IJCA-25501; 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
Provisional versus elective two-stent strategy for unprotected true left main bifurcation lesions: Insights from a FAILS-2 sub-study Hiroyoshi Kawamoto a,b,c, Alaide Chieffo a, Fabrizio D'Ascenzo d, Richard J. Jabbour a,b, Toru Naganuma c, Enrico Cerrato e, Fabrizio Ugo f, Marco Pavani d, Ferdinando Varbella e, Giacomo Boccuzzi f, Mauro Pennone d, Roberto Garbo f, Federico Conrotto d, Giuseppe Biondi-Zoccai h, Maurizio D'Amico d, Claudio Moretti d, Javier Escaned g, Fiorenzo Gaita d, Sunao Nakamura c, Antonio Colombo a,⁎ a
IRCCS Ospedale San Raffaele, Milan, Italy EMO-GVM Centro Cuore Columbus, Milan, Italy c New Tokyo Hospital, Matsudo, Japan d Citta della Salute e della Scienza, Turin, Italy e Ospedale degli Infermi Rivoli, Turin, Italy f Ospedale San Giovanni Bosco, Turin, Italy g Hospital San Carlos, Madrid, Spain h Sapienza University of Rome, Latina, Italy b
a r t i c l e
i n f o
Article history: Received 14 May 2017 Received in revised form 26 August 2017 Accepted 18 September 2017 Available online xxxx Keywords: Unprotected left main coronary artery True bifurcation lesions Drug-eluting stent Percutaneous coronary intervention
a b s t r a c t Background: This study sought to investigate the optimal percutaneous coronary intervention (PCI) strategy for true unprotected left main coronary artery (ULMCA) bifurcations. Methods: The FAILS-2 was a retrospective multi-center study including patients with ULMCA disease treated with second-generation drug-eluting stents. Of these, we compared clinical outcomes of a provisional strategy (PS; n = 216) versus an elective two-stent strategy (E2S; n = 161) for true ULMCA bifurcations. The primary endpoint was the incidence of major adverse cardiac events (MACEs) at 3-years. We further performed propensity-score adjustment for clinical outcomes. Results: There were no significant differences between the groups in terms of patient and lesion characteristics. 9.7% of patients in the PS group crossed over to a provisional two-stent strategy. MACEs were not significantly different between groups (MACE at 3-year; PS 28.1% vs. E2S 28.9%, adjusted p = 0.99). The rates of target lesion revascularization (TLR) on the circumflex artery (LCX) were numerically high in the E2S group (LCX-TLR at 3years; PS 11.8% vs. E2S 16.6%, adjusted p = 0.51). Conclusions: E2S was associated with a comparable MACE rate to PS for true ULMCA bifurcations. The rates of LCX-TLR tended to be higher in the E2S group although there was no statistical significance. Condensed abstract: This study sought to compare the clinical outcomes of a provisional strategy (PS) with an elective two-stent strategy (E2S) for the treatment of true unprotected left main coronary artery bifurcations. 377 Patients (PS 216 vs. E2S 161 patients) were evaluated, and 9.7% in the PS group crossed over to a twostent strategy. E2S was associated with a similar major adverse cardiac event rate at 3-years when compared to the PS strategy (PS 28.1% vs. E2S 28.9%, p = 0.99). However, the left circumflex artery TLR rate at 3-year tended to be higher in the E2S group (PS 11.8% vs. E2S 16.6%, p = 0.51). © 2017 Published by Elsevier Ireland Ltd.
1. Introduction
Abbreviations: ULMCA, unprotected left main coronary artery; PS, provisional stenting strategy; E2S, elective two-stent strategy; MACEs, major adverse cardiac events; TLR, target lesion revascularization. ⁎ Corresponding author at: IRCCS Ospedale San Raffaele, via Olgettina 60, 20132 Milano, Italy. E-mail address: [email protected] (A. Colombo).
Percutaneous coronary intervention (PCI) using drug-eluting stents (DES) has become an alternative for unprotected left main coronary artery (ULMCA) disease in patients with low-to-intermediate SYNTAX scores [1]. Previous studies have shown that PCI for ostial and/or midshaft lesions in ULMCA disease is associated with comparable clinical outcomes to coronary artery bypass grafting (CABG) [2,3]. However, the majority of stenoses involve distal ULMCA bifurcations, which are
https://doi.org/10.1016/j.ijcard.2017.09.207 0167-5273/© 2017 Published by Elsevier Ireland Ltd.
Please cite this article as: H. Kawamoto, et al., Provisional versus elective two-stent strategy for unprotected true left main bifurcation lesions: Insights from a FAILS-2 sub-study, Int J Cardiol (2017), https://doi.org/10.1016/j.ijcard.2017.09.207
2
H. Kawamoto et al. / International Journal of Cardiology xxx (2017) xxx–xxx
associated with an increase in procedural complexity when compared to ostial and/or mid-shaft lesions [4,5]. In addition, true bifurcations of the distal ULMCA are associated with higher rates of target lesion revascularization (TLR) [6]. Although a provisional strategy is currently recommended for most ULMCA bifurcation lesions [7–11], a systematic two-stent strategy remains a treatment option when treating complex bifurcations (e.g. true bifurcation lesions) to reduce the risk of acute left circumflex artery (LCX) occlusion. Recently, the EBC TWO (European Bifurcation Coronary TWO) randomized study, which compared provisional versus systematic culotte stenting for non-ULMCA true bifurcations reported comparable outcomes at 1-year [12]. However, little is known regarding the optimal strategy and clinical outcomes following different PCI strategies for true ULMCA bifurcations [13]. EBC MAIN study (European Bifurcation Club Left Main Study; ClinicalTrials.gov NCT02497014) is currently on going and will be the first randomized clinical trial to evaluate the optimal stenting strategy in true ULMCA bifurcation lesions [14]. Therefore, the aim of this study was to investigate mid-term outcomes of a provisional strategy (PS) versus an elective two-stent strategy (E2S) for true ULMCA bifurcations treated with second-generation DES from a multi-center registry. 2. Methods 2.1. Study population The FAILS 2 (Failure in Left Main Study with the second generation stents) study is a multi-center registry retrospectively including all consecutive patients with ULMCA stenoses treated with second-generation DES between July 2006 and March 2015. This study initially aimed to evaluate the incidence, clinical presentation and prognosis of restenosis after treatment of ULMCA disease with second-generation DES [15]. Of these, we compared clinical outcomes between a PS and an E2S for true ULMCA bifurcations. Five European centers and one Japanese center were involved. The indication to perform PCI rather than CABG was decided at each individual center. The decision to opt for a provisional or elective two-stent strategy was at the operators' discretion. In general, an E2S was employed when there was severe stenosis at the ostium of LCX or diffuse disease extending from the LCX ostium. Using the provisional strategy, stenting to the LCX was indicated by major dissections or compromised flow following side branch dilatation or kissing balloon inflation. All clinical or procedural data were site-reported. Clinical data during follow-up were obtained from hospital visits or telephonic contacts. Exclusion criteria for this sub-study included PCI for ostial/body lesions, non-true ULMCA bifurcations, acute myocardial infarction (MI), cardiogenic shock or unreviewable techniques for ULMCA bifurcations. We compared PS with E2S by intention-to-treat for true ULMCA bifurcations. 2.2. Study definitions ULMCA lesions were classified by visual assessment at each center according to the Medina classification [16]. A true bifurcation lesion was defined as Medina class 1-1-1, 1-0-1, or 0-1-1 [16]. MACEs were defined as a composite of all-cause death, MI, and overall target lesion revascularization (TLR). Overall TLR was defined as either repeat PCI or CABG for the ULMCA lesion stented previously including the proximal and distal edge segments of the stent, or at the ostium of the side branches (SBs). Furthermore, TLR of the left main stem (LM-TLR), LAD (LAD-TLR), and LCX (LCX-TLR) were separately evaluated. Death was considered cardiac in origin unless obvious non-cardiac causes were identified. The definition of MI was according to the Third Universal Definition of Myocardial Infarction [17]. Stent thrombosis (ST) was classified according to the Academic Research Consortium (ARC) definitions [18]. 2.3. Study endpoints The primary endpoint was the rate of MACE at 3-years. The secondary endpoints were each component of MACE, cardiac death, LM-TLR, LAD-TLR, LCX-TLR, and definite or probable ST. 2.4. Statistical analysis Continuous variables are presented as the mean ± standard deviation (SD). Differences in continuous variables between the groups were calculated with the Student t-test. Categorical data were compared using the chi-square or Fisher's exact tests. The cumulative clinical events were generated with Kaplan–Meier method, and reported as hazard ratios (HR; elective two-stent vs. provisional strategy) and 95% confidence interval (CI) using Cox regression analysis. Follow-up was censored at the date of the last followup or at 3 years. Because of the nonrandomized nature of this study, clinical outcomes were evaluated between unadjusted groups and again following propensity-score
adjustment. Adjusted ratios were calculated using Cox regression analysis with elective two-stent strategy (vs. provisional strategy) as a fixed dummy covariate and propensity score as the stratification variable [19,20]. Propensity score were calculated using covariates as following; stent-drug, Medina classification, LCX proximal disease, male, age, hypertension, diabetes mellitus, insulin-dependent diabetes mellitus, current smoking, dyslipidemia, previous myocardial infarction, previous PCI, chronic obstructive pulmonary disease, previous stroke, low ejection fraction (b35%), low estimated glomerular filtration rate (GFR) b60 ml/min/1.73 m2, acute coronary syndrome, SYNTAX score, radial access, IVUS use, three vessel disease, and treated vessel. The C-statistic was 0.66, and the Hosmer–Lemeshow p-value was 0.28, indicating good discrimination and calibration of the propensity-matching model, respectively. We performed multivariable Cox regression analysis to identify the independent risk factors of MACE during follow-up period. Variables used in the Cox regression model were all variables with values of p b 0.10 at univariate analysis and those judged to be clinically important. To avoid over-fitting, the number of independent variables entered into the final multivariable logistic regression model was limited to 1 for every 8–10 events. Analyses were performed using SPSS version 21.0 (SPSS Inc., Chicago, IL, USA). All reported p values were 2-sided, and values of p b 0.05 regarded as statistically significant.
Table 1 Baseline clinical and lesion characteristics.
Clinical characteristics Male Age (years) Hypertension Dyslipidemia Current smoker Diabetes Insulin-dependent Chronic kidney disease eGFR, ml/min/1.73 m2 eGFR b 60 ml/min/1.73 m2 Previous PCI Previous MI COPD Previous stroke Clinical presentation Stable angina Unstable angina LVEF (%) Lesion characteristics LAD disease LCX disease RCA disease 3VD SYNTAX score Low SYNTAX score Intermediate SYNTAX score High SYNTAX score (N33) IVUS Trans radial approach Stent type Biolimus-eluting stent Everolimus-eluting stent Zotarolimus-eluting stent Others Stent techniques Provisional two stent Crush Culotte Mini-crush T V Medina classification 0,1,1 1,0,1 1,1,1 LCX proximal disease (non-ostial)
Provisional (n = 216)
Elective two-stent (n = 161)
p Value
170 (78.7) 70.8 ± 9.9 181 (83.8) 150 (69.8) 24 (12.3) 98 (46.7) 30 (14.3)
128 (79.5) 70.4 ± 10.4 126 (78.3) 104 (66.2) 25 (18.2) 59 (38.6) 15 (9.9)
0.85 0.74 0.17 0.47 0.13 0.12 0.21
63.6 ± 29.4 91 (48.7) 114 (53.0) 80 (37.4) 17 (8.5) 13 (6.3)
60.4 ± 25.3 63 (47.4) 79 (51.0) 43 (28.1) 6 (4.5) 12 (8.3)
0.31 0.82 0.7 0.06 0.16 0.47 0.81
164 (75.9) 52 (24.1) 55.0 ± 12.5
124 (77.0) 37 (23.0) 55.6 ± 9.9
190 (88.0) 187 (86.6) 165 (76.4) 136 (63.0) 29.0 ± 10.0 53 (26.8) 70 (35.4) 75 (37.9) 48 (22.2) 24 (11.2)
134 (84.3) 135 (84.9) 132 (82.5) 106 (66.3) 29.9 ± 10.0 36 (23.5) 57 (37.3) 60 (39.2) 44 (27.3) 21 (13.1)
25 (11.6) 171 (79.2) 17 (7.9) 3 (1.4)
30 (18.6) 108 (67.1) 18 (11.2) 4 (2.5)
0.65
0.3 0.65 0.15 0.51 0.4 0.79
0.25 0.57 0.07
21 (9.7) 12 (7.5) 53 (32.9) 64 (39.8) 23 (14.3) 9 (5.6) 0.36 23 (10.6) 34 (15.7) 159 (73.6) 131 (60.6)
24 (14.9) 20 (12.4) 117 (72.7) 95 (59.7)
0.86
Data are presented as absolute numbers and percentages or mean ± standard deviation. eGFR = estimated glomerular filtration rate; PCI = percutaneous coronary intervention; MI = myocardial infarction; COPD = chronic obstructive pulmonary disease; LVEF = left ventricular ejection fraction; LAD = left anterior descending artery; LCX = left circumflex coronary artery; RCA = right coronary artery; VD = vessel disease; IVUS = intravascular ultrasound.
Please cite this article as: H. Kawamoto, et al., Provisional versus elective two-stent strategy for unprotected true left main bifurcation lesions: Insights from a FAILS-2 sub-study, Int J Cardiol (2017), https://doi.org/10.1016/j.ijcard.2017.09.207
H. Kawamoto et al. / International Journal of Cardiology xxx (2017) xxx–xxx
3
significantly higher in the PS group (PS 5.7% vs. E2S 0.8% at 1-year, and PS 8.3% vs. E2S 0.8% at 3-years, HR 0.09; 95% CI 0.01–0.66, p = 0.02). The rate of TLR at the LCX tended to be higher in the E2S group compared to the PS group (PS 9.6% vs. E2S 13.4% at 1-year, and PS 11.8% vs. E2S 16.6% at 3-years, HR 1.44; 95% CI 0.78–2.65, p = 0.25). Following propensity-score adjustment, there were no statistical differences regarding clinical outcomes including cardiac death (HR 0.33; 95% CI; 0.04–2.64, adjusted p value = 0.29). Amongst patients in the PS group, patients who required provisional two-stent strategy had a high LCX-TLR rate (n = 4, 21.5% at 1- and 3-years) (Fig. 1). When comparing groups as treated (single versus two-stent [provisional and elective]), there was a trend towards a higher LCX-TLR rate if a two-stent strategy was utilized (single-stent; 8.1% at 1-year and 10.6% at 3-year, two-stent; 14.5% at 1-year and 17.3% at 3-year, p = 0.11, adjusted p value = 0.08).
3. Results 3.1. Baseline characteristics Amongst a total of 1270 patients in this registry, ostial/body lesions (n = 199), non-true ULMCA bifurcations (n = 528), acute myocardial infarction or cardiogenic shock (n = 125), unreviewable techniques (n = 41) for ULMCA bifurcations were excluded. 377 patients (29.7%) were included in the final analysis (216 patients in the PS, and 161 patients in the E2S group). The median follow-up period was 818 (IQR 341–1244) days. Patient and lesion characteristics were comparable between the two groups (Table 1). The prevalence of diabetes and previous MI tended to be higher in the PS group (diabetes; PS 46.7% vs. E2S 38.6%, p = 0.12, and previous MI; 37.4% vs. 28.1%, p = 0.06). No difference was observed in SYNTAX score was 29.0 ± 10.0 in the PS group and 29.9 ± 10.0 in the E2S group (p = 0.40). The majority of distal ULM lesions were Medina 1,1,1 true bifurcations (Medina 1,1,1; PS 73.6% vs. E2S 72.7%, overall p value = 0.36). Intravascular ultrasound (IVUS) was utilized in 22.2% and 27.3% in the PS and E2S groups, respectively (p = 0.25). The everolimus-eluting stent was the most commonly used stent in both groups (PS 79.2% vs. E2S 67.1%, overall p value = 0.07). In the PS group, 9.7% of true ULMCA bifurcations crossed over to a provisional two-stent strategy. By contrast, the most commonly used stenting techniques in the E2S group were the mini-crush (39.8%), culotte (32.9%), and T-stenting (14.3%).
3.3. Predictors of MACE Univariate analysis revealed that predictors of MACE were diabetes (HR 1.94; 95% CI 1.26–2.99, p = 0.003), left ventricular ejection fraction b35% (HR 2.48; 95% CI 1.35–4.57, p = 0.004), chronic kidney disease (HR 1.90; 95% CI 1.18–3.07, p = 0.01), and unstable angina (HR 1.80; 95% CI 1.14–2.84, p = 0.01). Multivariable analyses indicated that diabetes, LVEF b 35%, and unstable angina were independent predictors of MACE [diabetes (HR 2.40; 95% CI 1.45–3.95, p = 0.001); LVEF b 35% (HR 2.38; 95% CI 1.12–4.76, p = 0.02); unstable angina (HR 1.79; 95% CI: 1.06–3.04, p = 0.03)] (Table 3).
3.2. Clinical outcomes
4. Discussion
Clinical event rates at 1- and 3-years are described in Table 2, with corresponding Kaplan–Meier curves shown in Fig. 1. MACE rates at 1and 3-years were comparable (PS 19.1% vs. E2S 17.2% at 1-year, and PS 28.1% vs. E2S 28.9% at 3-years, HR 0.94; 95% CI 0.61–1.44, p = 0.76) between groups. In addition, there were no significant differences in any of the other clinical outcomes expect for cardiac death that was
The main findings of this study are the following: 1) MACE and overall TLR rates between a provisional and elective two-stent strategy for true ULMCA bifurcations treated with second-generation DES were comparable during 3-year follow-up; 2) there was a trend towards a
Table 2 Clinical outcomes.
MACE At 1 year At 3 years All-cause death At 1 year At 3 years Cardiac death At 1 year At 3 years Overall TLR At 1 year At 3 years LMCA-TLR At 1 year At 3 years LAD-TLR At 1 year At 3 years LCX-TLR At 1 year At 3 years Myocardial infarction At 1 year At 3 years Definite or probable ST At 1 year At 3 years
Provisional (n = 216)
Elective two-stent (n = 161)
Elective two-stent vs. provisional
Absolute number
Cumulative incidence
Absolute number
Cumulative incidence
HR (95% CI)
p Value
Adjusted HR (95% CI)
p Value
37 50
19.1 28.1
24 35
17.2 28.9
0.94 (0.61–1.44)
0.76
1.01 (0.56–1.80)
0.99
15 23
7.6 13.4
5 12
3.5 11.3
0.69 (0.34–1.38)
0.29
0.93 (0.35–2.50)
0.89
11 15
5.7 8.3
1 1
0.8 0.8
0.09 (0.01–0.66)
0.02
0.33 (0.04–2.64)
0.29
23 30
12.9 17.9
19 24
14 19
1.08 (0.63–1.85)
0.78
0.99 (0.49–1.98)
0.97
3 7
1.7 4.6
2 3
1.4 2.2
0.56 (0.15–2.17)
0.40
0.38 (0.04–3.34)
0.38
8 9
4.5 5.2
2 3
1.4 2.3
0.44 (0.12–1.61)
0.21
0.69 (0.14–3.39)
0.65
17 20
9.6 11.8
18 21
13.4 16.6
1.44 (0.78–2.65)
0.25
1.29 (0.60–2.76)
0.51
4 6
2 3.3
0 0
0 0
0.02 (0.00–14.83)
0.24
NA
0.97
6 6
3 3
0 0
0 0
0.02 (0.00–14.30)
0.24
NA
0.98
MACE = major adverse cardiac event; TLR = target lesion revascularization; LMCA = left main coronary artery; LAD = left anterior descending artery; LCX = left circumflex coronary artery; ST = stent thrombosis; HR = hazard ratio; CI = confidence interval.
Please cite this article as: H. Kawamoto, et al., Provisional versus elective two-stent strategy for unprotected true left main bifurcation lesions: Insights from a FAILS-2 sub-study, Int J Cardiol (2017), https://doi.org/10.1016/j.ijcard.2017.09.207
4
H. Kawamoto et al. / International Journal of Cardiology xxx (2017) xxx–xxx
Fig. 1. Clinical outcomes. Kaplan–Meier curves are shown for (A) major adverse cardiac events (MACEs), (B) all-cause death, (C) target lesion revascularization (TLR) of the left circumflex coronary artery (LCX) by intention-to-treat analysis, and (D) TLR of the LCX according to as treated stenting techniques. Event rates shown in the figures are those calculated without propensity-score adjustment. PCI = percutaneous coronary intervention; ULMCA = unprotected left main coronary artery; 1S = single-stenting; 2S = two-stenting.
lower LCX TLR rate with a provisional single-stent strategy but this did not reach statistical significance; 3) diabetes, low ejection fraction, and unstable angina were independent predictors of MACE. 4.1. Provisional versus two-stent strategy A provisional single-stent strategy is generally considered to be the default strategy for the majority of bifurcation lesions including ULMCA lesions [8–11,21,22]. However, distal ULMCA bifurcation lesions have several anatomic features that should be differentiated from other bifurcations due to the following reasons: 1) it is the largest and the most proximal bifurcation in the coronary artery tree; 2) side branch (LCX) occlusion can be a rare but fatal complication during PCI; 3) the bifurcation angle is generally wider when compared to other bifurcations and 4) the ostium of LCX has hinge motion which can result in high restenosis rate [23,24]. Some retrospective studies have indicated that E2S is inferior to a single stent strategy for distal ULMCA disease, even with second-generation DES [10,11,25,26]. Furthermore, true ULMCA bifurcations were associated with high rates of TLR [6,27].
However, no randomized or retrospective studies have investigated the optimal stenting strategy for ‘true’ ULMCA bifurcation lesions. Of note, in this registry the incidence of MACE and overall TLR were similar between the PS and E2S during 3-year follow-up. It should be noted that the crossover rate to provisional two-stent from provisional single-stent strategy was only 9.7%. In the previous studies, a second stent into the SB was required in 17–51% of LMCA lesions treated with a single-stent strategy [28–32]. Even though there may have been a greater effort to avoid two-stent, clinical outcomes were comparable between the two groups and also consistent following propensity-score adjustment. 4.2. LCX TLR As expected, MACE was predominantly triggered by TLR. As previously reported [11,22,26], side branch restenosis is considered a major limitation for ULMCA PCI, especially for a two-stent strategy. Our study suggests that the provisional strategy for ULMCA when possible seems to be beneficial in terms of TLR rate on the LCX although there was no statistical difference compared to the E2S strategy. Of note,
Please cite this article as: H. Kawamoto, et al., Provisional versus elective two-stent strategy for unprotected true left main bifurcation lesions: Insights from a FAILS-2 sub-study, Int J Cardiol (2017), https://doi.org/10.1016/j.ijcard.2017.09.207
H. Kawamoto et al. / International Journal of Cardiology xxx (2017) xxx–xxx
5. Limitations
Table 3 Cox regression analyses for major adverse cardiac events. Covariates
Elective two-stent Male Age Hypertension Diabetes Current smoking Dyslipidemia Previous MI Previous PCI Low EF (b35%) eGFR b60 ml/min/1.73 m2 Unstable angina High SYNTAX score Femoral access (vs. radial) IVUS Three vessel disease Medina 1,1,1
Univariate
5
Multivariable
Hazard ratio (95% CI)
p Value Hazard ratio (95% CI)
0.94 (0.61–1.44) 0.63 (0.39–1.01) 1.02 (1.00–1.04) 1.22 (0.69–2.16) 1.94 (1.26–2.99) 0.72 (0.37–1.42) 0.85 (0.54–1.33) 1.17 (0.75–1.84) 0.88 (0.57–1.36) 2.48 (1.35–4.57) 1.90 (1.18–3.07) 1.80 (1.14–2.84) 1.49 (0.97–2.28) 0.91 (0.44–1.88) 0.61 (0.35–1.09) 1.12 (0.70–1.79) 1.10 (0.68–1.78)
0.76 0.05 0.1 0.5 0.003 0.35 0.48 0.49 0.57 0.004 0.01 0.01 0.07 0.79 0.09 0.64 0.69
p Value
1.14 (0.71–1.86) 0.58 0.80 (0.46–1.41) 0.44 1.00 (0.98–1.03) 0.98 2.40 (1.45–3.95) 0.001
2.38 (1.12–4.76) 1.59 (0.95–2.67) 1.79 (1.06–3.04) 1.22 (0.74–2.01)
0.02 0.08 0.03 0.43
0.75 (0.41–1.38) 0.35
CI = confidence interval; MI = myocardial infarction; PCI = percutaneous coronary intervention; EF = ejection fraction; eGFR = estimated glomerular filtration rate; IVUS = intravascular ultrasound.
The present study had the several limitations inherent to a nonrandomized, retrospective study. Despite the use of propensity-score adjustment, unmeasured confounders might have affected clinical outcomes. Secondly, procedural details such as the rates of kissing-balloon inflations, proximal optimization technique, or the usage of other devices were not available in all patients. Thirdly, the follow-up protocol was not standardized, especially in terms of angiographic follow-up and a high rate of planned angiographic follow-up in the E2S group may have contributed to TLR events. Finally, the varying experience of each operator or center may have affected outcomes that we could not evaluate in this registry. 6. Conclusions In patients undergoing PCI with second-generation DES for true ULMCA bifurcation lesions, E2S was associated with a comparable MACE rate to a PS strategy. This was consistent following propensityscore adjustment. However, the rates of TLR at the LCX tended to be higher in the E2S group. Randomized studies are required to elucidate the optimal PCI strategy for true ULMCA bifurcation lesions. Financial disclosures
crossing over to a two-stent strategy from a single-stent strategy had a high rate of restenosis at the LCX. These data suggest that greater effort should be paid to avoid a second stent to the LCX when a provisional stent strategy is employed. The severity of a SB ostial stenosis is commonly over-estimated when evaluated by angiography alone in comparison to physiological assessment [33]. Therefore, fractional flow reserve (FFR) or intravascular imaging might reduce the incidence of SB stenting, and therefore translate into better clinical outcomes. In addition, previous studies have demonstrated that TLR is associated with rate of planned angiographic follow-up [34–36]. However, we have to take into account that angiographic follow-up was more frequently performed in the E2S group (E2S 64.4% vs. PS 53.5%, p = 0.03). We cannot exclude that this could have affected TLR rates, especially at the LCX. This lead-time bias occurred ‘after’ the PCI procedure and therefore could not be taken into account using propensity-score adjustment. 4.3. Intravascular imaging Our study included patients treated in high-volume centers in Europe and Japan so that it represents contemporary PCI practice for ULMCA bifurcations. However, it is discouraging that the usage of intravascular ultrasound (IVUS) was only 24.4% even when treating true ULMCA bifurcations. IVUS is considered as an essential tool for ULMCA disease [37] and IVUS (or optical coherence tomography; OCT) seems to be useful in obtaining better clinical outcomes in addition to avoiding a second stent at the LCX [38,39]. IVUS use did not remain an independent predictor for MACE [HR 0.75 (0.41–1.38), p = 0.35] in our study. Larger studies are needed to demonstrate the impact of intravascular imaging when treating complex ULMCA disease. 4.4. Ongoing research The EBC MAIN is an ongoing, prospective, randomized study comparing a planned single-stent strategy to planned dual-stent strategy [14]. In this randomized study, although the planned two-stent technique is at the discretion of the operator, culotte, DK mini-crush, or T-stenting are recommended, and similar to our retrospective study. Although our study did not have information whether double kissing inflations were performed or not, our results are helpful and demonstrate useful insights when treating true ULMCA bifurcation lesions. The results from EBC MAIN study are eagerly awaited.
None. Conflict of interest statement All authors have no conflicts of interest to declare. Role of the funding source No funding was received related to this manuscript. Acknowledgements None. References [1] S. Windecker, P. Kolh, F. Alfonso, J.P. Collet, J. Cremer, V. Falk, et al., ESC/EACTS guidelines on myocardial revascularization: the task force on myocardial revascularization of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS) developed with the special contribution of the European Association of Percutaneous Cardiovascular Interventions (EAPCI), Eur. Heart J. 35 (2014) 2541–2619. [2] T. Naganuma, A. Chieffo, E. Meliga, D. Capodanno, S.J. Park, Y. Onuma, et al., Longterm clinical outcomes after percutaneous coronary intervention versus coronary artery bypass grafting for ostial/midshaft lesions in unprotected left main coronary artery from the DELTA registry: a multicenter registry evaluating percutaneous coronary intervention versus coronary artery bypass grafting for left main treatment, J. Am. Coll. Cardiol. Intv. 7 (2014) 354–361. [3] D.W. Park, K.B. Seung, Y.H. Kim, J.Y. Lee, W.J. Kim, S.J. Kang, et al., Long-term safety and efficacy of stenting versus coronary artery bypass grafting for unprotected left main coronary artery disease: 5-year results from the MAIN-COMPARE (revascularization for unprotected left main coronary artery stenosis: comparison of percutaneous coronary angioplasty versus surgical revascularization) registry, J. Am. Coll. Cardiol. 56 (2010) 117–124. [4] A. Chieffo, S.J. Park, M. Valgimigli, Y.H. Kim, J. Daemen, I. Sheiban, et al., Favorable long-term outcome after drug-eluting stent implantation in nonbifurcation lesions that involve unprotected left main coronary artery: a multicenter registry, Circulation 116 (2007) 158–162. [5] T. Palmerini, D. Sangiorgi, A. Marzocchi, C. Tamburino, I. Sheiban, M. Margheri, et al., Ostial and midshaft lesions vs. bifurcation lesions in 1111 patients with unprotected left main coronary artery stenosis treated with drug-eluting stents: results of the survey from the Italian Society of Invasive Cardiology, Eur. Heart J. 30 (2009) 2087–2094. [6] K. Tiroch, J. Mehilli, R.A. Byrne, S. Schulz, S. Massberg, K.L. Laugwitz, et al., Impact of coronary anatomy and stenting technique on long-term outcome after drug-eluting stent implantation for unprotected left main coronary artery disease, J. Am. Coll. Cardiol. Intv. 7 (2014) 29–36. [7] A. Chieffo, E. Meliga, A. Latib, S.J. Park, Y. Onuma, P. Capranzano, et al., Drug-eluting stent for left main coronary artery disease. The DELTA registry: a multicenter
Please cite this article as: H. Kawamoto, et al., Provisional versus elective two-stent strategy for unprotected true left main bifurcation lesions: Insights from a FAILS-2 sub-study, Int J Cardiol (2017), https://doi.org/10.1016/j.ijcard.2017.09.207
6
H. Kawamoto et al. / International Journal of Cardiology xxx (2017) xxx–xxx
registry evaluating percutaneous coronary intervention versus coronary artery bypass grafting for left main treatment, J. Am. Coll. Cardiol. Intv. 5 (2012) 718–727. [8] A. Colombo, J.W. Moses, M.C. Morice, J. Ludwig, D.R. Holmes Jr., V. Spanos, et al., Randomized study to evaluate sirolimus-eluting stents implanted at coronary bifurcation lesions, Circulation 109 (2004) 1244–1249. [9] T. Kimura, T. Morimoto, Y. Nakagawa, K. Kawai, S. Miyazaki, T. Muramatsu, et al., Very late stent thrombosis and late target lesion revascularization after sirolimuseluting stent implantation: five-year outcome of the j-Cypher Registry, Circulation 125 (2012) 584–591. [10] Y.B. Song, J.Y. Hahn, J.H. Yang, S.H. Choi, J.H. Choi, S.H. Lee, et al., Differential prognostic impact of treatment strategy among patients with left main versus non-left main bifurcation lesions undergoing percutaneous coronary intervention: results from the COBIS (Coronary Bifurcation Stenting) Registry II, J. Am. Coll. Cardiol. Intv. 7 (2014) 255–263. [11] M. Toyofuku, T. Kimura, T. Morimoto, Y. Hayashi, H. Ueda, K. Kawai, et al., Three-year outcomes after sirolimus-eluting stent implantation for unprotected left main coronary artery disease: insights from the j-Cypher registry, Circulation 120 (2009) 1866–1874. [12] D. Hildick-Smith, M.W. Behan, J.F. Lassen, A. Chieffo, T. Lefevre, G. Stankovic, et al., The EBC TWO Study (European Bifurcation Coronary TWO): a randomized comparison of provisional T-stenting versus a systematic 2 stent culotte strategy in large caliber true bifurcations, Circ. Cardiovasc. Interv. 9 (2016). [13] F. D'Ascenzo, M. Iannaccone, F. Giordana, A. Chieffo, S.O. Connor, L.C. Napp, et al., Provisional vs. two-stent technique for unprotected left main coronary artery disease after ten years follow up: a propensity matched analysis, Int. J. Cardiol. 211 (2016) 37–42. [14] A. Chieffo, D. Hildick-Smith, The European Bifurcation Club Left Main Study (EBC MAIN): rationale and design of an international, multicentre, randomised comparison of two stent strategies for the treatment of left main coronary bifurcation disease, EuroIntervention 12 (2016) 47–52. [15] F. D'Ascenzo, A. Chieffo, E. Cerrato, F. Ugo, M. Pavani, H. Kawamoto, et al., Incidence and management of restenosis after treatment of unprotected left main disease with second-generation drug-eluting stents (from failure in left main study with 2nd generation stents-cardiogroup III study), Am. J. Cardiol. 119 (2017) 978–982. [16] A. Medina, J. Suarez de Lezo, M. Pan, A new classification of coronary bifurcation lesions, Rev. Esp. Cardiol. 59 (2006) 183. [17] K. Thygesen, J.S. Alpert, A.S. Jaffe, M.L. Simoons, B.R. Chaitman, H.D. White, et al., Third universal definition of myocardial infarction, Eur. Heart J. 33 (2012) 2551–2567. [18] W.K. Laskey, C.W. Yancy, W.H. Maisel, Thrombosis in coronary drug-eluting stents: report from the meeting of the Circulatory System Medical Devices Advisory Panel of the Food and Drug Administration Center for Devices and Radiologic Health, December 7–8, 2006, Circulation 115 (2007) 2352–2357. [19] R.B. D'Agostino Jr., Propensity score methods for bias reduction in the comparison of a treatment to a non-randomized control group, Stat. Med. 17 (1998) 2265–2281. [20] D.B. Rubin, Estimating causal effects from large data sets using propensity scores, Ann. Intern. Med. 127 (1997) 757–763. [21] J.F. Lassen, N.R. Holm, A. Banning, F. Burzotta, T. Lefevre, A. Chieffo, et al., Percutaneous coronary intervention for coronary bifurcation disease: 11th consensus document from the European Bifurcation Club, EuroIntervention 12 (2016) 38–46. [22] K. Takagi, T. Naganuma, A. Chieffo, Y. Fujino, A. Latib, S. Tahara, et al., Comparison between 1- and 2-stent strategies in unprotected distal left main disease: the Milan and New-Tokyo registry, Circ. Cardiovasc. Interv. 9 (2016). [23] K. Amemiya, T. Domei, M. Iwabuchi, S. Shirai, K. Ando, M. Goya, et al., Impact of the bifurcation angle on major cardiac events after cross-over single stent strategy in unprotected left main bifurcation lesions: 3-dimensional quantitative coronary angiographic analysis, Am. J. Cardiovasc. Dis. 4 (2014) 168–176. [24] C. Girasis, V. Farooq, R. Diletti, T. Muramatsu, C.V. Bourantas, Y. Onuma, et al., Impact of 3-dimensional bifurcation angle on 5-year outcome of patients after percutaneous coronary intervention for left main coronary artery disease: a substudy of the SYNTAX trial (synergy between percutaneous coronary intervention with taxus and cardiac surgery), J. Am. Coll. Cardiol. Intv. 6 (2013) 1250–1260.
[25] Y.H. Kim, D.W. Park, S.W. Lee, S.C. Yun, C.W. Lee, M.K. Hong, et al., Long-term safety and effectiveness of unprotected left main coronary stenting with drug-eluting stents compared with bare-metal stents, Circulation 120 (2009) 400–407. [26] T. Palmerini, A. Marzocchi, C. Tamburino, I. Sheiban, M. Margheri, G. Vecchi, et al., Impact of bifurcation technique on 2-year clinical outcomes in 773 patients with distal unprotected left main coronary artery stenosis treated with drug-eluting stents, Circ. Cardiovasc. Interv. 1 (2008) 185–192. [27] S.J. Kang, J.M. Ahn, H. Song, W.J. Kim, J.Y. Lee, D.W. Park, et al., Comprehensive intravascular ultrasound assessment of stent area and its impact on restenosis and adverse cardiac events in 403 patients with unprotected left main disease, Circ. Cardiovasc. Interv. 4 (2011) 562–569. [28] D. Carrie, H. Eltchaninoff, T. Lefevre, M. Silvestri, P. Brunel, J. Fajadet, et al., Early and long-term results of unprotected left main coronary artery stenosis with paclitaxeleluting stents: the FRIEND (French multicentre RegIstry for stenting of uNprotecteD LMCA stenosis) registry, EuroIntervention 7 (2011) 680–688. [29] S.L. Chen, T. Santoso, J.J. Zhang, F. Ye, Xu YW, Q. Fu, et al., A randomized clinical study comparing double kissing crush with provisional stenting for treatment of coronary bifurcation lesions: results from the DKCRUSH-II (double kissing crush versus provisional stenting technique for treatment of coronary bifurcation lesions) trial, J. Am. Coll. Cardiol. 57 (2011) 914–920. [30] A. Colombo, E. Bramucci, S. Sacca, R. Violini, C. Lettieri, R. Zanini, et al., Randomized study of the crush technique versus provisional side-branch stenting in true coronary bifurcations: the CACTUS (coronary bifurcations: application of the crushing technique using sirolimus-eluting stents) study, Circulation 119 (2009) 71–78. [31] M.C. Morice, T.E. Feldman, M.J. Mack, E. Stahle, D.R. Holmes, A. Colombo, et al., Angiographic outcomes following stenting or coronary artery bypass surgery of the left main coronary artery: fifteen-month outcomes from the synergy between PCI with TAXUS express and cardiac surgery left main angiographic substudy (SYNTAX-LE MANS), EuroIntervention 7 (2011) 670–679. [32] N. Salvatella, M.C. Morice, O. Darremont, M. Tafflet, P. Garot, J.L. Leymarie, et al., Unprotected left main stenting with a second-generation drug-eluting stent: oneyear outcomes of the LEMAX pilot study, EuroIntervention 7 (2011) 689–696. [33] B.K. Koo, K.W. Park, H.J. Kang, Y.S. Cho, W.Y. Chung, T.J. Youn, et al., Physiological evaluation of the provisional side-branch intervention strategy for bifurcation lesions using fractional flow reserve, Eur. Heart J. 29 (2008) 726–732. [34] M.C. Morice, P.W. Serruys, A.P. Kappetein, T.E. Feldman, E. Stahle, A. Colombo, et al., Five-year outcomes in patients with left main disease treated with either percutaneous coronary intervention or coronary artery bypass grafting in the synergy between percutaneous coronary intervention with taxus and cardiac surgery trial, Circulation 129 (2014) 2388–2394. [35] Y.H. Kim, D.W. Park, J.M. Ahn, S.C. Yun, H.G. Song, J.Y. Lee, et al., Everolimus-eluting stent implantation for unprotected left main coronary artery stenosis. The PRECOMBAT-2 (premier of randomized comparison of bypass surgery versus angioplasty using sirolimus-eluting stent in patients with left main coronary artery disease) study, J. Am. Coll. Cardiol. Intv. 5 (2012) 708–717. [36] K. Takagi, A. Ielasi, J. Shannon, A. Latib, C. Godino, G. Davidavicius, et al., Clinical and procedural predictors of suboptimal outcome after the treatment of drug-eluting stent restenosis in the unprotected distal left main stem: the Milan and NewTokyo (MITO) registry, Circ. Cardiovasc. Interv. 5 (2012) 491–498. [37] S.J. Park, Y.H. Kim, D.W. Park, S.W. Lee, W.J. Kim, J. Suh, et al., Impact of intravascular ultrasound guidance on long-term mortality in stenting for unprotected left main coronary artery stenosis, Circ. Cardiovasc. Interv. 2 (2009) 167–177. [38] Y. Fujino, G.F. Attizzani, H.G. Bezerra, W. Wang, S. Tahara, H. Yamamoto, et al., Serial assessment of vessel interactions after drug-eluting stent implantation in unprotected distal left main coronary artery disease using frequency-domain optical coherence tomography, J. Am. Coll. Cardiol. Intv. 6 (2013) 1035–1045. [39] Y. Fujino, H.G. Bezerra, G.F. Attizzani, W. Wang, H. Yamamoto, D. Chamie, et al., Frequency-domain optical coherence tomography assessment of unprotected left main coronary artery disease-a comparison with intravascular ultrasound, Catheter. Cardiovasc. Interv. 82 (2013) E173–83.
Please cite this article as: H. Kawamoto, et al., Provisional versus elective two-stent strategy for unprotected true left main bifurcation lesions: Insights from a FAILS-2 sub-study, Int J Cardiol (2017), https://doi.org/10.1016/j.ijcard.2017.09.207
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Provisional versus elective two-stent strategy for unprotected true left main bifurcation lesions: Insights from a FAILS-2 sub-study Hiroyoshi Kawamoto a,b,c, Alaide Chieffo a, Fabrizio D'Ascenzo d, Richard J. Jabbour a,b, Toru Naganuma c, Enrico Cerrato e, Fabrizio Ugo f, Marco Pavani d, Ferdinando Varbella e, Giacomo Boccuzzi f, Mauro Pennone d, Roberto Garbo f, Federico Conrotto d, Giuseppe Biondi-Zoccai h, Maurizio D'Amico d, Claudio Moretti d, Javier Escaned g, Fiorenzo Gaita d, Sunao Nakamura c, Antonio Colombo a,⁎ a
IRCCS Ospedale San Raffaele, Milan, Italy EMO-GVM Centro Cuore Columbus, Milan, Italy c New Tokyo Hospital, Matsudo, Japan d Citta della Salute e della Scienza, Turin, Italy e Ospedale degli Infermi Rivoli, Turin, Italy f Ospedale San Giovanni Bosco, Turin, Italy g Hospital San Carlos, Madrid, Spain h Sapienza University of Rome, Latina, Italy b
a r t i c l e
i n f o
Article history: Received 14 May 2017 Received in revised form 26 August 2017 Accepted 18 September 2017 Available online xxxx Keywords: Unprotected left main coronary artery True bifurcation lesions Drug-eluting stent Percutaneous coronary intervention
a b s t r a c t Background: This study sought to investigate the optimal percutaneous coronary intervention (PCI) strategy for true unprotected left main coronary artery (ULMCA) bifurcations. Methods: The FAILS-2 was a retrospective multi-center study including patients with ULMCA disease treated with second-generation drug-eluting stents. Of these, we compared clinical outcomes of a provisional strategy (PS; n = 216) versus an elective two-stent strategy (E2S; n = 161) for true ULMCA bifurcations. The primary endpoint was the incidence of major adverse cardiac events (MACEs) at 3-years. We further performed propensity-score adjustment for clinical outcomes. Results: There were no significant differences between the groups in terms of patient and lesion characteristics. 9.7% of patients in the PS group crossed over to a provisional two-stent strategy. MACEs were not significantly different between groups (MACE at 3-year; PS 28.1% vs. E2S 28.9%, adjusted p = 0.99). The rates of target lesion revascularization (TLR) on the circumflex artery (LCX) were numerically high in the E2S group (LCX-TLR at 3years; PS 11.8% vs. E2S 16.6%, adjusted p = 0.51). Conclusions: E2S was associated with a comparable MACE rate to PS for true ULMCA bifurcations. The rates of LCX-TLR tended to be higher in the E2S group although there was no statistical significance. Condensed abstract: This study sought to compare the clinical outcomes of a provisional strategy (PS) with an elective two-stent strategy (E2S) for the treatment of true unprotected left main coronary artery bifurcations. 377 Patients (PS 216 vs. E2S 161 patients) were evaluated, and 9.7% in the PS group crossed over to a twostent strategy. E2S was associated with a similar major adverse cardiac event rate at 3-years when compared to the PS strategy (PS 28.1% vs. E2S 28.9%, p = 0.99). However, the left circumflex artery TLR rate at 3-year tended to be higher in the E2S group (PS 11.8% vs. E2S 16.6%, p = 0.51). © 2017 Published by Elsevier Ireland Ltd.
1. Introduction
Abbreviations: ULMCA, unprotected left main coronary artery; PS, provisional stenting strategy; E2S, elective two-stent strategy; MACEs, major adverse cardiac events; TLR, target lesion revascularization. ⁎ Corresponding author at: IRCCS Ospedale San Raffaele, via Olgettina 60, 20132 Milano, Italy. E-mail address: [email protected] (A. Colombo).
Percutaneous coronary intervention (PCI) using drug-eluting stents (DES) has become an alternative for unprotected left main coronary artery (ULMCA) disease in patients with low-to-intermediate SYNTAX scores [1]. Previous studies have shown that PCI for ostial and/or midshaft lesions in ULMCA disease is associated with comparable clinical outcomes to coronary artery bypass grafting (CABG) [2,3]. However, the majority of stenoses involve distal ULMCA bifurcations, which are
https://doi.org/10.1016/j.ijcard.2017.09.207 0167-5273/© 2017 Published by Elsevier Ireland Ltd.
Please cite this article as: H. Kawamoto, et al., Provisional versus elective two-stent strategy for unprotected true left main bifurcation lesions: Insights from a FAILS-2 sub-study, Int J Cardiol (2017), https://doi.org/10.1016/j.ijcard.2017.09.207
2
H. Kawamoto et al. / International Journal of Cardiology xxx (2017) xxx–xxx
associated with an increase in procedural complexity when compared to ostial and/or mid-shaft lesions [4,5]. In addition, true bifurcations of the distal ULMCA are associated with higher rates of target lesion revascularization (TLR) [6]. Although a provisional strategy is currently recommended for most ULMCA bifurcation lesions [7–11], a systematic two-stent strategy remains a treatment option when treating complex bifurcations (e.g. true bifurcation lesions) to reduce the risk of acute left circumflex artery (LCX) occlusion. Recently, the EBC TWO (European Bifurcation Coronary TWO) randomized study, which compared provisional versus systematic culotte stenting for non-ULMCA true bifurcations reported comparable outcomes at 1-year [12]. However, little is known regarding the optimal strategy and clinical outcomes following different PCI strategies for true ULMCA bifurcations [13]. EBC MAIN study (European Bifurcation Club Left Main Study; ClinicalTrials.gov NCT02497014) is currently on going and will be the first randomized clinical trial to evaluate the optimal stenting strategy in true ULMCA bifurcation lesions [14]. Therefore, the aim of this study was to investigate mid-term outcomes of a provisional strategy (PS) versus an elective two-stent strategy (E2S) for true ULMCA bifurcations treated with second-generation DES from a multi-center registry. 2. Methods 2.1. Study population The FAILS 2 (Failure in Left Main Study with the second generation stents) study is a multi-center registry retrospectively including all consecutive patients with ULMCA stenoses treated with second-generation DES between July 2006 and March 2015. This study initially aimed to evaluate the incidence, clinical presentation and prognosis of restenosis after treatment of ULMCA disease with second-generation DES [15]. Of these, we compared clinical outcomes between a PS and an E2S for true ULMCA bifurcations. Five European centers and one Japanese center were involved. The indication to perform PCI rather than CABG was decided at each individual center. The decision to opt for a provisional or elective two-stent strategy was at the operators' discretion. In general, an E2S was employed when there was severe stenosis at the ostium of LCX or diffuse disease extending from the LCX ostium. Using the provisional strategy, stenting to the LCX was indicated by major dissections or compromised flow following side branch dilatation or kissing balloon inflation. All clinical or procedural data were site-reported. Clinical data during follow-up were obtained from hospital visits or telephonic contacts. Exclusion criteria for this sub-study included PCI for ostial/body lesions, non-true ULMCA bifurcations, acute myocardial infarction (MI), cardiogenic shock or unreviewable techniques for ULMCA bifurcations. We compared PS with E2S by intention-to-treat for true ULMCA bifurcations. 2.2. Study definitions ULMCA lesions were classified by visual assessment at each center according to the Medina classification [16]. A true bifurcation lesion was defined as Medina class 1-1-1, 1-0-1, or 0-1-1 [16]. MACEs were defined as a composite of all-cause death, MI, and overall target lesion revascularization (TLR). Overall TLR was defined as either repeat PCI or CABG for the ULMCA lesion stented previously including the proximal and distal edge segments of the stent, or at the ostium of the side branches (SBs). Furthermore, TLR of the left main stem (LM-TLR), LAD (LAD-TLR), and LCX (LCX-TLR) were separately evaluated. Death was considered cardiac in origin unless obvious non-cardiac causes were identified. The definition of MI was according to the Third Universal Definition of Myocardial Infarction [17]. Stent thrombosis (ST) was classified according to the Academic Research Consortium (ARC) definitions [18]. 2.3. Study endpoints The primary endpoint was the rate of MACE at 3-years. The secondary endpoints were each component of MACE, cardiac death, LM-TLR, LAD-TLR, LCX-TLR, and definite or probable ST. 2.4. Statistical analysis Continuous variables are presented as the mean ± standard deviation (SD). Differences in continuous variables between the groups were calculated with the Student t-test. Categorical data were compared using the chi-square or Fisher's exact tests. The cumulative clinical events were generated with Kaplan–Meier method, and reported as hazard ratios (HR; elective two-stent vs. provisional strategy) and 95% confidence interval (CI) using Cox regression analysis. Follow-up was censored at the date of the last followup or at 3 years. Because of the nonrandomized nature of this study, clinical outcomes were evaluated between unadjusted groups and again following propensity-score
adjustment. Adjusted ratios were calculated using Cox regression analysis with elective two-stent strategy (vs. provisional strategy) as a fixed dummy covariate and propensity score as the stratification variable [19,20]. Propensity score were calculated using covariates as following; stent-drug, Medina classification, LCX proximal disease, male, age, hypertension, diabetes mellitus, insulin-dependent diabetes mellitus, current smoking, dyslipidemia, previous myocardial infarction, previous PCI, chronic obstructive pulmonary disease, previous stroke, low ejection fraction (b35%), low estimated glomerular filtration rate (GFR) b60 ml/min/1.73 m2, acute coronary syndrome, SYNTAX score, radial access, IVUS use, three vessel disease, and treated vessel. The C-statistic was 0.66, and the Hosmer–Lemeshow p-value was 0.28, indicating good discrimination and calibration of the propensity-matching model, respectively. We performed multivariable Cox regression analysis to identify the independent risk factors of MACE during follow-up period. Variables used in the Cox regression model were all variables with values of p b 0.10 at univariate analysis and those judged to be clinically important. To avoid over-fitting, the number of independent variables entered into the final multivariable logistic regression model was limited to 1 for every 8–10 events. Analyses were performed using SPSS version 21.0 (SPSS Inc., Chicago, IL, USA). All reported p values were 2-sided, and values of p b 0.05 regarded as statistically significant.
Table 1 Baseline clinical and lesion characteristics.
Clinical characteristics Male Age (years) Hypertension Dyslipidemia Current smoker Diabetes Insulin-dependent Chronic kidney disease eGFR, ml/min/1.73 m2 eGFR b 60 ml/min/1.73 m2 Previous PCI Previous MI COPD Previous stroke Clinical presentation Stable angina Unstable angina LVEF (%) Lesion characteristics LAD disease LCX disease RCA disease 3VD SYNTAX score Low SYNTAX score Intermediate SYNTAX score High SYNTAX score (N33) IVUS Trans radial approach Stent type Biolimus-eluting stent Everolimus-eluting stent Zotarolimus-eluting stent Others Stent techniques Provisional two stent Crush Culotte Mini-crush T V Medina classification 0,1,1 1,0,1 1,1,1 LCX proximal disease (non-ostial)
Provisional (n = 216)
Elective two-stent (n = 161)
p Value
170 (78.7) 70.8 ± 9.9 181 (83.8) 150 (69.8) 24 (12.3) 98 (46.7) 30 (14.3)
128 (79.5) 70.4 ± 10.4 126 (78.3) 104 (66.2) 25 (18.2) 59 (38.6) 15 (9.9)
0.85 0.74 0.17 0.47 0.13 0.12 0.21
63.6 ± 29.4 91 (48.7) 114 (53.0) 80 (37.4) 17 (8.5) 13 (6.3)
60.4 ± 25.3 63 (47.4) 79 (51.0) 43 (28.1) 6 (4.5) 12 (8.3)
0.31 0.82 0.7 0.06 0.16 0.47 0.81
164 (75.9) 52 (24.1) 55.0 ± 12.5
124 (77.0) 37 (23.0) 55.6 ± 9.9
190 (88.0) 187 (86.6) 165 (76.4) 136 (63.0) 29.0 ± 10.0 53 (26.8) 70 (35.4) 75 (37.9) 48 (22.2) 24 (11.2)
134 (84.3) 135 (84.9) 132 (82.5) 106 (66.3) 29.9 ± 10.0 36 (23.5) 57 (37.3) 60 (39.2) 44 (27.3) 21 (13.1)
25 (11.6) 171 (79.2) 17 (7.9) 3 (1.4)
30 (18.6) 108 (67.1) 18 (11.2) 4 (2.5)
0.65
0.3 0.65 0.15 0.51 0.4 0.79
0.25 0.57 0.07
21 (9.7) 12 (7.5) 53 (32.9) 64 (39.8) 23 (14.3) 9 (5.6) 0.36 23 (10.6) 34 (15.7) 159 (73.6) 131 (60.6)
24 (14.9) 20 (12.4) 117 (72.7) 95 (59.7)
0.86
Data are presented as absolute numbers and percentages or mean ± standard deviation. eGFR = estimated glomerular filtration rate; PCI = percutaneous coronary intervention; MI = myocardial infarction; COPD = chronic obstructive pulmonary disease; LVEF = left ventricular ejection fraction; LAD = left anterior descending artery; LCX = left circumflex coronary artery; RCA = right coronary artery; VD = vessel disease; IVUS = intravascular ultrasound.
Please cite this article as: H. Kawamoto, et al., Provisional versus elective two-stent strategy for unprotected true left main bifurcation lesions: Insights from a FAILS-2 sub-study, Int J Cardiol (2017), https://doi.org/10.1016/j.ijcard.2017.09.207
H. Kawamoto et al. / International Journal of Cardiology xxx (2017) xxx–xxx
3
significantly higher in the PS group (PS 5.7% vs. E2S 0.8% at 1-year, and PS 8.3% vs. E2S 0.8% at 3-years, HR 0.09; 95% CI 0.01–0.66, p = 0.02). The rate of TLR at the LCX tended to be higher in the E2S group compared to the PS group (PS 9.6% vs. E2S 13.4% at 1-year, and PS 11.8% vs. E2S 16.6% at 3-years, HR 1.44; 95% CI 0.78–2.65, p = 0.25). Following propensity-score adjustment, there were no statistical differences regarding clinical outcomes including cardiac death (HR 0.33; 95% CI; 0.04–2.64, adjusted p value = 0.29). Amongst patients in the PS group, patients who required provisional two-stent strategy had a high LCX-TLR rate (n = 4, 21.5% at 1- and 3-years) (Fig. 1). When comparing groups as treated (single versus two-stent [provisional and elective]), there was a trend towards a higher LCX-TLR rate if a two-stent strategy was utilized (single-stent; 8.1% at 1-year and 10.6% at 3-year, two-stent; 14.5% at 1-year and 17.3% at 3-year, p = 0.11, adjusted p value = 0.08).
3. Results 3.1. Baseline characteristics Amongst a total of 1270 patients in this registry, ostial/body lesions (n = 199), non-true ULMCA bifurcations (n = 528), acute myocardial infarction or cardiogenic shock (n = 125), unreviewable techniques (n = 41) for ULMCA bifurcations were excluded. 377 patients (29.7%) were included in the final analysis (216 patients in the PS, and 161 patients in the E2S group). The median follow-up period was 818 (IQR 341–1244) days. Patient and lesion characteristics were comparable between the two groups (Table 1). The prevalence of diabetes and previous MI tended to be higher in the PS group (diabetes; PS 46.7% vs. E2S 38.6%, p = 0.12, and previous MI; 37.4% vs. 28.1%, p = 0.06). No difference was observed in SYNTAX score was 29.0 ± 10.0 in the PS group and 29.9 ± 10.0 in the E2S group (p = 0.40). The majority of distal ULM lesions were Medina 1,1,1 true bifurcations (Medina 1,1,1; PS 73.6% vs. E2S 72.7%, overall p value = 0.36). Intravascular ultrasound (IVUS) was utilized in 22.2% and 27.3% in the PS and E2S groups, respectively (p = 0.25). The everolimus-eluting stent was the most commonly used stent in both groups (PS 79.2% vs. E2S 67.1%, overall p value = 0.07). In the PS group, 9.7% of true ULMCA bifurcations crossed over to a provisional two-stent strategy. By contrast, the most commonly used stenting techniques in the E2S group were the mini-crush (39.8%), culotte (32.9%), and T-stenting (14.3%).
3.3. Predictors of MACE Univariate analysis revealed that predictors of MACE were diabetes (HR 1.94; 95% CI 1.26–2.99, p = 0.003), left ventricular ejection fraction b35% (HR 2.48; 95% CI 1.35–4.57, p = 0.004), chronic kidney disease (HR 1.90; 95% CI 1.18–3.07, p = 0.01), and unstable angina (HR 1.80; 95% CI 1.14–2.84, p = 0.01). Multivariable analyses indicated that diabetes, LVEF b 35%, and unstable angina were independent predictors of MACE [diabetes (HR 2.40; 95% CI 1.45–3.95, p = 0.001); LVEF b 35% (HR 2.38; 95% CI 1.12–4.76, p = 0.02); unstable angina (HR 1.79; 95% CI: 1.06–3.04, p = 0.03)] (Table 3).
3.2. Clinical outcomes
4. Discussion
Clinical event rates at 1- and 3-years are described in Table 2, with corresponding Kaplan–Meier curves shown in Fig. 1. MACE rates at 1and 3-years were comparable (PS 19.1% vs. E2S 17.2% at 1-year, and PS 28.1% vs. E2S 28.9% at 3-years, HR 0.94; 95% CI 0.61–1.44, p = 0.76) between groups. In addition, there were no significant differences in any of the other clinical outcomes expect for cardiac death that was
The main findings of this study are the following: 1) MACE and overall TLR rates between a provisional and elective two-stent strategy for true ULMCA bifurcations treated with second-generation DES were comparable during 3-year follow-up; 2) there was a trend towards a
Table 2 Clinical outcomes.
MACE At 1 year At 3 years All-cause death At 1 year At 3 years Cardiac death At 1 year At 3 years Overall TLR At 1 year At 3 years LMCA-TLR At 1 year At 3 years LAD-TLR At 1 year At 3 years LCX-TLR At 1 year At 3 years Myocardial infarction At 1 year At 3 years Definite or probable ST At 1 year At 3 years
Provisional (n = 216)
Elective two-stent (n = 161)
Elective two-stent vs. provisional
Absolute number
Cumulative incidence
Absolute number
Cumulative incidence
HR (95% CI)
p Value
Adjusted HR (95% CI)
p Value
37 50
19.1 28.1
24 35
17.2 28.9
0.94 (0.61–1.44)
0.76
1.01 (0.56–1.80)
0.99
15 23
7.6 13.4
5 12
3.5 11.3
0.69 (0.34–1.38)
0.29
0.93 (0.35–2.50)
0.89
11 15
5.7 8.3
1 1
0.8 0.8
0.09 (0.01–0.66)
0.02
0.33 (0.04–2.64)
0.29
23 30
12.9 17.9
19 24
14 19
1.08 (0.63–1.85)
0.78
0.99 (0.49–1.98)
0.97
3 7
1.7 4.6
2 3
1.4 2.2
0.56 (0.15–2.17)
0.40
0.38 (0.04–3.34)
0.38
8 9
4.5 5.2
2 3
1.4 2.3
0.44 (0.12–1.61)
0.21
0.69 (0.14–3.39)
0.65
17 20
9.6 11.8
18 21
13.4 16.6
1.44 (0.78–2.65)
0.25
1.29 (0.60–2.76)
0.51
4 6
2 3.3
0 0
0 0
0.02 (0.00–14.83)
0.24
NA
0.97
6 6
3 3
0 0
0 0
0.02 (0.00–14.30)
0.24
NA
0.98
MACE = major adverse cardiac event; TLR = target lesion revascularization; LMCA = left main coronary artery; LAD = left anterior descending artery; LCX = left circumflex coronary artery; ST = stent thrombosis; HR = hazard ratio; CI = confidence interval.
Please cite this article as: H. Kawamoto, et al., Provisional versus elective two-stent strategy for unprotected true left main bifurcation lesions: Insights from a FAILS-2 sub-study, Int J Cardiol (2017), https://doi.org/10.1016/j.ijcard.2017.09.207
4
H. Kawamoto et al. / International Journal of Cardiology xxx (2017) xxx–xxx
Fig. 1. Clinical outcomes. Kaplan–Meier curves are shown for (A) major adverse cardiac events (MACEs), (B) all-cause death, (C) target lesion revascularization (TLR) of the left circumflex coronary artery (LCX) by intention-to-treat analysis, and (D) TLR of the LCX according to as treated stenting techniques. Event rates shown in the figures are those calculated without propensity-score adjustment. PCI = percutaneous coronary intervention; ULMCA = unprotected left main coronary artery; 1S = single-stenting; 2S = two-stenting.
lower LCX TLR rate with a provisional single-stent strategy but this did not reach statistical significance; 3) diabetes, low ejection fraction, and unstable angina were independent predictors of MACE. 4.1. Provisional versus two-stent strategy A provisional single-stent strategy is generally considered to be the default strategy for the majority of bifurcation lesions including ULMCA lesions [8–11,21,22]. However, distal ULMCA bifurcation lesions have several anatomic features that should be differentiated from other bifurcations due to the following reasons: 1) it is the largest and the most proximal bifurcation in the coronary artery tree; 2) side branch (LCX) occlusion can be a rare but fatal complication during PCI; 3) the bifurcation angle is generally wider when compared to other bifurcations and 4) the ostium of LCX has hinge motion which can result in high restenosis rate [23,24]. Some retrospective studies have indicated that E2S is inferior to a single stent strategy for distal ULMCA disease, even with second-generation DES [10,11,25,26]. Furthermore, true ULMCA bifurcations were associated with high rates of TLR [6,27].
However, no randomized or retrospective studies have investigated the optimal stenting strategy for ‘true’ ULMCA bifurcation lesions. Of note, in this registry the incidence of MACE and overall TLR were similar between the PS and E2S during 3-year follow-up. It should be noted that the crossover rate to provisional two-stent from provisional single-stent strategy was only 9.7%. In the previous studies, a second stent into the SB was required in 17–51% of LMCA lesions treated with a single-stent strategy [28–32]. Even though there may have been a greater effort to avoid two-stent, clinical outcomes were comparable between the two groups and also consistent following propensity-score adjustment. 4.2. LCX TLR As expected, MACE was predominantly triggered by TLR. As previously reported [11,22,26], side branch restenosis is considered a major limitation for ULMCA PCI, especially for a two-stent strategy. Our study suggests that the provisional strategy for ULMCA when possible seems to be beneficial in terms of TLR rate on the LCX although there was no statistical difference compared to the E2S strategy. Of note,
Please cite this article as: H. Kawamoto, et al., Provisional versus elective two-stent strategy for unprotected true left main bifurcation lesions: Insights from a FAILS-2 sub-study, Int J Cardiol (2017), https://doi.org/10.1016/j.ijcard.2017.09.207
H. Kawamoto et al. / International Journal of Cardiology xxx (2017) xxx–xxx
5. Limitations
Table 3 Cox regression analyses for major adverse cardiac events. Covariates
Elective two-stent Male Age Hypertension Diabetes Current smoking Dyslipidemia Previous MI Previous PCI Low EF (b35%) eGFR b60 ml/min/1.73 m2 Unstable angina High SYNTAX score Femoral access (vs. radial) IVUS Three vessel disease Medina 1,1,1
Univariate
5
Multivariable
Hazard ratio (95% CI)
p Value Hazard ratio (95% CI)
0.94 (0.61–1.44) 0.63 (0.39–1.01) 1.02 (1.00–1.04) 1.22 (0.69–2.16) 1.94 (1.26–2.99) 0.72 (0.37–1.42) 0.85 (0.54–1.33) 1.17 (0.75–1.84) 0.88 (0.57–1.36) 2.48 (1.35–4.57) 1.90 (1.18–3.07) 1.80 (1.14–2.84) 1.49 (0.97–2.28) 0.91 (0.44–1.88) 0.61 (0.35–1.09) 1.12 (0.70–1.79) 1.10 (0.68–1.78)
0.76 0.05 0.1 0.5 0.003 0.35 0.48 0.49 0.57 0.004 0.01 0.01 0.07 0.79 0.09 0.64 0.69
p Value
1.14 (0.71–1.86) 0.58 0.80 (0.46–1.41) 0.44 1.00 (0.98–1.03) 0.98 2.40 (1.45–3.95) 0.001
2.38 (1.12–4.76) 1.59 (0.95–2.67) 1.79 (1.06–3.04) 1.22 (0.74–2.01)
0.02 0.08 0.03 0.43
0.75 (0.41–1.38) 0.35
CI = confidence interval; MI = myocardial infarction; PCI = percutaneous coronary intervention; EF = ejection fraction; eGFR = estimated glomerular filtration rate; IVUS = intravascular ultrasound.
The present study had the several limitations inherent to a nonrandomized, retrospective study. Despite the use of propensity-score adjustment, unmeasured confounders might have affected clinical outcomes. Secondly, procedural details such as the rates of kissing-balloon inflations, proximal optimization technique, or the usage of other devices were not available in all patients. Thirdly, the follow-up protocol was not standardized, especially in terms of angiographic follow-up and a high rate of planned angiographic follow-up in the E2S group may have contributed to TLR events. Finally, the varying experience of each operator or center may have affected outcomes that we could not evaluate in this registry. 6. Conclusions In patients undergoing PCI with second-generation DES for true ULMCA bifurcation lesions, E2S was associated with a comparable MACE rate to a PS strategy. This was consistent following propensityscore adjustment. However, the rates of TLR at the LCX tended to be higher in the E2S group. Randomized studies are required to elucidate the optimal PCI strategy for true ULMCA bifurcation lesions. Financial disclosures
crossing over to a two-stent strategy from a single-stent strategy had a high rate of restenosis at the LCX. These data suggest that greater effort should be paid to avoid a second stent to the LCX when a provisional stent strategy is employed. The severity of a SB ostial stenosis is commonly over-estimated when evaluated by angiography alone in comparison to physiological assessment [33]. Therefore, fractional flow reserve (FFR) or intravascular imaging might reduce the incidence of SB stenting, and therefore translate into better clinical outcomes. In addition, previous studies have demonstrated that TLR is associated with rate of planned angiographic follow-up [34–36]. However, we have to take into account that angiographic follow-up was more frequently performed in the E2S group (E2S 64.4% vs. PS 53.5%, p = 0.03). We cannot exclude that this could have affected TLR rates, especially at the LCX. This lead-time bias occurred ‘after’ the PCI procedure and therefore could not be taken into account using propensity-score adjustment. 4.3. Intravascular imaging Our study included patients treated in high-volume centers in Europe and Japan so that it represents contemporary PCI practice for ULMCA bifurcations. However, it is discouraging that the usage of intravascular ultrasound (IVUS) was only 24.4% even when treating true ULMCA bifurcations. IVUS is considered as an essential tool for ULMCA disease [37] and IVUS (or optical coherence tomography; OCT) seems to be useful in obtaining better clinical outcomes in addition to avoiding a second stent at the LCX [38,39]. IVUS use did not remain an independent predictor for MACE [HR 0.75 (0.41–1.38), p = 0.35] in our study. Larger studies are needed to demonstrate the impact of intravascular imaging when treating complex ULMCA disease. 4.4. Ongoing research The EBC MAIN is an ongoing, prospective, randomized study comparing a planned single-stent strategy to planned dual-stent strategy [14]. In this randomized study, although the planned two-stent technique is at the discretion of the operator, culotte, DK mini-crush, or T-stenting are recommended, and similar to our retrospective study. Although our study did not have information whether double kissing inflations were performed or not, our results are helpful and demonstrate useful insights when treating true ULMCA bifurcation lesions. The results from EBC MAIN study are eagerly awaited.
None. Conflict of interest statement All authors have no conflicts of interest to declare. Role of the funding source No funding was received related to this manuscript. Acknowledgements None. References [1] S. Windecker, P. Kolh, F. Alfonso, J.P. Collet, J. Cremer, V. Falk, et al., ESC/EACTS guidelines on myocardial revascularization: the task force on myocardial revascularization of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS) developed with the special contribution of the European Association of Percutaneous Cardiovascular Interventions (EAPCI), Eur. Heart J. 35 (2014) 2541–2619. [2] T. Naganuma, A. Chieffo, E. Meliga, D. Capodanno, S.J. Park, Y. Onuma, et al., Longterm clinical outcomes after percutaneous coronary intervention versus coronary artery bypass grafting for ostial/midshaft lesions in unprotected left main coronary artery from the DELTA registry: a multicenter registry evaluating percutaneous coronary intervention versus coronary artery bypass grafting for left main treatment, J. Am. Coll. Cardiol. Intv. 7 (2014) 354–361. [3] D.W. Park, K.B. Seung, Y.H. Kim, J.Y. Lee, W.J. Kim, S.J. Kang, et al., Long-term safety and efficacy of stenting versus coronary artery bypass grafting for unprotected left main coronary artery disease: 5-year results from the MAIN-COMPARE (revascularization for unprotected left main coronary artery stenosis: comparison of percutaneous coronary angioplasty versus surgical revascularization) registry, J. Am. Coll. Cardiol. 56 (2010) 117–124. [4] A. Chieffo, S.J. Park, M. Valgimigli, Y.H. Kim, J. Daemen, I. Sheiban, et al., Favorable long-term outcome after drug-eluting stent implantation in nonbifurcation lesions that involve unprotected left main coronary artery: a multicenter registry, Circulation 116 (2007) 158–162. [5] T. Palmerini, D. Sangiorgi, A. Marzocchi, C. Tamburino, I. Sheiban, M. Margheri, et al., Ostial and midshaft lesions vs. bifurcation lesions in 1111 patients with unprotected left main coronary artery stenosis treated with drug-eluting stents: results of the survey from the Italian Society of Invasive Cardiology, Eur. Heart J. 30 (2009) 2087–2094. [6] K. Tiroch, J. Mehilli, R.A. Byrne, S. Schulz, S. Massberg, K.L. Laugwitz, et al., Impact of coronary anatomy and stenting technique on long-term outcome after drug-eluting stent implantation for unprotected left main coronary artery disease, J. Am. Coll. Cardiol. Intv. 7 (2014) 29–36. [7] A. Chieffo, E. Meliga, A. Latib, S.J. Park, Y. Onuma, P. Capranzano, et al., Drug-eluting stent for left main coronary artery disease. The DELTA registry: a multicenter
Please cite this article as: H. Kawamoto, et al., Provisional versus elective two-stent strategy for unprotected true left main bifurcation lesions: Insights from a FAILS-2 sub-study, Int J Cardiol (2017), https://doi.org/10.1016/j.ijcard.2017.09.207
6
H. Kawamoto et al. / International Journal of Cardiology xxx (2017) xxx–xxx
registry evaluating percutaneous coronary intervention versus coronary artery bypass grafting for left main treatment, J. Am. Coll. Cardiol. Intv. 5 (2012) 718–727. [8] A. Colombo, J.W. Moses, M.C. Morice, J. Ludwig, D.R. Holmes Jr., V. Spanos, et al., Randomized study to evaluate sirolimus-eluting stents implanted at coronary bifurcation lesions, Circulation 109 (2004) 1244–1249. [9] T. Kimura, T. Morimoto, Y. Nakagawa, K. Kawai, S. Miyazaki, T. Muramatsu, et al., Very late stent thrombosis and late target lesion revascularization after sirolimuseluting stent implantation: five-year outcome of the j-Cypher Registry, Circulation 125 (2012) 584–591. [10] Y.B. Song, J.Y. Hahn, J.H. Yang, S.H. Choi, J.H. Choi, S.H. Lee, et al., Differential prognostic impact of treatment strategy among patients with left main versus non-left main bifurcation lesions undergoing percutaneous coronary intervention: results from the COBIS (Coronary Bifurcation Stenting) Registry II, J. Am. Coll. Cardiol. Intv. 7 (2014) 255–263. [11] M. Toyofuku, T. Kimura, T. Morimoto, Y. Hayashi, H. Ueda, K. Kawai, et al., Three-year outcomes after sirolimus-eluting stent implantation for unprotected left main coronary artery disease: insights from the j-Cypher registry, Circulation 120 (2009) 1866–1874. [12] D. Hildick-Smith, M.W. Behan, J.F. Lassen, A. Chieffo, T. Lefevre, G. Stankovic, et al., The EBC TWO Study (European Bifurcation Coronary TWO): a randomized comparison of provisional T-stenting versus a systematic 2 stent culotte strategy in large caliber true bifurcations, Circ. Cardiovasc. Interv. 9 (2016). [13] F. D'Ascenzo, M. Iannaccone, F. Giordana, A. Chieffo, S.O. Connor, L.C. Napp, et al., Provisional vs. two-stent technique for unprotected left main coronary artery disease after ten years follow up: a propensity matched analysis, Int. J. Cardiol. 211 (2016) 37–42. [14] A. Chieffo, D. Hildick-Smith, The European Bifurcation Club Left Main Study (EBC MAIN): rationale and design of an international, multicentre, randomised comparison of two stent strategies for the treatment of left main coronary bifurcation disease, EuroIntervention 12 (2016) 47–52. [15] F. D'Ascenzo, A. Chieffo, E. Cerrato, F. Ugo, M. Pavani, H. Kawamoto, et al., Incidence and management of restenosis after treatment of unprotected left main disease with second-generation drug-eluting stents (from failure in left main study with 2nd generation stents-cardiogroup III study), Am. J. Cardiol. 119 (2017) 978–982. [16] A. Medina, J. Suarez de Lezo, M. Pan, A new classification of coronary bifurcation lesions, Rev. Esp. Cardiol. 59 (2006) 183. [17] K. Thygesen, J.S. Alpert, A.S. Jaffe, M.L. Simoons, B.R. Chaitman, H.D. White, et al., Third universal definition of myocardial infarction, Eur. Heart J. 33 (2012) 2551–2567. [18] W.K. Laskey, C.W. Yancy, W.H. Maisel, Thrombosis in coronary drug-eluting stents: report from the meeting of the Circulatory System Medical Devices Advisory Panel of the Food and Drug Administration Center for Devices and Radiologic Health, December 7–8, 2006, Circulation 115 (2007) 2352–2357. [19] R.B. D'Agostino Jr., Propensity score methods for bias reduction in the comparison of a treatment to a non-randomized control group, Stat. Med. 17 (1998) 2265–2281. [20] D.B. Rubin, Estimating causal effects from large data sets using propensity scores, Ann. Intern. Med. 127 (1997) 757–763. [21] J.F. Lassen, N.R. Holm, A. Banning, F. Burzotta, T. Lefevre, A. Chieffo, et al., Percutaneous coronary intervention for coronary bifurcation disease: 11th consensus document from the European Bifurcation Club, EuroIntervention 12 (2016) 38–46. [22] K. Takagi, T. Naganuma, A. Chieffo, Y. Fujino, A. Latib, S. Tahara, et al., Comparison between 1- and 2-stent strategies in unprotected distal left main disease: the Milan and New-Tokyo registry, Circ. Cardiovasc. Interv. 9 (2016). [23] K. Amemiya, T. Domei, M. Iwabuchi, S. Shirai, K. Ando, M. Goya, et al., Impact of the bifurcation angle on major cardiac events after cross-over single stent strategy in unprotected left main bifurcation lesions: 3-dimensional quantitative coronary angiographic analysis, Am. J. Cardiovasc. Dis. 4 (2014) 168–176. [24] C. Girasis, V. Farooq, R. Diletti, T. Muramatsu, C.V. Bourantas, Y. Onuma, et al., Impact of 3-dimensional bifurcation angle on 5-year outcome of patients after percutaneous coronary intervention for left main coronary artery disease: a substudy of the SYNTAX trial (synergy between percutaneous coronary intervention with taxus and cardiac surgery), J. Am. Coll. Cardiol. Intv. 6 (2013) 1250–1260.
[25] Y.H. Kim, D.W. Park, S.W. Lee, S.C. Yun, C.W. Lee, M.K. Hong, et al., Long-term safety and effectiveness of unprotected left main coronary stenting with drug-eluting stents compared with bare-metal stents, Circulation 120 (2009) 400–407. [26] T. Palmerini, A. Marzocchi, C. Tamburino, I. Sheiban, M. Margheri, G. Vecchi, et al., Impact of bifurcation technique on 2-year clinical outcomes in 773 patients with distal unprotected left main coronary artery stenosis treated with drug-eluting stents, Circ. Cardiovasc. Interv. 1 (2008) 185–192. [27] S.J. Kang, J.M. Ahn, H. Song, W.J. Kim, J.Y. Lee, D.W. Park, et al., Comprehensive intravascular ultrasound assessment of stent area and its impact on restenosis and adverse cardiac events in 403 patients with unprotected left main disease, Circ. Cardiovasc. Interv. 4 (2011) 562–569. [28] D. Carrie, H. Eltchaninoff, T. Lefevre, M. Silvestri, P. Brunel, J. Fajadet, et al., Early and long-term results of unprotected left main coronary artery stenosis with paclitaxeleluting stents: the FRIEND (French multicentre RegIstry for stenting of uNprotecteD LMCA stenosis) registry, EuroIntervention 7 (2011) 680–688. [29] S.L. Chen, T. Santoso, J.J. Zhang, F. Ye, Xu YW, Q. Fu, et al., A randomized clinical study comparing double kissing crush with provisional stenting for treatment of coronary bifurcation lesions: results from the DKCRUSH-II (double kissing crush versus provisional stenting technique for treatment of coronary bifurcation lesions) trial, J. Am. Coll. Cardiol. 57 (2011) 914–920. [30] A. Colombo, E. Bramucci, S. Sacca, R. Violini, C. Lettieri, R. Zanini, et al., Randomized study of the crush technique versus provisional side-branch stenting in true coronary bifurcations: the CACTUS (coronary bifurcations: application of the crushing technique using sirolimus-eluting stents) study, Circulation 119 (2009) 71–78. [31] M.C. Morice, T.E. Feldman, M.J. Mack, E. Stahle, D.R. Holmes, A. Colombo, et al., Angiographic outcomes following stenting or coronary artery bypass surgery of the left main coronary artery: fifteen-month outcomes from the synergy between PCI with TAXUS express and cardiac surgery left main angiographic substudy (SYNTAX-LE MANS), EuroIntervention 7 (2011) 670–679. [32] N. Salvatella, M.C. Morice, O. Darremont, M. Tafflet, P. Garot, J.L. Leymarie, et al., Unprotected left main stenting with a second-generation drug-eluting stent: oneyear outcomes of the LEMAX pilot study, EuroIntervention 7 (2011) 689–696. [33] B.K. Koo, K.W. Park, H.J. Kang, Y.S. Cho, W.Y. Chung, T.J. Youn, et al., Physiological evaluation of the provisional side-branch intervention strategy for bifurcation lesions using fractional flow reserve, Eur. Heart J. 29 (2008) 726–732. [34] M.C. Morice, P.W. Serruys, A.P. Kappetein, T.E. Feldman, E. Stahle, A. Colombo, et al., Five-year outcomes in patients with left main disease treated with either percutaneous coronary intervention or coronary artery bypass grafting in the synergy between percutaneous coronary intervention with taxus and cardiac surgery trial, Circulation 129 (2014) 2388–2394. [35] Y.H. Kim, D.W. Park, J.M. Ahn, S.C. Yun, H.G. Song, J.Y. Lee, et al., Everolimus-eluting stent implantation for unprotected left main coronary artery stenosis. The PRECOMBAT-2 (premier of randomized comparison of bypass surgery versus angioplasty using sirolimus-eluting stent in patients with left main coronary artery disease) study, J. Am. Coll. Cardiol. Intv. 5 (2012) 708–717. [36] K. Takagi, A. Ielasi, J. Shannon, A. Latib, C. Godino, G. Davidavicius, et al., Clinical and procedural predictors of suboptimal outcome after the treatment of drug-eluting stent restenosis in the unprotected distal left main stem: the Milan and NewTokyo (MITO) registry, Circ. Cardiovasc. Interv. 5 (2012) 491–498. [37] S.J. Park, Y.H. Kim, D.W. Park, S.W. Lee, W.J. Kim, J. Suh, et al., Impact of intravascular ultrasound guidance on long-term mortality in stenting for unprotected left main coronary artery stenosis, Circ. Cardiovasc. Interv. 2 (2009) 167–177. [38] Y. Fujino, G.F. Attizzani, H.G. Bezerra, W. Wang, S. Tahara, H. Yamamoto, et al., Serial assessment of vessel interactions after drug-eluting stent implantation in unprotected distal left main coronary artery disease using frequency-domain optical coherence tomography, J. Am. Coll. Cardiol. Intv. 6 (2013) 1035–1045. [39] Y. Fujino, H.G. Bezerra, G.F. Attizzani, W. Wang, H. Yamamoto, D. Chamie, et al., Frequency-domain optical coherence tomography assessment of unprotected left main coronary artery disease-a comparison with intravascular ultrasound, Catheter. Cardiovasc. Interv. 82 (2013) E173–83.
Please cite this article as: H. Kawamoto, et al., Provisional versus elective two-stent strategy for unprotected true left main bifurcation lesions: Insights from a FAILS-2 sub-study, Int J Cardiol (2017), https://doi.org/10.1016/j.ijcard.2017.09.207
