Proliferation Signal Inhibitors Reduce Severity of Cardiac Allograft Vasculopathy after Heart Transplantation

Abstract

Purpose The multicenter randomized trials of everolimus have demonstrated a significant reduction in 1st year maximal intimal thickness. It has been demonstrated from a validation study that 1st year intimal thickness >0.5 mm results in more angiographic abnormalities at 5 years after transplant. We sought to verify this finding by following our patients on everolimus at the time of heart transplant for 5 years and comparing them to age-match-sex controls. Methods and Materials Between 1994 and 2010, we evaluated 800 heart transplant patients and divided them into initial immunosuppression groups which included: Cyclosporine (CYA)/Mycophenolate (MMF), tacrolimus (TAC)/MMF and CYA/everolimus (EVR). Patients were followed for 5 years after heart transplantation for survival, freedom from cardiac allograft vasculopathy (CAV: any angiographic stenosis ≥30%) (including grades of CAV), freedom from non-fatal major adverse cardiac events (NF-MACE: MI, stroke, new-onset CHF, percutaneous cardiac intervention, need for defibrillator/pacemaker), and 1-year freedom from rejection. Results There was no significant difference in 5 year survival and freedom from CAV or NF-MACE among the 3 groups. However, review of CAV severity found no ISHLT grade 2-3 CAV in the CSA/EVR group compared to the CYA/MMF and TAC/MMF groups (0% vs 38% vs 31%) but numbers are small. Conclusions Patients treated with proliferation signal inhibitors at the time of heart transplantation appear to develop less severe CAV compared to patients not on proliferation signal inhibitors. A larger study is warranted to confirm these findings. Outcomes CYA/MMF (N=243) TAC/MMF (N=528) CYA/EVR (N=29) Log-Rank p-value 1-Year Freedom from Any-Treated Rejection 90% 87% 83% 0.417 5-Year Actuarial Survival 77% 83% 76% 0.106 5-Year Freedom from NF-MACE 84% 85% 83% 0.913 5-Year Freedom from CAV 83% 85% 93% 0.318 Total with CAV, n 42 79 2 CAV1, n (%) 26 (62%) 54 (69%) 2 (100%) CAV2, n (%) 8 (19%) 13 (16%) 0 (0%) CAV3, n (%) 8 (19%) 12 (15%) 0 (0%)