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Adjunctive lamotrigine therapy in patients with refractory seizures: a lifetime cost-utility analysis |
Messori A, Trippoli S, Becagli P, Cincotta M, Labbate M G, Zaccara G |
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Record Status This is a critical abstract of an economic evaluation that meets the criteria for inclusion on NHS EED. Each abstract contains a brief summary of the methods, the results and conclusions followed by a detailed critical assessment on the reliability of the study and the conclusions drawn. Health technology Using adjunctive lamotrigine (either 300mg or 500mg per day) therapy as add-on treatment to currently available antiepileptic drugs (AEDs) versus no adjunctive therapy (placebo-controlled, only AEDs) in the treatment of patients with refractory partial seizures.
Study population Patients between 18 and 65 years of age who had partial seizures and were refractory to treatment with currently available antiepileptic drugs (AEDs).
Setting Hospital. The economic study was carried out in Florence, Italy.
Dates to which data relate The effectiveness data were extracted from a paper published in 1993. The Quality-Adjusted Life Year (QALY) data were collected between February 1997 and July 1997. The data on the cost of lifetime treatment of epilepsywere derived from a paper published in 1994. The data relating to lamotrigine cost were obtained from the Red Book, 1995. The date for price data was not explicitly stated.
Source of effectiveness data The evidence for the clinical effectiveness of lamotrigine was derived from a single randomized trial. The estimate of QALYs was obtained from another single ad-hoc prospective study.
Link between effectiveness and cost data The costing was not performed on the same patient sample as that used in the effectiveness analysis. The costing was performed retrospectively.
Study sample Power calculations did not determine the sample size. A total of 216 patients were randomly assigned to placebo group (n=73), 300mg lamotrigine group (n=71), and 500mg lamotrigine group (n=72). In the pharmacoeconomic study only the cost and benefits related to the placebo group (n=73) were compared with those related to the500mg lamotrigine group (n=72) since the clinical result had revealed no significant differences in terms of clinical outcome measures between the placebo group and the 300mg lamotrigine group. As a consequence, the pharmacoeconomic analysis only contained a total of 145 patients. The sample size in the estimation of QALYs consisted of 81 patients with refractory epilepsy who entered an ad-hoc prospective study. The outcomes of the pharmacoeconomic analysis were normalised for a cohort of 100 patients for each of the two pharmacoeconomic study groups.
Study design The study was a double-blind, randomised controlled trial, carried out in 15 centres. The overall loss to follow up was 11.57% (25 patients). The duration of the follow-up period was 3 weeks in a 39-week initial effectiveness study. The duration of the pharmacoeconomic study was assumed to be life time.
Analysis of effectiveness The analysis of the clinical study was based on treatment completers only (although intention to treat was mentioned very briefly). The health outcome measures included seizure frequencies, the number of seizure days, investigator's global evaluation of patients' health status, the incidences of adverse events, quality of life (QOL) scores based on time-trade-off technique, and quality-adjusted life-years (QALYs) gained.
Effectiveness results The 500mg lamotrigine group had the highest rate of overall (24 weeks) median reduction in seizure frequency (36%) with respect to the baseline values. The corresponding values for the 300mg lamotrigine group and the placebo (no treatment) group were 20% and 8% respectively. The rate of reduction in seizure days (from week 13 to week 24) for the 500mg lamotrigine group, the 300mg lamotrigine group and the placebo group was 26.3%, 20.7% and 15.4%, respectively. According to the investigator's global measure, more than 40% of patients in the 500mg lamotrigine group experienced marked or moderate improvement after 24 weeks of treatment. The corresponding proportions for the 300mg lamotrigine group and the placebo group were less than 20% and 10%, respectively. In terms of all three above-mentioned measures the difference between the 500mg lamotrigine group and the placebo group was statistically significant (P<0.05), while the differences betweenthe 300mg lamotrigine group andthe placebo group were not.
Patients in both lamotrigine groups experienced statistically significantly more incidences of adverse events (generally mild or moderate in intensity and resolved over time) compared with the placebo group. The authors in the initial clinical study claimed that the analysis based on intention to treat confirmed the results reached based on treatment completers only.
In the QOL study, 81 patients were interviewed in order to be classified to one of five categories ranging from withdrawal with side-effects (level 1) to seizure free (level 5). The resulting mean QOL score for the five categories ranged from 0.40 (SD=0.07) for the level 1 patients to 0.96 (SD=0.04) for the level 5 patients. The statistical significance of the difference among the five levels of QOL scores was established by a one-way analysis of variance: F=54.8, df=4.76, P<0.001. The short-term (initial 6 months) QALYs for the treatment group (the 500mg lamotrigine group) ranged from 0 for the level 5 (seizure free) patients to 14.2 for the level 2 patients, with a total value of 25.3 and a normalised (per 100 patients) total of 35.1. The corresponding values for the control group (the placebo group) ranged from 0 for the level 5 patients to 15.9 for the level 2 patients,with a total value of 24.9 and a normalised total of 34.1.
The long-term (time period following the initial 6 months) QALYs for the treatment group ranged from 0 for the level 5 patients to 14.2 for the level 2 patients,with a total value of 771 and a normalised total of 1,071. The corresponding values for the control group ranged from 0 for the level 5 patients to 597 for the level 2 patients, with a total value of 754 and a normalised total of 1,033. The treatment group had a total value of 1,106.1 QALYs per 100 patients versus 1,067.1 for the control group. The discount rate for the QALYs was 6%.
Clinical conclusions The clinical results introduced lamotrigine therapy as a safe and effective add-on therapy and revealed "a dose-response relationship between administered lamotrigine dose and reduction in seizure frequency", seizure days and the overall marked or moderate improvement in patients' health status.
Modelling A standard pharmacoeconomic model was used to estimate the cost-utility ratio. No further details were given.
Measure of benefits used in the economic analysis Quality-Adjusted Life Years (QALYs) were used as the measure of benefits in the pharmacoeconomic study. Quality of life was assessed by interviews based on the time-trade-off technique.
Direct costs The costs were discounted. Resource utilisation was not reported separately from the costs. The lifetime cost items were reported separately for level 2, 3 and 4 patients. The cost components consisted of the costs of emergency services, inpatient hospital treatment (excluding treatment of drug reaction, surgical workup and operation), outpatient physicians visits, EEG services, CT scan and MRI, serum-level test (excluding drug reactions), drug-reaction costs, drug treatment costs, surgical workup, operation, and 500mg lamotrigine cost. The cost calculation was conducted from a societal perspective. The cost data (except for the lamotrigine cost) were extracted from an article published in 1994. The lamotrigine cost was obtained from the Red Book, 1995. A panel of nine experts estimated the costs for level 3 patients, (not produced in the source article), using the data from the source article. The date of the price data was not explicitly specified. Non-medical costs were not considered in the cost analysis.
Sensitivity analysis A one-way sensitivity analysis was performed by changing the QOL score for level 3 to investigate the possible impact on the cost-utility ratio.
Estimated benefits used in the economic analysis The short-term (initial 6 months) QALYs for the treatment group (the 500mg lamotrigine group) ranged from 0 (level 5 seizure free) to 14.2 (level 2 patients), with a total value of 25.3 and a normalised (per 100 patients) total of 35.1. The corresponding values for the control group (the placebo group) ranged from 0 (level 5) to 15.9 (level 2), with a total value of 24.9 and a normalised total of 34.1. The long-term (time period following the initial 6 months) QALYs for the treatment group ranged from 0 (level 5 patients) to 468 (level 2), with a total value of 771 and a normalised total of 1,071. The corresponding values for the control group ranged from 0 (level 5) to 597 (level 2), with a total value of 754 and a normalised total of 1,033. The treatment group had a total value of 1,106.1 QALYs per 100 patients versus 1,067.1 for the control group. The discount rate for the QALYs was 6%. The duration of the benefits was assumed to be lifetime.
Cost results The discount rate was 6%. The treatment group had an overall cost of $4,998,810 per 100 patients. The corresponding figure for the control group was $3,384,440 per 100 patients. The duration of the intervention and comparator costs was lifetime.
Synthesis of costs and benefits The incremental cost-utility ratio was calculated as a measure of the synthesis of the costs and benefits. The incremental cost-utility ratio of the adjunctive lamotrigine was $41,343 per QALY gained. The alteration of the QOL scores for level 3 in the sensitivity analysis did not impact dramatically upon the cost-utility ratio.
Authors' conclusions Adjunctive lamotrigine (500mg per day) in refractory epilepsy seems to have a worse pharmacoeconomic profile than many pharmacological treatments commonly used in areas other than epilepsy. Further data are needed to determine if lamotrigine can be equally effective at lower (and less costly) daily doses which could markedly improve its pharmacoeconomic characteristics.
CRD COMMENTARY - Selection of comparators The reason for the choice of the comparator is clear.
Validity of estimate of measure of benefit Since the QALYs were estimated using an ad-hoc study, and then arbitrarily combined with the clinical results of a randomised trial, there may be some doubts as to the internal validity of the benefit results.
Validity of estimate of costs Resource quantities were not reported separately from the costs. Adequate details of the methods of cost estimation were not given. Despite stating that the cost analysis was performed from a societal perspective the authors did not include non-medical or indirect costs in the cost analysis.
Other issues The authors combined the clinical results of a randomised trial with an ad-hoc study of QOL and an ad-hoc cost study in their pharmacoeconomic studywithout discussing the compatibility of these different components. Given the lack of a comprehensive sensitivity analysis, and statistical analysis of costs, the results need to be treated with some caution. The issue of generalisability to other settings or countries was not addressed.
Bibliographic details Messori A, Trippoli S, Becagli P, Cincotta M, Labbate M G, Zaccara G. Adjunctive lamotrigine therapy in patients with refractory seizures: a lifetime cost-utility analysis. European Journal of Clinical Pharmacology 1998; 53(6): 421-427 Other publications of related interest Matsuo F, Bergen D, Faught E et al. Placebo-controlled study of the efficacy and safety of lamotrigine in patients with partial seizures. Neurology 1993;43:2284-2291.
Indexing Status Subject indexing assigned by NLM MeSH Adjuvants, Pharmaceutic /economics /therapeutic use; Adult; Anticonvulsants /economics /therapeutic use; Cost of Illness; Cost-Benefit Analysis; Epilepsy /drug therapy /economics; Female; Humans; Male; Prospective Studies; Quality-Adjusted Life Years; Retrospective Studies; Triazines /economics /therapeutic use AccessionNumber 21998000468 Date bibliographic record published 31/01/1999 Date abstract record published 31/01/1999 |
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