First-generation drug-eluting stents have been proved to be very effective for the treatment of bare metal stent in-stent restenosis (BMS ISR). The efficacy of second-generation drug-eluting stents in this setting remains less well defined. The present study compared the long-term clinical outcome after treatment of BMS ISR using the second-generation everolimus-eluting stent (EES) to that after treatment using the paclitaxel-eluting stent (PES). A total of 174 patients with BMS ISR underwent percutaneous coronary intervention using a PES (95 patients) or an EES (79 patients) from 2003 to 2010. The patients in the PES and EES groups were followed up for 42.2 ± 22.2 and 18.3 ± 8.2 months, respectively. The primary end point of the study was survival free of major adverse cardiac events at 1 year. The secondary end points were survival free of the need for revascularization of the target lesion and definite stent thrombosis. The baseline clinical and angiographic parameters were comparable between the 2 groups. The freedom from major adverse cardiac event rate at 1 year of follow-up was 4.5% and 13.6% (p = 0.0663) for the EES and PES groups, respectively. The target lesion revascularization (TLR) rates were greater in the PES group at 1 year of follow-up compared to the EES group (1% vs 11.5%, p = 0.0193). The rate of myocardial infarction, death, and definite stent thrombosis for the EES and PES groups at 1 year of follow-up was 0% versus 4.2% (p = 0.0984), 3% versus 2.1% (p = 0.6855), and 0% versus 2.1% (p = 0.2382), respectively. The use of a PES for treatment of ISR was the only independent predictor of recurrent TLR at 1 year of follow-up (odds ratios 1.11, 95% confidence interval 1.05 to 1.18; p = 0.0193). During the complete follow-up period, the rates of TLR, myocardial infarction, death, major adverse cardiac events, and definite stent thrombosis were not different between the 2 treatment groups. In conclusion, EES resulted in reduced rates of TLR at 1 year of follow-up compared to PES when used for treatment of BMS ISR. However, at long-term follow-up, the event rates between EES and PES were comparable after treatment of BMS ISR.
The treatment of in-stent restenosis (ISR) remains among the most challenging problems in interventional cardiology. Recurrent restenosis after treatment of ISR has been reported to develop in ≤80% of lesions. The introduction of drug-eluting stents has significantly reduced the incidence of ISR compared to bare metal stents (BMSs) in de novo lesions. However, because of long-term safety concerns with drug-eluting stents, BMSs have remained an important backbone of percutaneous coronary intervention. The use of first-generation drug-eluting stents for treatment of BMS ISR has significantly improved the long-term outcome of these patients and has resulted in rapid replacement of previously used intracoronary brachytherapy. The everolimus-eluting stent (EES) as a second-generation drug-eluting stent has been very effective for the treatment of de novo coronary lesions. The efficacy and safety of the second-generation EES for the treatment of BMS ISR lesions remains less well defined. The present study compared the first-generation paclitaxel-eluting stent (PES) with the second-generation EES for the treatment of BMS ISR.
Methods
In this single-center study, 174 consecutive patients with BMS ISR who were treated with implantation of a PES or an EES were included. The patients were treated from June 2003 to February 2010. Of the 174 patients, 95 were treated with a PES and 79 with an EES. The patients were considered eligible if they presented with angina pectoris and/or a positive stress test and had significant angiographic ISR (>50% diameter stenosis) in a BMS. Patients were excluded if they had unprotected left main lesion, acute ST-segment elevation myocardial infarction, or recurrent ISR already previously treated with percutaneous transluminal coronary angiography, a drug-eluting stent, or brachytherapy. The ethical committee of the University Aachen approved the study.
Heparin was administered during the procedure according to standard practice. Aspirin (100 mg/day) and clopidogrel (300-mg loading dose) were started before the procedure. After the procedure, clopidogrel (75 mg/day) was administered, in addition to aspirin, for 6 months after elective stenting and for 9 to 12 months after stenting for acute coronary syndromes. No difference was found in the dual antiplatelet therapy between the 2 treatment groups. Glycoprotein IIb/IIIa inhibitors were given at the discretion of the operator. PESs (Taxus stent, Boston Scientific, Natick, Massachusetts) were available in lengths of 8 to 32 mm and diameters of 2.5 to 4 mm and EESs (Xience V stent, Abbott Vascular, Santa Clara, California) were available in lengths of 8 to 33 mm and diameters of 2.5 to 4 mm.
Procedural success was defined as <30% final diameter stenosis in the treated lesion and the absence of major clinical complications (in-hospital death, myocardial infarction, or emergency coronary bypass surgery). Patients were followed up for ≥12 months after the procedure by telephone interviews for any major adverse cardiac events defined as death from any cause, myocardial infarction, or the need for target lesion revascularization (TLR). In addition, the occurrence of definite stent thrombosis was determined from clinical events and confirmed by coronary angiography. The baseline clinical demographics, in-hospital complications, and occurrence of death, myocardial infarction, late recurrent coronary intervention, or definite stent thrombosis during follow-up were verified by independent hospital chart review and source documentation or from the records of the family physicians. Myocardial infarction was defined as the presence of new Q waves in >2 contiguous electrocardiogram leads or an elevation of creatine-kinase-MB at least 3 times the upper limit of normal.
Baseline and postprocedural coronary angiograms were digitally recorded and analyzed off-line at the angiographic core laboratory of the University Aachen by experienced personnel using a validated quantitative angiographic system (CAAS II System, Pie Medical Imaging, Maastricht, The Netherlands), who were unaware of the clinical status of the patients. The contrast-filled catheter tip was used as the calibration standard. All measurements were performed on cine angiograms recorded after the intracoronary administration of nitroglycerin. Quantitative measurements included the reference diameter, lesion length, and minimal luminal diameter in-lesion (defined as the in-stent segment plus the proximal and distal 5-mm edge segments) and in-stent (without an adjacent edge segment). The pattern of ISR was categorized according to the angiographic findings using previously described schematics.
The primary end point of the present study was survival free of major adverse cardiac events at 12 months. The secondary end points were survival free of major adverse cardiac events during the total follow-up period, survival free of TLR, and definite stent thrombosis. The need for TLR was determined by significant narrowing of the lumen within the stent or the lesion, including 5 mm distal or proximal to the stent (>50% angiographic diameter stenosis) in the presence of symptoms (in the case of multivessel disease, objective signs of ischemia related to the target lesion were required). Definite stent thrombosis was angiographically documented as complete occlusion or flow-limiting thrombus of a previously successfully treated artery in accordance with the Academic Research Consortium criteria. Stent thrombosis episodes were reported as early events ≤30 days after stent implantation, late events as those from 31 days to 1 year, and very late events as those >1 year after stent implantation.
Statistical analysis was performed using Med Calc version (SPSS, Chicago, Illinois). Categorical data are presented as frequencies and were compared using the Pearson chi-square test. Continuous data are presented as the mean ± SD and were compared using the Student t test or analysis of variance as adequate. To consider the different follow-up periods for the PES and EES groups, Kaplan-Meier curves for freedom from major adverse cardiac events, TLR, and stent thrombosis were analyzed. Univariate and multivariate regression analysis was performed to identify predictors for recurrent TLR and major adverse cardiac events after treatment of ISR using EESs or PESs. The included variables were the reference vessel diameter, ISR lesion length, pattern of ISR, minimal lumen diameter before intervention, minimal lumen diameter after intervention, lesion location in the left anterior descending artery, diabetes mellitus, and stent type used (EES vs PES). Only univariate parameters with p <0.2 were included in the multivariate analysis. Odds ratios are presented, along with their 95% confidence intervals. A p value of <0.05 was considered statistically significant.
Results
The baseline clinical characteristics are listed in Table 1 . Patients in the PES group were more frequently smokers and more often had arterial hypertension.
| Variable | Everolimus Stent (n = 79) | Paclitaxel Stent (n = 95) | p Value |
|---|---|---|---|
| Men | 68 (86%) | 81 (85%) | 0.948 |
| Age (years) | 67.5 ± 10.7 | 69.6 ± 9.6 | 0.165 |
| Multivessel coronary disease | 62 (78%) | 70 (74%) | 0.579 |
| Smoking | 37 (47%) | 65 (68%) | 0.006 |
| Systemic arterial hypertension | 60 (76%) | 84 (88%) | 0.049 |
| Hyperlipidemia ⁎ | 22 (28%) | 23 (24%) | 0.711 |
| Diabetes mellitus | 22 (28%) | 25 (26%) | 0.957 |
| Insulin use | 11 (14%) | 6 (6%) | 0.163 |
| Ejection fraction | |||
| ≥45% | 70 (89%) | 84 (88%) | 0.849 |
| <45% | 9 (11%) | 11 (11%) | 0.849 |
| Previous myocardial infarction | 35 (44%) | 48 (51%) | 0.506 |
| Previous coronary bypass | 7 (9%) | 14 (15%) | 0.346 |
The lesion characteristics and BMS restenosis types, in accordance with the Mehran-classification, were comparable between the 2 groups ( Table 2 ). Similarly, baseline angiographic parameters were comparable between the 2 groups with regard to lesion length, reference vessel diameter, and minimal lesion diameter and lesion location.
| Variable | EES Group (n = 79) | PES Group (n = 95) | p Value |
|---|---|---|---|
| Coronary lesion location | |||
| Left anterior descending | 23 (29%) | 42 (44%) | 0.061 |
| Right coronary artery | 36 (46%) | 30 (32%) | 0.863 |
| Left circumflex artery | 18 (23%) | 14 (15%) | 0.991 |
| Vein bypass | 2 (3%) | 9 (9%) | 0.125 |
| Pattern of in-stent restenosis ⁎ | |||
| Previous stent length (mm) | 21.9 ± 14.4 | 18.9 ± 10.2 | 0.156 |
| Focal (I) | 42 (53%) | 52 (55%) | 0.958 |
| Diffuse (II) | 23 (29%) | 30 (32%) | 0.860 |
| Proliferative (III) | 2 (3%) | 7 (7%) | 0.279 |
| Total occlusion (IV) | 6 (8%) | 6 (6%) | 0.975 |
| Before intervention | |||
| ISR lesion length (mm) | 10.8 ± 6.1 | 11.0 ± 6.3 | 0.835 |
| Reference luminal diameter (mm) | 2.53 ± 0.57 | 2.50 ± 0.51 | 0.678 |
| Minimal luminal diameter (mm) | 0.57 ± 0.35 | 0.60 ± 0.33 | 0.385 |
| After intervention | |||
| Reference luminal diameter (mm) | 2.77 ± 0.40 | 2.81 ± 0.48 | 0.600 |
| Minimal luminal diameter in stent (mm) | 2.41 ± 0.35 | 2.44 ± 0.49 | 0.846 |
| Minimal luminal diameter in lesion (mm) | 2.39 ± 0.37 | 2.40 ± 0.53 | 0.576 |
| Procedural characteristics | |||
| Implanted stent length (mm) | 19.7 ± 7.7 | 18.6 ± 8.2 | 0.356 |
| Stent diameter (mm) | 2.92 ± 0.31 | 3.02 ± 0.41 | 0.071 |
| Number of implanted stents | 1.20 ± 0.46 | 1.11 ± 0.38 | 0.177 |
⁎ Pattern I, focal (≤10 mm in length); pattern II, in-stent restenosis >10 mm within stent; pattern III, stent restenosis >10 mm extending outside stent; and pattern IV, totally occlusive in-stent restenosis.
The procedural data are also provided in Table 2 . No differences were found between the 2 treatment groups with regard to stent length, stent diameter, number of stents used per lesion, or previous stent length. Clinical follow-up data for the total follow-up period was obtained for 97% of the patients. Patients with a PES were followed for 42.2 ± 22.2 months and patients with an EES were followed for 18.3 ± 8.2 months.
The clinical event rates at 1 year are listed in Table 3 . At 1 year of follow-up, 3 major adverse cardiac events were observed in the EES group and 13 in the PES group (4.5% vs 13.6%, respectively, p = 0.0663). TLR was required in 1 patient in the EES group and 11 patients in the PES group (1.5% vs 11.5%, respectively, p = 0.0193). Two patients each died in the PES group (1 of sudden cardiac death and 1 of severe pneumonia) and the EES group (1 of sudden cardiac death and 1 of intracranial bleeding). No patient experienced myocardial infarction in the EES group, and 4 patients had nonfatal myocardial infarction in the PES group. Definite stent thrombosis occurred in 2 patients in the PES group (at 36 and 197 days from the index procedure) compared to no patient in the EES group at 1 year and during the complete follow-up period (2.1% vs 0%, respectively, p = 0.2382). The first patient was taking aspirin and clopidogrel at the time of the event and the second patient had interrupted clopidogrel 3 weeks before the event.
