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

Study population

The COBIS (Coronary Bifurcation Stenting) Registry II is a retrospective multicenter registry dedicated to bifurcation lesions treated with percutaneous coronary intervention (PCI) with DES. From January 2003 through December 2009, 2,897 consecutive patients were enrolled from 18 major coronary intervention centers in the Republic of Korea. The inclusion criteria were coronary bifurcation lesions treated solely with DES, a main vessel (MV) diameter ≥2.5 mm, and a side branch (SB) diameter ≥2.3 mm. The exclusion criteria were cardiogenic shock, cardiopulmonary resuscitation, and protected LM disease. This registry was funded by the Korean Society of Interventional Cardiology. The local institutional review board at each hospital approved this study and waived the requirement for informed consent for access to each institution's PCI registry.

Percutaneous coronary intervention

All interventions were performed according to current standard guidelines. All patients received dual oral antiplatelet therapy with 300 mg aspirin and either 300 or 600 mg clopidogrel before PCI unless they had previously received these medications. Intravenous heparin was administered to maintain an activated clotting time of 250 to 300 s. The access, type of DES, and use of intravascular ultrasound or glycoprotein IIb/IIIa receptor inhibitors were all left to the operator's discretion. Decisions to treat bifurcation lesions by a 1- or 2-stent technique were made by the individual operators. Aspirin was continued indefinitely, and the duration of clopidogrel treatment was also left to the operator's discretion.

Data collection and analysis

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 telephone contact, if necessary. All baseline and procedural cine coronary angiograms were reviewed and quantitatively analyzed at the angiographic core laboratory (the Cardiac and Vascular Center, Samsung Medical Center, Seoul, Republic of Korea) using standard qualitative and quantitative analyses and definitions (6). We determined the minimal lumen diameter (MLD) and reference diameter (RD) for each vessel. The percentage of diameter stenosis was calculated as: 100 × (RD − MLD)/RD. The bifurcation angle was defined as the angle between the distal MV and the SB at its origin using the angiographic projection with the widest separation of the 2 branches (7). Bifurcation lesions were classified according to the Medina classification, in which the proximal MV, distal MV, and SB components of the bifurcation are each assigned a score of 1 or 0 depending on the presence or absence of >50% stenosis (8). Medina classification type 1.1.1, 1.0.1, and 0.1.1 lesions were defined as true bifurcation lesions.

Study outcomes and definitions

The primary endpoint of the study was target lesion failure, defined as a composite of cardiac death, spontaneous myocardial infarction (MI), and target lesion revascularization during follow-up. Secondary endpoints were the individual components of the primary endpoint, composite of cardiac death or spontaneous MI, stent thrombosis, and target vessel revascularization.

All deaths were considered cardiac unless a definite noncardiac cause could be established. MI was defined as elevated cardiac enzymes (troponin or creatine kinase-myocardial band) greater than the upper limit of the normal with ischemic symptoms or electrocardiographic findings indicative of ischemia that was not related to the index procedure. Target lesion revascularization was defined as repeat PCI of the lesion within 5 mm of stent deployment or bypass graft surgery of the target vessel. Target vessel revascularization was the repeat revascularization of the target vessel by PCI or bypass graft surgery. Stent thrombosis was assessed based on the definitions of the Academic Research Consortium (9). An independent clinical event adjudicating committee reviewed all outcome data reported from the participating centers.

Statistical analyses

Continuous variables are presented as mean ± SD or the median and interquartile range and were compared using the t test or Wilcoxon rank sum test for continuous variables. Categorical variables are reported as frequencies (percentages) and were compared using the chi-square or Fisher exact test, as appropriate. Survival curves were constructed using Kaplan-Meier estimates and were compared using the log-rank test.

To ensure a rigorous adjustment for significant difference in patient characteristics according to treatment strategy and to avoid model overfitting based on few events in the endpoints, we used a weighted Cox proportional hazards model using inverse probability of treatment weighting (10). A propensity score analysis was performed with a logistic regression model from which the probability for the 2-stent strategy was calculated for each patient. In the weighted Cox multivariable model with inverse probability of treatment weighting methods, the weights for patients undergoing the 2-stent strategy were the inverse of 1 − propensity score, and weights for patients not undergoing the 2-stent strategy were the inverse of the propensity score. We also tested the significance of interactions between treatment strategy and location of bifurcation lesion on outcomes in these models.

All reported p values are 2-tailed, and p < 0.05 was considered significant. All analyses were performed using SAS version 9.1 (SAS Institute, Cary, North Carolina).

Patient characteristics

Of the 2,897 patients registered in the COBIS II registry, 2,044 patients (70.6%) had a non-LM bifurcation lesion and 853 (29.4%) had an LM bifurcation lesion. The 2-stent strategy was used more frequently in the LM bifurcation group than in the non-LM bifurcation group (40.3% vs. 20.8%, p < 0.01).

Baseline demographic, clinical, angiographic, and procedural characteristics according to bifurcation lesion locations and treatment strategies are shown in Tables 1 and 2. In the non-LM bifurcation group, patients undergoing the 2-stent strategy had a higher prevalence of left anterior descending artery bifurcation lesions and previous PCI than those undergoing the 1-stent strategy. In the LM bifurcation group, patients undergoing the 2-stent strategy were older and had a higher prevalence of previous PCI and acute coronary syndrome on admission than those undergoing the 1-stent strategy. Compared with patients undergoing the 1-stent strategy, those undergoing the 2-stent strategy were more likely to have multivessel disease and true bifurcation lesions on Medina classification and more frequently underwent final kissing balloon dilation, intravascular ultrasound, and remote-site intervention in both non-LM and LM bifurcation groups. The SYNTAX (Synergy between PCI with Taxus and Cardiac Surgery) score was significantly greater in patients undergoing the 2-stent strategy than in those undergoing the 1-stent strategy in both groups. Among the 2-stent group, the crush technique was used most frequently, followed by the T-stenting technique, kissing, or V-stenting technique, and culottes stenting technique in both non-LM and LM bifurcation groups.

Quantitative coronary angiographic analysis

In both LM and non-LM bifurcation groups, patients who underwent the 2-stent strategy had significantly smaller RD and MLD of the SB, a greater percentage of diameter stenosis of the SB, and a longer lesion length of the MV and SB than those in the 1-stent strategy group (Table 3). In the non-LM bifurcation group, the angle between the MV and SB was significantly smaller in patients in whom the 2-stent strategy was used than in those who underwent the 1-stent strategy, but in the LM bifurcation group, the angle between the MV and SB was similar.

Clinical outcomes according to bifurcation lesion locations and treatment strategies

Complete clinical follow-up data for major clinical events were obtained in 96.0% and 97.4% of patients who underwent the 1- and 2-stent strategies for non-LM bifurcation lesions (p = 0.18), and 96.3% and 96.5% for LM bifurcation lesions (p = 0.85), respectively. The median follow-up was 37 months (interquartile range: 25 to 53 months) in the non-LM bifurcation group and 35 months (interquartile range: 25 to 50 months) in the LM bifurcation group.

During the entire study period, 182 primary composite events occurred, including 20 cardiac deaths, 33 spontaneous MIs, and 147 target lesion revascularizations in the non-LM bifurcation group. In the LM bifurcation group, 114 primary composite events occurred, including 22 cardiac deaths, 20 spontaneous MIs, and 83 target lesion revascularizations. Observed clinical outcomes according to bifurcation lesion location and treatment strategy are shown in Table 4. In the non-LM bifurcation group, treatment with the 2-stent strategy was associated with a higher incidence of target lesion failure and target lesion revascularization, but not cardiac death and the composite of cardiac death or MI (Fig. 1).

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Figure 1

Kaplan-Meier Curves in Patients With Non-LM Bifurcation Lesions

(A) Kaplan-Meier curves for target lesion failure in patients undergoing the 1-stent strategy versus the 2-stent strategy. (B) Kaplan-Meier curves for cardiac death in patients undergoing the 1-stent strategy versus the 2-stent strategy. (C) Kaplan-Meier curves for cardiac death or myocardial infarction in patients undergoing the 1-stent strategy versus the 2-stent strategy. (D) Kaplan-Meier curves for target lesion revascularization in patients undergoing the 1-stent strategy versus the 2-stent strategy. LM = left main.

In contrast, among patients with the LM bifurcation lesions, patients who underwent the 2-stent strategy had a higher incidence of cardiac death, the composite of cardiac death or MI, target lesion revascularization, and target lesion failure (Fig. 2). In addition, definite or probable stent thrombosis occurred more frequently in the 2-stent group than in the 1-stent group.

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Figure 2

Kaplan-Meier Curves in Patients With LM Bifurcation Lesions

Kaplan-Meier curves for (A) target lesion failure, (B) cardiac death, (C) cardiac death or myocardial infarction, and (D) target lesion revascularization in patients undergoing the 1-stent strategy versus the 2-stent strategy. LM = left main.

After adjustments of clinical covariates using an inverse probability of treatment weighting method (Table 5), the adjusted risks for primary (hazard ratio [HR]: 1.39; 95% confidence interval [CI]: 0.99 to 1.94; p = 0.06) and any secondary endpoints were not significantly different according to treatment strategy except for target lesion revascularization in patients with non-LM bifurcation lesions. On the other hand, in the LM bifurcation group, the adjusted risks for the primary endpoint (HR: 2.38; 95% CI: 1.60 to 3.55; p < 0.01) and all secondary endpoints were significantly higher in patients treated with the 2-stent strategy than in those treated with the 1-stent strategy. There were statistically significant interactions between treatment strategies and bifurcation lesion locations for covariate-adjusted risks of target lesion failure (p = 0.01), target lesion revascularization (p = 0.03), and target vessel revascularization (p < 0.01). There was also a nonsignificant trend in the interaction between treatment strategy and bifurcation lesion location for the composite of cardiac death or MI (p = 0.06).

Study limitations

Our study's nonrandomized, observational design may have significantly affected the results due to confounding factors. The selection of treatment strategy and stent type was at the discretion of the operators. Some baseline and angiographic characteristics were unfavorable to the 2-stent group compared with the 1-stent group. This may contribute to differences in adverse outcomes between the 2 groups, and the impact of the 2-stent strategy on adverse clinical outcomes could become more relevant in patients with LM bifurcation lesions. Although we strove to reduce treatment-selection bias for treatment strategy and potential confounding using various risk-adjusted and inverse probability of treatment weighting, unmeasured confounders may be present. Another limitation is that a substantial portion of patients were treated with first-generation DES, which were found to be inferior to newer generation DES with regard to the occurrence of adverse clinical events. Our findings should be confirmed by adequately powered, randomized trials using newer generation DES.