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Economic evaluation of levetiracetam as an add-on therapy in patients with refractory epilepsy |
Sheehy O, St-Hillaire J M, Bernier G, Godfroid P, LeLorier J |
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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 The use of levetiracetam (LEV), a new antiepileptic agent, plus standard therapy (ST) for patients with refractory epilepsy. Three different dosage of levetiracetam were considered, 1,000 mg/day, 2,000 mg/day and 3,000 mg/day.
Economic study type Cost-effectiveness analysis.
Study population The study population comprised a hypothetical cohort of patients with refractory epilepsy.
Setting The setting was secondary care. The economic study was carried out in Canada.
Dates to which data relate Clinical estimates and some resource use data were derived from studies published between 2000 and 2003. The price year was 1999.
Source of effectiveness data The effectiveness evidence was derived from a synthesis of completed studies and experts' opinions.
Modelling A decision tree model was constructed to examine the clinical and economic impact of LEV+ST, compared with ST alone, in a hypothetical cohort of patients with refractory epilepsy. The time horizon of the model was 1 year. Patients were started with either 1,000mg/day of LEV or standard care. Then, patients could stay on that specific LEV dose in the case of success, move to a higher dose (2,000 mg/day first and 3,000 mg/day afterwards) after 1.5 months, or the medication could be stopped. It was also assumed that patients who experienced intolerable adverse events under higher doses of LEV could return to lower doses of LEV if they had experienced a relative benefit from lower doses. The model considered that patients who stopped LEV altogether returned to ST alone for the remaining time. A graphical representation of the decision tree was provided.
Outcomes assessed in the review The outcomes estimated from the literature were:
the rates of seizure-free status, withdrawal due to adverse events, and return to lower dosage levels with LEV;
the rate of seizure-free status with ST and rate of ST failure; and
the efficacy rates with LEV (three dosages) and ST.
Study designs and other criteria for inclusion in the review It was not stated whether a systematic review of the literature was undertaken to identify primary studies. However, clinical data were derived from three pivotal, prospective, double-blind, placebo-controlled multi-centre trials that had been carried out in the USA and Europe (total of 904 adult patients).
Sources searched to identify primary studies Criteria used to ensure the validity of primary studies The validity of the primary studies was ensured by the use of clinical trials.
Methods used to judge relevance and validity, and for extracting data Number of primary studies included Five primary studies were provided clinical evidence.
Methods of combining primary studies Investigation of differences between primary studies Results of the review In patients who started on LEV 1,000 mg/day, the rate of seizure-free status was 3.9% and the rate of withdrawal from LEV 1,000 mg due to adverse events was 6.9%.
In patients increased to LEV 2,000 mg (89.2%), the rate of seizure-free status was 5.3% and the rate of failure due to adverse events was 14.2% (28% returned to LEV 1,000 mg and 72% withdrew from LEV 2,000 mg).
In patients increased to LEV 3,000 mg (80.5%), the rate of seizure-free status was 7.2% and the rate of failure due to adverse events or a lack of efficacy was 67.2% (87.4% withdrew from LEV 3,000 mg due to the lack of efficacy and 12.6% withdrew due to adverse events (34.3% returned to LEV 2,000 mg and 65.7% withdrew from LEV)). The proportion retained on LEV 3,000 mg was 25.6%.
The rate of seizure-free status on ST was 0.7%, while the rate of failure was 99.3%.
Methods used to derive estimates of effectiveness A scientific advisory board comprising four experts was contacted so that they could review model assumptions and apply a correction factor to trial-based probabilities to account for relapses that could occur within an observation period of one year. Also, the panel of experts provided data for an alternative scenario were it was assumed that patients with at least one seizure per month might be eligible for surgery.
Estimates of effectiveness and key assumptions The assumptions made by the experts were used to corroborate clinical estimates derived from the literature. Five per cent (range: 5 - 50) of patients with one or more seizures were eligible for surgery and 65% of these were assumed to undergo temporal lobectomy.
Measure of benefits used in the economic analysis The summary benefit measure used was the number of seizure-free days (SFDs) gained over a 12-month period. This was obtained from the decision model.
Direct costs Discounting was not relevant since the costs were incurred during one year. The unit costs were presented separately from the quantities of resources used for most items. The health services included in the economic evaluation were the treatment of adverse events and seizures, hospital day for epilepsy, emergency room visits, regular visits to a neurologist, non-specialist medical visits and LEV. The former (treatment of adverse events and seizures) included the cost of hospitalisations for epilepsy, the cost of an emergency room visit, and the cost of unscheduled medical visits to a neurologist or to a general practitioner. The costs of standard AEDs were not included because they were common to both branches of the tree. The cost/resource boundary of the third-party payer was adopted. Resource use was mainly estimated from expert opinion, as well as using data extracted from the clinical trials. The costs came from Ontario data estimated from sources published between 1995 and 1999. The prices of different dosages of LEV were provided by the pharmaceutical company, and 2002 values converted to 1999 prices using the Consumer Price Index. The price year was 1999.
Statistical analysis of costs The costs were treated deterministically in the base-case.
Indirect Costs The indirect costs were not included in the economic evaluation.
Sensitivity analysis Extensive univariate sensitivity analyses were carried out to examine the robustness of the base-case estimates to variations in the model inputs. The ranges used were either derived from the clinical trials or set by the authors. In particular, for seizure-free status and SFDs, the 95% confidence interval (CI) was used. Other parameters (increase and decrease in LEV dosage, cost of adverse events, efficacy) were increased and decreased by 50% or 100%. Further, two alternative scenarios were considered. One examined the possibility that refractory epileptic patients may undergo temporal lobectomy. The other assessed the impact of introducing a new AED on the frequency of surgical evaluation and surgery for epilepsy.
Estimated benefits used in the economic analysis The number of SFDs per month was 22.85 for LEV 1,000 mg/day plus ST, 23.20 for LEV 2,000 mg/day plus ST, 23.30 for LEV 3,000 mg/day plus ST, and 21.62 for ST alone.
Thus, the number of SFDs per year was 279 with LEV+ST and 260 with ST alone. The difference was 19 SFDs per patient per year.
Cost results The total costs were Can$3,924 with LEV+ST and Can$2,403 with ST alone (difference Can$1,520).
In the scenario involving surgery for 5% of patients with at least one seizure per months the cost of treatment was Can$4,843 with LEV+ST and Can$4,061 with ST alone (difference Can$782).
In the scenario involving surgery for 50% of patients with at least one per month, the cost of treatment was Can$13,108 with LEV+ST and Can$18,979 with ST alone (cost-savings of Can$5,871).
Synthesis of costs and benefits An incremental cost-effectiveness ratio (ICER), expressed in terms of cost per SFD gained per patient per year, was calculated to combine the costs and benefits of LEV+ST in comparison with ST alone.
The ICER was Can$80.70 in the base-case scenario, and Can$41.5 in the scenario of surgery for 5% of patients with at least one seizure per month. LEV+ST was dominant (both more effective and less costly) than ST alone in the scenario of surgery for 50% of patients with at least one seizure per month.
The sensitivity analysis showed the robustness of the base-case results to variations in the model inputs.
The highest ICER was observed for the analysis where success probability was set to the value of the 95% CI lower bound (Can$109 per SFD gained per patient per year).
The most cost-effective situation for LEV occurred when surgery for 50% of patients was included in the model.
Authors' conclusions Levetiracetam (LEV) added to standard therapy (ST) for patients with refractory epilepsy increased drug costs, although these were partially offset by savings in other medical costs due to an increase in SFDs.
CRD COMMENTARY - Selection of comparators The selection of the comparator was appropriate as it reflected the conventional approach for patients with refractory epilepsy. You should decide whether this is a valid comparator in your own setting.
Validity of estimate of measure of effectiveness The effectiveness evidence came mainly from clinical trials, which appear to have been identified selectively. Experts' opinions were then used to corroborate literature-based data and to put them into the context of the Canadian model. The use of clinical trials highlights the robustness and validity of the clinical inputs, which were consistently varied in the sensitivity analysis.
Validity of estimate of measure of benefit The benefit measure was specific to the disease considered in the study and is not comparable with the benefits of other health care interventions. The authors stated that the use of SFDs addressed the patient's perspective. However, the impact of the interventions on quality of life was not addressed. The authors stated that the three main clinical trials used to estimate clinical data used quality of life scales that were specific to patients with epilepsy and were not designed for conversion into utilities. Thus, the quality-adjusted life-years (QALYs) could not be calculated. The authors added that QALYs are generally not suitable for use in areas such as epilepsy.
Validity of estimate of costs The perspective adopted in the study was explicitly stated. As such, all the relevant categories of costs were included in the analysis. Information on the unit costs was provided and data on resource use were reported for most items. The source of the costs was reported. Experts' opinions were used to define resource use. The costs were treated deterministically and only the costs of adverse events were varied in the sensitivity analysis. The price year was reported, which aids reflation exercises in other settings easy. Reasons for the exclusion of some categories of costs were provided. The authors highlighted that the indirect costs would have represented a large proportion of the total costs and could have impacted on the final results, but these were excluded because of the perspective adopted.
Other issues The authors compared their findings with those from a published study and found consistent results, although methodological differences between the two studies were pointed out. In terms of the issue of the generalisability of the study results to other settings, the authors stated that the extrapolation of clinical trial data to "real-word" clinical practice might be problematic. The study results referred to patients with refractory epilepsy and this was reflected in the authors' conclusions. The authors acknowledged some limitations of their study. For example, the use of placebo comparisons, the simplified model structure and the lack of extensive sensitivity analyses.
Implications of the study The study results supported the use of LEV added to ST for patients with refractory epilepsy.
Source of funding Funded by UCB Pharma, Braine-l'Alleud, Belgium.
Bibliographic details Sheehy O, St-Hillaire J M, Bernier G, Godfroid P, LeLorier J. Economic evaluation of levetiracetam as an add-on therapy in patients with refractory epilepsy. PharmacoEconomics 2005; 23(5): 493-503 Other publications of related interest Cereghino JJ, Biton V, Abou-Khalil B, et al. Levetiracetam for partial seizures: results of a double-blind, randomized clinical trial. Neurology 2000;55:236-42.
Shorvon SD, Lowenthal A, Janz D, et al. Multicenter, doubleblind, randomized, placebo-controlled trial of levetiracetam as add-on therapy in patients with refractory partial seizures. Epilepsia 2000;41:1179-86.
Ben Menachem E, Falter U. Efficacy and tolerability of levetiracetam 3000 mg/d in patients with refractory partial seizures: a multicenter, double-blind, responder-selected study evaluating monotherapy. Epilepsia 2000;41:1276-83.
Privitera MD, Edrich P, Godfroid P. Dose-response relationship of levetiracetam. European Journal of Neurology 2002;9 Suppl 2:180-1.
Markowitz MA, Mauskopf JA, Halpern MT. Cost-effectiveness model of adjunctive lamotrigine for the treatment of epilepsy. Neurology 1998;51:1026-33.
Indexing Status Subject indexing assigned by NLM MeSH Anticonvulsants /adverse effects /economics /therapeutic use; Cost-Benefit Analysis; Dose-Response Relationship, Drug; Drug Resistance; Drug Therapy, Combination; Epilepsy /drug therapy /economics /surgery; Humans; Models, Economic; Piracetam /adverse effects /analogs & derivatives /economics /therapeutic use AccessionNumber 22005008261 Date bibliographic record published 31/12/2005 Date abstract record published 31/12/2005 |
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