Comparison of the First- and Second-Generation Limus-Eluting Stents for Bifurcation Lesions From a Korean Multicenter Registry

– Different Efficacy in Left Main Bifurcation or 2-Stent Technique –

Abstract

Background: There are limited data on the relative efficacy of 1st- vs. 2nd-generation limus-eluting stents in bifurcation lesions.

Methods and Results: Our analysis of a Korean multicenter registry for bifurcated coronary lesions enrolled 1,762 patients treated with 2nd-generation everolimus-eluting stent (EES, n=348) or 1st-generation sirolimus-eluting stents (SES, n=1,414). In the overall population, EES was comparable to SES regarding major adverse cardiac events (MACE: composite of cardiac death, nonfatal myocardial infarction, and target vessel revascularization (TVR)), cardiac death, and TVR rates within a 2-year follow-up. In 1:3 propensity score-matched populations, EES showed a significantly lower MACE rate compared with SES (HR [95% CI], 0.53 [0.29–0.97]; P=0.039), mainly through a reduction in repeat revascularization (HR [95% CI], 0.47 [0.24–0.92]; P=0.027). EES was superior to SES in reducing TVR in patients with left main (LM) lesions (HR [95% CI], 0.21 [0.06–0.67]; P=0.008) or in patients treated with 2-stent technique PCI (HR [95% CI], 0.28 [0.09–0.91]; P=0.035). There was no difference in clinical outcomes between 2 stents in a non-LM bifurcation lesion or in patients treated with a 1-stent technique.

Conclusions: At 2-year follow-up, 1st- and 2nd-generation limus-eluting stents showed comparable clinical outcomes in general bifurcation lesions. EES was superior to SES after matching by propensity score, especially in patients with LM bifurcation or in those treated by a 2-stent technique. (Circ J 2015; 79: 544–552)

Bifurcation lesions, especially left main (LM) bifurcation lesions, still remain a challenge in percutaneous coronary intervention (PCI), although drug-eluting stents (DES) have markedly broadened the indications regarding lesion complexity.^1–4 Recently, 2nd-generation DES such as everolimus-eluting stents (EES) have rapidly replaced 1st-generation DES, demonstrating reduced numbers of major adverse cardiac events (MACE) or repeat revascularizations (TVR).^5–7 For the treatment of bifurcated coronary lesions, a few studies have reported comparable efficacy of sirolimus-eluting stents (SES), one of the most successful 1st-generation DES, to EES.^8,9 However, complicated subsets such as LM bifurcation lesions or lesions requiring complex stenting techniques still have not been sufficiently explored. Therefore, we sought to evaluate the efficacy and safety of EES for the treatment of bifurcation coronary lesions in comparison with SES, using the Korean multicenter large-scale COBIS (COronary BIfurcation Stenting) II registry.

Methods

Study Population and Korean Multicenter COBIS II Registry

The COBIS registry was a retrospective multicenter registry dedicated to bifurcation lesion PCI with DES, in which 16 major coronary intervention centers in Korea participated.¹⁰ The COBIS II registry is its successor, and enrolled consecutive patients from 18 major coronary intervention centers in Korea between January 2001 and December 2009. Inclusion criteria were: (1) coronary bifurcation lesion in a major epicardial artery, other than right coronary artery-right ventricular branch bifurcation, treated solely with DES; and (2) main vessel diameter ≥2.5 mm and side branch diameter ≥2.3 mm. Exclusion criteria were the presence of cardiogenic shock or history of cardiopulmonary resuscitation in the same hospitalization. In contrast to the prior COBIS registry, patients who underwent PCI for LM bifurcation lesion were not excluded from the COBIS II registry, which was sponsored by the Korean Society of Interventional Cardiology, and the protocol was approved by the local institutional review board at each hospital. Among 2,897 enrolled patients in the COBIS II registry database, patients treated with EES (n=348) or SES (n=1,414) were selected for the present study (Figure 1).

Figure 1.

Flowchart of study population. COBIS, Coronary Bifurcation Stenting registry; EES, everolimus-eluting stent; LM, left main; PCI, percutaneous coronary intervention; PES, paclitaxel-eluting stent; SES, sirolimus-eluting stent; ZES, zotarolimus-eluting stent.

PCI

Coronary interventions were performed according to the current standard procedural guidelines. Loading doses of aspirin and clopidogrel (300 mg and 300–600 mg, respectively) were administered to all patients before the coronary intervention unless they had previously received these medications. The choice of DES and the treatment strategy were left to the individual operator’s discretion. After the procedure, aspirin was continued indefinitely, and the duration of clopidogrel prescription was at the operator’s discretion. Systematic follow-up angiography was not mandatory.

Quantitative Coronary Angiography

All quantitative coronary angiographic (QCA) analysis was performed at the angiography core laboratory (Cardiac and Vascular Center, Samsung Medical Center, Seoul, Korea) using Centricity CA 1000 (GE, Waukesha, WI, USA).¹¹ Baseline reference diameter and minimal luminal diameter were measured at the proximal main vessel, distal main vessel, and the side branch vessel. Lesion length and bifurcation angle were also measured. Bifurcations were classified according to the Medina classification,¹² and types 1.1.1, 1.0.1, and 0.1.1 lesions were defined as true bifurcation lesions. SYNTAX score was also calculated at the core laboratory.

Clinical Follow-up and Endpoints

Clinical, angiographic, procedural, and outcome data were collected with the use of a web-based reporting system. Additional information was obtained by further inquiry into medical records or by telephone contact, if necessary. The primary endpoint of this study was the cumulative occurrence of MACE, defined as a composite of cardiac death, nonfatal myocardial infarction (MI) and TVR. All deaths were considered cardiac unless a definite noncardiac cause could be established. MI was defined as elevated cardiac enzymes (troponin or myocardial band fraction of creatine kinase) more than the upper limit of the normal value with ischemic symptoms or ECG findings indicative of ischemia that was not related to the index procedure. TVR was defined as repeat revascularization of the target vessel by PCI or bypass graft surgery. Periprocedural MI was not considered as MACE in our study. All outcome data reported from the participating centers were reviewed by an independent clinical event adjudicating committee.

Statistical Analysis

Student’s t-test and chi-square (or Fisher’s exact) test were used to compare means and proportion of baseline clinical and angiographic characteristics between the 2 stent groups. To address potential sources of bias and confounding in this retrospective study, propensity analysis was adopted.^13,14 Baseline clinical and angiographic features were incorporated into a nonparsimonious logistic regression model to compute the propensity score for stent choice. The included covariates were age, sex, hypertension, diabetes, hypercholesterolemia, smoking, prior MI, coronary angioplasty, ST-elevation MI, serum creatinine, hemoglobin level, left ventricular ejection fraction, LM bifurcation lesion, true bifurcation by Medina classification, main vessel and side branch vessel reference diameter and lesion length, SYNTAX score and interventional strategy. We then performed 1:3 propensity score-matching iteration by propensity score from initial 5 to 1 digit,^14,15 and matched 265 patients treated with EES to 795 patients treated with SES (c-statistics=0.655). Baseline characteristics of the 2 stent groups were compared again in this matched population. The Cox proportional hazard model was used to estimate the hazard ratio (HR) and 95% confidence interval (95% CI) for clinical outcomes of the 2 stent groups. In subgroup analyses, a test of interaction was used to confirm differential clinical outcomes of the 2 stents. All of the statistical analysis was performed using R version 2.15.1 and SPSS version 19.0, and P<0.05 was considered statistically significant.

Results

Baseline Characteristics of Overall Study Population

Among 2,897 patients enrolled in the COBIS II registry, 1,762 patients were treated with EES (n=348) or SES (n=1,414) and were included in this study (Figure 1). Baseline clinical, angiographic, QCA data, and procedural characteristics are presented in Table 1. Baseline clinical characteristics did not differ between the groups, except that the EES group had less frequent previous MI or coronary angioplasty than the SES group. Regarding the angiographic characteristics, the proportion of LM bifurcation lesions was higher in the EES group. The baseline QCA data showed that the EES group had shorter lesions and larger reference diameters in both the main and side branch vessels than the SES patients had. Medina classification and the prevalence of multivessel disease were not significantly different. Single-stent technique (main vessel stenting alone) was more frequently performed in the EES group, with stents of shorter length. In patients treated with a 1-stent technique, final kissing ballooning was less frequently performed in the EES group than in the SES group (EES vs. SES, 77 [28.3%] vs. 359 [36.2%]; P=0.015).

Table 1. Baseline Characteristics of the Overall Study Population of Patients Undergoing PCI for Coronary Bifurcation Lesion in COBIS II Registry

	EES (n=348)	SES (n=1,414)	P value
Clinical
Age, years	62.3±10.7	62.1±10.3	0.769
Male	259 (74.4)	990 (70.0)	0.105
Hypertension	207 (59.5)	790 (55.9)	0.223
Diabetes mellitus	100 (28.7)	400 (28.3)	0.868
Hypercholesterolemia	89 (25.6)	429 (30.3)	0.081
Current smoker	90 (25.9)	343 (24.3)	0.533
Previous MI	12 (3.4)	95 (6.7)	0.022
Previous coronary angioplasty	36 (10.3)	235 (16.6)	0.004
ST-elevation MI	43 (12.4)	144 (10.2)	0.239
Serum creatinine, mg/dl	1.06±0.87	1.10±0.89	0.436
LVEF, %	58.3±10.7	58.6±11.6	0.665
Angiography
Left main bifurcation	136 (39.1)	433 (30.6)	0.003
Bifurcation type*			0.129
True bifurcation
1, 1, 1	104 (29.9)	480 (33.9)
1, 0, 1	19 (5.5)	111 (7.9)
0, 1, 1	36 (10.3)	162 (11.5)
Non-true bifurcation
1, 1, 0	58 (16.7)	206 (14.6)
1, 0, 0	45 (12.9)	155 (11.0)
0, 1, 0	73 (21.0)	231 (16.3)
0, 0, 1	13 (3.7)	69 (4.9)
Multivessel disease	172 (49.4)	724 (51.2)	0.553
SYNTAX score	17.9±8.9	17.4±8.6	0.364
Quantitative coronary angiography
Main vessel
Lesion length, mm	16.1±10.7	19.4±12.8	<0.001
Proximal main vessel
Reference diameter, mm	3.56±0.62	3.43±0.64	0.001
MLD, mm	1.88±0.95	1.70±0.90	0.001
Distal main vessel
Reference diameter, mm	2.80±0.50	2.67±0.45	<0.001
MLD, mm	1.26±0.68	1.22±0.65	0.275
SB
Lesion length, mm	4.57±6.91	5.86±7.68	0.004
Reference diameter, mm	2.60±0.45	2.53±0.43	0.008
MLD, mm	1.52±0.75	1.36±0.71	<0.001
Angle between main and SBs	65.6±24.3	64.7±25.0	0.548
Procedural parameters
Interventional strategy			0.001
Main vessel stenting alone	272 (78.2)	992 (70.2)
Stent in both branches	76 (21.8)	422 (29.8)
T-stenting	23 (6.6)	154 (10.9)
Crushing	35 (10.1)	215 (15.2)
Culotte	6 (1.7)	7 (0.5)
Kissing stenting	10 (2.9)	44 (3.1)
Final kissing ballooning
1-stent technique	77 (28.3)	359 (36.2)	0.015
2-stent technique	69 (90.8)	367 (87.0)	0.353
Main vessel stent diameter ≥3.5 mm	169 (49.4)	648 (46.0)	0.259
Main vessel total stent length ≥24 mm	146 (42.7)	790 (56.1)	<0.001

Data are expressed as n (%) or mean±SD unless otherwise indicated. *According to the Medina classification. COBIS, Coronary Bifurcation Stenting; EES, everolimus-eluting stent; LVEF, left ventricular ejection fraction; MI, myocardial infarction; MLD, minimal luminal diameter; PCI, percutaneous coronary intervention; SB, side branch; SES, sirolimus-eluting stent.

Clinical Outcomes in the Overall Study Population

During a 2-year follow-up, cumulatively 141 MACE occurred, and the estimated 2-year MACE rate was 8.6%. In the EES and SES groups, the 2-year MACE rates were 7.2% and 9.0%, respectively, and the difference was not statistically significant (HR of EES vs. SES, 0.80; 95% CI, 0.51–1.27; P=0.345). Regarding cardiac death and TVR, there was no significant difference between the groups (HR for cardiac death [95% CI], 1.41 [0.46–4.37], P=0.552; HR for TVR, 0.73 [0.45–1.21], P=0.225) (Figures 2A–C).

Figure 2.

Clinical outcomes of the overall (A–C) and propensity score-matched populations (D–F). There was no significant difference in clinical outcomes between the SES and EES groups. CI, confidence interval; EES, everolimus-eluting stent; HR, hazard ratio; MACE, major adverse cardiac event; SES, sirolimus-eluting stent; TVR, target vessel revascularization.

Predictors for MACE in the Overall Study Population

In the overall study population, predictors for MACE were mostly angiographic parameters, not clinical characteristics, in the unadjusted Cox proportional hazard analysis. They were LM bifurcation, true bifurcation, multivessel disease, SYNTAX ≥23, use of 2-stent technique, longer lesion and stent length in the main vessel. Of these, 2-stent technique PCI (HR 2.40 [1.73–3.35]; P<0.001) and LM bifurcation (HR 2.30 [1.65–3.20]; P<0.001) were the strongest predictors for MACE (Table 2).

Table 2. Predictors for MACEs in Overall Study Population of Patients Undergoing PCI for Coronary Bifurcation Lesion in COBIS II Registry

	HR (95% CI)	P value
EES (vs. SES)	0.80 (0.51–1.27)	0.345
Age ≥75 years	1.02 (0.60–1.74)	0.941
Male	0.98 (0.68–1.41)	0.910
Diabetes	1.23 (0.86–1.76)	0.249
Hypertension	1.13 (0.81–1.59)	0.466
Previous PCI	1.30 (0.85–1.97)	0.226
STEMI	0.87 (0.49–1.54)	0.637
LVEF <40%	0.96 (0.45–2.06)	0.912
Left main bifurcation	2.30 (1.65–3.20)	<0.001
True bifurcation	1.41 (1.01–1.97)	0.045
Multivessel disease	1.91 (1.35–2.71)	<0.001
SYNTAX score ≥23	2.17 (1.53–3.07)	<0.001
2-stent technique	2.40 (1.73–3.35)	<0.001
Main vessel lesion length, per 1 mm	1.02 (1.01–1.03)	0.001
Stent length, per 1 mm*	1.01 (1.00–1.03)	0.034

*Stents implanted at proximal and distal main vessel were included in the measurement.

CI, confidence interval; HR, hazard ratio; MACE, major adverse cardiac event; STEMI, ST-segment elevation myocardial infarction. Other abbreviations as in Table 1.

Analysis in Propensity Score-Matched Population

Baseline Characteristics After 1:3 matching between the EES and SES groups using propensity score, a total of 265 patients treated with EES and 795 patients treated with SES were analyzed again. Baseline clinical, angiographic, QCA data, and procedural characteristics of the matched population are presented in Table S1. All the baseline clinical and angiographic characteristics of the 2 DES groups became balanced after propensity score-matching.

Clinical Outcomes in the Matched Population A total of 83 MACE occurred during the 2-year follow-up of the matched population (estimated MACE rate, 8.6%). Cox proportional hazard analysis revealed more favorable outcome with EES than with SES regarding the risk of MACE (HR, 0.53; 95% CI, 0.29–0.97; P=0.039) and TVR (HR, 0.47; 95% CI, 0.24–0.92; P=0.027). The risk of cardiac death was not significantly different between the EES and SES groups (HR, 1.25; 95% CI, 0.24–6.44; P=0.790) (Figures 2D–F). Subgroup analysis for MACE suggested more favorable outcomes with EES in patients treated with a 2-stent PCI technique, and in patients with LM bifurcation lesions (Table 3). Further analyses in these subgroups were performed.

Table 3. Subgroup Analysis for MACEs in Propensity Score-Matched Population Among Patients Undergoing PCI for Coronary Bifurcation Lesion in COBIS II Registry

	Total no. of patients	Estimated MACE rate at 2 years (%)		HR (95% CI)	P value	Interaction P value
		EES	SES
Intervention strategy
2-stent technique	245	5.0	18.8	0.27 (0.08–0.88)	0.030	0.159
1-stent technique	815	5.1	7.0	0.73 (0.36–1.52)	0.403
Left main bifurcation
Yes	401	4.5	15.5	0.27 (0.10–0.75)	0.012	0.059
No	659	5.5	6.2	0.94 (0.43–2.05)	0.868
True bifurcation
Yes	489	8.3	12.8	0.65 (0.32–1.34)	0.242	0.330
No	571	2.4	7.2	0.33 (0.10–1.08)	0.067
Multivessel disease
Yes	561	6.2	12.4	0.49 (0.23–1.03)	0.059	0.832
No	499	3.7	6.8	0.57 (0.20–1.64)	0.298
SYNTAX score
≥23	286	9.9	13.2	0.73 (0.30–1.78)	0.490	0.357
<23	774	3.4	8.5	0.41 (0.18–0.96)	0.040
Main vessel stent length
≥24	512	5.3	9.5	0.59 (0.25–1.41)	0.237	0.762
<24	542	5.0	9.6	0.50 (0.21–1.18)	0.111
Main vessel stent diameter
≥3.5 mm	511	2.1	9.6	0.18 (0.04–0.74)	0.018	0.044
<3.5 mm	543	8.1	9.4	0.90 (0.45–1.82)	0.772

Abbreviations as in Tables 1,2.

EES vs. SES in LM Bifurcation Lesions In PCI for LM bifurcation lesions, the use of EES lowered the risk of MACE compared with the use of SES (HR [95% CI], 0.27 [0.10–0.75]; P=0.012). The risk of TVR was also lower in the EES group than in the SES group (HR [95% CI], 0.21 [0.06–0.67]; P=0.008). In patients with non-LM bifurcation lesion, however, there was no significant difference between the 2 DES groups in terms of MACE (HR [95% CI], 0.94 [0.43–2.05]; P=0.868) and TVR (HR [95% CI], 0.96 [0.41–2.23]; P=0.922). The interaction P-value between the type of DES and LM bifurcation PCI was 0.059 for MACE and 0.038 for TVR (Figure 3). Regardless of LM bifurcation lesion, there was no significant difference in the incidence of cardiac death between the 2 DES groups (HR of EES in LM PCI: 2.88 [0.18–46.2], P=0.453; for non-LM PCI: 0.81 [0.09–7.22], P=0.848).

Figure 3.

Clinical outcomes of the matched population according to left main bifurcation lesions. Cumulative incidences of MACE (A,B) and TVR (C,D) in the propensity score-matched population after LM bifurcation (A,C) or non-LM bifurcation PCI (B,D). P-value for interaction between the stent type and the LM bifurcation PCI was 0.059 for MACE and 0.038 for TVR. CI, confidence interval; EES, everolimus-eluting stent; HR, hazard ratio; MACE, major adverse cardiac event; SES, sirolimus-eluting stent; TVR, target vessel revascularization.

EES vs. SES in 2-stent PCI technique When bifurcation lesions were treated by a 2-stent technique (Figure 4), MACE occurred less frequently after EES implantation than after SES implantation (HR [95% CI], 0.27 [0.08–0.88]; P=0.030), which was mainly driven by the lower TVR rate in the EES group (HR [95% CI], 0.28 [0.09–0.91]; P=0.035). In patients treated with a 1-stent technique, however, MACE and TVR rates showed no significant difference between the 2 DES groups. The interaction P-value between the type of DES and the intervention strategy was 0.159 for MACE and 0.261 for TVR. Regardless of the stenting strategy, there was no significant difference in the incidence of cardiac death between the 2 DES groups (HR of EES in 2-stent PCI: 0.03 [0.0–4.63E6], P=0.717; in 1-stent PCI: 1.59 [0.29–8.69], P=0.590).

Figure 4.

Clinical outcomes of the matched population according to the stenting strategy. Cumulative incidences of MACE (A,B) and TVR (C,D) in the propensity score-matched population after PCI using 2-stent technique (A,C) or 1-stent technique (B,D). P-value for interaction between the stent type and the stenting strategy was 0.159 for MACE and 0.261 for TVR. CI, confidence interval; EES, everolimus-eluting stent; HR, hazard ratio; MACE, major adverse cardiac event; SES, sirolimus-eluting stent; TVR, target vessel revascularization.

Safety Outcomes

In terms of cardiac death, no significant difference was indicated in either the overall or study population, or in the subgroup analyses. Regarding stent thrombosis, the estimated event rate at 2 years was 1.2% in EES (4 cases of probable stent thrombosis) and 0.6% in SES (4 definite plus 4 probable stent thrombosis). The difference between the EES and SES groups was not significant. Premature discontinuation of dual antiplatelet therapy within 6 months after DES implantation was not different between the 2 DES groups (5.0% in EES, 5.3% in SES group; P=0.824)

Discussion

This study used data from a nationwide multicenter registry in Korea to compare the clinical outcomes of patients after 1st- or 2nd-generation limus-eluting stent implantation in bifurcation lesions. In the overall study population of coronary bifurcation lesions, there was no significant difference in the incidence of MACE, cardiac death, and TVR up to 2 years between the 2 DES groups. However, after matching by propensity score, EES showed favorable outcomes compared with SES regarding MACE and TVR. These results might be derived by adjusting for LM bifurcation lesion PCI between the EES (39.1%) and SES (30.6%) groups. Although the EES group demonstrated shorter lesions and larger reference diameters of the main vessel before propensity score matching, these also might be related by the different proportion of LM bifurcation lesions between the 2 DES groups (lesion length: 17.5±13.6 in LM vs. 19.3±11.9 mm in non-LM lesion, P<0.001; reference diameter: 3.94±0.67 in LM vs. 3.26±0.51 mm in non-LM, P<0.001). Subgroup analysis revealed that the use of EES significantly decreased the risk of MACE TVR compared with the use of SES in LM bifurcation PCI, in contrast to the lack of difference in clinical outcomes between the 2 DESs after non-LM PCI. Also, the need for TVR was significantly lower with EES than with SES after 2-stent PCI technique.

Comparison of 1st- and 2nd-Generation DES in Prior Studies

Although the superiority of the 2nd-generation EES over 1st-generation DES has been repeatedly demonstrated, the comparison target has mostly been the paclitaxel-eluting stent (PES).^5–7 SES has been reported to have relatively similar efficacy to EES,^16,17 and our group also reported comparable efficacy between EES and SES in the EXCELLENT randomized trial.¹⁸ Two recent randomized clinical trials compared EES with SES for the treatment of bifurcation lesions and reported that there was no significant difference in clinical outcomes.^8,9 However, both studies were rather small, including only 10–15 patients treated for LM bifurcation lesions in each DES group. The number of patients treated by 2-stent PCI technique was even smaller (≈5 for each DES group). Because the large-scale COBIS II registry includes high-risk patients such as those with LM bifurcation lesions and patients treated by 2-stent PCI technique, the current study was able to compare real-world clinical outcomes of EES with those of SES in more complicated and challenging lesion subsets. And the result was that EES, compared with SES, significantly reduced TVR after adjustment for numerous variables by means of propensity score-matching. Moreover, these differences appeared to be greater in LM bifurcation PCI, especially when a 2-stent technique was required. The comparable clinical outcomes between the 2 DES in non-LM bifurcation PCI in this study may account for the results of the prior studies, in which the efficacy of EES and SES was similar.

Technique Strategy for Bifurcation Lesions

With increasing evidence on the preferable outcomes of the 1-stent technique compared with the 2-stent technique, the 1-stent technique PCI is often suggested as the first-line strategy for bifurcation PCI.^19–22 However, side branch vessel stenting is often advocated when a large territory is at risk, such as ostial stenosis of the left circumflex artery in a LM bifurcation lesion.^22,23 In the current study, more than one-third of the patients with LM bifurcation lesions underwent stent implantation of a side branch vessel (138/401, 34.4%), which was more frequent than in patients with non-LM bifurcation lesions (107/659, 16.2%; P<0.001). Moreover, 2-stent PCI was more frequently used for non-true bifurcation lesions when the target lesion was a LM bifurcation lesion (10.2% vs. 16.7%, P=0.023). Thus, it is necessary to improve clinical outcomes after inevitable 2-stent PCI technique for LM bifurcation lesions. From this perspective, it is noteworthy that our results highlight the potential benefit of EES over SES in such complicated coronary lesions. In the current study, the use of EES significantly decreased the risk of TVR compared with the use of SES in patients treated with a 2-stent technique, as well as in patients with LM bifurcation lesions. Further analysis of patients with LM bifurcation lesions treated with a 2-stent technique showed superiority of EES over SES in terms of MACE (HR [95% CI], 0.11 [0.02–0.82]; P=0.031) (Table S2) and TVR (HR [95% CI], 0.12 [0.02–0.85]; P=0.034). Additional propensity score-matching among the patients with LM bifurcation lesions (n=117 for EES, n= 351 for SES group in patients with LM lesions) did not alter this result (HR [95% CI], 0.12 [0.02–0.92], P=0.041).

On the other hand, LM bifurcation lesion and use of 2-stent technique were significant risk factors for MACE only in the SES group (LM lesion: HR [95% CI]=2.67 [1.66–4.30], P<0.001; 2-stent technique: 2.94 [1.84–4.70], P<0.001), whereas EES showed comparable outcomes in these subgroups (LM lesion: HR [95% CI]=0.77 [0.23–2.56], P=0.672; 2-stent technique: 1.07 [0.29–3.94], P=0.924). These results suggest that the 2-stent PCI technique may not be as inferior as generally accepted, especially with the use of contemporary 2nd- or 3rd-generation DES.

Mechanistic Considerations

The 2 DES compared in this study were limus-eluting stents. Therefore, the design of the DES, rather than the drug eluted from the stents, may affect clinical outcomes of PCI. The Xience V^® stent (EES; Abbott Vascular, Santa Clara, CA, USA) has an open-cell design with 3 connectors. The thickness of the stent struts is 81 μm, and of the polymer 7.6 μm. Another EES, the PROMUS Element^TM stent (Boston Scientific, Natick, MA, USA) has 2 connectors and the thickness of the stent struts ranges from 81 to 86 μm according to the stent size. The Cypher^® stent (SES; Cordis Corporation, Miami, FL, USA) has 6–7 connectors (7 connectors in Cypher for large vessels) with 140 μm strut thickness and 12.6 μm polymer thickness. The maximal cell opening is an important factor for side branch vessel intervention. A larger cell opening may be achieved more easily with stents having a small number of connectors and thinner struts.²⁴ Therefore, less connectors and thinner struts imply better procedural outcomes for side branch intervention, which may contribute to the lower MACE and TVR in the EES group after PCI for LM bifurcation lesions. A supportive result for this hypothesis is that the EES group showed less MACE than the SES group when stents of larger diameter (≥3.5 mm) were used (HR of EES, 0.18 [0.04–0.74], P=0.018) in this study, with significant interaction between the diameter and the type of DES for MACE (P=0.044) (Table 3). Stents ≥3.5 mm diameter were more frequently used for LM bifurcation lesions (66.2% in LM vs. 37.8% in non-LM lesions, P<0.001), and the advantageous stent design of EES in achieving large cell opening for side branch may have played a role. In addition, the aforementioned hypothesis is also supported by the result that the need for TVR after 2-stent PCI technique using SES tended to be higher at the side branch vessel (23/185, 12.4%) than at the main vessel (12/185, 6.5%; P=0.051) (Figure 5).

Figure 5.

Target sites for repeat revascularization after 1-stent or 2-stent technique intervention for left main bifurcation lesion. CI, confidence interval; EES, everolimus-eluting stent; HR, hazard ratio; LAD, left anterior descending; LCx, left circumflex; MACE, major adverse cardiac event; SES, sirolimus-eluting stent; TVR, target vessel revascularization.

Study Limitations

The current study was a nonrandomized, registry-based study, and might have been affected significantly by confounding factors. Although we repeated our analysis using a propensity score-matched population, there still remains the possibility of biases by unmeasured variables. Another limitation is that all TVR events may not be driven by ischemic symptoms. Although systematic follow-up angiography was not mandatory in this study, approximately 39% of the study population underwent coronary angiography within the 1st year of follow-up. In addition, this study was rather underpowered to evaluate safety outcomes such as cardiac death and stent thrombosis. Also, systemic angiographic follow-up would have provided detailed interpretation of the results of this study, which was not included in this study.

Conclusions

In this large-scale Korean multicenter registry for bifurcation coronary lesions, treating with 1st- or 2nd-generation limus-eluting stents demonstrated no significant difference in clinical outcomes in overall study population up to 2 years. However, EES was superior to SES after matching by propensity score, especially in patients with LM bifurcation or in those treated by 2-stent technique.

Disclosures

None.

Funding Sources

This registry was sponsored by the Korean Society of Interventional Cardiology, Seoul, Republic of Korea. Also this research was supported by the Bio & Medical Technology Development Program of the National Research Foundation (NRF) funded by the Korean government (MEST) [2010-0020258].

Supplementary Files

Supplementary File 1

Table S1. Baseline characteristics of propensity score-matched population among patients undergoing PCI for coronary bifurcation lesion in COBIS II registry

Table S2. Subgroup analysis for MACEs in subgroups of patients treated with 2-stent PCI technique

Please find supplementary file(s);

http://dx.doi.org/10.1253/circj.CJ-14-0802

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