Oral Sirolimus to Inhibit Recurrent In-Stent Stenosis - OSIRIS

Description:

The goal of the trial was to evaluate the use of oral sirolimus for prevention of recurrent restenosis in patients with in-stent restenosis compared with placebo.

Hypothesis:

Treatment with oral sirolimus will reduce the occurrence of recurrent restenosis.

Study Design

Study Design:

Patients Enrolled: 300
Mean Follow Up: One year
Mean Patient Age: Mean age 65 years
Female: 22
Mean Ejection Fraction: Mean baseline ejection fraction 55%

Patient Populations:

Presence of angina pectoris or exercise-induced ischemia in the presence of angiographically significant in-stent restenosis in native coronary arteries

Exclusions:

Acute coronary syndromes, severe infectious diseases, presence of severe kidney failure, or contraindications to the medication used in the study

Primary Endpoints:

Angiographic restenosis (≥50% stenosis) at six-month follow-up

Secondary Endpoints:

Combined incidence of death or MI at one year; target vessel revascularization (PCI or bypass surgery) by one year

Drug/Procedures Used:

Patients with in-stent restenosis on diagnostic angiography were randomized to usual-dose sirolimus (n=99), high-dose sirolimus (n=99), or placebo (n=102). Study drug was administered two days prior to percutaneous coronary intervention (PCI), the day of PCI, and for seven days following PCI. The usual-dose sirolimus group received 0 mg, 6 mg, 2 mg, and 2 mg on days 1, 2, 3 (PCI), and 4-10, respectively. The high-dose sirolimus group received 12 mg, 8 mg, 4 mg, and 2 mg, respectively.

Concomitant Medications:

Clopidogrel (75 mg/day) for at least six months, and 100 mg aspirin (100 mg twice daily) indefinitely

Principal Findings:

The target vessel was the left anterior descending artery in the majority of patients (50.5%, 43.4%, and 52.9% for usual-dose sirolimus, high-dose sirolimus, and placebo, respectively). Baseline stenosis was 66.2%, 65.4%, and 67.1%, respectively, while final diameter stenosis postintervention was 21.8% in each group. Sirolimus blood levels were 10.0 and 18.1 µg/l on the day of PCI and 6.6 and 10.5 µg/l on day 3 after the PCI for the usual-dose and high-dose groups (p<0.001 each).

Restenosis at six-month angiographic follow-up was lower in the high-dose group compared with placebo (22.1% vs. 42.2%), but there was no difference for the usual-dose group compared with placebo (38.6% vs. 42.2%). Minimum lumen diameter was larger in the high-dose group (1.66 mm for high-dose vs. 1.27 mm for usual-dose and 1.53 mm for placebo), while diameter stenosis was smaller in the high-dose group (38.1% vs. 45.8% for usual-dose and 43.7% for placebo).

Target vessel revascularization at one year trended lower in the high-dose group (15.2% vs. 25.5%), but again there was no difference between the usual-dose group and placebo (24.2% vs. 25.5%). There was no difference in death or myocardial infarction (MI) at one year (2.0% for high-dose, 3.0% for usual-dose, and 1.0% for placebo).

Interpretation:

Among patients with in-stent restenosis, treatment with high-dose oral sirolimus was associated with a lower rate of the primary endpoint of angiographic restenosis at six-month follow-up compared with placebo, but there was no treatment effect observed with usual-dose oral sirolimus compared with placebo.

Several large-scale randomized trials have shown a reduction in restenosis with sirolimus-eluting stents. However, the lesions treated have been de novo lesions and use of such stents for treatment of in-stent restenosis has not been evaluated in randomized trials (registries only). No benefit of oral sirolimus was reported in an earlier small (n=22), nonrandomized pilot study of patients at high risk for restenosis, but treatment with study drug was not administered until after the angioplasty.

The present study pretreated with sirolimus for two days prior to PCI in the high-dose group, indicating the timing of the administration may be important. Additionally, the sirolimus blood concentration at the time of the PCI correlated with late lumen loss while the three-day post-PCI sirolimus blood concentration was not as strongly correlated.

References:

Hausleiter J, Kastrati A, Mehilli J, et al. 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. Circulation 2004;110:790-5.

Clinical Topics: Invasive Cardiovascular Angiography and Intervention, Stable Ischemic Heart Disease, Chronic Angina

Keywords: Registries, Myocardial Infarction, Follow-Up Studies, Coronary Restenosis, Constriction, Pathologic, Coronary Vessels, Sirolimus, Angioplasty, Balloon, Coronary, Stents


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