Next-generation drug-eluting stents: a spirited step forward or more of the same.

THE GREAT REWARD FOR PRACTICING INTERVENtional cardiologists is the ability to help patients live longer as well as to reduce their symptoms and improve their quality of life. These objectives have been central since Gruentzig performed the first percutaneous balloon angioplasty in 1977. In an effort to demonstrate the safety and effectiveness of angioplasty, Gruentzig and other pioneers focused their initial studies on carefully selected patients with rigorous longitudinal follow-up. Gruentzig selected patients with less complex coronary stenosis, often single-vessel disease, to perform the “proof-of-concept” initial evaluation of angioplasty. These studies validated the concept that angioplasty relieved angina for patients with coronary stenosis. During this early era, however, percutaneous angioplasty was frequently complicated by abrupt vessel closure and repeat intervention, often for restenosis. Thus, percutaneous angioplasty was found to have potential beneficial effects in termsof symptomrelief, yet thesebenefitsneeded tobeweighed against deleterious effects such as myocardial infarction, repeat intervention, or need for bypass surgery. To conclusively test the safety and efficacy even at this early stage, Gruentzig called for randomized trials comparing percutaneous angioplasty with surgical revascularization. Although the tools available to achieve these goals have changed from balloon dilatation alone to bare-metal stents and recently to drug-eluting stents, the themes of measuring device effectiveness and patient outcomes remain central to the evaluation of coronary devices and the practice of interventional cardiology. Bare-metal stents were introduced in the early 1990s as a method to reduce abrupt vessel closure associated with percutaneous balloon angioplasty. Only after an improved understanding and demonstrated benefit of periprocedural pharmacotherapy with aspirin and a theinopyridine and high-pressure implantation techniques did coronary stents become widely used. After this expanded use, the need for urgent coronary artery bypass graft operations associated with percutaneous coronary intervention decreased markedly, to less than 1%. Drug-eluting stents were introduced into clinical practice in 2003 on the basis of studies demonstrating reduced angiographic late loss (ie, difference in minimal luminal diameter measured immediately postprocedure and at angiographic follow-up) and reduced need for repeat procedures in patients with de novo coronary stenosis. This breakthrough technology represented the possibility of reducing or eliminating restenosis, considered the remaining Achilles heel of interventional cardiology. Within 1 year of approval, use of drugeluting stents was near 80% in a national registry of patients with acute coronary syndrome. However, reports of late stent thrombosis emerged and led a US Food and Drug Administration (FDA) expert advisory panel to conclude in December 2006 that premarket studies for drug-eluting stents should be conducted in larger populations and with longer followup. Careful patient and lesion selection based on data from randomized controlled trials and patient adherence to clopidogrel therapy were identified as important determinants of outcome. These observations highlighted the complex interplay between patient factors, available drug-eluting stents, and subsequent pharmacotherapy. The search for new and improved drug-eluting stents continues. In this issue of JAMA, Stone and colleagues report the results of the SPIRIT III trial, a randomized trial comparing an everolimus-eluting stent with a paclitaxeleluting stent in patients with coronary artery disease. Everolimus is an analogue of rapamycin that inhibits cell cycle progression and smooth muscle proliferation. The drug is eluted from a biocompatible polymer that is mounted on a thin-strut, low-profile, cobalt-chromium stent. The investigators randomized 1002 patients with de novo coronary stenosis 28 mm or less in length and with reference vessel diameter between 2.5 and 3.75 mm to receive either an everolimus-eluting stent (n=669) or a paclitaxeleluting stent (n=333), with in-segment late loss at the time of 8-month protocol-mandated angiography (n=436) as the primary end point and noninferiority for target vessel failure (revascularization at any location within the target vessel) as a major secondary end point. For the trial to be considered for FDA approval, both the late loss end point and