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The cost effectiveness of tacrolimus versus microemulsified cyclosporin |
Orme M E, Jurewicz W A, Kumar N, McKechnie T L |
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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 Renal transplant patients were given tacrolimus immunosuppression to prevent graft rejection. Tacrolimus was administered orally at a dose of 0.1 mg/kg, 2 to 4 hours before the transplant. Methylprednisolone (500 mg) and azathioprine (1.5 mg/kg) were administered intravenously perioperatively. For maintenance therapy, the tacrolimus dose was initially 0.2 mg/kg per day in two divided doses, then adjusted to maintain a level of 5 to 15 microg/L. The patients were also given azathioprine (1.5 mg/kg per day) plus prednisolone as maintenance therapy. If an acute rejection episode occurred, methylprednisolone (500 mg/day) was given intravenously with the option of switching from tacrolimus. In some cases, muromonab CD3 or antithymocyte globulin therapy was given. The comparator was cyclosporin microemulsion (ME), administered at a dose of 4 mg/kg before the operation. After the operation, the dose was initially 8 mg/kg per day in two doses, then adjusted to maintain a level of 150 to 250 microg/L. In other respects the comparator treatment was the same as the tacrolimus treatment, except that patients could be switched to tacrolimus if an acute rejection episode occurred.
Economic study type Cost-effectiveness analysis; cost-utility analysis.
Study population The population comprised patients undergoing renal transplants. The patients had to be at least 18 years old and be suitable candidates for renal transplant according to the criteria of the UK National Health Service (NHS). They also had to give their informed consent.
Setting The setting was secondary care. The economic study was carried out in Cardiff, UK.
Dates to which data relate The effectiveness evidence and resource evidence both related to 1996 to 2000. 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 carried out prospectively on the same patients who provided the effectiveness data.
Study sample The authors referred to a clinical study. Few details of the methodology were reported in the economic evaluation. No power calculations were reported. It was unclear how the patients were selected. There were 179 patients in the study, 90 in the tacrolimus group and 89 in the cyclosporin group.
Study design This was a single-centre, open-label, randomised controlled trial. The patients were randomised to the groups by sequentially opening numbered, sealed envelopes. The patients were followed up for a median period of 2.7 years per patient.
Analysis of effectiveness The basis of the analysis was intention to treat. The primary health outcomes used were patient survival, graft survival and the number of patients with a rejection-free graft. There were no significant differences between the groups in the patients' characteristics at baseline. More specifically, in terms of the median age, donor age, total ischaemia time or body mass index.
Effectiveness results At 1 year, 94.4% of the tacrolimus group had survived versus 88.8% of the cyclosporin group.
Survival with a functioning graft was 87.8% for the tacrolimus group and 79.8% for the cyclosporin group.
The percentage with a rejection-free graft was 64.4% in the tacrolimus group and 52.8% in the cyclosporin group.
After 4 years, 89% of the tacrolimus group had survived versus 80% of the cyclosporin group.
Survival with a functioning graft was 81% for the tacrolimus group and 71% for the cyclosporin group.
The model was used to extrapolate the results after 4 years. The model predicted that, at 10 years, 64% of the tacrolimus group and 56% of the cyclosporin group would survive. In addition, 61% of the tacrolimus group and 52% of the cyclosporin group would survive with a functioning graft, and 36% of tacrolimus patients and 27% of cyclosporin patients would have survived rejection free.
Clinical conclusions The outcomes for renal transplant patients were better in the short and long term if they took tacrolimus rather than cyclosporin ME.
Modelling The results for 10 years after transplantation were extrapolated from the results of other research (Morris, see Other Publications of Related Interest) using modelling techniques. Monte Carlo simulations were used to assess the effect of uncertainty on the model.
Measure of benefits used in the economic analysis The measures of benefits used were the lives saved, extra patients with surviving graft, and extra rejection-free patients. The benefits were discounted at a rate of 1.5%.
Direct costs The costs were discounted at a rate of 6% and the benefits at 1.5%. The quantities and the costs were analysed separately. The costs of the health system were calculated in terms of inpatient hospitalisation, dialysis, ultrasound, all the different procedures, investigations and operations, and all types of medication. The unit costs were taken from the University of Wales Healthcare NHS Trust. Resource use estimates came from the effectiveness study and were projected for a further 5 years.
Statistical analysis of costs The costs were treated deterministically.
Indirect Costs The indirect costs were not included.
Sensitivity analysis Each cost component for the first 4 years was increased by 1%. A probabilistic sensitivity analysis was carried out based on the 95% confidence intervals of the cost parameters.
Estimated benefits used in the economic analysis The model showed that, of the 52 patients at 10 years in the cyclosporin ME group, 29 patients would survive, 27 would have a functioning graft and 14 would be rejection free.
In the tacrolimus group, 33 patient would survive, 32 would have a functioning graft and 19 would be rejection free. Therefore, there would be 4 extra patients surviving, 5 extra patients would have a functioning graft and 5 extra patients would be rejection free.
Cost results The annual per patient cost to the NHS ranged from 9,783 in year 1 to 965 in year 10 for the cyclosporin ME group. The corresponding cost in the tacrolimus group ranged from 9,900 in year 1 to 1,023 in year 10.
The costs of adverse effects were addressed in the costing.
Synthesis of costs and benefits The cost per survivor after 10 years was 37,265 in the tacrolimus group and 41,282 in the cyclosporin group.
The cost per patient after 10 years with a functioning graft was 39,157 in the tacrolimus group and 44,597 in the cyclosporin group.
The cost per rejection-free patient was 65,936 in the tacrolimus group and 86,896 in the cyclosporin ME group.
After 10 years, the incremental cost (tacrolimus versus cyclosporin ME) was 7,809 per survivor and 6,836 per additional patient with a functioning graft.
The sensitive cost parameters were the length of hospital stay and the cost of the immunosuppressive regimen.
A 1% increase in ward admission costs for the tacrolimus group resulted in an increase of 10% in the cumulative costs in year 10. A 1% increase in the cost of tacrolimus maintenance therapy increased the cumulative costs by 25% at year 10.
The probabilistic sensitivity analysis indicated a 95% confidence interval for the average incremental costs per survivor of 5,394 to 10,763.
Authors' conclusions Patients receiving renal transplants did better in both the short and long term if they took tacrolimus rather than cyclosporin microemulsion (ME) to prevent graft rejection. The authors considered the cost of this improvement in health outcomes to be reasonable.
CRD COMMENTARY - Selection of comparators The choice of cyclosporin ME was justified on the grounds that it was the best established alternative to tacrolimus as an immunosuppressant for renal transplant patients.
Validity of estimate of measure of effectiveness The effectiveness data were derived from a single study. The results for the first 4 years were derived from a randomised controlled trial, which was appropriate for the study question. The results for years 5 to 10 were modelled using the results from other studies, assuming that patient outcomes between the two groups would not be different once a patient had reached year 5. The study sample was representative of the study population in terms of geographical area, as all patients admitted were included in the study. The authors stated that the patient groups were not significantly different at baseline, although they did not give statistical results.
Validity of estimate of measure of benefit Several measures of benefit were used. These were taken directly from the effectiveness measures.
Validity of estimate of costs >From the study perspective adopted (the UK NHS), all the relevant categories of costs were included. The price of each cost component was included, although the costs per patient were not broken down into prices and quantities. The resource use quantities were taken from a single study. No statistical analyses of the quantities were performed. A sensitivity analysis on the length of hospital stay was carried out. The prices were taken from the authors' setting. No statistical analysis of the prices was performed. A sensitivity analysis of the individual costs was conducted. The price year was 1999.
Other issues The authors made appropriate comparisons of their results with the findings from other studies. They addressed the issue of generalisability by pointing out that length of stay in renal transplant units varies according to the unit. The authors did not present their results selectively and their conclusions reflected the scope of the analysis. The authors acknowledged the fact that results obtained from modelling may differ from what actually happens.
Implications of the study The authors recommended that similar research be carried out in a multi-centre study, which collects its own data to estimate the quality-adjusted life-years.
Bibliographic details Orme M E, Jurewicz W A, Kumar N, McKechnie T L. The cost effectiveness of tacrolimus versus microemulsified cyclosporin. PharmacoEconomics 2003; 21(17): 1263-1276 Other publications of related interest Booth-Clibborn N, Best L, Stein K. Tacrolimus after kidney transplantation: report to the Development and Evaluation Committee. Southampton: Wessex Institute; 1997. Report No.: 74.
Morris PJ. Renal transplant audit: UKTSSA Users Kidney Advisory group. UK: National Audit Office; 1995.
Indexing Status Subject indexing assigned by NLM MeSH Adult; Cost Savings; Cost-Benefit Analysis; Cyclosporine /administration & Drug Administration Schedule; Female; Graft Survival /immunology; Humans; Immunosuppressive Agents /administration & Kidney Failure, Chronic /drug therapy /economics /surgery; Kidney Transplantation /economics /immunology; Male; Middle Aged; Models, Economic; Prospective Studies; Randomized Controlled Trials as Topic; Tacrolimus /administration & Treatment Outcome; dosage /economics /therapeutic use; dosage /economics /therapeutic use; dosage /economics /therapeutic use AccessionNumber 22004008033 Date bibliographic record published 31/10/2004 Date abstract record published 31/10/2004 |
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