Biolimus-A9 Eluting Stent Implantion for Unprotected Left Main Coronary Artery Stenosis: 9-Month Strut Coverage as Assessed by Optical Coherence Tomography

Abstract: Objective. To evaluate strut coverage after biolimus-A9 eluting stent (BES) implantation for unprotected left main artery (ULMA) stenosis during follow-up and identify features associated with the length of uncovered stent segment, as assessed by frequency domain-optical coherence tomography (FD-OCT). Background. Incomplete stent strut coverage is a risk factor for late stent thrombosis. Long-term interaction between vessel wall and BES in the context of ULMA stenting has not been investigated in depth. Methods. We prospectively enrolled 32 patients with ULMA stenosis treated with BES. FD-OCT was performed at 9-month follow-up. Both malapposed and uncovered segment length were indexed for the segment between the distal and proximal cross-sections in which stent struts were circumferentially visible. Patients were divided into two groups according to the median value of maximal indexed uncovered segment length. Study endpoints were the rate of strut coverage and predictors of high uncovered segment length. Results. We analyzed 3622 struts. The rate of covered struts was 87%. A high correlation was found between malapposed and uncovered segment length (r = 0.82; P<.001). The median value of indexed-uncovered segment length was 0.308. On multivariable analysis, patients undergoing final kissing balloon were at lower risk of high uncovered segment length (odds ratio, 0.81; 95% confidence interval, 0.008-0.837; P=.04). Conclusion. In patients undergoing BES implantation for treatment of ULMA stenosis, the rate of 9-month strut coverage is high. The use of final kissing balloon reduces the risk of high uncovered stent segment length.

J INVASIVE CARDIOL 2015;27(2):70-77

Key words: left main disease, biolimus-eluting stent, optical coherence tomography

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Coronary artery bypass grafting (CABG) is the gold-standard treatment for significant left main coronary artery (LMCA) stenosis.^1,2 

Recent data from registries and randomized trials^3-8  support the use of percutaneous coronary intervention (PCI) with drug-eluting stent (DES) implantation as an alternative option to surgery in patients with low-to-intermediate anatomic complexity.^1,2 

However, despite favorable mid- and long-term results obtained with DES implantation, some clinical issues remained. Among them, the increased risk of late stent thrombosis associated with first-generation DES and its dismal consequences.⁹ On the other hand, second-generation DESs disclosed a better safety profile and have replaced first-generation DESs in clinical practice. Data from the 5-year follow-up of the LEADERS (Limus Eluted from A Durable versus ERodable Stent coating) trial¹⁰ showed that biodegradable polymer biolimus-A9 eluting stent (BES) implantation was associated with a significant reduction of very late (>1 year) stent thrombosis (ST) as compared to the durable polymer-based sirolimus-eluting stent.

Among factors associated with very late ST, impaired vessel healing associated with incomplete stent strut coverage during follow-up has been shown to play a relevant role.¹¹ Therefore, in the present study, we used frequency domain-optical coherence tomography (FD-OCT) to evaluate: (1) the rate of strut coverage at 9 months after BES implantation for LMCA stenosis; and (2) the clinical, angiographic, and procedural features associated with the length of uncovered stent segment. 

Methods

Patients. We prospectively included consecutive patients with symptomatic coronary artery disease (CAD) or documented myocardial ischemia who underwent BES implantation for the treatment of significant (≥50%) LMCA stenosis in a high-volume tertiary care interventional center. Exclusion criteria were: previous coronary artery bypass, severe renal dysfunction (estimated glomerular filtration rate ≤30 mgdL), contraindications to dual antiplatelet therapy, or a history of cancer. In all cases, a heart team composed of an interventional cardiologist and a surgeon reviewed the clinical and anatomic characteristics of patients and PCI was chosen as the revascularization strategy by consensus.

All patients provided written informed consent for participation in the study, and the study protocol was approved by the institutional ethics committee. 

Angiography and procedure. Stenosis ≥50% in the lumen of the LMCA or ≥70% in one or more of the other major epicardial vessels or their main branches was considered significant at visual estimation. PCI procedure, including use of 1 or more stents for distal lesions and type of bifurcation technique, was performed according to the operator’s preference with the exception of the mandatory use of BES (Nobori, Terumo Medical Corporation or Biomatrix, Biosensor Inc) for LMCA stenosis treatment. In cases of multivessel disease, the utilization of an alternative stent for lesions in different locations (either DES or bare-metal stent) was allowed. All PCI procedures were angiographic guided. During the procedure, use of prophylactic intraaortic balloon pump and use of glycoprotein IIb/IIIa inhibitors was at the operator’s discretion. All patients were on chronic aspirin treatment and received a 5000 U bolus of unfractioned heparin at the time of the PCI. Before or during the procedure, all patients received clopidogrel treatment. After PCI, each patient was prescribed aspirin 75-160 mg indefinitely and clopidogrel 75 mg for 1 year. Angiographic success was defined as residual stenosis <30% in the worse of two orthogonal views. Procedural success was defined as angiographic success in the absence of death, myocardial infarction (MI), or the need for further revascularization during hospitalization.

Angiographic analysis. Coronary angiograms were obtained before the intervention, after stenting, and at 9-month follow-up. The projection showing the maximal degree of stenosis was selected at baseline and was used for subsequent analysis. Quantitative coronary angiography (QCA) was performed with the CAAS II analysis system (Pie Medical). Off-line measurements were performed by two investigators blinded to patient information, and disagreements were solved by consensus. Angiographic restenosis was defined as diameter stenosis ≥50% by QCA within a previously stented segment (stent and 5 mm proximal and distal) at the follow-up angiogram.

Follow-up and definitions. During follow-up, coronary angiography was electively performed 9 months after the intervention or as clinically indicated by symptoms. The 3-year follow-up was performed by outpatient visit or telephone interview. 

Cardiac death was defined as death from cardiac cause, sudden death, or any death without another known cause. In-hospital re-MI was defined as the recurrence of typical clinical symptoms and new electrocardiographic changes with an increase of MB creatine-kinase (MB-CK) ≥50% of the previous levels. During follow-up, MI was defined as the occurrence of any value of troponin and/or CK-MB greater than the upper limit of normal if associated with clinical and/or electrocardiographic changes. 

Definite, probable, and possible ST were determined according to the Academic Research Consortium definitions.¹²Stroke was defined as the sudden onset of a focal neurologic deficit lasting more than 24 hours. Major bleeding was defined as bleeding requiring transfusion or surgery, reduction in hemoglobin of more than 5 g/dL, and intracranial haemorrhage. Minor bleeding was defined as local hematoma and any other clinically relevant bleeding that did not meet criteria for severity.

Target lesion revascularization (TLR) was defined as repeated PCI of the entire segment involving the implanted stent and the 5 mm distal and proximal borders adjacent to the stent. 

Target vessel revascularization (TVR) was defined as any repeat PCI or surgical bypass of any segment of the target vessel, defined as the entire major coronary vessel proximal and distal to the target lesion, including upstream and downstream branches and the target lesion itself.

OCT imaging. Frequency-domain OCT images were obtained using the C7-XROCT imaging system (LightLab Imaging, Inc, St. Jude Medical), at a pullback speed of 20 mm/s and after nitroglycerin administration with a non-occlusive technique. OCT images were evaluated off-line at our Institution by two investigators blinded to patient information. Disagreements were solved by consensus.

The region of interest (ROI) was the stented LMCA segment, defined as the segment between the distal and proximal cross-sections in which stent struts were circumferentially visible. Within the ROI, all cross-sectional images were initially screened for quality and excluded from the analysis if any portion of the stent was out of the screen and when more than 45° of the lumen border was not visible or if they had poor quality caused by residual blood or non-uniform rotation distorsion. Then, cross-sections at 1-mm intervals within the ROI were analyzed. When a frame was not analyzable, an alternative frame located within the two proximal or distal frames was selected for analysis.

Lumen and stent area were measured by an automated detection algorithm available in the LightLab proprietary software. Manual corrections were performed as appropriate, and neointimal hyperplasia areas were calculated as previously described.¹³ On strut level analysis, a malapposed strut was defined when  the distance between the strut center reflection and the vessel wall was ≥140 µm. This criterion was obtained by rounding up the sum of strut-polymer thickness of BES plus OCT resolution. Struts located at the ostium of side branches with no vessel wall behind were excluded from the analysis of apposition.

Struts were classified as covered if a layer of tissue was visible over all reflecting surfaces and uncovered if any part of the strut was visibly exposed to the lumen. Struts were further classified as embedded covered, protruding covered, uncovered apposed struts, and uncovered malapposed struts.¹⁴

The maximum uncovered segment length and malapposed segment length were defined as the number of consecutive frames at 1-mm intervals with uncovered struts or malapposed struts. Both uncovered segment length and malapposed length were indexed for the ROI.

Statistical analysis. Categorical variables are presented as numbers and frequencies and were compared by the Fisher exact tests. Continuous variables are expressed as mean ± standard deviation and compared by the Student t-test. Correlations between ratio of uncovered strut per section (RUST), ROI-indexed uncovered segment length, and ROI-indexed malapposed segment length were determined by Spearman’s rank correlation test.

Since the length of uncovered segment has recently emerged as a risk factor for late stent thrombosis in patients implanted with DES,¹¹ we divided our population in two groups according to the median value of ROI-indexed uncovered segment length. Using the group with high uncovered segment length (defined as patients with ROI-indexed uncovered stent segment length ≥ the median value) as a dependent variable, we performed a multivariable logistic regression to determine clinical, angiographic, and procedural factors independently associated with high uncovered segment length.

Given the small sample size, only variables associated with the uncovered segment length (P<.10) were entered in the multivariable analysis. A P-value <.05 in the two-tailed tests was considered significant. All analyses were performed with the SPSS 15.0 software (SPSS, Inc).

Results

We enrolled 40 consecutive patients with ULMA stenosis undergoing BES implantation. Every patient underwent clinical and angiographic follow-up at 9 months, when OCT examination was also performed. Among them, 8 patients were excluded because they had >50% of stent length with inappropriate OCT image quality due to residual blood. Mean age of these excluded patients was 68 ± 10 years. Most had multivessel disease (7/8) and were treated at bifurcation level (6/8). Reference vessel diameter was 3.76 ± 0.46 mm. No patient experienced clinical events. The final cohort of this study included 32 patients.

Clinical baseline characteristics are listed in Table 1. Mean age of the study population was 69 ± 12 years, 31 (97%) were male, and 18 (56%) had acute coronary syndrome at admission. Mean Syntax score⁶ was 28 ± 11.

Table 2 shows that 30 patients (94%) had multivessel disease and received a multivessel stent implantation. Complete revascularization was obtained in 22 cases (69%). LMCA was the culprit artery in 29 patients (91%). LMCA lesions were predominantly at bifurcation (n = 25; 78%), which was treated with 1 stent in most cases. Final kissing balloon was used in 21/25 cases (84%) of bifurcation treatment at operator’s discretion. The mean stent diameter and stent length for LMCA treatment were 3.4 ± 0.5 mm and 14.4 ± 4.9 mm, respectively.

Initial and 9-month QCA findings are summarized in Table 3. Mean late loss in the LMCA stent and at the side branch was 0.3 ± 0.42 mm and 0.12 ± 0.45 mm, respectively.

OCT findings. OCT findings are shown in Table 4. The OCT-determined stent length (ROI) to implanted stent length ratio was 0.79 ± 0.22 mm. Of 429 cross-sections collected by OCT, 392 cross-sections with 3622 struts were analyzed. The rate of covered struts was 87% (n = 3160). The RUST >30% highly correlated with both the ROI-indexed uncovered segment length (r = 0.74; P<.001), and to a lesser extent with the ROI-indexed malapposed segment length (r = 0.61; P<.001). Figure 1 shows that a very high correlation was found between ROI-indexed malapposed segment and uncovered segment length (r = 0.82; P<.001).

Table 5 shows clinical, angiographic, and procedural characteristics of patients according to the median value of the ROI-indexed uncovered segment length. Patients who did not receive a final kissing balloon [including those treated at the ostium (n = 6) and at the shaft (n = 3)] were more likely to belong to the group with high ROI-indexed uncovered segment length. At multivariable analysis (Figure 2), final kissing balloon was confirmed to be associated with a lower risk of uncovered segment length (odds ratio [OR] = 0.81; 95% confidence interval [CI], 0.008-0.837; P=.04).

Clinical events. No clinical events occurred during the index procedure. At 9-month follow-up, 6 patients underwent repeat PCI (4 for binary restenosis of LMCA stenting and 2 for progression of de novo lesions). The cases of binary restenosis occurred at bifurcation level. All patients received final kissing balloon and 3 were treated with a 2-stent technique. No differences in terms of LMCA binary restenosis were observed in patients with high uncovered segment length (n = 2) compared with patients who had low uncovered segment length (n = 2).

At 3-year follow-up, 1 patient belonging to the group with high uncovered segment length died from pulmonary neoplasm and 1 belonging to the other group died after transcatheter aortic valve implantation for severe aortic stenosis.

Discussion

The main findings of the present study are: (1) BES implantation for unselected patients with ULMA stenosis is associated with a high rate of strut coverage at 9-month follow-up; and (2) patients treated at bifurcation with final kissing balloon show better stent strut coverage. 

PCI with DES represents an alternative option in selected patients with ULMA stenosis.^1,2 However, safety concerns regarding the risk of late or very late ST are amplified in ULMA due to the large amount of jeopardized myocardium.¹⁵ Among factors associated with the risk of ST, incomplete stent strut coverage plays a crucial role.¹¹ The durable polymer carrier of first-generation DESs has been implicated as leading to persistent inflammatory response causing delayed and incomplete stent endothelialization, positive remodeling with late malapposition, and ultimately an increased risk of ST.¹⁶ The new-generation biodegradable-polymer BESs investigated in this study have been designed to partly overcome these limitations.¹⁰ 

Intravascular OCT is accurate to investigate interactions between stents and vessel wall and is currently used as a surrogate  for in vivo assessment of stent strut coverage.¹⁴ The currently available FD-OCT overcame the main drawbacks of first-generation time-domain OCT and made it possible to investigate vascular reaction to stent implantation of LMCA. Indeed, FD-OCT has an increased pullback speed (up to 25 mm/s), obviating the need for proximal balloon occlusive technique during image acquisition, and provides a larger field of view, enabling evaluation of large vessels. In a recent study, Fujino et al¹⁷ showed that FD-OCT during stent implantation of LMCA was safe and feasible. Compared with intravascular ultrasound image acquisition, OCT segment exploration was shorter, while it was more sensitive in detecting strut malapposition.¹⁷ This is related to the fact that to obtain a blood-cleared image by FD-OCT, blood must be adequately displaced by iodine contrast through a well-engaged guiding catheter that obscures visualization of the LMCA ostium. In our study, the percentage of stent length explored by OCT, calculated through the ROI to stent length ratio, was high (79 ± 22%). 

Overall, we found a fairly good stent strut coverage (87%), which can be considered an indirect sign of good vessel healing. This confirms and extends the OCT data from the LEADERS trial¹⁸ with the bioedegradable-polymer BES. Compared to OCT data from the LEADERS trial, the rate of covered struts at follow-up in our study was slightly lower (98% in LEADERS). This finding may partly reflect the higher complexity of LMCA treatment compared with treatment of other coronary segments (the LEADERS was an all-comer trial and consequently included different types of lesions and coronary locations). In fact, in our study, the majority of patients (78%) had distal LMCA stenosis that required treatment of the bifurcation, while in the LEADERS OCT substudy, the rate of bifurcation was much lower (11%).

In the present study, the uncovered segment length was highly correlated with the malapposed segment length. In a recent study enrolling 33 consecutive patients with LMCA stenosis treated with DES implantation at bifurcation, Fujino et al¹⁹ showed that 9-month malapposition rate was higher at the largest segments of ULMA (body vs distal and bifurcation segment). These results were mainly determined by acute stent strut malapposition. Our study confirmed that long-term strut malapposition is mainly correlated with procedural factors. For instance, the lack of final kissing balloon (4 bifurcation, 3 shaft, and 6 ostium treatments) was independently associated with the risk of longer uncovered segment length. Taken together, these findings underscore the importance of both accurate stent sizing and stent postdilatation procedure, especially in the largest portion of the LMCA. Notably, in the present study, all patients underwent angiography-guided BES implantation and with the exception of cases treated with kissing balloon only 1 patient received stent postdilatation. It is probable that IVUS or OCT-piloted PCI would have been useful to guide postdilatation and improve acute PCI results in terms of stent apposition.

Study limitations. The results of the present study should be interpreted with caution in light of some limitations. Although new-generation FD-OCT has allowed examination of the LMCA, the rate of unsuccessful imaging acquisition is high in unselected patients (20% in our study).

OCT was performed only at 9-month follow up; accordingly, it was not possible to distinguish whether late malapposition was previously present or if it was acquired. However, recent studies have shown that the main determinant of late malapposition is the postprocedural (acute) malapposition rather than positive remodeling of the vessel.¹⁹ Our study did not allow us to establish the clinical relevance of uncovered segment length in the context of LMCA-PCI. Indeed, this study definitely was not powered to detect differences in terms of ST in patients with high uncovered segment length as compared to those without. Yet no cases of clinical ST were observed at both 9-month and 3-year follow-up. 

Conclusion

In unselected patients undergoing BES implantation for treatment of LMCA stenosis, the rate of 9-month strut coverage is high. The risk of high uncovered stent segment length appears mainly related to procedural factors such as bifurcation treatment without final kissing balloon and stenting of the largest portion of the LMCA.

Acknowledgment. We are grateful to our catheterization laboratory technicians (Leonardo Santoro, Michele Gregori, Andrea Tommasini, Stefano Margutti, and Renzo Ventura) who provided us with high-quality digital angiograms for this study.

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From the Dipartimento di Medicina Specialistica Diagnostica e Sperimentale Azienda Ospedaliero-Universitaria, Policlinico St. Orsola/Malpigli, Bologna, Italy.

Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. The authors report no conflicts of interest regarding the content herein.

Manuscript submitted May 7, 2014, provisional acceptance given June 30, 2014, final version accepted July 17, 2014.

Address for correspondence: Nevio Taglieri, Dipartimento di Medicina Specialistica Diagnostica e Sperimentale, Azienda Ospedaliero-Universitaria, Policlinico St. Orsola/Malpigli, Via Massarenti 9, 40138, Bologna, Italy. Email: neviotaglieri@hotmail.it