Introduction
Drug-eluting stents (DES) dramatically reduce the rate of in-stent restenosis (ISR) after percutaneous coronary intervention (PCI). The new-generation DES with thinner metal struts and more biocompatible polymers contributed to a lower risk of ISR and thrombosis than the first-generation DES. Despite these improvements, ISR remains a major concern in patients undergoing PCI. ISR is caused by multiple biological, genetic, mechanical, and technical factors [1,2]. Moreover, repeat revascularization for ISR is associated with a high risk of recurrent ischemic events [3]. Stent edge restenosis (SER) is a type of ISR observed at the edge of the stent and identified as the prevailing limitation of ISR after stent implantation. It has been reported that the mechanism of SER was related to vessel injury by ballooning or stent implantation, the residual plaque, and the small lumen area in the stent edge segments [4–7]. In addition, mechanical stresses due to hinge motion are risk factors for SER incidents [8]. Although many studies and imaging evaluations have been conducted on the outcomes of ISR [9–12], few studies have focused on SER, and the optimal treatment for SER remains unclear.
Drug-coated balloons (DCB) are useful devices that, without a metal stent or polymer, supply lipophilic antiproliferative drugs into the target vessel to prevent neointimal hyperplasia. It is commonly known that using DCB is a beneficial option for treating de-novo coronary small vessel disease [13–15]. Moreover, previous studies have shown the efficacy and safety of DCB for treating ISR [16,17]; however, the outcome of DCB for SER has not yet been clarified. Thus, this study aimed to investigate the clinical outcomes after using DCB in SER lesions compared with new-generation DES.
Methods
Study population and design
This retrospective observational study was conducted at Gunma University Hospital between December 2013 and January 2019. A total of 382 patients were reviewed for inclusion in the study (Fig. 1, study flow diagram). Inclusion criteria were ≥18 years of age, the presence of ISR, and SER lesions. The exclusion criteria were as follows: treatment with coronary bypass surgery (CABG) or medication therapy alone; contraindications to antithrombotic medications; unsuccessful PCI (noncrossed guidewire or device, or residual stenosis of ≥70%); PCI with both DCB and DES in the same vessel; PCI in saphenous vein graft; and a lack of follow-up data. Patients were divided into DCB (patients treated with DCB) and DES groups (patients treated with DES). The SeQuent Please DCB (B Braun Melsungen AG, Melsungen, Germany) coated with paclitaxel was used to treat the SER lesions in the DCB group. The following new-generation stents were used in the DES group: Xience (Abbott Vascular, Santa Clara, California, USA, n = 40), Ultimaster (Terumo Corporation, Tokyo, Japan, n = 33), Synergy (Boston Scientific, Marlborough, Massachusetts, USA, n = 24), Resolute (Medtronic Inc., Santa Rosa, California, USA, n = 23), and Orsiro (Biotronik, Bulach, Switzerland, n = 11).
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Fig. 1: Study flow.
This study was performed in accordance with the recommendations of the Declaration of Helsinki (1975). The study protocol was approved by the Institutional Review Committee of Gunma University Hospital, and the requirement to obtain informed consent from the patients was waived due to the retrospective and observational nature of the study. Patient information, including clinical data and events, was acquired from electronic medical records, clinical visits, and telephone interviews with our hospital or a primary care physician.
Definitions and procedures
SER was defined as a percent diameter stenosis >50%, including lesions within 5 mm proximal or distal to the stent edge. PCI was performed according to standard clinical practice techniques. Before PCI, all patients were administered unfractionated heparin (100 U/kg, intravenously). The activated clotting time was maintained at >300 s during the procedure. DCB was used in compliance with the reported guidelines [18,19]. We followed the recommendation for DCB angioplasty, in which the inflation time was at least 30 s and inflation pressure was at least 7 atm. Imaging modalities, including intravascular ultrasound and optical coherence tomography (OCT), were used for all patients during PCI procedures. The operators determined the details of the PCI procedures, including lesion preparation, balloon selection for predilatation using a semi-compliant balloon, noncompliant balloon, or scoring balloon before DCB or DES, and selection of the device size, balloon pressure, and inflation time. Whether to use the imaging device and perform post-dilatation during the procedures was also left to the operators’ discretion. After PCI, patients received dual antiplatelet therapy (DAPT) for at least 2 months in the DCB group and 6 months in the DES group. The attending physician determined the duration of DAPT administration.
Outcomes
The primary outcome was the occurrence of target-vessel revascularization (TVR). TVR was defined as revascularization of the target vessel, including PCI and bypass surgery, which was performed only in the presence of symptoms and signs of ischemia that were confirmed by testing. The secondary outcomes were all-cause death, major adverse cardiovascular events (MACE), and target lesion revascularization (TLR). MACE was defined as a composite of fatal and nonfatal myocardial infarction (MI) and TLR as repeated clinically indicated percutaneous or surgical revascularization of target lesions. Moreover, nonfatal MI and probable or definite thrombosis were investigated in this study. We defined MI as an elevated cardiac enzyme level with ischemic symptoms or new pathological Q waves on electrocardiogram. According to the Academic Research Consortium [20], probable or definite thrombosis was defined.
Coronary angiography and quantitative and qualitative angiographic analyses
Quantitative and qualitative coronary angiographic analyses were performed in a core laboratory at Gunma University Hospital. Quantitative coronary angiography was performed to measure the reference diameter, minimum lumen diameter, lesion length, and percentage of stenosis before and after the DCB/DES procedure. Measurements were performed using a catheter for calibration and an edge detection system (Goodnet, Goodman Corp., Nagoya, Japan).
Statistics
Continuous variables were expressed as mean ± SD. Categorical variables were expressed as numbers and percentages. Statistical significance was set at P < 0.05. The differences in characteristics and events between the two groups were compared using the unpaired Student’s t-test or Mann–Whitney test for continuous variables; the chi-squared test or two-tailed Fisher’s exact test was used for discrete variables. The propensity score matching (PSM) analysis between the DCB and DES groups was performed to reduce potential confounding and selection bias. We performed propensity matching using the 1:1 nearest neighbor matching technique with a caliper distance of 0.2 times the SD of the logit of the propensity score. We set significant variables and nonsignificant variables that may be related to the outcome (following the parsimonious model), including age, sex, body mass index, hypertension, diabetes mellitus, dyslipidemia, smoking, acute coronary syndrome, chronic kidney disease, hemodialysis, periferal vascular disease, prior coronary artery bypass grafting, prior myocardial infarction, atrial fibrillation, left ventricular ejection fraction, prior DES, prior BMS, medication (the use of aspirin, P2Y12 inhibitor, anticoagulation), multivessel disease, left main coronary artery, bifurcation lesion, chronic total occlusion, lesion length, minimal lumen diameter, reference vessel diameter, and diameter stenosis. Multivariable logistic regression was performed using the minimum Akaike Information criterion for variable selection and all variables (P < 0.05) in the univariate analysis as candidates. Univariate Cox regression hazard ratio analysis was used to identify possible primary and secondary outcomes predictors. Multivariable logistic regression models were used to analyze the association between the DCB and DES groups. Hazard ratios were calculated and are presented with 95% confidence intervals (CI). Kaplan–Meier curves were drawn to estimate the time-to-event distributions for different endpoints, and the cumulative incidence of events was evaluated using log-rank tests. Statistical analysis was performed using IBM SPSS (Statistical Package for the Social Sciences) Statistics ver. 24.0 (International Business Machines Corporation, Armonk, New York, USA) and Stata ver.15.0 (Stata Corp LP, College Station, Texas, USA).
Results
This study included 291 patients with SER, 160 treated with DES, and 131 with DCB. The baseline demographic characteristics before matching are listed in Table 1. Compared to the DCB group, the DES group had more frequent diabetes (42.7% vs. 30.6%, P = 0.037) and acute coronary syndrome (26.0% vs. 14.4%, P = 0.017). Other characteristics were similar between the two groups. Table 2 summarizes the baseline procedural characteristics. The DES group showed a longer mean lesion length than that in the DCB group (22.6 ± 6.7 vs. 17.9 ± 6.0, P < 0.001). Chronic total occlusion lesions were treated more often in the DES group (9.2% vs. 2.5%, P = 0.018) than in the DCB group. There were also trends toward greater reference diameter and diameter stenosis in the DES group, although the differences were NS (2.81 ± 0.54 vs. 2.69 ± 0.55, P = 0.063, 75.6 ± 11.9 vs. 73.2 ± 11.6, P = 0.074, respectively). Predilatation during the procedures was performed in almost all groups (83.2% vs. 98.8%; P < 0.001). The scoring balloon was more frequently used for procedures in the DCB group than in the DES group (76.3% vs. 22.9%, P < 0.001), whereas noncompliant balloons were more frequently used in the DES group (31.3% vs. 12.5%, P < 0.001) than in the DCB group. The median follow-up period was 1080 days (interquartile range; 729–1080 days). Most patients underwent follow-up coronary angiography: 76.3% in the DES group and 83.2% in the DCB group. Table 3 shows both groups’ unadjusted primary and secondary endpoints during the follow-up period. The TVR rate in the DCB group was significantly lower than that in the DES group (17.5% vs. 30.5%, P = 0.012). Although MACE was also observed less frequently in the DCB group than in the DES group (21.2% vs. 32.1%, P = 0.044), the rate of all-cause death and TLR showed no significant difference between the two groups. Thrombosis occurred in only two cases in each group.
Table 1 -
Baseline characteristics before propensity matching
|
DCB (n = 160) |
DES (n = 131) |
P value |
SMD |
| Age (years) |
73.09 (10.33) |
72.40 (12.37) |
0.605 |
0.06 |
| Sex (male) |
109 (68.1) |
99 (75.6) |
0.192 |
0.166 |
| BMI (kg/m2) |
23.81 (4.25) |
24.28 (4.14) |
0.343 |
0.112 |
| Hypertension |
131 (81.9) |
109 (83.2) |
0.877 |
0.035 |
| Diabetes |
49 (30.6) |
56 (42.7) |
0.037 |
0.254 |
| Dyslipidemia |
97 (60.6) |
83 (63.4) |
0.716 |
0.056 |
| Family history |
57 (35.6) |
49 (37.4) |
0.807 |
0.037 |
| Smoking |
60 (37.5) |
56 (42.7) |
0.4 |
0.107 |
| ACS |
23 (14.4) |
34 (26.0) |
0.017 |
0.292 |
| CKD |
23 (14.4) |
26 (19.8) |
0.27 |
0.146 |
| Hemodialysis |
9 (5.6) |
11 (8.4) |
0.363 |
0.109 |
| PVD |
35 (21.9) |
38 (29.0) |
0.176 |
0.164 |
| Prior CABG |
12 (7.5) |
7 (5.3) |
0.487 |
0.088 |
| Prior MI |
29 (18.1) |
25 (19.1) |
0.88 |
0.025 |
| Atrial fibrillation |
18 (11.2) |
20 (15.3) |
0.382 |
0.119 |
| LVEF |
56.47 (9.38) |
55.65 (9.53) |
0.462 |
0.087 |
| Prior DES |
130 (81.2) |
111 (84.7) |
0.532 |
0.093 |
| Prior BMS |
29 (18.1) |
20 (15.3) |
0.534 |
0.077 |
| Medications |
| Aspirin |
130 (81.2) |
113 (86.3) |
0.27 |
0.136 |
| P2Y12 inhibitor |
118 (73.8) |
103 (78.6) |
0.408 |
0.115 |
| Anticoagulation |
21 (13.1) |
20 (15.3) |
0.615 |
0.061 |
Figures presented as numbers (percentages) or values are mean ± SD.
ACS, acute coronary syndrome; BMS, bare metal stent; CABG, coronary artery bypass grafting; CKD, chronic kidney dysfunction; DCB, drug-coated balloon; DES, drug-eluting stent; LVEF, left ventricular ejection fraction; MI, myocardial infarction; PVD, peripheral vascular disease; SMD, standardized mean difference.
Table 2 -
Angiographic and procedural characteristics before propensity matching
|
DCB (n = 160) |
DES (n = 131) |
P value |
SMD |
| Target vessel |
| Total number of lesions |
160 |
131 |
|
|
| Multivessel disease |
28 (17.5) |
27 (20.6) |
0.548 |
0.079 |
| Left main coronary artery |
5 (3.1) |
6 (4.6) |
0.551 |
0.076 |
| Left anterior descending coronary artery |
80 (50) |
66 (50.3) |
0.718 |
0.045 |
| Left circumflex coronary artery |
21 (13.1) |
18 (13.7) |
1 |
0.018 |
| Right coronary artery |
54 (33.8) |
41 (31.3) |
0.707 |
0.052 |
| Bifurcation |
26 (16.2) |
24 (18.3) |
0.643 |
0.055 |
| Ostial lesion |
15 (9.4) |
18 (13.7) |
0.268 |
0.137 |
| Chronic total occlusion |
4 (2.5) |
12 (9.2) |
0.018 |
0.287 |
| lesion length (mm) |
17.9 (6.0) |
22.6 (6.7) |
<0.001 |
0.732 |
| Minimal lumen diameter (mm) |
0.78 (0.36) |
0.71 (0.29) |
0.089 |
0.203 |
| Reference vessel diameter (mm) |
2.69 (0.55) |
2.81 (0.54) |
0.063 |
0.22 |
| Diameter stenosis (%) |
73.2 (11.6) |
75.6 (11.9) |
0.074 |
0.211 |
| Devices/procedure |
| Predilatation |
158 (98.8) |
109 (83.2) |
<0.001 |
0.564 |
| Scoring/cutting balloon |
122 (76.2) |
30 (22.9) |
<0.001 |
1.262 |
| Noncompliant balloon |
20 (12.5) |
41 (31.3) |
<0.001 |
0.467 |
| Diameter of DCB/DES (mm) |
2.65 (0.37) |
2.74 (0.37) |
0.03 |
0.257 |
| Length of DCB/DES (mm) |
19.29 (5.7) |
24.08 (6.5) |
<0.001 |
0.784 |
| Intravascular ultrasound use |
127 (79.4) |
110 (84.0) |
0.364 |
0.119 |
| OCT use |
33 (20.6) |
21 (16.0) |
0.364 |
0.119 |
| Maximal pressure (atm) |
12.42 (2.3) |
14.11 (3.2) |
<0.001 |
0.607 |
| Post minimum lumen diameter (mm) |
2.37 (0.49) |
2.43 (0.50) |
0.285 |
0.126 |
| Post-diameter stenosis (%) |
13.21 (4.6) |
13.27 (5.4) |
0.913 |
0.013 |
| Follow-up angiography (%) |
133 (83.1) |
100 (76.3) |
0.184 |
0.169 |
| Follow-up (days) |
892.5 (334.1) |
840.6 (353.1) |
0.2 |
0.151 |
Figures presented as numbers (percentages) or values are mean ± SD.
DCB, drug-coated balloon; DES, drug-eluting stent; OCT, optical coherence tomography; SMD, standardized mean difference.
Table 3 -
Clinical outcomes at follow-up before propensity matching
|
DCB (n = 160) |
DES (n = 131) |
P value |
Hazard ratio |
95% CI |
| TVR |
28 (17.5) |
40 (30.5) |
0.015 |
0.549 |
0.339–0.891 |
| All-cause death |
6 (3.8) |
7 (5.3) |
0.465 |
0.666 |
0.224–1.982 |
| MACE |
34 (21.2) |
42 (32.1) |
0.051 |
0.637 |
0.405–1.002 |
| TLR |
27 (16.9) |
34 (26.0) |
0.072 |
0.628 |
0.380–1.043 |
| MI |
4 (2.5) |
6 (4.6) |
0.288 |
0.504 |
0.142–1.785 |
| Thrombosis |
2 (1.2) |
2 (1.5) |
0.773 |
0.749 |
0.105–5.321 |
Figures presented as numbers (percentage).
CI, confidence interval; DCB, drug-coated balloon; DES, drug-eluting stent; MACE, major adverse cardiovascular events; MI, myocardial infarction; TLR, target lesion revascularization; TVR, target-vessel revascularization.
Because there were differences in the baseline clinical and lesion characteristics between the two groups, PSM was performed to assess patients with comparable baseline characteristics. After propensity matching, 88 matched pairs were extracted, and the groups were compared. Baseline clinical characteristics and periprocedural characteristics were well balanced between the two groups after PSM (Table 4).
Table 4 -
Baseline characteristics after propensity matching
|
DCB (n = 88) |
DES (n = 88) |
P value |
SMD |
| Age (years) |
70.91 ± 10.86 |
72.25 ± 12.88 |
0.456 |
0.113 |
| Sex (male) |
62 (70.5) |
61 (69.3) |
1 |
0.025 |
| BMI (kg/m2) |
24.10 ± 4.22 |
23.98 ± 4.15 |
0.843 |
0.03 |
| Hypertension |
72 (81.8) |
73 (83.0) |
1 |
0.03 |
| Diabetes |
36 (40.9) |
36 (40.9) |
1 |
<0.001 |
| Dyslipidemia |
55 (62.5) |
54 (61.4) |
1 |
0.023 |
| Family history |
34 (38.6) |
34 (38.6) |
1 |
<0.001 |
| Smoking |
39 (44.3) |
34 (38.6) |
0.541 |
0.116 |
| ACS |
19 (21.6) |
16 (18.2) |
0.706 |
0.085 |
| CKD |
15 (17.0) |
17 (19.3) |
0.845 |
0.059 |
| Hemodialysis |
5 (5.7) |
7 (8.0) |
0.766 |
0.09 |
| PVD |
20 (22.7) |
23 (26.1) |
0.726 |
0.079 |
| Prior CABG |
3 (3.4) |
5 (5.7) |
0.72 |
0.109 |
| Prior MI |
16 (18.2) |
15 (17.0) |
1 |
0.03 |
| Atrial fibrillation |
13 (14.8) |
11 (12.5) |
0.827 |
0.066 |
| LVEF (%) |
57.18 ± 9.85 |
56.67 ± 8.40 |
0.711 |
0.056 |
| Prior DES |
73 (83.0) |
74 (84.1) |
1 |
0.031 |
| Prior BMS |
15 (17.0) |
14 (15.9) |
1 |
0.031 |
| Aspirin |
73 (83.0) |
75 (85.2) |
0.837 |
0.062 |
| P2Y12 inhibitor |
70 (79.5) |
65 (73.9) |
0.476 |
0.135 |
| Anticoagulation |
13 (14.8) |
13 (14.8) |
1 |
<0.001 |
| Multivessel disease |
16 (18.2) |
18 (20.5) |
0.849 |
0.058 |
| Left main coronary artery |
3 (3.4) |
5 (5.7) |
0.72 |
0.109 |
| Left anterior descending coronary artery |
45 (51.1) |
45 (51.1) |
1 |
0.066 |
| Left circumflex coronary artery |
13 (14.8) |
11 (12.5) |
0.827 |
<0.001 |
| Right coronary artery |
27 (30.7) |
27 (30.7) |
1 |
<0.001 |
| Bifurcation |
17 (19.3) |
17 (19.3) |
1 |
0.075 |
| Ostial lesion |
8 (9.1) |
10 (11.4) |
0.804 |
0.068 |
| Chronic total occlusion |
2 (2.3) |
3 (3.4) |
1 |
0.045 |
| lesion length (mm) |
20.45 ± 5.93 |
20.19 ± 5.76 |
0.767 |
0.052 |
| Minimal lumen diameter (mm) |
0.76 ± 0.38 |
0.74 ± 0.26 |
0.732 |
0.076 |
| Reference vessel diameter (mm) |
2.75 ± 0.52 |
2.79 ± 0.54 |
0.613 |
0.064 |
| Diameter stenosis (%) |
74.18 ± 11.88 |
74.92 ± 11.53 |
0.672 |
|
Values are n (%).
ACS, acute coronary syndrome; CABG, coronary artery bypass grafting; CKD, chronic kidney dysfunction; DCB, drug-coated balloon; DES, drug-eluting stent; LVEF, left ventricular ejection fraction; MI, myocardial infarction; PVD, peripheral vascular disease; SMD, standardized mean difference.
Table 5 reports the hazard ratios for clinical outcomes in the matched populations. DCB angioplasty for SER treatment was associated with a lower risk of TVR than DES (hazard ratio: 0.549; 95% CI, 0.339–0.891) in the crude data. In contrast, the risk of TVR in the DCB group did not differ significantly from that in the DES group in the propensity score-matched population (hazard ratio: 0.965; 95% CI, 0.523–1.781). Similarly, there was no significant difference in all-cause death (hazard ratio: 0.507; 95% CI, 0.093–2.770), MACE (hazard ratio: 0.812; 95% CI, 0.451–1.462), and TLR (hazard ratio: 0.962; 95% CI, 0.505–1.833) between the two groups. Kaplan–Meier analysis demonstrated the incidence of TVR for the overall and matched populations in both groups (Fig. 2). For the overall population, the TVR rate in the DCB group was lower than that in the DES group (log-rank test, P = 0.013); however, there was no significant difference between the groups in the matched population (log-rank test, P = 0.707).
Table 5 -
Hazard ratios for the clinical outcomes in the matched population
|
Hazard ratio |
95% CI |
P value |
| TVR |
0.965 |
0.523–1.781 |
0.910 |
| All-cause death |
0.507 |
0.093–2.770 |
0.433 |
| MACE |
0.812 |
0.451–1.462 |
0.488 |
| MI |
0.962 |
0.505–1.833 |
0.432 |
| TLR |
0.506 |
0.093–2.763 |
0.906 |
| Thrombosis |
1.016 |
0.064–16.241 |
0.991 |
CI, confidence interval; MACE, major adverse cardiovascular events; MI, myocardial infarction; TLR, target lesion revascularization; TVR, target-vessel revascularization.
Fig. 2: Cumulative incidence of target-vessel revascularization (TVR) in (a) unmatched population and (b) matched population at follow-up.
The multivariate Cox proportional hazards regression is shown in Table 6. Cox proportional survival analysis revealed that acute coronary syndrome (hazard ratio: 0.530; 95% CI, 0.370–0.914; P = 0.022), hemodialysis (hazard ratio: 0.281; 95% CI, 0.133–0.591; P = 0.001), and lesion length (hazard ratio: 1.042; 95% CI, 1.005–1.080; P = 0.024) were identified as predictors of TVR after PCI procedures for SER treatment.
Table 6 -
Predictors of the target-vessel revascularization at Cox multivariate analysis
|
Hazard ratio |
95% CI |
P value |
| Age (years) |
1.023 |
0.998–1.048 |
0.068 |
| Male |
0.640 |
0.359–1.138 |
0.129 |
| Diabetes |
0.681 |
0.414–1.123 |
0.132 |
| ACS |
0.530 |
0.370–0.914 |
0.022 |
| Hemodialysis |
0.281 |
0.133–0.591 |
0.001 |
| PVD |
0.628 |
0.365–1.082 |
0.094 |
| Lesion length (mm) |
1.042 |
1.005–1.080 |
0.024 |
ACS, acute coronary syndrome; CI, confidence interval; PVD, peripheral vascular disease.
Discussion
This study demonstrates that the use of DCB in treating SER has clinical outcomes similar to those of DES. Although several studies have reported that the efficacy and safety of DCB for ISR were comparable to those of DES [2,20], this study has shown that DCB is also useful for patients with SER lesions. SER is caused by a combination of many factors, including negative vessel remodeling, plaque progression, and neointimal hyperplasia [21]. In particular, mechanical injury or hinge motion at the stent edge segment can result in neointimal hyperplasia. Moreover, stent underexpansion and residual plaque are risk factors for SER [22]. Thus, DCB angioplasty is considered well suited for SER because it has been reported to prevent neointimal hyperplasia and negative vessel remodeling [18]. The transfer of antiproliferative drugs from DCB inhibits neointimal growth, which might lead to reduced SER. In addition, DCB therapy has been shown to have further beneficial effects, such as plaque regression, healing responses, and positive vessel remodeling [23,24]. These effects can offset negative remodeling; however, treatment with DCB is reported to be less effective for ISR of DES than that for bare metal stenting [17,25,26]. In the study, patients after DES implantation consisted of 81.3% and 84.7% of the DCB and DES groups, respectively. Nevertheless, the clinical outcomes of the DCB group were comparable to those of the DES group. There were several potential reasons for this promising outcome of DCB for treating SER. One possibility is the use of imaging during the procedure. In fact, evaluation using imaging modalities, including intravascular ultrasound or OCT, was performed in all patients in this study. We used this imaging to assess lesions before and after DES implantation or before DCB angioplasty. This way, restenosis mechanisms that might make DCB treatment ineffective can be managed appropriately. For example, it is reasonable that DCB is not effective for lesions with stent underexpansion because the antiproliferative drugs released by the DCB would not be applied to the vessel walls. In addition, calcified lesions are a risk factor for TLR after DCB treatment [27]; however, it is widely accepted that full coverage of the plaque with DES is important, resulting in the stent edge segment being positioned in a vessel with as little plaque and calcification as possible [28]. These procedures are mandatory to reduce ISR and thrombosis after DES implantation. Nevertheless, despite these precautions, SER with a stent underexpansion or calcification may still occur. High-pressure balloons are more useful in these cases than DCB, which does not have the capability of high-pressure ballooning. If a stent underexpansion in SER is observed with an imaging device, it is more likely that predilatation with a high-pressure balloon will be used to obtain adequate expansion before DES implantation or DCB angioplasty. Accordingly, appropriate predilatation was performed for lesions with stent malapposition, stent underexpansion, or calcified lesions. Thus, imaging modalities are useful for clarifying the mechanisms of SER and increasing the likelihood of successful PCI.
The use of a scoring balloon for predilatation may also enhance the beneficial effects of DCB. Kufner et al. reported that the use of scoring balloons predilatation before DCB angioplasty prevented restenosis after DCB treatment [29]. A scoring balloon can provide sufficient lumen gain and prevent malignant dissection after ballooning. Furthermore, plaque and vessel cracks caused by the scoring balloon might lead to accelerated drug transfer [30]. In this study, scoring balloons were frequently used to modify lesions in the DCB group. As a result, the above-mentioned factors may have contributed to the favorable outcome of DCB treatment for SER, which is comparable to that of new-generation DES.
Metal-free DCB treatment has several advantages for patients. For instance, tortuous lesions are a risk factor for restenosis or stent fracture after stent implantation [31–33]. Moreover, SER can occur after stent implantation due to physical stress at the stent edge segment in tortuous vessels [4]. Thus, SER may be associated with tortuous vessels. Further stent implantation should be avoided; DCB is considered an important option for such vessels. In addition, overlap with the previous stent is inevitable when treating SER using DES, and stent overlap is associated with a higher risk of adverse clinical events such as MI and TLR [34,35]. Likewise, multiple long stent implantations are associated with a high risk of periprocedural MI and stent thrombosis [36,37]. It is important to avoid DES overlap and multiple DES implantations to prevent such clinical events. For these reasons, DCB is a useful option for SER treatment.
Limitations
This study has some limitations. First, the number of enrolled patients was small. In fact, there were very few incidents of death or thrombosis in this study. Therefore, larger sample sizes are needed to obtain more reliable results. Second, this was a retrospective, observational study, which might have led to a selection bias in DCB or DES indications. In addition, patients who underwent DES in this study tended to have more complex lesions than those who underwent DCB. Although PSM was conducted to adjust for confounding factors, it is possible that such factors could not be completely excluded. Consequently, randomized, double-blind studies are required to avoid these potential biases. Third, we assessed the study outcomes at 3 years; however, a longer follow-up period may be required to clarify accurate outcomes. Fourth, the DAPT duration determined by the attending physician was a concern in this study. We could not evaluate the details of the DAPT duration, which may be related to clinical outcomes. Finally, this study did not mention the assessment of ISR with imaging modalities. The association between clinical outcomes in patients who undergo PCI and the mechanism of ISR occurrence should be studied further.
Conclusion
This study showed that, after PSM, the rate of TVR in patients treated with DCB for SER was comparable to that in patients treated with new-generation DES. In addition, long-term outcomes of DCB treatment, including all-cause death, MACE, and TLR, were equivalent to those of DES treatment. Therefore, DCB is an important treatment option for patients with SER.
Acknowledgement
Conflicts of interest
There are no conflicts of interest.
References
1. Aoki J, Tanabe K. Mechanisms of drug-eluting stent restenosis. Cardiovasc Interv Ther 2021; 36:23–29.
2. Baan J Jr, Claessen BE, Dijk KB van, Vendrik J, van der Schaaf RJ, Meuwissen M, et al. A randomized comparison of paclitaxel-eluting balloon versus everolimus-eluting stent for the treatment of any in-stent restenosis: the DARE trial. JACC Cardiovasc Interv 2018; 11:275–283.
3. Tamez H, Secemsky EA, Valsdottir LR, Moussa ID, Song Y, Simonton CA, et al. Long-term outcomes of percutaneous coronary intervention for in-stent restenosis among Medicare beneficiaries. EuroIntervention 2021; 17:e380–e387.
4. Kim YG, Oh IY, Kwon YW, Han JK, Yang HM, Park KW, et al. Mechanism of edge restenosis after drug-eluting stent implantation. Angulation at the edge and mechanical properties of the stent. Circ J 2013; 77:2928–2935.
5. Sakurai R, Ako J, Morino Y, Sonoda S, Kaneda H, Terashima M, et al.; SIRIUS Trial Investigators. Predictors of edge stenosis following sirolimus-eluting stent deployment (a quantitative intravascular ultrasound analysis from the SIRIUS trial). Am J Cardiol 2005; 96:1251–1253.
6. Kitahara H, Okada K, Kimura T, Yock PG, Lansky AJ, Popma JJ, et al. Impact of stent size selection on acute and long-term outcomes after drug-eluting stent implantation in de novo coronary lesions. Circ Cardiovasc Interv 2017; 10. doi:
http://dx.doi.org/10.1161/CIRCINTERVENTIONS.116.004795.
7. Ino Y, Kubo T, Matsuo Y, Yamaguchi T, Shiono Y, Shimamura K, et al. Optical coherence tomography predictors for edge restenosis after everolimus-eluting stent implantation. Circ Cardiovasc Interv 2016; 9. doi:
http://dx.doi.org/10.1161/CIRCINTERVENTIONS.116.004231.
8. Jimba T, Ikutomi M, Tsukamoto A, Matsushita M, Yamasaki M. Effect of hinge motion on stent edge-related restenosis after right coronary artery treatment in the current drug-eluting stent era. Circ J 2021; 85:1959–1968.
9. 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 2021; 17:489–496.
10. Shlofmitz E, Torguson R, Zhang C, Mintz GS, Dheendsa A, Khalid N, et al. Impact of intravascular ultrasound on outcomes following PErcutaneous coronary interventioN for In-stent Restenosis (iOPEN-ISR study). Int J Cardiol 2021; 340:17–21.
11. Kang SJ, Mintz GS, Park DW, Lee SW, Kim YH, Whan Lee C, et al. Mechanisms of in-stent restenosis after drug-eluting stent implantation: intravascular ultrasound analysis: intravascular ultrasound analysis. Circ Cardiovasc Interv 2011; 4:9–14.
12. Shimono H, Kajiya T, Takaoka J, Miyamura A, Inoue T, Kitazono K, et al. Characteristics of recurrent in-stent restenosis after second- and third-generation drug-eluting stent implantation. Coron Artery Dis 2021; 32:36–41.
13. Jeger RV, Farah A, Ohlow MA, Mangner N, Möbius-Winkler S, Weilenmann D, et al.; BASKET-SMALL 2 Investigators. Long-term efficacy and safety of drug-coated balloons versus
drug-eluting stents for small coronary artery disease (BASKET-SMALL 2): 3-year follow-up of a randomised, non-inferiority trial. Lancet 2020; 396:1504–1510.
14. Cortese B, Di Palma G, Guimaraes MG, Piraino D, Orrego PS, Buccheri D, et al.
Drug-coated balloon versus drug-eluting stent for small coronary vessel disease: PICCOLETO II randomized clinical trial. JACC Cardiovasc Interv 2020; 13:2840–2849.
15. Song CX, Zhou C, Hou W, Yin Y, Lu S, Liu G, et al. Drug-eluting balloons versus
drug-eluting stents for small vessel coronary artery disease: a meta-analysis: a meta-analysis. Coron Artery Dis 2020; 31:199–205.
16. Kokkinidis DG, Prouse AF, Avner SJ, Lee JM, Waldo SW, Armstrong EJ. Second-generation
drug-eluting stents versus drug-coated balloons for the treatment of coronary in-stent restenosis: a systematic review and meta-analysis. Catheter Cardiovasc Interv 2018; 92:285–299.
17. Giacoppo D, Alfonso F, Xu B, Claessen BEPM, Adriaenssens T, Jensen C, et al.
Drug-coated balloon angioplasty versus drug-eluting stent implantation in patients with coronary stent restenosis. J Am Coll Cardiol 2020; 75:2664–2678.
18. Jeger RV, Eccleshall S, Wan Ahmad WA, Ge J, Poerner TC, Shin ES, et al.; International DCB Consensus Group. Drug-coated balloons for coronary artery disease: third report of the International DCB Consensus Group. JACC Cardiovasc Interv 2020; 13:1391–1402.
19. Ryan TJ, Faxon DP, Gunnar RM, Kennedy JW, King SB 3rd, Loop FD, et al. Guidelines for percutaneous transluminal coronary angioplasty. A report of the American College of Cardiology/American Heart Association Task Force on assessment of diagnostic and therapeutic cardiovascular procedures (subcommittee on percutaneous transluminal coronary angioplasty). Circulation 1988; 78:486–502.
20. Cutlip DE, Windecker S, Mehran R, Boam A, Cohen DJ, van Es GA, et al.; Academic Research Consortium. Clinical end points in coronary stent trials: a case for standardized definitions: a case for standardized definitions. Circulation 2007; 115:2344–2351.
21. Wang Y, Lou X, Xu X, Zhu J, Shang Y. Drug-eluting balloons versus
drug-eluting stents for the management of in-stent restenosis: a meta-analysis of randomized and observational studies. J Cardiol 2017; 70:446–453.
22. Gogas BD, Garcia-Garcia HM, Onuma Y, Muramatsu T, Farooq V, Bourantas CV, et al. Edge vascular response after percutaneous coronary intervention: an intracoronary ultrasound and optical coherence tomography appraisal: from radioactive platforms to first- and second-generation
drug-eluting stents and bioresorbable scaffolds. JACC Cardiovasc Interv 2013; 6:211–221.
23. Kang SJ, Cho YR, Park GM, Ahn JM, Kim WJ, Lee JY, et al. Intravascular ultrasound predictors for edge restenosis after newer generation drug-eluting stent implantation. Am J Cardiol 2013; 111:1408–1414.
24. Kleber FX, Schulz A, Waliszewski M, Hauschild T, Böhm M, Dietz U, et al. Local paclitaxel induces late lumen enlargement in coronary arteries after balloon angioplasty. Clin Res Cardiol 2015; 104:217–225.
25. Funayama N, Kayanuma K, Sunaga D, Yamamoto T. Serial assessment of de novo coronary lesions after
drug-coated balloon treatment analyzed by intravascular ultrasound: a comparison between acute coronary syndrome and stable angina pectoris. Int J Cardiol 2021; 330:35–40.
26. Zhu Y, Liu K, Kong X, Nan J, Gao A, Liu Y, et al. Comparison of
drug-coated balloon angioplasty vs. drug-eluting stent implantation for drug-eluting stent restenosis in the routine clinical practice: a meta-analysis of randomized controlled trials. Front Cardiovasc Med 2021; 8:766088.
27. Peng N, Liu W, Li Z, Wei J, Chen X, Wang W, et al. Drug-coated balloons versus everolimus-eluting stents in patients with in-stent restenosis: a pair-wise meta-analysis of randomized trials. Cardiovasc Ther 2020; 2020:1042329.
28. Cortese B, D’Ascenzo F, Fetiveau R, Balian V, Blengino S, Fineschi M, et al. Treatment of coronary artery disease with a new-generation
drug-coated balloon: final results of the Italian Elutax SV rEgistry-DCB-RISE. J Cardiovasc Med (Hagerstown) 2018; 19:247–252.
29. Costa MA, Angiolillo DJ, Tannenbaum M, Driesman M, Chu A, Patterson J, et al.; STLLR Investigators. Impact of stent deployment procedural factors on long-term effectiveness and safety of sirolimus-eluting stents (final results of the multicenter prospective STLLR trial). Am J Cardiol 2008; 101:1704–1711.
30. Kufner S, Joner M, Schneider S, Tölg R, Zrenner B, Repp J, et al.; ISAR-DESIRE 4 Investigators. Neointimal modification with scoring balloon and efficacy of
drug-coated balloon therapy in patients with restenosis in drug-eluting coronary stents. JACC Cardiovasc Interv 2017; 10:1332–1340.
31. Bonaventura K, Schwefer M, Yusof AKM, Waliszewski M, Krackhardt F, Steen P, et al. Systematic scoring balloon lesion preparation for
drug-coated balloon angioplasty in clinical routine: results of the PASSWORD observational study. Adv Ther 2020; 37:2210–2223.
32. Ino Y, Kubo T, Kitabata H, Shimamura K, Shiono Y, Orii M, et al. Impact of hinge motion on in-stent restenosis after sirolimus-eluting stent implantation. Circ J 2011; 75:1878–1884.
33. Park SM, Kim JY, Hong BK, Lee BK, Min PK, Rim S, et al. Predictors of stent fracture in patients treated with closed-cell design stents: sirolimus-eluting stent and its bare-metal counterpart, the BX velocity stent. Coron Artery Dis 2011; 22:40–44.
34. Kawai T, Umeda H, Ota M, Hattori K, Ishikawa M, Okumura M, et al. Do drug elution components increase the risk of fracture of sirolimus-eluting stents? Coron Artery Dis 2010; 21:298–303.
35. O’Sullivan CJ, Stefanini GG, Räber L, Heg D, Taniwaki M, Kalesan B, et al. Impact of stent overlap on long-term clinical outcomes in patients treated with newer-generation
drug-eluting stents. EuroIntervention 2014; 9:1076–1084.
36. Coughlan JJ, Aytekin A, Koch T, Wiebe J, Lenz T, Cassese S, et al. Long-term clinical outcomes after drug eluting stent implantation with and without stent overlap. Catheter Cardiovasc Interv 2022; 99:541–551.
37. Serruys PW, Foley DP, Suttorp MJ, Rensing BJWM, Suryapranata H, Materne P, et al. A randomized comparison of the value of additional stenting after optimal balloon angioplasty for long coronary lesions. J Am Coll Cardiol 2002; 39:393–399.
