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Economic evaluation of everolimus versus mycophenolate mofetil in combination with cyclosporine and prednisolone in de novo renal transplant recipients |
Holmes M, Chilcott J, Walters S, Whitby S, Akehurst R |
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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 study compared three different treatments to target risk factors for chronic rejection of renal transplants (such as occurrence of cytomegalovirus, CMV). The three treatment strategies included: everolimus (Certican, Novartis Pharma AG, Basel, Switzerland) 1.5 mg; everolimus 3 mg; mycophenolate mofetil (MMF) (CellCept, Roche Pharmaceuticals, Basel, Switzerland). The first dose of study medication was given within 48 hours of surgery, after which medication was given twice daily. All patients received cyclosporine (CsA) micro-emulsion (Neoral, Novartis AG) and prednisolone. Patients with suspected acute rejection underwent renal biopsy and were treated with additional immunosuppressive agents as required.
Economic study type Cost-effectiveness analysis.
Study population The study population comprised adult patients, in fourteen different countries, undergoing their first kidney transplant. No specific inclusion or exclusion criteria were reported.
Setting The study setting was secondary care. The economic study was carried out in the United Kingdom.
Dates to which data relate The effectiveness and resource use data dates were not reported. The price year was 1999.
Source of effectiveness data The effectiveness data were derived from a single study.
Link between effectiveness and cost data The costing was undertaken prospectively on the same patient sample as that used in the economic study.
Study sample No power calculations to determine the sample size were reported and no specific sample size appears to have been planned. 588 patients were included in the study. Of these, 194 were allocated to receive everolimus 1.5 mg, 198 to receive everolimus 3 mg and 196 to receive MMF 2g. Of the 194 patients receiving everolimus 1.5 mg, 58.8% were male, and the mean age of the group was 45.2 years. Of the 198 patients receiving everolimus 3 mg, 64.1% were male, and the mean age of the group was 44.1 years. 70.9% of the 196 patients in the MMF group were male, and the mean age of the group was 46.1 years.
Study design The study was based on a randomised, prospective, double blind, placebo-controlled trial undertaken in fourteen different countries (multi-centre trial). The subject allocation method used in the randomisation process was not reported. Patients were followed-up for a period of 12 months. 381 of the 588 initial patients completed the 12-month study.
Analysis of effectiveness The analysis of the clinical study was based on intention to treat. The primary health outcomes used in the analysis were a composite efficacy endpoint of biopsy-proven acute rejection, graft loss, death and loss to follow-up at 6 months, and graft loss, death or loss to follow-up at 12 months. According to the authors the study groups were well balanced in terms of race, height and weight across the treatment arms, and there were no significant differences between treatment groups in terms of demographic, clinical or laboratory parameters.
Effectiveness results There were no statistically significant differences across the treatment groups in terms of the primary composite end-points of efficacy failure at 6 or 12 months.
27% of the patients receiving everolimus 1.5 mg, 26% of those receiving everolimus 3 mg, and 30% of those receiving MMF had biopsy-proven acute rejection, graft loss, death or loss to follow-up at 6 months.
23% of patients receiving everolimus 1.5mg, 20% of those receiving everolimus 3mg, and 24% of those receiving MMF had biopsy-proven acute rejection at 12 months.
Clinical conclusions From the study it can be concluded that there were no statistically significant differences in terms of efficacy across the three treatments.
Measure of benefits used in the economic analysis No summary measure of benefit was derived. Since no significant differences were found in terms of health outcomes, the authors conducted a cost-minimisation analysis.
Direct costs Resource quantities and costs were reported separately. The direct costs included in the analysis were those of the hospital, which included the following: cost of hospitalisation, cost of diagnostic procedures (biopsies, ultrasounds or other visualisation techniques), laboratory tests, outpatient or emergency room visits, post-operative dialysis, immunosuppressive therapy or major use of concomitant medication. The cost of everolimus was unavailable at the time of analysis, and, therefore, the cost of MMF was excluded in order for an impartial comparison of costs to be made. For all other immunosuppressive drugs, the unit cost was the cost per milligram for the drug. Unit costs were obtained or estimated for each item of resource use in each country in order to provide a cost vector in the local currency. Where no country-specific unit costs were available (Russia, the Czech Republic and South Africa) median unit costs in Purchasing Power Parity (PPP) US dollars from the other countries were used instead. The study did not attempt to capture all of the costs of transplantation; only the costs that might be expected to vary according to immunosuppressive therapy were included. Discounting was not employed, as costs were estimated for a 12-month period only. The study reported average costs per patient. The price year was 1999. The authors stated that pooled resource data from all participating countries were used due to an absence of statistical evidence suggesting treatment-related differences were affected by country.
Statistical analysis of costs Resource use and costs were treated stochastically. Between groups analysis was performed by use of a one-way ANOVA test. If the one-way ANOVA, used to compare the mean outcomes across the three groups, resulted in a significant p-value, (p<0.05), then multiple pair-wise comparisons were undertaken by means of two independent sample t-tests to identify where the between-group differences lay. Bonferroni-corrected p-values were reported from the pair-wise comparisons.
Indirect Costs Indirect costs were not included in the analysis.
Currency US dollars ($). Local currency unit costs were converted to dollar costs by means of the purchasing power parity (PPP) rate.
Sensitivity analysis One-way sensitivity analysis was undertaken to assess the effect that different assumptions might have on mean cost.
Estimated benefits used in the economic analysis See the 'Effectiveness Results' section.
Cost results The only significant difference in the treatment cost concerned the cost of cyclosporine (CsA). The average cost of CsA was $4,454 for everolimus 1.5 mg, $4,124 for everolimus 3 mg, and $5,163 for MMF.
The mean difference between everolimus 1.5 mg and MMF was -$709 (95% CI: -$1,404 to -$14; p=0.04); the mean difference between everolimus 3 mg and MMF was -$1,038 (95% CI: -$1,730 to -$347; p=0.0001).
The mean overall cost of treatment was $33,715 per patient (95% CI: $30,013 - $37,417) with everolimus 1.5 mg, $38,519 (95% CI: $34,094 - $42,943) per patient with everolimus 3 mg, and $36,509 (95% CI: $32,430 - $40,587) per patient with MMF.
Differences between the three groups did not reach statistical significance.
Synthesis of costs and benefits Costs and benefits were not combined. Sensitivity analyses showed that the difference in costs between the groups remained unaffected after estimated costs for nephrectomy were included, or after the UK unit cost vector was applied to all data so that the impact of variations in the cost vector could be tested.
Authors' conclusions The authors concluded that their analysis of resource use and costs in the first 12-months after transplantation demonstrated equivalent health care costs for everolimus 1.5 mg or 3 mg compared with MMF within a CsA-based triple-therapy regimen.
CRD COMMENTARY - Selection of comparators Although no explicit justification was given for using mycophenolate mofetil (MMF) as the comparator, it would appear to represent a current practice in the authors' setting. You should decide if the comparator represents current practice in your own setting.
Validity of estimate of measure of effectiveness The study was based on a randomised, prospective, double blind, placebo-controlled trial, which was appropriate for the study question because well conducted randomised controlled trials are the gold standard study design when comparing different health interventions. It would appear that the study sample was representative of the study population. However, the authors did not detail the inclusion or exclusion criteria used for entry into the study. No power calculations were conducted and the sample size may have been too small to detect statistically significant differences. Furthermore, the authors did not list the 14 countries from which the study populations were derived. Patient groups were shown to be comparable in terms of demographic, clinical and laboratory parameters and the groups were well balanced in terms of race, age, height and weight across the treatment arms. Appropriate statistical techniques were used to test for differences between the three groups. Furthermore, outcomes were analysed on the basis of intention to treat.
Validity of estimate of measure of benefit The analysis of benefits was based upon the therapeutic equivalence of the treatment alternatives. The economic analysis therefore included only costs.
Validity of estimate of costs All categories of cost relevant to the hospital perspective adopted were included in the analysis. The authors did not attempt to capture all of the costs of transplantation, and only those costs expected to vary according to immunosuppressive therapy were included in the analysis. These omissions will probably not have affected the authors' conclusions. However, as the cost of everolimus was unavailable at the time of the study, the costs of everolimus and MMF were excluded. This, in essence, represents an assumption that both drugs will cost the same, which is uncertain. Hence, this omission has the potential to affect the authors' results, either in favour of MMF or in favour of everolimus. Costs and quantities were reported separately, which will enhance the generalisability of the results. Resource quantities were derived from the study, with all differences in resource use between the three groups being appropriately tested for significance using statistical analysis. Unit costs were derived from local settings, and were appropriately converted to PPP US dollars, to ease comparisons across the 14 countries. Sensitivity analyses of costs were conducted, and the mean differences in costs between the three countries were tested for statistical significance. Since all costs were incurred over a one-year period, discounting was unnecessary. The price year was reported, which will assist any inflationary exercises.
Other issues The authors did not make appropriate comparisons of their findings with those from other studies. The issue of generalisability to other settings was addressed in the study as it was based on results derived from 14 different countries, and the authors performed appropriate statistical and sensitivity analyses. The authors do not appear to have presented their results selectively, and their conclusions reflected the scope of the analysis. The authors did not report any further limitations of their study.
Implications of the study The authors highlighted the need for long-term cost analyses when new immunosuppressive regimens are being assessed. The authors reported that only long-term follow-up will provide a definitive answer to the question of whether use of everolimus results in both improved clinical outcomes and reduced healthcare costs over the lifetime of the graft. They also report that future studies should also be in a position to incorporate the relative costs of everolimus and MMF, which was not possible in this study.
Source of funding Funded by Novartis AG, Basel, Switzerland.
Bibliographic details Holmes M, Chilcott J, Walters S, Whitby S, Akehurst R. Economic evaluation of everolimus versus mycophenolate mofetil in combination with cyclosporine and prednisolone in de novo renal transplant recipients. Transplant International 2004; 17(4): 182-187 Other publications of related interest Eisen H, Dorent R, Mancini D, et al. Safety and efficacy of everolimus (RAD) as part of a triple immunosuppressive regimen in de novo cardiac transplant recipients: six month analysis. Journal of Heart and Lung Transplantation 2002;21:55.
Vitko S, Margreiter R, Wiemar W, et al. Everolimus (Certican) 12-month safety and efficacy versus mycophenolate mofetil in de novo renal transplant recipients. Transplantation 2004;78(10):1532-40.
Valantine H, Eisen H, Dorent R, et al. 12-month results of a multicentre study comparing efficacy and safety of everolimus to azathioprine in de novo cardiac transplant recipients. (Abstract 434) American Transplant Congress 26 April-1 May 2002, Washington DC, USA
Indexing Status Subject indexing assigned by NLM MeSH Adult; Cost-Benefit Analysis; Cyclosporine /economics /therapeutic use; Double-Blind Method; Drug Costs; Drug Therapy, Combination; Everolimus; Female; Great Britain; Humans; Immunosuppressive Agents /economics /therapeutic use; Kidney Transplantation /economics /immunology; Male; Middle Aged; Mycophenolic Acid /analogs & Prednisolone /economics /therapeutic use; Sirolimus /analogs & Time Factors; Treatment Outcome; derivatives /economics /therapeutic use; derivatives /economics /therapeutic use AccessionNumber 22004000774 Date bibliographic record published 31/05/2005 Date abstract record published 31/05/2005 |
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