Allograft vasculopathy
Preventing Cardiac Allograft Vasculopathy: Long-term Beneficial Effects of Mycophenolate Mofetil

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Background

The impact of long-term mycophenolate mofetil (MMF) treatment on the development of cardiac allograft vasculopathy (CAV) after heart transplantation is an area of much recent interest. This study analyzed the effects of various immunosuppressive combinations, including cyclosporine (CsA), azathioprine (Aza), tacrolimus (Tac) and MMF, on the time of onset, extent and progression of CAV.

Methods

Two hundred seventy-three consecutive heart transplant recipients (mean age: 51.2 ± 12.2 years; mean follow-up: 6.8 ± 1.9 years) were examined by coronary angiography on a yearly basis between 1995 and 2003. The extent of CAV was evaluated using a scoring system based on the severity of vessel stenosis. The onset of CAV was analyzed using Kaplan–Meier estimates and the log rank test for four treatment combinations, CsA/Aza (n = 47, 17.2%), CsA/MMF (n = 26, 9.5%), Tac/Aza (n = 62, 22.7%) and Tac/MMF (n = 138, 50.5%), and for the primary and the secondary immunosuppressants alone.

Results

The rate of freedom from CAV at 5 years was 47% with CsA/Aza, 66% with CsA/MMF, 60% with Tac/Aza and 70% with Tac/MMF. After 5 years, the Tac/MMF group showed a significantly lower incidence of CAV than the CsA/Aza group (log rank 7.58, p = 0.0059). CsA (n = 73) was compared with Tac (n = 200) and MMF (n = 164) with Aza (n = 109): the rate of freedom from CAV was 51.2% in CsA patients vs 66.1% in Tac patients (log rank 5.7, p = 0.017), and 54.6% in Aza patients vs 67% in MMF patients (log rank 4.36, p = 0.037). Multivariate Cox regression analysis revealed that MMF decreased the incidence of CAV significantly (p = 0.041). In this patient cohort, Tac or CsA medication was not an independent risk factor for incidence of CAV nor for decreased survival.

Conclusions

The choice of immunosuppression has an impact on the incidence of CAV. In terms of prevention of CAV, MMF is superior to Aza in either combination. A trend toward improved survival in MMF patients was noted. The lower number of rejection episodes in the MMF groups may have contributed to these results.

Section snippets

Patients

We analyzed the follow-up data of 273 consecutive adult orthotopic heart transplant recipients in the period from 1995 to 2003. The reasons for HTx were dilated cardiomyopathy (60.0%), ischemic cardiomyopathy (30.7%) and “other reasons” (9.3%). All patients included in this study were randomized into earlier studies, which compared different immunosuppressive regimens. For the period between 1994 and 1996, the combination Tac/Aza was compared with the combination CsA/Aza; in 1997, the first

Survival

The cumulative survival of the HTx patients included in this analysis was 83.1% after 1 year and 74.9% after 5 years. Considering the four treatment groups separately, survival rates at 1 and 5 years were 83%/68.1% in Group 1 (CsA/Aza), 92.3%/87.7% in Group 2 (CsA/MMF), 90.3%/80.5% in Group 3 (Tac/Aza) and 87.6%/81.3% in Group 4 (Tac/MMF), respectively (Figure 1).

Analysis of these data using the log rank test shows significantly better survival in Group 4 (Tac/MMF) than in Group 1 (CsA/Aza)

Discussion

In this study we have demonstrated that the choice of immunosuppressive regimen is an important factor for the prevention of CAV. This is the first report to show the superiority of MMF over Aza, in either combination, in a study with a large number of cases (n = 273) and a follow-up period of >5 years.

The survival of patients included in this study was 83.0% after 1 year and 76.9% after 4 years.

Survival was found to correlate with immunosuppressive drug regimen. Long-term prognosis was

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    Copyright © 2006 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.