Cyclosporine lowering with everolimus versus mycophenolate mofetil in heart transplant recipients

Long-term follow-up of the SHIRAKISS randomized, prospective study

Luciano Potena, Paola Prestinenzi, Isidoro G. Bianchi, Marco Masetti, Paolo Romani, Gaia Magnani, Francesco Fallani, Fabio Coccolo, Antonio Russo, Claudio Ponticelli, Claudio Rapezzi, Francesco Grigioni, Angelo Branzi

Research output: Contribution to journalArticle

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Abstract

Background: Cyclosporine nephrotoxicity negatively impacts long-term outcome after heart transplantation (HT). We previously reported 1-year results from a randomized study showing that cyclosporine-lowering strategies based on everolimus or mycophenolate mofetil (MMF) are equally effective for reducing progression of renal dysfunction. It is unknown whether this efficacy could be maintained over the long term. Methods: Thirty-four recipients 1 to 4 years after HT and with 25 to 60 ml/min of creatinine clearance (CrCl) were randomized to everolimus with a very low dose (C0: 50 to 90 ng/ml, n = 17) or MMF with low dose of cyclosporine (C0: 100 to 150 ng/ml, n = 17). Follow-up was prolonged up to 3 years, and calculated CrCl was the main efficacy measure. Results: Cyclosporine was maintained at 70% and 30% lower than baseline in the everolimus and MMF arms, respectively, throughout the 3-year study period. CrCl remained stable in the everolimus patients (+7% from baseline; p = 0.7), but improved in the MMF patients (+20% from baseline; p <0.01), with a trend toward improved values compared with everolimus patients (46 ± 12 vs 56 ± 15 ml/min; p = 0.06). Subgroup analysis revealed that baseline proteinuria markedly influenced the renal function response to everolimus: whereas in patients with baseline proteinuria CrCl significantly worsened (-20%; p = 0.04), it improved in those without (+15%; p = 0.03). Safety was comparable between the two study arms. Conclusions: Cyclosporine nephrotoxicity improved after a prolonged dose reduction in patients receiving MMF. The everolimus-based strategy provided a similar benefit only to patients without baseline proteinuria. While raising caution against the universal use of everolimus for kidney protection, our long-term results support the need for customized approaches in the management of drug toxicities in maintenance HT recipients.

Original languageEnglish
Pages (from-to)565-570
Number of pages6
JournalJournal of Heart and Lung Transplantation
Volume31
Issue number6
DOIs
Publication statusPublished - Jun 2012

Fingerprint

Mycophenolic Acid
Cyclosporine
Prospective Studies
Creatinine
Heart Transplantation
Proteinuria
Kidney
Everolimus
Transplant Recipients
Drug-Related Side Effects and Adverse Reactions
Maintenance
Safety

Keywords

  • cyclosporine
  • heart transplantation
  • immunosuppressive therapy
  • mTOR inhibitors
  • renal insufficiency

ASJC Scopus subject areas

  • Transplantation
  • Cardiology and Cardiovascular Medicine
  • Pulmonary and Respiratory Medicine
  • Surgery

Cite this

Cyclosporine lowering with everolimus versus mycophenolate mofetil in heart transplant recipients : Long-term follow-up of the SHIRAKISS randomized, prospective study. / Potena, Luciano; Prestinenzi, Paola; Bianchi, Isidoro G.; Masetti, Marco; Romani, Paolo; Magnani, Gaia; Fallani, Francesco; Coccolo, Fabio; Russo, Antonio; Ponticelli, Claudio; Rapezzi, Claudio; Grigioni, Francesco; Branzi, Angelo.

In: Journal of Heart and Lung Transplantation, Vol. 31, No. 6, 06.2012, p. 565-570.

Research output: Contribution to journalArticle

Potena, L, Prestinenzi, P, Bianchi, IG, Masetti, M, Romani, P, Magnani, G, Fallani, F, Coccolo, F, Russo, A, Ponticelli, C, Rapezzi, C, Grigioni, F & Branzi, A 2012, 'Cyclosporine lowering with everolimus versus mycophenolate mofetil in heart transplant recipients: Long-term follow-up of the SHIRAKISS randomized, prospective study', Journal of Heart and Lung Transplantation, vol. 31, no. 6, pp. 565-570. https://doi.org/10.1016/j.healun.2012.01.002
Potena, Luciano ; Prestinenzi, Paola ; Bianchi, Isidoro G. ; Masetti, Marco ; Romani, Paolo ; Magnani, Gaia ; Fallani, Francesco ; Coccolo, Fabio ; Russo, Antonio ; Ponticelli, Claudio ; Rapezzi, Claudio ; Grigioni, Francesco ; Branzi, Angelo. / Cyclosporine lowering with everolimus versus mycophenolate mofetil in heart transplant recipients : Long-term follow-up of the SHIRAKISS randomized, prospective study. In: Journal of Heart and Lung Transplantation. 2012 ; Vol. 31, No. 6. pp. 565-570.
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abstract = "Background: Cyclosporine nephrotoxicity negatively impacts long-term outcome after heart transplantation (HT). We previously reported 1-year results from a randomized study showing that cyclosporine-lowering strategies based on everolimus or mycophenolate mofetil (MMF) are equally effective for reducing progression of renal dysfunction. It is unknown whether this efficacy could be maintained over the long term. Methods: Thirty-four recipients 1 to 4 years after HT and with 25 to 60 ml/min of creatinine clearance (CrCl) were randomized to everolimus with a very low dose (C0: 50 to 90 ng/ml, n = 17) or MMF with low dose of cyclosporine (C0: 100 to 150 ng/ml, n = 17). Follow-up was prolonged up to 3 years, and calculated CrCl was the main efficacy measure. Results: Cyclosporine was maintained at 70{\%} and 30{\%} lower than baseline in the everolimus and MMF arms, respectively, throughout the 3-year study period. CrCl remained stable in the everolimus patients (+7{\%} from baseline; p = 0.7), but improved in the MMF patients (+20{\%} from baseline; p <0.01), with a trend toward improved values compared with everolimus patients (46 ± 12 vs 56 ± 15 ml/min; p = 0.06). Subgroup analysis revealed that baseline proteinuria markedly influenced the renal function response to everolimus: whereas in patients with baseline proteinuria CrCl significantly worsened (-20{\%}; p = 0.04), it improved in those without (+15{\%}; p = 0.03). Safety was comparable between the two study arms. Conclusions: Cyclosporine nephrotoxicity improved after a prolonged dose reduction in patients receiving MMF. The everolimus-based strategy provided a similar benefit only to patients without baseline proteinuria. While raising caution against the universal use of everolimus for kidney protection, our long-term results support the need for customized approaches in the management of drug toxicities in maintenance HT recipients.",
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AU - Prestinenzi, Paola

AU - Bianchi, Isidoro G.

AU - Masetti, Marco

AU - Romani, Paolo

AU - Magnani, Gaia

AU - Fallani, Francesco

AU - Coccolo, Fabio

AU - Russo, Antonio

AU - Ponticelli, Claudio

AU - Rapezzi, Claudio

AU - Grigioni, Francesco

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