Everolimus in Heart Transplantation: An Update

Table 1

Clinical studies of everolimus versus azathioprine or mycophenolate mofetil (MMF) in de novo heart transplant recipients.

Study	Design	Primary endpoint	Everolimus	Comparator	CsA 𝐶0 target range (ng/mL) by month	Induction therapy	Steroids
B253 [2]	24-month Multicenter Randomized Double-blind for months 0–12, open-label for months 12–24	Composite efficacy failure at 6 months	Fixed-dose^a 1.5 mg/day (𝑛=209); 3.0 mg/day (𝑛=211)	Azathioprine^a 1–3 mg/kg/day (𝑛=214)	All 3 groups: 1: 250–400; 2–6: 200–350; 7–24: 100–300	In individual centers only: ATG or muromonab-CD3	Prednisolone, initiated at 0.5–1.0 mg/kg/day, tapered to achieve 0.3–0.5 mg/kg/day by day 21 and ≥0.1 mg/kg/day by month 6
Lehmkuhl et al. 2007 [10]	12-month; Single center; Retrospective	Not applicable	Initial dose before transplant 0.75 mg, then mean 1.5–1.75 mg/day, and 𝐶0 3–8 ng/mL (𝑛=38)	MMF before transplant 1.0 g, then mean 1.5–2.5 g/day (𝑛=18)	Everolimus versus MMF: 1: 200–250, both groups; 2: 175–200 versus 200–250; 3-4: 150–175 versus 200–250; 5-6: 100–150 versus 150–200; 7–12: 80–120 versus 120–150	ATG 2.5 mg/kg/day on days 1 and 2	Initially, high-dose methylprednisolone, then prednisolone 1 mg/kg/day, tapered to achieve 0.1 mg/kg/day by month 12
A2411 [3]	12-month Multicenter; Randomized; Open-label	Noninferiority of renal function (calculated creatinine clearance at 6 months)	Initial dose^a 1.5 mg/day, 𝐶0 3–8 ng/mL (𝑛=92)	MMF^a 3.0 g/day; (𝑛=84)	Everolimus versus MMF: 1: 200–350, both groups; 2: 150–250 versus 200–350; 3-4: 100–200 versus 200–300; 5-6: 75–150 versus 150–250; 7–12: 50–100 versus 100–250	Antithymocyte antibodies (68.4% of patients) or; IL-2RA (25.9% of patients)	Prednisone, tapered to achieve ≥0.1 mg/kg/day by month 6 and 0.1–0.05 mg/kg/day from month 6 to 12
A2310 [9]	24 months; Multicenter; Randomized; Open-label	Noninferiority of composite efficacy failure at 12 months IVUS substudy: change in mean MIT at 12 months	Initial dose^a 1.5 mg/day, 𝐶0 3–8 ng/mL (𝑛=282) or 3.0 mg/day, 𝐶0 6–12 ng/mL (𝑛=168)	MMF^a 3.0 g/day; (𝑛=271)	Everolimus versus MMF: 1: 200–350, both groups; 2: 150–250 versus 200–350; 3-4: 100–200 versus 200–300; 5-6: 75–150 versus 150–250; 7–24: 50–100 versus 100–250	Center-specific: No induction or Thymoglobulin or basiliximab	Yes, according to local practice

ATG: antithymocyte globulin; CsA: cyclosporine; IL-2RA: interleukin-2 receptor antibody; IVUS: intravascular ultrasound; MIT: maximum intimal thickness.
^aFirst dose administered within 72 hours after transplant surgery.