A Comparison of Tacrolimus and Cyclosporine in Liver Transplantation: Effects on Renal Function and Cardiovascular Risk Status

Michael R. Lucey; Manal F. Abdelmalek; Rosemarie Gagliardi; Darla Granger; Curtis Holt; Igal Kam; Goran Klintmalm; Alan Langnas; Kirti Shetty; Andreas Tzakis; E. Steve Woodle


American Journal of Transplantation. 2005;5(5):1111-1119. 

In This Article


A total of 1065 patient records were entered; data were complete for 1011, while verification was required for 54 patients. Patient characteristics were comparable between groups with a few exceptions—primary non-function and median cold ischemia time were both greater in the cyclosporine group (p = 0.03 and p < 0.0001, respectively), while positive T-cell cross-match was greater in the tacrolimus group (p = 0.01; Table 1 ). In addition, a significant difference in UNOS status was evident between groups (p = 0.04), with a higher proportion of Status 1 patients in the tacrolimus group (8.3%) compared to the cyclosporine group (5.6%; Table 1 ).

The proportion of patients presenting with single and multiple diagnoses was not different between the groups, with overall rates of approximately 83% and 17%, respectively (data not shown). Pre-transplant diagnoses were similar between the groups, with the exception of the prevalence of hepatitis C virus (HCV) infection, which was higher in the cyclosporine group (p = 0.03; Table 1 ).

Patients received either tacrolimus (n = 594), cyclosporine (n = 450) or no calcineurin inhibitor (CNI) (n = 21) as initial immunosuppressive therapy. The proportion of patients receiving tacrolimus or cyclosporine over the 3-year period is shown in Figure 1. Mean daily doses of calcineurin inhibitors and corresponding trough blood concentrations were appropriate, given 5—15 ng/mL for the first 3 months and 5—12 ng/mL thereafter for tacrolimus, and 250—400 ng/mL for the first 6 months and 100—250 ng/mL thereafter for cyclosporine (data not shown).

Percentage of patients receiving tacrolimus, cyclosporine or no calcineurin inhibitor for maintenance immunosuppression following liver transplant.

Follow-up data on maintenance immunosuppression were not available beyond day 0 for 22 patients in the tacrolimus group and 20 in the cyclosporine group. Of patients switching from one primary immunosuppressant to the other (tacrolimus to cyclosporine or cyclosporine to tacrolimus), 70 patients (12.8%) switched from tacrolimus to cyclosporine, while 111 (26.7%) patients switched from cyclosporine to tacrolimus (p < 0.0001). Fifty-eight (10.6%) patients in the tacrolimus group and 81 (19.5%) patients in the cyclosporine group were switched during the first year following transplant.

The use of corticosteroids was highly prevalent in both cohorts at 1 month following transplantation (88.6%). The percentage of patients receiving corticosteroids was not different between the tacrolimus and cyclosporine groups at this time point. The use of corticosteroids decreased over the 3-year follow-up period in both the tacrolimus and cyclosporine cohorts. However, at months 12, 24 and 36 following transplantation, significantly more patients in the cyclosporine group were receiving corticosteroids (p < 0.00001; Figure 2).

Corticosteroid use overall and in patients receiving either tacrolimus or cyclosporine from months 1 to 36 following transplant. Significantly fewer patients treated with tacrolimus were on corticosteroids at 12, 24 and 36 months follow-up.

The median daily dose of corticosteroids was 18.75 mg (range: 0—150 mg) at 1 month and decreased to 2.5 mg (range: 0—30 mg) by 1 year (Figure 2). The median daily dose dropped to 0 mg for both 2 years (range: 0—40 mg) and 3 years (range: 0—60 mg) following transplantation. Patients on tacrolimus had significantly lower median daily oral doses of corticosteroids at both 1 month and 1 year after transplantation (p < 0.00001 and p < 0.01, respectively).

No significant difference between treatment groups was observed for either patient or graft survival (Figure 3). Patient survival rates, censored for graft loss, at 3 years after transplantation were 88.9% in the tacrolimus group and 87.8% in the cyclosporine group (p = 0.62). The total number of deaths observed over the 3-year period was 134. Graft survival rates 3 years following transplantation were 90.7% in the tacrolimus group and 90.4% in the cyclosporine group (p = 0.90). A total of 106 grafts were lost over the 3-year period. The unadjusted graft survival rate including both death and graft loss was 79.0%.

Kaplan-Meier estimates of 3-year patient (A) and graft survival (B) in the tacrolimus and cyclosporine treatment groups.

Treatment failures, defined as either death or graft loss, were not significantly different over the 3-year period when patients were stratified according to HCV status (data not shown). A failure rate of 20.3% was observed for HCV-negative patients and 26.2% for HCV-positive patients (p = 0.57). Treatment failure rates were not different between the treatment groups among HCV-negative patients, with 17.8% observed in the tacrolimus group and 19.3% in the cyclosporine group (p = 0.68). Similarly, no significant differences in treatment failure were observed between the groups among HCV-positive patients, with 25.0% for tacrolimus and 25.1% for cyclosporine (p = 0.88).

Primary causes of death were similar between treatment groups. The primary causes of death and overall frequency are depicted in Table 2 . Similarly, no cause of graft loss was observed more frequently in either treatment group. The causes of graft loss and overall frequency are shown in Table 2 .

The incidence of retransplantation over the 3-year period was low and comparable between the treatment groups. Seven percent of patients in the tacrolimus group and 6% in the cyclosporine group underwent retransplantation over the 36-month follow-up period (p = 0.49).

The cumulative expected number of any acute rejection event was not significantly different between the treatment groups for the first year (0.621 for tacrolimus vs. 0.733 for cyclosporine; p = 0.06) or over the 3-year period following transplantation (0.763 for tacrolimus vs. 0.880 for cyclosporine; p = 0.07; Figure 4A). In contrast, tacrolimus was associated with a significant reduction in the incidence of acute rejection episodes requiring anti-lymphocyte antibody therapy. This reduction was apparent during both the first year (0.044 for tacrolimus vs. 0.080 for cyclosporine; p = 0.02) and over the 3-year period after transplant (0.051 for tacrolimus vs. 0.093 for cyclosporine; p = 0.01; Figure 4B).

Mean baseline serum creatinine levels were equivalent between the tacrolimus and cyclosporine treatment groups (1.31 mg/dL and 1.20 mg/dL, respectively; p = 0.35). After transplantation, serum creatinine levels were significantly lower in patients receiving tacrolimus at all time points over the 3-year follow-up period (p < 0.0001 at all time points; Figure 5). In addition, the change in mean serum creatinine levels over months 3 through 36 post-transplant was significantly lower in patients treated with tacrolimus. The increase in mean serum creatinine from month 3 to 36 in patients receiving tacrolimus was 0.087 mg/dL as compared to 0.193 mg/dL for patients receiving cyclosporine (p = 0.003).

Tacrolimus was associated with a markedly better cardiovascular risk profile. Patients in the tacrolimus cohort had lower mean systolic blood pressure measurements at months 3 through 36 post-transplant (p < 0.001 at all time points; Figure 6). Similarly, diastolic blood pressure measurements were significantly lower in patients receiving tacrolimus at months 3 through 24 after transplant (p < 0.01 at all time points; Figure 6). Concomitant with better blood pressure measurements seen in patients receiving tacrolimus, there was a decreased requirement for anti-hypertensive agents through the 3 years of follow-up (p < 0.0001 at all time points; Figure 7).

One hundred and sixty-nine patients were diagnosed as having diabetes pre-transplant (on insulin or oral medications at the time of transplant), while 14 patients did not have a pre-transplant diabetes status reported. The remaining 882 patients (tacrolimus: 488, cyclosporine: 378) were considered at risk for the development of new-onset diabetes mellitus. New-onset requirement for anti-diabetic medications (oral agents and/or insulin) following transplantation is shown in Table 3 . The incidence of new-onset, insulin-requiring diabetes mellitus was comparable between treatment groups through the 3 years of follow-up ( Table 3 ).

Mean total cholesterol levels were lower in patients receiving tacrolimus at months 3 through 24 post-transplant compared to patients receiving cyclosporine (p < 0.01 at all time points; Figure 8). Mean serum triglycerides were also significantly lower in patients receiving tacrolimus for months 3 through 12 after transplant. Triglyceride measurements at 3 months were 169.64 mg/dL for tacrolimus- versus 231.03 mg/dL for cyclosporine-treated patients, at 6 months were 167.92 mg/dL for tacrolimus- versus 204.28 mg/dL for cyclosporine-treated patients and at 12 months were 169.57 mg/dL for tacrolimus- versus 216.84 mg/dL for cyclosporine-treated patients (p < 0.01 at all time points). The better serum lipid profile was observed in the tacrolimus cohort in spite of a reduced requirement for anti-hyperlipidemic agents (p < 0.0001 at 2 and 3 years; Figure 8).