Everolimus for the prevention of allograft rejection and vasculopathy in cardiac-transplant recipients.
BACKGROUND
Everolimus, a novel proliferation inhibitor and immunosuppressive agent, may suppress cardiac-allograft vasculopathy. We conducted a randomized, double-blind, clinical trial comparing everolimus with azathioprine in recipients of a first heart transplant.


METHODS
A total of 634 patients were randomly assigned to receive 1.5 mg of everolimus per day (209 patients), 3.0 mg of everolimus per day (211 patients), or 1.0 to 3.0 mg of azathioprine per kilogram of body weight per day (214 patients), in combination with cyclosporine, corticosteroids, and statins. The primary efficacy end point was a composite of death, graft loss or retransplantation, loss to follow-up, biopsy-proved acute rejection of grade 3A, or rejection with hemodynamic compromise.


RESULTS
At six months, the percentage of patients who had reached the primary efficacy end point was significantly smaller in the group given 3.0 mg of everolimus (27.0 percent, P<0.001) and the group given 1.5 mg of everolimus (36.4 percent, P=0.03) than in the azathioprine group (46.7 percent). Intravascular ultrasonography showed that the average increase in maximal intimal thickness 12 months after transplantation was significantly smaller in the two everolimus groups than in the azathioprine group. The incidence of vasculopathy was also significantly lower in the 1.5-mg group (35.7 percent, P=0.045) and the 3.0-mg group (30.4 percent, P=0.01) than in the azathioprine group (52.8 percent). The rates of cytomegalovirus infection were significantly lower in the 1.5-mg group (7.7 percent, P<0.001) and the 3.0-mg group (7.6 percent, P<0.001) than in the azathioprine group (21.5 percent). Rates of bacterial infection were significantly higher in the 3.0-mg group than in the azathioprine group. Serum creatinine levels were also significantly higher in the two everolimus groups than in the azathioprine group.


CONCLUSIONS
Everolimus was more efficacious than azathioprine in reducing the severity and incidence of cardiac-allograft vasculopathy, suggesting that everolimus therapy may alleviate this serious problem.
Eisen
Howard J
HJ
Section of Cardiology, Temple University, Philadelphia, PA 19140, USA. eisenh@tuhs.temple.edu
Tuzcu
E Murat
EM
Dorent
Richard
R
Kobashigawa
Jon
J
Mancini
Donna
D
Valantine-von Kaeppler
Hannah A
HA
Starling
Randall C
RC
Sørensen
Keld
K
Hummel
Manfred
M
Lind
Joan M
JM
Abeywickrama
Kamal H
KH
Bernhardt
Peter
P
D000328:Adult; D000368:Aged; D001379:Azathioprine / Q000009:adverse effects / Q000627:therapeutic use; D003327:Coronary Disease / Q000000981:diagnostic imaging / Q000517:prevention & control*; D003331:Coronary Vessels / Q000000981:diagnostic imaging / Q000473:pathology; D016572:Cyclosporine / Q000627:therapeutic use; D003586:Cytomegalovirus Infections / Q000453:epidemiology; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D000068338:Everolimus; D005260:Female; D006084:Graft Rejection / Q000503:physiopathology / Q000517:prevention & control*; D016027:Heart Transplantation / Q000009:adverse effects / Q000401:mortality; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000627:therapeutic use*; D008055:Lipids / Q000097:blood; D008297:Male; D008875:Middle Aged; D012086:Reoperation; D020123:Sirolimus / Q000009:adverse effects / Q000031:analogs & derivatives / Q000627:therapeutic use*; D014184:Transplantation, Homologous; D017539:Tunica Intima / Q000473:pathology; D018084:Ultrasonography, Interventional
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007166:Immunosuppressive Agents; D008055:Lipids; D016572:Cyclosporine; D000068338:Everolimus; D001379:Azathioprine; D020123:Sirolimus