Impact of prophylactic immediate posttransplant ganciclovir on development of 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 understood. The risk of developing TxCAD is increased by cytomegalovirus (CMV) infection and decreased by use of calcium blockers. Our group observed that prophylactic administration of ganciclovir early after heart transplantation inhibited CMV illness, and we now propose to determine whether this therapy also prevents TxCAD.


RESULTS
One hundred forty-nine consecutive patients (131 men and 18 women aged 48+/-13 years) were randomized to receive either ganciclovir or placebo during the initial 28 days after heart transplantation. Immunosuppression consisted of muromonab-CD3 (OKT-3) prophylaxis and maintenance 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 actuarial 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 blockers. 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 ganciclovir (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 ganciclovir 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 ganciclovir who are not treated with calcium blockers. Given the limitations imposed by post hoc analysis, a randomized clinical trial is required to address this issue.
Stanford University School of Medicine, Stanford, CA, USA.
H A
HA
Valantine
S Z
SZ
Gao
S G
SG
Menon
D G
DG
Renlund
S A
SA
Hunt
P
P
Oyer
E B
EB
Stinson
B W
BW
Brown
T C
TC
Merigan
J S
JS
Schroeder
D000206:Actuarial Analysis; D000328:Adult; D000368:Aged; D000914:Antibodies, Viral / Q000097:blood; D000998:Antiviral Agents / Q000627:therapeutic use*; D002121:Calcium Channel Blockers / Q000627:therapeutic use; D002423:Cause of Death; D003324:Coronary Artery Disease / Q000453:epidemiology / Q000209:etiology / Q000517:prevention & control* / Q000821:virology; D003587:Cytomegalovirus / Q000276:immunology; D003586:Cytomegalovirus Infections / Q000150:complications / Q000188:drug therapy / Q000453:epidemiology; D005260:Female; D005500:Follow-Up Studies; D015774:Ganciclovir / Q000627:therapeutic use*; D016027:Heart Transplantation / Q000009:adverse effects*; D006801:Humans; D007165:Immunosuppression Therapy / Q000009:adverse effects; D015994:Incidence; D008297:Male; D008875:Middle Aged; D011183:Postoperative Complications / Q000188:drug therapy / Q000453:epidemiology / Q000209:etiology / Q000517:prevention & control* / Q000821:virology; D016016:Proportional Hazards Models; D012086:Reoperation; D012306:Risk; D016036:Seroepidemiologic Studies; D016896:Treatment Outcome
D000914:Antibodies, Viral; D000998:Antiviral Agents; D002121:Calcium Channel Blockers; D015774:Ganciclovir