Introduction. Subjects and Methods. Study design and patient population We reviewed patient s angiographic findings and cli-

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1 Original ORIGINAL Article ARTICLE Korean Circulation J 2006;36: ISSN c 2006, The Korean Society of Circulation Utilization Pattern of Drug-Eluting Stents and Prognosis of Patients Who Underwent Drug-Eluting Stenting Comared with Bare Metal Stenting in the Real World Dong-Bin Kim, MD, Ki-Bae Seung, MD, Pum Joon Kim, MD, Sung-Ho Her, MD, Dong-Il Shin, MD, Jin-Man Cho, MD, Chul-Sool Park, MD, Doo-Soo Jeon, MD, Sang Hong Baek, MD, Wook-Sung Chung, MD, Jae-Hyung Kim, MD, Soon-Jo Hong, MD and Kyu-Bo Choi, MD Division of Cardiology, Deartment of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea ABSTRACT Background and Objectives:Currently, the drug-eluting stent (DES) has been widely used because of its excellent clinical outcome. We comared the utilization atterns and clinical outcomes between the DES and the bare metal stent (BMS) in the real world. Subjects and Methods:We retrosectively reviewed the stent registry at the Catholic Medical Center between January 2002 and October There were 1120 atients treated with DES (n=1837) who were comared to 910 atients who received BMS imlantation (n=1238). Results:Patients with de novo lesions in the DES grou more frequently had multivessel disease and received a greater number of stents than those in BMS grou (<0.001). The mean diameter of inserted stents was smaller in the DES grou (< 0.001). The follow-u rate for clinical and angiograhic evaluations at 6 months after stenting was 91% and 65% (n=592) in the BMS grou and 90% and 74% (n=829) in the DES grou, resectively. The rate of major adverse cardiac events (death, nonfatal myocardial infarction, or target vessel revascularization) at 6 months was 7.3% in the DES grou and 17.5% in the BMS grou (<0.001). The rates of target vessel revascularization in the DES grou and in the BMS grou were 4.2% and 12.9%, resectively (<0.001). Conclusion:The atients in the DES grou had longer length, smaller diameter and higher number of laced stents, comared to the BMS grou. The rates of revascularization and major adverse cardiac events in the DES grou were lower than those in the BMS grou. (Korean Circulation J 2006;36: ) KEY WORDS:Stents;Angiolasty;Prognosis. Introduction Restenosis is one of the main limitations of coronary stenting, with reorted rates as high as 50% in more comlex conditions. 1) Recently introduced drug-eluting stents(des) aear to be a breakthrough technology for the revention of restenosis. Observational studies 2) and randomized controlled clinical trials 3-6) have shown a substantial reduction in the restenosis rate with DES comared to conventional stents. However, all clinical trials comleted to date have included elective atients Received:June 1, 2005 Revision Received:October 13, 2005 Acceted:November 11, 2005 Corresondence:Ki-Bae Seung, MD, Division of Cardiology, Deartment of Internal Medicine, College of Medicine, The Catholic University of Korea, 505 Bano-dong, Seocho-gu, Seoul , Korea Tel: , Fax: kbseung@catholic.ac.kr with relatively straight forward lesions, and with low to moderate risk for restenosis. The effects of DES imlantation in comlex, unselected atients, in daily ractice, remain largely unknown. 7) Notably, restenosis in a small but significant roortion of atients in the SIRIUS trial, as well as other trials, occurred mainly in atients with diabetes, small vessels and long lesions. 4)8) Moreover, restenosis after DES imlantation has been recently shown to occur in association with comlex rocedures. 9) In the resent study, we evaluated the imact of DES on the outcomes of atients treated in the real world, comared to conventional bare metal stent(bms) imlantation. Subjects and Methods Study design and atient oulation We reviewed atient s angiograhic findings and cli- 178

2 Dong-Bin Kim, et al: Utilization Pattern of Drug-Eluting Stenting 179 nical data at Catholic Medical Center from January 2002 to October Almost a consecutive 1,120 atients with de novo lesions(n=1837) were treated with DES and they were comared to 910 atients who received BMS(n=1238) during the eriod just rior to the DES grou. We reviewed the stent registry at the Catholic Medical Center with the goal of evaluating the safety and efficacy of DES imlantation for atients treated in daily routine medical ractice. To include a atient oulation reresentative of the real world, we have used DES treated atients since November of As the default strategy for every ercutaneous coronary intervention, we used the sirolimus-eluting stent(cyher, Johnson & Johnson-Cordis unit, Miami Lakes, FL) and the aclitaxel-eluting stent(taxus, Boston Scientific, Natick, MA). A total of 1120 atients with de novo lesions were treated with DES and were included in the DES study grou. The aroriate DES size, diameter and length, were not always available and accounted for the most common reason for nonutilization of the DES. When DES could not be assed through stenotic lesions, or economic roblems were encountered, we substituted the BMS for the DES. Patients treated with DES were comared to a grou of atients treated with BMS for de novo lesions during the receding months. The resent study oulation was consequently comosed of 2,030 atients divided into two sequential cohorts, rimarily distinguished by the interventional strategy alied, either BMS or DES. Procedures and ost intervention medications All interventions were erformed according to current standard guidelines and the final interventional strategy was entirely left to the discretion of the oerator. Angiograhic success was defined if the luminal stenosis of at least one lesion was reduced to less than 30% of the luminal diameter by quantitative coronary angiograhy(qca, Pie Medical Imaging, Maastricht, Netherlands) in the resence of Thrombolysis In Myocardial Infarction(TIMI) grade 3 flow. The amount of stenosis of the target lesion, before and after the intervention, was calculated by QCA. Perirocedural antithrombotic medications were used according to the oerator s decision; all atients were advised to maintain lifelong asirin(100 mg/day). A course of at least 1-month ticloidine treatment(250 mg bid/day) was recommended for atients in the BMS grou. For atients treated with DES, cloidogrel(75 mg/day) or ticloidine(250 mg bid/day) were rescribed for at least 6 months. End oints definitions and clinical follow-u The rimary clinical end oint of the study was a comosite of major adverse cardiac events(mace) at 6 months defined as death, nonfatal myocardial infarction, or target vessel revascularization(tvr). A non- Q-wave AMI was defined as troonin I elevation above the uer limit of normal and creatine kinase-mb enzyme elevation 3 times the uer limit of the normal. When in addition to enzyme elevation, there were new athological Q waves observed on the electrocardiogram, the event was defined as a Q-wave AMI. Target lesion revascularization(tlr) was defined as a reeat revascularization with a stenosis 50% within the stent or in the 5-mm distal or roximal segments adjacent to the stent; TVR was defined as reeat revascularization within the treated vessel. Information about the in-hosital outcomes and ost discharge outcomes were obtained from medical records. Most atients received noninvasive testing for myocardial ischemia. During follow-u, coronary angiograhy was erformed as er routine follow-u or if clinically indicated by symtoms or documentation of myocardial ischemia. We tried to do angiograhic re-study on all atients after 6 months regardless of ischemic symtoms. Clinically driven reeat revascularization was defined as any intervention motivated by a significant luminal stenosis(>50% diameter stenosis) in the resence of anginal symtoms and/or roven myocardial ischemia in the target vessel territory by noninvasive testing. Statistical analysis Continuous data were exressed as mean±standard deviation(sd) and were comared by means of the Student unaired t-test. Categorical variables were resented as counts and ercentages and comared by means of the Chi-square test. All statistical tests were 2-tailed. Comutation was erformed using the SPSS statistical ackage, version 11.5(SPSS Inc, Chicago, IL). Results Patient characteristics Between January 2002 and October 2004, 910 atients received the DES and 1120 atients received the BMS. Clinical follow u at 6 months was achieved in 92% (n=857) in the DES and in 89% atients(n=997) in BMS grou(=0.12); Angiograhic follow-u was erformed on 62%(n=564) in the DES grou and 47% (n=526) in the BMS grous(<0.001). With the excetion of a significantly higher ercentage of hyertension, smoking and multivessel disease in the DES grou, the two grous were similar with resect to all other variables examined. The atient characteristics in the study oulation are resented in Table 1. Procedural characteristics The lesions in the two grous were treated similarly with the use of conventional techniques. We used cyher

3 180 Korean Circulation J 2006;36: Table 1. Baseline characteristics of atients treated with bare metal stents and drug eluting stents BMS grou (n=910) DES grou (n=1120) Age (year) 61.0± ±9.7 <0.639 Male (%) <0.732 Diabetes (%) <0.215 Hyertension (%) <0.029 Hyercholesterolemia (%) <0.116 Smoking (%) <0.001 Single vessel (%) <0.001 Multivessel (%) <0.001 Clinical resentation <0.732 Stable angina (%) Unstable angina (%) Acute myocardial infarction (%) Table 2. Angiograhic and rocedural characteristics of atients treated with bare metal stents and drug eluting stents BMS grou (n=910) DES grou (n=1120) Number of imlanted stents 1.52± ±0.76 <0.001 Total stented length er atient (mm) 21.5± ±18.3 <0.001 Angiograhic success of all lesions (%) <0.238 (n=1003, 81%) and taxus stents(n=235, 19%) in the DES grou. Bx velocity(n=409, 33%), Exress(n=223, 18%), Tsunami(n=186, 15%), Coroflex(n=99, 8%), S7(n=124, 10%), MAC(n=74, 6%), Multilink(n=111, 9%), and other stents(n=12, 1%) were used in BMS grou. Patients treated with DES had a significantly higher number of stents used(2.11±0.76 vs.1.52±0.62 in BMS grou)(<0.001). In addition, the total stented length er atient was longer in the DES grou(35.3± 18.3 mm vs. 21.5±13.0 mm in BMS grou)(<0.001). The rimary success rate as measured by angiograhy was similar in both grous(table 2). The reference diameter was significantly smaller in the DES grou(2.91±0.69 mm vs. 3.11±0.78 mm in BMS grou). Comlex lesions were more frequent in the DES grou(<0.001) and smaller diameters of the stents used were more frequent in the DES grou(<0.001) (Table 3). Clinical outcomes Follow-u clinical information was obtained from the medical record. The six-month risk for MACE was significantly reduced in the DES grou(7.3% vs. 17.5% in the BMS grou, <0.001). The TVR was significantly lower in the DES grou than in the BMS grou(4.2% vs. 12.9%, <0.001)(Table 4). Table 3. Angiograhic and rocedural characteristics of stents according to bare metal stents and drug eluting stents BMS grous (n=1238) Table 4. Six-month outcomes of atients treated with bare metal stents and drug eluting stents BMS grou (n=910) DES grous (n=1837) Reference diameter (mm) 3.11± ±0.71 <0.001 Treated artery <0.545 Left main artery (%) Left anterior descending artery (%) Left circumflex artery (%) Right coronary artery (%) ACC/AHA tye Tye A (%) <0.001 Tye B1 (%) <0.001 Tye B2 (%) <0.001 Tye C (%) <0.001 Mean diameter er stent (mm) 3.37± ±0.23 <0.001 Angiograhic success (%) <0.219 ACC/AHA: American College of Cardiology/American Heart Association, DES grou (n=1120) MACE (%) <0.001 Death (%) <0.200 Nonfatal MI (%) <0.338 TVR (%) <0.001 TLR (%) <0.001 Restenosis rate (%) <0.001 MACE: major adverse cardiovascular event, MI: myocardial infarction, TVR: target vessel revascularization, TLR: target lesion revascularization, Subgrou analysis Among the 602 atients with diabetes(30 ercent of the total study oulation; 255 atients in the BMS grou and 347 atients in the DES grou), the rates of 6-months MACEs were higher than those among atients without diabetes in both treatment grous(23.1% vs. 15.5% in BMS grous, 11.1% vs. 5.5% in DES grou, resectively <0.001). Patients with diabetes mellitus (DM) were older(64.4±12.3 years vs. 58.2±8.1 years, <0.001), and included a higher ercentage of males (68% vs. 61%, =0.027), comared to atients without DM. The reference diameters were 2.84±0.52 mm in the DM atients and 2.89±0.49 mm in the non-dm atients(=0.021). Lesion lengths were 31.5±18.1 mm in the DM atients and 27.8±17.8 mm in the non-dm atients(<0.001). The minimal lumen diameters of the DM atients were narrower than those of atient without DM, before(0.58±0.32 mm vs. 0.69±0.37 mm, <0.001) and after intervention(2.73±0.36 mm vs. 2.82±0.44 mm, <0.001). Late losses at 6 months were 0.42±0.61 mm in the DM atients and 0.26±0.48 mm in the non-dm atients(<0.001). Restenosis rates at

4 Dong-Bin Kim, et al: Utilization Pattern of Drug-Eluting Stenting 181 Table 5. Utilization attern of the drug eluting stent in diabetes mellitus atients Non-DM (n=773) Table 6. Utilization attern of drug eluting stents in atients with long lesions (lesion length >30 mm or overlaing stent) Post-rocedure Proximal 5 mm In-stent Distal 5 mm RD (mm) 2.83± ± ±0.39 MLD (mm) 2.61± ± ±0.46 % DS Follow-u duration: 5.6±2.5 months RD (mm) 2.78± ± ±0.39 MLD (mm) 2.45± ± ±0.46 % DS Late lumen loss (mm) 0.16± ± ±0.34 RD: reference diameter, MLD: minimal lumen diameter, DS: diameter stenosis 6 months were 8.1% in the DM atients and. 2.5% in the non-dm atients(<0.001)(table 5). The results of long-stenting were as follows. A total of 173 atients(178 lesions) were imlanted with 1 DES or 2 DES with overlaing stents in a coronary lesion more than 30 mm in length. Follow u angiograms were done in 57 atients among 173 atients. The total binary restenosis rate was 5.26%(3 of 57 atients). The mean clinical follow-u and angiograhic follow-u were, relatively, 6.3±4.1 months and 5.6±2.5 months. Follow-u angiograhy showed the late lumen losses at 6 months were 0.16±0.18 mm(roximal 5 mm of in-segment), 0.20±0.46 mm(within the stent) and 0.18± 0.34 mm(distal 5 mm of in-segment)(table 6). The rate of MACE in long-stenting at 6 months was 8.7%(15 of 173 atients). Discussion DM (n=347) Age (years) 58.2± ±12.3 <0.001 Male (%) <0.027 Reference diameter (mm) 2.89± ±0.52 <0.021 Lesion length (mm) 27.8± ±18.1 <0.001 Minimal lumen diameter (mm) Baseline 0.69± ±0.32 <0.001 After intervention 2.82± ±0.36 <0.002 Follow-u 2.58± ±0.74 <0.001 Late loss (mm) 0.26± ±0.61 <0.001 Restenosis rate (%) <0.001 DM: diabetes mellitus DES imlantation has been shown to markedly decrease the incidence of restenosis in the context of randomized trials. 3-6) However, these studies have enrolled atient oulations referred for elective intervention without comlex lesions. As a consequence, the findings from these studies cannot be directly extraolated to many atients treated in everyday ractice, where comlex, nonselected cases are the rule rather than the excetion. In the resent study, DES with aclitaxel or sirolimus was equivalent to BMS in terms of survival rate. However, DES imlantation was associated with a reduction in the rates of reeat revascularization and MACE at 1 year in unselected atients. Our results are suorted by trials conducted in Germany and the Netherlands. 10)11) Our study used a strategy that comared DES to conventional aroaches that used BMS in the re-des era. Although the two study grous were consecutively included over a total eriod of 3 years, some imortant differences were noted in the interventional strategy alied. Patients in the DES hase were treated with an aggressive interventional aroach, with a significant increase in the number and length of imlanted stents and a decrease in the diameter of the stents. Our findings may also reflect an attemt to accomlish more comlete lesion coverage and ensure uniform drug delivery over the entire diseased segment; this is imortant since stent discontinuity and edge injury have been recently shown to be associated with ost-des restenosis. 9) Moreover, the higher degree of comlexity of atients treated with DES(e.g., high rates of multivessel disease, tye C lesions) may translate into a change in the decision-making rocess romoted by the availability of DES. Although both study grous differed in some baseline and rocedural characteristics, which may somewhat limit an unbiased comarison between them, hyertension, smoking and multivessel disease would traditionally be exected to increase the incidence of late comlications in the DES treated atients. The three rincial determinants of restenosis after coronary-stent imlantation are DM status, the reference-vessel diameter and the lesion length. 12) In articular, atients with diabetes are rone to a diffuse and raidly rogressive form of atherosclerosis, which increases their likelihood of requiring revascularization. 13)14) The risk of restenosis was increased by aroximately 50 ercent among diabetic atients who received a BMS as comared with those without diabetes who received such a stent. 15) By contrast, the risk of restenosis was reduced by more than 80 ercent among atients with diabetes who received a DES. 16) The subgrou analysis of our DM atients showed that DES markedly reduced the incidence of restenosis when comared to BMS, both in atients without diabetes and in those with diabetes. Recent studies show the same results. 17)18) However, the restenosis rate is still higher in the DM grou desite DES. 16) Our results also showed that the restenosis rate is higher in the DM grou in the DES era. Revascularization strategies for DM atients with multivessel disease have two otions, ercutaneous coronary intervention or aortocoronary byass surgery. Aortocoronary

5 182 Korean Circulation J 2006;36: byass surgery is considered to be the referred revascularization strategy as reorted in the BARI study using a balloon technique. 19) However, recent data using the BMS has demonstrated comarable survival rates between PCI and CABG in the DM grous ) Therefore, using DES, for DM atients with multivessel disease, will imrove both the survival rate and MACE. Long stenting using BMS is an indeendent redictor of restenosis and adverse events. Long stenting is frequently associated with rolonged intracoronary maniulation due to multile and overlaing stent lacement, which may lead to injury to vessel wall integrity. Moreover, the greater metal density may otentially be associated with a higher degree of local vascular injury; these concerns may increase the risk of cardiac events and restenosis. The incidence of late comlications has been reorted to be directly roortional to the total length of stents imlanted. 23)24) Previously, Schalij et al reorted a 25% incidence of major adverse events for atients treated with the BMS at a mean stented length of 45 mm. 25) The Additional Value of NIR Stents for the Treatment of Long Coronary Lesions(ADVANCE) Study 26) showed the reorted MACE rate was 23%. However, recent studies with DES(Degertekin et al. 23) and Schofer et al. 24) ) showed a reduced restenosis as well as reduced MACEs rate. Our study also revealed the relatively low incidence of MACEs rate(8.9%) with a long length imlanted DESs(40±10.1 mm on average). Overall, the treatment results from DES were significantly better than BMS. However, the resence of diabetes and the treatment of long lesions were shown to indeendently increase the incidence of comlications. 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