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Immunosuppression: practice and trends

2004; Elsevier BV; Volume: 4; Linguagem: Inglês

10.1111/j.1600-6135.2004.00397.x

1600-6143

Dixon B. Kaufman, Ron Shapiro, Michael R. Lucey, Wida S. Cherikh, Rami Bustami, D.B. Dyke,

Transplantation: Methods and Outcomes

American Journal of TransplantationVolume 4, Issue s9 p. 38-53 Free Access Immunosuppression: practice and trends Dixon B. Kaufman, Corresponding Author Dixon B. Kaufman Northwestern University, Feinberg School of Medicine, Chicago, IL; Corresponding author: Dixon B. Kaufman, d-kaufman2@northwestern.eduSearch for more papers by this authorRon Shapiro, Ron Shapiro University of Pittsburgh, Pittsburgh, PA;Search for more papers by this authorMichael R. Lucey, Michael R. Lucey University of Wisconsin-Madison, School of Medicine, Madison, WI;Search for more papers by this authorWida S. Cherikh, Wida S. Cherikh United Network for Organ Sharing (UNOS), Richmond, VA;Search for more papers by this authorRami T. Bustami, Rami T. Bustami University Renal Research and Education Association, Ann Arbor, MI;Search for more papers by this authorDavid B. Dyke, David B. Dyke University of Michigan Health System, Ann Arbor, MISearch for more papers by this author Dixon B. Kaufman, Corresponding Author Dixon B. Kaufman Northwestern University, Feinberg School of Medicine, Chicago, IL; Corresponding author: Dixon B. Kaufman, d-kaufman2@northwestern.eduSearch for more papers by this authorRon Shapiro, Ron Shapiro University of Pittsburgh, Pittsburgh, PA;Search for more papers by this authorMichael R. Lucey, Michael R. Lucey University of Wisconsin-Madison, School of Medicine, Madison, WI;Search for more papers by this authorWida S. Cherikh, Wida S. Cherikh United Network for Organ Sharing (UNOS), Richmond, VA;Search for more papers by this authorRami T. Bustami, Rami T. Bustami University Renal Research and Education Association, Ann Arbor, MI;Search for more papers by this authorDavid B. Dyke, David B. Dyke University of Michigan Health System, Ann Arbor, MISearch for more papers by this author First published: 14 May 2004 https://doi.org/10.1111/j.1600-6135.2004.00397.xCitations: 146 Notes on Sources: : The articles in this report are based on the reference tables in the 2003 OPTN/SRTR Annual Report, which are not included in this publication. Many relevant data appear in the figures included here; other tables from the Annual Report that serve as the basis for this article include the following: Tables 5.6a–d, 6.6a–d, 7.6a–d, 8.6a–d, 9.6a–d, 10.6a–d, 11.6a–d, 12.6a–d, and 13.6a–d. All of these tables are also available online at http://www.ustransplant.org. Funding: : The Scientific Registry of Transplant Recipients (SRTR) is funded by contract #231-00-0116 from the Health Resources and Services Administration (HRSA). The views expressed herein are those of the authors and not necessarily those of the US Government. This is a US Government-sponsored work. There are no restrictions on its use. AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Abstract Over the past decade, immunosuppression therapy has undergone striking changes in the scale and pace by which new immunosuppressive molecules and antibodies have become incorporated into daily transplant medicine. An organ-by-organ review of data reveals several trends. The highest use of induction therapy (over 70% of patients) was reported for simultaneous pancreas kidney (SPK) and pancreas after kidney (PAK) transplants in 2002; use of induction therapy was less common in liver transplants (only 18%). Corticosteroids served as discharge maintenance immunosuppression in over 87% of the recipients of kidney, SPK, PAK and thoracic transplants, and in over 70% of pancreas transplant alone (PTA) recipients. Corticosteroid use in intestine transplants was reported in 64% of recipients in 2002. A shift in the calcineurin inhibitor used for maintenance immunosuppression from cyclosporine to tacrolimus for the majority of patients had occurred for kidney, PAK, SPK, PTA, liver, lung, and heart-lung by 2001. For heart transplants, cyclosporine remained the calcineurin inhibitor of choice; tacrolimus remained the predominant calcineurin inhibitor agent for intestine (since 1994). Use of antibody treatment for rejection during the first post-transplant year for most organs declined. Short-term outcomes have improved, based on the observation that rates of rejection within the first year post-transplant have diminished. Introduction This article analyzes solid organ transplantation over the 10-year time span of 1993–2002. This period has been distinguished by marked changes in the clinical practice of transplantation in general, and in immunosuppressive strategies in particular. Certain aspects of the evolutionary changes of immunotherapeutics are captured quite nicely by the OPTN/SRTR (Organ Procurement & Transplant Network/Scientific Registry of Transplant Recipients) data. Particularly strong components include the scale and pace by which the new immunosuppressive molecules and antibodies have become incorporated into the daily activities of transplant medicine. A careful organ-by-organ review of the data indicates how much has changed over the 10-year span beginning in 1993. Regarding the use of maintenance immunosuppression, practice patterns indicate a strong role of calcineurin inhibitor-based immunosuppression. Yet this was occurring during a time when the availability of generic versions of cyclosporine was expanding and the collective use of cyclosporines, generally, was rapidly diminishing. In its place has been a sustained transition to the use of tacrolimus. Similar trends were also observed with the antimetabolites azathioprine and mycophenolate mofetil—the latter being used in the vast majority of transplant recipients. Recent years have seen the advent of the novel agent rapamycin, although its use has not mimicked the rapid and consistently successful incorporation of tacrolimus and mycophenolate mofetil. This may be indicative of uncertainty regarding its role in maintenance immunosuppression in organ transplantation at this juncture. One practice trend in the use of maintenance immunotherapy that is not clearly elucidated by the data is the intensity of the immunosuppression. In one respect, it could be concluded that overall intensity has increased. Evidence of this viewpoint could be derived from increased use of the potent agents tacrolimus, mycophenolate mofetil, and rapamycin. From another perspective, there are clues that efforts are ongoing with aims of immunosuppression minimization. A hint of that is suggested by the subtle changes in the reduced application of chronic corticosteroid therapy. With more detailed data a more precise assessment could be deduced of the relative dosing schedules of the individual agents. Unfortunately, one of the limitations of the data is that it is relatively qualitative in nature. Specifics regarding the pharmacological exposure of the recipients to the individual agents are understandably beyond the SRTR aims at this time. Regarding antibody-based induction therapy, practice patterns indicate that its use and intensity are rising each year. There are consistent trends indicating a switch to T-cell depleting agents, especially rabbit antithymocyte globulin. The lack of quantitative data regarding the actual dosing and duration of therapy, however, does not allow trends to be determined in that context. Use of alemtuzumab (Campath® ILEX Pharmaceuticals, San Antonio, TX) induction therapy (as an alternative T-cell depleting agent) and rituximab (Rituxan® Genentech, South San Francisco, CA) immunotherapy (used in antibody desensitization protocols) are beginning to be incorporated into practice, but have not reached a degree of penetration to be meaningful from a macroscopic viewpoint. What follows is an examination of general practice trends in the use of maintenance and induction therapy being applied to kidney, pancreas, kidney-pancreas, liver, intestine, heart, heart-lung, and lung transplant recipients. It is the most complete, detailed, and up-to-date analysis of its kind available. Importantly, it is only through the collective efforts of the transplant community that this information is made available to transplant professionals and the multiple constituents with an interest in the field. Unless otherwise noted, the statistics in this article come from reference tables in the 2003 OPTN/SRTR Annual Report. Two companion articles in this report, ‘Transplant data: sources, collection, and caveats’ and ‘Analytical approaches for transplant research’, explain the methods of data collection, organization, and analysis that serve as the basis for this article (1, 2). Additional detail on the methods of analysis may be found in the reference tables themselves or in the Technical Notes of the OPTN/SRTR Annual Report, both available online at http://www.ustransplant.org. Kidney Transplantation Trends in induction therapy in kidney transplantation The period from 1993 to 2002 has seen a gradual but definitive shift toward routine use of antibody induction therapy. In 1993, 11% of patients undergoing kidney transplantation received antibody induction; by 2002 the proportion of kidney recipients who received antibody induction therapy was 65%. In addition to the increased use of antibody preparations for induction, there has been a marked shift in the type of antibody preparation (Figure 1). Muromonab-CD3 (OKT3® Orthobiotech, Bridgewater, NJ), which peaked in use in 1995 (administered to 25% of kidney transplant recipients) and accounted for virtually all the antibody used for induction, had fallen to 1% by 2002. Similar trends were observed for equine antithymocyte globulin (ATGAM® Pharmacia & Upjohn, Kalamazoo, MI). Equine antithymocyte globulin, which had peaked in use in 1997 (received by 16% of kidney transplant recipients), had fallen to 2% by 2002. The overwhelming majority of patients receiving antibody induction in 2002 received agents not available in 1993. These new agents included rabbit antithymocyte globulin (Thymoglobulin® SangStat Medical Corp., Fremont, CA), which accounted for 26% of patients, basiliximab (Simulect® Novartis, East Hanover, NJ), which accounted for 27%, and daclizumab (Zenapax® Roche, Nutley, NJ), which accounted for 13% of patients. It is interesting to note that although daclizumab received FDA approval prior to basiliximab, basiliximab very quickly became the most commonly used induction agent shortly after its approval by the FDA. This may be related to the smaller number of doses (two) associated with its approved use and the ability to give both doses during the initial hospitalization at the time of transplantation. Figure 1Open in figure viewerPowerPoint Trends in kidney transplantation induction immunosuppression, 1993–2002. Induction therapy was used less frequently in recipients of kidneys from living versus deceased donors, but additional SRTR analysis showed that the difference was small. In 2002, the proportion of living and deceased donor recipients receiving induction therapy was 62% and 67%, respectively. With respect to the type of induction agent used in recipients of kidneys from deceased donors, rabbit antithymocyte globulin was used most commonly (29%), followed by basiliximab (27%). The type of induction agent used most commonly, however, in recipients of kidneys from living donors was basiliximab (27%), followed by rabbit antithymocyte globulin (21%). Trends in maintenance immunosuppression therapy prior to discharge in kidney transplantation Calcineurin inhibitors. In 1993, 95% of patients undergoing kidney transplantation received cyclosporine; only 2% received tacrolimus (the latter had not yet been approved by the FDA) (Figure 2). The trend over the next 10 years has been a gradual but inexorable decline in the use of cyclosporine, down to 30% in 2002. Most of the cyclosporine used has been Neoral® (Novartis, East Hanover, NJ) 22% and Gengraf® (Abbott, Abbott Park, IL) 7%. Sandimmune® (Novartis, East Hanover, NJ) accounted for 1% and Eon® (Eon Labs, Laurelton, NY) for 0.2%. Tacrolimus use has increased steadily as cyclosporine use has decreased (Figure 2). In 2002, tacrolimus was used in 63% of kidney transplant recipients. The reasons for this conversion are most likely related to multicenter trial data that have suggested lower rates of acute rejection and lower rates of steroid-resistant rejection associated with tacrolimus (3, 4). Cosmetic issues, i.e. the absence of hirsutism with tacrolimus, have also played a role. Figure 2Open in figure viewerPowerPoint Trends in kidney transplant maintenance immunosuppression prior to discharge, 1993–2002. Antimetabolites and rapamycin. In 1993, azathioprine, the only routinely available antimetabolite, was used in 86% of kidney transplant recipients; by 2002 this had decreased to 2% (Figure 2). Mycophenolate mofetil, which was approved by the FDA in 1995, has seen its use increase to 79% of patients undergoing kidney transplantation. This high percentage rate has remained relatively constant over the last several years. In all, 81% of kidney recipients received some sort of antimetabolite in 2002. Rapamycin was received by 15% of the patients in 2002. This was down slightly from 17% in 2001. The most popular combination regimen in recent years has included tacrolimus and mycophenolate mofetil, which has been utilized in the majority of patients undergoing kidney (or pancreas) transplantation. This combination has been shown to be effective in several single and multicenter prospective randomized trials (4-6). Corticosteroids. In 1993, 99% of patients received corticosteroids, either in the form of intravenous methylprednisone or prednisone. In 2002, 91% of patients received corticosteroids, suggesting that there is a growing percentage of patients who are receiving either steroid avoidance or near avoidance protocols after kidney transplantation (7-9). Trends in maintenance immunosuppression therapy for the first year in kidney transplantation Calcineurin inhibitors. The data in this section mirror the data described in the previous section. Cyclosporine was used in 96% of kidney transplant recipients in 1992. This had decreased to 39% by 2001. In 2001, Neoral® accounted for the vast majority of cyclosporine use (31%), Gengraf® accounted for 9%, Sandimmune® 3%, and Eon® 0.3%. Tacrolimus, which had not yet been approved in 1992, accounted for 3% of kidney transplant patients; by 2001 this figure had increased to 64%, probably for the reasons discussed above. Antimetabolites and rapamycin. The use of antimetabolites remained high in 2001 at 83% in kidney transplant recipients, however this was down somewhat from 1999, when it was 89%. Azathioprine usage decreased from 87% in 1992 to 6% in 2001, and mycophenolate mofetil increased from 1% in 1992 to 80% in 2001. Rapamycin use increased from 0% in 1992 to 21% in 2001; virtually all this increase has occurred since its FDA approval in 1998. Corticosteroids. Corticosteroids again remain in use in virtually all patients undergoing kidney transplantation; this percentage has fallen very slightly from 99.5% in 1992 to 96% in 2001, suggesting that there is a small but growing percentage of patients who are no longer receiving corticosteroids. Trends in antirejection treatment in kidney transplantation The first important observation to be made about antirejection treatment is that the need for it has decreased dramatically. In 1992, the percentage of kidney transplant recipients undergoing antirejection treatment was 38%, by 2001 it was 17% (Figure 3). In terms of therapies for rejection, the overwhelming majority of cases were treated with corticosteroids, and this percentage has changed little over the years, remaining at 81% in 1992 and in 2001. Antibody therapy use has decreased over the years, from 53% in 1992 to 37% in 2001. The specific antibodies used to treat rejection, however, have changed dramatically (Figure 4). Antilymphocyte globulin (ALG), which peaked at 21% in 1993, has disappeared from practice. Muromonab-CD3, which peaked at 44% in 1993, is now down to 11%. The use of rabbit antithymocyte globulin, which was 0% in 1993, is now up to 18%. Interestingly, in 2001, the interleukin-2 (IL-2) receptor antagonists daclizumab and basiliximab were used in 3% and 5% of patients, respectively, as antirejection therapy, although there are little data supporting their use. Figure 3Open in figure viewerPowerPoint Trends in incidence of rejection at 1 year in kidney transplant recipients, 1993–2001. Figure 4Open in figure viewerPowerPoint Trends in antibody therapy for rejection episodes following kidney transplantation. Pancreas Transplantation Trends in induction therapy in pancreas transplantation The use of induction therapy has been shown to significantly improve pancreas graft survival rates in several subgroups. According to data from the International Pancreas Transplant Registry, the use of induction therapy in simultaneous pancreas-kidney (SPK) transplant recipients with systemic venous-enteric exocrine drainage significantly improves pancreas graft survival rates (10, 11). Interestingly, pancreas graft survival is not improved with induction therapy in the subgroups with portal venous-enteric or bladder drainage. Furthermore, SPK transplant recipients who receive induction therapy benefit from a reduced incidence and severity of biopsy-confirmed, treated, acute kidney rejection episodes. In recipients given anti-T-cell depleting induction agents, however, there was also a statistically significantly higher rate of CMV viremia/syndrome, especially in the subgroup of recipients who received organs from CMV serologically positive donors (12). For the numerically smaller groups of solitary pancreas recipients (pancreas after kidney (PAK) and pancreas transplant alone (PTA)), the addition of induction therapy is associated with a clinically significant improvement in pancreas graft survival rates. In the PAK category, the 3-year actuarial pancreas graft survival with induction therapy is 74% vs. 64% without. In the PTA category, the 1-year functional survival rate for recipients with induction therapy was 86% vs. 74% without. The use of antibody induction in pancreas transplant recipients has been relatively more common than in kidney transplantation. In SPK recipients, induction was used in 74% of patients in 2002. As in kidney transplantation, the specific agents have changed dramatically (Figure 5), so that while muromonab-CD3 was used in 56% of patients in 1995, use had decreased to 0.9% by 2002. Similarly, while equine antithymocyte globulin was used in 30% of cases undergoing SPK in 1997, use had decreased to 3% by 2002. Between 1993 and 2002, the use of rabbit antithymocyte globulin increased from 0% to 37%; the use of daclizumab increased from 0% to 16%; and the use of basiliximab increased from 0% to 25%. In PAK and PTA patients, the same trends are observed. In PAK, no antibody induction was used in 1993, but in only 28% of cases in 2002 was antibody induction not used. Most of the antibody induction in 2002 was with rabbit antithymocyte globulin (51%), daclizumab (26%), and basiliximab (8%). Similarly, in PTA patients, antibody induction was not used in 33% of patients in 2002; 58% received rabbit antithymocyte globulin, 34% received daclizumab, and 5% received basiliximab. Figure 5Open in figure viewerPowerPoint Trends in simultaneous kidney-pancreas transplantation induction immunosuppression, 1993–2002. Trends in maintenance immunosuppression therapy prior to discharge in pancreas transplantation Calcineurin inhibitors. The decrease in the use of cyclosporine between 1993 and 2002 has been even more pronounced in kidney-pancreas transplants (Figure 6). In 1993, 98% of patients received cyclosporine; this was down to 9% in 2002, with 7% receiving Neoral®, 2% receiving Gengraf®, 0.7% receiving Sandimmune®, and 0.2% receiving Eon®. Tacrolimus usage increased to 87% of SPK recipients in 2002, up from 0% in 1993. Similar findings have been noted in both PAK and PTA patients; tacrolimus use increased from 0% to 86% between 1993 and 2002 in PAK patients and from 10% to 95% in PTA patients. Figure 6Open in figure viewerPowerPoint Trends in SPK transplant maintenance immunosuppression prior to discharge, 1993–2002. Antimetabolites and rapamycin. As in kidney-pancreas transplants, antimetabolites continued to be used in the vast majority of patients, although this percentage decreased from 95% in 1993 to 80% in 2002 (Figure 6). Azathioprine usage fell from 95% to 0.9%, while mycophenolate mofetil has increased from 0% to 79%; this is down somewhat from 1999, where 88% of SPK patients received mycophenolate mofetil, and probably reflects the increased use of rapamycin. Rapamycin use in SPK patients increased from 0% in 1993 to as high as 20% in 2001; in 2002 it was down to 18%. In PAK patients, the use of antimetabolites decreased from 100% to 74%. Azathioprine usage decreased from 100% to 0.3%. Mycophenolate mofetil use increased from 0% to 74%, but this represents a decrease from a peak of 92% in 1997. In PAK patients, the use of rapamycin increased from 0% to a peak of 21% in 2001, down to 19% in 2002. In PTA patients, antimetabolite usage decreased from 87% in 1993 to 66% in 2002. Azathioprine usage again virtually disappeared, decreasing from 87% to 1%, and mycophenolate mofetil usage increased from 0% to 64%, the latter representing a decrease from 89% in 1997. In PTA patients, rapamycin usage increased steadily from 0% in 1993 to 16% in 2002. Corticosteroids. Corticosteroids were used in 99% of patients undergoing SPK in 1993; this has decreased over the last couple of years to 87% in 2002, reflecting an increased use of steroid-free protocols (13). In PAK patients, the data from the early 1990s seem somewhat incomplete, but the percentages from 1997 and 1998, with 95% and 99% receiving steroids, decreased slightly to 89% by 2002. For PTA patients, the same trends were observed. Trends in maintenance immunosuppression therapy for the first year in pancreas transplantation Calcineurin inhibitors. The change in the use of calcineurin inhibitors has again been more marked in kidney-pancreas transplants. Cyclosporine use decreased from 99.8% to 16% between 1992 and 2001; most of this again was with Neoral® 12%, Gengraf® 3%, Sandimmune® 2%, and Eon® 0.4%. In SPK recipients, tacrolimus use rose from 0.5% in 1992 to 89% in 2001. The findings in PAK and PTA patients were even more dramatic. In PAK patients, cyclosporine use decreased from 100% in 1992 to 15% in 2001; tacrolimus use increased from 0% to 93%. In PTA patients, cyclosporine use decreased from 89% to 8% between 1992 and 2001, and tacrolimus use increased from 11% in 1992 to 99% in 2001. Antimetabolites and rapamycin. Antimetabolite use decreased from 99% in 1992 to 79% in 2001 in kidney-pancreas transplants. There was a shift from azathioprine, which decreased from 99% to 2% during this time period, to mycophenolate mofetil, which went up from 0% to 78%. The latter number is a decrease from 1998, where 92% of SPK patients received mycophenolate mofetil; it probably reflects the increasing use of rapamycin. In PAK and PTA patients, the same trends are present. There has been a steady increase in the use of rapamycin in SPK patients, increasing from 0% to 27% between 1992 and 2001. This has been mirrored in PAK patients, rapamycin use has gone up from 0% to 29%. In PTA patients, rapamycin use has increased from 0% to 15% (the latter, however, presents a decrease from 2000, where 25% of PTA patients received rapamycin). Corticosteroids. Corticosteroid use in SPK patients decreased slightly from 100% in 1992 to 92% in 2001, reflecting an increased use of steroid-weaning protocols (14, 15). Steroid use, however, has remained relatively stable in PAK patients and is almost as high in PTA patients. Trends in antirejection treatment in pancreas transplantation As in kidney transplantation, there has been a marked reduction in the need for antirejection therapy. From 1992 to 2001, the incidence of rejection in SPK patients declined from 66% to 19%, in PAK patients from 45% to 14%, and in PTA patients from 54% to 13% (Figure 7). Antibody use decreased from 73% in 1992 to 29% in 2001 in SPK patients, and again the type of agents changed from muromonab-CD3 and equine antilymphoblast globulin (61% and 25%, respectively, in 1992) to rabbit antithymocyte globulin and muromonab-CD3 (accounting for 17% and 12% of patients, respectively, in 2001) (Figure 8). Corticosteroid usage has remained stable at just over 85%. In PAK and PTA patients, antibody therapies were used in a somewhat higher percentage of patients by 2001 (63% in PAK patients, 62% in PTA patients). The nature of these agents has also changed, as in the case of SPK. Figure 7Open in figure viewerPowerPoint Trends in incidence of rejection at 1 year in simultaneous kidney-pancreas transplant recipients, 1993–2001. Figure 8Open in figure viewerPowerPoint Trends in antibody therapy for rejection episodes following simultaneous kidney-pancreas transplantation. Liver Transplantation Trends in induction therapy in liver transplantation According to OPTN/SRTR data, between 1993 and 2001, the use of induction agents varied from 10% to 15% of recorded cases; by 2002 this figure had crept up to 18%. During the last 10 years, the induction agents of choice have undergone gradual change. Earlier in the era, muromonab-CD3 was the predominant agent used, reaching a zenith in 1995 when 10% of recipients received it. Since then, the use of muromonab-CD3 has declined to almost nil, whereas the use of monoclonal anti-IL2 receptor agents has increased, so that by 2002, 13% of recipients received either daclizumab or basiliximab (Figure 9). There also has been a modest resurgence in the use of rabbit antithymocyte globulin. Figure 9Open in figure viewerPowerPoint Trends in liver transplantation induction immunosuppression, 1993–2002. The reasons behind the gradual increased use of induction agents over the past 5 years are not clear. There are few studies to support or refute the use of antilymphocyte induction therapy in primary or repeated liver transplantation. One possible explanation is the introduction in 2002 of MELD-based allocation, in which liver transplantation candidates with renal failure receive priority; if such patients are being transplanted more quickly, it may reflect increased use of such agents as calcineurin inhibitor sparing agents in this population. Trends in maintenance immunosuppression therapy prior to discharge in liver transplantation Serial data from 1993 through 2002 show some consistent patterns of immunosuppressant use prior to discharge. Throughout the period, liver allograft recipients were managed on multiple drug regimens based on corticosteroids and calcineurin inhibitors. Consistently, at least 50% of recipients received an antimetabolite. During the period for which data have been collected, there have been minor and inconsistent variances in the prevalence of corticosteroid use, so that 90% of recipients were discharged on corticosteroids in 2002, compared with 95% in 1993 or 88% in 1995. Calcineurin inhibitors. In contrast, there have been striking shifts in drug selection among the calcineurin inhibitors and antimetabolites (Figure 10). For example, whereas cyclosporine (in any of its formulations) was administered to 83% of recipients prior to discharge in 1993, its rate of use has declined every year since then to reach its current nadir of 10% in 2002. Whether the newly introduced practice of monitoring the blood level 2 h (C2 monitoring) after ingestion rather than fasting trough levels will reverse this trend remains to be seen. The decline in use of cyclosporine has been mirrored by the increase in use of tacrolimus. Its use in immunosuppressant management prior to discharge increased every year from 1993 (18%) to 2002 (87%). Figure 10Open in figure viewerPowerPoint Trends in liver transplant maintenance immunosuppression prior to discharge, 1993–2002. Antimetabolites and rapamycin. Similarly, azathioprine was the antimetabolite of choice in 1993, being administered to 58% of recipients. This rate of use declined annually until 2001, when it reached a nadir of 3%. In 2002, azathioprine use showed a modest increase to 4%. At the same time azathioprine declined, mycophenolate mofetil gained in use, from 0.6% in 1993 to 48% in 2002 (Figure 10). These data suggest, but do not prove, that mycophenolate mofetil has replaced azathioprine in circumstances where the managing physicians believe that an antimetabolite is required. Finally, there has been a small increase in the use of rapamycin in the early postoperative period. It was administered to 9% and 10% of recipients in 2000 and 2001, respectively. Curiously, this prevalence of use declined to 7% in 2002, perhaps on account of reported difficulties with early postoperative management, such as wound healing and integrity of the vascular anastomoses. Trends in maintenance immunosuppression therapy for the first year in liver transplantation Perhaps the most surprising aspect of the OPTN/SRTR data on maintenance immunosuppression between discharge and the end of the first year is the unchanging results for use of corticosteroids. Thus, 93% of recipients in 1993 and 90% of recipien