- Email: [email protected]
Outcomes of First- Versus Second-Generation Drug-Eluting Stent Implanted for Right Coronary Artery Ostial Narrowing
Outcomes of First- Versus Second-Generation Drug-Eluting Stent Implanted for Right Coronary Artery Ostial Narrowing Ryuta Sugihara, MDa, Yasunori Ueda, MD, PhDb,*, Yuji Nishimoto, MDa, Kuniaki Takahashi, MDa, Ayaka Murakami, BSca, Keisuke Ueno, MDa, Yasuharu Takeda, MD, PhDa, Akio Hirata, MD, PhDa, Kazunori Kashiwase, MD, PhDa, Yoshiharu Higuchi, MD, PhDa, and Yoshio Yasumura, MD, PhDa Clinical outcome is generally poor when stents are implanted at right coronary artery ostial lesion (RCAos). We compared the clinical outcome between the first-generation drugeluting stent (first DES) and second-generation drug-eluting stent (second DES) used for RCAos. Consecutive 88 patients who underwent percutaneous coronary interventions of de novo RCAos using the first DES (33 patients) or second DES (55 patients) were analyzed. The incidence of major adverse cardiac events (MACE) defined as the composite of cardiac death, myocardial infarction attributed to right coronary artery, and target lesion revascularization within 2.5 years was compared. The incidence of MACE was significantly lower in second DES (11% vs 36%, p [ 0.010) than that in the first DES. Multivariate analysis revealed use of second DES (odds ratio 0.24, 95% CI 0.11 to 0.93, p [ 0.008) alone was significantly associated with MACE. In conclusion, second DES revealed better clinical outcome than the first DES when used in de novo RCAos. Ó 2016 Elsevier Inc. All rights reserved. (Am J Cardiol 2016;-:-e-)
The right coronary artery ostial lesion (RCAos) has been one of the difficult target lesions for the coronary intervention to have good clinical outcome. The first-generation DES (first DES) revealed better outcome for the treatment of RCAos than bare metal stents.1,2 The second-generation DES (second DES) demonstrated better clinical outcome in general than the first DES.3 However, the difficulty in the treatment of RCAos has not been solved4,5; and the clinical outcome after the treatment of RCAos has never been compared between the first DES and second DES. Therefore, we retrospectively compared the incidence of major adverse cardiac events (MACE) between the patients’ RCAos treated by the first DES and those treated by second DES. Methods Consecutive 88 patients who underwent percutaneous coronary intervention of de novo RCAos (defined as being within 3 mm from the ostia) using the first DES (33 patients) or second DES (55 patients) from June 2007 to May 2013 were retrospectively analyzed. The first 2nd DES was approved in Japan in 2012. Cypher sirolimus-eluting stent (C-SES; Cordis/Johnson & Johnson, New Brunswick, New Jersey) and Taxus paclitaxel-eluting stent (T-PES; Boston Scientific, Marlboro, Massachusetts) were defined as the a Cardiovascular Division, Osaka Police Hospital, Osaka, Japan; and Cardiovascular Division, Osaka National Hospital, Osaka, Japan. Manuscript received September 30, 2016; revised manuscript received and accepted November 22, 2016. This work was performed in the Osaka Police Hospital, Osaka, Japan. See page 4 for disclosure information. *Corresponding author: Tel: (þ81) 6-6942-1331; fax: (þ81) 6-69436467. E-mail address: [email protected] (Y. Ueda). b
0002-9149/16/$ - see front matter Ó 2016 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjcard.2016.11.038
first DES and Endeavor zotarolimus-eluting stent (E-ZES; Medtronic, Minneapolis, Minnesota), Resolute zotarolimuseluting stent (R-ZES; Medtronic, Minneapolis, Minnesota), Xience evelorimus-eluting stent (X-EES; Abbot laboratories, North Chicago, Illinois), Promus everolimus-eluting stent (P-EES; Boston Scientific, Marlboro, Massachusetts), and Nobori biolimus-eluting stent (N-BES; Terumo, Tokyo, Japan) were defined as the second DES. The incidence of MACE within 2.5 years was compared between the first and second DES. MACE was defined as the composite of cardiac death, myocardial infarction attributed to target vessel, and clinically driven target lesion revascularization (TLR). All patients were recommended to take dual antiplatelet therapy (aspirin 100 and ticlopidine 200 or clopidogrel 75 mg/day) for at least 12 months. The data on the medications were examined at the end of follow-up. Hypertension was defined as blood pressure >140/ 90 mm Hg or the use of antihypertensive drugs. Diabetes mellitus was defined as fasting blood glucose >126 mg/dl or the use of oral drugs for diabetes mellitus or insulin therapy. Dyslipidemia was defined as low-density lipoprotein cholesterol >140 mg/dl or the use of statin. Catheterization was performed through the femoral, brachial, or radial artery approach using a 6Fr or 7Fr sheath and catheters. Heparin (50 to 70 U/kg) was administered intravenously. Coronary angiogram was recorded by the Innova Cardiovascular imaging system (GE Healthcare Japan, Tokyo, Japan); and quantitative coronary angiographic analysis (QCA) was performed with the system. The percent diameter stenosis was measured by QCA on the first and the final coronary angiogram. The use of intravascular ultrasound (IVUS) was always encouraged to assess the geometry and complete stent www.ajconline.org
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apposition. IVUS performed before predilatation and after postdilatation were analyzed. Coronary calcification was defined by IVUS assessment as the presence of hyperechoic area (brighter than the reference adventitia) with acoustic shadowing of deeper arterial structures. The external elastic membrane area, lumen cross-sectional area (lumen CSA), and minimal lumen diameter (MLD) were measured at the MLD site. Stents were deployed to fully cover the target lesion so as not to place the edges in the plaque-rich area. Categorical variables were expressed as frequency and were compared by the chi-square or Fisher’s exact test. Continuous variables were expressed as mean SD and were compared by the unpaired Student’s t test. Multivariate analysis was performed to clarify the factors associated with MACE including male, age, current smoking, diabetes mellitus, hypertension, dyslipidemia, medications (statin, aspirin, ticlopidine/clopidogrel, and eicosapentanoic acid), lesion calcification, total stent length, reference lumen CSA, reference external elastic membrane area, and final lumen CSA as independent variables. The incidence of MACE was compared between first-DES and second-DES groups using Kaplan-Meier methods and log-rank test. All statistical analyses were regarded as significant when p value was <0.05. Statistical analysis was performed by SPSS, version 12 (SPSS Inc., Chicago, Illinois). Results The first DES used were 12 C-SES (37%) and 21 T-PES (63%). The second DES used were 5 E-ZES (9%), 11 RZES (20%), 32 X-EES (58%), 1 P-EES (2%), and 6 N-BES (11%). The patients’ characteristics (Table 1), lesion and procedural characteristics (Table 2), and QCA and IVUS parameters (Table 3) are presented in the tables. Dual antiplatelet therapy with aspirin and clopidogrel/ ticlopidine was continued >12 months in all enrolled patients excluding 4 patients in the second-DES group. Due to the drug allergy against clopidogrel, cilostazol was used instead in one patient from the beginning and in one patient from 6 months. Due to a minor bleeding event, clopidogrel was discontinued at 6 months in one patient and aspirin was discontinued at 8 months in one patient. The second-DES group had a significantly lower incidence of MACE and its component TLR than the first-DES group (Figures 1 and 2). The results of multivariate Cox regression analysis to clarify the factors associated with MACE are presented in Table 4. Discussion The incidence of MACE defined as the composite of cardiac death, myocardial infarction attributed to target vessel, and TLR was significantly lower in the second DES than that in the first DES when implanted in RCAos mainly due to the difference in the incidence of TLR. To the best of our knowledge, this is the first report that compared the clinical outcome between the first DES and second DES implanted in RCAos. The clinical and angiographic outcomes of the coronary intervention in RCAos have not been adequately good with plain old balloon angioplasty,6 bare metal stent,7 or rotablator.8 TLR after the implantation of the first DES has been
Table 1 Patients’ characteristics Variables
1st-DES (N ¼ 33)
2nd-DES (N ¼ 55)
P value
Men Age (years) Diabetes Mellitus Hypertension Dyslipidemia Current smoker Hyperuricemia Chronic kidney disease Hemodialysis requiring Acute myocardial infarction Previous myocardial infarction Previous percutaneous coronary intervention Height (cm) Weight (kg) Left ventricular ejection fraction (%) Medications*: Aspirin Clopidogrel/Ticlopidine Angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker b-blocker Statin Cilostazol Eicosapentaenoic acid Warfarin/Direct oral anticoagulants Beraprost
21 (64%) 6810 17 (52%) 28 (85%) 28 (85%) 6 (18%) 10 (30%) 19 (58%) 0 (0%) 4 (12%) 14 (42%) 20 (61%)
48 (87%) 6811 25 (45%) 51 (93%) 48 (87%) 15 (27%) 20 (36%) 25 (45%) 3 (5%) 11 (20%) 21 (38%) 32 (58%)
0.02 0.92 0.59 0.28 0.75 0.32 0.57 0.28 0.08 0.35 0.70 0.83
16011 6312 6212
1629 6513 6213
0.22 0.45 0.99
30 (91%) 28 (85%) 24 (73%)
43 (78%) 44 (80%) 43 (78%)
0.13 0.57 0.57
22 26 5 8 4 2
37 44 3 18 6 1
0.95 0.89 0.18 0.40 0.86 0.36
(67%) (79%) (15%) (24%) (12%) (6%)
(67%) (80%) (6%) (33%) (11%) (2%)
DES ¼ drug-eluting stent. * Medications at the end of follow-up.
Table 2 Lesion and procedural characteristics Variables Type B2/C* Calcification Chronic total occlusion Thrombus Rotablator use IVUS use Number of stents used Stent diameter at RCAos (mm) Total stent length (mm) Maximum inflation pressure (atm)
1st-DES
2nd-DES
P value
25 (76%) 21 (64%) 7 (21%) 8 (24%) 1 (3%) 30 (91%) 1.40.8 3.00.4 30.620.2 19.04.2
49 (89%) 30 (55%) 7 (13%) 14 (25%) 3 (5%) 53 (96%) 1.40.7 3.30.3 39.828.5 16.62.9
0.13 0.41 0.32 0.90 0.60 0.34 0.79 <0.01 0.11 <0.01
DES ¼ drug-eluting stent; IVUS ¼ intravascular ultrasound; RCAos ¼ right coronary artery ostium. * Complex lesion classified as type B2/C in accordance with the American College Cardiology/American Heart Association task classification.
reported greater in RCAos than in the nonostial lesions (14% vs 1.6% at 1 year and 28% vs 14% at 5 years).2,4 TLR after the implantation of the second DES has also been reported greater in RCAos than in the nonostial lesions (7.5% vs 1.6% at 2 years).5 Although the TLR at RCAos2 was reported lower with first DES than with bare metal stent (14% vs 36% at 1 year), the comparison between the first DES and second DES has not been reported so far. The
Coronary Artery Disease/DES at RCA Ostial Lesion
3
Table 3 Quantitative coronary angiogram and intravascular ultrasound parameters Variables QCA analysis: Pre-PCI %diameter stenosis (%) Post-PCI %diameter stenosis (%) IVUS analysis: Reference site EEMA (mm2) Lumen CSA (mm2) Pre-PCI MLD site EEMA (mm2) Lumen CSA (mm2) MLD (mm) Post-PCI MLD site Lumen CSA (mm2) MLD (mm)
1st-DES
2nd-DES
P value
92.37.1 1.56.1
93.87.5 0.94.7
0.34 0.60
19.96.3 8.14.0
19.25.1 9.44.2
0.58 0.18
17.45.5 5.32.5 2.3 0.6
17.95.3 3.21.1 1.8 0.3
8.8 3.3 3.1 0.6
9.82.3 3.30.4
0.73 <0.01 <0.01 0.09 0.06
CSA ¼ cross-sectional area; DES ¼ drug-eluting stent; EEMA ¼ external elastic membrane area; IVUS ¼ intravascular ultrasound; MLD ¼ minimum lumen diameter; PCI ¼ percutaneous coronary intervention; QCA ¼ quantitative coronary angiogram.
Figure 2. Comparison of MACE between first and second DES by KaplanMeier analysis. The incidence of MACE was significantly higher in the patients treated with first DES than in those treated with second DES (logrank p ¼ 0.001).
Table 4 Multivariate Cox regression analysis to clarify the factors associated with major adverse cardiac events Variables
nd
2 -DES Post-PCI lumen CSA Lesion calcification
Figure 1. Comparison between first and second DES of the incidence of clinical outcomes. The second DES group had a significantly lower incidence of MACE (11% vs 36%, p ¼ 0.01) and TLR (5% vs 33%, p ¼ 0.003) than the first DES group. Death ¼ cardiac death; MI ¼ myocardial infarction attributed to target vessel.
present study clearly demonstrated for the first time that second DES implanted in RCAos had significantly lower incidence of MACE (11% vs 36%) and TLR (5% vs 33%) at 2.5 years than the first DES even with a relatively small number of study patients. The previous studies have adduced several reasons for the high incidence of MACE after the intervention of RCAos. First, abundant elastic fibers in RCAos contribute to both early and late elastic recoil.9 Second, high prevalence of calcification and fibrosis10 in RCAos causes stent underexpansion that is one of major causes of in-stent restenosis11 and small vessel diameter that has been associated with high incidence of MACE.12,13 Third, stent fracture14 has been frequently induced by hinge motion in the first DES than in the second DES because they were thicker and less flexible. In the present study, both postepercutaneous coronary intervention MLD and lumen CSA were substantially larger in the second DES than those in the first DES, which might have influence on the lower MACE rate in the second DES than that in the
MACE Hazard ratio [95% CI]
P value
0.24 [0.08-0.69] 0.83 [0.68-1.08] 2.91 [0.82-10.34]
0.008 0.058 0.098
Stent type (second generation), gender, age, dyslipidemia, diabetes mellitus, current smoking, medications (aspirin, clopidgrel/ticlopidine, statin, and eicosapentaenoic acid), lesion calcification, total stent length, reference EEMA, reference lumen CSA, and post-PCI lumen CSA were included as variables. CI ¼ confidence interval; CSA ¼ cross-section area; DES ¼ drug-eluting stent; EEMA ¼ external elastic membrane area; MACE ¼ major adverse cardiac events; PCI ¼ percutaneous coronary intervention.
first DES. However, the post-PCI lumen CSA appeared as an independent predictor of MACE by multivariate analysis, although not statistically significant. We included more T-PES than C-SES as first DES in the present study and T-PES was reported to have higher TLR than C-SES15e17; therefore, the MACE of the first DES might have become relatively higher. Recently, neoatherosclerosis has been regarded as an important cause of very-late DES failure, and statin treatment has been suggested as an effective treatment to prevent it.18,19 However, statin use was not associated with MACE by multivariate analysis in the present study. In summary, the use of second DES versus first DES would contribute to the better clinical outcome for the intervention of RCAos. First, this study was a retrospective, nonrandomized, single-center small study; therefore, a further large-scale prospective study with longer term observation would be
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needed to confirm the findings. Second, both DES groups had various types of stents, and the results might be different depending on the stent types.
10.
Disclosures
11.
Dr Ueda receives research grant from Abbott Vascular Japan. The other authors (Drs Sugihara, Nishimoto, Takahashi, Murakami, Ueno, Takeda, Hirata, Kashiwase, Higuchi, Yasumura) have no conflicts of interest to disclose.
12.
1. Iakovou I, Ge L, Michev I, Sangiorgi G, Montorfano M, Airoldi F, Chieffo A, Stankovic G, Vitrella G, Carlino M, Corvaja N, Briguori C, Colombo A. Clinical and angiographic outcome after sirolimus-eluting stent implantation in aorto-ostial lesions. J Am Coll Cardiol 2004;44: 967e971. 2. Sakamoto H, Ishikawa T, Mutoh M, Imai K, Mochizuki S. Angiographic and clinical outcomes after sirolimus-eluting stent implantation to de novo ostial lesion of the right coronary artery -a retrospective study-. Circ J 2008;72:880e885. 3. Windecker S, Stortecky S, Stefanini GG, da Costa BR, Rutjes AW, Di Nisio M, Silletta MG, Maione A, Alfonso F, Clemmensen PM, Collet JP, Cremer J, Falk V, Filippatos G, Hamm C, Head S, Kappetein AP, Kastrati A, Knuuti J, Landmesser U, Laufer G, Neumann FJ, Richter D, Schauerte P, Sousa Uva M, Taggart DP, Torracca L, Valgimigli M, Wijns W, Witkowski A, Kolh P, Jüni P. Revascularisation versus medical treatment in patients with stable coronary artery disease: network meta-analysis. BMJ 2014;348:g3859. 4. Ko E, Natsuaki M, Toyofuku M, Morimoto T, Matsumura Y, Oi M, Motohashi Y, Takahashi K, Kawase Y, Tanaka M, Kitada M, Yuzuki Y, Tamura T, Inoue K, Mitsudo K, Kimura T. Sirolimuseluting stent implantation for ostial right coronary artery lesions: fiveyear outcomes from the j-Cypher registry. Cardiovasc Interv Ther 2014;29:200e208. 5. Lam MK, Sen H, Tandjung K, Löwik MM, Basalus MW, Mewes JC, Stoel MG, van Houwelingen KG, Linssen GC, Ijzerman MJ, Doggen CJ, von Birgelen C. Clinical outcome of patients with implantation of second-generation drug-eluting stents in the right coronary ostium: insights from 2-year follow-up of the TWENTE trial. Catheter Cardiovasc Interv 2015;85:524e531. 6. Topol EJ, Ellis SG, Fishman J, Leimgruber P, Myler RK, Stertzer SH, O’Neill WW, Douglas JS, Roubin GS, King SB 3rd. Multicenter study of percutaneous transluminal angioplasty for right coronary artery ostial stenosis. J Am Coll Cardiol 1987;9:1214e1218. 7. Jain SP, Liu MW, Dean LS, Babu R, Goods CM, Yadav JS, Al-Shaibi KF, Mathur A, Iyer SS, Parks JM, Baxley WA, Roubin GS. Comparison of balloon angioplasty versus debulking devices versus stenting in right coronary ostial lesions. Am J Cardiol 1997;79:1334e1338. 8. Motwani JG, Raymond RE, Franco I, Ellis SG, Whitlow PL. Effectiveness of rotational atherectomy of right coronary artery ostial stenosis. Am J Cardiol 2000;85:563e567. 9. Applegate RJ, Draughn T, Yarbrough WD, Little WC. Restenosis of a sirolimus drug-eluting stent: aorto-ostial involvement of the
13.
14. 15.
16.
17. 18.
19.
proximal right coronary artery. Catheter Cardiovasc Interv 2006;67: 391e395. Stewart JT, Ward DE, Davies MJ, Pepper JR. Isolated coronary ostial stenosis: observations on the pathology. Eur Heart J 1987;8: 917e920. Fujii K, Carlier SG, Mintz GS, Yang YM, Moussa I, Weisz G, Dangas G, Mehran R, Lansky AJ, Kreps EM, Collins M, Stone GW, Moses JW, Leon MB. Stent underexpansion and residual reference segment stenosis are related to stent thrombosis after sirolimus-eluting stent implantation: an intravascular ultrasound study. J Am Coll Cardiol 2005;45:995e998. Park DW, Hong MK, Suh IW, Hwang ES, Lee SW, Jeong YH, Kim YH, Lee CW, Kim JJ, Park SW, Park SJ. Results and predictors of angiographic restenosis and long-term adverse cardiac events after drug-eluting stent implantation for aorto-ostial coronary artery disease. Am J Cardiol 2007;99:760e765. Luz A, Hughes C, Magalhães R, Bisceglia T, Descoutures F, Tamamm K, Tchetche D, Sauguet A, Farah B, Fajadet J. Stent implantation in aorto-ostial lesions: long-term follow-up and predictors of outcome. EuroIntervention 2012;7:1069e1076. Sianos G, Hofma S, Ligthart JM, Saia F, Hoye A, Lemos PA, Serruys PW. Stent fracture and restenosis in the drug-eluting stent era. Catheter Cardiovasc Interv 2004;61:111e116. Nakamura M, Muramatsu T, Yokoi H, Okada H, Ochiai M, Suwa S, Hozawa H, Kawai K, Awata M, Mukawa H, Fujita H, Shiode N, Asano R, Tsukamoto Y, Yamada T, Yasumura Y, Ohira H, Miyamoto A, Takashima H, Ogawa T, Matsuyama Y, Nanto S; J-DESsERT investigators. Outcomes of the largest multi-center trial stratified by the presence of diabetes mellitus comparing sirolimuseluting stents (SES) and paclitaxel-eluting stents (PES) in patients with coronary artery disease. The Japan drug-eluting stents evaluation: a randomized trial (J-DESsERT). Cardiovasc Interv Ther 2015;30: 103e114. Windecker S, Remondino A, Eberli F, Jüni P, Räber L, Wenaweser P, Togni M, Billinger M, Tüller D, Seiler C, Roffi M, Corti R, Sütsch G, Maier W, Lüscher T, Hess O, Egger M, Meier B. Sirolimus-eluting and paclitaxel-eluting stents for coronary revascularization. N Engl J Med 2005;353:653e662. Sidhu S, Shafiq N, Malhotra S, Pandhi P, Grover A. A meta-analysis of trials comparing Cypher and Taxus stents in patients with obstructive coronary artery disease. Br J Clin Pharmacol 2006;61:720e726. Natsuaki M, Nakagawa Y, Morimoto T, Ono K, Shizuta S, Furukawa Y, Kadota K, Iwabuchi M, Kato Y, Suwa S, Inada T, Doi O, Takizawa A, Nobuyoshi M, Kita T, Kimura T; CREDO-Kyoto PCI/ CABG Registry Cohort-2 Investigators. Impact of statin therapy on late target lesion revascularization after sirolimus-eluting stent implantation (from the CREDO-Kyoto Registry Cohort-2). Am J Cardiol 2012;109: 1387e1396. Ueda Y, Matsuo K, Nishimoto Y, Sugihara R, Hirata A, Nemoto T, Okada M, Murakami A, Kashiwase K, Kodama K. In-stent yellow plaque at 1 year after implantation is associated with future event of very late stent failure: the DESNOTE study (Detect the Event of Very Late Stent Failure from the Drug-Eluting Stent Not Well Covered by Neointima Determined by Angioscopy). JACC Cardiovasc Interv 2015;8:814e821.
The right coronary artery ostial lesion (RCAos) has been one of the difficult target lesions for the coronary intervention to have good clinical outcome. The first-generation DES (first DES) revealed better outcome for the treatment of RCAos than bare metal stents.1,2 The second-generation DES (second DES) demonstrated better clinical outcome in general than the first DES.3 However, the difficulty in the treatment of RCAos has not been solved4,5; and the clinical outcome after the treatment of RCAos has never been compared between the first DES and second DES. Therefore, we retrospectively compared the incidence of major adverse cardiac events (MACE) between the patients’ RCAos treated by the first DES and those treated by second DES. Methods Consecutive 88 patients who underwent percutaneous coronary intervention of de novo RCAos (defined as being within 3 mm from the ostia) using the first DES (33 patients) or second DES (55 patients) from June 2007 to May 2013 were retrospectively analyzed. The first 2nd DES was approved in Japan in 2012. Cypher sirolimus-eluting stent (C-SES; Cordis/Johnson & Johnson, New Brunswick, New Jersey) and Taxus paclitaxel-eluting stent (T-PES; Boston Scientific, Marlboro, Massachusetts) were defined as the a Cardiovascular Division, Osaka Police Hospital, Osaka, Japan; and Cardiovascular Division, Osaka National Hospital, Osaka, Japan. Manuscript received September 30, 2016; revised manuscript received and accepted November 22, 2016. This work was performed in the Osaka Police Hospital, Osaka, Japan. See page 4 for disclosure information. *Corresponding author: Tel: (þ81) 6-6942-1331; fax: (þ81) 6-69436467. E-mail address: [email protected] (Y. Ueda). b
0002-9149/16/$ - see front matter Ó 2016 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjcard.2016.11.038
first DES and Endeavor zotarolimus-eluting stent (E-ZES; Medtronic, Minneapolis, Minnesota), Resolute zotarolimuseluting stent (R-ZES; Medtronic, Minneapolis, Minnesota), Xience evelorimus-eluting stent (X-EES; Abbot laboratories, North Chicago, Illinois), Promus everolimus-eluting stent (P-EES; Boston Scientific, Marlboro, Massachusetts), and Nobori biolimus-eluting stent (N-BES; Terumo, Tokyo, Japan) were defined as the second DES. The incidence of MACE within 2.5 years was compared between the first and second DES. MACE was defined as the composite of cardiac death, myocardial infarction attributed to target vessel, and clinically driven target lesion revascularization (TLR). All patients were recommended to take dual antiplatelet therapy (aspirin 100 and ticlopidine 200 or clopidogrel 75 mg/day) for at least 12 months. The data on the medications were examined at the end of follow-up. Hypertension was defined as blood pressure >140/ 90 mm Hg or the use of antihypertensive drugs. Diabetes mellitus was defined as fasting blood glucose >126 mg/dl or the use of oral drugs for diabetes mellitus or insulin therapy. Dyslipidemia was defined as low-density lipoprotein cholesterol >140 mg/dl or the use of statin. Catheterization was performed through the femoral, brachial, or radial artery approach using a 6Fr or 7Fr sheath and catheters. Heparin (50 to 70 U/kg) was administered intravenously. Coronary angiogram was recorded by the Innova Cardiovascular imaging system (GE Healthcare Japan, Tokyo, Japan); and quantitative coronary angiographic analysis (QCA) was performed with the system. The percent diameter stenosis was measured by QCA on the first and the final coronary angiogram. The use of intravascular ultrasound (IVUS) was always encouraged to assess the geometry and complete stent www.ajconline.org
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The American Journal of Cardiology (www.ajconline.org)
apposition. IVUS performed before predilatation and after postdilatation were analyzed. Coronary calcification was defined by IVUS assessment as the presence of hyperechoic area (brighter than the reference adventitia) with acoustic shadowing of deeper arterial structures. The external elastic membrane area, lumen cross-sectional area (lumen CSA), and minimal lumen diameter (MLD) were measured at the MLD site. Stents were deployed to fully cover the target lesion so as not to place the edges in the plaque-rich area. Categorical variables were expressed as frequency and were compared by the chi-square or Fisher’s exact test. Continuous variables were expressed as mean SD and were compared by the unpaired Student’s t test. Multivariate analysis was performed to clarify the factors associated with MACE including male, age, current smoking, diabetes mellitus, hypertension, dyslipidemia, medications (statin, aspirin, ticlopidine/clopidogrel, and eicosapentanoic acid), lesion calcification, total stent length, reference lumen CSA, reference external elastic membrane area, and final lumen CSA as independent variables. The incidence of MACE was compared between first-DES and second-DES groups using Kaplan-Meier methods and log-rank test. All statistical analyses were regarded as significant when p value was <0.05. Statistical analysis was performed by SPSS, version 12 (SPSS Inc., Chicago, Illinois). Results The first DES used were 12 C-SES (37%) and 21 T-PES (63%). The second DES used were 5 E-ZES (9%), 11 RZES (20%), 32 X-EES (58%), 1 P-EES (2%), and 6 N-BES (11%). The patients’ characteristics (Table 1), lesion and procedural characteristics (Table 2), and QCA and IVUS parameters (Table 3) are presented in the tables. Dual antiplatelet therapy with aspirin and clopidogrel/ ticlopidine was continued >12 months in all enrolled patients excluding 4 patients in the second-DES group. Due to the drug allergy against clopidogrel, cilostazol was used instead in one patient from the beginning and in one patient from 6 months. Due to a minor bleeding event, clopidogrel was discontinued at 6 months in one patient and aspirin was discontinued at 8 months in one patient. The second-DES group had a significantly lower incidence of MACE and its component TLR than the first-DES group (Figures 1 and 2). The results of multivariate Cox regression analysis to clarify the factors associated with MACE are presented in Table 4. Discussion The incidence of MACE defined as the composite of cardiac death, myocardial infarction attributed to target vessel, and TLR was significantly lower in the second DES than that in the first DES when implanted in RCAos mainly due to the difference in the incidence of TLR. To the best of our knowledge, this is the first report that compared the clinical outcome between the first DES and second DES implanted in RCAos. The clinical and angiographic outcomes of the coronary intervention in RCAos have not been adequately good with plain old balloon angioplasty,6 bare metal stent,7 or rotablator.8 TLR after the implantation of the first DES has been
Table 1 Patients’ characteristics Variables
1st-DES (N ¼ 33)
2nd-DES (N ¼ 55)
P value
Men Age (years) Diabetes Mellitus Hypertension Dyslipidemia Current smoker Hyperuricemia Chronic kidney disease Hemodialysis requiring Acute myocardial infarction Previous myocardial infarction Previous percutaneous coronary intervention Height (cm) Weight (kg) Left ventricular ejection fraction (%) Medications*: Aspirin Clopidogrel/Ticlopidine Angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker b-blocker Statin Cilostazol Eicosapentaenoic acid Warfarin/Direct oral anticoagulants Beraprost
21 (64%) 6810 17 (52%) 28 (85%) 28 (85%) 6 (18%) 10 (30%) 19 (58%) 0 (0%) 4 (12%) 14 (42%) 20 (61%)
48 (87%) 6811 25 (45%) 51 (93%) 48 (87%) 15 (27%) 20 (36%) 25 (45%) 3 (5%) 11 (20%) 21 (38%) 32 (58%)
0.02 0.92 0.59 0.28 0.75 0.32 0.57 0.28 0.08 0.35 0.70 0.83
16011 6312 6212
1629 6513 6213
0.22 0.45 0.99
30 (91%) 28 (85%) 24 (73%)
43 (78%) 44 (80%) 43 (78%)
0.13 0.57 0.57
22 26 5 8 4 2
37 44 3 18 6 1
0.95 0.89 0.18 0.40 0.86 0.36
(67%) (79%) (15%) (24%) (12%) (6%)
(67%) (80%) (6%) (33%) (11%) (2%)
DES ¼ drug-eluting stent. * Medications at the end of follow-up.
Table 2 Lesion and procedural characteristics Variables Type B2/C* Calcification Chronic total occlusion Thrombus Rotablator use IVUS use Number of stents used Stent diameter at RCAos (mm) Total stent length (mm) Maximum inflation pressure (atm)
1st-DES
2nd-DES
P value
25 (76%) 21 (64%) 7 (21%) 8 (24%) 1 (3%) 30 (91%) 1.40.8 3.00.4 30.620.2 19.04.2
49 (89%) 30 (55%) 7 (13%) 14 (25%) 3 (5%) 53 (96%) 1.40.7 3.30.3 39.828.5 16.62.9
0.13 0.41 0.32 0.90 0.60 0.34 0.79 <0.01 0.11 <0.01
DES ¼ drug-eluting stent; IVUS ¼ intravascular ultrasound; RCAos ¼ right coronary artery ostium. * Complex lesion classified as type B2/C in accordance with the American College Cardiology/American Heart Association task classification.
reported greater in RCAos than in the nonostial lesions (14% vs 1.6% at 1 year and 28% vs 14% at 5 years).2,4 TLR after the implantation of the second DES has also been reported greater in RCAos than in the nonostial lesions (7.5% vs 1.6% at 2 years).5 Although the TLR at RCAos2 was reported lower with first DES than with bare metal stent (14% vs 36% at 1 year), the comparison between the first DES and second DES has not been reported so far. The
Coronary Artery Disease/DES at RCA Ostial Lesion
3
Table 3 Quantitative coronary angiogram and intravascular ultrasound parameters Variables QCA analysis: Pre-PCI %diameter stenosis (%) Post-PCI %diameter stenosis (%) IVUS analysis: Reference site EEMA (mm2) Lumen CSA (mm2) Pre-PCI MLD site EEMA (mm2) Lumen CSA (mm2) MLD (mm) Post-PCI MLD site Lumen CSA (mm2) MLD (mm)
1st-DES
2nd-DES
P value
92.37.1 1.56.1
93.87.5 0.94.7
0.34 0.60
19.96.3 8.14.0
19.25.1 9.44.2
0.58 0.18
17.45.5 5.32.5 2.3 0.6
17.95.3 3.21.1 1.8 0.3
8.8 3.3 3.1 0.6
9.82.3 3.30.4
0.73 <0.01 <0.01 0.09 0.06
CSA ¼ cross-sectional area; DES ¼ drug-eluting stent; EEMA ¼ external elastic membrane area; IVUS ¼ intravascular ultrasound; MLD ¼ minimum lumen diameter; PCI ¼ percutaneous coronary intervention; QCA ¼ quantitative coronary angiogram.
Figure 2. Comparison of MACE between first and second DES by KaplanMeier analysis. The incidence of MACE was significantly higher in the patients treated with first DES than in those treated with second DES (logrank p ¼ 0.001).
Table 4 Multivariate Cox regression analysis to clarify the factors associated with major adverse cardiac events Variables
nd
2 -DES Post-PCI lumen CSA Lesion calcification
Figure 1. Comparison between first and second DES of the incidence of clinical outcomes. The second DES group had a significantly lower incidence of MACE (11% vs 36%, p ¼ 0.01) and TLR (5% vs 33%, p ¼ 0.003) than the first DES group. Death ¼ cardiac death; MI ¼ myocardial infarction attributed to target vessel.
present study clearly demonstrated for the first time that second DES implanted in RCAos had significantly lower incidence of MACE (11% vs 36%) and TLR (5% vs 33%) at 2.5 years than the first DES even with a relatively small number of study patients. The previous studies have adduced several reasons for the high incidence of MACE after the intervention of RCAos. First, abundant elastic fibers in RCAos contribute to both early and late elastic recoil.9 Second, high prevalence of calcification and fibrosis10 in RCAos causes stent underexpansion that is one of major causes of in-stent restenosis11 and small vessel diameter that has been associated with high incidence of MACE.12,13 Third, stent fracture14 has been frequently induced by hinge motion in the first DES than in the second DES because they were thicker and less flexible. In the present study, both postepercutaneous coronary intervention MLD and lumen CSA were substantially larger in the second DES than those in the first DES, which might have influence on the lower MACE rate in the second DES than that in the
MACE Hazard ratio [95% CI]
P value
0.24 [0.08-0.69] 0.83 [0.68-1.08] 2.91 [0.82-10.34]
0.008 0.058 0.098
Stent type (second generation), gender, age, dyslipidemia, diabetes mellitus, current smoking, medications (aspirin, clopidgrel/ticlopidine, statin, and eicosapentaenoic acid), lesion calcification, total stent length, reference EEMA, reference lumen CSA, and post-PCI lumen CSA were included as variables. CI ¼ confidence interval; CSA ¼ cross-section area; DES ¼ drug-eluting stent; EEMA ¼ external elastic membrane area; MACE ¼ major adverse cardiac events; PCI ¼ percutaneous coronary intervention.
first DES. However, the post-PCI lumen CSA appeared as an independent predictor of MACE by multivariate analysis, although not statistically significant. We included more T-PES than C-SES as first DES in the present study and T-PES was reported to have higher TLR than C-SES15e17; therefore, the MACE of the first DES might have become relatively higher. Recently, neoatherosclerosis has been regarded as an important cause of very-late DES failure, and statin treatment has been suggested as an effective treatment to prevent it.18,19 However, statin use was not associated with MACE by multivariate analysis in the present study. In summary, the use of second DES versus first DES would contribute to the better clinical outcome for the intervention of RCAos. First, this study was a retrospective, nonrandomized, single-center small study; therefore, a further large-scale prospective study with longer term observation would be
4
The American Journal of Cardiology (www.ajconline.org)
needed to confirm the findings. Second, both DES groups had various types of stents, and the results might be different depending on the stent types.
10.
Disclosures
11.
Dr Ueda receives research grant from Abbott Vascular Japan. The other authors (Drs Sugihara, Nishimoto, Takahashi, Murakami, Ueno, Takeda, Hirata, Kashiwase, Higuchi, Yasumura) have no conflicts of interest to disclose.
12.
1. Iakovou I, Ge L, Michev I, Sangiorgi G, Montorfano M, Airoldi F, Chieffo A, Stankovic G, Vitrella G, Carlino M, Corvaja N, Briguori C, Colombo A. Clinical and angiographic outcome after sirolimus-eluting stent implantation in aorto-ostial lesions. J Am Coll Cardiol 2004;44: 967e971. 2. Sakamoto H, Ishikawa T, Mutoh M, Imai K, Mochizuki S. Angiographic and clinical outcomes after sirolimus-eluting stent implantation to de novo ostial lesion of the right coronary artery -a retrospective study-. Circ J 2008;72:880e885. 3. Windecker S, Stortecky S, Stefanini GG, da Costa BR, Rutjes AW, Di Nisio M, Silletta MG, Maione A, Alfonso F, Clemmensen PM, Collet JP, Cremer J, Falk V, Filippatos G, Hamm C, Head S, Kappetein AP, Kastrati A, Knuuti J, Landmesser U, Laufer G, Neumann FJ, Richter D, Schauerte P, Sousa Uva M, Taggart DP, Torracca L, Valgimigli M, Wijns W, Witkowski A, Kolh P, Jüni P. Revascularisation versus medical treatment in patients with stable coronary artery disease: network meta-analysis. BMJ 2014;348:g3859. 4. Ko E, Natsuaki M, Toyofuku M, Morimoto T, Matsumura Y, Oi M, Motohashi Y, Takahashi K, Kawase Y, Tanaka M, Kitada M, Yuzuki Y, Tamura T, Inoue K, Mitsudo K, Kimura T. Sirolimuseluting stent implantation for ostial right coronary artery lesions: fiveyear outcomes from the j-Cypher registry. Cardiovasc Interv Ther 2014;29:200e208. 5. Lam MK, Sen H, Tandjung K, Löwik MM, Basalus MW, Mewes JC, Stoel MG, van Houwelingen KG, Linssen GC, Ijzerman MJ, Doggen CJ, von Birgelen C. Clinical outcome of patients with implantation of second-generation drug-eluting stents in the right coronary ostium: insights from 2-year follow-up of the TWENTE trial. Catheter Cardiovasc Interv 2015;85:524e531. 6. Topol EJ, Ellis SG, Fishman J, Leimgruber P, Myler RK, Stertzer SH, O’Neill WW, Douglas JS, Roubin GS, King SB 3rd. Multicenter study of percutaneous transluminal angioplasty for right coronary artery ostial stenosis. J Am Coll Cardiol 1987;9:1214e1218. 7. Jain SP, Liu MW, Dean LS, Babu R, Goods CM, Yadav JS, Al-Shaibi KF, Mathur A, Iyer SS, Parks JM, Baxley WA, Roubin GS. Comparison of balloon angioplasty versus debulking devices versus stenting in right coronary ostial lesions. Am J Cardiol 1997;79:1334e1338. 8. Motwani JG, Raymond RE, Franco I, Ellis SG, Whitlow PL. Effectiveness of rotational atherectomy of right coronary artery ostial stenosis. Am J Cardiol 2000;85:563e567. 9. Applegate RJ, Draughn T, Yarbrough WD, Little WC. Restenosis of a sirolimus drug-eluting stent: aorto-ostial involvement of the
13.
14. 15.
16.
17. 18.
19.
proximal right coronary artery. Catheter Cardiovasc Interv 2006;67: 391e395. Stewart JT, Ward DE, Davies MJ, Pepper JR. Isolated coronary ostial stenosis: observations on the pathology. Eur Heart J 1987;8: 917e920. Fujii K, Carlier SG, Mintz GS, Yang YM, Moussa I, Weisz G, Dangas G, Mehran R, Lansky AJ, Kreps EM, Collins M, Stone GW, Moses JW, Leon MB. Stent underexpansion and residual reference segment stenosis are related to stent thrombosis after sirolimus-eluting stent implantation: an intravascular ultrasound study. J Am Coll Cardiol 2005;45:995e998. Park DW, Hong MK, Suh IW, Hwang ES, Lee SW, Jeong YH, Kim YH, Lee CW, Kim JJ, Park SW, Park SJ. Results and predictors of angiographic restenosis and long-term adverse cardiac events after drug-eluting stent implantation for aorto-ostial coronary artery disease. Am J Cardiol 2007;99:760e765. Luz A, Hughes C, Magalhães R, Bisceglia T, Descoutures F, Tamamm K, Tchetche D, Sauguet A, Farah B, Fajadet J. Stent implantation in aorto-ostial lesions: long-term follow-up and predictors of outcome. EuroIntervention 2012;7:1069e1076. Sianos G, Hofma S, Ligthart JM, Saia F, Hoye A, Lemos PA, Serruys PW. Stent fracture and restenosis in the drug-eluting stent era. Catheter Cardiovasc Interv 2004;61:111e116. Nakamura M, Muramatsu T, Yokoi H, Okada H, Ochiai M, Suwa S, Hozawa H, Kawai K, Awata M, Mukawa H, Fujita H, Shiode N, Asano R, Tsukamoto Y, Yamada T, Yasumura Y, Ohira H, Miyamoto A, Takashima H, Ogawa T, Matsuyama Y, Nanto S; J-DESsERT investigators. Outcomes of the largest multi-center trial stratified by the presence of diabetes mellitus comparing sirolimuseluting stents (SES) and paclitaxel-eluting stents (PES) in patients with coronary artery disease. The Japan drug-eluting stents evaluation: a randomized trial (J-DESsERT). Cardiovasc Interv Ther 2015;30: 103e114. Windecker S, Remondino A, Eberli F, Jüni P, Räber L, Wenaweser P, Togni M, Billinger M, Tüller D, Seiler C, Roffi M, Corti R, Sütsch G, Maier W, Lüscher T, Hess O, Egger M, Meier B. Sirolimus-eluting and paclitaxel-eluting stents for coronary revascularization. N Engl J Med 2005;353:653e662. Sidhu S, Shafiq N, Malhotra S, Pandhi P, Grover A. A meta-analysis of trials comparing Cypher and Taxus stents in patients with obstructive coronary artery disease. Br J Clin Pharmacol 2006;61:720e726. Natsuaki M, Nakagawa Y, Morimoto T, Ono K, Shizuta S, Furukawa Y, Kadota K, Iwabuchi M, Kato Y, Suwa S, Inada T, Doi O, Takizawa A, Nobuyoshi M, Kita T, Kimura T; CREDO-Kyoto PCI/ CABG Registry Cohort-2 Investigators. Impact of statin therapy on late target lesion revascularization after sirolimus-eluting stent implantation (from the CREDO-Kyoto Registry Cohort-2). Am J Cardiol 2012;109: 1387e1396. Ueda Y, Matsuo K, Nishimoto Y, Sugihara R, Hirata A, Nemoto T, Okada M, Murakami A, Kashiwase K, Kodama K. In-stent yellow plaque at 1 year after implantation is associated with future event of very late stent failure: the DESNOTE study (Detect the Event of Very Late Stent Failure from the Drug-Eluting Stent Not Well Covered by Neointima Determined by Angioscopy). JACC Cardiovasc Interv 2015;8:814e821.