Impact of prophylactic immediate posttransplant ganciclovir on developmentof transplant atherosclerosis - A post hoc analysis of a randomized, placebo-controlled study

Background-Coronary artery disease occurs in an accelerated fashion in the donor heart after heart transplantation (TxCAD), but the cause is poorly un derstood. The risk of developing TxCAD is increased by cytomegalovirus (CMV ) infection and decreased by use of calcium blockers. Our group observed th at prophylactic administration of ganciclovir early after heart transplanta tion inhibited CMV illness; and we now propose to determine whether this th erapy also prevents TxCAD. Methods and Results-One hundred forty-nine consecutive patients (131 men an d 18 women aged 48 +/- 13 years) were randomized to receive either ganciclo vir or placebo during the initial 28 days after heart transplantation. Immu nosuppression consisted of muromonab-CD3 (OKT-3) prophylaxis and maintenanc e with cyclosporine, prednisone, and azathioprine. Mean follow-up time was 4.7 +/- 1.3 years. In a post hoc analysis of this trial designed to assess efficacy of ganciclovir for prevention of CMV disease, we compared the actu arial incidence of TxCAD, defined by annual angiography as the presence of any stenosis. Because calcium blockers have been shown to prevent TxCAD, we analyzed the results by stratifying patients according to use of calcium b lockers. TxCAD could not be evaluated in 28 patients because of early death or limited follow-up. Among the evaluable patients, actuarial incidence of TxCAD at follow-up (mean, 4.7 years) in ganciclovir-treated patients (n = 62) compared with placebo (n = 59) was 43 +/- 8% versus 60 +/- 10% (P < 0.1 ). By Cox multivariate analysis, independent predictors of TxCAD were donor age >40 years (relative risk, 2.7; CI, 1.3 to 5.5; P < 0.01) and no gancic lovir (relative risk, 2.1; CI, 1.1 to 5.3; P = 0.04) Stratification on the basis of calcium blocker use revealed differences in TxCAD incidence when g anciclovir and placebo were compared: no calcium blockers (n = 53), 32 +/- 11% (n = 28) for ganciclovir versus 62 +/- 16% (n = 25) for placebo (P < 0. 03); calcium blockers (n = 68), 50 +/- 14% (n = 33) for ganciclovir versus 45 +/- 12% (n = 35) for placebo (P = NS), Conclusions-TxCAD incidence appears to be lower in patients treated with ga nciclovir who are not treated with calcium blockers. Given the limitations imposed by post hoc analysis, a randomized clinical trial is required to ad dress this issue.