title: Effect of everolimus introduction on cardiac allograft vasculopathy--results of a randomized, multicenter trial.
abstract: BACKGROUND
  Everolimus reduces the progression of cardiac allograft vasculopathy (CAV) in de novo heart transplant (HTx) recipients, but the influence on established CAV is unknown.
  
  
  METHODS
  In this Nordic Certican Trial in Heart and lung Transplantation substudy, 111 maintenance HTx recipients (time post-HTx 5.8 ± 4.3 years) randomized to everolimus+reduced calcineurin inhibitor (CNI) or standard CNI had matching (intravascular ultrasound) examinations at baseline and 12 months allowing accurate assessment of CAV progression.
  
  
  RESULTS
  No significant difference in CAV progression was evident between the treatment groups (P = 0.30). When considering patients receiving concomitant azathioprine (AZA) therapy (n = 39), CAV progression was attenuated with everolimus versus standard CNI (Δmaximal intimal thickness 0.00 ± 0.04 and 0.04 ± 0.04 mm, Δpercent atheroma volume 0.2% ± 3.0% and 2.6% ± 2.5%, and Δtotal atheroma volume 0.25 ± 14.1 and 19.8 ± 20.4 mm(3), respectively [P < 0.05]). When considering patients receiving mycophenolate mofetil (MMF), accelerated CAV progression occurred with everolimus versus standard CNI (Δmaximal intimal thickness 0.06 ± 0.12 vs. 0.02 ± 0.06 mm and Δpercent atheroma volume 4.0% ± 6.3% vs. 1.4% ± 3.1%, respectively; P < 0.05). The levels of C-reactive protein and vascular cell adhesion molecule-1 declined significantly with AZA+everolimus, whereas MMF+everolimus patients demonstrated a significant increase in levels of C-reactive protein, vascular cell adhesion molecule-1, and von Willebrand factor.
  
  
  CONCLUSIONS
  Conversion to everolimus and reduced CNI does not influence CAV progression among maintenance HTx recipients. However, background immunosuppressive therapy is important as AZA+everolimus patients demonstrated attenuated CAV progression and a decline in inflammatory markers, whereas the opposite pattern was seen with everolimus+MMF. The different effect of everolimus when combined with AZA versus MMF could potentially reflect hitherto unknown interactions.
authors.affiliation: Department of Cardiology, Oslo University Hospital, Rikshospitalet, Oslo, Norway.
authors.forename: Satish
authors.initials: S
authors.lastname: Arora
authors.forename: Thor
authors.initials: T
authors.lastname: Ueland
authors.forename: Bertil
authors.initials: B
authors.lastname: Wennerblom
authors.forename: Vilborg
authors.initials: V
authors.lastname: Sigurdadottir
authors.forename: Hans
authors.initials: H
authors.lastname: Eiskjær
authors.forename: Hans E
authors.initials: HE
authors.lastname: Bøtker
authors.forename: Bjorn
authors.initials: B
authors.lastname: Ekmehag
authors.forename: Kjell
authors.initials: K
authors.lastname: Jansson
authors.forename: Svend-Aage
authors.initials: SA
authors.lastname: Mortensen
authors.forename: Kari
authors.initials: K
authors.lastname: Saunamaki
authors.forename: Svein
authors.initials: S
authors.lastname: Simonsen
authors.forename: Einar
authors.initials: E
authors.lastname: Gude
authors.forename: Bjørn
authors.initials: B
authors.lastname: Bendz
authors.forename: Dag
authors.initials: D
authors.lastname: Solbu
authors.forename: Pål
authors.initials: P
authors.lastname: Aukrust
authors.forename: Lars
authors.initials: L
authors.lastname: Gullestad
mesh_terms: D000368:Aged; D001379:Azathioprine / Q000627:therapeutic use; D002097:C-Reactive Protein / Q000378:metabolism; D065095:Calcineurin Inhibitors; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D000068338:Everolimus; D005260:Female; D005500:Follow-Up Studies; D016027:Heart Transplantation / Q000276:immunology*; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D015994:Incidence; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid / Q000031:analogs & derivatives / Q000627:therapeutic use; D012307:Risk Factors; D012537:Scandinavian and Nordic Countries; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000627:therapeutic use; D018084:Ultrasonography, Interventional; D019010:Vascular Cell Adhesion Molecule-1 / Q000097:blood; D014652:Vascular Diseases / Q000000981:diagnostic imaging / Q000453:epidemiology* / Q000517:prevention & control*; D014841:von Willebrand Factor / Q000378:metabolism
chemical_list: D065095:Calcineurin Inhibitors; D007166:Immunosuppressive Agents; D019010:Vascular Cell Adhesion Molecule-1; D014841:von Willebrand Factor; D002097:C-Reactive Protein; D000068338:Everolimus; D009173:Mycophenolic Acid; D001379:Azathioprine; D020123:Sirolimus