title: De novo sirolimus with low-dose tacrolimus versus full-dose tacrolimus with mycophenolate mofetil after heart transplantation--8-year results.
abstract: BACKGROUND
  Although acute cellular rejection after heart transplantation (HTX) can be controlled by full-dose calcineurin inhibitor (CNI)-based immunosuppressive regimens, cardiac allograft vasculopathy (CAV), nephrotoxicity, and malignancy remain ongoing problems. To evaluate the potential beneficial effects of sirolimus and CNI reduction, we compared de novo low-dose tacrolimus and sirolimus with standard tacrolimus and mycophenolate mofetil (MMF)-based immunosuppression after HTX.
  
  
  METHODS
  We analyzed a long-term follow-up cohort of 126 patients who underwent HTX during the period 1998-2005 and received either de novo low-dose tacrolimus/sirolimus (lowTAC/SIR; n = 61) or full-dose tacrolimus/MMF (TAC/MMF; n = 64).
  
  
  RESULTS
  Freedom from treatment switch was less in the low TAC/SIR group than in the TAC/MMF group (51.7% vs 73.0%, p = 0.038) 8 years after HTX. Freedom from acute rejection was 90.6% in the low TAC/SIR group vs 80.3% in the TAC/MMF group (p = 0.100). There was no difference in freedom from International Society for Heart and Lung Transplantation CAV grade ≥ 1 (55.4% vs 60.0%, p = 0.922), time until CAV diagnosis (4.2 ± 2.0 years vs 3.2 ± 2.4 years, p = 0.087), and CAV severity (p = 0.618). The benefit of reduced early maximum creatinine for low TAC/SIR treatment (1.8 ± 0.9 mg/dl vs 2.4 ± 1.1 mg/dl in TAC/MMF group, p < 0.001) did not continue 5 years and 8 years after HTX (1.4 ± 0.4 mg/dl vs 1.7 ± 1.2 mg/dl, p = 0.333, and 1.6 ± 1.1 mg/dl vs 1.6 ± 0.8 mg/dl, p = 0.957). The trend for superior survival at 5 years with low TAC/SIR treatment (93.1% vs 81.3% in TAC/MMF group, p = 0.051) could not be confirmed after 8 years (84.7% vs 75.0%, p = 0.138). Multivariate analysis at 8 years did not reveal any benefit of low TAC/SIR treatment.
  
  
  CONCLUSIONS
  Reduction of de novo CNI did not result in superior long-term renal function. Low-dose mechanistic target of rapamycin inhibition did not achieve any benefit in CAV prevention compared with full-dose TAC/MMF after HTX.
authors.affiliation: Department of Cardiac Surgery; Walter Brendel Centre of Experimental Medicine. Electronic address: Sonja.Guethoff@med.uni-muenchen.de.
authors.forename: Sonja
authors.initials: S
authors.lastname: Guethoff
authors.affiliation: Department of Cardiac Surgery; Transplantation Center.
authors.forename: Katja
authors.initials: K
authors.lastname: Stroeh
authors.affiliation: Department of Cardiac Surgery; Transplantation Center.
authors.forename: Carola
authors.initials: C
authors.lastname: Grinninger
authors.affiliation: Department of Cardiac Surgery.
authors.forename: Matthias A
authors.initials: MA
authors.lastname: Koenig
authors.affiliation: Walter Brendel Centre of Experimental Medicine.
authors.forename: Eike C
authors.initials: EC
authors.lastname: Kleinert
authors.affiliation: Institute for Medical Information Sciences, Biometry and Epidemiology.
authors.forename: Anna
authors.initials: A
authors.lastname: Rieger
authors.affiliation: Department of Cardiac Surgery; Walter Brendel Centre of Experimental Medicine.
authors.forename: Tanja
authors.initials: T
authors.lastname: Mayr
authors.affiliation: Department of Cardiology, Ludwig-Maximilians University, Munich, Germany.
authors.forename: Franz
authors.initials: F
authors.lastname: von Ziegler
authors.affiliation: Walter Brendel Centre of Experimental Medicine.
authors.forename: Bruno
authors.initials: B
authors.lastname: Reichart
authors.affiliation: Department of Cardiac Surgery.
authors.forename: Christian
authors.initials: C
authors.lastname: Hagl
authors.affiliation: Department of Cardiac Surgery; Transplantation Center.
authors.forename: René
authors.initials: R
authors.lastname: Schramm
authors.affiliation: Department of Cardiac Surgery; Transplantation Center.
authors.forename: Ingo
authors.initials: I
authors.lastname: Kaczmarek
authors.affiliation: Transplantation Center.
authors.forename: Bruno M
authors.initials: BM
authors.lastname: Meiser
mesh_terms: D000208:Acute Disease; D000328:Adult; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D005260:Female; D005500:Follow-Up Studies; D006084:Graft Rejection / Q000517:prevention & control*; D006085:Graft Survival / Q000187:drug effects; D016027:Heart Transplantation; D006801:Humans; D007168:IMP Dehydrogenase / Q000037:antagonists & inhibitors; D007165:Immunosuppression Therapy / Q000379:methods*; D007166:Immunosuppressive Agents / Q000008:administration & dosage; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives*; D012189:Retrospective Studies; D020123:Sirolimus / Q000008:administration & dosage*; D016559:Tacrolimus / Q000008:administration & dosage*; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D007166:Immunosuppressive Agents; D007168:IMP Dehydrogenase; D009173:Mycophenolic Acid; D020123:Sirolimus; D016559:Tacrolimus
keywords: HTX; cardiac allograft vasculopathy; de novo sirolimus; long-term study; low-dose tacrolimus; malignancy; nephrotoxicity