An economic evaluation of rizatriptan in the treatment of migraine Thompson M, Gawel M, Desjardins B, Ferko N, Grima D 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 present study compared rizatriptan with usual care and with various drugs from the triptan class (5-HT1B/1D agonists) for the treatment of moderate-to-severe migraine. Oral rizatriptan 10 mg was compared with sumatriptan 50 mg, sumatriptan 100 mg, naratriptan 2.5 mg, zolmitriptan 2.5 mg and usual care. Usual care was defined as an aggregate of medications weighted by the relative frequency of use of prescriptions over a 1-year period. The prescription medications included were combination analgesics with narcotics (99%), ergot derivatives (0.56%) and opioids alone (0.03%). Type of intervention Treatment. Economic study type Cost-utility analysis. Study population The target population comprised men and women who experienced moderate-to-severe migraines according to the International Headache Society (IHS) criteria, for whom other acute therapies (e.g. nonsteroidal anti-inflammatory drugs, simple analgesics) were insufficient or contraindicated. Setting The setting was primary and secondary care. The economic study was carried out in Canada. Dates to which data relate The effectiveness evidence was taken from studies published between 1994 and 2003. Health service resource use and costs were taken from 1995 to 2003. The price year was 2002. Source of effectiveness data The effectiveness data were derived from a review of completed studies, augmented with estimates. Modelling A decision analysis model was created to estimate the outcomes of migraine treatment in patients with a diagnosis of moderate-to-severe migraine, as defined by the IHS criteria. The model was constructed to cover a 24-hour time horizon since this represented the median duration of a migraine attack. Outcomes assessed in the review The clinical end points used as indicators of efficacy were "pain-free response at 2 hours", as this is the end point Page: 1 / 7
currently recommended by the IHS, and "sustained pain free for 2-24 hours". Therefore, the model outcomes depended on initial 2-hour pain-free response, maintenance of pain-free status, the use of rescue medication and use of medical services. Study designs and other criteria for inclusion in the review The majority of the studies were placebo-controlled trials. Clinical data were obtained from a meta-analysis for triptans (Ferrari et al. 2002, see 'Other Publications of Related Interest' below for bibliographic details) and from a naturalistic study for usual care (Adelman et al. 1996, see 'Other Publications of Related Interest' below for bibliographic details). Sources searched to identify primary studies Criteria used to ensure the validity of primary studies Methods used to judge relevance and validity, and for extracting data Number of primary studies included Twenty-eight primary studies were included in the review. Methods of combining primary studies A narrative method was used to combine the studies. Investigation of differences between primary studies Results of the review The base-case model inputs included the following events and probabilities. The probabilities for pain free at 2 hours were, for usual care 9.3%, naratriptan 22.4%, rizatriptan 40.1%, sumatriptan 28.8% and zolmitriptan 29.1%. The probabilities for sustained pain free at 2-24 hours were, for naratriptan 71.0%, rizatriptan 63.1%, sumatriptan 69.1% and zolmitriptan 65.3%. The probabilities for use of rescue medication were, for usual care 35.0%, naratriptan 22.5%, rizatriptan 22.5%, sumatriptan 22.5% and zolmitriptan 22.5%. The probabilities for pain free by 4 hours with rescue medication were, for usual care 22.0%, naratriptan 40.3%, rizatriptan 24.9%, sumatriptan 17.4% and zolmitriptan 23.8%. The probabilities with no rescue medication were, for usual care 14.7%, naratriptan 26.9%, rizatriptan 16.6%, sumatriptan 11.6% and zolmitriptan 15.8%. The probabilities for sustained pain free at 4-24 hours were, for usual care 83.3%, naratriptan 71.0%, rizatriptan 63.1%, sumatriptan 69.1% and zolmitriptan 65.3%. Page: 2 / 7
The utilities included for each of the outcome events in the decision tree were: 0.628 for sustained pain free at 2-24 hours (outcome A); 0.565 for not sustained pain free at 2-24 hours (outcome B), or for pain free at 4 hours (outcomes C, D, I and J); 0.022 for not pain free at 4 hours with physician or emergency department (ED) visits (outcomes E, F, G, K, L and M); and -0.068 for not pain free at 4 hours with no physician or ED visits (outcome H and N). The probabilities for resource use were 4.0% for physician visits only, 2.5% for ED visits only and 14.1% for hospitalisation visits. Methods used to derive estimates of effectiveness The study adopted estimates based on authors' assumptions. Estimates of effectiveness and key assumptions When a patient was not pain free within 2 hours from first-line therapy, they might choose to use rescue therapy (second dose) or to endure the attack. Rescue medication increased the chances of becoming pain free at 4 hours by 50%. For these patients with a second dose, it was assumed that no further medication or medical help was required. In the case of experiencing a recurrence after the second dose of migraine medication, patients treated with usual care took a third dose of usual care medication and patients treated with a triptan switched to usual care. Additional resource use (i.e. physician, ED, hospital) only occurred in patients who had not had a pain-free response at any time point over 24 hours. If patients consulted a physician during an attack, they did not require ED or hospital services. Only those patients that visited the ED were eligible for hospitalisation. In relation to the societal perspective, the productivity loss associated with clinical outcomes was the maximum productivity loss for each migraine attack, that is, 1 day's wage based on an 8-hour workday. If a migraine was resolved in 2 hours, 38.6 minutes in productive time were lost, whereas if it was resolved within 4 hours, 77.2 minutes were lost. If it was not resolved within the first 4 hours after treatment, 8 hours of productive time were lost. For unpaid work, the same amount of time was assumed to be lost as for paid work. Measure of benefits used in the economic analysis The measure of benefit was the quality-adjusted life-years (QALYs). The utility values for migraine were derived from published literature that used the Quality of Well-Being (QWB) Scale in adults with migraine (Sieber et al. 2000, see 'Other Publications of Related Interest' below for bibliographic details). Migraine effects were measured in QALYs per attack (assumed to last one day). Unique utility estimates were assigned to: patients who were pain free at 2 hours and sustained pain free from 2-24 hours; patients who did not achieve pain-free status until 4 hours and/or had a recurrence after being pain free at 2 or 4 hours; patients who were not pain free at 4 hours and required the use of health care resources; and patients who were never pain free and did nothing. Direct costs The costs of migraine treatment over the 24-hour mean attack duration were for hospitalisation, physician visits, ED visits and drugs. Fees for drug dispensing were not included. The costs reported were estimated on the basis of physician fee schedules, data from the Ontario Case Costing Project (unpublished data, 1994-1996), Statistics Canada, a report by the Canadian Coordinating Office for Health Technology Assessment and a published profile of ED costs Page: 3 / 7
by diagnosis. The drug costs for triptans were assigned formulary prices plus a 10% mark-up (maximum mark-up reimbursed). The daily costs per dose for usual care were derived from market share published data. Discounting was not carried out as the costs were incurred during less than 2 years. The estimations of the quantities and the costs were derived using modelling. All the costs were fully allocated and were adjusted using the Consumer Price Index for Canada (Health and Personal Care). The price year was 2002. Statistical analysis of costs No statistical analysis of the costs was reported. Indirect Costs The indirect costs were included for the societal perspective. Time loss per migraine attack was calculated for each strategy, based on published literature. Time lost from paid work was valued and reflected the mean weekly earnings for full-time employees in Canada. Wages for part-time employees were assumed to be 20% lower than those for fulltime employees. Two analyses were conducted, one with paid work only and the other with paid and unpaid work loss. Discounting was not carried out as the costs were incurred during less than 2 years. The quantities and the costs were analysed separately. The estimations of the quantities and the costs were derived from completed studies and authors assumptions. All the costs were adjusted using the Consumer Price Index for Canada (Health and Personal Care). The price year was 2002. Currency Canadian dollars (Can$). Sensitivity analysis Several one-way sensitivity analyses were performed to determine the sensitivity of the results to uncertainty in key model inputs. The variables explored were the efficacy and costs of usual care, the rate and costs of hospitalization, utility estimates, the rate of rescue medication, and the proportion of the general population with migraine who were employed. The upper and lower ranges reported were taken from published literature and from 80% confidence intervals. Estimated benefits used in the economic analysis The QALYs per attack were 0.00027 for usual care, 0.00075 for rizatriptan, 0.00064 for naratriptan, 0.00052 for sumatriptan and 0.00058 for zolmitriptan. Cost results From the health services perspective, the total resource costs were Can$9.44 for usual care, Can$24.78 for rizatriptan, Can$25.13 for naratriptan, Can$27.75 for sumatriptan and Can$25.69 for zolmitriptan. From the societal perspective and excluding unpaid work, the total resource costs were Can$69.09 for usual care, Can$65.91 for rizatriptan, Can$70.79 for naratriptan, Can$77.87 for sumatriptan and Can$73.50 for zolmitriptan. From the societal perspective and including unpaid work, the total resource costs were Can$103.38 for usual care, Can$89.86 for rizatriptan, Can$97.04 for naratriptan, Can$106.69 for sumatriptan and Can$100.98 for zolmitriptan. Synthesis of costs and benefits An incremental analysis was performed. It was shown graphically for incremental QALYs and for incremental effect expressed as the proportion with attack aborted. From the health services perspective, rizatriptan provided better efficacy at a higher cost than usual care. The Page: 4 / 7
incremental cost per attack aborted (defined as being pain free at 2 hours) was Can$49.82 and the incremental cost per QALY gained was Can$31,845. All other triptans were dominated by rizatriptan as they offered lower efficacy at a higher total cost. From the societal perspective (excluding unpaid work loss), rizatriptan dominated usual care since it was cost-saving and more effective than usual care. All other triptans were also dominated as they showed higher costs and lower efficacy. Trends for a societal perspective including unpaid work were similar. Authors' conclusions This study showed that incremental health benefits were obtained from the use of rizatriptan, instead of usual care, for patients with moderate-to-severe migraine. These benefits were achieved at an acceptable incremental cost to thirdparty payers in Canada. When a societal perspective was considered, the use of rizatriptan instead of usual care resulted in a net reduction of overall costs to society. Rizatriptan would appear to be more effective and less costly than the other triptans available in Canada. The results were based on the most current data available at the time of study and changes to key parameters, such as drug costs, might affect the results. CRD COMMENTARY - Selection of comparators The authors gave a justification for the comparators. Recent data suggested that triptans demonstrated superior efficacy when compared with placebo, while rizatriptan showed superior efficacy to several other triptans. You should judge whether these strategies are relevant in your own setting, or whether other comparators from other drugs could also be relevant. Validity of estimate of measure of effectiveness The authors did not report that a systematic review of the literature had been undertaken. Although this is a common practice with models, it does not always ensure that the best data available are used in the model. The authors used data from the available studies selectively. As such, one cannot be sure that all the relevant literature was identified. A positive feature was that meta-analyses were used to derive the effectiveness of triptans. The estimates of effectiveness were derived credibly from the studies identified. The authors used data from published sources, experts' opinions and their own assumptions. The effectiveness evidence was derived from a meta-analysis and randomised clinical trials, which are reliable sources from which to estimate effectiveness. The authors justified their assumptions with reference to the medical literature. The estimates were also investigated in sensitivity analyses using ranges from the literature and confidence intervals, which enhances the validity of the study. Validity of estimate of measure of benefit The authors used QALYs as a measure of benefits. The QALYs were estimated from a decision analysis model. This measure of benefit enables comparisons across health technologies. The methods to derive the utility weights were based on published literature that used the QWB Scale in adults known to experience migraine. Sensitivity analyses on the utility estimates were conducted using upper and lower 80% confidence intervals. Validity of estimate of costs The authors reported that the study had been conducted from two perspectives. For the societal perspective, productivity losses were included. These were reported in sufficient detail, although other patient costs (e.g. transportation) were not included. The unit costs were taken from published sources. No statistical analysis of the costs was undertaken. Sensitivity analyses of selected direct costs were conducted and were reported to have assessed the robustness of the estimates used. Discounting was not carried out, which was appropriate since the time horizon did not exceed two years. Reflation of the costs was carried out and the price year was reported, which will aid any future reflation exercise. Other issues Page: 5 / 7
The authors made appropriate comparisons of their findings with those from other studies. They did not explicitly address the generalisability of the results, but they did consider assessing the impact of population heterogeneity. The conclusions reflected the scope of the analysis. The authors stated that the study was subject to limitations common to all decision analysis models in that it combined data from numerous sources, required structural and data assumptions, and was subject to certain biases. The results were mostly sensitive to the utility estimates, which were available from two sources. The weighted efficacy value reflecting the usual care strategy was not available and, therefore, it was derived from a study that did not completely match drug usage patterns in their population. Implications of the study The authors stated that, even when the use of the most effective therapy is the best clinical option for the treatment of migraine patients, a balance must be found between clinical benefits, patient equity and the cost-effectiveness of therapy for publicly funded health care reimbursement. Source of funding Funded by Merck Frosst Inc, Burlington, ON, Canada. Bibliographic details Thompson M, Gawel M, Desjardins B, Ferko N, Grima D. An economic evaluation of rizatriptan in the treatment of migraine. PharmacoEconomics 2005; 23(8): 837-850 PubMedID 16097844 Other publications of related interest Ferrari MD, Goadsby PJ, Roon KI, et al. Triptans in migraine: detailed results and methods of a meta-analysis of 53 trials. Cephalalgia 2002;22:633-58. Adelman JU, Sharfman M, Johnson R, et al. Impact of oral sumatriptan on workplace productivity, health related quality of life, healthcare use, and patient satisfaction with medication in nurses with migraine. Am J Managed Care 1996;2:1407-16. Sieber WJ, David KM, Adams JE, et al. Assessing the impact of migraine on health-related quality of life: an additional use of the Quality of Well-Being Scale self-administered. Headache 2000;40:662-71. Indexing Status Subject indexing assigned by NLM MeSH Canada; Cost-Benefit Analysis; Decision Trees; Humans; Migraine Disorders /drug therapy; Reproducibility of Results; Serotonin Receptor Agonists /economics /therapeutic use; Triazoles /economics /therapeutic use; Tryptamines /economics /therapeutic use AccessionNumber 22005008326 Date bibliographic record published 31/03/2006 Date abstract record published 31/03/2006 Page: 6 / 7
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