Population characteristics are described in Table 1. In total, 139 patients were eligible of whom 61 (44%) were prescribed lamotrigine and 78 (56%) lacosamide. Patients on lacosamide compared to lamotrigine were more often male (69% [54/78] versus 44% [27/61], respectively, p=0.003), and received more often radiotherapy (74% [58/78] versus 49% [30/61], p=0.002) and systemic therapy (65% [51/78] versus 38% [23/61], p=0.001). Also, more patients in the lacosamide group had tumor involvement in the temporal lobe (63% [49/78] versus 46% [28/61], p=0.046). After a maximum of 36 months follow-up, in total, 35% (49/139) patients had died: 25% (15/61) in the lamotrigine group, compared to 44% (34/78) in the lacosamide group (p=0.067). The median time from date of diagnosis to initiation of lamotrigine or lacosamide was 16 months (IQR=35) and 21 months (IQR=47), respectively (p=0.268). Of the patients on lamotrigine, 41% (25/61) had developed progressive disease before starting lamotrigine, while this was 58% (45/78) in patients on lacosamide (p=0.051). Within the three months before the start of lamotrigine or lacosamide, this difference was 16% (10/61) versus 35% (27/78), respectively (p=0.016).
Baseline sociodemographic and clinical characteristics of patients included in this study were compared to the baseline of patients who were not prescribed lamotrigine or lacosamide (n=1296). Patients in the current study were significantly younger, had a higher KPS, and more often had a lower WHO grade (see Supplemental S1), reflecting that this is a selected population with more difficult to treat seizures.
Patients used either levetiracetam or valproic acid as a first-line AED, and significantly more patients in the lamotrigine group were initially prescribed valproic acid (56%, 34/61) compared to patients in the lacosamide group (33%, 26/78), p=0.008. Number of failures on other AEDs before switching to either lamotrigine or lacosamide was comparable with a median of 2 (IQR=1 and 2, respectively) in both groups. Most patients used lamotrigine or lacosamide in combination with another AED instead of monotherapy: 66% and 71%, respectively (p=0.534). Of these combinations, the combination with levetiracetam was most common in both groups (33% and 49% for lamotrigine and lacosamide respectively). Median total daily dosage of lamotrigine versus lacosamide at the moment of treatment failure due to uncontrolled seizures was 200 mg (IQR=200) versus 250 mg (IQR=250), p=0.548. When AED treatment failed due to intolerable AEs, median dosages were 100 mg (IQR=81) for lamotrigine versus 200 mg (IQR=100) for lacosamide, p=0.131.
Treatment failure rate
The cumulative incidence of treatment failure for any reason showed no significant difference between lamotrigine and lacosamide: 38% (95%CI: 26-51%) versus 30% (95%CI: 20-41%) (Figure 1 and Table 2). AED treatment was not independently associated with treatment failure in multivariable analyses: hazard ratio of 0.84 (95%CI: 0.46-1.56) (see Table 3). There was also no association between AED treatment and death during follow-up with an adjusted hazard ratio of 1.63 (95%CI:0.51-5.26) (see Table 4).
Level of efficacy
Having uncontrolled seizures was the main reason for patients to show AED treatment failure: 25% (15/61) of patients in the lamotrigine group versus 13% (10/78) of patients in the lacosamide group during the 36-month follow-up period. The cumulative incidence of treatment failure due to uncontrolled seizures at 12 months was 18% (95%CI: 9-29%) for lamotrigine and 11% (95%CI: 5-20%) for lacosamide. Supplemental S2 shows the cumulative incidence for specific treatment failure reasons and death; details can be found in Supplemental S3.
Level of toxicity
A total of 25 patients experienced treatment failure due to one (n=18), two (n=4), three (n=1) or four (n=2) AEs, encompassing 37 AEs reported in total within 36 months of follow-up. In the lamotrigine group, 18 AEs in 11 patients were observed which led to treatment failure, which was 19 AEs in 14 patients on lacosamide. Of all reported AEs, agitation (5/37), depression (4/37) and headache (3/37) were reported most often. Of the patients with agitation, 3/5 were on lamotrigine, as were 1/4 patients with depression and 1/3 patients with headache on lamotrigine. In both groups, most of the AEs occurred within the first three months (Figure 2). The cumulative incidences of treatment failure due to AEs at 12 months were 17% (95%CI: 9-28%) and 19% (95%CI: 11-29) for lamotrigine and lacosamide, respectively. Of all reported AEs, grade 3 or 4 counted for 17% (3/18) in the lamotrigine group, whereas no (0/19) grade 3 or 4 AEs were reported in the lacosamide group (p=0.264). Improvement of AEs after discontinuation of lamotrigine or lacosamide occurred in 72% of all grade AEs (13/18) in the lamotrigine group, compared to 53% (10/19) in the lacosamide group (p=0.083) [Supplemental S4 for detailed information on AEs].