|Randomized, prospective trial of cyclosporine monotherapy versus azathioprine-prednisone from three months after renal transplantation
|Hilbrands L B, Hoitsma A J, Koene K A
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.
Using cyclosporine monotherapy (CsA) or a combination of azathioprine (Aza) and prednisone (Pred) in patients receiving CsA and Pred during the first 3 months after renal transplantation.
Type of intervention
Secondary prevention and treatment.
Economic study type
Patients (aged under 65) having undergone renal transplantation, with no history of psychiatric disease or alcohol abuse, no history of malignancy, no signs of active hepatitis or carriage of hepatitis B surface antigen, without hemolytic uremic syndrome as original kidney disease, not using antiepileptic drugs, and not being allergic to Aza. In addition, patients were excluded if they had poor knowledge of the Dutch language.
Hospital. The economic study was carried out in The Netherlands.
Dates to which data relate
The resource use and effectiveness data corresponded to patients who underwent renal transplantation between June 1989 and June 1992. The prices used in the analysis were those prevailing in 1993-94.
Source of effectiveness data
Effectiveness data were derived from a single study.
Link between effectiveness and cost data
The costing was retrospectively undertaken on the same patient population as that used in the effectiveness analysis.
Power calculations were reported. For a postulated 2-year graft survival of 80% with Aza-Pred strategy, 80 patients allocated to each strategy were required to detect a 15% difference in graft survival with an 80% power. 236 patients underwent surgery and 185 of these were eligible for the study. The total number of patients available for randomization after three months of receiving CsA-Pred therapy after transplantation was 127. From that group 64 patients with an average age of 43 (13) years were randomly assigned to the CsA monotherapy at three months after transplantation, and 63 patients with an average age of 42 (14) years were allocated to the Aza-Pred group. 5 patients refused to participate in the study.
This was a randomized controlled trial carried out in a single centre. The median duration of follow-up with still-functioning grafts was 3.9 years (range: 2.7 - 5.6 years). The randomisation was carried out by the minimization method with "frequency matching" for the following characteristics: recipient's sex and age (boundary point, 40 years), presence of diabetes mellitus, type of previous renal replacement therapy (haemodialysis or continuous ambulatory peritoneal dialysis), history of previous transplantation, number of rejection episodes (0,1, or 2 and more), treatment with antithymocyteglobulin during the first three months, temporary interruption of CsA therapy (less than 10 or 10 and more days), graft function(creatinine clearance less than 50, 50-75, or more than 75 ml per minute), proteinuria (less than 0.1, 0.1-1.0, or more than 1.0 g/L), number of antihypertensive drugs (0, 1, 2, or 3 and more), and age of the donor (10 years or less, 11-50, or 51 and more).
Analysis of effectiveness
The analysis of effectiveness was based on the intention to treat principle. The primary health outcomes used in the analysis were graft functioning and survival (death with a functioning graft was considered as graft failure). The survival rates observed at one year and the estimated probabilities of graft survival at 5 years (by Kaplan-Meier method) were used as outcome measures. Graft functioning was represented by creatinine clearance levels (measured every three months). Event-free graft functioning and incidence of rejections were other outcome measures also reported. The groups were shown to be comparable in terms of demographic and clinical characteristics.
The 5-year graft survival probability was 78% in the intervention and 87% in the comparator groups, (p>0.05). Expected event-free survival at 5 years after transplantation was 48% for the intervention and 65% for the comparator, (p>0.05). For the comparator, the increase in estimated creatinine clearance was 19 (+/- 20%) (serum creatinine was reported to change from 151 (+/- 39) to 134 (+/- 34) micro mol./L at three and six months after transplantation, respectively) during the first three months after conversion (randomization). Over the same time period, the intervention group experienced a rise in creatinine levels of 7.5 (+/- 13.9%): serum creatinine level was reported to change from 158 (+/- 60) to 162 (+/- 46) micro mol./L at three and six months after transplantation, respectively. The p values of the changes were below 0.001 and 0.01, respectively. The values at 9 months after therapy conversion (1 year after transplantation) were 170 (+/- 49) micro mol./L for the intervention and 133 (+/- 34) for the comparator. p<0.001 for both intra-strategy (relative to values at 3 months after transplantation) and inter-strategy comparisons. The incidence of acute rejection within 4 weeks after therapy conversion was 3% in the intervention group, and 19% in the comparator group, (p=0.01).
The comparator resulted in health outcomes which were at least as good as those of the intervention, with a statistically significant improved graft functioning for the former relative to the latter.
Measure of benefits used in the economic analysis
No summary benefit measure was identified in the economic analysis, and only separate clinical outcomes were reported.
Costs were not discounted as they were calculated for the first year after transplantation. The resource quantities were not reported separately from the prices. The costs measured were those associated with operating costs (drugs, laboratory testing, anaesthesia, personnel) and cost of complications. The boundary adopted was the hospital. The cost estimation was based on actual data for patients who underwent renal transplantation between June 1989 and June 1992. The source of unit cost data was the hospital financial administration service (charges were used when reliable information on costs was not available), whereas data on resource use were obtained from medical records. The price date was 1993-1994. The analysis covered a period of one year after transplantation. The kidney acquisition costs were excluded from the analysis.
Statistical analysis of costs
Mean and standard deviations were reported. Wilcoxon's rank sum and signed rank test were used to compare the groups in terms of costs.
Dutch guilders (Dfl). The conversion rate was reported as Dfl 1 being about US$ 0.60.
No sensitivity analysis was conducted.
Estimated benefits used in the economic analysis
The average total treatment-related cost for the first year after transplantation for the intervention (CsA monotherapy) was Dfl 53,484(+/- 44,828), and for the comparator (Aza-Pred therapy) was Dfl40,882 (+/- 18,895), (p<0.05).
Synthesis of costs and benefits
The costs and benefits were not combined since the comparator (Aza-Pred therapy) turned out to be the weakly dominant strategy (with equal efficacy and lower costs).
The conversion to Aza-Pred three months after renal transplantation results in better graft functioning and lower costs than the conversion to CsA monotherapy after gradual withdrawal of Pred and reduction in the CsA dosage. Due to the high incidence of graft rejections none of these strategies offer a safe strategy to reduce the long-term side effects of CsA and Pred (the drug regimen used for the first three months after surgery) to a minimum.
CRD COMMENTARY - Selection of comparators
A justification was given for the choice of the comparator in that it was the standard therapy in the context in question in the study institution. You, as a database user, should consider whether this is a widely used health technology in your own setting.
Validity of estimate of measure of benefit
The internal validity of the study results is likely, given the study design used, the control of important prognostic factors and demographic characteristics, and the definition of primary outcomes chosen. However, one potential flaw in the study is the relatively small sample size.
Validity of estimate of costs
The quantities of resource use were not reported separately from the prices. However, adequate details of cost estimation were reported. The indirect costs and kidney acquisition costs were omitted from the analysis.
The issue of generalisability to other settings or countries was not addressed. The results were not presented selectively.
Source of funding
Supported by a research grant from Sandoz, Basel, Switzerland.
Hilbrands L B, Hoitsma A J, Koene K A. Randomized, prospective trial of cyclosporine monotherapy versus azathioprine-prednisone from three months after renal transplantation. Transplantation 1996; 61(7): 1038-1046
Subject indexing assigned by NLM
Adolescent; Adult; Aged; Azathioprine /administration & Blood Pressure /drug effects; Child; Cyclosporine /therapeutic use; Drug Therapy, Combination; Female; Health Care Costs; Humans; Immunosuppressive Agents /therapeutic use; Kidney Transplantation; Male; Middle Aged; Prednisone /administration & Prospective Studies; dosage; dosage
Date bibliographic record published
Date abstract record published