- Email: [email protected]
Two-Year Follow-Up of Outcomes of Second-Generation Everolimus-Eluting Stents Versus First-Generation Drug-Eluting Stents for Stenosis of Saphenous Vein Grafts Used as Aortocoronary Conduits
Two-Year Follow-Up of Outcomes of Second-Generation Everolimus-Eluting Stents Versus First-Generation Drug-Eluting Stents for Stenosis of Saphenous Vein Grafts Used as Aortocoronary Conduits 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* Second-generation everolimus-eluting stents (EESs) have demonstrated superiority in efficacy and safety compared with first-generation drug-eluting stents (DESs) in the treatment of native coronary artery lesions. The present study evaluated and compared the safety and efficacy of EESs and first-generation DESs in saphenous vein graft lesions. The EES group consisted of 88 patients with 96 lesions, and the first-generation DES group consisted of 243 patients with 317 lesions (sirolimus-eluting stents, n [ 212; paclitaxeleluting stents, n [ 105). The end points included target lesion revascularization, target vessel revascularization, major adverse cardiovascular events (composite of all-cause death, myocardial infarction, and target vessel revascularization), and definite stent thrombosis at 2 years. The groups had similar baseline characteristics and graft ages (128.1 – 77.5 vs 132.4 – 90.8 months, p [ 0.686). The EES group had more type C lesions and less embolic protection device use. The peak postprocedure values of creatinine kinase-MB and troponin I were similar between the 2 groups. Overall, major adverse cardiovascular events occurred in 18.2% of EES patients and 35.0% of first-generation DES patients (p [ 0.003), mainly driven by a lower target vessel revascularization rate (6.8% vs 24.5%, p <0.001). The target lesion revascularization rate was lower in the EES group (1.1% vs 11.6%, p [ 0.005). Stent thrombosis was low and similar between the 2 groups (0% vs 0.8%, p [ 1.000). On multivariate analysis, the type of DES implanted and graft age were the only independent predictors of major adverse cardiovascular events. In conclusion, the superiority of EESs compared with first-generation DESs shown in native artery lesions has been extended to saphenous vein graft lesions and should be considered as the DES of choice for this lesion type. Ó 2013 Elsevier Inc. All rights reserved. (Am J Cardiol 2013;112:61e67) Saphenous vein grafts (SVGs) are the most commonly used conduit for coronary artery bypass graft surgery; however, luminal narrowing of SVGs requiring repeat revascularization is a major clinical issue.1 Percutaneous coronary intervention for SVG lesions remains technically challenging. Drug-eluting stents (DESs) have reduced the incidence of restenosis and target vessel revascularization (TVR) in SVG lesions compared with bare metal stents, with no significant increases in mortality and stent thrombosis.2e5 Therefore, the 2011 guidelines for percutaneous coronary intervention have provided a class I recommendation for DES use in SVGs.6 Even after the introduction of first-generation DESs, however, SVG percutaneous coronary intervention was still associated with worse clinical outcomes compared with native artery
percutaneous coronary intervention.7,8 Also, the TVR rates at 2 years did not show a difference between DESs and bare metal stents.9,10 Second-generation DESs were designed to improve the clinical safety and efficacy compared with first-generation DESs. Recent randomized trials have demonstrated that second-generation everolimuseluting stents (EESs) are superior to paclitaxel-eluting stents through 2 years11,12 and provide safety and efficacy comparable to that of sirolimus-eluting stents13,14 in broad patient and lesion subsets. It is unknown, however, whether the use of second-generation EESs for SVG lesions improves long-term clinical outcomes compared with firstgeneration DESs. The present study compared the safety and efficacy of SVG stenosis between second-generation EESs and first-generation DESs at 2 years of follow-up.
Division of Cardiology, MedStar Washington Hospital Center, Washington, District of Columbia. Manuscript received January 11, 2013; revised manuscript received and accepted February 19, 2013. See page 66 for disclosure information. *Corresponding author: Tel: (202) 877-2812; fax: (202) 877-2715. E-mail address: [email protected] (R. Waksman).
Methods
0002-9149/13/$ - see front matter Ó 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjcard.2013.02.055
From May 2003 to January 2012, the patients included in our institution’s registry, who had undergone SVG percutaneous coronary intervention with EESs (Xience V, Abbot Vascular, Santa Clara, California; or PROMUS, Boston www.ajconline.org
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Table 1 Baseline clinical characteristics
Table 2 Angiographic and procedural characteristics
Variable
Variable
Age (yrs) Men African-American Systemic hypertension* Diabetes mellitus Hypercholesterolemia† Current smoker Family history of coronary artery disease Previous myocardial infarction Previous percutaneous coronary intervention Chronic renal insufficiencyz Peripheral vascular disease Clinical presentation Stable angina pectoris Unstable angina pectoris Acute myocardial infarction Congestive heart failure Cardiogenic shock Left ventricular ejection fraction
Second-Generation First-Generation p EES (n ¼ 88) DES (n ¼ 243) Value 70.1 10.1 66 (75.0%) 13 (14.8%) 85 (96.6%) 47 (54.0%) 196 (89.1%) 11 (12.5%) 49 (55.7%)
68.3 11.2 190 (78.2%) 35 (14.4%) 223 (91.8%) 118 (48.8%) 376 (89.1%) 27 (11.1%) 139 (59.7%)
0.177 0.540 0.933 0.128 0.400 1.000 0.726 0.519
37 (42.0%)
93 (38.3%)
0.611
35 (39.8%)
93 (38.3%)
0.800
18 (20.5%) 30 (34.1%)
47 (19.5%) 74 (30.6%)
0.848 0.544
23 (26.1%) 52 (59.1%) 4 (4.5%)
54 (22.3%) 135 (55.8%) 17 (7.0%)
0.468 0.592 0.415
26 (29.9%) 0 0.45 0.14
48 (20.7%) 3 (1.3%) 0.44 0.14
0.083 0.566 0.748
Data are presented as mean SD or n (%). * Blood pressure >140/90 mm Hg or the use of antihypertensive medication. † Included patients with a previously documented diagnosis of hypercholesterolemia treated with diet or medication; a new diagnosis could be made during this hospitalization with an elevated total cholesterol >160 mg/dl; did not include elevated triglycerides. z Previously diagnosed or treated with medication, diet, or dialysis by a physician; diagnosis at admission if baseline creatinine level >2.0 mg/dl.
Scientific, Natick, Massachusetts) or first-generation DESs (sirolimus-eluting stents, Cypher, Cordis, Miami Lakes, Florida; or paclitaxel-eluting stents, Taxus, Boston Scientific), were retrospectively included in the present study. The patients treated with concomitant DES and bare metal stent implantation during the same procedure were excluded. The clinical and demographic data and clinical events during hospitalization were collected from the hospital charts, reviewed by qualified personnel, who were unaware of the objectives of the present study, and entered prospectively into the database. Every patient underwent 30-day, 6-month, 1-year, and 2-year clinical follow-up by qualified personnel by way of telephone interview or office visits. The clinical events were adjudicated by source documentation by independent physicians not involved in the procedures. All patients gave written, informed consent before cardiac catheterization. The study complied with the Declaration of Helsinki. SVG percutaneous coronary intervention was performed using standard techniques for stent implantation according to the clinical guidelines current at procedure time. Stent choice and the use of other devices, including embolic protection devices, were at the operator’s discretion. All patients received aspirin 325 mg before the procedure and
Saphenous vein graft lesion location Proximal Mid Distal Aorto-ostial Lesion characteristics Graft age (mo) Restenotic lesion Lesion type (ACC/AHA classification) Type A Type B1/B2 Type C Preprocedure diameter stenosis (%)* Procedural data Stents (n) Stent diameter (mm) Stent length (mm) Total contrast amount (ml)† Embolic protection device Intravascular ultrasound Glycoprotein IIb/IIIa inhibitor† Intra-aortic balloon pump† Postprocedure outcomes Angiographic success Abrupt closure No-reflow
Second-Generation First-Generation p EES (n ¼ 96) DES (n ¼ 317) Value
19 47 17 6
(19.8%) (49.0%) (17.7%) (6.3%)
(36.0%) (35.4%) (16.9%) (8.1%)
0.003 0.017 0.851 0.548
132.4 90.8 6 (6.3%)
128.1 77.5 36 (11.4%)
0.686 0.145
6 (6.3%) 35 (36.5%) 55 (57.3%) 87 9
16 (5.2%) 191 (61.8%) 102 (33.0%) 87 10
0.686 <0.001 <0.001 0.796
1.5 3.08 19.1 166
0.9 0.35 13.1 76
111 109 52 25
1.5 3.26 20.6 180
0.7 1.45 6.8 84
0.932 0.083 0.294 0.157
22 (22.9%)
109 (34.5%)
0.033
40 (41.7%)
124 (40.3%)
0.806
1 (1.1%)
22 (9.1%)
0.012
6 (2.5%)
4 (4.5%)
0.467
96 (100.0%) 0 0
310 (98.1%) 1 (0.3%) 0
0.343 1.000 —
Data are presented as mean SD or n (%). ACC/AHA ¼ American College of Cardiology/American Heart Association. * By visual estimation. † Patient-based variables.
a clopidogrel loading dose of 300 to 600 mg or prasugrel 60 mg during or immediately after the procedure. Dual antiplatelet therapy consisting of aspirin and thienopyridines was continued for 12 months after stent implantation, followed by aspirin indefinitely. During percutaneous coronary intervention, patients received anticoagulation therapy with bivalirudin (0.75 mg/kg bolus followed by a 1.75 mg/kg/hour infusion) or unfractionated heparin (40 U/kg bolus with an additional dose to achieve an active clotting time of 250 to 300 seconds). The use of glycoprotein IIb/IIIa inhibitors (almost exclusively eptifibatide) was at the operator’s discretion. All patients underwent 12-lead electrocardiography and blood sampling for creatine kinase-MB enzymes and troponin I levels before and immediately after the procedure. When the creatine kinase-MB values or troponin I levels were higher than normal, blood samples were taken every 8 hours to determine the peak value.
Coronary Artery Disease/EES Versus First-Generation DES in SVG
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Table 3 In-hospital and 30-day outcomes
Table 4 Clinical events at 1 and 2 years of follow-up
Event
Event
In-hospital Death Cardiac death Q-wave myocardial infarction Maximum creatine kinase-MB (ng/ml) Maximum troponin I (ng/ml) Vascular complications Major bleeding Transfusion 30-Day follow-up Major adverse cardiovascular events Death Cardiac death Q-wave myocardial infarction Target vessel revascularization Target lesion revascularization Stent thrombosis
Second-Generation First-Generation p EES (n ¼ 88) DES (n ¼ 243) Value 0 0 0
2 (0.8%) 1 (0.4%) 2 (0.8%)
1.000 1.000 1.000
5.3 16.2
5.5 16.5
0.925
4.3 28.6
3.2 12.5
0.747
2 (2.3%) 1 (1.1%) 4 (4.6%)
9 (3.7%) 4 (1.6%) 6 (2.6%)
0.734 1.000 0.469
0
8 (3.3%)
0.115
0 0 0
4 (1.6%) 1 (0.4%) 2 (0.8%)
0.577 1.000 1.000
0
5 (2.1%)
0.330
0
0
—
0
1 (0.4%)
1.000
Data are presented as mean SD or n (%).
The primary end point was major adverse cardiovascular events (MACE) at 2 years, defined as the composite of allcause death, myocardial infarction, or TVR. Secondary end points included target lesion revascularization, TVR, and stent thrombosis at 2 years of follow-up. Angiographic success was defined as residual stenosis <30% with Thrombolysis In Myocardial Infarction flow grade 3 after the procedure. All-cause death was defined as death from any cause, cardiac and noncardiac. Myocardial infarction was defined as a total creatinine kinase of 2 times the upper limit of normal and/or creatine kinase-MB 20 ng/ml, together with symptoms and/or ischemic electrocardiographic changes. Q-wave myocardial infarction was defined as evidence of new pathologic Q waves in 2 contiguous leads on the 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-segments 5-mm proximal or distal to the initial stent edges. TVR was defined as any clinically driven percutaneous intervention or bypass grafting of the target vessel. Stent thrombosis was defined as definite stent thrombosis according to the Academic Research Consortium definitions.15 Major bleeding was defined as the composite of gastrointestinal bleeding, a 15% absolute decrease in the hematocrit, or a hematoma >4 cm in diameter. Continuous variables are expressed as the mean SD. Categorical variables are presented as numbers and percentages. Continuous variables were compared using an unpaired Student’s t test, and categorical variables using the chi-square test or Fisher’s exact test, as appropriate. Events
Second-Generation First-Generation EES (n ¼ 88) DES (n ¼ 243)
At 1 yr MACE Death Cardiac death Myocardial infarction Q-wave myocardial infarction NoneQ-wave myocardial infarction Target vessel revascularization Target lesion revascularization Stent thrombosis At 2 yrs MACE Death Cardiac death Myocardial infarction Q-wave myocardial infarction NoneQ-wave myocardial infarction Target vessel revascularization Target lesion revascularization Stent thrombosis
11 6 1 2 1
(12.5%) (6.8%) (1.1%) (2.4%) (1.1%)
56 21 5 10 2
(23.0%) (8.7%) (2.1%) (4.7%) (0.8%)
p Value 0.035 0.586 1.000 0.527 1.000
1 (1.1%)
8 (3.4%)
0.266
5 (5.9%)
37 (15.7%)
0.022
1 (1.1%)
15 (6.4%)
0.079
0
2 (0.8%)
1.000
16 11 4 3 1
(18.2%) (12.5%) (4.5%) (3.8%) (1.1%)
85 35 15 12 2
(35.0%) (14.8%) (6.2%) (5.6%) (0.8%)
0.003 0.618 0.790 0.767 1.000
2 (2.4%)
10 (4.7%)
0.524
6 (6.8%)
54 (24.5%)
<0.001
1 (1.1%)
25 (11.6%)
0.005
0
2 (0.8%)
1.000
Data are presented as n (%).
occurring between 1 and 2 years were compared with Fisher’s exact test after patients with the specified event at 1 year of follow-up were removed from the analysis. The results are presented as odds ratios, with the 95% confidence intervals. A multivariate Cox proportional model was used to determine the predictors of MACE. The variables were selected on the basis of overall clinical relevance, with particular attention given to clinical and procedural factors that would make MACE more likely. All variables with a p value of <0.1 on univariate analysis were subsequently entered into the multivariate models and expressed as hazard ratios, with 95% confidence intervals. MACE-free survival rates were calculated using the Kaplan-Meier method. The log-rank test was used to compare the survival curves between the 2 groups. p Values <0.05 were considered statistically significant. All statistical analyses were performed using the Statistical Analysis Systems, version 9.1 (SAS Institute, Cary, North Carolina). Results The present retrospective study included a total of 331 patients: 88 patients with 96 lesions treated with EESs and 243 patients with 317 lesions treated with first-generation DESs. For patients treated with first-generation DESs, 67% received sirolimus-eluting stents and 33% received paclitaxel-eluting stents. As summarized in Table 1, the baseline clinical characteristics were well matched, with no
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Table 5 Event rate from year 1 to year 2 Event
MACE Death Cardiac death Myocardial infarction TVR Target lesion revascularization Stent thrombosis
SecondGeneration EES (%)
FirstGeneration DES (%)
OR
95% CI
p Value
6.5 6.1 3.4 1.2
15.5 6.3 4.2 0.9
0.38 0.96 0.81 1.37
0.14e1.02 0.33e2.76 0.22e3.03 0.12e15.3
0.054 0.940 0.759 0.798
1.2 0
8.3 4.4
0.14 0.12
0.02e1.04 0.01e2.05
0.054 0.143
0
0
—
—
—
Table 6 Univariate and multivariate analyses for predictors of two-year major adverse cardiac events (MACE) Variable
Univariate Analysis HR
CI ¼ confidence interval; OR ¼ odds ratio.
significant differences. Although angiographic and procedural characteristics were generally similar between the 2 groups, some differences were noted (Table 2). Patients treated with EESs had more type C lesions (57.3% vs 33.0%, p <0.001). The stent diameter tended to be smaller in the EES group. However, no significant difference was found between the 2 groups in terms of graft age (EES 132.4 90.8 vs DES 128.1 77.5 months; p ¼ 0.686). During percutaneous coronary intervention, embolic protection devices and glycoprotein IIb/IIIa inhibitors were used more frequently in patients treated with first-generation DESs. Angiographic success was high in both groups. In our series, an angiographic no-reflow phenomenon was not observed after the procedure. As listed in Table 3, the incidence of in-hospital and 30-day adverse events was similar in both groups. The peak postprocedure values of creatinine kinase-MB and troponin I did not differ significantly between the 2 groups. Clinical follow-up data at 2 years were available for all patients. The clinical events at 1 and 2 years of follow-up are listed in Table 4. At 1 year, overall MACE had occurred in 11 patients (12.5%) who had received an EES and in 56 patients (23.0%) who had received a first-generation DES (p ¼ 0.035). This superiority was maintained at 2 years, with a MACE rate of 18.2% in the EES group and 35.0% in the first-generation DES group (p ¼ 0.003). The observed differences in the MACE rates at 1 and 2 years were attributable to lower TVR rates in the EES-treated patients (5.9% vs 15.7% at 1 year, p ¼ 0.022; 6.8% vs 24.5% at 2 years, p <0.001, respectively). All-cause mortality and myocardial infarction did not differ significantly between the 2 groups. Between 1 and 2 years, the differences in the event rates for MACE (p ¼ 0.054) and TVR (p ¼ 0.054) widened numerically (Table 5). The target lesion revascularization rates at 2 years were significantly lower in the patients treated with EESs (1.1% vs 11.6%, p ¼ 0.005). During follow-up, the cumulative incidence of definite stent thrombosis was low and similar in both groups (EES 0% vs 0.8%; p ¼ 1.000). Very late (1 to 2 years) definite stent thrombosis was not seen in either group. On multivariate analysis, the use of EESs compared with first-generation DESs was significantly associated with a lower occurrence of MACE (hazard ratio 0.54, 95% confidence interval 0.31 to 0.92, p ¼ 0.025). Graft age was
EES vs first-generation DES Graft age Embolic protection device use Stent number Stent length Stent diameter Type C lesion Restenosis lesion Intravascular ultrasound use Glycoprotein IIb/IIIa inhibitor use
95% CI
p Value
Multivariate Analysis HR
95% CI
p Value
0.47 0.27e0.80 0.005 0.54 0.31e0.92 0.025
1.00 1.00e1.01 0.038 1.00 1.00e1.01 0.029 1.50 1.00e2.25 0.051 1.41 0.91e2.18 0.125 1.27 1.01 0.98 1.08 1.48 1.25
1.01e1.60 1.00e1.03 0.81e1.17 0.72e1.61 0.87e2.53 0.84e1.86
0.043 1.26 0.98e1.63 0.066 0.134 — — — 0.788 — — — 0.724 — — — 0.152 — — — 0.272 — — —
1.72 0.90e3.31 0.103
—
—
—
Multivariate analysis included relevant variables for MACE with univariate p value <0.1. CI ¼ confidence interval; HR ¼ hazard ratio.
Figure 1. Kaplan-Meier curve for cumulative MACE in SVG lesions for EESs and first-generation DESs.
also found to be an independent predictor of MACE (hazard ratio 1.00, 95% confidence interval 1.00 to 1.01, p ¼ 0.029; Table 6). The Kaplan-Meier curve for MACE at 24 months is illustrated in Figure 1. Discussion The present study findings have demonstrated superiority in the efficacy of second-generation EESs compared with first-generation DESs when used in SVG lesions, with respect to MACE (composite of all-cause mortality, myocardial infarction, and TVR) but with no difference in the stent thrombosis rate. This superiority was driven by the lower target lesion revascularization and TVR rates in the EES-treated patients. Taken together, these findings suggest the increased antirestenotic efficacy of second-generation EESs in SVGs.
Coronary Artery Disease/EES Versus First-Generation DES in SVG
SVG failure is common after coronary artery bypass grafting and is associated with repeat revascularization.16 Because of the increased risks in mortality and morbidity with reoperative surgery, percutaneous coronary intervention is a preferable revascularization strategy when SVGs fail.17 The Saphenous Vein De novo (SAVED) trial reported that, compared with conventional balloon angioplasty, Palmaz-Schatz bare metal stents were associated with lower rates of major adverse events (26% vs 39%, p ¼ 0.04).18 Since then, most SVG percutaneous coronary interventions have been performed with stents. Subsequently, previous studies have compared bare metal stents and DESs in SVGs and have shown a reduction in repeat revascularization with DESs.2e5 Because previous studies have suggested the existence of a late catch-up phenomenon regarding TVR after DES implantation, long-term follow-up is particularly important.9,10 In the Death and Events at Long-term followup AnalYsis: Extended Duration with Cypher stent (DELAYED RRISC) trial, an initial benefit of DESs compared with bare metal stents in the reduction of repeat revascularization at 6 months was no longer seen at a median of 32 months.9 The Strategic Transcatheter Evaluation of New Therapies (STENT) registry, a large multicenter registry, found that DESs, compared with bare metal stents, reduced the incidence of TVR at 9 months but this advantage was lost at 2 years.10 However, in the present study, both target lesion revascularization and TVR rates were significantly lower for EESs at 2 years, with a continued benefit over time compared with first-generation DESs. Notably, the late catch-up phenomenon in target lesion revascularization (1.1% at 1 and 2 years) and TVR (5.9% at 1 year to 6.8% at 2 years) was not observed in EES-treated patients comparing year 1 and 2 at follow-up. Although a clear pathophysiologic explanation for these findings is lacking, superior design features such as thin (81 mm), fracture-resistant struts and a relatively thin, biocompatible polymer (7.6 mm) might have contributed to the improved antirestenotic efficacy with EES in SVGs. One pathologic study has shown that first-generation DES-treated SVG lesions had greater delayed healing, a greater percentage of uncovered struts (19.6% vs 5.1%, p ¼ 0.043), and less endothelialization (70.0% vs 98.3%, p ¼ 0.028) than bare metal stents.19 Stent fracture (DES 56% vs bare metal stent 11%, p ¼ 0.045) and late stent thrombosis (DES 44% vs bare metal stent 0%, p ¼ 0.023) were more frequent with DESs. Second-generation EESs have emerged as a safer DES with regard to lower stent thrombosis rates in patients with native coronary artery disease.20 In a rabbit iliac artery model, EESs showed more rapid endothelialization than sirolimus- and paclitaxeleluting stents.21 Furthermore, an optical coherence tomographic study demonstrated that at 12 months after implantation, EES use in SVGs was associated with lower rates of uncovered struts than the published first-generation DES (sirolimus- and paclitaxel-eluting stent) studies in native coronary arteries (3.8% vs 5.7%).22e24 These signals might explain in part the difference in performance of second-generation EES versus first-generation DES. It remains unclear whether 1 type of DES is more effective in SVG intervention. Previous studies comparing sirolimus-eluting stents and paclitaxel-eluting stents for
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SVG intervention did not demonstrate any significant differences in clinical outcomes.25e27 Furthermore, limited data are available on the outcomes of second-generation DESs in SVG intervention. The Stenting OF Saphenous Vein Grafts Xience V (SOS-Xience V) trial (data not yet unpublished), is a single-arm, nonrandomized, open-label, prospective study that examined the 12-month angiographic and clinical outcomes of 40 patients undergoing stenting of de novo SVG lesions with an EES.28 Angiographic followup at 12 months was performed in 27 patients, 4 (15%) of whom had in-stent restenosis requiring repeat revascularization. The 12-month incidence of MACE was 42.5%, greater than that seen in EES patients in our study (12.5%). In the present study, the cumulative incidence of MACE at 2 years of follow-up was significantly lower in the EES group (18.2% vs 35.0%, p ¼ 0.003), reflecting a lower rate of TVR in EES-treated patients (6.8% vs 24.5%, p <0.001). After adjustment for potential confounders, the difference between the 2 groups remained significant. To our knowledge, this is the first study showing the superiority of second-generation EESs compared with first-generation DESs in SVG intervention. However, even after EES implantation for diseased SVG, the greater occurrence (roughly double) of MACE at 2 years (18.2%) observed in our registry compared with the 2-year data published of native coronary artery disease (9.0% in the comparison of the everolimus-eluting Xience-V stent with the paclitaxel eluting Taxus Liberte stent in all-comers: a randomized open-label trial [COMPARE]12 and 8.3% in the Scandinavian Organization for Randomized Trials With Clinical Outcome IV [SORT OUT IV]13) indicates a need for native artery percutaneous coronary intervention, if technically feasible. Several potential limitations should be considered. Ours was an observational, retrospective, single-center registry with a relatively small sample size. In addition, the nonrandomized comparisons between EESs and first-generation DESs might have introduced a bias in the results. However, in general, the groups were well balanced in baseline clinical, angiographic, and procedural characteristics. Because angiographic follow-up was not performed, the restenosis rate might have been underestimated. However, routine angiographic surveillance after DES deployment has led to increased rates of repeat revascularization because of the oculostenotic treatment of mild to moderate lesions, which could magnify the DES benefit.29 The study was underpowered to detect differences in stent thrombosis. The incidence of definite stent thrombosis was very low in both groups. Larger scale and longer term follow-up studies are needed to determine whether using second-generation EESs in SVGs will decrease the risk of stent thrombosis. Our study included patients treated during a long-term period in which percutaneous coronary intervention techniques, including operator skill and adjunctive devices, have changed accordingly. This might have influenced the clinical outcomes. Finally, it was recently reported that in patients undergoing SVG percutaneous coronary intervention, discontinuation of long-term clopidogrel therapy was associated with death and myocardial infarction, irrespective of the stent type.30 Although all our patients were recommended to receive 12 months of dual antiplatelet therapy,
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data regarding compliance with dual antiplatelet therapy were not collected. This omission might have had an effect on the results; however, we found no significant differences between the 2 groups with regard to death and myocardial infarction. Disclosures The authors have no conflicts of interest to disclose. 1. Fitzgibbon GM, Kafka HP, Leach AJ, Keon WJ, Hooper GD, Burton JR. Coronary bypass graft fate and patient outcome: angiographic follow-up of 5,065 grafts related to survival and reoperation in 1,388 patients during 25 years. J Am Coll Cardiol 1996;28:616e626. 2. Vermeersch P, Agostoni P, Verheye S, Van den Heuvel P, Convens C, Bruining N, Van den Branden F, Van Langenhove G. Randomized double-blind comparison of sirolimus-eluting stent versus bare-metal stent implantation in diseased saphenous vein grafts: six-month angiographic, intravascular ultrasound, and clinical follow-up of the RRISC Trial. J Am Coll Cardiol 2006;48:2423e2431. 3. Lee MS, Yang T, Kandzari DE, Tobis JM, Liao H, Mahmud E. Comparison by meta-analysis of drug-eluting stents and bare metal stents for saphenous vein graft intervention. Am J Cardiol 2010;105: 1076e1082. 4. Brilakis ES, Lichtenwalter C, Abdel-karim AR, de Lemos JA, Obel O, Addo T, Roesle M, Haagen D, Rangan BV, Saeed B, Bissett JK, Sachdeva R, Voudris VV, Karyofillis P, Kar B, Rossen J, Fasseas P, Berger P, Banerjee S. Continued benefit from paclitaxel-eluting compared with bare-metal stent implantation in saphenous vein graft lesions during long-term follow-up of the SOS (Stenting of Saphenous Vein Grafts) trial. J Am Coll Cardiol Interv 2011;4:176e182. 5. Mehilli J, Pache J, Abdel-Wahab M, Schulz S, Byrne RA, Tiroch K, Hausleiter J, Seyfarth M, Ott I, Ibrahim T, Fusaro M, Laugwitz KL, Massberg S, Neumann FJ, Richardt G, Schömig A, Kastrati A. Drug-eluting versus bare-metal stents in saphenous vein graft lesions (ISAR-CABG): a randomised controlled superiority trial. Lancet 2011;378:1071e1078. 6. Levine GN, Bates ER, Blankenship JC, Bailey SR, Bittl JA, Cercek B, Chambers CE, Ellis SG, Guyton RA, Hollenberg SM, Khot UN, Lange RA, Mauri L, Mehran R, Moussa ID, Mukherjee D, Nallamothu BK, Ting HH. 2011 ACCF/AHA/SCAI guideline for percutaneous coronary intervention: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Society for Cardiovascular Angiography and Interventions. J Am Coll Cardiol 2011;58:e44ee122. 7. Hoffmann R, Hamm C, Nienaber CA, Levenson B, Bonzel T, Sabin G, Senges J, Zahn R, Tebbe U, Pfannebecker T, Richardt HG, Schneider S, Kelm M. Implantation of sirolimus-eluting stents in saphenous vein grafts is associated with high clinical follow-up event rates compared with treatment of native vessels. Coron Artery Dis 2007;18:559e564. 8. Brilakis ES, Rao SV, Banerjee S, Goldman S, Shunk KA, Holmes DR Jr, Honeycutt E, Roe MT. Percutaneous coronary intervention in native arteries versus bypass grafts in prior coronary artery bypass grafting patients: a report from the National Cardiovascular Data Registry. J Am Coll Cardiol Intv 2011;4:844e850. 9. Vermeersch P, Agostoni P, Verheye S, Van den Heuvel P, Convens C, Van den Branden F, Van Langenhove G. Increased late mortality after sirolimus-eluting stents versus bare-metal stents in diseased saphenous vein grafts: results from the randomized DELAYED RRISC trial. J Am Coll Cardiol 2007;50:261e267. 10. Brodie BR, Wilson H, Stuckey T, Nussbaum M, Laurent S, Bradshaw B, Humphrey A, Metzger C, Hermiller J, Krainin F, Juk S, Cheek B, Duffy P, Simonton CA; STENT Group. Outcomes with drug-eluting versus bare-metal stents in saphenous vein graft intervention results from the STENT (strategic transcatheter evaluation of new therapies) Group. J Am Coll Cardiol Intv 2009;2:1105e1112. 11. Stone GW, Rizvi A, Sudhir K, Newman W, Applegate RJ, Cannon LA, Maddux JT, Cutlip DE, Simonton CA, Sood P, Kereiakes DJ; SPIRIT IV Investigators. Randomized comparison of everolimus- and paclitaxel-eluting stents: 2 year follow up from the SPIRIT (Clinical Evaluation of the Xience V Everolimus Eluting Coronary Stent System) IV trial. J Am Coll Cardiol 2011;58:19e25.
12. Smits PC, Kedhi E, Royaards KJ, Joesoef KS, Wassing J, Rademaker-Havinga TA, McFadden E. 2-Year follow-up of a randomized controlled trial of everolimus- and paclitaxel-eluting stents for coronary revascularization in daily practice: COMPARE (comparison of the everolimus-eluting Xience-V stent with the paclitaxel eluting Taxus Liberte stent in all-comers: a randomized openlabel trial). J Am Coll Cardiol 2011;58:11e18. 13. Jensen LO, Thayssen P, Christiansen EH, Tilsted HH, Maeng M, Hansen KN, Kaltoft A, Hansen HS, Bøtker HE, Krusell LR, Ravkilde J, Madsen M, Thuesen L, Lassen JF; SORT OUT IV Investigators. 2-Year Patient-Related Versus Stent-Related Outcomes: The SORT OUT IV (Scandinavian Organization for Randomized Trials With Clinical Outcome IV) Trial. J Am Coll Cardiol 2012;60:1140e1147. 14. Kimura T, Morimoto T, Natsuaki M, Shiomi H, Igarashi K, Kadota K, Tanabe K, Morino Y, Akasaka T, Takatsu Y, Nishikawa H, Yamamoto Y, Nakagawa Y, Hayashi Y, Iwabuchi M, Umeda H, Kawai K, Okada H, Kimura K, Simonton CA, Kozuma K; RESET Investigators. Comparison of everolimus-eluting and sirolimus-eluting coronary stents: 1-year outcomes from the Randomized Evaluation of Sirolimuseluting Versus Everolimus-eluting stent Trial (RESET). Circulation 2012;126:1225e1236. 15. 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. 16. Lopes RD, Mehta RH, Hafley GE, Williams JB, Mack MJ, Peterson ED, Allen KB, Harrington RA, Gibson CM, Califf RM, Kouchoukos NT, Ferguson TB Jr, Alexander JH; Project of Ex Vivo Vein Graft Engineering via Transfection IV (PREVENT IV) Investigators. Relationship between vein graft failure and subsequent clinical outcomes after coronary artery bypass surgery. Circulation 2012;125:749e756. 17. Morrison DA, Sethi G, Sacks J, Henderson WG, Grover F, Sedlis S, Esposito R; Investigators of the Department of Veterans Affairs Cooperative Study #385, Angina With Extremely Serious Operative Mortality Evaluation. Percutaneous coronary intervention versus repeat bypass surgery for patients with medically refractory myocardial ischemia: AWESOME randomized trial and registry experience with post-CABG patients. J Am Coll Cardiol 2002;40:1951e1954. 18. Savage MP, Douglas JS Jr, Fischman DL, Pepine CJ, King SB III, Werner JA, Bailey SR, Overlie PA, Fenton SH, Brinker JA, Leon MB, Goldberg S. Stent placement compared with balloon angioplasty for obstructed coronary bypass grafts. Saphenous Vein De Novo Trial Investigators. N Engl J Med 1997;337:740e747. 19. Yazdani SK, Farb A, Nakano M, Vorpahl M, Ladich E, Finn AV, Kolodgie FD, Virmani R. Pathology of drug-eluting versus bare-metal stents in saphenous vein bypass graft lesions. J Am Coll Cardiol Intv 2012;5:666e674. 20. Palmerini T, Kirtane AJ, Serruys PW, Smits PC, Kedhi E, Kereiakes D, Sangiorgi D, Bacchi Reggiani L, Kaiser C, Kim HS, De Waha A, Ribichini F, Stone GW. Stent thrombosis with everolimus-eluting stents: meta-analysis of comparative randomized controlled trials. Circ Cardiovasc Interv 2012;5:357e364. 21. 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. 22. Papayannis AC, Michael TT, Yangirova D, Abdel-Karim AR, Kohlhaas J, Mahmood A, Addo T, Haagen D, Makke L, Roesle M, Rangan B, Banerjee S, Brilakis ES. Optical coherence tomography analysis of the stenting of saphenous vein graft (SOS) Xience V Study: use of the everolimus-eluting stent in saphenous vein graft lesions. J Invasive Cardiol 2012;24:390e394. 23. Katoh H, Shite J, Shinke T, Matsumoto D, Tanino Y, Ogasawara D, Sawada T, Miyoshi N, Kawamori H, Yoshino N, Hirata K. Delayed neointimalization on sirolimus-eluting stents: 6-month and 12-month follow up by optical coherence tomography. Circ J 2009;73: 1033e1037. 24. Guagliumi G, Costa MA, Sirbu V, Musumeci G, Bezerra HG, Suzuki N, Matiashvili A, Lortkipanidze N, Mihalcsik L, Trivisonno A, Valsecchi O, Mintz GS, Dressler O, Parise H, Maehara A, Cristea E, Lansky AJ, Mehran R, Stone GW. Strut coverage and late malapposition with paclitaxel-eluting stents compared with bare metal stents in acute myocardial infarction: optical coherence tomography substudy
Coronary Artery Disease/EES Versus First-Generation DES in SVG of the Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction (HORIZONS-AMI) trial. Circulation 2011;123:274e281. 25. Chu WW, Kuchulakanti PK, Wang B, Clavijo LC, Suddath WO, Pichard AD, Satler LF, Kent KM, Waksman R. Efficacy of sirolimuseluting stents as compared to paclitaxel-eluting stents for saphenous vein graft intervention. J Interv Cardiol 2006;19:121e125. 26. Gormez S, Erdim R, Erdogmus O, Civan M, Catakoglu AB, Gulbaran M, Demiroglu C, Aytekin V. Treatment of saphenous vein graft lesions with paclitaxel- and sirolimus-eluting stents: comparison of short- and long-term clinical outcomes. Anadolu Kardiyol Derg 2008;8: 431e436. 27. Lee MS, Hu PP, Aragon J, Shah AP, Oyama J, Dhoot J, Iqbal Z, Jones N, Penny W, Tobis J, Mahmud E, French W. Comparison of sirolimuseluting stents with paclitaxel-eluting stents in saphenous vein graft intervention (from a multicenter southern California registry). Am J Cardiol 2010;106:337e341.
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28. Brilakis ES, Papayannis AC, Abdel-Karim ARR, Michael TT, Mahmood A, Makke LB, Roesle M, Haagen D, Rangan BV, Banerjee S. Prospective evaluation of the Xience V everolimus-eluting stent in saphenous vein graft atherosclerosis: the Xience V-SVG angiographic study. J Am Coll Cardiol 2011;58:B59. 29. Uchida T, Popma J, Stone GW, Ellis SG, Turco MA, Ormiston JA, Muramatsu T, Nakamura M, Nanto S, Yokoi H, Baim DS. The clinical impact of routine angiographic follow-up in randomized trials of drugeluting stents: a critical assessment of “oculostenotic” reintervention in patients with intermediate lesions. J Am Coll Cardiol Intv 2010;3: 403e411. 30. Sachdeva A, Bavisetty S, Beckham G, Shen AY, Aharonian V, Mansukhani P, Stone GW, Leon M, Moses J, Moore N, Hyett R, Contreras R, Brar SS. Discontinuation of long-term clopidogrel therapy is associated with death and myocardial infarction after saphenous vein graft percutaneous coronary intervention. J Am Coll Cardiol 2012;60: 2357e2363.
percutaneous coronary intervention.7,8 Also, the TVR rates at 2 years did not show a difference between DESs and bare metal stents.9,10 Second-generation DESs were designed to improve the clinical safety and efficacy compared with first-generation DESs. Recent randomized trials have demonstrated that second-generation everolimuseluting stents (EESs) are superior to paclitaxel-eluting stents through 2 years11,12 and provide safety and efficacy comparable to that of sirolimus-eluting stents13,14 in broad patient and lesion subsets. It is unknown, however, whether the use of second-generation EESs for SVG lesions improves long-term clinical outcomes compared with firstgeneration DESs. The present study compared the safety and efficacy of SVG stenosis between second-generation EESs and first-generation DESs at 2 years of follow-up.
Division of Cardiology, MedStar Washington Hospital Center, Washington, District of Columbia. Manuscript received January 11, 2013; revised manuscript received and accepted February 19, 2013. See page 66 for disclosure information. *Corresponding author: Tel: (202) 877-2812; fax: (202) 877-2715. E-mail address: [email protected] (R. Waksman).
Methods
0002-9149/13/$ - see front matter Ó 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjcard.2013.02.055
From May 2003 to January 2012, the patients included in our institution’s registry, who had undergone SVG percutaneous coronary intervention with EESs (Xience V, Abbot Vascular, Santa Clara, California; or PROMUS, Boston www.ajconline.org
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Table 1 Baseline clinical characteristics
Table 2 Angiographic and procedural characteristics
Variable
Variable
Age (yrs) Men African-American Systemic hypertension* Diabetes mellitus Hypercholesterolemia† Current smoker Family history of coronary artery disease Previous myocardial infarction Previous percutaneous coronary intervention Chronic renal insufficiencyz Peripheral vascular disease Clinical presentation Stable angina pectoris Unstable angina pectoris Acute myocardial infarction Congestive heart failure Cardiogenic shock Left ventricular ejection fraction
Second-Generation First-Generation p EES (n ¼ 88) DES (n ¼ 243) Value 70.1 10.1 66 (75.0%) 13 (14.8%) 85 (96.6%) 47 (54.0%) 196 (89.1%) 11 (12.5%) 49 (55.7%)
68.3 11.2 190 (78.2%) 35 (14.4%) 223 (91.8%) 118 (48.8%) 376 (89.1%) 27 (11.1%) 139 (59.7%)
0.177 0.540 0.933 0.128 0.400 1.000 0.726 0.519
37 (42.0%)
93 (38.3%)
0.611
35 (39.8%)
93 (38.3%)
0.800
18 (20.5%) 30 (34.1%)
47 (19.5%) 74 (30.6%)
0.848 0.544
23 (26.1%) 52 (59.1%) 4 (4.5%)
54 (22.3%) 135 (55.8%) 17 (7.0%)
0.468 0.592 0.415
26 (29.9%) 0 0.45 0.14
48 (20.7%) 3 (1.3%) 0.44 0.14
0.083 0.566 0.748
Data are presented as mean SD or n (%). * Blood pressure >140/90 mm Hg or the use of antihypertensive medication. † Included patients with a previously documented diagnosis of hypercholesterolemia treated with diet or medication; a new diagnosis could be made during this hospitalization with an elevated total cholesterol >160 mg/dl; did not include elevated triglycerides. z Previously diagnosed or treated with medication, diet, or dialysis by a physician; diagnosis at admission if baseline creatinine level >2.0 mg/dl.
Scientific, Natick, Massachusetts) or first-generation DESs (sirolimus-eluting stents, Cypher, Cordis, Miami Lakes, Florida; or paclitaxel-eluting stents, Taxus, Boston Scientific), were retrospectively included in the present study. The patients treated with concomitant DES and bare metal stent implantation during the same procedure were excluded. The clinical and demographic data and clinical events during hospitalization were collected from the hospital charts, reviewed by qualified personnel, who were unaware of the objectives of the present study, and entered prospectively into the database. Every patient underwent 30-day, 6-month, 1-year, and 2-year clinical follow-up by qualified personnel by way of telephone interview or office visits. The clinical events were adjudicated by source documentation by independent physicians not involved in the procedures. All patients gave written, informed consent before cardiac catheterization. The study complied with the Declaration of Helsinki. SVG percutaneous coronary intervention was performed using standard techniques for stent implantation according to the clinical guidelines current at procedure time. Stent choice and the use of other devices, including embolic protection devices, were at the operator’s discretion. All patients received aspirin 325 mg before the procedure and
Saphenous vein graft lesion location Proximal Mid Distal Aorto-ostial Lesion characteristics Graft age (mo) Restenotic lesion Lesion type (ACC/AHA classification) Type A Type B1/B2 Type C Preprocedure diameter stenosis (%)* Procedural data Stents (n) Stent diameter (mm) Stent length (mm) Total contrast amount (ml)† Embolic protection device Intravascular ultrasound Glycoprotein IIb/IIIa inhibitor† Intra-aortic balloon pump† Postprocedure outcomes Angiographic success Abrupt closure No-reflow
Second-Generation First-Generation p EES (n ¼ 96) DES (n ¼ 317) Value
19 47 17 6
(19.8%) (49.0%) (17.7%) (6.3%)
(36.0%) (35.4%) (16.9%) (8.1%)
0.003 0.017 0.851 0.548
132.4 90.8 6 (6.3%)
128.1 77.5 36 (11.4%)
0.686 0.145
6 (6.3%) 35 (36.5%) 55 (57.3%) 87 9
16 (5.2%) 191 (61.8%) 102 (33.0%) 87 10
0.686 <0.001 <0.001 0.796
1.5 3.08 19.1 166
0.9 0.35 13.1 76
111 109 52 25
1.5 3.26 20.6 180
0.7 1.45 6.8 84
0.932 0.083 0.294 0.157
22 (22.9%)
109 (34.5%)
0.033
40 (41.7%)
124 (40.3%)
0.806
1 (1.1%)
22 (9.1%)
0.012
6 (2.5%)
4 (4.5%)
0.467
96 (100.0%) 0 0
310 (98.1%) 1 (0.3%) 0
0.343 1.000 —
Data are presented as mean SD or n (%). ACC/AHA ¼ American College of Cardiology/American Heart Association. * By visual estimation. † Patient-based variables.
a clopidogrel loading dose of 300 to 600 mg or prasugrel 60 mg during or immediately after the procedure. Dual antiplatelet therapy consisting of aspirin and thienopyridines was continued for 12 months after stent implantation, followed by aspirin indefinitely. During percutaneous coronary intervention, patients received anticoagulation therapy with bivalirudin (0.75 mg/kg bolus followed by a 1.75 mg/kg/hour infusion) or unfractionated heparin (40 U/kg bolus with an additional dose to achieve an active clotting time of 250 to 300 seconds). The use of glycoprotein IIb/IIIa inhibitors (almost exclusively eptifibatide) was at the operator’s discretion. All patients underwent 12-lead electrocardiography and blood sampling for creatine kinase-MB enzymes and troponin I levels before and immediately after the procedure. When the creatine kinase-MB values or troponin I levels were higher than normal, blood samples were taken every 8 hours to determine the peak value.
Coronary Artery Disease/EES Versus First-Generation DES in SVG
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Table 3 In-hospital and 30-day outcomes
Table 4 Clinical events at 1 and 2 years of follow-up
Event
Event
In-hospital Death Cardiac death Q-wave myocardial infarction Maximum creatine kinase-MB (ng/ml) Maximum troponin I (ng/ml) Vascular complications Major bleeding Transfusion 30-Day follow-up Major adverse cardiovascular events Death Cardiac death Q-wave myocardial infarction Target vessel revascularization Target lesion revascularization Stent thrombosis
Second-Generation First-Generation p EES (n ¼ 88) DES (n ¼ 243) Value 0 0 0
2 (0.8%) 1 (0.4%) 2 (0.8%)
1.000 1.000 1.000
5.3 16.2
5.5 16.5
0.925
4.3 28.6
3.2 12.5
0.747
2 (2.3%) 1 (1.1%) 4 (4.6%)
9 (3.7%) 4 (1.6%) 6 (2.6%)
0.734 1.000 0.469
0
8 (3.3%)
0.115
0 0 0
4 (1.6%) 1 (0.4%) 2 (0.8%)
0.577 1.000 1.000
0
5 (2.1%)
0.330
0
0
—
0
1 (0.4%)
1.000
Data are presented as mean SD or n (%).
The primary end point was major adverse cardiovascular events (MACE) at 2 years, defined as the composite of allcause death, myocardial infarction, or TVR. Secondary end points included target lesion revascularization, TVR, and stent thrombosis at 2 years of follow-up. Angiographic success was defined as residual stenosis <30% with Thrombolysis In Myocardial Infarction flow grade 3 after the procedure. All-cause death was defined as death from any cause, cardiac and noncardiac. Myocardial infarction was defined as a total creatinine kinase of 2 times the upper limit of normal and/or creatine kinase-MB 20 ng/ml, together with symptoms and/or ischemic electrocardiographic changes. Q-wave myocardial infarction was defined as evidence of new pathologic Q waves in 2 contiguous leads on the 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-segments 5-mm proximal or distal to the initial stent edges. TVR was defined as any clinically driven percutaneous intervention or bypass grafting of the target vessel. Stent thrombosis was defined as definite stent thrombosis according to the Academic Research Consortium definitions.15 Major bleeding was defined as the composite of gastrointestinal bleeding, a 15% absolute decrease in the hematocrit, or a hematoma >4 cm in diameter. Continuous variables are expressed as the mean SD. Categorical variables are presented as numbers and percentages. Continuous variables were compared using an unpaired Student’s t test, and categorical variables using the chi-square test or Fisher’s exact test, as appropriate. Events
Second-Generation First-Generation EES (n ¼ 88) DES (n ¼ 243)
At 1 yr MACE Death Cardiac death Myocardial infarction Q-wave myocardial infarction NoneQ-wave myocardial infarction Target vessel revascularization Target lesion revascularization Stent thrombosis At 2 yrs MACE Death Cardiac death Myocardial infarction Q-wave myocardial infarction NoneQ-wave myocardial infarction Target vessel revascularization Target lesion revascularization Stent thrombosis
11 6 1 2 1
(12.5%) (6.8%) (1.1%) (2.4%) (1.1%)
56 21 5 10 2
(23.0%) (8.7%) (2.1%) (4.7%) (0.8%)
p Value 0.035 0.586 1.000 0.527 1.000
1 (1.1%)
8 (3.4%)
0.266
5 (5.9%)
37 (15.7%)
0.022
1 (1.1%)
15 (6.4%)
0.079
0
2 (0.8%)
1.000
16 11 4 3 1
(18.2%) (12.5%) (4.5%) (3.8%) (1.1%)
85 35 15 12 2
(35.0%) (14.8%) (6.2%) (5.6%) (0.8%)
0.003 0.618 0.790 0.767 1.000
2 (2.4%)
10 (4.7%)
0.524
6 (6.8%)
54 (24.5%)
<0.001
1 (1.1%)
25 (11.6%)
0.005
0
2 (0.8%)
1.000
Data are presented as n (%).
occurring between 1 and 2 years were compared with Fisher’s exact test after patients with the specified event at 1 year of follow-up were removed from the analysis. The results are presented as odds ratios, with the 95% confidence intervals. A multivariate Cox proportional model was used to determine the predictors of MACE. The variables were selected on the basis of overall clinical relevance, with particular attention given to clinical and procedural factors that would make MACE more likely. All variables with a p value of <0.1 on univariate analysis were subsequently entered into the multivariate models and expressed as hazard ratios, with 95% confidence intervals. MACE-free survival rates were calculated using the Kaplan-Meier method. The log-rank test was used to compare the survival curves between the 2 groups. p Values <0.05 were considered statistically significant. All statistical analyses were performed using the Statistical Analysis Systems, version 9.1 (SAS Institute, Cary, North Carolina). Results The present retrospective study included a total of 331 patients: 88 patients with 96 lesions treated with EESs and 243 patients with 317 lesions treated with first-generation DESs. For patients treated with first-generation DESs, 67% received sirolimus-eluting stents and 33% received paclitaxel-eluting stents. As summarized in Table 1, the baseline clinical characteristics were well matched, with no
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Table 5 Event rate from year 1 to year 2 Event
MACE Death Cardiac death Myocardial infarction TVR Target lesion revascularization Stent thrombosis
SecondGeneration EES (%)
FirstGeneration DES (%)
OR
95% CI
p Value
6.5 6.1 3.4 1.2
15.5 6.3 4.2 0.9
0.38 0.96 0.81 1.37
0.14e1.02 0.33e2.76 0.22e3.03 0.12e15.3
0.054 0.940 0.759 0.798
1.2 0
8.3 4.4
0.14 0.12
0.02e1.04 0.01e2.05
0.054 0.143
0
0
—
—
—
Table 6 Univariate and multivariate analyses for predictors of two-year major adverse cardiac events (MACE) Variable
Univariate Analysis HR
CI ¼ confidence interval; OR ¼ odds ratio.
significant differences. Although angiographic and procedural characteristics were generally similar between the 2 groups, some differences were noted (Table 2). Patients treated with EESs had more type C lesions (57.3% vs 33.0%, p <0.001). The stent diameter tended to be smaller in the EES group. However, no significant difference was found between the 2 groups in terms of graft age (EES 132.4 90.8 vs DES 128.1 77.5 months; p ¼ 0.686). During percutaneous coronary intervention, embolic protection devices and glycoprotein IIb/IIIa inhibitors were used more frequently in patients treated with first-generation DESs. Angiographic success was high in both groups. In our series, an angiographic no-reflow phenomenon was not observed after the procedure. As listed in Table 3, the incidence of in-hospital and 30-day adverse events was similar in both groups. The peak postprocedure values of creatinine kinase-MB and troponin I did not differ significantly between the 2 groups. Clinical follow-up data at 2 years were available for all patients. The clinical events at 1 and 2 years of follow-up are listed in Table 4. At 1 year, overall MACE had occurred in 11 patients (12.5%) who had received an EES and in 56 patients (23.0%) who had received a first-generation DES (p ¼ 0.035). This superiority was maintained at 2 years, with a MACE rate of 18.2% in the EES group and 35.0% in the first-generation DES group (p ¼ 0.003). The observed differences in the MACE rates at 1 and 2 years were attributable to lower TVR rates in the EES-treated patients (5.9% vs 15.7% at 1 year, p ¼ 0.022; 6.8% vs 24.5% at 2 years, p <0.001, respectively). All-cause mortality and myocardial infarction did not differ significantly between the 2 groups. Between 1 and 2 years, the differences in the event rates for MACE (p ¼ 0.054) and TVR (p ¼ 0.054) widened numerically (Table 5). The target lesion revascularization rates at 2 years were significantly lower in the patients treated with EESs (1.1% vs 11.6%, p ¼ 0.005). During follow-up, the cumulative incidence of definite stent thrombosis was low and similar in both groups (EES 0% vs 0.8%; p ¼ 1.000). Very late (1 to 2 years) definite stent thrombosis was not seen in either group. On multivariate analysis, the use of EESs compared with first-generation DESs was significantly associated with a lower occurrence of MACE (hazard ratio 0.54, 95% confidence interval 0.31 to 0.92, p ¼ 0.025). Graft age was
EES vs first-generation DES Graft age Embolic protection device use Stent number Stent length Stent diameter Type C lesion Restenosis lesion Intravascular ultrasound use Glycoprotein IIb/IIIa inhibitor use
95% CI
p Value
Multivariate Analysis HR
95% CI
p Value
0.47 0.27e0.80 0.005 0.54 0.31e0.92 0.025
1.00 1.00e1.01 0.038 1.00 1.00e1.01 0.029 1.50 1.00e2.25 0.051 1.41 0.91e2.18 0.125 1.27 1.01 0.98 1.08 1.48 1.25
1.01e1.60 1.00e1.03 0.81e1.17 0.72e1.61 0.87e2.53 0.84e1.86
0.043 1.26 0.98e1.63 0.066 0.134 — — — 0.788 — — — 0.724 — — — 0.152 — — — 0.272 — — —
1.72 0.90e3.31 0.103
—
—
—
Multivariate analysis included relevant variables for MACE with univariate p value <0.1. CI ¼ confidence interval; HR ¼ hazard ratio.
Figure 1. Kaplan-Meier curve for cumulative MACE in SVG lesions for EESs and first-generation DESs.
also found to be an independent predictor of MACE (hazard ratio 1.00, 95% confidence interval 1.00 to 1.01, p ¼ 0.029; Table 6). The Kaplan-Meier curve for MACE at 24 months is illustrated in Figure 1. Discussion The present study findings have demonstrated superiority in the efficacy of second-generation EESs compared with first-generation DESs when used in SVG lesions, with respect to MACE (composite of all-cause mortality, myocardial infarction, and TVR) but with no difference in the stent thrombosis rate. This superiority was driven by the lower target lesion revascularization and TVR rates in the EES-treated patients. Taken together, these findings suggest the increased antirestenotic efficacy of second-generation EESs in SVGs.
Coronary Artery Disease/EES Versus First-Generation DES in SVG
SVG failure is common after coronary artery bypass grafting and is associated with repeat revascularization.16 Because of the increased risks in mortality and morbidity with reoperative surgery, percutaneous coronary intervention is a preferable revascularization strategy when SVGs fail.17 The Saphenous Vein De novo (SAVED) trial reported that, compared with conventional balloon angioplasty, Palmaz-Schatz bare metal stents were associated with lower rates of major adverse events (26% vs 39%, p ¼ 0.04).18 Since then, most SVG percutaneous coronary interventions have been performed with stents. Subsequently, previous studies have compared bare metal stents and DESs in SVGs and have shown a reduction in repeat revascularization with DESs.2e5 Because previous studies have suggested the existence of a late catch-up phenomenon regarding TVR after DES implantation, long-term follow-up is particularly important.9,10 In the Death and Events at Long-term followup AnalYsis: Extended Duration with Cypher stent (DELAYED RRISC) trial, an initial benefit of DESs compared with bare metal stents in the reduction of repeat revascularization at 6 months was no longer seen at a median of 32 months.9 The Strategic Transcatheter Evaluation of New Therapies (STENT) registry, a large multicenter registry, found that DESs, compared with bare metal stents, reduced the incidence of TVR at 9 months but this advantage was lost at 2 years.10 However, in the present study, both target lesion revascularization and TVR rates were significantly lower for EESs at 2 years, with a continued benefit over time compared with first-generation DESs. Notably, the late catch-up phenomenon in target lesion revascularization (1.1% at 1 and 2 years) and TVR (5.9% at 1 year to 6.8% at 2 years) was not observed in EES-treated patients comparing year 1 and 2 at follow-up. Although a clear pathophysiologic explanation for these findings is lacking, superior design features such as thin (81 mm), fracture-resistant struts and a relatively thin, biocompatible polymer (7.6 mm) might have contributed to the improved antirestenotic efficacy with EES in SVGs. One pathologic study has shown that first-generation DES-treated SVG lesions had greater delayed healing, a greater percentage of uncovered struts (19.6% vs 5.1%, p ¼ 0.043), and less endothelialization (70.0% vs 98.3%, p ¼ 0.028) than bare metal stents.19 Stent fracture (DES 56% vs bare metal stent 11%, p ¼ 0.045) and late stent thrombosis (DES 44% vs bare metal stent 0%, p ¼ 0.023) were more frequent with DESs. Second-generation EESs have emerged as a safer DES with regard to lower stent thrombosis rates in patients with native coronary artery disease.20 In a rabbit iliac artery model, EESs showed more rapid endothelialization than sirolimus- and paclitaxeleluting stents.21 Furthermore, an optical coherence tomographic study demonstrated that at 12 months after implantation, EES use in SVGs was associated with lower rates of uncovered struts than the published first-generation DES (sirolimus- and paclitaxel-eluting stent) studies in native coronary arteries (3.8% vs 5.7%).22e24 These signals might explain in part the difference in performance of second-generation EES versus first-generation DES. It remains unclear whether 1 type of DES is more effective in SVG intervention. Previous studies comparing sirolimus-eluting stents and paclitaxel-eluting stents for
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SVG intervention did not demonstrate any significant differences in clinical outcomes.25e27 Furthermore, limited data are available on the outcomes of second-generation DESs in SVG intervention. The Stenting OF Saphenous Vein Grafts Xience V (SOS-Xience V) trial (data not yet unpublished), is a single-arm, nonrandomized, open-label, prospective study that examined the 12-month angiographic and clinical outcomes of 40 patients undergoing stenting of de novo SVG lesions with an EES.28 Angiographic followup at 12 months was performed in 27 patients, 4 (15%) of whom had in-stent restenosis requiring repeat revascularization. The 12-month incidence of MACE was 42.5%, greater than that seen in EES patients in our study (12.5%). In the present study, the cumulative incidence of MACE at 2 years of follow-up was significantly lower in the EES group (18.2% vs 35.0%, p ¼ 0.003), reflecting a lower rate of TVR in EES-treated patients (6.8% vs 24.5%, p <0.001). After adjustment for potential confounders, the difference between the 2 groups remained significant. To our knowledge, this is the first study showing the superiority of second-generation EESs compared with first-generation DESs in SVG intervention. However, even after EES implantation for diseased SVG, the greater occurrence (roughly double) of MACE at 2 years (18.2%) observed in our registry compared with the 2-year data published of native coronary artery disease (9.0% in the comparison of the everolimus-eluting Xience-V stent with the paclitaxel eluting Taxus Liberte stent in all-comers: a randomized open-label trial [COMPARE]12 and 8.3% in the Scandinavian Organization for Randomized Trials With Clinical Outcome IV [SORT OUT IV]13) indicates a need for native artery percutaneous coronary intervention, if technically feasible. Several potential limitations should be considered. Ours was an observational, retrospective, single-center registry with a relatively small sample size. In addition, the nonrandomized comparisons between EESs and first-generation DESs might have introduced a bias in the results. However, in general, the groups were well balanced in baseline clinical, angiographic, and procedural characteristics. Because angiographic follow-up was not performed, the restenosis rate might have been underestimated. However, routine angiographic surveillance after DES deployment has led to increased rates of repeat revascularization because of the oculostenotic treatment of mild to moderate lesions, which could magnify the DES benefit.29 The study was underpowered to detect differences in stent thrombosis. The incidence of definite stent thrombosis was very low in both groups. Larger scale and longer term follow-up studies are needed to determine whether using second-generation EESs in SVGs will decrease the risk of stent thrombosis. Our study included patients treated during a long-term period in which percutaneous coronary intervention techniques, including operator skill and adjunctive devices, have changed accordingly. This might have influenced the clinical outcomes. Finally, it was recently reported that in patients undergoing SVG percutaneous coronary intervention, discontinuation of long-term clopidogrel therapy was associated with death and myocardial infarction, irrespective of the stent type.30 Although all our patients were recommended to receive 12 months of dual antiplatelet therapy,
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The American Journal of Cardiology (www.ajconline.org)
data regarding compliance with dual antiplatelet therapy were not collected. This omission might have had an effect on the results; however, we found no significant differences between the 2 groups with regard to death and myocardial infarction. Disclosures The authors have no conflicts of interest to disclose. 1. Fitzgibbon GM, Kafka HP, Leach AJ, Keon WJ, Hooper GD, Burton JR. Coronary bypass graft fate and patient outcome: angiographic follow-up of 5,065 grafts related to survival and reoperation in 1,388 patients during 25 years. J Am Coll Cardiol 1996;28:616e626. 2. Vermeersch P, Agostoni P, Verheye S, Van den Heuvel P, Convens C, Bruining N, Van den Branden F, Van Langenhove G. Randomized double-blind comparison of sirolimus-eluting stent versus bare-metal stent implantation in diseased saphenous vein grafts: six-month angiographic, intravascular ultrasound, and clinical follow-up of the RRISC Trial. J Am Coll Cardiol 2006;48:2423e2431. 3. Lee MS, Yang T, Kandzari DE, Tobis JM, Liao H, Mahmud E. Comparison by meta-analysis of drug-eluting stents and bare metal stents for saphenous vein graft intervention. Am J Cardiol 2010;105: 1076e1082. 4. Brilakis ES, Lichtenwalter C, Abdel-karim AR, de Lemos JA, Obel O, Addo T, Roesle M, Haagen D, Rangan BV, Saeed B, Bissett JK, Sachdeva R, Voudris VV, Karyofillis P, Kar B, Rossen J, Fasseas P, Berger P, Banerjee S. Continued benefit from paclitaxel-eluting compared with bare-metal stent implantation in saphenous vein graft lesions during long-term follow-up of the SOS (Stenting of Saphenous Vein Grafts) trial. J Am Coll Cardiol Interv 2011;4:176e182. 5. Mehilli J, Pache J, Abdel-Wahab M, Schulz S, Byrne RA, Tiroch K, Hausleiter J, Seyfarth M, Ott I, Ibrahim T, Fusaro M, Laugwitz KL, Massberg S, Neumann FJ, Richardt G, Schömig A, Kastrati A. Drug-eluting versus bare-metal stents in saphenous vein graft lesions (ISAR-CABG): a randomised controlled superiority trial. Lancet 2011;378:1071e1078. 6. Levine GN, Bates ER, Blankenship JC, Bailey SR, Bittl JA, Cercek B, Chambers CE, Ellis SG, Guyton RA, Hollenberg SM, Khot UN, Lange RA, Mauri L, Mehran R, Moussa ID, Mukherjee D, Nallamothu BK, Ting HH. 2011 ACCF/AHA/SCAI guideline for percutaneous coronary intervention: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Society for Cardiovascular Angiography and Interventions. J Am Coll Cardiol 2011;58:e44ee122. 7. Hoffmann R, Hamm C, Nienaber CA, Levenson B, Bonzel T, Sabin G, Senges J, Zahn R, Tebbe U, Pfannebecker T, Richardt HG, Schneider S, Kelm M. Implantation of sirolimus-eluting stents in saphenous vein grafts is associated with high clinical follow-up event rates compared with treatment of native vessels. Coron Artery Dis 2007;18:559e564. 8. Brilakis ES, Rao SV, Banerjee S, Goldman S, Shunk KA, Holmes DR Jr, Honeycutt E, Roe MT. Percutaneous coronary intervention in native arteries versus bypass grafts in prior coronary artery bypass grafting patients: a report from the National Cardiovascular Data Registry. J Am Coll Cardiol Intv 2011;4:844e850. 9. Vermeersch P, Agostoni P, Verheye S, Van den Heuvel P, Convens C, Van den Branden F, Van Langenhove G. Increased late mortality after sirolimus-eluting stents versus bare-metal stents in diseased saphenous vein grafts: results from the randomized DELAYED RRISC trial. J Am Coll Cardiol 2007;50:261e267. 10. Brodie BR, Wilson H, Stuckey T, Nussbaum M, Laurent S, Bradshaw B, Humphrey A, Metzger C, Hermiller J, Krainin F, Juk S, Cheek B, Duffy P, Simonton CA; STENT Group. Outcomes with drug-eluting versus bare-metal stents in saphenous vein graft intervention results from the STENT (strategic transcatheter evaluation of new therapies) Group. J Am Coll Cardiol Intv 2009;2:1105e1112. 11. Stone GW, Rizvi A, Sudhir K, Newman W, Applegate RJ, Cannon LA, Maddux JT, Cutlip DE, Simonton CA, Sood P, Kereiakes DJ; SPIRIT IV Investigators. Randomized comparison of everolimus- and paclitaxel-eluting stents: 2 year follow up from the SPIRIT (Clinical Evaluation of the Xience V Everolimus Eluting Coronary Stent System) IV trial. J Am Coll Cardiol 2011;58:19e25.
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28. Brilakis ES, Papayannis AC, Abdel-Karim ARR, Michael TT, Mahmood A, Makke LB, Roesle M, Haagen D, Rangan BV, Banerjee S. Prospective evaluation of the Xience V everolimus-eluting stent in saphenous vein graft atherosclerosis: the Xience V-SVG angiographic study. J Am Coll Cardiol 2011;58:B59. 29. Uchida T, Popma J, Stone GW, Ellis SG, Turco MA, Ormiston JA, Muramatsu T, Nakamura M, Nanto S, Yokoi H, Baim DS. The clinical impact of routine angiographic follow-up in randomized trials of drugeluting stents: a critical assessment of “oculostenotic” reintervention in patients with intermediate lesions. J Am Coll Cardiol Intv 2010;3: 403e411. 30. Sachdeva A, Bavisetty S, Beckham G, Shen AY, Aharonian V, Mansukhani P, Stone GW, Leon M, Moses J, Moore N, Hyett R, Contreras R, Brar SS. Discontinuation of long-term clopidogrel therapy is associated with death and myocardial infarction after saphenous vein graft percutaneous coronary intervention. J Am Coll Cardiol 2012;60: 2357e2363.