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Safety and Efficacy Outcomes of Overlapping Second-Generation Everolimus-Eluting Stents Versus First-Generation Drug-Eluting Stents
Safety and Efficacy Outcomes of Overlapping Second-Generation Everolimus-Eluting Stents Versus First-Generation Drug-Eluting Stents Hironori Kitabata, MD, PhD, Joshua P. Loh, MBBS, Lakshmana K. Pendyala, MD, Salem Badr, MD, Danny Dvir, MD, Israel M. Barbash, MD, Sa’ar Minha, MD, Rebecca Torguson, MPH, Fang Chen, MS, PhD, Lowell F. Satler, MD, William O. Suddath, MD, Kenneth M. Kent, MD, PhD, Augusto D. Pichard, MD, and Ron Waksman, MD* The safety and efficacy outcomes of stent overlap with second-generation drug-eluting stents (DES) have not been well established. This study aimed to compare the 1-year clinical outcomes of overlapping everolimus-eluting stents (EES) with those of overlapping firstgeneration DES. This retrospective analysis included 350 patients treated with overlapping EES (169 patients with 237 lesions), sirolimus-eluting stents (SES, 102 patients with 252 lesions), or paclitaxel-eluting stents (PES, 79 patients with 182 lesions). End points were major adverse cardiovascular events (MACE: defined as the composite of death, myocardial infarction, or target lesion revascularization), target vessel revascularization, and definite stent thrombosis at 1 year. During a follow-up of 1 year, overall MACE occurred in 6.5% of EES-, 16.8% of SES-, and 10.1% of PES-treated patients (p [ 0.026). Myocardial infarction was lowest in the EES group versus SES and PES groups (0 vs 1.0% vs 2.5%, respectively; p [ 0.080), and mortality was similar (3.6% vs 9.0% vs 5.1%, p [ 0.162). The EES patients showed a trend toward lower rates of 1-year target lesion revascularization (3.1% vs 8.2% vs 6.5%, p [ 0.181) and target vessel revascularization (3.7% vs 9.1% vs 11.7%, p [ 0.051) compared with the SES- and PES-treated patients. The cumulative incidence of definite stent thrombosis was lowest in the EES group (0 for EES vs 3.9% for SES vs 2.5% for PES, p [ 0.014). In conclusion, stent overlap with EES versus first-generation DES was associated with lower rates of MACE and stent thrombosis. Our results suggest that the use of EES when deploying overlapping stents is effective and safe. Ó 2013 Elsevier Inc. All rights reserved. (Am J Cardiol 2013;112:1093e1098) The introduction of drug-eluting stents (DES) has markedly reduced restenosis and the need for repeat revascularization compared with bare-metal stents (BMS).1,2 However, long-term safety concerns emerged with the use of first-generation DES,3,4 most likely related to delayed healing and impaired endothelialization.5 These findings may be more pronounced at overlapping DES sites because of increased drug concentration and polymer thickness. In fact, unlike nonoverlapping DES sites, overlapping DES segments induce greater neutrophils, eosinophils, and fibrin deposition, indicating impaired healing and increased inflammation.6 DES overlap appears to be associated with increased late lumen loss and restenosis rate compared with a single DES.7 However, earlier reports have produced conflicting results on outcomes of overlapping first-generation DES for the treatment of long lesions, reflecting the differences in follow-up intervals and frequency of angiographic follow-up among clinical studies.8e14 Moreover,
Division of Cardiology, MedStar Washington Hospital Center, Washington, District of Columbia. Manuscript received April 10, 2013; revised manuscript received and accepted May 20, 2013. See page 1097 for disclosure information. *Corresponding author: Tel: (202) 877-2812; fax: (202) 877-2715. E-mail address: [email protected] (R. Waksman). 0002-9149/13/$ - see front matter Ó 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjcard.2013.05.054
although the second-generation everolimus-eluting stents (EES) have been shown to be superior to first-generation DES in a number of settings15e17; the safety and efficacy of stent overlap with EES remains unknown. The aim of this study was to compare the 1-year clinical outcomes of overlapping second-generation EES with those of overlapping first-generation DES. Methods From April 2003 to December 2011, patients in whom native coronary arteries were treated with overlapping EES (Xience V, Abbott Vascular, Santa Clara, California or Promus, Boston Scientific, Natick, Massachusetts) or sirolimus-eluting stents (SES; Cypher, Cordis, Miami Lakes, Florida) or paclitaxel-eluting stents (PES; Taxus, Boston Scientific Corporation) were retrospectively included in this study from our institution’s registry. The choice of stent type was at the discretion of the operator. Stent overlap was defined as the presence of 2 stents within a single treated lesion and an overlapping stent zone of 1 mm, as determined by angiography.7 Total stent length per lesion was reported based on the cumulative length of the adjacent stents. We excluded patients who received a BMS. Patients who received heterogenous overlapping stents (e.g., SES-PES) were also excluded. Clinical and demographic www.ajconline.org
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Table 1 Baseline clinical characteristics Variable
EES (n ¼ 169)
Table 2 Lesion-based angiographic and procedural characteristics SES (n ¼ 102)
PES (n ¼ 79)
p
Age (yrs) 64.6 11.3 65.9 11.7 65.3 12.1 0.650 Men 122 (72.2) 59 (57.8) 43 (54.4) 0.008 Systemic hypertension* 156 (92.3) 72 (70.6) 63 (79.7) <0.001 Diabetes mellitus 70 (41.7) 34 (33.3) 28 (35.4) 0.346 81 (81.8) 69 (87.3) 0.161 Hypercholesterolemiaz 152 (89.9) Current smoker 36 (21.3) 21 (20.6) 15 (19.0) 0.916 Family history of CAD 81 (47.9) 55 (55.6) 39 (52.7) 0.463 Previous MI 40 (24.1) 15 (16.0) 23 (30.7) 0.075 Previous CABG 21 (12.5) 17 (17.0) 10 (13.0) 0.568 Previous PCI 59 (35.3) 26 (27.7) 30 (39.0) 0.265 28 (16.6) 9 (8.9) 12 (15.4) 0.201 Chronic renal insufficiency† Dialysis 0 2 (2.0) 1 (1.3) 0.135 Peripheral vascular 27 (16.0) 20 (19.8) 17 (21.8) 0.498 disease Clinical presentation Stable angina pectoris 64 (38.1) 41 (40.2) 23 (29.1) 0.268 Unstable angina 72 (42.9) 40 (39.2) 43 (54.4) 0.106 pectoris Acute MI 25 (14.9) 8 (7.8) 6 (7.6) 0.106 Cardiogenic shock 3 (1.8) 4 (4.0) 0 0.211 Number of diseased 1.7 0.7 1.9 0.8 1.6 0.8 0.121 vessels Chronic heart failure 17 (10.1) 16 (17.2) 11 (14.5) 0.244 Left ventricular 0.50 0.11 0.49 0.14 0.49 0.14 0.836 ejection fraction Data are presented as mean SD or n (%). CABG ¼ coronary artery bypass graft; CAD ¼ coronary artery disease; PCI ¼ percutaneous coronary intervention. * Blood pressure of >140/90 mm Hg or the use of antihypertensive drug. † Fasting cholesterol of >250 mg/dl or the use of lipid-lowering drug. z Previously diagnosed or treated with medication, diet, or dialysis by a physician. Diagnosis at admission if a baseline creatinine level >2.0 mg/dl is found.
data as well as clinical events during hospitalization were collected from hospital charts, reviewed by qualified personnel blinded to the objectives of the study, and entered prospectively into the database. Every patient underwent 30-day, 6-month, and 1-year clinical follow-up by qualified personnel through telephonic interview or office visit. Clinical events were adjudicated by source documentation by independent physicians not involved in the procedures. Written, informed consent was obtained from all patients before the cardiac catheterization. The study complied with the principles of the Declaration of Helsinki regarding investigations in humans. Percutaneous coronary intervention was performed by the standard manner according to clinical guidelines at the time of procedure. All patients received aspirin 325 mg before the procedure and a clopidogrel loading dose of 300 to 600 mg or prasugrel 60 mg during or immediately after stent implantation. Dual antiplatelet therapy consisting of aspirin (75 mg/day) and thienopyridines (75 mg/day clopidogrel or 10 mg/day prasugrel) was continued for 12 months after stent implantation, followed by aspirin indefinitely. During the procedure, patients were anticoagulated with bivalirudin (0.75 mg/kg bolus followed by a 1.75 mg/kg/h infusion) or unfractionated
Variable Targeted vessel Left main Left anterior descending Left circumflex Right Lesion location Proximal Mid Distal Ostial Restenostic lesion Lesion type (ACC/AHA classification) Type A Type B1/B2 Type C Diameter stenosis (%)* Procedural data Angiographic success Number of lesions treated/patient Number of implanted stents Stent diameter (mm) Total stent length per lesion (mm) Intravascular ultrasound use Abrupt closure No reflow
EES (n ¼ 237)
SES (n ¼ 252)
PES (n ¼ 182)
p
5 75 65 92
(2.1) (31.6) (27.4) (38.8)
3 107 44 95
(1.2) (42.5) (17.5) (37.7)
2 77 35 67
(1.1) (42.3) (19.2) (36.8)
0.721 0.024 0.019 0.914
54 104 72 2 4
(22.8) (43.9) (30.4) (0.8) (1.7)
140 61 35 6 11
(57.4) (25.0) (14.3) (2.5) (4.4)
77 59 34 12 11
(42.3) <0.001 (32.4) <0.001 (18.7) <0.001 (6.6) 0.002 (6.0) 0.063
18 (7.7) 66 (28.2) 150 (64.1) 84 12
15 (6.4) 166 (71.2) 52 (22.3) 87 11
5 (2.9) 0.115 126 (72.4) <0.001 43 (24.7) <0.001 85 9 0.028
236 (99.6) 1.4 0.7
234 (95.5) 2.1 1.1
179 (100) 2.0 0.9
<0.001 <0.001
2.5 0.7
2.0 0.9
2.2 0.8
<0.001
2.96 0.37 3.03 0.31 3.18 1.94 41.4 16.1 40.9 17.4 41.7 21.2
0.250 0.943
140 (59.1)
155 (64.9)
125 (69.4)
0.087
0 0
4 (1.8) 1 (0.5)
0 0
0.021 0.622
Data are presented as mean SD or n (%). ACC/AHA ¼ American College of Cardiology/American Heart Association; PCI ¼ percutaneous coronary intervention. * By visual estimation.
heparin (40 U/kg bolus with an additional dose to achieve an active clotting time of 250 seconds). The use of glycoprotein IIb/IIIa inhibitors (almost exclusively eptifibatide) was left to the discretion of the operator. The primary end point of the present study was major adverse cardiovascular events (MACE) at 12 months, defined as the composite of all-cause death, myocardial infarction (MI), or target lesion revascularization. Secondary end points included target lesion revascularization, target vessel revascularization, and definite stent thrombosis at 1 year. Angiographic success was defined as postprocedural stenosis of <30% with Thrombolysis In Myocardial Infarction flow grade 3. All-cause death was defined as death from any cardiac or noncardiac cause. MI was defined as a total creatine kinase of 2 the upper limit of normal and/or creatine kinase-MB 20 ng/ml, together with symptoms and/or ischemic electrocardiographic changes. Q-wave MI was defined as evidence of new pathologic Q waves (>0.4 second) in 2 contiguous leads on electrocardiogram. Target lesion revascularization was defined as any clinically driven repeat percutaneous intervention or bypass grafting of the treated lesion including in-stent and in-segment 5-mm proximal or distal to the initial stent
Coronary Artery Disease/Stent Overlap With DES Table 3 Clinical outcomes in-hospital, at 30-day, and at 1-year follow-up Variable In-hospital Emergent intra-aortic balloon pump All-cause death Cardiac death Q-wave MI Coronary artery bypass graft Acute renal failure Cerebrovascular accident Major bleeding 30-day follow-up MACE All-cause death Cardiac death Any MI Q-wave MI NoneQ-wave MI Target lesion revascularization Target vessel revascularization Stent thrombosis 1-yr follow-up MACE All-cause death Cardiac death Any MI Q-wave MI NoneQ-wave MI Target lesion revascularization Target vessel revascularization Stent thrombosis
EES SES PES (n ¼ 169) (n ¼ 102) (n ¼ 79)
p
7 (4.2)
5 (5.0)
1 (1.3)
0.468
2 (1.2) 2 (1.2) 0 0 4 (2.4) 1 (0.6) 3 (1.8)
4 (3.9) 3 (2.9) 1 (1.0) 0 5 (4.9) 0 2 (2.0)
2 (2.5) 1 (1.3) 1 (1.3) 0 3 (3.8) 0 1 (1.3)
0.331 0.567 0.264 — 0.479 1.000 1.000
3 (1.8) 3 (1.8) 2 (1.2) 0 0 0 0 1 (0.6) 0
5 4 3 1
(4.9) (3.9) (2.9) (1.0) 0 (1.0) (1.0) (1.0) (3.9)
4 2 1 1 1 0 3 4 2
(5.1) (2.5) (1.3) (1.3) (1.3) (1.3) (3.8) (5.1) (2.5)
0.199 0.508 0.567 0.265 0.226 0.516 0.022 0.045 0.014
11 (6.5) 6 (3.6) 3 (1.8) 0 0 0 5 (3.1) 6 (3.7) 0
17 9 4 1
(16.8) (9.0) (3.9) (1.0) 0 (1.0) (8.2) (9.1) (3.9)
8 4 3 2 1 1 5 9 2
(10.1) (5.1) (3.7) (2.5) (1.3) (1.3) (6.5) (11.7) (2.5)
0.026 0.162 0.501 0.080 0.228 0.266 0.181 0.051 0.014
1 1 1 4
1 8 9 4
Data are presented as n (%). PCI ¼ percutaneous coronary intervention.
edges. Target vessel revascularization was defined as any clinically driven percutaneous intervention or bypass grafting of the target vessel. Major bleeding was defined as the composite of gastrointestinal bleeding, a 15% absolute decrease in the hematocrit, or hematoma of >4 cm in diameter. Stent thrombosis was defined as definite stent thrombosis according to the Academic Research Consortium definition.18 All statistical analyses were performed using SAS, version 9.1 (SAS Institute, Cary, North Carolina). Data are presented as mean SD or number (%). Analyses of the differences among the 3 groups were performed using analysis of variance for continuous variables and the chi-square test or Fisher’s exact test for categorical variables. Cox proportional hazard analysis was performed to determine predictors of 1-year MACE. Variables were selected on the basis of overall clinical relevance, with particular attention paid to clinical and procedural factors that would make MACE more likely. Variables included in the model were male gender, systemic hypertension, stent type used, left anterior descending artery, type C lesion, total stent length per lesion, and number of implanted stents. After univariate analysis, all variables with a p value of <0.1 were incorporated into the multivariate analysis. The results are presented as adjusted hazard ratios with their 95% confidence intervals and p values. MACE-free
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survival rates and stent thrombosis rates were calculated using the Kaplan-Meier method. The log-rank test was used to compare the differences in curves among groups. Values of p <0.05 were considered to be statistically significant. Results A total of 350 patients treated with overlapping stents were included: EES: 169 patients, 237 lesions; SES: 102 patients, 252 lesions; and PES: 79 patients, 182 lesions. As listed in Table 1, baseline clinical characteristics were generally comparable among the 3 groups, save for male gender, systemic hypertension, and a history of MI. Angiographic and procedural characteristics are listed in Table 2. SES and PES were more frequently implanted in the left anterior descending coronary artery, whereas EES were more frequently implanted in the left circumflex artery. There were some differences among groups with respect to the lesion location. The EES group had more complex lesions as indicated by a roughly threefold higher rate of type C lesions compared with those of the SES and PES groups (64.1% vs 22.3% vs 24.7%, respectively, p <0.001). Although the average number of stents implanted per patient was higher in EES-treated patients, the total stent length per lesion was similar among the 3 groups. Angiographic success was lesser in the SES group. Abrupt closure after the procedure was observed in 1.8% of the SES group but did not occur in the EES and PES groups. Table 3 lists adverse clinical events. There were no significant differences with respect to in-hospital adverse events between the EES and first-generation DES groups. At 30 days, clinical event rates were similar among groups, except that lower incidences of target lesion revascularization, target vessel revascularization, and stent thrombosis were observed in the EES group. During 1-year follow-up, overall MACE occurred in 11 EES-treated patients (6.5%), 17 SES-treated patients (16.8%), and 8 PES-treated patients (10.1%; p ¼ 0.026 for all groups, p ¼ 0.014 for EES vs SES, and p ¼ 0.458 for EES vs PES, respectively; Figure 1) All-cause mortality was similar among the 3 groups (EES 3.6% vs SES 9.0% vs PES 5.1%, p ¼ 0.162). The rate of MI was the lowest in the EES group: EES 0 versus SES 1.0% versus PES 2.5% (p ¼ 0.080). At 1 year, EESs were associated with a numerically lower rate of target lesion revascularization compared with that of SES and PES, respectively (3.1% vs 8.2% vs 6.5%, p ¼ 0.181) but reached statistical significance only when compared with SES (p ¼ 0.033). There was a trend toward lower 1-year target vessel revascularization rates with EES compared with those of SES and PES, respectively (3.7% vs 9.1% vs 11.7%, p ¼ 0.051). The cumulative incidence of definite stent thrombosis was significantly lower in patients treated with EES (0%) than in patients treated with SES (3.9%, p ¼ 0.038 for EES vs SES) or PES (2.5%, p ¼ 0.189 for EES vs PES; p ¼ 0.014 for all groups). In our series, all stent thrombosis occurred within 30 days after implantation and no patients experienced late stent thrombosis during 1 to 12 months (Figure 2). There was no definite stent thrombosis observed in the EES group at all time points throughout 1-year follow-up. On univariate analysis, the use of SES was the strongest predictor of 1-year MACE (hazard ratio 2.31, 95% confidence
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Figure 1. Kaplan-Meier event-free survival curves for MACE according to stent type at 12 months.
Figure 2. Kaplan-Meier cumulative event curves for definite stent thrombosis according to stent type at 12 months.
interval 1.20 to 4.45, p ¼ 0.012). The total stent length was also significantly associated with the occurrence of MACE (hazard ratio 1.07, 95% confidence interval 1.01 to 1.13, p ¼ 0.027). However, multivariate analysis proved that compared with EES, the use of SES showed a borderline independent significant association with a higher incidence of MACE at 1 year after adjusting for important potential confounders (hazard ratio 1.87, 95% confidence interval 0.93 to 3.77, p ¼ 0.080; Table 4). Discussion The major findings of the present study are (1) stent overlap with second-generation EES was associated with
lower rates of the primary composite end points of all-cause mortality, MI, and target lesion revascularization compared with first-generation DES—with significant lower rates compared with SES and a trend toward lower rates compared with PES and (2) overlapping EES was associated with lower rates of 1-year definite stent thrombosis compared with those of SES and a trend for lower stent thrombosis compared with PES—with no reported events of stent thrombosis throughout 1-year follow-up. These findings suggest that overlap with second-generation EES is effective and safe. In routine clinical practice, stent overlap has been reported in >10% of patients undergoing percutaneous coronary intervention, mainly owing to excessive lesion length,
Coronary Artery Disease/Stent Overlap With DES Table 4 Univariate and multivariate analysis for predictors of 1-year major adverse cardiovascular events (MACE) Variable
Men Hypertension SES (vs EES) PES (vs EES) Left anterior descending Type C lesion Total stent length per lesion Number of implanted stents
Univariate Analysis HR
95% CI
0.54 0.83 2.31 0.98 1.17
0.28e1.03 0.34e1.98 1.20e4.45 0.45e2.15 0.61e2.24
p
Multivariate Analysis HR
95% CI
p
0.061 0.56 0.29e1.08 0.082 0.668 — — — 0.012 1.87 0.93e3.77 0.080 0.956 — — — 0.644 — — —
0.63 0.32e1.23 0.176 — — — 1.07 1.01e1.13 0.027 1.04 0.98e1.11 0.146 0.96 0.64e1.45 0.865
—
—
—
Multivariate analysis included relevant variables for MACE with univariate p value <0.1. CI ¼ confidential interval; HR ¼ hazard ratio; PCI ¼ percutaneous coronary intervention.
incomplete lesion coverage, or edge dissections.7 The introduction of first-generation DES has markedly attenuated the association between stent length and restenosis, and overlapping DESs have been shown to be associated with lower rates of MACE compared with overlapping BMS.10,19 However, there are limited data comparing the safety and efficacy of overlapping stents among different DES types. Furthermore, the clinical results of overlap with secondgeneration DES have not been well known. Chu et al11 compared clinical outcomes of overlapping SES versus PES. As a result, target lesion revascularization (5.5% vs 1.8%, p ¼ 0.30) and MACE (9.1% vs 5.4%, p ¼ 0.45) at 6 months were not significantly different between SES and PES groups. Similarly, Shishehbor et al13 observed no significant differences in safety or efficacy between overlapping SES and PES at a median follow-up of 24 months. Her et al20 analyzed the difference in MACE between first-generation and second-generation DES; stent overlap with second-generation DES showed a lesser occurrence of MACE (7.0% vs 11.8%, p ¼ 0.012). This study included 197 overlapping EES-treated patients. Fourteen (7.1%) of these patients experienced an MACE during follow-up. This event rate agrees with that observed in EES-treated patients from our registry (6.5%). Furthermore, in the present study, we found that overall MACE rates of patients who received overlapping EES were less than those of patients who received overlapping SES or PES (6.5% vs 16.8% vs 10.1%, p ¼ 0.026). Thus, compared with first-generation DES, the better clinical outcomes of EES observed in our study and the study by Her et al may be attributed mainly to the differences in stent design, such as strut thickness, delivery platform, polymer coating, drug, and drug release profile. Indeed, Otake et al,21 using intravascular ultrasound, reported that overlapping EESs were associated with significantly greater neointimal suppression in the singlestrut regions than were PESs, with a similar trend in the overlap region. Using optical coherence tomography, Mori et al22 have demonstrated that at the overlapped site,
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percentage neointimal hyperplasia and strut-level neointimal thickness in EES are significantly smaller than in SES. In addition, a BMS with thinner strut thickness has recently been shown to be associated with favorable vascular response, with a significant reduction of neointimal proliferation even at the site of overlap in a porcine model.23 Despite the benefits seen with EES, differences in MACE and target lesion revascularization rates between EES and PES did not reach statistical significance. Furthermore, after adjustment, the use of SES versus EES was no longer significantly associated with the risk of MACE (hazard ratio 1.87, 95% confidence interval 0.93 to 3.77, p ¼ 0.080). This could be because of the limited power of our study and a small study population. Therefore, our initial findings must be confirmed in an adequately powered randomized clinical trial. Second-generation EESs have emerged as a promising technology to improve the overall safety of first-generation DES, especially regarding the incidence of stent thrombosis. In the present study, the incidence of definite stent thrombosis at 1 year was lower in the EES group, with zero stent thrombosis at all time points during follow-up. This finding may be explained in part by the more biocompatible nonthrombogenic fluoropolymer on the EES surface, in addition to a thin strut design.24 Another potential explanation could be more rapid reendothelialization with EES compared with SES and PES, as documented in a rabbit iliac artery model.25 In fact, previous optical coherence tomographic studies have demonstrated that EES are associated with fewer uncovered struts and a lower incidence of intracoronary subclinical thrombus compared with SES and PES at follow-up.26,27 However, longer-term follow-up, particularly after dual antiplatelet therapy is terminated, is needed to determine whether the use of EES when deploying overlapping stents will improve the increased risk of late stent thrombosis >1 year after first-generation DES implantation, as was documented in a pooled analysis of 4 randomized controlled trials comparing SES or PES with BMS.2 Our study has several potential limitations. First, it is limited by a small sample size, its retrospective nature, and only 1-year follow-up. Moreover, this was a nonrandomized comparison among DESs. Therefore, there could be several potential biases in the results. Second, the present analysis included patients treated during a long-term period during which changes in percutaneous coronary intervention strategies (e.g., stent deployment techniques and duration of dual antiplatelet therapy) may have had an impact on the clinical outcomes, irrespective of the stent type used. Third, because this study lacks systematic angiographic follow-up data, we could not evaluate possible complications (stent fracture or aneurysmal formation) at the overlapping site nor the angiographic characteristics of restenosis, such as site and pattern. Finally, the reasons for stent overlap were not collected. Disclosures The authors have no conflicts of interest to disclose. 1. Kastrati A, Mehilli J, Pache J, Kaiser C, Valgimigli M, Kelbaek H, Menichelli M, Sabaté M, Suttorp MJ, Baumgart D, Seyfarth M, Pfisterer ME, Schömig A. An analysis of 14 trials comparing sirolimuseluting stents with bare-metal stents. N Engl J Med 2007;356: 1030e1039.
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2. Stone GW, Moses JW, Ellis SG, Schofer J, Dawkins KD, Morice MC, Colombo A, Schampaert E, Grube E, Kirtane AJ, Cutlip DE, Fahy M, Pocock SJ, Mehran R, Leon MB. Safety and efficacy of sirolimus- and paclitaxel-eluting coronary stents. N Engl J Med 2007;356:998e1008. 3. Clark DJ, Wong MC, Chan RK, Oliver LE, Ajani AE. Very late drugeluting stent thrombosis. Cardiovasc Revasc Med 2007;8:72e75. 4. Aytekin V, Erdim R, Gormez S, Demiroglu C. Very late thrombosis of paclitaxel-eluting stent. Cardiovasc Revasc Med 2008;9:275e277. 5. Finn AV, Nakazawa G, Joner M, Kolodgie FD, Mont EK, Gold HK, Virmani R. Vascular responses to drug eluting stents: importance of delayed healing. Arterioscler Thromb Vasc Biol 2007;27:1500e1510. 6. Finn AV, Kolodgie FD, Harnek J, Guerrero LJ, Acampado E, Tefera K, Skorija K, Weber DK, Gold HK, Virmani R. Differential response of delayed healing and persistent inflammation at sites of overlapping sirolimus- or paclitaxel-eluting stents. Circulation 2005;112:270e278. 7. Räber L, Jüni P, Löffel L, Wandel S, Cook S, Wenaweser P, Togni M, Vogel R, Seiler C, Eberli F, Lüscher T, Meier B, Windecker S. Impact of stent overlap on angiographic and long-term clinical outcome in patients undergoing drug-eluting stent implantation. J Am Coll Cardiol 2010;55:1178e1188. 8. Aoki J, Ong AT, Rodriguez Granillo GA, McFadden EP, van Mieghem CA, Valgimigli M, Tsuchida K, Sianos G, Regar E, de Jaegere PP, van der Giessen WJ, de Feyter PJ, van Domburg RT, Serruys PW. “Full metal jacket” (stented length > or ¼64 mm) using drug-eluting stents for de novo coronary artery lesions. Am Heart J 2005;150:994e999. 9. Tsagalou E, Chieffo A, Iakovou I, Ge L, Sangiorgi GM, Corvaja N, Airoldi F, Montorfano M, Michev I, Colombo A. Multiple overlapping drug-eluting stents to treat diffuse disease of the left anterior descending coronary artery. J Am Coll Cardiol 2005;45:1570e1573. 10. Kereiakes DJ, Wang H, Popma JJ, Kuntz RE, Donohoe DJ, Schofer J, Schampaert E, Meier B, Leon MB, Moses JW. Periprocedural and late consequences of overlapping Cypher sirolimus-eluting stents: pooled analysis of five clinical trials. J Am Coll Cardiol 2006;48:21e31. 11. Chu WW, Kuchulakanti PK, Torguson R, Wang B, Clavijo LC, Suddath WO, Pichard AD, Satler LF, Kent KM, Waksman R. Comparison of clinical outcomes of overlapping sirolimus- versus paclitaxel-eluting stents in patients undergoing percutaneous coronary intervention. Am J Cardiol 2006;98:1563e1566. 12. Chu WW, Kuchulakanti PK, Torguson R, Wang B, Clavijo LC, Suddath WO, Pichard AD, Satler LF, Kent KM, Waksman R. Impact of overlapping drug-eluting stents in patients undergoing percutaneous coronary intervention. Catheter Cardiovasc Interv 2006;67:595e599. 13. Shishehbor MH, Amini R, Raymond RE, Bavry AA, Brener SJ, Kapadia SR, Whitlow PL, Ellis SG, Bhatt DL. Safety and efficacy of overlapping sirolimus-eluting versus paclitaxel-eluting stents. Am Heart J 2008;155:1075e1080. 14. Sharp AS, Latib A, Ielasi A, Larosa C, Godino C, Saolini M, Magni V, Gerber RT, Montorfano M, Carlino M, Michev I, Chieffo A, Colombo A. Long-term follow-up on a large cohort of “full-metal jacket” percutaneous coronary intervention procedures. Circ Cardiovasc Interv 2009;2: 416e422. 15. Stone GW, Midei M, Newman W, Sanz M, Hermiller JB, Williams J, Farhat N, Caputo R, Xenopoulos N, Applegate R, Gordon P, White RM, Sudhir K, Cutlip DE, Petersen JL; SPIRIT III Investigators. 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
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26.
27.
of Patients with de novo Native Coronary Artery Lesions (SPIRIT) III trial. Circulation 2009;119:680e686. Kedhi E, Joesoef KS, McFadden E, Wassing J, van Mieghem C, Goedhart D, Smits PC. Second-generation everolimus-eluting and paclitaxel-eluting stents in real-life practice (COMPARE): a randomised trial. Lancet 2010;375:201e209. Räber L, Jüni P, Nüesch E, Kalesan B, Wenaweser P, Moschovitis A, Khattab AA, Bahlo M, Togni M, Cook S, Vogel R, Seiler C, Meier B, Windecker S. Long-term comparison of everolimus-eluting and sirolimus-eluting stents for coronary revascularization. J Am Coll Cardiol 2011;57:2143e2151. Cutlip DE, Windecker S, Mehran R, Boam A, Cohen DJ, van Es GA, Steg PG, Morel MA, Mauri L, Vranckx P, McFadden E, Lansky A, Hamon M, Krucoff MW, Serruys PW; Academic Research Consortium. Clinical end points in coronary stent trials: a case of standardized definitions. Circulation 2007;115:2344e2351. Dawkins KD, Grube E, Guagliumi G, Banning AP, Zmudka K, Colombo A, Thuesen L, Hauptman K, Marco J, Wijns W, Popma JJ, Weissman NJ, Koglin J, Russell ME. Safety and efficacy of multiple, overlapping polymer-based paclitaxel-eluting stents. EuroIntervention 2007;3:213e221. Her SH, Yoo KD, Park CS, Kim DB, Lee JM, Kim PJ, Kim HY, Chang K, Jeon DS, Chung WS, Seung KB, Kim JH. Long-term clinical outcomes of overlapping heterogeneous drug-eluting stents compared with homogeneous drug-eluting stents. Heart 2011;97:1501e1506. Otake H, Honda Y, Yamasaki M, Tsujino I, Shimohama T, Sakurai R, Hasegawa T, Waseda K, Ako J, Fitzgerald PJ. Vascular response to overlapping everolimus-eluting stents. Comparison with paclitaxeleluting stents. Circ J 2010;74:1023e1025. Mori N, Nishino M, Nakamura D, Lee Y, Yoshimura T, Taniike M, Nobuhiko Makino N, Kato H, Egami Y, Shutta R, Morita H, Tanouchi J, Yamada Y. Different neointimal response to overlapping segments between everolimus-eluting stents and sirolimus-eluting stents—optical coherence tomographic study. Circulation 2011;124:A12546. Jabara R, Geva S, Ribeiro HB, Chen JP, Hou D, Li J, King SB, Chronos N, Robinson KA. A third generation ultra-thin strut cobalt chromium stent: histopathological evaluation in porcine coronary arteries. EuroIntervention 2009;5:619e626. Kolandaivelu K, Swaminathan R, Gibson WJ, Kolachalama VB, Nguyen-Ehrenreich KL, Giddings VL, Coleman L, Wong GK, Edelman ER. Stent thrombogenicity early in high-risk interventional settings is driven by stent design and deployment and protected by polymer-drug coatings. Circulation 2011;123:1400e1409. Joner M, Nakazawa G, Finn AV, Quee SC, Coleman L, Acampado E, Wilson PS, Skorija K, Cheng Q, Xu X, Gold HK, Kolodgie FD, Virmani R. Endothelial cell recovery between comparator polymerbased drug-eluting stents. J Am Coll Cardiol 2008;52:333e342. Choi HH, Kim JS, Yoon DH, Hong KS, Kim TH, Kim BK, Ko YG, Choi D, Jang Y, Hong MK. Favorable neointimal coverage in everolimus-eluting stent at 9 months after stent implantation: comparison with sirolimus-eluting stent using optical coherence tomography. Int J Cardiovasc Imaging 2012;28:491e497. Takano M, Murakami D, Yamamoto M, Kurihara O, Murai K, Inami T, Kimata N, Ohba T, Seino Y, Mizuno K. Six-month follow-up evaluation for everolimus-eluting stents by intracoronary optical coherence tomography: comparison with paclitaxel-eluting stents. Int J Cardiol 2011 Nov 8. [Epub ahead of print]
Division of Cardiology, MedStar Washington Hospital Center, Washington, District of Columbia. Manuscript received April 10, 2013; revised manuscript received and accepted May 20, 2013. See page 1097 for disclosure information. *Corresponding author: Tel: (202) 877-2812; fax: (202) 877-2715. E-mail address: [email protected] (R. Waksman). 0002-9149/13/$ - see front matter Ó 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjcard.2013.05.054
although the second-generation everolimus-eluting stents (EES) have been shown to be superior to first-generation DES in a number of settings15e17; the safety and efficacy of stent overlap with EES remains unknown. The aim of this study was to compare the 1-year clinical outcomes of overlapping second-generation EES with those of overlapping first-generation DES. Methods From April 2003 to December 2011, patients in whom native coronary arteries were treated with overlapping EES (Xience V, Abbott Vascular, Santa Clara, California or Promus, Boston Scientific, Natick, Massachusetts) or sirolimus-eluting stents (SES; Cypher, Cordis, Miami Lakes, Florida) or paclitaxel-eluting stents (PES; Taxus, Boston Scientific Corporation) were retrospectively included in this study from our institution’s registry. The choice of stent type was at the discretion of the operator. Stent overlap was defined as the presence of 2 stents within a single treated lesion and an overlapping stent zone of 1 mm, as determined by angiography.7 Total stent length per lesion was reported based on the cumulative length of the adjacent stents. We excluded patients who received a BMS. Patients who received heterogenous overlapping stents (e.g., SES-PES) were also excluded. Clinical and demographic www.ajconline.org
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Table 1 Baseline clinical characteristics Variable
EES (n ¼ 169)
Table 2 Lesion-based angiographic and procedural characteristics SES (n ¼ 102)
PES (n ¼ 79)
p
Age (yrs) 64.6 11.3 65.9 11.7 65.3 12.1 0.650 Men 122 (72.2) 59 (57.8) 43 (54.4) 0.008 Systemic hypertension* 156 (92.3) 72 (70.6) 63 (79.7) <0.001 Diabetes mellitus 70 (41.7) 34 (33.3) 28 (35.4) 0.346 81 (81.8) 69 (87.3) 0.161 Hypercholesterolemiaz 152 (89.9) Current smoker 36 (21.3) 21 (20.6) 15 (19.0) 0.916 Family history of CAD 81 (47.9) 55 (55.6) 39 (52.7) 0.463 Previous MI 40 (24.1) 15 (16.0) 23 (30.7) 0.075 Previous CABG 21 (12.5) 17 (17.0) 10 (13.0) 0.568 Previous PCI 59 (35.3) 26 (27.7) 30 (39.0) 0.265 28 (16.6) 9 (8.9) 12 (15.4) 0.201 Chronic renal insufficiency† Dialysis 0 2 (2.0) 1 (1.3) 0.135 Peripheral vascular 27 (16.0) 20 (19.8) 17 (21.8) 0.498 disease Clinical presentation Stable angina pectoris 64 (38.1) 41 (40.2) 23 (29.1) 0.268 Unstable angina 72 (42.9) 40 (39.2) 43 (54.4) 0.106 pectoris Acute MI 25 (14.9) 8 (7.8) 6 (7.6) 0.106 Cardiogenic shock 3 (1.8) 4 (4.0) 0 0.211 Number of diseased 1.7 0.7 1.9 0.8 1.6 0.8 0.121 vessels Chronic heart failure 17 (10.1) 16 (17.2) 11 (14.5) 0.244 Left ventricular 0.50 0.11 0.49 0.14 0.49 0.14 0.836 ejection fraction Data are presented as mean SD or n (%). CABG ¼ coronary artery bypass graft; CAD ¼ coronary artery disease; PCI ¼ percutaneous coronary intervention. * Blood pressure of >140/90 mm Hg or the use of antihypertensive drug. † Fasting cholesterol of >250 mg/dl or the use of lipid-lowering drug. z Previously diagnosed or treated with medication, diet, or dialysis by a physician. Diagnosis at admission if a baseline creatinine level >2.0 mg/dl is found.
data as well as clinical events during hospitalization were collected from hospital charts, reviewed by qualified personnel blinded to the objectives of the study, and entered prospectively into the database. Every patient underwent 30-day, 6-month, and 1-year clinical follow-up by qualified personnel through telephonic interview or office visit. Clinical events were adjudicated by source documentation by independent physicians not involved in the procedures. Written, informed consent was obtained from all patients before the cardiac catheterization. The study complied with the principles of the Declaration of Helsinki regarding investigations in humans. Percutaneous coronary intervention was performed by the standard manner according to clinical guidelines at the time of procedure. All patients received aspirin 325 mg before the procedure and a clopidogrel loading dose of 300 to 600 mg or prasugrel 60 mg during or immediately after stent implantation. Dual antiplatelet therapy consisting of aspirin (75 mg/day) and thienopyridines (75 mg/day clopidogrel or 10 mg/day prasugrel) was continued for 12 months after stent implantation, followed by aspirin indefinitely. During the procedure, patients were anticoagulated with bivalirudin (0.75 mg/kg bolus followed by a 1.75 mg/kg/h infusion) or unfractionated
Variable Targeted vessel Left main Left anterior descending Left circumflex Right Lesion location Proximal Mid Distal Ostial Restenostic lesion Lesion type (ACC/AHA classification) Type A Type B1/B2 Type C Diameter stenosis (%)* Procedural data Angiographic success Number of lesions treated/patient Number of implanted stents Stent diameter (mm) Total stent length per lesion (mm) Intravascular ultrasound use Abrupt closure No reflow
EES (n ¼ 237)
SES (n ¼ 252)
PES (n ¼ 182)
p
5 75 65 92
(2.1) (31.6) (27.4) (38.8)
3 107 44 95
(1.2) (42.5) (17.5) (37.7)
2 77 35 67
(1.1) (42.3) (19.2) (36.8)
0.721 0.024 0.019 0.914
54 104 72 2 4
(22.8) (43.9) (30.4) (0.8) (1.7)
140 61 35 6 11
(57.4) (25.0) (14.3) (2.5) (4.4)
77 59 34 12 11
(42.3) <0.001 (32.4) <0.001 (18.7) <0.001 (6.6) 0.002 (6.0) 0.063
18 (7.7) 66 (28.2) 150 (64.1) 84 12
15 (6.4) 166 (71.2) 52 (22.3) 87 11
5 (2.9) 0.115 126 (72.4) <0.001 43 (24.7) <0.001 85 9 0.028
236 (99.6) 1.4 0.7
234 (95.5) 2.1 1.1
179 (100) 2.0 0.9
<0.001 <0.001
2.5 0.7
2.0 0.9
2.2 0.8
<0.001
2.96 0.37 3.03 0.31 3.18 1.94 41.4 16.1 40.9 17.4 41.7 21.2
0.250 0.943
140 (59.1)
155 (64.9)
125 (69.4)
0.087
0 0
4 (1.8) 1 (0.5)
0 0
0.021 0.622
Data are presented as mean SD or n (%). ACC/AHA ¼ American College of Cardiology/American Heart Association; PCI ¼ percutaneous coronary intervention. * By visual estimation.
heparin (40 U/kg bolus with an additional dose to achieve an active clotting time of 250 seconds). The use of glycoprotein IIb/IIIa inhibitors (almost exclusively eptifibatide) was left to the discretion of the operator. The primary end point of the present study was major adverse cardiovascular events (MACE) at 12 months, defined as the composite of all-cause death, myocardial infarction (MI), or target lesion revascularization. Secondary end points included target lesion revascularization, target vessel revascularization, and definite stent thrombosis at 1 year. Angiographic success was defined as postprocedural stenosis of <30% with Thrombolysis In Myocardial Infarction flow grade 3. All-cause death was defined as death from any cardiac or noncardiac cause. MI was defined as a total creatine kinase of 2 the upper limit of normal and/or creatine kinase-MB 20 ng/ml, together with symptoms and/or ischemic electrocardiographic changes. Q-wave MI was defined as evidence of new pathologic Q waves (>0.4 second) in 2 contiguous leads on electrocardiogram. Target lesion revascularization was defined as any clinically driven repeat percutaneous intervention or bypass grafting of the treated lesion including in-stent and in-segment 5-mm proximal or distal to the initial stent
Coronary Artery Disease/Stent Overlap With DES Table 3 Clinical outcomes in-hospital, at 30-day, and at 1-year follow-up Variable In-hospital Emergent intra-aortic balloon pump All-cause death Cardiac death Q-wave MI Coronary artery bypass graft Acute renal failure Cerebrovascular accident Major bleeding 30-day follow-up MACE All-cause death Cardiac death Any MI Q-wave MI NoneQ-wave MI Target lesion revascularization Target vessel revascularization Stent thrombosis 1-yr follow-up MACE All-cause death Cardiac death Any MI Q-wave MI NoneQ-wave MI Target lesion revascularization Target vessel revascularization Stent thrombosis
EES SES PES (n ¼ 169) (n ¼ 102) (n ¼ 79)
p
7 (4.2)
5 (5.0)
1 (1.3)
0.468
2 (1.2) 2 (1.2) 0 0 4 (2.4) 1 (0.6) 3 (1.8)
4 (3.9) 3 (2.9) 1 (1.0) 0 5 (4.9) 0 2 (2.0)
2 (2.5) 1 (1.3) 1 (1.3) 0 3 (3.8) 0 1 (1.3)
0.331 0.567 0.264 — 0.479 1.000 1.000
3 (1.8) 3 (1.8) 2 (1.2) 0 0 0 0 1 (0.6) 0
5 4 3 1
(4.9) (3.9) (2.9) (1.0) 0 (1.0) (1.0) (1.0) (3.9)
4 2 1 1 1 0 3 4 2
(5.1) (2.5) (1.3) (1.3) (1.3) (1.3) (3.8) (5.1) (2.5)
0.199 0.508 0.567 0.265 0.226 0.516 0.022 0.045 0.014
11 (6.5) 6 (3.6) 3 (1.8) 0 0 0 5 (3.1) 6 (3.7) 0
17 9 4 1
(16.8) (9.0) (3.9) (1.0) 0 (1.0) (8.2) (9.1) (3.9)
8 4 3 2 1 1 5 9 2
(10.1) (5.1) (3.7) (2.5) (1.3) (1.3) (6.5) (11.7) (2.5)
0.026 0.162 0.501 0.080 0.228 0.266 0.181 0.051 0.014
1 1 1 4
1 8 9 4
Data are presented as n (%). PCI ¼ percutaneous coronary intervention.
edges. Target vessel revascularization was defined as any clinically driven percutaneous intervention or bypass grafting of the target vessel. Major bleeding was defined as the composite of gastrointestinal bleeding, a 15% absolute decrease in the hematocrit, or hematoma of >4 cm in diameter. Stent thrombosis was defined as definite stent thrombosis according to the Academic Research Consortium definition.18 All statistical analyses were performed using SAS, version 9.1 (SAS Institute, Cary, North Carolina). Data are presented as mean SD or number (%). Analyses of the differences among the 3 groups were performed using analysis of variance for continuous variables and the chi-square test or Fisher’s exact test for categorical variables. Cox proportional hazard analysis was performed to determine predictors of 1-year MACE. Variables were selected on the basis of overall clinical relevance, with particular attention paid to clinical and procedural factors that would make MACE more likely. Variables included in the model were male gender, systemic hypertension, stent type used, left anterior descending artery, type C lesion, total stent length per lesion, and number of implanted stents. After univariate analysis, all variables with a p value of <0.1 were incorporated into the multivariate analysis. The results are presented as adjusted hazard ratios with their 95% confidence intervals and p values. MACE-free
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survival rates and stent thrombosis rates were calculated using the Kaplan-Meier method. The log-rank test was used to compare the differences in curves among groups. Values of p <0.05 were considered to be statistically significant. Results A total of 350 patients treated with overlapping stents were included: EES: 169 patients, 237 lesions; SES: 102 patients, 252 lesions; and PES: 79 patients, 182 lesions. As listed in Table 1, baseline clinical characteristics were generally comparable among the 3 groups, save for male gender, systemic hypertension, and a history of MI. Angiographic and procedural characteristics are listed in Table 2. SES and PES were more frequently implanted in the left anterior descending coronary artery, whereas EES were more frequently implanted in the left circumflex artery. There were some differences among groups with respect to the lesion location. The EES group had more complex lesions as indicated by a roughly threefold higher rate of type C lesions compared with those of the SES and PES groups (64.1% vs 22.3% vs 24.7%, respectively, p <0.001). Although the average number of stents implanted per patient was higher in EES-treated patients, the total stent length per lesion was similar among the 3 groups. Angiographic success was lesser in the SES group. Abrupt closure after the procedure was observed in 1.8% of the SES group but did not occur in the EES and PES groups. Table 3 lists adverse clinical events. There were no significant differences with respect to in-hospital adverse events between the EES and first-generation DES groups. At 30 days, clinical event rates were similar among groups, except that lower incidences of target lesion revascularization, target vessel revascularization, and stent thrombosis were observed in the EES group. During 1-year follow-up, overall MACE occurred in 11 EES-treated patients (6.5%), 17 SES-treated patients (16.8%), and 8 PES-treated patients (10.1%; p ¼ 0.026 for all groups, p ¼ 0.014 for EES vs SES, and p ¼ 0.458 for EES vs PES, respectively; Figure 1) All-cause mortality was similar among the 3 groups (EES 3.6% vs SES 9.0% vs PES 5.1%, p ¼ 0.162). The rate of MI was the lowest in the EES group: EES 0 versus SES 1.0% versus PES 2.5% (p ¼ 0.080). At 1 year, EESs were associated with a numerically lower rate of target lesion revascularization compared with that of SES and PES, respectively (3.1% vs 8.2% vs 6.5%, p ¼ 0.181) but reached statistical significance only when compared with SES (p ¼ 0.033). There was a trend toward lower 1-year target vessel revascularization rates with EES compared with those of SES and PES, respectively (3.7% vs 9.1% vs 11.7%, p ¼ 0.051). The cumulative incidence of definite stent thrombosis was significantly lower in patients treated with EES (0%) than in patients treated with SES (3.9%, p ¼ 0.038 for EES vs SES) or PES (2.5%, p ¼ 0.189 for EES vs PES; p ¼ 0.014 for all groups). In our series, all stent thrombosis occurred within 30 days after implantation and no patients experienced late stent thrombosis during 1 to 12 months (Figure 2). There was no definite stent thrombosis observed in the EES group at all time points throughout 1-year follow-up. On univariate analysis, the use of SES was the strongest predictor of 1-year MACE (hazard ratio 2.31, 95% confidence
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Figure 1. Kaplan-Meier event-free survival curves for MACE according to stent type at 12 months.
Figure 2. Kaplan-Meier cumulative event curves for definite stent thrombosis according to stent type at 12 months.
interval 1.20 to 4.45, p ¼ 0.012). The total stent length was also significantly associated with the occurrence of MACE (hazard ratio 1.07, 95% confidence interval 1.01 to 1.13, p ¼ 0.027). However, multivariate analysis proved that compared with EES, the use of SES showed a borderline independent significant association with a higher incidence of MACE at 1 year after adjusting for important potential confounders (hazard ratio 1.87, 95% confidence interval 0.93 to 3.77, p ¼ 0.080; Table 4). Discussion The major findings of the present study are (1) stent overlap with second-generation EES was associated with
lower rates of the primary composite end points of all-cause mortality, MI, and target lesion revascularization compared with first-generation DES—with significant lower rates compared with SES and a trend toward lower rates compared with PES and (2) overlapping EES was associated with lower rates of 1-year definite stent thrombosis compared with those of SES and a trend for lower stent thrombosis compared with PES—with no reported events of stent thrombosis throughout 1-year follow-up. These findings suggest that overlap with second-generation EES is effective and safe. In routine clinical practice, stent overlap has been reported in >10% of patients undergoing percutaneous coronary intervention, mainly owing to excessive lesion length,
Coronary Artery Disease/Stent Overlap With DES Table 4 Univariate and multivariate analysis for predictors of 1-year major adverse cardiovascular events (MACE) Variable
Men Hypertension SES (vs EES) PES (vs EES) Left anterior descending Type C lesion Total stent length per lesion Number of implanted stents
Univariate Analysis HR
95% CI
0.54 0.83 2.31 0.98 1.17
0.28e1.03 0.34e1.98 1.20e4.45 0.45e2.15 0.61e2.24
p
Multivariate Analysis HR
95% CI
p
0.061 0.56 0.29e1.08 0.082 0.668 — — — 0.012 1.87 0.93e3.77 0.080 0.956 — — — 0.644 — — —
0.63 0.32e1.23 0.176 — — — 1.07 1.01e1.13 0.027 1.04 0.98e1.11 0.146 0.96 0.64e1.45 0.865
—
—
—
Multivariate analysis included relevant variables for MACE with univariate p value <0.1. CI ¼ confidential interval; HR ¼ hazard ratio; PCI ¼ percutaneous coronary intervention.
incomplete lesion coverage, or edge dissections.7 The introduction of first-generation DES has markedly attenuated the association between stent length and restenosis, and overlapping DESs have been shown to be associated with lower rates of MACE compared with overlapping BMS.10,19 However, there are limited data comparing the safety and efficacy of overlapping stents among different DES types. Furthermore, the clinical results of overlap with secondgeneration DES have not been well known. Chu et al11 compared clinical outcomes of overlapping SES versus PES. As a result, target lesion revascularization (5.5% vs 1.8%, p ¼ 0.30) and MACE (9.1% vs 5.4%, p ¼ 0.45) at 6 months were not significantly different between SES and PES groups. Similarly, Shishehbor et al13 observed no significant differences in safety or efficacy between overlapping SES and PES at a median follow-up of 24 months. Her et al20 analyzed the difference in MACE between first-generation and second-generation DES; stent overlap with second-generation DES showed a lesser occurrence of MACE (7.0% vs 11.8%, p ¼ 0.012). This study included 197 overlapping EES-treated patients. Fourteen (7.1%) of these patients experienced an MACE during follow-up. This event rate agrees with that observed in EES-treated patients from our registry (6.5%). Furthermore, in the present study, we found that overall MACE rates of patients who received overlapping EES were less than those of patients who received overlapping SES or PES (6.5% vs 16.8% vs 10.1%, p ¼ 0.026). Thus, compared with first-generation DES, the better clinical outcomes of EES observed in our study and the study by Her et al may be attributed mainly to the differences in stent design, such as strut thickness, delivery platform, polymer coating, drug, and drug release profile. Indeed, Otake et al,21 using intravascular ultrasound, reported that overlapping EESs were associated with significantly greater neointimal suppression in the singlestrut regions than were PESs, with a similar trend in the overlap region. Using optical coherence tomography, Mori et al22 have demonstrated that at the overlapped site,
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percentage neointimal hyperplasia and strut-level neointimal thickness in EES are significantly smaller than in SES. In addition, a BMS with thinner strut thickness has recently been shown to be associated with favorable vascular response, with a significant reduction of neointimal proliferation even at the site of overlap in a porcine model.23 Despite the benefits seen with EES, differences in MACE and target lesion revascularization rates between EES and PES did not reach statistical significance. Furthermore, after adjustment, the use of SES versus EES was no longer significantly associated with the risk of MACE (hazard ratio 1.87, 95% confidence interval 0.93 to 3.77, p ¼ 0.080). This could be because of the limited power of our study and a small study population. Therefore, our initial findings must be confirmed in an adequately powered randomized clinical trial. Second-generation EESs have emerged as a promising technology to improve the overall safety of first-generation DES, especially regarding the incidence of stent thrombosis. In the present study, the incidence of definite stent thrombosis at 1 year was lower in the EES group, with zero stent thrombosis at all time points during follow-up. This finding may be explained in part by the more biocompatible nonthrombogenic fluoropolymer on the EES surface, in addition to a thin strut design.24 Another potential explanation could be more rapid reendothelialization with EES compared with SES and PES, as documented in a rabbit iliac artery model.25 In fact, previous optical coherence tomographic studies have demonstrated that EES are associated with fewer uncovered struts and a lower incidence of intracoronary subclinical thrombus compared with SES and PES at follow-up.26,27 However, longer-term follow-up, particularly after dual antiplatelet therapy is terminated, is needed to determine whether the use of EES when deploying overlapping stents will improve the increased risk of late stent thrombosis >1 year after first-generation DES implantation, as was documented in a pooled analysis of 4 randomized controlled trials comparing SES or PES with BMS.2 Our study has several potential limitations. First, it is limited by a small sample size, its retrospective nature, and only 1-year follow-up. Moreover, this was a nonrandomized comparison among DESs. Therefore, there could be several potential biases in the results. Second, the present analysis included patients treated during a long-term period during which changes in percutaneous coronary intervention strategies (e.g., stent deployment techniques and duration of dual antiplatelet therapy) may have had an impact on the clinical outcomes, irrespective of the stent type used. Third, because this study lacks systematic angiographic follow-up data, we could not evaluate possible complications (stent fracture or aneurysmal formation) at the overlapping site nor the angiographic characteristics of restenosis, such as site and pattern. Finally, the reasons for stent overlap were not collected. Disclosures The authors have no conflicts of interest to disclose. 1. Kastrati A, Mehilli J, Pache J, Kaiser C, Valgimigli M, Kelbaek H, Menichelli M, Sabaté M, Suttorp MJ, Baumgart D, Seyfarth M, Pfisterer ME, Schömig A. An analysis of 14 trials comparing sirolimuseluting stents with bare-metal stents. N Engl J Med 2007;356: 1030e1039.
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