Original Contribution

Repeat Drug-Eluting Stent Implantation for In-Stent Restenosis: First- or Second-Generation Stent

Kennosuke Yamashita, MD,  Masahiko Ochiai, MD, PhD,  Tadayuki Yakushiji, MD,  Seitarou Ebara, MD,  Toshitaka Okabe, MD,  Myong Hwa Yamamoto, MD,  Shigeo Saito, MD,  Koichi Hoshimoto, MD,
Naoei Isomura, MD,  Hiroshi Araki, MD, PhD,  Chiaki Obara, MD, PhD

Kennosuke Yamashita, MD,  Masahiko Ochiai, MD, PhD,  Tadayuki Yakushiji, MD,  Seitarou Ebara, MD,  Toshitaka Okabe, MD,  Myong Hwa Yamamoto, MD,  Shigeo Saito, MD,  Koichi Hoshimoto, MD,
Naoei Isomura, MD,  Hiroshi Araki, MD, PhD,  Chiaki Obara, MD, PhD

Abstract: Objective. To investigate the efficacy and safety of a second-generation drug-eluting stent (DES) for in-stent restenosis (ISR) after first-generation DES implantation. Background. The everolimus-eluting stent is a second-generation DES that is very effective for de novo coronary lesions. Methods. The subjects were 145 consecutive patients who underwent re-stenting, including 93 given a first-generation DES and 52 given a second-generation DES. The two groups were followed up for 37.8 ± 16.7 months and 13.8 ± 2.1 months, respectively. The primary endpoint was in-stent late luminal loss at 8-month angiographic follow-up. Results. Baseline clinical and angiographic parameters were similar in the 2 groups. Follow-up angiography showed that late luminal loss (0.26 ± 0.31 mm vs 0.58 ± 0.67 mm; P=.01), the binary restenosis rate (2.6% vs 16.7%; P=.03), and the target lesion revascularization (TLR) rate (1.9% vs 11.8%; log-rank = 0.04) were smaller in the second-generation group than in the first-generation group. There was no definite stent thrombosis in either group. During follow-up, there were no significant between-group differences of major adverse cardiac events without TLR, myocardial infarction, death, and death + myocardial infarction. Multivariate analysis demonstrated that using a first-generation DES was the only independent predictor of TLR after 1 year (odds ratio, 2.78; 95% confidence interval, 1.22-5.43; P=.03). Conclusion. When ISR occurs after DES implantation, treatment with a second-generation DES reduces late luminal loss, binary restenosis, and TLR after 1 year compared with a first-generation DES.

J INVASIVE CARDIOL 2012;24(11):574-578

Key words: restenosis, everolimus, sirolimus, stents, revascularization

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Introduction of the drug-eluting stent (DES) has significantly reduced the incidence of in-stent restenosis (ISR) and the need for repeat revascularization compared with the bare-metal stent (BMS).1-3 However, ISR still remains an important problem, especially in patients with complex lesions,4,5 and the optimum treatment for ISR after DES implantation remains unknown. The mechanisms underlying ISR are complicated, and may include mechanical, biological, and technical factors. So far, only one randomized controlled trial on the treatment of restenosis after DES implantation has been reported.6 Repeat DES implantation seems to be the preferable approach to managing such restenoses,7 but the optimum stent type is still unclear.8,9 The everolimus-eluting stent (EES), either a Xience V (Abbott Vascular) or a Promus (Boston Scientific Corporation), is a second-generation DES (2nd DES) that achieves significant reduction of 8-month angiographic late loss and 2-year target vessel failure and major adverse cardiovascular events  (MACE) compared with first-generation stents, such as the sirolimus-eluting stent (Cypher; Cordis Corporation) or the paclitaxel-eluting stent (Taxus; Boston Scientific Corp.).10,11

The EES has the thinnest struts (81 μm) of all DES types, and thus is expected to obtain more acute gain and a lower rate of restenosis. Thinner struts have already been reported to improve stent deliverability and the procedural outcome, as well as decreasing the restenosis rate.12 However, the efficacy and safety of the EES for treatment of ISR affecting a first-generation DES (1st DES) remains unclear. Accordingly, we compared the outcome between EES and 1st DES implantation in patients who had ISR of a 1st DES.

Methods

Subjects. Data were reviewed for 1536 consecutive patients who underwent elective percutaneous coronary intervention (PCI) at our center from February 2005 to December 2010. The present study included 145 consecutive patients with ISR of a 1st DES who underwent reintervention with 2 types of DES. Patients were considered eligible if they presented with angina pectoris and/or a positive stress test and had significant angiographic ISR (>50% diameter stenosis) after implantation of a 1st DES. Of the 145 patients, 93 patients underwent reimplantation of a 1st DES (Cypher, 27 patients; Taxus, 66 patients) during the period from February 2005 to January 2010, while the other 52 patients received an EES during the period from February to December 2010. At our center, we only used the 1st DES before January 2010. After that, we only employed the EES to minimize selection bias. All patients provided written informed consent.

PCI strategy and antiplatelet therapy. PCI was performed according to standard methods via a radial or femoral approach using a 6 Fr or larger guide catheter to facilitate subsequent quantitative coronary angiography (QCA). Treatment with oral aspirin was started prior to the procedure. Following sheath insertion, unfractionated heparin was administered as bolus doses of 150 U/kg during the procedure to maintain an activated clotting time (ACT) of 250 to 300 seconds (ACT was measured both before and during PCI). We attempted to implant a DES in all patients who underwent PCI if they had no contraindications, such as acute coronary syndromes, intolerance of aspirin and ticlopidine, and scheduled surgery (among others). Additional antiplatelet therapy with either clopidogrel (75 mg/day after a loading dose of 300 mg) or ticlopidine (200 mg/day) was started in all patients after PCI and was continued for at least 1 year.

Angiographic analysis. The minimum luminal diameter (MLD), reference diameter, and pre- and postprocedural percent diameter stenosis (DS) of the lesion were determined with an automated edge detection system (CASSII; PieMedical). Data were analyzed by a radiologist who was not involved in the study to avoid bias. The contrast-filled catheter tip was used as the calibration standard. All measurements were performed on cine angiograms recorded after intracoronary administration of nitroglycerin. QCA measurements were obtained on both an in-stent basis (confined to the stented region) and an in-segment basis (including the vessel 5 mm proximal and distal to the stent). Acute gain was defined as the difference between the postprocedural MLD and the preprocedural MLD, while late loss was defined as the difference between the postprocedural MLD and that at follow-up. The reference diameter was defined as the average of the proximal and distal reference diameters of the vessel before repeat PCI. Angiographic binary restenosis was defined as >50% diameter stenosis of the target lesion located within the stented region and the vessel 5 mm proximal and distal to the stent on follow-up angiography. The pattern of ISR was assessed using the Mehran classification.13

Endpoints and definitions. Angiographic follow-up was scheduled from 6 to 8 months after PCI. Patients were reviewed clinically at 12 months after PCI by telephone interview or hospital visit. The primary endpoint was late luminal loss (as determined by in-stent analysis) at angiographic follow-up. Secondary endpoints were binary angiographic restenosis (diameter stenosis >50%) at angiographic follow-up, the target lesion revascularization (TLR) rate at 12 months, and MACE (death, stroke, coronary artery bypass grafting, myocardial infarction, and definite stent thrombosis) at 12 months. TLR was performed for significant narrowing (>50% angiographic diameter stenosis) of the lumen within the stent or within the target segment (including 5 mm distal or proximal to the stent) associated with symptoms. In patients with multivessel disease, objective evidence of ischemia related to the target lesion was also required. Definite thrombosis was defined as angiographic detection of complete occlusion or flow-limiting thrombus in a previously patent treated artery according to the Academic Research Consortium criteria.14 The baseline demographic profile, in-hospital complications, and occurrence of death, myocardial infarction, late coronary intervention, or definite stent thrombosis during follow-up were verified by independent review of medical records and source documents or from the records of family physicians. Angiographic success was defined as <20% residual stenosis together with Thrombolysis in Myocardial Infarction grade 3 flow and the absence of major complications (in-hospital death, myocardial infarction, or emergency coronary bypass surgery).15 Myocardial infarction was defined by the detection of new Q-waves in >2 contiguous leads of the electrocardiogram or elevation of creatinine kinase-MB isozyme to at least 3 times the upper limit of normal.

Statistical analysis. Data were analyzed with JMP (SAS Institute) software using analysis of variance (ANOVA). Categorical data are expressed as frequencies and were compared using Pearson’s chi-square test with Bonferroni’s correction. Continuous variables are presented as the mean ± standard deviation and were compared using Student’s t-test or ANOVA with the Turkey-Kramer multiple comparison test. To adjust for the different follow-up periods of the 1st DES and EES groups, Kaplan-Meier curves were drawn to estimate freedom from TLR and freedom from MACE. Univariate and multivariate regression analyses were performed to identify predictors of TLR after treatment of ISR using a 1st DES or an EES. Univariate parameters showing P<.2 were included in the multivariate model. Odds ratios were calculated, along with 95% confidence intervals. A probability (P) value <.05 was considered statistically significant.

Results

The baseline clinical characteristics of the two groups are displayed in Table 1. Demographic characteristics were similar for the 2 groups. Lesion characteristics and restenosis morphology (Mehran classification) were also comparable between the 2 groups, as shown in Table 2. Moreover, baseline angiographic parameters were similar in both groups with regard to lesion length, reference vessel diameter, minimum lesion diameter, diameter stenosis, and lesion location. Procedural data are also given in Table 2. No differences were found between the groups, except for the implanted stent diameter, which was significantly greater in the 1st DES group. However, there was no significant difference in the postprocedural minimum stent area on intravascular ultrasound (IVUS). There was no difference in dual antiplatelet therapy during follow-up between the 2 groups. Angiographic follow-up data are shown in Table 3. Angiographic follow-up was possible for 72 patients (77.4%) in the 1st DES group and 38 patients (73.1%) in the EES group (P=.701). Most patients who refused angiographic follow-up were asymptomatic and had a negative test for inducible ischemia. The EES group showed less late luminal loss than the 1st DES group (0.26 ± 0.31 mm vs 0.58 ± 0.67 mm; P=.01). We also examined late luminal loss separately in the patients with each type of stent. There was a significant difference among the three stent types (P=.02), and the EES showed less late luminal loss than the Taxus stent (0.26 ± 0.31 mm vs 0.64 ± 0.72 mm; P=.02). However, there was no significant difference in other comparisons. Similarly, the restenosis rate was lower in the EES group than in the 1st DES group (2.6% vs 16.7%; P=.04). There was a significant difference among the three stent types and the rate of restenosis was less in the EES group than in the Taxus stent group (P=.01). There were no significant differences in other comparisons.

Kaplan-Meier curves for freedom from TLR after 1 year of follow-up in both groups are shown in Figure 1. Data for the entire follow-up period were obtained in 140/145 patients (97%). The 1st DES group was followed for 38.6 ± 16.5 months and the EES group was followed for 15.4 ± 3.6 months. TLR was significantly lower in the EES group (1.9% vs 11.8%; log-rank = 0.04). Figure 2 shows the Kaplan-Meier curves for freedom from MACE in patients without TLR. After 1 year of follow-up, 1 MACE occurred in the EES group versus 5 in the 1st DES group (1.9% vs 4.3%, respectively; P=.68). Four patients died in the 1st DES group (2 of heart failure and 2 of pneumonia) versus 1 in the EES group (pneumonia). No patient suffered from myocardial infarction in either group and there was no stent thrombosis in either group. As shown in Table 4, multivariate analysis demonstrated that use of 1st DES for treatment of ISR was the only independent predictor of TLR after 12 months of follow-up (odds ratio, 2.78; 95% confidence interval, 1.22-5.43; P=.03).

Discussion

The main findings of this study were as follows: First, EES implantation achieved less late luminal loss and a lower restenosis rate compared with 1st DES implantation for ISR. Second, EES implantation was associated with a significantly lower TLR rate at 1 year, but there was no significant difference of MACE in the patients without TLR. Third, as already demonstrated in previous studies, repeat DES implantation for the treatment of DES restenosis was a safe procedure. We did not perform a comparison with other procedures, such as routine balloon angioplasty or use of a cutting balloon, but stent thrombosis (a major potential risk) was not observed in our series.

Since DESs were introduced clinically, in-stent restenosis has been reduced and patients for whom use of BMS was not indicated (eg, small vessel lesions, dialysis, or complex lesions such as chronic total occlusion) have also become treatable. Moreover, DESs can be successfully used to treat restenosis of BMS. Therefore, DESs are currently used in more than 10 million patients.16
The restenosis rate after 1st DES implantation for de novo lesions in high-risk patients is reported to be 5% or more.5,16 Therefore, a large number of patients is expected to need treatment of 1st DES restenosis in the future.

When there are procedural problems such as stent underexpansion, repeat DES implantation for DES restenosis generally achieves a favorable outcome.17 Unlike the case for BMS, the mechanisms of DES restenosis are multiple and consensus has not yet been reached about the optimum type of stent for treating DES restenosis.

In the SPIRIT III study,18 EES implantation achieved a very small late loss of 0.16 mm, which was less than the loss of 0.19 mm obtained with the Cypher stent (SES) in the SIRIUS study.19 The EES has the thinnest struts among the commercially available stents, which may reduce the restenosis rate and the incidence of clinical events when these stents are used for ISR or for lesions in small vessels.12

In the present study, late loss was 0.26 ± 0.31 mm in the EES group, which was less than that of 0.58 ± 0.67 mm in the 1st DES group, and the restenosis rate was also a low 2.4%. Compared with the results of the ISAR-DESIRE study,6 which is the only randomized trial that has been done in this population, our EES group showed similar late loss and a similar restenosis rate to their EES group.
It is thought that proliferation of smooth muscle cells in the endothelium is the main cause of restenosis after DES or BMS implantation.20,21 However, the mechanism differs somewhat between DES and BMS restenosis, since the time of onset, morphological features, and histological findings are different. A previous retrospective study compared implantation of an EES (2nd DES) or a paclitaxel-eluting stent (1st DES) in patients with ISR of a BMS (n = 79 and n = 95, respectively).23 The results were comparable to those of our study, with TLR at 1 year at 2% and 12%, respectively (P=.0193). Regarding MACE, as in many other studies, we found no significant difference of mortality. The difference between the two groups was smaller than observed in the SPIRIT IV study22 or reported by Almalla et al.23

These findings suggest that marked suppression of endothelial proliferation by EES implantation reduces TLR but not MACE, after either BMS or DES restenosis.

There were no patients with stent thrombosis14 in our series. With repeat implantation, the polymer layer is doubled and this may increase the risk of stent thrombosis. In Japanese patients treated with an EES, stent thrombosis has a low incidence of about 0.5%.22 If the number of patients receiving EES becomes larger, the incidence of thrombosis may also increase, but repeat DES itself does not seem to be a risk factor for thrombosis and can be considered a safe treatment for ISR.
Study limitations. Our study has the following limitations. First, it was a single-center study with a limited sample size and outcomes were assessed retrospectively. However, the baseline characteristics of the two groups were well-matched, and each stent type was used in a different period. Thus, we avoided selection bias, and stent usage in daily practice was well simulated.
Second, only 70% of the patients could be followed angiographically, which means that data from the remaining 30% could have influenced our results. However, nearly 100% of the patients were followed to 12 months clinically, so the low TLR rate in the 2nd DES group is reliable.

Third, as in previous studies, ISR was classified according to the Mehran classification.13 Although this is useful for the classification of lesions, it is only based on visual observation of in-stent endothelial proliferation. Additional evaluation of the volume of intimal hyperplasia by IVUS or qualitative analysis (VH or iMAP) may be helpful.

Fourth, the chief potential problems with repeat DES are stent thrombosis and re-restenosis after implantation. When 3 stents are layered across a lesion, the thickness of the stent struts will prevent a large lumen from being obtained. Accordingly, drug-eluting balloon (DEB) may be another promising option for treatment of ISR and comparison of DES with DEB may be worthwhile in the future. Also, development of a bioabsorbable EES may be beneficial for management of in-stent restenosis,24 but further studies are required.

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From the Division of Cardiology and Cardiac Catheterization Laboratories, Showa University Northern Yokohama Hospital, Yokohama, Japan.
Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. The authors report no conflicts of interest regarding the content herein.
Manuscript submitted April 13, 2012, provisional acceptance given May 16, 2012, final version accepted June 19, 2012.
Address for correspondence: Kennosuke Yamashita, MD, Division of Cardiology and Cardiac Catheterization Laboratories, Showa University Northern Yokohama Hospital. Email: kennosuke.atmm3@gmail.com