Portal de Periódicos da CAPES

Immunosuppression: practice and trends

2003; Elsevier BV; Volume: 3; Linguagem: Inglês

10.1034/j.1600-6143.3.s4.5.x

1600-6143

J. Harold Helderman, William M. Bennett, Diane M. Cibrik, Dixon B. Kaufman, Andrew Klein, Steven K. Takemoto,

Organ and Tissue Transplantation Research

The history of solid organ transplantation can be viewed as the history of immunosuppressive strategies. It is not a stretch to divide the record of successful human transplantation into three eras that are characterized by different methods of immunosuppression. In the first of these periods (1954–1962), transplant scientists and clinicians searched for immunosuppressive strategies that would provide modest success and an acceptable level of adverse events. Surgical techniques for engrafting the kidney, liver and later the heart were also issues of experimentation in this period that may be called the 'Experimental Era'. Routine clinical transplantation was confined to identical twins sharing a kidney. The advent of azathioprine in 1962 increased the possibilities for successful human transplants, garnered a Nobel prize for innovative pharmacological progress, and launched a new historical era of organ transplantation, the 'Azathioprine Era'. During this period, kidney transplants could be offered to recipients of organs from living donor sources and even deceased donors with modest success. Graft survival hovered around 50% at 1 year, attended by high rejection rates, but patient survival was strong. Organ transplants could be performed, at least experimentally, in heart and liver recipients. In 1983, the 'Cyclosporine Era' was ushered in by the discovery of cyclosporin A and its provision for clinical use. As has been shown by a recent review of the OPTN/SRTR database, kidney transplant success has become superb, whether evaluated at early time points (1 year) or at later dates (as revealed in graft survival half lives) (1). In this third era, transplantation of extra-renal organs became routine, with excellent outcomes now observed for transplants of livers, pancreata, hearts, and even lungs. This article analyzes organ transplant history during the most recent decade as a function of immunosuppressive strategies. A careful organ-by-organ review of the OPTN/SRTR data indicates new trends that have arisen as novel molecules have become available for study and wider application. Since 1992, such trends have included the waning of cyclosporine, the rise of induction, the switch to newer cytotoxic agents, and the penetration of even more novel agents. This article will explore just those very trends, which may coalesce into a new historical era of organ transplant. Unless otherwise noted, the statistics in this article come from reference tables in the 2002 OPTN/SRTR Annual Report. Two companion articles in this report, 'Data Sources and Structure' and 'Analytical Approaches for Transplant Research', explain the methods of the data collection, organization, and analysis that serve as a basis for this article (2, 3). In 1992, the vast majority (91%) of kidney transplant recipients received no induction therapy with antilymphocyte preparations. Of those who did receive induction therapy, most received muromonab-CD3 (OKT3®). The use of induction therapy gradually increased from 1992 to 2001, by which time 59% of recipients received induction. Muromonab-CD3 was the predominant immunosuppressive agent used for induction through 1995. After that there was increasing use of antithymocyte globulin (ATG)— until the advent of anti-interleukin 2 receptor antibodies, basiliximab (Simulect®) and daclizumab (Zenapax®) in 1998, well-tolerated drugs that were used increasingly through 2001. In 2001, 26% of the 13 109 transplants for which information is available used basiliximab and 15% used daclizumab. Rabbit antithymocyte globulin (Thymoglobulin®) was used in 18% of transplants in 2001, an increase from its introduction in 1999. Muromonab-CD3 use has dropped to <1% of transplants, and ATG use, which peaked in 1997, dropped to 2%. Between 1992 and 2001, nearly all kidney recipients received corticosteroid therapy prior to hospital discharge (Figure 1), although the percentage of recipients receiving corticosteroids toward the end of this period dropped slightly (94% in 2001). Of the other maintenance immunosuppressive drugs used prior to hospital discharge, tacrolimus use grew rapidly in the latter half of the 1990s, being used by 55% of recipients in 2001, while use of cyclosporine-based calcineurin inhibition declined from 94% of recipients in 1992 to 39% in 2001. Antimetabolite use in 1992 was predominantly azathioprine, but by 2001 most transplant centers prescribed mycophenolate mofetil upon discharge. This trend of increasing mycophenolate mofetil use and declining azathioprine use began in 1995 and continued through 2001. Since 1996, rapamycin has also been employed, presumably in an attempt to spare other immunosuppressive drugs, and in particular to reduce the nephrotoxicity of calcineurin inhibitors. By 2001, 17% of transplant recipients received rapamycin upon hospital discharge. Cyclophosphamide (Cytoxan®) was among the other drugs used in the decade, though it was used for only 0.1–0.2% of patients. Of the various cyclosporine preparations, Neoral® use gradually declined from 1996 (59% of all patients) to 2001 (31%). By 2001, there was some increase in generic cyclosporine use, particularly Gengraf ® (5%), with a small proportion of the Eon preparation (0.1%). Thus generic cyclosporines have not accounted for much of the declining Neoral usage. Kidney transplant immunosuppression prior to discharge: cyclosporine vs. tacrolimus, 1993–2001. Source: 2002 OPTN/SRTR Annual Report, Table 5.6. For the first year following transplant, the great majority of kidney recipients used a combination of corticosteroids (97% in 2000, compared to 100% in 1992) and a calcineurin inhibitor during the first year. During this 10-year period, cyclosporine use dropped from 96% in 1992 to 53% of the 12 010 transplants done in 2000. There was a corresponding rise in tacrolimus use from 3% in 1992 to 52% in 2000. Thus for both discharge immunosuppression and maintenance through 1 year, the trend is similar, with increasing use of tacrolimus and declining use of cyclosporine in general and Neoral in particular. Similar to the discharge from hospital data, azathioprine use declined from 87% in 1992 to 8% in 2000, while mycophenolate mofetil use increased from 1% to 80%. In 2000, 16% of patients received rapamycin as part of their immunosuppressive medicine. It is not possible to tell the exact combinations used from the data available, and these data give no information about blood level monitoring, protocols, and dose. In 1992, corticosteroids were used in 81% of antirejection treatment episodes, dropping to 79% in 2000. However, in 2000, only 17% of transplants were followed by treatment for rejection episodes, compared to 38% in 1992. Of the episodes requiring antilymphocyte therapy, muromonab-CD3 was the predominant agent used through 1998, with an increasing use of rabbit antithymocyte globulin beginning in 1999. In 2000, rabbit antithymocyte globulin was used for 14% of the patients, compared to 16% of patients treated with muromonab-CD3. Although daclizumab and basiliximab are neither approved nor recommended for treatment of acute rejection, each was reported to be used in approximately 4% of acute rejection episodes in 2000. The exact sequence and dose regimens are not included in the available data. The trends toward more tacrolimus replacing cyclosporines are striking. The reasons for this shift are not certain, but may include better correlation of tacrolimus through increasing levels with clinical events, putatively less nephrotoxicity, and marketing practices. Mycophenolate mofetil use may be rising on perception of greater efficacy than azathioprine. Induction therapy is usually included in immunosuppressive protocols for recipients of whole-pancreas transplants. In fact, induction therapy is used with greater frequency for pancreas transplant recipients than for any other solid-organ recipients. One reason for this is that simultaneous kidney–pancreas (SPK), pancreas after kidney (PAK), and pancreas transplant alone (PTA) recipients all exhibit a higher risk of rejection than recipients of other solid-organ transplants. The use of induction therapy in pancreas transplantation has generally been guided by practical experience rather than by the results of formal randomized, prospective, multicenter trials. No FDA-approved immunosuppressive agents are on the market with a labeled indication of reducing rejection rates specifically for pancreas transplant recipients. Nonetheless, in 2001, 78% of solitary pancreas (PAK and PTA) transplant recipients and over 75% of SPK transplant recipients received induction therapy. By comparison, recipients of other solid-organ transplants received induction therapy in 2001 in the following proportions: 59% (kidney), 15% (liver), 50% (intestine), 44% (heart), 39% (lung), and 76% (heart–lung). Over the past 10 years some interesting trends have been observed in the frequency and type of the induction therapy agent used in solitary pancreas and SPK transplant recipients. For solitary pancreas transplant recipients, virtually 100% of the cases of induction therapy from 1994 through 1997 utilized either muromonab-CD3 or ATG. Since 1998, the use of daclizumab, basiliximab, and rabbit antithymocyte globulin has supplanted these. The proportion of solitary pancreas recipients receiving rabbit antithymocyte globulin increased from 0.7% in 1998 to 54% in 2001. The same trend holds true for recipients of SPK transplants. From 1992 to 1997, virtually all cases of induction therapy involved the use of either muromonab-CD3 or ATG. Between 1998 and 2001, basiliximab use rose from 7% to 32%, daclizumab use rose from 15% to 21%, and rabbit antithymocyte globulin use rose from 0.4% to 29%. When induction therapy is currently used in whole-pancreas transplantation, it is often a T-cell-depleting agent (57% in 2001) and/or an interleukin-2 receptor (IL-2R) antagonist (48% in 2001). For comparison, among recipients of other organ transplants who received induction therapy in 2001, the following proportions received T-cell-depleting induction therapy: 21% (kidney), 4% (liver), 22% (intestine), 28% (heart), 15% (lung), and 40% (heart–lung). For recipients of solitary pancreas transplants, 395 courses of induction therapy were given to 379 recipients. Many recipients received more than one induction agent—typically rabbit antithymocyte globulin and daclizumab. This strategy is a notable exception to how induction therapy is applied for the other solid organ transplants, including SPK transplantation. In 2001, rabbit antithymocyte globulin was used in slightly more than half of all cases in which induction therapy was applied; daclizumab and basiliximab accounted for 36% and 12% of cases of induction therapy, respectively. For recipients of SPK transplants in 2001, 53% of all induction therapy utilized an IL-2 receptor antagonist (32% basiliximab and 21% daclizumab), and in 36% of cases a T-cell-depleting agent was used (29% rabbit antithymocyte globulin, 4% muromonab-CD3 and 3% ATG). Maintenance immunosuppressive agents used for pancreas transplantation fall into the following categories: (a) corticosteroids, (b) calcineurin inhibitors (cyclosporine and tacrolimus), (c) antimetabolites (azathioprine and mycophenolate mofetil), and (d) other (rapamycin and cyclophosphamide). In 2001, solitary pancreas recipients received corticosteroids in 93% of cases, tacrolimus in 91% (cyclosporine 8%), mycophenolate mofetil in 74% (azathioprine 1%) and rapamycin in 19%. Therefore, in 2001, the most frequently used combination of maintenance therapy at discharge was tacrolimus, mycophenolate mofetil, and corticosteroids. The dominant use of tacrolimus today represents a marked shift from earlier eras. Tacrolimus was approved for marketing by the FDA for kidney transplantation in 1994. In 1992–93, cyclosporine accounted for virtually 100% of the calcineurin inhibitor use in pancreas transplantation. In 1994, 32% of solitary pancreas recipients received tacrolimus. Its use has increased yearly and reached 91% in 2001. The FDA approved mycophenolate mofetil for marketing for kidney transplantation in 1995, and it was used in only 14% of solitary pancreas transplant cases that year (azathioprine was used in 72% of cases). However, within 1 year, nearly 80% of solitary pancreas transplant recipients received mycophenolate mofetil, with only 12% receiving azathioprine. The use of azathioprine has diminished yearly and dropped to 1% usage in 2001. In 1999, the FDA approved the use of rapamycin for marketing for kidney transplantation. For pancreas transplantation, this agent is usually used in combination with a calcineurin inhibitor, and as a substitute for an antimetabolite. The use of rapamycin has been relatively slow to penetrate the market, compared to the rapid spread of tacrolimus and mycophenolate mofetil usage. In 2000 and 2001, rapamycin was used for 10% and 19% of solitary pancreas cases, respectively. Similar trends in the use of maintenance immunosuppression were also observed for recipients of SPK transplants. In 2001, 92% of the 820 SPK transplant recipients received corticosteroids, 86% tacrolimus (14% cyclosporine), 82% mycophenolate mofetil, and 19% rapamycin. Based on these data, one can extrapolate that the most common maintenance immunosuppressive regimen used in SPK transplant recipients included corticosteroids, tacrolimus, and mycophenolate mofetil. Trends in the uses of maintenance therapies over the past 10 years for SPK transplant recipients are depicted in 2, 3. The use of tacrolimus rose from 17% in 1994 to 86% in 2001. Because tacrolimus is used as a replacement for cyclosporine, cyclosporine usage has dropped from nearly 100% of cases in 1992 to only 14% of cases in 2001. Similar trends in the use of antimetabolites are seen with respect to azathioprine and mycophenolate mofetil. In 1992, azathioprine was used in nearly 100% of cases, dropping to 1% in 2001; mycophenolate mofetil usage grew from 25% in 1995 to 82% in 2001. From 2000 to 2001, rapamycin usage rose from 13% to 19% of cases. Kidney–pancreas transplant immunosuppression prior to discharge: cyclosporine vs. tacrolimus, 1993–2001. Source: 2002 OPTN/SRTR Annual Report, Table 8.6. Kidney–pancreas transplant immunosuppression prior to discharge: azathioprine, mycophenolate mofetil, and rapamycin, 1993–2001. Source: 2002 OPTN/SRTR Annual Report, Table 8.6. In 1992, over 93% of solitary pancreas transplant recipients received cyclosporine, a percentage that dropped to 15% by 2000. The use of tacrolimus increased from less than 7% in 1992 to over 90% in 2000. Mycophenolate mofetil was not used until 1995, when 59% of cases received it; in 2000, over 83% used it. Rapamycin usage rose from 11% in 1999 (its first year of marketing) to 24% in 2000. Similar trends in the escalating use of tacrolimus and mycophenolate mofetil and the declining use of cyclosporine and azathioprine among SPK transplant recipients were also exhibited. In 1992, virtually 100% of SPK transplant recipients received cyclosporine; by 2000, less than 25% received it. The use of tacrolimus increased from essentially 0% in 1992 to 84% in 2000. Mycophenolate mofetil usage nearly doubled from 44% in 1995 to 86% in 2000. Azathioprine has all but disappeared from use, dropping from 96% of cases in 1992 to 6% in 2000. Rapamycin use rose from 4% in 1999 to 20% in 2000. It is interesting to note that from 1992 to 2000 the incidence of rejection during the first year decreased dramatically for solitary pancreas (PAK and PTA) as well as SPK recipients (Figure 4). For recipients of solitary pancreas transplants, the proportion of patients reported to receive antirejection therapy in 1992 was 50%, though this may be an underrepresentation of the true proportion that actually experienced a rejection episode. By 2000, only 19% were reported to have received antirejection therapy during the first year. Similar trends are noted for the SPK transplant recipients (74% in 1992, 22% in 2000). For comparison, kidney-alone transplant recipients required antirejection treatment in 38% of cases in 1992 and 17% of cases in 2000. Incidence of rejection at 1 year in kidney, pancreas, and kidney–pancreas transplant recipients, 1992–2000. Source: 2002 OPTN/SRTR Annual Report, Tables 5.6, 6.6, 7.6, 8.6. The type of antirejection agent used for treatment of rejection entailed the individual or combined use of corticosteroids or T-cell-depleting agents. In 2000, the use of corticosteroids was the most frequently employed antirejection agent among solitary pancreas transplant recipients (85%) and SPK transplant recipients (80%). In 2000, recipients of a solitary pancreas transplant received T-cell-depleting agents in 80% of cases; the specific agents used were either muromonab-CD3 (45%) or rabbit antithymocyte globulin (34%). For recipients of SPK transplants, T-cell-depleting agents were given in 48% of cases; the two most frequently used T-cell-depleting agents were muromonab-CD3 (27%) and rabbit antithymocyte globulin (17%). Compared to kidney-alone transplant recipients, pancreas transplant recipients received more treatments with T-cell-depleting agents for treatment of rejection. In 2000, kidney alone transplant recipients received an anti-T-cell-depleting agent in 38% of cases. Trends in T-cell antibody antirejection therapy usage over the past 10 years in both solitary pancreas and SPK transplant recipients show that muromonab-CD3 is still the most commonly used agent. The use of rabbit antithymocyte globulin has progressively increased since 1998, and the use of the other antilymphocyte globulins has diminished significantly. The use of induction therapy for liver transplant recipients utilizing polyclonal antilymphocyte antibody preparations (ALG) or muromonab-CD3 peaked in 1995, at which time 10% of the 3365 liver recipients for whom immunosuppression data were available were treated with muromonab-CD3, a percentage that declined progressively through 2001. The use of these two products for induction has essentially been replaced by the chimeric and humanized anti-IL-2R monoclonal antibody preparations (basiliximab and daclizumab), each of which were selected for approximately 6% of the 4812 liver recipients in 2001. Rabbit antithymocyte globulin has been utilized infrequently in recent years (2% in 2001). There has been some recent enthusiasm for steroid-avoidance regimens in selected liver transplant recipients (4, 5). Over the last 4 years, there has been a small but progressive decline in the use of either prednisone or prednisolone for maintenance immunosuppression prior to discharge. By 2001, more than 11% of patients were discharged on steroid-free regimens. Steroid-avoidance protocols have often incorporated anti-IL-2R monoclonal antibody or polyclonal ATG induction therapy (4, 5), both of which were utilized with increasing frequency during this same period. Calcineurin inhibitors remained the backbone of early maintenance therapy throughout the 10-year period of review. From 1992 to 2001, 94–100% of patients were receiving either cyclosporine or tacrolimus prior to discharge. However, tacrolimus has replaced cyclosporine as the principal calcineurin inhibitor for maintenance therapy (Figure 5). Liver transplant immunosuppression prior to discharge: cyclosporine vs. tacrolimus, 1993–2001. Source: 2002 OPTN/SRTR Annual Report, Table 9.6. The introduction of Neoral did not appear to have a significant impact upon this latter trend. Generic cyclosporine preparations became available during 2000 and 2001 and accounted for fewer than 10% of the liver recipients receiving a cyclosporine-based regimen, or approximately 1% of all patients at discharge. Antimetabolite therapy was utilized in approximately 40–60% of patients over the 10-year study, and there did not seem to be a definable trend in total usage. The selection of specific antimetabolic agent, however, is remarkable for replacement of azathioprine with mycophenolate mofetil (Figure 6). In 1993, 58% of liver transplant recipients received azathioprine for maintenance therapy, compared to 3% in 2001, while mycophenolate mofetil usage increased consistently since its introduction and was prescribed prior to discharge for 48% of patients by 2001. Liver transplant immunosuppression prior to discharge: azathioprine vs. mycophenolate mofetil, 1993–2001. Source: 2002 OPTN/SRTR Annual Report, Table 9.6. As Figure 7 indicates, the incidence of graft rejection requiring treatment during the first year postliver transplant declined over the last decade (1435 cases in 2000). Similarly, the incidence of steroid-resistant rejection (i.e. rejection episodes requiring antibody therapy for rescue) has decreased. In 1992–93, muromonab-CD3 was prescribed for approximately one-third of all liver recipients with rejection episodes, compared to 6% in 2000 (Figure 8). This trend may be related, in part, to alterations in maintenance therapy instituted over the past decade (e.g. replacement of cyclosporine with tacrolimus as the primary calcineurin inhibitor) (6-8). The decline in muromonab-CD3 use has been accompanied by increases in anti-IL-2R products as well as rabbit antithymocyte globulin. Basiliximab, rabbit antithymocyte globulin, and daclizumab have all been used with increasing frequency to treat rejection over the past several years; each was used for approximately 3% of rejection episodes in 2000 (Figure 9). For those recipients who developed rejection episodes, the utilization of steroids did not change appreciably from 1992 (92%) to 2000 (90%). Incidence of rejection at 1 year in liver transplant recipients, 1992–2000. Source: 2002 OPTN/SRTR Annual Report, Table 9.6. Use of antibody therapy for rejection episodes following liver transplantation, 1992–2000. Source: 2002 OPTN/SRTR Annual Report, Table 9.6. Note: Many of the original data collection forms (and, therefore, the OPTN/SRTR database) list brand names for drugs rather than generic names. Trends in antibody therapy for rejection episodes following liver transplantation, 1996–2000. Source: 2002 OPTN/SRTR Annual Report, Table 9.6. Note: Many of the original data collection forms (and, therefore, the OPTN/SRTR database) list brand names for drugs rather than generic names. The interpretation of induction therapy trends in intestine transplant recipients is limited by the relatively small number of patients and incomplete reporting information in recent cohorts. Over the years 1999, 2000, and 2001, immunosuppression information was not available for 24%, 19%, and 18% of the 71, 79, and 111 intestine recipients, respectively. Nonetheless, with the availability of daclizumab in 1998, the use of antibody preparations for induction therapy increased substantially. In 1999, 2000 and 2001, some form of antibody induction was employed in 56% of 54 recipients, 67% of 64 recipients and 50% of 91 recipients, respectively, compared to only 8% of the 64 recipients in 1997. The most frequently selected preparation over the past 3 years has been daclizumab. Although a small number of intestine transplant recipients have been maintained on cyclosporine, the overwhelming majority have been placed on tacrolimus. This trend has not changed over time. Tacrolimus was selected for 100% of the 16 patients in 1992, 92% of 24 in 1996, and 97% in 2001 (information available for 76 patients). Corticosteroids were regularly used for nearly all patients until 2001, when steroid administration prior to discharge fell from 98% to 76%. This drop may be related, in part, to reports by Shapiro and others in which steroids were successfully withdrawn in pediatric intestine transplant recipients (9). Rapamycin, which was not used in 1998 or 1999, was used in 44% of patients in 2000. However, the addition of rapamycin as a maintenance therapy agent could not directly account for the decline in steroids in 2001, since rapamycin usage fell to 14% that year. Antimetabolites, used in over 50% of patients during 1996 and 1997, have fallen out of favor since that time. Mycophenolate mofetil was utilized in 44% of recipients in 1997, but only 3% of patients in 2001 (see Figure 10). The gastrointestinal toxicity of mycophenolate mofetil, as well as concerns regarding the development of tissue-invasive cytomegalovirus virus infections and post-transplant lymphoproliferative disorders, may have played a role in this trend (10, 11). Intestine transplant immunosuppression prior to discharge: use of mycophenolate mofetil, 1993–2001. Source: 2002 OPTN/SRTR Annual Report, Table 10.6. In intestine transplant recipients, the incidence of graft rejection requiring treatment during the first year declined from more than three-quarters of 22 patients in 1992 to less than one-half of 79 patients in 2000 (Figure 11). The most dramatic drop was noted from 1997 to 1998, when the incidence of treated rejection fell from 68% to 33%. This decline correlates with modifications made to the induction therapy regimens in intestine transplantation, specifically the use of daclizumab, which was not used at all in 1997, but was used in 37% of recipients in 1998. There were no other major changes in maintenance immunotherapy during this same period. Incidence of rejection at 1 year in intestine transplant recipients, 1992–2000. Source: 2002 OPTN/SRTR Annual Report, Table 10.6. The use of antilymphocyte antibody induction for heart transplantation increased over the past 10 years, from 9% of 2152 in 1992 to 44% of 2058 in 2001. In the past decade, muromonab-CD3 and ATG combined accounted for the majority of the induction used, ranging from 9% of all recipients in 1992 to 36% in 1994. Since 1994, the choice of these agents for induction slowly declined such that by 2001, the use of muromonab-CD3 and ATG for induction was down to 16% of induction cases. In contrast, rabbit antithymocyte globulin became more popular over the last 3 years, accounting for 3% of antibody induction in 1999 and increasing to 11% in 2001. In addition, the use of the anti-IL-2 receptor antibodies (daclizumab and basiliximab) for induction increased over the last four years. In 1998, 1% of recipients received induction with the anti-IL-2 receptor inhibitors, compared to 18% in 2001. The use of the anti-IL-2 receptor antibodies exceeded the use of ATG and muromonab-CD3 for induction in 2001. Daclizumab accounted for the majority of the anti-IL-2 receptor antibody used in 2001, and represented 13% of all recipients. From 1992 to 2001, the use of corticosteroids for heart transplantation prior to discharge from the hospital remained relatively unchanged, ranging from 94% to 97%. The use of cyclosporine declined over the same period. In 1992, 98% of heart transplant recipients were discharged from the hospital on cyclosporine, compared to only 71% in 2001. Between 1992 and 1995, the majority of recipients (83–98%) were on Sandimmune. In 1995, 4% of heart transplant recipients were discharged from the hospital on Neoral, with a substantial increase in 1996 to 58%. From 1997 to 2000, Neoral use remained fairly constant at approximately 72% of all recipients, falling in 2001 to 59%. In 2001, 8% of heart transplant recipients were discharged on Gengraf and only 4% of recipients were discharged on Sandimmune. Aside from the use of generic cyclosporine preparations, part of the decline in Neoral use at discharge can be attributed to the use of tacrolimus, whose use at discharge increased from 0.6% in 1993 to 29% in 2001. The use of antimetabolites (azathioprine and mycophenolate mofetil) at discharge remained fairly consistent and very common over the last 10 years, ranging from 82% to 96%. The use of azathioprine dropped sharply over the same period, from 95% in 1992 to 15% in 2001. Conversely, mycophenolate mofetil use at discharge increased dramatically, rising from 0.6% in 1993 to 79% in 2001. Cyclophosphamide use at discharge remained at a low level over the study period, ranging from 0.5% to 1.4%. On the other hand, the use of rapamycin has slowly increased, climbing from 0.1% in 1998 to 4% in 2001. The majority (88–96%) of heart transplant recipients were on corticosteroids 1 year after transplantation, similar to the time of discharge. The use of cyclosporine for maintenance immunosuppression declined from 99% in 1992 to 78% in 2000. In 2000, 69% of recipients were using Neoral, with 5% each on Gengraf and Sandimmune. Maintenance use of tacrolimus rose steadily since 1992, when only 1% of recipients used it 1 year post-transplant; 30% used it in 2000. Over the last 9 years, antimetabolites have been used somewhat less often for maintenance immunosuppression than initially at discharge, ranging from 86% to 97%. The percentage of patients on mycophenolate mofetil steadily increased from 17% in 1995 to 79% in 2000. Conversely, the percentage of patients maintained on azathioprine dropped from 97% in 1992 to 19% in 2000. The use of cyclophosphamide for maintenance immunosuppression also dropped, drifting downward slightly from 2% in 1992 to 0.7% in 2000. Rapamycin use rose from 0.1% in 1997 to 5% in 2000. In 2000, the most common maintenance therapy combination for heart transplant recipients consisted of corticosteroids, cyclosporine (Neoral) or tacrolimus, and mycophenolate mofetil. Approximately 40% of heart transplant recipients receive antirejection treatment and this figure remained fairly constant from 1992 to 2000, dipping slightly in 1996 and 1997. Regardless of the year of transplantation, the majority of heart transplant recipients received corticosteroids as part of their antirejection treatment regimen. The distribution of corticosteroid use for the treatment of rejection ranged from 88% to 92%. In 2000, 16% of the 2197 heart transplant patients received antibody therapy to reverse a rejection epis