Use of Rapamycin Slows Progression of Cardiac Transplantation Vasculopathy

Abstract

Background-Cardiac transplantation vasculopathy is the leading cause of late death in heart transplantation recipients.Rapamycin is an immunosuppressant drug with potent antiproliferative and antimigratory effects. We investigated whether rapamycin could prevent progression of graft vasculopathy in 46 patients (age, 54Ϯ10 years; 4.3Ϯ2.3 years after transplantation) with severe disease. Methods and Results-At annual cardiac catheterization, patients were randomly assigned to treatment with rapamycin (nϭ22) versus continued current immunosuppression (nϭ24). Clinical characteristics including recipient age and sex, underlying cause of congestive heart failure, donor age and sex, and ischemic time were recorded. Cardiac catheterization was graded with the use of a semiquantitative scale and repeated annually. Clinically significant adverse events were defined as death, need for angioplasty or bypass surgery, myocardial infarction, and a Ͼ25% worsening of the catheterization score. These events were monitored as primary study end points. Anti-HLA class I and II antibody production and lymphocyte growth assays were measured with each biopsy. Patients selected for rapamycin had azathioprine or mycophenolate mofetil discontinued and were given rapamycin. Outcomes were compared by means of log-rank analysis. There were no significant differences in baseline characteristics. Duration of follow-up was comparable (rapamycin, 689Ϯ261; control, 630Ϯ207 days; NS). In the rapamycin group, 3 patients reached primary end points versus 14 patients in the control group (PϽ0.001). There was no difference in baseline or subsequent anti-HLA class I or II antibody production. Conclusions-In

Canadian Cardiovascular Society Consensus Conference update on cardiac transplantation 2008: Executive Summary

“…High doses of steroids and ATG were associated with reduced progression and, in some cases, regression of ACAD in one small study (90), but the risks, including increased infection and malignancy, likely outweigh the benefits of this approach. Attenuation of the progression of ACAD has been seen in patients with established ACAD in whom sirolimus was added to CNI therapy (91). Similar results were seen in another study (92) in which rapamycin was used to replace CNI therapy; however, the incidence of rejection in the absence of CNI increased significantly.…”

“…Some data suggest that a tacrolimus-based immunosuppressive regimen is associated with less coronary intimal thickening than with a cyclosporine-based regimen (84). Newer immunosuppressive agents, including sirolimus and everolimus (85)(86)(87)(88)(89), have shown some early promise in reducing intimal thickening, but their routine use for this purpose requires additional study.…”

Randomized, Double-Blind, Placebo-Controlled Trial of Oral Sirolimus for Restenosis Prevention in Patients With In-Stent Restenosis

“…In the treatment of cardiac transplant vasculopathy, the long-term administration of sirolimus was not associated with an increased mortality. 4 Although it seems unlikely that the short, 10-day treatment with sirolimus is the cause for the rather late-occurring deaths, further studies may be needed to rule out a potential hazardous impact of this treatment regimen before this strategy is adopted in clinical routine.…”

“…3 Sirolimus, a naturally occurring macrolide immunosuppressant, has been approved by the US Food and Drug Administration as an agent to prevent acute rejection in renal transplantation patients, and it has been shown to slow the progression of accelerated arteriopathy after cardiac transplantation. 4 In experimental studies, sirolimus inhibited the proliferation of rodent and human vascular smooth muscle cells in vitro and porcine vascular smooth muscle cells in vivo by blocking cell cycle progression at the G 1 /S transition. 5,6 Sirolimus-eluting stents have shown promising results in restenosis prevention in de novo coronary arteries in several clinical trials, 7,8 but this strategy has not been evaluated in patients with ISR.…”

Myocardial perfusion imaging for cardiac allograft vasculopathy assessment: Evidence grows, but questions remain

“…1 Risk factor modification and early therapy with mammalian target of rapamycin (mTOR) inhibitors such as sirolimus may attenuate CAV progression. 2,3 Percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG) are useful for focal lesions but suboptimal in advanced disease because of diffuse disease, poor targets, and high restenosis rates. Retransplantation is effective, but raises ethical concerns, is severely hampered by organ shortage, and requires planning and waiting during which time clinical events can occur.…”