title: Long-term risk of adverse outcomes and new malignancies in patients treated with oral sirolimus for prevention of restenosis.
abstract: OBJECTIVE
  We sought to investigate the long-term efficacy of oral sirolimus therapy and its impact on the incidence of de novo malignancies in the OSIRIS (Oral Sirolimus to Inhibit Recurrent In-Stent Stenosis) trial population.
  
  
  BACKGROUND
  The OSIRIS trial showed a significant reduction of angiographic restenosis with an oral adjunctive sirolimus treatment for in-stent restenosis. The long-term efficacy of oral sirolimus therapy is unknown.
  
  
  METHODS
  Three hundred patients with in-stent restenosis were randomly assigned to receive placebo, a cumulative loading dose of 8 mg (usual-dose), or 24 mg (high-dose) of sirolimus over 3 days (2 days before and the day of intervention) followed by maintenance therapy of 2 mg/day for 7 days. The primary outcome of this analysis was the incidence of composite of death, myocardial infarction, and target vessel revascularization at 4-year follow-up. Secondary outcome was the incidence of newly diagnosed malignancies.
  
  
  RESULTS
  No significant differences were observed between placebo, usual-, and high-dose sirolimus treatment groups regarding primary outcome (33.3%, 39.4%, and 31.3%, respectively; p = 0.46), death (5.9%, 9.1%, and 11.1%, respectively; p = 0.41), target vessel revascularization (30.4%, 30.3%, and 22.2%, respectively; p = 0.33), and rate of newly diagnosed malignancies (7.8%, 3.0%, and 11.1%, respectively; p = 0.09).
  
  
  CONCLUSIONS
  The benefit in the reduced need for repeat intervention observed at 1 year with high-dose oral sirolimus therapy was attenuated over 4 years. Moreover, this regimen was associated with numerical yet not a significant increase in newly diagnosed malignancies without augmenting the malignancy-induced risk of death. (Oral Sirolimus for In-Stent Restenosis [OSIRUS] trial; NCT00859183).
authors.affiliation: Deutsches Herzzentrum, Technische Universität, Munich, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Kufner
authors.forename: Jörg
authors.initials: J
authors.lastname: Hausleiter
authors.forename: Gjin
authors.initials: G
authors.lastname: Ndrepepa
authors.forename: Stefanie
authors.initials: S
authors.lastname: Schulz
authors.forename: Olga
authors.initials: O
authors.lastname: Bruskina
authors.forename: Robert A
authors.initials: RA
authors.lastname: Byrne
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Fusaro
authors.forename: Adnan
authors.initials: A
authors.lastname: Kastrati
authors.forename: Albert
authors.initials: A
authors.lastname: Schömig
authors.forename: Julinda
authors.initials: J
authors.lastname: Mehilli
mesh_terms: D000284:Administration, Oral; D000368:Aged; D000369:Aged, 80 and over; D015906:Angioplasty, Balloon, Coronary / Q000009:adverse effects* / Q000401:mortality; D002317:Cardiovascular Agents / Q000008:administration & dosage / Q000009:adverse effects*; D017023:Coronary Angiography; D023903:Coronary Restenosis / Q000000981:diagnostic imaging / Q000401:mortality / Q000517:prevention & control*; D004311:Double-Blind Method; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000009:adverse effects*; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D009203:Myocardial Infarction / Q000209:etiology; D009369:Neoplasms / Q000139:chemically induced*; D018570:Risk Assessment; D020123:Sirolimus / Q000008:administration & dosage / Q000009:adverse effects*; D013997:Time Factors
chemical_list: D002317:Cardiovascular Agents; D007166:Immunosuppressive Agents; D020123:Sirolimus