Author + information
- Received December 13, 2013
- Revision received April 19, 2014
- Accepted April 23, 2014
- Published online November 1, 2014.
- Shao-Liang Chen, MD∗∗ (, )
- Imad Sheiban, MD†,
- Bo Xu, MBBS‡,
- Nigel Jepson, MD§,
- Chitprapai Paiboon, MD‖,
- Jun-Jie Zhang, PhD¶,
- Fei Ye, MD¶,
- Teugh Sansoto, MD#,
- Tak W. Kwan, MD∗∗,
- Michael Lee, MD††,
- Ya-Ling Han, MD‡‡,
- Shu-Zheng Lv, MD§§,
- Shang-Yu Wen, MD‖‖,
- Qi Zhang, MD¶¶,
- Hai-Chang Wang, MD##,
- Tie-Ming Jiang, MD∗∗∗,
- Yan Wang, MD†††,
- Liang-Long Chen, MD‡‡‡,
- Nai-Liang Tian, MD∗,
- Feng Cao, MD##,
- Chun-Guang Qiu, MD§§§,
- Yao-Jun Zhang, PhD¶ and
- Martin B. Leon, MD‖‖‖
- ∗Nanjing First Hospital, Nanjing Medical University, Nanjing, China
- †San Giovanni Battista Hospital, University of Turin, Turin, Italy
- ‡Beijing Fuwai Cardiovascular Hospital, Beijing, China
- §Hospital of Prince Wales, Sydney, New South Wales, Australia
- ‖Bangkok General Hospital, Bangkok, Thailand
- ¶Nanjing Heart Center, Nanjing, China
- #Medistra Hospital, University of Indonesia Medical School, Jakarta, Indonesia
- ∗∗Mount Sinai Beth Israel, New York, New York
- ††Queen Elizabeth Hospital, Kowloon, Hong Kong
- ‡‡Northern Hospital, Shenyang, China
- §§Beijing Anzhen Hospital, Capital Medical University, Beijing, China
- ‖‖Daqing Oil General Hospital, Daqing, China
- ¶¶Shanghai Ruijin Hospital, Shanghai, China
- ##Xijing Hospital, Xi’an Fourth Military Medical University, Xi’an, China
- ∗∗∗Tianjing Policemen Medical College Hospital, Tianjing, China
- †††Xia’Men Zhongshan Hospital, Xia’Men, China
- ‡‡‡Fujian Union Hospital, Fuzhou, China
- §§§Henan Provincial People’s Hospital, Zhenzhou, China
- ‖‖‖Heart Center, Columbia University, New York, New York
- ↵∗Reprint requests and correspondence:
Dr. Shao-Liang Chen, Nanjing First Hospital, Cardiology Department, 68 Changle Road, Nanjing 210006, China.
Objectives The present study established criteria to differentiate simple from complex bifurcation lesions and compared 1-year outcomes stratified by lesion complexity after provisional stenting (PS) and 2-stent techniques using drug-eluting stents.
Background Currently, no criterion can distinguish between simple and complex coronary bifurcation lesions. Comparisons of PS and 2-stent strategies stratified by lesion complexity have also not been reported previously.
Methods Criteria of bifurcation complexity in 1,500 patients were externally tested in another 3,660 true bifurcation lesions after placement of drug-eluting stents. The primary endpoint was the occurrence of a major adverse cardiac event (MACE) at 12 months. The secondary endpoint was the rate of stent thrombosis (ST).
Results Complex (n = 1,108) bifurcation lesions were associated with a higher 1-year rate of MACE (16.8%) compared with simple (n = 2,552) bifurcation lesions (8.9%) (p < 0.001). The in-hospital ST and 1-year target lesion revascularization rates after 2-stent techniques in the simple group (1.0% and 5.6%, respectively) were significantly different from those after PS (0.2% [p = 0.007] and 3.2% [p = 0.009], respectively); however, 1-year MACE rates were not significantly different between the 2 groups. For complex bifurcation lesions, 2-stent techniques had lower rates of 1-year cardiac death (2.8%) and in-hospital MACE (5.0%) compared with PS (5.3%, p = 0.047; 8.4%, p = 0.031).
Conclusions Complex bifurcation lesions had higher rates of 1-year MACE and ST. The 2-stent and PS techniques were overall equivalent in 1-year MACE. However, 2-stent techniques for complex lesions elicited a lower rate of cardiac death and in-hospital MACE but higher rates of in-hospital ST and revascularization at 1 year for simple lesions.
- coronary bifurcation lesion
- drug-eluting stent
- lesion complexity
- major adverse cardiac event
- stent thrombosis
Percutaneous coronary intervention of bifurcation lesions is technically challenging and is often associated with higher rates of in-stent restenosis. The ostial side branch (SB) is the most common site of in-stent restenosis (1,2) after placement of a drug-eluting stent. Patients with bifurcation lesions do not benefit from systematic 2-stent strategies, but provisional stenting (PS) using a jailed wire in the SB has been widely accepted as the gold standard in the majority of bifurcation lesions (1–6). This is based on several clinical trials (1–6); however, these trials have an important limitation of not being stratified according to the Medina classification (7). Inclusion of lesion complexity as a parameter in previous studies might have otherwise led to different stenting strategies, and consequently, the final clinical results might have been different (8–11).
Most importantly, current classifications do not provide more information about the complexity of bifurcation lesions (10). Therefore, it is too early to conclude that PS can be considered a final solution for coronary bifurcation lesions (10–12). Accordingly, the present DEFINITION (Definitions and impact of complEx biFurcation lesIons on clinical outcomes after percutaNeous coronary IntervenTIOn using drug-eluting steNts) study was designed to establish a practical, easy-to-use classification to differentiate simple from complex bifurcation lesions and analyze the effect of bifurcation complexity on clinical results after PS and 2-stent techniques.
Study design and patient population
Between January 2004 and July 2012, 5,160 patients with at least 1 Medina 1,1,1 and 0,1,1 coronary bifurcation lesion (7) were prospectively registered. For 1,500 patients from January 2004 to June 2006 (training group), confounding factors for composite major adverse cardiac events (MACE) were selected by logistic regression analysis. The rate of MACE stratified by each confounding factor and combinations of several confounding factors were calculated. Definitions of complex and simple bifurcation lesions were then established according to the predictive value of the confounding factors.
Finally, these definitions were externally tested in 3,660 patients (study group) between July 2006 and July 2012. Patients in the study group were divided into 2 pre-specific subgroups according to the criteria established from the training group: the simple and complex groups. The ethics committee of each participating center approved the study protocol, and each patient provided written consent.
Only Medina 1,1,1 and 0,1,1 coronary bifurcation lesions with an SB diameter ≥2.5 mm by visual estimation were included in the training and study groups. The following exclusion criteria were included: 1) SB diameter <2.5 mm; 2) ST-segment elevation myocardial infarction (MI) <1 week; 3) cardiogenic shock; 4) a history of coronary artery bypass grafting; 5) use of bare-metal stent; 6) in-stent restenotic lesions; 7) lesions being treated by classic crush stenting or the kissing stenting technique; and 8) patients who were already included in any other clinical study.
The selection of stenting techniques and of the transradial versus transfemoral approach was left to the physician's discretion. Stents for all implanted lesions were limus-eluting stents, including the Cypher (Cordis, Johnson & Johnson, Miami Lakes, Florida); Firebird or Firebird-2 (Microport Co., Shanghai, China); EXCEL, BIOMATRIX FLEX (Biosensor/Jiwei Co., Shandong, China); Partner (Lepu Med, Beijing, China); Xience or Xience Prime (Abbott Vascular, Santa Clara, California); and Endeavor or Endeavor Resolute (Medtronic, Minneapolis, Minnesota). Use of intravascular ultrasound was left to the physician's discretion. Stenting techniques have been described previously (3,4,12). Briefly, final kissing balloon inflation was recommended after all 2-stent strategies. Kissing balloon inflation was only used after PS if there were any of the following indications in the SB: Thrombolysis In Myocardial Infarction flow <3, type B dissection or greater, and residual diameter stenosis (DS) ≥70% by visual estimation. Stenting of the SB in the PS group was required if Thrombolysis In Myocardial Infarction flow was <3, the presence of type B dissection or greater, or residual DS was ≥70% after kissing balloon inflation. Finally, 2-stent techniques included double kissing (DK) crush, culotte, T and protrusion, and traditional T.
All patients were pre-treated with aspirin and clopidogrel. A 300-mg loading dose of clopidogrel was administered before the index procedure if patients were not pre-treated. Intravenous unfractionated heparin was used to maintain an activated clotting time between 250 and 300 s throughout the entire procedure. Creatine kinase-myocardial band and troponin were dynamically measured until 72 h post-procedure. After discharge, aspirin therapy was continued indefinitely (100 mg/day for life), and clopidogrel (75 mg/day) was continued for at least 12 months.
Clinical follow-up was performed during visits or through telephone contact at 1, 6, 8, and 12 months. Adverse events were monitored throughout the entire study period. Follow-up coronary angiography was not recommended unless clinically indicated for earlier intervention.
Study endpoints and definitions
The primary endpoint was the occurrence of MACE at 12 months, including cardiac death, MI, and target vessel revascularization (TVR). The secondary endpoint was the occurrence of stent thrombosis (ST). Academic Research Consortium definitions of MI, cardiac death, target lesion revascularization (TLR), TVR, angiographic and procedural success, and ST (13) were used. Lesion specificities were defined according to American Heart Association/American College of Cardiology criteria (14). Angiographic patterns of in-stent restenosis were defined by Mehran’s classification (15) and classified as classes I through IV. Bifurcation angle and vessel angulation were defined according to previous studies (16). Calcification was identified as readily apparent radiopacity within the vascular wall at the site of the stenosis, and it was classified as none/mild, moderate (i.e., radiopacity noted only during the cardiac cycle before contrast injection), and severe (i.e., radiopacity noted without cardiac motion before contrast injection, generally compromising both sides of the arterial lumen [Figure 1A]). Multiple lesions (Figure 1B) included multiple-vessel disease (defined as ≥70% stenosis in at least 1 major epicardial vessel and ≥50% stenosis in at least 1 other major vessel) or ≥2 lesions separated by at least a 5-mm normal segment in the target vessel. A thrombus-containing lesion was defined as a coronary strip, oval- or irregularly-shaped filling defect with retention of contrast medium or dye (Figure 1C). Estimated glomerular filtration rate was calculated according to the Modified Diet in Renal Disease formula (17).
Multiple anatomic factors for MACE were analyzed in patients from the training group, and factors with a p value ≤0.001 with the highest sensitivity and specificity were considered major criteria. Otherwise, factors with a p value >0.001 were treated as minor criteria. The rates of MACE stratified by combinations of each major criterion with any 1 or more minor criteria were calculated. Sensitivity and specificity of this classification for MACE were calculated with the receiver-operating characteristic curve. The definitions of complex and simple bifurcation lesions were later established according to the predictive value of major plus minor criteria.
Comparability of baseline characteristics between the complex and simple groups or between PS and 2-stent subgroups (based on intention-to-treat) was assessed using a 2-sample t test for continuous variables or the Fisher exact test for categorical variables. Analyses of the adjudicated primary and secondary outcomes were conducted on data from all patients using Kaplan-Meier estimates and Cox proportional hazards models. Hazard ratios, 95% confidence intervals, and p values were calculated using models adjusted for the pre-specified baseline factors listed in Tables 1 and 2⇓⇓. Statistical significance was taken as a 2-sided p value <0.05. All analyses were performed using the statistical program SPSS version 16.0 (IBM, Chicago, Illinois).
A total of 1,500 patients were included in the training group. Baseline clinical (Table 1), lesions, and procedural (Table 2) characteristics in the training group were comparable to those in the study group. Of the 1,500 patients in the training group, 1-year MACE rate was 16.5%, with MI, cardiac death, and TVR in 3.8%, 1.3%, and 14.6% of patients, respectively.
Establishment of criteria differentiating simplex from complex bifurcation lesions
Logistic regression of all lesion characteristics from patients in the training group listed in the Table 2 and entered into the model revealed 8 confounding factors that correlated with 1-year MACE (p < 0.05) (Table 3). Of these predictive factors, 2 parameters (for distal left main bifurcation: SB DS ≥70% and SB lesion length ≥10 mm; for nonleft main bifurcation: SB DS ≥90% and SB lesion length ≥10 mm) had the highest sensitivity (80%) and specificity (72% to 74%) for MACE (all p values <0.001), and these parameters were defined as major criteria; another 6 parameters with p values >0.001 were classified as minor criteria (Table 3). When each major criterion was combined with any 2 minor criteria, the sensitivity and specificity of this new stratification were ≥87% and 83%, respectively (Table 3).
According to our newly established criteria, 1,108 patients (30%) exhibited complex bifurcations, as shown in the study flowchart (Figure 2), and the remaining 2,552 patients (70%) were classified as having simple bifurcation lesions. Complex bifurcation lesions were more frequently observed in older male patients with more comorbidities (e.g., diabetes, acute MI, renal dysfunction, congestive heart failure), increased plasma platelet count, and severe inflammation.
Clinical outcomes of complex and simple bifurcation lesions in 3,660 patients in the study group
Generally, patients with complex bifurcation lesions had significantly higher in-hospital MACE rates compared with simple bifurcation lesions (6.8% vs. 4.2%, p < 0.001), which was mainly driven by increased MIs (6.8% vs. 3.8%, p < 0.001) (Table 4). The difference in MACE between the complex and simple subgroups became wider at the 1-year follow-up (16.8% vs. 8.9%; hazard ratio: 0.72; 95% confidence interval: 0.51 to 0.93; p < 0.001) (Figure 3A), and significant differences in all individual endpoints were observed between the 2 subgroups (Figures 3B to 3D). Notably, the incidence of overall ST in the complex group was 1.6%, which was significantly higher than 0.7% in the simple group (p = 0.026).
Comparison of clinical outcomes between the 2-stent and the PS subgroups
We first studied simple (n = 2,552) bifurcation lesions (as defined by our criteria) to examine the effect of PS (n = 1,961, 70%) versus 2-stent techniques (n = 591, 30%) and found that 2-stent techniques were associated with increased in-hospital ST (1.0% vs. 0.2%, p = 0.007) (Table 5). At 1-year follow-up, there were no significant differences in MACE, cardiac death, MI, and TVR between PS and 2-stent techniques in the simple group (Figure 4), although the TLR rate at 1 year (5.6%) in the 2-stent subgroup was significantly higher than that in the in PS subgroup (3.2%) (p = 0.009) (Table 5). Of 1,961 patients in the PS group, additional SB stenting was required in 3.0% (n = 59) of patients according to our angiographic criteria.
We examined complex bifurcation lesions in the second analysis (n = 1,108). We found a higher rate of in-hospital MACE (8.4%) in the PS subgroup (n = 571), which was significantly different from the 2-stent subgroup (5.0%, p = 0.026), mainly because of increased in-hospital MI rate in the PS group (Table 6). The rates of MACE, MI, and TVR at 1-year in the PS subgroup was not significantly different from that in 2-stent subgroup (Table 6, Figures 5A to 5D). However, PS was associated with a higher rate of 1-year cardiac death: 5.3% compared with 2.8% (p = 0.041) in the 2-stent subgroup (Table 6, Figure 5B). Of 571 patients in the PS subgroup, 18.1% (n = 103) crossed over to 2-stent techniques, and more final balloon kissing inflation was required (n = 165, 28.9%). These results were significantly different from the 14.7% in patients in the PS subgroup with simple bifurcation lesions (Tables 5 and 6).
We report newly established criteria for the differentiation of simple from complex coronary bifurcation lesions in a large patient cohort. The most important findings of the present study are the following: 1) the complex group after drug-eluting stent has more frequent composite MACE and ST than the simple group; and 2) 2-stent strategies for overall bifurcation lesions have 1-year MACE rates comparable to those with PS. However, patients with complex bifurcation lesions likely benefited from 2-stent techniques in terms of cardiac death.
Lessons from previous randomized clinical studies on bifurcation lesions
Previous studies have confirmed that systematically complex stenting strategies do not provide any advantage over PS for a given bifurcation lesion (1–7,18,19). As a result, PS of the SB has become the gold standard of care for bifurcation lesions. However, the DKCRUSH-II study (Double Kissing Crush versus Provisional Stenting Technique for Treatment of Coronary Bifurcation Lesions) (8) showed reduced TLR rates after the administration of DK crush over PS for Medina 1,1,1 and 0,1,1 bifurcation lesions. The possible explanations for this different result between the DKCRUSH-II study and others are mainly discrepancies in the study design and lesion complexity, which were documented as SB size (from 2.0 to >2.5 mm), location (distal left main or nonleft main) and patterns (with or without Medina 1,0,1) of bifurcation lesions, plaque burden (SB DS varying from 40% to >60%), SB lesion length (5 to >10 mm), calcified lesions, chronic total occlusion, acute MI, and the use of 2-stent techniques. The CACTUS (Coronary Bifurcations: Application of the Crushing Technique Using Sirolimus-Eluting Stents) study (5) reported severe plaque burdens (SB DS >60%) in SB, but classic crush stenting was the only 2-stent technique used, and this technique is inferior to culotte stenting (18) or DK crush stenting (3,8,20).
Based on the analyses mentioned above, there is an urgent need for a simple, comprehensive, and practical criteria that can differentiate simple from complex bifurcation lesions and guide the selection of an appropriate stenting approach (2-stent or PS), such as the SYNTAX (Synergy Between Percutaneous Coronary Intervention With Taxus and Cardiac Surgery) score (6,21) and NERS (New Risk Stratification) score (22).
Features of the present criteria
An advantage of the current criteria was the successful implementation in a large external patient population with true bifurcation lesions (Medina 1,1,1 and 0,1,1) and SB ≥2.5 mm in diameter. The Medina 1,0,1 bifurcation lesion, 1 of the true bifurcation lesions, is commonly treated using PS from intention-to-treatment, and these lesions were excluded from our analysis.
Our new criteria include several factors that contribute to reliable risk stratification: 2 levels of stratifications (i.e., 2 major and 6 minor elements); relatively large SB (indicating the high risk of myocardium at jeopardy); severe SB plaque burden (not proposed in the Medina classification); moderate to severe calcification and multiple lesions (2 known factors attributing to poor outcome); renal and left ventricular dysfunction (2 known predictors of clinical events); and thrombus-containing lesions (commonly seen in acute coronary syndrome) and longer or diffuse main vessel lesions (a known factor of poor stent expansion). Accordingly, the combination of 1 major and any 2 minor criteria would likely indicate the complexity of a bifurcation lesion or the high-risk patients much better than the conventional Medina classification, which relies on only main vessel and SB involvement.
Impact of bifurcation complexity on clinical outcomes
The most frequently used Medina classification (7) does not provide sufficient information about the real complexity of a given bifurcation lesion because of a lack of lesion specificities (10,11) and clinical variables. Moreover, several parameters (including relatively larger SB, long SB lesion, wide bifurcation angle, and high risk of hemodynamic deterioration associated with potential SB occlusion) have been introduced as indicators for ideal candidates for 2-stent techniques (9), but several questions are still debated. How large is larger? How long is longer? What are the accurate predictors of acute SB closure? Most importantly, these debated key points have not been systematically studied in a prospective clinical trial.
In general, our data clearly showed that complex bifurcation lesions were associated with more adverse events compared with simple bifurcation lesions in the entire cohort of bifurcation lesions, which indicates the enhanced predictive power of these newly established criteria. Our results support the concept that simpler is better for simple bifurcations, which account for 70% of bifurcation lesions from our data. Why is the 1-year rate of cardiac death after PS for complex bifurcation lesions double that of 2-stent techniques? We postulate that residual SB dissection (invisible on angiography) (23,24) and the progression of SB lesions (25) induced by kissing balloon inflation might be possible explanations, which is consistent with the DKCRUSH-II study (8) and intravascular ultrasound analysis (25,26). Otherwise, a well-defined PS technique (proximal optimized technique, imaging supported) would have likely shown improvements in clinical results (27–29), even for complex bifurcation lesions, as suggested by a consensus from the European Bifurcation Club (29).
Our newly established criteria provide a classification of the complexity of bifurcation lesions, demonstrated by more frequent MACE and individual endpoints after stenting complex bifurcation. Therefore, we are convinced that simpler is better for the treatment of simple bifurcation lesions. However, the benefits of 2-stent techniques for complex bifurcation lesions should be further evaluated in randomized studies.
The major limitation of the present study was its nonrandomized design, which would likely reduce the power of the final conclusions. The second limitation was that we did not calculate how much of the use of the 2-stent techniques was based on lesion complexity. The third limitation was the exclusion of the classic crush technique from the current study due to more frequent malapposition, as documented by several intravascular ultrasound studies (27,28), more cases of MACE and ST based on a previous clinical study (20), and its common inclusion in our DKCRUSH-I study (20). Fourth, kissing stenting techniques (including V stenting and simultaneous kissing stenting) were only used in 6 patients using bare-metal stents, and these patients were excluded from our analysis. Finally, quantitative coronary analysis was not systematically performed. Regardless, our data from such a large patient sample provides clinically-driven outcomes (avoiding the “stenosis-reflex”) in a real-world fashion.
The new criteria proposed in the present study can differentiate complex from simple bifurcation lesions: patients with complex bifurcation lesions had very poor clinical outcomes. Two-stent and PS techniques exhibited equivalent overall 1-year rates of MACE. A randomized clinical study is required to further elucidate the difference in clinical outcomes between 2-stent and PS techniques for complex bifurcation lesions stratified using our new criteria.
The authors appreciate the contributions of Tian Xu, Ling Lin, Hai-Mei Xu, and Ying-Ying Zhao to data collection and remote monitoring.
A Nanjing Municipal Healthy Bureau Outstanding Project (NMHBOP-20031280) grant supported the completion of this study. Dr. Chen is a Fellow at the Collaborative Innovation Center for Cardiovascular Disease Translational Medicine of Jiangsu Province, China. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- double kissing
- diameter stenosis
- major adverse cardiac event(s)
- myocardial infarction
- provisional stenting
- side branch
- stent thrombosis
- target lesion revascularization
- target vessel revascularization
- Received December 13, 2013.
- Revision received April 19, 2014.
- Accepted April 23, 2014.
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