Background— Sirolimus reduces acute rejection in renal transplant recipients and prevents vasculopathy in nonhuman primates and in-stent restenosis in humans. Its effects on rejection and transplant vasculopathy in human heart transplant recipients are unknown.

Methods and Results— In a randomized, open-label study, sirolimus was compared with azathioprine in combination with cyclosporine and steroids administered from the time of cardiac transplantation. We report 6-month rejection rates (primary end point), 12-month safety and efficacy data, and 6- and 24-month graft vasculopathy data in 136 cardiac allograft recipients randomly assigned (2:1) to sirolimus (n=92) or azathioprine (n=44). At 6 months, the proportion of patients with grade 3a or greater acute rejection was 32.4% for sirolimus 3 mg/d (P=0.027), 32.8% for sirolimus 5 mg/d (P=0.013), and 56.8% for azathioprine. Patient survival at 12 months was comparable among groups. Intracoronary ultrasound at 6 weeks, 6 months, and 2 years demonstrated highly significant progression of transplant vasculopathy in azathioprine-treated patients. At 6 months, a highly significant absence of progression in intimal plus medial proliferation and significant protection against luminal encroachment was evident in sirolimus-treated patients, and these effects were sustained at 2 years.

Conclusions— Sirolimus use from the time of transplantation approximately halved the number of patients experiencing acute rejection. The measurable development of transplant vasculopathy at 6 months and 2 years in patients receiving azathioprine was not observed in patients receiving sirolimus.