October 26, 2004
Starkweather, B.S. and Asher Kimchi M.D.
Sydney, Australia – Sirolimus
was shown to reduce the incidence of acute rejection and prevent
coronary artery disease in de novo heart transplant patients at
two years post-transplant in a randomized clinical trial.
A study published by Anne Keogh,
MD, et al, in the October 26, 2004 issue of Circulation aimed to
determine the effect of sirolimus, used from the time of
transplantation, on acute rejection and graft vasculopathy in
human heart transplantation. Both of these effects were critical
to evaluate, since acute rejection causes 12% of post-transplant
deaths within the first year and coronary vasculopathy causes
17% of deaths beyond three years.
Five cardiac transplant centers
in Australia and New Zealand enrolled 136 first heart transplant
recipients in a randomized, open-label study of 12 months
duration with a safety observation period up to 24 months.
All patients received
cyclosporine and steroids preoperatively and were randomly
assigned (2:1) to sirolimus or azathioprine within 8 hours of
transplantation. The treatment groups were sirolimus 3mg,
sirolimus 5mg, and azathioprine.
All patients were required to
take diltiazem, pravastatin, and trimethoprim/sulfamethoxazole
in addition to their treatment drug, as well as ganciclovir in
CMV mismatched recipients.
Patients were reviewed at weeks
1 to 4, 6, 8, and 10; months 3 to 8, 10, and 12; and then every
3 months in the safety phase. Endomyocardial biopsy was
performed at each visit to assess acute rejection status.
Furthermore, patients coronary
artery grafts were assessed using selective coronary angiography
and intracoronary ultrasound (ICUS) at 6 weeks, 6 months, and 2
The primary endpoint was the
first occurrence of biopsy confirmed acute rejection within 6
months of transplantation. Secondary endpoints were patient
survival, renal function, safety and laboratory parameters and
At 6 months, acute rejection
occurred in 32.4% of patients receiving sirolimus 3mg and 32.8%
in the sirolimus 5mg group, compared to 56.8% in the group
ICUS evaluation at 6 months
showed significant narrowing in the mean coronary lumen area in
the azathioprine-treated patients, while both groups receiving
sirolimus showed no such increase in coronary vasculopathy. At 2
years, sirolimus patients demonstrated dramatically less
transplant coronary disease, with significant preservation of
coronary artery lumen. These results indicate that sirolimus
prevented the development of vasculopathy.
Patients treated with sirolimus
showed a lower incidence of CMV systemic syndrome, however, they
also had a higher incidence of pneumonia and an increase in mean
serum creatinine levels at 12 months.
Overall, sirolimus treated
patients had a significant relative reduction in acute rejection
(42% sirolimus 3mg, 43% sirolimus 5mg) in the first 6 months
after transplantation. Furthermore, there was significant
prevention of graft vasculopathy not just at 6 months but also
at 2 years in these patients.
Sirolimus 3 mg had efficacy
similar to sirolimus 5mg, with lower toxicity. Therefore,
sirolimus 3mg/d is the recommended dosage in this patient
In conclusion, sirolimus therapy
used from the time of cardiac transplantation markedly reduced
the proportion of patients experiencing acute rejection and
coronary vascular disease, with effects still sustained at 2
Co-authors were Meroula
Richardson, MD; Peter Ruygrok, MD; Phillip Spratt, MD; Andrew
Galbraith, MD; Gerry O’Driscoll, MD; Peter Macdonald, MD, PhD;
Don Esmore, MD; David Muller, MD; Steve Faddy, MSc, Med