Primary and mid-term outcome of sirolimus-eluting stent implantation with angiographic guidance alone

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1 Journal of Cardiology (2008) 51, Primary and mid-term outcome of sirolimus-eluting stent implantation with angiographic guidance alone Hajime Fujimoto, Susumu Tao, Tomotaka Dohi, Sachiko Ito, Jun Masuda, Mitani Haruo, Yo Fujimoto, Akiko Maehara, Tetsu Yamaguchi, Sugao Ishiwata, Minoru Ohno Department of Cardiovascular Center Medicine, Toranomon Hospital, Toranomon, Minato-ku, Tokyo , Japan Received 26 June 2007; accepted 14 September 2007 KEYWORDS Intravascular ultrasound; Percutaneous coronary intervention (PCI); Restenosis Summary Background: Usefulness and efficacy of intravascular ultrasound (IVUS) for the implantation of sirolimus-eluting stent (SES) is controversial. We investigated the primary and mid-term results of SES deployment with angiographic guidance comparing with IVUS guidance, retrospectively. Methods and results: SESs were deployed in 480 de novo lesions of 459 patients (341 lesions treated without IVUS and 139 lesions treated using IVUS); 368 lesions underwent follow-up coronary angiography. Late luminal loss, in-stent restenosis (ISR) rate and target lesion revascularization (TLR) rate were not significantly different between the non-ivus group and the IVUS group. There was no acute thrombosis or other major adverse cardiac events except for TLR in both groups. Multivariate logistic regression analysis showed that SES implantation without IVUS was not an independent risk factor for restenosis. On the other hand, in one case, target-vessel revascularization was difficult because of the mal-apposition of the SES previously implanted without IVUS. Conclusions: For lesions for which stent size and endpoint are decided from angiographic information alone, angio-guided SES implantation is safe and provides a good mid-term outcome that is comparable to the IVUS-guided SES stent deployment., while IVUS may be helpful to decide stent size for complex lesions and reduce possible complications Japanese College of Cardiology. Published by Elsevier Ireland Ltd. All rights reserved. Corresponding author. Tel.: x7185; fax: address: hafujimoto-circ@umin.ac.jp (H. Fujimoto) /$ see front matter 2008 Japanese College of Cardiology. Published by Elsevier Ireland Ltd. All rights reserved. doi: /j.jjcc

2 Angiographically guided SES implantation 19 Background For percutaneous coronary intervention (PCI), intravascular ultrasound (IVUS) is useful for deciding the adequate stent size and endpoint of the procedure [1,2]. In the bare metal stent era, maximal expansion of the stent without vessel injury was thought to be important to reduce restenosis. Several studies reported that IVUS guidance of bare metal stent implantation results in better clinical outcome compared with angiographic guidance alone [3,4]. Recently, drug-eluting stents are widely used. Several randomized trials have shown that the implantation of sirolimus-eluting stents (SESs) significantly reduces the rates of restenosis and target-vessel revascularization by inhibiting neointima formation [5 8]. In addition, several succeeding clinical studies in the Japanese population showed the safety and efficacy of SES for randomly selected patients [9,10]. For the implantation of SESs, it is recommended to fully cover the plaque, and adequately expand the stents without mal-apposition to prevent restenosis and thrombosis [11]. From such a point of view, several studies suggest that IVUS is useful in SES implantation for deciding an adequate stent size, and the endpoint of the procedure, resulting in good short- and longterm outcomes [12 14]. On the other hand, some interventionists insist that IVUS is not necessary to decide the stent size and to get the good outcome. In addition, when PCI is performed, IVUS is not always available for reasons such as restrictions of manpower and procedure time. Usefulness and necessity of IVUS for stent implantation is a major issue of controversy regarding such interventional procedures. In this study, to clarify the safety and efficacy of SES implantation with angiographic guidance alone, we investigated the primary and mid-term results of SES implantation using angiographic guidance alone. Materials and methods Patients From July 2004 to November 2006, 459 patients (with total of 480 lesions) underwent SES (Cypher stent [Johnson and Johnson, New Brunswick, NJ, USA]) implantation in their coronary arteries. Clinical outcomes of the 459 patients at 8 months after PCI were investigated. As a rule, all patients underwent coronary angiography (CAG) 6 12 months after SES deployment for the purpose of clinical follow-up, not for the study. Among the 459 patients, 348 patients (with total of 368 lesions) underwent follow-up CAG. For these 368 lesions, quantitative coronary angiography (QCA) data at the follow-up CAG were analyzed. Primary and secondary endpoints The primary endpoint was a composite of major adverse cardiac events (death from cardiac causes, myocardial infarction, and ischemia-driven revascularization of the target lesion) within 8 months. Secondary endpoints included ischemia-driven revascularization of the target lesion, targetvessel revascularization, and target-vessel failure (defined as a composite of death from cardiac causes, myocardial infarction, and ischemia-driven target-vessel revascularization). Target lesion revascularization was defined as revascularization for a stenosis within the stent or in the adjacent 5 mm of the distal or proximal edge of the stent. Revascularization of the target lesion was considered to be driven by ischemia if the stenosis of any target lesion was at least 50% of the diameter of the vessel on the basis of quantitative coronary angiography in the presence of ischemic signs or symptoms, or if the stenosis was at least 75% of the diameter of the vessel even in the absence of ischemic signs or symptoms. Successful stenting was defined as a final stenosis of less than 50% of the vessel diameter after implantation of the study stent, and treatment success was defined as a final stenosis of less than 50% of the vessel diameter with the use of any percutaneous intervention. Criteria for the use of IVUS IVUS was used to deploy SESs in specific lesions for which the determination of stent size or endpoint was difficult using angiographic information alone. Quantitative coronary angiography Coronary angiograms were digitally recorded at baseline, post procedure, and at follow-up and were assessed at an angiographic core laboratory with an automated edge-detection system by experienced personnel unaware of the patients coronary risk profiles. All measurements were performed on cineangiograms recorded after the intracoronary or sublingual administration of nitroglycerin. The same single, worst-view projection was used at all times. A contrast-filled non-tapered catheter tip was used for calibration. The reference diameter was determined by interpolation. Quantitative measurements included the diameter

3 20 H. Fujimoto et al. of the reference vessel, the minimal luminal diameter, and the extent of diametric stenosis (defined as the diameter of the reference vessel minus the minimal luminal diameter, divided by the reference diameter and multiplied by 100). In-stent restenosis (ISR) was defined as stenosis of at least 50% of the minimal luminal diameter in the stented area at the follow-up angiography. In-segment restenosis was set as stenosis of at least 50% of the minimal luminal diameter in the stented area and within the margins of 5 mm proximal and distal to each stent edge. Results Baseline characteristics For 327 of the 459 patients enrolled in the study, SESs were deployed without IVUS guidance (non- IVUS group), while for the other 132 patients IVUS was used for SES deployment (IVUS group). The characteristics of the patients included in the study are shown in Table 1. The ratio of established coronary risk factors was not statistically significantly different between the non-ivus group and the IVUS group. Statistical analysis Quantitative data are presented as mean with standard deviation (S.D.), and categorical data as frequencies (percentages). Continuous variables were compared using the unpaired t-test. Binary variables were compared by means of the Student s t-test. To identify the risk factors of restenosis, multivariate logistic models were used. Odds ratios were calculated as an estimate of relative risk of restenosis associated with the possible risk factors as well as use of IVUS. Statistical significance was defined as P value of less than All statistical analyses were performed using JMP 5 software (SAS Institute, Cary, North Carolina, USA). Table 1 Baseline patient characteristics Non-IVUS (327 patients) IVUS (132 patients) Age (year) 66.0 ± ± Male Hypertension Hyperlipidemia Diabetes mellitus Smoking Hemodialysis Obesity Family history Medication Statin ACE inhibitor ARB Calcium channel blocker -Blocker P Table 2 Lesion and procedural characteristics Non-IVUS (341 lesions) IVUS (139 lesions) Stent length per 20.2 ± ± lesion (mm) Stent diameter 2.99 ± ± per lesion (mm) Final balloon 3.02 ± ± diameter (mm) Final inflation 13.8 ± ± pressure (atm) Lesion length 17.1 ± ± (mm) Number of stents Kissing balloon technique PTCRA Left anterior descending coronary artery Left circumflex artery Right coronary artery Left main trunk lesion Saphenous vein graft lesion Type A Type B Type B Type C Bifurcated lesion Chronic total occlusion PTCRA: percutaneous transluminal coronary rotational atherectomy. P

4 Angiographically guided SES implantation 21 Table 3 Clinical events at 8 months after PCI Non-IVUS (n = 341) IVUS (n = 138) Primary success rate Acute or late 0 0 thrombosis Cardiac death 0 0 Myocardial 0 0 infarction Cerebrovascular 0 0 events TLR rate TLR: target lesion revascularization. Lesions and procedural characteristics The characteristics of the lesion and procedures are shown in Table 2. Lesion and procedure characteristics including stent size, stent length, number of stents, etc., were not significantly different between non-ivus group and IVUS group. Clinical outcome Clinical outcomes at 8 months after PCI are shown in Table 3. Stent implantation failed in one patient in the non-ivus group, because the stent could not be optimally dilated due to severe calcification. As with the rest of the patients, neither acute nor late thrombosis occurred in any patient. Cardiac death, myocardial infarction, and cerebrovascular events also did not occur in any patient. The rates of target lesion revascularization (TLR) were 3.8% in the non- IVUS group and 3.6% in the IVUS group (P = 0.91). In one patient who underwent SES implantation without IVUS, a new stenotic lesion but not a restenosis lesion was found in the distal portion of the treated coronary artery at follow-up CAG. When target-vessel revascularization (TVR) was performed, the guide wire passed through the outside of the SES because of mal-apposition. The proximal edge of the SES was crushed during the TVR procedure, and as a result, we had to implant another SES at the proximal portion of the previously implanted SES as well as at the distal new lesion. Angiographic analysis In all, 368 lesions (271 in the non-ivus group and 97 in the IVUS group) underwent follow-up CAG. Angiographic analyses data of the 368 lesions are shown in Table 4. Reference diameter, minimal lumen diameter, and percent diametric stenosis at pre- P, post-, and follow-up CAG were not statistically significantly different between the non-ivus group and the IVUS group. Late loss was also not statistically significantly different between the non-ivus group and IVUS group. In-stent restenosis rates of the two groups were 4.8% in the non-ivus group and 5.2% in the IVUS group and they were not statistically significantly different (P = 0.89). Logistic regression analysis We performed logistic regression analysis to determine the risk factors of restenosis after SES implantation. Univariate and multivariate logistic regression analysis revealed that the hemodialysis and lesion length were statistically significant risk factors of restenosis (Table 5). However, SES implantation without IVUS was not an independent risk factor for restenosis (odds ratio [OR] of IVUS use for restenosis was 0.95, 95% confidence interval [CI]: 0.31, 2.95; P = 0.93 from multivariate logistic regression analysis). Discussion The major finding of our study is that SES implantation without IVUS is safe and effective in reducing restenosis and target lesion revascularization as long as stent size can be decided angiographically. IVUS is a useful device that provides precise information about the lesion length, vessel diameter, and other characteristics of the vessel. For the implantation of bare metal stents, full expansion of the stent and obtaining large minimal lumen area is thought to be important to reduce ISR. It was reported that IVUS-guided stent implantation provides a larger stent lumen diameter, resulting in a better long-term outcome than stent implantation with angiographic guidance [3]. Thus far, much effort has been aimed during PCI at obtaining a large stent diameter without vessel injury. But SES has a well-known efficacy for suppression of neointima formation by a pharmaceutical mechanism, and it seems unnecessary to expand SES to a size comparable to bare metal stents to ensure a good outcome. Our data suggest that IVUS is not necessary to adequately expand the SES and get a good outcome in many cases. In a sense, it may be said that SESs have made the PCI procedure simpler and easier than in the bare metal stent era. But our data do not preclude the use of IVUS in all SES implantations. IVUS is useful for SES implantation in lesions for which it is difficult to determine the lesion length and vessel diameter

5 22 H. Fujimoto et al. Table 4 Serial QCA data Non-IVUS (271 lesions) IVUS (97 lesions) P PCI-f/u CAG period (month) 7.8 ± ± Reference diameter (mm) Preintervention 2.78 ± ± Postintervention 2.81 ± ± Follow-up 2.82 ± ± MLD (mm) Preintervention 0.36 ± ± Postintervention Proximal 2.63 ± ± In-stent 2.58 ± ± Distal 2.58 ± ± Follow-up Proximal 2.47 ± ± In-stent 2.39 ± ± Distal 2.40 ± ± Diametric stenosis Preintervention 86.9 ± ± Postintervention Proximal 6.2 ± ± In-stent 8.7 ± ± Distal 8.9 ± ± Follow-up Proximal 12.5 ± ± In-stent 15.4 ± ± Distal 14.8 ± ± Late loss (mm) Proximal 0.17 ± ± In-stent 0.19 ± ± Distal 0.15 ± ± Binary restenosis Proximal In-stent Distal In-segment from angiographic information alone, resulting in a good primary and mid-term clinical outcome. For example, for the PCI of left main trunk lesions, precise evaluation of the distribution and amount of plaque using IVUS was reported to be important in deciding PCI strategy [15,16]. Precise evaluation of lesion length and vessel diameter is also difficult in chronic total occlusion lesions and diffuse lesions. In combination with IVUS, SESs may make it possible to treat complex lesions that could not be treated in the BMS era. It is therefore prudent to select appropriate cases for IVUS-guided stent implantation. In addition, we treated a patient who underwent SES implantation without IVUS and had difficulty in TVR because of mal-apposition of the previously implanted SES. From this case, we learned that mal-apposition of SES may cause difficulty at TVR and much attention must be given to avoid mal-apposition when SES is implanted without IVUS. IVUS may be helpful to reduce such incidental complications. This study was a retrospective study with a small number of patients. Some of the lesions and procedural characteristics were different between the non-ivus group and the IVUS group. But the main objective was not a rigid comparison of the result of SES implantation using angiographic guidance versus IVUS guidance. Rather, we intended to show the safety and efficacy of angiographically guided SES implantation except in cases where it is difficult to decide stent size and endpoint from angiographic information alone. Also, we intended to confirm

6 Table 5 Logistic regression analysis for the coronary risk factors, lesion characteristics, and use of IVUS in relation to restenosis after SES implantation Univariate logistic regression Multivariate logistic regression OR (95% CI) P OR (95% CI) P Male 0.59 ( ) ( ) 0.26 Age (per year) 0.96 ( ) ( ) 0.97 Hypertension 0.61 ( ) ( ) 0.23 Diabetes mellitus 2.43 ( ) ( ) 0.26 Hyperlipidemia 0.49 ( ) ( ) 0.38 Smoking 1.37 ( ) ( ) 0.97 Hemodialysis 4.80 ( ) ( ) Lesion length (per mm) 1.07 ( ) ( ) Vessel diameter (per mm) 0.76 ( ) ( ) 0.60 Chronic total occlusion 3.13 ( ) ( ) 0.77 IVUS guidance ( ) 0.93 Angiographically guided SES implantation 23

7 24 H. Fujimoto et al. that IVUS is an effective tool for deciding the stent size and endpoint when it is difficult to determine this from angiographic information alone, and that it ensures a good outcome. A randomized study with a larger patient population will be necessary to obtain adequate evidence. Conclusion In conclusion, with respect to lesions for which stent size and endpoint are decided from angiographic information alone, angio-guided SES implantation is safe and provides a good mid-term outcome comparable to that of IVUS-guided SES deployment. However, IVUS may be a useful tool to decide stent size for complex lesions and reduce possible complications. References [1] Kasaoka S, Tobis JM, Akiyama T, Reimers B, Di Mario C, Wong ND, et al. Angiographic and intravascular ultrasound predictors of in-stent restenosis. J Am Coll Cardiol 1998;32: [2] Hoffmann R, Mintz GS, Mehran R, Pichard AD, Kent KM, Satler LF, et al. Intravascular ultrasound predictors of angiographic restenosis in lesions treated with Palmaz-Schatz stents. J Am Coll Cardiol 1998;31:43 9. [3] Fitzgerald PJ, Oshima A, Hayase M, Metz JA, Bailey SR, Baim DS, et al. Final results of the Can Routine Ultrasound Influence Stent Expansion (CRUISE) study. Circulation 2000;102: [4] Oemrawsingh PV, Mintz GS, Schalij MJ, Zwinderman AH, Jukema JW, van der Wall EE. TULIP Study. Thrombocyte activity evaluation and effects of Ultrasound guidance in Long Intracoronary stent Placement. Intravascular ultrasound guidance improves angiographic and clinical outcome of stent implantation for long coronary artery stenoses: final results of a randomized comparison with angiographic guidance (TULIP Study). Circulation 2003;107:62 7. [5] Morice MC, Serruys PW, Sousa JE, Fajadet J, Ban Hayashi E, Perin M, et al. A randomized comparison of a sirolimus-eluting stent with a standard stent for coronary revascularization. N Engl J Med 2002;346: [6] Moses JW, Leon MB, Popma JJ, Fitzgerald PJ, Holmes DR, O Shaughnessy C, et al. Sirolimus-eluting stents versus standard stents in patients with stenosis in a native coronary artery. N Engl J Med 2003;349: [7] Schofer J, Schluter M, Gershlick AH, Wijns W, Garcia E, Schampaert E, et al. Sirolimuseluting stents for treatment of patients with long atherosclerotic lesions in small coronary arteries: double-blind, randomised controlled trial (E-SIEIUS). Lancet 2003;362: [8] Schampaert E, Cohen EA, Schluter M, Reeves F, Traboulsi M, Title LM, et al. The Canadian study of the sirolimuseluting stent in the treatment of patients with long de novo lesions in small native coronary arteries (C-SIRIUS). J Am Coll Cardiol 2004;43: [9] Gaku N, Kengo T, Aoki J, Onuma Y, Yamamoto H, Higashikuni Y, et al. Clinical and angiographic outcomes of sirolimuseluting stents implantation in Japanese patients in daily practice. Circ J 2006;70: [10] Suzuki S, Kamihata H, Hata T, Hayashi F, Miura A, Yoshinaga M, et al. Success rate of implantation and mid-term outcomes of the sirolimus-eluting stent. Circ J 2007;71: [11] Nakamura M, Wada M, Hara H, Kozuma K, Otsuka Y, Miyazaki S. Angiographic and clinical outcomes of a pharmacokinetic study of sirolimus-eluting stents: lesson from restenosis cases. Circ J 2005;69: [12] Seung KB, Kim YH, Park DW, Lee BK, Lee CK, Hong MK, et al. Effectiveness of sirolimus-eluting stent implantation for the treatment of ostial left anterior descending artery stenosis with intravascular ultrasound guidance. J Am Coll Cardiol 2005;46: [13] Sakurai R, Ako J, Morino Y, Sonoda S, Kaneda H, Terashima M, et al. Predictors of edge stenosis following sirolimuseluting stent deployment (a quantitative intravascular ultrasound analysis from the SIRIUS trial). Am J Cardiol 2005;96: [14] Takebayashi H, Kobayashi Y, Mintz GS, Carlier SG, Fujii K, Yasuda T, et al. Intravascular ultrasound assessment of lesions with target vessel failure after sirolimuseluting stent implantation. Am J Cardiol 2005;95: [15] Fassa AA, Wagatsuma K, Higano ST, Mathew V, Barsness GW, Lennon RJ, et al. Intravascular ultrasound-guided treatment for angiographically indeterminate left main coronary artery disease: a long-term follow-up study. J Am Coll Cardiol 2005;45: [16] Shiran A, Mintz GS, Leiboff B, Kent KM, Pichard AD, Satler LF, et al. Serial volumetric intravascular ultrasound assessment of arterial remodeling in left main coronary artery disease. Am J Cardiol 1999;83: Available online at