24-Month Safety and Efficacy of Concentration Controlled Everolimus with Reduced Cyclosporine Versus Mycophenolate Mofetil in 721 De Novo Heart Transplant Recipients: Results from the A2310 Study

Introduction: A2310 (NCT00300274) study was designed to evaluate the efficacy and safety of everolimus with reduced cyclosporine A (rCsA) versus mycophenolate mofetil (MMF) with standard CsA (sCsA) in de novo heart transplant recipients (HTxR). The 12-month (M) results showed that everolimus had comparable efficacy to MMF, but inferior renal function, possibly related to non-adherence to reduction of CsA exposure. The 12M results also showed that everolimus is associated with significantly less incidence of cardiac allograft vasculopathy. Herein we report the final 24M results. Methods: In this Phase III, 24M, multi-center, open-label, controlled study 721 HTxR were randomized to either 1.5 mg everolimus (C0: 3-8 ng/mL; n=282)+rCsA or 3.0 mg everolimus (C0: 6-12 ng/mL; n=168)+rCsA or 3.0 g MMF+sCsA (n=271) at 1:1:1 ratio. All patients received steroids ± induction (thymoglobulin or basiliximab). Here, only the everolimus 1.5 mg vs. MMF result is presented because the enrollment into the everolimus 3.0 mg group was prematurely stopped due to early increased mortality. The 24M endpoints include composite efficacy failure (biopsy-proven acute rejection, acute rejection associated with hemodynamic compromise, graft loss/re-transplant, death, or loss to follow-up) and its components, renal function (estimated glomerular filtration rate by Modification of Diet in Renal Disease formula-4), and adverse events. Results: At M24, rates of composite efficacy failure were comparable between everolimus 1.5 mg (39.4%) and MMF groups (41.3%) with an event rate difference of -2.0% (97.5% CI: -11.3%, 7.4%; pre-specified margin of 13%) in favor of everolimus (Table). After the early decline of renal function observed in everolimus patients reported in the 12M analysis, renal function remained stable between 12M and 24M in everolimus group (58.8 vs. 58.8 mL/min/1.73 m2), as well as in MMF group (64.4 vs. 65.3 mL/min/1.73 m2). The mean difference in eGFR at M24 was -6.5 mL/min/1.73 m2 (97.5% CI: -11.9, -1.0) in favor of MMF. Eight deaths were reported in the everolimus 1.5 mg vs. 12 in MMF group between M12 and M24. Viral infections were more frequent with MMF and bacterial infections occurred slightly more often with everolimus, consistent with the data seen at M12.Table: [Incidence rates of efficacy and safety endpoints]Conclusions: After 24M of follow-up in de novo HTxR, everolimus (C0: 3-8 ng/mL) with rCsA retained similar efficacy as the control, and a reassuring safety profile compared to M12 results. In particular, by the end of this extended follow-up period death rate appeared balanced between the two study groups and renal function in the everolimus group was still inferior but no further decline was observed.