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Long-Term Risk of Adverse Outcomes and New Malignancies in Patients Treated With Oral Sirolimus for Prevention of Restenosis

Sebastian Kufner, MD^_*, Jörg Hausleiter, MD^_*, Gjin Ndrepepa, MD^_*, Stefanie Schulz, MD^_*, Olga Bruskina, MD^_*, Robert A. Byrne, MB^_*, Massimiliano Fusaro, MD, Adnan Kastrati, MD^_*, Albert Schömig, MD^_*,, Julinda Mehilli, MD^_*,_* for the OSIRIS Trial Investigators

^_* Deutsches Herzzentrum, Technische Universität, Munich, Germany
1. Medizinische Klinik rechts der Isar, Technische Universität, Munich, Germany

^_* Reprint requests and correspondence: Dr. Julinda Mehilli, Deutsches Herzzentrum, Lazarettstr. 36, 80636 München, Germany (Email: mehilli{at}dhm.mhn.de).

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)

Key Words: angioplasty • restenosis • sirolimus • stents • malignancies

Abbreviations and Acronyms   DES = drug-eluting stent(s)   ISR = in-stent restenosis   MI = myocardial infarction   PCI = percutaneous coronary intervention   TVR = target vessel revascularization