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; paclitaxel-eluting 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.
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. 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. Therefore, the 2011 guidelines for percutaneous coronary intervention have provided a class I recommendation for DES use in SVGs. 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. Also, the TVR rates at ≥2 years did not show a difference between DESs and bare metal stents. 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 everolimus-eluting stents (EESs) are superior to paclitaxel-eluting stents through 2 years and provide safety and efficacy comparable to that of sirolimus-eluting stents 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 first-generation 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.
Methods
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 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 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.
The primary end point was major adverse cardiovascular events (MACE) at 2 years, defined as the composite of all-cause 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. 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 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 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 = 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.
| Variable | Second-Generation EES (n = 88) | First-Generation DES (n = 243) | p Value |
|---|---|---|---|
| Age (yrs) | 70.1 ± 10.1 | 68.3 ± 11.2 | 0.177 |
| Men | 66 (75.0%) | 190 (78.2%) | 0.540 |
| African-American | 13 (14.8%) | 35 (14.4%) | 0.933 |
| Systemic hypertension ∗ | 85 (96.6%) | 223 (91.8%) | 0.128 |
| Diabetes mellitus | 47 (54.0%) | 118 (48.8%) | 0.400 |
| Hypercholesterolemia † | 196 (89.1%) | 376 (89.1%) | 1.000 |
| Current smoker | 11 (12.5%) | 27 (11.1%) | 0.726 |
| Family history of coronary artery disease | 49 (55.7%) | 139 (59.7%) | 0.519 |
| Previous myocardial infarction | 37 (42.0%) | 93 (38.3%) | 0.611 |
| Previous percutaneous coronary intervention | 35 (39.8%) | 93 (38.3%) | 0.800 |
| Chronic renal insufficiency ‡ | 18 (20.5%) | 47 (19.5%) | 0.848 |
| Peripheral vascular disease | 30 (34.1%) | 74 (30.6%) | 0.544 |
| Clinical presentation | |||
| Stable angina pectoris | 23 (26.1%) | 54 (22.3%) | 0.468 |
| Unstable angina pectoris | 52 (59.1%) | 135 (55.8%) | 0.592 |
| Acute myocardial infarction | 4 (4.5%) | 17 (7.0%) | 0.415 |
| Congestive heart failure | 26 (29.9%) | 48 (20.7%) | 0.083 |
| Cardiogenic shock | 0 | 3 (1.3%) | 0.566 |
| Left ventricular ejection fraction | 0.45 ± 0.14 | 0.44 ± 0.14 | 0.748 |
∗ 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.
‡ Previously diagnosed or treated with medication, diet, or dialysis by a physician; diagnosis at admission if baseline creatinine level >2.0 mg/dl.
| Variable | Second-Generation EES (n = 96) | First-Generation DES (n = 317) | p Value |
|---|---|---|---|
| Saphenous vein graft lesion location | |||
| Proximal | 19 (19.8%) | 111 (36.0%) | 0.003 |
| Mid | 47 (49.0%) | 109 (35.4%) | 0.017 |
| Distal | 17 (17.7%) | 52 (16.9%) | 0.851 |
| Aorto-ostial | 6 (6.3%) | 25 (8.1%) | 0.548 |
| Lesion characteristics | |||
| Graft age (mo) | 132.4 ± 90.8 | 128.1 ± 77.5 | 0.686 |
| Restenotic lesion | 6 (6.3%) | 36 (11.4%) | 0.145 |
| Lesion type (ACC/AHA classification) | |||
| Type A | 6 (6.3%) | 16 (5.2%) | 0.686 |
| Type B1/B2 | 35 (36.5%) | 191 (61.8%) | <0.001 |
| Type C | 55 (57.3%) | 102 (33.0%) | <0.001 |
| Preprocedure diameter stenosis (%) ∗ | 87 ± 9 | 87 ± 10 | 0.796 |
| Procedural data | |||
| Stents (n) | 1.5 ± 0.9 | 1.5 ± 0.7 | 0.932 |
| Stent diameter (mm) | 3.08 ± 0.35 | 3.26 ± 1.45 | 0.083 |
| Stent length (mm) | 19.1 ± 13.1 | 20.6 ± 6.8 | 0.294 |
| Total contrast amount (ml) † | 166 ± 76 | 180 ± 84 | 0.157 |
| Embolic protection device | 22 (22.9%) | 109 (34.5%) | 0.033 |
| Intravascular ultrasound | 40 (41.7%) | 124 (40.3%) | 0.806 |
| Glycoprotein IIb/IIIa inhibitor † | 1 (1.1%) | 22 (9.1%) | 0.012 |
| Intra-aortic balloon pump † | 6 (2.5%) | 4 (4.5%) | 0.467 |
| Postprocedure outcomes | |||
| Angiographic success | 96 (100.0%) | 310 (98.1%) | 0.343 |
| Abrupt closure | 0 | 1 (0.3%) | 1.000 |
| No-reflow | 0 | 0 | — |
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.
| Event | Second-Generation EES (n = 88) | First-Generation DES (n = 243) | p Value |
|---|---|---|---|
| In-hospital | |||
| Death | 0 | 2 (0.8%) | 1.000 |
| Cardiac death | 0 | 1 (0.4%) | 1.000 |
| Q-wave myocardial infarction | 0 | 2 (0.8%) | 1.000 |
| Maximum creatine kinase-MB (ng/ml) | 5.3 ± 16.2 | 5.5 ± 16.5 | 0.925 |
| Maximum troponin I (ng/ml) | 4.3 ± 28.6 | 3.2 ± 12.5 | 0.747 |
| Vascular complications | 2 (2.3%) | 9 (3.7%) | 0.734 |
| Major bleeding | 1 (1.1%) | 4 (1.6%) | 1.000 |
| Transfusion | 4 (4.6%) | 6 (2.6%) | 0.469 |
| 30-Day follow-up | |||
| Major adverse cardiovascular events | 0 | 8 (3.3%) | 0.115 |
| Death | 0 | 4 (1.6%) | 0.577 |
| Cardiac death | 0 | 1 (0.4%) | 1.000 |
| Q-wave myocardial infarction | 0 | 2 (0.8%) | 1.000 |
| Target vessel revascularization | 0 | 5 (2.1%) | 0.330 |
| Target lesion revascularization | 0 | 0 | — |
| Stent thrombosis | 0 | 1 (0.4%) | 1.000 |
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 = 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 = 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 = 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 = 0.054) and TVR (p = 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 = 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 = 1.000). Very late (1 to 2 years) definite stent thrombosis was not seen in either group.
| Event | Second-Generation EES (n = 88) | First-Generation DES (n = 243) | p Value |
|---|---|---|---|
| At 1 yr | |||
| MACE | 11 (12.5%) | 56 (23.0%) | 0.035 |
| Death | 6 (6.8%) | 21 (8.7%) | 0.586 |
| Cardiac death | 1 (1.1%) | 5 (2.1%) | 1.000 |
| Myocardial infarction | 2 (2.4%) | 10 (4.7%) | 0.527 |
| Q-wave myocardial infarction | 1 (1.1%) | 2 (0.8%) | 1.000 |
| Non–Q-wave myocardial infarction | 1 (1.1%) | 8 (3.4%) | 0.266 |
| Target vessel revascularization | 5 (5.9%) | 37 (15.7%) | 0.022 |
| Target lesion revascularization | 1 (1.1%) | 15 (6.4%) | 0.079 |
| Stent thrombosis | 0 | 2 (0.8%) | 1.000 |
| At 2 yrs | |||
| MACE | 16 (18.2%) | 85 (35.0%) | 0.003 |
| Death | 11 (12.5%) | 35 (14.8%) | 0.618 |
| Cardiac death | 4 (4.5%) | 15 (6.2%) | 0.790 |
| Myocardial infarction | 3 (3.8%) | 12 (5.6%) | 0.767 |
| Q-wave myocardial infarction | 1 (1.1%) | 2 (0.8%) | 1.000 |
| Non–Q-wave myocardial infarction | 2 (2.4%) | 10 (4.7%) | 0.524 |
| Target vessel revascularization | 6 (6.8%) | 54 (24.5%) | <0.001 |
| Target lesion revascularization | 1 (1.1%) | 25 (11.6%) | 0.005 |
| Stent thrombosis | 0 | 2 (0.8%) | 1.000 |
| Event | Second-Generation EES (%) | First-Generation DES (%) | OR | 95% CI | p Value |
|---|---|---|---|---|---|
| MACE | 6.5 | 15.5 | 0.38 | 0.14–1.02 | 0.054 |
| Death | 6.1 | 6.3 | 0.96 | 0.33–2.76 | 0.940 |
| Cardiac death | 3.4 | 4.2 | 0.81 | 0.22–3.03 | 0.759 |
| Myocardial infarction | 1.2 | 0.9 | 1.37 | 0.12–15.3 | 0.798 |
| TVR | 1.2 | 8.3 | 0.14 | 0.02–1.04 | 0.054 |
| Target lesion revascularization | 0 | 4.4 | 0.12 | 0.01–2.05 | 0.143 |
| Stent thrombosis | 0 | 0 | — | — | — |
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