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

Disclosures

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

In This Article

Discussion

The present study, which demonstrated excellent patient and graft survival for up to 3 years among liver transplant recipients treated with tacrolimus- and cyclosporine-based immunosuppressive protocols in routine use in 1997—1998, complements similar observations in prior multicenter, prospectively randomized clinical trials.[12—14] Analyses by treatment group, in the present study, showed that freedom from retransplantation was comparable at 3 years for patients receiving tacrolimus (93%) or cyclosporine (94%). The rates of patient and graft survival observed in the present study were approximately 10% higher, at 88% and 90%, respectively, than those associated with tacrolimus and cyclosporine in national and international databases and studies.[13—17] It is possible that the higher rates of patient and graft survival observed herein may reflect our reliance on liver transplant centers performing more than 60 transplants per annum in this retrospective analysis, although the impact of center size on outcome after liver transplantation remains controversial.[18,19]

We observed no difference in treatment failure, defined as death or graft loss, over the 3-year period according to HCV status. In the same way, no differences were seen between the treatment groups for HCV-positive or -negative patients. This is in contrast to the North American Phase 3 registration study comparing tacrolimus and cyclosporine, in which patient survival at 5 years was found to be significantly higher among HCV-positive patients treated with tacrolimus compared with cyclosporine.[14]

Previous studies have documented a lower incidence of acute rejection in liver transplant patients receiving tacrolimus at both 1 and 3 years following transplantation.[9,12,13] Conversion from cyclosporine to tacrolimus has also been efficacious in controlling acute and chronic rejection.[20,21] Furthermore, a recent prospective, randomized clinical trial in primary liver allograft recipients, wherein a composite endpoint consisting of death, retransplantation or treatment failure for immunological reasons was used, demonstrated a treatment benefit of tacrolimus over cyclosporine at 1 year.[9] In the present study, the incidence of acute rejection was found to be similar among patients in the tacrolimus and cyclosporine cohorts for the 3-year follow-up period. However, significantly fewer tacrolimus-treated patients had acute rejection requiring anti-lymphocyte antibody therapy.

Cardiovascular disease and renal failure are important causes of mortality and morbidity following liver transplantation.[2,3,6,22] For example, in a single-center retrospective study of 110 liver allograft recipients at a median of 3.9 years following transplant, there were 25 ischemic cardiovascular events compared to an expected number of 8.15 in the matched population (relative risk: 3.07; 95% CI: 1.98—4.53], whereas the number of deaths from cardiovascular disease among the allograft recipients was 18 compared with an expected number of 7.03 (relative risk: 2.56; 95% CI: 1.52—4.05).[3] In a study of 69 321 American recipients of non-renal organs between 1990 and 2000, the 5-year incidence of chronic renal failure in recipients of orthotopic liver transplantation was 18.1%, and the use of cyclosporine compared to tacrolimus was associated with an increased risk of chronic renal failure (relative risk: 1.25; p < 0.001).[2]

Our primary objectives were to study renal and cardiovascular function in liver transplant recipients managed according to immunosuppressive protocols in common use in 1997 and 1998. Our data show that, despite comparable baseline serum creatinine levels in the two treatment groups, patients receiving cyclosporine demonstrated significantly higher levels of serum creatinine and a greater change in serum creatinine (delta serum creatinine) compared with the tacrolimus cohort at all time points following transplantation. Similar results have been reported by two independent groups.[6,23]

In our study, patients in the cyclosporine cohort demonstrated significantly higher systolic and diastolic blood pressure measurements compared to patients in the tacrolimus group. Coincident with the elevations in blood pressure, more anti-hypertensive agents were required by patients in the cyclosporine group through all 3 years of follow-up. The prevalence of hypertension in cyclosporine-treated patients is consistent with evidence in the literature both from the United Network for Organ Sharing (UNOS) database as cited above and from single-center studies.[5,6,23]

In the present study, the incidence of new-onset diabetes mellitus was comparable between the cyclosporine and tacrolimus treatment groups at all time points following transplantation. In contrast, two recent prospective clinical trials showed higher rates of new-onset diabetes mellitus among liver transplant recipients receiving tacrolimus therapy.[9,10] Still other studies have found that the choice of calcineurin inhibitor does not affect the incidence of new onset diabetes in the first 3 years following liver transplantation.[6,24]

In this study, patients receiving tacrolimus had markedly lower total cholesterol levels over the 3-year follow-up period. The accompanying requirement for anti-hyperlipidemic agents was significantly lower in the tacrolimus cohort at 2 and 3 years. These results corroborate previous studies that have documented better lipid profiles associated with tacrolimus compared with cyclosporine[5,7] and those in which liver transplant recipients underwent conversion from cyclosporine to tacrolimus.[25,26]

The use of corticosteroids was significantly greater in patients in the cyclosporine cohort compared to the tacrolimus cohort at all times after the first post-operative month. In part, this reflects clinical practice in the era under observation and has been noted by other authors.[6] Given that corticosteroids may lead to hyperglycemia, hypertension and hyperlipidemia, it is possible that their greater use in the cyclosporine cohort may have ameliorated the diabetogenic impact of tacrolimus, while exacerbating the hypertensive and hyperlipidemic effects of cyclosporine. The present study does not support this contention regarding blood pressure in that the absolute levels of systolic pressure are maintained over the 36 months rather than declining with the gradual reduction in corticosteroid use. Similarly, when we consider the lipid profiles, while taking into account the greater use of anti-lipidemic agents as time goes on, we note that there is greater use of anti-lipidemics in the cyclosporine cohort at 36 months when the use of corticosteroids is least. This observation is in accord with the results of Aguirrezabalaga and colleagues who found that blood lipid levels were significantly greater in liver transplant recipients treated with cyclosporine compared to those receiving tacrolimus at times when corticosteroid use was not significantly different.[27] Similarly, Trotter et al. found that using a immunosuppressive protocol based on sirolimus, a calcineurin inhibitor and no or at most 3 days of prednisone, hypercholesterolemia was significantly more common in the cyclosporine-treated patients.[8] Finally, we note that the rate of diabetes in either cohort did not change in the last 24 months of observation, despite a reduction by half in the use of corticosteroids in the study cohort. Consequently, we infer that the choice of calcineurin inhibitor may have a substantial impact on hypertension and lipid profile.

This study was undertaken to examine renal and cardiovascular toxicity profiles in a large number of liver allograft recipients to assess not only the effects of calcineurin inhibitors but also the longitudinal practice patterns on patient outcome. As such, a univariate analysis was used to compare data in the cyclosporine and tacrolimus cohorts. Use of a multivariate analysis would have allowed for consideration of the effect on specific outcomes of pre-transplant factors other than selection of calcineurin inhibitor. Thus, multivariate analysis of peri-transplant variables to look for associations with specified outcome variables would be interesting in its own right. At the same time, we believe that use of a multivariate analysis for this study would have sacrificed the insights related to the comparison of the effect of the two calcineurin inhibitors gained from serial observation of the data set at intervals across 36 months.

There are limitations to our study. All retrospective studies are open to selection bias. We believe that our cohort size, reiterative data gathering and verification procedures limited such bias. First, the use of a recent cohort limits the bias due to changing patterns of practice. Second, the cohorts were constructed based on the initial choice of immunosuppressant. However, patients in the cyclosporine cohort were switched to tacrolimus significantly more frequently over the 3-year follow-up period. Thus, our data represent an underestimation of the advantage of tacrolimus over cyclosporine, further dampening any potential selection bias. Third, our study, which was based on standard clinical practice at participating centers in 1997 and 1998, demonstrated a significantly greater use of corticosteroids in the cyclosporine cohort compared with the tacrolimus cohort. As discussed above, the use of corticosteroids may have had an impact on the development of diabetes and influenced the prevalence of hypertension and hyperlipidemia in the patients receiving cyclosporine. Finally, it is worth noting that while many statistically significant differences in renal and cardiovascular clinical markers were observed between tacrolimus-treated and cyclosporine-treated cohorts, we have not shown that these markers were associated with significant mortality or graft loss in this study group during the period of follow-up.

In summary, we found that both tacrolimus- and cyclosporine-based immunosuppressive regimens in routine clinical use provided excellent patient and graft survival through 3 years following liver transplantation. Tacrolimus was associated with better renal function, lipid profile and blood pressure. The incidence of new-onset diabetes mellitus was similar in the tacrolimus and cyclosporine cohorts. The advantages of tacrolimus therapy on renal and cardiovascular risk profiles suggest possible benefits for the health of liver allograft recipients. However, larger, prospective studies with longer follow-up are warranted to evaluate the consequences of renal and cardiovascular risk changes that accompany long-term immunosuppressive agent administration.

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