Abstract
Background:
Little is known of the relationship between optical coherence tomography (OCT) findings and recurrent restenosis after paclitaxel-coated balloon (PCB) angioplasty for drug-eluting stent in-stent restenosis (DES-ISR). To identify the predictors of recurrent restenosis after PCB angioplasty, we investigated quantitative and qualitative OCT findings during PCB angioplasty for DES-ISR.
Methods and Results:
In all, 222 DES-ISR lesions treated by PCB angioplasty with OCT assessment and followed-up angiographically at 6 months were divided into restenotic and non-restenotic lesions on the basis of the presence or absence of restenosis at follow-up. There was a significantly higher proportion of the heterogeneous tissue pattern in restenotic than non-restenotic lesions (26.5% vs. 11.0%, respectively; P=0.02). The OCT-derived post-procedural minimal lumen and stent areas were significantly smaller in restenotic lesions, but the intima area was similar in both groups. Post-procedural stent underexpansion, defined as a stent diameter : size of the previous stent ratio <1.0, was more frequently observed in restenotic than non-restenotic lesions (33.3% vs. 17.4%, respectively; P=0.02). Multivariate analysis identified a heterogeneous tissue pattern (odds ratio [OR] 2.92; 95% confidence interval [CI] 1.32–6.47; P=0.006) and post-procedural stent underexpansion (OR 2.36; 95% CI 1.15–4.85; P=0.04) as independent predictors of recurrent restenosis.
Conclusions:
The heterogeneous tissue pattern and insufficient post-procedural minimal lumen area, caused primarily by stent underexpansion, may be associated with restenosis after PCB angioplasty for DES-ISR.
The treatment of patients with in-stent restenosis (ISR) remains a challenge, and paclitaxel-coated balloon (PCB) angioplasty is considered a standard therapeutic option for ISR.1–8
Although PCB angioplasty for drug-eluting stent (DES)-ISR is recommended as a Class 1a therapeutic option in current guidelines, recurrent restenosis after PCB angioplasty still occurs.9
Recently, post-procedural percentage diameter stenosis and insufficient expansion at the initial ballooning have been reported as risk factors for recurrent restenosis, and obtaining a greater acute gain contributes to improved clinical outcomes.10,11
Previous studies by intravascular ultrasound indicate that stent underexpansion and neointimal hyperplasia are the mechanisms responsible for ISR after DES implantation.12,13
However, there are currently inadequate data on intracoronary imaging during PCB angioplasty to evaluate the cause of recurrent restenosis after PCB angioplasty. Optical coherence tomography (OCT) is an intravascular imaging modality that has higher resolution than intravascular ultrasound.14
Excellent contrast among lumen, vessel, and stent in OCT images allows accurate measurement of lumen and stent. The aim of this study was to investigate the relationship between quantitative and qualitative OCT findings and angiographic outcomes after PCB for DES-ISR.
Methods
Subjects
We investigated 548 DES-ISR lesions exclusively treated with PCB angioplasty for the first time between September 2008 and December 2016; of these 329 lesions had been assessed by OCT. Subsequently, image analysis and 6-month follow-up angiography were performed. Finally, 222 lesions were included in this study and were classified into 2 groups on the basis of the presence or absence of restenosis: 49 with restenosis (restenosis group) and 173 without restenosis (non-restenosis group;
Figure 1).
SeQuent Please PCB catheters (B. Braun Melsungen, Vascular Systems, Berlin, Germany) were used in this study. Patients who had undergone repeated PCB angioplasty or had been treated with a combination of PCB and DES were excluded from the study. Informed consent was obtained from all patients for both the procedure and subsequent data collection and analysis for research purposes. The study was approved by the Institutional Ethics Committee of Kurashiki Central Hospital.
Interventional Procedure
All patients were pretreated with aspirin (100 mg daily) and ticlopidine (200 mg daily)/clopidogrel (75 mg daily) or prasugrel (3.75 mg daily). Aspirin and ticlopidine/clopidogrel/prasugrel treatment was recommended for at least 6 months. The procedures at initial intervention and re-intervention for restenosis were performed according to standard clinical guidelines. In all cases, the intervention strategy and the use of adjunct devices and pharmacotherapy were at the discretion of the operator based on angiographic and intravascular imaging findings. Predilatation was performed on all ISR lesions. The length of the PCB was chosen to overlap with the lesion by at least 2 mm at the proximal and distal margins. The recommended inflation time for PCB was 60 s.
OCT Procedure
The OCT procedure has been reported previously.15
Briefly, OCT was performed to obtain information on the entire target vessel before and after intervention. Between July 2008 and September 2011, time-domain OCT was performed using a 0.016-inch OCT catheter (ImageWire; Light Lab Imaging, Westford, MA, USA). The OCT catheter was advanced to the distal end of the stent through a 3-Fr occlusion balloon catheter. To remove blood from the field of view, the occlusion balloon was inflated up to 0.6 atm at a proximal site of the lesion, and warm Ringer’s lactate solution was infused into the coronary artery from the distal tip of the occlusion balloon catheter at a rate of 0.7 mL/s. Between October 2011 and December 2016, frequency-domain OCT was performed using a monorail-type OCT imaging catheter (Dragonfly; St. Jude Medical, St. Paul, MN, USA). The OCT catheter was advanced to the distal end of the stent along a 0.014-inch coronary guide wire. A contrast agent was infused to remove blood from the field of view. The entire lesion length was imaged with an automated pull-back device, and the target vessel was clearly visualized by OCT. Between September 2013 and December 2016, optical frequency domain imaging (OFDI) was also performed using a monorail-type OFDI catheter (FastView imaging catheter; Terumo, Tokyo, Japan). OFDI images were acquired by the same method as those of frequency-domain OCT.
Angiographic Analysis
Quantitative coronary angiograms were analyzed using QCA-CMS (Medis Medical Imaging Systems, Leiden, The Netherlands). All angiograms were analyzed in a random sequence by 2 experienced observers who were blinded to the clinical characteristics of the patients. Coronary angiograms were obtained in multiple views after the administration of intracoronary nitrate. The reference diameter, minimal lumen diameter, percent diameter stenosis, and lesion length were measured before and after the procedure and at follow-up. Measurements were performed at the target lesion treated by PCB angioplasty within 5 mm proximal and distal to the treated area. ISR was classified according to the classification of Mehran et al.16
Multifocal lesions were classified as non-focal-type restenotic lesions. Stent fracture was defined as the complete separation of stent segments or stent struts confirmed by follow-up angiography and was evaluated in multiple views.17
An independent view and the agreement of 2 independent cardiologists who were blinded to the clinical and procedural data were required for the angiographic diagnosis of stent fracture to assess interobserver variability. When opinions differed, the evaluation was performed by a third observer, and a final decision regarding the diagnosis of stent fracture was made by consensus.
Image Analysis and Definition of OCT Findings
The OCT/OFDI data were stored digitally and analyzed with an OCT imaging system (Light Lab Imaging), an ILUMIEN OCT imaging system (St. Jude Medical), and a LUNAWAVE imaging system (Terumo). Quantitative analyses were performed at the minimum lumen area (MLA) site before and after the procedure. The MLA and stent area (SA) were traced manually, and the intima area (IA) was automatically calculated. Percent IA (%IA) was calculated as IA divided by SA. Differences in MLA, SA, and IA before and after the procedure were defined as initial gain, ∆SA, and ∆IA, respectively (Figure 2). Stent underexpansion was defined as a stent diameter : size of the previous stent ratio <1.0. For a qualitative analysis, restenotic tissue characteristics were classified into 3 patterns and the restenotic backscatter was classified into 2 types.15,18
The 3 restenotic tissue patterns were as follows: (1) homogeneous pattern, restenotic tissue that has uniform optical properties and does not show any focal variations in backscattering patterns; (2) heterogeneous pattern, restenotic tissue that has focally changing optical properties and shows various backscattering patterns; and (3) layered pattern, restenotic tissue that consists of concentric layers with different optical properties, namely are an abluminal high-scattering layer and an abluminal low-scattering layer. Restenotic tissue backscatter was classified as either high (i.e., the majority of the tissue shows high backscatter and appears bright) or as low (i.e., the majority of tissue shows low backscatter and appears dark or black). OCT analysis was performed by 2 experienced physicians who were blinded to the clinical and angiographic lesion characteristics.19
When opinions differed, a final decision was reached by discussion.
Angiographic follow-up was routinely scheduled at 6 months after the procedure. Follow-up angiograms were obtained earlier if clinically indicated. Binary restenosis at follow-up was defined as stenosis occupying ≥50% of the diameter.
Statistical Analysis
Categorical variables were compared using the Chi-squared test. Continuous variables are expressed as the mean±SD and were compared using Student’s t-test or the Wilcoxon rank-sum test depending on the normality of data distribution. Continuous variables were compared between 3 groups by analysis of variance (ANOVA). Multiple lesions in the same patient were assumed to be independent of each other. In all cases, P<0.05 was considered significant.
A multivariable logistic regression model was used to identify independent risk factors for recurrent restenosis. The variables used in the multivariable analysis were selected when they were shown to significantly affect the dependent variables in the univariate analysis or empirically known to have predictive values. To avoid overfitting, the number of independent variables placed in a multivariable analysis was limited to 1 for every 10 events. Independent variables are expressed as odds ratios (ORs) with 95% confidence intervals (CIs). Inter- and intraobserver variability in the diagnosis of tissue morphology was evaluated by Cohen’s kappa. Statistical analyses were performed using JMP 9.0 (SAS, Cary, NC, USA).
Results
Baseline and Procedural Data
Recurrent restenosis was observed in 49 lesions (22.1%). Baseline clinical, angiographic, and procedural characteristics are summarized in
Table 1. In terms of previous stents, 43.3% were first-generation DES (sirolimus-eluting stents, 28.4%; paclitaxel-eluting stents, 9.9%; and zotarolimus-eluting stents, 5.0%), whereas 56.7% were newer-generation DES (everolimus-eluting stents, 35.1%; biolimus-eluting stents, 15.8%; Resolute zotarolimus-eluting stents, 3.6%; and Ultimaster sirolimus-eluting stents, 2.3%). There were no significant differences in the proportion of stent-in-stent restenosis, stent size, and stent length between the restenosis and non-restenosis groups. The proportion of stent fracture was higher in the restenosis group, but the difference was not statistically significant. Predilatation was performed in all lesions. Mean maximal inflation pressure was 20.0±5.8 atm, and maximal inflation pressure did not differ significantly between the 2 groups. A scoring balloon was used in 56.9% of lesions. The proportion of scoring balloon use was relatively higher in the restenosis group, but the difference did not reach statistical significance.
Table 1.
Baseline Clinical, Angiographic, and Procedural Characteristics Overall and in the Restenosis and Non-Restenosis Groups Separately
| |
Overall |
Restenosis
(n=49) |
Non-restenosis
(n=173) |
P value |
| Age (years) |
68.9±9.6 |
68.2±9.6 |
71.2±9.5 |
0.06 |
| Age >80 years |
17 (7.7) |
6 (12.2) |
11 (6.4) |
0.17 |
| Men |
183 (82.4) |
36 (73.5) |
147 (85.0) |
0.06 |
| Hypertension |
171 (77.0) |
40 (81.6) |
131 (75.7) |
0.39 |
| Diabetes mellitus |
110 (49.6) |
20 (40.8) |
90 (52.0) |
0.17 |
| Insulin therapy |
30 (13.5) |
6 (12.2) |
24 (13.9) |
0.77 |
| Dyslipidemia |
152 (68.5) |
31 (63.3) |
121 (69.9) |
0.37 |
| Current smoking |
7 (3.2) |
2 (4.1) |
5 (2.9) |
0.67 |
| eGFR (mL/min/1.73 m2) |
62.3±26.1 |
60.8±24.1 |
62.7±26.8 |
0.66 |
| Hemodialysis |
20 (9.0) |
3 (6.1) |
17 (9.8) |
0.42 |
| Previous stent type |
|
|
|
0.14 |
| Sirolimus-eluting stent |
63 (28.4) |
8 (16.3) |
55 (31.8) |
|
| Paclitaxel-eluting stent |
22 (9.9) |
9 (18.4) |
13 (7.5) |
|
| Zotarolimus-eluting stent |
11 (5.0) |
3 (6.1) |
8 (4.6) |
|
| Everolimus-eluting stent |
78 (35.1) |
19 (38.8) |
59 (34.1) |
|
| Biolimus-eluting stent |
35 (15.8) |
6 (12.2) |
29 (16.8) |
|
| Resolute zotarolimus-eluting stent |
8 (3.6) |
3 (6.1) |
8 (4.6) |
|
| Ultimaster sirolimus-eluting stent |
5 (2.3) |
2 (4.1) |
3 (1.7) |
|
| Stent-in-stent |
49 (22.1) |
11 (22.5) |
38 (22.0) |
0.94 |
| Previous stent size (mm) |
2.84±0.40 |
2.81±0.40 |
2.88±0.39 |
0.28 |
| Previous stent length (mm) |
24.6±7.3 |
25.4±9.1 |
24.4±6.7 |
0.36 |
| Previous stent fracture |
31 (14.0) |
11 (22.5) |
20 (11.6) |
0.06 |
| Lesion locations |
| Left main trunk |
2 (0.9) |
0 (0) |
2 (1.2) |
0.86 |
| Left anterior descending |
86 (38.7) |
18 (36.7) |
68 (39.3) |
|
| Left circumflex |
27 (12.2) |
6 (12.2) |
21 (12.1) |
|
| Right |
107 (48.2) |
25 (51.0) |
82 (47.4) |
|
| Target of bifurcation lesions |
30 (13.5) |
7 (14.3) |
23 (13.3) |
0.86 |
| Target of ostial lesions |
13 (5.9) |
2 (4.1) |
11 (6.4) |
0.55 |
| Restenosis patterns |
|
|
|
0.09 |
| Focal margin |
6 (2.7) |
1 (2.0) |
5 (2.9) |
|
| Focal body |
111 (50.0) |
93 (53.8) |
18 (36.7) |
|
| Multifocal |
18 (8.1) |
7 (14.3) |
11 (6.4) |
|
| Diffuse |
75 (33.8) |
18 (36.7) |
57 (33.0) |
|
| Proliferative |
12 (5.4) |
5 (10.2) |
7 (4.1) |
|
| Focal type restenosis |
135 (60.8) |
26 (53.1) |
109 (63.0) |
0.21 |
| Initial procedure data |
| PTCRA at primary PCI |
20 (9.0) |
16 (9.3) |
4 (8.2) |
0.81 |
| Post-procedural MLD (mm) |
2.43±0.44 |
2.43±0.45 |
2.43±0.41 |
0.92 |
| Post-procedural %DS |
18.3±8.7 |
17.1±7.4 |
18.6±9.1 |
0.29 |
| Index procedure data |
| Predilatation |
| Use of scoring balloon |
124 (56.9) |
30 (62.5) |
94 (55.3) |
0.37 |
| Balloon diameter (mm) |
2.86±0.41 |
2.81±0.40 |
2.87±0.42 |
0.35 |
| Inflation pressure (atm) |
20.0±5.8 |
20.6±4.55 |
20.7±5.2 |
0.91 |
| Paclitaxel-coated balloon |
| Balloon diameter (mm) |
2.86±0.41 |
2.81±0.40 |
2.92±0.42 |
0.35 |
| Inflation pressure (atm) |
13.3±1.3 |
13.2±1.3 |
13.3±1.3 |
0.78 |
| Before procedure |
| %DS |
68.4±14.7 |
70.6±14.0 |
67.7±14.9 |
0.22 |
| MLD (mm) |
0.90±0.46 |
0.80±0.42 |
0.93±0.46 |
0.08 |
| Lesion length (mm) |
16.4±9.4 |
18.5±10.3 |
15.8±9.0 |
0.08 |
| Reference vessel diameter (mm) |
2.87±0.42 |
2.78±0.44 |
2.90±0.42 |
0.07 |
| After procedure |
| %DS |
27.0±10.0 |
27.7±13.2 |
26.8±9.0 |
0.57 |
| MLD (mm) |
2.11±0.41 |
2.05±0.45 |
2.14±0.39 |
0.16 |
Unless specified otherwise, values are given as the mean±SD or n (%). %DS, percentage diameter stenosis; eGFR, estimated glomerular filtration rate; MLD, minimal lumen diameter; PCI, percutaneous coronary intervention; PTCRA, percutaneous transluminal coronary rotational atherectomy.
Angiographic findings before the procedure were not significantly different between the 2 groups. Angiographic minimal lumen diameter after the procedure was relatively smaller in the restenosis group, but the difference was not statistically significant.
Medication use and laboratory measurement at the index procedure are summarized in
Table S1. There were no significant differences in the medication status and lipid profile between the 2 groups.
OCT Findings
The OCT findings are summarized in
Table 2. Before the procedure, there were no significant differences between the restenosis and non-restenosis groups in MLA (1.22±0.65 vs. 1.39±0.61 mm2; P=0.10), SA (5.80±2.49 vs. 6.21±2.14 mm2; P=0.26), and IA (4.58±2.45 vs. 4.77±2.01 mm2; P=0.56). After the procedure, MLA and SA were significantly smaller in the restenosis group (4.14±1.66 vs. 4.90±1.76 mm2
[P=0.01] and 7.15±2.74 vs. 8.00±2.52 mm2
[P=0.04], respectively), but there was no significant difference in IA between the 2 groups (2.99±1.76 vs. 3.06±1.63 mm2, respectively; P=0.79). Although there was no significant difference in ∆IA between the 2 groups (1.59±1.42 vs. 1.74±1.33 mm2; P=0.49), initial gain and ∆SA were significantly smaller in the restenosis than non-restenosis group (2.94±1.63 vs. 3.49±1.67 mm2
[P=0.04] and 1.34±1.02 vs. 1.80±1.28 mm2
[P=0.02], respectively). The proportion of preprocedural stent underexpansion did not differ significantly between the 2 groups (75.0% vs. 72.1%; P=0.69), whereas the proportion of post-procedural stent underexpansion was significantly higher in the restenosis than non-restenosis group (33.3% vs. 17.4%; P=0.02).
Table 2.
Optical Coherence Tomography Findings of Lesions With and Without Restenosis
| |
Restenosis
(n=49) |
Non-restenosis
(n=173) |
P value |
| Before procedure |
| Minimal lumen diameter (mm) |
1.22±0.30 |
1.30±0.28 |
0.07 |
| Minimal lumen area (mm2) |
1.22±0.65 |
1.39±0.61 |
0.10 |
| Stent diameter (mm) |
2.66±0.57 |
2.77±0.47 |
0.16 |
| Stent area (mm2) |
5.80±2.49 |
6.21±2.14 |
0.26 |
| Intimal area (mm2) |
4.58±2.45 |
4.77±2.01 |
0.56 |
| % Intima area |
76.6±12.2 |
76.3±9.6 |
0.87 |
| Tissue characteristics |
|
|
0.02 |
| Homogeneous |
26 (53.1) |
105 (60.7) |
|
| Heterogeneous |
13 (26.5) |
19 (11.0) |
|
| Layered |
10 (20.4) |
49 (28.3) |
|
| Tissue backscatter |
|
|
0.97 |
| High |
31 (63.3) |
109 (63.0) |
|
| Low |
18 (36.7) |
64 (37.0) |
|
| Underexpansion |
36 (75.0) |
124 (72.1) |
0.69 |
| After procedure |
| Minimal lumen diameter (mm) |
2.25±0.46 |
2.45±0.44 |
0.01 |
| Minimal lumen area (mm2) |
4.14±1.66 |
4.90±1.76 |
0.01 |
| Stent diameter (mm) |
2.96±0.57 |
3.16±0.49 |
0.02 |
| Stent area (mm2) |
7.15±2.74 |
8.00±2.52 |
0.04 |
| Intimal area (mm2) |
2.99±1.76 |
3.06±1.63 |
0.79 |
| % Intima area |
40.7±14.3 |
38.2±12.6 |
0.23 |
| Initial gain (mm2) |
2.94±1.63 |
3.49±1.67 |
0.04 |
| ΔStent diameter (mm) |
0.30±0.22 |
0.39±0.26 |
0.04 |
| ΔStent area (mm2) |
1.34±1.02 |
1.80±1.28 |
0.02 |
| ΔIntima area (mm2) |
1.59±1.42 |
1.74±1.33 |
0.49 |
| Underexpansion |
16 (33.3) |
30 (17.4) |
0.02 |
Unless specified otherwise, values are given as the mean±SD or n (%).
Quantitative OCT findings according to restenotic tissue pattern are given in
Table 3. Preprocedural MLA was significantly larger in the group with the heterogeneous pattern than for the other 2 patterns. Although preprocedural SA area was also larger in the group with heterogeneous pattern compared with the other 2 patterns, the difference was not statistically significant. Post-procedural MLA, SA, and IA did not differ significantly between the 3 groups.
Table 3.
Association Between Restenotic Tissue Patterns and Quantitative Optical Coherence Tomography Findings
| |
Tissue pattern |
P value |
Homogeneous
(n=131) |
Layered
(n=59) |
Heterogeneous
(n=32) |
| Before procedure |
| Minimal lumen diameter (mm) |
1.28±0.27 |
1.23±0.23 |
1.37±0.38 |
0.06 |
| Minimal lumen area (mm2) |
1.35±0.57 |
1.23±0.43 |
1.61±0.96 |
0.016 |
| Stent diameter (mm) |
2.73±0.49 |
2.66±0.47 |
2.92±0.51 |
0.06 |
| Stent area (mm2) |
6.05±2.24 |
5.77±2.11 |
6.89±2.28 |
0.07 |
| Intima area (mm2) |
4.71±2.09 |
4.55±2.09 |
5.29±2.24 |
0.26 |
| % Intima area |
76.4±9.61 |
76.7±9.12 |
75.2±13.8 |
0.79 |
| Underexpansion |
95 (73.8) |
44 (75.9) |
21 (65.6) |
0.57 |
| After procedure |
| Minimal lumen diameter (mm) |
2.39±0.46 |
2.35±0.40 |
2.54±0.50 |
0.13 |
| Minimal lumen area (mm2) |
4.70±1.79 |
4.47±1.48 |
5.29±2.01 |
0.1 |
| Stent diameter (mm) |
3.11±0.52 |
3.04±0.48 |
3.24±0.51 |
0.22 |
| Stent area (mm2) |
7.79±2.66 |
7.46±2.35 |
8.45±2.66 |
0.21 |
| Intima area (mm2) |
3.08±1.60 |
2.99±1.62 |
3.16±1.62 |
0.88 |
| % Intima area |
39.4±13.0 |
39.1±13.6 |
37.4±14.0 |
0.76 |
| Initial gain (mm2) |
3.35±1.63 |
3.24±1.46 |
3.67±2.04 |
0.48 |
| ΔStent diameter (mm) |
0.37±0.25 |
0.38±0.27 |
0.32±0.25 |
0.52 |
| ΔStent area (mm2) |
1.73±1.25 |
1.69±1.31 |
1.55±1.12 |
0.76 |
| ΔIntima area (mm2) |
1.67±1.27 |
1.55±1.31 |
2.12±1.68 |
0.15 |
| Underexpansion |
27 (20.8) |
11 (19.0) |
8 (25.0) |
0.80 |
Unless specified otherwise, values are given as the mean±SD or n (%).
The variables placed in multivariable analysis for recurrent restenosis included previous stent fracture, heterogeneous tissue pattern, and post-procedural stent underexpansion. Multivariable analysis revealed that previous stent fracture, heterogeneous tissue pattern, and post-procedural stent underexpansion were independent risk factors for recurrent restenosis (Table 4).
Table 4.
Univariate and Multivariate Analyses for Recurrent Restenosis
| |
Univariate |
Multivariate |
| OR (95% CI) |
P value |
OR (95% CI) |
P value |
| Previous stent fracture |
2.21 (0.97–5.01) |
0.06 |
2.46 (1.03–5.72) |
0.04 |
| Heterogeneous restenotic pattern |
2.92 (1.32–6.47) |
0.006 |
3.21 (1.39–7.30) |
0.006 |
| Post-procedural stent underexpansion |
2.36 (1.15–4.85) |
0.02 |
2.20 (1.04–4.60) |
0.04 |
CI, confidence interval; OR, odds ratio.
The OCT findings regarding first- and newer-generation DES are summarized in
Table 5. Preprocedural MLA, SA, and IA did not differ significantly between the restenosis and non-restenosis groups in patients receiving either first- or newer-generation DES. However, in patients who received a first-generation DES, the proportion of the heterogeneous pattern differed significantly between the restenosis and non-restenosis groups; the difference was not significant for those receiving newer-generation DES. In the newer-generation DES group, post-procedural MLA and SA were significantly smaller, and the proportion of stent underexpansion was significantly higher in the restenosis group; in comparison, there was no significant difference in these parameters between the 2 groups in those receiving first-generation DES.
Table 5.
Optical Coherence Tomography Findings on First- and Newer-Generation Drug-Eluting Stents
| |
First-generation DES |
Newer-generation DES |
Restenosis
(n=20) |
Non-restenosis
(n=76) |
P value |
Restenosis
(n=20) |
Non-restenosis
(n=76) |
P value |
| Before procedure |
| Minimal lumen diameter (mm) |
1.24±0.20 |
1.30±0.27 |
0.36 |
1.21±0.32 |
1.30±0.28 |
0.12 |
| Minimal lumen area (mm2) |
1.24±0.36 |
1.38±0.60 |
0.31 |
1.22±0.79 |
1.40±0.62 |
0.2 |
| Stent diameter (mm) |
2.83±0.59 |
2.83±0.47 |
0.99 |
2.53±0.90 |
2.72±0.05 |
0.07 |
| Stent area (mm2) |
6.57±2.70 |
6.52±2.22 |
0.93 |
5.28±2.27 |
5.93±2.07 |
0.15 |
| Intima area (mm2) |
5.33±2.55 |
2.13±5.14 |
0.72 |
4.06±2.29 |
4.53±1.88 |
0.26 |
| % Intima area |
79.2±9.1 |
77.3±9.6 |
0.45 |
74.8±13.9 |
75.4±9.4 |
0.77 |
| Tissue characteristics |
|
|
0.03 |
|
|
0.32 |
| Homogeneous |
8 (40.0) |
45 (59.2) |
|
18 (62.1) |
60 (61.9) |
|
| Heterogeneous |
7 (35.0) |
8 (10.5) |
|
6 (20.7) |
11 (11.3) |
|
| Layered |
5 (25.0) |
23 (30.3) |
|
5 (17.2) |
26 (26.8) |
|
| Tissue backscatter |
| High |
11 (55.0) |
46 (60.5) |
0.65 |
20 (69.0) |
63 (65.0) |
0.69 |
| Low |
9 (45.0) |
30 (39.5) |
|
9 (31.0) |
34 (35.1) |
|
| Underexpansion |
11 (57.9) |
45 (60.0) |
0.87 |
25 (86.2) |
79 (81.4) |
0.55 |
| After procedure |
| Minimal lumen diameter (mm) |
2.19±0.37 |
2.37±0.43 |
0.11 |
2.28±0.52 |
2.51±0.45 |
0.02 |
| Minimal lumen area (mm2) |
3.92±1.20 |
4.54±1.64 |
0.12 |
4.29±1.92 |
5.16±1.81 |
0.03 |
| Stent diameter (mm) |
3.14±0.55 |
3.18±0.47 |
0.79 |
2.83±0.56 |
3.14±0.51 |
0.006 |
| Stent area (mm2) |
8.02±2.71 |
8.07±2.40 |
0.93 |
6.54±2.64 |
7.91±2.62 |
0.01 |
| Intima area (mm2) |
4.09±1.86 |
3.52±1.47 |
0.15 |
2.22±1.21 |
2.75±1.56 |
0.1 |
| % Intima area |
49.9±9.64 |
43.6±12.1 |
0.03 |
34.4±13.7 |
34.6±12.3 |
0.95 |
| Initial gain (mm2) |
2.70±1.11 |
3.16±1.49 |
0.2 |
3.10±1.91 |
3.76±1.71 |
0.08 |
| ΔStent diameter (mm) |
0.31±0.22 |
0.34±0.28 |
0.63 |
0.30±0.22 |
0.42±0.25 |
0.02 |
| ΔStent area (mm2) |
1.45±1.04 |
1.56±0.14 |
0.74 |
1.27±1.02 |
1.98±1.26 |
0.006 |
| ΔIntima area (mm2) |
1.24±1.22 |
1.68±1.38 |
0.21 |
1.83±1.52 |
1.79±1.30 |
0.87 |
| Underexpansion |
4 (21.1) |
14 (18.7) |
0.81 |
12 (41.4) |
16 (58.6) |
0.007 |
Unless specified otherwise, values are given as the mean±SD or n (%). DES, drug-eluting stent.
Inter- and intraobserver reproducibility was assessed in 30 randomly selected lesions. In all cases, kappa values were excellent for both inter- and intraobserver reproducibility (0.91 and 0.91, respectively, for restenotic tissue structure; 0.84 and 0.85, respectively, for restenotic tissue backscatter).
Discussion
In this study we investigated the association between OCT findings and mid-term angiographic outcomes. The main findings of the study were: (1) the heterogeneous pattern was associated with recurrent restenosis at follow-up; (2) smaller post-procedural MLA, caused primarily by persistent stent underexpansion, was also a main cause of recurrent restenosis; and (3) previous stent fracture, heterogeneous pattern, and stent underexpansion were independent risk factors for recurrent restenosis.
Previous studies have reported that residual stenosis is a risk factor for recurrent restenosis after PCB angioplasty for DES-ISR.20,21
A recent study reported that insufficient expansion at the initial ballooning was also a risk factor for recurrent restenosis.11
Accordingly, the mechanism underlying insufficiently acquired acute gain has become a concern; persistent stent underexpansion and insufficient intimal compression seem to contribute to it. However, the degree to which these factors affect acquired acute gain remains unknown in angiographic analysis. In this OCT imaging study, post-procedural MLA and SA were significantly smaller in the restenosis group, but post-procedural IA did not differ significantly between the 2 groups. Insufficiently acquired acute gain appeared to be caused primarily by stent underexpansion rather than inadequate intimal compression. Interestingly, pre- and post-procedural %IA were similar in the 3 restenosis tissue patterns. In this study, high-pressure predilatation using a non-compliant balloon was performed, and a scoring balloon was used in approximately 50% of treated lesions. In these procedural settings, %IA decreased by 40% in all 3 restenotic tissue pattern groups, and intimal compression was seemingly not a serious issue. Preprocedural stent underexpansion was observed in 70% of treated lesions, but the proportion of preprocedural stent underexpansion did not differ significantly between the restenosis and non-restenosis groups. In contrast, the proportion of post-procedural stent underexpansion was significantly higher in the restenosis group. To minimize the occurrence of recurrent restenosis, sufficient lesion preparation is mandatory; however, residual underexpansion even after these preparations is a serious problem. Post-procedural stent underexpansion may have been more affected by lesion characteristics at the time of initial stent implantation rather than procedural problems. For these lesions, other lesion preparation methods, such as stent ablation using rotational atherectomy, may be considered to prevent recurrent restenosis. During the procedure, the degree of stent expansion before PCB angioplasty should be taken into consideration, as well as the neointimal tissue pattern.
The restenosis rate after PCB angioplasty for lesions with the heterogeneous pattern has been reported to be higher than for lesions with a homogeneous or layered pattern.15
In the present study, the heterogeneous tissue pattern was one of the independent risk factors for restenosis after PCB angioplasty for DES-ISR. In a previous report, excessive inflammation, fibrin accumulation, organized thrombus, and in-stent atherosclerosis were similarly shown as a dark appearance without a clear border on OCT images compared with autopsy data.22
Although the histopathology of a heterogeneous structure remains unclear, PCB angioplasty is speculated to cause thrombogenicity in these lesions, and an organized thrombus inhibits the transfer of an antiproliferative drug to the vessel wall and results in incomplete suppression of neointimal hyperplasia.23
Therefore, PCB angioplasty may not be very effective on DES-ISR lesions with the heterogeneous pattern.
We previously reported in-stent occlusion and ostial right coronary artery lesions as independent risk factors for recurrent restenosis after PCB angioplasty for DES-ISR,21
which differs from the results of the present study. In the present study, occluded lesions were excluded due to the lack of preprocedural imaging, and most the ostial lesions were also excluded because acquisition of OCT images was difficult. These differences in the baseline characteristics of the study sample may explain the differences in the results between the present and previous study. In addition, the results of this study suggest that the risk factors for recurrent restenosis are different between first- and newer-generation DES. The inflammation caused by hypersensitivity reaction to drugs and polymers of DES has been reported to play an important role in neointimal regrowth, especially with first-generation DES.24,25
We speculate that the effect of the heterogeneous pattern on restenosis is relatively strong in first-generation DES-ISR. In contrast, the proportion of pre- and post-procedural stent underexpansion was higher for newer-generation DES-ISR. Appropriate preparation with a high-pressure balloon before PCB angioplasty may be important when treating newer-generation DES-ISR. These differences between first- and newer-generation DES-ISR should be confirmed by further studies with a large sample size.
Study Limitations
The present study has several limitations. First, the study is a retrospective study, and there may have been bias in lesion selection. Because lesions with severe stenosis or occlusion, especially those in small vessels, were excluded from the study sample, the results of the present study cannot be applied to all restenotic lesions. Second, the period of enrollment was relatively long. Third, the definitions of the tissue structure and tissue backscatter have some limitations. Because the tissue structure and backscatter are influenced by intimal thickness and, in some cases, various types of the tissue structure and backscatter coexisted at the same site, determining the predominant pattern was difficult in some cases. However, the inter- and intraobserver reproducibility of the results of OCT analysis was generally good. Finally, selection of stent size and assessment of stent expansion using intravascular imaging including intravascular ultrasound and OCT was not necessarily performed in all lesions at the initial procedure. However, post-procedural minimal lumen diameter and percentage diameter stenosis at the initial procedure were not significantly different between lesions with and without recurrent restenosis.
Conclusions
The heterogeneous tissue pattern and insufficiently acquired post-procedural MLA, caused primarily by persistent stent underexpansion, may be associated with restenosis after PCB angioplasty for DES-ISR.
Acknowledgments
The authors thank Miho Kobayashi, Makiko Kanaike, and Yoshimi Sano for their secretarial assistance. The authors also thank Hayato Shimizu and his colleagues for technical assistance.
Conflict of Interest
The authors declare no conflicts of interest.
Supplementary Files
Supplementary File 1
Table S1.
Medications and laboratory test values overall and in the restenosis and non-restenosis groups separately
Please find supplementary file(s);
http://dx.doi.org/10.1253/circj.CJ-18-0464
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