title: Safety, tolerability, and efficacy of cyclosporine microemulsion in heart transplant recipients: a randomized, multicenter, double-blind comparison with the oil-based formulation of cyclosporine--results at 24 months after transplantation.
abstract: BACKGROUND
  The widespread use of cyclosporine has improved the survival of cardiac transplant patients as a result of reduced morbidity and mortality from rejection and infection. The original oil-based form of cyclosporine demonstrated unpredictable absorption resulting in an increased frequency of acute and chronic rejection in patients with poor bioavailability. The primary end. points of the present, prospective, randomized multicenter, double-blind trial were to compare the efficacy of the micro-emulsion form of cycolsporine (CsA-NL) with the oil-based formulation as determined by cardiac allograft and recipient survival and the incidence and severity of the acute rejection episodes and to determine the safety and tolerability of CsA-NL compared with Sandimmune CsA-(SM) in the study population. The 6-month analysis of the study showed reduced number of CsA-NL patients requiring antilymphocyte antibody therapy for rejection, fewer International Society of Heart and Lung Transplantation grade > or =3A rejections in female patients and fewer infections. Our report represents the final analysis of the results 24 months after transplantation.
  
  
  METHODS
  A total of 380 patients undergoing de novo cardiac transplants at 24 centers in the United States, Canada, and Europe were enrolled in this double-blind, randomized trial evaluating the efficacy and safety of CsA-NL versus CsA-SM. Acute allograft rejection was diagnosed by endomyocardial biopsy and graded according to the International Society of Heart and Lung Transplantation nomenclature. Kaplan-Meier analysis and Fisher's exact test were used for comparisons between groups.
  
  
  RESULTS
  After 24 months, allograft and recipient survival were identical in both groups. There were fewer CsA-NL patients (6.9%) requiring antilymphocyte antibody therapy for rejection than in the CsA-SM-treated patient group (17.7%, P=0.002). There were fewer discontinuations of study drug for treatment failures in the CsA-NL groups (7; 3.7%) compared with the CsA-SM group (18; 9.4%, P=0.037). The average corticosteroid dose was lower in the CsA-NL group (0.37 mg/kg/day) compared with the CsA-SM group (0.48 mg/kg/day, P=0.034) over the 24-month study period. Overall, there was no difference in blood pressure or creatinine between the two study groups.
  
  
  CONCLUSIONS
  The final results of this multi-center, randomized study of two forms of cyclosporine confirmed that there were fewer episodes of rejection requiring antilymphocyte antibodies and fewer study discontinuations for treatment failures in CsA-NL-treated patients compared to those treated with CsA-SM. The use of CsA-NL did not predispose these patients to a higher risk of adverse events.
authors.affiliation: Temple University School of Medicine, Philadelphia, Pennsylvania, USA.
authors.forename: H J
authors.initials: HJ
authors.lastname: Eisen
authors.forename: R E
authors.initials: RE
authors.lastname: Hobbs
authors.forename: S F
authors.initials: SF
authors.lastname: Davis
authors.forename: M
authors.initials: M
authors.lastname: Carrier
authors.forename: D M
authors.initials: DM
authors.lastname: Mancini
authors.forename: A
authors.initials: A
authors.lastname: Smith
authors.forename: H
authors.initials: H
authors.lastname: Valantine
authors.forename: H
authors.initials: H
authors.lastname: Ventura
authors.forename: M
authors.initials: M
authors.lastname: Mehra
authors.forename: J L
authors.initials: JL
authors.lastname: Vachiery
authors.forename: B K
authors.initials: BK
authors.lastname: Rayburn
authors.forename: C C
authors.initials: CC
authors.lastname: Canver
authors.forename: G
authors.initials: G
authors.lastname: Laufer
authors.forename: M R
authors.initials: MR
authors.lastname: Costanzo
authors.forename: J
authors.initials: J
authors.lastname: Copeland
authors.forename: G
authors.initials: G
authors.lastname: Dureau
authors.forename: O H
authors.initials: OH
authors.lastname: Frazier
authors.forename: R
authors.initials: R
authors.lastname: Dorent
authors.forename: P J
authors.initials: PJ
authors.lastname: Hauptman
authors.forename: C
authors.initials: C
authors.lastname: Kells
authors.forename: R
authors.initials: R
authors.lastname: Masters
authors.forename: J L
authors.initials: JL
authors.lastname: Michaud
authors.forename: I
authors.initials: I
authors.lastname: Paradis
authors.forename: D G
authors.initials: DG
authors.lastname: Renlund
authors.forename: J
authors.initials: J
authors.lastname: Vanhaecke
authors.forename: B
authors.initials: B
authors.lastname: Mellein
authors.forename: E A
authors.initials: EA
authors.lastname: Mueller
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002626:Chemistry, Pharmaceutical; D016572:Cyclosporine / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D004655:Emulsions / Q000008:administration & dosage; D016027:Heart Transplantation / Q000276:immunology*; D006801:Humans; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009821:Oils / Q000008:administration & dosage; D013810:Therapeutic Equivalency; D013997:Time Factors
chemical_list: D004655:Emulsions; D009821:Oils; D016572:Cyclosporine