Sirolimus in de novo heart transplant recipients reduces acute rejection and prevents coronary artery disease at 2 years: a randomized clinical trial

Circulation. 2004 Oct 26;110(17):2694-700. doi: 10.1161/01.CIR.0000136812.90177.94. Epub 2004 Jul 19.


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.

Publication types

  • Clinical Trial
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Disease
  • Adult
  • Azathioprine / therapeutic use
  • Coronary Artery Disease / prevention & control*
  • Creatinine / blood
  • Follow-Up Studies
  • Graft Rejection / diagnostic imaging
  • Graft Rejection / epidemiology
  • Graft Rejection / prevention & control*
  • Heart Transplantation* / mortality
  • Humans
  • Immunosuppressive Agents / administration & dosage
  • Immunosuppressive Agents / adverse effects
  • Immunosuppressive Agents / therapeutic use*
  • Infections / epidemiology
  • Lipids / blood
  • Sirolimus / administration & dosage
  • Sirolimus / adverse effects
  • Sirolimus / therapeutic use*
  • Survival Analysis
  • Ultrasonography


  • Immunosuppressive Agents
  • Lipids
  • Creatinine
  • Azathioprine
  • Sirolimus