|
|
| |||||||||||||||||||||||||||||||
Background Tacrolimus (FK 506), a macrolide compound isolated from a bacterium, is a potent immunosuppressant with activity in solid-organ transplants. Most immunosuppressive regimens for liver transplantation are based on cyclosporine.
Methods We conducted an open-label, randomized, multicenter trial to compare the efficacy and safety of tacrolimus-based and cyclosporine-based immunosuppressive regimens for patients receiving a first liver transplant. A total of 478 adults and 51 children (
Results According to Kaplan-Meier analysis, actuarial patient-survival rates at day 360 were 88 percent for both the tacrolimus and cyclosporine groups (P = 0.85; 95 percent confidence interval for the difference, -5.4 to 6.6 percent), and graft-survival rates were 82 percent and 79 percent, respectively (P = 0.55; 95 percent confidence interval for the difference, -4.8 to 9.7 percent). Acute rejection occurred in 154 patients in the tacrolimus group and 173 patients in the cyclosporine group (P<0.002), corticosteroid-resistant rejection occurred in 43 and 82 patients, respectively (P<0.001), and refractory rejection occurred in 6 and 32 patients, respectively (P<0.001). Tacrolimus was associated with a higher incidence of adverse events requiring withdrawal from the study, primarily nephrotoxicity and neurotoxicity; 37 patients in the tacrolimus group and 13 in the cyclosporine group discontinued the study because of adverse events (P<0.001).
Conclusions After one year, immunosuppressive regimens based on tacrolimus and cyclosporine were comparable in terms of patient and graft survival. Tacrolimus was associated with significantly fewer episodes of acute, corticosteroid-resistant, or refractory rejection, but substantially more adverse events requiring discontinuation of the drug.
12 years of age) were randomly assigned at the time of transplantation to receive tacrolimus (n = 263) or cyclosporine (n = 266) and were followed for one year. The primary end points were patient and graft survival at one year. The secondary end points were the incidence of acute rejection, corticosteroid-resistant rejection, and refractory rejection (continued rejection after two courses of corticosteroids and an intervening course of muromonab-CD3).
Tacrolimus (FK 506), a macrolide compound isolated from Streptomyces tsukubaensis, has potent immunosuppressive properties6,7. In the laboratory, tacrolimus inhibits the mixed-lymphocyte reaction, the formation of interleukin-2 by T lymphocytes, and the formation of other soluble mediators, including interleukin-3 and interferon gamma. As an immunosuppressive agent, tacrolimus is approximately 100 times more potent than cyclosporine8,9,10,11,12. In animals, it prevents graft rejection and prolongs graft survival in experimental liver, kidney, and heart transplantations13,14,15,16,17,18. The immunosuppressive properties of tacrolimus have been confirmed in people undergoing liver, kidney, and heart transplantations19,20,21,22,23,24,25,26,27,28. On the basis of these preliminary results, we conducted an open-label, multicenter, randomized trial to compare the efficacy and safety of tacrolimus-based and cyclosporine-based immunosuppressive regimens in patients undergoing primary liver transplantation.
Methods
Patient Eligibility
The study was conducted at 12 centers in the United States between August 1990 and October 1992. The protocol was approved by the institutional review board at each center, and the patients gave written informed consent before enrollment. Eligible patients had end-stage liver disease and were approved by the patient-selection committee at each center on the basis of specific criteria. Premenopausal women were required to have a negative pregnancy test at entry into the study and to use effective birth-control practices.
Patients were excluded if they were undergoing multiple-organ transplantation, had previously received a liver transplant, or were receiving an ABO-incompatible transplant. Pregnant or nursing women were excluded, as were patients with serious infections, vasculitis, or arteritis; patients requiring anticoagulants or thrombolytic agents (except those with Budd-Chiari syndrome); and patients with cancer, renal failure (defined as a serum creatinine concentration exceeding 2.0 mg per deciliter [180 µmol per liter], glomerular filtration rate below 30 ml per minute, or dependency on dialysis), stage IV hepatic encephalopathy, or seropositivity for the human immunodeficiency virus.
Treatment
Before liver transplantation, the patients were randomly assigned in blocks of four to the treatment groups according to a computer-generated code that the investigators did not know. Initially, patients randomly assigned to tacrolimus (Prograf, Fujisawa USA, Deerfield, Ill.) received a dose of 0.075 mg per kilogram of body weight in a 4-hour intravenous infusion every 12 hours until the medicine could be taken orally. Because of early reports of renal dysfunction with tacrolimus, the intravenous dose was subsequently reduced to 0.05 mg per kilogram and administered over a 12-hour period twice daily. Before the protocol was revised, 48 patients received the higher dose of tacrolimus. The first dose was started 6 to 24 hours after liver transplantation but was delayed for up to 48 hours if urinary output was 20 ml per hour. Oral tacrolimus was begun at a dose of 0.15 mg per kilogram every 12 hours. The dose was based on ideal body weight unless the patient's weight was less than ideal, in which case actual weight was used. The dose was adjusted in the event of adverse effects of the study drug, rejection, or a trough plasma level of less than 0.2 or more than 5 ng per milliliter. The maximal dose of tacrolimus allowed in the protocol was 0.6 mg per kilogram per day orally or 0.44 mg per kilogram per day intravenously. Plasma levels of tacrolimus were determined initially at a central laboratory and eventually at each clinical site. Plasma was separated at 37 °C and analyzed by enzyme-linked immunosorbent assay with liquid-liquid extraction29.
The patients also received hydrocortisone (1000 mg intravenously) during or immediately after surgery, followed by methylprednisolone (100 mg intravenously or orally, decreasing by 20 mg daily over a period of five days). Treatment with oral prednisone (20 mg per day) or its equivalent was initiated in adults when tolerated, and the dose was tapered to 5 mg per day over a period of three months. Children received prednisone (10 mg per kilogram) or an equivalent dose of methylprednisolone intravenously, and the dose was decreased by 2 mg per kilogram per day over a period of five days. Thereafter, prednisone was continued at a dose of 0.3 mg per kilogram per day and gradually tapered to 0.1 mg per kilogram per day over a period of three months.
Immunosuppressive regimens based on cyclosporine (Sandimmune, Sandoz Pharmaceuticals, East Hanover, N.J.) varied among centers. At 10 centers, cyclosporine (1 mg per kilogram intravenously every 12 hours) and azathioprine (Imuran, Burroughs Wellcome, Research Triangle Park, N.C., at a daily dose of 2 mg per kilogram intravenously) were given preoperatively and corticosteroids were initiated during the procedure. At one center (University of Nebraska; 31 patients), preoperative cyclosporine was initiated at a dose of 2 mg per kilogram intravenously every 12 hours for one to two days, followed by a dose of 5 mg per kilogram orally every 12 hours, and steroids were begun intraoperatively. At another center (University of California, San Francisco; 27 patients), azathioprine at a dose of 2 mg per kilogram intravenously or orally once daily was begun preoperatively and continued for the duration of the study, Minnesota antilymphoblast globulin at a daily dose of 10 mg per kilogram was begun on the first postoperative day and continued for five days, steroids were begun intraoperatively, and cyclosporine was started on day 4. At all 12 centers, the adult maintenance dose of steroids in the cyclosporine group was a prednisone equivalent of 200 mg daily beginning the first day after transplantation, and the dose was tapered to 20 mg by day 6, 15 mg by day 60, 12.5 mg by day 180, and 10 mg by day 360. In children, prednisone or its equivalent was begun at a dose of 10 mg per kilogram per day on postoperative day 1, decreased by 2 mg per kilogram per day over a period of five days, and then adjusted at the investigator's discretion. Cyclosporine levels were measured according to the method used at each study site and were adjusted to maintain trough whole blood concentrations between 250 and 400 ng per milliliter as measured by a method specific for the parent compound or its equivalent.
Treatment of Rejection Episodes
All the patients had liver biopsies on days 7, 28, and 360 after transplantation and when rejection was suggested by a deterioration in liver function (changes in total bilirubin, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, or 
-glutamyltransferase concentrations) or the appearance of clinical signs (fever, jaundice, pruritus, ascites, or hepatic tenderness). Whenever rejection was suggested, the diagnosis was confirmed by histologic findings on liver biopsy. The diagnosis required that biliary obstruction, hepatic vascular insufficiency, viral hepatitis, and cytomegalovirus be ruled out by ultrasonography, cholangiography, and when indicated, appropriate viral serologic analyses and cultures. In adults, the first episode of rejection was treated with one or two intravenous doses of 1000 mg of methylprednisolone followed by six days of prednisone or its equivalent, starting at a dose of 200 mg per day and tapering to a dose of 20 mg per day. Children received intravenous methylprednisolone at a dose of 20 mg per kilogram followed by six days of prednisone or its equivalent, starting at a dose of 10 mg per kilogram per day and tapering to a dose of 0.3 mg per kilogram per day.
When abnormal liver-function tests and clinical signs of rejection persisted after the completion of a course of corticosteroids, the possibility of corticosteroid-resistant rejection was considered. A liver biopsy showing evidence of rejection was required to confirm corticosteroid-resistant rejection. Muromonab-CD3 (OKT3, Orthoclone, Ortho Pharmaceuticals, Raritan, N.J.) was then given once daily at a dose of 5 mg per day intravenously in adults or 2.5 mg per day intravenously in children and continued for 10 to 14 days. Refractory rejection was defined as continued rejection, as documented by liver biopsy, after a course of corticosteroids, muromonab-CD3, and a second course of corticosteroids. Patients with refractory rejection could, at the discretion of the treating physicians, continue taking the study drug, switch to treatment with the alternative study drug, be treated with other investigational immunosuppressive agents, receive additional therapy outside the study, or undergo a second transplantation.
For each patient, a physical examination was performed and a complete medical history and 12-lead electrocardiogram were obtained just before transplantation and one year later. Routine laboratory tests including urinalysis, hematologic analysis, assessment of coagulation, and serum chemical analyses were performed before transplantation and 7, 14, 28, 180, and 360 days afterward. Specific viral studies were performed as determined at each site. The glomerular filtration rate was measured before transplantation and at days 28 and 360. Adverse events of new onset or increased severity were recorded for every patient during the entire study.
Statistical Analysis
The sample size was calculated to detect a 10 percent difference between tacrolimus and cyclosporine in the one-year rate of graft survival with 80 percent power at the 5 percent level of significance (by two-sided test). The primary end points were patient survival and graft survival at one year. Secondary end points included acute rejection, the use of muromonab-CD3 for corticosteroid-resistant rejection, and refractory rejection. All patients were followed for a minimum of 12 months after transplantation or until death. Analysis was by intention to treat and included all patients who underwent randomization and transplantation. Events were attributed to treatment beginning on the day after surgery. Patient and graft survival was estimated for each of the treatment groups with the Kaplan-Meier method30. Differences between the estimated survival curves for each treatment were analyzed with the Wilcoxon test. Confidence intervals were computed 12 months after transplantation31. Before data were pooled across sites, the potential interaction of treatment and study site was examined. Comparisons of laboratory-test results were based on group mean values over time and changes from base line.
Results
The patients were enrolled from August 1990 to October 1991; 529 patients were enrolled, underwent transplantation, and received at least one dose of the study drugs (263 received tacrolimus and 266 received cyclosporine). Of these, 30 patients receiving tacrolimus and 21 receiving cyclosporine were 12 years of age or younger. An additional 26 patients underwent randomization but were not enrolled because they did not meet the eligibility requirements after transplantation. One patient was randomly assigned to cyclosporine but treated with tacrolimus; this patient was included in the analysis. Eighty-eight percent of the 598 patients screened for the study were enrolled. No significant differences in base-line characteristics or the cause of liver failure were observed between treatment groups (Table 1).
|
Table 2 shows the number of patients who died or underwent a second transplantation or in whom rejection occurred during the one-year follow-up. Kaplan-Meier estimates of one-year patient and graft survival were not significantly different between treatment groups (Figure 1). Actuarial rates of patient survival at day 360 were 88 percent for both treatment groups (P = 0.85; 95 percent confidence interval for the difference, -5.4 to 6.6 percent), and graft-survival rates at day 360 were 82 percent for the tacrolimus group and 79 percent for the cyclosporine group (P = 0.55; 95 percent confidence interval for the difference, -4.8 to 9.7 percent). Sixty-four patients, 31 in the tacrolimus group and 33 in the cyclosporine group, died during the study or after being withdrawn from it. A total of 52 patients (24 given tacrolimus and 28 given cyclosporine) underwent a second transplantation for primary nonfunction of the liver graft (11 given tacrolimus and 10 given cyclosporine), vascular or biliary complications (8 given tacrolimus and 10 given cyclosporine), rejection (5 given tacrolimus and 4 given cyclosporine), or recurrent hepatitis (4 given cyclosporine). Analysis of treatment according to study site revealed no significant differences between treatment groups in patient or graft survival across centers at 6 and 12 months, except at the Mayo Clinic, where significantly better patient survival (P = 0.018) and graft survival (P = 0.008) were reported at one year in the tacrolimus group.
|
|
|
Table 3 shows the reasons for withdrawal from the trial. Thirty-seven patients in the tacrolimus group and 13 in the cyclosporine group were withdrawn from the study (P<0.001) at the discretion of the physician because of adverse events, most commonly nephrotoxicity and neurotoxicity in both groups. Detailed information on adverse events is given in Table 4.
|
|
Hyperkalemia was reported more frequently in the tacrolimus group, although mean serum potassium values were within the normal range in both groups. Hyperglycemia was reported more frequently in the tacrolimus group than in the cyclosporine group, but the incidence gradually decreased after transplantation. Among the patients who were not dependent on insulin before transplantation, 11 of those receiving tacrolimus and 5 of those receiving cyclosporine continued to require insulin therapy by day 360. Neoplasms were diagnosed in 5 patients receiving tacrolimus and 19 receiving cyclosporine; all but 5 cases were detected more than one month after transplantation. Four deaths, all in the cyclosporine group, were attributed to laryngeal cancer, renal-cell carcinoma, hepatic adenoma, or large B-cell lymphoma.
Discussion
We compared a regimen of tacrolimus and low-dose corticosteroids with the best cyclosporine-based regimen at each institution. This design helped ensure that the liver-transplantation results in the control group would be comparable to the highest success rate at the institution. After one year of follow-up, the rates of patient and graft survival were comparable between treatment groups but were substantially higher than comparable survival rates reported by the United Network for Organ Sharing or the University of Pittsburgh with cyclosporine-based therapy1,32. The higher rates of patient and graft survival may reflect the exclusion of high-risk patients and the use of the best available cyclosporine regimen at each site.
The tacrolimus-based regimen was significantly better than the cyclosporine-based regimen at preventing acute, corticosteroid-resistant, and refractory rejection. Fewer tacrolimus-treated patients had refractory rejection requiring withdrawal from the study and the use of an alternative immunosuppressive agent despite the administration of lower doses of corticosteroids and avoidance of the use of azathioprine. The low number of second transplantations for refractory rejection may have been due, in part, to the effectiveness of tacrolimus in treating patients in the cyclosporine group who had refractory rejection.
Nephrotoxicity, neurotoxicity, impaired glucose metabolism, hypertension, infection, and gastrointestinal disturbances were common in both treatment groups. The majority of adverse events occurred early, and the incidence decreased over time, often in association with a reduction in the dose of tacrolimus or cyclosporine. Fourteen percent of the patients treated with tacrolimus discontinued treatment because of adverse events, as compared with 5 percent of the patients treated with cyclosporine. Standard cyclosporine-based therapy was available to patients given tacrolimus who had adverse events, whereas tacrolimus, as an experimental drug at the time, was not available to patients given cyclosporine who had adverse events.
A high incidence of nephrotoxicity has been reported with both tacrolimus and cyclosporine33,34,35,36,37,38,39. In our study, although nephrotoxicity was reported more often with tacrolimus, the mean glomerular filtration rate and serum creatinine concentration were similar in the two groups. Nephrotoxicity is related in part to the dose of the drug and its levels in plasma, and the decrease in nephrotoxicity over time may reflect both a decrease in the dose of tacrolimus and a more rapid conversion to oral therapy as experience with the medication increased. Although hyperkalemia was reported in both groups, it was clinically manageable with a decrease in the dose of tacrolimus or treatment with sodium polystyrene sulfonate or fludrocortisone. The higher incidence of diarrhea, nausea, and vomiting with tacrolimus is troublesome but not surprising, since tacrolimus is a macrolide, a class of drugs frequently associated with gastrointestinal upset.
Recently, a multicenter European study comparing tacrolimus and cyclosporine in a randomized, open-label trial had similar results40. Analysis of data on 545 recipients of a primary liver transplant 12 months after transplantation showed that the rates of patient and graft survival were not significantly different between groups but that tacrolimus was associated with significantly fewer episodes of acute, refractory acute, and chronic rejection. The most serious adverse events -- renal impairment, disturbances of glucose metabolism, and neurologic complications -- were more common in the group receiving tacrolimus.
In summary, we found that a regimen of tacrolimus and low-dose corticosteroids was comparable to regimens based on cyclosporine in its ability to prevent rejection after liver transplantation. Tacrolimus was more effective than cyclosporine in preventing acute, corticosteroid-resistant, and refractory rejection but was associated with an increased incidence of adverse events.
Supported by Fujisawa USA Inc., Deerfield, Ill.
Source Information
Dr. Klintmalm assumes full responsibility for the overall content and integrity of the manuscript.Members of the U.S. Multicenter FK506 Liver Study Group are listed in the Appendix.
Address reprint requests to Dr. Goran B. Klintmalm at Baylor University Medical Center, 3500 Gaston Ave., Dallas, TX 75246.
References
The members of the U.S. Multicenter FK506 Liver Study Group are as follows: R.W. Busuttil and S. McDiarmid (UCLA, Los Angeles); G.B. Klintmalm and R. Goldstein (Baylor University Medical Center, Dallas); C.M. Miller and M. Schwartz (Mt. Sinai Medical Center, New York); B.W. Shaw (University of Nebraska, Omaha); J.P. Roberts and M.F. Hebert (University of California, San Francisco); C.O. Esquivel and P. Nakazato (California Pacific Medical Center, San Francisco); R.H. Wiesner and R.A.F. Krom (Mayo Clinic, Rochester, Minn.); M. Kalayoglu and A.M. D'Alessandro (University of Wisconsin, Madison); J.W. Marsh and M.G. Peters (Washington University School of Medicine, St. Louis); J. Burdick and A. Klein (Johns Hopkins Hospital, Baltimore); W.D. Lewis and R. Jenkins (New England Deaconess Hospital, Boston); J.R. Thistlethwaite and J.C. Emond (University of Chicago, Chicago); W.J. Jusko and R. D'Ambrosio (State University of New York, Buffalo); and D. Buell and W.E. Fitzsimmons (Fujisawa, USA, Deerfield, Ill.).
| |||||||||||||||||||||||||||||||
This article has been cited by other articles:
HOME | SUBSCRIBE | SEARCH | CURRENT ISSUE | PAST ISSUES | COLLECTIONS | PRIVACY | TERMS OF USE | HELP | beta.nejm.org Comments and questions? Please contact us. The New England Journal of Medicine is owned, published, and copyrighted © 2010 Massachusetts Medical Society. All rights reserved. |
Previous
