Predictors of 6-Month Angiographic Restenosis inside Bare-Metal Stent in Chinese Patients with Coronary Artery Disease

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1 Original Article Acta Cardiol Sin 2009;25:1 6 Coronary Artery Disease Predictors of 6-Month Angiographic Restenosis inside Bare-Metal Stent in Chinese Patients with Coronary Artery Disease Yung-Lung Chen, Hon-Kan Yip, Chien-Jen Chen, Cheng-Hsu Yang, Chih-Yuan Fang, Yuan-Kai Hsieh, Chi-Ling Hang and Chiung-Jen Wu Background: Bare-metal stents are widely used in Chinese population with coronary artery disease. Many reports of predictors of in-stent restenosis (ISR) are available from trials mainly conducted in the Western population. However, predictors of ISR in Chinese population are rarely described. Methods: This study enrolled 609 patients who had procedural success of coronary stenting with bare-metal stents and 6-month angiographic follow-up from January 1998 to December 2000 in our hospital. The baseline characteristics, angiographic and procedural parameters of these patients were collected into our database. The definition of ISR was more than 50 stenosis at the intervention site. Results: Two hundred and fifty-one patients (41.2 ) had ISR and 358 patients without ISR. By univariate analysis, the predictors of ISR were diabetes mellitus, multi-vessel disease, left anterior descending artery lesion, complex lesion, small vessel and stent sizes, long stent and lesion lengths and small post-procedure minimal luminal diameter. By multivariate analysis, the independent predictors of ISR were post-procedure minimal luminal diameter (OR: 1.969, 95 CI: ; p < 0.001), diabetes mellitus (OR: 1.831, 95 CI: ; p = 0.001), complex lesion (OR: 1.827, 95 CI: ; p = 0.036), and left anterior descending artery involvement (OR: 1.498, 95 CI: ; p = 0.033). Conclusion: In this study, post-procedure minimal luminal diameter, presence of diabetes mellitus, complex lesions and left anterior descending artery involvement are predictive of 6-month angiographic restenosis inside bare-metal stents in Chinese population. Key Words: Stent Restenosis Coronary artery disease INTRODUCTION Coronary artery stenting has been used to optimize Received: November 3, 2008 Accepted: Febtuary 5, 2009 Department of Internal Medicine, Chang Gung Memorial Hospital- Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan. Address correspondence and reprint requests to: Dr. Chiung-Jen Wu, Division of Cardiology, Department of Internal Medicine, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Chang Gung University College of Medicine, 123, Ta Pei Road, Niao Sung Lane, Kaohsiung County 83301, Taiwan. Tel: ext. 8300; Fax: ; feymanchen@yahoo.com.tw the coronary lumen 1 and reduce peri-procedural complications since ,3 Many randomized trials have demonstrated that coronary artery stenting with bare-metal stents significantly decreases the incidence of target lesion restenosis when comparing with balloon angioplasty. 4,5 Although coronary stenting with bare-metal stents avoids acute recoil and reduces negative vascular remodeling, in-stent restenosis (ISR) occurs in of patients receiving successful coronary stenting and requires subsequent revascularization. 4-7 In our previous study, Chinese patients with 6-month angiographic restenosis inside bare-metal stents had adversely clinical outcome in the long-term follow-up. 8 Although drug- 1 Acta Cardiol Sin 2009;25:1 6

2 Yung-Lung Chen et al. eluting stenting markedly reduced the incidence of restenosis comparing with bare-metal stenting, 9-11 it is relatively costly for routine application and the issue of stent thrombosis is still of concern. 12,13 So, determining patients with high risk of ISR would be very important clinically in our daily practice. However, those reports of predictors of ISR are available from trials mainly conducted in the Western population. Predictors of ISR in Chinese population are rarely described. Thus, the purpose of this study was to investigate predictors of ISR in a large cohort of Chinese patients with coronary artery disease. METHODS Patient population: From January 1998 to December 2000, 609 consecutive patients underwent successful percutaneous coronary stenting with bare-metal stents [acute coronary syndrome in 529 patients (86.9 ) and angina pectoris in 80 patients (13.1 )] and had 6-month angiographic follow-up examinations. A total of 687 coronary stents were implanted in 609 patients. Procedural success was defined as successful stent implantation with residual stenosis less than 30 and Thrombolysis in Myocardial Infarction (TIMI) grade 3 flow in the target vessel. 14 Patients with peri-procedural complications, such as perforation, non-st elevation myocardial infarction, no reflow phenomenon, ventricular tachyarrhythmia, acute stroke or procedure-associated mortality, were excluded from this study. Coronary artery stenting, angiographic analysis and six-month coronary angiography follow-up: Procedure and protocol of coronary artery stenting and angiographic analysis have been described previously in detail. 8,15 In patients undergoing multivessel intervention, angiographic variables of one randomly assigned lesion were entered into the analysis. Aspirin 100 mg once daily was prescribed except for patients with history of aspirin intolerance. Patients were also treated with ticlopidine 250 mg twice daily or clopidogrel 75 mg once daily for 1 month following stenting. Target lesion restenosis was defined as more than 50 diameter stenosis at the target lesion site on the follow-up angiogram. Definition of lesion was according to the modified American College of Cardiology/American Heart Association classification Task Force. 16 Data collection: The baseline and follow-up data were obtained: age; gender; coronary risk factors; angiographic morphology and results of diseased vessels. Patients who were compatible with the definition of dyslipidemia recommended by the National Cholesterol Education Program 17 or had received any kind of lipid lowering therapy before undergoing catheterization were considered with dyslipidemia. Renal insufficiency was defined as creatinine level 1.5 mg/dl. Statistical analysis: Data are expressed as the mean standard deviation. Differences in continuous variables were analyzed by unpaired t-test and categorical variables by Chi-square test. All the variables with p value less than 0.1 were entered into the multivariate analysis model. Multivariate analysis was conducted using stepwise logistic regression analysis to determine independent predictors of ISR. Statistical analyses utilized SPSS for Windows version 10 (SPSS, Inc., IL, USA). A twosided P value less than 0.05 was considered statistically significant. RESULTS Baseline clinical and angiographic predictors of in-stent restenosis: Table 1 lists the baseline clinical characteristics for patients in this study. There were 251 patients (41.2 ) with ISR, including 39 patients (6.4 ) with in-stent coronary occlusion, and 358 patients (58.8 ) with no ISR on 6-month follow-up angiography. Both groups were matched for age (p = 0.175) and gender (p = 0.569). Patients with ISR had a significantly higher prevalence of diabetes mellitus (40.6 vs. 26.5, p < 0.001) and renal insufficiency (16.0 vs. 10.4, p = 0.04) than patients without ISR. Additionally, patients with ISR underwent coronary re-intervention earlier than patients without ISR due to recurrent symptoms ( vs months, p < 0.001). By univariate analysis, the incidences of multi-vessel disease (67.7 vs. 59.5, p = 0.038), left anterior descending artery involvement (70.5 vs. 58.4, p = 0.002) and complex lesions (92.0 vs. 85.5, p = 0.014) were significantly higher in patients with ISR than in patients without ISR. The pre-procedure reference vessel diameter ( vs mm, p < 0.001), stent size (3.12 Acta Cardiol Sin 2009;25:1 6 2

3 Predictors of In-stent Restenosis Table 1. Univariate analysis of baseline clinical characteristics between patients with in-stent restenosis and patients without in-stent restenosis Variables Patients with in-stent restenosis (n = 251) Patients without in-stent restenosis (n = 358) p value Age (yrs) Male 203 (80.9 ) 296 (82.7 ) Diabetes mellitus 102 (40.6 ) 095 (26.5 ) <0.001 Hypertension 137 (54.6 ) 213 (59.5 ) Dyslipidemia 146 (58.2 ) 220 (61.5 ) Current smoker 124 (49.4 ) 173 (48.3 ) Prior myocardial infarction 031 (12.4 ) 042 (11.7 ) Acute coronary syndrome 222 (88.4 ) 307 (85.8 ) Acute myocardial infarction 098 (39.0 ) 136 (38.0 ) Renal insufficiency 040 (16.0 ) 037 (10.4 ) Old stroke 015 (6.0 ) 017 (4.7 ) Atrial fibrillation 022 (8.8 ) 031 (8.7 ) blockers 183 (72.9 ) 275 (76.8 ) Aspirin 218 (86.9 ) 304 (84.9 ) Clopidogrel 043 (17.1 ) 071 (19.8 ) Statins 126 (50.2 ) 194 (54.2 ) Ca-channel blockers 107 (42.6 ) 127 (35.5 ) ACEI/ARB 174 (69.3 ) 210 (58.7 ) Time to reintervention (months) < Data are expressed as mean SD or number ( ) of patients. ACEI: angiotensin-converting enzyme inhibitor; ARB: type 1 angiotensin receptor blockers. Renal insufficiency: creatinine 1.5 mg/dl vs mm, p < 0.001), post-procedure minimal luminal diameter ( vs mm, p < 0.001), and acute gain ( vs mm, p < 0.001) of patients with ISR were significantly smaller than those of patients without ISR (Table 2). Although the difference did not reach statistical significance, stent length was longer in patients with ISR than in patients without ISR ( vs mm, p = 0.05). Multiple stepwise logistic regression analysis identified post-procedure minimal luminal diameter (OR: 1.969, 95 CI: , p < 0.001), presence of diabetes mellitus (OR: 1.831, 95 CI: , p = 0.001), complex lesions (OR: 1.827, 95 CI: , p = 0.036), and left anterior descending artery involvement (OR: 1.498, 95 CI: , p = 0.033) as independent predictors of ISR (Table 3). DISCUSSION This study examined the predictors of 6-month angiographic restenosis inside bare-metal stents following successful coronary stenting. This study yields one important finding. Post-procedure minimal luminal diameter, presence of diabetes mellitus, complex lesions and left anterior descending artery involvement are predictive of development of 6-month ISR in Chinese population. Predictors of six-month in-stent restenosis: Intracoronary stents substantially reduce angiographic restenosis and target lesion revascularization in large ( 3.0 mm) vessels when compared with balloon angioplasty. 4,5 Consequently, stenting now is utilized in 80 of percutaneous coronary interventions at numerous centers, and the problem of ISR has grown proportionately. 7 Fischman et al. 5 showed that a small post-procedure minimal lumen diameter and lesion located in the left anterior descending coronary artery are associated with restenosis following stent placement. Elezi et al. 18 showed that patients with small vessels (< 2.8 mm) have a higher incidence of restenosis following stent implantation than patients with large vessels (> 3.2 mm), and unusually high risk for ISR is confined to those patients with small vessels and concomitant risk 3 Acta Cardiol Sin 2009;25:1 6

4 Yung-Lung Chen et al. Table 2. Univariate analysis of baseline angiographic findings between patients with in-stent restenosis and patients without in-stent restenosis Angiographic findings Patients with in-stent restenosis (n = 251) Patients without in-stent restenosis (n = 358) p value Multi-vessel disease 170 (67.7 ) 213 (59.5 ) LVEF ( ) LAD involvement 177 (70.5 ) 209 (58.4 ) Complex lesion (B2+C) 231 (92.0 ) 306 (85.5 ) Ostial lesion 025 (10.7 ) 031 (8.6 ) CTO lesion 026 (10.4 ) 022 (6.1 ) Bifurcation lesion 041 (16.5 ) 043 (12.0 ) Calcified lesion 062 (24.8 ) 073 (20.4 ) Presence of thrombus 112 (45.0 ) 164 (46.1 ) Presence of dissection 028 (11.2 ) 046 (12.9 ) Pre-MLD (mm) Pre-RVD (mm) < Stent length (mm) Stent size (mm) < Balloon/vessel ratio Maximal inflation pressure (Bar) Post-MLD (mm) < Acute gain (mm) < Data are expressed as mean SD or number ( ) of patients. LVEF: left ventricular ejection fraction; LAD: left anterior descending artery; CTO: chronic total occlusion; MLD: minimal luminal diameter; RVD: reference vessel diameter. Table 3. Multiple stepwise logistic regression analysis of baseline clinical and angiographic features in predicting in-stent restenosis after coronary angioplasty Variables OR 95 CI p value Post-MLD (mm) < Diabetes mellitus Complex lesion (B2+C) LAD involvement LAD: left anterior descending artery; MLD: minimal luminal diameter; OR: odds ratio. factors such as diabetes and complex lesions. The incidence of restenosis is high in diabetics as a result of accelerated atherosclerosis in percutaneous coronary interventional studies An increased restenosis rate among patients with diabetes is associated with endothelial dysfunction, dysregulation of growth factor production, and increased platelet aggregation and thrombogenicity Clinical evidence also exists that insulin and an insulin-resistant state have a role in the pathogenesis of restenosis in diabetic patients. 21 Complex lesion severity, as categorized according to American College of Cardiology/American Heart Association (ACC/AHA) classification, is proportional to plaque burden and lesion length. A long lesion, with its substantial plaque burden, is a primary source of smooth muscle cells that then proliferate and form neointima. 23,24 These data with regard to predictors of ISR in Chinese population were very rare. Tang et al. 25 showed age, residual stenosis and final minimal luminal diameter were significant predictors of ISR in Chinese population by univariate analysis. However, the standard coronary risk factors did not show any significant correlation with restenosis in their study mainly due to patient sample size being to small to show any significance (only 161 stents deployed in 114 patients). They concluded that the restenosis rate in Chinese population was comparable to that in previously published trials from population in the West. In our study with large patient population, predictors of angiographic restenosis inside bare-metal stents by multivariate analysis were almost the same as those in Western population. Thus, we propose that strategies to prevent ISR in the published trials mainly from the Western population may also be applicable to Chinese population. Acta Cardiol Sin 2009;25:1 6 4

5 Predictors of In-stent Restenosis Clinical implications: Routine angiographic follow-up is difficult in daily clinical practice. Schuhlen et al. 26 showed that angiographic restenosis detected by routine follow-up angiography is an independent predictor of a high 4-year mortality rate in patients with coronary stent placement. Tu et al. 10 reported that drugeluting stents are more effective than bare-metal stents in reducing target vessel revascularization in patients who had more than two of three risk factors for restenosis, including diabetes mellitus, small vessels and long lesions. Our study showed the most powerful predictors of angiographic restenosis inside bare-metal stent were post-procedure minimal luminal diameter, presence of diabetes mellitus, complex lesions and left anterior descending artery involvement. Thus, all patients with these risk factors may need more aggressive risk modification and likely warrant consideration of drug-eluting stenting and aggressive angiographic follow-up. Study limitations: This study has several limitations. First, this was a retrospective analysis of an interventional database in which patients were consecutively enrolled. Second, this study was performed in the era of bare-metal stents. Thus, this study could not provide information regarding any difference in predictors of angiographic restenosis between bare-metal stents and drug-eluting stents in Chinese population. CONCLUSIONS In this study, post-procedure minimal luminal diameter, presence of diabetes mellitus, complex lesions and left anterior descending artery involvement were predictive of 6-month angiographic restenosis inside baremetal stents in Chinese population. These predictors are almost the same as those in the Western population. REFERENCES 1. Schatz RA, Baim DS, Leon M, et al. Clinical experience with the Palmaz-Schatz coronary stent: initial results of a multicenter study. Circulation 1991;83: Roubin GS, Cannon AD, Agrawal SK, et al. Intracoronary stenting for acute and threatened closure complicating percutaneous transluminal coronary angioplasty. Circulation 1992; 85: Ellis SG, Vandormael MG, Cowley MJ, et al. Coronary morphologic and clinical determinants of procedural outcome with angioplasty for multivessel coronary disease: implications for patient selection. Multivessel Angioplasty Prognosis Study Group. Circulation 1990;82: Serruys PW, de Jaegere P, Kiemeneij F, et al. A comparison of balloon-expandable-stent implantation with balloon angioplasty in patients with coronary artery disease. Benestent Study Group. N Engl J Med 1994;331: Fischman DL, Leon MB, Baim DS, et al. A randomized comparison of coronary-stent placement and balloon angioplasty in the treatment of coronary artery disease. Stent Restenosis Study Investigators. N Engl J Med 1994;331: Serruys PW, Emanuelsson H, van der Giessen W, et al. Heparin-coated Palmaz-Schatz stents in human coronary arteries: early outcome of the Benestent-II Pilot Study. Circulation 1996;93: Lowe HC, Oesterle SN, Khachigian LM. Coronary in-stent restenosis: current status and future strategies. J Am Coll Cardiol 2002;39: Chen YL, Chen MC, Wu CJ, et al. Impact of 6-month angiographic restenosis inside bare-metal stents on long-term clinical outcome in patients with coronary artery disease. Int Heart J 2007;48: Marx SO, Jayaraman T, Go Lo, Marks AR. Rapamycin-FKBP inhibits cell cycle regulators of proliferation in vascular smooth muscle cells. Circ Res 1995;76: Tu JV, Bowen J, Chiu M, et al. Effectiveness and safety of drugeluting stents in Ontario. N Engl J Med 2007;357: Li AH, Liau CS, Chuang WP, et al. Phosphorylcholine-coated dexamethasone eluting stent in the prevention of restenosis: a randomized trial in a single hospital. Acta Cardiol Sin 2007;23: Pfisterer ME, Kaiser CA, Bader F, et al. Late clinical events after clopidogrel discontinuation may limit the benefit of drug-eluting stents. J Am Coll Cardiol 2006; 48: Stone GW, Moses JW, Ellis SG, et al. Safety and efficacy of sirolimus- and paclitaxel-eluting coronary stents. N Engl J Med 2007;356: The TIMI Study Group. The Thrombolysis in Myocardial Infarction (TIMI) Trial: Phase 1 findings. N Engl J Med 1985:312: Yip HK, Wu CJ, Chang HW, et al. Comparison of impact of primary percutaneous transluminal coronary angioplasty and primary stenting on short-term mortality in patients with cardiogenic shock and evaluation of prognostic determinants. Am J Cardiol 2001;87: Kastrati A, Schomig A, Elezi S, et al. Prognostic value of the modified American College of Cardiology/American Heart Association stenosis morphology classification for long-term angiographic and clinical outcome after coronary stent placement. Circulation 1999;100: National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Third Report of the 5 Acta Cardiol Sin 2009;25:1 6

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