International Journal of Cardiology 174 (2014) 13–17
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Dedicated two-stent technique in complex bifurcation percutaneous coronary intervention with use of everolimus-eluting stents: The EES-bifurcation study Nisharahmed I. Kherada, Samantha Sartori, Matthew I. Tomey, Marco G. Mennuni, Omar A. Meelu, Swathi Roy, Bibhu D. Mohanty, Usman Baber, Robert Pyo, Jason C. Kovacic, Joseph Sweeny, Pedro Moreno, Prakash Krishnan, George D. Dangas, Roxana Mehran ⁎, Samin K. Sharma, Annapoorna S. Kini The Zena and Michael A. Wiener Cardiovascular Institute, The Icahn School of Medicine at Mount Sinai, New York, NY, United States
a r t i c l e
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Article history: Received 13 December 2013 Accepted 9 March 2014 Available online 15 March 2014 Keywords: Bifurcation lesion Complex percutaneous coronary intervention Everolimus-eluting stent
a b s t r a c t Objectives: To compare the outcomes of initial one-stent (1S) versus dedicated two-stent (2S) strategies in complex bifurcation percutaneous coronary intervention (PCI) using everolimus-eluting stents (EES). Background: PCI of true bifurcation lesions is technically challenging and historically associated with reduced procedural success and increased restenosis. Prior studies comparing initial one-stent (1S) versus dedicated two-stent (2S) strategies using first-generation drug-eluting stents have shown no reduction in ischemic events and more complications with a 2S strategy. Methods: We performed a retrospective study of 319 consecutive patients undergoing PCI at a single referral center with EES for true bifurcation lesions, defined by involvement of both the main vessel (MV) and side branch (SB). Baseline, procedural characteristics, quantitative coronary angiography and clinical outcomes in-hospital and at one year were compared for patients undergoing 1S (n = 175) and 2S (n = 144) strategies. Results: Baseline characteristics were well-matched. 2S strategy was associated with greater SB acute gain (0.65 ± 0.41 mm vs. 1.11 ± 0.47 mm, p b 0.0001). In-hospital serious adverse events were similar (9% with 2S vs. 8% with 1S, p = 0.58). At one year, patients treated by 2S strategy had non-significantly lower rates of target vessel revascularization (5.8% vs. 7.4%, p = 0.31), myocardial infarction (7.8% vs. 12.2%, p = 0.31) and major adverse cardiovascular events (16.6% vs. 21.8%, p = 0.21). Conclusion: In this study of patients undergoing PCI for true coronary bifurcation lesions using EES, 2S strategy was associated with superior SB angiographic outcomes without excess complications or ischemic events at one year. © 2014 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Coronary bifurcation lesions account for approximately 20% of all percutaneous coronary interventions (PCI). True bifurcation lesions [1], defined by N 50% luminal diameter reduction within 5 mm of the bifurcation carina involving both the main vessel (MV) and side branch ostium (consistent with Medina classifications 1,1,1; 1,0,1; or 0,1,1) [2], pose challenges to PCI, including proximal–distal vessel mismatch, Abbreviations: 1S, initial one-stent; 2S, dedicated two-stent; DES, drug-eluting stents; EES, everolimus-eluting stents; FKBI, final kissing balloon inflation; MACE, major adverse cardiovascular events; MI, myocardial infarction; MV, main vessel; PCI, percutaneous coronary intervention; QCA, quantitative coronary angiography; SB, side branch; TLR, target lesion revascularization; TVR, target vessel revascularization. ⁎ Corresponding author at: Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1030, New York, NY 10029-6574, United States. Tel.: +1 212 659 9691; fax: +1 646 537 8547. E-mail address: [email protected] (R. Mehran).
http://dx.doi.org/10.1016/j.ijcard.2014.03.029 0167-5273/© 2014 Elsevier Ireland Ltd. All rights reserved.
complex angulation, calcification and tendency to plaque shift. Historically, bifurcation PCI has been associated with reduced procedural success and increased restenosis, particularly at side branch ostia. Although drug-eluting stents (DES) have reduced the rates of restenosis following complex PCI, including bifurcation PCI, stent implantation in side branch ostia is technically demanding, requiring special techniques to avoid main vessel compromise, inadequate coverage and under expansion [3]. It is controversial whether PCI for bifurcation lesions should preferentially involve an initial one-stent (1S) strategy with provisional stenting of the side branch or a dedicated two-stent (2S) strategy. In a recent meta-analysis of five studies evaluating 1145 patients undergoing bifurcation PCI (616 1S, 529 2S) with DES, there was no difference between strategies in rates of side branch or main vessel restenosis, target lesion revascularization (TLR) or all-cause mortality [4]. Generalization from these findings is limited, however, by exclusive use of firstgeneration DES, variable duration of follow-up and variable data reporting. In the SPIRIT-IV randomized controlled trial, second-
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generation everolimus-eluting stents (EES), in comparison with firstgeneration (paclitaxel-eluting) DES, resulted in lower rates of target lesion failure, with similar outcomes in simple and complex lesions [5]. In a meta-analysis of 13 randomized trials, EES were associated with the lowest risks among DES subtypes of both stent thrombosis and restenosis [6]. The objective of this study was to compare the efficacy and safety of 1S versus 2S strategies in patients undergoing true bifurcation PCI using EES in a tertiary referral center. 2. Methods 2.1. Study design and participants We conducted a retrospective cohort study of consecutive patients undergoing PCI for true bifurcation lesions using EES between February 2010 and December 2011 at a single academic medical center. Inclusion criteria included the presence of a de novo target lesion with true bifurcation morphology, as defined above and bifurcation PCI using only EES. We divided patients into two study groups based on retrospective determination of a dedicated 2S strategy or an initial 1S strategy (with provisional side branch stenting). Group assignment was determined based on review of procedural documentation and comprehensive assessment of technique as recorded via cineangiography. Exclusion criteria included the use of stents other than EES, small caliber MV (b2.5 mm) or SB (b2.0 mm) and ST-segment elevation myocardial infarction. All participants provided routine written informed consent at the time of PCI and the institutional review board provided approval for the study. 2.2. Study definitions and clinical endpoints Clinical outcomes were ascertained for the index hospitalization and at 1-year via our institution's Heart Care Plus database. Deaths were ascertained via the Social Security Death Index. The primary efficacy endpoint was major adverse cardiovascular events (MACE) at 1 year, defined as a composite of death, myocardial infarction (MI) and target-vessel revascularization (TVR). MI was defined as new pathologic Q waves in N2 contiguous leads (excluding periprocedural MI). Non-Q-wave MI (NQWMI) was defined as rise in creatine kinase-MB isoform (CK-MB) mass N8× the upper limit of normal together with clinical signs of MI, in the absence of pathologic Q waves. TLR was defined as repeat revascularization by PCI or surgery of the target segment (inclusive of 5 mm proximal or distal to the stent) for clinical indications and/or demonstration of inducible myocardial ischemia. TVR was defined as repeat revascularization by PCI or surgery of the target vessel for ischemia (excluding TLR). In hospital serious adverse events were defined as periprocedural death, MI, stroke, TVR by PCI or coronary artery bypass graft surgery, hemodialysis, congestive heart failure and blood transfusion. Periprocedural MI was defined as an increase in CK-MB mass ≥3× the upper limit of normal within 24 h of the index PCI. Stent thrombosis (ST) was defined using the Academic Research Consortium definition [7]. Acute gain from PCI was defined as the change in the minimum lumen diameter from baseline to the final procedural angiogram. 2.3. Quantitative coronary angiography Quantitative coronary angiography (QCA) was performed in all participants for baseline and final angiograms post-PCI. Analysis was conducted using dedicated software (QCA-QAngioXA 7.3, Medis, Leiden, Netherlands) using a standard analytic protocol developed in collaboration with Medis and performed by analysts (NK, MM) trained at the study site by an experienced operator (GD). Analysts were not blinded to procedural strategy or stenting technique, which was categorized according to published descriptions [8]. Intraprocedural complications were identified, including dissection, perforation, slowflow, no-reflow and abrupt closure, attributed to the MV or SB and classified as persistent or not. Measurements of bifurcation lesions were made using two segments: [1] a combined MV, comprised of the proximal MV (PMV) and distal MV (DMV), with boundaries defined by the 5 mm proximal and distal to the implanted stent; and [2] the SB, with boundaries defined by the ostium and 5 mm distal to the ballooned or stented area. QCA measurements included angulation between the DMV and SB, reference vessel diameter (RVD), minimal lumen diameter (MLD), percent diameter stenosis (%DS) and lesion length. 2.4. Statistical analysis Baseline demographic and clinical characteristics, QCA and procedural characteristics were tabulated for subjects undergoing 1S versus 2S strategies. Continuous variables are presented as mean (standard deviation) and compared using an unpaired Student's t-test. Categorical variables are presented as frequency (percentage) and compared using Pearson's chi-squared test. Survival analysis for 1S versus 2S strategies was performed using the Kaplan–Meier curves and the log-rank test. Multivariate analysis was performed using a Cox regression model, with candidate variables for analysis chosen via backward stepwise selection. Significance levels for removal and addition of covariates from the model were 0.1 and 0.2, respectively. p values b 0.05 were considered statistically significant. All statistical analyses were performed using STATA version 12.1 (StataCorp LP, College Station, Texas).
3. Results A total of 319 patients were analyzed, including 175 patients treated with an initial 1S strategy and 144 patients treated with a dedicated 2S strategy; 7 patients (4%) undergoing an initial 1S strategy crossed over to undergo placement of a second stent. Baseline demographic and clinical characteristics, including home medications and laboratory assays, were well-matched (Table 1), with the exception of New York Heart Association class III or IV symptoms of congestive heart failure, which were more common in patients undergoing a 1S strategy (10.3% vs. 4.2%, p = 0.03). The majority of patients presented with stable coronary artery disease (77%).
3.1. Angiographic and procedural characteristics Angiographic and procedural characteristics are presented in Table 2. Anatomic complexity was similar, as evidenced by no differences in SYNTAX score, which was b22 in both groups and ACC/AHA lesion classification. The majority of bifurcation lesions in both groups were located in the left anterior descending artery. Most bifurcation lesions were classified as Medina [1,1,1]; Medina [1,0,1] was more often observed in the 1S strategy group, whereas Medina [0,1,1] was more often observed in the 2S strategy group. There were no significant
Table 1 Baseline characteristics. 1S strategy (n = 175)
2S strategy (n = 144)
p value
64.6 ± 11.4 72 46 95 96 2.9 11 40 21 9.1 2.9 4.0 11 10 39
65.1 ± 12.4 69 37 96 98 1.4 6.9 50 23 6.2 0.7 4.8 15 4.2 35
0.67 0.61 0.11 0.86 0.47 0.37 0.22 0.07 0.79 0.33 0.15 0.70 0.31 0.03 0.52 0.51
40 8.0
31 10
Laboratory data pre-PCI eGFR, mL/min/1.73 m2 CRP, mg/L Leukocytes, ×103/μL Hemoglobin, g/dL Platelets, ×103/μL LDL cholesterol, mg/dL
81.4 ± 28.3 4.7 ± 9.0 7.2 ± 1.9 13.8 ± 1.4 203.9 ± 59.8 78.4 ± 33.1
81.8 ± 65.0 4.6 ± 8.8 7.3 ± 2.0 13.8 ± 1.7 211.1 ± 63.0 78.6 ± 30.1
0.93 0.92 0.69 0.90 0.32 0.96
Medications pre-PCI Clopidogrel Prasugrel Aspirin Beta blocker Statins ACEI/ARB Ranolazine Calcium antagonist Long-acting nitrate
45 9.1 89 72 77 59 7.4 22 15
45 10 86 71 78 53 6.9 26 14
0.98 0.72 0.52 0.83 0.77 0.28 0.86 0.39 0.83
Age, years Sex, male Diabetes mellitus Hypertension Hyperlipidemia Peripheral artery disease Prior myocardial infarction Family history Prior PCI Prior stroke or TIA Prior coronary artery bypass surgery Atrial fibrillation Current smoking CHF with NYHA III–IV at presentation ACS at presentation CCS classification III IV
Values are presented as % or mean ± standard deviation, as appropriate. 1S = initial one-stent; 2S = dedicated two-stent; ACS = acute coronary syndrome; ACEI = angiotensin-converting enzyme inhibitor; ARB = angiotensin receptor blocker; CCS = Canadian Cardiovascular Society; CHF = congestive heart failure; CRP = C-reactive protein; eGFR = estimated glomerular filtration rate; LDL = low-density lipoprotein; MI = myocardial infarction; PCI = percutaneous coronary intervention; TIA = transient ischemic attack.
N.I. Kherada et al. / International Journal of Cardiology 174 (2014) 13–17 Table 2 Angiographic and procedural characteristics.
Access site, femoral Bifurcation territory Left main coronary artery Left anterior descending artery Left circumflex artery Right coronary artery Lesion type, restenotic Medina class 0,1,1 1,0,1 1,1,1 Calcification Heavy Moderate No/mild Ulcer lesion Proximal tortuosity Mild Moderate Severe ACC/AHA lesion classification B1 B2 C Syntax score Peri-procedural GPI use MV pre-stent lesion modification Simple balloon Rotational atherectomy Cutting balloon SB pre-stent lesion modification Simple balloon Rotational atherectomy Cutting balloon 2S technique SKS V Mini-crush T TAP Culotte Any intraprocedural complication Both MV & SB MV only SB only Any persistent intraprocedural complication Only MV Only SB Final kissing balloon Fluoroscopy time, minutes Contrast volume, mL MV total stent length, mm SB total stent length, mm MV stent diameter, mm SB stent diameter, mm Cross-over from 1S to 2S strategy
1S strategy (n = 175)
2S strategy (n = 144)
p value
94
99
0.48 0.13
6.3 76 12 5.1 7.4
16 63 12 6.9 3.4
26 8.0 66
34 2.1 64
25 18 55 6.5
26 23 49 7.5
74 22 2.8
79 16 2.8
4.5 64 30 19.5 ± 9.5 n 26
4.2 62 33 18.6 ± 9.5 25
0.47 0.79
58 20 20
68 24 18
0.07 0.42 0.66
40 2.3 43
59 6.9 36
0.001 0.04 0.18 –
– – – – – –
38 25 18 9.1 6.9 2.1
0.12 0.03
0.36
0.68 0.39
0.91
15
mini-crush, T-stenting, TAP and culotte approaches. Total fluoroscopy time was similar between groups. Contrast volume was significantly lower with a 2S strategy (164.7 ± 63.1 mL vs. 146.4 ± 43.5 mL, p = 0.01). Persistent intraprocedural complications were rare, but more common among patients assigned to a 1S strategy (6 vs. 1 event), in whom complications occurred exclusively in SB. Rates of any intraprocedural complication were similar between the groups. 3.2. Quantitative coronary angiography Results of QCA analysis are depicted in Table 3. Whereas baseline measurements of MV RVD, %DS, MLD and lesion length were similar, baseline measurements of SB differed, with a dedicated 2S strategy associated with significantly higher SB RVD and lesion length. Bifurcation angulation was similar. Following PCI, MV measurements were again similar, whereas SB measurements again differed, with a 2S strategy associated with lower %DS (34.35 ± 19.42% vs. 22.63 ± 8.99%, p b 0.0001), larger MLD (1.44 ± 0.53 mm vs. 1.95 ± 0.42 mm, p b 0.0001) and greater acute gain (0.65 ± 0.41 mm vs. 1.11 ± 0.47 mm, p b 0.0001). 3.3. Clinical outcomes In-hospital serious adverse events were similar in 1S and 2S groups (8.0% vs. 9.0%, p = 0.58, Table 4). At one year, the primary efficacy endpoint (MACE) was recorded in 18.3% patients assigned to a 1S strategy and 13.2% patients assigned to a 2S strategy. Observed differences in MACE were not significant by the log-rank test (p = 0.2) or multivariable adjusted Kaplan–Meier estimates (21.8% vs. 16.6%, hazard ratio [HR] 0.70, 95% confidence interval [CI] 0.39–1.23, p = 0.21; Fig. 1). No ST occurred. There were no differences in mortality (2.3% vs. 2.1%, HR = 0.74, 95% CI = 0.12–4.48, p = 0.75), MI (12.2% vs. 7.8%, HR = 0.68, 95% CI 0.32–1.43, p = 0.31), TLR (4.8% vs. 5.9%, HR = 0.98, 95% CI = 0.34–4.04, p = 0.80) or TVR (7.4% vs. 5.8%, HR = 0.60, 95% CI = 0.23–1.60, p = 0.31, Fig. 2) between 1S versus 2S strategy at 1 year follow-up. (See Table 5.) 4. Discussion
0.09 1.1 8.5 9.7
1.4 3.5 4.9
0.0 3.4 45 22.2 ± 12.7 164.7 ± 63.1 21.9 ± 5.8 – 3.1 ± 0.4 – 4.0
0.7 0.0 77 22.0 ± 11.7 146.4 ± 43.5 21.5 ± 5.5 19.0 ± 7.3 3.04 ± 0.3 2.69 ± 0.3 –
This is the largest cohort study to evaluate comparative efficacy of 1S and 2S strategies for PCI of true coronary bifurcation lesions in the era of 0.04
b0.001 0.91 0.01 0.54 0.01
Values are presented as % or mean ± standard deviation, as appropriate. 1S = initial one-stent; 2S = dedicated two-stent; ACC = American College of Cardiology; AHA = American Heart Association; GPI = glycoprotein IIb/IIIa inhibitor; MV = main vessel; SB = side branch; SD = standard deviation.
differences in lesion calcification, ulceration and proximal tortuosity. Small minorities of cases in each group were associated with prior coronary artery bypass graft surgery or in-stent restenosis. Alongside differences in stenting strategy, several additional procedural differences existed between the two groups. Lesion modification for the side branch using balloon angioplasty (40% vs. 59%, p = 0.001) or rotational atherectomy (2.3% vs. 6.9%, p = 0.04) was more common with a 2S strategy. Final kissing balloon inflation was significantly more common with a 2S strategy (45% vs. 77%, p b 0.001). The most common technique employed as part of a dedicated 2S strategy was simultaneous kissing stent placement (38%), followed by V-stenting,
Table 3 Quantitative coronary angiography.
Bifurcation angle, degrees Baseline MV RVD MV % DS MV MLD MV lesion length SB RVD SB % DS SB MLD SB lesion length Final MV RVD MV % DS MV MLD MV acute gain SB RVD SB % DS SB MLD SB acute gain
1S strategy (n = 175)
2S strategy (n = 144)
p value
58.64 ± 21.70
56.71 ± 19.76
2.81 65.64 0.97 18.28 2.26 56.47 0.83 7.23
± ± ± ± ± ± ± ±
0.47 14.17 0.44 11.44 0.36 19.46 0.51 3.33
2.84 66.08 0.97 16.37 2.49 60.43 0.84 12.22
± ± ± ± ± ± ± ±
0.49 14.47 0.47 7.51 0.49 18.17 0.34 5.67
0.62 0.78 0.98 0.08 b0.001 0.06 0.91 b0.0001
2.82 23.19 2.17 1.20 2.17 34.35 1.44 0.65
± ± ± ± ± ± ± ±
0.42 9.96 0.43 0.50 0.41 19.42 0.53 0.41
2.85 21.26 2.24 1.26 2.52 22.63 1.95 1.11
± ± ± ± ± ± ± ±
0.44 9.15 0.40 0.52 0.49 8.99 0.42 0.47
0.51 0.07 0.12 0.29 b0.0001 b0.0001 b0.0001 b0.0001
0.41
Values are presented as mean ± standard deviation. % DS = percent diameter stenosis; 1S = initial one-stent; 2S = dedicated two-stent; MLD = minimum lumen diameter; MV = main vessel; RVD = reference vessel diameter; SB = side branch.
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Table 4 In hospital adverse events.
Death Myocardial infarction Stroke Coronary artery bypass surgery Blood transfusion Composite in-hospital serious adverse events
1S strategy (n = 175)
2S strategy (n = 144)
p value
1 (0.5) 11 (6.3) 0 (0.0) 1 (0.5) 1 (0.5) 14 (8.0)
0 (0.0) 9 (6.2) 0 (0.0) 0 (0.0) 4 (2.8) 13 (9.0)
0.36 0.99 – 0.36 0.11 0.58
Values are presented as n (%). 1S = initial one-stent; 2S = dedicated two-stent.
second-generation DES. In this single-center retrospective experience, a dedicated 2S strategy was associated with superior SB angiographic outcomes (including lower %DS, larger MLD and greater acute gain) and no significant difference in a composite of death, MI and TVR at one year. Of note, rates of serious adverse events observed with a dedicated 2S technique in our study were numerically lower than those observed with 2S technique in earlier bifurcation PCI studies [9,10]. Two additional observations are important in interpreting these data. First, despite the technical challenges associated with bifurcation PCI, in this study, a dedicated 2S strategy was safe, with a low rate of intraprocedural complications and only one persistent intraprocedural complication. Indeed, a 1S strategy was associated with a higher likelihood of persistent intraprocedural complications. Second, MACE were uncommon in comparison to previous reports (for example, 15.2% at 9 months following complex PCI in an earlier study) [9]. Explanations for these differences are speculative and given that all procedures occurred at a single academic center with specialized expertise in complex PCI, it is possible that our results may not be generalizable. Alternatively, it is conceivable that lower event rates are related in part to both the newer EES platform and incremental advances in interventional technique. One example of this is the use of final kissing balloon inflation (FKBI). In this registry, whereas frequency of FKBI with a 2S strategy (77%) was comparable to prior reports, the use of FKBI with a 1S strategy (45%) was more frequent in comparison to rates of attempted and successful FKBI with a 1S strategy in earlier reports (31% and 29%, respectively) [9,11]. Observations from optical coherence tomography have suggested potential mechanisms of benefit of FKBI in bifurcation PCI with a 1S strategy, including reductions in jailing stent struts, thrombus attachment and uncovered struts [12].
Fig. 2. Target vessel revascularization at one year–time-to-event curves for cumulative incidence of TVR in patients undergoing complex bifurcation PCI with everolimus-eluting stents using a 1S or 2S strategy up to 1 year. (*HR adjusted for age and gender. 1S = initial one-stent; 2S = dedicated 2-stent; HR = hazard ratio; TVR = target vessel revascularization).
For patients assigned to a 2S strategy, specific techniques incorporating FKBI have been associated with superior outcomes. In our study, a plurality of patients assigned to a 2S strategy (38%) were treated with a simultaneous kissing stent (SKS) technique, which has been associated with high procedural (100%) and clinical success (97%), low inhospital (3%) and 30-day (5%) MACE and low TLR at 9 months (4%) [13]. A recently published modification to SKS technique, incorporating high-pressure FKBI, has shown similarly good results, with 11% TLR and 3% ischemia-driven TLR at 4.5 years mean follow-up [14]. Analogously, excellent results have been observed with a novel 2S technique involving mandatory FKBI, the double kissing crush (DKCRUSH), in comparison with classic crush technique [15], 1S strategy with provisional SB stenting [16] and culotte technique (for left main bifurcation lesions) [17]. It is of interest that, despite superior angiographic outcomes with a 2S strategy, there was no difference in long-term ischemic events, including no differences in the component individual endpoints of TLR (6.0% vs. 9.0%, HR 0.81, 95% CI 0.44–1.50, p = 0.51) or TVR (8.6% vs. 9.0%, HR 0.60, 95% CI 0.21–1.66, p = 0.32). As this finding is consistent with previous data using earlier generations of stents [18–21], it is plausible that the null hypothesis is correct. Our results are also compatible with findings of a recently published small randomized study (n = 70 lesions, 86% true bifurcations) comparing 1S and 2S strategies (T-stenting), in which there was no difference in binary restenosis at 9 months (overall, 12.1%), albeit a higher rate of side branch restenosis with a 1S strategy [22]. Alternatively, given the small number of events, it is possible that this study was underpowered to detect a true difference in clinical outcomes between 1S and 2S strategies.
Table 5 Clinical outcomes.
Death MI TLR TVR MACE Fig. 1. Major adverse cardiac events at one year–time-to-event curves for cumulative incidence of MACE in patients undergoing complex bifurcation PCI with everolimus-eluting stents using a 1S or 2S strategy up to 1 year. (*HR adjusted for age and gender. 1S = initial one-stent; 2S = dedicated 2-stent; HR = hazard ratio; MACE = major adverse cardiac events).
1S strategy (n = 175)
2S strategy (n = 144)
Hazard ratioa
95% CI
p value
2.3 [0.7–7.0] 12.2 [7.9–18.9] 4.8 [2.0–11.1] 7.4 [3.8–14.3] 21.8 [15.6–30.0]
2.1 [0.5–8.0] 7.8 [4.4–13.6] 5.9 [2.5–13.6] 5.8 [2.5–13.5] 16.6 [10.8–25.2]
0.74 0.68 0.98 0.60 0.70
0.12–4.48 0.32–1.43 0.34–4.04 0.23–1.60 0.39–1.23
0.75 0.31 0.80 0.31 0.21
Kaplan–Meier estimates at one year are presented as % [95% confidence interval]. 1S = initial one-stent; 2S = dedicated two-stent; MACE = major adverse cardiac events, defined as death, MI and TVR; MI = myocardial infarction; TLR = target lesion revascularization; TVR = target vessel revascularization. a Hazard Ratio adjusted for age and sex, and calculated over entire study period.
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Importantly, our results differ from those of a recent analysis of British Bifurcation Coronary Study (BBC ONE) and the NORDIC Bifurcation Study (NORDIC I). In a pooled analysis of 913 patients in the two randomized trials using patient-level data, Behan and colleagues found a significant increase in the composite of death, MI and TVR in association with complex bifurcation PCI as compared with a 1S strategy (17.3% vs. 10.1%, HR 1.84, 95% CI 1.28–2.66, p = 0.001), which was consistent across subgroups of patients with true bifurcations, wide-angled bifurcations, large (≥2.75 mm) SB, longer ostial SB lesions and equivalentsized MV and SB [23]. Factors potentially contributing to the observed difference in outcomes in BBC ONE and NORDIC I included inclusion of lesions that were not true bifurcations, inappropriate use of a 2S strategy in patients without complex bifurcation lesions, inadequate use of final kissing balloon inflation in patients with complex bifurcation lesions, reliance on visual determination (rather than QCA) of true bifurcation lesions and shorter follow-up. In the recent randomized Nordic–Baltic Bifurcation IV trial of complex true bifurcation PCI, there was no significant benefit at 6 months in association with a dedicated 2S strategy [24]. Long-term follow-up is needed to see if a trend toward reduction in MACE in the 2S group becomes significant over time. 4.1. Study limitations Limitations of the study include retrospective, observational design; relatively small sample size given low event rates; lack of routine angiographic follow-up; and potential for unmeasured covariates of assignment to a 1S or 2S strategy, inherent to our study's observational design. Several different techniques were applied as part of a dedicated 2S strategy, at operator discretion and the study was underpowered to evaluate differences in angiographic and clinical outcomes associated with different approaches. As this study evaluated only EES, results may not be generalizable to other DES. 5. Conclusions In this study of patients undergoing PCI using EES for true coronary bifurcation lesions at a single referral center specialized in complex PCI, a dedicated 2S strategy was safe and associated with superior SB angiographic outcomes without any differences in a composite of death, MI, TLR and TVR compared to 1S strategy. Disclosures Dr. Mehran has received institutional research grant support from The Medicines Co., Bristol-Myers Squibb/Sanofi-Aventis and Lilly/ Daiichi Sankyo, and consulting fees from Abbott Vascular, AstraZeneca, Boston Scientific, Covidien, CSL Behring, Janssen Pharmaceuticals, Maya Medical, and Merck and Regado Biosciences. Dr. Kini serves on the speakers' bureau of the ACC and has received consulting fees from WebMD. Dr. Sharma serves on the speakers' bureau of Abbott Vascular, Angioscore, Boston Scientific, Lilly/Daiichi Sankyo and The Medicines Co. Dr. Dangas serves on the advisory board and has received lecture honoraria from Bristol-Myers Squibb/Sanofi-Aventis. Dr. Kovacic has received honoraria from AstraZeneca and research support from the National Institutes of Health (K08HL111330), The Leducq Foundation
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(Transatlantic Network of Excellence Award) and AstraZeneca. All other authors report no relevant conflicts of interest. References [1] Brar SS, Gray WA, Dangas G, et al. Bifurcation stenting with drug-eluting stents: a systematic review and meta-analysis of randomised trials. EuroIntervention 2009;5:475–84. [2] Medina A, Suarez de Lezo J, Pan M. A new classification of coronary bifurcation lesions. Rev Esp Cardiol 2006;59:183. [3] Sharma SK, Kini AS. Coronary bifurcation lesions. Cardiol Clin 2006;24:233–46. [4] Athappan G, Ponniah T, Jeyaseelan L. True coronary bifurcation lesions: metaanalysis and review of literature. J Cardiovasc Med (Hagerstown) 2010;11:103–10. [5] Stone GW, Rizvi A, Newman W, et al. Everolimus-eluting versus paclitaxel-eluting stents in coronary artery disease. N Engl J Med 2010;362:1663–74. [6] Baber U, Mehran R, Sharma SK, et al. Impact of the everolimus-eluting stent on stent thrombosis: a meta-analysis of 13 randomized trials. J Am Coll Cardiol Oct 4 2011;58(15):1569–77. [7] Cutlip DE, Windecker S, Mehran R, et al. Clinical endpoints in coronary stent trials. A case for standardized definitions. Circulation 2007;115:2344–51. [8] Sharma SK, Sweeny J, Kini AS. Coronary bifurcation lesions: a current update. Cardiol Clin 2010;28:55–70. [9] Hildick-Smith D, de Belder AJ, Cooter N, et al. Randomized trial of simple versus complex drug-eluting stenting for bifurcation lesions: the British Bifurcation Coronary Study: old, new and evolving strategies. Circulation 2010;121:1235–43. [10] Colombo A, Bramucci E, Saccà S, 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 SirolimusEluting Stents) Study. Circulation 2009;119:71–8. [11] Sgueglia GA, Chevalier B. Kissing balloon inflation in percutaneous coronary interventions. J Am Coll Cardiol Intv 2012;5:803–11. [12] Hariki H, Shinke T, Otake H, et al. Potential benefit of final kissing balloon inflation after single stenting for the treatment of bifurcation lesions—insights from optical coherence tomography observations. Circ J 2013;77:1193–201. [13] Sharma SK. Simultaneous kissing drug-eluting stent technique for percutaneous treatment of bifurcation lesions in large-size vessels. Catheter Cardiovasc Interv 2005;65:10–6. [14] Isaaz K, Bayle S, Lamaud M, et al. Immediate and long-term results of a modified simultaneous kissing stenting for percutaneous coronary intervention of coronary artery bifurcation lesions. J Invasive Cardiol 2013;25:126–31. [15] Zhang JJ, Chen SL, Ye F, et al. Double kissing crush technique for treatment of true coronary bifurcation lesions: two-year clinical outcomes from DKCRUSH-1 study. Chin Med J (Engl) 2009;122:736–40. [16] Chen SL, Santoso T, Zhang JJ, 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 2011;57:914–20. [17] Chen SL, Xu B, Han YL, et al. Comparison of double kissing crush versus Culotte stenting for unprotected distal left main bifurcation lesions: results from a multicenter, randomized, prospective DKCRUSH-III study. J Am Coll Cardiol 2013;61:1482–8. [18] Colombo A, Moses JW, Morice MC, et al. Randomized study to evaluate sirolimuseluting stents implanted at coronary bifurcation lesions. Circulation 2004;109:1244–9. [19] Pan M, de Lezo JS, Medina A, et al. Rapamycin-eluting stents for the treatment of bifurcated coronary lesions: a randomized comparison of a simple versus complex strategy. Am Heart J 2004;148:857–64. [20] Iakovou I, Ge L, Colombo A. Contemporary stent treatment of coronary bifurcations. J Am Coll Cardiol 2005;46:1446–55. [21] Tsuchida K, Colombo A, Lefèvre T, et al. The clinical outcome of percutaneous treatment of bifurcation lesions in multivessel coronary artery disease with the sirolimus-eluting stent: insights from the Arterial Revascularization Therapies Study part II (ARTS II). Eur Heart J 2007;28:433–42. [22] Ruiz-Salmerón RJ, Valenzuela LF, Pérez I, et al. Approach to coronary bifurcation lesions using the everolimus-eluting stent: comparison between a simple strategy and a complex strategy with T-stenting. Rev Esp Cardiol 2013;66:636–43. [23] Behan MW, Holm NR, Curzen NP. Simple or complex stenting for bifurcation coronary lesions: a patient-level pooled-analysis of the Nordic Bifurcation Study and the British Bifurcation Coronary Study. Circ Cardiovasc Interv 2011;4:57–64. [24] Kumsars I. NORDIC–BALTIC BIFURCATION IV: a prospective, randomized trial of a two-stent strategy vs. a provisional stent strategy in true coronary bifurcation lesions. Presented at San Francisco, CA: Transcatheter Cardiovascular Therapeutics (TCT); October 30, 2013.
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International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Dedicated two-stent technique in complex bifurcation percutaneous coronary intervention with use of everolimus-eluting stents: The EES-bifurcation study Nisharahmed I. Kherada, Samantha Sartori, Matthew I. Tomey, Marco G. Mennuni, Omar A. Meelu, Swathi Roy, Bibhu D. Mohanty, Usman Baber, Robert Pyo, Jason C. Kovacic, Joseph Sweeny, Pedro Moreno, Prakash Krishnan, George D. Dangas, Roxana Mehran ⁎, Samin K. Sharma, Annapoorna S. Kini The Zena and Michael A. Wiener Cardiovascular Institute, The Icahn School of Medicine at Mount Sinai, New York, NY, United States
a r t i c l e
i n f o
Article history: Received 13 December 2013 Accepted 9 March 2014 Available online 15 March 2014 Keywords: Bifurcation lesion Complex percutaneous coronary intervention Everolimus-eluting stent
a b s t r a c t Objectives: To compare the outcomes of initial one-stent (1S) versus dedicated two-stent (2S) strategies in complex bifurcation percutaneous coronary intervention (PCI) using everolimus-eluting stents (EES). Background: PCI of true bifurcation lesions is technically challenging and historically associated with reduced procedural success and increased restenosis. Prior studies comparing initial one-stent (1S) versus dedicated two-stent (2S) strategies using first-generation drug-eluting stents have shown no reduction in ischemic events and more complications with a 2S strategy. Methods: We performed a retrospective study of 319 consecutive patients undergoing PCI at a single referral center with EES for true bifurcation lesions, defined by involvement of both the main vessel (MV) and side branch (SB). Baseline, procedural characteristics, quantitative coronary angiography and clinical outcomes in-hospital and at one year were compared for patients undergoing 1S (n = 175) and 2S (n = 144) strategies. Results: Baseline characteristics were well-matched. 2S strategy was associated with greater SB acute gain (0.65 ± 0.41 mm vs. 1.11 ± 0.47 mm, p b 0.0001). In-hospital serious adverse events were similar (9% with 2S vs. 8% with 1S, p = 0.58). At one year, patients treated by 2S strategy had non-significantly lower rates of target vessel revascularization (5.8% vs. 7.4%, p = 0.31), myocardial infarction (7.8% vs. 12.2%, p = 0.31) and major adverse cardiovascular events (16.6% vs. 21.8%, p = 0.21). Conclusion: In this study of patients undergoing PCI for true coronary bifurcation lesions using EES, 2S strategy was associated with superior SB angiographic outcomes without excess complications or ischemic events at one year. © 2014 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Coronary bifurcation lesions account for approximately 20% of all percutaneous coronary interventions (PCI). True bifurcation lesions [1], defined by N 50% luminal diameter reduction within 5 mm of the bifurcation carina involving both the main vessel (MV) and side branch ostium (consistent with Medina classifications 1,1,1; 1,0,1; or 0,1,1) [2], pose challenges to PCI, including proximal–distal vessel mismatch, Abbreviations: 1S, initial one-stent; 2S, dedicated two-stent; DES, drug-eluting stents; EES, everolimus-eluting stents; FKBI, final kissing balloon inflation; MACE, major adverse cardiovascular events; MI, myocardial infarction; MV, main vessel; PCI, percutaneous coronary intervention; QCA, quantitative coronary angiography; SB, side branch; TLR, target lesion revascularization; TVR, target vessel revascularization. ⁎ Corresponding author at: Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1030, New York, NY 10029-6574, United States. Tel.: +1 212 659 9691; fax: +1 646 537 8547. E-mail address: [email protected] (R. Mehran).
http://dx.doi.org/10.1016/j.ijcard.2014.03.029 0167-5273/© 2014 Elsevier Ireland Ltd. All rights reserved.
complex angulation, calcification and tendency to plaque shift. Historically, bifurcation PCI has been associated with reduced procedural success and increased restenosis, particularly at side branch ostia. Although drug-eluting stents (DES) have reduced the rates of restenosis following complex PCI, including bifurcation PCI, stent implantation in side branch ostia is technically demanding, requiring special techniques to avoid main vessel compromise, inadequate coverage and under expansion [3]. It is controversial whether PCI for bifurcation lesions should preferentially involve an initial one-stent (1S) strategy with provisional stenting of the side branch or a dedicated two-stent (2S) strategy. In a recent meta-analysis of five studies evaluating 1145 patients undergoing bifurcation PCI (616 1S, 529 2S) with DES, there was no difference between strategies in rates of side branch or main vessel restenosis, target lesion revascularization (TLR) or all-cause mortality [4]. Generalization from these findings is limited, however, by exclusive use of firstgeneration DES, variable duration of follow-up and variable data reporting. In the SPIRIT-IV randomized controlled trial, second-
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generation everolimus-eluting stents (EES), in comparison with firstgeneration (paclitaxel-eluting) DES, resulted in lower rates of target lesion failure, with similar outcomes in simple and complex lesions [5]. In a meta-analysis of 13 randomized trials, EES were associated with the lowest risks among DES subtypes of both stent thrombosis and restenosis [6]. The objective of this study was to compare the efficacy and safety of 1S versus 2S strategies in patients undergoing true bifurcation PCI using EES in a tertiary referral center. 2. Methods 2.1. Study design and participants We conducted a retrospective cohort study of consecutive patients undergoing PCI for true bifurcation lesions using EES between February 2010 and December 2011 at a single academic medical center. Inclusion criteria included the presence of a de novo target lesion with true bifurcation morphology, as defined above and bifurcation PCI using only EES. We divided patients into two study groups based on retrospective determination of a dedicated 2S strategy or an initial 1S strategy (with provisional side branch stenting). Group assignment was determined based on review of procedural documentation and comprehensive assessment of technique as recorded via cineangiography. Exclusion criteria included the use of stents other than EES, small caliber MV (b2.5 mm) or SB (b2.0 mm) and ST-segment elevation myocardial infarction. All participants provided routine written informed consent at the time of PCI and the institutional review board provided approval for the study. 2.2. Study definitions and clinical endpoints Clinical outcomes were ascertained for the index hospitalization and at 1-year via our institution's Heart Care Plus database. Deaths were ascertained via the Social Security Death Index. The primary efficacy endpoint was major adverse cardiovascular events (MACE) at 1 year, defined as a composite of death, myocardial infarction (MI) and target-vessel revascularization (TVR). MI was defined as new pathologic Q waves in N2 contiguous leads (excluding periprocedural MI). Non-Q-wave MI (NQWMI) was defined as rise in creatine kinase-MB isoform (CK-MB) mass N8× the upper limit of normal together with clinical signs of MI, in the absence of pathologic Q waves. TLR was defined as repeat revascularization by PCI or surgery of the target segment (inclusive of 5 mm proximal or distal to the stent) for clinical indications and/or demonstration of inducible myocardial ischemia. TVR was defined as repeat revascularization by PCI or surgery of the target vessel for ischemia (excluding TLR). In hospital serious adverse events were defined as periprocedural death, MI, stroke, TVR by PCI or coronary artery bypass graft surgery, hemodialysis, congestive heart failure and blood transfusion. Periprocedural MI was defined as an increase in CK-MB mass ≥3× the upper limit of normal within 24 h of the index PCI. Stent thrombosis (ST) was defined using the Academic Research Consortium definition [7]. Acute gain from PCI was defined as the change in the minimum lumen diameter from baseline to the final procedural angiogram. 2.3. Quantitative coronary angiography Quantitative coronary angiography (QCA) was performed in all participants for baseline and final angiograms post-PCI. Analysis was conducted using dedicated software (QCA-QAngioXA 7.3, Medis, Leiden, Netherlands) using a standard analytic protocol developed in collaboration with Medis and performed by analysts (NK, MM) trained at the study site by an experienced operator (GD). Analysts were not blinded to procedural strategy or stenting technique, which was categorized according to published descriptions [8]. Intraprocedural complications were identified, including dissection, perforation, slowflow, no-reflow and abrupt closure, attributed to the MV or SB and classified as persistent or not. Measurements of bifurcation lesions were made using two segments: [1] a combined MV, comprised of the proximal MV (PMV) and distal MV (DMV), with boundaries defined by the 5 mm proximal and distal to the implanted stent; and [2] the SB, with boundaries defined by the ostium and 5 mm distal to the ballooned or stented area. QCA measurements included angulation between the DMV and SB, reference vessel diameter (RVD), minimal lumen diameter (MLD), percent diameter stenosis (%DS) and lesion length. 2.4. Statistical analysis Baseline demographic and clinical characteristics, QCA and procedural characteristics were tabulated for subjects undergoing 1S versus 2S strategies. Continuous variables are presented as mean (standard deviation) and compared using an unpaired Student's t-test. Categorical variables are presented as frequency (percentage) and compared using Pearson's chi-squared test. Survival analysis for 1S versus 2S strategies was performed using the Kaplan–Meier curves and the log-rank test. Multivariate analysis was performed using a Cox regression model, with candidate variables for analysis chosen via backward stepwise selection. Significance levels for removal and addition of covariates from the model were 0.1 and 0.2, respectively. p values b 0.05 were considered statistically significant. All statistical analyses were performed using STATA version 12.1 (StataCorp LP, College Station, Texas).
3. Results A total of 319 patients were analyzed, including 175 patients treated with an initial 1S strategy and 144 patients treated with a dedicated 2S strategy; 7 patients (4%) undergoing an initial 1S strategy crossed over to undergo placement of a second stent. Baseline demographic and clinical characteristics, including home medications and laboratory assays, were well-matched (Table 1), with the exception of New York Heart Association class III or IV symptoms of congestive heart failure, which were more common in patients undergoing a 1S strategy (10.3% vs. 4.2%, p = 0.03). The majority of patients presented with stable coronary artery disease (77%).
3.1. Angiographic and procedural characteristics Angiographic and procedural characteristics are presented in Table 2. Anatomic complexity was similar, as evidenced by no differences in SYNTAX score, which was b22 in both groups and ACC/AHA lesion classification. The majority of bifurcation lesions in both groups were located in the left anterior descending artery. Most bifurcation lesions were classified as Medina [1,1,1]; Medina [1,0,1] was more often observed in the 1S strategy group, whereas Medina [0,1,1] was more often observed in the 2S strategy group. There were no significant
Table 1 Baseline characteristics. 1S strategy (n = 175)
2S strategy (n = 144)
p value
64.6 ± 11.4 72 46 95 96 2.9 11 40 21 9.1 2.9 4.0 11 10 39
65.1 ± 12.4 69 37 96 98 1.4 6.9 50 23 6.2 0.7 4.8 15 4.2 35
0.67 0.61 0.11 0.86 0.47 0.37 0.22 0.07 0.79 0.33 0.15 0.70 0.31 0.03 0.52 0.51
40 8.0
31 10
Laboratory data pre-PCI eGFR, mL/min/1.73 m2 CRP, mg/L Leukocytes, ×103/μL Hemoglobin, g/dL Platelets, ×103/μL LDL cholesterol, mg/dL
81.4 ± 28.3 4.7 ± 9.0 7.2 ± 1.9 13.8 ± 1.4 203.9 ± 59.8 78.4 ± 33.1
81.8 ± 65.0 4.6 ± 8.8 7.3 ± 2.0 13.8 ± 1.7 211.1 ± 63.0 78.6 ± 30.1
0.93 0.92 0.69 0.90 0.32 0.96
Medications pre-PCI Clopidogrel Prasugrel Aspirin Beta blocker Statins ACEI/ARB Ranolazine Calcium antagonist Long-acting nitrate
45 9.1 89 72 77 59 7.4 22 15
45 10 86 71 78 53 6.9 26 14
0.98 0.72 0.52 0.83 0.77 0.28 0.86 0.39 0.83
Age, years Sex, male Diabetes mellitus Hypertension Hyperlipidemia Peripheral artery disease Prior myocardial infarction Family history Prior PCI Prior stroke or TIA Prior coronary artery bypass surgery Atrial fibrillation Current smoking CHF with NYHA III–IV at presentation ACS at presentation CCS classification III IV
Values are presented as % or mean ± standard deviation, as appropriate. 1S = initial one-stent; 2S = dedicated two-stent; ACS = acute coronary syndrome; ACEI = angiotensin-converting enzyme inhibitor; ARB = angiotensin receptor blocker; CCS = Canadian Cardiovascular Society; CHF = congestive heart failure; CRP = C-reactive protein; eGFR = estimated glomerular filtration rate; LDL = low-density lipoprotein; MI = myocardial infarction; PCI = percutaneous coronary intervention; TIA = transient ischemic attack.
N.I. Kherada et al. / International Journal of Cardiology 174 (2014) 13–17 Table 2 Angiographic and procedural characteristics.
Access site, femoral Bifurcation territory Left main coronary artery Left anterior descending artery Left circumflex artery Right coronary artery Lesion type, restenotic Medina class 0,1,1 1,0,1 1,1,1 Calcification Heavy Moderate No/mild Ulcer lesion Proximal tortuosity Mild Moderate Severe ACC/AHA lesion classification B1 B2 C Syntax score Peri-procedural GPI use MV pre-stent lesion modification Simple balloon Rotational atherectomy Cutting balloon SB pre-stent lesion modification Simple balloon Rotational atherectomy Cutting balloon 2S technique SKS V Mini-crush T TAP Culotte Any intraprocedural complication Both MV & SB MV only SB only Any persistent intraprocedural complication Only MV Only SB Final kissing balloon Fluoroscopy time, minutes Contrast volume, mL MV total stent length, mm SB total stent length, mm MV stent diameter, mm SB stent diameter, mm Cross-over from 1S to 2S strategy
1S strategy (n = 175)
2S strategy (n = 144)
p value
94
99
0.48 0.13
6.3 76 12 5.1 7.4
16 63 12 6.9 3.4
26 8.0 66
34 2.1 64
25 18 55 6.5
26 23 49 7.5
74 22 2.8
79 16 2.8
4.5 64 30 19.5 ± 9.5 n 26
4.2 62 33 18.6 ± 9.5 25
0.47 0.79
58 20 20
68 24 18
0.07 0.42 0.66
40 2.3 43
59 6.9 36
0.001 0.04 0.18 –
– – – – – –
38 25 18 9.1 6.9 2.1
0.12 0.03
0.36
0.68 0.39
0.91
15
mini-crush, T-stenting, TAP and culotte approaches. Total fluoroscopy time was similar between groups. Contrast volume was significantly lower with a 2S strategy (164.7 ± 63.1 mL vs. 146.4 ± 43.5 mL, p = 0.01). Persistent intraprocedural complications were rare, but more common among patients assigned to a 1S strategy (6 vs. 1 event), in whom complications occurred exclusively in SB. Rates of any intraprocedural complication were similar between the groups. 3.2. Quantitative coronary angiography Results of QCA analysis are depicted in Table 3. Whereas baseline measurements of MV RVD, %DS, MLD and lesion length were similar, baseline measurements of SB differed, with a dedicated 2S strategy associated with significantly higher SB RVD and lesion length. Bifurcation angulation was similar. Following PCI, MV measurements were again similar, whereas SB measurements again differed, with a 2S strategy associated with lower %DS (34.35 ± 19.42% vs. 22.63 ± 8.99%, p b 0.0001), larger MLD (1.44 ± 0.53 mm vs. 1.95 ± 0.42 mm, p b 0.0001) and greater acute gain (0.65 ± 0.41 mm vs. 1.11 ± 0.47 mm, p b 0.0001). 3.3. Clinical outcomes In-hospital serious adverse events were similar in 1S and 2S groups (8.0% vs. 9.0%, p = 0.58, Table 4). At one year, the primary efficacy endpoint (MACE) was recorded in 18.3% patients assigned to a 1S strategy and 13.2% patients assigned to a 2S strategy. Observed differences in MACE were not significant by the log-rank test (p = 0.2) or multivariable adjusted Kaplan–Meier estimates (21.8% vs. 16.6%, hazard ratio [HR] 0.70, 95% confidence interval [CI] 0.39–1.23, p = 0.21; Fig. 1). No ST occurred. There were no differences in mortality (2.3% vs. 2.1%, HR = 0.74, 95% CI = 0.12–4.48, p = 0.75), MI (12.2% vs. 7.8%, HR = 0.68, 95% CI 0.32–1.43, p = 0.31), TLR (4.8% vs. 5.9%, HR = 0.98, 95% CI = 0.34–4.04, p = 0.80) or TVR (7.4% vs. 5.8%, HR = 0.60, 95% CI = 0.23–1.60, p = 0.31, Fig. 2) between 1S versus 2S strategy at 1 year follow-up. (See Table 5.) 4. Discussion
0.09 1.1 8.5 9.7
1.4 3.5 4.9
0.0 3.4 45 22.2 ± 12.7 164.7 ± 63.1 21.9 ± 5.8 – 3.1 ± 0.4 – 4.0
0.7 0.0 77 22.0 ± 11.7 146.4 ± 43.5 21.5 ± 5.5 19.0 ± 7.3 3.04 ± 0.3 2.69 ± 0.3 –
This is the largest cohort study to evaluate comparative efficacy of 1S and 2S strategies for PCI of true coronary bifurcation lesions in the era of 0.04
b0.001 0.91 0.01 0.54 0.01
Values are presented as % or mean ± standard deviation, as appropriate. 1S = initial one-stent; 2S = dedicated two-stent; ACC = American College of Cardiology; AHA = American Heart Association; GPI = glycoprotein IIb/IIIa inhibitor; MV = main vessel; SB = side branch; SD = standard deviation.
differences in lesion calcification, ulceration and proximal tortuosity. Small minorities of cases in each group were associated with prior coronary artery bypass graft surgery or in-stent restenosis. Alongside differences in stenting strategy, several additional procedural differences existed between the two groups. Lesion modification for the side branch using balloon angioplasty (40% vs. 59%, p = 0.001) or rotational atherectomy (2.3% vs. 6.9%, p = 0.04) was more common with a 2S strategy. Final kissing balloon inflation was significantly more common with a 2S strategy (45% vs. 77%, p b 0.001). The most common technique employed as part of a dedicated 2S strategy was simultaneous kissing stent placement (38%), followed by V-stenting,
Table 3 Quantitative coronary angiography.
Bifurcation angle, degrees Baseline MV RVD MV % DS MV MLD MV lesion length SB RVD SB % DS SB MLD SB lesion length Final MV RVD MV % DS MV MLD MV acute gain SB RVD SB % DS SB MLD SB acute gain
1S strategy (n = 175)
2S strategy (n = 144)
p value
58.64 ± 21.70
56.71 ± 19.76
2.81 65.64 0.97 18.28 2.26 56.47 0.83 7.23
± ± ± ± ± ± ± ±
0.47 14.17 0.44 11.44 0.36 19.46 0.51 3.33
2.84 66.08 0.97 16.37 2.49 60.43 0.84 12.22
± ± ± ± ± ± ± ±
0.49 14.47 0.47 7.51 0.49 18.17 0.34 5.67
0.62 0.78 0.98 0.08 b0.001 0.06 0.91 b0.0001
2.82 23.19 2.17 1.20 2.17 34.35 1.44 0.65
± ± ± ± ± ± ± ±
0.42 9.96 0.43 0.50 0.41 19.42 0.53 0.41
2.85 21.26 2.24 1.26 2.52 22.63 1.95 1.11
± ± ± ± ± ± ± ±
0.44 9.15 0.40 0.52 0.49 8.99 0.42 0.47
0.51 0.07 0.12 0.29 b0.0001 b0.0001 b0.0001 b0.0001
0.41
Values are presented as mean ± standard deviation. % DS = percent diameter stenosis; 1S = initial one-stent; 2S = dedicated two-stent; MLD = minimum lumen diameter; MV = main vessel; RVD = reference vessel diameter; SB = side branch.
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Table 4 In hospital adverse events.
Death Myocardial infarction Stroke Coronary artery bypass surgery Blood transfusion Composite in-hospital serious adverse events
1S strategy (n = 175)
2S strategy (n = 144)
p value
1 (0.5) 11 (6.3) 0 (0.0) 1 (0.5) 1 (0.5) 14 (8.0)
0 (0.0) 9 (6.2) 0 (0.0) 0 (0.0) 4 (2.8) 13 (9.0)
0.36 0.99 – 0.36 0.11 0.58
Values are presented as n (%). 1S = initial one-stent; 2S = dedicated two-stent.
second-generation DES. In this single-center retrospective experience, a dedicated 2S strategy was associated with superior SB angiographic outcomes (including lower %DS, larger MLD and greater acute gain) and no significant difference in a composite of death, MI and TVR at one year. Of note, rates of serious adverse events observed with a dedicated 2S technique in our study were numerically lower than those observed with 2S technique in earlier bifurcation PCI studies [9,10]. Two additional observations are important in interpreting these data. First, despite the technical challenges associated with bifurcation PCI, in this study, a dedicated 2S strategy was safe, with a low rate of intraprocedural complications and only one persistent intraprocedural complication. Indeed, a 1S strategy was associated with a higher likelihood of persistent intraprocedural complications. Second, MACE were uncommon in comparison to previous reports (for example, 15.2% at 9 months following complex PCI in an earlier study) [9]. Explanations for these differences are speculative and given that all procedures occurred at a single academic center with specialized expertise in complex PCI, it is possible that our results may not be generalizable. Alternatively, it is conceivable that lower event rates are related in part to both the newer EES platform and incremental advances in interventional technique. One example of this is the use of final kissing balloon inflation (FKBI). In this registry, whereas frequency of FKBI with a 2S strategy (77%) was comparable to prior reports, the use of FKBI with a 1S strategy (45%) was more frequent in comparison to rates of attempted and successful FKBI with a 1S strategy in earlier reports (31% and 29%, respectively) [9,11]. Observations from optical coherence tomography have suggested potential mechanisms of benefit of FKBI in bifurcation PCI with a 1S strategy, including reductions in jailing stent struts, thrombus attachment and uncovered struts [12].
Fig. 2. Target vessel revascularization at one year–time-to-event curves for cumulative incidence of TVR in patients undergoing complex bifurcation PCI with everolimus-eluting stents using a 1S or 2S strategy up to 1 year. (*HR adjusted for age and gender. 1S = initial one-stent; 2S = dedicated 2-stent; HR = hazard ratio; TVR = target vessel revascularization).
For patients assigned to a 2S strategy, specific techniques incorporating FKBI have been associated with superior outcomes. In our study, a plurality of patients assigned to a 2S strategy (38%) were treated with a simultaneous kissing stent (SKS) technique, which has been associated with high procedural (100%) and clinical success (97%), low inhospital (3%) and 30-day (5%) MACE and low TLR at 9 months (4%) [13]. A recently published modification to SKS technique, incorporating high-pressure FKBI, has shown similarly good results, with 11% TLR and 3% ischemia-driven TLR at 4.5 years mean follow-up [14]. Analogously, excellent results have been observed with a novel 2S technique involving mandatory FKBI, the double kissing crush (DKCRUSH), in comparison with classic crush technique [15], 1S strategy with provisional SB stenting [16] and culotte technique (for left main bifurcation lesions) [17]. It is of interest that, despite superior angiographic outcomes with a 2S strategy, there was no difference in long-term ischemic events, including no differences in the component individual endpoints of TLR (6.0% vs. 9.0%, HR 0.81, 95% CI 0.44–1.50, p = 0.51) or TVR (8.6% vs. 9.0%, HR 0.60, 95% CI 0.21–1.66, p = 0.32). As this finding is consistent with previous data using earlier generations of stents [18–21], it is plausible that the null hypothesis is correct. Our results are also compatible with findings of a recently published small randomized study (n = 70 lesions, 86% true bifurcations) comparing 1S and 2S strategies (T-stenting), in which there was no difference in binary restenosis at 9 months (overall, 12.1%), albeit a higher rate of side branch restenosis with a 1S strategy [22]. Alternatively, given the small number of events, it is possible that this study was underpowered to detect a true difference in clinical outcomes between 1S and 2S strategies.
Table 5 Clinical outcomes.
Death MI TLR TVR MACE Fig. 1. Major adverse cardiac events at one year–time-to-event curves for cumulative incidence of MACE in patients undergoing complex bifurcation PCI with everolimus-eluting stents using a 1S or 2S strategy up to 1 year. (*HR adjusted for age and gender. 1S = initial one-stent; 2S = dedicated 2-stent; HR = hazard ratio; MACE = major adverse cardiac events).
1S strategy (n = 175)
2S strategy (n = 144)
Hazard ratioa
95% CI
p value
2.3 [0.7–7.0] 12.2 [7.9–18.9] 4.8 [2.0–11.1] 7.4 [3.8–14.3] 21.8 [15.6–30.0]
2.1 [0.5–8.0] 7.8 [4.4–13.6] 5.9 [2.5–13.6] 5.8 [2.5–13.5] 16.6 [10.8–25.2]
0.74 0.68 0.98 0.60 0.70
0.12–4.48 0.32–1.43 0.34–4.04 0.23–1.60 0.39–1.23
0.75 0.31 0.80 0.31 0.21
Kaplan–Meier estimates at one year are presented as % [95% confidence interval]. 1S = initial one-stent; 2S = dedicated two-stent; MACE = major adverse cardiac events, defined as death, MI and TVR; MI = myocardial infarction; TLR = target lesion revascularization; TVR = target vessel revascularization. a Hazard Ratio adjusted for age and sex, and calculated over entire study period.
N.I. Kherada et al. / International Journal of Cardiology 174 (2014) 13–17
Importantly, our results differ from those of a recent analysis of British Bifurcation Coronary Study (BBC ONE) and the NORDIC Bifurcation Study (NORDIC I). In a pooled analysis of 913 patients in the two randomized trials using patient-level data, Behan and colleagues found a significant increase in the composite of death, MI and TVR in association with complex bifurcation PCI as compared with a 1S strategy (17.3% vs. 10.1%, HR 1.84, 95% CI 1.28–2.66, p = 0.001), which was consistent across subgroups of patients with true bifurcations, wide-angled bifurcations, large (≥2.75 mm) SB, longer ostial SB lesions and equivalentsized MV and SB [23]. Factors potentially contributing to the observed difference in outcomes in BBC ONE and NORDIC I included inclusion of lesions that were not true bifurcations, inappropriate use of a 2S strategy in patients without complex bifurcation lesions, inadequate use of final kissing balloon inflation in patients with complex bifurcation lesions, reliance on visual determination (rather than QCA) of true bifurcation lesions and shorter follow-up. In the recent randomized Nordic–Baltic Bifurcation IV trial of complex true bifurcation PCI, there was no significant benefit at 6 months in association with a dedicated 2S strategy [24]. Long-term follow-up is needed to see if a trend toward reduction in MACE in the 2S group becomes significant over time. 4.1. Study limitations Limitations of the study include retrospective, observational design; relatively small sample size given low event rates; lack of routine angiographic follow-up; and potential for unmeasured covariates of assignment to a 1S or 2S strategy, inherent to our study's observational design. Several different techniques were applied as part of a dedicated 2S strategy, at operator discretion and the study was underpowered to evaluate differences in angiographic and clinical outcomes associated with different approaches. As this study evaluated only EES, results may not be generalizable to other DES. 5. Conclusions In this study of patients undergoing PCI using EES for true coronary bifurcation lesions at a single referral center specialized in complex PCI, a dedicated 2S strategy was safe and associated with superior SB angiographic outcomes without any differences in a composite of death, MI, TLR and TVR compared to 1S strategy. Disclosures Dr. Mehran has received institutional research grant support from The Medicines Co., Bristol-Myers Squibb/Sanofi-Aventis and Lilly/ Daiichi Sankyo, and consulting fees from Abbott Vascular, AstraZeneca, Boston Scientific, Covidien, CSL Behring, Janssen Pharmaceuticals, Maya Medical, and Merck and Regado Biosciences. Dr. Kini serves on the speakers' bureau of the ACC and has received consulting fees from WebMD. Dr. Sharma serves on the speakers' bureau of Abbott Vascular, Angioscore, Boston Scientific, Lilly/Daiichi Sankyo and The Medicines Co. Dr. Dangas serves on the advisory board and has received lecture honoraria from Bristol-Myers Squibb/Sanofi-Aventis. Dr. Kovacic has received honoraria from AstraZeneca and research support from the National Institutes of Health (K08HL111330), The Leducq Foundation
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