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Newsletter
Drug-Eluting Coronary StentsCarl Schwartz, MD
Over 1.5 million percutaneous coronary interventions (PCI) are performed annually worldwide.1 All percutaneous procedures cause stretch and injury to the targeted vessel as a result of compression and fracture of the atheromatous plaque and the intima of the vessel wall.2 Acutely, flow is improved across the newly dilated vessel segment, however, narrowing occurs over the next several months as a result of local thrombosis, vessel recoil, and vessel remodeling involving neo-intimal hyperplasia. Anti-thrombotic and anti-platelet medicines have decreased the incidence of thrombotic complications, while intracoronary stents prevent vessel recoil, and the negative remodeling of the vessel. While high pressure deployment of stents and the use of anti-thrombotic and anti-platelet medications have decreased the incidence of thrombotic complications in the first three months from 20-25% to 0.5%, the incidence of non-thrombotic in-stent stenosis (ISS) within 6-12 months of deployment ranges from 10-40%.3 Stents were initially designed to prevent vessel remodeling after angioplasty, however, vessel injury and subsequent neo-intimal hyperplasia occurs at the edges or struts of the stent, and is the predominant cause of ISS. The mechanism involves the interaction of coagulation/thrombosis, inflammation, and proliferation and migration of smooth muscle cells, fibroblasts, and additional inflammatory cells. Endothelization of the coronary stent occurs over the first three to nine months after stent deployment. The organization of thrombus and subsequent cell proliferation constitutes neo-intimal hyperplasia. These result in thickening of the vessel wall narrowing the vessel lumen. Drug-eluting stents (DES) have emerged as a solution for ISS. They are coated with one or more drugs, which are released locally at the site of vessel injury. Primarily these drugs are directed at preventing, or at least attenuating cell proliferation and neo-intimal hyperplasia, which occur in response to injury of the vessel wall at the edges of the stent. The DES is a three-component system including a catheter deployed stent, a drug carrier, and a drug which possesses specific properties that interfere with local neo-intimal proliferation.4,5 To date a number of pharmacological agents have been investigated of which two have achieved measurable success.1,2,4-8 Sirolimus (rapamycin) is an antifungal agent with unique antiproliferative and powerful immunosuppressant properties.4 More specifically, Sirolimus inhibits regulators of cell-cycle progression, cell growth, migration of vascular smooth muscle cells, and inflammation.1,4 These effects have been reported to persist for at least 90 days, and possibly as long as 2-3 years.1 Paclitaxil is a potent antiproliferative or antimitotic agent, which inhibits cell proliferation, and migration.1 These effects decrease proliferation of vascular smooth muscle and intimal thickening and hyperplasia. Benefits are noted for at least 90 days and as long as 9-12 months. Initial investigations with sirilimus-eluting stents showed significant reduction in rates of restenosis based on angiography and intravascular ultrasound obtained at two-year follow-up9. For patients with single de-novo lesions, the rate of restenosis assessed after six months for sirolumus-eluting stents was 0% compared to 26% for bare metal stents.3,7 For high risk patients with more complex coronary lesions, restenosis was reduced by 75% for sirolumis eluting stents.3,5 Paclitaxel eluting stents reduced ISS from 20-27% for bare metal stents to 0-9% depending on the dose and delivery rate for up to 12 months.3,5,6,8,10 Tissue toxicities are similar to other anti-proliferative therapies and include mucositis, gastrointestinal irritation, and alopecia.1 Other side effects include hypersensitivity reactions, cardiotoxicities, neutropenia, peripheral neuropathy, arthralgias, and myalgias.1 However, these adverse effects are minimized by the local delivery of these medications using DES. Furthermore, both sirolimus and paclitaxel are lipophilic and readily enter the cell wall where they are retained, while systemic levels are insignificant after the first day.11 Although these initial data are promising, anecdotal reports of DES placed in diabetic patients or for small vessels or bifurcating lesions indicate a higher rate of restenosis5. Initial data of treatment of ISS with DES showed early (< 6 month) anti-proliferative effect. This was not maintained at 12 months as noted by a 61% restenosis rate.12 Furthermore, data is not complete for saphenous vein graft lesions, left main coronary lesions, heavily calcified vessels, total coronary occlusions, and thrombosed vessels. When these data are included the rate of ISS may be as high as 59%.1 Data for patients after acute myocardial infarction or previous failures of brachytherapy are also not yet reported. The combination of antithrombotic medications and DES has reduced both early and late (9-12 months) ISS to less than 10% in selected coronary lesions. These therapies are likely to reduce the volume of patients undergoing surgical revascularization by as much as 21%.13 Although DESs constitute a major advancement in PCI by reducing ISS within the first 9-12 months, the long term outcome and cost-benefit analysis have not been fully investigated. Until progression of native disease and long term (>12 months) stent-related neo-intimal hyperplasia are prevented, a significant percentage of patients, initially treated with PCI, will eventually present for surgery, but with a more complicated history of multiple PCIs and possible myocardial injury. References:
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