Author + information
- Received June 5, 2018
- Revision received September 5, 2018
- Accepted September 7, 2018
- Published online December 17, 2018.
- Tae-Min Rhee, MDa,
- Kyung Woo Park, MD, PhDa,∗ (, )
- Chi-Hoon Kim, MDb,
- Jeehoon Kang, MDa,
- Jung-Kyu Han, MD, PhDa,
- Han-Mo Yang, MD, PhDa,
- Hyun-Jae Kang, MD, PhDa,
- Bon-Kwon Koo, MD, PhDa and
- Hyo-Soo Kim, MD, PhDa,∗ ()
- aDepartment of Internal Medicine and Cardiovascular Center, Seoul National University Hospital, Seoul, South Korea
- bSejong General Hospital, Sejong Heart Institute, Bucheon, South Korea
- ↵∗Address for correspondence:
Dr. Kyung Woo Park OR Dr. Hyo-Soo Kim, Department of Internal Medicine, Cardiovascular Center, Seoul National University Hospital, 101 Daehak-ro, Jongro-gu, Seoul 03080, South Korea.
Objectives The aim of this study was to investigate clinical outcomes after left main coronary artery (LM) bifurcation percutaneous coronary intervention (PCI) and the impact of the duration of dual antiplatelet therapy (DAPT) according to treatment strategy.
Background There are limited data regarding the optimal PCI strategy for LM bifurcation lesions with new-generation drug-eluting stents.
Methods A patient-level pooled analysis of 5 nationwide multicenter registries was performed. Rates of target lesion failure, thrombotic adverse cardiovascular events, and their individual components at 3-year were analyzed. Subgroup analysis according to DAPT duration was performed.
Results From 13,172 patients undergoing PCI with new-generation drug-eluting stents, a total of 700 patients were treated for LM bifurcation lesions, 567 with a 1-stent strategy and 133 with a 2-stent strategy. Rates of target lesion failure and target lesion revascularization were higher in the 2-stent group, driven mainly by complex lesion profiles. Risks for thrombotic adverse cardiovascular events and its components were comparable between the 2 strategies. Subgroup analysis showed that risks for target lesion failure and thrombotic adverse cardiovascular events in the 2-stent group were significantly higher than in the 1-stent group in those with DAPT interruption <1 year, while they were similar in those receiving DAPT maintenance ≥1 year.
Conclusions Up to 20% of patients who underwent LM bifurcation PCI eventually required a 2-stent strategy, which was as safe as a 1-stent strategy with the use of new-generation drug-eluting stents. Careful pre-emptive case selection as well as prolonged DAPT may be necessary when considering a 2-stent strategy in LM PCI given its higher rate of repeat revascularization and lesion failure than the 1-stent approach.
- left main coronary artery
- new-generation drug-eluting stent(s)
- percutaneous coronary intervention
The left main coronary artery (LM) bifurcation lesion is among the most challenging lesion subsets in percutaneous coronary intervention (PCI), because the LM supplies perfusion for more than one-half of the total myocardium (1) and because of the risk for compromise of the left circumflex artery. LM disease is detected in 5% to 7% of patients undergoing coronary angiography, in 80% to 90% of whom the distal LM bifurcation is involved (2,3). Although it was previously considered a lesion subset requiring bypass surgery (4), recent development of new-generation drug-eluting stents (DES) has shown comparable safety of PCI in patients with low to intermediate disease burden (5–9).
To date, the principle of bifurcation PCI can be summarized as “keep it simple and safe,” and the provisional 1-stent approach is accepted as the default strategy in the treatment of LM bifurcation (1). A planned 2-stent strategy can be considered primarily in lesions with true bifurcation, with significant ostial disease in a large side branch (SB), or with high risk for SB compromise (2). In particular for LM bifurcation PCI, in which the fate of SBs has a significant impact on prognosis, the threshold for the 2-stent strategy is lower because of the periprocedural risk for bailout stenting in the provisional approach (10). Currently in the era of new-generation DES, we lack data regarding the efficacy and safety of the 1- or 2-stent strategies in LM bifurcation PCI (11). Furthermore, as a lesion subset requiring complex procedures, there is a paucity of data on the effects of various procedure-related factors, including the duration of dual antiplatelet therapy (DAPT) on outcomes.
Thus, using a patient-level pooled cohort of 5 nationwide, multicenter registries dedicated to new-generation DES, we sought to perform a comprehensive analysis regarding outcomes after a 1- or 2-stent strategy in LM bifurcation PCI and the modifiable predictors affecting its clinical outcomes.
Pooled patient population
The study population of the present study was from the Grand-DES registry, incorporating 5 different multicenter registries in Korea (NCT03507205). The EXCELLENT prospective cohort and the EXCELLENT-PRIME registry were dedicated for durable polymer–coated everolimus-eluting stents (XIENCE V/Promus and XIENCE Prime) or first-generation sirolimus-eluting stents (Cypher), the HOST-RESOLINTE and RESOLUTE-Korea registries for durable polymer–coated zotarolimus-eluting stents (Resolute Integrity and Endeavor Resolute) or first-generation Endeavor-ZES, and the HOST-BIOLIMUS-3000-Korea registry for biodegradable polymer–coated biolimus-eluting stents (Biomatrix, Biomatrix Flex, and Nobori). From 2008 through 2014, all registries enrolled all comers without any exclusion criteria except patient’s withdrawal of consent. The final sample size of the Grand-DES registry was 17,286 patients from 55 participating centers in Korea. Among these patients, 13,172 patients who were treated with new-generation DES (durable polymer–coated everolimus-eluting stents, durable polymer–coated zotarolimus-eluting stents, or biodegradable polymer–coated biolimus-eluting stents) were subject for analysis. After excluding those without bifurcation lesions or with non-LM bifurcation lesions, 700 patients with LM bifurcation lesions remained as the final study population (Figure 1). The study was conducted according to the principles of the Declaration of Helsinki, and its protocol was approved by the ethics committee at each participating center. All patients provided written informed consent at enrollment.
Follow-up, data collection, and analysis
After index PCI, clinical follow-up was performed at 1, 3, 9, and 12 months and then annually up to 3 years. Angiographic follow-up was optional at the 9-month visit. For any clinical event, all relevant medical records were reviewed and adjudicated by an external clinical event committee. Using the unique individual identification numbers of the Korean nationwide health care system, the vital status of 100% of patients was crosschecked. The median follow-up duration was 1,125.0 days (interquartile range: 1,097.8 to 1,141.0 days).
Interventional procedure and medications
When PCI was indicated, coronary interventions were performed according to current standard techniques. The choices of PCI strategy (1 stent or 2 stents), type of stent, pre-dilation, post-stenting adjunctive balloon inflation, and use of intravascular ultrasound (IVUS) were left to the operators’ discretion. All patients received a loading dose of aspirin or were on long-term therapy before the procedure. A loading dose of 300 to 600 mg of clopidogrel was administered to all patients who were not on clopidogrel prior to the procedure. After the index procedure, all patients received DAPT (aspirin at least 100 mg/day plus clopidogrel), and the decision of optimal DAPT duration was left to the primary physician. The group with DAPT interruption <1 year was defined as discontinuation of DAPT before 1 year for any cause.
Outcomes and definitions
The primary outcome was target lesion failure (TLF; a composite of cardiac death, target vessel myocardial infarction [MI], and clinically driven target lesion revascularization [CD-TLR]) and thrombotic adverse cardiovascular events (TACE; a composite of cardiac death, all-cause MI, and definite or probable stent thrombosis [ST]). Secondary outcomes were the individual clinical outcomes including the components of composite outcomes. Individual outcomes including death, MI, CD-TLR, and ST were defined according to Academic Research Consortium definitions.
Continuous variables are expressed as mean ± SD and categorical variables as numbers and percentages. Variables were compared using the Student’s t-test or chi-square test as appropriate. Cumulative event rates were calculated on the basis of Kaplan-Meier censoring estimates, and comparison of clinical outcomes was performed using the log-rank test. Hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated using a Cox proportional hazard regression model. A multivariate Cox regression model was used to adjust for uneven distribution of baseline characteristics and to identify independent predictors of the composite outcome. Covariates included in the model were selected if they were significantly different between the 2 groups or had predictive values, which are listed as follows: age, sex, diabetes mellitus, chronic kidney disease, peripheral vascular disease, acute MI at presentation, history of MI, left ventricular dysfunction with ejection fraction <40%, 3-vessel disease, true bifurcation, severe calcification, in-stent restenosis, and type of implanted stent. To adjust for possible confounders, clinical outcomes were compared in the propensity score–matched cohort. A multivariate logistic regression model was used to generate propensity scores, which indicate the probability that one would be treated using the 2-stent strategy. A 1:1 matching process without replacement was performed using a greedy algorithm with a caliper width of 0.4 SDs, yielding 122 patients in the 2-stent group matched with 122 control subjects in the 1-stent group. Percentage standardized differences after propensity score matching in the present study were within ±10% across all covariates, demonstrating successful balance achievement between 2 groups (Online Table 1). Comparisons of the composite outcomes between the 1- and 2-stent groups according to the exploratory subgroups of interest were followed, and the interaction between treatment effect and these covariates was assessed using the Cox regression model. All probability values were 2-sided, and p values <0.05 were considered to indicate statistical significance. Further detailed descriptions regarding outcome definitions and statistical analysis are presented in the Online Appendix.
Baseline characteristics of study population
The baseline characteristics of the entire population and those for the 2-stent and 1-stent group are shown in Table 1. There were mostly no significant differences in baseline demographics and cardiovascular risk factors between the 2 groups. The proportion of the patients with MI history or left ventricular dysfunction was higher in the 2-stent group than in the 1-stent group. The duration of DAPT and proportion of patients maintaining DAPT at each follow-up point were similar. For the lesion characteristics, there were several differences (Table 2). The proportion of true bifurcation lesions was significantly higher in the 2-stent group, with Medina 1,1,1 bifurcation observed in 79.7% of those in the 2-stent group and in only 22.8% in the 1-stent group. The proportion of patients with 3-vessel disease or in-stent restenosis at the target lesion was also higher in the 2-stent group than the 1-stent group. There were no differences in the type of implanted stent between the 2 groups. The proportion of IVUS-guided PCI and high-pressure post-dilation with final kissing balloon (FKB) was significantly higher in the 2-stent group, while the procedural success rate was equivalent. Baseline characteristics by DAPT interruption groups are presented in Online Tables 2 and 3.
Clinical outcomes according to treatment strategy
Table 3 presents the composite and individual clinical outcomes at 3 years according to PCI strategy. The crude rate of TLF was higher in the 2-stent group, although the difference was not statistically significant after adjustment using the multivariate Cox regression (adjusted HR: 1.67; 95% CI: 0.98 to 2.82; p = 0.055) or after propensity score matching (adjusted HR: 1.93; 95% CI: 0.96 to 3.91; p = 0.067). The difference in TLF was driven mainly by the higher rate of CD-TLR in the 2-stent group, while the difference in CD-TLR was also insignificant after adjustment. TACE showed equivalent results between the 2 groups (Figure 2), and there was no difference in terms of cardiac death, all-cause MI, and definite or probable ST, which were individual components of TACE (Online Figure 1). The results were consistent after adjustment by multivariate Cox regression or propensity score matching.
There were no significant interactions across most exploratory subgroups classified by major clinical or lesion factors (Figure 3). Although no significant interaction was observed between the subgroups by IVUS-guided PCI, the TLF rates trended lower in the group with IVUS-guided PCI compared with those without IVUS-guided PCI, regardless of PCI strategy (Online Figure 2).
On Kaplan-Meier analysis, the risk for both TLF and TACE was significantly higher in the 2-stent group compared with the 1-stent group for the subgroup with DAPT interruption <1 year. However, the difference was markedly attenuated and no longer statistically significant in the group with DAPT maintenance ≥1 year (Figure 4). Table 4 shows the interaction between duration of DAPT and stenting strategy for the entire study period, which was marginally significant, and the period beyond post-PCI 1 year (in those event free at 1 year), which was statistically significant. In the subgroup with DAPT interruption <1 year who were event free at 1 year post-PCI, the risk for both TLF (HR: 11.45; 95% CI: 2.73 to 47.95; p = 0.001) and TACE (HR: 7.84; 95% CI: 2.11 to 29.22; p = 0.002) were significantly higher in the 2-stent group compared with the 1-stent group. These increased risks in the 2-stent group were not observed in the subgroup with DAPT maintenance ≥1 year, with significant interactions between DAPT duration and stenting strategy for both TLF (p for interaction = 0.012) and TACE (p for interaction = 0.004).
There were no significant differences between subgroups regarding any bleeding or TIMI (Thrombolysis in Myocardial Infarction) major bleeding events. The net clinical benefit assessed by the net adverse cardiovascular events showed a significantly higher event rate only in the 2-stent group with DAPT interruption <1 year (Online Table 4).
Independent predictors of composite outcomes
The independent predictors of 3-year TLF are shown in Table 5. In the 1-stent group, only patient-related factors were identified, while in the 2-stent group, predictors included both lesion- and procedure-related factors. DAPT interruption <1 year was the only modifiable independent predictor of TLF in the 2-stent group (HR: 3.810; 95% CI: 1.564 to 9.282; p = 0.003). However, it was not a predictor of TLF in the 1-stent group.
In this pooled analysis of large-scale multicenter registries dedicated to new-generation DES, we observed some important findings that not only reflect but are relevant to current practice regarding LM bifurcation PCI. Our dataset showed that physicians chose or ended up using the 2-stent strategy in up to 20% of patients who underwent LM bifurcation PCI. Although the crude risk for TLF or CD-TLR was higher in the 2-stent group, the difference was driven mainly by the worse baseline lesion profiles in the 2-stent group. In terms of hard endpoints, including cardiac death, MI, and ST, the 2 strategies showed comparable results. In the subgroup with DAPT interruption <1 year, the risk for TLF and TACE was significantly higher in the 2-stent group than in the 1-stent group. However, this difference was not observed in those receiving DAPT maintenance ≥1 year. DAPT interruption <1 year was identified as an independent and modifiable predictor of TLF in the 2-stent group but not in the 1-stent group.
LM bifurcation PCI with 1- or 2-stent strategy in the new-generation DES era
Previous observational studies using first-generation DES showed that the provisional 1-stent approach was associated with better outcomes than a planned 2-stent approach in LM bifurcation PCI (11–13). Hence, the planned 2-stent strategy is recommended only for complex LM bifurcation lesions, including true bifurcation, with significant SB ostial disease or with high risk for SB compromise (1). Recently, the 2-stent strategy showed improved outcomes with new-generation DES and the introduction of novel techniques. Notably, in the DKCRUSH-V trial, which was the only randomized trial directly comparing 2 strategies to date, the planned 2-stent strategy in true LM bifurcation lesions using the double-kissing crush technique demonstrated superior results in terms of ST, target vessel MI, and TLF compared with the provisional 1-stent approach (14). However, there are limited data from real-world registries of new-generation DES.
The present study showed that nearly 20% of patients eventually required a 2-stent strategy for LM bifurcation PCI. We also found that the risk for CD-TLR was significantly higher before adjustment and still tended to be higher after adjustment in the 2-stent group, although the risk for safety outcomes was similar. Because the 2-stent group had more complex and significant SB lesions to start with, the difference in TLR rates is somewhat anticipated, and a crude comparison between 2 groups regarding TLR may not be so clinically relevant. Furthermore, these results may have been affected not only by a significantly higher proportion of complex lesion profiles in the 2-stent group but also by several unmeasured confounding factors, such as the severity of SB stenosis, bifurcation angle, or SB lesion length. These results are different from the previous results of the COBIS II registry, in which the clinical outcomes, even including death or MI, significantly favored 1 stent rather than 2 stents in LM bifurcation lesions (11). The major difference between COBIS II and the present study is in the type of implanted stent. Unlike the COBIS II, which used new-generation DES in <20% of patients, the present study used new-generation DES such as biodegradable polymer–coated biolimus-eluting stents, durable polymer–coated everolimus-eluting stents, and durable polymer–coated zotarolimus-eluting stents in 100% of enrolled patients. In contrast, a study using the Korean Bifurcation Pooled Cohort demonstrated that there was no difference between the 1-stent and 2-stent techniques in bifurcation PCI only in the new-generation DES group (15).
We believe that our findings have some clinical implications. Regardless of the driving factors, it is true that the 2-stent strategy in general resulted in worse clinical outcomes compared with the 1-stent strategy. Given these results, interventionists, when faced with LM bifurcation lesions, need to be judicious in both the decision to perform PCI and its strategy. Moreover, when PCI with 2 stents is absolutely necessary or if the case ends up requiring a 2-stent approach, the maintenance of DAPT beyond 1 year will be more critical for outcome than in patients treated with 1 stent. With the provisional 1 stent approach, the need for bailout stenting increases. In such conditions, the risks for stent delivery failure, misplacement or underexpansion of the SB stent, and edge dissection increase, which could lead to significant adverse clinical outcomes, especially in the LM bifurcation intervention setting (16,17). In this regard, the criteria for lesions that require an upfront 2-stent strategy would be particularly important.
There are obviously certain conditions in which 2 stents are necessary, depending on several factors. However, it would be more helpful if more specific criteria for case selection could be suggested. Notably, in the ongoing EBC MAIN trial (NCT02497014), outcomes after 1- and 2-stent strategies will be compared using strict criteria, including true bifurcation with Medina 1,1,1 or 0,1,1 type and diameter of both left anterior descending and circumflex coronary arteries >2.75 mm, as well as the LM bifurcation lesion with objective evidence of significant ischemia (18). The results of this randomized trial are expected to be an important milestone to establish the optimal criteria for selecting LM bifurcation PCI strategy. Certain 2-stent techniques such as the double-kissing crush technique may improve outcomes with the 2-stent technique even further, as shown in a recent randomized trial (14). There are also factors such as prolonged use of DAPT that may affect outcomes in LM bifurcation intervention, which are discussed in the next section.
Differential impact of DAPT duration on the efficacy and safety of 1- or 2-stent strategy
In the present study, we found that DAPT interruption <1 year had a significant impact on prognosis in only patients receiving 2 stents. Although the observational nature of the present analysis did not allow an analysis on the basis of the intention-to-treat principle for DAPT duration, the results were also consistent in the 1-year event-free landmark analysis performed as a sensitivity analysis. In addition to showing significant subgroup interaction, DAPT interruption <1 year was an independent predictor of 3-year TLF in only the 2-stent group but was not a predictor of TLF in the 1-stent group. The comparison of net composite endpoints incorporating TACE and TIMI major bleeding highlighted again that the DAPT interruption <1 year after PCI with a 2-stent strategy might be more harmful in terms of ischemic events than the beneficial effect on the bleeding events. Currently, analysis limited to specific lesion subsets such as LM bifurcation is scarce and difficult to achieve sufficient sample size. In the present study, we analyzed relatively robust homogeneous subgroups of LM bifurcation, though limited by insufficient statistical power, and found that DAPT maintenance over 1 year may be essential for lesions treated using the 2-stent technique. Although the results should be taken as hypothesis generating at best, our findings do shed light on an important issue for clinicians and provide clues for future clinical studies.
There is no clear evidence for an optimal DAPT duration after PCI for LM or bifurcation lesions to date. Because most previous studies maintained at least 1-year DAPT in all patients, the effect of DAPT duration on the outcomes of different PCI strategies could not be evaluated (2,19–21). Giustino et al. (22) demonstrated in their pooled analysis of 6 randomized trials that bifurcation with 2 stents showed higher thrombotic propensity and that ischemic events were significantly reduced by long-term DAPT for 1 year in the group with complex PCI. Also, a recent subanalysis of the DAPT trial showed that complex lesions, including unprotected LM, bifurcation lesions with SB ≥2.5 mm, or lesion length ≥30 mm, which are likely to undergo PCI with a 2-stent strategy, had significantly increased ischemic risk (23). Therefore, it may be necessary to maintain DAPT for more than 1 year when the lesions are treated with the 2-stent technique. Looking at our findings from another angle, because the shorter duration DAPT was safe and the beneficial effect of prolonged DAPT minimal in the 1-stent group, we may be able to discontinue or interrupt DAPT when needed even in patients who undergo PCI for LM bifurcation lesions if they received the 1-stent technique. Further studies are warranted to determine how different DAPT durations affect ischemic and bleeding outcomes with the 2 strategies.
Insights from subgroup analysis regarding procedure-related factors
Although subgroup analysis showed no significant interaction, a tendency toward better clinical outcomes was observed in the group with IVUS-guided PCI than without IVUS-guided PCI. A careful lesion evaluation using intracoronary imaging is strongly recommended in bifurcation PCI to ensure optimal procedural results and prevent lesion failure (2,24). The FKB followed by proximal optimization technique is also recommended, especially for the 2-stent strategy (1). In the present study, we found that high-pressure post-dilation with FKB did not significantly affect outcomes after the 1- or 2-stent approach. The accumulation of improvements in the aforementioned procedure-related factors might further reduce the risk for lesion failure.
First, because this study was an observational analysis of a prospective registry, the 1- or 2-stent groups did not have balanced clinical and lesion characteristics. This limitation arising from the study design also did not allow us to systematically control the details of DAPT interruption or maintenance.
Second, the cause of DAPT interruption was associated with events such as mortality in about 15% of patients. This suggests that DAPT interruption itself may have been a simple marker of higher event rate. However, to overcome this limitation, we conducted a 1-year event-free analysis, which presented consistent results with the original analysis.
Third, we could not perform dedicated quantitative coronary angiographic analysis, and thus the results were based on lesion characteristics collected at the index procedure. Therefore, information on lesion factors such as the severity of SB stenosis or bifurcation angle was not available. Instead, we focused mainly on the analysis of overall clinical outcomes and the effect of DAPT duration rather than that of the detailed lesion subset.
Fourth, novel P2Y12 inhibitors were not used in the present study, and information regarding clopidogrel resistance and/or platelet function was not systematically collected during the study period.
Finally, the collection of procedure-related factors was insufficient. In particular, the proportion of cases in which bailout SB stenting was performed after initial provisional 1-stent technique was not available. In addition, although we had data on whether FKB dilation was performed, there were no data on the use of noncompliant balloons and the proportion of those who underwent proximal optimization technique.
A considerable proportion of patients with LM bifurcation lesions require PCI with a 2-stent strategy in real-world practice. Although the 2-stent strategy was as safe as the 1-stent approach with the use of new-generation DES, careful pre-emptive case selection and DAPT maintenance ≥1 year may be necessary for the 2-stent approach, given its higher rate of repeat revascularization and other clinical outcomes compared with the 1-stent approach.
WHAT IS KNOWN? The provisional 1-stent approach is considered the default strategy in the treatment of coronary bifurcation lesions, but the efficacy and safety of the 1- and 2-stent strategies for the LM bifurcation lesions are not clear in the era of new-generation DES. There are limited data regarding the effect of the duration of DAPT on long-term clinical outcomes after LM bifurcation intervention.
WHAT IS NEW? In this pooled analysis of nationwide, multicenter registries dedicated to the new-generation DES, up to 20% of LM bifurcation lesions were treated using the 2-stent approach. We found that 1- and 2-stent strategies for LM bifurcation lesions showed similar clinical outcomes in terms of hard endpoints (cardiac death, MI, and definite or probable ST). A higher rate of TLF was observed in the 2-stent group, driven mainly by more complex lesion profiles. DAPT interruption <1 year had a significant impact on 3-year outcomes in only the 2-stent group but not the 1-stent group.
WHAT IS NEXT? Carefully selecting the appropriate patients and maintaining DAPT over 1 year may be necessary to prevent lesion failure in those receiving 2 stents. Further randomized trials should determine the specific criteria that prefer the 2-stent strategy and clarify how different DAPT durations affect clinical outcomes with both 1- and 2-stent strategies for LM bifurcation lesions.
This study was supported in part by a grant from the Korean Society of Interventional Cardiology (0620164170 [2016-3225]). The authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- clinically driven target lesion revascularization
- confidence interval
- dual antiplatelet therapy
- drug-eluting stent(s)
- final kissing balloon
- hazard ratio
- intravascular ultrasound
- left main coronary artery
- myocardial infarction
- percutaneous coronary intervention
- side branch
- stent thrombosis
- thrombotic adverse cardiovascular event(s)
- target lesion failure
- Received June 5, 2018.
- Revision received September 5, 2018.
- Accepted September 7, 2018.
- 2018 American College of Cardiology Foundation
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