Everolimus for Cardiac Allograft Vasculopathy—Every Patient, at any Time?

Abstract

In this issue, Arora et al. (1) attempt to address the question of whether the addition of everolimus to a calcineurin-based immunosuppression regimen can attenuate the progression of cardiac allograft vasculopathy (CAV) years after heart transplantation. Currently, CAV remains one of the most important factors limiting long-term survival in heart transplant patients. Despite significant advances in immunosuppression and posttransplant care resulting in a progressive decline in allograft rejection and improved survival, the incidence of CAV has changed little, with 30% of patients developing the disease within 5 years of transplantation. A major advance in the management of CAV came with the availability of proliferation signal inhibitors (PSIs), sirolimus and everolimus. These agents are a class of antiproliferative agents shown to inhibit smooth muscle cell proliferation, a key component in the development of CAV. In a study by Keogh et al. (2), the use of sirolimus in 136 de novo heart transplant patients was associated with decreased development of CAV at 2 years compared with patients receiving azathioprine. In a subsequent sentinel multicenter study by Eisen et al. (3), more than 600 patients were randomized to everolimus or azathioprine (both in combination with cyclosporine) within 72 hr of transplantation. Intravascular ultrasonography (IVUS) showed that the average increase in maximal intimal thickness at 12 months was significantly smaller with everolimus compared with azathioprine. This finding was important as it has been demonstrated that a significant increase in maximal intimal thickness at 1 year is associated with higher posttransplant mortality at 5 years (4). Although the benefit of early use of PSIs in heart transplantation seems established, it is unclear whether they provide any benefit to prevent or slow the progression of CAV when initiated later after heart transplantation. In a small study by Mancini et al. (5), 46 patients with severe CAV at a mean 4.3 years after transplantation were randomly assigned to sirolimus or continued on maintenance therapy with mycophenolate mofetil (MMF) or azathioprine (all groups with continued cyclosporine therapy). Patients treated with sirolimus demonstrated slowed angiographic disease progression and improved clinical outcomes. However, to date, no randomized study using IVUS has assessed late immunosuppression change to slow the development of CAV. In this study, to address the aforementioned point, Arora et al. randomized 111 patients on calcineurin inhibitor (CNI) and azathioprine or MMF who were more than 5 years from transplant to the addition of everolimus with reduced-dose CNI or continuing CNI with azathioprine or MMF. All study patients underwent IVUS at study entry and 12 months later. This study represented a subpopulation of the Nordic Certican Trial in Heart and Lung Transplantation randomized trial, a study investigating the efficacy of everolimus with reduced-dose CNI in reducing renal dysfunction in heart and lung transplant recipients. The authors found that the addition of everolimus and reduced CNI at a mean 5.8 years after transplant did not influence CAV progression by IVUS. However, in the subgroup of patients receiving everolimus, reduced-dose CNI, and concomitant azathioprine therapy, CAV progression and a number of inflammatory markers implicated in CAV were attenuated compared with the control CNI group. To the contrary, the subgroup of patients receiving everolimus, reduced-dose CNI, and MMF was associated with accelerated CAV and a parallel increase in inflammatory markers. Although these results are of great interest, the applicability of these findings to the contemporary management of heart transplant recipients remains in question. Unique to this study, the design of the protocol allowed addition of everolimus to preexisting therapy with MMF or azathioprine both in combination with cyclosporine. In clinical practice, most clinicians switch antiproliferative medications as opposed to adding them. The discordant effects of everolimus and azathioprine to everolimus and MMF (both with continued cyclosporine therapy) raise the question of a yet unidentified adverse drug interaction in which MMF may abrogate the effects of everolimus. The findings are certainly hypothesis generating and merit further investigation. The study also includes predominantly cyclosporine-treated patients. In the current era, most heart transplant programs use tacrolimus-based immunosuppression. The three-arm study (6) suggested that patients on tacrolimus with sirolimus and tacrolimus with MMF benefited from lower rates of rejection when compared with cyclosporine with MMF with respect to lower rates of rejection. Although this study raises some important questions, the results should be kept in perspective. The evidence to date suggests benefit for the use of PSI for prevention of CAV when used early after heart transplantation. Confirmation of the results of this study would require adequately powered studies to evaluate the use of combination antiproliferative agents and CNI, with appropriate predefined endpoints, and mechanistic studies to elucidate potential drug interaction.