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      Advantageous effects of immunosuppression with tacrolimus in comparison with cyclosporine A regarding renal function in patients after heart transplantation

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          Abstract

          Background

          Nephrotoxicity is a serious adverse effect of calcineurin inhibitor therapy in patients after heart transplantation (HTX).

          Aim

          In this retrospective registry study, renal function within the first 2 years after HTX in patients receiving de novo calcineurin inhibitor treatment, that is, cyclosporine A (CSA) or tacrolimus (TAC), was analyzed. In a consecutive subgroup analysis, renal function in patients receiving conventional tacrolimus (CTAC) was compared with that of patients receiving extended-release tacrolimus (ETAC).

          Methods

          Data from 150 HTX patients at Heidelberg Heart Transplantation Center were retrospectively analyzed. All patients were continuously receiving the primarily applied calcineurin inhibitor during the first 2 years after HTX and received follow-up care according to center practice.

          Results

          Within the first 2 years after HTX, serum creatinine increased significantly in patients receiving CSA ( P<0.0001), whereas in patients receiving TAC, change of serum creatinine was not statistically significant ( P=not statistically significant [ns]). McNemar’s test detected a significant accumulation of patients with deterioration of renal function in the first half year after HTX among patients receiving CSA ( P=0.0004). In patients receiving TAC, no significant accumulation of patients with deterioration of renal function during the first 2 years after HTX was detectable (all P=ns). Direct comparison of patients receiving CTAC versus those receiving ETAC detected no significant differences regarding renal function between patients primarily receiving CTAC or ETAC treatment during study period (all P=ns).

          Conclusion

          CSA is associated with a more pronounced deterioration of renal function, especially in the first 6 months after HTX, in comparison with patients receiving TAC as baseline immunosuppressive therapy.

          Most cited references27

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          The registry of the International Society for Heart and Lung Transplantation: thirty-first official adult heart transplant report--2014; focus theme: retransplantation.

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            Tacrolimus with mycophenolate mofetil (MMF) or sirolimus vs. cyclosporine with MMF in cardiac transplant patients: 1-year report.

            The most advantageous combination of immunosuppressive agents for cardiac transplant recipients has not yet been established. Between November 2001 and June 2003, 343 de novo cardiac transplant recipients were randomized to receive steroids and either tacrolimus (TAC) + sirolimus (SRL), TAC + mycophenolate mofetil (MMF) or cyclosporine (CYA) + MMF. Antilymphocyte induction therapy was allowed for up to 5 days. The primary endpoint of >/=3A rejection or hemodynamic compromise rejection requiring treatment showed no significant difference at 6 months (TAC/MMF 22.4%, TAC/SRL 24.3%, CYA/MMF 31.6%, p = 0.271) and 1 year (p = 0.056), but it was significantly lower in the TAC/MMF group when compared only to the CYA/MMF group at 1 year (23.4% vs. 36.8%; p = 0.029). Differences in the incidence of any treated rejection were significant (TAC/SRL = 35%, TAC/MMF = 42%, CYA/MMF = 59%; p /=3A rejections or hemodynamic compromise rejections and an improved side-effect profile.
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              Tacrolimus versus cyclosporine as primary immunosuppression after heart transplantation: systematic review with meta-analyses and trial sequential analyses of randomised trials.

              We conducted a systematic review of randomized trials to compare the benefits and harms of tacrolimus versus cyclosporine as primary immunosuppression after heart transplantation. We searched electronic databases and bibliographies up to April 2010. Our review followed the Cochrane and PRISMA guidelines. The meta-analysis included 10 randomized trials with 952 patients. Tacrolimus was significantly superior to cyclosporine (both formula-combined) with regard to hypertension (relative risk [RR] 0.8; 95% confidence interval [CI] 0.69-0.93, p = 0.003), hyperlipidaemia (RR 0.57; 95% CI 0.44-0.74, p < 0.0001), hirsutism (RR 0.17 95% CI 0.04-0.62, p = 0.008), and gingival hyperplasia (RR 0.07 95% CI 0.01-0.37, p = 0.002). No significant differences between the two calcineurin inhibitors were found with regard to acute rejections causing haemodynamic instability, diabetes, renal dysfunction, infection, malignancy, or neurotoxicity. Tacrolimus was significantly superior to microemulsion cyclosporine with regard to mortality (RR 0.64; 95% CI 0.42-0.96, p = 0.03), acute severe biopsy-proven rejection (RR 0.71; 95% CI 0.56-0.90, p = 0.004), hyperlipidaemia (RR 0.57; 95% CI 0.41-0.79, p = 0.0009), hirsutism (RR 0.17 95% CI 0.04-0.62, p = 0.008), and gingival hyperplasia (RR 0.07; 95% CI 0.01-0.37, p = 0.002). Tacrolimus was significantly superior to oil-based cyclosporine with regard to hypertension (RR 0.66; 95% CI 0.54-0.80, p < 0.0001), and hyperlipidaemia (RR 0.57; 95% CI 0.38-0.87, p = 0.009). Tacrolimus seems to be superior to cyclosporine in heart transplant patients with regard to hypertension, hyperlipidaemia, gingival hyperplasia and hirsutism. In addition, tacrolimus seems to be superior to microemulsion cyclosporine in heart transplant patients with regard to a number of outcomes, including death. More trials with a low risk of bias are needed to determine if the results of the present meta-analysis can be confirmed.
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Drug Design, Development and Therapy
                Dove Medical Press
                1177-8881
                2015
                24 February 2015
                : 9
                : 1217-1224
                Affiliations
                [1 ]Department of Cardiology, Angiology, Pneumology, University of Heidelberg, Heidelberg, Germany
                [2 ]Department of Cardiac Surgery, University of Heidelberg, Heidelberg, Germany
                [3 ]Institute for Medical Biometry and Informatics, University of Heidelberg, Heidelberg, Germany
                Author notes
                Correspondence: Andreas O Doesch, Medizinische Klinik III, Kardiologie, Angiologie, Pulmologie, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany, Tel +49 6221 56 39936, Fax +49 6221 56 4105, Email andreas.doesch@ 123456med.uni-heidelberg.de
                Article
                dddt-9-1217
                10.2147/DDDT.S79343
                4346008
                0f03c857-390b-4bed-a5db-387d6b85fb35
                © 2015 Helmschrott et al. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License

                The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

                History
                Categories
                Original Research

                Pharmacology & Pharmaceutical medicine
                heart transplantation,renal function,extended-release tacrolimus

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