title: Cyclosporine reduction in the presence of everolimus: 3-month data from a Canadian pilot study of maintenance cardiac allograft recipients.
abstract: BACKGROUND
  Concentration-controlled everolimus with concomitant cyclosporine (CsA) dose reduction in renal transplantation permits preservation of kidney function without loss of efficacy. Data are lacking regarding everolimus with reduced-dose CsA in maintenance cardiac transplant patients.
  
  
  METHODS
  In a multicenter, open-label, single-arm pilot study, concentration-controlled everolimus was initiated in patients receiving CsA microemulsion (Neoral) with/without mycophenolate mofetil (MMF) or azathioprine, and with/without corticosteroids. On the day of everolimus initiation, MMF/azathioprine was discontinued and CsA dose was reduced by 25% with further reductions as required in response to decreasing calculated glomerular filtration rate (cGFR).
  
  
  RESULTS
  Of the 36 patients enrolled (intent-to-treat [ITT]), 27 underwent CsA dose reduction as planned (per protocol [PP]). During Week 1, the CsA dose was reduced by 23.3 +/- 7.3% in the ITT population (p < 0.0001) and 26.9 +/- 2.9% in the PP population (p < 0.0001). Mean cGFR (Nankivell) was 68.9 +/- 14.5 ml/min at baseline and 64.4 +/- 14.3 ml/min at Week 12 in the ITT population (p = 0.021), and 69.5 +/- 14.4 ml/min and 66.6 +/- 8.6 ml/min in the PP cohort (p = 0.132). cGFR at Week 12 met the criterion for non-inferiority vs baseline. One case of acute rejection of Grade >or=3A occurred (2.7%). There was no graft loss or death. Hemoglobin and hematocrit levels decreased significantly, whereas cholesterol and triglyceride levels increased (all p < 0.0001).
  
  
  CONCLUSIONS
  This pilot study suggests that initiation of concentration-controlled everolimus with a concomitant 25% reduction in CsA dose in maintenance heart transplant patients is associated with no significant decline in renal function, and no indication of increased rejection to Month 3 post-conversion. Evaluation of more substantial CsA dose reductions is required.
authors.affiliation: Department of Cardiology, Toronto General Hospital, Toronto, Ontario, Canada. heather.ross@uhn.on.ca
authors.forename: Heather
authors.initials: H
authors.lastname: Ross
authors.forename: Peter
authors.initials: P
authors.lastname: Pflugfelder
authors.forename: Haissam
authors.initials: H
authors.lastname: Haddad
authors.forename: Marcelo
authors.initials: M
authors.lastname: Cantarovich
authors.forename: Michael
authors.initials: M
authors.lastname: White
authors.forename: Andrew
authors.initials: A
authors.lastname: Ignaszewski
authors.forename: Jonathan
authors.initials: J
authors.lastname: Howlett
authors.forename: Marc
authors.initials: M
authors.lastname: Vaillancourt
authors.forename: Richard
authors.initials: R
authors.lastname: Dorent
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Burton
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002170:Canada; D016001:Confidence Intervals; D016572:Cyclosporine / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D000068338:Everolimus; D005260:Female; D006084:Graft Rejection / Q000188:drug therapy / Q000517:prevention & control*; D006085:Graft Survival; D016027:Heart Transplantation / Q000276:immunology* / Q000379:methods / Q000401:mortality; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage*; D008297:Male; D008875:Middle Aged; D010865:Pilot Projects; D018570:Risk Assessment; D016037:Single-Blind Method; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives*; D018709:Statistics, Nonparametric; D016019:Survival Analysis; D014181:Transplantation Immunology / Q000187:drug effects*; D014184:Transplantation, Homologous; D016896:Treatment Outcome
chemical_list: D007166:Immunosuppressive Agents; D016572:Cyclosporine; D000068338:Everolimus; D020123:Sirolimus