In recent years, coronary stent placement has become an established treatment for patients with coronary artery disease.1,2 However, in-stent restenosis has been reported to occur in 20–30% of patients, and the restenosis rate after treatment for in-stent restenosis is also high (> 30%), regardless of treatment modalities, including balloon angioplasty,3–5 rotational atherectomy,6,7 and repeat stenting. The effectiveness of stent therapy can be questioned, particularly in patients with recurrent restenosis after stent implantation. If the factors for recurrent restenosis can be predicted after stent implantation, other more effective strategies for treatment may be considered. In this study, we examined the incidence of recurrent restenosis in patients after Palmaz-Schatz (P-S) stent implantation to identify the factors affecting recurrent restenosis after stenting. MATERIALS AND METHODS Study group. From January 1997 to December 1997, a total of 197 consecutive patients underwent successful coronary stent implantation using one P-S stent at Komatsushima Red Cross Hospital. The stent implantation technique has been described previously.1 Before stent implantation, 81 mg of aspirin, calcium blockers, and depending on the lesion morphology, nitrate or beta blockers were administered. All patients received 10,000 units of heparin intravenously prior to PTCA. After stent implantation, aspirin (162 mg) and ticlopidine (200 mg) were administered for at least 1 month. Coronary stents were implanted under fluoroscopic guidance. The balloon size and inflation pressure were at the operator’s discretion. Adequacy of the final result was based solely on the angiographic assessment. At the time of stenting, patients were asked to return for a 6-month follow-up angiogram, regardless of the presence or absence of symptoms. Coronary angiography was performed earlier if clinically indicated. Angiographic follow-up was performed at a mean of 5.8 ± 1.6 months after coronary stenting in 170 patients (86%). Restenosis was defined as a diameter stenosis >= 50% at the time of follow-up angiography. When in-stent restenosis was confirmed, repeat balloon angioplasty was performed. Three months after repeat balloon angioplasty, coronary angiography was again performed. If a second restenosis was confirmed, balloon angioplasty was repeated and then assessed by angiography 3 months later. After coronary stent implantation, 100 patients (Group A: 64 ± 8 years; M:F = 82:18) never restenosed, in Group B 49 patients (64 ± 9 years; M:F = 41:8) restenosed once, and 21 patients in Group C (65 ± 10 years; M:F = 11:10) restenosed more than twice. The 3 groups were analyzed. Angiographic analysis. Quantitative analyses were performed independently by two experienced interventional cardiologists. Lesions were classified according to the American College of Cardiology/American Heart Association (ACC/AHA) classification system.8 Coronary calcification was defined by fluoroscopy. Angiographic coronary dissections after pre-dilation were identified according to the criteria of the National Heart, Lung, and Blood Institute Percutaneous Transluminal Coronary Angioplasty Registry9 and classified as either minor dissections (types A and B) or major dissections (types C–F). Patterns of in-stent restenosis were divided into focal and diffuse type according to angiography by Mehran et al.10 Before and after the intervention, as well as at follow-up angiography, efforts were made to control coronary vasomotor tone through intracoronary nitroglycerin administration. The analysis was performed using orthogonal end-diastolic cine frames demonstrating the stenosis in its most severe and nonforeshortened projections, using a computer-assisted, automated edge-detection algorithm (Cardio 500, Kontron Electronics, BILDANALYSE, München, Germany). The contrast-filled catheter was used as the calibration standard. Reference vessel size was determined from the post-procedural images. Statistical analysis. Statistical analysis was performed with Statview version 5.0 (Abacus Concepts, Inc., Berkeley, California). All continuous variables are expressed as mean ± SD and categorical variables as percentages. Comparisons between groups were performed using the chi-square test to analyze differences in categorical variables, and the T test for continuous variables. A p value RESULTS Baseline characteristics. Baseline patient clinical data are summarized in Table 1. Three groups were similar with respect to age, previous myocardial infarction, previous PTCA, and the presence of hyperlipidemia and hypertension. Group C had a greater proportion of women and a higher incidence of diabetes mellitus. Angiographic findings (Table 2). Three groups had similar angiographic findings, except that Group C had slightly longer lesions (11.9 ± 5.4 vs. 9.0 ± 3.9; p Procedural results and angiographic follow-up (Table 3). After pre-dilation, the incidence of major coronary dissection was similar in the three groups (9% vs. 3%). The diameter stenosis after pre-dilation (50 ± 10 vs. 39 ± 10; p Multivariate analysis (Table 4). Logistic regression analysis was used to identify the independent predictors of recurrent in-stent restenosis. Diameter stenosis after stenting (OR = 1.084; p = 0.0022), female (OR = 4.262; p = 0.0135), and diameter stenosis after pre-dilatation (OR = 1.042; p = 0.0233) were found to predict recurrent restenosis after stenting. DISCUSSION The initial multicenter study by Schatz et al.11 demonstrated the safety and efficacy of the implantation of the Palmaz-Schatz coronary stent. This study was soon followed by two randomized trials: the Belgian Netherlands STENT study (BENESTENT I)1 and the Stent REStenosis Study (STRESS)2 that compared P-S stent implantation with balloon angioplasty. These studies have demonstrated relatively low rates of angiographic and clinical restenosis. The use of coronary stents has increased dramatically in the past few years. Recent studies, performed in highly selected patients, have shown that the risk of restenosis is reduced, but not abolished, after coronary stenting.1,2 Coronary stents reduce restenosis by producing an excellent initial angiographic result and by eliminating elastic recoil and adverse vascular remodeling.12 However, these devices have not been shown to diminish (and may actually increase) the magnitude of neointimal hyperplasia. Intravascular ultrasound (IVUS) studies in humans have confirmed that in-stent restenosis is primarily due to neointimal proliferation.12 The treatment for in-stent restenosis is still not well established. Therefore, identifying the risk factors for in-stent restenosis may optimize the use of coronary stenting in the treatment of coronary artery disease. Previous studies have already described risk factors for in-stent restenosis. Patient-related factors include diabetes mellitus, unstable angina, chronic hemodialysis, and smoking. Lesion-related factors include lesion length (> 20 mm), multiple vessel total occlusions, collateral circulation, and ostial and bifurcation lesions. Procedural factors include a post-procedure residual stenosis > 30%.13–18 At our institution, there were 21 patients of recurrent restenosis after coronary stenting between January through December of 1997. This study was undertaken to predict the factors that contribute to recurrent restenosis after coronary stenting. Our study demonstrates that there are several characteristics associated with recurrent restenosis after stent implantation: 1) female gender, 2) final diameter stenosis, and 3) diameter stenosis after predilatation. Elezi et al.19 analyzed the clinical and angiographic outcome of diabetic patients following successful coronary stent placement, and compared these results with those achieved after stenting in nondiabetic patients. They found that diabetes is an independent risk factor for a poorer angiographic and clinical outcome. Furthermore, coronary stent placement did not appear to eliminate the excessive cardiovascular risk in diabetic patients after coronary intervention. Lau et al.20 also reported that there is a high incidence of in-stent restenosis in diabetic patients, particularly in small vessels. Diabetes is thought to be an important factor promoting neointimal proliferation. Excessive neointimal reaction in the setting of diabetes probably results from complex hormonal and biochemical alterations.21 These might cause accelerated smooth muscle cell proliferation after coronary stenting.22–24 But diabetes mellitus has not been a recurrent in-stent restenosis predictor in this study. This might be due to comparatively large reference diameter of the coronary artery assessed. In this study, the diameter stenosis after predilation and after stenting was greater and the incidence of diffuse in-stent restenosis was higher after stenting in recurrent restenosis patients. Mehran et al.10 reported that diffuse type of ISR represents a spectrum of increasing severity (exaggerated neointimal hyperplasia), and the very high rate of subsequent revascularization after interventional therapy with currently available treatment modalities in patients with diffuse type ISR. Therefore, it is suggested that the quality of pre- and post-dilatation is related to the recurrence of restenosis after stenting. Serruys et al.25 reported that factors predicting in-stent restenosis include percent diameter stenosis after stent implantation and vessel diameter using intravascular ultrasound. After all, if stents are implanted in lesions without proper pre-dilation, the stent struts against the vessel wall become the incomplete apposition and diffuse type of in-stent restenosis is likely to occur. This may be a relevant point considering the current interest in direct stenting.26,27 Direct stenting is the method of stenting without balloon predilatation. It is reported that the in-hospital and long-term outcomes in patients undergoing a coronary intervention are equivalent when comparing stenting without balloon predilatation with balloon angioplasty followed by stenting.27 However, this study is the results of direct stenting for selected patients and all lesions are not suitable for direct stenting. Therefore, to avoid the recurrent in-stent restenosis, IVUS guidance before direct stenting is necessary to concern whether the target lesion could be dilatated properly with balloon or not. Extensive data show that brachytherapy reduces recurrent in-stent restenosis.28–30 The report was the Coronary Radiation to Inhibit Intimal Proliferation Post Stenting (SCRIPS) Trial, in which most of the lesions were in-stent restenosis lesions.28 The WRIST Trial specifically addressed treatment of in-stent restenosis.29 Of note, more than half of the lesions had a reduction in intimal hyperplasia between radiation and follow-up. Therefore, brachytherapy should be considered for in-stent restenotic patients with recurrent predictors. Study limitations. This was a retrospective analysis of the clinical and angiographic data derived from the group of consecutively patients after stenting. There is a tremendous limitation deriving from the small number of patients with recurrent restenosis analyzed in this study. The stents used are Palmaz-Schatz which are no longer widely used, so the results of this study are not necessary suitable for new generative stents. Diameter stenosis after predilatation might be a rather imprecise predictor because no specific predilatation protocol was implemented in this study. Coronary calcification is not estimated precisely on account of the fact that calcification is difficult to quantify angiographically. No other interventional techniques for in-stent restenosis, such as cutting balloon and rotablator, were used in this study. Thus, our results should be restricted to angiography-guided stenting and balloon angioplasty for in-stent restenosis. Whether these tools can lower the probability of recurrent restenosis after stenting remains unknown. However, our findings should be considered preliminary and require further verification from large, prospective trials. Conclusion This comparative study clearly demonstrates that there are several characteristics that predict recurrent in-stent restenosis. These include 1) female gender, 2) final diameter stenosis, and diameter stenosis after predilatation.
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