The everolimus-eluting stent

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1 SPIRIT IV trial design: A large-scale randomized comparison of everolimus-eluting stents and paclitaxel-eluting stents in patients with coronary artery disease Eugenia Nikolsky, MD, PhD, a Alexandra J. Lansky, MD, a Krishnankutty Sudhir, MD, PhD, d Julie Doostzadeh, PhD, b Donald E. Cutlip, MD, b Robert Piana, MD, c Xiaolu Su, MS, d Roseann White, MA, d Charles A. Simonton, MD, d and Gregg W. Stone, MD a New York, NY; Boston, MA; Nashville, TN; and Santa Clara, CA Background In the 300-patient SPIRIT II and 1002-patient SPIRIT III randomized trials, the everolimus-eluting stent (EES) compared to the paclitaxel-eluting stent (PES) resulted in reduced angiographic late loss (a primary end point in both trials), noninferior rates of 9-month target vessel failure (a primary end point in SPIRIT III), and reduced rates of target lesion revascularization and major adverse cardiac events (secondary end points). However, neither trial was powered for superiority for clinical end points, and the routine performance of angiographic follow-up may have artificially exaggerated the absolute benefits of EES. The relative efficacy of these 2 stents in patients with diabetes mellitus also remains controversial. We therefore designed a large-scale randomized trial without angiographic follow-up to further assess the differences between these 2 stent platforms. Study Design SPIRIT IV is an ongoing prospective, active-controlled, single-blinded, multicenter clinical trial in which 3690 patients with native coronary artery disease have been randomized 2:1 to EES versus PES. Patients with up to 3 de novo native coronary artery lesions (maximum 2 lesions per epicardial vessel) with length 28 mm and reference vessel diameter 2.5 to 4.25 mm were enrolled at 66 US clinical sites. Clinical follow-up at 30, 180, and 270 days; 1 year; and then yearly for up to 5 years is underway. The primary end point is the rate of ischemia-driven target lesion failure at 1 year, a composite measure of safety and efficacy consisting of cardiac death, target vessel myocardial infarction, or ischemia-driven target lesion revascularization, with the trial powered for sequential noninferiority and superiority testing. Summary SPIRIT IV is the largest randomized comparison of 2 DES with completed enrollment. The absence of routine angiographic follow-up will allow an accurate assessment of the absolute differences in the clinical safety and efficacy profile between these devices. The magnitude of the study will also permit significant insights to be gained into the relative performance of the 2 stents in important subgroups, including patients with diabetes mellitus. (Am Heart J 2009;158: e2.) The development, clinical validation, and widespread use of drug-eluting stents (DES) have revolutionized the treatment of patients with coronary artery disease. Largescale, prospective, multicenter double-blind randomized trials have provided strong evidence that sirolimus-eluting From the a Columbia University Medical Center and The Cardiovascular Research Foundation, New York, NY, b Harvard Clinical Research Institute, Boston, MA, c Vanderbilt University Medical Center, Nashville, TN, and d Abbott Vascular, Santa Clara, CA. ClinicalTrials.gov number NCT Submitted May 5, 2009; accepted July 16, Reprint requests: Gregg W. Stone, MD, Columbia University Medical Center The Cardiovascular Research Foundation 111 E. 59th St., 11th Floor New York, NY gs2184@columbia.edu /$ - see front matter 2009, Mosby, Inc. All rights reserved. doi: /j.ahj stents (SES), paclitaxel-eluting stents (PES), and zotarolimus-eluting stents (ZES) significantly reduce angiographic restenosis and enhance event-free survival compared with bare-metal stents (BMS) after implantation in native coronary arteries. 1-4 However, higher rates of late and very late stent thrombosis with SES and PES, likely due to delayed and incomplete endothelialization compared with BMS, have raised safety concerns with DES as a class. 5-8 Because specific stent design and/or polymer features may impact DES performance, numerous studies have focused on the comparative assessment of various DES, with conflicting results Furthermore, different DES have significantly different rates of angiographic late loss, 1-4,9,11,12 which may result in dissimilar rates of repeat revascularization, especially if routine angiographic follow-up is performed. 9,12

2 American Heart Journal Volume 158, Number 4 Nikolsky et al 521 Table I. Angiographic follow-up results from the SPIRIT II and SPIRIT III randomized trials Angiographic end points (per lesion) SPIRIT II SPIRIT III PES (n = 86) EES (n = 237) P PES (n = 158) EES (n = 342) P Minimal luminal diameter (mm) In-stent 2.27 ± ± ± ± In-segment 2.08 ± ± ± ± Diameter stenosis (%) In-stent 20.9 ± ± ± ± In-segment 27.1 ± ± ± ± Late loss (mm) In-stent 0.37 ± ± 0.29 b ± ± In-segment 0.15 ± ± ± ± Binary restenosis (%) In-stent 3.5% 1.3% % 2.3%.06 In-segment 5.8% 3.4% % 4.7%.07 At 6 months in SPIRIT II and at 8 months in SPIRIT III. The clinical need thus exists for enhanced stent designs which offer improved safety and efficacy profiles compared to the earlier stent platforms. Given the favorable outcomes of the current generation of DES, however, large randomized trials are required to determine whether differences exist between the present devices or whether incremental gains may be realized with next generation stent designs. In the present article, we describe the rationale and clinical study design for a large-scale prospective, randomized trial evaluating a novel stent design which has thus far shown promise to improve outcomes in patients with coronary artery disease. The everolimus-eluting stent The everolimus-eluting stent (EES, manufactured and distributed by Abbott Vascular, Santa Clara, CA, as XIENCE V, also distributed as PROMUS by Boston Scientific, Natick, MA) is a balloon expandable stent manufactured from a flexible cobalt chromium alloy with a multicellular design and in strut thickness which is coated with a thin (7.8 μm) nonadhesive, durable, biocompatible acrylic polymer and fluorinated copolymer releasing everolimus. 16 Everolimus [40-O-(2-hydroxyethyl)-rapamycin], a semisynthetic macrolide immunosuppressant, inhibits growth factor-stimulated cell proliferation by causing cell-cycle arrest in the late G1 stage, thereby suppressing neointimal formation. 17,18 Comparative analysis in an in vivo rabbit aortoiliac model has shown more rapid endothelialization with the EES compared to SES, PES, and ZES. 19 Clinical trials are required, however, to determine whether this finding translates into improved human safety or efficacy. After a small first-in-man trial in which the EES was shown to reduce angiographic late loss in comparison with the bare-metal MULTI-LINK VISION stent, 20 the safety and efficacy of the EES was further studied in larger randomized trials of patients with noncomplex lesions in Table II. Clinical results at 1-year from the pooled SPIRIT II and SPIRIT III randomized trials PES (n = 410) EES (n = 892) P Death, all-cause 1.8% 1.3%.48 Death, cardiac 1.0% 0.6%.39 Myocardial infarction 4.0% 2.3%.08 Death or myocardial infarction 5.2% 3.3%.09 Cardiac death or 4.5% 2.7%.10 myocardial infarction Stent thrombosis, 0.8% 0.7%.90 protocol defined Stent thrombosis, 0.8% 0.8%.93 definite/probable Ischemia-driven TLR 5.8% 3.1%.02 Ischemia-driven TVR remote 3.8% 2.7%.32 Major adverse 10.0% 5.2%.002 cardiac events Target vessel failure 10.7% 7.6%.06 Event rates represent Kaplan-Meier estimates. By Academic Research Consortium definition. 41 which EES was compared to the widely used TAXUS PES (Boston Scientific). In both the 300-patient randomized SPIRIT II trial and the 1002-patient randomized SPIRIT III trial, EES proved superior to PES in terms of the primary end point of in-stent late loss at 6 months (SPIRIT II) 21 and in-segment late loss at 8 months (SPIRIT III) (Table I). 22 In the SPIRIT III trial, EES was also found to be noninferior to PES for the coprimary end point of ischemia-driven target vessel failure (cardiac death, myocardial infarction [MI] or ischemia-driven target vessel revascularization [TVR]) at 9 months. 22 In a pooled analysis from the 1302 patients in the SPIRIT II and SPIRIT III trials, EES resulted in reduced rates of major adverse cardiac events (MACE; cardiac death, MI or ischemia-driven target lesion revascularization [TLR]: 5.2% vs 10.0%, P =.02) at 1 year, driven by a significantly reduced rate of TLR (3.1% vs 5.8%, P =.02)

3 522 Nikolsky et al American Heart Journal October 2009 and a trend toward less cardiac death or MI (2.7% vs 4.5%, P =.10), with nonsignificantly different rates of stent thrombosis (0.7% vs 0.8%, P =.90) (Table II). 23 These findings have been robust to 2 years. In SPIRIT III, treatment with EES compared with PES resulted in a significant 32% reduction in target vessel failure (10.7% vs 15.4%, P =.04) and a 45% reduction in MACE (7.3% vs 12.8%, P =.004) at 2 years. 24 However, neither SPIRIT II nor SPIRIT III were powered for statistical superiority testing in clinical end points, nor were they adequately sized to elicit potential differences in low frequency safety events between the 2 stent platforms. Of note, routine angiographic follow-up was prespecified in all patients at 6 months in SPIRIT II and in 564 patients at 8 months in SPIRIT III, a protocol-specific process which may artificially enhance the absolute difference in TLR between 2 stents by provoking angiographically induced revascularization procedures, the so-called oculostenotic reflex. 25,26 Although this process may not affect the relative difference in clinical efficacy between 2 stents, 22,26 routine angiographic follow-up should ideally not be performed prior to the primary clinical end points if an accurate and realistic assessment of treatment related differences is to be obtained. 27 Moreover, in a small substudy of the SPIRIT II trial, incremental angiographic late loss was noted in the EES group but not in the PES group between 6 and 24 months (Serruys PW, unpublished data). Although this finding may or may not have been spurious, and no reduction in the relative clinical efficacy of the EES compared to PES between 6 and 24 months was noted in the pivotal SPIRIT III trial, 24 a very large clinical study without angiographic follow-up and with long-term follow-up is required to allay concerns of a loss of benefit with the EES over time. Drug-eluting stents in patients with diabetes mellitus The presence of diabetes mellitus (particularly insulinrequiring diabetes) has been a consistent, independent predictor of restenosis in most stent trials and registries. 28,29 DES compared to BMS reduce restenosis in both diabetic and non diabetic patients Although some SES studies have raised questions regarding the relative efficacy of rapamycin analogue-eluting stents in patients with diabetes, 11,31 implantation of SES compared with BMS resulted in reduced rates of angiographic and clinical restenosis in a modest-sized randomized trial of patients with diabetes mellitus. 30 Although no randomized trials of PES versus BMS restricted to a diabetic cohort have been conducted, diabetic patients had significantly reduced binary angiographic restenosis and TLR rates when treated with PES versus BMS in sub-analyses from both from the TAXUS IV trial 32 and the pooled TAXUS II, IV, V and VI trials, 33 with comparable rates among diabetic and non diabetic patients treated with PES. Data from several direct randomized comparisons, registries, and meta-analyses of SES and PES in diabetics have been reported (although most have described the results observed among a diabetic subgroup from a larger randomized trial population) In these studies, although SES was typically associated with lower instent late loss by angiography and reduced neointimal hyperplasia by IVUS at follow-up compared with PES in diabetic patients, the clinical outcomes data have been conflicting, with most of the studies not finding significant differences in the rates of TLR and MACE between the 2 stent types in patients with diabetes. However, all of these studies have been significantly underpowered to define whether there are true differences in clinical safety or efficacy between SES and PES in diabetic patients. The data from the SPIRIT trials has further contributed to this controversy (Figure 1). Although underpowered for subgroup analysis, the benefits of EES compared to PES in reducing clinical and angiographic restenosis were present in most subgroups in the SPIRIT trials. However, among 337 patients with diabetes randomized in SPIRIT II and SPIRIT III trials, EES compared to PES resulted in nonsignificant differences in the 1-year rates of TLR (despite a significant reduction in late loss), whereas both late loss and TLR were markedly reduced with EES in 886 patients without diabetes. A significant interaction was noted between the presence of diabetes and stent type on the occurrence of TLR, driven by unexpectedly lower TLR rates among patients with diabetes treated with PES compared to those without diabetes treated with PES. It has been hypothesized that paclitaxel's direct effect on microtubule disruption leading to inhibition of signal transduction pathways regulated by insulin may otherwise offset the deleterious effects of diabetes on increasing neointimal hyperplasia. 39 It should be noted that no studies have demonstrated statistically significantly improved outcomes with PES compared to either SES or EES among patients with diabetes. Nonetheless, given the small numbers of randomized patients in the subgroups reported to date, more information is required to determine the relative safety and efficacy of PES compared to EES in patients with diabetes and other important subgroups. The SPIRIT IV clinical trial Study design and population. SPIRIT IV is an ongoing prospective, randomized, active-controlled, single-blinded, multicenter clinical trial aimed at assessing the safety and efficacy of the XIENCE V EES compared to the Food and Drug Administration approved commercially available TAXUS EXPRESS-2 PES in the treatment of patients with up to 3 de novo native coronary artery lesions (maximum of 2 lesions per epicardial vessel). The design of the study is shown in Figure 2, and the study organization is provided in the Appendix A.

4 American Heart Journal Volume 158, Number 4 Nikolsky et al 523 Figure 1 Primary end point of 8-month angiographic in-segment late loss (A) and the 2-year rates of target lesion revascularization (B) among patients with and without diabetes randomized to receive the EES versus the PES in the SPIRIT II and SPIRIT III trials. Enrollment was planned in approximately 3690 patients at up to 80 US sites with lesions 28 mm in length in epicardial vessels with reference vessel diameter 2.5 to 4.25 mm. Principal inclusion and exclusion criteria appear in Appendix B and were more liberal than in SPIRIT III by the permitted enrollment of patients with up to 3 lesions in 3 separate coronary arteries (2 lesions maximal per vessel), ostial right coronary artery lesions, and some bifurcation involvement as described below. After successful balloon predilatation of the target lesion, patients were randomized in a 2:1 ratio to receive the EES or the PES, respectively, stratified by the presence versus absence of diabetes mellitus, and complex versus noncomplex lesion characteristics (defined as triple-vessel treatment or dual lesion per vessel treatment; lesions involving the ostium of the right coronary artery; bifurcation lesions in which the side branch is 2 mm in diameter; or bifurcation lesions in which the ostium of the side branch is N50% stenosed). SPIRIT IV is a single-blinded study. The operator performing the procedure is not blinded to the study stent. However, patients and caregivers outside of the cardiac catheterization laboratory are blinded to the treatment assignment, and the study site personnel were trained not to disclose the treatment assignment to the patient. Additionally, site personnel not present at the index procedure conduct the clinical follow-up using a standard interview script in order to reduce bias and maintain subject blinding. The authors of this manuscript are solely responsible for the design and conduct of this study, all study analyses, the drafting and editing of the paper and its final contents. The study was funded by Abbott Vascular (Santa Clara, CA). Study device and implantation procedure. Everolimus-eluting stents are available in lengths of 8, 18, and 28 mm, with diameters of 2.5, 3.0, 3.5, and 4.0 mm. Paclitaxeleluting stents are available in lengths of 8, 12, 16, 20, 24, 28, and 32 mm, with diameters of 2.5, 2.75, 3.0, 3.5, and 4.0 mm. A minimum of 3 mm of non-diseased tissue on either side of the lesion is recommended to be covered by the study stent. Treatment of up to 3 de novo native coronary artery lesions is permitted, with a maximum of 2 lesions per epicardial vessel. Predilatation of the target lesion(s) is required. Randomization is done only after predilatation is successfully completed without complications (visually estimated diameter stenosis b50%, TIMI grade 3 flow, post-dilatation lesion length within the requirements of the protocol, and no angiographic complications or prolonged chest pain). If stent overlap is needed, a 1- to 4-mm overlap segment is recommended for the XIENCE V EES. Per the TAXUS IFU, no overlapping is allowed for the PES to minimize periprocedural MI rates. 3

5 524 Nikolsky et al American Heart Journal October 2009 Figure 2 Patient flow and follow-up in the SPIRIT IV trial. All patients are treated with aspirin 300 mg pre procedure. A 300-mg loading dose of clopidogrel bisulfate between 6 and 72 hours before the implant procedure is recommended and required in all cases no later than 1 hour after the procedure. Following the index procedure, all patients receiving a study stent are maintained on aspirin 80 mg daily throughout the duration of the trial, and clopidogrel 75 mg daily for at least 6 months (12 or longer recommended). 40 Either unfractionated heparin or bivalirudin is permitted for procedural anticoagulation. The decision to use glycoprotein IIb/IIIa inhibitors is per the discretion of the investigator. Following the index procedure, patients will have a telephone contact or office visit at 30, 180, and 270 days, as well as at 1 year and yearly thereafter for up to 5 years. The data will be collected on clinical end points including death, MI, TLR, TVR, non-tvr, and stent thrombosis as well as information on protocol medications (aspirin and a thienopyridine) and concomitant medications. Clinical end points and definitions. The primary clinical end point of the SPIRIT-IV trial is ischemia-driven target lesion failure (TLF) at 1 year, a composite measure of safety and efficacy consisting of cardiac death, target vessel MI (Q-wave or non Q-wave), and ischemia-driven TLR by percutaneous coronary intervention (PCI) or coronary artery bypass graft. The major secondary efficacy end point is ischemia-driven TLR, and the major secondary safety end point is composite cardiac death or target vessel MI. Additional clinical safety and efficacy end points include ischemia-driven target vessel failure and MACE and their components at each follow-up period, all-cause death, death or MI, TVR, all revascularizations (ischemic and non ischemic), and stent thrombosis. Component definitions of the end points appear in Appendix C. Stent thrombosis (both early and late) will be adjudicated according to the definitions proposed by the Academic Research Consortium. 41 All principal analyses will be conducted according to intention-to-treat principles. Subgroup analyses will be conducted in patients with and without diabetes, patients with single and multiple treated lesions, and those with long lesions requiring overlapping EES versus lesions covered with a single PES 32 mm in length. Other subgroup analyses of the primary and secondary composite end points and their individual components will be analyzed including but not limited to the age, gender, number of treated lesions, target vessel, reference vessel diameter, lesion length and number of implanted stents. All subgroup analyses are considered secondary and hypothesis generating. Multivariable

6 American Heart Journal Volume 158, Number 4 Nikolsky et al 525 logistic regression analyses will be used to identify significant predictors of all primary and key secondary end points on an individual patient level. Power analysis and statistics. Sequential noninferiority and superiority testing with hierarchical end point analysis will be performed to control type I error according to the following order: ischemia-driven TLF (noninferiority), ischemia-driven TLR (noninferiority), ischemia-driven TLF (superiority), ischemia-driven TLR (superiority), cardiac death or target vessel MI (noninferiority), and cardiac death or target vessel MI (superiority). For the primary end point of ischemia-driven TLF at 1 year, assuming an 8.2% event rate in both groups 24 and a noninferiority margin of 3.1% and allowing for 5% of patients lost to follow-up, randomizing 3690 patients 2:1 EES:PES, will afford 90% power to demonstrate noninferiority with a 1-sided α of.025. For superiority testing, assuming the true ischemia-driven TLF rates at 1 year for EES and PES are 5.3% and 8.2%, respectively, the study has 90% power to demonstrate that EES has a lower ischemia-driven TLF rate then PES with a 2-sided α of.05. For the major secondary efficacy end point of ischemiadriven TLR at 1 year, assuming a 4.4% event rate in both groups 24 and a noninferiority margin of 2.1%, randomizing 3690 patients 2:1 EES:PES, will afford 90% power to demonstrate noninferiority between EES and PES using a 1-sided α of.05. Assuming the true ischemia-driven TLR rates for EES and PES at 1 year are 2.5% and 4.4% respectively, the study has 90% power to demonstrate that EES has a lower ischemia-driven TLR rate then PES with a 2-sided α of.05. Finally, for the major secondary safety end point of cardiac death or target vessel MI at 1 year, assuming a 4.3% event rate in both groups 24 and a noninferiority margin of 2.1%, randomizing 3690 patients 2:1 EES:PES, will afford 90% power to demonstrate non-inferiority between EES and PES with a 1-sided α of.05. Assuming the true ischemia-driven TLR rates at 1-year for EES and PES are 2.4% and 4.3% respectively, the study has 91% power to demonstrate that EES has a lower ischemia-driven TLR rate then PES with a 2-sided α of.05. Data management. An independent Clinical Events Committee, blinded to study stent assignment, will adjudicate all events including death, MI, TLR, TVR, and stent thrombosis. An independent Data Safety Monitoring Board blinded to study treatment will perform regular review of the clinical safety data and may recommend study discontinuation or modification. All angiograms at baseline and in patients with clinically driven events will be evaluated by an independent angiographic core laboratory (Cardiovascular Research Foundation, New York, NY) blinded to study stent. Study status and summary. Enrollment of the SPIRIT- IV trial begun on August 10, 2006, and concluded on July 30, 2008, with 3690 patients randomized at 66 US sites. As such, SPIRIT IV is the largest randomized comparison of 2 DES with completed enrollment, and will afford important insights to the relative performance of EES and PES beyond the previously performed smaller SPIRIT trials. Specifically, the magnitude of the study will afford tighter point estimates between the 2 stent types for low frequency safety end points such as death, MI and stent thrombosis to be determined. The absence of routine angiographic follow-up will allow an accurate assessment of the absolute differences in the clinical safety and efficacy profile between these 2 stent platforms. Followup to 5 years will determine whether any late differences in clinical benefit exist. The size of the study will also permit significant insights to be gained into the relative performance of the 2 stents in important subgroups, including patients with diabetes mellitus (as N1100 patients with diabetes have been enrolled, a larger cohort than the entire SPIRIT III trial). Clinical follow-up is ongoing, and the principal results will be reported in the fall of References 1. Moses JW, Leon MB, Popma JJ, et al. Sirolimus-eluting stents versus standard stents in patients with stenosis in a native coronary artery. N Engl J Med 2003;349: Stone GW, Ellis SG, Cox DA, et al. A polymer-based, paclitaxeleluting stent in patients with coronary artery disease. N Engl J Med 2004;350: Stone GW, Ellis SG, Cannon L, et al. Comparison of a polymer-based paclitaxel-eluting stent with a bare metal stent in patients with complex coronary artery disease: a randomized controlled trial. JAMA 2005; 294: Fajadet J, Wijns W, Laarman GJ, et al. Randomized, double-blind, multicenter study of the Endeavor zotarolimus-eluting phosphorylcholine-encapsulated stent for treatment of native coronary artery lesions: clinical and angiographic results of the ENDEAVOR II trial. Circulation 2006;114: Finn AV, Joner M, Nakazawa G, et al. Pathological correlates of late drug-eluting stent thrombosis: strut coverage as a marker of endothelialization. Circulation 2007;115: Camenzind E, Steg PG, Wijns W. Stent thrombosis late after implantation of first-generation drug-eluting stents: a cause for concern. Circulation 2007;115: Daemen J, Wenaweser P, Tsuchida K, et al. Early and late coronary stent thrombosis of sirolimus-eluting and paclitaxel-eluting stents in routine clinical practice: data from a large two-institutional cohort study. Lancet 2007;369: Lagerqvist B, James SK, Stenestrand U, et al. Long-term outcomes with drug-eluting stents versus bare-metal stents in Sweden. N Engl J Med 2007;356: Windecker S, Remondino A, Eberli FR, et al. Sirolimus-eluting and paclitaxel-eluting stents for coronary revascularization. N Engl J Med 2005;353: Goy JJ, Stauffer JC, Siegenthaler M, et al. A prospective randomized comparison between paclitaxel and sirolimus stents in the real world of interventional cardiology: the TAXi trial. J Am Coll Cardiol 2005;45: Morice MC, Colombo A, Meier B, et al. Sirolimus-vs paclitaxel-eluting stents in de novo coronary artery lesions: the REALITY trial: a randomized controlled trial. JAMA 2006;295:

7 526 Nikolsky et al American Heart Journal October Mehilli J, Dibra A, Kastrati A, et al. Randomized trial of paclitaxel-and sirolimus-eluting stents in small coronary vessels. Eur Heart J 2006;27: Galløe AM, Thuesen L, Kelbaek H, et al. Comparison of paclitaxel-and sirolimus-eluting stents in everyday clinical practice: the SORT OUT II randomized trial. JAMA 2008;299: Schömig A, Dibra A, Windecker S, et al. A meta-analysis of 16 randomized trials of sirolimus-eluting stents versus paclitaxeleluting stents in patients with coronary artery disease. J Am Coll Cardiol 2007;50: Lassen JF, Rasmussen K, Galløe A, et al. SORT-OUT III: A Prospective, Randomized Comparison of Zotarolimus-eluting and Sirolimus-eluting Stents in Patients with Coronary Artery Disease. Paper presented at: Transcatheter Therapeutics October 16, Washington, DC; Sheiban I, Villata G, Bollati M, et al. Next-generation drug-eluting stents in coronary artery disease: focus on everolimus-eluting stent (Xience V). Vasc Health Risk Manag 2008;4: Schuler W, Sedrani R, Cottens S, et al. SDZ RAD, a new rapamycin derivative: pharmacological properties in vitro and in vivo. Transplantation 1997;64: Carter AJ, Brodeur A, Collingwood R, et al. Experimental efficacy of an everolimus eluting cobalt chromium stent. Catheter Cardiovasc Interv 2006;68: Joner M, Nakazawa G, Finn AV, et al. Endothelial cell recovery between comparator polymer-based drug-eluting stents. J Am Coll Cardiol 2008;52: Serruys PW, Ong ATL, Piej JJ, et al. A randomised comparison of a durable polymer everolimus-eluting coronary stent with a bare metal coronary stent. EuroIntervention 2005;1: Serruys PW, Ruygrok P, Neuzner J, et al. A randomised comparison of an everolimus-eluting coronary stent with a paclitaxel-eluting coronary stent: the SPIRIT II trial. EuroIntervention 2006;2: Stone GW, Midei M, Newman W, et al. Comparison of an everolimuseluting stent and a paclitaxel-eluting stent in patients with coronary artery disease: a randomized trial. JAMA 2008;299: Miu R, Serruys PW, Stone GW. Performance of everolimus-eluting stents: pooled analysis from the SPIRIT trials. J of Intervent Cardiol 2009 [In press]. 24. Stone GW, Midei M, Newman W, et al. Randomized comparison of everolimus-eluting and paclitaxel-eluting stents: two-year clinical follow-up from the Clinical Evaluation of the Xience V Everolimus Eluting Coronary Stent System in the Treatment of Patients with de novo Native Coronary Artery Lesions (SPIRIT) III trial. Circulation 2009;119: ten Berg J, Kelder J, Suttorp M, et al. Influence of planned six-month follow-up angiography on large outcome after percutaneous coronary intervention: a randomized study. J Am Coll Cardiol 2001;38: Pinto DS, Stone GW, Ellis SG, et al. Impact of routine angiographic follow-up on the clinical benefits of paclitaxel-eluting stents: results from the TAXUS-IV trial. J Am Coll Cardiol 2006;48: Stone GW, Lansky AJ, Pocock SJ, et al. Paclitaxel-eluting stents versus bare-metal stents in acute myocardial infarction. N Engl J Med 2009; 360: Iijima R, Ndrepepa G, Mehilli J, et al. Impact of diabetes mellitus on long-term outcomes in the drug-eluting stent era. Am Heart J 2007; 154: Popma JJ, Leon MB, Moses JW, et al. Quantitative assessment of angiographic restenosis after sirolimus-eluting stent implantation in native coronary arteries. Circulation 2004;110: Sabate M, Jimenez-Quevedo P, Angiolillo DJ, et al. Randomized comparison of sirolimus-eluting stent versus standard stent for percutaneous coronary revascularization in diabetic patients: the Diabetes and Sirolimus-Eluting Stent (DIABETES) Trial. Circulation 2005;112: Moussa I, Leon MB, Baim DS, et al. Impact of sirolimus-eluting stents on outcome in diabetic patients: a SIRIUS (SIRolImUS-coated Bx Velocity balloon-expandable stent in the treatment of patients with de novo coronary artery lesions) substudy. Circulation 2004;109: Hermiller JB, Raizner A, Cannon L, et al. Outcomes with the polymerbased paclitaxel-eluting TAXUS stent in patients with diabetes mellitus: the TAXUS-IV trial. J Am Coll Cardiol 2005;45: Kimura M, Mintz GS, Weissman NJ, et al. Meta-analysis of the effects of paclitaxel-eluting stents versus bare metal stents on volumetric intravascular ultrasound in patients with versus without diabetes mellitus. Am J Cardiol 2008;101: Dibra A, Kastrati A, Mehilli J, et al. Paclitaxel-eluting or sirolimuseluting stents to prevent restenosis in diabetic patients. N Engl J Med 2005;353: Ong AT, Aoki J, van Mieghem CA, et al. Comparison of short- (one month) and long- (twelve months) term outcomes of sirolimus-versus paclitaxel-eluting stents in 293 consecutive patients with diabetes mellitus (from the RESEARCH and T-SEARCH registries). Am J Cardiol 2005;96: Maeng M, Jensen LO, Galloe AM, et al. Comparison of the sirolimus-- eluting versus paclitaxel-eluting coronary stent in patients with diabetes mellitus: the diabetes and drug-eluting stent (DiabeDES) randomized angiography trial. Am J Cardiol 2009;103: Kim JS, Lee BH, Ko YG, et al. Comparison of sirolimus-eluting stent and paclitaxel-eluting stent for long-term cardiac adverse events in diabetic patients: the Korean Multicenter Angioplasty Team (KOMATE) Registry. Catheter Cardiovasc Interv 2008;72: Mahmud E, Bromberg-Marin G, Palakodeti V, et al. Clinical efficacy of drug-eluting stents in diabetic patients: a meta-analysis. J Am Coll Cardiol 2008;51: Mitsuuchi Y, Johnson SW, Selvakumaran M, et al. The phosphatidylinositol 3-kinase/AKT signal transduction pathway plays a critical role in the expression of p21waf1/cip1/sdi1 induced by cisplatin and paclitaxel. Cancer Res 2000;60: King IIIrd SB, Smith Jr SC, Hirshfeld Jr JW, et al focused update of the ACC/AHA/SCAI 2005 guideline update for percutaneous coronary intervention: a report of the American College of Cardiology/American Heart Association Task Force on Practice guidelines. J Am Coll Cardiol 2008;51: Cutlip DE, Windecker S, Mehran R, et al, on behalf of the Academic Research Consortium. Academic Research Consortium, clinical endpoints in coronary stent trials: a case for standardized definitions. Circulation 2007;115:

8 American Heart Journal Volume 158, Number 4 Nikolsky et al 526.e1 Appendix A. SPIRIT IV study organization and processes Sponsor: Abbott Vascular, Inc., Santa Clara, CA. Principal Investigator: GW Stone, Columbia University Medical Center and the Cardiovascular Research Foundation, New York, NY. Steering Committee: GW Stone (Chair), Columbia University Medical Center and the Cardiovascular Research Foundation; Abbott Vascular, Inc: K Sudhir (Senior Medical Director, Global Clinical Science); T Engels (Director, Clinical Affairs); W Pierson (Director, Global Clinical Science); J Doostzadeh (Senior Advisor, Global Clinical Science); L Jonnvithula (Associate Director, Global Safety); J Coe (Associate Director, Clinical Research); B Nishimoto (Project Manager). Randomization: Client Services Interactive Technologies, ICON Clinical Research, North Wales, PA; L Lawson (Director). Electronic Data Capture: Phase Forward, Waltham, MA. Image Management Services: CardioNow, Encinitas, CA; B. Adelmann (Vice President). Angiographic Core Laboratory: Cardiovascular Research Foundation, New York, NY; AJ Lansky (Director). Site Monitoring: Paragon, Irvine, CA; M Harvill (President and COO), T Lucente (Director, Global Project Operations), Paragon, Irvine, CA; P Patel (Program Director) Paragon, Irvine, CA; M Plaunt (Vice President, Global Operations), Paragon, Irvine, CA. Safety Monitoring: Harvard Clinical Research Institute, Boston, MA; D Cutlip (Executive Director); Abbott Vascular, Inc, P Sood (Director), G. Thompson (Director). Clinical Events Committee: Harvard Clinical Research Institute, Boston, MA; D Cutlip (Executive Director). Data Safety Monitoring Board: R Piana (Chair), Vanderbilt University Medical Center, Nashville, Tennessee; Axio Research, Seattle, WA. Data Management and Biostatistical Analysis: Abbott Vascular, Inc: M Mirgoli (Director, Data Management); X Su (Director, Biostatistics). Appendix B. SPIRIT IV inclusion and exclusion criteria Clinical inclusion criteria 1. Age 18 years 2. Stable or unstable angina, silent ischemia or positive functional study 3. Acceptable candidate for coronary artery bypass graft surgery 4. Able to provide written informed consent 5. Agree to undergo all protocol-required follow-up procedures 6. Females of child-bearing potential Clinical exclusion criteria 1. A known diagnosis of acute myocardial infarction preceding the index procedure (creatine kinase [CK] MB 2 times upper limit of normal) and CK and CK- MB have not returned within normal limits at the time of procedure 2. Current unstable arrhythmias 3. A known left ventricular ejection fractionb30% 4. A heart transplant or any other organ transplant or on a waiting list for any organ transplant 5. Subject is receiving or scheduled to receive anticancer therapy for malignancy within 30 days prior to or after the procedure 6. Subject is receiving immunosuppressive therapy 7. Known serious immunosuppressive disease or severe autoimmune disease that requires chronic immunosuppressive therapy 8. Chronic anticoagulation therapy 9. A known hypersensitivity or contraindication to aspirin, both heparin and bivalirudin, both clopidogrel and ticlopidine, everolimus, cobalt, chromium, nickel, tungsten, acrylic and fluoro polymers or contrast sensitivity that cannot be adequately pre-medicated 10. Elective surgery that will require discontinuing either aspirin or clopidogrel is planned within the first 9 months after the procedure 11. A platelet count b100,000 cells/mm 3 or N700,000 cells/mm 3, a WBC ofb3,000 cells/mm 3, or documented or suspected liver disease

9 526.e2 Nikolsky et al American Heart Journal October Serum creatinine level of N2.5 mg/dl or on dialysis 13. A history of bleeding diathesis or coagulopathy or will refuse blood transfusions 14. Subject has had a significant gastrointestinal or urinary bleed within the past 6 months 15. A cerebrovascular accident or transient ischemic attack within the past 6 months 16. Extensive peripheral vascular disease that precludes safe 6 French sheath insertion 17. Patient has other medical illness or known history of substance abuse that may cause non-compliance with the protocol, confound the data interpretation or is associated with a life expectancy of b1 year 18. Participation in another clinical study that has not yet reached its primary end point 19. Pregnant or nursing subjects and those who plan pregnancy in the period up to 1-year following index procedure. Angiographic inclusion criteria 1. De novo target lesion(s) with a visually estimated length of 28 mm, stenosis of 50% but b100% and a TIMI flow of 1 in a native coronary artery with diameter of 2.5 mm to 4.25 mm; treatment of up to 3 target lesions, maximum of 2 target lesions per epicardial vessel 2. Non-study PCI for lesions in a target vessel or its side branches is allowed if done 9 months prior to the index procedure 3. Non-study PCI for lesions in a non-target vessel involving: a) Successful and uncomplicated (visually estimated diameter stenosis b50%, TIMI Grade-3 flow, no electrocardiogram changes, prolonged chest pain, or angiographic complications) bare-metal stent, balloon dilatation, cutting balloon, atherectomy, thrombectomy, and laser treatments are allowed if done 24 hours prior to the index procedure or during (before randomization) the index procedure. For interventions done within 24 to 48 hours prior to the index procedure, CK and CK-MB must be assessed to be b2 times the upper limit of normal at the time of the index procedure. NOTE: Procedures within the 24-hour period preceding the index procedure are not permitted b) Unsuccessful or complicated bare-metal stent, balloon dilatation, cutting balloon, atherectomy, thrombectomy, and laser treatments are allowed if done 30 days prior to the index procedure c) Drug-eluting stent treatment is allowed if done 90 days prior to the index procedure 4. Non-study PCI for lesion(s) in a target vessel or its side branches or non target vessel are allowed if done 9 months after the index procedure Angiographic exclusion criteria 1. Left main coronary artery location including left main ostial location 2. Lesion located within 2 mm of the origin of the left anterior descending artery (LAD) or left circumflex artery (LCX) 3. Lesion located within an arterial or saphenous vein graft or distal to a diseased arterial or saphenous vein graft 4. Lesion involves a bifurcation with the side branch 2 mm in diameter and the ostium of the side branch had N50% stenosed by visual estimation 5. Lesion involves a side branch requiring pre-dilatation 6. Total occlusion (TIMI flow 0) prior to wire crossing 7. Excessive tortuosity proximal to or within the lesion 8. Extreme angulation ( 90 ) proximal to or within the lesion 9. Heavy calcification 10. In-stent restenotic target lesion 11. Prior brachytherapy in any epicardial vessel or their side branches 12. The target vessel contains thrombus 13. Another clinically significant lesion in the target vessel is present that requires or has a high probability of requiring PCI during the index procedure 14. Another lesion in a target or non-target vessel (including all side branches) is present that requires or has a high probability of requiring PCI within 9 months after the index procedure Appendix C. End point definitions End point Cardiac death Myocardial infarction Ischemia-driven target lesion revascularization Ischemia-driven target vessel revascularization Ischemia-driven target vessel failure Definition Death due to acute MI; cardiac perforation/pericardial tamponade; arrhythmia or conduction abnormality; cerebrovascular accident within 30 days of the procedure or cerebrovascular accident suspected of being related to the procedure; and death due to complications of the procedure, including bleeding, vascular repair, transfusion reaction, or bypass surgery; or any death in which a cardiac cause cannot be excluded. An elevation of CK to 2 times the upper limit of normal with elevated CK-MB in the absence or presence of new pathological Q waves on the electrocardiogram (non Q- and Q-wave MI, respectively). The basis for evaluating whether MI is related to the target vessel will be the presence of electrocardiographic signs of acute ischemia in the territory of the target vessel and/or on the index event angiogram, if available. All MIs that cannot be clearly attributed to a vessel other than the target vessel will be considered related to the target vessel. Repeat percutaneous intervention of the target lesion (including 5-mm margins on both edges of a stent) or bypass surgery of the target vessel associated with 1 of the following: (1) positive functional ischemia study; (2) ischemic symptoms and angiographic minimal lumen diameter stenosis 50% by core laboratory quantitative coronary angiography (QCA); or (3) angiographic diameter stenosis 70% by core laboratory QCA without either ischemic symptoms or a positive functional study. Repeat percutaneous intervention of the target vessel or bypass surgery of the target vessel associated with 1 of the following: (1) positive functional ischemia study; (2) ischemic symptoms and angiographic minimal lumen diameter stenosis 50% by core laboratory QCA; or (3) angiographic diameter stenosis 70% by core laboratory QCA without either ischemic symptoms or a positive functional study. The target vessel consists of the target lesions plus any additional lesions in the main epicardial artery or branches containing in the target lesion. Cardiac death, myocardial infarction, and/or ischemia-driven target lesion revascularization or target vessel revascularization.