The Cost Effectiveness of Mycophenolate Mofetil in the First Year after Primary Cadaveric Transplant

Transcription

1 The Cost Effectiveness of Mycophenolate Mofetil in the First Year after Primary Cadaveric Transplant SEAN D. SULLIVAN,* LOUIS P. GARRISON, JR., JENNIE H. BEST,t and MEMBERS OF THE U.S. RENAL TRANSPLANT MYCOPHENOLATE MOFETIL STUDY GROUP *Depart,ne,its of Pharmacy and Health Services, University of Washington, Seattle, Washington; and tglobal Pharinacoeconoinic Research, Roche Pharmaceuticals, Palo Alto, California. Abstract. Mycophenolate mofetil (MMF) has been shown to reduce the incidence of acute graft rejection in three controlled trials of cadaveric renal transplantation. In a U.S. trial using quadruple sequential induction therapy as control, the MMF 2-g treatment group had an acute rejection rate 40.6% lower than control in the first posttransplant year (27.9% MMFtreated versus 47.0% control). The purpose of this analysis is to evaluate the economic implications of these clinical differemces. The analysis relies on resource use data from the trial and other sources. Medical costs were estimated using a societal perspective and excluded the cost of the transplant procedune and organ acquisition. The two groups were compared in terms of treatment for acute rejection and opportunistic imfectiom, graft survival, dialysis use, and maintenance immunosuppression. The results suggest that, on average, when compared with standard therapy, patients treated with MMF are likely to have lower rejection-related treatment costs because of a lower incidence of rejection ($6237 versus $3702), lower dialysis and graft failure costs because of improved graft survival ($20,104 versus $16,972), no difference in opportunistic infection treatment costs ($1962 versus $1962), and higher additional immunosuppression costs ($855 versus $5 1 70). Taken together, these results suggest that patients treated with MMF are, on average, likely to have slightly lower first-year costs ($29,158 versus $27,807) compared with control, indicating that MMF treatment is cost-effective in the first year. These results remaimed stable under sensitivity analyses, with plausible variatiom in the rates of acute rejection, graft survival, and infection. (J Am Soc Nephrol 8: , 1997) In 1996, an estimated 33 1,8 15 patients were treated for endstage renal disease (ESRD) in the United States, up from 279,282 in I 994 ( I ). Life expectancy and the quality of life of chronic kidney failure patients have improved dramatically because of dialysis and kidney transplantation, but not without substantial costs. These two treatment modalities generated medical costs of approximately $10 billion nationally in 1996 (1). These costs are shared by all U.S. citizens through the federally funded Medicare program (which provides insurance benefits for more than 92% of people on dialysis treatment and 93% of renal transplant recipients) and the private health insurance industry. Annual dialysis treatment costs per person in 1995 averaged approximately $50,000, and the average costs of renal transplantation, kidney acquisition, and maintenance care during the first year approached $103,000, of which about $65,000 is spent for the initial transplant procedure and related care (1). Recent analyses have shown that transplantation is more cost- Received February Accepted April 22, See Appendix for participating investigators and affiliated organizations. Correspondence to Dr. Sean D. Sullivan, School of Pharmacy. Box , University of Washington, Seattle, WA / $03.00/0 Journal of the American Society of Nephrology Copyright by the American Society of Nephrology effective than dialysis, despite greater first-year costs. These studies conclude that the cost advantage favors transplantation, as long as average graft survival exceeds 4 to 5 yr (2-5). New immunosuppressive agents that reduce the incidence of acute rejection and improve graft survival represent important therapeutic advances for transplant recipients. Previous economic models have shown that the costs of adding agents such as cyclosporime to a maintenance immunosuppression regimen are offset by reductions in rejection-related hospital stays duning the first year after transplantation, thus making tnansplantation more cost-effective than dialysis (6-8). Of course, the limited supply of donor organs reduces the likelihood that cost-effective transplantation will be available to all ESRD patients. Indeed, in 1995 more than 28,883 mdividuals were on the waiting list for kidney transplantation (1). To take full advantage of a limited organ supply, it has become increasingly important to improve the effectiveness of transplantation with better immunosuppressive therapy. Mycophenolate mofetil (MMF; CellCept#{174} Roche Pharmaceuticals, Palo Alto, CA) was recently introduced in the United States as a new agent to be used in combination with cyclosporine and corticosteroids for the prophylaxis of organ rejection in patients receiving allogeneic renal transplants. Data from a U.S. quadruple therapy induction trial demonstrated a statistically and clinically significant reduction in the incidence of biopsy-proven acute rejection or treatment failure at 6 mo (47.6% in the control group versus % in the MMF 2-g treatment group [P = ]) (9). In addition, there was some

2 Economic Evaluation of MMF 1593 indication that the use of MMF may be associated with improved graft survival in the first year. In today s cost-conscious climate, however, clinical superiority alone is often not sufficient for the adoption of new technologies. Expenditures for new medical care treatments, including innovations in dialysis and transplantation, are under increasing scrutiny by health insurers and managed care onganizations. In the case of immunosuppressive agents, health insurers are demanding evidence of significant clinical benefits in terms of reducing acute and/or chronic rejection and improving graft and/or patient survival before they will consider adopting the new therapy. Although it is not possible to determine definitively what the actual financial impact of any new technology will be, economic analysis offers a way to estimate the likely effects of a new treatment before it is used in clinical practice. The purpose of this article is to estimate the economic consequences of improved clinical outcomes of renal transplantation in MMF-treated patients and to compare these data with control (standard regimen) patients from the same trial. The analysis focuses on the first posttransplant year-the period for which clinical trial data are available. A discussion of the potential long-term economic implications of MMF therapy is also presented. Materials and Methods Medical costs and effectiveness of the recommended dose of MMF (1.0 g twice daily) were compared with a standard regimen that included azathioprine (1 to 2 mg/kg per d) for the prevention of acute rejection after primary cadaveric renal transplantation in the United States, using an economic evaluation model constructed to reflect the clinical and economic components of patient care in the first yean after transplantation. The model excludes the costs of organ acquisition and the transplant procedure itself. Included in the evaluation were: (1) the financial impact associated with a difference in the incidence and treatment of acute rejection; (2) the financial impact associated with a difference in graft survival and related dialysis costs; (3) potential cost differences in adverse event treatment incidence and treatment-related costs; (4) direct cost savings from azathioprine replacement; and (5) the additional cost of MMF therapy. (The base case economic model and accompanying calculations and annotations are available upon request from the primary author.) The perspective is that of society; costs are in 1995 U.S. dollars. The analysis considers the impact on patient quality of life by adjusting for patients rating of health status under transplantation versus dialysis. Data Sources A randomized, controlled 14-center quadruple-induction therapy trial (n = 499) served as the primary source of clinical and medical resource use data for this study. The trial compared two dosage levels of MMF ( 1.0 g twice daily and 1.5 g twice daily) and treatment with azathioprine (standard therapy). Subjects in each of the three treatment groups were administered cyclosporine, corticosteroids, and antithymocyte globulin sequential induction therapy. The clinical results have been reported previously (9). For the economic analyses, clinical trial data from patients treated with the Food and Drug Administration-approved 2-g (I g twice daily) dose of MMF were compared with data of patients treated with azathioprine. Treated acute rejection rates, graft failure rates, and medical care utilization data obtained directly from the U.S. trial were used as inputs to the economic analysis. Additional data were obtained from American Hospital Association annual reports (hospital per diem cost estimates); Medicare End-Stage Renal Disease program reports (annual dialysis and functioning graft expenditures); and literaturebased patient preference (utility) estimates. Medical care utilization data, including length of hospital stay, rejection-related treatments, and cytomegalovirus (CMV) infection treatments were obtained prospectively as part of the U.S. clinical trial. The annual costs of dialysis and maintenance for a functioning graft were obtained from the most recent Medicare ESRD program data published by the Health Care Financing Administration. The societal cost of an inpatient day for a typical large, tertiary care hospital was based on published 1994 American Hospital Association annual data (adjusted to 1995 values) and included an estimate of clinician time (10). Costs for outpatient rejection treatment services were estimated from a sample of data obtained from a large Midwestem transplantation center. Physician services data were derived from the Medicare Resource-Based Relative Value System fee schedule. The one-time cost of graft loss, including donor nephrectomy, was obtained from ESRD program data on annual hospital use for patients experiencing graft loss. The mean daily cost per milligram of azathioprine, IV steroids and oral steroids, and antilymphocyte therapy was calculated using 1995 IMS National Prescription Audit data. The mean daily retail cost of MMF was obtained from the manufacturer and adjusted to reflect an estimated 20% mark-up on ex-manufacturer price to the retail level. Unit cost estimates for all medical inputs are given in Table 1. This analysis did not include cost estimates of the initial transplantation procedure, surgical fees, or organ acquisition (including donor nephrectomy), because these were not expected to differ between treatment groups. It also did not include estimates of indirect financial impacts (e.g., due to work loss or productivity declines). Clinical and Economic Endpoints The primary efficacy endpoint from a clinical perspective was biopsy-proven rejection or treatment failure within the first 6 mo after transplantation. Treatment failure was defined as graft loss, death, or premature withdrawal from the study for any reason without prior biopsy-proven rejection. From an economic perspective, however, not all treatment failures represent equivalent outcomes, and biopsyproven rejection may not be the best gauge of usual care practice. Patients actually treated for rejection will generate additional resource costs regardless of whether their rejection is confirmed by biopsy. Thus, for the economic evaluation, treated (rather than biopsy-proven) acute rejection while on study drug was the primary endpoint. The treated acute rejection rate was defined as the proportion of patients receiving administration of 3 or more d of IV steroid therapy or 1 or more d of antilymphocyte therapy, regardless of biopsy status. The primary clinical efficacy endpoint, therefore, may be viewed as a conservative, composite measure that is a useful way of combining the major study outcomes in an intent-to-treat framework. The endpoint for economic evaluation is an operational definition that should approximate clinicians reported rejection rates, making it the more economically relevant endpoint for this analysis. Graft Failure Improved graft survival reduces costs in that ongoing dialysis or retransplantation is more expensive than the cost of maintaining a functioning graft. Furthermore, there is an expectation based on historical data that differences in graft survival are related, in part, to

3 1594 Journal of the American Society of Nephrology Table 1. Unit cost estimates (1995 U.S. dollars) Item Cost Source Inpatient per day $1215 AHA Annual Summary Inpatient physician fee $90.00 Medicare fee schedule Outpatient transplant clinic visit $150 Midwestern Transplant Center Daily antilymphocyte therapy (OKT3) $535 IMS National Prescription Audit Daily azathioprime (drug only) $2.59 IMS National Prescription Audit Daily IV steroid (drug only) $0.78 IMS National Prescription Audit Daily MMF (drug only) $15.00 Roche, 20% retail mark-up One-time cost of graft failure $19,575 HCFA ESRD Annual Report Monthly cost of dialysis patients $4793 HCFA ESRD Annual Report Monthly cost to maintain functioning graft $ HCFA ESRD Annual Report a AHA, American Hospital Association; MMF, mycophenolate mofetil; HCFA, Health Care Financing Administration; ESRD, end-stage renal disease. differences in acute rejection. Data from the United Network for Organ Sharing (UNOS) on 3 1,896 transplant recipients indicate that patients with at least one rejection episode in the first 6 mo had, on average, a 72% graft survival rate at the end of the first year. Patients who did not experience a rejection episode within 6 mo had a 1-yr graft survival rate of 95% ( 1 1). During the clinical study, 16 standard regimen patients (9.8%) and seven MMF 2-g patients (4.2%) experienced graft failure within the first year. Of these, I I standard regimen and six MMF patients lost their graft because of rejection (9). Overall, then, approximately five to six additional grafts per 100 patients were lost in the standard regimen control group compared with the MMF group. Adverse Events The incidence of adverse events was determined on the basis of a clinical evaluation of the safety summary data from the U.S. controlled clinical trial. The incidence and types of adverse events were similar between the MMF 2-g (daily) and control treatment groups, with the exception of a higher incidence of diarrhea, certain other infrequent gastrointestinal adverse events, and clinically important leukopenia among the MMF patients (9). These types of adverse events are unlikely to produce major cost differences between the groups because they can generally be managed by dose adjustment or with low-cost medications. Our analysis focuses on only those adverse events that may lead to costly treatment. The clinical trial summary publication (9) reports that, on an intent-to-treat basis, the percentage of patients with CMV viremia/ syndrome was slightly lower in the MMF I.0-g twice daily group compared with the standard regimen group (14.5% versus 15.2%), whereas the percentage with CMV tissue invasive disease was higher in the MMF group (9. 1% versus 6.1%). These differences, although not statistically significant, might be clinically and economically important because they involve complicated and expensive treatments. To identify the potential economic consequences of these differences, an evaluation of the relative frequency of CMV disease leading to treatment with ganciclovir in both the azathioprine and MMF treatment groups was undertaken. In addition, an assessment of the patterns and cost of care (including hospitalization) for ganciclovir-treated patients with CMV disease was performed. The use of ganciclovir by the clinical centers was not determined by the trial protocol and therefore was assumed to reflect standard center practice. Early Termination An analysis of premature withdrawals from the U.S. trial showed that there was little difference in the rate of early termination between the two treatment groups (19.3% standard therapy versus 15.6% MMF), particularly with respect to incidence and type of adverse events (5.4% in both treatment groups). There was, however, a greater rate of termination in the standard regimen treatment group (8.4%) compared with the MMF group (2.4%) due to an unsatisfactory therapeutic response. The acute rejection experience of patients who terminated early is reflected in the overall differential in the treated rejection rate between the two study groups. Because patients who terminated prematurely were not followed for incidence of rejection or rejection treatment after their termination date, the estimates of the rejection treatment patterns are based primarily on patients who remained on study drug for at least 6 mo. Although there could be some potential bias related to this, the direction of the bias is not clear, and the size of the bias is likely to be small and inconsequential in terms of the overall results. Results Trial results showed that the treated acute rejection rate after primary cadaveric renal transplantation was 40.6% lower after 12 mo with the (1 g twice daily) MMF regimen compared with the standard regimen (27.9% versus 47.0%). This represents a % absolute reduction in acute rejection. (These rates indude all enrolled patients until either premature termination or 12 mo on study drug, whichever came first.) For patients who remained on the study drug for at least 6 mo and who were treated for rejection, the mean number of steroid treatments per person was 1.07 (mean duration, 4.4 d) and the mean number of antilymphocyte treatments per person was 0.47 (mean duration, 10.5 d). The first-year economic impact of substituting MMF for azathioprine as part of a quadruple therapy prevention regimen of cyclosporine, corticosteroids, and sequential induction was estimated in terms of the cost of treating acute rejection episodes, potential differences in graft survival leading to reductions in dialysis and graft failure treatment costs, differences in adverse event treatment costs, azathioprine cost savings, and the cost of adding MMF (Table 2).

4 Economic Evaluation of MMF 1595 Table 2. Summary of mean per person first-year economic impacts (1995 U.S. dollars): Base cas& Components Standard Regimen Rejection treatment costs $6237 $3702 MMF Graft failure and subsequent $20,104 $16,972 dialysis costs Replacement of azathioprine $885 $0 CMV disease treatment costs $1962 $1962 MMF retail price $0 $5170 Total first-year costs $29,158 $27,807 a CMV, cytomegalovirus. Other abbreviations as in Table I. These results suggest that, compared with standard therapy, patients treated with 2 g of MMF are likely to experience: (1) lower annual rejection-related treatment costs because of improvement in the nate of acute rejection; (2) lower annual dialysis treatment costs because of improved graft survival; (3) no difference in annual opportunistic infection treatment costs; and (4) higher annual immunosuppression costs. Overall, the mean per person first-year cost was $27,807 in the MMF group compared with $29,158 in the standard quadruple regimen group-a 4.6% cost reduction. Extrapolated to a hypothetical cohort of 100 transplants, the estimated cost savings would be approximately $ 135, 100 in the first year after transplantation. By this analysis, treatment with MMF is a dominant therapy in terms ofcost effectiveness, i.e., showing improved health outcomes at reduced cost. Sensitivity Analyses To test the impact of different assumptions about clinical effectiveness and safety on these economic estimates, several sensitivity analyses were conducted by varying assumptions about acute rejection, graft failure rates, and the incidence of CMV infection and the possible use of preemptive therapy with ganciclovir. Differences in 1-Yr Acute Rejection. From a clinical perspective, the most important element of the model is the acute rejection rate. To test the sensitivity of the results to variation in this parameter estimate, the MMF treatment group presumptive acute rejection rate was varied by ± 10 and 20% of the base case estimate (Table 3). A 10% reduction in the MMF acute rejection rate resulted in a smaller (5.8%) incremental difference in annual costs between the two treatment groups. As the absolute difference in the rejection rate becomes smaller between the two treatment groups, the first-year cost savings for this component are correspondingly reduced. Differences in 1-Yr Graft Failure. Because the clinical trial was not designed to have sufficient power for statistical assessment of the difference in graft failure at 1 yr and because the base case assumption of the difference in graft failure between the two treatment arms (5.6%) was derived from the trial, an assumption had to be made about whether the observed difference was plausible, given the known association between acute rejection and graft survival. To assess this, an estimate of expected graft failure was derived using UNOS data on 1-yr graft survival as a function of rejection history and the observed acute rejection rates from the U.S. trial. From this information, the percentage of patients with a functioning graft at the end of the first year of treatment was estimated to be 84.8% (standard regimen) and 893% (MMF), a 4.5% absolute difference. This difference is consistent with, yet more consenvative than, the U.S. trial estimate of a 5.6% absolute difference. Our sensitivity analyses use a range of values that include the UNOS-derived estimate, as well as a no-difference assumption between the two treatment groups. For the base case, the first-year mean number of days of graft survival were estimated from trial data to be and in the standard regimen and MMF regimen groups, respectively. Total graft loss in the base case analysis, including death with function and graft failure, was estimated to be 12.2% in the standard regimen group and 8.4% in the MMF group. The average conditional probability of death given graft failure was 19.0% in the standard regimen group and 29.0% in the MMF group. Mean time to graft failure, to death following graft failure, or to death with a functioning graft were estimated from trial data to be 2. 17, 1.94, and 3.50 mo, nespectively, for the standard regimen group and 4.87, 3.45, and 3.20 mo, respectively, for the MMF group. When the absolute difference in graft failure was decreased Table 3. Sensitivity analyses of acute rejection and graft failure rates on first-year costsa Item Standard Regimen MMF Cost Difference Base case $29,158 $27, % acute rejection rate (base case) (47.0%) (27.9%) MMF rejection rate +20% $29,158 $28, % MMF rejection rate +10% $29,158 $28, % MMF rejection rate - 10% $29,158 $27, % MMF rejection rate -20% $29,158 $27, % graft failure rate (base case) (9.8%) (4.2%) absolute difference of 4.5% (UNOS) $29,158 $28, % absolute difference of 0.0% $29,158 $30, % a UNOS, United Network for Organ Sharing. Other abbreviations as in Table 1.

5 1596 Journal of the American Society of Nephrology from the base case value to the value derived from the UNOS calculation (4.5%), the overall financial impact remained in favor of the MMF treatment arm, with the average estimated difference being $956 less for MMF patients (versus standard regimen) in the first year. Given that acute rejection is an important cause of early graft failure, new immunosuppressive regimens that reduce acute rejection would generally be expected to improve overall graft survival, unless graft failures due to other causes increase. Due to the high cost of dialysis treatment, some improvement in graft survival is an important factor in the overall economic impact of a new immunosuppressive regimen. For example, an assumption of no difference in graft sunvival between the two groups would eliminate any economic benefits that would have resulted from reductions in dialysisrelated treatment costs, as well as any improvements in qualityadjusted survival. Under this extreme scenario, the implied mean first-year cost would be $29, I 58 in the standard regimen group compared with $30,275 in the MMF group (a 3.8% difference). This difference of $1 I 17 would represent approximately 22% of the first-year cost of MMF, indicating that nearly 80% of the first-year cost of MMF would be offset by savings in other areas. Differences in Adverse Events. In general, there were no clinically important differences in the incidence of adverse events between the standard regimen group and the MMF group. It is plausible, however, that the greater immunosuppression achieved with MMF might lead to a higher incidence of CMV disease. The clinical trial results are suggestive of such an impact at the higher MMF ( 1.5 g twice daily) dose. Analysis of the adverse event data from the clinical trial indicated, however, that MMF at 1.0 g twice daily is comparable to the standard regimen with respect to the incidence of CMV infection. These results were the basis for the no-difference estimate in the base case analysis. However, the incidence of CMV disease reported from the clinical trial data included both treated and untreated episodes. Because not all reported incidences of CMV disease were treated, examining those CMV infection episodes that were treated may give a better insight into the economic significance of this opportunistic infection. Thus, reported ganciclovir use for treatment of CMV disease was examined for all patients in the study, including those who prematurely terminated; % of standard therapy regimen patients received ganciclovir to treat CMV infections compared with 1 8.6% of MMF patients. Although this difference is not statistically significant, it has the potential to be economically important. Consistent with the treatment patterns observed in the U.S. clinical trial, it was assumed that typical CMV viremia/syndrome treatment was for 14 d (8 impatient d and 6 outpatient d) and that typical CMV tissue invasive disease treatment was 26 d (5 inpatient d and 21 outpatient d). On average, standard regimen patients treated with ganciclovir for CMV had slightly more episodes of CMV viremia/syndrome treatment (0.88 versus 0.8 1) and slightly fewer episodes of CMV tissue invasive disease (0.24 versus 0.39). Taken together, these assumptions result in an additional $482 in estimated, per-patient, CMV disease treatment costs in the MMF group. Compared with the base case, and averaged over all patients (both treated and untreated for CMV disease), the per-patient, first-year cost savings for patients in the MMF arm would be reduced to $870, from the base case estimate of $1350. Differences in Medical Care Use and Costs. inpatient Days. The unit cost for an inpatient hospital day was varied by adjusting the base case value by plus and minus 10% (Table 4). A 10% reduction in the price of a hospital day decreased the absolute cost difference between study groups from 4.6% ($ 135 1) in the base case to 3.8% ($ 1074). Increasing the per-day hospital cost in the evaluation by 10% resulted in an estimated absolute cost difference of 5.5% ($1657) in favor of MMF treatment versus standard therapy. Corticosteroid Treatment. In the trial, clinical centers were given some flexibility to treat acute rejections, as per their usual center clinical practice. The main exception was related to the initial corticosteroid regimen. Some centers admitted patients for the entire treatment course, whereas others used a mix of inpatient and outpatient settings for treatment. Data from the U.S. clinical trial (and used in the base case economic analysis) indicated that 82% of all steroid-treated rejection days, and 77% of all OKT3-treated rejection days, were completed in the impatient setting. The impact of acute rejection therapy on mean and relative costs of shifting to more outpatient provision was examined. For example, assuming that 50% of all rejection treatment days are provided outside the hospital, the mean expected annual cost pen patient is reduced 4.5% ($1293) in the standard regimen group and 2.8% ($767) in the MMF group. Thus, the net cost savings would be lower (by $526) than in the base case scenario. Table 4. Sensitivity analyses of hospital pen day and MMF drug cost estimates Item Standard Regimen MMF Difference Base case $29,158 $27, % hospital per day/md fee (base case) ($1305) ($1305) -lopencent $28,380 $27, % +l0percent $30,014 $28, % retail daily cost of MMF (base case) ($0.00) ($15.00) assume 10% retail mark-up $29,158 $27, % assume 5% retail mark-up $29,158 $27, %

6 Economic Evaluation of MMF 1597 Discussion This study compares the first-year costs and effectiveness of MMF 2 g/d to azathioprine, in combination with a maintenance regimen of cyclosporine and prednisome, for the prevention of acute renal allograft rejection. Overall, the mew regimen that included MMF was associated with a clinically significant improvement in first-year rejection outcome, showed some indication of better graft survival, and-in the base case economic evaluation-was estimated to have lower first-year costs from a societal perspective. As might be expected, sensitivity analyses of the base case clinical parameters suggest that the main economic finding of this analysis depends on the assumptions about differences in the first-year acute rejection and graft failure rates between the two alternative treatments. The differences in acute rejection rates in the U.S. clinical trial were consistent, in absolute terms, with those found in the other MMF prevention trials (12, 1 3), thus supporting the base case parameter estimates for acute rejection. This analysis was based on the recommended MMF dose of 2 g/d, but it should also be noted that there are likely to be some patients (e.g., in high-risk subgroups) who could benefit from a MMF 3 g/d regimen. Additional trials and analyses are needed to evaluate the risks and benefits of this higher dose in specific subgroups of patients. This analysis used clinical trial data to compare the economic effectiveness of one treatment with another, a method that has many recognized limitations (14,15). Among these, the lack of follow-up for patients who prematurely terminated raises some complex issues for this analysis. The economic model used here aims to approximate effectiveness, i.e., the expected patterns under regular use, rather than efficacy, which refers to the results in an ideal clinical trial setting. Investigatons in clinical trials are blinded to study drug and can be expected to treat patients somewhat differently after clinical efficacy is established and when they know which drug the patient is receiving. Hence, premature termination rates in a trial may not be a good predictor of actual termination rates in the real world. Similarly, the outcomes of patients after they terminate from a trial may not be very helpful in projecting future effectiveness. Another potential issue of the premature terminations is their impact on the measurement of medical care resource use, which was not followed in this trial after patient termination from the study. A detailed analysis of rejection treatment patterns (i.e., the number, types, and duration of treatments) did not find any significant differences between study arms during the first 6 posttransplamt months, a period when the vast majority of rejections occur. Hence, these patterns were assumed to be identical in the two study arms in the economic analysis. As a result, the key economic factor becomes the absolute difference in the rate of treated rejection in the cornparisom arms, and these estimates are based on an intent-totreat analysis for the entire first year. Although this observed rate of treated rejection might also be affected by premature termination, there are several reasons to believe that the observed differential will hold outside the trial setting. Compared with the MMF 2-g arm, patients in the azathioprime group who prematurely terminated in the first 6 mo were more likely (approximately 60% versus 40%) to experience rejection. An alternative explanation is that MMF 2-g patients withdrew earlier and were more likely to expenience rejection posttermination. This seems unlikely given that the time to premature termination was slightly longer in the MMF 2-g arm. Furthermore, even if 60% of MMF 2-g patients who prematurely terminated would have eventually experienced rejection, the MMF 2-g rejection rate would rise from 27.9 to 3 1.5%, which is within the range covered by the sensitivity analyses reported here. From a societal perspective, hospital cost estimates in economic evaluation models should reflect actual resource consumption and opportunity costs. Rather than identifying and estimating costs of each resource unit for each patient in the clinical trial, an average, per day cost across all types of patients was used. In theory, this approach provides an estimate of the cost of resources consumed by the average patient, reflecting both operating and capital expenditures for a typical day in the hospital. This approach avoids the well-known problems associated with using hospital changes as a proxy for costs and provides a reasonable approximation from a health system point of view. The estimate could well be conservative, because no special adjustment is made for any potential reductiom in the use of costly diagnostic procedures due, for example, to a lower rate of rejection with MMF. In particular, renal biopsies to detect rejection, although required by the study protocol, are also commonly used at many centers. Because no explicit account is made for them, this analysis may understate the savings from reduced rejection with MMF. An additional limitation to this study is the first-year analysis time frame. It would be difficult to model the longer-term consequences of MMF compared with azathiopnine unless more data were available from follow-up studies. The U.S. trial includes a 3-yr follow-up analysis, which will provide some of the necessary information. Given the uncertainties about longterm clinical and economic outcomes, at this stage, a quantitative assessment of the potential long-term economic impacts of improved acute rejection with MMF is beyond the scope of this analysis; however, some qualitative comments are offered. Clearly, because the large majority of rejection episodes occur within the first 6 mo after transplantation, there are likely to be very few additional cost reductions associated with avoiding additional acute rejections. Also, because azathioprine use is tapered for some patients over the long term, daily azathioprime cost savings will also he lower. Any additional cost offsets and quality of life benefits are likely to be seen with further improvements in graft survival, which avoids costly and unpleasant dialysis. The likely long-term impact of an MMF regimen on graft survival is difficult to predict at this early stage of development. At issue is how graft survival in later years under MMF will compare with that under a standard regimen. Of course, even if there were no additional long-term graft survival benefits, the five or so additional grafts saved per 100 recipients at the end of the first year would continue to generate long-term

7 I 598 Journal of the American Society of Nephrology cost savings, if only through reduction in dialysis treatment costs. In addition, two other important benefits may be observed. First, because a history of acute rejection has historically been the greatest risk factor for chronic rejection and long-term graft survival, the lower rate of acute rejection under MMF may portend a lower chronic rejection rate (16-18). Second, although it has not been demonstrated clinically, there are well-defined biological reasons to suggest that MMF may have a direct effect on the rate of chronic rejection, operating independently of the influence through acute rejection (19). If so, this could further extend graft life. Long-term patient follow-up is required to test this hypothesis. Improvements in average graft life will also be of additional economic value to society through more subtle, systemwide effects. For example, improved rejection and graft outcomes will lead to fewer graft failures and costly retransplants. The potential benefits to society of fewer retransplant procedures are that the scarce organ supply will be used for more first transplants and time spent on dialysis while awaiting transplamtation will be reduced. Over time, it would be expected that a greaten proportion of patients on the waiting list for transplants would, in fact, receive them, leaving fewer people dependent on dialysis. This would reduce systemwide costs and improve overall system efficiency. In summary, this study demonstrates that an immunosuppressive regimen that includes MMF is cost-effective compared with azathioprine for the prevention of acute rejection of primary cadavenic renal allografts, because the improved thenapeutic benefits are obtained at a somewhat lower overall cost of treatment. Plausible variation in the key clinical parameters of acute rejection and graft loss did not substantially affect the overall result. Long-term cost effectiveness will need to be determined after more data are available on the effects of MMF on graft failure, chronic rejection, retransplantation, and patient survival beyond the first year of treatment. Appendix U.S. Renal Transplant Mvcophenolate Mofetil Studs Group Members Sang Cho, M.D., Boston University Medical Center, Boston, MA; Gabriel Danovitch, M.D., University of California at Los Angeles Medical Center, Los Angeles. CA: Mark Deierhoi, M.D., University of Alabama, Birmingham, AL; Ronald Fenguson, M.D., Ph.D., Ohio State University. Columbus, OH; Thomas Gonwa, M.D., Baylor University Medical Center, Dallas Transplant Institute, and Methodist Medical Center, Dallas, TX; Ernest Hodge, M.D., Cleveland Clinic Foundation, Cleveland, OH; Christopher Johnson, M.D., Medical College ofwiscomsin, Milwaukee, WI; Joshua Miller, M.D., University of Miami, Miami, FL; John Neylan, M.D., Emory Clinic, Atlanta, GA; Douglas Norman, M.D., Oregon Health Sciences University, Portland, OR; Mark Pescovitz, M.D., Indiana University Medical Center, Indianapolis, IN; Hans W. Sollimgen, M.D., University of Wisconsin. Madison, WI; Steve Tomlanovich, M.D., University of California at San Francisco, Sam Francisco, CA; Sam Weinstein, M.D., Tampa General Hospital, Tampa, FL. Acknowledgments This study was supported by a grant from Roche/Syntex Development Research. The authors are indebted to Essy Mozaffari and Nancy I. Neil for providing technical assistance. References 1. 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