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.