- Email: [email protected]
Meta-Analysis of FK 506 and Mycophenolate Mofetil Refractory Rejection Trials in Renal Transplantation
Meta-Analysis of FK 506 and Mycophenolate Mofetil Refractory Rejection Trials in Renal Transplantation E.S. Woodle, M.L. Jordan, D. Facklam, R. Shapiro, and G.M. Danovitch for the Refractory Rejection Meta-Analysis Study Group
F
K 506 (ProGraf) and mycophenolate mofetil (MMF) (RS61443, CellCept) have been individually evaluated as therapy for refractory renal allograft rejection in multicenter1,2 and large single center (Pittsburgh) trials3 that were similar, but not identical in their design and analysis. These studies have shown that both agents provide effective therapy for refractory acute renal allograft rejection. There is currently no comparative data available between FK 506 and MMF in the treatment of refractory acute renal allograft rejection. To facilitate comparison of the results from these trials, a reanalysis of data from the US Multicenter Tacrolimus Kidney Transplantation Rescue Study Group (US MC/TAC) and the Pittsburgh single center study (PITT/TAC) was conducted based on the analytical approach used in the US Multicenter Mycophenolate Mofetil Renal Refractory Rejection Study (US MC/MMF).
METHODS The US MC/TAC and PITT/TAC databases were reopened and analyzed using inclusion and exclusion criteria from the US MC/ MMF. Data were also analyzed in the same manner as reported for the US MC/MMF.
RESULTS
Table 1 presents data after 6 months of refractory rejection therapy. Four groups of data are presented including (1)
corticosteroid therapy limb of the US MC/MMF study (US MC/Corticosteroids), (2) MMF therapy limb of the US MC/MMF study (US MC/MMF), (3) FK 506 therapy from the US MC/TAC study (US MC/TAC), and (4) FK 506 therapy from the PITT/TAC study (PITT/TAC). No statistical differences were noted with respect to graft or patient survival, or mean serum creatinine levels. Statistically significant differences were noted in recurrent rejection rates between both FK 506 groups and either corticosteroid or MMF therapy. Statistically significant differences in antilymphocyte antibody (Ab) therapy for recurrent rejection were also noted between corticosteroid therapy and the MMF group and both FK 506 groups. DISCUSSION
This meta-analysis was performed in a manner distinct from other meta-analyses. Rather than compare published results, the actual databases of two of the three studies were reopened and the data analyzed so that the patients, as well From the Department of Surgery, University of Chicago, Chicago, Illinois, USA. Address reprint requests to Dr E.S. Woodle, Department of Surgery, Room J-517, 5841 South Maryland Ave, Chicago, Ill 60637.
Table 1. Data After 6 Months of Refractory Rejection Therapy Data
US Multicenter Corticosteroid
US Multicenter MMF
US Multicenter FK 506
No. of Patients Graft survival (%) Patient survival (%) Mean serum creatinine (mmol/L) Recurr rejection therapy (%) Antilymph Ab therapy (%) Serious adverse events (%) CMV (%) PTLD (%)
73 75 98 218 36 25 44 17 1
77 88 97 182 25 10\ 56 23 4
54 88 98 203 11*† 2*† 21*† 4*† 2
Pittsburgh FK 506
70 87 96 192 4*ठ0ठ14ठ2*ठ1
Statistical significance (P , .05). *UC MC/TAC v US MC/Corticosteroids. † UC MC/TAC v US MC/MMF. ‡ PITT TAC v US MC/Corticosteroids. § PITT TAC v US MC/MMF. \ US MC/MMF v US MC/Corticosteroids.
© 1998 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010
0041-1345/98/$19.00 PII S0041-1345(98)00249-8
Transplantation Proceedings, 30, 1297–1298 (1998)
1297
1298
as the methods for data analysis, were comparable. Thus, this approach provides a more meaningful comparison than is usually obtained in the standard meta-analytic approach. In general, the results of this meta-analysis show similar efficacy for FK 506 and MMF in terms of patient and graft survival and renal function. FK 506 resulted in lower rates of recurrent rejection and antilymphocyte Ab therapy for recurrent rejection, serious adverse events, and cytomegalovirus (CMV) disease. One explanation for the high rate of serious adverse events in the MMF group is the high dosing regimen (3 g/d) that was used. In summary, the results of FK 506 and MMF therapy for refractory acute renal allograft rejection are comparable and both provide acceptable alternatives to corticosteroids. The results of cortico-
WOODLE, JORDAN, FACKLAM ET AL
steroid therapy for refractory acute renal allograft rejection are associated with significant rates of recurrent rejection and morbidity. Given the results that can be obtained with FK 506 or MMF, corticosteroids therefore no longer represent an acceptable alternative for treating refractory acute renal allograft rejection. REFERENCES 1. The Tacrolimus Kidney Transplantation Rescue Study Group: Transplantation 62:594, 1996 2. The Mycophenolate Mofetil Renal Refractory Rejection Study Group: Clin Transplant 10:131, 1996 3. Jordan ML, Naraghi R, Shapiro R, et al: Transplantation 63:223, 1997
F
K 506 (ProGraf) and mycophenolate mofetil (MMF) (RS61443, CellCept) have been individually evaluated as therapy for refractory renal allograft rejection in multicenter1,2 and large single center (Pittsburgh) trials3 that were similar, but not identical in their design and analysis. These studies have shown that both agents provide effective therapy for refractory acute renal allograft rejection. There is currently no comparative data available between FK 506 and MMF in the treatment of refractory acute renal allograft rejection. To facilitate comparison of the results from these trials, a reanalysis of data from the US Multicenter Tacrolimus Kidney Transplantation Rescue Study Group (US MC/TAC) and the Pittsburgh single center study (PITT/TAC) was conducted based on the analytical approach used in the US Multicenter Mycophenolate Mofetil Renal Refractory Rejection Study (US MC/MMF).
METHODS The US MC/TAC and PITT/TAC databases were reopened and analyzed using inclusion and exclusion criteria from the US MC/ MMF. Data were also analyzed in the same manner as reported for the US MC/MMF.
RESULTS
Table 1 presents data after 6 months of refractory rejection therapy. Four groups of data are presented including (1)
corticosteroid therapy limb of the US MC/MMF study (US MC/Corticosteroids), (2) MMF therapy limb of the US MC/MMF study (US MC/MMF), (3) FK 506 therapy from the US MC/TAC study (US MC/TAC), and (4) FK 506 therapy from the PITT/TAC study (PITT/TAC). No statistical differences were noted with respect to graft or patient survival, or mean serum creatinine levels. Statistically significant differences were noted in recurrent rejection rates between both FK 506 groups and either corticosteroid or MMF therapy. Statistically significant differences in antilymphocyte antibody (Ab) therapy for recurrent rejection were also noted between corticosteroid therapy and the MMF group and both FK 506 groups. DISCUSSION
This meta-analysis was performed in a manner distinct from other meta-analyses. Rather than compare published results, the actual databases of two of the three studies were reopened and the data analyzed so that the patients, as well From the Department of Surgery, University of Chicago, Chicago, Illinois, USA. Address reprint requests to Dr E.S. Woodle, Department of Surgery, Room J-517, 5841 South Maryland Ave, Chicago, Ill 60637.
Table 1. Data After 6 Months of Refractory Rejection Therapy Data
US Multicenter Corticosteroid
US Multicenter MMF
US Multicenter FK 506
No. of Patients Graft survival (%) Patient survival (%) Mean serum creatinine (mmol/L) Recurr rejection therapy (%) Antilymph Ab therapy (%) Serious adverse events (%) CMV (%) PTLD (%)
73 75 98 218 36 25 44 17 1
77 88 97 182 25 10\ 56 23 4
54 88 98 203 11*† 2*† 21*† 4*† 2
Pittsburgh FK 506
70 87 96 192 4*ठ0ठ14ठ2*ठ1
Statistical significance (P , .05). *UC MC/TAC v US MC/Corticosteroids. † UC MC/TAC v US MC/MMF. ‡ PITT TAC v US MC/Corticosteroids. § PITT TAC v US MC/MMF. \ US MC/MMF v US MC/Corticosteroids.
© 1998 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010
0041-1345/98/$19.00 PII S0041-1345(98)00249-8
Transplantation Proceedings, 30, 1297–1298 (1998)
1297
1298
as the methods for data analysis, were comparable. Thus, this approach provides a more meaningful comparison than is usually obtained in the standard meta-analytic approach. In general, the results of this meta-analysis show similar efficacy for FK 506 and MMF in terms of patient and graft survival and renal function. FK 506 resulted in lower rates of recurrent rejection and antilymphocyte Ab therapy for recurrent rejection, serious adverse events, and cytomegalovirus (CMV) disease. One explanation for the high rate of serious adverse events in the MMF group is the high dosing regimen (3 g/d) that was used. In summary, the results of FK 506 and MMF therapy for refractory acute renal allograft rejection are comparable and both provide acceptable alternatives to corticosteroids. The results of cortico-
WOODLE, JORDAN, FACKLAM ET AL
steroid therapy for refractory acute renal allograft rejection are associated with significant rates of recurrent rejection and morbidity. Given the results that can be obtained with FK 506 or MMF, corticosteroids therefore no longer represent an acceptable alternative for treating refractory acute renal allograft rejection. REFERENCES 1. The Tacrolimus Kidney Transplantation Rescue Study Group: Transplantation 62:594, 1996 2. The Mycophenolate Mofetil Renal Refractory Rejection Study Group: Clin Transplant 10:131, 1996 3. Jordan ML, Naraghi R, Shapiro R, et al: Transplantation 63:223, 1997