting [17]. Personal expectations and other subjective factors may influence the results. Still, our real-world experience demonstrates that BRV is a welltolerated and easy-to-handle new AED. Its relatively modest efficacy still allowed us to achieve marked beneficial effects in selected patients with difficult-to-treat epilepsies. Conflicts of interest statement BJS has received speaker’s honoraria from Desitin, Eisai, Novartis, OmniaMed, and UCB. He was a paid consultant of Actelion, B. Braun, Eisai, Shire, and UCB. CK has received speaker’s honoraria from Desitin, Eisai and UCB. AMS has received speaker’s honoraria from Desitin, Eisai, and UCB. She was a paid consultant of Eisai and UCB. MB, IB, BH, TI, RK, JS have no conflict of interest to disclose. Funding This study was not funded by any external sources. References [1] Brandt C, May TW, Bien CG. Brivaracetam as adjunctive therapy for the treatment of partial-onset seizures in patients with epilepsy: the current evidence base. Ther Adv Neurol Disord 2016;9:474–82. [2] Lattanzi S, Cagnetti C, Foschi N, Provinciali L, Silvestrini M. Brivaracetam addon for refractory focal epilepsy: a systematic review and meta-analysis. Neurology 2016;86:1344–52. [3] Steinhoff BJ, Bacher M, Bast T, Kornmeier R, Kurth C, Scholly J, Staack AM, Wisniewski I. First clinical experiences with perampanel – the Kork experience in 74 patients. Epilepsia 2014;55(Suppl. 1):16–8.
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[4] Steinhoff BJ, Staack AM, Hillenbrand BC. Randomized comtrolled antiepileptic drug trials miss almost all patients with ongoing seizures. Epilepsy Behav 2016;66:45–8. [5] Biton V, Berkovic S, Abou-Khalil B, Sperling M, Johnson M, Lu S. Brivaracetam as adjunctive treatment for uncontrolled partial epilepsy in adults: a phase III randomized, double-blind, placebo-controlled trial. Epilepsia 2014;55:57–66. [6] French J, Costantini C, Brodsky A, Von Rosenstiel P, NO1193 Study Group. Adjunctive brivaracetam for refractory partial-onset seizures: a randomized, controlled trial. Neurology 2010;75:519–25. [7] Klein P, Schiemann J, Sperling MR, Whitesides J, Liang W, Stalvey T, Brandt C, Kwan P. A randomized, double-blind, placebo-controlled, multicenter, parallel-group study to evaluate the efficacy and safety of adjunctive brivaracetam in adult patients with uncontrolled partial-onset seizures. Epilepsia 2015;56:1890–8. [8] Kwan P, Trinka E, Van Paeschen W, Rektor I, Johnson M, Lu S. Adjunctive brivaracetam for uncontrolled focal and generalized epilepsies: results of a phase III, double-blind, randomized, placebo-controlled, flexible-dose trial. Epilepsia 2014;55:38–46. [9] Ryvlin P, Werhahn K, Blaszczyk B, Johnson M, Lu S. Adjunctive brivaracetam in adults with uncontrolled focal epilepsy: results from a double-blind, randomized, placebo-controlled trial. Epilepsie 2014;55:47–56. [10] Van Paeschen W, Hirsch E, Johnson M, Falter U, van Rosenstiel P. Efficacy and tolerability of adjunctive brivaracetam in adults with uncontrolled partialonset seizures A phase IIb, randomized, controlled trial. Epilepsia 2013;54:89– 97.
[11] Ben-Menachem E, Mamenieskiene R, Quarato PP, Klein P, Gamage J, Schiemann J, Johnson ME, Whitesides J, McDonough B, Eckhardt K. Efficacy and safety of brivaracetam for partial-onset seizures in 3 pooled clinical studies. Neurology 2016;87:314–23. [12] Kurth C, Kockelmann E, Steinhoff BJ. Clinical outcomes of perampanel vs lacosamide in cohorts of consecutive patients with severely refractory epilepsies – a monocentric retrospective analysis of systematically collected data from the German Kork Epilepsy Center. Seizure 2016;45:47–51. [13] Schiller Y, Najjar Y. Quantifying the response to antiepileptic drugs: effect of past treatment history. Neurology 2008;70:54–65. [14] Klitgaard H, Matagne A, Nicolas JM, Gillard M, Lamberty Y, De Ryck M, Kaminski RM, Leclercq K, Niespodziany I, Wolff C, Wood M, Hannestad J, Kervyn S, Kenda B. Brivaracteam: rationale for discovery and preclinical profile of a selective SV2A ligand for epilepsy treatment. Epilepsia 2016;57:538–48. [15] Stockis A, Sargentini-Maier ML, Brodie MJ. Pharmacokinetic interaction of brivaracetam on carbamazepine in adult patients with epilepsy, with and without valproate co-administration. Epilepsy Res 2016;128:163–8. [16] Wood MD, Gillard M. Evidence for a differential interaction of brivaracetam and levetiracetam with the synaptic vesicle 2A protein. Epilepsia 2017;58:255–62. [17] Blachut B, Hoppe C, Surges R, Stahl J, Elger CE, Helmstaedter C. Counting seizures: the primary outcome measure in epileptology from the patient’s perspective. Seizure 2015;29:97–103.
Contents lists available at ScienceDirect
Seizure journal homepage: www.elsevier.com/locate/yseiz
Real-life experience with brivaracetam in 101 patients with difficult-to -treat epilepsy—A monocenter survey Bernhard J. Steinhoff* , Matthias Bacher, Iancu Bucurenciu, Barbara Hillenbrand, Tassanai Intravooth, Reinhold Kornmeier, Christoph Kurth, Jakob Stockinger, Anke M. Staack Kork Epilepsy Center, Kehl-Kork, Germany
A R T I C L E I N F O
A B S T R A C T
Article history: Received 27 January 2017 Received in revised form 27 February 2017 Accepted 17 March 2017 Available online xxx
Purpose: To assess the efficiency of brivaracetam under real-world conditions in a tertiary referral epilepsy center. Methods: We consecutively collected patients treated at our center with brivaracetam (BRV). After a minimum observation period of six months we retrospectively analyzed the efficiency of BRV. Results: Data of 101 patients (mean age 42 years, range 18–81 years, 54 females,) were analyzed. The median number of antiepileptic drugs (AEDs) used prior to BRV was 10 (range 2–18). The initial dose of BRV was at least 50 mg per day, the mean maintenance dose at cut-off was 168.6 mg (median 200 mg, range 50–400 mg). Efficacy data were assessed for the last three months or at the time of the last observation carried forward if BRV had been discontinued prematurely. Responder rate was 27.8% (n = 28) with 7% seizure-free patients. Adverse events (AEs) occurred in 37 patients (37%). Most frequent AEs were dizziness (16%) and somnolence (11%). Psychiatric adverse events comprised irritability, aggression, depression and psychosis in single cases. Retention rate after six months was 51.5%. Main reason for discontinuation was a lack of efficacy. In 43 cases LEV and BRV were switched. The switch was performed abruptly without complications. In 26 cases (60%) BRV was discontinued and re-switched to LEV within weeks, mainly due to a lack of better efficacy. After the switch from LEV to BRV we even saw an aggravation both of seizure frequency and severity in 5 cases. Retention rate in patients who had not been on LEV was 57%. Conclusion: In our hands BRV appeared to be well tolerated and easy to handle. The retention rate was influenced by patients who were switched from LEV and re-switched because BRV was not more efficient. Switching from and re-switching to LEV was easy. © 2017 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.
Keywords: Brivaracetam Antiepileptic drugs Epilepsy Real world experience
1. Introduction Like levetiracetam (LEV), brivaracetam (BRV) is a ligand of the synaptic vesicle protein SV2A. This mechanism is thought to be the principle one [1,2]. BRV was recently approved for the adjunctive treatment of adults and adolescents 16 years with partial seizures with and without secondary generalization in the European Union and the
* Corresponding author at: Epilepsiezentrum Kork, Landstraße 1, 77694 KehlKork, Germany. E-mail address: [email protected] (B.J. Steinhoff).
United States [1]. It was introduced to the market in Germany in February of 2016. The Kork Epilepsy Center is one the largest traditional epilepsy centers in Germany offering 122 in-patient beds and more than 6.000 out-patient appointments per year. As a consequence, many of our patients suffer from difficult-to-treat epilepsy syndromes with ongoing seizures in spite of numerous previous therapeutic strategies [3,4]. As soon as a new antiepileptic drug (AED) is marketed many of those patients who have been urgently waiting or a new treatment option will be treated with such a new AED within a relatively short period of time [3]. This report comprises patients who were treated with BRV from the time of launch in February of 2016 on. After a minimum observation time of six months, i.e., in November of 2016, we
http://dx.doi.org/10.1016/j.seizure.2017.03.010 1059-1311/© 2017 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.
12
B.J. Steinhoff et al. / Seizure 48 (2017) 11–14
made a cut-off and retrospectively analyzed efficacy and tolerability of BRV. 2. Patients and methods From February of 2016 on we consecutively collected data from adult out- and inpatients of the Kork Epilepsy Center who were treated with BRV. Data comprised age, etiology, classification of epileptic seizures and syndromes, baseline AED medication and seizure frequency according to patient’s diary or inpatient observation by our staff. BRV was always started according to a bid regimen with 25 mg bid, 50 mg bid or 100 mg bid, respectively. Patients on levetiracetam (LEV) were switched abruptly to BRV according to a ratio as follows: 1000 mg LEV were replaced by 50 mg BRV, 2000 mg LEV by 100 mg BRV and 3000 mg LEV by 200 mg BRV. BRV was increased, decreased or stopped according to the clinical course. We stopped recruiting in May of 2016. Patients were consecutively followed and contacted monthly. In case of any question, adverse event, or any other clinically relevant problem, patients had the opportunity to contact us by telephone, fax or e mail at any time. In an emergency case admission to the hospital was possible. Efficacy data comprised the seizure count and the assessment of seizure type on the basis of the patient’s reports and diaries. All patients used seizure diaries. During their hospital stays seizures were classified and documented by the staff. The seizure frequency was evaluated for the last three months prior to the individual cutoff and compared to a retrospective baseline of three months prior to the initiation of adjunctive BRV. If patients had discontinued prematurely this observation period was shortened accordingly. Patients who discontinued BRV due to tolerability reasons within one month were counted as non-responders concerning seizure frequency. Tolerability and adverse events were updated at least monthly. Patients were asked for any adverse events they observed. In addition a list of potential adverse events like dizziness, fatigue, somnolence, ataxia, dysarthia, blurred vision, diplopia, irritability, aggression, depression and psychotic symptoms was covered during the interview. Cut-off for the data analysis presented here was in November of 2016, so that the minimum observation period was 6 months (if patients had been started with BRV in May). Adverse events were assessed at the time of the last observation both in patients who were still on BRV in November of 2016 and in patients who had discontinued the drug in the meantime. Retention was documented monthly. 3. Results We included 101 patients. Mean age was 42 years with a range between 18 and 81 years. Fifty-four patients (53%) were female. Etiology was distributed as follows: Structural causes were apparent in 71%; the etiology was unclear in 27%. In one case each a genetic cause with a mutation in the SCN1A gene and elevated anti-GAD antibodies were evident. In all patients partialonset seizures occurred, three of them had only generalized tonicclonic seizures with presumably partial onset. The remaining 98 patients (97%) had partial-onset seizures with and without secondary generalization. Secondary generalized tonic-clonic seizures (GTCS) were apparent in 86 cases (85%); the seizures of the remaining 15 patients did not tend to generalize. The median number of antiepileptic drugs (AEDs) used prior to BRV was 10 (range 2–18). When BRV was initiated, three patients were on a monotherapy with LEV and switched to an off-label monotherapy with BRV. The remaining 98 patients got BRV as adjunctive AED. Their baseline treatment consisted of one AED in 35%, of two AEDs in 46%, of three AEDs in 16%, and of 4 AEDs in 4%.
In patients on baseline monotherapy the most commonly used AED was lamotrigine (LTG). The new AEDs that were introduced to Germany most recently and that are still available are lacosamide (LCM) eslicarbazepine acetate (ESL) and perampanel (PER). These belonged to the baseline medication in 18, 10 and 10%, respectively and were even used in off-label monotherapy occasionally (LCM: n = 6, ESL: n = 4, PER: n = 1). In 43% LEV and BRV were switched. The switch was performed abruptly and did not cause problems. The initial dose of BRV was at least 50 mg per day, the mean maintenance dose at cut-off was 168.6 mg (median 200 mg, range 50–400 mg). Considering efficacy 27.8% (n = 28) was responders with a seizure reduction by at least 50% per month over the last three months. Seven of these patients (7% of all) were completely seizure-free. All seizure-free patients were on a baseline monotherapy or on a combination of 2 AEDs. The number of previously used AEDs was lower than in the whole patient group (median = 6, range 2–8). Mean BRV dose in the seizure-free patients was 135.8 mg and thus lower than in the whole patient group. Among the 89 patients with GTCs including 3 patients with GTCS only 10 were seizure-free under BRV (11.2%). Fourteen patients took doses beyond the recommended maximum 200 mg per day according to the labeling. In five of them, additional response was seen. However, in 2 of these 5 responders we had to decrease the dose of 250 mg and 300 mg, respectively, again due to dizziness. Adverse events (AEs) occurred in 37 patients (37%). Most frequent AEs were dizziness (16%) and somnolence (11%). Psychiatric advents were assessed by personal examination and comprised irritability, aggression, depression and psychosis in single cases. We observed no hematological, cardiovascular or dermatological complications. In several cases carbamazepine epoxide was markedly elevated under the influence of BRV which led to dizziness which resolved after reduction of carbamazepine. In another case a severe hyponatremia of 123 mmol/l occurred with BRV and ESL only after the introduction of BRV which resolved after the discontinuation of BRV due to a lack of efficacy. Table 1 summarizes the adverse events. Retention rate after six months was 51.5% (n = 52). The main reason for discontinuation was a lack of efficacy (30.6%) according to the patient’s opinion. In no case did patients wish to discontinue BRV due to a lack of efficacy if they observed a reduction of seizure frequency of at least 50%. Adverse events were the only reason for discontinuation in 3 cases only. Two patients complained about dizziness, one of each about additional ataxia and somnolence, respectively. The third patient discontinued due to marked somnolence and irritability. In the remaining cases both lack of efficacy and tolerability issues led to the discontinuation of BRV. In 26 cases (60%) BRV was discontinued and re-switched to LEV resulting in a retention rate of 40%, mainly since the efficacy of adjunctive BRV was not clearly superior. Tolerability was the reason for a switch in 6 patients only. Three of them benefitted because of less irritability (n = 2) or somnolence (n = 1). After the Table 1 Adverse events. Adverse event
%
N
Dizziness Somnolence Ataxia Increase of seizure frequency/severity Irritability Depression Psychosis Headache Nausea
15.8 9.9 5.0 5.0 4.0 2.0 2.0 1.0 1.0
16 10 5 5 4 2 2 1 1
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switch from LEV to BRV we saw an aggravation both of seizure frequency and severity with an increase or a new onset of SGTC in 5 cases. An increase of the frequency of GTCS was seen in one other patient. Retention rate in patients who had not been on LEV was 57%. 4. Discussion With every new AED we hope to considerably reduce the number of patients who still experience ongoing seizure in spite of numerous therapeutic options, including various previous AEDs and sometimes even neurostimulation or epilepsy surgery. The marketing of a new AED requires that efficacy and safety were shown convincingly in randomized placebo-controlled trials. In two phase II and four phase III trials adjunctive BRV was tested in patients with difficult-to-treat and still active epilepsies with partial-onset seizures [5–11]. This led to the labeling for adjunctive treatment of patients with partial-onset seizures from the age of 16 years on with a daily dose recommendation between 50 mg and 200 mg [1]. Still, since most patients with drug-resistant epilepsies are missed by pivotal AED trials [4] we have no good evidence for the practical value of a new AED prior to its use in the real world. The patient population in our survey certainly represented a severely intractable group. The median number of previous AEDs was 10, and many of them were still on the latest AEDs that had been introduced prior to BRV. In our hands the responder rate was 27.8%. In a very similar setting we observed a responder rate of 45.9% with adjunctive PER [3] and of 48.6% with PER and 28.6% with LCM, respectively [12]. The rate of seizure freedom with BRV in our study was 7% and thus also in the range of LCM (4.3%) and below the results we achieved with PER at our center (13.5% and 14.3%, respectively) [3,12]. The ultimate goal of any antiepileptic therapy is freedom from seizures. Although a rate of 7% seizure-free patients may be rather disappointing at first glance, one has to consider that the probability of achieving this in our group of patients is certainly much lower than in newly-onset epilepsies [13]. Still, seizure freedom rates were only 2.5%, 5.1% and 4.0% with adjunctive BRV doses of 50 mg, 100 mg, and 200 mg, respectively according to the pooled data of the pivotal trials [11] and this comparably low in patients with hitherto intractable epilepsies. The group of seizurefree patients with adjunctive BRV represented a probably slightly less drug-resistant population than the whole group, because the history of previous AEDs was less extensive. Still, the median was 6 previous AEDs and thus high enough to suggest a markedly reduced probability of achieving freedom of seizures [13]. Eleven percent of the patients with GTCS were free of these seizures during the observation period under treatment with BRV. However, one has to consider that the frequency of GTCS is not too high in many patients so that in some of these patients the freedom of GTCS might have resulted from the spontaneous course rather than from BRV. Longer observation periods are necessary to address the efficacy in patients with GTCS appropriately. Tolerability of BRV was very good. If we compare our results with the survey we conducted with LCM and PER in an identical setting, a rate of 36% AEs is remarkable in this group of patients with a sometimes considerable drug load. AE rates were 54% and 73%, respectively, for PER and 45.7% for adjunctive LCM [3,12]. The distribution of AEs was similar to the results of the phase II and III trials [5–11]. Considering the mode of action of BRV it is somewhat surprising that dizziness is one of the most common AE: It is very rarely seen with LEV and was not necessarily predictable because BRV is supposed to act even more potently and selectively at the SV2A binding site compared to LEV [14]. The differing AE profile may be due to the differing interaction with the SV2A protein that was recently reported [15]. Although psychiatric adverse events
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were rare, they still occured both in patients who were switched to BRV from LEV and in patients where BRV was added. The interaction between BRV and carbamazepine that leads to an increase of carbamazepine epoxide [16] may be clinically relevant since toxic symptoms such as dizziness may occur. If patients are switched from LEV to BRV, the possibility of seizure aggravation should be considered which happened in 5 cases (11.6% of all switched patients). The previous seizure situation was re-established in them when they were back to LEV. Retention rate is a parameter that usually nicely reflects the efficiency of a new AED because both efficacy and tolerability have an impact on the probability of staying on an adjunctive AED or of discontinuing it. However, due to new legislation aimed at regulating the German drug market which is effective from 2011 on, there was the fear that one year after launch the BRV might be withdrawn from the German market, after the Federal Joint Committee (Gemeinsamer Bundesausschuss, G-BA), the highest decision-making body of the joint self-government of physicians, dentists, hospitals and health insurance funds in Germany, had ruled that no evidence of an additional benefit of BRV over comparative therapies had been provided. This had happened previously with retigabine and perampanel. The profile of BRV that allows the very rapid initiation of a maintenance dose [1,2,5–11] and the sudden and complete switch from LEV and a re-switch if necessary encouraged us in many cases to introduce BRV but also to judge it more critically than previous adjunctive new AEDs. According to our experiences with perampanel there is only a realistic chance of achieving reimbursement via International drug supply after a withdrawal from the German market if a marked benefit could be demonstrated. Therefore we certainly discontinued BRV more closely in line with an apparent influence on the retention rate. Real-world data such as that in this paper certainly have methodological limitations. The protocol is not standardized. At least in out-patients, efficacy and tolerability data are highly influenced by the quality of self-reporting [17]. Personal expectations and other subjective factors may influence the results. Still, our real-world experience demonstrates that BRV is a welltolerated and easy-to-handle new AED. Its relatively modest efficacy still allowed us to achieve marked beneficial effects in selected patients with difficult-to-treat epilepsies. Conflicts of interest statement BJS has received speaker’s honoraria from Desitin, Eisai, Novartis, OmniaMed, and UCB. He was a paid consultant of Actelion, B. Braun, Eisai, Shire, and UCB. CK has received speaker’s honoraria from Desitin, Eisai and UCB. AMS has received speaker’s honoraria from Desitin, Eisai, and UCB. She was a paid consultant of Eisai and UCB. MB, IB, BH, TI, RK, JS have no conflict of interest to disclose. Funding This study was not funded by any external sources. References [1] Brandt C, May TW, Bien CG. Brivaracetam as adjunctive therapy for the treatment of partial-onset seizures in patients with epilepsy: the current evidence base. Ther Adv Neurol Disord 2016;9:474–82. [2] Lattanzi S, Cagnetti C, Foschi N, Provinciali L, Silvestrini M. Brivaracetam addon for refractory focal epilepsy: a systematic review and meta-analysis. Neurology 2016;86:1344–52. [3] Steinhoff BJ, Bacher M, Bast T, Kornmeier R, Kurth C, Scholly J, Staack AM, Wisniewski I. First clinical experiences with perampanel – the Kork experience in 74 patients. Epilepsia 2014;55(Suppl. 1):16–8.
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