Author + information
- Received October 10, 2014
- Revision received December 1, 2014
- Accepted December 4, 2014
- Published online April 20, 2015.
- Shao-Liang Chen, MD∗,†∗ (, )
- Fei Ye, MD∗,
- Jun-Jie Zhang, PhD∗,
- Tian Xu, MBBS‡,
- Nai-Liang Tian, MD‡,
- Zhi-Zhong Liu, PhD‡,
- Song Lin, MD§,
- Shou-Jie Shan, MD∗,
- Zhen Ge, MD∗,
- Wei You, MD‡,
- Yue-Qiang Liu, MD§,
- Xue-Song Qian, MD‖,
- Feng Li, MD¶,
- Song Yang, MD#,
- Tak W. Kwan, MD∗∗,
- Bo Xu, MBBS†† and
- Gregg W. Stone, MD‡‡∗∗ ()
- ∗Nanjing First Hospital, Nanjing Medical University, Nanjing, China
- †Collaborative Innovation Center for Cardiovascular Disease Translational Medicine and Clinical Medical Research Center of Jiangsu Province, China
- ‡Nanjing Heart Center, Nanjing, China
- §Jintan Municipal People's Hospital, Jintan, China
- ‖Zhangjiagang People's Hospital, Zhangjiagang, China
- ¶Huainan Oriental General Hospital, Huainan, China
- #Yixin People’s Hospital, Yixin, China
- ∗∗Beth Israel Hospital, New York, New York
- ††Beijing Fuwai Cardiovascular Hospital, Beijing, China
- ‡‡Columbia University Medical Center and the Cardiovascular Research Foundation, New York, New York
- ↵∗Reprint requests and correspondence:
Dr. Shao-Liang Chen, Cardiology Department, Nanjing First Hospital, 68 Changle Road, Nanjing 210006, China.
- ↵∗∗Dr. Gregg W. Stone, Columbia University Medical Center, The Cardiovascular Research Foundation, 111 East 59th Street, 11th Floor, New York, New York 10022.
Objectives This study sought to compare the outcomes of fractional flow reserve (FFR)–guided and angiography (Angio)–guided provisional side-branch (SB) stenting for true coronary bifurcation lesions.
Background Angio-guided provisional SB stenting after stenting of the main vessel provides favorable outcomes for the majority of coronary bifurcation lesions. Whether an FFR-guided provisional stenting approach is superior has not been studied.
Methods A total of 320 patients with single Medina 1,1,1 and 0,1,1 coronary bifurcation lesions undergoing stenting with a provisional SB approach were randomly assigned 1:1 to Angio-guided and FFR-guided groups. SB stenting was performed for Thrombolysis In Myocardial Infarction flow grade <3, ostial SB stenosis >70%, or greater than type A dissection after main vessel stenting in the Angio-guided group and for SB-FFR <0.80 in the FFR-guided group. The primary endpoint was the 1-year composite rate of major adverse cardiac events (cardiac death, myocardial infarction, and clinically driven target vessel revascularization).
Results Comparing the Angio-guided and FFR-guided groups, treatment of the SB (balloon or stenting) was performed in 63.1% and 56.3% of lesions respectively (p = 0.07); stenting of the SB was attempted in 38.1% and 25.9%, respectively (p = 0.01); and, when attempted, stenting was successful in 83.6% and 73.3% of SBs, respectively (p = 0.01). The 1-year composite major adverse cardiac event rate was 18.1% in both groups (hazard ratio: 0.91, 95% confidence interval: 0.48 to 1.88; p = 1.00). The 1-year target vessel revascularization and stent thrombosis rates were 6.9% and 5.6% (p = 0.82) and 1.3% and 0.6% (p = 0.56) in the Angio-guided and FFR-guided groups, respectively.
Conclusions In this multicenter, randomized trial, angiographic and FFR guidance of provisional SB stenting of true coronary bifurcation lesions provided similar 1-year clinical outcomes. (Randomized Study on DK Crush Technique Versus Provisional Stenting Technique for Coronary Artery Bifurcation Lesions; ChiCTR-TRC-07000015)
- coronary bifurcation lesions
- fractional flow reserve
- major adverse cardiac events
- stent thrombosis
Despite improvements in devices and technique, percutaneous coronary intervention (PCI) of true bifurcation lesions remains challenging, with relatively unfavorable long-term clinical outcomes after implanting drug-eluting stents (DES) (1–9). Numerous studies have shown that a provisional side-branch (SB) approach (with balloon angioplasty in most cases when SB treatment is needed) after main-vessel (MV) stenting results in favorable outcomes for most bifurcations. Given the well-described discordance between angiographic severity and functional lesion significance (10–12), fractional flow reserve (FFR)-guided SB stenting might improve outcomes (13–15). However, SB crossing with an FFR pressure wire may be technically challenging, and whether FFR-guided provisional SB stenting is superior to angiography-guided provisional SB stenting has never been evaluated. Accordingly, we performed a randomized trial to compare these 2 approaches with provisional SB treatment in true coronary bifurcation lesions.
The DKCRUSH-VI (Double Kissing Crush Versus Provisional Stenting Technique for Treatment of Coronary Bifurcation Lesions VI) study was conducted in 8 centers in China. The protocol was approved by the ethics committee at each hospital, and all patients provided written, informed consent.
Inclusion and exclusion criteria
Patients 18 years of age and older with silent ischemia, stable or unstable angina with a single true coronary bifurcation lesion (Medina 1,1,1 or 0,1,1), diameter of stenosis (DS) ≥50% in both the MV and SB, each with a reference vessel diameter ≥2.5 to ≤4.0 mm were included. The length of the MV and SB lesions had to be completely covered by 2 stents, unless a balloon- or stent-induced dissection necessitated a third stent.
Exclusion criteria included myocardial infarction (MI) within 1 month; left ventricular ejection fraction <30%; previous coronary artery bypass graft surgery; target vessel stenting or stroke within 6 months; a distal left main coronary artery trifurcation lesion with a nonrecanalized right coronary artery chronic total occlusion; calcification requiring rotational atherectomy; planned surgery necessitating antiplatelet therapy interruption within 6 months post-PCI; study drug contraindication or intolerance; estimated glomerular filtration rate <40 ml/min/1.73 m2 (Modification of Diet in Renal Disease formula); platelet count <10 × 109/l; liver dysfunction; pregnancy; expected life span <1 year; and inability to provide informed consent.
Randomization and procedures
Patients were randomly assigned in a 1:1 ratio to FFR-guided or angiography (Angio)-guided SB assessment and treatment. PCI was performed exclusively with DES. In both groups, pre-dilating the MV and SB before MV stenting was left to operator discretion. The SB was wired in all patients, however, before any MB dilations.
In the Angio group, after MV stenting, the SB was dilated followed by kissing balloon inflation (KBI) if any of the following criteria in the SB were present (Figure 1): Thrombolysis In Myocardial Infarction (TIMI) flow grade <3, dissection greater than type A, or ostial SB stenosis >70% (visually assessed). If any of these criteria persisted after KBI, the SB was recrossed through a distal MV stent cell, and SB stenting was performed using the T-stenting and small protrusion technique (TAP technique), followed by final KBI using noncompliant balloons at ≥16 atm (9).
In the FFR group, after MV stenting, a pressure wire was passed through a distal MV stent cell into the SB and was used for all subsequent PCIs. KBI was performed if the SB FFR was <0.80 (Figure 1), after which FFR was remeasured. SB stenting (TAP technique) was performed only if the SB FFR was still <0.80, followed by final KBI using noncompliant balloons at ≥16 atm (9).
The proximal optimal technique was used in all cases in both groups. Intravascular ultrasound was used at operator discretion. Anticoagulation was achieved with unfractionated heparin (activated clotting time 250 to 300 s), with glycoprotein IIb/IIIa inhibitors selectively. A 300-mg pre-PCI clopidogrel loading dose was administered if no long-term clopidogrel use. Troponin I and creatine kinase-myocardial band levels were measured 6 times within 72 h post-procedure. Aspirin (100 mg/d) was continued indefinitely, and clopidogrel (75 mg/d) for ≥12 months.
SB FFR measurement
After 200 to 300 μg of intracoronary nitroglycerin, the pressure wire transducer (Radi Medical Systems, Uppsala, Sweden) was normalized to the guide catheter pressure in the aorta and then passed across the MV stent struts and positioned ≥10 mm distal to the SB lesion. If the pressure wire could not be passed into the SB, a microcatheter over a conventional floppy wire in the SB was used to exchange the pressure wire. If the microcatheter could not enter the SB or diminished flow or greater than type B dissection was present, the ostial SB was first dilated with a 1.2-mm diameter balloon. Hyperemia was induced by an intravenous adenosine infusion (180 μg/kg/min). FFR <0.80 was considered functionally significant (10).
Clinical follow-up was performed at 1, 6, and 12 months. Routine angiographic follow-up was scheduled at 13 months unless required sooner. Follow-up FFR of the SB was performed in the FFR-guided group. A clinical events committee blinded to randomization adjudicated all adverse events.
Quantitative coronary angiography
Angiograms were analyzed offline using a validated automated edge-detection coronary bifurcation system (CAAS version 5.7, Pie Medical Imaging BV, Maastricht, the Netherlands). Bifurcation lesions (9) were divided into the proximal MV, distal MV (DMV), and SB segments, each including 5-mm stent-adjacent margins. Measurements included reference vessel diameter, minimal lumen diameter, DS, acute gain, and late loss. Quantitative coronary angiography (QCA) was performed by an independent core laboratory (China Cardiovascular Research Foundation, Beijing, China).
Study endpoints and definitions
The primary endpoint was the 1-year rate of major adverse cardiac events (MACE), the composite of cardiac death, MI, or ischemia-driven target vessel revascularization (TVR). Secondary endpoints included individual MACE components, stent thrombosis (ST), and restenosis.
All deaths were considered cardiac in origin unless noncardiac causes were certain. MI was defined as a creatine kinase-myocardial band increase to more than 3 times the upper limit of normal in ≥2 samples (16). ST was defined according to the Academic Research Consortium definite or probable criteria (17). Angiographic success for the SB was defined as TIMI flow grade 3 and for the MV as TIMI flow grade 3 with QCA residual DS <20%. Procedural success was defined as angiographic success with no in-hospital MACE. The pre-specified definition of angiographic restenosis varied according to location and treatment group. In both the Angio-guided and FFR-guided groups, restenosis of the proximal MV, DMV, and any stented SB was defined as QCA DS >50%. Restenosis in a nonstented SB was defined as QCA DS >70% in the Angio-guided group and as follow-up FFR <0.80 in the FFR-guided group. In a post-hoc analysis, restenosis for all SB lesions was defined as QCA DS >50%.
Based on studies by Koo et al. (15) and others (3–9), we estimated 1-year MACE rates of 5% and 15% in the FFR-guided and Angio-guided groups, respectively. Accordingly, a sample size of 150 patients per group provided 80% power to demonstrate superiority. Assuming 5% loss to follow-up, recruitment of 160 patients per group was planned.
Continuous variables are presented as mean ± SD and were compared using t or Mann-Whitney test as appropriate. Categorical variables were compared with the chi-square or Fisher exact test. Event-free survival estimates were generated by Kaplan-Meier methodology and compared using the log-rank test. All tests are 2-sided, and p < 0.05 was considered significant. All analyses were performed with SPSS Version 16.0 (SPSS Inc., Chicago, Illinois).
Between November 27, 2011 and June 25, 2013, 320 patients with true coronary bifurcation lesions were randomized to Angio guidance (n = 160) or FFR guidance (n = 160). Baseline clinical and lesion characteristics were well matched between groups (Tables 1 to 3⇓⇓). Approximately 85% of bifurcation lesions were Medina 1,1,1 and were most commonly left anterior descending artery/diagonal bifurcations, although notably ∼9% involved the distal left main coronary artery.
Pre-dilation of the MV was performed in 72.5% of lesions in each group, but was rarely performed in the SB (6.9% and 1.9% in the Angio-guided and FFR-guided groups, respectively) before MV stenting. MV stenting was successful in all 320 patients. Immediately after MV stenting, 12 SBs (3.8%) (7 in the Angio-guided group and 5 in the FFR-guided group) were acutely closed, of which 10 (6 and 4, respectively) were successfully reopened (Table 3).
After MV stenting, FFR measurement of the SB was achieved in 145 of 160 lesions (90.6%) and was <0.80 in 75 of 145 (52.0%). After balloon dilation of these 75 lesions, the SB FFR remained <0.80 in 26 (13.8%). Of the 15 of 160 lesions (9.4%) in which SB FFR could not be measured (despite KBI using a 1.2-mm SB balloon [Figure 2]), FFR measurements were subsequently obtained in 12 lesions after larger balloon dilation; 4 had SB FFR <0.80 and 8 had FFR ≥0.80. In total, FFR remained <0.80 after balloon angioplasty in 30 lesions (18.8%), 22 of which (73.3%) had SB stents successfully implanted.
After MV stenting, SB stents were required in 61 lesions (38.1%) after balloon angioplasty because of dissection greater than type A (n = 11), TIMI flow grade <3 (n = 3), and ostial SB stenosis >70% (n = 47) (Figure 3). SB stents were successfully deployed in 51 of 61 lesions (83.6%).
Thus, comparing the Angio-guided and FFR-guided groups, any treatment of the SB (balloon or stenting) was performed in 63.1% and 56.3% of lesions, respectively (p = 0.07); stenting of the SB was attempted in 38.1% and 25.9%, respectively (p = 0.01), and stents were implanted in 31.9% and 13.8%, respectively (p = 0.01).
In-hospital MI occurred in 12.5% and 11.9% of Angio-guided and FFR-guided patients, respectively (p = 0.86), mostly non–Q-wave MIs. There were no in-hospital deaths, TVRs or STs (Table 4).
One-year clinical follow-up was available for 100% of patients. The 1-year composite MACE rate (primary endpoint) was 18.1% in both groups (hazard ratio: 0.91, 95% confidence interval: 0.48 to 1.88, p = 1.00) (Table 4, Figure 4A), with the most common event being MI (13.8% vs. 11.9%, p = 0.74) (Figure 4B). Definite/probable ST occurred in 1.3% and 0.6% of patients in the Angio-guided and FFR-guided groups, respectively (p = 0.56), and TVR was required in 6.9% and 5.6% patients, respectively (p = 0.82) (Figure 4C).
There were no significant QCA differences in the proximal MV between the groups at follow-up (Table 5). However, late loss was greater in the DMV in the Angio-guided group (0.27 ± 0.46 mm vs. 0.15 ± 0.30 mm, p = 0.02), as was binary restenosis (9.9% vs. 1.7%, p = 0.02). Specifically, DMV restenosis was greatest in Angio-guided lesions in which the SB was treated by either balloon angioplasty or stenting rather than not treated (Figure 5).
Regarding the SB, because fewer stents were used for the SB in the FFR-guided group, in general, the FFR group had less late loss but greater DS (Table 6). In the FFR group, SB FFR <0.80 at follow-up (FFR restenosis) was present in 4 untreated SBs (7.1%) and in 5 treated SBs (8.1%) (p = 0.84) (Figure 5). Using the post-hoc QCA definition of any DS >50% in the SB, restenosis was present in 14 (11.8%) versus 25 (21.2%) of SBs in the Angio-guided and FFR-guided groups, respectively (hazard ratio: 2.74, 95% confidence interval: 1.99 to 4.02; p = 0.04).
The present study is the first randomized trial comparing FFR-guided and Angio-guided approaches in true coronary bifurcation lesions in which provisional SB stenting was intended. We found the following. 1) Accessing the SB and obtaining SB FFR measurements was feasible in 90.6% of cases and compared with Angio-guidance resulted in fewer SB PCIs, including fewer stents being implanted in the SB. 2) Nonetheless, the 1-year rates of composite MACE were identical (18.1%) with both FFR-guided and Angio-guided provisional T stenting. 3) Angiographic restenosis in the DMV and SB was slightly more frequent with the Angio-guided approach, although the differences were modest and did not translate into differences in clinical event rates.
Angiography alone is most commonly used to guide the decision whether and how to treat SBs in coronary bifurcation lesions. However, the discrepancy between angiographic DS and FFR (with angiography often leading to overtreatment of non–flow-limiting lesions) suggests that outcomes might be improved by physiological assessment. In this regard, FFR has become the gold standard for assessing the functional significance of a coronary lesion (10,18–20). The FAME (Fractional Flow Reserve Versus Angiography for Multivessel Evaluation) (10,20) and DEFER (19) studies demonstrated enhanced event-free survival after FFR-guided compared with Angio-guided PCI in nonbifurcation lesions, with fewer stents used and reduced cost. Because most SBs supply only a moderate amount of myocardium, an FFR-guided provisional stent strategy may be particularly desirable, obviating stenting in many cases.
In addition, after MV stent implantation, ostial SB lesions frequently appear angiographically more severe due to dissection, spasm, thrombus, metal strut protrusion, and/or most commonly plaque or carina shift (2,21). Similar to nonbifurcation lesions, discordance is often present between angiographic DS and FFR in SBs after MV stenting (11–13,15,22–26). Koo et al. (15) found that only 27% of SBs with angiographic DS >75% had FFR <0.75, and no SB lesion with angiographic DS <75% had functionally significant FFR. Conversely, after MV stenting in the DKCRUSH-IV study (13), FFR was <0.80 in 12% of angiographic nonsignificant SB lesions, an observation confirmed by Ahn et al. (22). In the present study, FFR was <0.80 in 52% of 145 lesions after MV stenting. FFR was positive in an additional 4 of 12 cases in which PCI with a 2.0-mm balloon was required to facilitate FFR wire-crossing. The higher rate of functionally significant SB stenoses in the present trial compared with past studies is most likely due to differences in Medina classification, vessel size, and lesion length of the bifurcation lesions in these studies.
Previous studies have demonstrated that an angiographically guided provisional SB approach (with stenting reserved for severe DS, dissection, and/or TIMI flow grade <3) is effective for most coronary bifurcation lesions (3–9). However, the angiographic triggers prompting SB stenting have varied in these studies, and the optimal angiographic criteria are uncertain. Conversely, there are few data regarding outcomes after FFR-guided provisional bifurcation stenting. In the nonrandomized study by Koo et al. (15), stenting of 20 of 97 SBs with FFR <0.75 after MV stenting was associated with fewer MACE than in an Angio-guided historical control population (4.6% vs. 13.0%) (3–9). In the present randomized trial, although FFR-guided SB assessment resulted in somewhat less SB intervention and fewer stents being implanted, the 1-year rate of composite MACE was identical to that with the simpler Angio-guided approach, with similar rates of TVR and ST.
Passing the pressure wire through MV stent struts into the SB may be challenging. Ahn et al. (21) reported that SB FFR could not be measured in 11 of 241 cases (4.6%) after MV stenting, due to failure to pass the pressure wire (n = 7) and wire-induced SB dissection (n = 4). Similarly, the FFR SB access failure rate in the current multicenter study was 9.4%, although it decreased to 1.9% after KBI using 2.0-mm diameter balloons. Additionally, we were unable to pass stents in 18 of 91 SBs (19.8%). These observations demonstrate that provisional SB stenting is technically demanding, warranting continued development of dedicated bifurcation stents and strategies.
Because of the small amount of myocardium supplied, many SB lesions are not functionally significant, and MV rather than SB restenosis is responsible for most TVRs (3–9). Consequently, technique optimization should be directed at ensuring freedom from MV restenosis while keeping the SB patent. However, we found that almost all SB restenotic lesions extended into the DMV, and as such, the higher SB restenosis rate in the Angio-guided group contributed to greater late loss and restenosis in the DMV in these patients. This finding may be explained by protrusion of SB struts into the DMV, especially if the bifurcation angle is narrow and KBI is suboptimal (27,28). Abnormal shear stress at the ostial SB and DMV may also be involved (29).
Given the nearly identical 1-year MACE rates with both approaches, either the Angio-guided or FFR-guided technique may be recommended for provisional SB stenting of true coronary bifurcation lesions. The FFR-guided technique may result in somewhat fewer stents being implanted and a slightly lower long-term restenosis rate, but is technically challenging and requires the upfront cost of a pressure wire in all patients. Formal cost accounting was not performed in this study.
FFR <0.80 was somewhat arbitrarily chosen to define functional significance, Although the results would likely have been similar with a different threshold, we cannot exclude slight differences. Although MACE rates were higher than the sample size estimates, the present study cannot exclude small clinical outcome differences between the 2 approaches. Moreover, the absence of any SB treatment in ∼40% of cases further lessens the ability to show differences between the groups. However, only Medina 1,1,1 and 0,1,1 bifurcations were included in the present study, and the low follow-up event rates suggest that a provisional single-stent approach is appropriate for many such lesions. Operators were necessarily unblinded, which may have introduced bias and influenced procedural decisions (e.g., whether to pre-dilate, total fluoroscopy time). Finally, the optimal stent technique and role of dedicated devices in highly complex bifurcations deserves further study.
Based on the results of the current multicenter randomized trial, FFR-guided and Angio-guided provisional SB stenting of true coronary bifurcation lesions are associated with similar 1-year MACE rates.
FFR is the gold standard for the assessment of the functional significance of lesions in the coronary artery, and FFR-guided implantation of a DES for either stable or unstable coronary artery disease is reported to be associated with less frequent clinically worse events. However, FFR-guided DES implantation for coronary bifurcation lesions has not been assessed by a randomized, multicenter study. Moreover, a provisional SB stenting technique guided by angiography is effective for a great majority of bifurcation lesions. Accordingly, this study was designed to compare the difference in 1-year MACE rate between FFR-guided and angiography-guided provisional SB stenting for bifurcation lesions defined as Medina 1,1, and 0,1,1 lesions with a minimal SB diameter of 2.5 mm. Our results showed that an FFR-guided procedure had the same 1-year MACE rate as the angiography-guided procedure. Interestingly, we also found that the failure rate of deploying a DES in SB in the 2 groups was not low, indicating the limitation of provisional stenting for more complex bifurcation lesions. Additionally, measuring SB FFR after MV stenting was not successful in almost 9% of SBs, suggesting the disadvantage of the FFR-guided procedure for anatomically complex SB lesions. As a result, coronary bifurcation lesions should be stratified according to lesion complexity, and further clinical trials are required to determine the superiority of FFR-guided provisional stenting over the anatomy-oriented provisional SB stenting technique.
The authors thank Lin Ling, Yin-Yin Zhao, Ling-Ling Liu, and Jing Kan, for their contributions to data collection and monitoring. They also acknowledge Professors Bao-Xiang Duan and Ming-Fan Zha, Directors of the Independent Members, for analyzing clinical events.
This study was funded by the Jiangsu Provincial Special Program of Medical Science (BL2013001). Dr. Stone is a past consultant for Boston Scientific. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- drug-eluting stent(s)
- distal main vessel
- diameter of stenosis
- fractional flow reserve
- kissing balloon inflation
- major adverse cardiac event(s)
- myocardial infarction
- main vessel
- percutaneous coronary intervention
- quantitative coronary angiography
- side branch
- stent thrombosis
- Thrombolysis In Myocardial Infarction
- target vessel revascularization
- Received October 10, 2014.
- Revision received December 1, 2014.
- Accepted December 4, 2014.
- American College of Cardiology Foundation
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