The SMART-STRATEGY II study was a prospective, randomized, open-label, multicenter trial comparing conservative vs aggressive strategies for provisional SB intervention during LM bifurcation PCI at 15 centers in Korea between March 2013 and December 2016 (ClinicalTrials.gov, NCT01798433). The study protocol was approved by the local institutional review boards. Written informed consent was obtained from all participants. Inclusion criteria were as follows: a) age ≥ 20 years; b) a LM bifurcation lesion on coronary angiography with a reference diameter of the main branch (left anterior descending artery) and SB (left circumflex artery) ≥ 2.5mm by visual estimation; c) significant myocardial ischemia in the main branch or SB diameter stenosis> 75% or 50%-75% with angina and/or objective evidence of ischemia in the noninvasive stress test; and d) patients who voluntarily signed the written informed consent form. Exclusion criteria were as follows: a) patients with coronary artery stenosis only in the SB ostium of the LM bifurcation lesion (Medina 0.0.1 lesion); b) patients with known hypersensitivity or contraindication to heparin, aspirin, clopidogrel, or biolimus; or c) patients who previously underwent stent implantation in the target lesion prior to enrollment. All of the study patients in this trial met the inclusion criteria and none of the exclusion criteria.

Patients were stratified according to whether they had a non-true bifurcation lesion (SB stenosis diameter <50%) or true bifurcation lesion (SB stenosis diameter ≥ 50%). Patients were then randomized 1:1 to a conservative or aggressive strategy group for provisional SB intervention after MV stenting (figure 1). For non-true bifurcation lesions, the conservative strategy included MV stenting alone without FKB. The aggressive strategy included MV stenting followed by mandatory FKB. For true bifurcation lesions, the conservative strategy was SB ballooning followed by kissing ballooning for an SB stenosis diameter ≥ 75% after MV stenting. SB stenting was only performed when the SB stenosis diameter was ≥ 50% or there was a SB dissection. The aggressive strategy included an elective 2-stent approach for the MV and SB. In all cases, the choice of the 2-stenting technique was made at the operator's discretion. Intravascular ultrasound use was recommended, but not mandatory. For the stent implantation, the BioMatrix stent (Biosensors Interventional Technologies Pte. Ltd, Singapore) was used except when it was clinically unavailable. After the index procedure, measurement of the myocardial band fraction of creatine kinase was mandatory.

Figure 1.

Study protocol. FKB, final kissing balloon; RS, residual stenosis; SB, side branch.

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Angiograms were obtained in the 15 participating centers using portable storage devices and sent to the core laboratory (Cardiac and Vascular Center, Samsung Medical Center, Korea). All cine coronary angiograms were reviewed and quantitatively analyzed at the Core Laboratory by 2 independent experienced staff members. Quantitative coronary analysis was performed for LM bifurcation lesions before and after the intervention using the same projections with the optimal view. Routine follow-up angiography was recommended at 9 months after the index procedure. However, the rate of follow-up angiography was 54.9% (113 out of 206 patients).

The primary end point was the occurrence of target lesion failure (TLF), a composite of cardiac death, myocardial infarction, or target lesion revascularization at 1 year of follow-up. The secondary end points included the individual components of the primary end point: cardiac death or myocardial infarction, stent thrombosis, and target vessel revascularization at 1 year of follow-up. All deaths were considered cardiac unless a definite noncardiac cause could be established. Myocardial infarction was defined as elevated cardiac enzymes (troponin or the myocardial band fraction of creatine kinase) greater than the upper limit of normal that occurred with ischemia symptoms or electrocardiogram findings indicative of ischemia that were unrelated to the index procedure. Procedure-related myocardial infarction was defined as an elevated myocardial band fraction of creatine kinase more than 3 times above the upper limit of normal within 48hours of the index procedure. Target lesion revascularization was defined as repeat PCI of the lesion within 5mm of stent deployment. Target vessel revascularization was defined as repeat PCI or bypass graft surgery of the target vessel. Stent thrombosis was defined as definite or probable stent thrombosis according to the definitions of the Academic Research Consortium.13

Data regarding the primary and secondary end points were obtained through office visits or by telephone contact 1, 6, 9, and 12 months after the index procedure. For validation, information regarding vital status was obtained until September 2018 from the National Population Registry of the Korea National Statistical Office using a unique personal identification number. When available, each participating center was encouraged to collect additional follow-up information up to 3 years after the index procedure.

The expected rate of TLF was 5% in the conservative strategy group and 14% in the aggressive strategy group in patients with a non-true LM bifurcation lesion; the corresponding rates in those with a true bifurcation lesion were 7% in the conservative strategy group and 14% in the aggressive strategy group .5,14,15 With 5% type I error, 80% power, and a 5% drop-out rate, a total of 700 patients were needed (350 with a non-true bifurcation lesion and 350 with a true bifurcation lesion) to show that the conservative strategy was superior to the aggressive strategy. However, the SMART-STRATEGY II study was terminated early due to slow enrollment.

All data were analyzed according to the intention-to-treat principle. Categorical variables are summarized as numbers with percentages and were compared using Pearson chi-square or Fisher exact test. Continuous variables are presented as means with standard deviations and were compared using an independent t-test or Wilcoxon rank-sum test according to distribution normality. Time-to-event hazard curves were plotted using Kaplan-Meier estimates and were compared using a log-rank test. To ascertain variables independently associated with 1-year TLF, multivariable Cox regression was performed using clinically relevant covariates, including age, male sex, dyslipidemia, current smoking, diabetes, hypertension, chronic kidney disease, previous myocardial infarction, left ventricular ejection fraction, performance of follow-up angiography, treatment strategy, type of bifurcation lesion (true or non-true), bifurcation angle, length of MV disease, and presence of significant SB ostial stenosis (≥ 50%) after the index procedure.

All of the probability values are 2-tailed and P values <.05 were considered statistically significant. R software version 3.4.3 (R Foundation for Statistical Computing) was used for all statistical analyses.

A total of 206 patients with a LM bifurcation lesion (160 non-true bifurcation lesions and 46 true bifurcation lesions) were included in this study. The baseline clinical characteristics are shown in table 1 and were well-matched between the conservative and aggressive strategy groups. Regarding the procedural characteristics, there were no significant differences in vascular access, number of diseased vessels, Medina classification of the LM lesion, and intravascular ultrasound use between the 2 strategies in patients with non-true and true bifurcation lesions (table 2). All study patients were receiving dual antiplatelet therapy at the index procedure, and the rate of 1-year dual antiplatelet therapy did not differ between the conservative and aggressive strategy groups (97.0% vs 97.1%, P=.962).

Procedural outcomes are shown in table 3. Among patients with a non-true bifurcation lesion, the mean amount of contrast dye used was significantly smaller in the conservative than aggressive strategy group (221.1±77.7mL vs 259.9±117.9mL, P=.017). The mean fluoroscopic time and the rate of procedure-related myocardial infarction were not significantly different between the 2 strategies. During the procedure, 7 patients (9.0%) in the conservative strategy group underwent kissing balloon inflation due to SB compromise during the procedure. Among patients with a true bifurcation lesion, there were no significant differences in the fluoroscopic time, amount of contrast dye, and rate of procedure-related myocardial infarction between the conservative and aggressive strategy groups.

Baseline characteristics and procedural outcomes according to treatment strategy in the overall population are presented in table 1 of the supplementary data, table 2 of the supplementary data, and table 3 of the supplementary data.

Quantitative coronary analysis was possible in 200 patients (97.1%) at baseline and in 113 patients at 9 months (54.5% of the conservative strategy group and 55.2% of the aggressive strategy group, P=.910) (figure 2 and table 4 of the supplementary data). Among non-true bifurcations lesions, there were no significant differences in the minimal lumen diameter of the SB or in binary (re)stenosis between the conservative and aggressive strategy groups after the index procedure and at follow-up. There were no significant differences in the MV in quantitative coronary analysis.

Figure 2.

Study population.

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Among true bifurcation lesions, the conservative strategy had a lower minimal lumen diameter of the SB (2.1±0.9 vs 2.9±0.5mm; P=.001) after the index procedure than the aggressive strategy. SB (re)stenosis occurred in 6 patients (40.0%) in the conservative strategy group and in 3 patients (25.0%) in the aggressive strategy group; the difference was not significant (P=.681). There were no significant differences in the MV in quantitative coronary analysis.

The median follow-up duration was 1028 days. Of a total of 206 patients, 200 (97.1%) completed the planned 1-year clinical follow-up (figure 2 and table 4). One-year TLFs were not significantly different between the conservative and aggressive strategies among patients with a non-true bifurcation lesion (6.5% vs 4.9%; hazard ratio [HR], 1.31; 95% confidence interval [95%CI], 0.35-4.88; P=.687) and among those with a true bifurcation lesion (17.6% vs 21.7%; HR, 0.76; 95%CI, 0.20-2.83; P=.683) (figure 3). The incidences of cardiac death, myocardial infarction, target lesion revascularization, and stent thrombosis were also not significantly different between the strategies. Out of 11 target lesion revascularizations during the first year after the index procedure, 3 events were due to angiographic restenosis incidentally found in follow-up angiography. Clinical outcomes according to treatment strategy in the overall population are presented in table 5 of the supplementary data.

Figure 3.

Target lesion failure at 1 year. A: non-true bifurcation lesion. B: true bifurcation lesion. 95%CI, 95% confidence interval; HR, hazard ratio; MI, myocardial infarction; TLF, target lesion failure.

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Of a total of 206 patients, 116 (56.3%) completed the 3-year follow-up. At 3 years, there were no significant differences in clinical outcomes between the conservative and aggressive strategies (table 6 of the supplementary data).

In multivariable Cox analysis, factors independently associated with 1-year TLF were a true bifurcation lesion (HR, 4.94; 95%CI, 1.60-15.21; P=.005), bifurcation angle (per 10°; HR, 0.78; 95%CI, 0.61-1.00; P=.046), and chronic kidney disease (HR, 5.45; 95%CI, 1.16-25.64; P=.032).