Comparison of 1-Month and 12-Month Vessel Responses Between the Polymer-Free Biolimus A9-Coated Stent and the Durable Polymer Everolimus-Eluting Stent

Abstract

Background: A polymer-free biolimus A9-coated stent (PF-BCS) may achieve better arterial healing than a durable polymer drug-eluting stent owing to its polymer-free feature.

Methods and Results: This multicenter, prospective, observational study enrolled 105 patients (132 lesions) who underwent PF-BCS (51 patients, 71 lesions) or durable polymer everolimus-eluting stent (DP-EES, 54 patients, 61 lesions) implantation. Serial coronary angioscopy (CAS) and optical coherence tomography (OCT) examinations were performed at 1 and 12 months, and the serial vessel responses were compared between PF-BCS and DP-EES. The primary outcome measure was the incidence of subclinical intrastent thrombus on CAS. The secondary outcome measures were: adequate strut coverage (≥40 μm) on OCT and maximum yellow color grade on CAS. The incidence of thrombus was high at 1 month (100% vs. 93%, P=0.091), but decreased at 12 months (18% vs. 25%, P=0.56), without a significant difference between PF-BCS and DP-EES. The adequate strut coverage rate was significantly higher (84±14% vs. 69±22%, P<0.001) and yellow color was significantly less intense (P=0.012) at 12 months in PF-BCS than in DP-EES; however, they were not significantly different at 1 month (adequate strut coverage: 47±21% vs. 50±17%, P=0.40; yellow color: P=0.99).

Conclusions: Although the thrombogenicity of PF-BCS was similar to that of DP-EES, the adequate coverage and plaque stabilization rates of PF-BCS were superior to those of DP-EES at 12 months.

Drug-eluting stents (DESs) have been widely used in percutaneous coronary intervention (PCI) for stenosis in the coronary artery. However, although DESs have dramatically decreased the incidence of restenosis compared to bare-metal stents (BMSs),¹ late and very late stent thrombosis (ST), which causes acute myocardial infarction and sudden death due to sudden-onset thrombus, have become a new issue.² Accordingly, the current guidelines of the American College of Cardiology/American Heart Association and the European Society of Cardiology generally recommend dual-antiplatelet therapy (DAPT) for 6 months in patients with chronic coronary syndrome treated with a DES, although a shorter duration can be considered based on the high-bleeding risk.^3,4 In the latest Japanese guideline, 1–12 months’ duration of DAPT is recommended based on the presence or absence of high bleeding and thrombotic risks.⁵

The polymer-free and carrier-free biolimus A9-coated stent (PF-BCS) (BioFreedom^TM, Biosensors Interventional Technologies, Singapore) is a novel stent, which has no polymer that releases drugs within 30 days.⁶ The LEADERS FREE trial demonstrated that compared to BMS, PF-BCS had better safety and efficacy at 12 months.⁷ Judging from the polymer-free feature and the results of this trial, PF-BCS can lead to better arterial healing, and, in turn, adequate smooth muscle cell proliferation and re-endothelialization.⁸

The fast-release zotarolimus-eluting stent, Endeavor^TM (Medtronic, Minneapolis, MN, USA), has a faster drug release duration at 14 days⁹ and higher late loss¹⁰ than other DESs. Importantly, the Endeavor^TM has a 4% incidence of thrombus adhesion at 12 months, which is lower than that of other DESs at 15–47%.^11–14 Therefore, PF-BCS, which has a relatively fast drug release, can achieve a lower incidence of thrombus adhesion at 12 months.

Coronary angioscopy (CAS) and optical coherence tomography (OCT) can evaluate vessel response following stent implantation. Subclinical intrastent thrombus on CAS is considered a surrogate marker of delayed endothelialization during arterial repair.¹¹ However, vessel responses in the early and middle phases following PF-BCS deployment have not been elucidated to date. Therefore, this prospective observational study aimed to serially compare the vessel responses between PF-BCS and DES at 1 and 12 months after stent implantation using CAS and OCT.

Methods

Study Design and Patients

The COLLABORATION study is a multicenter (4 centers), prospective, observational study (Supplementary Appendix). The main inclusion criteria were: patients with chronic coronary syndrome, multi-vessel disease in native coronary arteries, implantation of a PF-BCS or a durable polymer everolimus-eluting stent (DP-EES, Xience^TM, Abbott Vascular, Santa Clare, CA, USA) at the initial PCI, an indication for staged PCI for the residual lesion at 1±0.5 months after the initial PCI, and patients who were scheduled for follow-up coronary angiography 12±2 months after the initial PCI. The main exclusion criterion was patients with acute coronary syndrome. The other inclusion and exclusion criteria are shown in Supplementary Table. All stents were implanted in de novo lesions in native coronary arteries. The patients received clopidogrel (75 mg/day) or prasugrel (3.75 mg/day), in addition to aspirin (100 mg/day) at least 1 week before PCI.

This study was approved by each hospital’s Ethics Committee, and it adhered to the tenets of the Declaration of Helsinki. All patients provided written informed consent to participate in the study.

Angiographic Procedure and Analysis

Coronary angiography was performed after the administration of unfractionated heparin (5,000 IU) into the radial, brachial, or femoral artery via the inserted sheath, and of isosorbide dinitrate into the coronary artery. The view showing the most severe stenosis was selected for quantitative coronary angiography, which was subsequently performed using a computerized angiographic analysis system (QAngioXA 7.3; Medis Medical Imaging Systems, Leiden, the Netherlands) at the same angle of projection before and immediately after PCI.¹⁵

CAS Procedure and Analysis

CAS was performed for the initial lesion at the time of the staged PCI and at the 12-month follow up using a smart-i angioscopic catheter (i Heart Medical, Tokyo, Japan) or Forwardlooking^TM (Taisho Biomed Instruments, Osaka, Japan). The detailed procedure is described in Supplementary Methods. Angioscopic images were analyzed to determine: (1) the dominant, maximum, and minimum degree of neointimal coverage (NIC) over the stent; (2) the yellow color grade of the stented segment; and (3) the presence of intra-stent thrombus. NIC over the stent was classified into 4 grades, as previously described:¹⁶ grade 0, stent struts fully visible, similar to immediately after implantation; grade 1, stent struts bulging into the lumen, although covered, still transparently visible; grade 2, stent struts embedded in the neointima, but translucently visible; and grade 3, stent struts fully embedded and invisible on angioscopy. The yellow color was graded as follows: grade 0, white; grade 1, light yellow; grade 2, yellow; grade 3, intense yellow.¹⁷ Thrombus was defined as a material adhering to the luminal surface or protruding into the lumen.¹⁸ The degree of thrombus adhesion was graded as: grade 0 (none), no thrombus; grade 1 (focal), several spotty thrombi; and grade 2 (diffuse), thrombus extending between the struts. The reproducibility is shown in Supplementary Methods.

OCT Procedure and Analysis

OCT was performed for the initial lesion immediately before and after PCI and at staged PCI and at the 12-month follow up using the OPTIS Mobile System (Abbott Vascular, Santa Clare, CA, USA). The detailed procedure and analyses before and immediately after PCI are shown in Supplementary Methods. At the follow up, struts were divided into 3 categories: covered (existence of any tissue on the strut), uncovered, and malapposed. In particular, tissue strut coverage with neointimal hyperplasia ≥40 μm was defined as adequate coverage.^8,19 The neointima was defined as the tissue between the luminal and stent contour and estimated in all frames in the stent. Further, it was classified as either a homogenous high signal pattern or low signal pattern; a neointima with a homogenous high signal pattern was identified as having signal-rich regions with low attenuation, whereas a neointimal with a low signal pattern was identified as having focally changing optical properties and showing various backscattering patterns or consisting of concentric layers with different optical properties: an abluminal high-scattering layer and an abluminal low-scattering layer.²⁰ A calcified neointima had a well-delineated, signal-poor region with sharp borders. A lipid neointima had signal-poor regions with diffuse borders and high attenuation.²¹ Neoatherosclerosis was defined as a lipid or calcified neointima.²² The reproducibility is shown in Supplementary Methods.²³ Abnormal intraluminal tissue was defined as irregular tissue protruding into the lumen.

Outcome Measures

The primary outcome measure was the incidence of CAS-detected subclinical intrastent thrombus 12 months after implantation. The secondary outcome measures were CAS and OCT findings at 1 month; CAS findings, except for subclinical intrastent thrombus, at 12 months; and OCT findings at 12 months.

Statistical Analysis

Sample size calculation is shown in Supplementary Methods. Data are shown as mean and standard deviation (SD) for continuous variables or as percentages for discrete variables, unless otherwise indicated. Intergroup differences were tested using Welch’s t-test for continuous variables, the Mann-Whitney U-test for ordinal discrete variables, and the Chi-squared test for other discrete variables. Ordinal logistic model and linear regression model analyses were performed to determine the impact of PF-BCS on CAS and OCT findings at 1 and 12 months, respectively. The parameters that were significantly different between PF-BCS and DP-EES were chosen as covariables. Results of the model are presented as odds ratio or regression coefficients with 95% confidence intervals (CIs). All statistical analyses were performed using R version 3.6.0 (R Development Core Team, Vienna, Austria). P values <0.05 were considered statistically significant.

Results

Patient Characteristics

Overall, 105 patients (132 lesions) were enrolled; among them, 51 patients (71 lesions) received PF-BCS and 54 (61 lesions) received DP-EES (Figure 1). Target lesion revascularization (TLR) occurred before follow-up examinations for 2 lesions from 2 patients. Of these, because 1 patient had 2 lesions, the other lesion without TLR could not be followed up at 12 months. In addition, 4 (5 lesions) and 3 (3 lesions) patients in the PF-BCS and DP-EES groups, respectively, could not be followed up. Finally, 45 (63 lesions) and 51 (58 lesions) patients in the PF-BCS and DP-EES group, respectively, underwent a 12-month follow up. There were no significant differences in baseline patient characteristics between the groups (Table 1). With respect to lesion characteristics, the distribution of the target vessel was different between the groups, and although the pre-PCI quantitative coronary angiography data were similar, the reference vessel diameter and minimum lumen diameter were larger in the PF-BCS group. For procedural characteristics, stent and post-dilatation balloon diameters were larger in the PF-BCS group. Stent implantation pressure was higher in the PF-BCS group, although the pre- and post-dilatation balloon pressures were similar (Table 1).

Figure 1.

Study Flow Chart. In total, 105 patients (132 lesions) who underwent initial percutaneous coronary intervention (PCI) with the polymer-free biolimus A9-coated stent (PF-BCS, 51 patients [71 lesions]) or durable polymer everolimus-eluting stent (DP-EES, 54 patients [61 lesions]) were enrolled. PCI was performed in all patients 1 month after the initial PCI. Coronary angioscopy (CAS) was performed 1 month after and optical coherence tomography (OCT) was performed immediately after and 1 month after the initial PCI. Target lesion revascularization (TLR) occurred before follow up for 2 lesions in 2 patients. Of these, because 1 patient had 2 lesions, the other lesion without TLR could not be followed up at 12 months. In addition, 12-month follow up could not be performed for 5 lesions from 4 patients in the PF-BCS group and 3 lesions from 3 patients in the DP-EES group. Finally, CAS and OCT were performed 12 months after initial PCI for 63 lesions from 45 patients in the PF-BCS group and 58 lesions from 51 patients in the DP-EES group.

Table 1. Baseline Patient Characteristics

	PF-BCS group	DP-EES group	P value
Patient characteristics
Number of patients (n)	45	51
Male, n (%)	41 (91)	38 (75)	0.063
Age, years	72±9	72±11	0.86
Body mass index, kg/m2	23.9±3.1	24.2±3.8	0.60
Current smoking, n (%)	15 (33)	13 (25)	0.54
Hypertension, n (%)	35 (78)	43 (84)	0.58
Dyslipidemia, n (%)	45 (100)	46 (90)	0.090
Diabetes mellitus, n (%)	21 (47)	26 (51)	0.83
Previous history of PCI, n (%)	17 (38)	11 (22)	0.13
Previous history of CABG, n (%)	1 (2)	2 (4)	1.00
Chronic heart disease, n (%)	4 (9)	5 (10)	1.00
Atrial fibrillation, n (%)	7 (16)	8 (16)	1.00
Cerebrovascular vascular disease, n (%)	5 (11)	6 (12)	1.00
Medication use at the time of initial PCI, n (%)
Aspirin	45 (100)	51 (100)	N/A
P2Y12 inhibitor, n (%)			0.35
Prasugrel	34 (76)	33 (65)
Clopidogrel	11 (24)	18 (35)
Anticoagulant, n (%)			0.59
DOAC	5 (11)	7 (14)
Warfarin	0 (0)	1 (2)
None	40 (89)	43 (84)
Statin	43 (96)	44 (86)	0.23
Duration from initial PCI
To staged PCI, days	32±5	32±6	0.93
To 1-year follow up, days	369±36	364±33	0.45
Presence of symptoms, n (%)	22 (49)	29 (57)	0.56
Triple vessel disease, n (%)	11 (24)	8 (16)	0.44
Lesion and procedural characteristics
Number of lesions, n	63	58
Target vessel, n (%), LAD/LCX/RCA	13 (21)/27 (43)/ 23 (37)	26 (45)/14 (24)/ 18 (31)	0.012
ACC/AHA classification, n (%), A/B1/B2/C	2 (3)/8 (13)/ 10 (16)/43 (68)	5 (9)/6 (10)/ 6 (10)/41 (71)	0.97
Chronic total occlusion, n (%)	5 (8)	1 (2)	0.25
Bifurcation, n (%)	16 (25)	18 (31)	0.55
Moderate-to-severe calcification, n (%)	10 (16)	17 (29)	0.085
Pre-PCI QCA data
Lesion length, mm	25±16	25±15	0.76
Reference vessel diameter, mm	2.66±0.52	2.58±0.65	0.48
Minimum lumen diameter, mm	0.79±0.41	0.79±0.36	0.96
Diameter stenosis, %	70±14	70±12	0.78
Post-PCI QCA data
Reference vessel diameter, mm	3.16±0.45	2.87±0.54	0.002
Minimum lumen diameter, mm	2.70±0.42	2.43±0.48	0.001
Diameter stenosis, %	14±7	15±7	0.43
Pre-dilatation, n (%)	55 (87)	53 (91)	0.67
Pre-dilatation balloon diameter, mm	2.55±0.44	2.50±0.48	0.65
Pre-dilatation balloon pressure, atm	12±4	12±3	0.78
Atherectomy device use, n (%)	2 (3)	6 (10)	0.15
Stent diameter, mm	2.94±0.41	2.77±0.52	0.045
Total stent length, mm	31±18	33±16	0.63
Stent implantation pressure, atm	7±3	11±2	<0.001
Overlapping stents, n (%)	16 (25)	9 (16)	0.26
Post-dilatation, n (%)	63 (100)	55 (95)	0.21
Post-dilatation balloon diameter, mm	3.37±0.52	3.08±0.54	0.003
Post-dilatation balloon pressure, mm	18±4	17±3	0.81

Data are presented as mean±SD or n (%). ACC/AHA, American College of Cardiology/American Heart Association; CABG, coronary artery bypass grafting; DOAC, direct oral anticoagulant; DP-EES, durable polymer everolimus-eluting stent; LAD, left anterior descending artery; LCX, left circumflex artery; PCI, percutaneous coronary intervention; PF-BCS, polymer-free biolimus A9-coated stent; QCA, quantitative coronary angiography; RCA, right coronary artery.

The duration of DAPT was similar between the PF-BCS group and DP-EES group (313±113 days vs. 300±119 days, P=0.57). As follow-up coronary angiography at 12 months demonstrated that in-stent restenosis was detected in 6 lesions from 6 patients in the PF-BCS group and TLR occurred for these lesions after the angiography, they were excluded from the imaging analyses.

CAS Findings

Evaluations could not be performed due to poor image quality for 4 lesions in the DP-EES group at 1 month (0% vs. 7%, P=0.11), and for 8 lesions in the PF-BCS group and 14 in the DP-EES group at 12 months (13% vs. 24%, P=0.16). In both groups, although subclinical intrastent thrombus was highly common at 1 month after implantation (100% vs. 93%, P=0.091), its incidence decreased at 12 months (18% vs. 25%, P=0.56), with no significant between-group differences. The 1- and 12-month thrombus grade was also similar between the groups (Figure 2A). Although similar at 1 month, the dominant, maximum, and minimum NIC grades were higher in the PF-BCS group at 12 months (Figure 2B–D). Further, although the maximum yellow color grade was similar at 1 month, it was lower in the PF-BCS group at 12 months (Figure 2E).

Figure 2.

Serial thrombus grade, neointimal coverage (NIC) grade, and maximum yellow color grade evaluated by coronary angioscopy at 1 and 12 months after the initial percutaneous coronary intervention (PCI). (A) Thrombus grade. The thrombus grade is similar between the polymer-free biolimus A9-coated stent (PF-BCS) and durable polymer everolimus-eluting stent (DP-EES) groups at 1 (P=0.66) and 12 (P=0.43) months. (B) Dominant NIC grade. Although similar at 1 month (P=0.70), the dominant NIC grade was higher in PF-BCS than in DP-EES at 12 months (P=0.001). (C) Maximum NIC grade. Although similar at 1 month (P=0.18), the maximum NIC grade was higher in PF-BCS than in DP-EES at 12 months (P<0.001). (D) Minimum NIC grade. Although similar at 1 month (P=1.0), the maximum NIC grade was higher in PF-BCS than in DP-EES at 12 months (P=0.010). (E) Maximum yellow color grade. Although similar at 1 month (P=0.99), the maximum yellow color grade at 12 months was lower in PF-BCS than in DP-EES (P=0.012).

OCT Findings

Two lesions in the PF-BCS group and 5 in the DP-EES group at 1 month (3% vs. 9%, P=0.37) and 11 lesions in the PF-BCS group and 12 in the DP-EES group at 12 months (17% vs. 21%, P=0.83) could not be evaluated due to poor image quality. Plaque constituent was similar between PF-BCS and DP-EES groups before PCI (Table 2). Except for the minimum lumen diameter and maximum malapposition distance, the other OCT parameters immediately after PCI were similar between the groups (Table 2). OCT findings at 1 and 12 months after the initial PCI are shown in Table 3. Although they were similar at 1 month, the covered strut and adequate strut coverage rates were higher in the PF-BCS group at 12 months. The malapposed strut rate was higher in the DP-EES group at both 1 and 12 months. Although they were similar between the groups at 1 month, the maximum and mean neointimal thicknesses were thicker in the PF-BCS group at 12 months. The frequency of neointima with homogeneous high signal pattern was higher in the DP-EES group at 1 month; however, the rate was similar at 12 months.

Table 2. Optical Coherence Tomography Analysis Findings Before and Immediately After PCI

	PF-BCS group	DP-EES group	P value
Before PCI
Plaque constituents, %
Calcified	24.57±30.25	22.11±32.00	0.71
Fibrous	12.75±17.56	11.69±18.90	0.78
Lipid	43.71±30.69	46.97±31.26	0.62
Normal	18.97±15.21	19.22±12.54	0.93
Immediately after PCI
Analyzed stent length per lesion, mm	29.78±16.11	31.17±15.48	0.64
Mean reference lumen area, mm2	6.47±2.83	6.32±2.74	0.80
Distal reference lumen area, mm2	5.57±2.43	5.11±2.84	0.38
Proximal reference lumen area, mm2	7.39±3.65	7.72±3.32	0.63
Mean reference lumen diameter, mm	2.79±0.57	2.74±0.58	0.68
Distal reference lumen diameter, mm	2.60±0.56	2.51±0.68	0.43
Proximal reference lumen diameter, mm	2.99±0.66	3.06±0.65	0.58
Minimum lumen area site
Lumen area, mm2	5.42±1.86	4.77±2.14	0.097
Minimum lumen diameter, mm	2.57±0.42	2.38±0.56	0.059
Mean lumen diameter, mm	3.12±1.08	2.85±1.04	0.19
Mean lumen area, mm2	6.99±2.31	6.19±2.62	0.097
Minimum stent area site
Stent area, mm2	5.28±1.83	4.79±2.12	0.20
Minimum stent diameter, mm	2.63±0.86	2.42±0.52	0.12
Mean stent diameter, mm	3.07±0.94	2.83±1.08	0.24
Mean stent area, mm2	6.93±2.28	6.16±2.58	0.11
Stent expansion index	0.85±0.21	0.78±0.22	0.16
Protrusion, n (%)
Smooth	52 (88)	44 (96)	0.31
Disrupted	35 (58)	30 (64)	0.71
Irregular	18 (30)	20 (43)	0.25
Stent edge dissection, n (%)
Distal edge	4 (7)	3 (6)	1.00
Proximal edge	8 (14)	6 (12)	1.00
Distal or proximal edge	10 (18)	8 (17)	1.00
Analyzed struts per lesion, n	189.98±96.59	203.86±97.58	0.46
Percentage of struts (%)
Embedded strut	22.93±20.06	23.12±23.44	0.96
Apposed strut	72.48±18.86	68.94±22.62	0.38
Malapposed strut	4.59±4.62	7.95±8.67	0.016
Maximum embedded distance, μm	161.02±109.65	186.94±117.62	0.24
Mean embedded distance, μm	40.10±23.78	46.22±24.29	0.19
Maximum malapposition distance, mm	281.82±154.53	379.53±244.61	0.027

Data are presented as mean±SD or n (%). DP-EES, durable-polymer everolimus-eluting stent; PCI, percutaneous coronary intervention; PF-BCS, polymer-free biolimus A9-coated stent.

Table 3. Optical Coherence Tomography Analysis Findings at 1 and 12 Months After Percutaneous Coronary Intervention

	1 month			12 months
	PF-BCS group	DP-EES group	P value	PF-BCS group	DP-EES group	P value
Analyzed stent length per lesion, mm	30.99±17.94	32.30±17.31	0.69	29.77±15.41	33.42±16.31	0.26
Minimum lumen area, mm2	5.16±2.05	4.75±2.34	0.32	3.96±1.89	4.07±2.08	0.77
Maximum lumen area, mm2	9.11±3.48	8.23±3.18	0.16	7.42±2.64	7.71±3.10	0.62
Mean lumen area, mm2	7.15±2.39	6.35±2.54	0.088	5.77±2.19	5.79±2.39	0.98
Minimum lumen diameter, mm	2.50±0.46	2.39±0.56	0.24	2.24±0.51	2.26±0.53	0.88
Maximum lumen diameter, mm	3.36±0.58	3.16±0.61	0.075	3.16±0.60	3.20±0.66	0.74
Mean lumen diameter, mm	2.95±0.48	2.77±0.55	0.075	2.70±0.50	2.71±0.55	0.93
Minimum stent area, mm2	5.46±1.99	5.05±2.24	0.31	5.04±1.92	4.71±2.04	0.41
Maximum stent area, mm2	9.04±3.03	7.87±3.08	0.045	8.49±2.58	8.03±2.85	0.41
Mean stent area, mm2	7.28±2.28	6.46±2.56	0.076	6.83±2.19	6.36±2.35	0.31
Minimum stent diameter, mm	2.59±0.46	2.47±0.55	0.23	2.52±0.46	2.42±0.51	0.35
Maximum stent diameter, mm	3.34±0.54	3.09±0.60	0.023	3.32±0.53	3.20±0.63	0.33
Mean stent diameter, mm	3.00±0.46	2.81±0.53	0.046	2.94±0.47	2.84±0.52	0.32
Mean reference lumen area, mm2	6.74±2.60	6.52±2.73	0.68	6.04±2.27	5.87±2.66	0.76
Distal reference lumen area, mm2	6.01±2.68	5.41±2.79	0.26	5.21±2.36	4.90±2.82	0.56
Proximal reference lumen area, mm2	7.53±3.16	7.77±3.30	0.71	6.81±2.72	6.97±3.03	0.80
Mean reference lumen diameter, mm	2.86±0.54	2.79±0.59	0.53	2.71±0.50	2.64±0.58	0.52
Distal reference lumen diameter, mm	2.69±0.60	2.54±0.65	0.21	2.53±0.57	2.40±0.67	0.32
Proximal reference lumen diameter, mm	3.03±0.61	3.07±0.67	0.80	2.88±0.57	2.91±0.60	0.86
Area stenosis, %	22.16±17.37	26.39±18.10	0.23	31.63±16.69	30.14±18.58	0.77
Analyzed struts per lesion, n	164.07±113.31	190.47±112.98	0.22	219.80±123.86	275.39±161.87	0.063
Percentage of struts
Covered strut	82.07±19.84	80.26±16.43	0.60	98.91±2.02	97.46±3.76	0.024
Adequate strut coverage	46.52±21.48	49.56±16.87	0.40	84.00±14.45	68.54±22.46	<0.001
Uncovered apposed strut	16.31±18.65	15.71±13.08	0.84	0.88±1.75	1.77±2.66	0.057
Uncovered malapposed strut	1.64±2.27	3.91±5.56	0.007	0.22±0.54	0.76±1.68	0.040
Maximum malapposition distance, mm	317.65±195.68	412.82±263.60	0.082	354.44±146.21	453.33±281.01	0.27
Maximum neointimal thickness, μm	228.20±129.85	230.38±102.66	0.92	485.49±200.12	330.65±140.28	<0.001
Mean neointimal thickness, μm	47.80±24.51	46.96±18.43	0.84	140.29±55.33	83.47±36.96	<0.001
Low signal pattern, %	67.01±35.11	39.68±35.59	<0.001	2.90±8.08	3.86±10.27	0.62
Homogeneous high signal pattern, %	32.99±35.11	61.13±35.67	<0.001	96.04±10.09	95.97±10.27	0.97
Neoatherosclerosis, n (%)	0 (0)	1 (2)	0.95	5 (10)	1 (2)	0.26
Abnormal intraluminal tissue, n (%)	10 (16)	3 (6)	0.13	1 (2)	1 (2)	1.00

Data are presented as mean±SD or n (%). DP-EES, durable polymer everolimus-eluting stent; PF-BCS, polymer-free biolimus A9-coated stent; –, not available.

Multivariate Analysis of the Impact of PF-BCS

The multivariate analysis adjusted for the covariates, such as the location of the target vessel, post-PCI reference vessel diameter, post-PCI minimum lumen diameter, stent diameter, stent implantation pressure, post-dilatation balloon diameter and the rates of embedded and malapposed struts immediately after PCI showed that PF-BCS had a positive impact on dominant, maximum, and minimum NIC grades and maximum yellow color grade at 12 months, although it had no impact on 1-month CAS findings and 12-month thrombus grade (Table 4). In terms of the OCT findings, it showed that PF-BCS had no impact on OCT findings at 1 month, except for the frequencies of neointima with low signal pattern and homogeneous high signal pattern. Meanwhile, although PF-BCS also had no impact on the covered strut rates, malapposed strut rates, maximum malapposition distance, maximum neointimal thickness, or qualitative neointimal characteristics at 12 months, it had an impact on the adequate strut coverage rate and mean neointimal thickness at 12 months (Table 4). Representative cases are shown in Figure 3.

Table 4. Univariate and Multivariate Analysis of the Impact of PF-BCS

CAS findings		1 month			12 months
		OR	95% CI	P value	OR	95% CI	P value
Thrombus grade	Univariate	1.216	0.515~2.870	0.66	0.638	0.244~1.672	0.36
	Multivariate	4.034	0.757~21.486	0.10	0.818	0.149~4.487	0.82
Dominant neointimal coverage grade	Univariate	1.267	0.572~2.804	0.56	4.070	1.883~8.799	<0.001
	Multivariate	0.498	0.125~1.985	0.32	8.577	2.445~30.084	<0.001
Maximum neointimal coverage grade	Univariate	1.882	0.845~4.192	0.12	4.972	2.224~11.118	<0.001
	Multivariate	0.491	0.127~1.897	0.30	11.434	2.857~45.752	<0.001
Minimum neointimal coverage grade	Univariate	0.847	0.202~3.563	0.82	5.068	1.862~13.799	0.001
	Multivariate	1.356	0.015~120.698	0.89	27.087	5.479~133.916	<0.001
Maximum yellow color grade	Univariate	0.993	0.502~1.963	0.98	0.290	0.133~0.635	0.002
	Multivariate	0.599	0.206~1.736	0.36	0.168	0.049~0.583	0.005
OCT findings		Coefficient	95% CI	P value	Coefficient	95% CI	P value
Covered strut	Univariate	1.803	−5.020~8.625	0.60	1.444	0.234~2.653	0.020
	Multivariate	4.110	−5.549~13.769	0.40	1.147	−0.305~2.598	0.12
Adequate strut coverage	Univariate	−3.035	−10.282~4.211	0.41	15.462	7.920~23.003	<0.001
	Multivariate	−1.068	−11.583~9.448	0.84	11.498	1.169~21.827	0.030
Malapposed strut	Univariate	−2.265	−3.805~−0.725	0.004	−0.546	−1.043~−0.050	0.031
	Multivariate	−1.467	−3.279~0.344	0.11	−0.294	−0.853~0.265	0.30
Maximum malapposition distance	Univariate	−95.173	−204.879~14.532	0.088	−98.889	−309.523~111.746	0.34
	Multivariate	4.325	−160.426~169.076	0.96	−167.193	−457.382~122.996	0.24
Maximum neointimal thickness	Univariate	−2.181	−46.087~41.726	0.92	154.838	84.455~225.221	<0.001
	Multivariate	−21.959	−84.910~40.991	0.49	76.233	−24.129~176.594	0.135
Mean neointimal thickness	Univariate	0.841	−7.307~8.989	0.84	56.820	37.636~76.004	<0.001
	Multivariate	−1.125	−13.099~10.849	0.85	43.476	15.484~71.468	0.003
Neointima with low signal pattern	Univariate	27.326	12.663~41.989	<0.001	−0.951	−4.659~2.756	0.61
	Multivariate	33.181	11.106~55.257	0.004	−3.879	−9.404~1.645	0.17
Neointima with homogeneous high signal pattern	Univariate	−28.136	−42.744~−13.529	<0.001	0.066	−4.042~4.174	0.97
	Multivariate	−34.804	−56.833~−12.775	0.002	3.549	−2.559~9.656	0.25
Neointima with neoatherosclerosis	Univariate	−0.389	−1.113~0.336	0.29	0.885	−0.208~1.978	0.11
	Multivariate	–	–	–	0.331	−1.314~1.975	0.69

CAS, coronary angioscopy; CI, confidence interval; OCT, optical coherence tomography; OR, odds ratio; PF-BCS, polymer-free biolimus A9-coated stent.

Figure 3.

Representative case. (A) Serial intravascular imaging findings after polymer-free biolimus A9-coated stent (PF-BCS) implantation. Percutaneous coronary intervention (PCI) was performed in the middle part of the left descending artery of male patient aged 73 years, who had an implantation of PF-BCS measuring 3.5 mm×14 mm. Final coronary angiography (CAG) shows an adequate angiographic result (a). Optical coherence tomography (OCT) shows adequate stent expansion with no stent malapposition (b–d). The 1- and 12-month follow-up assessments with OCT and coronary angioscopy (CAS) were performed at 28 and 332 days after the initial PCI, respectively. On the 1-month OCT, the covered strut, adequate strut coverage, and malapposed strut rates were 99.31%, 77.24%, and 0%, respectively (e–g). The 1-month CAS shows grade 3 yellow color and grade 0 dominant neointimal coverage (NIC) with a grade 2 thrombus (h–j). On the 12-month OCT, the covered strut, adequate strut coverage, and malapposed strut rates were 100%, 100%, and 0%, respectively (k–m). The 12-month CAS shows grade 0 yellow color and grade 3 dominant NIC without any thrombus (n–p). (B) Serial intravascular imaging findings after durable polymer everolimus-eluting stent (DP-EES) implantation. PCI was performed in the middle part of the left descending artery in a male patient aged 54 years, with the implantation of DP-EES measuring 3.0 mm×23 mm. Final CAG shows an adequate angiographic result (a). OCT shows adequate stent expansion with 6.86% of malapposed struts (b–d). The 1- and 12-month follow up with OCT and CAS were performed at 32 and 364 days after the initial PCI, respectively. On the 1-month OCT, the covered strut, adequate strut coverage, and malapposed strut rates were 77.14%, 60.00%, and 3.81%, respectively (e–g). The 1-month CAS shows grade 1 yellow color grade and grade 1 dominant NIC with a grade 2 thrombus (h–j). On the 12-month OCT, the covered strut, adequate strut coverage, and malapposed strut rates were 93.87%, 38.04%, and 1.84%, respectively (k–m). The 12-month CAS showed grade 0 yellow color and grade 1 dominant NIC with grade 1 thrombus (n–p). Red arrows indicate the presence of subclinical intrastent thrombus. Dashed light red line and dashed light blue line indicate the implantation sites of PF-BCS (3.5 mm×14 mm) and DP-EES (3.0 mm×23 mm), respectively.

Discussion

The vessel responses in the early and middle phases after PF-BCS deployment have not been clarified to date. In this study, we found the following results (Figure 4): first, at 1 month, CAS and OCT findings were similar between PF-BCS and DP-EES groups, except for the malapposed strut rate. Second, at 12 months, although the incidence of sub-clinical intrastent thrombus was similar, the NIC grade was significantly higher and the yellow color grade was significantly lower on CAS in PF-BCS than in DP-EES. Further, the covered strut and adequate strut coverage rates on OCT were significantly higher, and neointimal thickness was significantly thicker in PF-BCS, whereas the malapposed strut rate was higher in DP-EES. Third, after adjusting for the covariates, PF-BCS influenced NIC grade and maximum color grade at 12 months on CAS, and the adequate strut coverage rate and mean neointimal thickness at 12 months on OCT.

Figure 4.

Central Illustration. In both groups, the incidence of thrombus was initially increased but then decreased, with no significant difference between the polymer-free biolimus A9-coated stent (PF-BCS) and durable polymer everolimus-eluting stent (DP-EES) groups at 1 (100% vs. 93%, P=0.091) and 12 (18% vs. 25%, P=0.56) months. The thrombus grades at 1 and 12 months were similar between the groups; however, although the adequate strut coverage rate was similar at 1 month, it was significantly higher in the PF-BCS group at 12 months. Further, the yellow color grade on CAS was significantly lower in the PF-BCS group. NIH, neointimal hyperplasia.

Subclinical intrastent thrombus was detected in almost all stents at 1 month, and the incidence decreased to approximately 20% in both stents at 12 months. The initial phase of arterial healing after stent implantation involves thrombus adhesion.⁸ However, the presence of an intrastent thrombus 9 months after first-generation DES implantation is an independent predictor of endothelial dysfunction.¹¹ Furthermore, intrastent thrombus detected 9 months after second-generation DES is significantly associated with future major adverse events.²⁴ In this study, we additionally compared the 12-month OCT findings between lesions with and without subclinical intrastent thrombus. The adequate strut coverage rate, which is an indicator of better arterial healing, was lower in lesions with subclinical intrastent thrombus than in those without (60.51±24.40% vs. 81.58±15.97%, P=0.002), whereas the incidence of neoatherosclerosis, which is an abnormal vascular response,²⁵ was similar between lesions with and without subclinical intrastent thrombus (6% vs. 7%, P=1.00). These findings indicate that subclinical intrastent thrombus, which is detected in most DES patients at 1 month after implantation, is an initial sign of arterial healing and not an undesirable finding. Further, intrastent thrombus (detected approximately 12 months after implantation) is a marker of poor re-endothelialization and a sign of future adverse events. Thus, subclinical intrastent thrombus at 12 months is not indicative of an abnormal vascular response, but rather of delayed arterial healing.²⁵ In our study, the incidence of intrastent thrombus was similar for PF-BCS and DP-EES, indicating a similar arterial healing status and thrombogenicity for both.

Jinnouchi et al reported that neointimal thickness ≥40 μm on OCT is the most accurate cut-off value for identifying healthy strut coverage, which was defined as luminal endothelial cells with 2 abluminal layers of smooth muscles cells and a matrix.⁸ In this study, although neointimal thickness was similar and <50% in both stents at 1 month, the adequate strut coverage rate (≥40 μm) was significantly higher for PF-BCS than for DP-EES at 12 months. PF-BCS has a stainless steel platform with strut thickness of 112–120 μm and a micro-structured abluminal surface to optimize drug delivery. Drug-dose is 15.6 μg BA9/mm stent lengths. This enables drug-to-vessel wall tissue to transfer from the stent to be complete within 28 days of treatment leaving the implant behind as a BMS.^6,26 In contrast, DP-EES consists of the cobalt chromium platform with a durable polymer and 100 µg/cm² everolimus, a synthetic derivative of sirolimus (40-O-[2-hydroxyethyl]-rapamycin). The 6- to 8-µm-thick polymer is composed of acrylic and fluorinated polymers and releases ~80% of the drug within 30 days, with nearly all the drug released within 4 months.⁹ The main differences between the 2 stents are the elution period of the drug and the absence or presence of the polymer. Smooth muscle cell proliferation would progress 1 month after PF-BCS implantation because it becomes almost similar to a BMS, which would have resulted in better arterial healing.

The STOPDAPT-2 Randomized Clinical Trial demonstrated that 1-month DAPT has superior efficacy and safety compared to 12-month DAPT in patients treated with DP-EES.²⁷ This finding indicates that 1-month DAPT is adequate for preventing ST, suggesting adequate arterial healing, even during the early phase. However, arterial healing continues after 1 month, as evidenced by the identification of intrastent thrombus on CAS in almost all stents. Further, the adequate strut coverage rate on OCT did not reach 50%. In addition, pathologically, re-endothelialization extends beyond 1 month after PF-BCS or DP-EES implantation.⁸ There is a discrepancy between the clinical trial and intravascular imaging or pathological findings. Some struts do not get embedded adequately immediately after PCI, and some protrude into the lumen. Although high endothelial shear stress is created on top of the struts, resulting in platelet activation, the flow reversal that creates low endothelial shear stress causes local aggregation of activated platelet and promotes the thrombogenic process behind the protruding strut.²⁸ Then, when the strut is covered by some tissue, the protruding part decreases, resulting in low thrombogenicity. In this study, approximately 80% of the struts were covered by some tissue at 1 month in both PF-BCS and DP-EES, contributing to decreased thrombogenicity, and the stented segment could thus have adequate intravascular status to prevent ST. As a result, even without complete re-endothelialization, PF-BCS and DP-EES can achieve an adequate intravascular status to prevent ST with single antiplatelet therapy; this would contribute to good clinical outcomes with 1-month of DAPT. However, judging from an approximately 100% rate of intrastent thrombus and only about half of the rate of adequate strut coverage at 1 month, caution should be used when adopting an ultra-short DAPT strategy for all patients.

This study has some limitations. First, the possibility of selection bias could not be ruled out because of the prospective observational design. Second, the whole stented segment could not be completely evaluated on CAS in some cases because of limitations in the visual field, especially in angulated or tortuous lesions. However, in such cases, changing the guidewire sometimes improved the visual field. Third, the qualitative definitions of tissue structure and tissue backscatter have some limitations, as these are influenced by the intima thickness and the position of the OCT catheter relative to the vessel wall. Fourth, morphological evaluation was impossible due to the poor quality of OCT images in some lesions. Fifth, although PF-BCS did not influence OCT-neoatherosclerosis after the multivariate analysis, the incidence of OCT-neoatherosclerosis was numerically higher in PF-BCS than in DP-EES. Further investigations are necessary to elucidate the impact of OCT-neoatherosclerosis on future clinical outcomes. Sixth, although TLR occurred only in the PF-BCS group, the sample size was relatively small, and it was impossible to execute statistical calibration for TLR. However, the result was considerable issue, and one of the causes would be the relatively thicker strut (112–120 μm) of PF-BCS because the thicker struts elicited higher thrombogenicity leading to more restenosis and worse clinical outcomes.^29–31 This issue may be overcome by the novel thin-strut (84–88 μm) cobalt chromium PF-BCS,²⁶ and further investigation for the novel thin-strut PF-BCS would be necessary. Finally, the impact of the combination of CAS and OCT findings on future adverse events is unknown, and further clinical follow ups are necessary to elucidate these issues.

Conclusions

Although PF-BCS had similar thrombogenicity compared to DP-EES at 1 and 12 months, it achieved superior adequate strut coverage and plaque stabilization at 12 months. Considering the 100% intrastent thrombus rate and the approximate 50% rate of adequate strut coverage at 1 month, caution should be used when adopting an ultra-short DAPT strategy for all patients.

Acknowledgments

We wish to thank Drs. Taku Toyoshima, Naoko Higashino, and Sho Nakao for their expertise in data collection; Mr. Naoya Kurata, Mr. Takashi Sumikawa, Mr. Hiroki Oyama, Mr. Kazutoshi Ito, Mr. Yusuke Katagiri, Mr. Kohei Nanri, and Ms. Haruna Miyaguchi for their expertise in performing CAS and OCT examinations; Mr. Yuji Kiyose, Mr. Tomohiro Yamanaka, Dr. Bolrathanak Oeun, and Dr. Kazuya Shinouchi for their expertise in OCT analysis; and Ms. Saori Kashu and Ms. Akiko Abe for their expertise in data aggregation.

Sources of Funding

This study was supported by Abbot Medical Japan, Cardinal Health Japan, Taisho Biomed Instruments Co., Ltd., and Biosensors Japan.

Disclosures

I.M. has received a scholarship fund from Abbott Medical Japan. T.M. has received a research grant from Abbott Medical Japan. Y.S. has received a scholarship fund from Abbott Medical Japan.

T.U. and Y.S. are members of Circulation Journal’s Editorial Team.

IRB Information

This study was approved by the Medical Ethics Committees of Osaka University Graduate School of Medicine (approval number 18049).

Data Availability

Our study data will not be made available to other researchers for purposes of reproducing the results because of institutional review board restrictions.

Supplementary Files

Please find supplementary file(s);

http://dx.doi.org/10.1253/circj.CJ-22-0098

References

• 1.   Morice MC, Serruys PW, Sousa JE, Fajadet J, Ban Hayashi E, Perin M, et al. A randomized comparison of a sirolimus-eluting stent with a standard stent for coronary revascularization. N Engl J Med 2002; 346: 1773–1780.
• 2.   McFadden EP, Stabile E, Regar E, Cheneau E, Ong AT, Kinnaird T, et al. Late thrombosis in drug-eluting coronary stents after discontinuation of antiplatelet therapy. Lancet 2004; 364: 1519–1521.
• 3.   Levine GN, Bates ER, Bittl JA, Brindis RG, Fihn SD, Fleisher LA, et al. 2016 ACC/AHA guideline focused update on duration of dual antiplatelet therapy in patients with coronary artery disease: A report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines: An update of the 2011 ACCF/AHA/SCAI guideline for percutaneous coronary intervention, 2011 ACCF/AHA guideline for coronary artery bypass graft surgery, 2012 ACC/AHA/ACP/AATS/PCNA/SCAI/STS guideline for the diagnosis and management of patients with stable ischemic heart disease, 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction, 2014 AHA/ACC guideline for the management of patients with non-ST-elevation acute coronary syndromes, and 2014 ACC/AHA guideline on perioperative cardiovascular evaluation and management of patients undergoing noncardiac surgery. Circulation 2016; 134: e123–e155.
• 4.   Valgimigli M, Bueno H, Byrne RA, Collet JP, Costa F, Jeppsson A, et al. 2017 ESC focused update on dual antiplatelet therapy in coronary artery disease developed in collaboration with EACTS: The Task Force for dual antiplatelet therapy in coronary artery disease of the European Society of Cardiology (ESC) and of the European Association for Cardio-Thoracic Surgery (EACTS). Eur Heart J 2018; 39: 213–260.
• 5.   Nakamura M, Kimura K, Kimura T, Ishihara M, Otsuka F, Kozuma K, et al. JCS 2020 guideline focused update on antithrombotic therapy in patients with coronary artery disease. Circ J 2020; 84: 831–865.
• 6.   Tada N, Virmani R, Grant G, Bartlett L, Black A, Clavijo C, et al. Polymer-free biolimus a9-coated stent demonstrates more sustained intimal inhibition, improved healing, and reduced inflammation compared with a polymer-coated sirolimus-eluting cypher stent in a porcine model. Circ Cardiovasc Interv 2010; 3: 174–183.
• 7.   Urban P, Meredith IT, Abizaid A, Pocock SJ, Carrié D, Naber C, et al. Polymer-free drug-coated coronary stents in patients at high bleeding risk. N Engl J Med 2015; 373: 2038–2047.
• 8.   Jinnouchi H, Otsuka F, Sato Y, Bhoite RR, Sakamoto A, Torii S, et al. Healthy strut coverage after coronary stent implantation: An ex vivo human autopsy study. Circ Cardiovasc Interv 2020; 13: e008869.
• 9.   Garg S, Serruys PW. Coronary stents: Current status. J Am Coll Cardiol 2010; 56: S1–S42.
• 10.   Eisenstein EL, Leon MB, Kandzari DE, Mauri L, Edwards R, Kong DF, et al. Long-term clinical and economic analysis of the Endeavor zotarolimus-eluting stent versus the cypher sirolimus-eluting stent: 3-year results from the ENDEAVOR III trial (Randomized controlled trial of the Medtronic Endeavor drug [ABT-578] eluting coronary stent system versus the cypher sirolimus-eluting coronary stent system in de novo native coronary artery lesions). JACC Cardiovasc Interv 2009; 2: 1199–1207.
• 11.   Mitsutake Y, Ueno T, Yokoyama S, Sasaki K, Sugi Y, Toyama Y, et al. Coronary endothelial dysfunction distal to stent of first-generation drug-eluting stents. J Am Coll Cardiol Intv 2012; 5: 966–973.
• 12.   Awata M, Kotani J, Uematsu M, Morozumi T, Watanabe T, Onishi T, et al. Serial angioscopic evidence of incomplete neointimal coverage after sirolimus-eluting stent implantation: Comparison with bare-metal stents. Circulation 2007; 116: 910–916.
• 13.   Ishihara T, Awata T, Sera F, Fujita M, Watanabe T, Iida O, et al. Arterial repair 4 months after zotarolimus-eluting stent implantation observed on angioscopy. Circ J 2013; 77: 1186–1192.
• 14.   Dai K, Matsuoka H, Kawakami H, Sato T, Watanabe K, Nakama Y, et al. Comparison of chronic angioscopic findings of bare metal stents, 1st-generation drug-eluting stents and 2nd-generation drug-eluting stents: Multicenter study of intra-coronary angioscopy after stent (MICASA). Circ J 2016; 80: 1916–1921.
• 15.   Suzuki N, Asano T, Nakazawa G, Aoki J, Tanabe K, Hibi K, et al. Clinical expert consensus document on quantitative coronary angiography from the Japanese Association of Cardiovascular Intervention and Therapeutics. Cardiovasc Interv Ther 2020; 35: 105–116.
• 16.   Kotani J, Awata M, Nanto S, Uematsu M, Oshima F, Minamiguchi H, et al. Incomplete neointimal coverage of sirolimus-eluting stents: Angioscopic findings. J Am Coll Cardiol 2006; 47: 2108–2111.
• 17.   Ishihara T, Tsujimura T, Okuno S, Iida O, Asai M, Masuda M, et al. Early- and middle-phase arterial repair following bioresorbable- and durable-polymer drug-eluting stent implantation: An angioscopic study. Int J Cardiol 2019; 285: 27–31.
• 18.   Mitsutake Y, Yano H, Ishihara T, Matsuoka H, Ueda Y, Ueno T. Consensus document on the standard of coronary angioscopy examination and assessment from the Japanese Association of Cardiovascular Intervention and Therapeutics. Cardiovasc Interv Ther 2022; 37: 35–39.
• 19.   Saito S, Krucoff MW, Nakamura S, Mehran R, Maehara A, Al-Khalidi HR, et al. Japan-United States of America harmonized assessment by randomized multicentre study of OrbusNEich’s Combo StEnt (Japan-USA HARMONEE) study: Primary results of the pivotal registration study of combined endothelial progenitor cell capture and drug-eluting stent in patients with ischaemic coronary disease and non-ST-elevation acute coronary syndrome. Eur Heart J 2018; 39: 2460–2468.
• 20.   Tada T, Kadota K, Hosogi S, Miyake K, Amano H, Nakamura M, et al. Association between tissue characteristics evaluated with optical coherence tomography and mid-term results after paclitaxel-coated balloon dilatation for in-stent restenosis lesions: A comparison with plain old balloon angioplasty. Eur Heart J Cardiovasc Imaging 2014; 15: 307–315.
• 21.   Nakamura D, Attizzani GF, Toma C, Sheth T, Wang W, Soud M, et al. Failure mechanisms and neoatherosclerosis patterns in very late drug eluting and bare-metal stent thrombosis. Circ Cardiovasc Interv 2016; 9: e003785.
• 22.   Nakamura D, Lee Y, Yoshimura T, Taniike M, Makino N, Kato H, et al. Different serial changes in the neointimal condition of sirolimus-eluting stents and paclitaxel-eluting stents: An optical coherence tomographic study. EuroIntervention 2014; 10: 924–933.
• 23.   Nakamura D, Dohi T, Ishihara T, Kikuchi A, Mori N, Yokoi K, et al. Predictors and outcomes of neoatherosclerosis in patients with in-stent restenosis. EuroIntervention 2020; 17: 489–496.
• 24.   Okuno S, Ishihara T, Iida O, Asai M, Masuda M, Okamoto S, et al. Association of subclinical intrastent thrombus detected 9 months after implantation of 2nd-generation drug-eluting stent with future major adverse cardiac events: A coronary angioscopic study. Circ J 2018; 82: 2299–2304.
• 25.   Nakazawa G. Stent thrombosis of drug eluting stent: Pathological perspective. J Cardiol 2011; 58: 84–91.
• 26.   Sabaté M, Okkels Jensen L, Tilsted HH, Moreno R, García Del Blanco B, Macaya C, et al. Thin- versus thick-strut polymer-free biolimus-eluting stents: The BioFreedom QCA randomised trial. EuroIntervention 2021; 17: 233–239.
• 27.   Watanabe H, Domei T, Morimoto T, Natsuaki M, Shiomi H, Toyota T, et al. Effect of 1-month dual antiplatelet therapy followed by clopidogrel vs 12-month dual antiplatelet therapy on cardiovascular and bleeding events in patients receiving PCI: The STOPDAPT-2 Randomized Clinical Trial. JAMA 2019; 321: 2414–2427.
• 28.   Serruys PW, Suwannasom P, Nakatani S, Onuma Y. Snowshoe versus ice skate for scaffolding of disrupted vessel wall. J Am Coll Cardiol Intv 2015; 8: 910–913.
• 29.   Kolandaivelu K, Swaminathan R, Gibson WJ, Kolachalama VB, Nguyen-Ehrenreich KL, Giddings VL, et al. Stent thrombogenicity early in high-risk interventional settings is driven by stent design and deployment and protected by polymer-drug coatings. Circulation 2011; 123: 1400–1409.
• 30.   Pache J, Kastrati A, Mehilli J, Schühlen H, Dotzer F, Hausleiter J, et al. Intracoronary stenting and angiographic results: Strut thickness effect on restenosis outcome (ISAR-STEREO-2) trial. J Am Coll Cardiol 2003; 41: 1283–1288.
• 31.   Madhavan MV, Howard JP, Naqvi A, Ben-Yehuda O, Redfors B, Prasad M, et al. Long-term follow-up after ultrathin vs. conventional 2nd-generation drug-eluting stents: A systematic review and meta-analysis of randomized controlled trials. Eur Heart J 2021; 42: 2643–2654.