Sirolimus-Eluting Stent in Coronary Lesions - SIRIUS

Description:

This study evaluates the efficacy of sirolimus-eluting coated stent in native coronary lesions.

Hypothesis:

To establish the safety and efficacy of the sirolimus-eluting BX Velocity stent in reducing target vessel failure in de novo native coronary artery lesions compared with the uncoated BX Velocity stent.

Study Design

Study Design:

Patients Enrolled: 1,101
Mean Follow Up: 9 months
Female: 28

Patient Populations:

Men and women with de novo native coronary lesions requiring single-vessel treatment of higher risk lesions (2.5-3.5 mm diameter and 15-30 mm length).

Exclusions:

Recent MI (<24 hr); unprotected left main disease; ostial location; total occlusion (TIMI 0 flow); angiographic evidence of thrombus; calcified lesion which cannot be predilated; left ventricular ejection fraction (LVEF) <25%; impaired renal function; pretreatment with devices other than balloon angioplasty; allergy to aspirin, clopidogrel, or ticlopidine; prior or planned intervention within 30 days.

Primary Endpoints:

Failure of the target vessel (a composite of death from cardiac causes, MI, and repeated percutaneous or surgical revascularization of the target vessel) within 270 days.

Secondary Endpoints:

Major adverse coronary events (MACE) at 1, 6, 9, 12, 24, and 36 months; angiographic binary restenosis (>50% diameter stenosis) at 8 months; in-stent and in-lesion minimum lumen diameter (MLD) at 8 months; TVR at 9 months; device success, lesion success, and procedure success (in-hospital); economic factors: index hospitalization costs, length of stay, and repeat hospitalizations (for up to 12 months).

Drug/Procedures Used:

Sirolimus (rapamycin) vs placebo to reduce target vessel failure within 9 months of revascularization

Principal Findings:

At the 8 month follow-up, in-stent restenosis was 91% lower in the sirolimus-eluting stent arm compared with the bare stent arm (3.2% vs 35.4%, p<0.001). Likewise, in-segment restenosis was 75% lower in the sirolimus-eluting stent arm (8.9% vs 36.3%, p<0.001). Late lumen loss was lower in the sirolimus-eluting stent arm, whether in the proximal margin (0.17 mm vs 0.33 mm, p<0.001), in-stent (0.17 mm vs 1.0 mm, p<0.001) or in the distal margin (0.04 mm vs 0.24 mm, p<0.001). The primary endpoint of target vessel failure (cardiac death/MI/TVR) at 9 months was lower in the sirolimus-eluting stent arm (8.6% vs 21.0%, p<0.001) as was MACE (7.1% vs 18.9%), driven primarily by a reduction in target lesion revascularization (4.1% vs 16.6%, p<0.001). Similar angiographic results of reduced in-stent restenosis rates were seen in the diabetic subgroup (n=279) (8.3% vs 48.5%, 83% relative reduction, p<0.001), the LAD lesion subgroup (n=462) (2.0% vs 41.6%, 95% relative reduction, p<0.001), and the overlapping stent subgroup (n=344) (7.1% vs 42.7%, p<0.001). In-segment late loss was significantly lower in the sirolimus-eluting stent arm in vessels of all sizes: small vessels, ~2.3 mm (0.31 mm vs 0.77 mm, p<0.001), medium vessels, ~2.8 mm (0.21 mm vs 0.86 mm, p<0.001) and large vessels, ~3.3 mm (0.19 mm vs 0.81 mm, p<0.001).

Interpretation:

The prevention of in-stent restenosis, which is primarily caused by coronary neointimal hyperplasia, has been a target of PCI research for many years and has proven extremely difficult to overcome. A promising new approach to the prevention of in-stent restenosis,the implantation of drug-eluting(drug-releasing) stents is now undergoing clinical evaluation. Coated stents slowly release drugs that inhibit smooth-muscle-cell proliferation, neointimal hyperplasia, or inflammation. Sirolimus (rapamycin) is a naturally occurring antibiotic approved by the U.S. Food and Drug Administration as Rapamune® in 1999 as an immunosuppressive agent used in kidney transplantation. It inhibits smooth-muscle-cell proliferation and migration by interrupting certain aspects of cellular metabolism and thereby preventing mitosis. The cell nonetheless remains viable. Interestingly, in a porcine restenosis model exploring the effect of the drug on in-stent neointimal hyperplasia, sirolimus alone was significantly better than sirolimus combined with dexamethasone (p<0.0001) or dexamethasone alone (p<0.001). It was shown to inhibit markers of cell cycle progression and expression of inflammatory cytokines. Furthermore, there was rapid and sustained endothelial regrowth and no early or late stent thrombosis. Recent trials involving sirolimus-eluting stents have shown considerable success. There have been initial data from 3 different studies: First In Man (FIM), In-Stent Restenosis (ISR), and Randomized, Double-blind Study with the Sirolimus-eluting Bx Velocity balloon Expandable Stent in the Treatment of Patients with De Novo Native Coronary Artery Lesions (RAVEL). Preliminary evidence with a total of 188 patients has suggested that at 6 months and 1 year, drug-eluting stents may suppress intimal thickening and reduce the risk of restenosis. It is important to note that long-term data are not yet available, enthusiasm must be tempered by caution. On question is if we are simply delaying the restenosis process, and in fact are not aborting it. The SIRIUS patient cohort is interesting in that the enrolled patients have a more challenging anatomy and substrate than RAVEL; specifically, the SIRIUS patients have longer lesions (15-30 mm vs <18 mm) and smaller vessels. Multiple angiographic parameters were improved with use of the sirolimus-eluting stent, even in these more technically challenging patients, including significant reductions in 8 month restenosis and late lumen loss, with similar observations in many subgroups including diabetics, LAD lesions, overlapping stents, and various vessel sizes. The primary clinical endpoint was also reduced at 9 months, although this was primary driven by a reduction in TVR with no difference in death or MI. While clearly beneficial in the reduction of restenosis and in the need for TVR, the increased cost of drug eluting stents and the impact on the health economic system remains to be determined. FDA approval was given to the BX coated sirolimus stent for treatment in native vessels of 2.5 to 3.5 mm in patients outside of the setting of acute MI. The efficacy of coated stents in saphenous vein graft, in larger and smaller vessels, in the setting of acute MI, and in the setting of in-stent restenosis remains to be determined.

References:

1. Moses JW, et al. Sirolimus-eluting stents versus standard stents in patients with stenosis in a native coronary artery. N Engl J Med 2003;349:1315-23.
2. Effect on arterial intimal thickening. Transplantation 1993;55:1409-18.
3. Inhibition of cell cycle regulators of proliferation. Circ Res 1995;76:412-7.
4. Inhibition of vascular SMC migration. J Clin Invest 1996;98:2277-83.
5. Angiography and IVUS study. Circulation 2001;103:192-5.
6. Reduction of neointimal formation in porcine study. Circulation 2001;104:1188-93.
7. Suppression of neointimal proliferation: 1 year FU. Circulation 2001;104:2007-11.
8. Restenosis elimination – 6 month FU. Eur Heart J 2001;22:2125-30.
9. SIRIUS trial results, presented at TCT 2002.
10. Holmes DR, et al. Analysis of 1-Year Clinical Outcomes in the SIRIUS Trial. Circulation. 2004;109:634-640.

Clinical Topics: Invasive Cardiovascular Angiography and Intervention, Atherosclerotic Disease (CAD/PAD), Interventions and Coronary Artery Disease

Keywords: Mitosis, Coronary Artery Disease, Follow-Up Studies, Cytokines, Cell Proliferation, Blood Platelets, United States Food and Drug Administration, Thrombosis, Saphenous Vein, Medicare, Cell Cycle, Inflammation, Health Personnel, Kidney Transplantation, Drug-Eluting Stents, Diagnosis-Related Groups, Medicaid, Immunosuppressive Agents, Centers for Medicare and Medicaid Services (U.S.), Sirolimus, Hyperplasia, Marketing, Dexamethasone, Stents, Metals, Polymers, Coronary Vessels, Diabetes Mellitus


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