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Economic assessment of the secondary prevention of ischaemic stroke with dipyridamole plus aspirin (Aggrenox/Asasantin) in France |
Marissal J P, Selke B, Amarenco P |
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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 aspirin 25 mg plus dipyridamole 200 mg, twice daily, for the secondary prevention of ischaemic stroke.
Economic study type Cost-effectiveness analysis.
Study population The study population comprised a hypothetical cohort of individuals eligible for secondary prevention of ischaemic stroke.
Setting The setting was secondary care. The economic study was carried out in France.
Dates to which data relate The effectiveness data and most resource use data were derived from studies published between 1991 and 1996. The price year was 1997.
Source of effectiveness data The effectiveness evidence was derived from a synthesis of completed studies.
Modelling It was unclear whether a model was used to assess the final costs and benefits of the alternative therapies examined in the study.
Outcomes assessed in the review The outcomes estimated from the literature were:
epidemiological data, such as incidence of first ever strokes; and
efficacy data associated with the three strategies under study, including rates of fatal and nonfatal stroke, and rates of fatal and nonfatal myocardial infarction (MI).
Study designs and other criteria for inclusion in the review It was unclear whether a systematic review of the literature was undertaken to identify the primary studies. In effect, it seems that the primary studies have been identified selectively. The efficacy data were estimated from the ESPS-2, while most epidemiological data came from a stroke registry. The ESPS-2 was a randomised, double-blind controlled trial that enrolled 6,602 patients who received placebo, aspirin 25 mg twice daily, dipyridamole 200 mg twice daily, or combination therapy twice daily. The ESPS-2 had a follow-up of 24 months.
Sources searched to identify primary studies Criteria used to ensure the validity of primary studies The use of data derived from a double-blinded, placebo-controlled trial with a large sample size enhances the robustness of the clinical data used in the analysis.
Methods used to judge relevance and validity, and for extracting data Number of primary studies included Two primary studies provided clinical evidence.
Methods of combining primary studies The primary estimates were not combined since each study provided a series of clinical data.
Investigation of differences between primary studies Results of the review The rate of nonfatal stroke was 12.73% (+/- 0.82%) in the placebo group, 10.13% (+/- 0.74%) in the aspirin group, 9.79% (+/- 0.73%) in the dipyridamole group, and 7.21% (+/- 0.64%) in the combination group, (p<0.001).
The rate of fatal stroke was 1.33% (+/- 0.28%) in the placebo group, 1.21% (+/- 0.27%) in the aspirin group, 1.69% (+/- 0.32%) in the dipyridamole group, and 1.21% (+/- 0.27%) in the combination group, (p non significant).
The rate of nonfatal MI was 1.76% (+/- 0.32%) in the placebo group, 1.03% (+/- 0.25%) in the aspirin group, 2.00% (+/- 0.34%) in the dipyridamole group, and 1.09% (+/- 0.26%) in the combination group, (p = 0.01).
The rate of fatal MI was 0.97% (+/- 0.24%) in the placebo group, 1.33% (+/- 0.28%) in the aspirin group, 0.91% (+/- 0.23%) in the dipyridamole group, and 1.03% (+/- 0.25%) in the combination group, (p non significant).
The combined treatment with dipyridamole plus aspirin was therefore associated with a significant decrease in the risk of fatal and nonfatal stoke when compared with dipyridamole alone (RR 0.72, 95% confidence interval, CI: 0.58 - 0.90) and aspirin alone (RR 0.74, 95% CI: 0.59 - 0.92). There was no statistical difference in terms of all-cause death and in the combined stroke (fatal and nonfatal) and all-cause death end point.
Epidemiological data were not reported.
Measure of benefits used in the economic analysis The summary benefit measure used was the number of strokes avoided with the combined intervention in comparison with either monotherapy.
Direct costs The analysis of the costs was carried out from the perspective of the French social security system. The direct medical costs included were study drugs and stroke recurrence. Stroke recurrence depended upon the severity of disease and included short- and long-term hospital care, ambulatory medicine, nursing care, physiotherapy and drugs. The unit costs were not presented separately from the quantities of resources used. The costs associated with stroke were presented as macro-categories but stratified by level of severity (from Rankin 0 = no disability to Rankin 4 and 5 = severe disability). Drug prices were estimated using official reimbursement costs. The dosages used in the clinical trial were considered, and it was assumed that the number of visits were the same in each treatment arm. The costs of stroke were estimated from a cost study where Social Security reimbursement fees were used for most items. Adverse events were not considered in the base-case because of the lack of reliable data. The price year was 1997, and costs estimated in subsequent years were deflated to 1997 values. An annual discount rate of 5% was applied, although the time horizon of the analysis was unclear.
Statistical analysis of costs Statistical analyses were performed to deal with the issue of variability in the cost estimates.
Indirect Costs The indirect costs (i.e. costs associated with sick leave) were included in the analysis from the Social Security perspective. The costs were estimated using data on workforce characteristics and annual wages. Details of the cost calculation were provided. The unit costs were presented separately from the quantities of resources used. As in the analysis of the direct costs, the price year was 1997 and an annual discount rate of 5% was applied.
Currency US dollars ($) converted from French francs.
Sensitivity analysis A Monte Carlo simulation was performed to calculate CIs around the costs, benefits and cost-effectiveness ratios. The simulation was carried out in a hypothetical cohort of 10,000 cases according to several parameters. Specifically, the efficacy parameters of the different preventive strategies according to the severity of the recurrence, the direct costs of stroke recurrence per degree of severity of episode, and the proportion of employed workers at the time of stroke recurrence. The impact of the cost of adverse events was also considered in the sensitivity analysis.
Estimated benefits used in the economic analysis The number of avoided strokes with combination therapy (in a hypothetical cohort of 10,000 individuals) was 1,831 (95% CI: 60 - 3,624) over aspirin and 1,646 (95% CI: -97 - 3,418) over dipyridamole.
Cost results The cost per treated patient was $2,669 (95% CI: 2,051 - 3,310) with aspirin, $2,974 (95% CI: 2,314 - 3,652) with dipyridamole, and $2,185 (95% CI: 1,665 - 2,699) with combination therapy. Thus, the combination therapy was less costly than the two monotherapies. The extra drug cost was more than compensated for by a reduction in the cost associated with ischaemic strokes and indirect costs.
Synthesis of costs and benefits Incremental cost-effectiveness ratios (net benefit per avoided stroke) were calculated to combine the costs and benefits of the alternative prevention strategies. However, the combination therapy was dominant in comparison with aspirin or dipyridamole alone (less costly and more effective).
The authors estimated that the net benefit per avoided stroke with the combination therapy was $23,932 (95% CI: -32,609 - 35,772) over aspirin and $31,555 (95% CI: 4,921 - 74,515) over dipyridamole. Both results were statistically significant. These results appear irrelevant given that the combination therapy was dominant. The calculation of a ratio in these circumstances is unnecessary and could be misleading.
An ad hoc calculation of adverse events showed that the average cost of adverse effects had to be greater than $8,600 to significantly affect the cost-effectiveness of the combination therapy. This is quite unlikely since most side effects of the combination therapy are of a mild nature.
Authors' conclusions The use of aspirin 25 mg plus dipyridamole 200 mg, twice daily, for the secondary prevention of ischaemic stroke might be cost-effective in France.
CRD COMMENTARY - Selection of comparators The selection of the comparators (i.e. either monotherapy) was appropriate. In particular, aspirin represented a widely used preventive strategy and dipyridamole was a recently available treatment. The dosages were clearly stated and were chosen on the basis of the clinical trial that provided the efficacy data. The reasons why other potential comparators (e.g. clopidogrel) were excluded were given. You should decide whether they are valid comparators in your own setting.
Validity of estimate of measure of effectiveness The effectiveness evidence was estimated from published studies, which appear to have been identified selectively rather than through a review of the literature. Most of the clinical data came from a well-conducted clinical trial, which would usually be associated with robust estimates. Some details of the characteristics of the trial were reported. Other data were estimated from a French registry, which represents a typical source of disease incidence data. The issue of variability in the efficacy data was addressed in the statistical simulation. The authors noted that a limitation of the analysis was the use of epidemiological data derived from the early 1990s, which might not reflect actual disease patterns.
Validity of estimate of measure of benefit The summary benefit measure was specific to the disease considered in the study. It is not comparable with the benefits of other health care interventions.
Validity of estimate of costs The cost analysis was consistent with the perspective adopted in the study. The unit costs and the quantities of resources used were not given separately since most of the costs were presented as macro-categories. The costs were mainly derived using reimbursement fees, which were specific to the French setting. Therefore, caution is required when extrapolating the results of this cost analysis to other settings. The price year was given, which aids reflation exercises in other time periods. Statistical analyses of the costs were carried out to define CIs around mean estimates. The costs of disease were based on disease severity, which represents an important determinant of total costs. Further, a hypothetical calculation of adverse events confirmed the robustness of the base-case estimates.
Other issues The authors reported the results from other economic evaluations based on the ESPS-2 trial, but they did not compare their findings with those from other studies. The issue of the generalisability of the study results to other settings was not explicitly addressed, although CIs were provided for costs and benefits. However, the impact of changes in individual parameters was not estimated. It is unclear why cost-effectiveness ratios were calculated, given that the combination therapy resulted in being the dominant strategy. The study referred to patients requiring secondary prevention of ischaemic stroke and this was reflected in the authors' conclusions.
Implications of the study The study results suggested that aspirin 25 mg plus dipyridamole 200 mg, taken twice daily for the secondary prevention of ischaemic stroke, could be recommended as a cost-effective strategy for the management of patients who had already experienced ischaemic stroke.
Source of funding Supported by a grant from Boehringer Ingelheim, France.
Bibliographic details Marissal J P, Selke B, Amarenco P. Economic assessment of the secondary prevention of ischaemic stroke with dipyridamole plus aspirin (Aggrenox/Asasantin) in France. PharmacoEconomics 2004; 22(10): 661-670 Other publications of related interest Scott G, Scott HM. Application of the findings of the European Stroke Prevention Study 2 (ESPS-2) to a New Zealand ischaemic stroke cost analysis. Pharmacoeconomics 1997;12:667-74.
Chambers M, Hutton J, Gladman J. Cost-effectiveness analysis of antiplatelet therapy in the prevention of recurrent stroke in the UK. Pharmacoeconomics 1999;16(5 Pt 2):577-93.
Sarasin FP, Gaspoz JM, Bounameaux H. Cost-effectiveness of new antiplatelet regimens used as secondary prevention of stroke or transient ischemic attack. Arch Intern Med 2000;160:2773-8.
Marissal JP, Selke B, Lebrun T. Economic assessment of the secondary prevention of ischaemic events with lysine acetylsalicylate. Pharmacoeconomics 2000;18:185-200.
Indexing Status Subject indexing assigned by NLM MeSH Adolescent; Adult; Aged; Aspirin /administration & Aspirin, Dipyridamole Drug Combination; Confidence Intervals; Cost-Benefit Analysis; Dipyridamole /administration & Double-Blind Method; Drug Combinations; Female; France; Humans; Male; Middle Aged; Monte Carlo Method; Randomized Controlled Trials as Topic; Retrospective Studies; Stroke /economics /prevention & control; dosage /economics; dosage /economics AccessionNumber 22004008323 Date bibliographic record published 31/05/2006 Date abstract record published 31/05/2006 |
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