Everolimus With Reduced Cyclosporine Versus MMF With Standard Cyclosporine in De Novo Heart Transplant Recipients

Background. Pharmacokinetic modeling supports trough monitoring of everolimus, but prospective data comparing this approach versus mycophenolate mofetil (MMF) in de novo cardiac transplant recipients are currently unavailable. Methods. In a 12-month multicenter open-label study, cardiac transplant patients received everolimus (trough level 3-8 ng/mL) with reduced cyclosporine A (CsA) or MMF (3 g/day) with standard CsA, both with corticosteroids +/- induction therapy. Results. In total, 176 patients were randomized (everolimus 92, MMF 84). Mean creatinine clearance was 72.5 +/- 27.9 and 76.8 +/- 32.1 mL/min at baseline, 65.4 +/- 24.7 and 72.2 +/- 26.2 mL/min at month 6, and 68.7 +/- 27.7 and 71.8 +/- 29.8 mL/min at month 12 with everolimus and MMF, respectively. The primary endpoint was not met since calculated CrCl at month 6 posttransplant was 6.9 mL/min lower with everolimus, exceeding the predefined margin of 6 mL/min. However, by month 12 the between-group difference had narrowed versus baseline (3.1 mL/min). All efficacy endpoints were noninferior for everolimus versus MMF. The 12-month incidence of biopsy-proven acute rejection International Heart and Lung Transplantation grade more than or equal to 3A was 21 of 92 (22.8%) with everolimus and 25 of 84 (29.8%) with MMF. Adverse events were consistent with class effects including less-frequent cytomegalovirus infection with everolimus (4 [4.4%]) than MMF (14 [16.9%], P=0.01). Conclusion. Concentration-controlled everolimus with reduced CsA results in similar renal function and equivalent efficacy compared with MMF with standard CsA at 12 months after cardiac transplantation.