- Email: [email protected]
Zotarolimus-Eluting Stents in Patients with Native Coronary Artery Disease: Clinical and Angiographic Outcomes in 1,317 Patients
Zotarolimus-Eluting Stents in Patients with Native Coronary Artery Disease: Clinical and Angiographic Outcomes in 1,317 Patients Anthony Gershlick, BSc, MB, BS,a,* David E. Kandzari, MD,b Martin B. Leon, MD,c William Wijns, MD, PhD,d Ian T. Meredith, MBBS, PhD,e Jean Fajadet, MD,f Jeffrey J. Popma, MD,g Peter J. Fitzgerald, MD, PhD,h and Richard E. Kuntz, MD, MSc,i for the ENDEAVOR Investigators Early studies of a cobalt-based alloy stent coated with the novel antiproliferative agent zotarolimus and a phosphorylcholine polymer have demonstrated significant reductions in angiographic restenosis and target vessel revascularization compared with bare metal stents. However, the generalizability of the angiographic outcomes and clinical benefit of zotarolimus-eluting stents (ZESs) to a more real-world patient population is undetermined. Clinical and angiographic outcomes in 1,317 patients treated with the ZES in the first 4 trials of the Endeavor ZES (Medtronic Vascular, Santa Rosa, CA) clinical trials program were pooled for systematic analysis. Protocol-specified follow-up angiography was performed at 8 or 12 months for a subset of 750 of these patients, and clinical follow-up was performed at 9 months after the index procedures in all patients. Diabetes mellitus was present in 22.5% of patients, the mean reference vessel diameter was 2.73 mm, and the mean lesion length was 14.59 mm. At 8 months (12 months for ENDEAVOR I), mean ⴞ SD in-stent late luminal loss was 0.61 ⴞ 0.49 mm. In-stent late luminal loss was greatest in larger caliber (>2.9 mm) vessels (0.65 ⴞ 0.49 mm) and longer (>16.3 mm) lesions (0.70 ⴞ 0.52 mm) but did not statistically vary according to diabetic status. At 9 months, overall rates of target lesion revascularization (TLR) and major adverse cardiac events (MACE) were 4.9% and 7.7%, respectively. The rate of TLR at 12 months was not significantly different relative to diabetes and lesion length >16.3 mm (7.2% and 7.7%, respectively), although TLR was significantly more common when reference vessel diameter was <2.5 mm (8.5%; p ⴝ 0.013). At 24 months, overall rates of TLR and MACE were 6.5% and 9.9%, respectively. The overall 24-month rate of stent thrombosis was 0.3%, with no events occurring >14 days after the procedure. Despite varied clinical and angiographic characteristics, treatment with the ZES is associated with consistently low rates of TLR and overall major adverse events, including stent thrombosis. Although these findings indicate the efficacy and safety of the ZES over the time course of the first 4 ENDEAVOR clinical trials, additional ongoing study with more open patient inclusion criteria (including long lesions, small vessels, bifurcations, etc) will be important for discerning whether comparable clinical outcomes can be extended to lesion subsets of higher complexity. © 2007 Elsevier Inc. All rights reserved. (Am J Cardiol 2007;100[suppl]:45M–55M)
Despite considerable reductions in angiographic restenosis and the need for repeat revascularization procedures, continued attention a
University Hospitals of Leicester School of Medicine, Leicester, United Kingdom; bDuke Clinical Research Institute, Durham, North Carolina, USA; c Columbia University Medical Center and the Cardiovascular Research Foundation, New York, New York, USA; dCardiovascular Center Aalst, Aalst, Belgium; e Monash Medical Centre and Monash University, Melbourne, Australia; fClinique Pasteur, Toulouse, France; gHarvard Clinical Research Institute and Brigham and Women’s Hospital, Boston, Massachusetts, USA; hCenter for Cardiovascular Technology, Stanford University Medical Center, Stanford, California, USA; and i Medtronic, Inc., Minneapolis, Minnesota, USA. This study was supported by Medtronic Vascular, Santa Rosa, California. 0002-9149/07/$ – see front matter © 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2007.08.021
to the safety, efficacy, and deliverability of first-generation drugeluting stents (DESs) has led to the development of new antiproliferative agents with alternative stent platforms and different drug carrier systems. Zotarolimus is a novel pharmacologic therapy that shares similar structure and biologic activity with the antirestenotic agent sirolimus (Figure 1). The effectiveness of zotarolimus as an antiproliferative agent has been recently investigated as part
Statement of author disclosure: Please see the Author Disclosures section at the end of this article. *Address for reprints: Anthony Gershlick, MD, University of Leicester School of Medicine, Glenfield General Hospital, Leicester LE3 9QP, United Kingdom. E-mail address: [email protected]. www.AJConline.org
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mer– based coronary stent eluting zotarolimus in patients with de novo native coronary lesions.
Figure 1. Chemical structure of zotarolimus and sirolimus.
of a cobalt-based alloy stent platform integrated with a biomimetic phosphorylcholine polymer (Endeavor; Medtronic Vascular, Santa Rosa, CA). To date, 4 clinical trials evaluating the safety and efficacy of zotarolimus-eluting stents (ZESs) have been completed: ENDEAVOR I, a first-in-human study1; ENDEAVOR II, a randomized controlled study comparing the ZES with a bare metal stent (BMS)2; the ENDEAVOR II Continued Access Registry (ENDEAVOR II CA)3; and ENDEAVOR III, a randomized trial comparing the ZES with the sirolimus-eluting stent (SES).4 Despite similar enrollment criteria among these studies, the relative benefits of the ZES have been more varied. In ENDEAVOR II, compared with the BMS, treatment with the ZES was associated with marked improvements in angiographic restenosis and repeat target lesion revascularization (TLR).2 Alternatively, randomized comparison with the SES in ENDEAVOR III demonstrated overall similar clinical outcomes despite significantly higher angiographic restenosis and late luminal loss with the ZES.3 Beyond the context of any single trial, however, the consistency of the clinical benefit of the ZES in a more extensive patient population and more varied physician practice is undetermined. We therefore performed a combined analysis of these trials to examine the collective safety, clinical efficacy, and angiographic outcomes associated with the deployment of a phosphorylcholine poly-
Methods Overview of trials and study population: The ENDEAVOR clinical trials program comprises a series of prospective, multicenter, multinational trials enrolling patients with symptomatic ischemic heart disease due to de novo stenotic lesions (⬎50% angiographic diameter stenosis by visual estimate) in native coronary arteries. In ENDEAVOR I, ENDEAVOR II, ENDEAVOR II CA, and ENDEAVOR III, patients who underwent elective percutaneous coronary revascularization were treated with the ZES, BMS, or SES (Table 1). ENDEAVOR I was a nonrandomized first-inhuman evaluation of the ZES in 100 patients with de novo native coronary lesions ⱕ15 mm in length and with reference diameters of 3.0 –3.5 mm.1 In ENDEAVOR II, 1,197 patients with de novo native coronary lesions of 14 –27 mm in length and with reference vessel diameters of 2.25–3.5 mm were randomized in a double-blinded fashion to treatment with the ZES or BMS.2 Criteria for inclusion in the nonrandomized, open-label ENDEAVOR II CA (n ⫽ 296) were identical to the criteria for inclusion in ENDEAVOR II, except that a subgroup of patients (n ⫽ 126) were treated with direct stenting (ie, no predilation) at the discretion of the investigators.3 In ENDEAVOR III, 436 patients were randomized in a single-blinded 3:1 fashion to treatment with either the ZES or SES.4 Criteria for enrollment in ENDEAVOR III were also similar to the criteria for enrollment in ENDEAVOR II, although the minimum reference vessel diameter was 2.5 mm (compared with 2.25 mm in ENDEAVOR II). In all 4 trials, patients were excluded if they experienced recent (⬍72 hours) myocardial infarction (MI), had undergone previous stent placement within the target vessel or any other vessel within 30 days of the index procedure, or had any general contraindications to the revascularization procedure and routine pharmacologic therapies. Principal angiographic exclusion criteria were a left ventricular ejection fraction ⬍0.30, stenosis ⬎40% elsewhere in the target vessel (other than the target lesion), the involvement of a side branch ⱖ2.0 mm in diameter, unprotected left main coronary disease, total occlusions and Thrombolysis in Myocardial Infarction (TIMI) grade ⬍2 flow in the treatment vessel, and the presence of disease in other vessels with percentage diameter stenosis ⬎50%. All studies were approved by the institutional review boards or ethics committees at all enrolling sites, and consecutive eligible patients provided written informed consent before the interventional procedures. Device description: The Endeavor DES is a cobaltbased alloy stent with a phosphorylcholine polymer5 loaded with zotarolimus at dose concentration of 10 g/mm stent length. In a porcine coronary model, stents coated with a phosphorylcholine polymer and zotarolimus were associ-
Gershlick et al/Zotarolimus-Eluting Stents
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Table 1 The clinical trials program of the Endeavor zotarolimus-eluting stent (ZES)* Trial
n
ENDEAVOR I
ENDEAVOR II
100
1,197
ENDEAVOR II CA
296
ENDEAVOR III
436
Design
Lesion Inclusion Criteria
Angiographic Follow-Up in ZES Group (n)
Primary End Point(s)
Open-label, nonrandomized
3.0–3.5 mm RVD; length ⱕ15 mm
92 (at 12 mo)
Double-blind, randomized, 1:1 ZES:BMS Open-label, nonrandomized Single-blind, randomized, 3:1 ZES:SES
2.25–3.5 mm RVD; length 14–27 mm 2.25–3.5 mm RVD; length 14–27 mm 2.5–3.5 mm RVD; length 14–27 mm
264 (at 8 mo)
30-day MACE and 4-mo in-segment late luminal loss 9-mo target vessel failure 30-day MACE
117 (at 8 mo) 277 (at 8 mo)
8-mo angiographic in-segment late luminal loss
BMS ⫽ bare metal stent; ENDEAVOR II CA ⫽ ENDEAVOR II Continued Access Registry; MACE ⫽ major adverse cardiac events; RVD ⫽ reference vessel diameter; SES ⫽ sirolimus-eluting stent; ZES ⫽ zotarolimus-eluting stent. * Medtronic Vascular, Santa Rosa, CA.
Table 2 Baseline patient clinical and angiographic characteristics for the Endeavor zotarolimus-eluting stent* Characteristic Clinical‡ Age (yr) Male sex (%) Diabetes mellitus (%) Hypertension (%) History of smoking (%) Hyperlipidemia (%) Previous myocardial infarction (%) Angina class III/IV (%) Previous percutaneous revascularization (%) Previous coronary bypass surgery (%) Angiographic Target vessel§ (%) Left anterior descending coronary artery Left circumflex coronary artery Right coronary artery Type B2/C lesions§ (%) Reference vessel diameter† (mm) Lesion length§ (mm) No. of diseased vessels‡ (%) 1 2 3 Left ventricular ejection fraction‡ (%)
p Value†
ENDEAVOR I (n ⫽ 100)
ENDEAVOR II (n ⫽ 598)
ENDEAVOR II CA (n ⫽ 296)
ENDEAVOR III (n ⫽ 323)
58.74 ⫾ 10.08 (100) 79.0 (79/100) 16.0 (16/100) 53.1 (52/98) 34.0 (34/100) 91.8 (90/98) 47.0 (47/100) 34.6 (27/78) 19.0 (19/100)
61.58 ⫾ 10.53 (597) 77.2 (461/597) 18.2 (108/595) 63.3 (377/596) 35.3 (207/587) 80.5 (476/591) 39.7 (236/594) 54.4 (261/480) 21.7 (129/595)
64.25 ⫾ 9.69 (296) 75.0 (222/296) 25.8 (76/295) 81.7 (241/295) 27.1 (79/291) 75.3 (220/292) 29.2 (86/295) 39.3 (103/262) 32.8 (97/296)
61.42 ⫾ 10.58 (323) 65.3 (211/323) 29.7 (96/323) 70.7 (227/321) 66.5 (212/319) 83.5 (268/321) 19.9 (64/321) 59.3 (156/263) 22.6 (73/323)
2.0 (2/100)
4.7 (28/597)
5.1 (15/296)
5.3 (17/323)
43.0 (43/100)
43.4 (255/588)
50.5 (150/297)
41.2 (133/323)
44.4 (581/1,308)
23.0 (23/100) 34.0 (34/100) 49.0 (49/100) 2.96 ⫾ 0.47 (100) 10.94 ⫾ 3.13 (100)
22.3 (131/588) 34.4 (202/588) 78.4 (461/588) 2.74 ⫾ 0.48 (588) 14.05 ⫾ 5.57 (580)
22.6 (67/297) 26.9 (80/297) 74.4 (221/297) 2.63 ⫾ 0.45 (297) 16.49 ⫾ 7.86 (293)
23.2 (75/323) 35.6 (115/323) 67.2 (217/323) 2.75 ⫾ 0.46 (323) 14.96 ⫾ 6.20 (322)
22.6 (296/1,308) 33.0 (431/1,308) 72.5 (948/1,308) 2.73 ⫾ 0.47 (1,308) 14.59 ⫾ 6.33 (1,295)
65.0 (65/100) 29.0 (29/100) 6.0 (6/100) 65.23 ⫾ 12.34 (40)
64.8 (387/597) 23.5 (140/597) 11.7 (70/597) 61.53 ⫾ 12.00 (455)
54.1 (160/296) 26.4 (78/296) 19.6 (58/296) 62.68 ⫾ 10.99 (237)
62.2 (201/323) 29.1 (94/323) 8.7 (28/323) 55.66 ⫾ 9.11 (307)
⬍0.001 ⬍0.001 ⬍0.001 ⬍0.001 ⬍0.001 0.001 ⬍0.001 ⬍0.001 0.002 0.610
Combined (N ⫽ 1,317) 61.93 ⫾ 10.41 (1,316) 73.9 (973/1,316) 22.5 (296/1,313) 68.5 (897/1,310) 41.0 (532/1,297) 81.0 (1054/1,302) 33.1 (433/1,310) 50.5 (547/1,083) 24.2 (318/1,314) 4.7 (62/1,316)
0.249
⬍0.001 ⬍0.001 ⬍0.001 0.002
⬍0.001
61.8 (813/1,316) 25.9 (341/1,316) 12.3 (162/1,316) 60.20 ⫾ 11.40 (1,039)
ENDEAVOR II CA ⫽ ENDEAVOR II Continued Access Registry. * Medtronic Vascular, Santa Rosa, CA. † p values are based on analysis of variance for continuous outcomes, Fisher’s exact test for dichotomous outcomes, the Cochran-Mantel-Haenszel statistic (modified ridit scores) for ordinal outcomes with ⬎2 categories, and the Cochran-Mantel-Haenszel statistic (general association) for nominal outcomes with ⬎2 categories. ‡ Patient-level analysis. § Lesion-level analysis.
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Table 3 Procedural characteristics and results for the Endeavor zotarolimus-eluting stent* Variable
ENDEAVOR I (n ⫽ 100)
ENDEAVOR II (n ⫽ 598)
ENDEAVOR II CA (n ⫽ 296)
ENDEAVOR III (n ⫽ 323)
No. of Endeavor stents‡
1.12 ⫾ 0.43 (100) 20.06 ⫾ 7.65 (100) 3.22 ⫾ 0.25 (100) 13.12 ⫾ 2.51 (100)
1.13 ⫾ 0.38 (591) 23.40 ⫾ 6.71 (591) 3.08 ⫾ 0.37 (591) 13.67 ⫾ 2.84 (591)
1.21 ⫾ 0.45 (297) 24.94 ⫾ 9.02 (295) 3.03 ⫾ 0.37 (295) 13.63 ⫾ 2.83 (294)
1.14 ⫾ 0.40 (323) 23.60 ⫾ 7.32 (317) 3.07 ⫾ 0.39 (317) 13.57 ⫾ 2.52 (318)
Total stent length‡ (mm) Minimum stent diameter‡ (mm) Maximum stent deployment pressure‡ (atm) ⬎1 stent implanted‡ (%) Minimal luminal diameter‡ (mm) Before procedure In lesion After procedure In stent In segment Diameter stenosis‡ (%) Before procedure In lesion After procedure In stent In segment Device success‡ (%) Procedural success§ (%)
8.0 (8/100)
11.3 (67/591)
20.0 (59/295)
11.8 (38/323)
p Value†
Combined (N ⫽ 1,317)
0.047
1.15 ⫾ 0.41 (1,311) 23.54 ⫾ 7.59 (1,303) 3.08 ⫾ 0.37 (1,303) 13.59 ⫾ 2.74 (1,303)
⬍0.001
0.321
0.001
13.1 (172/1,309)
0.88 ⫾ 0.33 (100)
0.83 ⫾ 0.34 (587)
0.78 ⫾ 0.33 (297)
0.92 ⫾ 0.41 (323)
⬍0.001
0.85 ⫾ 0.36 (1,307)
2.84 ⫾ 0.35 (100) 2.52 ⫾ 0.42 (100)
2.59 ⫾ 0.43 (586) 2.21 ⫾ 0.49 (587)
2.56 ⫾ 0.43 (296) 2.24 ⫾ 0.46 (296)
2.67 ⫾ 0.42 (323) 2.27 ⫾ 0.45 (323)
⬍0.001
2.62 ⫾ 0.43 (1,305) 2.25 ⫾ 0.48 (1,306)
70.32 ⫾ 9.80 (100)
69.69 ⫾ 10.84 (587)
70.03 ⫾ 11.83 (297)
66.81 ⫾ 12.40 (323)
5.37 ⫾ 7.51 (100) 16.54 ⫾ 8.40 (100) 100.0 (100/100) 100.0 (100/100)
6.06 ⫾ 10.44 (586) 20.42 ⫾ 10.26 (587) 98.8 (583/590) 96.4 (569/590)
5.27 ⫾ 9.45 (296) 17.76 ⫾ 9.57 (296) 98.3 (292/297) 93.6 (277/296)
4.33 ⫾ 9.77 (323) 19.38 ⫾ 9.25 (323) 98.8 (319/323) 98.1 (317/323)
⬍0.001
⬍0.001
0.091 ⬍0.001 0.717 0.003
69.11 ⫾ 11.46 (1,307) 5.40 ⫾ 9.87 (1,305) 19.26 ⫾ 9.81 (1,306) 98.8 (1,294/1,310) 96.5 (1,263/1,309)
ENDEAVOR II CA ⫽ ENDEAVOR II Continued Access Registry. * Medtronic Vascular, Santa Rosa, CA. † p values are based on analysis of variance for continuous outcomes and Fisher’s exact test for dichotomous outcomes. ‡ Lesion-level analysis. § Patient-level analysis.
ated with significant reductions in neointimal area and percentage area stenosis (⬎50% at 28 days).6 It has been shown in preclinical studies that approximately 95% of zotarolimus is eluted from the stent within 15 days of implantation, although drug concentrations within surrounding vascular tissue may be detected as late as 30 days after stent deployment (data on file, Medtronic Vascular). Depending on the trial, the ZES was available in diameters ranging from a minimum of 2.25 mm to a maximum of 3.5 mm and in lengths from 9 –30 mm. Interventional procedure and adjunctive drug therapies: In each study, revascularization was to be performed on a single de novo lesion with no more than 1 study stent allowed, except in instances of insufficient lesion coverage or as a “bailout” procedure for dissection or thrombus. Except for a direct-stenting subgroup in ENDEAVOR II CA, all lesions were predilated with
balloon angioplasty, and the protocols specified that stent length should be 3–5 mm longer than the lesion for adequate coverage. Stents were expanded to achieve ⬍10% residual stenosis by visual estimate in the treated segment, using a combination of the stent deployment balloon and, at the discretion of operators, subsequent postdilation balloons. Before revascularization, all patients were treated with aspirin (75–325 mg/day) and clopidogrel (75 mg/day) for ⱖ 48 hours. After the procedure, all patients were to be treated with dual-antiplatelet therapy for ⱖ3 months and with aspirin therapy indefinitely. In those patients not receiving ⱖ48 hours of dual-antiplatelet therapy before the procedure, a loading dose of clopidogrel (300 – 600 mg) was administered before or during the procedure. Unfractionated heparin was administered to achieve an activated clotting time ⱖ250 seconds, or 200 –250 sec-
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Table 4 Combined angiographic outcomes at 8 months and 12 months* for the Endeavor zotarolimus-eluting stent† Variable Late luminal loss (mm) In stent In segment Minimal luminal diameter (mm) In stent In segment Diameter stenosis (%) In stent In segment Binary restenosis (%) In stent In segment Proximal margin Distal margin
p Value‡
ENDEAVOR I (n ⫽ 92)
ENDEAVOR II (n ⫽ 264)
ENDEAVOR II CA (n ⫽ 117)
ENDEAVOR III (n ⫽ 277)
0.58 ⫾ 0.44 (92) 0.43 ⫾ 0.44 (92)
0.62 ⫾ 0.46 (262) 0.36 ⫾ 0.46 (262)
0.58 ⫾ 0.58 (117) 0.39 ⫾ 0.56 (117)
0.62 ⫾ 0.49 (277) 0.36 ⫾ 0.46 (277)
0.804
2.26 ⫾ 0.49 (92) 2.08 ⫾ 0.47 (92)
1.99 ⫾ 0.56 (264) 1.86 ⫾ 0.55 (264)
1.92 ⫾ 0.65 (117) 1.81 ⫾ 0.61 (117)
2.06 ⫾ 0.57 (277) 1.91 ⫾ 0.53 (277)
⬍0.001
21.75 ⫾ 15.35 (92) 28.00 ⫾ 13.41 (92)
27.91 ⫾ 17.30 (264) 32.67 ⫾ 16.27 (264)
27.67 ⫾ 21.95 (117) 31.93 ⫾ 20.54 (117)
24.90 ⫾ 17.45 (277) 30.42 ⫾ 15.57 (277)
0.017
4.3 (4/92) 5.4 (5/92) 0 (0/90) 1.1 (1/91)
9.5 (25/264) 13.3 (35/264) 3.5 (9/257) 1.9 (5/262)
15.4 (18/117) 17.1 (20/117) 3.7 (4/109) 3.4 (4/116)
9.7 (27/277) 12.3 (34/277) 1.5 (4/265) 1.4 (4/276)
0.067 0.071 0.135 0.593
0.573
0.002
0.093
Combined (n ⫽ 750) 0.61 ⫾ 0.49 (748) 0.37 ⫾ 0.48 (748) 2.04 ⫾ 0.58 (750) 1.90 ⫾ 0.55 (750) 26.01 ⫾ 18.03 (750) 31.15 ⫾ 16.48 (750) 9.9 (74/750) 12.5 (94/750) 2.4 (17/721) 1.9 (14/745)
ENDEAVOR II CA ⫽ ENDEAVOR II Continued Access Registry. * 12-month angiographic results for ENDEAVOR I and 8-month angiographic results for ENDEAVOR II, ENDEAVOR II CA, and ENDEAVOR III. † Medtronic Vascular, Santa Rosa, CA. ‡ p values are based on analysis of variance for continuous outcomes and Fisher’s exact test for dichotomous outcomes.
onds if an intravenous glycoprotein IIb/IIIa inhibitor was used. Treatment with additional device therapies (eg, atherectomy) was not permitted. Data management and core laboratories: Clinical events were assessed during hospitalization and at clinic visits at 30 days and at 9 months after the index procedure (12 months for ENDEAVOR I). Clinical and angiographic results from all trials were submitted to a central data coordinating facility (Cardiovascular Data Analysis Center, Harvard Clinical Research Institute, Harvard Medical School, Boston, MA). Coronary angiograms obtained at baseline and at follow-up were reviewed by an independent angiographic core laboratory (Brigham and Women’s Angiographic Core Laboratory, Boston, MA). Standard image acquisition was performed using ⱖ2 angiographic projections of the stenosis before and after stent placement and administration of intracoronary nitrate. Qualitative analysis was performed using a validated automated edge detection algorithm (CMS; MEDIS Medical Imaging Systems, Leiden, The Netherlands),7 and lesions were characterized according to the modified American College of Cardiology (ACC) and American Heart Association (AHA) classification.8 A 5–10-mm segment of reference vessel proximal and distal to the stenosis was used to calculate the average reference vessel diameter at baseline, after stent implantation, and at follow-up. Quantitative analysis was performed to evaluate the in-stent region (bordered by the stent margins) as well as the in-segment region (in-stent region plus 5-mm margins proximal and distal to the stent).
Study end points and definitions: The primary objective of this pooled analysis of patients treated with the ZES was to evaluate clinically driven TLR at 30 days and at 9, 12, and 24 months after the index procedure. Additional clinical safety and efficacy end points included major adverse cardiac events (MACE; composite of allcause death, MI, emergent coronary artery bypass grafting, and clinically driven TLR) and the individual components of the composite end point at 30 days and at 9 months, stent thrombosis (acute coronary syndrome with angiographic or autopsy confirmation of thrombosis), clinically driven target vessel revascularization (TVR) at 9 months, and target vessel failure (TVF) (cardiac death, MI, and clinically driven TVR) at 9 months. Device success was defined as a ⬍50% diameter stenosis of the target lesion (determined by the core angiographic laboratory) with the assigned study stent, and procedure success was defined as lesion success and no in-hospital MACE. All clinical end points were adjudicated by an independent clinical events committee, and except for ENDEAVOR I and ENDEAVOR II CA, reviewers were blinded to patient treatment assignments. Angiographic efficacy end points included the 8-month (12 months for ENDEAVOR I) in-stent and in-segment assessments of late luminal loss and binary restenosis. Late luminal loss was defined as the difference between the minimal luminal diameter at the completion of the stenting procedure and the minimal luminal diameter (MLD) measured at angiographic follow-up.
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Angiographic binary restenosis was defined as a stenosis ⱖ50% of the luminal diameter of the target lesion (determined by the core angiographic laboratory). Percentage diameter stenosis was defined as (1 ⫺ [MLD/reference vessel diameter]) ⫻ 100, and acute gain was defined as the MLD immediately after the procedure minus the MLD before the procedure. Restenosis patterns were characterized according to established criteria.9 Statistical methods: From the individual trials, patients were analyzed for all efficacy and safety end points on the basis of the intention-to-treat principle. Baseline characteristics of study patients were summarized in terms of frequencies and percentages for categorical variables and by means with standard deviations for continuous variables. Clinical and angiographic outcomes were compared among ZES subgroups (diabetic status or tertiles evenly divided according to lesion length and vessel diameter). Categorical variables were compared using Fisher’s exact test or the Cochran-Mantel-Haenszel test, and continuous variables were compared using the 2-sample Student’s t test or analysis of variance. Cumulative event-free survival was summarized as Kaplan-Meier estimates. A p value of 0.05 was established as the level of statistical significance for all tests. All analyses were performed using SAS version 8.2 or higher (SAS Institute Inc., Cary, NC).
Results Patient characteristics: A total of 1,317 patients who underwent elective percutaneous coronary revascularization and were treated with the ZES in 4 clinical trials were evaluated. Baseline angiographic evaluation was available for all patients; follow-up clinical evaluation was available for 1,315 patients at 30 months, for 1,306 patients at 9 months, for 1,300 patients at 12 months, and for 1,282 patients at 24 months; angiographic follow-up was completed for 658 patients from ENDEAVOR II, ENDEAVOR II CA, and ENDEAVOR III at 8 months and for 92 patients from ENDEAVOR I at 12 months. Altogether, the mean age was 61.9 years, 24.2% of patients had undergone previous percutaneous coronary intervention, 41.0% had histories of smoking, and 22.5% had diabetes mellitus (Table 2). Most patients (61.8%) had singlevessel coronary disease, and 33.1% of patients had histories of MI. Approximately half of the patients were classifiable in Canadian Cardiovascular Society (CCS) angina class III or IV. Overall, the mean ⫾ SD lesion length was 14.59 ⫾ 6.33 mm, and the average reference vessel diameter was 2.73 ⫾ 0.47 mm. Most lesions (44.4%) were located in the left anterior descending coronary artery, and 72.5% of lesions were characterized as type B2 or C according to the modified ACC and AHA classification.8 Procedural and angiographic outcomes: The average number of Endeavor stents per target lesion was 1.15, with multiple stents placed in 172 lesions (13.1%; Table 3). The maximum inflation pressure during stent deployment was
13.59 ⫾ 2.74 atm. Intravenous glycoprotein IIb/IIIa inhibitors were administered in 19.1% of patients. Overall device and procedure success rates were 98.8% and 96.5%, respectively (Table 3). Angiographic follow-up was performed at 8 months for 658 patients and at 12 months for 92 patients (92% of the ENDEAVOR I cohort). Overall, in-stent and in-segment binary restenosis occurred in 9.9% and 12.5% of patients, respectively (Table 4). For patients with in-stent angiographic binary restenosis at follow-up, the mean in-stent percentage diameter stenosis was 66.84 ⫾ 13.45%, and 37.8% had ⱖ70% in-stent percentage diameter stenosis. For patients with in-segment angiographic binary restenosis at follow-up, the mean in-segment percentage diameter stenosis was 65.44 ⫾ 12.62%, and 31.9% had ⱖ70% in-segment percentage diameter stenosis. In-stent and in-segment late luminal loss were 0.61 ⫾ 0.49 and 0.37 ⫾ 0.48 mm, respectively. There were no differences in restenosis within the proximal or distal margins of the stents among the 4 trials. Thirty-day, 9-month, 12-month, and 24-month clinical outcomes: At 30 days, the rate of MACE was 2.7%, principally driven by the occurrence of non–Q wave MIs (2.3%; Table 5). Stent thrombosis occurred in 4 patients (0.3%). Adverse events, in particular MI, did not statistically vary among patients treated with single versus multiple stents (2.4% vs 3.5%; p ⫽ 0.43). Clinical follow-up at 9 months was completed for 1,306 patients (99%; Table 5). There were no additional occurrences of stent thrombosis beyond 14 days of initial revascularization. Death and MI had occurred in 0.8% and 2.6% of patients treated with the ZES. Rates of TLR and TVR were 4.9% and 7.4%, respectively. Specifically, repeat TLR occurred in 6.5% who underwent compulsory angiographic follow-up and in 2.7% of patients who did not. For patients who underwent 8-month angiographic follow-up (12 months for the 92 patients from ENDEAVOR I), Figure 2 relates the probability of TLR with angiographic late luminal loss, demonstrating that the likelihood of repeat revascularization begins with an in-stent late luminal loss threshold of approximately 0.6 mm and escalates markedly above values ⬎1.0 mm. For patients who underwent repeat TLR, the mean in-stent and in-segment percentage diameter stenoses at angiographic follow-up were 59.59 ⫾ 26.25% and 66.97 ⫾ 16.13%, respectively. Figure 3 shows actuarial event-free survival at 9 months for TLR, MACE, and TVF. At 12 months, the rate of MACEs was 8.8%, the rate of death was 0.9%, the rate of MI was 2.7%, and the rate of TLR was 5.9%. Clinical follow-up at 24 months was completed for 1,282 patients (97.3%; Table 5). Again, no additional cases of stent thrombosis occurred beyond 14 days of initial revascularization. At 24 months, the overall rate of MACE was 9.9%, the rate of death was 1.7%, the rate of MI was 2.9%, and the rate of TLR was 6.5%. Subgroup analyses: Among clinically relevant subgroups treated with the ZES, 8-month angiographic in-stent
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Table 5 Combined clinical events at 30 days, 9 months, 12 months, and 24 months for the Endeavor zotarolimus-eluting stent*† Variable 30 days MACE (%) Death (%) MI (%) Q wave (%) Non–Q wave (%) Emergent CABG (%) TLR (%) TVR (%) Target vessel failure (%) Stent thrombosis (%) 9 mo MACE (%) Death (%) MI (%) Q wave (%) Non–Q wave (%) Emergent CABG (%) TLR (%) TVR (%) Target vessel failure (%) Stent thrombosis (%) 12 mo MACE (%) Death (%) MI (%) Q wave (%) Non–Q wave (%) Emergent CABG (%) TLR (%) TVR (%) Target vessel failure (%) Stent thrombosis (%) 24 mo MACE (%) Death (%) MI (%) Q wave (%) Non–Q wave (%) Emergent CABG (%) TLR (%) TVR (%) Target vessel failure (%) Stent thrombosis (%)
ENDEAVOR II (n ⫽ 598)
ENDEAVOR II CA (n ⫽ 296)
ENDEAVOR III (n ⫽ 323)
p Value‡
Combined (N ⫽ 1,317)
1 (1/100) 0 (0/100) 1 (1/100) 0 (0/100) 1 (1/100) 0 (0/100) 1 (1/100) 1 (1/100) 1 (1/100) 1 (1/100)
2.9 (17/596) 0.2 (1/596) 2.7 (16/596) 0.3 (2/596) 2.3 (14/596) 0 (0/596) 0.8 (5/596) 1.2 (7/596) 3.2 (19/596) 0.5 (3/596)
5.4 (16/296) 0 (0/296) 4.7 (14/296) 0.3 (1/296) 4.4 (13/296) 0.3 (1/296) 0.3 (1/296) 1.4 (4/296) 5.7 (17/296) 0 (0/296)
0.6 (2/323) 0 (0/323) 0.6 (2/323) 0 (0/323) 0.6 (2/323) 0 (0/323) 0 (0/323) 0 (0/323) 0.6 (2/323) 0 (0/323)
0.002 1.000 0.007 0.698 0.014 0.301 0.269 0.148 0.001 0.233
2.7 (36/1,315) 0.1 (1/1,315) 2.5 (33/1,315) 0.2 (3/1,315) 2.3 (30/1,315) 0.1 (1/1,315) 0.5 (7/1,315) 0.9 (12/1,315) 3 (39/1,315) 0.3 (4/1,315)
2 (2/100) 0 (0/100) 1 (1/100) 0 (0/100) 1 (1/100) 0 (0/100) 2 (2/100) 2 (2/100) 2 (2/100) 1 (1/100)
7.3 (43/592) 1.2 (7/592) 2.7 (16/592) 0.3 (2/592) 2.4 (14/592) 0 (0/592) 4.6 (27/592) 5.6 (33/592) 7.9 (47/592) 0.5 (3/592)
10.6 (31/293) 0.7 (2/293) 5.1 (15/293) 0.3 (1/293) 4.8 (14/293) 0.3 (1/293) 5.1 (15/293) 8.9 (26/293) 13 (38/293) 0 (0/293)
7.5 (24/321) 0.6 (2/321) 0.6 (2/321) 0 (0/321) 0.6 (2/321) 0 (0/321) 6.2 (20/321) 11.2 (36/321) 11.8 (38/321) 0 (0/321)
0.033 0.776 0.004 0.698 0.007 0.301 0.381 0.002 0.001 0.234
7.7 (100/1,306) 0.8 (11/1,306) 2.6 (34/1,306) 0.2 (3/1,306) 2.4 (31/1,306) 0.1 (1/1,306) 4.9 (64/1,306) 7.4 (97/1,306) 9.6 (125/1,306) 0.3 (4/1,306)
2 (2/98) 0 (0/98) 1 (1/98) 0 (0/98) 1 (1/98) 0 (0/98) 2 (2/98) 2 (2/98) 2 (2/98) 1 (1/98)
8.8 (52/590) 1.4 (8/590) 2.7 (16/590) 0.3 (2/590) 2.4 (14/590) 0 (0/590) 5.9 (35/590) 7.5 (44/590) 10 (59/590) 0.5 (3/590)
12.3 (36/292) 0.7 (2/292) 5.5 (16/292) 0.3 (1/292) 5.1 (15/292) 0.3 (1/292) 6.5 (19/292) 11.6 (34/292) 15.8 (46/292) 0 (0/292)
7.8 (25/320) 0.6 (2/320) 0.6 (2/320) 0 (0/320) 0.6 (2/320) 0 (0/320) 6.6 (21/320) 12.2 (39/320) 12.8 (41/320) 0 (0/320)
0.010 0.664 0.002 0.697 0.004 0.300 0.368 0.002 ⬍.001 0.232
8.8 (115/1,300) 0.9 (12/1,300) 2.7 (35/1,300) 0.2 (3/1,300) 2.5 (32/1,300) 0.1 (1/1,300) 5.9 (77/1,300) 9.2 (119/1,300) 11.4 (148/1,300) 0.3 (4/1,300)
3.1 (3/98) 1 (1/98) 1 (1/98) 0 (0/98) 1 (1/98) 0 (0/98) 2 (2/98) 4.1 (4/98) 4.1 (4/98) 1 (1/98)
9.9 (58/583) 2.1 (12/583) 2.9 (17/583) 0.3 (2/583) 2.6 (15/583) 0 (0/583) 6.5 (38/583) 8.4 (49/583) 11.1 (65/583) 0.5 (3/583)
12.8 (37/288) 1.4 (4/288) 5.9 (17/288) 0.3 (1/288) 5.6 (16/288) 0.3 (1/288) 7.3 (21/288) 12.5 (36/288) 16.3 (47/288) 0 (0/288)
9.3 (29/313) 1.6 (5/313) 0.6 (2/313) 0 (0/313) 0.6 (2/313) 0 (0/313) 7 (22/313) 13.7 (43/313) 14.4 (45/313) 0 (0/313)
0.032 0.916 0.001 0.698 0.002 0.301 0.267 0.007 0.004 0.232
9.9 (127/1,282) 1.7 (22/1,282) 2.9 (37/1,282) 0.2 (3/1,282) 2.7 (34/1,282) 0.1 (1/1,282) 6.5 (83/1,282) 10.3 (132/1,282) 12.6 (161/1,282) 0.3 (4/1,282)
ENDEAVOR I (n ⫽ 100)
CABG ⫽ coronary artery bypass grafting; ENDEAVOR II CA ⫽ ENDEAVOR II Continued Access Registry; MACE ⫽ major adverse cardiac events; MI ⫽ myocardial infarction; TLR ⫽ target lesion revascularization; TVR ⫽ target vessel revascularization. * Medtronic Vascular, Santa Rosa, CA. † Data are expressed as percentage (number). ‡ p values are based on Fisher’s exact test.
late luminal loss (12 months for the 92 patients from ENDEAVOR I) did not significantly differ between patients with and without diabetes, but in-stent late luminal loss was significantly greater (0.65 ⫾ 0.49 mm; p ⫽ 0.038) in larger caliber vessels (⬎2.9 mm diameter) and also significantly greater (0.70 ⫾ 0.52 mm; p ⫽ 0.004) in longer lesions (⬎16.3 mm) (Table 6). However, despite higher late luminal loss in vessels with larger reference diameters, in-stent angiographic restenosis was significantly more common in
vessels with ⬍2.5 mm diameter (18.1%; p ⬍0.001). In-stent restenosis was numerically higher in patients with diabetes, although the difference was not statistically significant. Insegment late luminal loss also tended to be greater for patients with diabetes compared with those without diabetes (0.43 ⫾ 0.49 vs 0.36 ⫾ 0.47 mm; p ⫽ 0.082). Despite angiographic differences, however, neither target vessel failure nor MACE statistically varied relative to diabetes, vessel diameter, or lesion length (Table 7). The rate of TLR
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Figure 2. Logistic regression relation between in-stent late luminal loss and the probability of target lesion revascularization (TLR) for patients treated with zotarolimus-eluting stents (n ⫽ 750).
Figure 3. Kaplan-Meier event-free survival to 9 months for patients treated with zotarolimus-eluting stents (n ⫽ 1,306): 9-month freedom from target lesion revascularization (TLR), 93.3%; 9-month freedom from major adverse cardiac events (MACE), 90.4%; 9-month freedom from target vessel failure (TVF), 87.9%.
at 12 months was not significantly different relative to diabetes and lesion length ⬎16.3 mm (7.2% and 7.7%, respectively), although it was significantly more common when the reference vessel diameter was ⬍2.5 mm (8.5%; p ⫽ 0.013).
Discussion Pooled analysis of clinical trials in patients with coronary disease of simple and moderate complexity support the favorable efficacy and safety associated with the antiproliferative agent zotarolimus and a phosphorylcholine polymer. Collectively, among 1,317 patients treated in the context of the first 4 clinical trials of the Endeavor ZES, the 9- and 24-month rates of clinically driven (ie, symptomatic or with
⬎70% diameter stenosis) TLR were 4.9% and 6.5%, respectively, and there were no occurrences of stent thrombosis beyond 14 days after initial revascularization. Despite more variable angiographic results in clinically relevant subgroups, clinical outcomes are comparatively uniform, with no major differences in the occurrence of target vessel failure or overall MACE. These findings robustly support the efficacy and safety of the device and provide grounds for the further evaluation of the ZES in lesions of greater complexity and patients at higher clinical risk. Across the 4 ENDEAVOR trials considered in this analysis, clinical and angiographic outcomes have also been remarkably consistent, despite the inclusion of a broad global sample of patients treated at varied physician practices. For example, in-stent angiographic binary restenosis was 9.5% and 9.7% in the multinational (not including the
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Table 6 Angiographic outcomes at 8 and 12 months* among Endeavor zotarolimus-eluting stent† subgroups‡ Variable
Lesion length (mm) ⬍11.2 11.2–16.3 ⬎16.3 Vessel diameter (mm) ⬍2.5 2.5–2.9 ⬎2.9 Diabetes mellitus No Yes
In-Stent Late Luminal Loss (mm)
p Value§
In-Segment Late Luminal Loss (mm)
p Value§
In-Stent Binary Angiographic Restenosis (%)
p Value§
In-Segment Binary Angiographic Restenosis (%)
p Value§
0.56 ⫾ 0.48 (262) 0.57 ⫾ 0.45 (249) 0.70 ⫾ 0.52 (229)
0.004
0.33 ⫾ 0.47 (262) 0.33 ⫾ 0.44 (249) 0.47 ⫾ 0.50 (229)
0.001
9.5% (25/262) 5.6% (14/249) 14.4% (33/229)
0.005
13.4% (35/262) 8.0% (20/249) 16.2% (37/229)
0.019
0.62 ⫾ 0.53 (237) 0.54 ⫾ 0.43 (241) 0.65 ⫾ 0.49 (270)
0.038
0.36 ⫾ 0.49 (237) 0.31 ⫾ 0.44 (241) 0.45 ⫾ 0.49 (270)
0.005
18.1% (43/237) 5.0% (12/241) 7.0% (19/270)
⬍0.001
21.1% (50/237) 8.3% (20/241) 8.9% (24/270)
⬍0.001
0.60 ⫾ 0.49 (577) 0.63 ⫾ 0.49 (171)
0.533
0.36 ⫾ 0.47 (577) 0.43 ⫾ 0.49 (171)
0.082
9.2% (53/579) 12.3% (21/171)
0.243
11.7% (68/579) 15.2% (26/171)
0.238
* 12-month angiographic results for ENDEAVOR I and 8-month angiographic results for ENDEAVOR II, the ENDEAVOR II Continued Access Registry, and ENDEAVOR III. † Medtronic Vascular, Santa Rosa, CA. ‡ Data are expressed as mean ⫾ SD or percentage (number). § p values for the test of equality of means (percentages) across subgroups.
Table 7 Clinical events at 12 months among Endeavor zotarolimus-eluting stent* subgroups† Variable
Lesion length (mm) ⬍11.2 11.2–16.3 ⬎16.3 Vessel diameter (mm) ⬍2.5 2.5–2.9 ⬎2.9 Diabetes No Yes
Target Lesion Revascularization (%)
p Value‡
Major Adverse Cardiac Events (%)
p Value‡
Target Vessel Failure (%)
p Value‡
5.6% (24/426) 4.5% (19/423) 7.7% (33/430)
0.141
8.0% (34/426) 7.3% (31/423) 11.2% (48/430)
0.116
10.1% (43/426) 9.9% (42/423) 14.0% (60/430)
0.119
8.5% (37/436) 3.7% (15/407) 5.6% (25/449)
0.013
10.6% (46/436) 7.6% (31/407) 8.5% (38/449)
0.314
13.5% (59/436) 10.3% (42/407) 10.2% (46/449)
0.231
5.6% (56/1,004) 7.2% (21/293)
0.326
0.484
10.7% (107/1,004) 14.0% (41/293)
0.118
8.6% (86/1,004) 9.9% (29/293)
* Medtronic Vascular, Santa Rosa, CA. Data are expressed as percentage (number). ‡ p values for the test of equality of means (percentages) across subgroups. †
United States) ENDEAVOR II trial and the United States– based ENDEAVOR III trial, respectively, and in-stent late luminal loss did not differ.2,4 Although the enrollment criteria of these trials were more restrictive than real-world circumstances, the results remained consistently positive despite an increasing frequency of patients with diabetes and against the background of a relatively high proportion of moderately complex lesion morphologies. Analyzing the clinical outcomes in patients who underwent angiographic follow-up from the 4 ENDEAVOR trials considered in this analysis also enables a better understanding of the complex relation between angiographic variables (eg, late luminal loss), the probability of a clinical event (eg, TLR), and clinical characteristics (eg, diabetes, reference vessel diameter, and lesion length). Specifically, whereas in-stent late luminal loss was significantly greater in vessels
with the longest lesions (Table 6), rates of angiographic binary restenosis and TLR followed a different pattern (Table 7). Despite similar late luminal loss in smaller caliber arteries compared with vessels of intermediate diameter, angiographic restenosis and TLR were significantly more common in association with smaller vessels, suggesting that differences in clinical outcomes may become more apparent as lesion complexity increases. In particular, the finding that TLR is greatest in small caliber vessels (Table 7), especially in patients with diabetes with longer lesions (8.9% for patients with diabetes with lesion lengths of 11.2–16.3 mm, 7.0% for patients with diabetes with lesion lengths ⬎16.3 mm), suggests the existence of an angiographic late luminal loss threshold, above which the likelihood of clinical restenosis increases. Whether this interaction is specific to the Endeavor stent or is instead similarly observed with other
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DESs also merits further investigation in a greater number of patients with more complex lesions (eg, bifurcation, chronic total occlusion, unprotected left main coronary artery) and clinical characteristics (eg, acute MI, chronic renal failure). It does appear likely that similar results may be found to occur with other DESs. In the TAXUS V trial, for example, the 9-month TLR rate was 10.4% in patients treated with a 2.25-mm diameter PES and with an average lesion length of 16.4 mm.10 Perhaps the most noteworthy consistency among these trials relates to safety of the ZES, particularly with regard to the absence of late stent thrombosis. Furthermore, among the 750 ZES patients (57%) with angiographic follow-up (at 8 months for 658 patients from ENDEAVOR II, ENDEAVOR II CA, and ENDEAVOR III and at 12 months for 92 patients from ENDEAVOR I) and the 617 ZES patients (47%) with intravascular ultrasound follow-up, there have been no occurrences of aneurysm formation and only a single case of newly observed late-acquired incomplete stent apposition (P. J. Fitzgerald, personal communication). One potential explanation for the absence of late stent thrombosis may relate to the thromboresistant properties of the biomimetic phospholipid polymer (phosphorylcholine) used to carry and deliver zotarolimus.5 In addition, the higher late luminal loss with the ZES may permit more rapid and complete healing of the treated segment surface without promoting excessive deep wall remodeling and aneurysm formation.4 It is uncertain whether or to what extent the outcomes observed with the ZES in the context of the enrollment criteria of these first 4 trials of the Endeavor ZES will prove generalizable to a broader unselected patient population. Furthermore, although the absence of late stent thrombosis associated with the ZES over the term of follow-up in these trials is promising, follow-up in a larger patient cohort and for a longer duration is needed, considering the infrequent occurrence of this outcome and the fact that events may occur well beyond 1 year of DES placement.11,12 Additional ongoing study with more open patient inclusion criteria (including long lesions, small vessels, bifurcations, etc) will be important for discerning whether comparable clinical outcomes can be extended to lesion subsets of higher complexity.
Author Disclosures The authors who contributed to this article have disclosed the following industry relationships. Jean Fajadet, MD, has served as a consultant for Cordis Corporation. Peter J. Fitzgerald, MD, PhD, has served as a consultant for Cordis Corporation, Boston Scientific, Abbott Vascular, Medtronic, Inc., CardioMind, Inc., REVA Medical Inc., Devax, Inc., Biosensors International Pte Ltd., XTENT, Inc., and Setagon, Inc. Anthony Gershlick, BSc, MB, BS, is a member of the speakers bureau for Medtronic, Inc., Cordis Corporation,
Boston Scientific, Abbott Vascular, Eli Lilly and Company, and sanofi-aventis; has served as a consultant for Medtronics, Inc., Cordis Corporation, Boston Scientific, Abbott Vascular, Eli Lilly and Company, and sanofiaventis; has served as an advisory board member for Medtronic, Inc., Cordis Corporation, Boston Scientific, Abbott Vascular, Eli Lilly and company, and sanofiaventis; has received research/grant support from Medtronic, Inc., Cordis Corporation, Boston Scientific, Abbott Vascular, Eli Lilly and Company, and sanofiaventis. David E. Kandzari, MD, is an employee of Cordis Corporation; served as a consultant to Medtronic, Inc.; served as an advisory board member for Medtronic, Inc.; and has received research/grant support from Medtronic, Inc. Richard E. Kuntz, MD, MSc, is an employee and a stockholder of Medtronic, Inc. Martin B. Leon, MD, has served as a consultant to Volcano Corporation; and has served as an advisory board member for Cordis Corporation, Medtronic, Inc., Boston Scientific, and Abbott Vascular. Ian T. Meredith, MBBS, PhD, has served as an advisory board member for Medtronic, Inc. and Boston Scientific. Jeffrey J. Popma, MD, is a member of the Speakers’ Bureau for sanofi-aventis, Pfizer Inc., and Bristol-Myers Squibb; has served as a consultant to Biosensors International and Cordis Corporation; and has received grant/research support from ev3, Abbott Vascular, Boston Scientific, Cordis Corporation, and Medtronic, Inc. William Wijns, MD, PhD, serves as an advisory board member for Bristol-Myers Squibb, GlaxoSmithKline, Medtronic, Inc., Cordis Corporation; Boston Scientific, TopSpin Medical, and Abbott Vascular. 1. Meredith I, Ormiston J, Whitbourn R, Kay I, Muller D, Bonan R, Popma J, Cutlip D, Fitzgerald P, Prpic R, Kuntz R. First-in-human study of the Endeavor ABT-578-eluting phosphorylcholine-encapsulated stent system in de novo native coronary artery lesions: Endeavor I Trial. EuroIntervention 2005;2:157–164. 2. Fajadet J, Wijns W, Laarman GJ, Kuck KH, Ormiston J, Munzel T, Popma JJ, Fitzgerald PJ, Bonan R, Kuntz RE. Randomized, doubleblind, 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;114:798 – 806. 3. Schultheiss HP, Grube E, Kuck KH, Suttorp MJ, Heuer H, Bonnier H, Popma JJ, Kuntz RE, Fadajet J, Wijns W. Safety of direct stenting with the Endeavor stent: results of the Endeavor II continued access registry. EuroIntervention 2007;3:76 – 81. 4. Kandzari DE, Leon MB, Popma JJ, Fitzgerald PJ, O’Shaughnessy C, Ball MW, Turco M, Applegate RJ, Gurbel PA, Midei MG, et al. Comparison of zotarolimus-eluting and sirolimus-eluting stents in patients with native coronary artery disease: a randomized controlled trial. J Am Coll Cardiol 2006;48:2440 –2447. 5. Hayward JA, Chapman D. Biomembrane surfaces as models for polymer design: the potential for haemocompatibility. Biomaterials 1984;5:135–142.
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of in-stent restenosis: classification and implications for long-term outcome. Circulation 1999;100:1872–1878. 10. Stone GW, Ellis SG, Cannon L, Mann JT, Greenberg JD, Spriggs D, O’Shaughnessy CD, DeMaio S, Hall P, Popma JJ, Koglin J, Russell ME. 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;294:1215–1223. 11. Iakovou I, Schmidt T, Bonizzoni E, Ge L, Sangiorgi GM, Stankovic G, Airoldi F, Chieffo A, Montorfano M, Carlino M, et al. Incidence, predictors, and outcome of thrombosis after successful implantation of drug-eluting stents. JAMA 2005;293:2126 –2130. 12. Ong AT, McFadden EP, Regar E, de Jaegere PP, van Domburg RT, Serruys PW. Late angiographic stent thrombosis (LAST) events with drug-eluting stents. J Am Coll Cardiol 2005;45:2088 –2092.
Despite considerable reductions in angiographic restenosis and the need for repeat revascularization procedures, continued attention a
University Hospitals of Leicester School of Medicine, Leicester, United Kingdom; bDuke Clinical Research Institute, Durham, North Carolina, USA; c Columbia University Medical Center and the Cardiovascular Research Foundation, New York, New York, USA; dCardiovascular Center Aalst, Aalst, Belgium; e Monash Medical Centre and Monash University, Melbourne, Australia; fClinique Pasteur, Toulouse, France; gHarvard Clinical Research Institute and Brigham and Women’s Hospital, Boston, Massachusetts, USA; hCenter for Cardiovascular Technology, Stanford University Medical Center, Stanford, California, USA; and i Medtronic, Inc., Minneapolis, Minnesota, USA. This study was supported by Medtronic Vascular, Santa Rosa, California. 0002-9149/07/$ – see front matter © 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2007.08.021
to the safety, efficacy, and deliverability of first-generation drugeluting stents (DESs) has led to the development of new antiproliferative agents with alternative stent platforms and different drug carrier systems. Zotarolimus is a novel pharmacologic therapy that shares similar structure and biologic activity with the antirestenotic agent sirolimus (Figure 1). The effectiveness of zotarolimus as an antiproliferative agent has been recently investigated as part
Statement of author disclosure: Please see the Author Disclosures section at the end of this article. *Address for reprints: Anthony Gershlick, MD, University of Leicester School of Medicine, Glenfield General Hospital, Leicester LE3 9QP, United Kingdom. E-mail address: [email protected]. www.AJConline.org
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mer– based coronary stent eluting zotarolimus in patients with de novo native coronary lesions.
Figure 1. Chemical structure of zotarolimus and sirolimus.
of a cobalt-based alloy stent platform integrated with a biomimetic phosphorylcholine polymer (Endeavor; Medtronic Vascular, Santa Rosa, CA). To date, 4 clinical trials evaluating the safety and efficacy of zotarolimus-eluting stents (ZESs) have been completed: ENDEAVOR I, a first-in-human study1; ENDEAVOR II, a randomized controlled study comparing the ZES with a bare metal stent (BMS)2; the ENDEAVOR II Continued Access Registry (ENDEAVOR II CA)3; and ENDEAVOR III, a randomized trial comparing the ZES with the sirolimus-eluting stent (SES).4 Despite similar enrollment criteria among these studies, the relative benefits of the ZES have been more varied. In ENDEAVOR II, compared with the BMS, treatment with the ZES was associated with marked improvements in angiographic restenosis and repeat target lesion revascularization (TLR).2 Alternatively, randomized comparison with the SES in ENDEAVOR III demonstrated overall similar clinical outcomes despite significantly higher angiographic restenosis and late luminal loss with the ZES.3 Beyond the context of any single trial, however, the consistency of the clinical benefit of the ZES in a more extensive patient population and more varied physician practice is undetermined. We therefore performed a combined analysis of these trials to examine the collective safety, clinical efficacy, and angiographic outcomes associated with the deployment of a phosphorylcholine poly-
Methods Overview of trials and study population: The ENDEAVOR clinical trials program comprises a series of prospective, multicenter, multinational trials enrolling patients with symptomatic ischemic heart disease due to de novo stenotic lesions (⬎50% angiographic diameter stenosis by visual estimate) in native coronary arteries. In ENDEAVOR I, ENDEAVOR II, ENDEAVOR II CA, and ENDEAVOR III, patients who underwent elective percutaneous coronary revascularization were treated with the ZES, BMS, or SES (Table 1). ENDEAVOR I was a nonrandomized first-inhuman evaluation of the ZES in 100 patients with de novo native coronary lesions ⱕ15 mm in length and with reference diameters of 3.0 –3.5 mm.1 In ENDEAVOR II, 1,197 patients with de novo native coronary lesions of 14 –27 mm in length and with reference vessel diameters of 2.25–3.5 mm were randomized in a double-blinded fashion to treatment with the ZES or BMS.2 Criteria for inclusion in the nonrandomized, open-label ENDEAVOR II CA (n ⫽ 296) were identical to the criteria for inclusion in ENDEAVOR II, except that a subgroup of patients (n ⫽ 126) were treated with direct stenting (ie, no predilation) at the discretion of the investigators.3 In ENDEAVOR III, 436 patients were randomized in a single-blinded 3:1 fashion to treatment with either the ZES or SES.4 Criteria for enrollment in ENDEAVOR III were also similar to the criteria for enrollment in ENDEAVOR II, although the minimum reference vessel diameter was 2.5 mm (compared with 2.25 mm in ENDEAVOR II). In all 4 trials, patients were excluded if they experienced recent (⬍72 hours) myocardial infarction (MI), had undergone previous stent placement within the target vessel or any other vessel within 30 days of the index procedure, or had any general contraindications to the revascularization procedure and routine pharmacologic therapies. Principal angiographic exclusion criteria were a left ventricular ejection fraction ⬍0.30, stenosis ⬎40% elsewhere in the target vessel (other than the target lesion), the involvement of a side branch ⱖ2.0 mm in diameter, unprotected left main coronary disease, total occlusions and Thrombolysis in Myocardial Infarction (TIMI) grade ⬍2 flow in the treatment vessel, and the presence of disease in other vessels with percentage diameter stenosis ⬎50%. All studies were approved by the institutional review boards or ethics committees at all enrolling sites, and consecutive eligible patients provided written informed consent before the interventional procedures. Device description: The Endeavor DES is a cobaltbased alloy stent with a phosphorylcholine polymer5 loaded with zotarolimus at dose concentration of 10 g/mm stent length. In a porcine coronary model, stents coated with a phosphorylcholine polymer and zotarolimus were associ-
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Table 1 The clinical trials program of the Endeavor zotarolimus-eluting stent (ZES)* Trial
n
ENDEAVOR I
ENDEAVOR II
100
1,197
ENDEAVOR II CA
296
ENDEAVOR III
436
Design
Lesion Inclusion Criteria
Angiographic Follow-Up in ZES Group (n)
Primary End Point(s)
Open-label, nonrandomized
3.0–3.5 mm RVD; length ⱕ15 mm
92 (at 12 mo)
Double-blind, randomized, 1:1 ZES:BMS Open-label, nonrandomized Single-blind, randomized, 3:1 ZES:SES
2.25–3.5 mm RVD; length 14–27 mm 2.25–3.5 mm RVD; length 14–27 mm 2.5–3.5 mm RVD; length 14–27 mm
264 (at 8 mo)
30-day MACE and 4-mo in-segment late luminal loss 9-mo target vessel failure 30-day MACE
117 (at 8 mo) 277 (at 8 mo)
8-mo angiographic in-segment late luminal loss
BMS ⫽ bare metal stent; ENDEAVOR II CA ⫽ ENDEAVOR II Continued Access Registry; MACE ⫽ major adverse cardiac events; RVD ⫽ reference vessel diameter; SES ⫽ sirolimus-eluting stent; ZES ⫽ zotarolimus-eluting stent. * Medtronic Vascular, Santa Rosa, CA.
Table 2 Baseline patient clinical and angiographic characteristics for the Endeavor zotarolimus-eluting stent* Characteristic Clinical‡ Age (yr) Male sex (%) Diabetes mellitus (%) Hypertension (%) History of smoking (%) Hyperlipidemia (%) Previous myocardial infarction (%) Angina class III/IV (%) Previous percutaneous revascularization (%) Previous coronary bypass surgery (%) Angiographic Target vessel§ (%) Left anterior descending coronary artery Left circumflex coronary artery Right coronary artery Type B2/C lesions§ (%) Reference vessel diameter† (mm) Lesion length§ (mm) No. of diseased vessels‡ (%) 1 2 3 Left ventricular ejection fraction‡ (%)
p Value†
ENDEAVOR I (n ⫽ 100)
ENDEAVOR II (n ⫽ 598)
ENDEAVOR II CA (n ⫽ 296)
ENDEAVOR III (n ⫽ 323)
58.74 ⫾ 10.08 (100) 79.0 (79/100) 16.0 (16/100) 53.1 (52/98) 34.0 (34/100) 91.8 (90/98) 47.0 (47/100) 34.6 (27/78) 19.0 (19/100)
61.58 ⫾ 10.53 (597) 77.2 (461/597) 18.2 (108/595) 63.3 (377/596) 35.3 (207/587) 80.5 (476/591) 39.7 (236/594) 54.4 (261/480) 21.7 (129/595)
64.25 ⫾ 9.69 (296) 75.0 (222/296) 25.8 (76/295) 81.7 (241/295) 27.1 (79/291) 75.3 (220/292) 29.2 (86/295) 39.3 (103/262) 32.8 (97/296)
61.42 ⫾ 10.58 (323) 65.3 (211/323) 29.7 (96/323) 70.7 (227/321) 66.5 (212/319) 83.5 (268/321) 19.9 (64/321) 59.3 (156/263) 22.6 (73/323)
2.0 (2/100)
4.7 (28/597)
5.1 (15/296)
5.3 (17/323)
43.0 (43/100)
43.4 (255/588)
50.5 (150/297)
41.2 (133/323)
44.4 (581/1,308)
23.0 (23/100) 34.0 (34/100) 49.0 (49/100) 2.96 ⫾ 0.47 (100) 10.94 ⫾ 3.13 (100)
22.3 (131/588) 34.4 (202/588) 78.4 (461/588) 2.74 ⫾ 0.48 (588) 14.05 ⫾ 5.57 (580)
22.6 (67/297) 26.9 (80/297) 74.4 (221/297) 2.63 ⫾ 0.45 (297) 16.49 ⫾ 7.86 (293)
23.2 (75/323) 35.6 (115/323) 67.2 (217/323) 2.75 ⫾ 0.46 (323) 14.96 ⫾ 6.20 (322)
22.6 (296/1,308) 33.0 (431/1,308) 72.5 (948/1,308) 2.73 ⫾ 0.47 (1,308) 14.59 ⫾ 6.33 (1,295)
65.0 (65/100) 29.0 (29/100) 6.0 (6/100) 65.23 ⫾ 12.34 (40)
64.8 (387/597) 23.5 (140/597) 11.7 (70/597) 61.53 ⫾ 12.00 (455)
54.1 (160/296) 26.4 (78/296) 19.6 (58/296) 62.68 ⫾ 10.99 (237)
62.2 (201/323) 29.1 (94/323) 8.7 (28/323) 55.66 ⫾ 9.11 (307)
⬍0.001 ⬍0.001 ⬍0.001 ⬍0.001 ⬍0.001 0.001 ⬍0.001 ⬍0.001 0.002 0.610
Combined (N ⫽ 1,317) 61.93 ⫾ 10.41 (1,316) 73.9 (973/1,316) 22.5 (296/1,313) 68.5 (897/1,310) 41.0 (532/1,297) 81.0 (1054/1,302) 33.1 (433/1,310) 50.5 (547/1,083) 24.2 (318/1,314) 4.7 (62/1,316)
0.249
⬍0.001 ⬍0.001 ⬍0.001 0.002
⬍0.001
61.8 (813/1,316) 25.9 (341/1,316) 12.3 (162/1,316) 60.20 ⫾ 11.40 (1,039)
ENDEAVOR II CA ⫽ ENDEAVOR II Continued Access Registry. * Medtronic Vascular, Santa Rosa, CA. † p values are based on analysis of variance for continuous outcomes, Fisher’s exact test for dichotomous outcomes, the Cochran-Mantel-Haenszel statistic (modified ridit scores) for ordinal outcomes with ⬎2 categories, and the Cochran-Mantel-Haenszel statistic (general association) for nominal outcomes with ⬎2 categories. ‡ Patient-level analysis. § Lesion-level analysis.
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Table 3 Procedural characteristics and results for the Endeavor zotarolimus-eluting stent* Variable
ENDEAVOR I (n ⫽ 100)
ENDEAVOR II (n ⫽ 598)
ENDEAVOR II CA (n ⫽ 296)
ENDEAVOR III (n ⫽ 323)
No. of Endeavor stents‡
1.12 ⫾ 0.43 (100) 20.06 ⫾ 7.65 (100) 3.22 ⫾ 0.25 (100) 13.12 ⫾ 2.51 (100)
1.13 ⫾ 0.38 (591) 23.40 ⫾ 6.71 (591) 3.08 ⫾ 0.37 (591) 13.67 ⫾ 2.84 (591)
1.21 ⫾ 0.45 (297) 24.94 ⫾ 9.02 (295) 3.03 ⫾ 0.37 (295) 13.63 ⫾ 2.83 (294)
1.14 ⫾ 0.40 (323) 23.60 ⫾ 7.32 (317) 3.07 ⫾ 0.39 (317) 13.57 ⫾ 2.52 (318)
Total stent length‡ (mm) Minimum stent diameter‡ (mm) Maximum stent deployment pressure‡ (atm) ⬎1 stent implanted‡ (%) Minimal luminal diameter‡ (mm) Before procedure In lesion After procedure In stent In segment Diameter stenosis‡ (%) Before procedure In lesion After procedure In stent In segment Device success‡ (%) Procedural success§ (%)
8.0 (8/100)
11.3 (67/591)
20.0 (59/295)
11.8 (38/323)
p Value†
Combined (N ⫽ 1,317)
0.047
1.15 ⫾ 0.41 (1,311) 23.54 ⫾ 7.59 (1,303) 3.08 ⫾ 0.37 (1,303) 13.59 ⫾ 2.74 (1,303)
⬍0.001
0.321
0.001
13.1 (172/1,309)
0.88 ⫾ 0.33 (100)
0.83 ⫾ 0.34 (587)
0.78 ⫾ 0.33 (297)
0.92 ⫾ 0.41 (323)
⬍0.001
0.85 ⫾ 0.36 (1,307)
2.84 ⫾ 0.35 (100) 2.52 ⫾ 0.42 (100)
2.59 ⫾ 0.43 (586) 2.21 ⫾ 0.49 (587)
2.56 ⫾ 0.43 (296) 2.24 ⫾ 0.46 (296)
2.67 ⫾ 0.42 (323) 2.27 ⫾ 0.45 (323)
⬍0.001
2.62 ⫾ 0.43 (1,305) 2.25 ⫾ 0.48 (1,306)
70.32 ⫾ 9.80 (100)
69.69 ⫾ 10.84 (587)
70.03 ⫾ 11.83 (297)
66.81 ⫾ 12.40 (323)
5.37 ⫾ 7.51 (100) 16.54 ⫾ 8.40 (100) 100.0 (100/100) 100.0 (100/100)
6.06 ⫾ 10.44 (586) 20.42 ⫾ 10.26 (587) 98.8 (583/590) 96.4 (569/590)
5.27 ⫾ 9.45 (296) 17.76 ⫾ 9.57 (296) 98.3 (292/297) 93.6 (277/296)
4.33 ⫾ 9.77 (323) 19.38 ⫾ 9.25 (323) 98.8 (319/323) 98.1 (317/323)
⬍0.001
⬍0.001
0.091 ⬍0.001 0.717 0.003
69.11 ⫾ 11.46 (1,307) 5.40 ⫾ 9.87 (1,305) 19.26 ⫾ 9.81 (1,306) 98.8 (1,294/1,310) 96.5 (1,263/1,309)
ENDEAVOR II CA ⫽ ENDEAVOR II Continued Access Registry. * Medtronic Vascular, Santa Rosa, CA. † p values are based on analysis of variance for continuous outcomes and Fisher’s exact test for dichotomous outcomes. ‡ Lesion-level analysis. § Patient-level analysis.
ated with significant reductions in neointimal area and percentage area stenosis (⬎50% at 28 days).6 It has been shown in preclinical studies that approximately 95% of zotarolimus is eluted from the stent within 15 days of implantation, although drug concentrations within surrounding vascular tissue may be detected as late as 30 days after stent deployment (data on file, Medtronic Vascular). Depending on the trial, the ZES was available in diameters ranging from a minimum of 2.25 mm to a maximum of 3.5 mm and in lengths from 9 –30 mm. Interventional procedure and adjunctive drug therapies: In each study, revascularization was to be performed on a single de novo lesion with no more than 1 study stent allowed, except in instances of insufficient lesion coverage or as a “bailout” procedure for dissection or thrombus. Except for a direct-stenting subgroup in ENDEAVOR II CA, all lesions were predilated with
balloon angioplasty, and the protocols specified that stent length should be 3–5 mm longer than the lesion for adequate coverage. Stents were expanded to achieve ⬍10% residual stenosis by visual estimate in the treated segment, using a combination of the stent deployment balloon and, at the discretion of operators, subsequent postdilation balloons. Before revascularization, all patients were treated with aspirin (75–325 mg/day) and clopidogrel (75 mg/day) for ⱖ 48 hours. After the procedure, all patients were to be treated with dual-antiplatelet therapy for ⱖ3 months and with aspirin therapy indefinitely. In those patients not receiving ⱖ48 hours of dual-antiplatelet therapy before the procedure, a loading dose of clopidogrel (300 – 600 mg) was administered before or during the procedure. Unfractionated heparin was administered to achieve an activated clotting time ⱖ250 seconds, or 200 –250 sec-
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Table 4 Combined angiographic outcomes at 8 months and 12 months* for the Endeavor zotarolimus-eluting stent† Variable Late luminal loss (mm) In stent In segment Minimal luminal diameter (mm) In stent In segment Diameter stenosis (%) In stent In segment Binary restenosis (%) In stent In segment Proximal margin Distal margin
p Value‡
ENDEAVOR I (n ⫽ 92)
ENDEAVOR II (n ⫽ 264)
ENDEAVOR II CA (n ⫽ 117)
ENDEAVOR III (n ⫽ 277)
0.58 ⫾ 0.44 (92) 0.43 ⫾ 0.44 (92)
0.62 ⫾ 0.46 (262) 0.36 ⫾ 0.46 (262)
0.58 ⫾ 0.58 (117) 0.39 ⫾ 0.56 (117)
0.62 ⫾ 0.49 (277) 0.36 ⫾ 0.46 (277)
0.804
2.26 ⫾ 0.49 (92) 2.08 ⫾ 0.47 (92)
1.99 ⫾ 0.56 (264) 1.86 ⫾ 0.55 (264)
1.92 ⫾ 0.65 (117) 1.81 ⫾ 0.61 (117)
2.06 ⫾ 0.57 (277) 1.91 ⫾ 0.53 (277)
⬍0.001
21.75 ⫾ 15.35 (92) 28.00 ⫾ 13.41 (92)
27.91 ⫾ 17.30 (264) 32.67 ⫾ 16.27 (264)
27.67 ⫾ 21.95 (117) 31.93 ⫾ 20.54 (117)
24.90 ⫾ 17.45 (277) 30.42 ⫾ 15.57 (277)
0.017
4.3 (4/92) 5.4 (5/92) 0 (0/90) 1.1 (1/91)
9.5 (25/264) 13.3 (35/264) 3.5 (9/257) 1.9 (5/262)
15.4 (18/117) 17.1 (20/117) 3.7 (4/109) 3.4 (4/116)
9.7 (27/277) 12.3 (34/277) 1.5 (4/265) 1.4 (4/276)
0.067 0.071 0.135 0.593
0.573
0.002
0.093
Combined (n ⫽ 750) 0.61 ⫾ 0.49 (748) 0.37 ⫾ 0.48 (748) 2.04 ⫾ 0.58 (750) 1.90 ⫾ 0.55 (750) 26.01 ⫾ 18.03 (750) 31.15 ⫾ 16.48 (750) 9.9 (74/750) 12.5 (94/750) 2.4 (17/721) 1.9 (14/745)
ENDEAVOR II CA ⫽ ENDEAVOR II Continued Access Registry. * 12-month angiographic results for ENDEAVOR I and 8-month angiographic results for ENDEAVOR II, ENDEAVOR II CA, and ENDEAVOR III. † Medtronic Vascular, Santa Rosa, CA. ‡ p values are based on analysis of variance for continuous outcomes and Fisher’s exact test for dichotomous outcomes.
onds if an intravenous glycoprotein IIb/IIIa inhibitor was used. Treatment with additional device therapies (eg, atherectomy) was not permitted. Data management and core laboratories: Clinical events were assessed during hospitalization and at clinic visits at 30 days and at 9 months after the index procedure (12 months for ENDEAVOR I). Clinical and angiographic results from all trials were submitted to a central data coordinating facility (Cardiovascular Data Analysis Center, Harvard Clinical Research Institute, Harvard Medical School, Boston, MA). Coronary angiograms obtained at baseline and at follow-up were reviewed by an independent angiographic core laboratory (Brigham and Women’s Angiographic Core Laboratory, Boston, MA). Standard image acquisition was performed using ⱖ2 angiographic projections of the stenosis before and after stent placement and administration of intracoronary nitrate. Qualitative analysis was performed using a validated automated edge detection algorithm (CMS; MEDIS Medical Imaging Systems, Leiden, The Netherlands),7 and lesions were characterized according to the modified American College of Cardiology (ACC) and American Heart Association (AHA) classification.8 A 5–10-mm segment of reference vessel proximal and distal to the stenosis was used to calculate the average reference vessel diameter at baseline, after stent implantation, and at follow-up. Quantitative analysis was performed to evaluate the in-stent region (bordered by the stent margins) as well as the in-segment region (in-stent region plus 5-mm margins proximal and distal to the stent).
Study end points and definitions: The primary objective of this pooled analysis of patients treated with the ZES was to evaluate clinically driven TLR at 30 days and at 9, 12, and 24 months after the index procedure. Additional clinical safety and efficacy end points included major adverse cardiac events (MACE; composite of allcause death, MI, emergent coronary artery bypass grafting, and clinically driven TLR) and the individual components of the composite end point at 30 days and at 9 months, stent thrombosis (acute coronary syndrome with angiographic or autopsy confirmation of thrombosis), clinically driven target vessel revascularization (TVR) at 9 months, and target vessel failure (TVF) (cardiac death, MI, and clinically driven TVR) at 9 months. Device success was defined as a ⬍50% diameter stenosis of the target lesion (determined by the core angiographic laboratory) with the assigned study stent, and procedure success was defined as lesion success and no in-hospital MACE. All clinical end points were adjudicated by an independent clinical events committee, and except for ENDEAVOR I and ENDEAVOR II CA, reviewers were blinded to patient treatment assignments. Angiographic efficacy end points included the 8-month (12 months for ENDEAVOR I) in-stent and in-segment assessments of late luminal loss and binary restenosis. Late luminal loss was defined as the difference between the minimal luminal diameter at the completion of the stenting procedure and the minimal luminal diameter (MLD) measured at angiographic follow-up.
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Angiographic binary restenosis was defined as a stenosis ⱖ50% of the luminal diameter of the target lesion (determined by the core angiographic laboratory). Percentage diameter stenosis was defined as (1 ⫺ [MLD/reference vessel diameter]) ⫻ 100, and acute gain was defined as the MLD immediately after the procedure minus the MLD before the procedure. Restenosis patterns were characterized according to established criteria.9 Statistical methods: From the individual trials, patients were analyzed for all efficacy and safety end points on the basis of the intention-to-treat principle. Baseline characteristics of study patients were summarized in terms of frequencies and percentages for categorical variables and by means with standard deviations for continuous variables. Clinical and angiographic outcomes were compared among ZES subgroups (diabetic status or tertiles evenly divided according to lesion length and vessel diameter). Categorical variables were compared using Fisher’s exact test or the Cochran-Mantel-Haenszel test, and continuous variables were compared using the 2-sample Student’s t test or analysis of variance. Cumulative event-free survival was summarized as Kaplan-Meier estimates. A p value of 0.05 was established as the level of statistical significance for all tests. All analyses were performed using SAS version 8.2 or higher (SAS Institute Inc., Cary, NC).
Results Patient characteristics: A total of 1,317 patients who underwent elective percutaneous coronary revascularization and were treated with the ZES in 4 clinical trials were evaluated. Baseline angiographic evaluation was available for all patients; follow-up clinical evaluation was available for 1,315 patients at 30 months, for 1,306 patients at 9 months, for 1,300 patients at 12 months, and for 1,282 patients at 24 months; angiographic follow-up was completed for 658 patients from ENDEAVOR II, ENDEAVOR II CA, and ENDEAVOR III at 8 months and for 92 patients from ENDEAVOR I at 12 months. Altogether, the mean age was 61.9 years, 24.2% of patients had undergone previous percutaneous coronary intervention, 41.0% had histories of smoking, and 22.5% had diabetes mellitus (Table 2). Most patients (61.8%) had singlevessel coronary disease, and 33.1% of patients had histories of MI. Approximately half of the patients were classifiable in Canadian Cardiovascular Society (CCS) angina class III or IV. Overall, the mean ⫾ SD lesion length was 14.59 ⫾ 6.33 mm, and the average reference vessel diameter was 2.73 ⫾ 0.47 mm. Most lesions (44.4%) were located in the left anterior descending coronary artery, and 72.5% of lesions were characterized as type B2 or C according to the modified ACC and AHA classification.8 Procedural and angiographic outcomes: The average number of Endeavor stents per target lesion was 1.15, with multiple stents placed in 172 lesions (13.1%; Table 3). The maximum inflation pressure during stent deployment was
13.59 ⫾ 2.74 atm. Intravenous glycoprotein IIb/IIIa inhibitors were administered in 19.1% of patients. Overall device and procedure success rates were 98.8% and 96.5%, respectively (Table 3). Angiographic follow-up was performed at 8 months for 658 patients and at 12 months for 92 patients (92% of the ENDEAVOR I cohort). Overall, in-stent and in-segment binary restenosis occurred in 9.9% and 12.5% of patients, respectively (Table 4). For patients with in-stent angiographic binary restenosis at follow-up, the mean in-stent percentage diameter stenosis was 66.84 ⫾ 13.45%, and 37.8% had ⱖ70% in-stent percentage diameter stenosis. For patients with in-segment angiographic binary restenosis at follow-up, the mean in-segment percentage diameter stenosis was 65.44 ⫾ 12.62%, and 31.9% had ⱖ70% in-segment percentage diameter stenosis. In-stent and in-segment late luminal loss were 0.61 ⫾ 0.49 and 0.37 ⫾ 0.48 mm, respectively. There were no differences in restenosis within the proximal or distal margins of the stents among the 4 trials. Thirty-day, 9-month, 12-month, and 24-month clinical outcomes: At 30 days, the rate of MACE was 2.7%, principally driven by the occurrence of non–Q wave MIs (2.3%; Table 5). Stent thrombosis occurred in 4 patients (0.3%). Adverse events, in particular MI, did not statistically vary among patients treated with single versus multiple stents (2.4% vs 3.5%; p ⫽ 0.43). Clinical follow-up at 9 months was completed for 1,306 patients (99%; Table 5). There were no additional occurrences of stent thrombosis beyond 14 days of initial revascularization. Death and MI had occurred in 0.8% and 2.6% of patients treated with the ZES. Rates of TLR and TVR were 4.9% and 7.4%, respectively. Specifically, repeat TLR occurred in 6.5% who underwent compulsory angiographic follow-up and in 2.7% of patients who did not. For patients who underwent 8-month angiographic follow-up (12 months for the 92 patients from ENDEAVOR I), Figure 2 relates the probability of TLR with angiographic late luminal loss, demonstrating that the likelihood of repeat revascularization begins with an in-stent late luminal loss threshold of approximately 0.6 mm and escalates markedly above values ⬎1.0 mm. For patients who underwent repeat TLR, the mean in-stent and in-segment percentage diameter stenoses at angiographic follow-up were 59.59 ⫾ 26.25% and 66.97 ⫾ 16.13%, respectively. Figure 3 shows actuarial event-free survival at 9 months for TLR, MACE, and TVF. At 12 months, the rate of MACEs was 8.8%, the rate of death was 0.9%, the rate of MI was 2.7%, and the rate of TLR was 5.9%. Clinical follow-up at 24 months was completed for 1,282 patients (97.3%; Table 5). Again, no additional cases of stent thrombosis occurred beyond 14 days of initial revascularization. At 24 months, the overall rate of MACE was 9.9%, the rate of death was 1.7%, the rate of MI was 2.9%, and the rate of TLR was 6.5%. Subgroup analyses: Among clinically relevant subgroups treated with the ZES, 8-month angiographic in-stent
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Table 5 Combined clinical events at 30 days, 9 months, 12 months, and 24 months for the Endeavor zotarolimus-eluting stent*† Variable 30 days MACE (%) Death (%) MI (%) Q wave (%) Non–Q wave (%) Emergent CABG (%) TLR (%) TVR (%) Target vessel failure (%) Stent thrombosis (%) 9 mo MACE (%) Death (%) MI (%) Q wave (%) Non–Q wave (%) Emergent CABG (%) TLR (%) TVR (%) Target vessel failure (%) Stent thrombosis (%) 12 mo MACE (%) Death (%) MI (%) Q wave (%) Non–Q wave (%) Emergent CABG (%) TLR (%) TVR (%) Target vessel failure (%) Stent thrombosis (%) 24 mo MACE (%) Death (%) MI (%) Q wave (%) Non–Q wave (%) Emergent CABG (%) TLR (%) TVR (%) Target vessel failure (%) Stent thrombosis (%)
ENDEAVOR II (n ⫽ 598)
ENDEAVOR II CA (n ⫽ 296)
ENDEAVOR III (n ⫽ 323)
p Value‡
Combined (N ⫽ 1,317)
1 (1/100) 0 (0/100) 1 (1/100) 0 (0/100) 1 (1/100) 0 (0/100) 1 (1/100) 1 (1/100) 1 (1/100) 1 (1/100)
2.9 (17/596) 0.2 (1/596) 2.7 (16/596) 0.3 (2/596) 2.3 (14/596) 0 (0/596) 0.8 (5/596) 1.2 (7/596) 3.2 (19/596) 0.5 (3/596)
5.4 (16/296) 0 (0/296) 4.7 (14/296) 0.3 (1/296) 4.4 (13/296) 0.3 (1/296) 0.3 (1/296) 1.4 (4/296) 5.7 (17/296) 0 (0/296)
0.6 (2/323) 0 (0/323) 0.6 (2/323) 0 (0/323) 0.6 (2/323) 0 (0/323) 0 (0/323) 0 (0/323) 0.6 (2/323) 0 (0/323)
0.002 1.000 0.007 0.698 0.014 0.301 0.269 0.148 0.001 0.233
2.7 (36/1,315) 0.1 (1/1,315) 2.5 (33/1,315) 0.2 (3/1,315) 2.3 (30/1,315) 0.1 (1/1,315) 0.5 (7/1,315) 0.9 (12/1,315) 3 (39/1,315) 0.3 (4/1,315)
2 (2/100) 0 (0/100) 1 (1/100) 0 (0/100) 1 (1/100) 0 (0/100) 2 (2/100) 2 (2/100) 2 (2/100) 1 (1/100)
7.3 (43/592) 1.2 (7/592) 2.7 (16/592) 0.3 (2/592) 2.4 (14/592) 0 (0/592) 4.6 (27/592) 5.6 (33/592) 7.9 (47/592) 0.5 (3/592)
10.6 (31/293) 0.7 (2/293) 5.1 (15/293) 0.3 (1/293) 4.8 (14/293) 0.3 (1/293) 5.1 (15/293) 8.9 (26/293) 13 (38/293) 0 (0/293)
7.5 (24/321) 0.6 (2/321) 0.6 (2/321) 0 (0/321) 0.6 (2/321) 0 (0/321) 6.2 (20/321) 11.2 (36/321) 11.8 (38/321) 0 (0/321)
0.033 0.776 0.004 0.698 0.007 0.301 0.381 0.002 0.001 0.234
7.7 (100/1,306) 0.8 (11/1,306) 2.6 (34/1,306) 0.2 (3/1,306) 2.4 (31/1,306) 0.1 (1/1,306) 4.9 (64/1,306) 7.4 (97/1,306) 9.6 (125/1,306) 0.3 (4/1,306)
2 (2/98) 0 (0/98) 1 (1/98) 0 (0/98) 1 (1/98) 0 (0/98) 2 (2/98) 2 (2/98) 2 (2/98) 1 (1/98)
8.8 (52/590) 1.4 (8/590) 2.7 (16/590) 0.3 (2/590) 2.4 (14/590) 0 (0/590) 5.9 (35/590) 7.5 (44/590) 10 (59/590) 0.5 (3/590)
12.3 (36/292) 0.7 (2/292) 5.5 (16/292) 0.3 (1/292) 5.1 (15/292) 0.3 (1/292) 6.5 (19/292) 11.6 (34/292) 15.8 (46/292) 0 (0/292)
7.8 (25/320) 0.6 (2/320) 0.6 (2/320) 0 (0/320) 0.6 (2/320) 0 (0/320) 6.6 (21/320) 12.2 (39/320) 12.8 (41/320) 0 (0/320)
0.010 0.664 0.002 0.697 0.004 0.300 0.368 0.002 ⬍.001 0.232
8.8 (115/1,300) 0.9 (12/1,300) 2.7 (35/1,300) 0.2 (3/1,300) 2.5 (32/1,300) 0.1 (1/1,300) 5.9 (77/1,300) 9.2 (119/1,300) 11.4 (148/1,300) 0.3 (4/1,300)
3.1 (3/98) 1 (1/98) 1 (1/98) 0 (0/98) 1 (1/98) 0 (0/98) 2 (2/98) 4.1 (4/98) 4.1 (4/98) 1 (1/98)
9.9 (58/583) 2.1 (12/583) 2.9 (17/583) 0.3 (2/583) 2.6 (15/583) 0 (0/583) 6.5 (38/583) 8.4 (49/583) 11.1 (65/583) 0.5 (3/583)
12.8 (37/288) 1.4 (4/288) 5.9 (17/288) 0.3 (1/288) 5.6 (16/288) 0.3 (1/288) 7.3 (21/288) 12.5 (36/288) 16.3 (47/288) 0 (0/288)
9.3 (29/313) 1.6 (5/313) 0.6 (2/313) 0 (0/313) 0.6 (2/313) 0 (0/313) 7 (22/313) 13.7 (43/313) 14.4 (45/313) 0 (0/313)
0.032 0.916 0.001 0.698 0.002 0.301 0.267 0.007 0.004 0.232
9.9 (127/1,282) 1.7 (22/1,282) 2.9 (37/1,282) 0.2 (3/1,282) 2.7 (34/1,282) 0.1 (1/1,282) 6.5 (83/1,282) 10.3 (132/1,282) 12.6 (161/1,282) 0.3 (4/1,282)
ENDEAVOR I (n ⫽ 100)
CABG ⫽ coronary artery bypass grafting; ENDEAVOR II CA ⫽ ENDEAVOR II Continued Access Registry; MACE ⫽ major adverse cardiac events; MI ⫽ myocardial infarction; TLR ⫽ target lesion revascularization; TVR ⫽ target vessel revascularization. * Medtronic Vascular, Santa Rosa, CA. † Data are expressed as percentage (number). ‡ p values are based on Fisher’s exact test.
late luminal loss (12 months for the 92 patients from ENDEAVOR I) did not significantly differ between patients with and without diabetes, but in-stent late luminal loss was significantly greater (0.65 ⫾ 0.49 mm; p ⫽ 0.038) in larger caliber vessels (⬎2.9 mm diameter) and also significantly greater (0.70 ⫾ 0.52 mm; p ⫽ 0.004) in longer lesions (⬎16.3 mm) (Table 6). However, despite higher late luminal loss in vessels with larger reference diameters, in-stent angiographic restenosis was significantly more common in
vessels with ⬍2.5 mm diameter (18.1%; p ⬍0.001). In-stent restenosis was numerically higher in patients with diabetes, although the difference was not statistically significant. Insegment late luminal loss also tended to be greater for patients with diabetes compared with those without diabetes (0.43 ⫾ 0.49 vs 0.36 ⫾ 0.47 mm; p ⫽ 0.082). Despite angiographic differences, however, neither target vessel failure nor MACE statistically varied relative to diabetes, vessel diameter, or lesion length (Table 7). The rate of TLR
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Figure 2. Logistic regression relation between in-stent late luminal loss and the probability of target lesion revascularization (TLR) for patients treated with zotarolimus-eluting stents (n ⫽ 750).
Figure 3. Kaplan-Meier event-free survival to 9 months for patients treated with zotarolimus-eluting stents (n ⫽ 1,306): 9-month freedom from target lesion revascularization (TLR), 93.3%; 9-month freedom from major adverse cardiac events (MACE), 90.4%; 9-month freedom from target vessel failure (TVF), 87.9%.
at 12 months was not significantly different relative to diabetes and lesion length ⬎16.3 mm (7.2% and 7.7%, respectively), although it was significantly more common when the reference vessel diameter was ⬍2.5 mm (8.5%; p ⫽ 0.013).
Discussion Pooled analysis of clinical trials in patients with coronary disease of simple and moderate complexity support the favorable efficacy and safety associated with the antiproliferative agent zotarolimus and a phosphorylcholine polymer. Collectively, among 1,317 patients treated in the context of the first 4 clinical trials of the Endeavor ZES, the 9- and 24-month rates of clinically driven (ie, symptomatic or with
⬎70% diameter stenosis) TLR were 4.9% and 6.5%, respectively, and there were no occurrences of stent thrombosis beyond 14 days after initial revascularization. Despite more variable angiographic results in clinically relevant subgroups, clinical outcomes are comparatively uniform, with no major differences in the occurrence of target vessel failure or overall MACE. These findings robustly support the efficacy and safety of the device and provide grounds for the further evaluation of the ZES in lesions of greater complexity and patients at higher clinical risk. Across the 4 ENDEAVOR trials considered in this analysis, clinical and angiographic outcomes have also been remarkably consistent, despite the inclusion of a broad global sample of patients treated at varied physician practices. For example, in-stent angiographic binary restenosis was 9.5% and 9.7% in the multinational (not including the
Gershlick et al/Zotarolimus-Eluting Stents
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Table 6 Angiographic outcomes at 8 and 12 months* among Endeavor zotarolimus-eluting stent† subgroups‡ Variable
Lesion length (mm) ⬍11.2 11.2–16.3 ⬎16.3 Vessel diameter (mm) ⬍2.5 2.5–2.9 ⬎2.9 Diabetes mellitus No Yes
In-Stent Late Luminal Loss (mm)
p Value§
In-Segment Late Luminal Loss (mm)
p Value§
In-Stent Binary Angiographic Restenosis (%)
p Value§
In-Segment Binary Angiographic Restenosis (%)
p Value§
0.56 ⫾ 0.48 (262) 0.57 ⫾ 0.45 (249) 0.70 ⫾ 0.52 (229)
0.004
0.33 ⫾ 0.47 (262) 0.33 ⫾ 0.44 (249) 0.47 ⫾ 0.50 (229)
0.001
9.5% (25/262) 5.6% (14/249) 14.4% (33/229)
0.005
13.4% (35/262) 8.0% (20/249) 16.2% (37/229)
0.019
0.62 ⫾ 0.53 (237) 0.54 ⫾ 0.43 (241) 0.65 ⫾ 0.49 (270)
0.038
0.36 ⫾ 0.49 (237) 0.31 ⫾ 0.44 (241) 0.45 ⫾ 0.49 (270)
0.005
18.1% (43/237) 5.0% (12/241) 7.0% (19/270)
⬍0.001
21.1% (50/237) 8.3% (20/241) 8.9% (24/270)
⬍0.001
0.60 ⫾ 0.49 (577) 0.63 ⫾ 0.49 (171)
0.533
0.36 ⫾ 0.47 (577) 0.43 ⫾ 0.49 (171)
0.082
9.2% (53/579) 12.3% (21/171)
0.243
11.7% (68/579) 15.2% (26/171)
0.238
* 12-month angiographic results for ENDEAVOR I and 8-month angiographic results for ENDEAVOR II, the ENDEAVOR II Continued Access Registry, and ENDEAVOR III. † Medtronic Vascular, Santa Rosa, CA. ‡ Data are expressed as mean ⫾ SD or percentage (number). § p values for the test of equality of means (percentages) across subgroups.
Table 7 Clinical events at 12 months among Endeavor zotarolimus-eluting stent* subgroups† Variable
Lesion length (mm) ⬍11.2 11.2–16.3 ⬎16.3 Vessel diameter (mm) ⬍2.5 2.5–2.9 ⬎2.9 Diabetes No Yes
Target Lesion Revascularization (%)
p Value‡
Major Adverse Cardiac Events (%)
p Value‡
Target Vessel Failure (%)
p Value‡
5.6% (24/426) 4.5% (19/423) 7.7% (33/430)
0.141
8.0% (34/426) 7.3% (31/423) 11.2% (48/430)
0.116
10.1% (43/426) 9.9% (42/423) 14.0% (60/430)
0.119
8.5% (37/436) 3.7% (15/407) 5.6% (25/449)
0.013
10.6% (46/436) 7.6% (31/407) 8.5% (38/449)
0.314
13.5% (59/436) 10.3% (42/407) 10.2% (46/449)
0.231
5.6% (56/1,004) 7.2% (21/293)
0.326
0.484
10.7% (107/1,004) 14.0% (41/293)
0.118
8.6% (86/1,004) 9.9% (29/293)
* Medtronic Vascular, Santa Rosa, CA. Data are expressed as percentage (number). ‡ p values for the test of equality of means (percentages) across subgroups. †
United States) ENDEAVOR II trial and the United States– based ENDEAVOR III trial, respectively, and in-stent late luminal loss did not differ.2,4 Although the enrollment criteria of these trials were more restrictive than real-world circumstances, the results remained consistently positive despite an increasing frequency of patients with diabetes and against the background of a relatively high proportion of moderately complex lesion morphologies. Analyzing the clinical outcomes in patients who underwent angiographic follow-up from the 4 ENDEAVOR trials considered in this analysis also enables a better understanding of the complex relation between angiographic variables (eg, late luminal loss), the probability of a clinical event (eg, TLR), and clinical characteristics (eg, diabetes, reference vessel diameter, and lesion length). Specifically, whereas in-stent late luminal loss was significantly greater in vessels
with the longest lesions (Table 6), rates of angiographic binary restenosis and TLR followed a different pattern (Table 7). Despite similar late luminal loss in smaller caliber arteries compared with vessels of intermediate diameter, angiographic restenosis and TLR were significantly more common in association with smaller vessels, suggesting that differences in clinical outcomes may become more apparent as lesion complexity increases. In particular, the finding that TLR is greatest in small caliber vessels (Table 7), especially in patients with diabetes with longer lesions (8.9% for patients with diabetes with lesion lengths of 11.2–16.3 mm, 7.0% for patients with diabetes with lesion lengths ⬎16.3 mm), suggests the existence of an angiographic late luminal loss threshold, above which the likelihood of clinical restenosis increases. Whether this interaction is specific to the Endeavor stent or is instead similarly observed with other
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DESs also merits further investigation in a greater number of patients with more complex lesions (eg, bifurcation, chronic total occlusion, unprotected left main coronary artery) and clinical characteristics (eg, acute MI, chronic renal failure). It does appear likely that similar results may be found to occur with other DESs. In the TAXUS V trial, for example, the 9-month TLR rate was 10.4% in patients treated with a 2.25-mm diameter PES and with an average lesion length of 16.4 mm.10 Perhaps the most noteworthy consistency among these trials relates to safety of the ZES, particularly with regard to the absence of late stent thrombosis. Furthermore, among the 750 ZES patients (57%) with angiographic follow-up (at 8 months for 658 patients from ENDEAVOR II, ENDEAVOR II CA, and ENDEAVOR III and at 12 months for 92 patients from ENDEAVOR I) and the 617 ZES patients (47%) with intravascular ultrasound follow-up, there have been no occurrences of aneurysm formation and only a single case of newly observed late-acquired incomplete stent apposition (P. J. Fitzgerald, personal communication). One potential explanation for the absence of late stent thrombosis may relate to the thromboresistant properties of the biomimetic phospholipid polymer (phosphorylcholine) used to carry and deliver zotarolimus.5 In addition, the higher late luminal loss with the ZES may permit more rapid and complete healing of the treated segment surface without promoting excessive deep wall remodeling and aneurysm formation.4 It is uncertain whether or to what extent the outcomes observed with the ZES in the context of the enrollment criteria of these first 4 trials of the Endeavor ZES will prove generalizable to a broader unselected patient population. Furthermore, although the absence of late stent thrombosis associated with the ZES over the term of follow-up in these trials is promising, follow-up in a larger patient cohort and for a longer duration is needed, considering the infrequent occurrence of this outcome and the fact that events may occur well beyond 1 year of DES placement.11,12 Additional ongoing study with more open patient inclusion criteria (including long lesions, small vessels, bifurcations, etc) will be important for discerning whether comparable clinical outcomes can be extended to lesion subsets of higher complexity.
Author Disclosures The authors who contributed to this article have disclosed the following industry relationships. Jean Fajadet, MD, has served as a consultant for Cordis Corporation. Peter J. Fitzgerald, MD, PhD, has served as a consultant for Cordis Corporation, Boston Scientific, Abbott Vascular, Medtronic, Inc., CardioMind, Inc., REVA Medical Inc., Devax, Inc., Biosensors International Pte Ltd., XTENT, Inc., and Setagon, Inc. Anthony Gershlick, BSc, MB, BS, is a member of the speakers bureau for Medtronic, Inc., Cordis Corporation,
Boston Scientific, Abbott Vascular, Eli Lilly and Company, and sanofi-aventis; has served as a consultant for Medtronics, Inc., Cordis Corporation, Boston Scientific, Abbott Vascular, Eli Lilly and Company, and sanofiaventis; has served as an advisory board member for Medtronic, Inc., Cordis Corporation, Boston Scientific, Abbott Vascular, Eli Lilly and company, and sanofiaventis; has received research/grant support from Medtronic, Inc., Cordis Corporation, Boston Scientific, Abbott Vascular, Eli Lilly and Company, and sanofiaventis. David E. Kandzari, MD, is an employee of Cordis Corporation; served as a consultant to Medtronic, Inc.; served as an advisory board member for Medtronic, Inc.; and has received research/grant support from Medtronic, Inc. Richard E. Kuntz, MD, MSc, is an employee and a stockholder of Medtronic, Inc. Martin B. Leon, MD, has served as a consultant to Volcano Corporation; and has served as an advisory board member for Cordis Corporation, Medtronic, Inc., Boston Scientific, and Abbott Vascular. Ian T. Meredith, MBBS, PhD, has served as an advisory board member for Medtronic, Inc. and Boston Scientific. Jeffrey J. Popma, MD, is a member of the Speakers’ Bureau for sanofi-aventis, Pfizer Inc., and Bristol-Myers Squibb; has served as a consultant to Biosensors International and Cordis Corporation; and has received grant/research support from ev3, Abbott Vascular, Boston Scientific, Cordis Corporation, and Medtronic, Inc. William Wijns, MD, PhD, serves as an advisory board member for Bristol-Myers Squibb, GlaxoSmithKline, Medtronic, Inc., Cordis Corporation; Boston Scientific, TopSpin Medical, and Abbott Vascular. 1. Meredith I, Ormiston J, Whitbourn R, Kay I, Muller D, Bonan R, Popma J, Cutlip D, Fitzgerald P, Prpic R, Kuntz R. First-in-human study of the Endeavor ABT-578-eluting phosphorylcholine-encapsulated stent system in de novo native coronary artery lesions: Endeavor I Trial. EuroIntervention 2005;2:157–164. 2. Fajadet J, Wijns W, Laarman GJ, Kuck KH, Ormiston J, Munzel T, Popma JJ, Fitzgerald PJ, Bonan R, Kuntz RE. Randomized, doubleblind, 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;114:798 – 806. 3. Schultheiss HP, Grube E, Kuck KH, Suttorp MJ, Heuer H, Bonnier H, Popma JJ, Kuntz RE, Fadajet J, Wijns W. Safety of direct stenting with the Endeavor stent: results of the Endeavor II continued access registry. EuroIntervention 2007;3:76 – 81. 4. Kandzari DE, Leon MB, Popma JJ, Fitzgerald PJ, O’Shaughnessy C, Ball MW, Turco M, Applegate RJ, Gurbel PA, Midei MG, et al. Comparison of zotarolimus-eluting and sirolimus-eluting stents in patients with native coronary artery disease: a randomized controlled trial. J Am Coll Cardiol 2006;48:2440 –2447. 5. Hayward JA, Chapman D. Biomembrane surfaces as models for polymer design: the potential for haemocompatibility. Biomaterials 1984;5:135–142.
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