SYDNEY, Australia, Oct. 25 /PRNewswire/ -- A study published today in the journal Circulation shows that sirolimus used from the time of heart transplantation, provides sustained protection against coronary allograft vasculopathy whilst also halving acute organ rejection in these patients.
Cardiac allograft vasculopathy, an aggressive form of coronary artery disease, involves the narrowing and blocking of the coronary arteries. This disease occurs in 50%(1) or more of heart transplant patients in the first five years after transplantation. It is the most common cause of death in these patients with its importance growing with time after the transplant. Acute rejection is responsible for early deaths in the first year post heart transplant whereas cardiac allograft vasculopathy causes 17% of all deaths beyond 3 years.(2)
Commenting on the research Associate Professor Anne Keogh from St Vincent’s Hospital, Sydney said, “Cardiac allograft vasculopathy is the major challenge in heart transplant patients. Treatment for this relentlessly progressive complication has to date been disappointing. Cholesterol lowering agents and calcium channel blockers have some protective effect but they do not eliminate the problem. This exciting drug -- the mTOR inhibitor sirolimus -- actually substantially prevents its development in heart transplant patients. This is well in line with its effects in regular coronary artery disease to stop in-stent retenosis -- a fact known now for several years.”
Five cardiac transplant centres from Australia and New Zealand enrolled 136 heart recipients in this open label study. Following heart transplantation patients were randomised to receive sirolimus or azathioprine in combination with cyclosporine and steroids. Of the 136 patients, 34 received sirolimus 3mg, 57 received sirolimus 5mg, and 43 received azathioprine, with only 2 patients (1 azathioprine, 1 sirolimus 5mg) not receiving any study medication. Of these 136 patients, 41% underwent investigator requested Intracoronary Ultrasound (ICUS) at 2 years to ascertain whether benefits on vasculopathy might be sustained.
Intracoronary ultrasound and coronary angiography were performed at 6 weeks, 6 months and 2 years and compared between the 2 groups. At 2 years, all parameters of cardiac allograft vasculopathy had progressed markedly in those patients on azathioprine. In contrast, the development of vasculopathy was not observed in patients receiving sirolimus. The results confirm that sirolimus used from the time of transplantation is associated with marked protection from cardiac allograft vasculopathy.
Intracoronary ultrasound measurements at 2 years AZA SRL p-Value (SRL vs AZA) Maximal intima & media thickness (mm) 0.9 +/- 0.4 0.5 +/- 0.3 0.0865 Mean intima & media thickness (mm) 0.32 +/- 0.19 0.22 +/- 0.16 0.0048 Mean intima & media area (mm2) 3.8 +/- 2.2 2.8 +/- 2.0 0.0397 Mean lumen diameter (mm) 3.4 +/- 0.7 3.8 +/- 0.6 0.0042 Mean lumen area (mm2) 9.4 +/- 3.8 11.7 +/- 3.7 0.0047 Mean vessel area (mm2) 13.3 +/- 4.4 14.6 +/- 4.5 0.1600 Plaque volume (mm2 ) 7.1 +/- 4.7 5.7 +/- 4.1 0.1105 Plaque burden (%) 28.7 +/- 15.3 18.3 +/- 11.3 0.0002
“The findings of this study are compelling and very exciting. The prevention of graft vasculopathy, not just at 6 months but also at 2 years, suggests that the choice of initial immunosuppressive therapy can influence long term outcomes for heart transplant patients with regard to coronary artery disease. Over 90% of all heart transplant recipients in both Australia and New Zealand for the whole period were able to be enrolled in the study which means sirolimus is of practical use in the majority,” said Associate Professor Keogh.
Additional study findings:
Acute rejection in the first 6 months was almost halved when sirolimus was substituted for azathioprine. Notably, this reduction was achieved without an increase in diabetes mellitus, high blood pressure or cholesterol and with comparable survival. Both malignancy and cytomegalovirus infections tended to actually be lower. The benefit on malignancy is expected to increase with time.
Acute rejection - At 6 months, acute rejection occurred in 32.4% of patients receiving sirolimus 3mg (p=0.027) and 32.8% receiving sirolimus 5mg (p=0.013), compared with 56.8% receiving azathioprine Survival - Survival rates at 12 months did not differ significantly (85.3% sirolimus 3mg, 86.2% sirolimus 5mg, 90.9% azathioprine, log-rank p=0.746)
In addition the results of the study are actively in line with coronary artery stents coated with sirolimus used in regular coronary artery disease, where occlusion rates are reduced to a minimum-putting this type of stent in great demand.
References (1) Avery RK. Cardiac-Allograft Vasculopathy. NEJM. 2003 349:829-830. (2) Taylor DO et al. The registry of the International Society for Heart and Lung Transplantation: twentieth official adult heart transplant report - 2003. J Heart Lung Transplant. 2003;22;6:616-624.
St Vincent’s Hospital, Sydney
CONTACT: David Faktor, Public Affairs & Communications Manager,+02 8382 2866, 0405 497 510, for St Vincent’s Hospital, Sydney