Sirolimus in De Novo Heart Transplant Recipients - Sirolimus in De Novo Heart Transplant Recipients


The goal of the study was to evaluate the effect of sirolimus compared with azathioprine on acute cellular rejection and graft vasculopathy in human heart transplantation.

Study Design

Study Design:

Patients Enrolled: 136
Mean Follow Up: Two years

Patient Populations:

Age ≥18 years, white cell count ≥4.0 x 109/l, platelet count ≥100 x 109/l, and contraception for women of childbearing age


Multiple organ transplants, serum creatinine >265 µmol/l, familial hypercholesterolemia, pretransplantation cholesterol >387 mg/dl, previous investigational agents, antibody induction, lung infiltrate, systemic infection, and solid-organ malignancy within five years

Primary Endpoints:

Incidence of first occurrence of biopsy-confirmed acute rejection (≥grade 3a) within six months of transplantation or any presumed clinical rejection resulting in treatment

Secondary Endpoints:

Survival, renal function, safety and laboratory parameters, and ICUS parameters

Drug/Procedures Used:

Patients were randomized (2:1) within eight hours of transplantation in an open-label manner to treatment with sirolimus (3 mg or 5 mg; n=92) or azathioprine (n=44). A subgroup of patients underwent coronary angiography and intracoronary ultrasound (ICUS) at six weeks, six months, and two years.

Concomitant Medications:

All patients received cyclosporine and steroids preoperatively. Patients also received diltiazem (180-240 mg/day), pravastatin (40 mg/day), trimethoprim/sulfamethoxazole twice weekly, and intravenous ganciclovir (5 mg/kg per day three times weekly for six weeks).

Principal Findings:

The primary endpoint of acute rejection at six months occurred less frequently in the sirolimus 3 mg arm and sirolimus 5 mg arm compared with the azathioprine group (32.4% and 32.8% vs. 56.8%, respectively; p=0.027 for sirolimus 3 mg vs. placebo and p=0.013 for sirolimus 5 mg vs. placebo). There was no difference in survival at 12 months (85.3% sirolimus 3 mg, 86.2% sirolimus 5 mg, 90.9% azathioprine; log-rank p=0.746). Mean serum creatinine levels at 12 months were significantly higher in the sirolimus 5 mg group compared with the azathioprine group (165.1 vs. 125.4 µmol/l; p<0.001), but the sirolimus 3 mg group did not differ from the azathioprine group (127.7 µmol/l).

In the subgroup of patients with paired ICUS measures at six weeks and six months and two years, all measures of transplant vasculopathy showed progression in the azathioprine group. In the sirolimus group (both doses combined), there was no progression of transplant vasculopathy measures. The differences in ICUS measures between the treatment groups were significant.


Among patients undergoing heart transplantation, treatment with sirolimus was associated with less acute rejection at six months compared with treatment with azathioprine. Additionally, measures of graft vasculopathy were better in the sirolimus group, an important finding given the early post-transplantation loss of coronary lumen diameter and distal disease. Another recent study evaluated everolimus compared with azathioprine and found a similar beneficial effect on acute rejection and transplant vasculopathy at two years.


Keogh A, Richardson M, Ruygrok P, et al. Sirolimus in de novo heart transplant recipients reduces acute rejection and prevents coronary artery disease at 2 years. A randomized clinical trial. Circulation 2004;110:r10-r16.

Clinical Topics: Cardiac Surgery, Invasive Cardiovascular Angiography and Intervention, Noninvasive Imaging, Atherosclerotic Disease (CAD/PAD), Cardiac Surgery and Heart Failure, Heart Transplant, Interventions and Coronary Artery Disease, Interventions and Imaging, Angiography, Nuclear Imaging

Keywords: Coronary Artery Disease, Contraception, Platelet Count, Coronary Angiography, Azathioprine, Graft Rejection, Immunosuppressive Agents, Sirolimus, Creatinine, Heart Transplantation

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