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Lacosamide tolerability in adult patients with partial-onset seizures: Impact of planned reduction and mechanism of action of concomitant antiepileptic drugs
Epilepsy & Behavior 57 (2016) 155–160
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Lacosamide tolerability in adult patients with partial-onset seizures: Impact of planned reduction and mechanism of action of concomitant antiepileptic drugs Nancy Foldvary-Schaefer a,⁎, Joanna S. Fong b, Shannon Morrison c, Lu Wang c, James Bena c a b c
Cleveland Clinic Neurological Institute, Cleveland, OH, United States University of Pittsburgh Department of Neurology, Pittsburgh, PA, United States Quantitative Health Sciences, Cleveland Clinic, Cleveland, OH, United States
a r t i c l e
i n f o
Article history: Received 18 January 2016 Accepted 6 February 2016 Available online xxxx Keywords: Lacosamide Tolerability Mechanism of action Standardized dose
a b s t r a c t Objective: We evaluated the impact of planned dose reduction and mechanism of action of concomitant AEDs on tolerability in adults with partial-onset seizures undergoing lacosamide (LCM) titration. Methods: Data were collected at baseline and 3–6 and 12–24 months post-LCM initiation. Subjects were categorized as having planned reduction of concomitant AEDs or not; AEDs were categorized as traditional sodium channel blockers (TSCB) or non-TSCB (NTSCB). Groups with/without planned reduction were compared on the presence and number of treatment-emergent adverse events (TEAEs) using chi-square tests or logistic regression and on time to LCM discontinuation with time-to-event methods controlling for standardized (STD) AED dose, a measure of concomitant AED load. Similar analyses were performed comparing subjects taking TSCB and NTSCB agents and used to identify relationships with ≥50% decreases in seizure frequency. Results: One hundred six adults (mean age 41.4 ± 13.4; 50% male) underwent LCM titration from June 2009–2011 with complete data. Reduction of concomitant AEDs was planned at the time of LCM initiation in 59 (55.7%) subjects. Fewer subjects with planned reduction had TEAEs (49.2% vs. 68.1%; p = 0.05), and these subjects had a lower risk of TEAEs (OR 0.36; p = 0.019) after adjusting for STD AED dose. The hazard ratio (95% CI) for LCM discontinuation was 0.46 (0.23, 0.94) in subjects with planned reduction of concomitant AEDs vs. others (p = 0.033) and 3.29 (1.01, 10.70) in subjects taking TSCB vs. NTSCB agents (p = 0.048). Among all cases, those who ever had TEAEs had significantly higher STD dose at both follow-up visits (p = 0.033 and p = 0.023, respectively). Seizure outcomes were not significantly different between groups at the last follow-up assessment. Significance: Planned reduction of concomitant AEDs during LCM initiation and the use of NTSCB agents only are associated with a reduced risk of TEAEs and LCM discontinuation in adults with partial-onset seizures. This study extends prior observations by considering total AED load in the assessment of tolerability and supports the benefits of early reduction of concomitant AEDs during LCM initiation. © 2016 Elsevier Inc. All rights reserved.
1. Introduction Lacosamide (LCM) is the first of the third generation antiepileptic drugs (AEDs) approved as adjunctive therapy for the treatment of partial-onset seizures in the U.S. in 2008 and monotherapy in 2014. Unlike traditional sodium channel blocking (TSCB) agents that affect fast sodium channel inactivation, LCM acts through selective enhancement of sodium channel slow inactivation [1]. In the management of pharmacoresistant epilepsy, AEDs having different, presumably complimentary, mechanisms of action are often combined in hopes of optimizing effectiveness and tolerability. In a post hoc exploratory analysis ⁎ Corresponding author: Cleveland Clinic Neurological Institute, 9500 Euclid Avenue, FA20, Cleveland, OH 44195, United States. Tel: +1 216 445 2990; fax: +1 216 636 0090. E-mail address: [email protected] (N. Foldvary-Schaefer).
http://dx.doi.org/10.1016/j.yebeh.2016.02.007 1525-5050/© 2016 Elsevier Inc. All rights reserved.
involving patients with partial-onset seizures from three, randomized, double-blind, placebo-controlled LCM clinical trials [2–4], in contrast to patients taking TSCB agents, those not taking TSCB agents had fewer treatment-emergent adverse events (TEAEs) resulting in a lower rate of LCM discontinuation [5]. We performed a retrospective analysis studying the impact of planned reduction and mechanism of action (at least one TSCB vs. NTSCB) of concomitant AEDs on tolerability and effectiveness of adjunctive LCM in adults with partial-onset seizures in a tertiary care epilepsy center. 2. Methods This was a retrospective study involving adult patients treated in the Cleveland Clinic Epilepsy Center. The study was approved by the Cleveland Clinic Institutional Review Board. Queries of the electronic
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medical record (EMR) and the Cleveland Clinic Knowledge Program (KP) Epilepsy Center database were performed to identify patients meeting inclusion criteria. The KP is an electronic patient-reported data collection system consisting of disease-specific standardized assessments completed at each outpatient clinic encounter. 2.1. Sample characteristics Inclusion: • at least 18 years of age; • partial-onset seizures based on clinical history, semiology, and/or EEG incompletely controlled on current AED regimen; • initiated on oral LCM as part of standard clinical care following the manufacturer's recommended titration (starting dose of 50 mg bid, increasing by 100 mg per week as needed based on the discretion of the prescribing provider); and • Completed KP assessment at baseline (at or within three months prior to LCM initiation; Visit 1), 3–6 months post-LCM initiation (Visit 2) and 12–24 months post-LCM initiation (Visit 3). Exclusion: • inadequate historical data such as questionable reporting of TEACs or seizures due to impaired mental status and/or inadequate caretaker observations and • uncertain dosing of LCM and/or concomitant AEDs. 2.2. Data collection • Demographic data • Epilepsy-related characteristics including monthly seizure frequency, total daily dosage, and dose adjustments (increase, increase and decrease, or no change vs. decrease) of concomitant AEDs at each visit. • Type and number of TEAEs - CNS: dizziness, headache, drowsiness, insomnia, ataxia, blurred vision, diplopia, coordination abnormalities, somnolence - Cardiovascular: hypotension, bradycardia, cardiac arrhythmia, cardiovascular collapse - Gastrointestinal: nausea, vomiting - Dermatologic: rash - Other • Duration of LCM treatment and median LCM dose at follow-up visits • Reason for LCM discontinuation - TEAE - lack of effectiveness - cost - other - unknown 2.3. Data analysis Concomitant AEDs were classified as: • traditional sodium channel blockers (TSCB): carbamazepine, lamotrigine, oxcarbazepine, phenytoin; • nontraditional sodium channel blockers (non-TSCB): valproic acid, topiramate, zonisamide, felbamate; and • nonsodium channel blockers (NSCB): gabapentin, pregabalin, levetiracetam, rufinamide, primidone, phenobarbital, benzodiazepines. Subjects were grouped based on whether or not their concomitant AED regimen included a TSCB agent regardless of the number and type of additional AEDs taken. Subjects taking one or more of the TSCB agents were assigned to the TSCB group. Because of the small number of subjects taking NSCB only, the NSCB and non-TSCB groups were combined and referred to as NTSCB.
Subjects were categorized as having planned reduction of concomitant AEDs or not based on documentation by the epilepsy provider. A standardized variable of the amount of concomitant AED(s) taken daily at each visit was determined for each subject based on the Defined Daily Dose (DDD), a measure of the average maintenance dose needed for adults obtained from the World Health Organization website [6]. The ratio of the each concomitant AED daily dose to the DDD was determined and then summed over all drugs in a given regimen to produce a standardized AED dose (STD dose). Values N1 indicate that dose regimens are higher than average. Categorical variables were summarized using frequencies and percentages. The relationship between planned AED reduction and TEAE (presence/absence) was described using Pearson chi-square tests, while the relationship between planned reduction and number of TEAEs was described using Wilcoxon rank sum tests. Logistic regression models and proportional odds models were used to evaluate whether relationships between planned reduction or LCM discontinuation and TEAEs were affected by STD dose of concomitant AEDs. These methods were also used to identify relationships with ≥50% decreases in seizure frequency (responder rate). Analyses were performed for the entire sample and the TSCB subgroup. Kaplan–Meier estimates and Cox proportional hazards models were used to evaluate the effect of planned reduction on time to LCM discontinuation unadjusted and adjusted for baseline STD dose of concomitant AEDs. For cases where the overall tests were significant, multiple comparisons using a Bonferroni-corrected significance level of 0.017 (0.05/3) were performed. Results of the multiple comparisons are included as footnotes where appropriate. Analyses were performed using SAS software (version 9; Cary, NC).
3. Results A total of 106 adults seen in the Cleveland Clinic Epilepsy Center who underwent oral LCM titration between 6/9/2009 and 6/9/2011 out of 422 patients with prescriptions for LCM written during this period were included. Excluded cases did not have outpatient clinic data at the required time points. Sample characteristics are shown in Table 1. Baseline characteristics of subjects with and without planned AED reduction were similar with the exception of race; a higher percentage of subjects with planned reduction were white (98.3 vs. 85.1%; p = 0.021). Subjects on multiple AEDs including TSCBs had significantly higher median baseline STD dose and were more likely to have a STD dose greater or equal to the mean compared with those on TSCBs only or NTSCBs (p b 0.001). Visit 2 and Visit 3 occurred 177 ± 32 (122–242) and 372 ± 49 (253–486) days, respectively, after LCM initiation. The median [P25, P75] LCM dosage at Visit 2 and Visit 3 was 300[150,400] and 300[0,400], respectively. At Visit 2, LCM daily dosage was as follows: 30 (28%): 400 mg, 11 (10%): N400 mg, 46 (44%): b 400 mg, and 19 (18%) had discontinued LCM. At Visit 3, LCM daily dosage was: 24 (23%): 400 mg, 20 (18%): N400 mg, 30 (29%): b400 mg, and 32 (30%) had discontinued LCM. In total, 61 (56%) subjects had at least one TEAE. A single TEAE was reported in 37 (60.7%) subjects with TEAEs. The TEAEs were classified as CNS-related in 86.4% and CNS/GI-related in 6.8% of cases. The majority of TEAEs (55/61; 90.2%) were reported at Visit 2. The reason for LCM discontinuation was TEAE in 25 (78.1%) and lack of effectiveness in 9 (28.1%) subjects (groups not mutually exclusive). Subjects who ever had TEAEs had a significantly higher median STD dose of concomitant AEDs at Visit 2 than those who had never had a TEAE (2.5 vs. 2.0; p = 0.031) and Visit 3 (2.7 vs. 1.9; p = 0.021). However, the difference between groups (TEAE vs. no TEAE) in STD AED dose when including LCM was not significant at Visit 2 (3.3[2.3,4.6] vs. 3.0[2.5,4.3]; p = 0.74) by which time the majority of TEAEs had been reported, suggesting that the change in concomitant AED dose was related to the reduction in TEAEs, not the overall drug burden including LCM.
N. Foldvary-Schaefer et al. / Epilepsy & Behavior 57 (2016) 155–160 Table 1 Baseline sample characteristics.
Table 3 Relationship between planned AED reduction and TEAEs/LCM discontinuation.
Factor
N = 106
Gender, male Race, white Age, year Seizure frequency, per month AED polytherapy STD dose Median Mean STD dose relative to mean Less than Greater or equal to Concomitant AED classification TSCBs only Multiple with TSCB NTSCB Non-TSCB only NSCB only Multiple without TSCB
53 (50.0) 98 (92.5) 40.0 [18.0,88.0] 5.0 [1.5,15.5] 90 (84.9)
Unadjusted
2.7 [2.0,4.5] 3.3 ± 1.8 63 (59.4) 43 (40.6) 19 (17.9) 62 (58.5) 25 (23.6) 10 (9.4) 4 (3.8) 11 (10.4)
Frequencies (percentages) for categorical variables; medians [quartiles] or mean ± sd for continuous variables. Non-TSCB: non-traditional sodium channel blocking agent; NSCB: non-sodium channel blocking agent. AED: antiepileptic drug; STD: standardized; TSCB: traditional sodium channel blocking agent; NTSCB: includes non-TSCB and NSCB agents.
Table 2 summarizes the relationship between planned AED reduction and TEAE variables. Subjects without planned reduction or those with both increases and decreases in concomitant AEDs were more likely to have a TEAE at any time (p = 0.050) and to have discontinued LCM (p = 0.041) compared with those with planned reduction. When limiting the analysis to subjects on TSCB agents only, statistical significance was not observed between groups, although TEAEs and LCM discontinuation were more common and the number of TEAEs greater in subjects with no reduction or both increases and decreases in concomitant AEDs. Median LCM daily dose was significantly greater in subjects with planned reduction than others at Visit 2 (300 mg vs. 200 mg; p = 0.001) and Visit 3 (400 mg vs. 200 mg; p = 0.01). Analyses adjusting for STD dose of concomitant AEDs are shown in Table 3. The odds ratio for having a TEAE anytime or by Visit 2 was significant indicating that subjects with planned reduction were at a decreased risk of TEAEs. In particular, the odds of subjects with planned AED reduction having a TEAE were 36% of the odds of a TEAE in subjects without planned reduction, and when TEAEs occurred, these subjects Table 2 TEAE variables by planned AED reduction group. Factor
Level
TEAE anytime TEAE Visit 2 TEAE# anytime 0 1 2 3 4
Total
Decrease
No changes/increases & decreases
N
(%)
N
(%)
61 55
29 26
49.2 44.8
32 29
68.1 63.0
45 37 14 6 4
31 15 7 2 4
52.5 25.4 11.9 3.4 6.8
14 22 7 4 0
29.8 46.8 14.9 8.5 0.0
LCM discontinued
p-Value
0.050P 0.065P 0.11W
0.13W 50 33 13 4 4 32
33 14 6 1 4 13
56.9 24.1 10.3 1.7 6.9 22.0
Adjusted
Outcome
OR (95% CI)
p-Value
OR (95% CI)
p-Value
TEAE presence anytime TEAE presence Visit 2 TEAE number anytime TEAE number Visit 2 LCM discontinued
0.45 (0.20, 1.01) 0.48 (0.22, 1.05) 0.54 (0.27, 1.11) 0.56 (0.27, 1.16) 0.42 (0.18, 0.97)
0.052 0.066 0.090 0.17 0.043
0.36 (0.16, 0.84) 0.40 (0.17, 0.91) 0.44 (0.21, 0.93) 0.46 (0.22, 0.99) 0.40 (0.17, 0.96)
0.019 0.029 0.031 0.046 0.040
Adjusting for standardized AED dose at baseline. P-values from statistically significant results are shown in bold. TEAE: Treatment-emergent adverse event.
were also less likely to have multiple TEAEs. Similarly, the odds for LCM discontinuation in subjects with planned AED reduction were 40% of subjects without planned reduction when adjusting for STD AED dose. While the odds ratios were similar in the direction and magnitude in subjects on TSCB agents only, none of the factors were statistically significant. Table 4 shows the relationship between AED mechanism group and TEAE variables. Subjects on NTSCB agents were significantly less likely to have a TEAE anytime (p b 0.001) and at Visit 2 (p = 0.002) and had fewer TEAEs anytime and at Visit 2 (p b 0.001) compared with those taking TSCBs. As illustrated in Table 5, when adjusting for STD AED dose, subjects taking NTSCB agents were significantly less likely to discontinue LCM than those taking TSCB agents only. While median LCM daily dose was not significantly different between groups at Visit 2, significant differences were observed at Visit 3 (TSCB: 150 mg, multiple including TSCB: 225 mg; NTSCB: 400 mg; p = 0.021). Kaplan–Meier estimates of time to LCM discontinuation based on planned reduction and AED mechanism group are shown in Fig. 1. As illustrated in the upper panel, the hazard ratio (95% CI) for LCM discontinuation was 0.46 (0.23, 0.94) in subjects with planned reduction vs. all others (p = 0.033). Relative to subjects taking NTSCB agents, those on TSCB agents only were significantly more likely to discontinue LCM (hazard ratio 3.29 (1.01, 10.70); p = 0.048) as shown in the lower panel. Seizure outcome data are shown in Table 6. There was no difference in baseline seizure frequency by planned AED reduction or mechanism group. Subjects with planned reduction were significantly less likely to achieve a ≥50% seizure reduction at Visit 2 only. Overall, subjects experienced a 28% decrease in median seizure frequency at Visit 2 and a 49% decrease at Visit 3 compared with baseline. After adjusting for baseline
Table 4 TEAE variables by AED mechanism group.
TEAE# Visit 2 0 1 2 3 4
157
17 19 7 3 0 19
37.0 41.3 15.2 6.5 0.0 40.4
0.041P
p-Values are from Pearson chi-square tests where marked (P) or Wilcoxon Rank Sum tests where marked (W). P-values from statistically significant results are shown in bold. TEAE: treatment-emergent adverse event.
Factor
TSCB only (N = 19)
Multiple with TSCB (N = 62)
NTSCB (N = 25)
TEAE anytime TEAE Visit 2 TEAE# anytime 0 1 2 3 4 TEAE # Visit 2 0 1 2 3 4 LCM discontinued
14 (73.7) 12 (63.2)
41 (66.1) 38 (62.3)
6 (24.0) 5 (20.8)
3 (15.8) 8 (42.1) 6 (31.6) 2 (10.5) 0 (0.0)
22 (35.5) 24 (38.7) 8 (12.9) 4 (6.5) 4 (6.5)
20 (80.0) 5 (20.0) 0 (0.0) 0 (0.0) 0 (0.0)
7 (36.8) 6 (31.6) 5 (26.3) 1 (5.3) 0 (0.0) 9 (47.4)
23 (37.7) 23 (37.7) 8 (13.1) 3 (4.9) 4 (6.6) 19 (30.6)
20 (83.3) 4 (16.7) 0 (0.0) 0 (0.0) 0 (0.0) 4 (16.0)
p-Value b0.001Pa,b 0.002Pa,b b0.001Ka,b
b0.001Ka,b
0.080F
p-Values are from Pearson chi-square tests where marked (P), Fisher's Exact tests where marked (F), or Kruskal–Wallis tests where marked (K). P-values from statistically significant results are shown in bold. a TSCB only vs. NTSCB is significant. b Multiple with TSCB vs. NTSCB is significant.
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Table 5 Relationship between AED mechanism group and TEAEs and LCM discontinuation. Outcome
TEAE anytime TEAE Visit 2 TEAE# anytime TEAE# Visit 2 LCM discontinued
vs. NTSCB
Multiple with TSCB TSCBs only Multiple with TSCB TSCBs only Multiple with TSCB TSCBs only Multiple with TSCB TSCBs only Multiple with TSCB TSCBs only
Unadjusted results
Adjusted results
OR (95% CI)
p-Value
OR (95% CI)
p-Value
6.18 (2.15, 17.81) 8.87 (2.25, 35.0) 6.28 (2.06, 19.11) 6.51 (1.68, 25.29) 8.32 (2.74, 25.24) 17.39 (4.61, 65.61) 8.79 (2.66, 29.01) 9.66 (2.43, 38.31) 2.32 (0.70, 7.69) 4.73 (1.17, 19.12)
b0.001 0.002 0.001 0.007 b0.001 b0.001 b0.001 b0.001 0.17 0.030
5.26 (1.73, 15.95) 9.00 (2.27, 35.71) 5.57 (1.75, 17.73) 6.62 (1.70, 25.75) 7.29 (2.31, 23.11) 17.77 (4.70, 67.22) 7.98 (2.34, 27.30) 9.78 (2.47, 38.83) 2.38 (0.67, 8.37) 4.72 (1.17, 19.11)
0.003 0.002 0.004 0.006 b0.001 b0.001 b0.001 0.001 0.18 0.030
Adjusting for standardized AED dose at baseline. P-values from statistically significant results are shown in bold. TEAE: Treatment-emergent adverse event.
STD dose, the odds of achieving a ≥ 50% seizure reduction in subjects with planned reduction were 37% of all others (no change or increase and decrease in AEDs) at Visit 2 (p = 0.02) and 64% (0.28, 1.47) at Visit 3 (p = 0.29). While none of the other comparisons were significant, the odds of responding for subjects on TSCBs only were 3.66 times that of the NTSCB group (p = 0.06). 4. Discussion This study extends prior observations regarding tolerability and effectiveness of adjunctive LCM therapy in adults with partial-onset seizures. Our key findings are: 1) planned reduction of concomitant AEDs during LCM initiation was associated with a reduced likelihood of having a TEAE or discontinuing LCM; 2) after adjusting for STD dose of concomitant AEDs, the significance of these findings increased, and subjects with planned reduction also had a longer time to LCM discontinuation despite higher LCM daily dosage; 3) subjects who ever had TEAEs had significantly higher STD dose at 3–6 months and 12–24 months compared with those who had never had a TEAE; 4) subjects taking NTSCB agents were less likely to have a TEAE and had fewer TEAEs compared with those taking TSCBs; 5) after adjusting for STD dose of concomitant AEDs, subjects taking NTSCB agents were also less likely to discontinue LCM despite higher LCM daily dose; and 6) a nearly 50%
Fig. 1. Kaplan–Meier estimates and hazard ratios with 95% confidence intervals for time to LCM discontinuation.
decrease in median seizure frequency was observed at 12–24 months, although subjects with planned reduction of concomitant AEDs were less likely to respond at 3–6 months than others. In contrast to TSCBs that act via the fast inactivation of voltage-gated sodium channels, LCM has a unique mechanism of action by enhancing the slow inactivation of neuronal sodium channels [1]. In a post hoc exploratory analysis using pooled phase II/III trial data involving 1308 adults with partial-onset seizures treated with LCM 200–600 mg/day, responder rates were greater, and incidences of TEAEs were lower in subjects taking NTSCB than in subjects taking TSCB agents [5]. As these trials were not designed to compare outcomes by the mechanism of concomitant AEDs, groups were not perfectly matched for epilepsyrelated characteristics, and the NTSCB group had a higher percentage of subjects taking only one concomitant AED and a lower median baseline seizure frequency, although still pharmacoresistant. Our investigation adds to the few observational studies of adjunctive LCM therapy in pharmacoresistant populations, only one large enough to explore outcomes by concomitant AED mechanism [7–10]. A prospective, multicenter Spanish study of 158 patients with partial epilepsy followed for 12 months after LCM initiation reported higher responder rate (65% vs. 38%), seizure free rate (35% vs. 17%), and lower TEAE rate (33% vs. 58%) in those receiving NTSCB (N = 49) versus TSCB agents (N = 104) [7]. However, the groups were not balanced as patients on TSCB agents had a longer duration of epilepsy, greater mean number of previous AEDs, and greater mean number of concomitant AEDs during LCM initiation (2.5 vs. 1.7). Dizziness was the most common TEAE, consistent with our findings, randomized clinical trials [11], and a long-term open-label extension study [12]. One prior study investigated the effect of planned AED reduction on tolerability during LCM initiation. Among 23 patients who underwent rapid LCM titration to 400–800 mg per day with simultaneous tapering of TSCBs, most TEAEs were mild, CNS-related, and transient, occurring only during the titration phase [13]. In contrast to the pooled phase II/ III trial data, no significant relationship between LCM dose and the presence of TEAEs was found at 3, 6, 9, or 12 months suggesting that neurotoxicity associated with LCM initiation may be minimized by reducing concomitant AEDs. While median daily LCM dose was lower in our sample at 12–24 months, we also found a reduced incidence of TEAEs in subjects who underwent planned AED reduction, an association that was strengthened after adjusting for STD dose of concomitant AEDs. Our study was based on a naturalistic cohort collected during the first 24 months postmarketing of LCM when the majority of epilepsy providers in our system were just beginning to gain experience with this new AED. While our providers initiated LCM according to the manufacturer's guidelines, the ultimate course of therapy was determined by individual prescribers treating individual patients. Therefore, our findings are more representative of a real-world setting compared with those derived from premarket clinical trials. Given that several years have passed, these results may not necessarily reflect current
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Table 6 Relationship between seizure outcome and planned reduction and mechanism groups. Factor
Overall (N = 106)
Decrease (N = 59)
No changes/increases & decrease (N = 47)
p-Value
Baseline Frequency/month Percentage of baseline⁎ Visit 2 Visit 3 ≥50% reduced Visit 2 ≥50% reduced Visit 3
5.0[1.5,15.5]
4.0[1.5,11.5]
7.3[1.5,30.0]
0.26W
0.72[0.20,1.06] 0.51[0.15,1.03] 38 (39.6) 44 (45.8)
0.46[0.11,1.07] 0.46[0.09,1.01] 22 (53.7) 21 (51.2)
0.85[0.34,1.05] 0.87[0.18,1.35] 16 (29.1) 23 (41.8)
0.15W 0.32W 0.015P 0.36P
Factor
TSCBs only (N = 19)
Multiple w/ TSCB (N = 62)
NTSCBs (N = 25)
p-Value
Baseline frequency/month Percentage of baseline⁎ Visit 2 Visit 3 ≥50% reduced Visit 2 N50% reduced Visit 3
3.8[0.33,12.0]
8.0[1.5,25.0]
4.0[1.00,8.0]
0.20K
0.70[0.25,1.42] 0.22[0.02,0.76] 6 (37.5) 10 (62.5)
0.77[0.18,1.01] 0.56[0.18,1.05] 22 (37.9) 27 (46.6)
0.51[0.18,1.26] 0.88[0.27,1.51] 10 (45.5) 7 (31.8)
0.88K 0.26K 0.81P 0.17P
Data missing for 10 subjects. P-values from statistically significant results are shown in bold. Values represent median [P25, P75] or N (column %). p-Values are from Pearson chi-square tests where marked (P), Wilcoxon rank sum tests where marked (W), or Kruskal–Wallis tests where marked (K). ⁎ Data log-transformed before analysis.
practices and treatment outcomes. However, our results are strengthened by rigorous group practices including EMR-based medication reconciliation, seizure data entry, and assessment of tolerability during all outpatient visits, thereby reducing practice and documentation variability between providers. Despite the real-world nature of our study and the flexibility of dosing of LCM and concomitant AEDs, over 50% of patients experienced TEAEs, and 30.2% discontinued LCM, the majority due to TEAEs. These estimates are comparable with those of the pooled phase II/III trials in which 17–38% of subjects discontinued LCM titrated to 600 mg daily in some cases and slightly greater than the results of a recent prospective study involving 520 adults with less pharmacoresistant epilepsy in whom LCM was added to one baseline AED (TEAEs in 48.5% and LCM discontinuation in 18.4% after 6 months) [14,15]. Most TEAEs in our study were CNS in nature, dizziness being the most common, and were reported in the first 3 months of therapy consistent with clinical trial data [11]. Nearly 85% of our subjects were taking multiple AEDs at baseline with a median STD dose of 2.7 and seizure frequency of 5.0, suggesting a highly pharmacoresistant population. Our work underscores the importance of considering baseline AED load when evaluating tolerability in clinical practice. We used a published method of standardizing AED dosage to estimate AED load based on the hypothesis that the occurrence and severity of TEAEs are influenced by the total AED dose taken daily and not the number of AEDs prescribed [16,17]. Estimates of AED load in epilepsy research are rare and not currently incorporated into clinical trials. While our sample is substantially smaller than the pooled phase II/III trial analysis and was not subjected to the same methodological constraints of a clinical trial, we also found a reduced incidence of TEAEs in patients taking NTSCB agents undergoing LCM titration compared with that in patients taking TSCB agents while adjusting for baseline AED load, thereby minimizing a major confounder of AED comparison studies. Drug load was recently considered in 7 patients with pharmacoresistant epilepsy who developed neurotoxicity on LCM in combination with TSCB agents that resolved with dose reduction of concomitant AEDs [18]. At the time of TEAEs, mean STD dose was 3.3, slightly higher than that of the total sample of 37 subjects taking LCM and TSCB agents (mean 2.9) and the 6 patients taking LCM without TSCB agents (2.3). A STD dose reduction of 0.24 ameliorated TEACs in these cases. In the pooled phase II/III LCM trial analysis, 62.4% of subjects were taking 2, and 22% were taking 3 concomitant AEDs rendering it likely that drug load contributed to TEAE incidence and LCM discontinuation as it did in our sample and this series. In one of the few analyses using this methodology, no correlation between STD dose and scores on the Adverse
Event Profile was found, leading the investigators to suggest rather that TEAEs are determined more by individual susceptibility, drug type, and physician skill [19]. Further work in this area is warranted given the impact of high drug load on cognition, mood, and quality of life in persons with epilepsy, and cost of AED therapy. In addition to tolerability measures, we found no significant difference in responder rate between groups defined by planned reduction or mechanism of action at Visit 3, 12–24 months post-LCM initiation. While subjects with AED reduction were less likely to achieve ≥50% seizure reduction at Visit 2, 3–6 months post-LCM initiation, the odds of responding were 4-fold greater with planned AED reduction in the TSCB group. We were unable to make a direct comparison between SCB (other than traditional) and NSCB groups because of the sample size. With the exception of the subjects not taking any TSCBs, the percentage of subjects responding increased over time. The pooled data analyses from phase II/III trials found that LCM effectively reduces seizures regardless of concomitant AED regimen, although 84% of patients were taking more than one concomitant AED and, therefore, subgroups in the concomitant AED analysis were not mutually exclusive [14]. 5. Conclusions Planned reduction of concomitant AED therapy and use of NTSCB agents during LCM initiation are associated with a reduced risk of TEAEs and LCM discontinuation in adults with pharmacoresistant partial-onset epilepsy, findings that were further strengthened after adjusting for baseline STD dose of concomitant AEDs. We believe that total AED burden should be considered in the assessment of tolerability and other epilepsy outcomes. Our study provides support for early dose reduction of concomitant AEDS at the start of LCM therapy in adults with partial onset seizures. Acknowledgments The authors thank the Knowledge Program Data Registry of the Cleveland Clinic, Cleveland, OH for providing the data used in these analyses. This work was supported by an investigator-initiated grant from UCB, Pharma (US IIS #2011-CNS-5). Disclosure of conflict of interest Nancy Foldvary-Schaefer receives investigator-initiated grant support from UCB, Pharma and is a speaker for Jazz Pharma.
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The other authors have no conflict of interest to disclose. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. References [1] Errington AC, Stohr T, Heers C, Lees G. The investigational anticonvulsant lacosamide selectively enhances slow inactivation of voltage-gated sodium channels. Mol Pharmacol 2008;73:157–69. [2] Ben-Menachem E, Biton V, Jatuzis D, Abou-Khalil B, Doty P, Rudd GD. Efficacy and safety of oral lacosamide as adjunctive therapy in adults with partial-onset seizures. Epilepsia 2007;48(7):1308–17. [3] Chung S, Sperling MR, Biton B, Krauss G, Hebert D, Rudd GD, et al. Lacosamide as adjunctive therapy for partial-onset seizures: a randomized controlled trial. Epilepsia 2010;51(6):958–67. [4] Halász P, Kälviäinen R, Mazurkiewicz-Beldzińska M, Rosenow F, Doty P, Hebert D, et al. Adjunctive lacosamide for partial-onset seizures: efficacy and safety results from a randomized controlled trial. Epilepsia 2009;50(3):443–53. [5] Sake J-K, Hebert D, Isojarvi J, Doty P, De Backer M, Davies K, et al. A pooled analysis of lacosamide clinical trial data grouped by mechanism of action of concomitant AEDs. CNS Drugs 2010;12:1055–68. [6] World Health Organization. www.whocc.no/ddd/application_for_ddd_alterations/. [Last accessed Jan 15, 2016]. [7] Vilanueva V, Lopez-Gomariz E, Lopez-Trigo J, Serratosa JM, Gonza´lez-Gira´ldez B, Parra J, et al. Rational polytherapy with lacosamide in clinical practice: results of a Spanish cohort analysis RELACOVA. Epilepsy Behav 2012;23:298–304. [8] Wehner T, Bauer S, Hamer HM, Hattemer K, Immisch I, Knake S, et al. Six months of postmarketing experience with adjunctive lacosamide in patients with pharmacoresistant focal epilepsy at a tertiary epilepsy center in Germany. Epilepsy Behav 2009;16:423–5. [9] Guilhoto LMFF, Loddenkemper T, Gooty VD, Rotenberg A, Takeoka M, Duffy F, et al. Experience with lacosamide in a series of children with drug-resistant focal epilepsy. Pediatr Neurol 2011;44:414–9.
[10] Gavatha M, Ioannou I, Papavasiliou AS. Efficacy and tolerability of oral lacosamide as adjunctive therapy in pediatric patients with pharmacoresistant focal epilepsy. Epilepsy Behav 2011;20:691–3. [11] Zaccara G, Perucca P, Loiacono G, Giovannelli F, Verrotti G. The adverse event profile of lacosamide: a systematic review and meta-analysis of randomized controlled trials. Epilepsia 2013;54(1):66–74. [12] Husain A, Chung S, Faught E, Isojarvi J, McShea C, Doty P. Long-term safety and efficacy in patients with uncontrolled partial-onset seizures treated with adjunctive lacosamide: results from a phase III open-label extension trial. Epilepsia 2012; 53(3):521–8. [13] Edwards HB, Cole AG, Griffiths AS, Lin B, Bean A, Krauss GL. Minimizing pharmacodynamic interactions of high doses of lacosamide. Acta Neurol Scand 2012;125: 228–33. [14] Chung S, Ben-Menachem E, Sperling MR, Rosenfeld W, Fountain NB, Benbadis S, et al. Examining the clinical utility of lacosamide: pooled analyses of three phase II/III clinical trials. CNS Drugs 2010;24:1041–54. [15] Runge U, Arnold S, Brandt C, Reinhardt F, Kühn F, Isensee K, et al. A noninterventional study evaluating the effectiveness and safety of lacosamide added to monotherapy in patients with epilepsy with partial-onset seizures in daily clinical practice: the VITOBA study. Epilepsia 2015;56(12):1921–30. [16] Deckers CL, Hekster YA, Keyser A, van Lier HJJ, Meinardi H, Renier WO. Monotherapy versus polytherapy for epilepsy: a multicenter double-blind randomized study. Epilepsia 2001;42:1387–94. [17] Lammers MW, Hekster YA, Keyser A, Meinardi H, Renier WO, van Lier H. Monotherapy or polytherapy for epilepsy revisited: a quantitative assessment. Epilepsia 1995; 36:440–6. [18] Novy J, Patsalos PN, Sander JW, Sisodiy SM. Lacosamide neurotoxicity associated with concomitant use of sodium channel-blocking antiepileptic drugs: a pharmacodynamic interaction? Epilepsy Behav 2011;20:20–3. [19] Canevini MP, De Sarro G, Galimberti CA, Gatti G, Licchetta L, Malerba A, et al. Relationship between adverse effects of antiepileptic drugs, number of coprescribed drugs, and drug load in a large cohort of consecutive patients with drug-refractory epilepsy. Epilepsia 2010;51:797–804.
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Epilepsy & Behavior journal homepage: www.elsevier.com/locate/yebeh
Lacosamide tolerability in adult patients with partial-onset seizures: Impact of planned reduction and mechanism of action of concomitant antiepileptic drugs Nancy Foldvary-Schaefer a,⁎, Joanna S. Fong b, Shannon Morrison c, Lu Wang c, James Bena c a b c
Cleveland Clinic Neurological Institute, Cleveland, OH, United States University of Pittsburgh Department of Neurology, Pittsburgh, PA, United States Quantitative Health Sciences, Cleveland Clinic, Cleveland, OH, United States
a r t i c l e
i n f o
Article history: Received 18 January 2016 Accepted 6 February 2016 Available online xxxx Keywords: Lacosamide Tolerability Mechanism of action Standardized dose
a b s t r a c t Objective: We evaluated the impact of planned dose reduction and mechanism of action of concomitant AEDs on tolerability in adults with partial-onset seizures undergoing lacosamide (LCM) titration. Methods: Data were collected at baseline and 3–6 and 12–24 months post-LCM initiation. Subjects were categorized as having planned reduction of concomitant AEDs or not; AEDs were categorized as traditional sodium channel blockers (TSCB) or non-TSCB (NTSCB). Groups with/without planned reduction were compared on the presence and number of treatment-emergent adverse events (TEAEs) using chi-square tests or logistic regression and on time to LCM discontinuation with time-to-event methods controlling for standardized (STD) AED dose, a measure of concomitant AED load. Similar analyses were performed comparing subjects taking TSCB and NTSCB agents and used to identify relationships with ≥50% decreases in seizure frequency. Results: One hundred six adults (mean age 41.4 ± 13.4; 50% male) underwent LCM titration from June 2009–2011 with complete data. Reduction of concomitant AEDs was planned at the time of LCM initiation in 59 (55.7%) subjects. Fewer subjects with planned reduction had TEAEs (49.2% vs. 68.1%; p = 0.05), and these subjects had a lower risk of TEAEs (OR 0.36; p = 0.019) after adjusting for STD AED dose. The hazard ratio (95% CI) for LCM discontinuation was 0.46 (0.23, 0.94) in subjects with planned reduction of concomitant AEDs vs. others (p = 0.033) and 3.29 (1.01, 10.70) in subjects taking TSCB vs. NTSCB agents (p = 0.048). Among all cases, those who ever had TEAEs had significantly higher STD dose at both follow-up visits (p = 0.033 and p = 0.023, respectively). Seizure outcomes were not significantly different between groups at the last follow-up assessment. Significance: Planned reduction of concomitant AEDs during LCM initiation and the use of NTSCB agents only are associated with a reduced risk of TEAEs and LCM discontinuation in adults with partial-onset seizures. This study extends prior observations by considering total AED load in the assessment of tolerability and supports the benefits of early reduction of concomitant AEDs during LCM initiation. © 2016 Elsevier Inc. All rights reserved.
1. Introduction Lacosamide (LCM) is the first of the third generation antiepileptic drugs (AEDs) approved as adjunctive therapy for the treatment of partial-onset seizures in the U.S. in 2008 and monotherapy in 2014. Unlike traditional sodium channel blocking (TSCB) agents that affect fast sodium channel inactivation, LCM acts through selective enhancement of sodium channel slow inactivation [1]. In the management of pharmacoresistant epilepsy, AEDs having different, presumably complimentary, mechanisms of action are often combined in hopes of optimizing effectiveness and tolerability. In a post hoc exploratory analysis ⁎ Corresponding author: Cleveland Clinic Neurological Institute, 9500 Euclid Avenue, FA20, Cleveland, OH 44195, United States. Tel: +1 216 445 2990; fax: +1 216 636 0090. E-mail address: [email protected] (N. Foldvary-Schaefer).
http://dx.doi.org/10.1016/j.yebeh.2016.02.007 1525-5050/© 2016 Elsevier Inc. All rights reserved.
involving patients with partial-onset seizures from three, randomized, double-blind, placebo-controlled LCM clinical trials [2–4], in contrast to patients taking TSCB agents, those not taking TSCB agents had fewer treatment-emergent adverse events (TEAEs) resulting in a lower rate of LCM discontinuation [5]. We performed a retrospective analysis studying the impact of planned reduction and mechanism of action (at least one TSCB vs. NTSCB) of concomitant AEDs on tolerability and effectiveness of adjunctive LCM in adults with partial-onset seizures in a tertiary care epilepsy center. 2. Methods This was a retrospective study involving adult patients treated in the Cleveland Clinic Epilepsy Center. The study was approved by the Cleveland Clinic Institutional Review Board. Queries of the electronic
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medical record (EMR) and the Cleveland Clinic Knowledge Program (KP) Epilepsy Center database were performed to identify patients meeting inclusion criteria. The KP is an electronic patient-reported data collection system consisting of disease-specific standardized assessments completed at each outpatient clinic encounter. 2.1. Sample characteristics Inclusion: • at least 18 years of age; • partial-onset seizures based on clinical history, semiology, and/or EEG incompletely controlled on current AED regimen; • initiated on oral LCM as part of standard clinical care following the manufacturer's recommended titration (starting dose of 50 mg bid, increasing by 100 mg per week as needed based on the discretion of the prescribing provider); and • Completed KP assessment at baseline (at or within three months prior to LCM initiation; Visit 1), 3–6 months post-LCM initiation (Visit 2) and 12–24 months post-LCM initiation (Visit 3). Exclusion: • inadequate historical data such as questionable reporting of TEACs or seizures due to impaired mental status and/or inadequate caretaker observations and • uncertain dosing of LCM and/or concomitant AEDs. 2.2. Data collection • Demographic data • Epilepsy-related characteristics including monthly seizure frequency, total daily dosage, and dose adjustments (increase, increase and decrease, or no change vs. decrease) of concomitant AEDs at each visit. • Type and number of TEAEs - CNS: dizziness, headache, drowsiness, insomnia, ataxia, blurred vision, diplopia, coordination abnormalities, somnolence - Cardiovascular: hypotension, bradycardia, cardiac arrhythmia, cardiovascular collapse - Gastrointestinal: nausea, vomiting - Dermatologic: rash - Other • Duration of LCM treatment and median LCM dose at follow-up visits • Reason for LCM discontinuation - TEAE - lack of effectiveness - cost - other - unknown 2.3. Data analysis Concomitant AEDs were classified as: • traditional sodium channel blockers (TSCB): carbamazepine, lamotrigine, oxcarbazepine, phenytoin; • nontraditional sodium channel blockers (non-TSCB): valproic acid, topiramate, zonisamide, felbamate; and • nonsodium channel blockers (NSCB): gabapentin, pregabalin, levetiracetam, rufinamide, primidone, phenobarbital, benzodiazepines. Subjects were grouped based on whether or not their concomitant AED regimen included a TSCB agent regardless of the number and type of additional AEDs taken. Subjects taking one or more of the TSCB agents were assigned to the TSCB group. Because of the small number of subjects taking NSCB only, the NSCB and non-TSCB groups were combined and referred to as NTSCB.
Subjects were categorized as having planned reduction of concomitant AEDs or not based on documentation by the epilepsy provider. A standardized variable of the amount of concomitant AED(s) taken daily at each visit was determined for each subject based on the Defined Daily Dose (DDD), a measure of the average maintenance dose needed for adults obtained from the World Health Organization website [6]. The ratio of the each concomitant AED daily dose to the DDD was determined and then summed over all drugs in a given regimen to produce a standardized AED dose (STD dose). Values N1 indicate that dose regimens are higher than average. Categorical variables were summarized using frequencies and percentages. The relationship between planned AED reduction and TEAE (presence/absence) was described using Pearson chi-square tests, while the relationship between planned reduction and number of TEAEs was described using Wilcoxon rank sum tests. Logistic regression models and proportional odds models were used to evaluate whether relationships between planned reduction or LCM discontinuation and TEAEs were affected by STD dose of concomitant AEDs. These methods were also used to identify relationships with ≥50% decreases in seizure frequency (responder rate). Analyses were performed for the entire sample and the TSCB subgroup. Kaplan–Meier estimates and Cox proportional hazards models were used to evaluate the effect of planned reduction on time to LCM discontinuation unadjusted and adjusted for baseline STD dose of concomitant AEDs. For cases where the overall tests were significant, multiple comparisons using a Bonferroni-corrected significance level of 0.017 (0.05/3) were performed. Results of the multiple comparisons are included as footnotes where appropriate. Analyses were performed using SAS software (version 9; Cary, NC).
3. Results A total of 106 adults seen in the Cleveland Clinic Epilepsy Center who underwent oral LCM titration between 6/9/2009 and 6/9/2011 out of 422 patients with prescriptions for LCM written during this period were included. Excluded cases did not have outpatient clinic data at the required time points. Sample characteristics are shown in Table 1. Baseline characteristics of subjects with and without planned AED reduction were similar with the exception of race; a higher percentage of subjects with planned reduction were white (98.3 vs. 85.1%; p = 0.021). Subjects on multiple AEDs including TSCBs had significantly higher median baseline STD dose and were more likely to have a STD dose greater or equal to the mean compared with those on TSCBs only or NTSCBs (p b 0.001). Visit 2 and Visit 3 occurred 177 ± 32 (122–242) and 372 ± 49 (253–486) days, respectively, after LCM initiation. The median [P25, P75] LCM dosage at Visit 2 and Visit 3 was 300[150,400] and 300[0,400], respectively. At Visit 2, LCM daily dosage was as follows: 30 (28%): 400 mg, 11 (10%): N400 mg, 46 (44%): b 400 mg, and 19 (18%) had discontinued LCM. At Visit 3, LCM daily dosage was: 24 (23%): 400 mg, 20 (18%): N400 mg, 30 (29%): b400 mg, and 32 (30%) had discontinued LCM. In total, 61 (56%) subjects had at least one TEAE. A single TEAE was reported in 37 (60.7%) subjects with TEAEs. The TEAEs were classified as CNS-related in 86.4% and CNS/GI-related in 6.8% of cases. The majority of TEAEs (55/61; 90.2%) were reported at Visit 2. The reason for LCM discontinuation was TEAE in 25 (78.1%) and lack of effectiveness in 9 (28.1%) subjects (groups not mutually exclusive). Subjects who ever had TEAEs had a significantly higher median STD dose of concomitant AEDs at Visit 2 than those who had never had a TEAE (2.5 vs. 2.0; p = 0.031) and Visit 3 (2.7 vs. 1.9; p = 0.021). However, the difference between groups (TEAE vs. no TEAE) in STD AED dose when including LCM was not significant at Visit 2 (3.3[2.3,4.6] vs. 3.0[2.5,4.3]; p = 0.74) by which time the majority of TEAEs had been reported, suggesting that the change in concomitant AED dose was related to the reduction in TEAEs, not the overall drug burden including LCM.
N. Foldvary-Schaefer et al. / Epilepsy & Behavior 57 (2016) 155–160 Table 1 Baseline sample characteristics.
Table 3 Relationship between planned AED reduction and TEAEs/LCM discontinuation.
Factor
N = 106
Gender, male Race, white Age, year Seizure frequency, per month AED polytherapy STD dose Median Mean STD dose relative to mean Less than Greater or equal to Concomitant AED classification TSCBs only Multiple with TSCB NTSCB Non-TSCB only NSCB only Multiple without TSCB
53 (50.0) 98 (92.5) 40.0 [18.0,88.0] 5.0 [1.5,15.5] 90 (84.9)
Unadjusted
2.7 [2.0,4.5] 3.3 ± 1.8 63 (59.4) 43 (40.6) 19 (17.9) 62 (58.5) 25 (23.6) 10 (9.4) 4 (3.8) 11 (10.4)
Frequencies (percentages) for categorical variables; medians [quartiles] or mean ± sd for continuous variables. Non-TSCB: non-traditional sodium channel blocking agent; NSCB: non-sodium channel blocking agent. AED: antiepileptic drug; STD: standardized; TSCB: traditional sodium channel blocking agent; NTSCB: includes non-TSCB and NSCB agents.
Table 2 summarizes the relationship between planned AED reduction and TEAE variables. Subjects without planned reduction or those with both increases and decreases in concomitant AEDs were more likely to have a TEAE at any time (p = 0.050) and to have discontinued LCM (p = 0.041) compared with those with planned reduction. When limiting the analysis to subjects on TSCB agents only, statistical significance was not observed between groups, although TEAEs and LCM discontinuation were more common and the number of TEAEs greater in subjects with no reduction or both increases and decreases in concomitant AEDs. Median LCM daily dose was significantly greater in subjects with planned reduction than others at Visit 2 (300 mg vs. 200 mg; p = 0.001) and Visit 3 (400 mg vs. 200 mg; p = 0.01). Analyses adjusting for STD dose of concomitant AEDs are shown in Table 3. The odds ratio for having a TEAE anytime or by Visit 2 was significant indicating that subjects with planned reduction were at a decreased risk of TEAEs. In particular, the odds of subjects with planned AED reduction having a TEAE were 36% of the odds of a TEAE in subjects without planned reduction, and when TEAEs occurred, these subjects Table 2 TEAE variables by planned AED reduction group. Factor
Level
TEAE anytime TEAE Visit 2 TEAE# anytime 0 1 2 3 4
Total
Decrease
No changes/increases & decreases
N
(%)
N
(%)
61 55
29 26
49.2 44.8
32 29
68.1 63.0
45 37 14 6 4
31 15 7 2 4
52.5 25.4 11.9 3.4 6.8
14 22 7 4 0
29.8 46.8 14.9 8.5 0.0
LCM discontinued
p-Value
0.050P 0.065P 0.11W
0.13W 50 33 13 4 4 32
33 14 6 1 4 13
56.9 24.1 10.3 1.7 6.9 22.0
Adjusted
Outcome
OR (95% CI)
p-Value
OR (95% CI)
p-Value
TEAE presence anytime TEAE presence Visit 2 TEAE number anytime TEAE number Visit 2 LCM discontinued
0.45 (0.20, 1.01) 0.48 (0.22, 1.05) 0.54 (0.27, 1.11) 0.56 (0.27, 1.16) 0.42 (0.18, 0.97)
0.052 0.066 0.090 0.17 0.043
0.36 (0.16, 0.84) 0.40 (0.17, 0.91) 0.44 (0.21, 0.93) 0.46 (0.22, 0.99) 0.40 (0.17, 0.96)
0.019 0.029 0.031 0.046 0.040
Adjusting for standardized AED dose at baseline. P-values from statistically significant results are shown in bold. TEAE: Treatment-emergent adverse event.
were also less likely to have multiple TEAEs. Similarly, the odds for LCM discontinuation in subjects with planned AED reduction were 40% of subjects without planned reduction when adjusting for STD AED dose. While the odds ratios were similar in the direction and magnitude in subjects on TSCB agents only, none of the factors were statistically significant. Table 4 shows the relationship between AED mechanism group and TEAE variables. Subjects on NTSCB agents were significantly less likely to have a TEAE anytime (p b 0.001) and at Visit 2 (p = 0.002) and had fewer TEAEs anytime and at Visit 2 (p b 0.001) compared with those taking TSCBs. As illustrated in Table 5, when adjusting for STD AED dose, subjects taking NTSCB agents were significantly less likely to discontinue LCM than those taking TSCB agents only. While median LCM daily dose was not significantly different between groups at Visit 2, significant differences were observed at Visit 3 (TSCB: 150 mg, multiple including TSCB: 225 mg; NTSCB: 400 mg; p = 0.021). Kaplan–Meier estimates of time to LCM discontinuation based on planned reduction and AED mechanism group are shown in Fig. 1. As illustrated in the upper panel, the hazard ratio (95% CI) for LCM discontinuation was 0.46 (0.23, 0.94) in subjects with planned reduction vs. all others (p = 0.033). Relative to subjects taking NTSCB agents, those on TSCB agents only were significantly more likely to discontinue LCM (hazard ratio 3.29 (1.01, 10.70); p = 0.048) as shown in the lower panel. Seizure outcome data are shown in Table 6. There was no difference in baseline seizure frequency by planned AED reduction or mechanism group. Subjects with planned reduction were significantly less likely to achieve a ≥50% seizure reduction at Visit 2 only. Overall, subjects experienced a 28% decrease in median seizure frequency at Visit 2 and a 49% decrease at Visit 3 compared with baseline. After adjusting for baseline
Table 4 TEAE variables by AED mechanism group.
TEAE# Visit 2 0 1 2 3 4
157
17 19 7 3 0 19
37.0 41.3 15.2 6.5 0.0 40.4
0.041P
p-Values are from Pearson chi-square tests where marked (P) or Wilcoxon Rank Sum tests where marked (W). P-values from statistically significant results are shown in bold. TEAE: treatment-emergent adverse event.
Factor
TSCB only (N = 19)
Multiple with TSCB (N = 62)
NTSCB (N = 25)
TEAE anytime TEAE Visit 2 TEAE# anytime 0 1 2 3 4 TEAE # Visit 2 0 1 2 3 4 LCM discontinued
14 (73.7) 12 (63.2)
41 (66.1) 38 (62.3)
6 (24.0) 5 (20.8)
3 (15.8) 8 (42.1) 6 (31.6) 2 (10.5) 0 (0.0)
22 (35.5) 24 (38.7) 8 (12.9) 4 (6.5) 4 (6.5)
20 (80.0) 5 (20.0) 0 (0.0) 0 (0.0) 0 (0.0)
7 (36.8) 6 (31.6) 5 (26.3) 1 (5.3) 0 (0.0) 9 (47.4)
23 (37.7) 23 (37.7) 8 (13.1) 3 (4.9) 4 (6.6) 19 (30.6)
20 (83.3) 4 (16.7) 0 (0.0) 0 (0.0) 0 (0.0) 4 (16.0)
p-Value b0.001Pa,b 0.002Pa,b b0.001Ka,b
b0.001Ka,b
0.080F
p-Values are from Pearson chi-square tests where marked (P), Fisher's Exact tests where marked (F), or Kruskal–Wallis tests where marked (K). P-values from statistically significant results are shown in bold. a TSCB only vs. NTSCB is significant. b Multiple with TSCB vs. NTSCB is significant.
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Table 5 Relationship between AED mechanism group and TEAEs and LCM discontinuation. Outcome
TEAE anytime TEAE Visit 2 TEAE# anytime TEAE# Visit 2 LCM discontinued
vs. NTSCB
Multiple with TSCB TSCBs only Multiple with TSCB TSCBs only Multiple with TSCB TSCBs only Multiple with TSCB TSCBs only Multiple with TSCB TSCBs only
Unadjusted results
Adjusted results
OR (95% CI)
p-Value
OR (95% CI)
p-Value
6.18 (2.15, 17.81) 8.87 (2.25, 35.0) 6.28 (2.06, 19.11) 6.51 (1.68, 25.29) 8.32 (2.74, 25.24) 17.39 (4.61, 65.61) 8.79 (2.66, 29.01) 9.66 (2.43, 38.31) 2.32 (0.70, 7.69) 4.73 (1.17, 19.12)
b0.001 0.002 0.001 0.007 b0.001 b0.001 b0.001 b0.001 0.17 0.030
5.26 (1.73, 15.95) 9.00 (2.27, 35.71) 5.57 (1.75, 17.73) 6.62 (1.70, 25.75) 7.29 (2.31, 23.11) 17.77 (4.70, 67.22) 7.98 (2.34, 27.30) 9.78 (2.47, 38.83) 2.38 (0.67, 8.37) 4.72 (1.17, 19.11)
0.003 0.002 0.004 0.006 b0.001 b0.001 b0.001 0.001 0.18 0.030
Adjusting for standardized AED dose at baseline. P-values from statistically significant results are shown in bold. TEAE: Treatment-emergent adverse event.
STD dose, the odds of achieving a ≥ 50% seizure reduction in subjects with planned reduction were 37% of all others (no change or increase and decrease in AEDs) at Visit 2 (p = 0.02) and 64% (0.28, 1.47) at Visit 3 (p = 0.29). While none of the other comparisons were significant, the odds of responding for subjects on TSCBs only were 3.66 times that of the NTSCB group (p = 0.06). 4. Discussion This study extends prior observations regarding tolerability and effectiveness of adjunctive LCM therapy in adults with partial-onset seizures. Our key findings are: 1) planned reduction of concomitant AEDs during LCM initiation was associated with a reduced likelihood of having a TEAE or discontinuing LCM; 2) after adjusting for STD dose of concomitant AEDs, the significance of these findings increased, and subjects with planned reduction also had a longer time to LCM discontinuation despite higher LCM daily dosage; 3) subjects who ever had TEAEs had significantly higher STD dose at 3–6 months and 12–24 months compared with those who had never had a TEAE; 4) subjects taking NTSCB agents were less likely to have a TEAE and had fewer TEAEs compared with those taking TSCBs; 5) after adjusting for STD dose of concomitant AEDs, subjects taking NTSCB agents were also less likely to discontinue LCM despite higher LCM daily dose; and 6) a nearly 50%
Fig. 1. Kaplan–Meier estimates and hazard ratios with 95% confidence intervals for time to LCM discontinuation.
decrease in median seizure frequency was observed at 12–24 months, although subjects with planned reduction of concomitant AEDs were less likely to respond at 3–6 months than others. In contrast to TSCBs that act via the fast inactivation of voltage-gated sodium channels, LCM has a unique mechanism of action by enhancing the slow inactivation of neuronal sodium channels [1]. In a post hoc exploratory analysis using pooled phase II/III trial data involving 1308 adults with partial-onset seizures treated with LCM 200–600 mg/day, responder rates were greater, and incidences of TEAEs were lower in subjects taking NTSCB than in subjects taking TSCB agents [5]. As these trials were not designed to compare outcomes by the mechanism of concomitant AEDs, groups were not perfectly matched for epilepsyrelated characteristics, and the NTSCB group had a higher percentage of subjects taking only one concomitant AED and a lower median baseline seizure frequency, although still pharmacoresistant. Our investigation adds to the few observational studies of adjunctive LCM therapy in pharmacoresistant populations, only one large enough to explore outcomes by concomitant AED mechanism [7–10]. A prospective, multicenter Spanish study of 158 patients with partial epilepsy followed for 12 months after LCM initiation reported higher responder rate (65% vs. 38%), seizure free rate (35% vs. 17%), and lower TEAE rate (33% vs. 58%) in those receiving NTSCB (N = 49) versus TSCB agents (N = 104) [7]. However, the groups were not balanced as patients on TSCB agents had a longer duration of epilepsy, greater mean number of previous AEDs, and greater mean number of concomitant AEDs during LCM initiation (2.5 vs. 1.7). Dizziness was the most common TEAE, consistent with our findings, randomized clinical trials [11], and a long-term open-label extension study [12]. One prior study investigated the effect of planned AED reduction on tolerability during LCM initiation. Among 23 patients who underwent rapid LCM titration to 400–800 mg per day with simultaneous tapering of TSCBs, most TEAEs were mild, CNS-related, and transient, occurring only during the titration phase [13]. In contrast to the pooled phase II/ III trial data, no significant relationship between LCM dose and the presence of TEAEs was found at 3, 6, 9, or 12 months suggesting that neurotoxicity associated with LCM initiation may be minimized by reducing concomitant AEDs. While median daily LCM dose was lower in our sample at 12–24 months, we also found a reduced incidence of TEAEs in subjects who underwent planned AED reduction, an association that was strengthened after adjusting for STD dose of concomitant AEDs. Our study was based on a naturalistic cohort collected during the first 24 months postmarketing of LCM when the majority of epilepsy providers in our system were just beginning to gain experience with this new AED. While our providers initiated LCM according to the manufacturer's guidelines, the ultimate course of therapy was determined by individual prescribers treating individual patients. Therefore, our findings are more representative of a real-world setting compared with those derived from premarket clinical trials. Given that several years have passed, these results may not necessarily reflect current
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Table 6 Relationship between seizure outcome and planned reduction and mechanism groups. Factor
Overall (N = 106)
Decrease (N = 59)
No changes/increases & decrease (N = 47)
p-Value
Baseline Frequency/month Percentage of baseline⁎ Visit 2 Visit 3 ≥50% reduced Visit 2 ≥50% reduced Visit 3
5.0[1.5,15.5]
4.0[1.5,11.5]
7.3[1.5,30.0]
0.26W
0.72[0.20,1.06] 0.51[0.15,1.03] 38 (39.6) 44 (45.8)
0.46[0.11,1.07] 0.46[0.09,1.01] 22 (53.7) 21 (51.2)
0.85[0.34,1.05] 0.87[0.18,1.35] 16 (29.1) 23 (41.8)
0.15W 0.32W 0.015P 0.36P
Factor
TSCBs only (N = 19)
Multiple w/ TSCB (N = 62)
NTSCBs (N = 25)
p-Value
Baseline frequency/month Percentage of baseline⁎ Visit 2 Visit 3 ≥50% reduced Visit 2 N50% reduced Visit 3
3.8[0.33,12.0]
8.0[1.5,25.0]
4.0[1.00,8.0]
0.20K
0.70[0.25,1.42] 0.22[0.02,0.76] 6 (37.5) 10 (62.5)
0.77[0.18,1.01] 0.56[0.18,1.05] 22 (37.9) 27 (46.6)
0.51[0.18,1.26] 0.88[0.27,1.51] 10 (45.5) 7 (31.8)
0.88K 0.26K 0.81P 0.17P
Data missing for 10 subjects. P-values from statistically significant results are shown in bold. Values represent median [P25, P75] or N (column %). p-Values are from Pearson chi-square tests where marked (P), Wilcoxon rank sum tests where marked (W), or Kruskal–Wallis tests where marked (K). ⁎ Data log-transformed before analysis.
practices and treatment outcomes. However, our results are strengthened by rigorous group practices including EMR-based medication reconciliation, seizure data entry, and assessment of tolerability during all outpatient visits, thereby reducing practice and documentation variability between providers. Despite the real-world nature of our study and the flexibility of dosing of LCM and concomitant AEDs, over 50% of patients experienced TEAEs, and 30.2% discontinued LCM, the majority due to TEAEs. These estimates are comparable with those of the pooled phase II/III trials in which 17–38% of subjects discontinued LCM titrated to 600 mg daily in some cases and slightly greater than the results of a recent prospective study involving 520 adults with less pharmacoresistant epilepsy in whom LCM was added to one baseline AED (TEAEs in 48.5% and LCM discontinuation in 18.4% after 6 months) [14,15]. Most TEAEs in our study were CNS in nature, dizziness being the most common, and were reported in the first 3 months of therapy consistent with clinical trial data [11]. Nearly 85% of our subjects were taking multiple AEDs at baseline with a median STD dose of 2.7 and seizure frequency of 5.0, suggesting a highly pharmacoresistant population. Our work underscores the importance of considering baseline AED load when evaluating tolerability in clinical practice. We used a published method of standardizing AED dosage to estimate AED load based on the hypothesis that the occurrence and severity of TEAEs are influenced by the total AED dose taken daily and not the number of AEDs prescribed [16,17]. Estimates of AED load in epilepsy research are rare and not currently incorporated into clinical trials. While our sample is substantially smaller than the pooled phase II/III trial analysis and was not subjected to the same methodological constraints of a clinical trial, we also found a reduced incidence of TEAEs in patients taking NTSCB agents undergoing LCM titration compared with that in patients taking TSCB agents while adjusting for baseline AED load, thereby minimizing a major confounder of AED comparison studies. Drug load was recently considered in 7 patients with pharmacoresistant epilepsy who developed neurotoxicity on LCM in combination with TSCB agents that resolved with dose reduction of concomitant AEDs [18]. At the time of TEAEs, mean STD dose was 3.3, slightly higher than that of the total sample of 37 subjects taking LCM and TSCB agents (mean 2.9) and the 6 patients taking LCM without TSCB agents (2.3). A STD dose reduction of 0.24 ameliorated TEACs in these cases. In the pooled phase II/III LCM trial analysis, 62.4% of subjects were taking 2, and 22% were taking 3 concomitant AEDs rendering it likely that drug load contributed to TEAE incidence and LCM discontinuation as it did in our sample and this series. In one of the few analyses using this methodology, no correlation between STD dose and scores on the Adverse
Event Profile was found, leading the investigators to suggest rather that TEAEs are determined more by individual susceptibility, drug type, and physician skill [19]. Further work in this area is warranted given the impact of high drug load on cognition, mood, and quality of life in persons with epilepsy, and cost of AED therapy. In addition to tolerability measures, we found no significant difference in responder rate between groups defined by planned reduction or mechanism of action at Visit 3, 12–24 months post-LCM initiation. While subjects with AED reduction were less likely to achieve ≥50% seizure reduction at Visit 2, 3–6 months post-LCM initiation, the odds of responding were 4-fold greater with planned AED reduction in the TSCB group. We were unable to make a direct comparison between SCB (other than traditional) and NSCB groups because of the sample size. With the exception of the subjects not taking any TSCBs, the percentage of subjects responding increased over time. The pooled data analyses from phase II/III trials found that LCM effectively reduces seizures regardless of concomitant AED regimen, although 84% of patients were taking more than one concomitant AED and, therefore, subgroups in the concomitant AED analysis were not mutually exclusive [14]. 5. Conclusions Planned reduction of concomitant AED therapy and use of NTSCB agents during LCM initiation are associated with a reduced risk of TEAEs and LCM discontinuation in adults with pharmacoresistant partial-onset epilepsy, findings that were further strengthened after adjusting for baseline STD dose of concomitant AEDs. We believe that total AED burden should be considered in the assessment of tolerability and other epilepsy outcomes. Our study provides support for early dose reduction of concomitant AEDS at the start of LCM therapy in adults with partial onset seizures. Acknowledgments The authors thank the Knowledge Program Data Registry of the Cleveland Clinic, Cleveland, OH for providing the data used in these analyses. This work was supported by an investigator-initiated grant from UCB, Pharma (US IIS #2011-CNS-5). Disclosure of conflict of interest Nancy Foldvary-Schaefer receives investigator-initiated grant support from UCB, Pharma and is a speaker for Jazz Pharma.
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