We searched for any RCT comparing the effectiveness of two or more different pharmacological interventions for epilepsy in adults with refractory focal epilepsy, against a placebo. We included in our search strategy all the interventions currently used for the treatment of refractory focal epilepsy (acetazolamide, carbamazepine, clobazam, clonazepam, eslicarbazepine acetate, felbamate, gabapentin, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, phenytoin, pregabalin, phenobarbital, primidone, sodium valproate, sulthiame, tiagabine, topiramate, vigabatrin, and zonisamide).
were identified that compared lacosamide (200 and 400 mg) as adjunctive therapy versus placebo, for adults with partial-onset seizures with or without secondary generalizations. No RCT was found to compare lacosamide with other AEDs for children, young people, or adults with refractory focal seizures.
All three multicenter RCTs included only adults with partial onset seizures for at least 2 years, without any seizure-free period longer than 21 days during the 4–8 weeks prior to their enrolment to the trial. Pregnant women or adults with a history of alcohol or drug abuse were excluded.
All three trials lasted 24–26 weeks (8-week baseline period, 4–6 week titration, and 12-week maintenance period).
Two of the three included studies18
had low risk of bias, as assessed by GRADE criteria, whereas the third RCT1
had a high risk of bias, as there was no information regarding its blinding, method of randomization, and allocation concealment. In addition, two of the studies1
had high drop-out rates in the lacosamide groups compared with placebo. shows full details of the quality assessment of included studies (following GRADE criteria).
Clinical evidence profile: lacosamide versus placebo
Results from the meta-analysis of the three RCTs, with 1105 participants, suggested that lacosamide, as an adjunctive treatment, is more clinically effective than placebo in increasing the proportion of patients with at least a 50% reduction in seizure frequency (RR 1.67 [1.35 to 2.07]), though the confidence in this effect is low due to the very serious limitations of the overall quality assessment ().
No difference was found between the efficacy of lacosamide and placebo with regards to achievement of seizure freedom and for the proportion of patients who withdrew due to lack of efficacy.
In terms of experience of adverse events, it was found that lacosamide given as adjunctive treatment may cause a significantly higher proportion of adults with refractory epilepsy to withdraw due to adverse events compared with placebo (RR 2.91 [1.79 to 4.72]). There was a significantly higher proportion of patients on lacosamide adjunctive therapy, compared with those on placebo, who experienced dizziness, vomiting, diplopia, or blurred vision, although there was uncertainty in terms of the magnitude of the clinical effect of the last three adverse events (). No difference was found between lacosamide and placebo, for headache, fatigue, upper respiratory infection, somnolence, and nausea, although the confidence in these results is very low, as there were very serious study limitations.
No evidence was found for the other efficacy outcomes, such as time to first seizure, time to exit/withdrawal of allocated treatment, time to 12-month remission, and cognitive or quality of life outcomes.
Health economics evidence
At the time the systematic review of health economic literature was undertaken, no studies evaluating the cost effectiveness of lacosamide as adjunctive therapy in the treatment of refractory focal epilepsy were identified. An original economic model was developed to compare all licensed AEDs, including lacosamide, used as adjunctive therapy in adults with refractory focal seizures. The analysis took a UK National Health Service perspective, with costs expressed in 2009–2010 pound sterling. A 15-year time horizon was considered relevant and sufficiently long enough to capture the important costs and consequences of treatment. The expected costs and benefits, expressed as QALYs, were estimated for the time spent on each therapy. The performance of alternative AEDs was estimated using incremental cost effectiveness ratios (defined as the added cost of a given strategy divided by its added benefit, compared with the next most expensive strategy). The effectiveness of different AEDs was based on clinical evidence from pair-wise meta-analyses of placebo-controlled trials.
Results for lacosamide are summarized in and indicate that as adjunctive therapy, it is associated with increased costs (£2849) and improved health outcomes (0.043 more QALYs) compared with continuation of existing therapy alone (placebo). Although the expected additional costs of lacosamide are statistically significant (95% confidence interval [CI]: £570 to £5128 more), the expected benefits are more uncertain (95% CI: 1.277 fewer QALYs to 1.363 more QALYs). The incremental cost-effectiveness ratio for lacosamide compared with placebo is £66,256 per QALY gained, placing it beyond the NICE-willingness-to-pay threshold of £20,000.
Results of the cost-effectiveness analysis of adjunctive lacosamide
Compared with the mean costs and benefits of other adjunctive therapies currently licensed for the treatment of refractory focal seizures (), including gabapentin, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, and topiramate, the model found lacosamide likely to be more costly and to generate slightly fewer QALYs; however, these differences did not reach significance. These results were consistent across a range of sensitivity analyses. The cost-effectiveness rank was calculated based on the incremental net benefit for each drug compared with placebo, at a willingness-to-pay threshold of £20,000 per QALY gained.
Total costs and benefits of all adjunctive AEDs compared to placebo
Linking evidence to recommendations
As part of the guideline development and stemming from the evidence review, the GDG deliberated that if first-line treatments are ineffective or not tolerated, carbamazepine, lamotrigine, levetiracetam, oxcarbazepine, sodium valproate, topiramate, clobazam, or gabapentin, should be offered as adjunctive treatment to children, young people, and adults, with focal seizures. Furthermore, it was recommended that when adjunctive treatment is not effective or not tolerated in children, young people, or adults, with refractory focal seizures, the following recommendation should apply:
[O]ther AEDs that may be considered by the tertiary epilepsy specialist are eslicarbazepine acetate, lacosamide, phenobarbital, phenytoin, pregabalin, tiagabine, vigabatrin and zonisamide. Carefully consider the risk–benefit ratio when using vigabatrin because of the risk of an irreversible effect on visual fields.20
The recommendation was based on evidence of both clinical and cost effectiveness, and the proportion of people achieving a 50% reduction in seizure frequency was considered to be critical for decision-making. Lacosamide was included as part of the recommended AEDS to be used in a tertiary epilepsy center. This was based on the direct evidence for adults with focal-onset seizures for at least 2 years that showed that more participants who received lacosamide as an adjunctive treatment had at least 50% reduction in seizure frequency compared with those taking placebo. From the evidence reviewed, other AEDs, such as zonisamide, eslicarbazepine acetate, tiagabine, vigabatrin, and pregabalin, were also found to show evidence of efficacy in some patients and may benefit those who have not responded to and/or who have experienced adverse effects with AEDs. The guideline assumed that prescribers will use a drug’s summary of product characteristics to inform decisions made with individual patients, and recommended some drugs for indications for which they did not have a UK marketing authorisation at the date of publication, if there was good evidence to support that use.
However, from the evidence retrieved, more participants on lacosamide experienced adverse events and withdrawal from treatment compared with those on placebo. Therefore, the GDG noted that the balance of benefit and harm needs to be carefully monitored in all patients. Further, it must be recognized that different individuals may have different responses to various AEDs. A significant consideration in this recommendation, based on clinical expertise, was the recognition that vigabatrin has a harmful and irreversible side-effects profile, as it is associated with retinal toxicity causing visual impairment. These side effects occur over the longer term and were not observed in any of the short-term trials combined in the analysis.
The evidence reviewed in relation to the clinical effectiveness of lacosamide as an adjunctive treatment had serious limitations. The quality of the evidence was low, as most of the trials that were included in the evidence base had unclear or no details of the randomization, allocation concealment, or blinding that was done and had a higher dropout rate in the lacosamide arm. Therefore, the estimates of lacosamide effect need to be interpreted with caution.
A decision model was built to weigh the clinical benefits of each adjunctive AED, measured by seizure control and seizure reduction, compared with the harm from adverse events, as measured by withdrawals from treatment due to adverse events. Compared with placebo, the benefits gained from adjunctive lacosamide were modest and uncertain, whereas the costs were significantly high. Compared with other AEDs licensed for adjunctive therapy in focal seizures, lacosamide was associated with fewer QALYs and higher costs. Therefore, the GDG felt that lacosamide, along with eslicarbazepine acetate, pregabalin, tiagabine, and zonisamide, should not be recommended among initial adjunctive therapy options. Rather, these drugs should be considered only for cases where other, more cost-effective drugs, such as gabapentin, lamotrigine, levetiracetam, oxcarbazepine, and topiramate, are contraindicated or have been tried and were either ineffective or not tolerated. The limitations of the original analyses, particularly where assumptions had to be made, related to a paucity of data on longer term effectiveness and discontinuation, limited health-state utility data, and the limited data to inform estimates of NHS resource use.
The GDG consensus opinion was that management should be discussed with patients or that they should be offered referral to a tertiary epilepsy specialist, if adjunctive treatment with AEDs is ineffective or not tolerated, because achieving successful treatment may be complex. They noted that long-term experience with some of these drugs (pregabalin, lacosamide, zonisamide, and eslicarbazepine acetate) is limited, and that future research, as outlined below, is needed.