Edge Vascular Response After Resorption of the Everolimus-Eluting Bioresorbable Vascular Scaffold　– A 5-Year Serial Optical Coherence Tomography Study –

Abstract

Background: The edge vascular response (EVR) has been linked to important prognostic implications in patients treated with permanent metallic stents. We aimed to investigate the relationship of EVR with the geometric changes in the everolimus-eluting bioresorbable scaffold using serial optical coherence tomography (OCT) analysis.

Methods and Results: In the first-in-man ABSORB trial, 28 patients (29 lesions) underwent serial OCT at 4 different time points (Cohort B1: post-procedure, 6, 24, and 60 months [n=13]; Cohort B2: post-procedure, 12, 36, and 60 months [n=15]) following implantation of the scaffold. In Cohort B1, there was no significant luminal change at the distal or proximal edge segment throughout the entire follow-up. In contrast, there was a significant reduction of the lumen flow area (LFA) of the scaffold between post-procedure and 6 months (−1.03±0.49 mm² [P<0.001]), whereas between 6 and 60 months the LFA remained stable (+0.31±1.00 mm² [P=0.293]). In Cohort B2, there was a significant luminal reduction of the proximal edge between post-procedure and 12 months (−0.57±0.74 mm² [P=0.017]), whereas the lumen area remained stable (−0.26±1.22 mm² [P=0.462]) between 12 and 60 months. The scaffold LFA showed a change similar to that observed in Cohort B1.

Conclusions: Our study demonstrated a reduction in the scaffold luminal area in the absence of major EVR, suggesting that the physiological continuity of the lumen contour is restored long term. (Circ J 2016; 80: 1131–1141)

The advent of the metallic stent has been a major breakthrough in the treatment of patients with ischemic coronary artery disease. In the era of the bare-metal stent (BMS), the edge vascular response (EVR) was defined as a reduction in the lumen area mainly from an increase in plaque/media and lumen area within the first 1–2 mm of the device.^1,2 In the era of radioactive stents, EVR became a more prominent effect.³ In the drug-eluting stent (DES) era, although several studies have demonstrated effective inhibition of neointimal hyperplasia, the EVR was mostly focal and located at the proximal stent edge.^4–7 The rigidity of the metal encaging the vessel can potentially lead to a life-long loss of pulsatility and distensibility of the coronary arterial wall in the stented segment and a compliance mismatch between the stented and adjacent segments of the vessel. In the bioresorbable scaffold (BRS) era, a variety of polymers with different chemical compositions, mechanical properties, and bioresorption duration became available. The polymer most frequently used is poly-L-lactide (PLLA).⁸ After completion of the bioresorption process, the struts become integrated into the surrounding vessel wall,^9,10 and the strut voids are no longer visible on optical coherence tomography (OCT) at 5 years after implantation.¹¹ Our group has previously demonstrated no major changes in lumen area at both the distal and proximal edges of the scaffold at 6 months using intravascular ultrasound (IVUS) analysis. However, at long-term follow-up (1 and 2 years), especially at the proximal edge, there was a slight but statistically significant lumen loss (LL) without any significant change in the lumen area of the distal edge.^12,13

Editorial p 1100

The aim of the present study was to describe the EVR and its relationship with the scaffold throughout the entire follow-up period of 60 months using serial OCT analysis.

Methods

Study Design and Study Device

The ABSORB Cohort B trial (clinicaltrials.gov NCT00856856, Study Sponsor Abbott Vascular) is a non-randomized, multicenter, single-arm prospective, open-label trial that included 101 patients (102 lesions) treated with the 2nd-generation Absorb scaffold. The first 45 patients (Cohort B1) underwent intravascular imaging follow-up with OCT at 6, 24, and 60 months, whereas the other 56 patients (B2) underwent the same at 12, 36, and 60 months follow-up.

The Absorb scaffold (Abbott Vascular, Santa Clara, CA, USA) consists of a PLLA scaffold, a coating layer of poly-D,L-lactide (PDLLA) and the antiproliferative drug everolimus, a pair of radiopaque platinum markers at the proximal and distal ends of the scaffold, and a balloon catheter delivery system.¹⁴ The details of the study and treatment procedure have been previously described.^15–18

OCT Image Acquisition

Over the past 5 years OCT techniques have evolved. OCT acquisition in this study was performed using 4 different commercially available systems: the M2 and M3 Time-Domain Systems and the C7 and C8 Fourier-Domain Systems (LightLab Imaging, Westford, MA, USA). OCT images were acquired at a frame rate of 15.6, 20, 100, 180 frames/s with a pullback speed of 2, 3, 20, 18 mm/s in the M2 (n=11), M3 (n=11), C7 (n=174), and C8 (n=39), respectively. All image acquisition was performed according to the recommended procedure for each OCT system.¹⁹ None of the OCT images was acquired with the occlusion technique.^16–18 If the 5-mm edge segment had a side branch with an ostium diameter ≥1.5 mm, the analysis included only those frames between the scaffold margin and the ostium of the side branch. If the ostium diameter of the side branch was less than 1.5 mm, the frames at the ostium of the side branch were excluded. In addition, we excluded subjects who required a bailout stent, subjects with a scaffold implantation adjacent to a previously deployed stent, subjects in whom the edge segment was not fully documented, and frames with insufficient assessment of the entire lumen circumference because of inadequate blood clearance, air bubbles or contrast filling the extremity of the OCT catheter.²⁰

OCT Data Analysis

The OCT images acquired post-procedure and at follow-up were analyzed off-line, using proprietary LightLab software (St. Jude Medical Inc, MA, USA) and Q-IVUS 3.0 (Medis Medical Imaging systems, Leiden, The Netherlands). Truly serial OCT data were used in patients who underwent OCT examinations at all 4 time points. Lumen flow area (LFA) of the scaffold segment and the 5-mm segments adjacent to both edges were analyzed at 1-mm intervals by an independent core laboratory (Cardialysis, Rotterdam, The Netherlands). Adjusting for the pullback speed, the analysis of continuous cross-sections was performed at each 1-mm longitudinal interval.^16–18

As a specific additional approach, frame-by-frame analyses were performed for the 5-mm edge segment and the transitional region between the edge and scaffold segment. The transitional region was defined as a 4-mm region including both the 2 mm of the lumen vessel adjacent to the scaffold edge and the 2-mm margins of the scaffold. The LFA (ie, the effective lumen filled by circulating blood) was defined as the lumen area minus the strut area.^16,21 At follow-up, LFA was equal to the lumen area if no malapposed struts were found. Details of the LFA measurements have been previously described.²¹

Definition of the Scaffolded Segment

At 3 years, most of the scaffold struts remained visible as a black core, so the scaffold edges were defined as the first and last cross-sections with circumferentially visible struts.¹³ At 5 years, the struts are no longer visible, so only the platinum marker was visualized as evidence and location of the bioresorbed scaffold. However, in a few patients visualization of the marker was masked by the guidewire shadow. Furthermore, poor image acquisition because of inadequate blood clearance, contrast filling the OCT catheter, artifact from tangential signal drop out, or other reflective structures (eg, mineralization) was a limiting factor. Accordingly, in the present study localization of the edges of the scaffold was performed as follows: (1) when both the proximal and distal markers could be identified, the scaffold segment was defined as the segment between the first cross-section of the distal marker and the last cross-section of the proximal marker; (2) when the marker could not be clearly identified, we used anatomical landmarks on previous OCT images and another imaging modality, such as coronary angiography or IVUS, to localize the edge of the bioresorbed body of the scaffold; (3) when the marker could be identified only on one side, the scaffold length (18 mm) was used to assume the localization of the other edge of the scaffold.

IVUS Greyscale Analysis

Treated vessels post-procedure were examined with phased array IVUS catheters (EagleEye^TM; Volcano Corporation, Rancho Cordova, CA, USA) using a pullback speed of 0.5 mm/s.^16–18,22 The region of interest, beginning 5 mm distal to and extending 5 mm proximal to the treated segment, was examined. Lumen area, vessel area, plaque burden at the edge segment, and significant residual reference segment stenosis,²³ defined as a reference minimum lumen (CSA <4 mm²) plus plaque burden <70%, are shown in Table 1.

Table 1. Lesion Characteristics and Procedural Parameters at the Lesion Level in Patients With Serial OCT Analysis

Variable	B1+B2 (n=29)	B1 (n=13)	B2 (n=16)	P value (B1 vs. B2)
Target-lesion vessel (LAD/LCx/RCA)	15/6/8	6/4/3	9/2/5	0.87
AHA classification (A/B1/B2/C)	0/20/8/0	0/10/3/0	0/10/5/0	0.56
Stent implantation
Scaffold size diameter, mm	3.0	3.0	3.0	–
Scaffold inflation pressure, atm	13.17±2.90	14.15±2.51	12.37±3.03	0.51
Expected scaffold diameter, mm	3.30±0.11	3.32±0.90	3.26±0.13	0.40
Expected scaffold area, mm2	8.58±0.55	8.67±0.47	8.38±0.65	0.41
Post-dilatation
Balloon dilatation after device implantation, n (%)	19/29 (65.5)	9/13 (69.2)	10/16 (62.5)	0.71
Maximal diameter of post-dilatation balloon (nominal pressure), mm	3.18±0.19	3.22±0.23	3.15±0.17	0.49
Post-dilatation balloon area (nominal pressure), mm2	7.98±0.82	8.31±0.90	7.61±0.64	0.09
Length of post-dilatation balloon inflation, mm	11.70±3.13	11.22±3.11	12.09±3.23	0.55
Maximal post-dilatation balloon inflation, atm	17.79±5.32	18.00±6.00	17.60±4.95	0.86
No. of inflations performed	2.26±2.00	2.22±1.99	2.44±2.19	0.94
Ratio of post-dilatation balloon nominal diameter to nominal stent diameter	1.06±0.05	1.08±0.06	1.04±0.04	0.09
Scaffold-artery ratio on postprocedural OCT
Ratio of nominal scaffold diameter to mean reference diameter	1.10±0.14	1.11±0.17	1.10±0.11	0.77
Ratio of post-dilatation balloon nominal diameter to mean reference diameter	1.16±0.13	1.20±0.16	1.14±0.09	0.27
Ratio of expected scaffold diameter according to dilatation pressure to mean reference diameter	1.21±0.15	1.22±0.15	1.20±0.10	0.56
Postprocedural OCT findings
Mean reference lumen area, mm2	6.20±1.65	6.14±2.06	6.31±1.51	0.71
Mean reference diameter, mm	2.76±0.34	2.77±0.43	2.75±0.27	0.94
Mean scaffold area, mm2	7.56±0.98	7.59±1.38	7.66±0.91	0.79
Minimal scaffold area, mm2	6.19±0.93	6.23±1.28	6.33±0.76	0.72
Expansion index	1.04±0.21	1.05±0.16	1.04±0.20	0.74
Percentage of residual area stenosis (%RAS)	−4.16±21.20	−5.35±16.06	−3.80±19.95	0.73
Edge segment after procedure
Proximal non-flow-limiting edge dissection, number (%)	7/26 (26.9)	2/10 (20.0)	5/16 (31.3)	0.53
Distal non-flow-limiting edge dissection, number (%)	6/27 (22.2)	3/13 (23.1)	3/14 (21.4)	0.92
2-mm scaffold margin after procedure
Proximal intra-scaffold dissection, n (%)	8/29 (27.6)	3/13 (23.1)	5/16 (31.3)	0.62
Distal intra-scaffold dissection, n (%)	3/28 (10.7)	0/13	3/15 (20.0)	0.09
Proximal intra-scaffold thrombus, n (%)	3/29 (10.3)	1/13 (7.7)	2/16 (12.5)	0.67
Distal intra-scaffold thrombus, n (%)	2/28 (7.1)	1/13 (7.7)	1/15 (6.7)	0.92
Tissue prolapse at proximal 2-mm margin of scaffold, n (%)	22/29 (75.9)	11/13 (84.6)	11/16 (75.9)	0.32
Tissue prolapse at distal 2-mm margin of scaffold, n (%)	23/28 (82.1)	12/15 (80.0)	11/13 (84.6)	0.75
Greyscale IVUS findings at the reference segment
Proximal mean reference lumen area, mm2	7.55±2.10	7.62±2.64	7.50±1.66	0.89
Distal mean reference lumen area, mm2	6.37±1.36	5.98±0.98	6.64±1.56	0.28
Proximal mean vessel area, mm2	14.15±3.48	14.03±4.64	14.24±2.41	0.89
Distal mean vessel area, mm2	11.10±3.51	10.26±3.78	11.69±3.33	0.36
Residual plaque burden at proximal edge segment, %	46.05±10.26	44.65±11.93	47.16±9.06	0.56
Residual plaque burden at distal edge segment, %	38.83±17.40	36.66±18.46	40.34±17.22	0.64
Significant residual stenosis at the proximal edge segment, n (%)	1/23 (4.3)	1/11 (9.1)	0	–
Significant residual stenosis at the distal edge segment, n (%)	1/22 (4.5)	0	1/13 (7.7)	–

IVUS, intravascular ultrasound; LAD, left anterior descending; LCx, left circumflex artery; OCT, optical coherence tomography; RCA, right coronary artery.

Assessment of Procedural Performance and Postprocedural Findings on OCT

According to the IVUS-MUSIC criteria,²⁴ we calculated the expansion index (=minimum scaffold area/reference lumen area), the percentage of residual area stenosis (%RAS: =[reference lumen area-minimum scaffold area]/reference lumen area×100), and the scaffold-artery ratio (the ratio of nominal scaffold diameter to the mean reference diameter, the ratio of the post-dilatation balloon nominal diameter to the mean reference diameter, and the ratio of expected scaffold diameter from pressure to mean reference diameter). The procedural details are summarized in Table 1 and the adequacy of expansion was evaluated based on the MUSIC criteria.

The frequency of non-flow-limiting edge dissection, which was identified on postprocedural OCT, is shown in Table 1, as well as intra-scaffold dissection, tissue protrusion, and thrombus, which were identified in the 2-mm margin of the scaffold segment in accordance with previous reports.^25,26

Statistical Analysis

Continuous variables are presented as mean±standard deviation (SD) or median and interquartile range. Normality of the data was determined with the Shapiro-Wilk test and verified by histogram. For the overall assessment, Wilcoxon signed-rank test adjusted by the Bonferroni correction was used to compare EVR within groups at different time points, while for the truly serial follow-up assessment, paired t-test or Wilcoxon signed-rank test was used to compare EVR within groups at different time points without adjustment. A P-value <0.05 was considered statistically significant. All statistical analyses were performed with IBM SPSS Statistics 22 (IBM Co, NY, USA) and MedCalc (ver. 14.12.0, MedCalc Software, Ostend, Belgium).

Results

Study Population and OCT Image Acquisition

A total of 235 OCT pullbacks were analyzed in 90 patients (Cohort B1: 40 patients, 40 lesions; Cohort B2: 50 patients, 51 lesions). At 5-year follow-up, OCT was performed in 52 patients (53 lesions) [Cohort B1: 22 patients (22 lesions); Cohort B2: 30 patients (31 lesions)] (Figures S1A,B). According to the criteria described in the Methods section, we excluded a total of 14 distal edges and 15 proximal edges for the following reasons: 4 edges were not documented on the pullback; 2 edges had overlap with a previously deployed DES; 4 edges had been treated with bailout DES deployment; 1 edge because of DES overlapping the scaffold segment for target lesion revascularization (TLR), and the remaining 18 edges because of a large side branch (≥1.5 mm), insufficient assessment of the entire lumen, or inadequate contrast clearance.

During the 5-year follow-up, of the entire cohort of 101 patients, 11 patients underwent TLR, and 1 of them underwent TLR twice during the entire follow-up. Of these 11 patients (12 TLR), only 3 patients had preprocedural OCT images and were noted to have TLR for edge restenosis (2 proximal, 1 distal). These 3 cases were excluded and thus the study reports exclusively the evolution of the edges in patients who had an uneventful follow-up.

Over the entire follow-up period, 13 patients (13 lesions) of Cohort B1 and 15 patients (16 lesions) of Cohort B2 had serial OCT follow-up images (Figures S2A,B).

Assessment of Procedural Performance on Postprocedural OCT

The scaffold-artery ratio, which indicates the adequate and appropriate ratio for optimal scaffold expansion, was 1.10±0.14 for the ratio of nominal scaffold diameter to the mean reference diameter, and 1.16±0.13 for the ratio of the post-dilatation balloon nominal diameter to the mean reference diameter (Table 1).

Table 1 shows the procedural details and OCT performance parameters that were used to evaluate the stent expansion and scaffold-artery ratio. The expansion index was 1.04±0.21 and the %RAS was −4.16±21.20, suggesting that optimal scaffold expansion was achieved in this population.

Edge dissections were identified at the proximal edge segment (26.9%), and at the distal edge segment (22.2%) immediately post-procedure. Tissue prolapse was identified in most of the lesions; however, there was no more than 500 μm of tissue prolapse (data not shown). Greyscale IVUS analysis showed no large plaque burden of the edge segment (proximal: 46.05±10.26%, distal: 38.83±17.40%). Only 1 significant residual stenosis at the proximal edge segment and 1 significant residual stenosis at the distal edge segment were identified.

Change in the LFA of the Scaffold Segment

Figure 1A shows the LFA of the entire scaffold segment as well as the proximal and distal 5-mm edges. The 4 time points are illustrated by the different lines: the black line illustrates the postprocedural contour of the edge and scaffold, which is over-expanded with respect to the edge with a “step-up” and a “step down” at the site of the scaffold implantation. The major change in the first 12 months was a reduction in flow area without any further change in the luminal dimensions after 12 months, so the LFA curves of 12, 36, and 60 months are more or less superimposed in Figure 1A. Figure 1B shows similar profile for the patients who had serial OCT at 6, 24, and 60 months.

Figure 1.

Mean values of the lumen area of the target segment with every 1-mm analysis. Lumen area of the entire scaffold segment as well as the proximal and distal 5-mm edges. The 4 time points are illustrated by lines of different colors. (A) Cohort B2 at 12, 36 and 60 months; (B) Cohort B1 at 6, 24 and 60 months. The respective absolute values and the delta changes as well as the statistical significance are tabulated in Tables 2A,B.

EVR and the Change in Lumen Area of the Scaffold Subsegment

The mean LFA, minimal LFA, as well as the changes in the mean LFA over time for both edges and scaffolds at all the time points in the 2 cohorts are shown in the Table S1. The lumen area of the distal edges did not change significantly throughout the entire follow-up period, but there was a trend toward a decrease in the lumen area of the proximal edges over the same period (7.17±2.45 mm² post-procedure vs. 6.05±1.80 mm² at 60 months [P=0.214] for Cohort B1; 7.95±3.50 mm² post-procedure vs. 6.12±1.71 mm² at 60 months [P=0.022] for Cohort B2). After the initial and significant decreases in the mean and minimal LFA of the scaffold documented at either 6 months or 12 months, no further significant changes in these parameters were observed.

To further assess the changes in the lumen area of the edge segment, truly serial assessment was performed at 6, 24 and 60 months (Cohort B1) and at 12, 36 and 60 months (Cohort B2) (Tables 2A,B; Figures 2A,B).

Table 2. Changes in Lumen Area at Both the Distal and Proximal Edges on Serial OCT Analysis (A) Cohort B2 at 12, 36 and 60 Months, (B) Cohort B1 at 6, 24 and 60 Months

(A)	BL (n)	1Y (n)	3Y (n)	5Y (n)	1Y-BL Difference P value	3Y-1Y Difference P value	5Y-3Y Difference P value	5Y-1Y Difference P value	3Y-BL Difference P value	5Y-BL Difference P value
Distal edge 5 mm (mm2)	5.71±1.82 (n=13)	5.70±1.21 (n=14)	5.41±1.59 (n=14)	5.41±1.41 (n=13)	+0.07±1.09 0.821	−0.29±0.79 0.191	0.00±0.78 0.985	−0.29±0.82 0.209	−0.15±0.92 0.591	−0.22±1.34 0.584
Distal scaffold (mm2)	7.35±1.02 (n=16)	5.75±1.26 (n=16)	5.73±1.77 (n=16)	5.45±1.75 (n=16)	−1.60±1.21 <0.001	−0.02±0.89 0.926	−0.28±1.04 0.301	−0.30±1.13 0.307	−1.62±1.77 0.002	−1.90±1.72 <0.001
Mid-scaffold (mm2)	7.13±1.31 (n=16)	5.48±0.83 (n=16)	5.84±1.12 (n=16)	5.69±1.14 (n=16)	−1.66±1.21 <0.001	+0.37±0.78 0.079	−0.15±0.70 0.394	+0.21±0.84 0.331	−1.29±1.47 0.003	−1.45±1.53 0.002
Proximal scaffold (mm2)	7.51±1.17 (n=16)	5.80±0.67 (n=16)	5.93±1.07 (n=16)	5.88±1.01 (n=16)	−1.70±1.16 <0.001	+0.13±0.90 0.584	−0.05±0.66 0.782	+0.08±0.90 0.727	−1.58±1.46 0.001	−1.62±1.38 <0.001
Whole scaffold (mm2)	7.32±0.89 (n=16)	5.68±0.74 (n=16)	5.75±1.06 (n=16)	5.66±1.10 (n=16)	−1.63±1.00 <0.001	+0.07±0.76 0.724	−0.09±0.43 0.418	−0.02±0.81 0.917	−1.57±1.07 <0.001	−1.65±1.10 <0.001
Proximal edge 5 mm (mm2)	7.20±1.75 (n=13)	6.70±1.53 (n=13)	6.36±1.61 (n=12)	6.22±1.83 (n=13)	−0.57±0.74 0.017	−0.12±0.73 0.564	−0.14±0.94 0.596	−0.26±1.22 0.462	−0.84±1.27 0.027	−0.98±1.66 0.047
(B)	BL (n)	6M (n)	2Y (n)	5Y (n)	6M-BL Difference P value	2Y-6M Difference P value	5Y-2Y Difference P value	5Y-6M Difference P value	2Y-BL Difference P value	5Y-BL Difference P value
Distal edge 5 mm (mm2)	4.94±1.23 (n=12)	5.39±1.83 (n=12)	4.95±1.26 (n=10)	5.61±2.08 (n=11)	+0.59±0.89 0.0520	−0.21±1.09 0.542	+0.21±0.78 0.391	+0.22±1.03 0.479	+0.22±0.86 0.433	+0.74±1.31 0.088
Distal scaffold (mm2)	7.27±1.40 (n=13)	5.78±1.61 (n=13)	5.58±1.73 (n=13)	6.30±2.14 (n=13)	−1.50±0.69 <0.001	−0.20±0.98 0.477	+0.72±0.73 0.004	+0.52±1.57 0.253	−1.70±0.95 <0.001	−0.97±1.51 0.039
Mid-scaffold (mm2)	7.19±1.48 (n=13)	6.16±1.29 (n=13)	6.44±1.80 (n=13)	6.67±1.72 (n=13)	−1.03±0.74 <0.001	+0.28±1.80 0.589	+0.23±1.34 0.544	−0.52±1.56 0.222	0.51±1.43 0.201	−0.75±2.01 0.251
Proximal scaffold (mm2)	7.42±1.11 (n=13)	6.12±0.95 (n=13)	6.52±1.67 (n=13)	6.12±1.47 (n=13)	−1.31±0.83 <0.001	+0.40±1.64 0.396	−0.40±1.51 0.361	+0.00±1.05 0.996	−0.91±1.46 0.045	−1.31±0.73 <0.001
Whole scaffold (mm2)	7.06±1.23 (n=13)	6.04±1.19 (n=13)	6.17±1.44 (n=13)	6.34±1.51 (n=13)	−1.03±0.49 <0.001	+0.13±1.28 0.716	+0.17±0.63 0.338	+0.31±1.00 0.293	−0.90±1.16 0.016	−0.72±0.96 0.019
Proximal edge 5 mm (mm2)	6.37±3.18 (n=11)	6.63±2.68 (n=11)	6.73±2.70 (n=11)	6.69±2.61 (n=10)	+0.32±1.33 0.488	+0.09±0.66 0.612	−0.04±0.72 0.855	−0.06±0.80 0.801	−0.43±0.91 0.191	−0.22±1.31 0.625

Values are presented as mean±standard deviation. The edge segments were evaluated by Wilcoxon signed-rank test, while the subsegments of scaffold were evaluated by paired t-test. A significant level for each paired comparison is 0.05. BL, baseline; OCT, optical coherence tomography; 6M, 6 months; 1Y, 1 year; 2Y, 2 years; 3Y, 3 years; 5Y, 5 years.

Figure 2.

Change in lumen area of both edges and in-scaffold through the entire follow-up. (A) Cohort B2 at 12, 36 and 60 months: mean lumen area of the 18-mm in-scaffold segment decreased from baseline to 12-month (black line), extending into the first 1-mm proximal edge. There is a continuous pattern of luminal reduction extending from the in-scaffold margin to the first 1-mm of both the distal and proximal edges from baseline to 12 months; however, significant luminal reduction in-scaffold extends into only the first 1-mm proximal edge. (B) Cohort B1 at 6, 24 and 60 months: mean lumen area of the 18-mm in-scaffold segment decreased from baseline to 6-month (black line); however, there is no further significant change in the following 54 months. There is a trend toward an increase at the 5-mm distal edge in the first 6 months following device implantation without a following significant change from 6 to 60 months. In contrast, there is no significant change in lumen area at the proximal edge segment throughout the entire follow-up in this cohort. The 200-μm analysis at the transitional region reveals that although there is a continuous pattern of luminal reduction extending from the in-scaffold margin to the first 1-mm of both the distal and proximal edges in the first 6 months, significant lumen reduction is observed only at the in-scaffold margin.

At 12, 36 and 60 months (B2), there was a significant reduction of the LFA at the distal margin between post-procedure and 12 months (at the 1-mm margin: 6.92±1.15 mm² vs. 5.60±1.75 mm², and 2-mm margin: 7.36±1.04 mm² vs. 5.64±1.30 mm², both P-values=0.001) (Table 2A; Figure 2A). However, there were no significant changes of the LFA at either the 1-mm or 2-mm distal margins of the scaffold between 12 months and 60 months (at the 1-mm margin: 5.60±1.75 mm² vs. 4.99±2.19 mm² [P=0.116]; at the 2-mm margin: 5.64±1.30 mm² vs. 5.18±1.96 mm² [P=0.211]) (Figure 2A).

At 6, 24 and 60 months (B1), there was a trend toward an increase in the lumen area of the distal edge (4.94±1.23 mm² post-procedure vs. 5.39±1.83 mm² at 6 months [P=0.052]; 5.61±2.08 mm² at 60 months [P=0.088, vs. post-procedure]) (Table 2B; Figure 2B). There was also a significant reduction of the LFA at both the 1-mm and 2-mm distal margins of the scaffold between post-procedure and 6 months (at the 1-mm margin: 7.05±1.23 mm² vs. 5.86±1.76 mm² [P=0.005], and at the 2-mm margin: 7.20±1.52 mm² vs. 5.82±1.71 mm² [P=0.001]) (Figure 2B).

At 12, 36 and 60 months (B2), the proximal edge lumen area of the first 1-mm edge decreased significantly between post-procedure and 12 months (7.49±1.45 mm² vs. 6.55±1.08 mm² [P=0.019]). In contrast there was no significant change of the lumen area at the first 1-mm edge between 12 months and 60 months (6.55±1.08 mm² vs. 5.81±1.22 mm² [P=0.508]) (Figure 2A).

At 6, 24 and 60 months (B1), no significant change was observed in the lumen of the proximal edge segment (6.37±3.18 mm² post-procedure, 6.63±2.68 mm² at 6 months, 6.73±2.70 mm² at 24 months, 6.69±2.61 mm² at 60 months, P=0.889) (Table 2B; Figure 2B).

In this cohort (B1), the 2-mm proximal margin of the scaffold segment also showed a significant reduction of LFA at the 2-mm proximal margin of the scaffold between post-procedure and 6 months (at the 1-mm margin: 7.05±1.43 mm² vs. 6.04±1.19 mm² [P=0.003]; at the 2-mm margin: 7.94±1.54 mm² vs. 5.94±1.28 mm² [P=0.002]) (Figure 2B). A similar change was observed at 12, 36 and 60 months (B2) between post-procedure and 12 months (at the 1-mm margin: 8.15±1.04 mm² vs. 6.17±1.85 mm² [P=0.002]; at the 2-mm margin: 7.83±1.06 mm² vs. 5.78±1.38 mm² [P=0.001]) (Figure 2A). However, there was no change in the LFA in the 2-mm proximal margin of the scaffold between 12 months and 60 months (at the 1-mm margin: 6.17±1.85 mm² vs. 5.95±1.47 mm² [P=0.638]; at the 2-mm margin: 5.78±1.38 mm² vs. 5.94±1.42 mm² [P=0.532]) (Figure 2A).

Discussion

The main findings of the present study are: (1) in the first 12 months following device implantation, there was a significant reduction of the lumen of the scaffold, while in the following 48 months no significant change was demonstrated; (2) the change in lumen area at the edge segment within the first year can be more precisely localized in the so-called transitional region and the lumen reduction at the edges seems to be geometric prolongation of the scaffold reduction; (3) the scaffold segment and the lumen area in the transitional region no longer change after the first year of follow-up and the lumen contour of the edges aligned with the contour of the scaffold after 1 year; (4) no cases of TLR for either proximal or distal edge restenosis occurred after 3 years.

Because of the long-term follow-up and serial follow-up, this study was limited to a small number of observations. In view of the limited number of patients documented so far worldwide, we believed that Cohorts B1 and B2 should be pooled because both have follow-up at 5 years. Although some cases of aneurysmal changes were responsible for some heterogeneity of the lumen contours in Cohort B1 and there are some differences in the temporal changes of lumen area measurements between the 2 cohorts, the lumen contours of both cohorts presented a similar profile through the entire period (Figures 1A,B).

In order to fully document and evaluate the temporal changes in luminal contours, we deliberately selected cases of patients with truly serial OCT analyses. Furthermore, from a nosologic point of view, EVR and edge restenosis have to be differentiated. EVR is a general observation made at the scaffold edges, whereas edge restenosis is a truly pathologic phenomenon resulting from focal exuberance of neointima eventually combined with constrictive remodeling and progression of the atherosclerotic process.² For this reason and to fully understand EVR we excluded the 3 cases of edge restenosis that could be related to other pathologic mechanisms such as the presence of active plaque at the edge of the scaffold, defect in the manufacturing process and coating of the scaffold edge or intense barotrauma during post-dilatation outside the scaffold. All these specific phenomena could induce true restenosis of the edge.²⁷

The present study describes a frame interval of 200 μm, the transition between the native vessel wall and the neointima that has fully integrated the polymeric material.

Previously, a late vascular response to DES was primarily attributed to a delay in strut healing because of subsequent drug toxicity and polymer-induced inflammation followed by hypersensitivity reactions.^27,28 A preclinical study in non-atherosclerotic pigs treated with the Absorb scaffold showed the disappearance of inflammatory response associated with the scaffold after 2, 3, or 4 years, as evidenced by the absence of the polylactide at 3 years and its replacement by malleable proteoglycan, which was demonstrated by gel permeation chromatography.⁹ However, those findings were derived from a non-diseased vessel, and could be at variance with the inflammatory response observed in a diseased vessel.

In clinical studies, we have demonstrated the return of vasomotion of the scaffold segment at 12 months, which indicates that the device has lost its mechanical integrity at around 12 months.¹⁷ Other clinical studies have shown that the malleable matrix of proteoglycan, which fills the strut void of the scaffold, can be pushed outward and expanded; the expansion of the scaffold matrix compensates for the continuing growth of neointimal hyperplasia between and on the top of the struts.²²

In the present study, the postprocedural luminal dimensions of the scaffold and edge were characterized by a “step-up and step-down” in luminal area measurements (Figure 3) that implies excellent deployment and expansion of the device without systematic OCT or IVUS guidance, as performed by Mattesini et al²⁹ or according to the MUSIC Study criteria.²⁴ Although non-flow-limiting edge dissection occurred frequently, these 2 cohorts have good long-term OCT results that were presumably related to the small residual plaque burden at the edge segment immediately post-procedure.

Figure 3.

Representative longitudinal images at both edges and in-scaffold at post-procedure and 60 months. The longitudinal image shows both the edges and the postprocedural scaffold, with a “step-up and step-down” at the site of the scaffold implantation. In the following 48 months, the target vessel evolves to resemble a “straight tube” because of the filling of the gap between the initial expansion of the scaffold and the final lumen at 60 months. BL, baseline; LFA, lumen flow area.

We show that the growth of neointimal tissue between baseline and 12 months fills almost perfectly the gap between the initial expansion of the strut and the final lumen at 60 months, because the dimension of the lumen did not change between 12, 36, and 60 months (Figure 3).

Previously, using the first iteration of the device with a faster bioresorption we demonstrated that scaffold implantation transiently reduced vascular compliance, which disappeared after 24 months.^15,30 After completion of bioresorption, unlike a metal cage, the disappearance of the “step up-step down” in vascular compliance and the cyclic strain at the scaffold edges might theoretically correct the early disturbances in shear stress at the edges and finally lead to laminar flow in the scaffold segment, including the transitional region, and the distal and proximal edge segments (Figure 4).^30,31 Moreover, exposing the endothelial cells to a homogeneous shear stress can potentially prevent neointimal growth and neoatherosclerosis in the late phase in all regions (scaffold, transitional region, and edge segment).^32–35

Figure 4.

Compliance mismatch after scaffold implantation with alteration in flow. In this diagram the mismatch in compliance created by the scaffold (red dotted line) is indicated as a “bump” in the vessel wall compared with the proximal and distal segments. Instantaneous vortices fields calculated by a mathematical model are also shown, indicating the presence of turbulence at the proximal and distal edges. Instantaneous vorticity fields reconstructed according to Tortoriello A, et al.³¹ (Reproduced with permission from Brugaletta S, et al.³⁰)

According to the results from the late phase (between 2–3 and 5 years), the favorable lumen evolution of the scaffold itself apparently abrogated the EVR phenomenon. At the present time there is no comparable late observation of metallic DES.

Clinical Implications

Although metallic stented segments showed positive vessel remodeling up to 2 years,^36,37 and no late analysis is available, in contrast the latest report of the ABSORB Cohort B trial at 5 years demonstrated a decrease in plaque media together with adaptive, constrictive remodeling of the vessel area on IVUS analysis at 5 years.³⁸ Our study demonstrated a reduction of the scaffold luminal area in the absence of major EVR, suggesting that the physiological continuity of the lumen contour is restored long term. Loss of the mechanical property of the scaffold allows restoration of the endothelial shear stress, which is the frictional force on the vessel lining as blood flows through it, and cyclic strain, which is the force generated by the stretching of the vessel wall during systole and is affected by vessel distensibility. Furthermore, the interaction of shear stress and cyclic strain controls cell signaling. Cyclic strain stimulates eNOS gene regulation and steady-state levels of prostacyclin are increased when the shear stress force is applied in a pulsatile fashion.³⁹ The present study showed no late LL, so we could expect fewer cases of late TLR.

Study Limitations

This was an observational study and the OCT assessment was limited to a small number of observations, which were, however, serial and performed long term. We used 2 different OCT systems (TD- and FD-OCT) because OCT techniques evolved over the study period. Validity of the OCT measurements between 2 different systems has been established.⁴⁰ Regarding size discrepancy between the 2 modalities, we minimized it because none of the OCT images was acquired using the occlusion technique.^16–18,22

An inherent limitation of a first-in-man trial is that the lesion subset may be relatively simple and likely not reflective of “real-world lesions”. The postprocedural luminal dimensions of the scaffold and edge were characterized by a “step-up and step-down” in luminal area measurements (Figure 3), which implied excellent deployment and expansion of the device that in itself may constitute a favorable selection bias bound to the “first in man” nature of the study; Mattesini et al have reported a similar luminal area increase when a metallic DES or BRS was implanted under OCT guidance.²⁹ In the BMS era the IVUS-MUSIC criteria for optimal BMS implantation resulted in the lowest binary restenosis rate (9.7%) ever observed.²⁴

In order to fully document and evaluate the temporal changes in luminal contour, we deliberately selected cases of patients with truly serial OCT analyses. To fully understand EVR, we excluded the 3 cases of edge restenosis (see Discussion).

There were some differences in the sequential and temporal changes of OCT area measurements between Cohorts B1 and B2 which may raise a concern about the potential patient heterogeneity. The small sample size precludes a formal univariate or multivariable analysis of the differences between cohorts.

Conclusions

The key observation was global reduction of the scaffolded lumen in the absence of major EVR, suggesting that the physiological continuity of the lumen boundaries after bioresorption of the scaffold are restored long term.

Disclosures

S.V. is an employee of Abbott Vascular. P.W.S. and Y.O. are members of the advisory board of Abbott Vascular. All other authors report no conflicts of interest in relation to this manuscript.

Appendix

List of Investigators Contributing to OCT Image Acquisition in the ABSORB Cohort B Trial

Robert-Jan van Geuns, MD, PhD (n=14); Evald Christiansen, MD (n=12); Dariusz Dudek, MD (n=8); Dougal McClean, MD (n=7); Jacques Koolen, MD, PhD (n=7); John A Ormiston, MB, ChB, PhD (n=7); Bernard Chevalier, MD (n=7); Stefan Windecker, MD (n=6); Pieter C. Smits, MD, PhD (n=6); Bernard de Bruyne, MD, PhD (n=5); Robert Whitbourn, MD (n=3).

Supplementary Files

Supplementary File 1

Figure S1. (A) Study profile through the entire follow-up.

Figure S2. Study profile of the serial OCT analysis.

Table S1. Mean lumen area and changes over time at both edges and in-scaffold (A) cohort B2 at 12, 36 and 60 months, (B) cohort B1 at 6, 24 and 60 months

Please find supplementary file(s);

http://dx.doi.org/10.1253/circj.CJ-15-1325

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