1 Division of General Internal Medicine, University of Pennsylvania, Philadelphia, PA, 2 Center for Clinical and Genetic Economics, Duke Clinical Research Institute, Durham, NC, 3 University of Michigan Medical Center, Ann Arbor, MI, 4 Novartis Pharmaceuticals, East Hanover, NJ, USA
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Abstract |
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Methods. A multi-centre open-label clinical trial was conducted among renal transplant recipients in the US, in which patients were randomized into two induction therapy regimens: basiliximab and antithymocyte globulin (ATG) as part of a quadruple immunosuppressive regimen. Medical resources used and a EuroQol visual analogue scale (VAS) rating of quality of life were collected prospectively for the 135 dosed subjects for a period of 1 year post-treatment. We analysed the differences between treatment groups in 1-year costs and 1-year quality-adjusted survival. We also conducted a post hoc analysis of outcomes among the subgroup of patients identified as high risk.
Results. A significant difference was observed in first-year post-treatment costs (basiliximab, $45857; ATG, $54729; difference, $8872 (95% CI, $1169 to $16573). The savings from basiliximab can be attributed to the less expensive induction therapy (basiliximab, $2378; ATG, $8670; difference, $6292 (95% CI, $5165 to $7419)) and other savings during the initial hospitalization totalling $2609. One-year quality-adjusted survival was the same in both groups (basiliximab, 81.5; ATG, 81.1; difference, 0.45 (95% CI, -5.9 to 6.8)). The results of the post hoc analysis of the 48 high-risk patients were comparable to the analysis of all patients.
Conclusions. These results demonstrate lower first-year post-treatment costs in renal-transplant recipients receiving basiliximab compared to ATG with no differences in quality-adjusted survival. The results also suggest similar differences among high-risk subjects.
Keywords: cost and cost analysis; cost effectiveness; immunoprophylaxis; immunosuppressive agents; kidney transplant; quality of life
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Introduction |
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Basiliximab is a chimeric monoclonal antibody that exerts its immunosuppressive activity by binding to the 55-kDa chain of the IL-2 receptor with an affinity approximating that of IL-2 itself. It competes with IL-2 and inhibits IL-2-driven proliferative responses to antigens and mitogens. Studies have shown basiliximab to be an effective immunoprophylactic in kidney transplantation [2]. Basiliximab is indicated in combination with CsA and corticosteroids for the prophylaxis of organ rejection in renal transplant patients. Unlike other induction therapies that require several doses given over a period of weeks [3,4], basiliximab is administered only twice, once within 2 h before surgery and again 4 days post-transplantation. It has been hypothesized that reductions in both the number of doses required and the shorter dosing period leads to a reduction in health care resource use and possibly to an improvement in subjects' health-related quality of life. The objective of the present study was to determine whether basiliximab demonstrates these economic and quality of life advantages over a polyclonal antithymocyte antibody preparation, equine antithymocyte globulin, in a US multi-centre, open-label trial in adult renal transplant recipients.
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Subjects and methods |
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The patients studied were all those for whom there was at least one dose of study medication given. Three patients were randomized to treatment but not dosed because either they lacked venous access, had a peri-operative myocardial infarction, or the study closed prior to transplantation. The study sample had 70 patients in the basiliximab arm and 65 patients in the ATG arm. Follow-up of patients continued for 12 months from the date of transplantation or until death, whichever was earlier.
The clinical results showed no statistically significant differences between basiliximab and ATG for acute clinical rejection (33% basiliximab, 32% ATG), biopsy-proven acute rejections (19% basiliximab, 18% ATG), second transplants (7% basiliximab, 9% ATG), delayed graft function (23% basiliximab, 34% ATG), 6-month survival (94% basiliximab, 97% ATG), and 1-year survival (94% basiliximab, 98% ATG). These results are shown elsewhere [5].
Measurements
Resource use. Data characterizing resource use were prospectively collected for each patient in the study for the initial hospitalization, for subsequent transplant-related rehospitalizations, for outpatient visits, and for medication use in inpatient and outpatient settings. For the initial hospitalization and for subsequent hospitalizations, data on the length of stay, days in the ICU, and procedures were collected. Bills for the initial hospitalization were collected from 40 patients. For outpatient visits, the date of each visit, the reason for the visit, and the procedures performed were recorded. For drug use, names, dosages, and duration of use were recorded.
Health-related quality of life. At baseline, day 4, and weeks 1, 2, 4, 12, 24, and 52, patients completed the visual analogue scale (VAS) from the EuroQol instrument. This scale represents a preference-based measure of health-related quality of life. It is a global health state evaluation that requires the patient to locate their current health state on scale ranging between 0 (Worst imaginable health state) and 100 (Best imaginable health state). The EuroQol has been viewed as a patient preference measure in other clinical trials [6].
Valuation of resource use
Costs from hospital bills. Hospital bills were used to represent the costs of the initial hospitalization (excluding physician fees and study medications that do not appear on the bills). When bills were available (40 patients), total charges were used, when bills were unavailable (95 patients) total charges were estimated using a linear regression imputation technique. Billed hospital charges included all charges from the date of randomization until the date of discharge (organ acquisition costs were incurred prior to randomization). The estimation of charges for those without bills was based on the services used during the hospitalization: length of stay in regular hospital ward, squared length of stay in regular hospital ward, length of stay in intensive care unit (ICU) and hospital drug costs. The R2 for the imputation regression was 0.77. Charges were converted to costs using a hospital-wide Medicare cost to charge ratio [7]. For a complete accounting of costs during the initial hospitalization we added separate estimates of physician fees and costs of the immunosuppressive drugs and study drugs, since these medications were supplied without cost by the sponsor in the trial.
Costs from physician fees. Physician fees incurred during the initial hospitalization are not billed by the hospital and hence were estimated separately. Costs were estimated for regular physician visits and for the time required to perform procedures using the reimbursement amounts developed for the United States Medicare system by the Health Care Financing Administration. The Physicians Current Procedural Terminology (CPT) is used to define physician procedures for reimbursement. We defined the level of service by the physician on day 1 as comprehensive (CPT=99215) and on subsequent days as limited (CPT=99213). Physician fees for procedures are also coded based on the Work Relative Value Units (RVUs) for the CPT codes of the procedures performed. Work RVUsxCost per RVU ($38) were used as the estimate of the cost of physician time [8].
Study drugs. The total doses of study drug per patient were recorded in their respective case report forms (CRFs). The costs for basiliximab and antithymocyte globulin were calculated based on average wholesale prices (AWP). The price of basiliximab was $1224 per dose and the price of antithymocyte globulin was $262.24 per 250 mg ampoule [9].
Other drugs. The daily cost of other immunosuppressant drugs were determined by the sum of the product of the average cost per day and the total daily dose for each drug. Average cost per day were estimated using 1997 AWPs. For all drugs, it was assumed that the generic was given if available during the time of the study. A separate itemization of costs for non-immunosuppressive drugs taken during the initial hospitalization were not included because the cost of these drugs were included in the hospital bills.
Cost of rehospitalizations. The cost of rehospitalizations were estimated by coding a Diagnosis Related Group (DRG) for each reason for rehospitalization and then multiplying the days of the rehospitalization by the average cost per day of that particular DRG. Average cost per day was estimated as the Medicare reimbursement divided by the average total days [10].
Outpatient costs. Outpatient costs were estimated as the sum of procedure costs, doctor visits, and drugs. Procedure costs were estimated by using the Total RVUxCost per RVU ($38) for each procedure. Visits were coded as a limited level 3 visit and the corresponding RVU was used to cost that visit. Average cost per day for non-immunosuppressant drugs were estimated using 1997 AWPs and the usual adult dose for each drug.
Analysis
Patient characteristics. For each of the treatment groups we reported means (continuous variables) and percentages (categorical variables) for the set of potential predictors of costs and outcomes measured when patients were randomly assigned to one of the two treatment groups. We also reported the P value from the parametric test of differences between the two treatment groups.
Resource use. For each of the treatment groups, means of resources used by type of resource are reported. The difference in mean resource use between the groups and the 95% CI pertaining to that difference are also reported.
Costs. Costs were analysed using univariate and multivariate analysis. For the univariate analysis, costs are reported in 1997 dollars for each component of costs. The costs for each treatment group, the difference in costs between treatment groups and the 95% CI pertaining to that difference are also reported. Costs were analysed using ordinary least-squares regression. Given the tendency of the cost distribution to be skewed, we estimated two regression specifications, one using total costs as the dependent variable, and the other using the log of total costs, to insure our estimates were not sensitive to distributional assumptions. Prior to the analysis, the criteria of lowest mean squared error was established to select the regression to be reported as the primary analysis and the regression to be reported as sensitivity analysis. The regression of total costs was used to represent the primary analysis given its lower mean squared error; however, both results are reported as a sensitivity analysis.
Quality of life. EuroQol VAS scores were adjusted for survival by entering a score of zero for the interviews missed because of death. We included means, standard errors, and comparisons of mean scores at baseline, at day 4, and at 1, 2, 4, 12, 24, and 52 weeks. The quality-adjusted survival curve was estimated for the year since treatment by multiplying survival probability by the mean VAS score at each follow-up interview. The total 1-year quality-adjusted life year was estimated as the area under the quality-adjusted survival curve.
Statistical tests. For tests of differences between treatment groups, t-tests and rank-sum tests were used for the continuous variables and chi-squared tests and Fisher's exact tests were used for the categorical variables. The P value of the t-tests and chi-squared tests and whether the inference drawn regarding statistical significance differs between the parametric and non-parametric tests are reported. All tests were two-sided and a P value of 0.05 was the threshold for significance.
Subgroup analysis by risk group. An exploratory analysis was performed on high-risk and low-risk patients. The high-risk subgroup was defined as the set of patients who were either African Americans, had panel-reactive antibodies (PRA) >30% at baseline or had a cold ischaemia time >24 h. All other patients are considered to be low risk. Differences in costs and quality-adjusted survival between the treatment groups were tested by repeating the analyses described above on these two subgroups.
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Results |
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Demographic variables were similar for both treatment groups as shown in Table 1. The sample was 58% male and the racial composition was as follows: 81% Caucasian, 16% Black, and 3% Other. The only notable difference is the average age of study patients: 45 years in the basiliximab group and 50 years in the ATG group.
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Resource use
The longer length of stay during the initial hospitalization for the ATG group was not statistically significant (9.0 vs 8.2 days; 95% CI, -0.9 to 2.5). The ATG group had more rehospitalizations (1.7 vs 1.4; 95% CI, -0.24 to 0.83), and outpatient visits (3.0 vs 2.3; 95% CI, -0.3 to 1.7) and the basiliximab group had more patients on dialysis (8 vs 7) and more dialysis days (1.21 vs 1.04; 95% CI, -1.36 to 1.69). Differences between treatment groups of individual resource items were not statistically significant.
Costs
Table 2 lists, by treatment group, total univariate costs and detailed costs for initial hospitalization and post-discharge. Total costs were higher in the ATG group. Univariate costs were $54729 in the ATG group and $45857 in the basiliximab group for a difference of $8872 (95% CI of $1169 to $16573). This difference was driven entirely by the difference in costs during the initial hospitalization. The lower cost per treatment course of basiliximab compared to antithymocyte globulin resulted in a savings of $6292 per patient (95% CI, $5165 to $7419). The other costs incurred during the initial hospitalization resulted in a savings of $2609 (95% CI, -$2362 to $7581). The differences in other hospital costs are driven by the length of stay and not costs per day; the per-day non-therapy hospital costs are virtually identical in the two treatment groups ($2959 basiliximab and $2989 ATG). Post-discharge costs were virtually identical in the two treatment groups. After adjusting for the six patients lost to follow-up, the post-discharge costs were $19183 and $19213 in the ATG and basiliximab groups respectively for a difference of -$30 (95% CI, -$4757 to $4697).
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Quality of life
The VAS scores for each treatment group by time are shown in Table 3. For both groups, VAS scores are nearly identical at baseline. For ATG the quality-of-life scores rise from 68 to 81 in the first month and for basiliximab the quality-of-life scores rise from 67 to 80 in the first month. After the first month, the scores are consistently in the low eighties for both groups. There are no statistically significant differences in quality-of-life scores at any point in time during the first year.
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Subgroup analysis
High-risk patients
There were 24 high-risk patients in the ATG group and 24 high-risk patients in the basiliximab group. The total 1-year cost of treatment was $59258 for the patients in the ATG group and $46035 for the patients in the basiliximab group for a cost difference of $13223 (95% CI, $409 to $26577). After adjusting for severity of the patients in the two groups using multivariate analysis, the cost difference increased to $18188.
The quality-adjusted life year was 80.0 in the ATG group and 76.2 in the basiliximab group for an outcome difference of 3.8 (95% CI, -9 to 17). While not statistically significant, this is a substantial difference, given the small sample sizes. However, this difference can be explained entirely by the higher baseline severity of the basiliximab high-risk group. Their baseline VAS scores were 70.5 compared with baseline VAS scores of 73.3 for the ATG group.
Low-risk patients
There were 41 low-risk patients in the ATG group and 46 low-risk patients in the basiliximab group. The total 1-year costs of treatment was $51690 for the patients in the ATG group and $46010 for the patients in the basiliximab group for a cost difference of $5686 (95% CI, -1555 to 4194). Severity adjusted results are very similar. Drug costs explain the entire cost difference with the drug therapy costing $8257 in the ATG group and $2786 in the basiliximab group. There were no differences in quality of life.
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Discussion |
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Basiliximab has been shown to decrease acute rejection episodes in the first year after renal transplantation in the context of addition to a double-therapy regimen of CsA and prednisone [2,11]. A meta-analysis showed an improvement in allograft survival when receiving antilymphocyte antibody as induction therapy in addition to triple-therapy regimen of CsA, azathioprine, and prednisone, yet no single randomized clinical trial showed a statistically significant effect [12] and the addition of basiliximab to a triple therapy of CsA, MMF, and prednisone has not been studied to the same extent. This clinical study offers evidence that the addition of basiliximab to a triple-therapy regimen is very well tolerated. Yet the need for antibody induction therapy has been debated for some time [13].
With regard to the polyclonal antilymphocytic agents and OKT3, the literature would support the use of antibody induction in certain high-risk groups (e.g. African Americans, high PRA, and re-transplants) [14]. The exploratory analysis of high-risk patients in this paper suggests substantial savings can be realized with basiliximab over ATG. Savings are also realized with basiliximab over ATG among low-risk patients; however, routine induction in lower risk groups is controversial as to the risk/benefit ratio (decreased rejection vs increased infection and cost). Further study as to whether the benefits of induction outweigh the risks among low-risk patients is needed.
Limitations
The patients in the ATG arm were administered horse ATG, as rabbit ATG had yet to be approved when the study was initiated. This study does not address the question of whether the cost advantages of basiliximab over ATG would remain if rabbit ATG were used instead of horse ATG. We note that even if drug costs for rabbit ATG are 2030% less than horse ATG (same cost per vial, but rabbit ATG may be given at a lower dose or for a shorter duration [9]), the cost advantage of basiliximab would be in the range of $6000 to $7000 and even larger for the high-risk patients. The evidence of efficacy differences between rabbit and horse ATG from clinical trials [1517] suggest graft survival rates may be higher with rabbit ATG, although this finding was not statistically significant.
A second limitation was related to data collection. Inpatient billing data were collected from only one treatment centre to develop the costs for the initial hospitalization, although these cost data were applied to all study patients. While information from one centre may not be representative of all hospitals in this study, the detailed information we collected about the costs of treatment from that centre improved the precision of our cost estimates.
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Conclusion |
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Acknowledgments |
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Notes |
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References |
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