title: Tacrolimus and cyclosporine have differential effects on the risk of development of bronchiolitis obliterans syndrome: results of a prospective, randomized international trial in lung transplantation.
abstract: BACKGROUND
  Chronic lung allograft dysfunction, which manifests as bronchiolitis obliterans syndrome (BOS), is recognized as the primary cause of morbidity and mortality after lung transplantation. In this study we assessed the efficacy and safety of two de novo immunosuppression protocols to prevent BOS.
  
  
  METHODS
  Our study approach was a multicenter, prospective, randomized (1:1) open-label superiority investigation of de novo tacrolimus vs cyclosporine, with both study arms given mycophenolate mofetil and prednisolone after lung transplantation. Cytolytic induction therapy was not employed. Patients were stratified at entry for cystic fibrosis. Primary outcome was incidence of BOS 3 years after transplant (intention-to-treat analysis). Secondary outcomes were survival and incidence of acute rejection, infection and other adverse events.
  
  
  RESULTS
  Group demographic data were well matched: 110 of 124 tacrolimus vs 74 of 125 cyclosporine patients were treated per protocol (p < 0.01 by chi-square test). Cumulative incidence of BOS Grade ≥1 at 3 years was 11.6% (tacrolimus) vs 21.3% (cyclosporine) (cumulative incidence curves, p = 0.037 by Gray's test, pooled over strata). Univariate proportional sub-distribution hazards regression confirmed cyclosporine as a risk for BOS (HR 1.97, 95% CI 1.04 to 3.77, p = 0.039). Three-year cumulative incidence of acute rejection was 67.4% (tacrolimus) vs 74.9% (cyclosporine) (p = 0.118 by Gray's test). One- and 3-year survival rates were 84.6% and 78.7% (tacrolimus) vs 88.6% and 82.8% (cyclosporine) (p = 0.382 by log-rank test). Cumulative infection rates were similar (p = 0.91), but there was a trend toward new-onset renal failure with tacrolimus (p = 0.09).
  
  
  CONCLUSIONS
  Compared with cyclosporine, de novo tacrolimus use was found to be associated with a significantly reduced risk for BOS Grade ≥1 at 3 years despite a similar rate of acute rejection. However, no survival advantage was detected.
authors.affiliation: Department of Cardiovascular Surgery, University Heart Center Hamburg, Martinistrasse 52, Hamburg, Germany. treede@uke.de
authors.forename: Hendrik
authors.initials: H
authors.lastname: Treede
authors.forename: Allan R
authors.initials: AR
authors.lastname: Glanville
authors.forename: Walter
authors.initials: W
authors.lastname: Klepetko
authors.forename: Christina
authors.initials: C
authors.lastname: Aboyoun
authors.forename: Eik
authors.initials: E
authors.lastname: Vettorazzi
authors.forename: Raffael
authors.initials: R
authors.lastname: Lama
authors.forename: Carlos
authors.initials: C
authors.lastname: Bravo
authors.forename: Christiane
authors.initials: C
authors.lastname: Knoop
authors.forename: John-David
authors.initials: JD
authors.lastname: Aubert
authors.forename: Hermann
authors.initials: H
authors.lastname: Reichenspurner
mesh_terms: D000328:Adult; D001989:Bronchiolitis Obliterans / Q000453:epidemiology* / Q000401:mortality / Q000517:prevention & control*; D016572:Cyclosporine / Q000009:adverse effects / Q000627:therapeutic use*; D005260:Female; D005500:Follow-Up Studies; D006084:Graft Rejection / Q000453:epidemiology; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000627:therapeutic use; D015994:Incidence; D007391:International Cooperation; D016040:Lung Transplantation / Q000401:mortality; D008297:Male; D008875:Middle Aged; D017063:Outcome Assessment, Health Care; D011446:Prospective Studies; D012307:Risk Factors; D015996:Survival Rate; D013577:Syndrome; D016559:Tacrolimus / Q000009:adverse effects / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D007166:Immunosuppressive Agents; D016572:Cyclosporine; D016559:Tacrolimus