Elsevier

The Lancet

Volume 362, Issue 9390, 4 October 2003, Pages 1093-1099
The Lancet

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Sirolimus-eluting stents for treatment of patients with long atherosclerotic lesions in small coronary arteries: double-blind, randomised controlled trial (E-SIRIUS)

https://doi.org/10.1016/S0140-6736(03)14462-5Get rights and content

Summary

Background

Sirolimus-eluting stents have been developed to prevent restenosis in the treatment of coronary artery disease. We investigated the risk of restenosis with use of sirolimus-eluting stents compared with bare-metal stents to assess possible differences.

Methods

We enrolled 352 patients in whom one coronary artery required treatment, with diameter 2·5–3·0 mm and lesion length 15–32 mm. We randomly assigned patients sirolimus-eluting stents (n=175) or bare-metal stents (control, n=177). At 8 months we assessed differences in minimum lumen diameter and binary restenosis within the lesion (restenosis of ≤50% diameter, including 5 mm vessel segments proximal and distal to stented segment). Patients were also followed up for 9 months for major adverse cardiac events. Analysis was by intention to treat.

Findings

Stent implantation was successful in 100% of sirolimus-stent patients and 99·4% of controls. The mean diameter of treated coronary arteries was 2·55 mm (SD 0·37) and mean lesion length was 15·0 mm (6·0). Multiple stents were implanted in 170 (48%) patients. At 8 months, minimum lumen diameter was significantly higher with sirolimus-eluting stents than with control stents (2·22 vs 1·33 mm, p<0·0001). The rate of binary restenosis was significantly reduced with sirolimus-eluting stents compared with control stents (5·9 vs 42·3%, p=0·0001). Significantly fewer patients with sirolimus-eluting stents had major adverse cardiac events at 9 months than did controls (8·0 vs 22·6%, p=0·0002), due mainly to a lower need for target-lesion revascularisations (4·0 vs 20·9%, p<0·0001).

Interpretation

Sirolimus-eluting stents are better than bare-metal stents for treatment of single long atherosclerotic lesions in a coronary vessel smaller than 3 mm in diameter.

Published online Sept 30, 2003. http://image.thelancet.com/extras/03art9099web.pdf

Introduction

In the past decade, stent implantation has become the treatment of choice among patients with coronary artery disease.1, 2, 3 Re-establishment of coronary blood flow with subsequent relief of symptoms can be readily achieved in most patients. However, in-stent restenosis within 3–8 months is the weakness of coronary artery stenting even if heparin-coated stents are used. Dependent on various confounding factors, such as the presence or absence of diabetes mellitus, the size of the targeted coronary artery, the length of the coronary lesion, and the degree of vessel patency achieved by the intervention, restenosis at the site of stent implantation is seen in 15–60% of patients.4, 5, 6, 7, 8 Neointimal hyperplasia as a response to vessel-wall injury has been identified as the mechanism underlying coronary restenosis after stent implantation.9 Intracoronary radiation therapy is available to treat in-stent restenosis,10, 11, 12, 13 but concepts have evolved to allow the local delivery from the stent of pharmaceutical agents to suppress neointimal hyperplasia.

One such agent is sirolimus, a potent immuno-suppressive agent, which inhibits cytokine-mediated and growth-factor-mediated proliferation of lymphocytes and smooth-muscle cells, ultimately by inducing cell-cycle arrest in the late G1 phase.14 Sirolimus can be incorporated in a stent coating, from which it is released after stent insertion.

In clinical trials of this stent to date,15, 16 only patients with new lesions in native coronary arteries have been enrolled, and they have followed a staged pattern, with increasing lesion severity determined by vessel size and lesion length. In one pilot study, treatment was restricted to the implantation of one 18 mm stent in vessels 3·0–3·5 mm in size,15 whereas in the subsequent Randomized Study with the Sirolimus-Coated Bx Velocity Balloon-Expandable Stent in the Treatment of Patients with de Novo Native Coronary Artery Lesions (RAVEL) trial16 vessel sizes of 2·5–3·5 mm were allowed, yet lesions still had to be covered with one stent. In the European multicenter, randomized, double-blind study of the SIRolImUS-coated Bx Velocity balloon-expandable stent in the treatment of patients with de novo coronary artery lesions (E-SIRIUS) trial, we investigated risk of restenosis among patients who had long atherosclerotic lesions, potentially requiring multiple stents, in small coronary arteries. We compared use of a sirolimus-eluting stent with treatment with a bare-metal stent of identical architecture.

Section snippets

Patients

Between August, 2001, and February, 2002, we enrolled patients in 35 European clinical centres. Eligible patients had to be aged 18 years or older, with a documented diagnosis of angina pectoris (Canadian Cardiovascular Society classification I-IV),17 unstable angina pectoris (Braunwald classification B and C, I or II),18 or silent ischaemia. Patients with single-vessel or multivessel coronary disease were eligible, but had to have only one new lesion with an estimated stenosis of more than 50%

Methods

We used bare-metal Bx Velocity stents (control) and coated sirolimus-eluting Bx Velocity stents (both Cordis, Miami Lakes, FL, USA), which are balloon-expandable, tubular, stainless steel stents, premounted and crimped on rapid-exchange balloon-dilation catheters. The sirolimus-eluting stents had a 5μm coating consisting of a blend of 33% sirolimus and 67% non-erodable polymer. The drug-polymer matrix contains 140 μg sirolimus per cm2 surface area. A drug-free polymer layer on top of the

Statistical analysis

At each participating centre, all patients' data were prospectively recorded on case report forms, which were forwarded to the study coordinating centre with the respective clinical centre. Data were unmasked when the 9 month clinical follow-up information from all patients had been obtained. All data were held at the study coordinating centre, but the report researchers had full access to them.

We based the sample size on the hypothesis that instent minimum lumen diameter by quantitative

Role of the funding source

Representatives of the study sponsor assisted in the statistical design of this trial. The study sponsor had no role in the data analysis and data interpretation, in the writing of the report, or in the decision to submit the report for publication.

Results

We enrolled 353 patients. One patient, who had initially been randomised, was excluded because he did not receive the assigned study stent. Thus, 352 patients entered the trial for endpoint analysis, of whom 175 received the sirolimus-eluting stent and 177 the standard uncoated stent (figure 1). Patients' characteristics at baseline are shown in table 1. There was a higher, but not statistically different, prevalence of patients with diabetes in the control group. The groups were similar for

Discussion

Sirolimus-eluting stents improved the rate of event-free survival. Compared with previous studies,15, 16 the patients enrolled in our study represent a higher clinical risk profile for restenosis: the restenosis rate at 8 months in controls was 42·3%, compared with 26·6% in RAVEL.16 42% of our patients had experienced a previous myocardial infarction and 33% were current smokers. Further factors contributing to the increased risk of restenosis in our study patients were the small mean reference

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