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Drug-Eluting versus Bare-Metal Stents in Large Coronary Arteries Christoph Kaiser, M.D., Soeren Galatius, M.D., Paul Erne, M.D., Franz Eberli, M.D., Hannes Alber, M.D., Hans Rickli, M.D., Giovanni Pedrazzini, M.D., Burkhard Hornig, M.D., Osmund Bertel, M.D., Piero Bonetti, M.D., Stefano De Servi, M.D., Hans-Peter Brunner-La Rocca, M.D., Ingrid Ricard, Ph.D., and Matthias Pfisterer, M.D., for the BASKET–PROVE Study Group*

A bs t r ac t Background From University Hospital Basel, Basel (C.K., H.-P.B.-L., I.R., M.P.); State Hospital, Lucerne (P.E.); Triemli Hospital, Zurich (F.E.); State Hospital, St. Gallen (H.R.); Cardiocentro, Lugano (G.P.); Clara Hospital, Basel (B.H.); Cardiovascular Center Zurich, Zurich (O.B.); and State Hospital, Chur (P.B.) — all in Switzerland; Gentofte University Hospital, Hellerup, Denmark (S.G.); University Hospital, Innsbruck, Austria (H.A.); Ospedale Civile di Legnano, Milan, Italy (S.D.S.); and Maastricht University Medical Center, Maastricht, the Netherlands (H.-P.B.-L.). Address reprint requests to Dr. Kaiser at the Department of Cardiology, University Hospital, CH 4031 Basel, Switzerland, or at ckaiser@ uhbs.ch. *Members of the Basel Stent Kosten-­ Effektivitäts Trial–Prospective Validation Examination (BASKET–PROVE) Study Group are listed in the Supplementary Appendix, available at NEJM.org. This article (10.1056/NEJMoa1009406) was published on November 16, 2010, at NEJM.org. N Engl J Med 2010;363:2310-9. Copyright © 2010 Massachusetts Medical Society.

Recent data have suggested that patients with coronary disease in large arteries are at increased risk for late cardiac events after percutaneous intervention with firstgeneration drug-eluting stents, as compared with bare-metal stents. We sought to confirm this observation and to assess whether this increase in risk was also seen with second-generation drug-eluting stents. Methods

We randomly assigned 2314 patients needing stents that were 3.0 mm or more in diameter to receive sirolimus-eluting, everolimus-eluting, or bare-metal stents. The primary end point was the composite of death from cardiac causes or nonfatal myocardial infarction at 2 years. Late events (occurring during months 7 to 24) and targetvessel revascularization were the main secondary end points. Results

The rates of the primary end point were 2.6% among patients receiving sirolimuseluting stents, 3.2% among those receiving everolimus-eluting stents, and 4.8% among those receiving bare-metal stents, with no significant differences between patients receiving either drug-eluting stent and those receiving bare-metal stents. There were also no significant between-group differences in the rate of late events or in the rate of death, myocardial infarction, or stent thrombosis. Rates of target-vessel revascularization for reasons unrelated to myocardial infarction were 3.7% among patients receiving sirolimus-eluting stents, 3.1% among those receiving everolimus-eluting stents, and 8.9% among those receiving bare-metal stents. The rate of target-vessel revascularization was significantly reduced among patients receiving either drugeluting stent, as compared with a bare-metal stent, with no significant difference between the two types of drug-eluting stents. Conclusions

In patients requiring stenting of large coronary arteries, no significant differences were found among sirolimus-eluting, everolimus-eluting, and bare-metal stents with respect to the rate of death or myocardial infarction. With the two drug-eluting stents, similar reductions in rates of target-vessel revascularization were seen. (Funded by the Basel Cardiovascular Research Foundation and the Swiss National Foundation for Research; Current Controlled Trials number, ISRCTN72444640.) 2310

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Drug-Eluting vs. Bare-Metal Stents in Large Arteries

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irst-generation drug-eluting coronary-artery stents (which release siroli­ mus or paclitaxel) have been shown to reduce the risk of restenosis after percutaneous coronary intervention, as compared with bare-metal stents. However, these drug-eluting stents have also been associated with a risk of late stent thrombosis, which in turn may be associated with death from cardiac causes or nonfatal myocardial infarction.1,2 For patients with stenoses in large coronary arteries, requiring stents of 3.0 mm or more in diameter, the benefits of the use of drug-eluting stents have been considered especially uncertain for two reasons. First, in these patients, the benefit of reducing the rate of restenosis is relatively small, as compared with the benefit seen in patients with small-vessel stents.3,4 Second, acute thrombotic occlusion of large coronary arteries usually leads to sudden death or myocardial infarction, whereas small-vessel occlusions may remain clinically undetected. Unfortunately, there have been only a few retrospective subgroup analyses or registries of largevessel stenting,5-7 even though the majority of patients in need of stent placement have lesions in large coronary arteries. In contrast, in smallvessel stenting, a particular benefit of drug-eluting stents has been repeatedly shown.8-14 In the 18-month analysis of the Basel Stent KostenEffektivitäts Trial (BASKET),15 among patients with stenoses in large coronary arteries who received drug-eluting stents, as compared with patients receiving bare-metal stents, there was no significant reduction in the rate of target-vessel revascularization and there was an increased rate of death from cardiac causes or nonfatal myocardial infarction 6 months after the procedure. In contrast, a beneficial effect of drug-eluting stents, as compared with bare-metal stents, was seen in the small-vessel subgroup. This difference was still present 3 years after stenting.16 Similar findings were reported in a study from Canada.17 However, these observations were based on retrospective analyses. We evaluated the relative efficacy of first-generation drug-eluting stents and bare-metal stents placed in large coronary arteries, in a large, prospective, randomized, multicenter trial, called the BASKET–Prospective Validation Examination (BASKET–PROVE). The study was also designed to evaluate whether the risk–benefit balance seen with first-generation drug-eluting stents would be similar with second-generation drug-eluting stents.

Me thods Study Design

The study design and methods have been described in detail previously.18 The protocol was designed by the steering committee and approved by the ethics committee at each center. The study protocol and a complete list of study group members in the Supplementary Appendix are available with the full text of this article at NEJM.org. The study was sponsored by the Basel Cardiovascular Research Foundation and the Swiss National Foundation for Research. The sponsors had no role in the design or conduct of the study, the analysis or interpretation of the data, or the decision to submit the manuscript for publication. All stents were purchased by the participating hospitals, and reimbursement by health insurers was exactly the same as that for patients not enrolled in the trial. The authors vouch for the accuracy and completeness of the data and all analyses. Patients

Patients who presented at participating centers in Switzerland, Denmark, Austria, and Italy between March 5, 2007, and May 15, 2008, were evaluated for enrollment in the trial. Eligible patients were those who presented with chronic or acute coronary disease, who underwent angioplasty with stenting, and who required only stents that were 3.0 mm or more in diameter. No restrictions were placed on the number of treated lesions or vessels, the length of treated lesions, or the number of stents placed. Patients were excluded if they had cardiogenic shock; in-stent restenosis or thrombosis of stents placed before the study; unprotected left main coronary artery (i.e., with no functioning bypass graft) or substantial stenosis in a bypass graft; plans for any surgery within 12 months; a need for oral anticoagulation, an increased risk of bleeding, or known intolerance to or suspected noncompliance with long-term antiplatelet therapy; or circumstances that would have made follow-up impossible. In addition, patients requiring stents larger than 4.0 mm in diameter were excluded because no sirolimuseluting stents of this size were available. All patients provided written informed consent. Study Procedures

Patients were randomly assigned in a 1:1:1 ratio to receive a first-generation sirolimus-eluting stent (Cypher Select, Cordis), a bare-metal (cobalt–chro-

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mium) stent (Vision, Abbott Vascular), or a secondgeneration everolimus-eluting stent (Xience V, Abbott Vascular). Randomization was carried out in permuted blocks of 12 for each center with the use of sealed envelopes. Angioplasty and stenting were performed according to standard techniques chosen at the discretion of each interventional cardiologist. The same type of stent was used in patients with multiple lesions and in those undergoing staged procedures. All patients were prescribed aspirin at a daily dose of 75 to 100 mg indefinitely and clopidogrel at a daily dose of 75 mg for 1 year, after a loading dose of 300 mg or 600 mg, regardless of stent type. Therapeutic agents for secondary prevention, such as statins, were prescribed according to current guidelines. Clinical follow-up by means of questionnaires developed for this study was performed at 12 months and 24 months. Follow-up angiography and revascularization were performed only if clinically indicated. Data on all patients were collected by local investigators, recorded on electronic casereport forms, and transmitted over the Internet to a central database at the University of Basel. A central monitoring team verified all submitted information. End Points and Definitions

The primary end point was death from cardiac causes or nonfatal myocardial infarction at 2 years. The main secondary end points included the efficacy end point of target-vessel revascularization and the safety end point of late death from cardiac causes or nonfatal myocardial infarction. Late events were defined as those occurring 7 to 24 months after the intervention, on the basis of analyses previously performed in the BASKET trial19 and on angiographic studies of the timing of restenosis.20 Other secondary analyses included rates of death from cardiac causes or any cause, nonfatal myocardial infarction, stent thrombosis, and the composite of death from any cause, nonfatal myocardial infarction, or target-vessel revascularization. Death from cardiac causes was defined as any death without a clear extracardiac cause. Myocardial infarction was defined as a clinical event with typical electrocardiographic or enzymatic changes.21 Repeat revascularizations were subdivided into those related to myocardial infarction and those not related to myocardial infarction in order to avoid double-counting of infarct-related 2312

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events. Stent thrombosis was defined according to the criteria of the Academic Research Consortium.22 Bleeding events were defined according to Thrombolysis in Myocardial Infarction (TIMI) criteria.23 Off-label use of stenting was defined as stenting in patients who presented with an acute coronary syndrome, stenting of more than one lesion per vessel, stenting of two or more vessels, stenting of lesions that were 27 mm or longer, stenting of bifurcation lesions, or stenting of chronic total occlusions. An independent critical events committee adjudicated all clinical end points. This assessment was conducted in a blinded fashion for the initial two thirds of events. However, as a result of illness of one of the study monitors, there was a delay in adjudicating the final one third of events. Because of time constraints for the completion of the analysis, these files were adjudicated without blinding. Statistical Analysis

The sample size for the trial was estimated on the basis of findings from the 18-month results of BASKET.15 Among the 558 patients who received stents that were 3 mm or more in diameter, the composite end point of death from cardiac causes or nonfatal myocardial infarction occurred in 6.0% of recipients of bare-metal stents and in 11.2% of recipients of drug-eluting stents during months 7 to 18 (P