Does Clopidogrel Each Day Keep Stent Thrombosis Away?

Abstract

THE POLYMER-BASED ELUTION OF ANTIPROLIFERATIVE medications from a metal stent prosthesis has been demonstrated to suppress neointimal proliferative response to stent-vessel injury and to reduce consequent late arterial lumen loss and restenosis. In randomized controlled trials, drug-eluting stents compared with bare-metal stents caused a 70% to 80% reduction in binary ( 50%) angiographic restenosis and a 50% to 70% reduction in repeat target lesion or vessel revascularization. Furthermore, comprehensive follow-up to 1 year demonstrated no evidence for any excess in the incidence of death, myocardial infarction (MI), or stent thrombosis for either treatment strategy. Thus, based on pivotal clinical trial evidence for both the relative safety and efficacy of drug-eluting stents, the US Food and Drug Administration approved both Cypher, the sirolimus-eluting stent, in 2002, as well as TAXUS, the paclitaxel-eluting stent device, in 2004. Subsequently, multiple other drug-eluting stent platforms have become available outside of the United States. Following approval of the sirolimus-eluting stent, sweeping adoption of this promising new technology into clinical practice occurred as it appeared that restenosis, the Achilles heel of bare-metal stenting, had finally been cured. Indeed, the pace of drug-eluting stent utilization outstripped any available clinical trial–based evidence for support, and drug-eluting stent deployment “off label” soon accounted for up to half of all use. However, some leaders questioned, “Should standard practice patterns undergo marked immediate changes when fewer than 2000 patients have been studied in 3 clinical trials?” In the initial US Food and Drug Administration panel discussionsprecedingapprovalof the sirolimus-elutingstent,however, a probing question was posed by a panel member, “What is the error level for a 1000 patient randomized study? Could we miss a 1% adverse outcome?” Indeed, with longer duration clinical follow-up in larger numbers of patients, an important observation has been made. The aggregate follow-up ofmultiple randomizedcomparative trialsofdrug-eluting stents vs bare-metal stents demonstrates a low frequency (approximately 0.5% absolute) relative increase in the incidence of very late stent thrombosis, which becomes evident only after 9 to 12 months and appears to extend to 3 to 4 years. The relative incremental risk approximates 0.2% per year (total increment 0.46%-0.57% through 3 years) for the types of patients included in these trials and appears similar for both drugeluting stent devices. Several postulates regarding pathogenesis of late stent thrombosis were proposed, with the most plausible being that the same drug/polymer combinations that effectively reduce instent smooth muscle cell hyperplasia may also cause slower, less complete arterial healing and endothelial coverage, as has been noted on both angioscopic and pathological examination. Beyond this, delayed endothelialization and healing due to polymer-related hypersensitivity, inflammation, or both, as well as acquired late incomplete stent apposition due to vessel positive remodeling in the stented arterial segment, have all been incriminated as potential causes of late drug-eluting stent thrombosis, particularly once combination antiplatelet therapy (aspirin plus thienopyridine) is discontinued. Indeed, discontinuation of clopidogrel within 30 days and even within 6 months following drug-eluting stent deployment has been associated with stent thrombosis, death, or both. The benefit of extending clopidogrel therapy beyond 6 months has been debated. News media reports have increased public awareness and generated serious concern about late drugeluting stent thrombosis. In this issue of JAMA, the article by Eisenstein and colleagues provides constructive information valuable to current and future patients treated with drug-eluting stents by examining the optimal duration of clopidogrel therapy following implantation of drug-eluting and bare-metal stents. The authors provide observations from consecutive patients who received either bare-metal stents (n=3165) or drug-eluting stents (n=1501) between January 1, 2000, and July 31, 2005, at Duke Heart Center. Landmark analyses were performed among patients who were event-free (no death,