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Sirolimus Reduces Acute Rejection and Coronary Artery Disease in De Novo Heart Transplant Patients  

October 26, 2004

By Ashley 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 years.

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 ICUS parameters.

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 receiving azathioprine.

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 population.

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 years.

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

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