|Economic evaluation of nimesulide versus diclofenac in the treatment of osteoarthritis in France, Italy and Spain
|Tarricone R, Martelli E, Parazzini F, Darba J, Le Pen C, Rovira J
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.
The use of two drug therapies, nimesulide and diclofenac, for the treatment of osteoarthritis (OA). Both drugs are nonsteroidal anti-inflammatory drugs (NSAIDs), which although beneficial in reducing pain and inflammation, may result in potentially serious consequences in terms of gastrointestinal toxicity.
Economic study type
The study population comprised patients suffering from OA who were receiving NSAIDs to reduce the pain and inflammation.
The setting was primary care. The economic study was carried out in France, Italy and Spain.
Dates to which data relate
The effectiveness evidence related to studies published in 1998 and 1999. The dates during which the quantity of resources used was gathered were not reported. The price year was 1999.
Source of effectiveness data
The effectiveness evidence was derived from a review of published studies.
A decision tree model was constructed to simulate the treatment of GIAEs. Also, to simulate the related costs in the two groups of OA patients who received either nimesulide or diclofenac. Gastric (nausea, vomiting or dyspepsia, pyrosis or gastralgia, and gastric erosion) and intestinal (diarrhoea, abdominal pain, and constipation) adverse events were considered.
Outcomes assessed in the review
The outcomes assessed in the review of the literature were the probability values for the occurrence of GIAEs per week of exposure to nimesulide and diclofenac, assuming a constant risk of adverse effects over time.
Study designs and other criteria for inclusion in the review
Only data derived from randomised clinical trials were used. In particular, two studies were also double-blind.
Sources searched to identify primary studies
The main source was the MEDLINE database. MEDLINE was searched until June 1999 for studies on OA, published in the English language. Manual searches of the literature were also conducted to identify further 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
Three primary studies were used in the review. The sponsoring company provided a fourth study, which was excluded on account of it being unpublished.
Methods of combining primary studies
The results of the primary studies were combined through a meta-analysis, and 95% confidence intervals (CIs) were reported for each estimate.
Investigation of differences between primary studies
Results of the review
The estimated mean rate of nausea, vomiting or dyspepsia was 0.019 (95% CI: 0.014 - 0.026) with nimesulide and 0.032 (95% CI: 0.026 - 0.039) with diclofenac.
The rate of pyrosis or gastralgia was 0.002 (95% CI: 0.001 - 0.005) with nimesulide and 0.004 (95% CI: 0.002 - 0.007) with diclofenac.
The mean rate of gastric erosion was 0.002 (95% CI: 0.001 - 0.006) with nimesulide and 0.001 (95% CI: 0.0002 - 0.004) with diclofenac.
The mean rate of diarrhoea was 0.012 (95% CI: 0.009 - 0.017) with nimesulide and 0.012 (95% CI: 0.009 - 0.017) with diclofenac.
The rate of abdominal pain was 0.008 (95% CI: 0.005 - 0.013) with nimesulide and 0.012 (95% CI: 0.009 - 0.017) with diclofenac.
The mean rate of constipation was 0.003 (95% CI: 0.002 - 0.007) with nimesulide and 0.003 (95% CI: 0.0002 - 0.006) with diclofenac.
The mean rate of gastric adverse events was 0.022 (95% CI: 0.018- 0.030; total sample of 55 patients) with nimesulide and 0.037 (95% CI: 0.031 - 0.045; overall sample of 119 patients) with diclofenac.
The mean rate of intestinal adverse events was 0.023 (95% CI: 0.018- 0.029; total sample of 69 patients) with nimesulide and 0.027 (95% CI: 0.022 - 0.034; total sample of 85 patients) with diclofenac.
All the probability values were estimated for 1 week of treatment. Overall, the risk of adverse events was lower for nimesulide than for diclofenac.
Measure of benefits used in the economic analysis
A cost-minimisation analysis was conducted since the two drugs were considered to be equally effective. However, an analysis should only be considered as cost-minimisation if it is demonstrated in the paper that the effectiveness is equal. Since this was not the case in this paper, and given the absence of a summary benefit measure, this was considered to be a cost-consequences analysis.
Discounting was irrelevant due to the short time horizon of the analysis. The quantities and the costs were reported separately. The resource/cost boundary adopted was that of the NHS. The economic analysis included the costs of medical and nursing staff, utilities, equipment, overheads, and drugs. The cost of each item was derived from national tariffs and official price lists. Non-reimbursable drugs were not included. Partially reimbursable drugs were only quantified for their reimbursed part, according to the perspective adopted in the study. The quantities of resources were estimated on the basis of an experts' panel, and were mainly related to the number of general practitioner visits during the study period. The total costs of each treatment were obtained using modelling. The price year was 1999. When more recent cost data were used, they were deflated to the 1999 values.
Statistical analysis of costs
No statistical test of difference was reported, although the costs of adverse events were treated stochastically.
The indirect costs were not included.
Numerous sensitivity analyses were conducted to investigate the robustness of the results and the uncertainty around some data, which were derived from both a review of the literature (effectiveness) and experts' opinions (resources). A two-way sensitivity analysis was conducted by varying the incidence rates of gastric and intestinal adverse effects over a range of values determined by the 95% CIs. A one-way sensitivity analysis (tornado diagram) was performed on the resource estimates using the most and the least conservative expert advice as the maximum and minimum values.
Estimated benefits used in the economic analysis
See the 'Effectiveness Results' section.
The acquisition costs of nimesulide per patient were EUR 4.84 in France, EUR 7.74 in Italy, and EUR 7.68 in Spain. The acquisition costs of diclofenac per patient were EUR 5.93 in France, EUR 9.24 in Italy, and EUR 7.86 in Spain.
Regardless of the drug used, the cost of a single episode of nausea, vomiting or dyspepsia was EUR 13.44 (range: 1.45 - 20.57) in France, EUR 24.57 (range: 9.01 - 30.81) in Italy, and EUR 102.6 (range: 100.75 - 106.22) in Spain.
The cost of an episode of pyrosis or gastralgia was EUR 26.91 (range: 5.22 - 68.71) in France, EUR 22.73 (range: 10.14 - 79.90) in Italy, and EUR 160.76 (range: 158.45 - 165.29) in Spain.
The cost of abdominal pain was EUR 25.83 (range: 2.48 - 69.74) in France, EUR 8.65 (range: 1.99 - 11.0) in Italy, and EUR 103.9 (range: 102.36 - 106.92) in Spain.
The cost of an episode of diarrhoea was EUR 8.63 (range: 1.98 - 19.0) in France, EUR 12.93 (range: 9.46 - 18.47) in Italy, and EUR 61.47 (range: 60.32 - 63.73) in Spain.
The cost of constipation was EUR 9.23 (range: 0.43 - 18.9) in France, EUR 17.59 (range: 14.12 - 23.13) in Italy, and EUR 61.8 (range: 60.64 - 64.06) in Spain.
The cost of an episode of gastric erosion was EUR 127.44 (range: 14.01 - 194.95) in France, EUR 115.52 (range: 115.52 - 143.07) in Italy, and EUR 410.27 (range: 408.73 - 413.29) in Spain.
From the decision model, the total costs per case of 2-weeks' therapy with nimesulide (including eventual side-effects) were EUR 7 in France, EUR 10 in Italy, and EUR 17 in Spain. Similarly, the total costs per case of 2-weeks' therapy with diclofenac (including eventual side-effects) were EUR 8 in France, EUR 12 in Italy, and EUR 21 in Spain. The incremental (nimesulide - diclofenac) costs per case were EUR 1.5 in France, EUR 2 in Italy, and EUR 3.6 in Spain. The sensitivity analyses were stated to have shown that nimesulide was always cost-saving. The Tornado diagrams showed that the cost of nimesulide was less than that of diclofenac, up to the limit of the 95% CI for the cost of adverse events.
Synthesis of costs and benefits
The cost-minimisation analysis indicated that nimesulide was cost-saving in comparison with diclofenac, in France, Italy, and Spain. This was due not only to the lower drug acquisition cost, but also to the lower risk of treatment-related gastrointestinal adverse effects (GIAEs), which resulted in costs to the National Health Service (NHS). Sensitivity analyses showed that the result of the analysis was robust to wide variations in both the costs and effectiveness data.
CRD COMMENTARY - Selection of comparators
The rationale for the selection of the comparator was clear. Diclofenac was chosen because it represented one of the most common NSAIDs used for the treatment of OA, while nimesulide was selected because it was believed to reduce the incidence of GIAEs. You should consider whether they represent currently used technologies in your own setting.
Validity of estimate of measure of effectiveness
The probability values used in the model were derived from a meta-analysis of three primary studies identified in the literature. However, the authors highlighted several drawbacks. First, some publication bias could exist in the current literature, therefore influencing the quantitative results obtained in the analysis. Second, the populations of the three primary studies were not comparable in terms of their age, gender and clinical characteristics. This should have been considered in the process of combining the probability values, especially with respect to the age of the patients, which is a crucial determinant of the risk of GIAEs. Third, the computation of the overall incidence rate of GIAEs did not take into account the different sample size of the primary studies. Therefore, the final estimation could have be driven by the value reported in the largest study.
The statement that this was a cost-minimisation study was not supported by the actual data. In fact, given the uncertainty, there is likely to be some difference in effectiveness for most individuals, which should be valued by the incremental change in resources. However, the results presented show that, in terms of adverse events, on average, nimesulide appears to be better.
Validity of estimate of measure of benefit
No summary measure of benefit was used.
Validity of estimate of costs
All the costs relevant to the perspective adopted in the study appear to have been included in the analysis. The costs and the quantities were reported separately, thus enhancing the external validity of the analysis. However, as recognised by the authors, the estimation of resources was based on experts' assumptions and not on actual data. This could have reduce the reliability of the data used. Tariffs were used, rather than the true costs. However, this was justified by the perspective adopted (that of the NHS) and, as a consequence, the costs were quite specific to the study setting.
The issue of the generalisability of the results was partially addressed by performing sensitivity analyses, which were satisfactorily reported. The authors made few comparisons of their findings with those from other studies. Finally, the authors' conclusions seem to be in keeping with the population studied.
Implications of the study
The authors stated that, if the study results were applied to the entire populations of France, Italy and Spain, the adoption of nimesulide rather than diclofenac would result in cost-savings to the NHS. These would range from a minimum of EUR 17,500,000 in France to a maximum of EUR 30,000,000 in Spain. Further research should focus on studies considering a long-term time horizon for the inclusion of other side-effects and extra costs. These conclusions should be viewed in the light of the caveats described.
Source of funding
Supported in part by Helsinn Healthcare SA, Lugano, Switzerland.
Tarricone R, Martelli E, Parazzini F, Darba J, Le Pen C, Rovira J. Economic evaluation of nimesulide versus diclofenac in the treatment of osteoarthritis in France, Italy and Spain. Clinical Drug Investigation 2001; 21(7): 453-464
Subject indexing assigned by CRD
Anti-Inflammatory Agents, Non-Steroidal /therapeutic use /economics /adverse effects; Costs and Cost Analysis; Cyclooxygenase Inhibitors /therapeutic use /economics /adverse effects; Diclofenac /therapeutic use /economics /adverse effects; France; Health Care Costs; Italy; Meta-Analysis; Osteoarthritis /drug therapy /prevention & Spain; control /economics
Date bibliographic record published
Date abstract record published