|An economic model of 2-hour post-dose ciclosporin monitoring in renal transplantation
|Keown P A, Kiberd B, Balshaw R, Khorasheh S, Marra C, Belitsky P, Kalo Z
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.
This study examined the therapeutic monitoring of microemulsion ciclosporin (Neoral) by 2-hour post-dose drug concentrations (C2) after renal transplantation. In particular, the C2 strategy monitored the ciclosporin levels in a serum sample taken from the patient 2 hours after taking an oral dose of ciclosporin; the target range for week 1 was 1,500 to 2,200 microg/L.
Economic study type
The study population comprised a hypothetical cohort of patients with end-stage renal disease who were scheduled to undergo renal transplantation and to receive immunosuppression with ciclosporin microemulsion formulation.
The setting was a hospital. The economic study was carried out in Canada.
Dates to which data relate
The clinical data were obtained from studies published between 1999 and 2002. The resource use data came from studies published between 1996 and 2002. The price year was 1999.
Source of effectiveness data
The effectiveness evidence was derived from a synthesis of completed studies and authors' assumptions.
A published decision tree model was used to evaluate the direct medical costs and outcomes associated with the two different monitoring strategies for microemulsion ciclosporin. The model reflected current Canadian practice. The model incorporated hospitalisation time, the use and dose of immunosuppressive drugs, the incidence of acute rejection, the probability of graft loss, and other materially important outcomes throughout the first year post-transplant. The structure of the model was reported. The time horizon of the model was one year, which corresponded to the first year post-transplantation.
In a secondary analysis, the model was extended to provide an estimate of the economic implications of the two monitoring strategies over a 5-year time horizon. Assumptions were made to estimate the long-term clinical and economic inputs.
Outcomes assessed in the review
The outcomes estimated from the literature were:
the probability of being within the therapeutic drug concentration range,
the probability of being below the therapeutic drug concentration range,
the rate of acute rejection when the drug concentration was in the therapeutic range,
the rate of acute rejection when the drug concentration was below the therapeutic range,
the number of acute rejection episodes (AREs) per patient with acute rejection, and
the incidence of graft loss.
Study designs and other criteria for inclusion in the review
It was not stated whether a systematic review of the literature was undertaken to identify the primary studies. Three randomised clinical trials were the main source of evidence. The characteristics of the patients (mean age 45 +/- 12 years; 65% men) were reported for the cohort obtained from the three randomised trials. No information was provided on the designs of the other studies.
Sources searched to identify primary studies
Criteria used to ensure the validity of primary studies
The validity of the primary studies was, in part, ensured by using clinical trials as the source of evidence.
Methods used to judge relevance and validity, and for extracting data
Number of primary studies included
Six primary studies provided the effectiveness data.
Methods of combining primary studies
The data from three trials were pooled as they formed a single group of patients. Other data were combined using a narrative approach.
Investigation of differences between primary studies
Results of the review
The probability of being within the therapeutic drug concentration range was 0.5 with the C0 strategy and 0.73 with the C2 strategy.
The probability of being below the therapeutic drug concentration range was 0.5 with the C0 strategy and 0.27 with the C2 strategy.
The rate of acute rejection when the drug concentration was in the therapeutic range was 10% with both monitoring systems.
The rate of acute rejection when the drug concentration was below the therapeutic range was 40% with both approaches.
The mean number of AREs per patient with acute rejection was 1.42 with both monitoring strategies.
The incidence of graft loss was 10% with the C0 strategy and 8.6% with the C2 strategy.
Methods used to derive estimates of effectiveness
The authors made some assumptions in the decision model.
Estimates of effectiveness and key assumptions
The authors assumed that patient survival and the number of acute rejections were the same in both strategies. In addition, the ciclosporin blood levels would be interpreted correctly and the resulting decision-making and clinical response would be appropriate and rational.
Other assumptions were also made to extrapolate the results of the base-case model to a 5-year time horizon. In particular, the difference in ciclosporin monitoring strategies in terms of graft survival was assumed to carry forward throughout the following 4 years.
Measure of benefits used in the economic analysis
The summary benefit measure used was the incidence of AREs. This was estimated using the decision model. The number-needed-to-treat to benefit one patient in terms of ARE avoided (NNTB) and the reduction in the length of initial hospitalisation were also reported as relevant model outputs. Discounting was also not applied in the 5-year analysis.
Discounting was applied only in the 5-year model and an annual rate of 3% was used. The unit costs were not presented separately from the quantities of resources used. The health services included in the economic evaluation were related to initial hospitalisation for transplantation surgery, the occurrence and treatment of AREs, care of functioning grafts, graft loss, dialysis, maintenance immunosuppressive drugs, follow-up hospitalisations (excluding hospitalisation for the treatment of acute rejections), and the treatment of infections and other adverse events requiring hospitalisation. Resources used for ciclosporin monitoring and the treatment of ambulatory-based adverse events not requiring hospitalisation were not included in the model because they were assumed to be almost equivalent between the monitoring strategies.
The cost/resource boundary of the third-party payer was adopted. Resource use was estimated from published data. The costs came from a detailed 5-year prospective multi-centre economic evaluation of renal transplantation in Canada. All the costs were inflated to 1999 values using the health care component of the Canadian Consumer Price Index.
Statistical analysis of costs
The costs were treated deterministically in the base-case.
The indirect costs were not included.
Univariate sensitivity analyses were carried out to examine the robustness of the cost results to variations in the key model inputs. Multivariate sensitivity analyses were also performed. The ranges of values were derived from the literature as well as from experts' opinions.
Estimated benefits used in the economic analysis
The incidence of AREs was 25% with the C0 strategy and 18% with the C2 strategy.
There was a reduction of 0.42 days in the length of initial hospitalisation with the C2 strategy.
The NNTB for the C2 strategy compared with the C0 strategy was 15.
The first-year total costs per patient were Can$46,857 with the C0 strategy and Can$45,306 with the C2 strategy, with savings of Can$1,551 associated with C2. Cost-savings were mainly attributable to the reduced costs associated with the treatment of AREs, the avoidance of graft loss and the avoidance of return to dialysis. Savings were obtained despite a higher immunosuppressive cost.
In the 5-year model, the total costs per patient were Can$146,879 for the C0 strategy and Can$142,569 for the C2 strategy, resulting in a net savings of Can$4,310 for C2. The sensitivity analysis revealed that the most influential parameter for the cost-differences between the two strategies was hospitalisation time, followed by the risk of acute rejection and graft loss. However, the results of the sensitivity analysis suggested that the cost-savings associated with the C2 strategy were robust to variations in the model inputs. In general, the C2 strategy was always less costly than the C0 strategy. The exception was when the difference in days of initial hospitalisation was 1 additional day in the C2 strategy compared with the C0 strategy C0, then the cost-difference was Can$19 in favour of the C0 strategy (the threshold point occurred at 0.98 days).
Synthesis of costs and benefits
An incremental cost-effectiveness ratio was not actually calculated since the C2 monitoring strategy led to better outcomes and lower costs than the C0 strategy.
After renal transplantation, ciclosporin monitoring at 2 hours post-dose (C2 strategy) resulted in a reduction in untoward clinical events (acute rejection episodes and graft loss) and a decreased total treatment cost in comparison with trough concentration (C0) monitoring.
CRD COMMENTARY - Selection of comparators
The authors justified the choice of the comparators. In particular, C0 represented the traditional monitoring approach and C2 was the new monitoring strategy under examination. You should decide whether they are valid comparators in your own setting.
Validity of estimate of measure of effectiveness
The effectiveness evidence came mainly from published data. It was not stated whether a review of the literature was performed, and the primary studies appear to have been identified selectively. Some information on the primary studies was provided. The use of data derived from clinical trials ensured the validity of the clinical estimates. The issue of uncertainty around the clinical estimates was explicitly addressed and sensitivity analyses were carried out on the clinical inputs. Conservative assumptions were made to extend the results of 1-year trials to a 5-year analysis.
Validity of estimate of measure of benefit
The summary benefit measure was specific to the disease considered in the study and is not comparable with the benefits of other health care interventions. The authors stated that estimates of the impact of the interventions on quality of life were not available.
Validity of estimate of costs
The perspective adopted in the study was explicitly stated. As such, it appears that all the relevant categories of costs have been included in the analysis. However, the unit costs were not clearly reported separately from the quantities of resources used, which limits the possibility of replicating the analysis in other settings. A detailed breakdown of the cost items was not provided. The source of the data was reported. The resource use data were derived from a variety of sources. The costs were treated deterministically, but uncertainty in the economic estimates was investigated in a sensitivity analysis. The price year was stated, which aids reflation exercises in other settings. The authors noted that earlier studies had shown that C2 monitoring did not result in an increase in the indirect costs.
The authors stated that their findings were consistent with those from published studies, which were also used to validate the clinical output of the model. The issue of the generalisability of the study results to other settings was implicitly addressed in the sensitivity analyses, which enhance the external validity of the results. The authors stated that ranges wider than those observed in the literature were used in the sensitivity analysis in order to reflect greater uncertainty. The authors noted that the short time horizon of the model represented a limitation of the validity of the analysis.
Implications of the study
The study results supported the use of C2 monitoring after renal transplantation. The authors stated that access to more detailed patient-level data would permit further extensions to the time horizon of the model and the use of probabilistic sensitivity analyses to examine the robustness of the model results.
Source of funding
Funded by Novartis Pharma, Basel, Switzerland.
Keown P A, Kiberd B, Balshaw R, Khorasheh S, Marra C, Belitsky P, Kalo Z. An economic model of 2-hour post-dose ciclosporin monitoring in renal transplantation. PharmacoEconomics 2004; 22(10): 621-632
Other publications of related interest
The Canadian Neoral Study Group. Pharmacokinetics of Neoral during the first two weeks following renal transplantation. Transplantation 2001;72:1024-32.
Mahalati K, Belitsky P, West I, et al. Approaching the therapeutic window for cyclosporine in kidney transplantation: a prospective study. Journal of the American Society of Nephrology 2001;12:828-33.
Laupacis A, KeownP, Pus N, et al. A study of the quality of life and cost-utility of renal transplantation. Kidney International 1996;50:235-42.
Keown PA, Balshaw R, Krueger H, et al. An economic model of simulect in renal transplantation. Transplantation 2001;71:1573-9.
Subject indexing assigned by NLM
Adult; Cost-Benefit Analysis; Cyclosporine /economics /pharmacokinetics; Drug Monitoring /economics; Female; Graft Rejection /economics; Health Care Costs; Hospitalization /economics; Humans; Immunosuppressive Agents /economics /pharmacokinetics; Incidence; Kidney Transplantation /economics; Male; Middle Aged; Models, Economic; Predictive Value of Tests; Prospective Studies; Risk; Time Factors
Date bibliographic record published
Date abstract record published