Management of end-stage renal disease (ESRD)

Transcription

1 Economic evaluation of kidney transplantation versus hemodialysis in patients with end-stage renal disease in Hungary Background Kidney transplantation is generally acknowledged as the more clinically effective and more cost-effective option in managing patients with endstage renal disease, compared with dialysis. This study looked for confirmatory evidence in a Hungarian population. Methods Patients (n = 242) with end-stage renal disease who received cadaveric kidney transplantation during 1994 were followed up for 3 years. They were compared with patients (n = 840) receiving hemodialysis who were on a waiting list for transplantation. Data were collected retrospectively. Treatments were compared for clinical efficacy and for cost-effectiveness. Results At month 36, the standard mortality hazard function was 3.5 times higher in the group receiving hemodialysis (P<.0001) than in the transplant recipients. Average treatment costs per patient over the 3 years were also significantly higher (P<.0001) in the hemodialysis group than in the group that received transplants. The cost of 1 year gained by transplantation was significantly less (P<.0001) than the cost associated with hemodialysis. Conclusions Compared with hemodialysis, kidney transplantation provides greater survival benefits to patients with end-stage renal disease, at less cost. (Progress in. 2001;11: ) Zoltán Kaló, MSc, MD, Jeno Járay, MD, PhD, and Júlia Nagy, PhD Novartis Hungary Ltd, Budapest, Hungary (ZK), Semmelweis University, Budapest (JJ), and Gyógyinfok, Hungarian Ministry of Health, Szekszárd, Hungary (JN) To purchase reprints contact: The InnoVision Group 101 Columbia, Aliso Viejo, CA Phone (800) (ext 532) or (949) (ext 532) Fax (949) reprints@aacn.org Management of end-stage renal disease (ESRD) by kidney replacement therapy has advanced significantly in the past 25 years. Refinements in hemodialysis and peritoneal dialysis techniques in combination with individualized drug therapy and dietary modifications have allowed patients to maintain reasonable health for 20 years or more. Advances in dialysis facilities, dialysis solutions, and dialyzers have in various degrees contributed to the improved survival rates seen in patients maintained on dialysis, together with increased knowledge of, and ability to manage, treatment-related complications. 1 However, it is now generally accepted that kidney transplantation is a more effective, as well as more cost-effective, therapeutic option than hemodialysis in patients with ESRD, providing substantial benefits in quality of life at reduced long-term costs. 2-7 The lower costs associated with transplantation have been mainly attributed to the cost differential between maintenance immunosuppression compared with routine dialysis. In addition, the increased morbidity associated with dialysis and the financial benefits of improved productive capacity (opportunity costs) in patients who no longer require dialysis are also factors in this context. 3 Leaving aside patients in whom transplantation is contraindicated, lack of donor organs (living or cadaveric) is the most important factor in limiting the number of patients with ESRD who are offered transplantation. This study is the first comprehensive Eastern Euro pean assessment of the economics of cadaveric kidney transplantation versus hemodialysis in a developing country (Hungary), which has recently experienced major changes in healthcare policy with respect to organ donation. The prevalence of ESRD in Hungary has in creased in recent years, 8 leading to a rapid growth in the number of dialyzed patients. However, the kidney transplantation rate did not grow to the same extent, prompting the Hungarian Ministry of Welfare (renamed the Ministry of Health in July 1998) to investigate ways in which the organ donation rate might be increased. To this end, in November 1997, the Ministry established a Health 188 Progress in, Vol 11, No. 3, September 2001

2 Kidney transplantation versus hemodialysis in patients with end-stage renal disease Economics Working Group. Participating organizations included the National Health Insurance Fund (NHIF), the Hungarian Nephrological Society, Semmelweis Medical Uni versity, Gyógyinfok (a department of the Ministry of Health responsible for collecting and analyzing performance data relating to healthcare providers), and Novartis Hungary Ltd, as well as representatives from the Ministry of Health itself. In February 1998, this working group was subsumed within the Health Technology Assessment Department of Medinfo, the Medical Information Centre of the Ministry of Health. The task of the working group was to conduct an economic evaluation of cadaveric kidney transplantation compared with hemodialysis in a Hungarian population to quantify, over a 3-year period, the benefits (both to individual patients and society) from maximizing the availability of donor organs. The results of this evaluation are reported in this study. Methods Patient Population Patient files were collected from the Hungarian subset of the European Dialysis and Transplant Association (EDTA) database maintained at the Hungarian Nephrological Society. Two groups of patients with ESRD were selected for the purposes of the study. The first group (n = 242) comprised all patients who received a cadaveric kidney transplant in Hungary during For this group the investigation period started on their day of transplantation (day 0) and continued for exactly 3 years. In 1994, no living donor kidney transplantations were undertaken in Hungary. The second group (n = 840) comprised patients receiving hemodialysis who were on a waiting list for transplantation on July 1, These patients were all potential candidates for transplantation if a graft had been available on that day. For this group the investigation period ended on June 30, The subgroup (n = 410) who received kidney transplants during the 3-year study period were excluded on the day of transplantation (n = 170 in 1995, n = 82 in 1996, n = 35 in 1997). The 123 patients who received kidney transplants in the second half of 1994 were subsequently included in the transplantation group after being excluded from the dialysis group. Patients receiving peritoneal dialysis (as opposed to hemodialysis) were excluded from the investigation, because of the small numbers involved. In 1994, only 30% of patients receiving dialysis in Hungary were on a transplant waiting list. Dialysis patients not on a waiting list were significantly older (mean age, 59.9 years) than listed patients (mean age, 44.9 years). Since patients with serious comorbidities and high surgical risk are not generally accepted for transplantation, the mortality hazard of patients not on a waiting list is greater than that of listed patients. In another study, we have shown that the crude (not ad justed for age) survival rate at 2 years for dialysis pa tients not on a waiting list for transplantation was only 62.2%. 9 Data Collection Data were collected retrospectively. Demograph - ic and mortality data were extracted from the EDTA database and were complete for the entire study period. Resource utilization units for healthcare services such as dialysis, transplantation, and transportation were taken from the database of the NHIF. Gyógyinfok provided details of acute inpatient care, based on the number of diagnosis-related group points 10 registered to each patient. Assessment of outpatient care was based on protocols provided by the Hungarian Nephrological Society. Only the costs of basic drug therapy such as immunosuppression for patients who received transplants and erythropoietin for patients who underwent hemodialysis were assessed, on the basis of data from the NHIF. Statistical Methods Mortality data were analyzed using the standardized mortality hazard function, the standardized survival function, the relative and absolute risk reduction of mortality, and the number of patients needed to treat by transplantation to avoid 1 death. The mortality and survival figures reported in this article refer to a standard 41.8-year-old patient with a 2.55-year history of ESRD. Results for the 3-year study period were subsequently extrapolated to 5 years, on the basis of the assumption that the mortality hazard function would remain the same during years 4 and 5. This assumption has serious limitations, but the working group wished to assess longer-term survival. However, final conclusions are based on the 3-year data. To eliminate confounding variables such as age, sex, and length of ESRD before commencement of the investigation period, Cox regression analysis 11 was used to calculate mortality differences. Differences between the 2 groups in the proportion of men versus women (Table 1) had no significant effect on mortality, and this variable was therefore excluded from the analysis. However, patients who underwent hemodialysis were older, and had a longer mean period of renal replacement therapy. These differences had a significant effect on mortality and were therefore included in the regression analy sis as explanatory variables. Cost Analysis Costs were standardized by applying an average cost to each procedure. Resource utilization units were converted into monetary terms by multiplying them by the procedure fee of the NHIF that was valid in July This method avoids any need to correct for inflation, since all resource utilization units Progress in, Vol 11, No. 3, September

3 Kaló et al Table 1 Demographics of the patient populations. Group 1 patients are those who received transplants during Group 2 patients are those receiving hemodialysis on a waiting list for transplantation on July 1, 1994, who subsequently received or did not receive kidney transplants. Group 1 (n=242) Group 2 (n=840) Subsequently received transplants (n=410) Did not receive transplants (n=430) Age, mean (SD), years Male sex, % Period from first renal replacement therapy, mean (SD), years 41.8 (12.3) (2.8) 40.6 (12.8) (2.4) 49.0 (11.7) (2.8) applied during the 3-year study period are converted identically. Costs were converted from Hungarian forints (Ft) to US dollars (US$) by using the method of purchasing power parities for gross domestic product. Purchasing power parities are currency conversion rates that both convert to a common currency and equalize the purchasing power of different currencies, thus eliminating the differences in price levels between countries in the process of conversion. In 1997, the conversion rate was Ft = US$1. Parametric statistical techniques were used to calculate the P value for the difference between the mean treatment costs of hemodialysis compared with kidney transplantation. The basic analysis was undertaken using a real discount rate of 0%. Sensitivity analyses were subsequently conducted using 3% and 6% discount rates. Three different methods were used to analyze treatment costs: 3-year public expenses per patient, 3-year public expenses per year of life saved, and cumulative expense flow per patient. Results Mortality Among the 242 patients who received transplants, 40 (16.5%) died before the third anniversary of receiving their transplant, and an additional 44 patients (18.2%) suffered graft loss, although 7 patients in this latter group received successful retransplants during the 3-year investigation period. The standardized mortality hazard function (Figure 1) indicated that the risk of mortality in patients who received transplants, compared with those undergoing hemodialysis, was significantly higher in the earlier months following transplantation. However, after 7.1 months, the mortality rate for the transplant recipients fell below that of the dialysis patients and remained below it thereafter until month 36, when the hazard rate of mortality for patients continuing on dialysis was 3.5 times greater. This difference was highly statistically significant (P<.0001). Survival For a considerable period, the survival of the dialysis patients exceeded, and at month 6 was statistically superior to, that of the transplant recipients (Figure 2). However, after 20.6 months, the survival of the transplant recipients exceeded that of the dialysis patients. At month 36, the difference in survival between the groups was 5.6% in favor of the transplant recipients, a relative risk reduction of 27.7%, and a difference that again approached statistical significance (P=.06). From month 37, the extrapolated results (Figure 2) clearly show an increasing survival advantage for the transplant recipients. Based on the absolute and relative reductions in mortality rates (5.6% and 27.7%) at month 36 given above, the number needed to treat by transplantation to avoid 1 death was Consequently, of every 18 patients who received transplants, 1 patient would be dead after 3 years without transplantation. The equivalent extrapolated figures for month 60 are 13.4%, 42.5%, and 7.5, indicating an increasing trend in favor of transplantation. Costs The Hungarian NHIF spent an average of US$ (SD $47584), applying a 0% discount rate, on each patient receiving hemodialysis over the period (Table 2). The minimum amount spent was zero, where the patient died on day 1 of the investigation period; the maximum amount spent was US$ By comparison, and again applying a 0% discount rate, transplant recipients (Table 2) cost the NHIF an average of US$70297 (SD $29860) over the same period. The minimum amount spent was US $29474 for a patient 190 Progress in, Vol 11, No. 3, September 2001

4 Kidney transplantation versus hemodialysis in patients with end-stage renal disease Table 2 Average costs (applying a 0% discount rate) payable by the Hungarian National Health Insurance Fund over the study period per patient receiving hemodialysis or kidney transplant. All sums expressed in US$ in terms of fees valid in Healthcare service * Hemodialysis Transport for dialysis Outpatient care For patients with functioning graft For patients on dialysis Waiting list costs Inpatient care (excluding transplantation) Medication Immunosuppressive therapy (outpatient) Dialysis drugs (eg, erythropoietin, calcitriol) Total 3-year costs per patient Mean (SD) Cost of hemodialysis, US$ (waiting list) (34419) (14023) 977 (381) 329 (128) 1969 (3532) (5293) (47548) Mean (SD) Cost of transplantation, US$ (4945) (24 126) 1722 (4965) 732 (306) 151 (331) 51 (112) 2345 (2854) (10 571) 2102 (4657) (29 860) *Including the cost of donor reporting, donor management, and donor procurement for each patient, and the cost of a second kidney transplant for 7 patients. who died on the day following surgery; the maximum amount spent was US$ Thus, on average, hemodialysis was more costly than transplantation over the 3-year study period by US$ (Ft 3.3 million) per patient (Table 2), even though the transplant group included patients both with good clinical outcome and those with graft loss. This difference was highly statistically significant (P<.0001). Overall, each kidney transplant represented a 35.6% potential cost reduction in the treatment of patients with ESRD. Recalculation of costs using 3% and 6% discount rates (Table 3) did not affect the statistically significant status of the results. Cost per Years of Life Gained The cost differential between transplantation and hemodialysis becomes even more marked when survival rates are incorporated in the analysis (Table 4). The NHIF used fewer resources to gain 1 year of life by kidney transplantation, compared with dialysis. The cost difference was US$ (Ft 1.57 million), a highly statistically significant figure (P<.0001). One year of life was gained 40.8% more cheaply using transplantation, compared with dialysis. Analysis of the cumulative expenses flow per patient (Figure 3) shows that transplantation requires early (up front) investment, but that such investment pays off after a mean of 12.6 months. Trans plan - tation was 3.2% more costly than dialysis at the end of year 1, but provided significant cost savings at the end of years 2 and 3. Discussion Patients with ESRD can be maintained in reasonable health with dialysis, but there is little doubt that the great majority of such patients will benefit from kidney transplantation, provided that a suitable donor organ is available. If the extended survival and improved quality of life offered by transplant surgery is also associated with long-term savings in healthcare Table 3 Average costs and 95% confidence intervals payable by the Hungarian National Health Insurance Fund over the study period per patient receiving hemodialysis or kidney transplant, applying 0%, 3%, and 6% discount rates. All sums expressed in US dollars in terms of fees valid in Cost of hemodialysis (waiting list) Cost of transplantation Discount rate, % Mean, US$ 95% confidence interval, US$ Mean, US$ 95% confidence interval, US$ P <.0001 <.0001 <.0001 Progress in, Vol 11, No. 3, September

5 Kaló et al costs, national authorities would be well advised to promote organ donation by every ethical means. The cost-effectiveness of kidney transplantation has already been investigated in a number of international studies. 2-5 All have shown conclusively that, compared with dialysis, transplantation is both more effective (in terms of survival and quality of life) and more cost-effective (in terms of reduced healthcare costs for improved clinical outcomes). This study, the first of its kind from an eastern European country, has confirmed these findings: over the 3-year study period, transplant recipients had an increased survival advantage associated with reduced treatment costs. Although every relevant Hungarian patient from the year 1994 was included in the analysis, the study was not sufficiently powered numerically to show statistically significant advantages for transplantation compared with hemo dialysis. However, at month 36 the hazard rate of mortality (Figure 1) was significantly (P<.0001) in favor of transplantation, whereas the survival rate (Figure 2) showed a substantial trend (P=.06) in favor of transplantation. There are other good reasons to believe that kidney transplantation provides clinically significant survival benefits over dialysis. First, survival differences between the 2 groups continued to diverge after month 36, when the survival results were extrapolated by assuming similar mortality trends (Figure 2). Second, international results are either similar to the trends shown in this study, or demonstrate greater survival benefits for kidney transplantation over dialysis than those shown in this study We did not investigate quality of life in kidney transplant recipients, compared with patients maintained on hemodialysis. However, international studies have shown that transplant recipients enjoy an improved quality of life, a finding that many would regard as intuitively obvious. Treatment costs over the 3-year study period were significantly less for transplant recipients than for patients maintained on hemodialysis. On average, hemodialysis was US$ more costly than transplantation, indicating that the NHIF could save US$ if 1 potential donor (with 2 kidneys) is not lost for transplantation. Although transplantation requires early investment compared with hemodialysis, costs equalize at 12.6 months (Figure 3), after which the level of cumulative expenses favors transplantation. A dialysis patient represents almost no costs if he or she dies shortly after the start of the investigation period, and the survival rate of dialysis patients was less than for transplant recipients. By contrast, transplant patients are associated with a minimum cost of care by virtue of surgical and related expenses. Thus the cost-saving potential of kidney transplantation is even greater when the positive effect of mortality on resource utilization is eliminated. The average cost of a year of life gained is US$ less for transplantation than for hemodialysis (Table 4). For many years Hungary had a presumed consent policy with regard to organ donation: if the patient had not confirmed (in writing or orally) that he or she objected to the removal of organs after death, organs were permitted to be removed. In 1997, a new health act introduced a more restrictive policy, with the result that organ donation fell in 1998 by about one third (from 309 to 233 transplanted kidneys). How - ever, as a result of this study, the Hungarian parliament reintroduced the presumed consent policy, and has also increased fees payable for donor identification by 200%. Other initiatives, such as adapting the Donor Action Programme, establishing a donor coordinating network, and integrating Hungarotransplant Mortality hazard, % Dialysis (waiting list) Survival rate, % Dialysis (waiting list) Investigation period Extrapolation period Months Figure 1 Standardized mortality hazard function in transplant patients, compared to those remaining on hemodialysis, at various time points throughout the study. Lines cross at 7.1 months (cut-off point). Difference at 36 months in favor of transplantation P< Months Figure 2 Standardized survival function in transplant patients, compared to those remaining on dialysis, at various time points throughout the study, and extrapolated from month 37 to month 60. Lines cross at 20.6 months (cut-off point). Difference at 36 months in favor of transplantation P = Progress in, Vol 11, No. 3, September 2001

6 Kidney transplantation versus hemodialysis in patients with end-stage renal disease US$ (in thousands) Months Dialysis (waiting list) Figure 3 Cumulative costs (applying a 0% discount rate) payable by the Hungarian National Health Insurance Fund over the study period per patient receiving hemodialysis or kidney transplant. All sums expressed in US dollars (US$) in terms of fees valid in into the activities of international organizations, are currently under discussion. These developments are welcome, but much remains to be done in Hungary to increase organ donation rates and to achieve more positive social attitudes to transplantation. We conclude that, compared with hemodialysis, kidney transplantation provides survival benefits at 3 years after surgery, and it does so at a reduced level of healthcare costs. should be the preferred strategy for the management of patients with ESRD. Such a strategy requires the promotion of organ transplantation by all responsible government agencies, working in cooperation with voluntary organizations and patient groups. Acknowledgments The authors would like to thank Stephen Sheingold and Sean Tunis for consultancy services provided to the Health Table 4 Costs payable by the Hungarian National Health Insurance Fund per 1 year of life gained over the study period in patients receiving hemodialysis or kidney transplants. All sums expressed in US$ in terms of fees valid in Healthcare service Dialysis Transport for dialysis Outpatient care Inpatient care Medication Total per 1 year of life gained Cost for hemodialysis (waiting list), US$ Cost for transplantation, US$ Technology Assessment Programme of the Hungarian Ministry of Health, on behalf of the US Agency for International Development. This study was funded by the Hungarian Ministry of Welfare in and by Medinfo, the Medical Information Centre of the Ministry of Health, in The authors would also like to thank the Hungarian Health Economic Working Groups for their contributions: Márta Hídvégi of the Hungarian Nephrological Society (HNS) for data retrieval from the EDTA register; István Kiss (HNS) and Ádám Remport (HNS) for providing outpatient protocols; Zsolt Kiss and Zoltán Nagy of the NHIF for analyzing resource utilization data from the NHIF database; and Áron Megyesi for acting as the study statistician. References 1. David S, Cambi V. Hemodialysis and peritoneal dialysis. Medicine. 1995;23: Klarman HE, Francis JO, Rosenthal GD. Cost effectiveness analysis applied to the treatment of chronic renal disease. Med Care. 1968;6(1): Karlberg I, Nyberg G. Cost effectiveness studies of renal transplantation. Int J Technol Assess Health Care. 1995;11: Evans RW, Kitzmann DJ. An economic analysis of kidney transplantation. Surg Clin N Am. 1998;78: de Wit GA, Ramstein PG, de Charro FT. Economic evaluation of end-stage renal disease treatment. Health Policy. 1998;44: Ludbrook A. A cost-effectiveness analysis of the treatment of chronic renal failure. Appl Economics. 1981;13: Eggers P. Comparison of treatment costs between dialysis and transplantation. Semin Nephrol. 1992;12: Járay J, Hidvégi M, Kaló Z, Nagy J. Forecasting the number of patients with end-stage renal disease [in Hungarian]. Orv Hetil. 2000;141: Kaló Z. Dializis vs vesetranszplantácio összehasonlitó költség-hatékonysági elemzés. Paper presented at: Eastern- Hungarian Symposium; September 25, 1998; Debrecen, Hungary. 10. Gyógyinfok. DRG code list (HBCS 3.2.). Available at: Accessed November 1, Lawless JF. Statistical Models and Methods for Lifetime Data. New York, NY: Wiley; Port FK, Wolfe RA, Mauger EA, Berling DP, Jiang K. Com - parison of survival probabilities for dialysis patients vs cadaveric renal transplant recipients. JAMA. 1993;270: Hariharan S, Johnson CP, Bresnahan BA, Taranto SE, McIntosh MJ, Stablein D. Improved graft survival after renal transplantation in the United States, 1988 to N Engl J Med. 2000;342: Hunsicker LG. A survival advantage for renal transplantation [editorial]. N Engl J Med. 1999;341: Wolfe RA, Ashby VB, Milford EL, et al. Comparison of mortality in all patients on dialysis, patients on dialysis awaiting transplantation, and recipients of a first cadaveric transplant. N Engl J Med. 1999;341: USRDS (United States Renal Data System) 1999 Annual Data Report. V. Patient mortality and survival. Am J Kid Dis. 1999;34(suppl 1): Parsons D, Harris D. Review of quality of life in chronic renal failure. Pharmacoeconomics. 1997;12: Laupacis A, Keown P, Pus N, et al. A study of the quality of life and cost utility of renal transplantation. Kidney Int. 1996;50: Evans RW, Manninen DL, Garrison LP, et al. The quality of life of patients with end-stage renal disease. N Engl J Med. 1985;312: Russell JD, Beecroft ML, Ludwom D, et al. The quality of life in renal transplantation a prospective study ;54: Gudex CM. Health-related quality of life in end-stage renal failure. Qual Life Res. 1995;4: Progress in, Vol 11, No. 3, September