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HERAKLESwas a 1‐year randomized, multicenter trial. Patients were randomized at 3 months after kidney transplantation to remain on cyclosporine‐based therapy, switch to everolimus without a calcineurin inhibitor (CNI), or switch to everolimus with low‐exposure cyclosporine. Overall, 417 of 497 (83.9%) patients from the core study entered a 4‐year extension study. The randomized regimen was continued to year 5 in 75.9%, 41.9% and 24.6% of patients in the standard‐CNI,CNI‐free and low‐CNIgroups, respectively. Adjusted estimated GFRat year 5 was significantly higher in the CNI‐free group versus standard CNI(difference 7.2 mL/min/1.73 m2, P< .001) or low CNI(difference 7.6 mL/min/1.73 m2, P< .001). For patients who continued randomized therapy for 5 years, differences were 14.4 mL/min/1.73 m2and 10.1 mL/min/1.73 m2, respectively. Biopsy‐proven acute rejection occurred during the 4‐year extension study in 7.6%, 8.6%, and 9.0% of patients in the standard‐CNI,CNI‐free and low‐CNIgroups, respectively (P= .927). In conclusion, conversion to a CNI‐free everolimus regimen 3 months after kidney transplantation improved long‐term graft function, particularly in patients who continued the CNI‐free regimen. Low CNIwith everolimus did not improve renal function. Efficacy was comparable between groups but frequent immunosuppression changes should be taken into account. Five‐year follow‐up data from patients randomized at three months after kidney transplantation to receive standard calcineurin inhibitor (CNI) therapy, everolimus‐based CNI‐free therapy, or everolimus with low‐exposure CNI show that early CNI withdrawal maintains better long‐term renal function without an increase in biopsy‐proven acute rejection, with a similar rate of infections and a low rate of discontinuations due to adverse events in all three treatment groups.

In a 24‐month, multicenter, open‐label, randomized trial, 715 de novokidney transplant recipients were randomized at 10–14 weeks to convert to everolimus (n = 359) or remain on standard calcineurin inhibitor (CNI) therapy (n = 356; 231 tacrolimus; 125 cyclosporine), all with mycophenolic acid and steroids. The primary endpoint, change in estimated glomerular filtration rate (eGFR) from randomization to month 12, was similar for everolimus versus CNI: mean (standard error) 0.3(1.5) mL/min/1.732versus −1.5(1.5) mL/min/1.732(p = 0.116). Biopsy‐proven acute rejection (BPAR) at month 12 was more frequent under everolimus versus CNIoverall (9.7% vs. 4.8%, p = 0.014) and versus tacrolimus‐treated patients (2.6%, p < 0.001) but similar to cyclosporine‐treated patients (8.8%, p = 0.755). Reporting on de novodonor‐specific antibodies (DSA) was limited but suggested more frequent anti‐HLAClass I DSAunder everolimus. Change in left ventricular mass index was similar. Discontinuation due to adverse events was more frequent with everolimus (23.6%) versus CNI(8.4%). In conclusion, conversion to everolimus at 10–14 weeks posttransplant was associated with renal function similar to that with standard therapy overall. Rates of BPARwere low in all groups, but lower with tacrolimus than everolimus. In a multicenter, open‐label, randomized trial of de novokidney transplant recipients, conversion to everolimus at 10–14 weeks posttransplant is associated with similar renal function as in patients who continue to standard tacrolimus or cyclosporine therapy, with low rates of biopsy‐proven acute rejection in all groups, but lower rates with tacrolimus than everolimus.