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Evaluation of the cost effectiveness of sirolimus versus tacrolimus for immunosuppression following renal transplantation in the UK |
McEwan P, Dixon S, Baboolal K, Conway P, Currie C J |
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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 examined immunosuppressive therapy (sirolimus versus tacrolimus) to prevent graft rejection in renal transplantations.
Economic study type Cost-effectiveness analysis and cost-utility analysis.
Study population The study population comprised a hypothetical cohort of adult renal transplantation patients.
Setting The setting was secondary care. The economic study was carried out in the UK.
Dates to which data relate The effectiveness evidence came from studies published between 1994 and 2005. The costs were presented in 2003 prices.
Source of effectiveness data The effectiveness evidence was derived from published studies.
Modelling A discrete event stochastic simulation model was used to examine the costs and benefits of tacrolimus and sirolimus. This type of model enables the simulation of individual patient pathways. Two time horizons were considered, 20 years and 10 years. The simulated individuals progressed through the model in monthly cycles utilising the appropriate risk functions to test for the occurrence of relevant clinical outcomes. The simulation first tested whether the individual had died within the current month. If death occurred, the simulation for that individual ended and the model recommenced with the next person. If the individual remained alive, the simulation next tested for actual rejection and graft failure events.
Outcomes assessed in the review The outcomes estimated from the literature were:
patient survival (incidence of deaths),
graft survival,
haemodialysis,
peritoneal dialysis,
re-transplants,
acute rejection episodes (AREs), and
utility.
Study designs and other criteria for inclusion in the review The risk functions for each clinical end point were derived from a database of transplant cases performed at the University Hospital of Wales, Cardiff, spanning the period 1978 to 2001 (McEwan et al. 2005, see 'Other Publications of Related Interest' below for bibliographic details). This information was supplemented with data from the Rapamune Maintenance Regimen (RMR) study. No other studies appear to have been included.
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 Five primary studies were the main source of evidence. Two of these provided information on risk and clinical events, while three provided information on utility.
Methods of combining primary studies Three estimates of utility were combined to give mean weighted estimates for individuals with and without a functioning graft.
Investigation of differences between primary studies Results of the review The numbers of events per 1,000 patients over 10 years were as follows:
deaths, 302 for sirolimus, and 309 (RMR study) and 312 (Cardiff study) for tacrolimus;
graft failures, 119 for sirolimus, and 324 (RMR study) and 332 (Cardiff study) for tacrolimus;
haemodialysis events, 48,243 for sirolimus, and 127,829 (RMR study) and 129,341 (Cardiff study) for tacrolimus;
peritoneal dialysis events, 40,872 for sirolimus, and 105,249 (RMR study) and 110,318 (Cardiff study) for tacrolimus;
re-transplants, 44 for sirolimus, and 123 (RMR study) and 130 (Cardiff study) for tacrolimus;
AREs, 229 for sirolimus, and 260 (RMR study) and 265 (Cardiff study) for tacrolimus.
The mean utility score ranged from 0.41 to 0.54 for dialysis and from 0.71 to 0.79 for transplant.
Methods used to derive estimates of effectiveness The authors made assumptions to derive some estimates of effectiveness.
Estimates of effectiveness and key assumptions Taking mean weighted estimates of utility resulted in a difference of 0.27 utilities for a individual maintained with a functioning graft versus dialysis.
No utility decrement associated with AREs was included as this was thought to be an acute transient effect.
The period of time in a health state was adjusted by the relative utility of that state.
Measure of benefits used in the economic analysis Three summary measures of benefit were used in the analysis. These were functioning graft-years gained, life-years gained and quality-adjusted life-years (QALYs) gained. The utility scores for the dialysis and transplant states were identified from a review of the literature, and a meta-analysis was conducted. No utility decrement associated with AREs was included as this was thought to be an acute transient effect. The QALYs were estimated using the simulation model. The outcomes were discounted at an annual rate of 1.5%.
Direct costs The health service costs included in the analysis were event costs and treatment costs. The event costs covered the hospital, acute rejection, transplant, graft loss and dialysis. The treatment costs covered sirolimus, tacrolimus, maintenance, immunosuppressives, antihypertensives, prophylaxis, treatment for cardiovascular conditions, bone loss and anaemia. The costs reflected local costs, although national reference costs and drug costs were included where possible. The unit costs were reported separately from the resource quantities, and were expressed in 2003 prices. The model was used to predict events, while resource use was associated with each of these events. Since the time horizon of the model was more than 2 years, the costs were appropriately discounted at a rate of 6%. Several assumptions were made in the derivation of the costs, and the opinions (on treatment regimens) of a physician and author were used to estimate drug costs.
Statistical analysis of costs The costs were treated deterministically.
Indirect Costs The indirect costs were not included.
Sensitivity analysis One-way sensitivity analysis was conducted on those aspects of the model with the greatest uncertainty. In particular, degree of maintaining graft function, degree of switching from sirolimus to tacrolimus, administration of sirolimus, patient characteristics and the discount rate. The limits for each parameter were selected using appropriate dispersions for the respective parameter, calculated either de novo or from published data.
Estimated benefits used in the economic analysis The authors did not report the life-years gained or the QALYs gained.
Over the 10-year time horizon, the sirolimus profile showed gains of 0.72 and 0.75 discounted years of a functioning graft over tacrolimus when using the RMR and Cardiff profiles, respectively, for serum creatinine levels.
Over a 20-year time horizon, the sirolimus profile showed further improvements, with average discounted gains in years of a functioning graft of 1.8 and 1.9 for the RMR and Cardiff creatinine profiles, respectively.
Cost results The authors did not report the total costs for each intervention.
The discounted simulation costs per life-year gained over a 10-year time horizon were 43,031 for sirolimus, and 48,128 (RMR profile) and 54,496 (Cardiff profile) for tacrolimus.
The discounted simulation costs per life-year gained over a 20-year time horizon were 62,120 for sirolimus, and 75,265 (RMR profile) and 81,972 (Cardiff profile) for tacrolimus.
Synthesis of costs and benefits The incremental cost per life-year gained and cost per QALY gained showed dominance using either the RMR or Cardiff profile for both the 10-year and 20-year time horizons. In other words, sirolimus was less costly and more effective than tacrolimus.
Authors' conclusions The authors concluded that this study predicts increased graft survival, through reduced need for dialysis, improved quality of life and reduced costs for sirolimus. The study also suggests that sirolimus may be more cost-effective than tacrolimus for the primary prevention of graft rejection in renal transplant recipients in the UK. Sirolimus was economically "dominant" under almost all scenarios investigated. This finding was robust to statistical economic analysis and univariate sensitivity analysis.
CRD COMMENTARY - Selection of comparators The choice of the comparator, tacrolimus, was explicitly justified, as it is widely used as an immunosuppressant and to prevent acute rejection in renal transplantations. You should decide if this represents a commonly used technology in your own setting.
Validity of estimate of measure of effectiveness The model was populated with data from two large-scale studies, one a review of data collected from a hospital over a 34-year period, and the other a study of 525 patients in 57 centres in Europe, Canada and Australia. The authors presented the results of the model for tacrolimus separately for these two studies, thereby attempting to consider the impact of differences between the studies when estimating effectiveness.
Validity of estimate of measure of benefit The measures of benefit used in the economic analysis were the functioning graft-years gained, life-years gained and QALYs gained. These measures of benefit were derived from the model and were appropriate. The authors reported the methods used to derive the estimates. The model, a stochastic simulation model, appears to have been appropriate for the estimation of events and long-term benefits. Neither the life-years gained nor the QALYs gained were reported.
Validity of estimate of costs The perspective adopted (i.e. that of the UK NHS) was explicitly stated. All the relevant categories of cost were included in the analysis. The unit costs were reported separately from the resource quantities, thus enhancing the reproducibility of the study in other settings. Resource use was estimated within the model as clinical events. The costs were treated deterministically. No sensitivity analyses of the prices were conducted to assess the robustness of the estimates used, although sensitivity analyses of other model parameters were undertaken. The price year was reported. Discounting was conducted, which was appropriate given that the time horizon of the model spanned more than 2 years. The total costs for each intervention were not reported.
Other issues The authors justified some of the assumptions made in their model with reference to published data. However, they did not compare their findings with those from other studies, so the degree to which their results agree with those from published studies cannot be objectively assessed. The issue of the generalisability of the results to other settings was not directly addressed. The authors do not appear to have presented their results selectively and the scope of the analysis was clearly reflected in the authors' conclusions. It would have been helpful had the authors reported the results more clearly. The authors reported some limitations to their study. For example, the survival equations used to predict the transition from various states in the model were based on a database containing creatinine values for both tacrolimus- and cyclosporine-treated patients, which implies similar rates of graft failure in both groups.
Implications of the study Sirolimus should be used in preference to tacrolimus in individuals who receive a graft following renal failure. Future research should update the model when longer-term trial data become available.
Bibliographic details McEwan P, Dixon S, Baboolal K, Conway P, Currie C J. Evaluation of the cost effectiveness of sirolimus versus tacrolimus for immunosuppression following renal transplantation in the UK. PharmacoEconomics 2006; 24(1): 67-79 Other publications of related interest McEwan P, Baboolal K, Dixon S, Conway P, Currie CJ. Patterns of graft and patient survival following renal transplantation and evaluation of serum creatinine as a predictor of survival: a review of data collected from one clinical centre over 34 years. Curr Med Res Opin 2005;21:1793-800
Indexing Status Subject indexing assigned by NLM MeSH Adult; Cost-Benefit Analysis; Female; Graft Rejection /prevention & Great Britain; Humans; Immunosuppressive Agents /economics /therapeutic use; Kidney Transplantation; Male; Sirolimus /economics /therapeutic use; Tacrolimus /economics /therapeutic use; control AccessionNumber 22006008105 Date bibliographic record published 31/08/2006 Date abstract record published 31/08/2006 |
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