Prevention of Transplant Atherosclerosis With Everolimus and Anti-cytomegalovirus Therapy (PROTECT)

Cardiac allograft vasculopathy (CAV) is the major cause of long-term graft failure in heart transplant recipients. Although several immune-mediated and metabolic risk factors have been implicated in the pathogenesis of CAV, no effective therapy is currently available to treat established CAV and prevent its adverse outcomes. Therefore, the main clinical strategy is based on prevention and treatment of factors known to trigger its development. Although the mechanism is vague, cytomegalovirus (CMV) infection is believed to play a key role in CAV progression.

Two strategies involving administration of specific anti-CMV agents are recommended for prevention of CMV infection/disease: universal prophylaxis and preemptive therapy. The pros and cons of the two strategies are still debated, in the absence of randomized studies addressing graft-related outcomes and viral mechanisms of graft damage, and without any clear evidence of superiority of either approach.

The investigators conceived this randomized prospective project to compare the effect of preemptive anti-CMV strategy with universal anti-CMV prophylaxis on CMV infection and on one-year increase in coronary intimal thickening. Patients will be additionally randomized to receive either mycophenolate mofetil or everolimus, in light of the possible anti-CMV properties of everolimus.

• Heart Transplantation
• Cardiac Allograft Vasculopathy
• Cytomegalovirus Infection

• Drug: Pre-emptive strategy with valganciclovir plus everolimus
  Patients will be monitored for CMV infection and receive valganciclovir only for positive PCR or antigenemia. Everolimus plus cyclosporine and prednisone will be used for maintenance immunosuppression
• Drug: Prophylaxis with valganciclovir plus mycophenolate
  Patients will receive 3 months of oral valganciclovir with mycophenolate and standard cyclosporine and prednisone for maintenance immunosuppression
• Drug: Prophylaxis with valganciclovir plus everolimus
  Patients will receive valganciclovir for 3 months after transplant. Everolimus plus reduced cyclosporine and prednisone will be used for maintenance immunosuppression
• Drug: Pre-emptive mycophenolate
  Patients will be monitored for CMV infection and receive valganciclovir only for positive PCR or antigenemia. Mycophenolate plus standard cyclosporine and prednisone will be used for maintenance immunosuppression

• Experimental: Pre-emptive everolimus
  Intervention: Drug: Pre-emptive strategy with valganciclovir plus everolimus
• Experimental: Prophylaxis mycophenolate
  Intervention: Drug: Prophylaxis with valganciclovir plus mycophenolate
• Experimental: Prophylaxis Everolimus
  Intervention: Drug: Prophylaxis with valganciclovir plus everolimus
• Active Comparator: Pre-emptive mycophenolate
  Intervention: Drug: Pre-emptive mycophenolate

• Potena L, Grigioni F, Magnani G, Lazzarotto T, Musuraca AC, Ortolani P, Coccolo F, Fallani F, Russo A, Branzi A. Prophylaxis versus preemptive anti-cytomegalovirus approach for prevention of allograft vasculopathy in heart transplant recipients. J Heart Lung Transplant. 2009 May;28(5):461-7.
• Potena L, Valantine HA. Cytomegalovirus-associated allograft rejection in heart transplant patients. Curr Opin Infect Dis. 2007 Aug;20(4):425-31. Review.
• Hill JA, Hummel M, Starling RC, Kobashigawa JA, Perrone SV, Arizón JM, Simonsen S, Abeywickrama KH, Bara C. A lower incidence of cytomegalovirus infection in de novo heart transplant recipients randomized to everolimus. Transplantation. 2007 Dec 15;84(11):1436-42.

Inclusion Criteria:

• Age ≥ 18y
• Heart or heart-kidney combined transplant
• Positive CMV serology at the time of transplant
• Glomerular filtration rate ≥ 20 ml/min/1.73m2 with MDRD at randomization.
• Written informed consent

Exclusion Criteria:

• Panel Reactive Antibody ≥50%
• Less than 1000/mmc neutrophils at the time of randomization
• Less than 30,000/mmc platelets at the time of randomization
• Clinical significant infection in the 2 weeks prior to transplant
• Glomerular filtration rate < 20 ml/min/1.73m2 estimated with MDRD formula at the time of randomization or hemodialysis treatment
• Intolerance towards valganciclovir, everolimus, mycophenolate or cyc-losporine
• Known contraindication to statin use
• Negative CMV serology at the time of transplant
• HIV positive testing
• Severe comorbidities that, based on investigator's judgment, contraindicate study drugs or procedures
• Potentially childbearing women who refuse to use contraceptives
• Participation to an interventional study in the 2 preceding weeks
• Unwillingness or inability to follow study procedure and to sign written in-formed consent