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Original Contribution
Comparison Between Sirolimus- and Paclitaxel-Eluting Stents
for the Treatment of Chronic Total Occlusions
May 2006
Percutaneous coronary intervention (PCI) of chronic total occlusion (CTO) lesions has a lower success rate and is technically demanding despite advances in equipment and operator experience.1–3 Although several studies showed favorable results with bare metal stent (BMS) implantation in CTO lesions, there are still significantly higher rates of restenosis (32–55%) and reocclusion (8–12%) after BMS implantation.4–9 Several studies have demonstrated that drug-eluting stents (DES) significantly reduced the rate of restenosis in the treatment of relatively simple or complex nonocclusive lesions.10–14 Recent studies have shown more favorable results with DES implantation in CTO lesions compared to BMS implantation.15–17 However, studies comparing sirolimus-eluting stents (SES) with paclitaxel-eluting stents (PES) for CTO lesions are limited. This study aims to evaluate the differences in the safety and efficacy between SES and PES implantation in CTO lesions.
Materials and Methods
Study population. The study included 136 patients who underwent successful recanalization of CTO lesions from March 2003 to December 2004. The study population consisted of patients hospitalized for stable or unstable angina thought to be caused by a CTO lesion or acute myocardial infarction where the noninfarct-related artery was occluded. SES (Cypher™, Cordis Corp., Miami, Florida) were implanted in 107 patients with 107 lesions, and PES (Taxus®, Boston Scientific Corp., Natick, Massachusetts) were implanted in 29 patients with 29 lesions. The selection of the type of DES was left to the operator’s discretion.
Exclusion criteria were severe left ventricular dysfunction (ejection fraction Definitions. A CTO was defined as an occlusion on angiography with no luminal continuity and with Thrombolysis In Myocardial Infarction (TIMI) flow grade 0 or 1.18 All patients included had a vessel occlusion estimated to be at least one month’s duration based on either a history of myocardial infarction (MI), sudden onset or worsening of chest pain, or the time between the diagnosis made on coronary angiography and PCI.19 Death, nonfatal MI and target lesion revascularization (TLR) were considered to be major adverse cardiac events (MACE). All deaths were considered cardiac unless otherwise demonstrated. The diagnosis of Q-wave MI was based on the presence of new pathologic Q-waves on the electrocardiogram. Non-Q-wave MI was defined as a 3-fold rise in total creatine kinase, with an increase in its MB isoenzyme, without new abnormal Q-waves. TLR was defined as any repeat PCI or coronary artery bypass graft surgery of the target lesion.
Stenting procedure and adjunctive pharmacotherapy. The stenting procedure was performed using a standard femoral approach, and stiff guidewires were usually used to cross the lesion.20 After predilatation, the stents were deployed by inflating the stent delivery balloon at nominal pressure and, if necessary, adjunct high-pressure balloon dilatation was performed to achieve angiographic optimization (residual diameter stenosis Angiographic analysis. For quantitative analysis, the angiograms taken just before and after the procedure and at follow up were selected for each patient. All measurements were performed in two orthogonal views after intracoronary injection of 0.2 mg of nitroglycerin. An end-diastolic frame in the projection best showing the lesion severity was selected. Quantitative coronary angiographic analysis was performed by an online analysis system (ANCOR V2.0, Siemens, Germany). Follow-up coronary angiography was routinely conducted at 6 months after the index procedure or earlier if clinically indicated by symptoms or documentation of myocardial ischemia. Binary restenosis was defined as > 50% diameter stenosis at the 6-month follow up angiogram measured at any point within the stented segment and the reference segments. The acute gain was calculated as the difference between the minimal lumen diameter before and after the procedure. The late lumen loss was calculated from the difference in the minimal lumen diameter between the postprocedure and 6-month follow-up period.
**i*Statistical analysis. Categorical variables are presented as absolute numbers and percent values. Continuous variables are expressed as mean ± standard deviation (SD). Differences between groups were assessed using the Chi-square or Fisher’s exact test for categorical variables, and with the unpaired Student’s t-test for continuous variables. We used a Cox proportional-hazard model to compare clinical outcomes such as TLR and MACE between the two groups. Kaplan-Meier analysis was performed to estimate the cumulative rates of survival and event-free survival. The log-rank test was used to compare MACE-free survival between the two groups. All tests were two-tailed, and a p-value of (SPSS, Inc., version 12.0, Chicago, Illinois).
Results
Baseline clinical and angiographic characteristics are shown in Table 1. There were no significant differences in baseline clinical and angiographic characteristics between the two groups. The procedural and quantitative angiographic results are presented in Table 2. There were no significant differences between the two groups in terms of reference vessel size, lesion length and stent length. The PES group had a significantly larger postprocedural minimal lumen diameter than the SES group (2.9 ± 0.3 mm vs. 2.7 ± 0.4 mm; p = 0.007). Angiographic follow up at 6 months was performed in 85/107 (79%) patients of the SES group and in 21/29 (72%) patients of the PES group (p = 0.4). Restenosis rates at follow up were 9.4% in the SES group and 28.6% in the PES group (p = 0.020). Late loss was also significantly smaller in the SES group (0.4 ± 0.8 mm vs. 0.8 ± 0.8 mm; p = 0.025). There were 4 focal and 4 diffuse in-stent restenosis lesions in the SES group, and 3 focal and 3 diffuse in-stent restenosis lesions in the PES group. Two restenosis lesions in the SES group received repeat PCI, and 2 lesions with restenosis received coronary artery bypass graft surgery. The other 4 restenotic lesions in the SES group did not require repeat revascularization because of intermediate severity of angiographic diameter stenosis without symptoms of angina or evidence of ischemia on stress test and thallium study. In the PES group, 2 patients with restenosis (1 focal and 1 diffuse in-stent restenosis) underwent repeat revascularization, and the other 4 patients were treated medically.
In-hospital and 1-year clinical outcomes. In-hospital and long-term clinical outcomes are presented in Table 3. During the hospitalization, sudden death occurred in 1 patient in the PES group due to acute stent thrombosis. Non-Q-wave MIs were observed in 9 patients in the SES group and in 3 patients in the PES group. Clinical follow up at 1 year was available for all patients in the two groups. TLR was performed in 4 patients (3.7%) in the SES group and 2 patients (6.9%) in the PES group, which did not reach significant statistical difference. At 1 year, the cumulative MACE-free survival rate was 95.8% in the SES group compared with 85.8% in the PES group (p = 0.049) (Figure 1).
Discussion
This study demonstrates that SES implantation showed more favorable results regarding angiographic and clinical outcomes in patients with CTO lesions compared with PES implantation. The major finding of this study is that the angiographic restenosis rate and late loss were significantly lower, and the MACE-free survival rate at 12 months was significantly higher in the SES group compared with the PES group.
Several previous studies have established the challenge of PCI on CTO lesions because of the lower success rate and high incidence of restenosis (29–45%).21,22 Previous studies have demonstrated that revascularization of CTO lesions is beneficial because it restores blood flow to a hibernating myocardium and thus improves symptoms, left ventricular function and exercise capacity.3,23–25 Generally, the indication for recanalization of a CTO is ischemia related to the occluded vessel. According to the “open artery” concept, recanalization of an occluded coronary artery could have long-term benefits in terms of morbidity and mortality after MI.26,27
After the introduction of DES, several studies demonstrated that DES markedly reduce the incidence of angiographic restenosis and repeat revascularization in selected patients with relatively noncomplex lesions.11,12,14 In patients with CTO lesions, there are several trials comparing the efficacy of DES with BMS,15–17 but studies comparing SES with PES are limited.
The restenosis rates in stent implantation have been inversely related to the postprocedural minimal lumen diameter and the number of stents utilized.28 In the present study, although the number of stents used was not different between the two groups, and postprocedural minimal lumen diameter in the PES group was even greater than in the SES group, the restenosis rate in the SES group was lower than in the PES group. More favorable angiographic results in the SES group can be explained by several factors responsible for the difference between the SES and the PES groups. Sirolimus is a macrolide antibiotic with a cytostatic mechanism, whereas paclitaxel is regarded as a cytotoxic agent.29 The polymer coating of the PES allows for elution of only 10% of the drug over 2 months, whereas that of the SES allows for elution of 100% of the drug, most of which occurs within 1 month.30 In addition, differences in stent design may be another factor. The closed-cell design of the SES is better than the open-cell design of the PES in terms of even distribution of the drug in the arterial wall.29,30
The restenosis rate observed in the SES group of our study was comparable with that in the previous study by Hoye et al.15 in patients with CTO lesions, whereas the late loss was significantly higher in our study. The restenosis rate in the PES group of our study was significantly higher than that in the previous study by Werner et al.16 The exact reason for these differences is unclear, but possibilities contributing to the more complex angiographic characteristics in our study may include longer lesion length and stent length. The late loss in the SES group was higher than in the SIRIUS (Sirolimus-Eluting Balloon-Expandable Stent in the Treatment of Patients with de Novo Native Coronary-Artery Lesions) trial,12 and the late loss in the PES group was higher than in the TAXUS IV trial.14 The reason for these differences might be related to the fact that we limited our study population to patients with CTO lesions, and it is comparable to previous studies of BMS in patients with CTO lesions.4–9
The significant reduction in late loss of 50% in the SES group (0.4 ± 0.8 mm vs. 0.8 ± 0.8 mm; p = 0.025) translated into 66% reduction in the rate of binary restenosis (9.4% vs. 28.6%; p = 0.020) (Table 2). The greater reduction of late loss with the SES shown by angiographic follow-up data in the present study and recent studies31–33 can explain the reduced rate of restenosis in the SES group, and thus the supremacy of the SES over the PES.
Unlike the angiographic data, the clinical follow-up data did not show significant differences. There was a trend toward decreased MACE in the SES group, but it did not achieve statistical significance because the total number of MACE was too small in both groups. Although the SES implantation was not associated with a significant reduction in the rates of TLR and MACE, the SES group showed a substantially improved MACE-free survival rate without increased risk of Q-wave MI or stent thrombosis as compared with the PES group.
Study limitations. This study was not randomized and used a retrospective comparative population. Also, angiographic follow up was not obtained for all patients due to the following reasons: some patients refused to give consent (n = 19), some were older than 75 years of age (n = 6), some had malignancies (n = 2), and some had an allergic reaction to dye (n = 3). However, those who did not undergo repeat angiography were all asymptomatic at clinical follow up except for 1 death in the PES group. The relatively small sample size of the PES group may be an important limitation of the present study because the study does not have the power to detect potential differences between the two study groups with regard to infrequent clinical events such as death and MI.
Conclusions
The implantation of SES for the treatment of CTO lesions resulted in a reduced rate of restenosis and an increased MACE-free survival rate compared with PES implantation. Although continued clinical follow up is necessary, these data support the routine use of SES when occluded coronary arteries are reopened.
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