Long-term cardiovascular risk in transplantation--insights from the use of everolimus in heart transplantation.
Everolimus is a potent immunosuppressive agent that has anti-proliferative activity. The benefits of everolimus vs azathioprine in de novo heart transplant recipients were assessed in a randomized, double-blind study. Patients (n = 634) were randomized to receive everolimus (1.5 mg/day or 3.0 mg/day) or azathioprine; all patients received steroids and full-dose ciclosporin (CsA). The primary endpoint was the incidence of efficacy failure [biopsy-proven acute rejection (BPAR), graft loss, death or loss to follow-up]. The incidence of cardiac allograft vasculopathy (CAV) was assessed by intravascular ultrasound. The incidence and hospitalization costs of major adverse cardiac events (MACE) were assessed after 4 years. The incidence of efficacy failure was significantly reduced with everolimus compared with azathioprine at 12, 24 and 48 months (P < 0.05), largely because of a lower incidence of BPAR. An increase in serum creatinine levels was seen with everolimus compared with azathioprine, likely attributed to CsA nephrotoxicity. There was a significantly larger increase in vascular intimal thickness with azathioprine than with everolimus (P <or= 0.01), which was accompanied by a significantly lower incidence of CAV in the everolimus groups. After 4 years, the incidence of MACE was higher with azathioprine than with either dose of everolimus. MACE-related treatment costs were estimated at 431,428 dollars for azathioprine, 136,664 dollars for everolimus 1.5 mg/day (68% saving) and 191,957 dollars for everolimus 3.0 mg/day (56% saving). Everolimus is significantly more effective than azathioprine in preventing efficacy failure in de novo heart transplant recipients and is also associated with reduced incidence and severity of CAV and MACE at 4 years post-transplant. The reduced 4-year incidence of MACE is likely to lead to substantially reduced hospitalization costs. Since cardiovascular morbidity and mortality are important factors in the long-term survival of renal transplant recipients, applying lessons from the use of everolimus in heart transplantation may further improve the understanding of managing cardiovascular risk in renal transplantation.
Eisen
Howard
H
Cardiology Division, Drexel University College of Medicine, Philadelphia, PA 19102, USA. heisen@drexelmed.edu
D001379:Azathioprine / Q000627:therapeutic use; D002318:Cardiovascular Diseases / Q000453:epidemiology / Q000209:etiology / Q000517:prevention & control*; D016572:Cyclosporine / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D000068338:Everolimus; D005938:Glucocorticoids / Q000627:therapeutic use; D006084:Graft Rejection / Q000000981:diagnostic imaging / Q000453:epidemiology / Q000209:etiology / Q000517:prevention & control*; D016027:Heart Transplantation / Q000009:adverse effects*; D017721:Hospital Costs / Q000706:statistics & numerical data; D006801:Humans; D016867:Immunocompromised Host; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D010414:Pennsylvania / Q000453:epidemiology; D011183:Postoperative Complications / Q000453:epidemiology / Q000209:etiology; D012307:Risk Factors; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000627:therapeutic use; D017539:Tunica Intima / Q000187:drug effects / Q000473:pathology; D014463:Ultrasonography
D005938:Glucocorticoids; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D000068338:Everolimus; D001379:Azathioprine; D020123:Sirolimus