Clinical Investigations

Clinical Investigations Clinical Outcomes for Single Stent and Multiple Stents in Contemporary Practice Qiao Shu Bin, MD; Liu Sheng Wen, MD; Xu Bo, BS; Chen Jue, MD; Liu Hai Bo, MD; Yang Yue Jin, MD; Chen Ji Lin, MD; Gao Run Lin, MD Department of Cardiology, Cardiovascular Institute and Fuwai Hospital, Chinese Academy of Medical Sciences and Peking UnionMedicalCollege, Beijing, China Address for correspondence: Qiao Shu Bin, MD Department of Cardiology Cardiovascular Institute and Fuwai Hospital Chinese Academy of Medical Sciences and Peking Union Medical College Beijing 167 BeiLiShi Rd. 100037, China qiaosb@live.cn Background: Stents had been demonstrated to be safe and effective in the treatment of severe coronary artery disease (CAD); however, the current knowledge on percutaneous coronary intervention (PCI) in treating patients requiring 2 or more stents placements is still limited. Hypothesis: Patients who required 2 or more stents might have worse clinical outcomes. Methods: A total of 2371 patients who underwent stenting were divided into a single stenting group (n = 1233) and a multiple stenting group (n = 1138). We assessed the cumulative incidence of major adverse cardiac events (death, acute myocardial infarction, and target-vessel revascularization) and stent thrombosis during 1-year follow-up. Results: The 1-year unadjusted cumulative incidence of major adverse cardiac events was 7.7% in the multiple stenting group and 5.4% in the single stenting group (P = 0.02 by log-rank test). After adjustment, there was a trend toward a lower rate of 1-year major adverse cardiac events in the single stenting group than in the multiple stenting group (P = 0.09). A nonsignificant trend was also detected in favor of the single stenting group, as compared with the multiple stenting group, at the rate of acute myocardial infarction (1.3% vs 1.7%, P = 0.89) and at the rate of target-vessel revascularization (4.5% vs 5.4%, P = 0.08). Conclusions: Although the use of a single stent in coronary artery disease has less incidence of adverse cardiac events at 1 year as compared with the use of multiple stents, the difference was not statistically significant. Introduction Since the era of balloon angioplasty, stents had been demonstrated to be substantially safe and effective in the treatment of severe coronary artery disease (CAD) in the field of interventional cardiology. 1 Use of drug-eluting stents (DES) has been demonstrated to further reduce in-stent restenosis and the need for new revascularization procedures compared with conventional bare-metal stents (BMS). 2,3 Even in patients with multivessel diseases, only 1 lesion per patient was treated, with up to 2 stents per patient. 4,5 It is unrealistic to expect the design and conduct of controlled trials to include all possible clinical presentations, alone or in combination, such as multivessel disease and multiple lesions. In the daily practice of percutaneous coronary intervention (PCI), the proportions of patients with multi-lesions or multivessel diseases who had to be implanted with multiple stents or with different types of stents are increasing. In some conditions, lesions executed with stent implantation or treated with more than 1 stent might not be necessary. Furthermore, the current knowledge on PCI in treating patients requiring 2 or more stent placements is still limited. To further pursue this interesting area in the real-world, we conducted this study to analyze the patients who underwent PCI with implantation of stents and compared the clinical outcomes of single stents with multiple stent implantation. Methods Study Design and Patient Population Between April 2004 and April 2005, 2371 patients in the Fuwai hospital underwent PCI with stent implantation. Based on the number of coronary stents implanted, patients were assigned to a single stenting group (n = 1233) and a multiple stenting group (n = 1138). Interventional strategy and device use, including type of stent, were left to the discretion of the attending physicians. Antiplatelet treatment was prescribed according to current standards of treatment, including lifelong aspirin for all patients, 1 month of ticlopidine (250 mg BID) or clopidogrel (75 mg/day) treatment for patients treated with BMS, and the same treatment for at least 3 months for patients treated with DES. Definitions and Follow-Up The primary endpoint of the survey was the occurrence of major adverse cardiac events (MACE), defined as: (1) death from cardiac causes, (2) nonfatal acute myocardial infarction (MI), and (3) target-vessel revascularization (TVR). Myocardial infarction (MI) during follow-up was diagnosed by local cardiologists at the hospital of admission according to standard criteria (rise in the creatine kinase level to more than twice the upper limit of normal with an Received: July 19, 2008 Accepted with revision: August 18, 2008 E33

Clinical Investigations continued increased creatine kinase-mb [CK-MB] and newly developed Q waves). Target-vessel revascularization was defined as a reintervention (coronary artery bypass graft [CABG] or PCI) driven by any lesion located in the same epicardial vessel. The protocol of our study did not include routine angiography for any subgroup of patients; therefore, virtually all reinterventions can be considered clinically driven. Clinically driven repeat revascularization was defined as any intervention motivated by a significant luminal stenosis (>50% diameter stenosis) in the presence of anginal symptoms and/or proven myocardial ischemia in the target vessel territory by noninvasive testing. Stent thrombosis was defined according to a standardized definition proposed by the Academic Research Consortium (ARC). 6 Follow-up was obtained directly and independently through analysis of the hospital discharge records and the mortality registries. During each patient s hospital stay, we recorded all adverse events during follow-up visits at 6 months and at 12 months; we also recorded all serious adverse cardiac events (death from cardiac causes, nonfatal acute MI, TVR). Statistical Analysis Continuous variables were expressed as mean±sd and were compared with the Student unpaired t test. Categorical variables were expressed as counts and percentages, and the χ 2 test was used for comparison. The cumulative incidence of adverse events was estimated according to the Kaplan-Meier method and compared by the log-rank test. Because of the observed differences in baseline characteristics between the treatment groups, a propensity score analysis was performed by use of a logistic regression model for treatment with single stenting vs multiple stenting. A multiple logistic regression model was constructed with the following variables considered as candidates: age, gender, hypertension, hyperlipidemia, peripheral vascular disease, diabetes mellitus, history of MI, smoking status, prior PCI, prior CABG, number of vessel disease, only use of DES, American College of Cardiology/American Heart Association (ACC/AHA) type C lesion, left main stenting, ostial lesion, chronic total occlusion >3 months, bifurcation, instent restenosis, and bypass graft lesions. The logistic model by which the propensity score was estimated showed good predictive value (C-statistic = 0.811), and calibration characteristics by the Hosmer-Lemeshow test (P = 0.13). The score was then incorporated into subsequent proportionalhazards models as a covariate. Multivariable analyses were performed to identify independent predictors of MACE and TVR using the following variables: age, sex, hypertension, hyperlipidimia, peripheral vascular disease, diabetes mellitus, prior PCI, prior CABG, prior MI, number of vessel disease, number of stents deployed, only use of DES, ACC/AHA type C lesion, left main stenting, ostial lesion, chronic total occlusion >3 months, bifurcation, instent restenosis, and bypass graft lesions. Multiple-variable predictors were chosen by a stepwise procedure with an entry criterion of 0.10 with a stay criterion 0.05. P values of <0.05 were considered to indicate statistical significance. All analyses were performed with the SAS 9.1 system (SAS Institute, Inc., Cary, NC). Results Baseline Characteristics and Procedural Results Between April 2003 and April 2004, 1233 patients were treated with single stent (1360 lesions treated, 1233 stents implanted), and 1138 patients were treated with 2 stents (2573 lesions treated, 2791 stents implanted), with all patients having been visited at 6-months and 12-months follow-up. A number of differences were observed in demographics (Table 1) and in angiographic or procedural characteristics (Table 2) between the 2 groups. Being male and having hyperlipidemia were more frequently observed in the multiple stenting group, which also showed higher rates Table 1. Baseline Clinical Characteristics of Patients Treated with a Single Stent or Multiple Stents Variable Single Stent (n = 1233) Multiple Stents (n = 1138) P Value Male 77.8 88.8 0.002 Age 57.6±11.2 58.1±10.6 0.28 Hypertension 57.8 59.8 0.34 Diabetes mellitus 19.8 22.7 0.09 Hyperlipidemia 30.3 34.4 0.04 Prior PCI 18.4 15.2 0.04 Prior CABG 2.3 2.2 0.90 Prior myocardial 45.4 47.0 0.44 infarction Current smoker 35.7 41.5 0.003 Ejection fraction 58.0±27.0 56.4±26.8 0.15 Clinical presentation Stable angina 29.7 30.4 0.97 pectoris a Unstable angina 52.1 50.2 0.36 pectoris Acute MI 18.2 19.4 0.44 Values are percent or mean±sd. a Including silent ischemia. Abbreviations: PCI, percutaneous coronary intervention; CABG, coronary artery bypass graft; MI, myocardial infarction. E34

Table 2. Angiographic Lesion Characteristics and Procedural Details of the Study Groups Variable Single Stent (n = 1360) a Multiple Stents (n = 2573) a P Value Treated coronary vessel Left anterior descending 51.9 38.9 <0.001 Left circumflex 19.8 25.8 <0.001 Right 25.2 32.7 <0.001 Left main 2.5 2.1 0.47 Bypass graft 0.5 0.4 0.44 No. of lesions treated 1.1±0.3 2.2±0.8 <0.001 No. of implanted stents 1±0 2.6±0.8 <0.001 No. of vessels diseased 1.7±0.8 2.4±0.7 <0.001 Type C 29.0 41.3 <0.001 Bifurcation 32.4 35.5 0.06 Ostial lesion 13.5 12.4 0.36 Chronic total occlusion >3 mo 4.2 6.0 0.02 In-stent restenosis lesion 5.3 3.2 0.002 Stent type 0.27 Multi-Link 38.2 39.8 Drive 12.3 10.8 Cypher Select 30.6 28.3 Taxus Express 2 12.0 13.5 Firebird 4.1 4.9 Other 2.7 2.7 DES 46.8 46.7 0.95 Average lesion length, b mm 17.0±7.3 20.9±12.3 <0.001 Average stent length, mm 21.1±6.7 28.9±14.6 <0.001 Reference vessel diameter, b mm 3.2±1.7 3.0±0.5 <0.001 MLD, b mm 0.4±0.7 0.4±0.4 0.82 Only use of DES c 46.8 30.5 <0.001 Procedure complications c,d 0.8 0.6 0.57 Procedure success c 98.8 98.5 0.73 Values are percent or mean±sd. a Total number of lesions. b Visual estimation. c Referred to 1233 patients in the single stenting group and 1138 patients in the multiple stenting group. d Indicates the complications that occurred during or as a result of a procedure which includes systemic and peripheral complications such as myocardial infarction, death, arrhythmia, coronary perforation, coronary artery dissection, contrast nephropathy, vascular complications, and so forth. Abbreviations: MLD, minimum lumen diameter; DES, drug-eluting stents; Multi-Link (Guidant, CA, USA); Drive (Medtronic, Inc.); Cypher Select (Johnson & Johnson); Taxus Express 2 (Boston Scientific); Firebird (MicroPort). E35

Clinical Investigations continued of smoking as well. The multiple stents were also implanted more than single stents in the treatment of the right coronary artery, left circumflex coronary artery, type C lesions, chronic total occlusion >3 months, small vessels, and long lesions. The proportion of type of stent and DES were similar between the 2 groups; however, patients who only used DES were more frequent in the single stenting group. Procedural success was achieved in >98% and complications were seen in <1% of the procedures in both groups. Clinical Outcomes The 6-months and 1-year unadjusted cumulative incidence of MACE were shown in Table 3. There were no significant differences between the single stenting group and the multiple stenting group in 6-months cumulative incidence of death, acute myocardial infarction (AMI), and TVR. However, the 1-year cumulative incidence of MACE (death, AMI, or TVR) was significantly lower in the single stenting group than in the multiple stenting group (3.2% vs 4.9%, Table 3. One-Year Unadjusted and Propensity Score-Adjusted Cumulative Incidence of MACE in the Study Groups Variable Single Stent (n = 1233) Multiple Stents (n = 1138) P Value Unadjusted Follow-up at 6 mo MACE 3.2 4.9 0.04 Death from cardiac causes 0.4 0.4 0.90 AMI 0.9 1.6 0.13 TVR 2.3 3.4 0.09 CABG 0.4 0.4 0.83 PCI 1.9 3.2 0.04 Stent thrombosis 0.5 0.8 0.35 Acute and subacute (<30 d) 0.3 0.5 0.45 Late (30 d to 6 mo) 0.2 0.3 0.45 Follow-up at 12 mo MACE 5.4 7.7 0.02 Death from cardiac causes 1.0 1.1 0.24 AMI 1.3 1.7 0.45 TVR 3.9 6.1 0.01 CABG 1.0 0.9 0.81 PCI 2.9 5.5 0.002 Propensity score-adjusted Follow-up at 6 mo MACE 3.5 4.6 0.28 Death from cardiac causes 0.4 0.4 0.33 AMI 1.1 1.4 0.20 TVR 2.4 3.3 0.74 CABG 0.2 0.4 0.12 PCI 2.2 2.9 0.32 Stent thrombosis 0.6 0.8 0.42 E36

Table 3. (Continued) Variable Single Stent (n = 1233) Multiple Stents (n = 1138) P Value Acute and subacute (24 h to 30 d) 0.4 0.5 0.60 Late (30 d to 6 mo) 0.2 0.3 0.22 Follow-up at 12 mo MACE 6.0 7.3 0.09 Death from cardiac causes 1.0 1.1 0.42 AMI 1.3 1.7 0.89 TVR 4.5 5.4 0.08 CABG 0.8 1.1 0.26 PCI 3.7 4.3 0.009 Values are percentages. P values are by log-rank test for unadjusted incidence and by multiple logistic regression model for propensity score-adjusted incidence. Abbreviations: MACE, major adverse cardiac events; AMI, acute myocardial infaction; TVR, target-vessel revascularization; CABG, coronary artery bypass graft; PCI, percutaneous coronary intervention. P = 0.04). Notably, the incidence of angiographic stent thrombosis did not appear significantly different in the 2 groups (0.5% vs 0.8%, P = 0.35). At 1 year, the cumulative incidence of death and AMI was also similar in the 2 groups. Patients treated with a single stent had significantly less TVR (3.9% vs 6.1%, P = 0.01) and MACE (5.4% vs 7.7%, P = 0.02) at 1 year than patients treated with multiple stents. To adjust for differences in baseline clinical and angiographic characteristics, a propensity score analysis of the data was carried out as previously described. As shown in Figure 1 and Table 3, the 1-year incidence of MACE was lower in the single stenting group compared with the multiple stenting group (6.0% vs 7.3%; hazard ratio [HR]: 0.78, 95% confidence interval [CI]: 0.55 1.12, P = 0.09), and this was driven mainly by the reduction in TVR (4.5% vs 5.4%, HR: 0.71, 95% CI: 0.47 1.07, P = 0.08). Although trends were observed in favor of the single stenting group, none of these differences were significant. Conversely, the 1-year cumulative risk of death and MI were similar in the 2 cohorts of patients. Predictors of Adverse Events Table 4 lists the multivariate predictors of 1-year adverse events. In the overall population, the factors associated with 1-year MACE were prior PCI, prior CABG, type C lesion, ostial lesion, and only use of DES. The predictors of 1-year TVR were being male, prior PCI, prior CABG, the number of stents deployed, and only use of DES. Cumulative probability of events, % 8.0 6.0 4.0 2.0 0.0 Hazard ratio 0.78 (95% C10.55 to 1.12) p =0.09 Multiple stenting 73% Single stenting 6.0% 0 100 200 300 400 Days Figure 1. Propensity score-adjusted 1-year cumulative incidence of major adverse cardiac events (MACE) in patients treated with single stent and in patients treated with multiple stents. Discussion The major finding of this study is that in a real-world complex population, the cumulative incidence of MACE a composite of death from cardiac causes, nonfatal acute MI, and TVR at 1 year was 6.0% in the single stenting group and 7.1% in the multiple stenting group. The adjusted risk ratio was 0.78, which was not statistically significant. This was mainly due to the difference in the incidence of TVR (71% relative risk reduction), with no effect on mortality. There was also a trend in favor of the single stenting group in the rates of individual adverse events, but no single endpoint reached statistical significance. However, the available data comparing these 2 strategies of stenting in elective PCI are limited and controversial. 7 9 In the pre-des period, Pan et al compared the clinical outcome of patients with long diffuse stenosis treated by 3 different stent strategies, which were composed of 1 single long stent, overlapped multiple E37

Clinical Investigations continued Table 4. Clinical, Procedural, and Angiographic Multivariable Predictors of 1-Year MACE and TVR Variable HR 95% CI P Value MACE TVR Only use of DES 0.44 0.30 0.64 <0.001 Prior PCI 1.53 1.03 2.26 0.03 Prior CABG 2.62 1.36 5.03 0.004 Type C lesion 1.41 1.03 1.94 0.03 Ostial lesion 1.56 1.01 2.42 0.04 Male 2.37 1.27 4.42 0.007 Only use of DES 0.45 0.29 0.70 <0.001 Prior PCI 1.80 1.17 2.77 0.007 Prior CABG 3.64 1.83 7.24 <0.001 No. of implanted stents 1.18 1.00 1.39 0.05 Abbreviations: MACE, major adverse cardiac events; DES, drug-eluting stents; PCI, percutaneous coronary intervention; CABG, coronary artery bypass graft; TVR, target-vessel revascularization. stents, and multiple non-overlapped stents strategy; the 2- year cumulative incidence of MACE (death, acute MI, or repeat revascularization) were similar in 3 groups. 7 In the DES period, another retrospective analysis showed that the patients who required 3 sirolimus-eluting stents (SES) implantations had significantly higher rates of MI, TVR, and MACE compared with the patients with the same risk profiles who underwent PCI with a single SES implantation. 8 There are a number of possible explanations for the differences between the results of this study and those of previous studies. First, we compared a strategy of usage of multiple stents with the usage of a single stent in the daily practice of PCI, but not a specific type of stent. Second, 2 study groups were consecutively included over a total period of only 1 year, some important differences were noted in the interventional strategy applied, which may somewhat limit an unbiased comparison between them. However, it is worth noting that not all differences would be traditionally expected to increase the incidence of late complications. Nevertheless, the treatment effect of single stenting was not significant higher than multiple stenting after propensity score-adjustment. Third, the study design did not include angiographic follow-up. Recurrent stenosis observed during routine follow-up angiography could have led to reintervention without symptoms or objective evidence of ischemia, thus increasing the event rate. We did not observe a difference in the rates of stent thrombosis between our 2 study groups. Acute or subacute stent thrombosis occurred in 4 patients (0.3%) in the single stenting group and 6 patients (0.5%) in the multiple stenting group. We also found no evidence of an increase in the rate of late stent thrombosis, a topic that has recently caused concerninthedesera. 10 Recently, the Rapamycin-Eluting Stent Evaluated at Rotterdam Cardiology Hospital registry and a meta-analysis study also demonstrated that the risk of stent thrombosis of DES was similar to BMS. 11,12 Therefore, whether the number of stents deployed and the type of stents used have an effect on stent thrombosis was not determined. We analyzed the predictors of clinical outcomes in all patients. These analyses confirmed that the use of only DES is independently associated with a reduction in MACE and TVR in the general population. We also showed the predictive value of prior PCI, prior CABG, and a number of angiographic and procedural features, such as type C lesion, ostial lesion, with regard to MACE or TVR (Table 4). Furthermore, we demonstrated that the number of stents deployed was an independent risk factor of TVR, but not of MACE, which was consistent with other observations. 11,13 Our findings might indicate the number of stents deployed mainly effect the need for repeated revascularization procedures. Study Limitations This study suffers limitations of observational nonrandomized studies. On the other hand, it carries important and complementary information derived from real-world practice, given the inclusion of patients and lesions often excluded from randomized trials. The present study is also a single-center experience and lacks systematic angiographic follow-up. Furthermore, it is unlikely that a randomized study will be conducted in the context in which this study was performed, with virtually no exclusion criteria. Finally, we performed a propensity analysis to overcome the pitfalls of nonrandomized comparisons of health care interventions, which are known to be a valuable approach for taking adequately into account the potential confounding effect attributable to between-groups imbalances. 14 Conclusions In conclusion, our study did not show a significant benefit associated with single stenting in coronary artery disease, as compared with multiple stenting in daily practice. However, the use of multiple stents in PCI should be undertaken with great caution. References 1. Popma JJ, Kuntz RE, Baim DS. A decade of improvement in the clinical outcomes of percutaneous coronary intervention for multivessel coronary artery disease. Circulation. 2002;106: 1592 1594. 2. Morice MC, Serruys PW, Sousa JE, et al. A randomized comparison of a sirolimus-eluting stent with a standard stent for coronary revascularization. NEnglJMed. 2002;346:1773 1780. E38

3. Stone GW, Ellis SG, Cox DA, et al. A polymer-based, paclitaxeleluting stent in patients with coronary artery disease. NEnglJ Med. 2004;350:221 231. 4. Morice MC, Serruys PW, Sousa JE, et al. Randomized study with the sirolimus-coated bx velocity balloon-expandable stent in the treatment of patients with de novo native coronary artery lesions. A randomized comparison of a sirolimus-eluting stent with a standard stent for coronary revascularization. NEnglJMed. 2002;346:1773 1780. 5. Holmes DR Jr, Leon MB, Moses JW, et al. Analysis of 1-year clinical outcomes in the SIRIUS trial: a randomized trial of a sirolimuseluting stent versus a standard stent in patients at high risk for coronary restenosis. Circulation. 2004;109:634 640. 6. Mauri L, Hsieh WH, Massaro JM, Ho KK, D Agostino R, Cutlip DE. Stent thrombosis in randomized clinical trials of drug-eluting stents. NEnglJMed. 2007;356:1020 1029. 7. Pan M, Suárez de Lezo J, Medina A, et al. Influence of stent treatment strategies in the long-term outcome of patients with long diffuse coronary lesions. Catheter Cardiovasc Interv. 2003; 58:293 300. 8. Chu WW, Kuchulakanti PK, Rha SW, et al. Impact of three or more versus a single sirolimus-eluting stent on outcomes in patients who undergo percutaneous coronary intervention. Am J Cardiol. 2006;97:606 610. 9. Chu WW, Kuchulakanti PK, Torguson R, et al. Impact of three or more sirolimus-eluting stents versus pacilitaxel-eluting stents on clinical outcomes in patients undergoing percutaneous coronary intervention. Catheter Cardiovasc Interv. 2006; 68: 62 66. 10. Kastrati A, Mehilli J, Pache J, et al. Analysis of 14 trials comparing sirolimus-eluting stents with bare-metal stents. N Engl J Med. 2007;356:1030 1039. 11. Lemos PA, Serruys PW, van Domburg RT, et al. Unrestricted utilization of sirolimus-eluting stents compared with conventional bare stent implantation in the real world : the Rapamycin-Eluting Stent Evaluated At Rotterdam Cardiology Hospital (RESEARCH) registry. Circulation. 2004;109:190 195. 12. Stone GW, Moses JW, Ellis SG, et al. Safety and efficacy of sirolimus- and pacilitaxel-eluting coronary stents. NEnglJMed. 2007;356:998 1008. 13. Kastrati A, Schümig A, Elezi S, et al. Predictive factors of restenosis after coronary stent placement. J Am Coll Cardiol. 1997; 30:1428 1436. 14. Deeks JJ, Dinnes J, D Amico R, et al; International Stroke Trial Collaborative Group; European Carotid Surgery Trial Collaborative Group. Evaluating non-randomised intervention studies. Health Technol Assess. 2003;7:iii x: 1 173. E39