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Impact of target vessel on long-term cardiac mortality after successful chronic total occlusion percutaneous coronary intervention: Insights from a Japanese multicenter registry
IJCA-25319; No of Pages 6 International Journal of Cardiology xxx (2017) xxx–xxx
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
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Article history: Received 2 April 2017 Received in revised form 6 July 2017 Accepted 24 July 2017 Available online xxxx
Department of Cardiology, New Tokyo Hospital, Chiba, Japan Department of Cardiology, Imperial College London, United Kingdom c Division of Cardiology, Fukuyama Cardiovascular Hospital, Hiroshima, Japan d Department of Internal Medicine II, University of Yamanashi, Faculty of Medicine, Yamanashi, Japan e Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan f Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center, Osaka, Japan
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Satoru Mitomo a, Toru Naganuma a, Richard J. Jabbour b, Katsumasa Sato c, Hideo Takebayashi c, Tsuyoshi Kobayashi d, Jun-ei Obata d, Kenji Sakamoto e, Kenichi Tsujita e, Kiyotaka Kugiyama d, Hisao Ogawa f, Sunao Nakamura a,⁎
a b s t r a c t
Background: The impact of successful chronic total occlusion (S-CTO) percutaneous coronary intervention (PCI) on cardiac mortality may differ depending on target CTO vessel; however, to date this has not yet been adequately evaluated. The aim of this study was to investigate the impact of target vessel on cardiac mortality after S-CTO PCI. Methods: From January 2004 to December 2011, 1517 CTO PCIs were performed in 4 Japanese centers and enrolled in a multicenter registry. Cases were retrospectively analyzed and divided per target vessel treated. The primary endpoint was cardiac mortality during the follow-up period. Results: During the study period, 1424 CTOs with 1 main vessel CTO per patient were analyzed (left anterior descending artery [LAD]: 487, right coronary artery [RCA]: 599, left circumflex [LCx]: 338). 92.3% (n = 1314) of cases were S-CTO PCIs. The median follow-up period was 1677 (interquartile range; 811–2463) days. In LAD and RCA CTOs, S-CTO PCI was associated with a lower cardiac mortality rate at 5-year follow-up when compared with unsuccessful CTO (U-CTO) (2.6% vs 9.7%, p = 0.01, 2.6% vs 27.3%, p b 0.01, respectively). This finding was not present with LCx CTO PCI (2.2% vs 0.0%, p = 0.53). Cox regression analysis demonstrated that LAD and RCA S-CTO PCI were independent predictors of a lower cardiac mortality rate (LAD; HR: 0.18, 95% CI: 0.06–0.56; p b 0.01; RCA; HR: 0.24, 95% CI: 0.09–0.65; p b 0.01). Conclusions: S-CTO LAD and RCA PCI were associated with a lower long-term cardiac mortality after CTO PCI. This finding was not observed with LCx CTO PCI. © 2017 Published by Elsevier Ireland Ltd.
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associated with a relief in anginal symptoms and an improvement in ejection fraction (EF) and mortality [1,2]. Although CTO PCI remains challenging, the success rate of CTO PCI has increased with innovations in devices, including dedicated wires and microcatheters, as well as the development of techniques including the retrograde approach [3,4]. Furthermore, the development of new generation drug-eluting stents (DES) have further improved outcomes [5,6]. Although CTO PCI is becoming widely performed across the globe, most prior studies have reported overall clinical outcomes. Therefore, whether there are potential differences in outcomes depending on CTO target vessel treated remains unclear. The aim of this study was to evaluate the impact of target CTO vessel on cardiac mortality from a Japanese multicenter registry.
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Impact of target vessel on long-term cardiac mortality after successful chronic total occlusion percutaneous coronary intervention: Insights from a Japanese multicenter registry
Keywords: Percutaneous coronary intervention Chronic total occlusion Target vessel Cardiac mortality
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1. Introduction
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Chronic total occlusion (CTO) percutaneous coronary intervention (PCI) has been shown in numerous observational studies to be
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Abbreviations: ACEi, angiotensin convert enzyme inhibitor; ARB, angiotensin receptor blocker; BMS, bare metal stent; CABG, coronary artery bypass grafting; CTO, chronic total occlusion; DAPT, dual antiplatelet therapy; DES, drug-eluting stent; LAD, left anterior descending artery; LCx, left circumflex artery; LVEF, left ventricular ejection fraction; MB, main branch; MI, myocardial infarction; PCI, percutaneous coronary intervention; POBA, plain old balloon angioplasty; RCA, right coronary artery; SB, side branch; ST, stent thrombosis; TIMI, Thrombolysis In Myocardial Infarction; TLR, target lesion revascularization. ⁎ Corresponding author at: Department of Cardiology, New Tokyo Hospital, 1271 Wanagaya, Matsudo, Chiba 270-2232, Japan. E-mail address: [email protected] (S. Nakamura).
http://dx.doi.org/10.1016/j.ijcard.2017.07.098 0167-5273/© 2017 Published by Elsevier Ireland Ltd.
Please cite this article as: S. Mitomo, et al., Impact of target vessel on long-term cardiac mortality after successful chronic total occlusion percutaneous coronary intervention..., Int J Cardiol (2017), http://dx.doi.org/10.1016/j.ijcard.2017.07.098
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S. Mitomo et al. / International Journal of Cardiology xxx (2017) xxx–xxx
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2.2. Procedure
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CTO PCI was performed by well-experienced operators in each center. The selection of devices including wires, micro-catheters and stent type was left to the operator's discretion. The PCI strategy including approach (antegrade or retrograde), lesion preparation, post-dilatation, and using intravascular imaging was also dependent on the operator's decision. Patients were administered dual antiplatelet therapy (DAPT) which consisted of aspirin (100 mg/day) and either ticlopidine (200 mg/day) or clopidogrel (75 mg/day) with an aim to continue for at least 12 months after stent implantation.
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2.3. Definitions
89 90 91 92 93 94 95
CTO was defined as complete obstruction of the vessel with Thrombolysis In Myocardial Infarction (TIMI) flow of 0 with an estimated duration of the occlusion N3 months [7,8]. Lesion complexity was assessed for the presence of calcification detected on fluoroscopy, proximal tortuosity, vessel angulation N45°, and the morphology of the entry point. Procedural success was defined as a final diameter stenosis b30% with TIMI 3 flow. Complete revascularization was defined as revascularization for all vessels which had a significant stenosis evaluated by angiography and/or positive stress test results.
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2.4. Study endpoints and follow-up
97 98 99 100 101 102 103 104 105 106 107 108 109 110 111
The primary endpoint was cardiac mortality during the follow-up period. Cardiac mortality was defined as death presumed to be due to cardiovascular disease or without clinical or postmortem evidence of other causes. Secondary endpoints were follow-up all-cause mortality, myocardial infarction (MI), target lesion vascularization (TLR), target vessel revascularization (TVR), and definite/probable stent thrombosis (ST). MI was defined as an elevation of creatinine kinase-MB fraction or troponin-T/troponin-I greater than the upper limit of normal with concomitant anginal symptoms or ischemic findings on electrocardiography [9]. TLR was defined as repeat revascularization for lesions within the CTO previously treated or in the adjacent 5 mm. TVR was defined as repeat PCI in the target vessel. ST was defined according to Academic Research Consortium definition [9]. Demographic, lesion, and procedural data were collected from medical records and angiograms reviewed in each of institutes by experienced clinicians. Clinical follow-up was performed on all subjects by either clinical visit or telephone interview. Follow-up angiography was performed either by physician's request or the presence of symptoms warranting repeat angiography/suspected myocardial ischemia.
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2.5. Statistics
113 114 115 116 117 118 119 120 121 122 123 124 125
To evaluate the impact of successful CTO (S-CTO) PCI on outcomes, cases were divided into two groups per CTO PCI success, and the overall cohort and subgroup per CTO vessel. Categorical variables were presented as frequencies and were analyzed using the chisquared or Fisher exact tests as appropriate. Continuous variables were presented as mean ± standard deviation (SD) or median with interquartile range (IQR) and compared using the Student-t or Wilcoxon rank-sum where applicable. The cumulative incident rates during the follow-up period were estimated using Kaplan-Meier method and were compared using the Log-rank test. To identify predictors of cardiac mortality after CTO PCI, multivariable analysis using Cox regression method was performed in each subgroup of target CTO vessel. Covariates that were clinically significant or statistically relevant after univariate analysis were included in the final model. A p value b0.05 was considered as statistically significant. Statistical analyses were performed using SPSS version 22.0 (IBM Inc., Chicago, IL).
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3. Results
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3.1. Overall population
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3.1.1. Baseline, lesion, and procedural characteristics (Supplemental Table 1) We performed 1517 CTO PCIs during the study period; of which, 93 cases were excluded per the predefined criteria, leaving 1424 included cases that were retrospectively analyzed (Supplemental Fig. 1). Right
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3.1.2. Clinical outcomes (successful vs unsuccessful) and predictors of cardiac mortality The median follow-up was 1677 (IQR; 811–2463) days. The cumulative cardiac mortality rate at 5-year follow-up was significantly lower in the S-CTO PCI group when compared with unsuccessful CTO (U-CTO) PCI (2.5% vs 15.9%, p b 0.001) (Fig. 1). Of them, there were 3 cases which occurred within 7 days post procedure. After U-CTO LAD PCI, a 72-year-old male with low EF (20%) presented with ventricular tachycardia (day 0) and a 87 year-old male with low EF (20%) developed acute heart failure (day 2). Another case was a 76 year-old male with EF 45% who presented with sudden death 3 days after S-CTO PCI for RCA, which was classified as probable ST. Regarding secondary endpoints, cumulative incidence rates of all-cause mortality, TLR, and TVR were significantly lower in the S-CTO PCI group (8.2% vs 21.2%; p b 0.001, 25.0% vs 42.1%; p b 0.01, 32.1% vs 45.7%; p = 0.03, respectively) (Supplemental Fig. 2), but there were no differences in both MI (S-CTO: 1.0% vs U-CTO: 1.1%; p = 0.75) and ST (S-CTO: 0.6% vs U-CTO: 1.3%; p = 0.43) between the two groups. In total population, S-CTO PCI (HR: 0.28, 95% CI: 0.13–0.58; p = 0.001), chronic kidney disease (CKD) (HR: 2.29, 95% CI: 1.08–4.88: p = 0.03), hemodialysis (HR: 4.80, 95% CI: 2.23–10.35: p b 0.001), and LVEF (HR: 0.96, 95% CI: 0.94–0.98: p b 0.001) were independent predictors of cardiac mortality after CTO PCI (Supplemental Table 2).
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From January 2004 to December 2011, we retrospectively analyzed all CTO PCI cases from 4 Japanese centers (New Tokyo Hospital; Chiba, Fukuyama cardiovascular hospital; Hiroshima, Yamanashi university; Yamanashi, Kumamoto university; Kumamoto). Cases were excluded if: 1) there was no clinical follow-up; and 2) they involved a CTO of the left main trunk, N2 vessels, or bypass grafts. All main vessel CTOs were included and there were no hypoplastic LCx or RCA CTO cases. Regarding side branch (SB) CTOs, posterior-descending branches were included and defined according to anatomical dominancy. SB CTO cases including diagonal, posterolateral, and obtuse marginal were excluded if a small vessel (b2.25 mm) and/or supplying a small territory, which were evaluated angiographically by well-experienced CTO operators in each institution.
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coronary artery (RCA) CTOs were the most common (599 cases; 42.1%), followed by left anterior descending artery (LAD) (487cases; 34.2%), and left circumflex (LCx) (338cases; 23.7%) CTOs. Regarding baseline characteristics, LAD CTO patients were less likely to have had previous PCI (41.5%), coronary artery bypass grafting (CABG) (4.7%), or cardiac surgery (3.3%) compared with the other 2 CTO lesions (p b 0.01, respectively). In the overall cohort, there was a high rate of complete revascularization (N80%), and patients were generally on optimal medical therapy for ischemic heart disease. There were differences in target vessel CTO lesion characteristics including the presence of bifurcations, tortuosity and vessel angulation (p b 0.01). This was reflected in the CTO procedural characteristics, since there were differences in stent diameter, total stent number and length used between target vessel CTO treated. Of note, a high rate of DES implantation (approximately 80%), procedural success (N 90%), and angiographic follow-up (N 85%) was obtained in every CTO vessel treated.
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Fig. 1. Kaplan-Meier curve of cumulative cardiac mortality after successful and unsuccessful CTO PCI in overall population.
Please cite this article as: S. Mitomo, et al., Impact of target vessel on long-term cardiac mortality after successful chronic total occlusion percutaneous coronary intervention..., Int J Cardiol (2017), http://dx.doi.org/10.1016/j.ijcard.2017.07.098
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S. Mitomo et al. / International Journal of Cardiology xxx (2017) xxx–xxx
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3.2.1. Baseline, lesion and procedural characteristics (Table 1) In the LAD CTO subgroup, 450 (92.4%) out of 487 cases were S-CTO. Baseline characteristics were well balanced between S-CTO and U-CTO PCI. U-CTO patients had slightly lower EFs (51.9 ± 13.4 vs 56.1 ± 12.2; P = 0.06) and a higher proportion were taking angiotensin receptor blocker (ARB)/angiotensin convert enzyme inhibitor (ACEi) (73.5% vs 55.8%; p = 0.03). Regarding lesion characteristics, U-CTOs were longer in lesion length (28.0 ± 18.8 mm vs 21.1 ± 11.2 mm; p = 0.04), involved less bifurcations (40.5% vs 57.8%; p = 0.03) and had less grade 3 collaterals (29.7% vs 68.7%p b 0.01). Regarding procedural characteristics, there were some significant differences including total implanted stent length because U-CTO included incomplete PCI cases or failure cases without any stent implantation.
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Table 1 Baseline, lesion and procedural characteristics in each target CTO vessel. LAD (N = 487)
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Patient characteristics Age, years Male gender, n (%) Hypertension, n (%) Dyslipidemia, n (%) Diabetes, n (%) Insulin dependent diabetes, n (%) Chronic kidney disease (60 N eGFR), n (%) Hemodialysis, n (%) Peripheral artery disease, n (%) Previous PCI, n (%) Previous CABG, n (%) Previous cardiac surgery, n (%) Previous stroke, n (%) LVEF, % Medication β blocker, n (%) ACEi/ARB, n (%) Ca channel blocker, n (%) Nitrogen/nicorandil, n (%) Statin, n (%)
RCA (N = 599) Unsuccessful (N = 37)
p value*
Successful (N = 547)
67.4 ± 10.4 360 (80.0) 382 (85.3) 328 (73.1) 220 (49.4) 25 (5.6) 152 (34.9) 29 (6.5) 47 (10.4) 181 (40.2) 21 (4.7) 15 (3.3) 38 (8.8) 56.1 ± 12.2
68.7 ± 10.4 28 (75.7) 31 (86.1) 29 (80.6) 17 (47.2) 2 (5.6) 15 (41.7) 2 (5.6) 7 (18.9) 21 (56.8) 2 (5.4) 1 (2.7) 4 (11.1) 51.9 ± 13.4
0.48 0.33 0.56 0.22 0.47 0.67 0.26 0.59 0.10 0.04 0.54 0.65 0.41 0.06
66.0 ± 10.6 455 (83.2) 448 (82.5) 400 (73.5) 240 (44.3) 39 (7.2) 200 (37.5) 32 (5.9) 81 (14.8) 268 (49.0) 65 (11.9) 53 (9.7) 37 (7.2) 55.9 ± 11.7
Unsuccessful (N = 52)
LCx (N = 338)
p value**
Successful (N = 317)
Unsuccessful (N = 21)
p value***
64.5 ± 9.8 42 (80.8) 42 (80.8) 34 (65.4) 31 (59.6) 9 (17.3) 16 (32.0) 10 (19.2) 18 (34.6) 40 (76.9) 7 (13.5) 5 (9.6) 6 (14.3) 53.8 ± 14.3
0.33 0.39 0.44 0.14 0.02 0.02 0.27 b0.01 b0.01 b0.01 0.44 0.61 0.10 0.32
66.1 ± 9.8 269 (84.9) 263 (83.2) 226 (71.7) 144 (45.6) 17 (5.4) 124 (39.9) 22 (7.0) 44 (13.9) 174 (54.9) 35 (11.0) 32 (10.1) 30 (9.8) 53.8 ± 13.1
71.1 ± 10.3 17 (81.0) 17 (81.0) 14 (66.7) 11 (51.2) 2 (9.5) 11 (55.0) 1 (4.8) 8 (38.1) 17 (81.0) 1 (4.8) 1 (4.8) 1 (4.8) 52.3 ± 15.4
0.02 0.41 0.49 0.39 0.35 0.34 0.14 0.57 b0.01 0.02 0.32 0.37 0.44 0.62
0.18 0.03 0.42 0.46 0.58
238 (47.4) 302 (60.2) 217 (43.2) 93 (18.5) 328 (65.3)
16 (33.3) 22 (45.8) 20 (41.7) 9 (18.8) 24 (51.1)
0.04 0.04 0.48 0.55 0.04
136 (44.7) 171 (56.1) 147 (48.2) 65 (21.3) 193 (63.3)
8 (40.0) 14 (70.0) 8 (40.0) 5 (25.0) 11 (55.0)
0.43 0.16 0.32 0.44 0.30
3.0 ± 1.7 21.1 ± 11.2
2.7 ± 0.4 28.0 ± 18.8
0.30 0.04
3.0 ± 0.4 27.2 ± 17.2
2.8 ± 0.3 42.4 ± 29.0
b0.01 b0.01
2.7 ± 1.4 18.9 ± 8.7
2.5 ± 0.3 24.5 ± 10.0
0.54 b0.01
138 (30.7) 28 (6.2) 59 (13.1) 260 (57.8) 248 (55.1) 9 (2.0) 309 (68.7) 235 (52.2)
6 (16.2) 1 (2.7) 4 (10.8) 15 (40.5) 19 (52.8) 1 (2.7) 11 (29.7) 16 (43.2)
0.17 0.33 0.46 0.03 0.76 0.55 b0.01 0.19
116 (21.1) 139 (25.4) 152 (27.8) 182 (33.3) 292 (53.8) 19 (3.5) 412 (75.3) 317 (58.0)
16 (30.8) 16 (30.8) 16 (30.8) 17 (32.7) 30 (57.7) 5 (9.6) 23 (44.2) 26 (50.0)
0.27 0.25 0.38 0.53 0.35 0.05 b0.01 0.17
69 (21.8) 79 (24.9) 86 (27.1) 146 (46.1) 167 (52.8) 7 (2.2) 204 (64.4) 186 (58.7)
4 (19.0) 6 (28.6) 4 (19.0) 9 (45.0) 11 (52.4) 0 (0.0) 6 (28.6) 12 (57.1)
0.51 0.44 0.30 0.56 0.65 0.64 b0.01 0.53
444 (98.7) 6 (1.3)
37 (100.0) 0 (0.0)
0.62 0.82
524 (95.8) 23 (4.2)
51 (98.1) 1 (1.9)
0.37 0.20
313 (98.7) 4 (1.3)
21 (100.0) 0 (0.0)
0.77 0.60
23 (5.1) 42 (9.4) 385 (85.5) 1.4 ± 0.6 2.9 ± 1.1 35.1 ± 16.5 46.3. ± 20.2 214 (47.7) 197.8 ± 79.7 385 (85.6)
8 (21.6) 3 (8.1) 15 (40.5) 1.3 ± 0.7 2.6 ± 0.4 27.0 ± 18.9 34.4 ± 22.5 15 (40.5) 162.4 ± 88.6 28 (75.7)
0.001 0.55 b0.001 0.35 0.44 0.03 0.02 0.26 0.02 0.09
21 (3.9) 52 (9.5) 474 (86.6) 1.6 ± 0.7 3.0 ± 0.4 43.0 ± 22.1 56.2 ± 27.0 225 (41.1) 202.0 ± 79.1 486 (89.0)
18 (34.6) 5 (9.6) 20 (38.5) 1.5 ± 1.1 2.9 ± 0.4 40.8 ± 30.1 50.8 ± 38.6 9 (17.6) 137.4 ± 75.0 42 (80.8)
b0.01 0.57 b0.01 0.65 0.19 0.72 0.50 b0.01 b0.01 0.07
27 (8.5) 29 (9.1) 261 (82.3) 1.3 ± 0.5 2.6 ± 0.3 28.9 ± 12.6 32.8 ± 15.3 142 (44.8) 182.3 ± 78.8 286 (90.2)
7 (33.3) 2 (9.5) 4 (19.0) 1.5 ± 0.5 2.5 ± 0.2 28.0 ± 15.0 34.0 ± 12.4 9 (42.9) 203.1 ± 106.5 14 (66.7)
b0.01 0.60 b0.01 0.33 0.45 0.86 0.85 0.52 0.39 b0.01
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19 (55.9) 25 (73.5) 12 (35.3) 6 (17.6) 21 (61.8)
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Procedural characteristics Antegrade approach, n (%) Retrograde approach, n (%) Methods of revascularization POBA, n (%) BMS implantation, n (%) DES implantation, n (%) Number of implanted stents for CTO lesion, n (%) Mean stent diameter, mm Total stent length for CTO lesion, mm Total stent length for CTO vessel, mm Intravascular imaging guidance, n (%) Total amount of contrast medium, ml Follow-up angiography, n (%)
195 196
Successful (N = 450)
194 (46.1) 235 (55.8) 163 (38.7) 85 (20.2) 260 (61.8)
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Lesion characteristics Reference vessel diameter, mm CTO lesion length, mm Lesion complexity Calcification, n (%) Tortuosity, n (%) Angulation (N45°), n (%) Bifurcation, n (%) Blunt type entry point, n (%) Reattempt, n (%) Collaterals Rentrop grade = 3, n (%) Multi vessel disease, n (%)
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3.3.1. Baseline, lesion and procedural characteristics (Table 1) In the RCA CTO subset, there were 547 (91.3%) S-CTO cases and 52 (8.7%) U-CTO cases. U-CTO patients were more likely to be diabetic (59.6% vs 44.3%, p = 0.02; insulin dependent 17.3% vs 7.2%, p = 0.02),
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3.3. RCA CTO subgroup; successful vs unsuccessful
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3.2.2. Clinical outcomes The median follow-up was 1677 (IQR; 759–2510) days. S-CTO was associated with significantly less cardiac mortality when compared with U-CTO (cumulative rate at 5-year follow-up: 2.6% vs 9.7%; p = 0.01) (Fig. 2A). There were no statistical differences in secondary endpoint at 5-year follow-up between the two groups except for lower rates of TLR and TVR in the S-CTO PCI group (21.4% vs 42.5%, p b 0.01, 34.5% vs 45.3%, p = 0.04, respectively) (Supplemental Table 3).
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3.2. LAD CTO subgroup; successful vs unsuccessful
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Values are n (%) or mean ± SD. ACEi = angiotensin convert enzyme inhibitor, ARB = angiotensin receptor blocker, BMS = bare metal stent, CTO = chronic total occlusion, CABG = coronary artery bypass graft, DES = drug-eluting stent, GFR = glomerular filtration ratio, LAD = left anterior descending artery, LCx = left circumflex, LVEF = left ventricular ejection fraction, POBA = plane old balloon angioplasty. p value: successful vs unsuccessful in LAD (*), RCA (**), LCx (***), respectively.
Please cite this article as: S. Mitomo, et al., Impact of target vessel on long-term cardiac mortality after successful chronic total occlusion percutaneous coronary intervention..., Int J Cardiol (2017), http://dx.doi.org/10.1016/j.ijcard.2017.07.098
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S. Mitomo et al. / International Journal of Cardiology xxx (2017) xxx–xxx
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3.4. LCx CTO subgroup; successful vs unsuccessful
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3.4.1. Baseline, lesion and procedural characteristics (Table 1) In LCX CTO subset, there were 317 (93.8%) S-CTO cases and 21 (6.2%) U-CTO cases. Baseline characteristics were generally well balanced between the S-CTO and U-CTO groups. However, patients with U-CTO
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Table 2 Multivariate analysis of cardiac mortality after successful CTO PCI in LAD and RCA.
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3.4.3. Predictors of cardiac mortality: each target CTO vessel (Table 2) The results of multivariable analysis using Cox-regression method are demonstrated in Table 2. In the LAD CTO subgroup, SCTO PCI (HR: 0.18, 95% CI: 0.06–0.56; p b 0.01), hemodialysis (HR: 6.41, 95% CI: 1.92–21.35: p b 0.01), and LVEF (HR: 0.95, 95% CI: 0.91–0.99: p b 0.01) were independent predictors of cardiac mortality after CTO PCI. In the RCA CTO subgroup, S-CTO PCI was also an independent predictor of cardiac mortality after CTO PCI (HR: 0.24, 95% CI: 0.09–0.65; p b 0.01).
239 240
p value
LAD (number of events: 17 cases) Age Diabetes Insulin dependent diabetes CKD Hemodialysis LVEF before PCI Multi-vessel disease Successful LAD CTO PCI
1.03 (0.97–1.09) 2.33 (0.89–6.73) 4.71 (1.33–16.73) 3.20 (1.16–8.01) 9.32 (3.17–27.46) 0.94 (0.91–0.97) 1.08 (0.42–2.80) 0.18 (0.06–0.56)
0.26 0.12 0.02 0.24 b0.01 b0.01 0.88 b0.01
RCA (number of events: 27 cases) Age Diabetes Insulin dependent diabetes CKD Hemodialysis LVEF before PCI Multi-vessel disease Successful RCA CTO PCI
1.02 (0.98–1.06) 4.43 (1.65–11.94) 3.47 (1.29–9.34) 7.90 (2.64–23.68) 16.97 (6.85–41.99) 0.92 (0.89–0.95) 2.10 (0.84–5.28) 0.12 (0.05–0.27)
0.34 b0.01 0.01 b0.01 b0.01 b0.01 0.11 b0.01
N
Univariate HR (95% CI)
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230
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3.3.2. Clinical outcomes The median follow-up was 1606 (IQR; 799–2543) days. S-CTO was associated with a reduction in cardiac mortality when compared with U-CTO (cumulative rate at 5-year follow-up: 2.6% vs 27.3%; p b 0.01) (Fig. 2B). Regarding secondary endpoints, all-cause mortality, TLR, and TVR were significantly lower with S-CTO PCI (9.2% vs 33.3%; p b 0.01, 27.9% vs 45.0%, p b 0.01, 33.0% vs 48.2%, p = 0.03, respectively); however, MI and ST were not (1.3% vs 0%; p = 0.55, 0.2% vs 0%, p = 0.76, respectively) (Supplemental Table 3).
3.4.2. Clinical outcomes The median follow-up was 1763 (IQR; 929–2488) days. Regarding cardiac mortality, there was no significant difference between the SCTO and U-CTO groups (cumulative rate at 5-year follow-up: 2.2% vs 0.0%; p = 0.53) (Fig. 2C). In secondary endpoints, there was a similar occurrence of all-cause mortality (7.9 vs 6.7; p = 0.79) and MI (0.5% vs 0.0%; p = 0.81) between the 2 groups. TLR and TVR were significantly lower with S-CTO PCI (26.4% vs 37.4%, p = 0.03, 29.6% vs 41.6%, p b 0.01, respectively) (Supplemental Table 3).
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were older (66.1 ± 9.8 vs 71.1 ± 10.3; p = 0.02), were more likely to have peripheral artery disease (13.9% vs 38.1%; p b 0.01), and a prior history of PCI (54.9% vs 81.0%; p = 0.02). U-CTO lesions were longer (18.9 ± 8.7 mm vs 24.5 ± 10.0 mm, p b 0.01) with less grade 3 collaterals (64.4% vs 28.6%, p b 0.01); however, lesion complexities were similar between the 2 groups. DES implantation was performed frequently in S-CTO (82.3% vs 19.0%; p b 0.01).
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and have renal failure requiring hemodialysis (19.2% vs 5.9%, p b 0.01). U-CTOs were smaller in vessel diameter (2.8 ± 0.3 mm vs 3.0 ± 0.4 mm, p b 0.01), longer in lesion length (42.4 ± 29.0 mm vs 27.2 ± 17.2 mm, p b 0.01), and were less likely to have grade 3 collaterals (44.2% vs 75.3%, p b 0.01). U-CTOs were more likely to be a reattempted procedure (9.6% vs 3.5%, p = 0.05); however, there were no differences in other lesion complexities between the two groups. Regarding procedural characteristics, some significant differences including the rate of plain old balloon angioplasty (POBA) or DES implantation were present between the 2 groups, largely because of U-CTO PCI including incomplete PCI cases.
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Fig. 2. Kaplan-Meier curve of cumulative cardiac mortality after successful and unsuccessful CTO PCI in each target CTO vessel (2A: LAD, 2B: RCA, 2C: LCx).
Cox regression adjusted HR (95% CI)
p value
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b0.01 b0.01
0.17 (0.05–0.54)
b0.01
7.09 (2.35–21.37) 0.93 (0.90–0.96)
b0.01 b0.01
0.24 (0.09–0.65)
b0.01
CKD = chronic kidney disease, HR = hazard ratio. Other abbreviations as Table 1.
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Our study contains several limitations. First, our study was retrospective, which has numerous caveats when interpreting results. Second, the decision to perform CTO PCI was dependent on the operator, so an element of selection bias cannot be excluded. Third, the procedural strategy was left to operator's discretion, which may have affected our results, although the success rate of CTO PCI was over 90% which indicates that the operators were generally highly skilled in performing CTO PCI. Fourth, data regarding myocardial viability and ischemic territory evaluated with scintigraphy were not included and solely relying on angiographic findings may not be sufficient to evaluate dominancy. Finally, silent events including asymptomatic reocclusion cannot be completely excluded; however, this number is likely to be small given the high rate of angiographic follow-up (N 85%).
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Successful LAD and RCA CTO PCI were associated with a lower long-term cardiac mortality after CTO PCI. This finding was not observed with LCx CTO PCI. Our findings might guide operators to carefully consider the indication for CTO PCI. Further prospective investigations with standardized methods are required to confirm our results. Supplementary data to this article can be found online at http://dx. doi.org/10.1016/j.ijcard.2017.07.098.
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The main findings of this study are: 1) Long-term cardiac mortality was significantly lower after successful LAD or RCA CTO PCI; but no such association was observed after LCx CTO PCI; 2) Successful LAD and RCA CTO PCI, hemodialysis and LVEF were identified as independent predictors of cardiac mortality after CTO PCI. In multiple previous observational studies, it has been reported that S-CTO PCI is associated with a relief of anginal symptoms, the avoidance of subsequent CABG and a decrease in long-term mortality [10,11]. As a result, in major guidelines, CTO PCI is indicated with a class IIa recommendation when an improvement of sufficient ischemic territory and relief of anginal symptoms are expected after recanalization [12,13]. While in the previous studies reporting an improvement in long-term mortality after S-CTO PCI, N 70% of S-CTO were LAD or RCA [10,11,14], prognostic differences may exist depending on target CTO vessel treated. There are some reports in the literature of the differential impact of target CTO vessel on mortality after successful CTO PCI. Safely et al. reported that only S-CTO LAD PCI was associated with an improvement in 5-year mortality and not S-CTO PCI of LCx and RCA [15]. However, this study had the following limitations which may have affected the results: 1) In the overall population of the study, the mean LVEF was b40%; 2) only 18% patients received stent implantation (DES in only 3 cases) and 3) 20% had residual dissection. Additionally, data regarding follow-up angiography and repeat revascularization were not reported; therefore, successful recanalization at the initial procedure may not have guaranteed long-term patency. Furthermore, there was no differentiation between the treatment of SB CTOs or main branch (MB) CTOs (each percentage was not available). In another study, Bimmer E et al. reported an improvement of longterm mortality after S-CTO PCI in LAD and LCx and not of the RCA. Importantly, a higher rate of stent implantation (N 90%) with DES (N60%) was used [16]. However, sufficient data regarding medical therapy, anatomical information such as dominancy and long-term patency were not included. To the best of our knowledge, our study has the following strengths not present in prior reports: 1) Only CTOs supplying an angiographically large territory were included; 2) There was a higher rate of follow-up angiography (N85%); 3) Data regarding medication therapy was reported. We included generally MB CTOs since the impact of an occluded SB on cardiac mortality is theoretically smaller. However, in the RCA, both distal branches cannot be viewed as SB because they supply the inferior wall. With the LCx, the feeding territory of each occluded SB should be considered because there are some anatomical variations. In our study, N 75% of CTO lesions were located at the proximal/middle LCx MB and distal CTOs were treated only if the LCx was dominant; therefore, all of them can be presumed to feed a large territory of posterolateral wall. During the follow-up period, N85% overall population underwent follow-up angiography and 75% of S-CTO cases did not experience TLR. Reocclusion was detected in 9% of total S-CTO and all of them were recanalized again, which could guarantee a higher rate of long-term patency of S-CTO. There are no randomized trials comparing clinical outcomes after treatment of CTOs between PCI alone and PCI with optimal medication therapy; however, the importance of optimal medication therapy for ischemic heart disease is well known [17–20]. In our study, the introduction of medication therapy was well balanced between S-CTO and U-CTO in each subgroup except in the RCA group. In the RCA group, this could partly be explained by the higher prevalence of CKD
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and hemodialysis in the U-CTO group when compared with the S-CTO group, which could therefore limit the use of certain drugs including ACEi and ARB in the U-CTO group. In our study, there was no improvement in long-term cardiac mortality after S-CTO LCx PCI (in other words, even after U-CTO LCx PCI, cardiac mortality remained low when compared with LAD and RCA; 0.0%, 22.6% and 32.2%, respectively). The results seem to conflict with previous reports; however, Takagi et al. reported that severe proximal LCx restenosis after LMT stenting was not independently related to long-term mortality even if feeding a large territory [21]. Furthermore, it might be suggested that the prognosis of ischemia in the LCx territory is dependent on whether it is acute or chronic. For example, a poor prognosis was reported in case with acute occlusion of LCx after LMT stenting, whereas, even large feeding territory, a proximal LCx CTO was reported with asymptomatic and stable clinical status [22]. Therefore, LCx ischemia might not affect to long-term mortality, if it is chronic. A theoretical reason for the results could be that the territory supplied by the LCx may be compensated by either the LAD and/or RCA, functionally or structurally, which could result in a prevention of LV remodeling or LVEF reduction. Further investigations with serial quantitative evaluations such as echocardiography or cardiac magnetic resonance imaging are needed to investigate our findings and hypothesis. On the other hand, RCA S-CTO PCI was related to significantly lower cardiac mortality in our study. It was speculated that the higher prevalence of diabetes and hemodialysis in U-CTO group may partially have influenced higher mortality in the group; however, S-CTO PCI was independently predictive of cardiac mortality after multivariable analysis. Furthermore, approximately 70% of RCA CTO were located in proximal-mid RCA; therefore, the ischemic territory could be assumed to be a sufficiently large one.
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The authors have no conflicts of interest to disclose. Acknowledgements None.
Please cite this article as: S. Mitomo, et al., Impact of target vessel on long-term cardiac mortality after successful chronic total occlusion percutaneous coronary intervention..., Int J Cardiol (2017), http://dx.doi.org/10.1016/j.ijcard.2017.07.098
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Article history: Received 2 April 2017 Received in revised form 6 July 2017 Accepted 24 July 2017 Available online xxxx
Department of Cardiology, New Tokyo Hospital, Chiba, Japan Department of Cardiology, Imperial College London, United Kingdom c Division of Cardiology, Fukuyama Cardiovascular Hospital, Hiroshima, Japan d Department of Internal Medicine II, University of Yamanashi, Faculty of Medicine, Yamanashi, Japan e Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan f Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center, Osaka, Japan
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Satoru Mitomo a, Toru Naganuma a, Richard J. Jabbour b, Katsumasa Sato c, Hideo Takebayashi c, Tsuyoshi Kobayashi d, Jun-ei Obata d, Kenji Sakamoto e, Kenichi Tsujita e, Kiyotaka Kugiyama d, Hisao Ogawa f, Sunao Nakamura a,⁎
a b s t r a c t
Background: The impact of successful chronic total occlusion (S-CTO) percutaneous coronary intervention (PCI) on cardiac mortality may differ depending on target CTO vessel; however, to date this has not yet been adequately evaluated. The aim of this study was to investigate the impact of target vessel on cardiac mortality after S-CTO PCI. Methods: From January 2004 to December 2011, 1517 CTO PCIs were performed in 4 Japanese centers and enrolled in a multicenter registry. Cases were retrospectively analyzed and divided per target vessel treated. The primary endpoint was cardiac mortality during the follow-up period. Results: During the study period, 1424 CTOs with 1 main vessel CTO per patient were analyzed (left anterior descending artery [LAD]: 487, right coronary artery [RCA]: 599, left circumflex [LCx]: 338). 92.3% (n = 1314) of cases were S-CTO PCIs. The median follow-up period was 1677 (interquartile range; 811–2463) days. In LAD and RCA CTOs, S-CTO PCI was associated with a lower cardiac mortality rate at 5-year follow-up when compared with unsuccessful CTO (U-CTO) (2.6% vs 9.7%, p = 0.01, 2.6% vs 27.3%, p b 0.01, respectively). This finding was not present with LCx CTO PCI (2.2% vs 0.0%, p = 0.53). Cox regression analysis demonstrated that LAD and RCA S-CTO PCI were independent predictors of a lower cardiac mortality rate (LAD; HR: 0.18, 95% CI: 0.06–0.56; p b 0.01; RCA; HR: 0.24, 95% CI: 0.09–0.65; p b 0.01). Conclusions: S-CTO LAD and RCA PCI were associated with a lower long-term cardiac mortality after CTO PCI. This finding was not observed with LCx CTO PCI. © 2017 Published by Elsevier Ireland Ltd.
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associated with a relief in anginal symptoms and an improvement in ejection fraction (EF) and mortality [1,2]. Although CTO PCI remains challenging, the success rate of CTO PCI has increased with innovations in devices, including dedicated wires and microcatheters, as well as the development of techniques including the retrograde approach [3,4]. Furthermore, the development of new generation drug-eluting stents (DES) have further improved outcomes [5,6]. Although CTO PCI is becoming widely performed across the globe, most prior studies have reported overall clinical outcomes. Therefore, whether there are potential differences in outcomes depending on CTO target vessel treated remains unclear. The aim of this study was to evaluate the impact of target CTO vessel on cardiac mortality from a Japanese multicenter registry.
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Impact of target vessel on long-term cardiac mortality after successful chronic total occlusion percutaneous coronary intervention: Insights from a Japanese multicenter registry
Keywords: Percutaneous coronary intervention Chronic total occlusion Target vessel Cardiac mortality
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Chronic total occlusion (CTO) percutaneous coronary intervention (PCI) has been shown in numerous observational studies to be
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Abbreviations: ACEi, angiotensin convert enzyme inhibitor; ARB, angiotensin receptor blocker; BMS, bare metal stent; CABG, coronary artery bypass grafting; CTO, chronic total occlusion; DAPT, dual antiplatelet therapy; DES, drug-eluting stent; LAD, left anterior descending artery; LCx, left circumflex artery; LVEF, left ventricular ejection fraction; MB, main branch; MI, myocardial infarction; PCI, percutaneous coronary intervention; POBA, plain old balloon angioplasty; RCA, right coronary artery; SB, side branch; ST, stent thrombosis; TIMI, Thrombolysis In Myocardial Infarction; TLR, target lesion revascularization. ⁎ Corresponding author at: Department of Cardiology, New Tokyo Hospital, 1271 Wanagaya, Matsudo, Chiba 270-2232, Japan. E-mail address: [email protected] (S. Nakamura).
http://dx.doi.org/10.1016/j.ijcard.2017.07.098 0167-5273/© 2017 Published by Elsevier Ireland Ltd.
Please cite this article as: S. Mitomo, et al., Impact of target vessel on long-term cardiac mortality after successful chronic total occlusion percutaneous coronary intervention..., Int J Cardiol (2017), http://dx.doi.org/10.1016/j.ijcard.2017.07.098
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CTO PCI was performed by well-experienced operators in each center. The selection of devices including wires, micro-catheters and stent type was left to the operator's discretion. The PCI strategy including approach (antegrade or retrograde), lesion preparation, post-dilatation, and using intravascular imaging was also dependent on the operator's decision. Patients were administered dual antiplatelet therapy (DAPT) which consisted of aspirin (100 mg/day) and either ticlopidine (200 mg/day) or clopidogrel (75 mg/day) with an aim to continue for at least 12 months after stent implantation.
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CTO was defined as complete obstruction of the vessel with Thrombolysis In Myocardial Infarction (TIMI) flow of 0 with an estimated duration of the occlusion N3 months [7,8]. Lesion complexity was assessed for the presence of calcification detected on fluoroscopy, proximal tortuosity, vessel angulation N45°, and the morphology of the entry point. Procedural success was defined as a final diameter stenosis b30% with TIMI 3 flow. Complete revascularization was defined as revascularization for all vessels which had a significant stenosis evaluated by angiography and/or positive stress test results.
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The primary endpoint was cardiac mortality during the follow-up period. Cardiac mortality was defined as death presumed to be due to cardiovascular disease or without clinical or postmortem evidence of other causes. Secondary endpoints were follow-up all-cause mortality, myocardial infarction (MI), target lesion vascularization (TLR), target vessel revascularization (TVR), and definite/probable stent thrombosis (ST). MI was defined as an elevation of creatinine kinase-MB fraction or troponin-T/troponin-I greater than the upper limit of normal with concomitant anginal symptoms or ischemic findings on electrocardiography [9]. TLR was defined as repeat revascularization for lesions within the CTO previously treated or in the adjacent 5 mm. TVR was defined as repeat PCI in the target vessel. ST was defined according to Academic Research Consortium definition [9]. Demographic, lesion, and procedural data were collected from medical records and angiograms reviewed in each of institutes by experienced clinicians. Clinical follow-up was performed on all subjects by either clinical visit or telephone interview. Follow-up angiography was performed either by physician's request or the presence of symptoms warranting repeat angiography/suspected myocardial ischemia.
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To evaluate the impact of successful CTO (S-CTO) PCI on outcomes, cases were divided into two groups per CTO PCI success, and the overall cohort and subgroup per CTO vessel. Categorical variables were presented as frequencies and were analyzed using the chisquared or Fisher exact tests as appropriate. Continuous variables were presented as mean ± standard deviation (SD) or median with interquartile range (IQR) and compared using the Student-t or Wilcoxon rank-sum where applicable. The cumulative incident rates during the follow-up period were estimated using Kaplan-Meier method and were compared using the Log-rank test. To identify predictors of cardiac mortality after CTO PCI, multivariable analysis using Cox regression method was performed in each subgroup of target CTO vessel. Covariates that were clinically significant or statistically relevant after univariate analysis were included in the final model. A p value b0.05 was considered as statistically significant. Statistical analyses were performed using SPSS version 22.0 (IBM Inc., Chicago, IL).
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3.1.1. Baseline, lesion, and procedural characteristics (Supplemental Table 1) We performed 1517 CTO PCIs during the study period; of which, 93 cases were excluded per the predefined criteria, leaving 1424 included cases that were retrospectively analyzed (Supplemental Fig. 1). Right
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3.1.2. Clinical outcomes (successful vs unsuccessful) and predictors of cardiac mortality The median follow-up was 1677 (IQR; 811–2463) days. The cumulative cardiac mortality rate at 5-year follow-up was significantly lower in the S-CTO PCI group when compared with unsuccessful CTO (U-CTO) PCI (2.5% vs 15.9%, p b 0.001) (Fig. 1). Of them, there were 3 cases which occurred within 7 days post procedure. After U-CTO LAD PCI, a 72-year-old male with low EF (20%) presented with ventricular tachycardia (day 0) and a 87 year-old male with low EF (20%) developed acute heart failure (day 2). Another case was a 76 year-old male with EF 45% who presented with sudden death 3 days after S-CTO PCI for RCA, which was classified as probable ST. Regarding secondary endpoints, cumulative incidence rates of all-cause mortality, TLR, and TVR were significantly lower in the S-CTO PCI group (8.2% vs 21.2%; p b 0.001, 25.0% vs 42.1%; p b 0.01, 32.1% vs 45.7%; p = 0.03, respectively) (Supplemental Fig. 2), but there were no differences in both MI (S-CTO: 1.0% vs U-CTO: 1.1%; p = 0.75) and ST (S-CTO: 0.6% vs U-CTO: 1.3%; p = 0.43) between the two groups. In total population, S-CTO PCI (HR: 0.28, 95% CI: 0.13–0.58; p = 0.001), chronic kidney disease (CKD) (HR: 2.29, 95% CI: 1.08–4.88: p = 0.03), hemodialysis (HR: 4.80, 95% CI: 2.23–10.35: p b 0.001), and LVEF (HR: 0.96, 95% CI: 0.94–0.98: p b 0.001) were independent predictors of cardiac mortality after CTO PCI (Supplemental Table 2).
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From January 2004 to December 2011, we retrospectively analyzed all CTO PCI cases from 4 Japanese centers (New Tokyo Hospital; Chiba, Fukuyama cardiovascular hospital; Hiroshima, Yamanashi university; Yamanashi, Kumamoto university; Kumamoto). Cases were excluded if: 1) there was no clinical follow-up; and 2) they involved a CTO of the left main trunk, N2 vessels, or bypass grafts. All main vessel CTOs were included and there were no hypoplastic LCx or RCA CTO cases. Regarding side branch (SB) CTOs, posterior-descending branches were included and defined according to anatomical dominancy. SB CTO cases including diagonal, posterolateral, and obtuse marginal were excluded if a small vessel (b2.25 mm) and/or supplying a small territory, which were evaluated angiographically by well-experienced CTO operators in each institution.
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70 71 72 73 74 75 76 77 78 79
coronary artery (RCA) CTOs were the most common (599 cases; 42.1%), followed by left anterior descending artery (LAD) (487cases; 34.2%), and left circumflex (LCx) (338cases; 23.7%) CTOs. Regarding baseline characteristics, LAD CTO patients were less likely to have had previous PCI (41.5%), coronary artery bypass grafting (CABG) (4.7%), or cardiac surgery (3.3%) compared with the other 2 CTO lesions (p b 0.01, respectively). In the overall cohort, there was a high rate of complete revascularization (N80%), and patients were generally on optimal medical therapy for ischemic heart disease. There were differences in target vessel CTO lesion characteristics including the presence of bifurcations, tortuosity and vessel angulation (p b 0.01). This was reflected in the CTO procedural characteristics, since there were differences in stent diameter, total stent number and length used between target vessel CTO treated. Of note, a high rate of DES implantation (approximately 80%), procedural success (N 90%), and angiographic follow-up (N 85%) was obtained in every CTO vessel treated.
R O
2.1. Study population
P
69
D
2. Methods
U
N
C
O
R
R
E
C
T
68
E
2
Fig. 1. Kaplan-Meier curve of cumulative cardiac mortality after successful and unsuccessful CTO PCI in overall population.
Please cite this article as: S. Mitomo, et al., Impact of target vessel on long-term cardiac mortality after successful chronic total occlusion percutaneous coronary intervention..., Int J Cardiol (2017), http://dx.doi.org/10.1016/j.ijcard.2017.07.098
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184 185
3.2.1. Baseline, lesion and procedural characteristics (Table 1) In the LAD CTO subgroup, 450 (92.4%) out of 487 cases were S-CTO. Baseline characteristics were well balanced between S-CTO and U-CTO PCI. U-CTO patients had slightly lower EFs (51.9 ± 13.4 vs 56.1 ± 12.2; P = 0.06) and a higher proportion were taking angiotensin receptor blocker (ARB)/angiotensin convert enzyme inhibitor (ACEi) (73.5% vs 55.8%; p = 0.03). Regarding lesion characteristics, U-CTOs were longer in lesion length (28.0 ± 18.8 mm vs 21.1 ± 11.2 mm; p = 0.04), involved less bifurcations (40.5% vs 57.8%; p = 0.03) and had less grade 3 collaterals (29.7% vs 68.7%p b 0.01). Regarding procedural characteristics, there were some significant differences including total implanted stent length because U-CTO included incomplete PCI cases or failure cases without any stent implantation.
t1:1 t1:2 Q1
Table 1 Baseline, lesion and procedural characteristics in each target CTO vessel. LAD (N = 487)
t1:55 t1:56 t1:57
Patient characteristics Age, years Male gender, n (%) Hypertension, n (%) Dyslipidemia, n (%) Diabetes, n (%) Insulin dependent diabetes, n (%) Chronic kidney disease (60 N eGFR), n (%) Hemodialysis, n (%) Peripheral artery disease, n (%) Previous PCI, n (%) Previous CABG, n (%) Previous cardiac surgery, n (%) Previous stroke, n (%) LVEF, % Medication β blocker, n (%) ACEi/ARB, n (%) Ca channel blocker, n (%) Nitrogen/nicorandil, n (%) Statin, n (%)
RCA (N = 599) Unsuccessful (N = 37)
p value*
Successful (N = 547)
67.4 ± 10.4 360 (80.0) 382 (85.3) 328 (73.1) 220 (49.4) 25 (5.6) 152 (34.9) 29 (6.5) 47 (10.4) 181 (40.2) 21 (4.7) 15 (3.3) 38 (8.8) 56.1 ± 12.2
68.7 ± 10.4 28 (75.7) 31 (86.1) 29 (80.6) 17 (47.2) 2 (5.6) 15 (41.7) 2 (5.6) 7 (18.9) 21 (56.8) 2 (5.4) 1 (2.7) 4 (11.1) 51.9 ± 13.4
0.48 0.33 0.56 0.22 0.47 0.67 0.26 0.59 0.10 0.04 0.54 0.65 0.41 0.06
66.0 ± 10.6 455 (83.2) 448 (82.5) 400 (73.5) 240 (44.3) 39 (7.2) 200 (37.5) 32 (5.9) 81 (14.8) 268 (49.0) 65 (11.9) 53 (9.7) 37 (7.2) 55.9 ± 11.7
Unsuccessful (N = 52)
LCx (N = 338)
p value**
Successful (N = 317)
Unsuccessful (N = 21)
p value***
64.5 ± 9.8 42 (80.8) 42 (80.8) 34 (65.4) 31 (59.6) 9 (17.3) 16 (32.0) 10 (19.2) 18 (34.6) 40 (76.9) 7 (13.5) 5 (9.6) 6 (14.3) 53.8 ± 14.3
0.33 0.39 0.44 0.14 0.02 0.02 0.27 b0.01 b0.01 b0.01 0.44 0.61 0.10 0.32
66.1 ± 9.8 269 (84.9) 263 (83.2) 226 (71.7) 144 (45.6) 17 (5.4) 124 (39.9) 22 (7.0) 44 (13.9) 174 (54.9) 35 (11.0) 32 (10.1) 30 (9.8) 53.8 ± 13.1
71.1 ± 10.3 17 (81.0) 17 (81.0) 14 (66.7) 11 (51.2) 2 (9.5) 11 (55.0) 1 (4.8) 8 (38.1) 17 (81.0) 1 (4.8) 1 (4.8) 1 (4.8) 52.3 ± 15.4
0.02 0.41 0.49 0.39 0.35 0.34 0.14 0.57 b0.01 0.02 0.32 0.37 0.44 0.62
0.18 0.03 0.42 0.46 0.58
238 (47.4) 302 (60.2) 217 (43.2) 93 (18.5) 328 (65.3)
16 (33.3) 22 (45.8) 20 (41.7) 9 (18.8) 24 (51.1)
0.04 0.04 0.48 0.55 0.04
136 (44.7) 171 (56.1) 147 (48.2) 65 (21.3) 193 (63.3)
8 (40.0) 14 (70.0) 8 (40.0) 5 (25.0) 11 (55.0)
0.43 0.16 0.32 0.44 0.30
3.0 ± 1.7 21.1 ± 11.2
2.7 ± 0.4 28.0 ± 18.8
0.30 0.04
3.0 ± 0.4 27.2 ± 17.2
2.8 ± 0.3 42.4 ± 29.0
b0.01 b0.01
2.7 ± 1.4 18.9 ± 8.7
2.5 ± 0.3 24.5 ± 10.0
0.54 b0.01
138 (30.7) 28 (6.2) 59 (13.1) 260 (57.8) 248 (55.1) 9 (2.0) 309 (68.7) 235 (52.2)
6 (16.2) 1 (2.7) 4 (10.8) 15 (40.5) 19 (52.8) 1 (2.7) 11 (29.7) 16 (43.2)
0.17 0.33 0.46 0.03 0.76 0.55 b0.01 0.19
116 (21.1) 139 (25.4) 152 (27.8) 182 (33.3) 292 (53.8) 19 (3.5) 412 (75.3) 317 (58.0)
16 (30.8) 16 (30.8) 16 (30.8) 17 (32.7) 30 (57.7) 5 (9.6) 23 (44.2) 26 (50.0)
0.27 0.25 0.38 0.53 0.35 0.05 b0.01 0.17
69 (21.8) 79 (24.9) 86 (27.1) 146 (46.1) 167 (52.8) 7 (2.2) 204 (64.4) 186 (58.7)
4 (19.0) 6 (28.6) 4 (19.0) 9 (45.0) 11 (52.4) 0 (0.0) 6 (28.6) 12 (57.1)
0.51 0.44 0.30 0.56 0.65 0.64 b0.01 0.53
444 (98.7) 6 (1.3)
37 (100.0) 0 (0.0)
0.62 0.82
524 (95.8) 23 (4.2)
51 (98.1) 1 (1.9)
0.37 0.20
313 (98.7) 4 (1.3)
21 (100.0) 0 (0.0)
0.77 0.60
23 (5.1) 42 (9.4) 385 (85.5) 1.4 ± 0.6 2.9 ± 1.1 35.1 ± 16.5 46.3. ± 20.2 214 (47.7) 197.8 ± 79.7 385 (85.6)
8 (21.6) 3 (8.1) 15 (40.5) 1.3 ± 0.7 2.6 ± 0.4 27.0 ± 18.9 34.4 ± 22.5 15 (40.5) 162.4 ± 88.6 28 (75.7)
0.001 0.55 b0.001 0.35 0.44 0.03 0.02 0.26 0.02 0.09
21 (3.9) 52 (9.5) 474 (86.6) 1.6 ± 0.7 3.0 ± 0.4 43.0 ± 22.1 56.2 ± 27.0 225 (41.1) 202.0 ± 79.1 486 (89.0)
18 (34.6) 5 (9.6) 20 (38.5) 1.5 ± 1.1 2.9 ± 0.4 40.8 ± 30.1 50.8 ± 38.6 9 (17.6) 137.4 ± 75.0 42 (80.8)
b0.01 0.57 b0.01 0.65 0.19 0.72 0.50 b0.01 b0.01 0.07
27 (8.5) 29 (9.1) 261 (82.3) 1.3 ± 0.5 2.6 ± 0.3 28.9 ± 12.6 32.8 ± 15.3 142 (44.8) 182.3 ± 78.8 286 (90.2)
7 (33.3) 2 (9.5) 4 (19.0) 1.5 ± 0.5 2.5 ± 0.2 28.0 ± 15.0 34.0 ± 12.4 9 (42.9) 203.1 ± 106.5 14 (66.7)
b0.01 0.60 b0.01 0.33 0.45 0.86 0.85 0.52 0.39 b0.01
R
19 (55.9) 25 (73.5) 12 (35.3) 6 (17.6) 21 (61.8)
R
Procedural characteristics Antegrade approach, n (%) Retrograde approach, n (%) Methods of revascularization POBA, n (%) BMS implantation, n (%) DES implantation, n (%) Number of implanted stents for CTO lesion, n (%) Mean stent diameter, mm Total stent length for CTO lesion, mm Total stent length for CTO vessel, mm Intravascular imaging guidance, n (%) Total amount of contrast medium, ml Follow-up angiography, n (%)
195 196
Successful (N = 450)
194 (46.1) 235 (55.8) 163 (38.7) 85 (20.2) 260 (61.8)
N C O
Lesion characteristics Reference vessel diameter, mm CTO lesion length, mm Lesion complexity Calcification, n (%) Tortuosity, n (%) Angulation (N45°), n (%) Bifurcation, n (%) Blunt type entry point, n (%) Reattempt, n (%) Collaterals Rentrop grade = 3, n (%) Multi vessel disease, n (%)
U
t1:6 t1:7 t1:8 t1:9 t1:10 t1:11 t1:12 t1:13 t1:14 t1:15 t1:16 t1:17 t1:18 t1:19 t1:20 t1:21 t1:22 t1:23 t1:24 t1:25 t1:26 t1:27 t1:28 t1:29 t1:30 t1:31 t1:32 t1:33 t1:34 t1:35 t1:36 t1:37 t1:38 t1:39 t1:40 t1:41 t1:42 t1:43 t1:44 t1:45 t1:46 t1:47 t1:48 t1:49 t1:50 t1:51 t1:52 t1:53 t1:54
3.3.1. Baseline, lesion and procedural characteristics (Table 1) In the RCA CTO subset, there were 547 (91.3%) S-CTO cases and 52 (8.7%) U-CTO cases. U-CTO patients were more likely to be diabetic (59.6% vs 44.3%, p = 0.02; insulin dependent 17.3% vs 7.2%, p = 0.02),
R O
Target CTO vessel
t1:4 t1:5
194
P
t1:3
3.3. RCA CTO subgroup; successful vs unsuccessful
D
182 183
186 187
E
180 181
T
178 179
C
177
E
175 176
3.2.2. Clinical outcomes The median follow-up was 1677 (IQR; 759–2510) days. S-CTO was associated with significantly less cardiac mortality when compared with U-CTO (cumulative rate at 5-year follow-up: 2.6% vs 9.7%; p = 0.01) (Fig. 2A). There were no statistical differences in secondary endpoint at 5-year follow-up between the two groups except for lower rates of TLR and TVR in the S-CTO PCI group (21.4% vs 42.5%, p b 0.01, 34.5% vs 45.3%, p = 0.04, respectively) (Supplemental Table 3).
F
3.2. LAD CTO subgroup; successful vs unsuccessful
O
172
3
Values are n (%) or mean ± SD. ACEi = angiotensin convert enzyme inhibitor, ARB = angiotensin receptor blocker, BMS = bare metal stent, CTO = chronic total occlusion, CABG = coronary artery bypass graft, DES = drug-eluting stent, GFR = glomerular filtration ratio, LAD = left anterior descending artery, LCx = left circumflex, LVEF = left ventricular ejection fraction, POBA = plane old balloon angioplasty. p value: successful vs unsuccessful in LAD (*), RCA (**), LCx (***), respectively.
Please cite this article as: S. Mitomo, et al., Impact of target vessel on long-term cardiac mortality after successful chronic total occlusion percutaneous coronary intervention..., Int J Cardiol (2017), http://dx.doi.org/10.1016/j.ijcard.2017.07.098
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F
4
207 208 209 210
218
3.4. LCx CTO subgroup; successful vs unsuccessful
219
222
3.4.1. Baseline, lesion and procedural characteristics (Table 1) In LCX CTO subset, there were 317 (93.8%) S-CTO cases and 21 (6.2%) U-CTO cases. Baseline characteristics were generally well balanced between the S-CTO and U-CTO groups. However, patients with U-CTO
t2:1 t2:2
Table 2 Multivariate analysis of cardiac mortality after successful CTO PCI in LAD and RCA.
t2:23
E
C
t2:3
3.4.3. Predictors of cardiac mortality: each target CTO vessel (Table 2) The results of multivariable analysis using Cox-regression method are demonstrated in Table 2. In the LAD CTO subgroup, SCTO PCI (HR: 0.18, 95% CI: 0.06–0.56; p b 0.01), hemodialysis (HR: 6.41, 95% CI: 1.92–21.35: p b 0.01), and LVEF (HR: 0.95, 95% CI: 0.91–0.99: p b 0.01) were independent predictors of cardiac mortality after CTO PCI. In the RCA CTO subgroup, S-CTO PCI was also an independent predictor of cardiac mortality after CTO PCI (HR: 0.24, 95% CI: 0.09–0.65; p b 0.01).
239 240
p value
LAD (number of events: 17 cases) Age Diabetes Insulin dependent diabetes CKD Hemodialysis LVEF before PCI Multi-vessel disease Successful LAD CTO PCI
1.03 (0.97–1.09) 2.33 (0.89–6.73) 4.71 (1.33–16.73) 3.20 (1.16–8.01) 9.32 (3.17–27.46) 0.94 (0.91–0.97) 1.08 (0.42–2.80) 0.18 (0.06–0.56)
0.26 0.12 0.02 0.24 b0.01 b0.01 0.88 b0.01
RCA (number of events: 27 cases) Age Diabetes Insulin dependent diabetes CKD Hemodialysis LVEF before PCI Multi-vessel disease Successful RCA CTO PCI
1.02 (0.98–1.06) 4.43 (1.65–11.94) 3.47 (1.29–9.34) 7.90 (2.64–23.68) 16.97 (6.85–41.99) 0.92 (0.89–0.95) 2.10 (0.84–5.28) 0.12 (0.05–0.27)
0.34 b0.01 0.01 b0.01 b0.01 b0.01 0.11 b0.01
N
Univariate HR (95% CI)
U
t2:4 t2:5 t2:6 t2:7 t2:8 t2:9 t2:10 t2:11 t2:12 t2:13 t2:14 t2:15 t2:16 t2:17 t2:18 t2:19 t2:20 t2:21 t2:22
R
220 221
R
215 216
O
213 214
C
211 212
230
T
217
3.3.2. Clinical outcomes The median follow-up was 1606 (IQR; 799–2543) days. S-CTO was associated with a reduction in cardiac mortality when compared with U-CTO (cumulative rate at 5-year follow-up: 2.6% vs 27.3%; p b 0.01) (Fig. 2B). Regarding secondary endpoints, all-cause mortality, TLR, and TVR were significantly lower with S-CTO PCI (9.2% vs 33.3%; p b 0.01, 27.9% vs 45.0%, p b 0.01, 33.0% vs 48.2%, p = 0.03, respectively); however, MI and ST were not (1.3% vs 0%; p = 0.55, 0.2% vs 0%, p = 0.76, respectively) (Supplemental Table 3).
3.4.2. Clinical outcomes The median follow-up was 1763 (IQR; 929–2488) days. Regarding cardiac mortality, there was no significant difference between the SCTO and U-CTO groups (cumulative rate at 5-year follow-up: 2.2% vs 0.0%; p = 0.53) (Fig. 2C). In secondary endpoints, there was a similar occurrence of all-cause mortality (7.9 vs 6.7; p = 0.79) and MI (0.5% vs 0.0%; p = 0.81) between the 2 groups. TLR and TVR were significantly lower with S-CTO PCI (26.4% vs 37.4%, p = 0.03, 29.6% vs 41.6%, p b 0.01, respectively) (Supplemental Table 3).
R O
205 206
223 224
P
203 204
were older (66.1 ± 9.8 vs 71.1 ± 10.3; p = 0.02), were more likely to have peripheral artery disease (13.9% vs 38.1%; p b 0.01), and a prior history of PCI (54.9% vs 81.0%; p = 0.02). U-CTO lesions were longer (18.9 ± 8.7 mm vs 24.5 ± 10.0 mm, p b 0.01) with less grade 3 collaterals (64.4% vs 28.6%, p b 0.01); however, lesion complexities were similar between the 2 groups. DES implantation was performed frequently in S-CTO (82.3% vs 19.0%; p b 0.01).
D
201 202
and have renal failure requiring hemodialysis (19.2% vs 5.9%, p b 0.01). U-CTOs were smaller in vessel diameter (2.8 ± 0.3 mm vs 3.0 ± 0.4 mm, p b 0.01), longer in lesion length (42.4 ± 29.0 mm vs 27.2 ± 17.2 mm, p b 0.01), and were less likely to have grade 3 collaterals (44.2% vs 75.3%, p b 0.01). U-CTOs were more likely to be a reattempted procedure (9.6% vs 3.5%, p = 0.05); however, there were no differences in other lesion complexities between the two groups. Regarding procedural characteristics, some significant differences including the rate of plain old balloon angioplasty (POBA) or DES implantation were present between the 2 groups, largely because of U-CTO PCI including incomplete PCI cases.
E
199 200
O
Fig. 2. Kaplan-Meier curve of cumulative cardiac mortality after successful and unsuccessful CTO PCI in each target CTO vessel (2A: LAD, 2B: RCA, 2C: LCx).
Cox regression adjusted HR (95% CI)
p value
6.41(1.92–21.35) 0.95 (0.91–0.99)
b0.01 b0.01
0.17 (0.05–0.54)
b0.01
7.09 (2.35–21.37) 0.93 (0.90–0.96)
b0.01 b0.01
0.24 (0.09–0.65)
b0.01
CKD = chronic kidney disease, HR = hazard ratio. Other abbreviations as Table 1.
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Our study contains several limitations. First, our study was retrospective, which has numerous caveats when interpreting results. Second, the decision to perform CTO PCI was dependent on the operator, so an element of selection bias cannot be excluded. Third, the procedural strategy was left to operator's discretion, which may have affected our results, although the success rate of CTO PCI was over 90% which indicates that the operators were generally highly skilled in performing CTO PCI. Fourth, data regarding myocardial viability and ischemic territory evaluated with scintigraphy were not included and solely relying on angiographic findings may not be sufficient to evaluate dominancy. Finally, silent events including asymptomatic reocclusion cannot be completely excluded; however, this number is likely to be small given the high rate of angiographic follow-up (N 85%).
345
6. Conclusions
358
Successful LAD and RCA CTO PCI were associated with a lower long-term cardiac mortality after CTO PCI. This finding was not observed with LCx CTO PCI. Our findings might guide operators to carefully consider the indication for CTO PCI. Further prospective investigations with standardized methods are required to confirm our results. Supplementary data to this article can be found online at http://dx. doi.org/10.1016/j.ijcard.2017.07.098.
359 360
Conflicts of interest
367
F
5. Limitations
O
264 265
R O
262 263
C
260 261
E
258 259
R
256 257
R
254 255
N C O
253
U
251 252
P
The main findings of this study are: 1) Long-term cardiac mortality was significantly lower after successful LAD or RCA CTO PCI; but no such association was observed after LCx CTO PCI; 2) Successful LAD and RCA CTO PCI, hemodialysis and LVEF were identified as independent predictors of cardiac mortality after CTO PCI. In multiple previous observational studies, it has been reported that S-CTO PCI is associated with a relief of anginal symptoms, the avoidance of subsequent CABG and a decrease in long-term mortality [10,11]. As a result, in major guidelines, CTO PCI is indicated with a class IIa recommendation when an improvement of sufficient ischemic territory and relief of anginal symptoms are expected after recanalization [12,13]. While in the previous studies reporting an improvement in long-term mortality after S-CTO PCI, N 70% of S-CTO were LAD or RCA [10,11,14], prognostic differences may exist depending on target CTO vessel treated. There are some reports in the literature of the differential impact of target CTO vessel on mortality after successful CTO PCI. Safely et al. reported that only S-CTO LAD PCI was associated with an improvement in 5-year mortality and not S-CTO PCI of LCx and RCA [15]. However, this study had the following limitations which may have affected the results: 1) In the overall population of the study, the mean LVEF was b40%; 2) only 18% patients received stent implantation (DES in only 3 cases) and 3) 20% had residual dissection. Additionally, data regarding follow-up angiography and repeat revascularization were not reported; therefore, successful recanalization at the initial procedure may not have guaranteed long-term patency. Furthermore, there was no differentiation between the treatment of SB CTOs or main branch (MB) CTOs (each percentage was not available). In another study, Bimmer E et al. reported an improvement of longterm mortality after S-CTO PCI in LAD and LCx and not of the RCA. Importantly, a higher rate of stent implantation (N 90%) with DES (N60%) was used [16]. However, sufficient data regarding medical therapy, anatomical information such as dominancy and long-term patency were not included. To the best of our knowledge, our study has the following strengths not present in prior reports: 1) Only CTOs supplying an angiographically large territory were included; 2) There was a higher rate of follow-up angiography (N85%); 3) Data regarding medication therapy was reported. We included generally MB CTOs since the impact of an occluded SB on cardiac mortality is theoretically smaller. However, in the RCA, both distal branches cannot be viewed as SB because they supply the inferior wall. With the LCx, the feeding territory of each occluded SB should be considered because there are some anatomical variations. In our study, N 75% of CTO lesions were located at the proximal/middle LCx MB and distal CTOs were treated only if the LCx was dominant; therefore, all of them can be presumed to feed a large territory of posterolateral wall. During the follow-up period, N85% overall population underwent follow-up angiography and 75% of S-CTO cases did not experience TLR. Reocclusion was detected in 9% of total S-CTO and all of them were recanalized again, which could guarantee a higher rate of long-term patency of S-CTO. There are no randomized trials comparing clinical outcomes after treatment of CTOs between PCI alone and PCI with optimal medication therapy; however, the importance of optimal medication therapy for ischemic heart disease is well known [17–20]. In our study, the introduction of medication therapy was well balanced between S-CTO and U-CTO in each subgroup except in the RCA group. In the RCA group, this could partly be explained by the higher prevalence of CKD
313 314
D
249 250
and hemodialysis in the U-CTO group when compared with the S-CTO group, which could therefore limit the use of certain drugs including ACEi and ARB in the U-CTO group. In our study, there was no improvement in long-term cardiac mortality after S-CTO LCx PCI (in other words, even after U-CTO LCx PCI, cardiac mortality remained low when compared with LAD and RCA; 0.0%, 22.6% and 32.2%, respectively). The results seem to conflict with previous reports; however, Takagi et al. reported that severe proximal LCx restenosis after LMT stenting was not independently related to long-term mortality even if feeding a large territory [21]. Furthermore, it might be suggested that the prognosis of ischemia in the LCx territory is dependent on whether it is acute or chronic. For example, a poor prognosis was reported in case with acute occlusion of LCx after LMT stenting, whereas, even large feeding territory, a proximal LCx CTO was reported with asymptomatic and stable clinical status [22]. Therefore, LCx ischemia might not affect to long-term mortality, if it is chronic. A theoretical reason for the results could be that the territory supplied by the LCx may be compensated by either the LAD and/or RCA, functionally or structurally, which could result in a prevention of LV remodeling or LVEF reduction. Further investigations with serial quantitative evaluations such as echocardiography or cardiac magnetic resonance imaging are needed to investigate our findings and hypothesis. On the other hand, RCA S-CTO PCI was related to significantly lower cardiac mortality in our study. It was speculated that the higher prevalence of diabetes and hemodialysis in U-CTO group may partially have influenced higher mortality in the group; however, S-CTO PCI was independently predictive of cardiac mortality after multivariable analysis. Furthermore, approximately 70% of RCA CTO were located in proximal-mid RCA; therefore, the ischemic territory could be assumed to be a sufficiently large one.
E
4. Discussion
T
248
5
The authors have no conflicts of interest to disclose. Acknowledgements None.
Please cite this article as: S. Mitomo, et al., Impact of target vessel on long-term cardiac mortality after successful chronic total occlusion percutaneous coronary intervention..., Int J Cardiol (2017), http://dx.doi.org/10.1016/j.ijcard.2017.07.098
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[15]
[16]
[17]
[18]
[19]
[20]
[21]
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[14]
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Please cite this article as: S. Mitomo, et al., Impact of target vessel on long-term cardiac mortality after successful chronic total occlusion percutaneous coronary intervention..., Int J Cardiol (2017), http://dx.doi.org/10.1016/j.ijcard.2017.07.098
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