A randomized controlled trial of tacrolimus versus cyclosporine after lung transplantation. Tacrolimus and cyclosporine have differential effects on the risk of development of bronchiolitis obliterans syndrome: results of a prospective, randomized international trial in lung transplantation. Cyclosporine A versus tacrolimus in combination with mycophenolate mofetil and steroids as primary immunosuppression after lung transplantation: one-year results of a 2-center prospective randomized trial. A comparison of tacrolimus (FK506) and cyclosporine for immunosuppression after cadaveric renal transplantation. FK506 Kidney Transplant Study Group. Randomised trial comparing tacrolimus (FK506) and cyclosporin in prevention of liver allograft rejection. European FK506 Multicentre Liver Study Group. Randomized trial of tacrolimus (Prograf) in combination with azathioprine or mycophenolate mofetil versus cyclosporine (Neoral) with mycophenolate mofetil after cadaveric kidney transplantation. Multicenter randomized trial comparing tacrolimus (FK506) and cyclosporine in the prevention of renal allograft rejection: a report of the European Tacrolimus Multicenter Renal Study Group. Efficacy and safety of tacrolimus compared with ciclosporin microemulsion in renal transplantation: a randomised multicentre study. Tacrolimus-Basiliximab versus Cyclosporine-Basiliximab in renal transplantation "de novo": acute rejection and complications.
The optimal maintenance immunosuppressive regimen after lung transplantation is uncertain.
                We conducted a randomized controlled trial of tacrolimus versus cyclosporine in combination with azathioprine and prednisone after lung transplantation. Ninety adults were randomized to tacrolimus (n = 44) or cyclosporine (n = 46). The primary end point was a composite of a cumulative acute rejection A score of 3 or higher, a cumulative lymphocytic bronchitis B score of 4 or higher, or the onset of bronchiolitis obliterans syndrome (BOS) stage 0-p.
                Recipients randomized to cyclosporine were significantly more likely to develop the primary end point than those randomized to tacrolimus. During the study period, the primary end point developed in 39 of 46 cyclosporine subjects compared with 24 of 44 tacrolimus subjects (p = 0.002); acute rejection or lymphocytic bronchitis end points developed in 29 of 46 cyclosporine subjects compared with 18 of 44 tacrolimus subjects (p = 0.036). Furthermore, BOS stage 0-p was more likely to develop in the cyclosporine group than in the tacrolimus group, but this was not statistically significant (log-rank p = 0.1). In addition, there was a trend to a higher incidence of diabetes among those in the tacrolimus group, but there was no significant difference in graft survival or the total number of infections, or in the incidence of hypertension, chronic kidney disease, or cancer between the 2 groups.
                Tacrolimus is associated with a lower burden of acute rejection and lymphocytic bronchitis and a trend to a greater freedom from BOS stage 0-p than cyclosporine after lung transplantation. Chronic lung allograft dysfunction, which manifests as bronchiolitis obliterans syndrome (BOS), is recognized as the primary cause of morbidity and mortality after lung transplantation. In this study we assessed the efficacy and safety of two de novo immunosuppression protocols to prevent BOS.
                Our study approach was a multicenter, prospective, randomized (1:1) open-label superiority investigation of de novo tacrolimus vs cyclosporine, with both study arms given mycophenolate mofetil and prednisolone after lung transplantation. Cytolytic induction therapy was not employed. Patients were stratified at entry for cystic fibrosis. Primary outcome was incidence of BOS 3 years after transplant (intention-to-treat analysis). Secondary outcomes were survival and incidence of acute rejection, infection and other adverse events.
                Group demographic data were well matched: 110 of 124 tacrolimus vs 74 of 125 cyclosporine patients were treated per protocol (p < 0.01 by chi-square test). Cumulative incidence of BOS Grade ≥1 at 3 years was 11.6% (tacrolimus) vs 21.3% (cyclosporine) (cumulative incidence curves, p = 0.037 by Gray's test, pooled over strata). Univariate proportional sub-distribution hazards regression confirmed cyclosporine as a risk for BOS (HR 1.97, 95% CI 1.04 to 3.77, p = 0.039). Three-year cumulative incidence of acute rejection was 67.4% (tacrolimus) vs 74.9% (cyclosporine) (p = 0.118 by Gray's test). One- and 3-year survival rates were 84.6% and 78.7% (tacrolimus) vs 88.6% and 82.8% (cyclosporine) (p = 0.382 by log-rank test). Cumulative infection rates were similar (p = 0.91), but there was a trend toward new-onset renal failure with tacrolimus (p = 0.09).
                Compared with cyclosporine, de novo tacrolimus use was found to be associated with a significantly reduced risk for BOS Grade ≥1 at 3 years despite a similar rate of acute rejection. However, no survival advantage was detected.
                Copyright © 2012 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved. Cyclosporine (INN: ciclosporin) A or tacrolimus have been used mostly in combination with azathioprine as primary immunosuppression after lung transplantation. Benefit or risk deriving from the combination with mycophenolate mofetil are yet unknown.
                In a prospective, 2-center, open randomized trial, the combination of cyclosporine A, mycophenolate mofetil, and steroids was compared with tacrolimus, mycophenolate mofetil, and steroids as primary therapy after primary lung transplantation. All patients underwent induction therapy with rabbit antithymocyte globulin for 3 days. The 2 groups were compared with regard to patient survival, freedom from acute rejection, bronchiolitis obliterans, infectious episodes, and side effects.
                Between September 1997 and April 1999, 74 lung transplant recipients were randomized to receive either cyclosporine A (n = 37) or tacrolimus (n = 37). Groups were comparable with regard to age, sex, transplant procedure, and cytomegalovirus match. Mean follow-up was 507 +/- 258 and 508 +/- 248 days, respectively. Six- and 12-month survival was similar in both groups (89% vs 84% and 82% vs 71%, respectively; P =.748 at 12 months). Two patients from the cyclosporine A group were retransplanted. Freedom from acute rejection at 6 and 12 months was comparable between groups (46% vs 51% and 35% vs 46%, respectively; P =.774 at 12 months). The mean number of treated acute rejection episodes per 100 patient-days was higher in the cyclosporine A than in the tacrolimus group, but the difference was not statistically significant (0.32 +/- 0.42 vs 0.22 +/- 0.30, respectively; P =.097). Four patients from the cyclosporine A group had to be switched to tacrolimus to control ongoing rejection, whereas no patient from the tacrolimus group had to be switched to cyclosporine A. There was a trend toward more infections (0.7 +/- 0.36 vs 0.55 +/- 0.31, P =.059) in the cyclosporine A group. New-onset diabetes mellitus was observed in the tacrolimus group only (11% vs 0%, P =.151), whereas there was a higher incidence of hypertension (60% vs 11%, P =.03) in the cyclosporine A group.
                This 2-center, prospective randomized study showed high immunosuppressive potency of both cyclosporine A and tacrolimus in combination with mycophenolate mofetil. No significant difference in incidence of acute rejection was observed between the 2 groups. Moreover, survival and incidence of infection were similar. Incidence of drug-related adverse events were similar, yet their spectrum was different. Tacrolimus (FK506), a macrolide molecule that potently inhibits the expression of interleukin 2 by T lymphocytes, represents a potential major advance in the management of rejection following solid-organ transplantation. This randomized, open-label study compared the efficacy and safety of tacrolimus-based versus cyclosporine-based immunosuppression in patients receiving cadaveric kidney transplants.
                A total of 412 patients were randomized to tacrolimus (n=205) or cyclosporine (n=207) after cadaveric renal transplantation and were followed for 1 year for patient and graft survival and the incidence of acute rejection.
                One-year patient survival rates were 95.6% for tacrolimus and 96.6% for cyclosporine (P=0.576). Corresponding 1-year graft survival rates were 91.2% and 87.9% (P=0.289). There was a significant reduction in the incidence of biopsy-confirmed acute rejection in the tacrolimus group (30.7%) compared with the cyclosporine group (46.4%, P=0.001), which was confirmed by blinded review, and in the use of antilymphocyte therapy for rejection (10.7% and 25.1%, respectively; P<0.001). Impaired renal function, gastrointestinal disorders, and neurological complications were commonly reported in both treatment groups, but tremor and paresthesia were more frequent in the tacrolimus group. The incidence of posttransplant diabetes mellitus was 19.9% in the tacrolimus group and 4.0% in the cyclosporine group (P<0.001), and was reversible in some patients.
                Tacrolimus is more effective than cyclosporine in preventing acute rejection in cadaveric renal allograft recipients, and significantly reduces the use of antilymphocyte antibody preparations. Tacrolimus was associated with a higher incidence of neurologic events, which were rarely treatment limiting, and with posttransplant diabetes mellitus, which was reversible in some patients. Studies in the USA and Japan have shown that tacrolimus (FK506) is a potent immunosuppressant. To compare the efficacy and safety of tacrolimus-based and conventional cyclosporin-based immunosuppressive regimens we recruited 545 liver transplant recipients from eight European centres into a randomised open trial. Analysis of the data at 12 months post-transplant showed that tacrolimus was associated with a significant reduction in acute, refractory acute, and chronic rejection episodes. The rates were, for acute rejection, tacrolimus 40.5% vs 49.8% cyclosporin (p = 0.040; absolute difference 9.3% [95% CI 0.9-17.8%]). For refractory acute and chronic rejections the comparisons were 0.8% vs 5.3% (p = 0.005) and 1.5% vs 5.3% (p = 0.032). There results were seen despite significantly lower corticosteroid usage. The incidence of infection was also lower in patients receiving tacrolimus. Patient and graft survival rates were not significantly different (tacrolimus 82.9% and 77.5%; cyclosporin 77.5% and 72.6%). Safety data were comparable--the most serious events being renal impairment, disturbances of glucose metabolism, and neurological complications--but these events were more common in the tacrolimus group. In this trial tacrolimus had advantages over cyclosporin in respect of lower rejection rates, even though less concurrent immunosuppression was administered. Our clinical trial was designed to investigate the optimal combination of immunosuppressants for renal transplantation.
                A randomized three-arm, parallel group, open label, prospective study was performed at 15 North American centers to compare three immunosuppressive regimens: tacrolimus + azathioprine (AZA) versus cyclosporine (Neoral) + mycophenolate mofetil (MMF) versus tacrolimus + MMF. All patients were first cadaveric kidney transplants receiving the same maintenance corticosteroid regimen. Only patients with delayed graft function (32%) received antilymphocyte induction. A total of 223 patients were randomized, transplanted, and followed for 1 year.
                There were no significant differences in baseline demography between the three treatment groups. At 1 year the results are as follows: acute rejection 17% (95% confidence interval 9%, 26%) in tacrolimus + AZA; 20% (confidence interval 11%, 29%) in cyclosporine + MMF; and 15% (confidence interval 7%, 24%) in tacrolimus + MMF. The incidence of steroid resistant rejection requiring antilymphocyte therapy was 12% in the tacrolimus + AZA group, 11% in the cyclosporine + MMF group, and 4% in the tacrolimus + MMF group. There were no significant differences in overall patient or graft survival. Tacrolimus-treated patients had a lower incidence of hyperlipidemia through 6 months posttransplant. The incidence of posttransplant diabetes mellitus requiring insulin was 14% in the tacrolimus + AZA group, 7% in the cyclosporine + MMF and 7% in the tacrolimus + MMF groups.
                All regimens yielded similar acute rejection rates and graft survival, but the tacrolimus + MMF regimen was associated with the lowest rate of steroid resistant rejection requiring antilymphocyte therapy. To confirm the results of a number of studies conducted in Europe, the United States, and Japan, this multicenter, randomized trial compared the 12-month efficacy and safety of tacrolimus- and cyclosporine-based immunosuppressive regimens in the prevention of renal allograft rejection.
                A total of 448 renal transplant recipients were recruited from 15 centers and assigned to receive triple-drug therapy consisting of tacrolimus (n=303) or cyclosporine (n=145) in conjunction with azathioprine and low-dose corticosteroids.
                At 12 months after transplantation, tacrolimus therapy was associated with a significant reduction in the frequency of both acute (tacrolimus 25.9% vs. cyclosporine 45.7%; P<0.001 [absolute difference: 19.8%, 95% confidence interval: 10.0-29.6%]) and corticosteroid-resistant rejection (11.3% vs. 21.6%; P=0.001 [absolute difference: 10.3%, 95% confidence interval: 2.5-18.2%]). Actuarial 1-year patient (tacrolimus 93.0% vs. cyclosporine 96.5%; P=0.140) and graft survival rates (82.5% vs. 86.2%; P=0.380) did not differ significantly between the two treatment groups. Overall, the safety profiles of the tacrolimus- and cyclosporine-based regimens were quite comparable. Infections, renal impairment, neurological complications, and gastrointestinal complaints were frequently reported but were mostly reversible in both groups. Higher incidences of elevated serum creatinine, tremor, diarrhea, hyperglycemia, diabetes mellitus, and angina pectoris were reported in the tacrolimus treatment group, whereas acne, arrhythmia, gingival hyperplasia, and hirsutism were more frequent with cyclosporine treatment.
                The significant reduction in the incidence of episodes of allograft rejection observed with tacrolimus therapy may have important long-term implications given the prognostic influence of rejection on graft survival. In previous comparative studies tacrolimus was superior to the standard formulation of ciclosporin in preventing acute rejection after renal transplantation. We have compared the microemulsion formulation of ciclosporin with tacrolimus in a multicentre randomised trial.
                The 6-month open study involved 560 patients in 50 European centres. 287 patients were randomly assigned tacrolimus and 273 ciclosporin microemulsion plus azathioprine and corticosteroids. The initial oral daily doses were 0.30 mg/kg for tacrolimus and 8-10 mg/kg for ciclosporin. The primary endpoint was the proportion of patients with biopsy-proven acute rejection and the time to this event.
                The two study groups were similar in terms of baseline characteristics. Three patients did not receive study treatment or did not undergo transplantation (one tacrolimus, two ciclosporin). The rate of biopsy-confirmed acute rejection was significantly lower with tacrolimus than with ciclosporin microemulsion (56 patients [19.6%] vs 101 [37.3%]; 17.7% difference [95% CI 10.3-25.1]; p<0.0001). Biopsy-confirmed corticosteroid-resistant rejection was also significantly lower with tacrolimus (27 [9.4%] vs 57 [21.0%]; 11.6% difference [5.7-17.5]; p<0.0001). Cross-over between therapies because of biopsy-proven rejection was judged necessary in one of 286 (0.3%) tacrolimus-group patients and 27 of 271 (10.0%) ciclosporin-group patients (p<0.0001). There were no significant differences in survival of patients or grafts or in renal function. The overall frequency of adverse events was similar in the two groups, though hypertension and hypercholesterolaemia were more common in the ciclosporin group and tremor and hypomagnesaemia were more frequent in the tacrolimus group.
                Tacrolimus was significantly more effective than ciclosporin microemulsion in preventing acute rejection after renal transplantation and had a superior cardiovascular-risk profile. Optimal immunosuppression is essential to maintain kidney allograft viability but minimizing toxicity is also fundamental.
                This article compares immunosuppressants, corticosteroids, cyclosporine, tacrolimus, and basiliximab, which are used in the treatment regimens for renal transplantation. The analyses evaluated their effectiveness to prevent acute rejection episodes and to reduce the appearance of other complications, mainly infectious disease complications.
                Ninety-five patients were analysed during the first year after primary renal transplantation. These patients were included in a random way in 3 different groups according to the immunosuppressant drug therapy: Group I (35 patients) received corticosteroids + CsA; Group II (35 patients) received corticosteroids + CsA + Basiliximab; Group III (25 patients) received corticosteroids + Tacrolimus + Basiliximab.
                Among the 95 patients, 9 presented with an acute rejection episode in Group I. None in Group II, and one in group III. With reference to the infectious disease complications, the incidence of oral herpes was one case in Group I, 4 cases in Group II, and 2 cases in group III.
                Treatment with Basiliximab produced a significantly lower incidence of acute rejection cases and an increase in infectious disease complications, such as lip herpes.
Tacrolimus may be superior to cyclosporin regarding bronchiolitis obliterans syndrome, lymphocytic bronchitis, treatment withdrawal, and arterial hypertension, but may be inferior regarding development of diabetes. No difference in mortality and acute rejection was observed between patients treated with tacrolimus and cyclosporin. There were few studies comparing tacrolimus and cyclosporin after lung transplantation, and the numbers of patients and events in the included studies were limited. Furthermore, the included studies were deemed to be at high risk of bias. Hence, more RCTs are needed to assess the results of the present review. Such studies ought to be conducted with low risks of systematic errors (bias) and of random errors (play of chance).