Cardiovasc Interv and Ther DOI 10.1007/s12928-014-0297-x
ORIGINAL ARTICLE
Long-term clinical outcomes after sirolimus-eluting stent implantation for unprotected left main coronary artery disease Hirooki Higami • Hiroki Shiomi • Shunichiro Niki • Junichi Tazaki • Masao Imai • Naritatsu Saito • Takeru Makiyama • Satoshi Shizuta • Tetsuo Shioi • Koh Ono • Takeshi Kimura
Received: 19 February 2014 / Accepted: 22 August 2014 Ó Japanese Association of Cardiovascular Intervention and Therapeutics 2014
Abstract Previous studies reporting long-term (C5 year) clinical outcome in patients with unprotected left main coronary artery (LMCA) disease undergoing drug-eluting stent (DES) implantation are currently limited, although late adverse events beyond 1 year are one of the major concerns of DES. We evaluated long-term clinical outcomes in 134 consecutive patients who underwent sirolimus-eluting stents (SES) for unprotected LMCA lesion in a single center from 2004 to 2009. The median follow-up duration was 3.8 (range: 0.5–7.9) years. Eight patients suffered from serious cardiovascular events potentially related to LMCA lesion (primary outcome measure) (sudden cardiac death: N = 5, emergent coronary revascularization for the LMCA lesion: N = 2, and acute congestive heart failure related to LMCA lesion: N = 1) with the cumulative 5-year incidence of only 4.4 %. The cumulative 5-year incidence of all-cause death, cardiac death, target vessel myocardial infarction, definite stent thrombosis, and target-lesion revascularization was 26.5, 8.1, 0, 0, and 12.9 %, respectively. In a subgroup analysis, the cumulative incidence of the primary outcome measure was significantly higher in patients with 2-stenting (N = 27) than in patients with 1-stenting (N = 107) (14.0 and 2.2 %,
Electronic supplementary material The online version of this article (doi:10.1007/s12928-014-0297-x) contains supplementary material, which is available to authorized users. H. Higami H. Shiomi (&) J. Tazaki M. Imai N. Saito T. Makiyama S. Shizuta T. Shioi K. Ono T. Kimura Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan e-mail: [email protected] S. Niki Department of Cardiovascular Medicine, National Hospital Organization Kyoto Medical center, Kyoto, Japan
P \ 0.001). All 8 patients with serious adverse events had a true bifurcation lesion and 5 patients received 2-stenting for the LMCA lesion. SES implantation in patients with unprotected LMCA lesion was associated with a favorable longterm outcome with acceptably low rate of serious adverse event potentially related to LMCA lesion. However, complex LMCA lesions necessitating 2-stenting strategy might be associated with higher risk for serious adverse events. Keywords Left main coronary artery disease Coronary stent Percutaneous coronary intervention Coronary bifurcation Prognosis
Introduction Percutaneous coronary intervention (PCI) for unprotected left main coronary artery (LMCA) disease has become more popular in daily clinical practice after introduction of drug-eluting stents (DES). The favorable mid-term outcomes of PCI for unprotected LMCA disease from several clinical trials and registries led to change clinical guidelines, and PCI for unprotected LMCA disease is regarded as Class II a recommendation in patients with less anatomical complexity or high surgical risk [1–12]. On the other hand, late adverse events such as late restenosis and very late stent thrombosis (VLST) that occurred more than [1] year after DES implantation were reported to be one of the major concerns after implantation of the first-generation DES [4, 13]. Late restenosis and VLST of LMCA could be a very serious adverse event due to the large amount of myocardium subtended by LMCA. However, previous studies reporting long-term (C5 year) clinical outcome in patients with unprotected LMCA disease treated by PCI using DES are currently limited, especially in
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Japan [14–20]. To address this issue, we investigated longterm outcomes of the consecutive patients with unprotected LMCA disease treated by PCI using sirolimus-eluting stents (SES) in a single center.
study included all-cause death, cardiac death, SCD, targetvessel MI, definite or probable ST of the LMCA lesion, target-lesion revascularization (TLR) of the LMCA lesion, and any coronary revascularization.
Methods Table 1 Baseline clinical, lesion, and procedural characteristics
Study design and patient population
Patient characteristics Age (years)
The current study population consisted of 134 consecutive patients who underwent PCI with SES for de novo unprotected LMCA disease at Kyoto University Hospital between September 2004 and December 2009. During the study period, SES implantation was adopted as the default strategy for PCI in patients with ULMCA disease. PCI was performed in patients who were considered to have an unacceptably high risk for coronary artery bypass grafting (CABG) or who preferred PCI rather than CABG. All procedures and medical therapies including the duration of dual antiplatelet therapy (DAPT) were left to the discretion of each attending physician. The detailed of the study design and patients’ enrollment in this study have been described previously [21]. Written informed consent on the procedure and follow-up protocol was obtained from all patients before the procedure was performed.
Age C80 years
N = 134 71.5 ± 9.5 26 (19 %)
Male gender
102 (76 %)
Body mass index C25
39 (29 %)
Ejection fraction (%)
58.3 ± 14.1
Ejection fraction \30 % Heart failure
4 (3.0 %) 17 (13 %)
Prior myocardial infarction
26 (19 %)
Prior PCI
43 (32 %)
Angina symptom
98 (73 %)
Acute coronary syndrome
24 (18 %)
Diabetes mellitus
64 (46 %)
History of hypertension
92 (69 %)
Dyslipidemia
88 (66 %)
Current smoker
43 (32 %)
Chronic kidney disease (eGFR \30 mL/min/1.73 m2)
16 (12 %)
Dialysis
12 (9 %)
Angiographic characteristics
Definitions and clinical endpoints The LMCA disease was regarded as unprotected if there was no patent bypass graft to the left anterior descending coronary artery or left circumflex coronary artery. Demographic, angiographic, and procedural data were collected from hospital charts according to the pre-specified definitions. Angiographic data included lesion location of LMCA (ostial/shaft or distal bifurcation), extent of coronary artery disease [isolated LMCA, LMCA ? 1-vessel disease (1VD), LMCA ? 2-vessel disease (2VD), or LMCA ? 3-vessel disease (3VD)], the synergy between percutaneous coronary intervention with taxus and cardiac surgery (SYNTAX) score, and stenting strategy (1-stenting or 2-stenting). The SYNTAX score was calculated using the SYNTAX score calculator (available at http://www.syntaxscore.com). Regarding stenting strategy, 2-stenting strategy was defined as stenting of both the main and side branches and 1-stenting strategy as stenting from LMCA to the main branch alone. The primary outcome measure for the current analysis was serious cardiovascular event potentially related to LMCA lesion, including sudden cardiac death (SCD), target-vessel myocardial infarction (MI), stent thrombosis (ST) of the LMCA lesion, emergent coronary revascularization of LMCA, or acute congestive heart failure related to LMCA lesion. Other clinical endpoints assessed in this
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Distal LMCA bifurcation involvement
120 (90 %)
Left dominance
39 (29 %)
Extent of coronary artery disease Isolated LMCA
14 (11 %)
LMCA ?1 vessel disease
31 (23 %)
LMCA ?2 vessel disease
62 (46 %)
LMCA ? 3 vessel disease
27 (20 %)
Chronic total occlusion
17 (12 %)
SYNTAX score
32.8 ± 9.4
Medina bifurcation classification of LMCA (1.1.1)
63 (47 %)
(1.1.0)
49 (37 %)
(1.0.1)
8 (6 %)
(1.0.0)
14 (11 %)
Procedural characteristics Number of stents implanted for LMCA
1.62 ± 0.8
Total stent length for LMCA (mm)
36.1 ± 20.2
Stent diameter for LMCA(mm)
3.44 ± 0.2
Final kissing balloon technique
98 (73 %)
Elective 2-stenting
21 (16 %)
Final 2-stenting
27 (20 %)
Follow-up coronary angiography
104 (78 %)
Data were presented as number (%) or mean ± SD unless otherwise noted PCI percutaneous coronary artery intervention, eGFR estimated glomerular filtration rate, LMCA left main coronary artery, and SYNTAX synergy between percutaneous coronary intervention with taxus and cardiac surgery
Long-term outcomes after PCI using SES for ULMCAD
During follow-up, death was regarded as cardiac in origin unless obvious non-cardiac causes could be identified. MI was defined according to the definition in the Arterial Revascularization Therapy Study [22]. ST was defined according to the Academic Research Consortium (ARC) definition. Stroke was defined as a symptomatic cerebrovascular event confirmed by imaging studies. TLR was defined as either PCI or CABG due to restenosis or thrombosis of LMCA that included the proximal and distal edge segments as well as the ostium of the side branches. Any coronary revascularization was defined as either PCI or CABG for any reasons. Follow-up information was obtained by hospital-chart review and/or telephone contact with the patient, relatives, or referring practitioners. The median follow-up duration of the surviving patients was 3.76 [interquartile range (IQR): 3.0–5.3 and range: 0.5–7.9) years.
were presented as numbers and percentages, and were compared with the Chi square or Fisher’s exact test, as appropriate. Cumulative incidences of clinical events were estimated by the Kaplan–Meier method and differences were assessed using the log-rank test. For the subgroup analyses, we evaluated the differences of clinical outcomes according to lesion location of LMCA (bifurcation versus non-bifurcation), extent of coronary artery disease (isolated LMCA or LMCA ? 1VD versus LMCA ? 2VD/3VD), SYNTAX score (]33 versus \33), and stenting strategy (1-stenting versus 2-stenting). All statistical tests were two-tailed. P values\0.05 were considered statistically significant. Statistical analyses were performed with the JMP 7 software (SAS Institute Inc., Cary, NC, USA).
Statistical analysis
Results
Continuous variables were expressed as the mean and standard deviation (SD) or median and IQR/range, and were compared with Student’s t test or Wilcoxon rank-sum test on the basis of their distributions. Categorical variables
Baseline characteristics The study population reflected the real-world clinical practice, including large proportions of patients with
Table 2 Patients with serious cardiovascular event potentially related to LMCA lesion No.
Age
Sex
Event
Survival outcome
Interval (days)
Stenting strategy
SYNTAX score
No. of diseased vessel
Restenosis of LMCA
1
79
M
SCD
Death
51
Bifurcation /1-stenting
42
LMCA ? 1VD
No
2
82
F
SCD
Death
251
Bifurcation
39
LMCA ? 2VD
/2-stenting 3
68
F
SCD
Death
427
4
75
M
SCD
Death
786
Bifurcation
Comment
Yes 1 TLR (PCI)
39
LMCA ? 3VD
No
21
LMCA ? 2VD
No
21
LMCA ? 1VD
HD
/2-stenting Bifurcation /2-stenting 5
68
M
NSTEMI
Alive
1024
Bifurcation /1-stenting
Yes 3 TLR
Emergency CABG
(2 PCI, and 1 CABG) 6
68
M
ACS/ CHF
Death
2419
Bifurcation /2 stenting
41
LMCA ? 2VD
7
57
M
ACS
Alive
2548
Bifurcation
32
LMCA ? 2VD
/1-stenting
Yes 2 TLR (PCI)
Brainstem hemorrhage
Yes
Emergency CABG/HD
2 TLR (1 PCI, and 1 CABG)
8
55
M
SCD
Death
2496
Bifurcation /2 stenting
37
LMCA ? 2VD
Yes
HD
3 TLR (PCI)
Serious cardiovascular event potentially related to LMCA lesion included SCD, target-vessel MI, ST of the LMCA lesion, emergent coronary revascularization of LMCA, or acute congestive heart failure related to LMCA lesion SYNTAX synergy between percutaneous coronary intervention with taxus and cardiac surgery, LMCA left main coronary artery, SCD sudden cardiac death, VD vessel disease, TLR target-lesion revascularization, PCI percutaneous coronary intervention, HD hemodialysis, CABG coronary artery bypass grafting, NSTEMI non-ST-segment elevation myocardial infarction, ACS acute coronary syndrome, CHF congestive heart failure, MI myocardial infarction, and ST stent thrombosis
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advanced age, diabetes mellitus, and renal insufficiency (Table 1). Regarding the lesion characteristics, the vast majority of patients (90 %) had a distal bifurcation LMCA lesion. Almost two-thirds of the patients had multi-vessel coronary artery disease in addition to LMCA disease. The mean SYNTAX score in this study population was very high (32.8 ± 9.4) (Table 1). Regarding the procedural characteristics, 107 (80 %) patients were treated with 1-stenting strategy, whereas 27 (20 %) patients were treated with final 2-stenting strategy. Elective 2-stent strategy had been adopted in 21 patients (Table 1). Modified T-stenting was the most frequently used 2-stenting technique in the current study [18 patients (13.4 %)]. Long-term clinical outcomes During the entire follow-up period, 8 patients suffered from serious cardiovascular events potentially related to LMCA lesion (primary outcome measure) (SCD: N = 5, emergent coronary revascularization for acute coronary syndrome related to LMCA lesion: N = 2, and acute congestive heart failure related to LMCA lesion: N = 1) (Table 2). Six of these 8 events occurred beyond 1-year after the index PCI. However, cumulative 5-year incidence of the primary outcome measure was low (4.4 %) (Fig. 1a). Of note, there was only one target-vessel MI event (1.1 %), and no ST of the LMCA lesion during follow-up. The cumulative 5-year incidence of all-cause death, cardiac death, and SCD was 26.5, 8.1, and 3.4 %, respectively (Fig. 1b). The cumulative 5-year incidence of TLR for the LMCA lesion was 12.9 % (Fig. 1c). Regarding the characteristics of 8 patients with serious LMCA-related adverse events, most patients had severe comorbidities and complex lesion and procedural characteristics, such as hemodialysis (N = 3), bifurcation LMCA lesion (N = 8), and PCI with 2-stenting strategy (N = 5). The SYNTAX scores in these patients were very high (Table 2). Among the 5 patients with SCD, 2 patients had prior TLR for restenosis of LMCA, while the other 3 patients had no history of TLR. Both patients with emergent coronary revascularization underwent CABG with the diagnosis of acute coronary syndrome due to recurrent restenosis of LMCA after first TLR by PCI (Fig. 2a). Another patient with serious adverse event potentially related to LMCA lesion suffered from acute congestive heart failure with restenosis of LMCA lesion as one of the etiologies of heart failure (Fig. 2b). Subgroup analyses: lesion location, extent of coronary artery disease, SYNTAX score, and stenting strategy As the subgroup analyses, the cumulative incidences of the primary outcome measure and TLR were compared
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Fig. 1 Kaplan–Meier curves for the cardiovascular events. a Serious cardiovascular event potentially related to LMCA lesion (Primary outcome measure; SCD, target-vessel MI, ST of the LMCA lesion, emergent coronary revascularization of LMCA, or acute congestive heart failure related to LMCA lesion), b all-cause death, cardiac death, and sudden cardiac death, and c TLR and any coronary revascularization. LMCA left main coronary artery, SCD sudden cardiac death, MI myocardial infarction, ST stent thrombosis, and TLR target-lesion revascularization
Long-term outcomes after PCI using SES for ULMCAD
Fig. 2 Representative cases with serious cardiovascular event potentially related to LMCA lesion. a NSTEMI due to restenosis of LMCA. A 68 years old male with diabetes, hypertension and dyslipidemia underwent PCI for unprotected LMCA using SES with 1-stenting KBT strategy for the true bifurcation lesion (i pre-PCI, and ii post-PCI). The patient received repeated PCI twice for restenosis at stent distal edge of LAD. The patient suffered from NSTEMI due to restenosis of LMCA at 1024 days after the index PCI and underwent emergency CABG (iii). b Acute congestive heart failure due to restenosis of LMCA. A 68 years old male with diabetes and on maintenance hemodialysis underwent PCI using SES for the true bifurcation LMCA lesion with 2-stenting strategy (T-stenting) (i prePCI, and ii post-PCI).The patient had undergone TLR for restenosis of LMCA lesion at 562 days after the index PCI. He developed acute
congestive heart failure in the course of minor cerebellar infarction at 2419 days after index PCI. Urgent coronary angiography revealed recurrent restenosis of LMCA lesion (iii). The patient underwent second TLR by PCI with repeated SES implantation. However, the proximal LAD lesion could not be adequately dilated even with highpressure inflation using non-compliant balloon (iv), resulting in suboptimal angiographic result (v). Brain stem hemorrhage occurred 12 h after the final PCI (vi). CABG coronary artery bypass grafting, KBT kissing balloon technique, LAD left anterior descending coronary artery, LMCA left main coronary artery, NSTEMI non-STsegment elevation myocardial infarction, PCI percutaneous coronary intervention, SES sirolimus-eluting stent, and TLR target-lesion revascularization
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according to the location of LMCA lesion, extent of coronary artery disease, SYNTAX score, and stenting strategy. There was no serious adverse event potentially related to LMCA lesion in patients with non-bifurcation lesion, although the cumulative 5-year incidence of primary outcome measure event was not significantly different between the patients with bifurcation lesion and those
with non-bifurcation lesion (4.9 versus 0 %, P = 0.26) (Fig. 2a). The cumulative 5-year incidence of TLR tended to be higher in patients with bifurcation lesion than in those with non-bifurcation lesion (14.6 versus 0 %, P = 0.12). The cumulative 5-year incidence of serious adverse event potentially related to LMCA lesion was not significantly different between the patients with isolated LMCA/
Fig. 3 Subgroup analyses for the serious cardiovascular event potentially related to LMCA lesion (primary outcome measure). a Bifurcation versus non-bifurcation, b LMCA ? 2VD/3VD versus Isolated LMCA or LMCA ? 1VD, c SYNTAX score ]33 versus SYNTAX score \33, and d LMCA 2-stenting versus LMCA 1-stenting LMCA left main coronary artery, and VD vessel disease
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Long-term outcomes after PCI using SES for ULMCAD
LMCA ? 1VD and the patients with LMCA ? 2VD/ LMCA ? 3VD (5.6 versus 3.9 %, P = 0.71) (Fig. 2b). The cumulative 5-year incidence of TLR was also similar between the 2 groups (13.5 versus 12.4 %, P = 0.75). The cumulative 5-year incidence of serious adverse event potentially related to LMCA lesion as well as that of TLR was not significantly different between the patients with high SYNTAX score (]33) and those with low SYNTAX score (\33) (5.0 versus 4.0 %, P = 0.22, and 8.6 versus 18.0 %, P = 0.32, respectively) (Fig. 3c). Regarding the stenting strategy for the LMCA lesion, the 2-stenting strategy for bifurcation as compared with 1-stenting strategy was associated with significantly higher cumulative 5-year incidence of serious adverse event potentially related to LMCA lesion (14.0 versus 2.2 %, P \ 0.001) (Fig. 3d). The 2-stenting strategy as compared with 1-stenting strategy was also associated with significantly higher cumulative 5-year incidence of TLR (22.3 versus 10.8 %, P = 0.03).
Discussion The main findings of this study were as follows; (1) SES implantation in patients with unprotected LMCA lesion was associated with a favorable long-term outcome with acceptably low rates of TLR and serious adverse event potentially related to LMCA lesion; (2) however, bifurcation 2-stenting strategy for the LMCA lesion as compared with 1-stenting strategy was associated with higher rates of TLR and serious adverse event potentially related to LMCA lesion. In this single center study, the long-term risk for serious adverse events potentially related to LMCA lesion was acceptably low (4.4 % at 5 year). We included SCD as a component of the composite primary outcome measure representing the LMCA-related event. The cumulative incidence of SCD (3.4 % at 5 years) in this study could not be ignorable, although the absolute incidence of SCD in this study was comparable with that in the previous study [15].However, it was not certain whether these fatal events were causally related to the stented LMCA lesion, although 2 out of these 5 patients with SCD had a history of TLR for restenosis of the LMCA lesion. Notably, there was no definite/probable ST of the LMCA lesion in this consecutive series of patients with very complex clinical and angiographic characteristics. Although the cumulative long-term incidence of ST in the LMCA lesion has not been evaluated by the adequately sized meta-analysis, the cumulative incidences of ST in several previous reports were consistently very low [14–20]. Despite apparent long-term safety of LMCA stenting using DES, we should note that 6 out of 8 serious LMCA-
related events occurred beyond 1 year after SES implantation. In the bare-metal stent (BMS) era, relatively high rate of restenosis within the first year had hindered widespread application of PCI in patients with unprotected LMCA disease [2, 7, 23, 24]. The introduction of DES with its potent anti-restenosis efficacy obviously expanded the indication of PCI in patients with unprotected LMCA disease. However, recent several reports suggested that late restenosis leading to TLR beyond 1 year after SES implantation occurred constantly at a rate of 2 %/year without attenuation up to 5 year after SES implantation, which was rarely seen after BMS implantation [13, 25, 26]. Late restenosis as compared with early restenosis was reported to be more often associated with acute coronary syndrome presentation [26]. Acute coronary syndrome related to restenosis of the LMCA lesion is not a benign event, and therefore, current and future development of DES should focus more on late restenosis. Selection of appropriate candidates for PCI is an important issue in the treatment of patients with unprotected LMCA disease. In consistent with the previous reports, 2-stenting strategy for bifurcation was associated with higher risk for serious adverse event potentially related to LMCA lesion as compared with 1-stenting strategy. [4, 11–13]. Unless the operative risk is prohibitively high, CABG might still be a standard choice in patients with unprotected LMCA disease with severe anatomical complexity necessitating 2-stenting strategy [14]. On the other hands, PCI seems to be a reasonable choice in patients with unprotected LMCA disease treatable by single stenting strategy, those with non-bifurcation lesion in particular. In the current study, extent of coronary artery disease in territories other than the LMCA lesion was not associated with increased risk for serious adverse event potentially related to LMCA lesion. However, in the SYNTAX trial, long-term clinical outcome of PCI as compared with CABG was significantly worse in LMCA patients with SYNTAX score C32 [27]. Therefore, CABG would still be a standard choice in LMCA patients associated with extensive coronary artery disease.
Study limitations There are several limitations to the present study. First, and most importantly, this single center observational study did not have a control group treated with PCI using BMS or CABG. However, the vast majority of patients treated with PCI in this study received DES as a default strategy in our hospital, and therefore, the safety of DES use in patients with unprotected LMCA disease could be evaluated in the ‘real-world clinical practice’. Second, the relatively small
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number of patients enrolled in this study made it difficult to draw any definitive conclusions on the long-term outcomes of DES including the relationship of stenting strategy with clinical outcomes in patients with unprotected LMCA disease. Third, the cumulative incidence of SCD could not be ignorable, although the overall risk for adverse cardiovascular events was relatively low and it was not certain whether these SCDs were causally related to the stented LMCA lesion. Forth, the treatment strategy for bifurcation lesions was not based on randomized assignment in this observational study. Fifth, TLR events in the present study included both clinically and angiographically driven events. The clinical significance of angiographically driven TLR of the LMCA lesion remains unclear. Finally, DES used in the current study is no longer used in the current clinical practice. Investigation of long-term outcome of LMCA stenting using the second-generation DES, which is expected to reduce the risk of late adverse events such as VLST and late TLR, should be warranted to provide further guidance in the selection of coronary revascularization modalities in patients with unprotected LMCA disease.
Conclusions Sirolimus-eluting stent implantation in patients with unprotected LMCA lesion was associated with a favorable long-term outcome with acceptably low rate of serious adverse event potentially related to LMCA lesion. However, complex LMCA lesions necessitating 2-stenting strategy might be associated with higher risk for serious adverse events. Acknowledgments The authors thank paramedical assistants of catheterization laboratory in Kyoto University Hospital.
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revascularization therapies study). Semin Interv Cardiol. 1999;4:209–19. Takagi T, Stankovic G, Finci L, Toutouzas K, Chieffo A, Spanos V, et al. Results and long-term predictors of adverse clinical events after elective percutaneous interventions on unprotected left main coronary artery. Circulation. 2002;106:698–702. Park S-J, Park S, Hong M-K i, Lee CW, Lee J-H, Kim J–J. Longterm (three-year) outcomes after stenting of unprotected left main coronary artery stenosis in patients with normal left ventricular function. Am J Cardiol. 2003;91:12–6. Yamaji K, Kimura T, Morimoto T, Nakagawa Y, Inoue K, Soga Y, et al. Very long-term (15 to 20 years) clinical and angiographic outcome after coronary bare metal stent implantation. Circ. Cardiovasc. Interv. 2010;3:468–75. Natsuaki M, Morimoto T, Furukawa Y, Nakagawa Y, Kimura T, et al. Late adverse events after implantation of sirolimus-eluting stent and bare-metal stent: long-term(5-7 years) follow-up of the CREDO-Kyoto Registry Cohort-2. Circ. Cardiovasc Interv. 2014; in-press. Serruys PW, Morice M-C, Kappetein AP, Colombo A, Holmes DR, Mack MJ, et al. Percutaneous coronary intervention versus coronary-artery bypass grafting for severe coronary artery disease. N Engl J Med. 2009;360:961–72.
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ORIGINAL ARTICLE
Long-term clinical outcomes after sirolimus-eluting stent implantation for unprotected left main coronary artery disease Hirooki Higami • Hiroki Shiomi • Shunichiro Niki • Junichi Tazaki • Masao Imai • Naritatsu Saito • Takeru Makiyama • Satoshi Shizuta • Tetsuo Shioi • Koh Ono • Takeshi Kimura
Received: 19 February 2014 / Accepted: 22 August 2014 Ó Japanese Association of Cardiovascular Intervention and Therapeutics 2014
Abstract Previous studies reporting long-term (C5 year) clinical outcome in patients with unprotected left main coronary artery (LMCA) disease undergoing drug-eluting stent (DES) implantation are currently limited, although late adverse events beyond 1 year are one of the major concerns of DES. We evaluated long-term clinical outcomes in 134 consecutive patients who underwent sirolimus-eluting stents (SES) for unprotected LMCA lesion in a single center from 2004 to 2009. The median follow-up duration was 3.8 (range: 0.5–7.9) years. Eight patients suffered from serious cardiovascular events potentially related to LMCA lesion (primary outcome measure) (sudden cardiac death: N = 5, emergent coronary revascularization for the LMCA lesion: N = 2, and acute congestive heart failure related to LMCA lesion: N = 1) with the cumulative 5-year incidence of only 4.4 %. The cumulative 5-year incidence of all-cause death, cardiac death, target vessel myocardial infarction, definite stent thrombosis, and target-lesion revascularization was 26.5, 8.1, 0, 0, and 12.9 %, respectively. In a subgroup analysis, the cumulative incidence of the primary outcome measure was significantly higher in patients with 2-stenting (N = 27) than in patients with 1-stenting (N = 107) (14.0 and 2.2 %,
Electronic supplementary material The online version of this article (doi:10.1007/s12928-014-0297-x) contains supplementary material, which is available to authorized users. H. Higami H. Shiomi (&) J. Tazaki M. Imai N. Saito T. Makiyama S. Shizuta T. Shioi K. Ono T. Kimura Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan e-mail: [email protected] S. Niki Department of Cardiovascular Medicine, National Hospital Organization Kyoto Medical center, Kyoto, Japan
P \ 0.001). All 8 patients with serious adverse events had a true bifurcation lesion and 5 patients received 2-stenting for the LMCA lesion. SES implantation in patients with unprotected LMCA lesion was associated with a favorable longterm outcome with acceptably low rate of serious adverse event potentially related to LMCA lesion. However, complex LMCA lesions necessitating 2-stenting strategy might be associated with higher risk for serious adverse events. Keywords Left main coronary artery disease Coronary stent Percutaneous coronary intervention Coronary bifurcation Prognosis
Introduction Percutaneous coronary intervention (PCI) for unprotected left main coronary artery (LMCA) disease has become more popular in daily clinical practice after introduction of drug-eluting stents (DES). The favorable mid-term outcomes of PCI for unprotected LMCA disease from several clinical trials and registries led to change clinical guidelines, and PCI for unprotected LMCA disease is regarded as Class II a recommendation in patients with less anatomical complexity or high surgical risk [1–12]. On the other hand, late adverse events such as late restenosis and very late stent thrombosis (VLST) that occurred more than [1] year after DES implantation were reported to be one of the major concerns after implantation of the first-generation DES [4, 13]. Late restenosis and VLST of LMCA could be a very serious adverse event due to the large amount of myocardium subtended by LMCA. However, previous studies reporting long-term (C5 year) clinical outcome in patients with unprotected LMCA disease treated by PCI using DES are currently limited, especially in
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Japan [14–20]. To address this issue, we investigated longterm outcomes of the consecutive patients with unprotected LMCA disease treated by PCI using sirolimus-eluting stents (SES) in a single center.
study included all-cause death, cardiac death, SCD, targetvessel MI, definite or probable ST of the LMCA lesion, target-lesion revascularization (TLR) of the LMCA lesion, and any coronary revascularization.
Methods Table 1 Baseline clinical, lesion, and procedural characteristics
Study design and patient population
Patient characteristics Age (years)
The current study population consisted of 134 consecutive patients who underwent PCI with SES for de novo unprotected LMCA disease at Kyoto University Hospital between September 2004 and December 2009. During the study period, SES implantation was adopted as the default strategy for PCI in patients with ULMCA disease. PCI was performed in patients who were considered to have an unacceptably high risk for coronary artery bypass grafting (CABG) or who preferred PCI rather than CABG. All procedures and medical therapies including the duration of dual antiplatelet therapy (DAPT) were left to the discretion of each attending physician. The detailed of the study design and patients’ enrollment in this study have been described previously [21]. Written informed consent on the procedure and follow-up protocol was obtained from all patients before the procedure was performed.
Age C80 years
N = 134 71.5 ± 9.5 26 (19 %)
Male gender
102 (76 %)
Body mass index C25
39 (29 %)
Ejection fraction (%)
58.3 ± 14.1
Ejection fraction \30 % Heart failure
4 (3.0 %) 17 (13 %)
Prior myocardial infarction
26 (19 %)
Prior PCI
43 (32 %)
Angina symptom
98 (73 %)
Acute coronary syndrome
24 (18 %)
Diabetes mellitus
64 (46 %)
History of hypertension
92 (69 %)
Dyslipidemia
88 (66 %)
Current smoker
43 (32 %)
Chronic kidney disease (eGFR \30 mL/min/1.73 m2)
16 (12 %)
Dialysis
12 (9 %)
Angiographic characteristics
Definitions and clinical endpoints The LMCA disease was regarded as unprotected if there was no patent bypass graft to the left anterior descending coronary artery or left circumflex coronary artery. Demographic, angiographic, and procedural data were collected from hospital charts according to the pre-specified definitions. Angiographic data included lesion location of LMCA (ostial/shaft or distal bifurcation), extent of coronary artery disease [isolated LMCA, LMCA ? 1-vessel disease (1VD), LMCA ? 2-vessel disease (2VD), or LMCA ? 3-vessel disease (3VD)], the synergy between percutaneous coronary intervention with taxus and cardiac surgery (SYNTAX) score, and stenting strategy (1-stenting or 2-stenting). The SYNTAX score was calculated using the SYNTAX score calculator (available at http://www.syntaxscore.com). Regarding stenting strategy, 2-stenting strategy was defined as stenting of both the main and side branches and 1-stenting strategy as stenting from LMCA to the main branch alone. The primary outcome measure for the current analysis was serious cardiovascular event potentially related to LMCA lesion, including sudden cardiac death (SCD), target-vessel myocardial infarction (MI), stent thrombosis (ST) of the LMCA lesion, emergent coronary revascularization of LMCA, or acute congestive heart failure related to LMCA lesion. Other clinical endpoints assessed in this
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Distal LMCA bifurcation involvement
120 (90 %)
Left dominance
39 (29 %)
Extent of coronary artery disease Isolated LMCA
14 (11 %)
LMCA ?1 vessel disease
31 (23 %)
LMCA ?2 vessel disease
62 (46 %)
LMCA ? 3 vessel disease
27 (20 %)
Chronic total occlusion
17 (12 %)
SYNTAX score
32.8 ± 9.4
Medina bifurcation classification of LMCA (1.1.1)
63 (47 %)
(1.1.0)
49 (37 %)
(1.0.1)
8 (6 %)
(1.0.0)
14 (11 %)
Procedural characteristics Number of stents implanted for LMCA
1.62 ± 0.8
Total stent length for LMCA (mm)
36.1 ± 20.2
Stent diameter for LMCA(mm)
3.44 ± 0.2
Final kissing balloon technique
98 (73 %)
Elective 2-stenting
21 (16 %)
Final 2-stenting
27 (20 %)
Follow-up coronary angiography
104 (78 %)
Data were presented as number (%) or mean ± SD unless otherwise noted PCI percutaneous coronary artery intervention, eGFR estimated glomerular filtration rate, LMCA left main coronary artery, and SYNTAX synergy between percutaneous coronary intervention with taxus and cardiac surgery
Long-term outcomes after PCI using SES for ULMCAD
During follow-up, death was regarded as cardiac in origin unless obvious non-cardiac causes could be identified. MI was defined according to the definition in the Arterial Revascularization Therapy Study [22]. ST was defined according to the Academic Research Consortium (ARC) definition. Stroke was defined as a symptomatic cerebrovascular event confirmed by imaging studies. TLR was defined as either PCI or CABG due to restenosis or thrombosis of LMCA that included the proximal and distal edge segments as well as the ostium of the side branches. Any coronary revascularization was defined as either PCI or CABG for any reasons. Follow-up information was obtained by hospital-chart review and/or telephone contact with the patient, relatives, or referring practitioners. The median follow-up duration of the surviving patients was 3.76 [interquartile range (IQR): 3.0–5.3 and range: 0.5–7.9) years.
were presented as numbers and percentages, and were compared with the Chi square or Fisher’s exact test, as appropriate. Cumulative incidences of clinical events were estimated by the Kaplan–Meier method and differences were assessed using the log-rank test. For the subgroup analyses, we evaluated the differences of clinical outcomes according to lesion location of LMCA (bifurcation versus non-bifurcation), extent of coronary artery disease (isolated LMCA or LMCA ? 1VD versus LMCA ? 2VD/3VD), SYNTAX score (]33 versus \33), and stenting strategy (1-stenting versus 2-stenting). All statistical tests were two-tailed. P values\0.05 were considered statistically significant. Statistical analyses were performed with the JMP 7 software (SAS Institute Inc., Cary, NC, USA).
Statistical analysis
Results
Continuous variables were expressed as the mean and standard deviation (SD) or median and IQR/range, and were compared with Student’s t test or Wilcoxon rank-sum test on the basis of their distributions. Categorical variables
Baseline characteristics The study population reflected the real-world clinical practice, including large proportions of patients with
Table 2 Patients with serious cardiovascular event potentially related to LMCA lesion No.
Age
Sex
Event
Survival outcome
Interval (days)
Stenting strategy
SYNTAX score
No. of diseased vessel
Restenosis of LMCA
1
79
M
SCD
Death
51
Bifurcation /1-stenting
42
LMCA ? 1VD
No
2
82
F
SCD
Death
251
Bifurcation
39
LMCA ? 2VD
/2-stenting 3
68
F
SCD
Death
427
4
75
M
SCD
Death
786
Bifurcation
Comment
Yes 1 TLR (PCI)
39
LMCA ? 3VD
No
21
LMCA ? 2VD
No
21
LMCA ? 1VD
HD
/2-stenting Bifurcation /2-stenting 5
68
M
NSTEMI
Alive
1024
Bifurcation /1-stenting
Yes 3 TLR
Emergency CABG
(2 PCI, and 1 CABG) 6
68
M
ACS/ CHF
Death
2419
Bifurcation /2 stenting
41
LMCA ? 2VD
7
57
M
ACS
Alive
2548
Bifurcation
32
LMCA ? 2VD
/1-stenting
Yes 2 TLR (PCI)
Brainstem hemorrhage
Yes
Emergency CABG/HD
2 TLR (1 PCI, and 1 CABG)
8
55
M
SCD
Death
2496
Bifurcation /2 stenting
37
LMCA ? 2VD
Yes
HD
3 TLR (PCI)
Serious cardiovascular event potentially related to LMCA lesion included SCD, target-vessel MI, ST of the LMCA lesion, emergent coronary revascularization of LMCA, or acute congestive heart failure related to LMCA lesion SYNTAX synergy between percutaneous coronary intervention with taxus and cardiac surgery, LMCA left main coronary artery, SCD sudden cardiac death, VD vessel disease, TLR target-lesion revascularization, PCI percutaneous coronary intervention, HD hemodialysis, CABG coronary artery bypass grafting, NSTEMI non-ST-segment elevation myocardial infarction, ACS acute coronary syndrome, CHF congestive heart failure, MI myocardial infarction, and ST stent thrombosis
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advanced age, diabetes mellitus, and renal insufficiency (Table 1). Regarding the lesion characteristics, the vast majority of patients (90 %) had a distal bifurcation LMCA lesion. Almost two-thirds of the patients had multi-vessel coronary artery disease in addition to LMCA disease. The mean SYNTAX score in this study population was very high (32.8 ± 9.4) (Table 1). Regarding the procedural characteristics, 107 (80 %) patients were treated with 1-stenting strategy, whereas 27 (20 %) patients were treated with final 2-stenting strategy. Elective 2-stent strategy had been adopted in 21 patients (Table 1). Modified T-stenting was the most frequently used 2-stenting technique in the current study [18 patients (13.4 %)]. Long-term clinical outcomes During the entire follow-up period, 8 patients suffered from serious cardiovascular events potentially related to LMCA lesion (primary outcome measure) (SCD: N = 5, emergent coronary revascularization for acute coronary syndrome related to LMCA lesion: N = 2, and acute congestive heart failure related to LMCA lesion: N = 1) (Table 2). Six of these 8 events occurred beyond 1-year after the index PCI. However, cumulative 5-year incidence of the primary outcome measure was low (4.4 %) (Fig. 1a). Of note, there was only one target-vessel MI event (1.1 %), and no ST of the LMCA lesion during follow-up. The cumulative 5-year incidence of all-cause death, cardiac death, and SCD was 26.5, 8.1, and 3.4 %, respectively (Fig. 1b). The cumulative 5-year incidence of TLR for the LMCA lesion was 12.9 % (Fig. 1c). Regarding the characteristics of 8 patients with serious LMCA-related adverse events, most patients had severe comorbidities and complex lesion and procedural characteristics, such as hemodialysis (N = 3), bifurcation LMCA lesion (N = 8), and PCI with 2-stenting strategy (N = 5). The SYNTAX scores in these patients were very high (Table 2). Among the 5 patients with SCD, 2 patients had prior TLR for restenosis of LMCA, while the other 3 patients had no history of TLR. Both patients with emergent coronary revascularization underwent CABG with the diagnosis of acute coronary syndrome due to recurrent restenosis of LMCA after first TLR by PCI (Fig. 2a). Another patient with serious adverse event potentially related to LMCA lesion suffered from acute congestive heart failure with restenosis of LMCA lesion as one of the etiologies of heart failure (Fig. 2b). Subgroup analyses: lesion location, extent of coronary artery disease, SYNTAX score, and stenting strategy As the subgroup analyses, the cumulative incidences of the primary outcome measure and TLR were compared
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Fig. 1 Kaplan–Meier curves for the cardiovascular events. a Serious cardiovascular event potentially related to LMCA lesion (Primary outcome measure; SCD, target-vessel MI, ST of the LMCA lesion, emergent coronary revascularization of LMCA, or acute congestive heart failure related to LMCA lesion), b all-cause death, cardiac death, and sudden cardiac death, and c TLR and any coronary revascularization. LMCA left main coronary artery, SCD sudden cardiac death, MI myocardial infarction, ST stent thrombosis, and TLR target-lesion revascularization
Long-term outcomes after PCI using SES for ULMCAD
Fig. 2 Representative cases with serious cardiovascular event potentially related to LMCA lesion. a NSTEMI due to restenosis of LMCA. A 68 years old male with diabetes, hypertension and dyslipidemia underwent PCI for unprotected LMCA using SES with 1-stenting KBT strategy for the true bifurcation lesion (i pre-PCI, and ii post-PCI). The patient received repeated PCI twice for restenosis at stent distal edge of LAD. The patient suffered from NSTEMI due to restenosis of LMCA at 1024 days after the index PCI and underwent emergency CABG (iii). b Acute congestive heart failure due to restenosis of LMCA. A 68 years old male with diabetes and on maintenance hemodialysis underwent PCI using SES for the true bifurcation LMCA lesion with 2-stenting strategy (T-stenting) (i prePCI, and ii post-PCI).The patient had undergone TLR for restenosis of LMCA lesion at 562 days after the index PCI. He developed acute
congestive heart failure in the course of minor cerebellar infarction at 2419 days after index PCI. Urgent coronary angiography revealed recurrent restenosis of LMCA lesion (iii). The patient underwent second TLR by PCI with repeated SES implantation. However, the proximal LAD lesion could not be adequately dilated even with highpressure inflation using non-compliant balloon (iv), resulting in suboptimal angiographic result (v). Brain stem hemorrhage occurred 12 h after the final PCI (vi). CABG coronary artery bypass grafting, KBT kissing balloon technique, LAD left anterior descending coronary artery, LMCA left main coronary artery, NSTEMI non-STsegment elevation myocardial infarction, PCI percutaneous coronary intervention, SES sirolimus-eluting stent, and TLR target-lesion revascularization
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according to the location of LMCA lesion, extent of coronary artery disease, SYNTAX score, and stenting strategy. There was no serious adverse event potentially related to LMCA lesion in patients with non-bifurcation lesion, although the cumulative 5-year incidence of primary outcome measure event was not significantly different between the patients with bifurcation lesion and those
with non-bifurcation lesion (4.9 versus 0 %, P = 0.26) (Fig. 2a). The cumulative 5-year incidence of TLR tended to be higher in patients with bifurcation lesion than in those with non-bifurcation lesion (14.6 versus 0 %, P = 0.12). The cumulative 5-year incidence of serious adverse event potentially related to LMCA lesion was not significantly different between the patients with isolated LMCA/
Fig. 3 Subgroup analyses for the serious cardiovascular event potentially related to LMCA lesion (primary outcome measure). a Bifurcation versus non-bifurcation, b LMCA ? 2VD/3VD versus Isolated LMCA or LMCA ? 1VD, c SYNTAX score ]33 versus SYNTAX score \33, and d LMCA 2-stenting versus LMCA 1-stenting LMCA left main coronary artery, and VD vessel disease
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Long-term outcomes after PCI using SES for ULMCAD
LMCA ? 1VD and the patients with LMCA ? 2VD/ LMCA ? 3VD (5.6 versus 3.9 %, P = 0.71) (Fig. 2b). The cumulative 5-year incidence of TLR was also similar between the 2 groups (13.5 versus 12.4 %, P = 0.75). The cumulative 5-year incidence of serious adverse event potentially related to LMCA lesion as well as that of TLR was not significantly different between the patients with high SYNTAX score (]33) and those with low SYNTAX score (\33) (5.0 versus 4.0 %, P = 0.22, and 8.6 versus 18.0 %, P = 0.32, respectively) (Fig. 3c). Regarding the stenting strategy for the LMCA lesion, the 2-stenting strategy for bifurcation as compared with 1-stenting strategy was associated with significantly higher cumulative 5-year incidence of serious adverse event potentially related to LMCA lesion (14.0 versus 2.2 %, P \ 0.001) (Fig. 3d). The 2-stenting strategy as compared with 1-stenting strategy was also associated with significantly higher cumulative 5-year incidence of TLR (22.3 versus 10.8 %, P = 0.03).
Discussion The main findings of this study were as follows; (1) SES implantation in patients with unprotected LMCA lesion was associated with a favorable long-term outcome with acceptably low rates of TLR and serious adverse event potentially related to LMCA lesion; (2) however, bifurcation 2-stenting strategy for the LMCA lesion as compared with 1-stenting strategy was associated with higher rates of TLR and serious adverse event potentially related to LMCA lesion. In this single center study, the long-term risk for serious adverse events potentially related to LMCA lesion was acceptably low (4.4 % at 5 year). We included SCD as a component of the composite primary outcome measure representing the LMCA-related event. The cumulative incidence of SCD (3.4 % at 5 years) in this study could not be ignorable, although the absolute incidence of SCD in this study was comparable with that in the previous study [15].However, it was not certain whether these fatal events were causally related to the stented LMCA lesion, although 2 out of these 5 patients with SCD had a history of TLR for restenosis of the LMCA lesion. Notably, there was no definite/probable ST of the LMCA lesion in this consecutive series of patients with very complex clinical and angiographic characteristics. Although the cumulative long-term incidence of ST in the LMCA lesion has not been evaluated by the adequately sized meta-analysis, the cumulative incidences of ST in several previous reports were consistently very low [14–20]. Despite apparent long-term safety of LMCA stenting using DES, we should note that 6 out of 8 serious LMCA-
related events occurred beyond 1 year after SES implantation. In the bare-metal stent (BMS) era, relatively high rate of restenosis within the first year had hindered widespread application of PCI in patients with unprotected LMCA disease [2, 7, 23, 24]. The introduction of DES with its potent anti-restenosis efficacy obviously expanded the indication of PCI in patients with unprotected LMCA disease. However, recent several reports suggested that late restenosis leading to TLR beyond 1 year after SES implantation occurred constantly at a rate of 2 %/year without attenuation up to 5 year after SES implantation, which was rarely seen after BMS implantation [13, 25, 26]. Late restenosis as compared with early restenosis was reported to be more often associated with acute coronary syndrome presentation [26]. Acute coronary syndrome related to restenosis of the LMCA lesion is not a benign event, and therefore, current and future development of DES should focus more on late restenosis. Selection of appropriate candidates for PCI is an important issue in the treatment of patients with unprotected LMCA disease. In consistent with the previous reports, 2-stenting strategy for bifurcation was associated with higher risk for serious adverse event potentially related to LMCA lesion as compared with 1-stenting strategy. [4, 11–13]. Unless the operative risk is prohibitively high, CABG might still be a standard choice in patients with unprotected LMCA disease with severe anatomical complexity necessitating 2-stenting strategy [14]. On the other hands, PCI seems to be a reasonable choice in patients with unprotected LMCA disease treatable by single stenting strategy, those with non-bifurcation lesion in particular. In the current study, extent of coronary artery disease in territories other than the LMCA lesion was not associated with increased risk for serious adverse event potentially related to LMCA lesion. However, in the SYNTAX trial, long-term clinical outcome of PCI as compared with CABG was significantly worse in LMCA patients with SYNTAX score C32 [27]. Therefore, CABG would still be a standard choice in LMCA patients associated with extensive coronary artery disease.
Study limitations There are several limitations to the present study. First, and most importantly, this single center observational study did not have a control group treated with PCI using BMS or CABG. However, the vast majority of patients treated with PCI in this study received DES as a default strategy in our hospital, and therefore, the safety of DES use in patients with unprotected LMCA disease could be evaluated in the ‘real-world clinical practice’. Second, the relatively small
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number of patients enrolled in this study made it difficult to draw any definitive conclusions on the long-term outcomes of DES including the relationship of stenting strategy with clinical outcomes in patients with unprotected LMCA disease. Third, the cumulative incidence of SCD could not be ignorable, although the overall risk for adverse cardiovascular events was relatively low and it was not certain whether these SCDs were causally related to the stented LMCA lesion. Forth, the treatment strategy for bifurcation lesions was not based on randomized assignment in this observational study. Fifth, TLR events in the present study included both clinically and angiographically driven events. The clinical significance of angiographically driven TLR of the LMCA lesion remains unclear. Finally, DES used in the current study is no longer used in the current clinical practice. Investigation of long-term outcome of LMCA stenting using the second-generation DES, which is expected to reduce the risk of late adverse events such as VLST and late TLR, should be warranted to provide further guidance in the selection of coronary revascularization modalities in patients with unprotected LMCA disease.
Conclusions Sirolimus-eluting stent implantation in patients with unprotected LMCA lesion was associated with a favorable long-term outcome with acceptably low rate of serious adverse event potentially related to LMCA lesion. However, complex LMCA lesions necessitating 2-stenting strategy might be associated with higher risk for serious adverse events. Acknowledgments The authors thank paramedical assistants of catheterization laboratory in Kyoto University Hospital.
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Long-term outcomes after PCI using SES for ULMCAD
19.
20.
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