Long-term risk of adverse outcomes and new malignancies in patients treated with oral sirolimus for prevention of restenosis.

OBJECTIVES 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).