Published Online
on August 9, 2004

A more recent version of this article appeared on August 17, 2004

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Submitted on April 1, 2004
Revised on June 22, 2004
Accepted on June 23, 2004

Randomized, Double-Blind, Placebo-Controlled Trial of Oral Sirolimus for Restenosis Prevention in Patients With In-Stent Restenosis. The Oral Sirolimus to Inhibit Recurrent In-stent Stenosis (OSIRIS) Trial

Jörg Hausleiter MD^*, Adnan Kastrati MD, Julinda Mehilli MD, Michael Vogeser MD, Dietlind Zohlnhöfer MD, Helmut Schühlen MD, Christoph Goos , Jürgen Pache MD, Franz Dotzer MD, Gisela Pogatsa-Murray MD, Josef Dirschinger MD, Uwe Heemann MD, Albert Schömig MD, for the OSIRIS Investigators

From the Deutsches Herzzentrum München, Klinik an der TU München (J.H., A.K., J.M., C.G., J.P., G.P.-M., A.S.), Institut für Klinische Chemie, Klinikum Großhadern, Ludwig-Maximilians-Universität (M.V.), I. Medizinische Klinik des Klinikums rechts der Isar, Technische Universität (D.Z., H.S., J.D.), and II. Medizinische Klinik des Klinikums rechts der Isar, Technische Universität (U.H.), Munich, and the Medizinische Klinik I des Klinikums Garmisch-Partenkirchen, Garmisch-Partenkirchen (F.D.), Germany.

^* To whom correspondence should be addressed. E-mail: hausleiter{at}dhm.mhn.de.

Background--Despite recent advances in interventional cardiology, including the introduction of drug-eluting stents for de novo coronary lesions, the treatment of in-stent restenosis (ISR) remains a challenging clinical issue. Given the efficacy of systemic sirolimus administration to prevent neointimal hyperplasia in animal models and to halt and even reverse the progression of allograft vasculopathy, the aim of the present double-blind, placebo-controlled study was to evaluate the efficacy of a 10-day oral sirolimus treatment with 2 different loading regimens for the prevention of recurrent restenosis in patients with ISR.

Methods and Results--Three hundred symptomatic patients with ISR were randomly assigned to 1 of 3 treatment arms: placebo or usual-dose or high-dose sirolimus. Patients received a cumulative loading dose of 0, 8, or 24 mg of sirolimus 2 days before and the day of repeat intervention followed by maintenance therapy of 2 mg/d for 7 days. Angiographic restenosis at 6-month angiography was the primary end point of the study. Restenosis was significantly reduced from 42.2% to 38.6% and to 22.1% in the placebo, usual-dose, and high-dose sirolimus groups, respectively (P=0.005). Similarly, the need for target vessel revascularization was reduced from 25.5% to 24.2% and to 15.2% in the placebo, usual-dose, and high-dose groups, respectively (P=0.08). The sirolimus blood concentration on the day of the procedure correlated significantly with the late lumen loss at follow-up (P<0.001).

Conclusions--In patients with ISR, an oral adjunctive sirolimus treatment with an intensified loading regimen before coronary intervention resulted in a significant improvement in the angiographic parameters of restenosis.

Key words: restenosis • stents • trials • angioplasty

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