Prevention of acute rejection and allograft vasculopathy by everolimus in cardiac transplants recipients: a 24-month analysis.
BACKGROUND
Everolimus is an immunosuppressive agent that reduces cardiac allograft vasculopathy. This report presents the 24-month results of a multicenter trial of everolimus vs azathioprine in heart transplantation.


METHODS
A total of 634 patients were randomized to receive 1.5 mg everolimus, 3 mg everolimus or azathioprine, with cyclosporine and steroids. A 12-month, double-blind, double-dummy period was followed by a 12-month open-label period.


RESULTS
At 24 months, the percentage of patients reaching the composite efficacy end-points was significantly lower with everolimus (1.5 mg: 45.9%, p = 0.016; 3 mg: 36.0%, p < 0.001) than with azathioprine (57.5%). The change in maximal intimal thickness from baseline to 24 months was significantly smaller with everolimus 1.5 mg (0.07 mm, p = 0.014) and 3 mg (0.06 mm, p = 0.004) compared with azathioprine (0.15 mm). The 24-month incidence of vasculopathy was 33.3% with everolimus 1.5 mg, 45.5% with everolimus 3 mg and 58.3% with azathioprine (p = 0.017 vs everolimus 1.5 mg). Incidence of cytomegalovirus infection was 3-fold lower in patients receiving everolimus compared with azathioprine (7.2% and 7.1% in the 1.5-mg and 3-mg everolimus cohorts, respectively, and 21% in the azathioprine group; p < 0.0001). Median serum creatinine levels at 24 months were higher with everolimus than with azathioprine, but decreased when cyclosporine exposure was reduced (everolimus 1.5 mg: baseline 167 micromol, after 6 months 157.5 micromol; everolimus 3 mg: baseline 185.6 micromol, after 6 months 160 micromol; azathioprine: baseline 123.3 micromol, after 6 months 127 micromol).


CONCLUSIONS
Everolimus significantly reduced acute rejection and limited the progression of allograft vasculopathy at 24 months compared with azathioprine. Although graft and patient survival was comparable at 24 months, everolimus therapy may improve longer-term outcomes after heart transplantation.
Viganò
Mario
M
Department of Cardiac Surgery, San Matteo Hospital, Pavia, Italy.
Tuzcu
Murat
M
Benza
Raymond
R
Boissonnat
Pascale
P
Haverich
Axel
A
Hill
James
J
Laufer
Guenther
G
Love
Robert
R
Parameshwar
Jayan
J
Pulpón
Luis Alonso
LA
Renlund
Dale
D
Abeywickrama
Kamal
K
Cretin
Nathalie
N
Starling
Randall C
RC
Eisen
Howard J
HJ
D000293:Adolescent; D000305:Adrenal Cortex Hormones / Q000627:therapeutic use; D000328:Adult; D000368:Aged; D001379:Azathioprine / Q000627:therapeutic use; D016572:Cyclosporine / Q000627:therapeutic use; D004311:Double-Blind Method; D000068338:Everolimus; D006084:Graft Rejection / Q000453:epidemiology / Q000473:pathology / Q000517:prevention & control*; D016027:Heart Transplantation / Q000276:immunology* / Q000473:pathology; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D007677:Kidney Function Tests; D008875:Middle Aged; D012449:Safety; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000627:therapeutic use; D014184:Transplantation, Homologous / Q000473:pathology; D016896:Treatment Outcome
D000305:Adrenal Cortex Hormones; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D000068338:Everolimus; D001379:Azathioprine; D020123:Sirolimus