Abstract
Background: Endovascular therapy (EVT) with a drug-coated balloon (DCB) is an established treatment for patients with atherosclerotic lesions in the femoropopliteal (FP) artery, including complex lesions. Currently, 3 types of DCBs are available, but the most effective DCB for FP chronic total occlusive (CTO) lesions is unknown.
Methods and Results: In this retrospective, single-center study, we enrolled 539 consecutive patients (562 FP lesions) treated with EVT between January 2018 and December 2022. Of these patients, 161 with FP CTO lesions who underwent EVT with DCBs were included. Propensity-score matching was performed to compare the clinical outcomes of the high-dose (HD) and low-dose (LD) DCB groups, resulting in the analysis of 56 matched pairs. Primary patency and freedom from target lesion revascularization were significantly higher with HD-DCB than with LD-DCB (89.9% vs. 70.8%, respectively P=0.03; and 93.6% vs. 79.7%, respectively, P=0.046). Multivariate analysis showed that a larger minimum lumen area and the use of HD-DCB (vs. LD-DCB) were favorable predictors of primary patency at 1 year, while a small vessel diameter (≤4.5 mm) was an unfavorable predictor.
Conclusions: For FP CTO lesions, EVT performed with HD-DCB is superior to that with LD-DCB.
Advances in medical devices have markedly improved the outcomes of endovascular therapy (EVT) for femoropopliteal (FP) artery occlusion. Among them, drug-coated balloons (DCBs) have gained prominence in the treatment of FP artery disease, particularly in regard to the “leave nothing behind” approach,1,2 which minimizes the implantation of permanent devices, thereby reducing potential long-term complications related to stent implantation.3–5
Several clinical trials have shown the efficacy of EVT using DCBs for FP lesions.6–8 Currently, 3 types of DCBs are available in Japan for this purpose: IN.PACT Admiral (Medtronic Vascular, Santa Clara, CA, USA), Lutonix (Becton Dickson and Company, Franklin Lakes, NJ, USA), and Ranger (Boston Scientific, Marlborough, MA, USA). On the basis of the paclitaxel concentration usage (3.5 μg/mm2
or 2.0 μg/mm2),6–8 the IN.PACT Admiral is considered to be a high-dose (HD) DCB, while Lutonix and Ranger are defined as low-dose (LD) DCBs.9–12 Although it is generally accepted that the efficacy of HD-DCB and LD-DCB does not significantly differ when treating simple lesions,9–11 the optimal choice for complex lesions such as chronic total occlusive (CTO) lesions has not been definitively established.
In this study we compared the efficacy of HD-DCB and LD-DCB in the treatment of FP artery CTO lesions, with the goal of clarifying guidance on the optimal DCB strategy for these challenging lesions and thereby enhancing clinical decision-making and patient outcomes in EVT.
Methods
Study Population
This retrospective, single-center, observational study initially enrolled 539 consecutive patients (562 lesions) with FP artery disease who underwent EVT at Miyazaki Medical Association Hospital between January 2018 and December 2022. Of them, 79 patients (79 lesions) with recurrent FP lesions, 197 patients (197 lesions) with stenotic lesions, and 102 patients (102 lesions) who were treated with modalities other than DCB were excluded. In addition, 23 lesions treated in the contralateral limb of the same patient were excluded. Ultimately, the study population consisted of 161 patients with FP CTO lesions (161 lesions) who underwent EVT with 1 of the aforementioned DCB types (IN.PACT Admiral, Lutonix, or Ranger) (Figure 1). Follow-up information was obtained from hospital charts or by contacting patients or referring physicians. The median follow-up duration was 470 (interquartile range, 238–881) days.
This study was conducted in accordance with the tenets of the Declaration of Helsinki and approved by the Institutional Review Board of Miyazaki Medical Association Hospital (no. 2024-30).
EVT Procedure
The ipsilateral common femoral artery or contralateral common femoral artery was selected as the approach site. In this study, the guiding sheath was 5 or 6 Fr. After insertion of the guiding sheath, 5,000 IU of heparin was injected, with 1,000 IU administered every hour thereafter. We used a 0.014-inch guidewire supported by a microcatheter for all patients undergoing initial antegrade approaches with fluoroscopy imaging. After crossing the FP lesion, the lesion was evaluated using intravascular ultrasound (IVUS). The entire lesion was first dilated from 2.0 mm to 4.0 mm, followed by predilatation with an optimally sized balloon. Based on angiographic or IVUS findings, additional balloon dilation was performed using a scoring balloon or high-pressure balloon as needed. After balloon angioplasty, the DCB was inflated for 180s. The type, length, and size of the balloon, as well as the selection of DCB, were left to the discretion of each operator. All patients were advised to continue LD aspirin therapy (81–162 mg/day) and a P2Y12 inhibitor (75 mg of clopidogrel daily or 3.75 mg of prasugrel daily) for a minimum of 1 month after EVT.
Quantitative Vascular Angiography (QVA) Analysis
QVA analysis was performed at baseline and after EVT using an automated edge-detection system (CAAS 5.9; Pie Medical Imaging BV, Maastricht, The Netherlands). Analyses were performed by 2 experienced observers (K.N. and Y.H.) who were blinded to the patients’ characteristics.
Definitions
The primary outcome of the study was primary patency, and the secondary outcomes were freedom from target lesion revascularization (TLR), freedom from recurrent occlusion, overall survival, and limb salvage. Primary patency was defined as the absence of restenosis and TLR. Restenosis was defined as a peak systolic velocity ratio >2.4 or occlusion, both observed on duplex ultrasound, or >50% diameter stenosis or occlusion on follow-up angiography. TLR was defined as the need for revascularization. Limb salvage was defined as the avoidance of amputation above the ankle. The degree of lesion calcification on angiography was assessed using the Peripheral Arterial Calcification Scoring System (PACSS).13 The degree of vascular dissection was classified into 1 of 6 grades (A–F) according to previously reported criteria for coronary artery dissection.14 Procedural success was defined as residual stenosis <50% without grade D or higher.15
The IN.PACT Admiral is defined as a HD-DCB because its paclitaxel concentration is 3.5 μg/mm2, whereas the Ranger and Lutonix are defined as LD-DCBs because their concentration is 2.0 μg/mm2. Non-ambulatory status was defined as being either in a wheelchair or bedridden at the time of admission. Risk factors of cardiovascular disease were hypertension (>140/90 mmHg or use of antihypertensive medications), dyslipidemia (high-density lipoprotein cholesterol <40 mg/dL, low-density lipoprotein cholesterol ≥140 mg/dL, or use of lipid-lowering medications) and diabetes mellitus (fasting plasma glucose level ≥126 mg/dL, plasma glucose level ≥200 mg/dL 2 h after an oral glucose tolerance test, hemoglobin A1c ≥6.5%, or use of medications for diabetes mellitus). Chronic kidney disease was defined as renal dysfunction or a glomerular filtration rate <60 mL/min/1.73 m2
on admission.
Follow-up Assessment
After discharge, patients were followed by their physicians in an outpatient setting. Follow-up intervals and methods were left to the physician’s discretion. Typically, patients were seen 1, 3, 6, and 12 months after EVT. TLR was clinically indicated for patients with recurrent symptoms related to limb ischemia.
Statistical Analysis
To avoid the potential effects of a nonrandomized study design, a propensity score was calculated using a multivariate logistic regression model with the use of HD-DCB or LD-DCB as the dependent valuable. Continuous variables are presented as means and standard deviations or medians and interquartile ranges, as appropriate. Categorical variables are expressed as numbers and percentages. Primary patency, freedom from TLR, freedom from occlusion, overall survival, and limb salvage were assessed using the Kaplan-Meier method; differences were evaluated using the log-rank test. A multivariable Cox proportional hazards model was used to identify predictors of 1-year restenosis, with adjustment for variables that had a P value <0.1 in the univariate analysis. Results are expressed as hazard ratios (HRs) with 95% confidence intervals (CIs). All analyses were performed using SPSS version 19 (IBM Corp., Somers, NY, USA), and statistical significance was considered at P<0.05 in a two-tailed test.
Results
Patients’ and Lesion Characteristics
Of the 161 patients, 102 and 59 were classified into the HD-DCB and LD-DCB groups, respectively. Patients and lesions characteristics are shown in Table 1. Compared with patients in the LD-DCB group, those in the HD-DCB group were younger and the lesion length was shorter.
Table 1.
Patients’ and Lesion Characteristics
| |
Before matching |
After matching |
HD-DCB
(n=102) |
LD-DCB
(n=59) |
P value |
HD-DCB
(n=56) |
LD-DCB
(n=56) |
P value |
| Age, years |
73.8±8.5 |
77.6±8.5 |
0.004 |
75.6±7.5 |
77.1±8.2 |
0.31 |
| Male, n (%) |
66 (64.7) |
39 (66.1) |
1.00 |
34 (60.7) |
37 (66.1) |
0.70 |
| BMI |
23.1±3.5 |
22.3±3.3 |
0.15 |
22.7±3.4 |
22.3±3.3 |
0.48 |
| Non-ambulatory, n (%) |
14 (13.7) |
15 (25.4) |
0.09 |
9 (16.1) |
14 (25.0) |
0.35 |
| Hypertension, n (%) |
97 (95.1) |
54 (91.5) |
0.50 |
53 (94.6) |
52 (92.9) |
1.00 |
| Dyslipidemia, n (%) |
86 (84.3) |
47 (79.7) |
0.52 |
46 (82.1) |
46 (82.1) |
1.00 |
| Diabetic mellitus, n (%) |
53 (52.0) |
33 (55.9) |
0.74 |
27 (48.2) |
31 (55.4) |
0.57 |
| Current smoker, n (%) |
15 (14.7) |
8 (13.6) |
1.00 |
6 (10.7) |
8 (14.3) |
0.78 |
| CKD, n (%) |
63 (61.8) |
40 (67.8) |
0.50 |
39 (69.6) |
37 (66.1) |
0.84 |
| eGFR |
50.7±25.0 |
46.5±21.8 |
0.29 |
46.7±23.6 |
47.5±21.5 |
0.86 |
| Hemodialysis, n (%) |
15 (14.7) |
8 (13.6) |
1.00 |
9 (16.1) |
7 (12.5) |
0.79 |
| Chronic heart failure, n (%) |
12 (11.8) |
9 (15.3) |
0.63 |
7 (12.5) |
9 (16.1) |
0.79 |
| Ischemic heart disease, n (%) |
43 (42.2) |
21 (35.6) |
0.50 |
23 (41.1) |
21 (37.5) |
0.85 |
| Atrial fibrillation, n (%) |
6 (5.9) |
6 (10.2) |
0.36 |
5 (8.9) |
5 (8.9) |
1.00 |
| Cerebral infarction, n (%) |
5 (4.9) |
8 (13.6) |
0.07 |
5 (8.9) |
8 (14.3) |
0.56 |
| CLTI, n (%) |
19 (18.6) |
19 (32.2) |
0.06 |
14 (25.0) |
17 (30.4) |
0.52 |
| Rutherford class |
|
|
0.36 |
|
|
0.55 |
| 2 |
33 (32.4) |
18 (30.5) |
|
15 (26.8) |
18 (32.1) |
|
| 3 |
50 (49.0) |
22 (37.3) |
|
27 (48.2) |
21 (37.5) |
|
| 4 |
5 (4.9) |
5 (8.5) |
|
4 (7.1) |
5 (8.9) |
|
| 5 |
11 (9.8) |
12 (20.3) |
|
7 (12.5) |
11 (19.6) |
|
| 6 |
3 (2.9) |
2 (3.4) |
|
3 (5.4) |
1 (1.8) |
|
| Aspirin, n (%) |
83 (81.4) |
43 (72.9) |
0.24 |
44 (78.6) |
41 (73.2) |
0.66 |
| P2Y12-inhibitor, n (%) |
95 (93.1) |
58 (98.3) |
0.26 |
54 (96.4) |
55 (98.2) |
1.00 |
| Cilostazol, n (%) |
13 (12.7) |
10 (16.9) |
0.49 |
6 (10.7) |
9 (16.1) |
0.58 |
| Warfarin, n (%) |
3 (2.9) |
0 (0) |
0.30 |
2 (3.6) |
0 (0) |
0.50 |
| DOAC, n (%) |
13 (12.7) |
13 (22.0) |
0.18 |
9 (16.1) |
12 (21.4) |
0.63 |
| RAS-inhibitor, n (%) |
61 (59.8) |
33 (55.9) |
0.74 |
31 (55.4) |
32 (57.1) |
1.00 |
| β-blocker, n (%) |
27 (26.5) |
20 (33.9) |
0.37 |
15 (26.8) |
20 (35.7) |
0.42 |
| Statin, n (%) |
71 (69.6) |
43 (72.9) |
0.72 |
36 (64.3) |
43 (76.8) |
0.21 |
| Insulin, n (%) |
8 (7.8) |
6 (10.2) |
0.77 |
5 (8.9) |
5 (8.9) |
1.00 |
| PACSS grade |
|
|
0.22 |
|
|
0.22 |
| 0 |
53 (52.0) |
31 (52.5) |
|
28 (50) |
30 (53.6) |
|
| 1 |
21 (20.6) |
9 (15.3) |
|
12 (21.4) |
8 (14.3) |
|
| 2 |
11 (10.8) |
10 (16.9) |
|
4 (7.1) |
9 (16.1) |
|
| 3 |
6 (5.9) |
0 (0) |
|
3 (5.4) |
0 (0) |
|
| 4 |
11 (10.8) |
9 (15.3) |
|
9 (16.1) |
9 (16.1) |
|
| TASCII classification |
|
|
0.49 |
|
|
0.53 |
| Class A, n (%) |
1 (1.0) |
2 (3.4) |
|
0 (0) |
2 (3.6) |
|
| Class B, n (%) |
37 (36.3) |
16 (27.1) |
|
14 (25) |
15 (26.8) |
|
| Class C, n (%) |
19 (18.6) |
11 (18.6) |
|
13 (23.2) |
11 (19.6) |
|
| Class D, n (%) |
45 (44.1) |
30 (50.8) |
|
29 (51.8) |
28 (50) |
|
| GLASS FP grade |
|
|
0.62 |
|
|
0.84 |
| Grade 1, n (%) |
6 (5.9) |
2 (3.4) |
|
2 (3.6) |
2 (3.6) |
|
| Grade 2, n (%) |
14 (13.7) |
9 (15.3) |
|
6 (10.7) |
9 (16.1) |
|
| Grade 3, n (%) |
39 (38.2) |
18 (30.5) |
|
20 (35.7) |
17 (30.4) |
|
| Grade 4, n (%) |
43 (42.1) |
30 (50.8) |
|
28 (50) |
28 (50) |
|
| History of treatment for aortoiliac lesions, n (%) |
65 (63.7) |
40 (67.8) |
0.73 |
34 (60.7) |
37 (66.1) |
0.70 |
| Additional treatment for below-the-knee arteries, n (%) |
5 (4.9) |
8 (13.6) |
0.07 |
3 (5.4) |
6 (10.7) |
0.49 |
| Including popliteal artery |
49 (48.0) |
32 (54.2) |
0.51 |
28 (50) |
30 (53.6) |
0.85 |
| No. of runoff vessels |
1.78±0.80 |
1.73±0.85 |
0.68 |
1.73±0.77 |
1.77±0.85 |
0.82 |
| No runoff, n (%) |
6 (5.9) |
6 (10.2) |
0.36 |
2 (3.6) |
6 (10.7) |
0.27 |
| Runoff vessel |
|
|
0.67 |
|
|
0.20 |
| 0 |
6 (5.9) |
6 (10.2) |
|
5 (8.9) |
6 (10.7) |
|
| 1 |
28 (27.5) |
13 (22.3) |
|
20 (35.7) |
10 (17.9) |
|
| 2 |
50 (49.0) |
31 (5.1) |
|
23 (41.1) |
31 (55.4) |
|
| 3 |
18 (17.6) |
9 (15.3) |
|
8 (14.3) |
9 (16.1) |
|
| Previous ABI |
0.45±0.23 |
0.48±0.23 |
0.54 |
0.47±0.25 |
0.47±0.23 |
0.94 |
| Reference diameter, mm |
5.12±0.81 |
5.32±0.71 |
0.12 |
5.31±0.73 |
5.31±0.71 |
0.99 |
| Lesion length, cm |
27.8±9.2 |
32.8±11.0 |
0.002 |
29.7±8.9 |
32.2±10.9 |
0.20 |
| CTO length, cm |
17.0±8.1 |
18.0±9.0 |
0.47 |
17.8±7.7 |
17.7±9.0 |
0.91 |
| Nodular calcification, n (%) |
8 (7.8) |
5 (8.5) |
1.00 |
4 (7.1) |
5 (8.9) |
1.00 |
| Small vessel diameter (≤4.5 mm), n (%) |
25 (24.5) |
9 (15.3) |
0.23 |
12 (21.4) |
9 (16.1) |
0.63 |
| IVUS findings |
| Proximal EEM, mm |
6.37±0.77 |
6.43±0.95 |
0.72 |
6.35±0.80 |
6.37±0.78 |
0.89 |
| Proximal lumen, mm |
5.24±0.77 |
5.43±0.65 |
0.11 |
5.14±0.76 |
5.83±0.89 |
0.06 |
| Distal EEM, mm |
5.80±0.83 |
5.83±0.75 |
0.81 |
5.72±0.81 |
5.86±0.75 |
0.33 |
| Distal lumen, mm |
4.71±0.67 |
4.87±0.64 |
0.15 |
4.65±0.64 |
4.89±0.65 |
0.06 |
| MLA, mm2 |
1.83±0.70 |
1.81±0.86 |
0.89 |
1.85±0.81 |
1.83±0.87 |
0.92 |
| Calcification arc >180°, n (%) |
18 (17.6) |
10 (16.9) |
1.00 |
13 (23.2) |
10 (17.9) |
0.64 |
Values are presented as mean±SD or n (%). ABI, ankle-brachial index; BMI, body mass index; CKD, chronic kidney disease; CLTI, chronic limb-threatening ischemia; CTO, chronic total occlusion; DOAC, direct oral anticoagulant; EEM, external elastic membrane; FP, femoropopliteal; GLASS, Global Limb Anatomic Staging System; HD-DCB, high-dose drug-coated balloon; IVUS, intravascular ultrasound; LD-DCB, low-dose drug-coated balloon; MLA, minimum lumen area; PACSS, Peripheral Arterial Calcification Scoring System; RAS, renin-angiotensin system; TASC, Trans-Atlantic Inter-Society Consensus.
Because of the significant differences in patient and lesion characteristics between groups, propensity-score matching was performed before comparing clinical outcomes; 56 matched pairs of patients were included in the analysis. Patient and lesion characteristics were comparable between groups, including reference diameter on QVA (HD-DCB vs. LD-DCB: 5.31±0.73 vs. 5.31±0.71 mm, P=0.22), lesion length (HD-DCB vs. LD-DCB: 29.7±8.9 vs. 32.2±10.9 cm, P=0.20) and CTO lesion length (HD-DCB vs. LD-DCB: 17.8±7.7 vs. 17.7±9.0cm, P=0.91) (Table 1). Overall, this study included a high percentage of patients with intermittent claudication (Rutherford class 2 or 3), but there was no significant difference between the groups (HD-DCB vs. LD-DCB: 75.0% vs. 69.6%, respectively, P=0.56). In addition, the percentage of patients with severe calcification defined as PACSS grade 3 or 4 was approximately 20% in both groups (HD-DCB vs. LD-DCB: 21.5% vs. 16.1%, respectively, P=0.22).
Procedural Characteristics
Procedural characteristics are shown in Table 2. The DCB length was significantly shorter in the HD-DCB group than in the LD-DCB group. Because of this difference, propensity-score matching was performed before comparing clinical outcomes; 56 matched pairs of patients were included in the analysis, and procedural characteristics were comparable between groups. There were no significant differences in the preparation method, such as balloon diameter, balloon length, number of balloons, use of scoring balloon and chocolate balloon, between groups. After using a DCB, postprocedural minimum lumen diameter on QVA (HD-DCB vs. LD-DCB: 1.04±0.58 vs. 0.97±0.52 mm, P=0.49), and postprocedural minimum lumen area (HD-DCB vs. LD-DCB: 14.0±3.7 vs. 14.4±4.4 mm2, P=0.58) were similar in both groups. In both groups, the percentage of patients with residual stenosis >50% was very low, the percentage of dissection ≥grade C was approximately 30%, and the procedural success rate was approximately 80% (Table 2).
Table 2.
Procedural Characteristics
| |
Before matching |
After matching |
HD-DCB
(n=102) |
LD-DCB
(n=59) |
P value |
HD-DCB
(n=56) |
LD-DCB
(n=56) |
P value |
| Balloon diameter, mm |
5.48±0.61 |
5.66±0.63 |
0.07 |
5.53±0.53 |
5.67±0.64 |
0.23 |
| Balloon length, mm |
153.9±60.6 |
172.2±75.8 |
0.12 |
155.2±61.1 |
166.4±73.1 |
0.38 |
| Number of balloons, n |
2.38±0.82 |
2.32±0.82 |
0.65 |
2.38±0.65 |
2.14±0.59 |
0.66 |
| Use of scoring balloon, n (%) |
31 (30.4) |
21 (35.6) |
0.60 |
17 (30.4) |
20 (35.7) |
0.69 |
| Use of chocolate balloon, n (%) |
15 (14.7) |
11 (18.6) |
0.51 |
10 (17.9) |
11 (19.6) |
0.81 |
| DCB diameter, mm |
5.55±0.57 |
5.71±0.67 |
0.11 |
5.57±0.54 |
5.71±0.68 |
0.22 |
| DCB length, mm |
303.9±93.4 |
340.1±114.5 |
0.02 |
317.9±90.0 |
340.7±117.1 |
0.25 |
| Number of DCBs, n |
2.26±0.66 |
2.15±0.58 |
0.28 |
2.35±0.62 |
2.12±0.58 |
0.06 |
| Dissection grade, n (%) |
|
|
0.07 |
|
|
0.32 |
| None |
14 (13.7) |
16 (27.1) |
|
10 (17.9) |
16 (28.6) |
|
| A |
18 (17.6) |
4 (6.8) |
|
11 (19.6) |
4 (7.1) |
|
| B |
37 (36.3) |
19 (32.2) |
|
18 (32.1) |
18 (32.1) |
|
| C |
17 (16.7) |
9 (15.3) |
|
7 (12.5) |
8 (14.3) |
|
| D |
16 (15.7) |
11 (18.6) |
|
10 (17.9) |
10 (17.9) |
|
| E and F |
0 (0) |
0 (0) |
|
0 (0) |
0 (0) |
|
| Provisional stenting, n (%) |
0 (0) |
0 (0) |
1.00 |
0 (0) |
0 (0) |
1.00 |
| Postprocedural stenosis, % |
20.3±11.3 |
17.9±9.0 |
0.17 |
19.4±10.8 |
17.6±9.1 |
0.33 |
| Postprocedural MLD, mm |
1.12±0.63 |
1.07±0.62 |
0.63 |
1.04±0.58 |
0.97±0.52 |
0.49 |
| Postprocedural stenosis >50%, n (%) |
3 (2.9) |
3 (5.1) |
0.67 |
1 (1.8) |
2 (3.6) |
1.00 |
| Postprocedural MLA (mm2) |
14.3±3.8 |
14.5±4.3 |
0.83 |
14.0±3.7 |
14.4±4.4 |
0.58 |
| Procedural success, n (%) |
85 (83.3) |
50 (84.7) |
1.00 |
45 (80.4) |
46 (82.1) |
1.00 |
| Procedural complications, n (%) |
14 (13.7) |
9 (16.1) |
0.82 |
8 (14.3) |
8 (14.3) |
1.00 |
| Slow-flow phenomenon, n (%) |
10 (9.8) |
9 (15.3) |
0.32 |
6 (10.7) |
8 (14.3) |
0.78 |
| Pseudoaneurysm, n (%) |
0 (0) |
0 (0) |
1.00 |
0 (0) |
0 (0) |
1.00 |
| Hematoma, n (%) |
4 (3.9) |
0 (0) |
0.30 |
1 (1.8) |
0 (0) |
1.00 |
| Arteriovenous fistula, n (%) |
0 (0) |
0 (0) |
1.00 |
0 (0) |
0 (0) |
1.00 |
| Vascular rupture, n (%) |
1 (1.0) |
0 (0) |
1.00 |
0 (0) |
0 (0) |
1.00 |
| Wire perforation, n (%) |
0 (0) |
0 (0) |
1.00 |
0 (0) |
0 (0) |
1.00 |
| Transfusion, n (%) |
3 (2.9) |
0 (0) |
0.30 |
2 (3.6) |
0 (0) |
0.50 |
| Post ABI |
0.83±0.16 |
0.81±0.16 |
0.36 |
0.82±0.17 |
0.82±0.16 |
1.00 |
| DCB |
| IN.PACT, n (%) |
102 (100) |
– |
– |
56 (100) |
– |
– |
| Ranger, n (%) |
– |
48 (81.4) |
– |
– |
45 (80.4) |
– |
| Lutonix, n (%) |
– |
11 (18.6) |
– |
– |
11 (19.6) |
– |
Values are presented as mean±SD or n (%). DCB, drug-coated balloon; MLD, minimum lumen diameter. Other abbreviations as in Table 1.
Clinical Outcomes at 1 Year
In the crude model, the primary patency at 1 year was significantly higher with HD-DCBs than with LD-DCBs (87.0% vs. 68.6%, respectively, P=0.019) (Supplementary Figure 1). After propensity-score matching, the primary patency at 1 year was still significantly higher with HD-DCBs than with LD-DCBs (89.9% vs. 70.8%, respectively, P=0.03), as was the rate of freedom from TLR (93.6% vs. 79.7%, respectively, P=0.046) (Figures 2,3). By contrast, there were no significant differences in freedom from recurrent occlusion, overall survival, or limb salvage (HD-DCB vs. LD-DCB: 96.2% vs. 88.6%, respectively, P=0.22; 92.9% vs. 93.9%, respectively, P=0.72; and 100% vs. 96.1%, respectively, P=0.15) (Figure 3). Significant differences in primary patency (IN.PACT vs. Lutonix vs. Ranger: 90.2% vs. 54.5% vs. 75.7%, respectively, P=0.006) and freedom from TLR (IN.PACT vs. Lutonix vs. Ranger: 93.9% vs. 62.3% vs. 84.6%, respectively, P=0.012) were found among the DCB types, although primary patency and TLR did not differ between IN.PACT and Ranger or Ranger and Lutonix (Supplementary Figures 2,3).
Predictors of Primary Patency at 1 Year
Multivariate Cox proportional hazards analysis showed that small vessel diameter (≤4.5 mm) was an unfavorable predictor of primary patency at 1 year (HR, 0.24; 95% CI, 0.07–0.87), while larger postprocedural minimum lumen area and the use of a HD-DCB were favorable predictors (HR, 1.21; 95% CI, 1.02–1.44; and HR, 3.08; 95% CI, 1.02–9.34, respectively) (Table 3).
Table 3.
Cox Proportional Hazards Analysis of 1-Year Primary Patency
| |
Unadjusted analysis |
Adjusted analysis |
| HR |
95% CI |
P value |
HR |
95% CI |
P value |
| Age (per 1 year) |
1.00 |
0.97–1.04 |
0.73 |
|
|
|
| Male |
0.77 |
0.27–2.23 |
0.63 |
|
|
|
| Non-ambulatory |
0.35 |
0.12–1.03 |
0.055 |
0.64 |
0.18–2.31 |
0.49 |
| Hemodialysis |
1.28 |
0.26–6.25 |
0.76 |
|
|
|
| CLTI |
0.99 |
0.32–3.07 |
0.99 |
|
|
|
| Grade D dissection |
1.03 |
0.27–3.96 |
1.03 |
|
|
|
| Popliteal artery involvement |
0.50 |
0.17–1.44 |
0.20 |
|
|
|
| Lesion length (per 10 mm) |
0.99 |
0.95–1.05 |
0.93 |
|
|
|
| Small vessel (diameter ≤4.5 mm) |
0.22 |
0.07–0.65 |
0.006 |
0.24 |
0.07–0.87 |
0.03 |
| PACSS grade 4 |
0.61 |
0.18–2.13 |
0.44 |
|
|
|
| Nodular calcification |
0.24 |
0.06–0.98 |
0.046 |
0.44 |
0.08–2.51 |
0.36 |
| Procedural success |
0.98 |
0.25–3.77 |
0.97 |
|
|
|
| Slow-flow phenomenon |
0.60 |
0.30–1.21 |
0.16 |
|
|
|
| Postprocedural MLA (per 1 mm2) |
1.27 |
1.09–1.49 |
0.027 |
1.21 |
1.02–1.44 |
0.03 |
| HD-DCB (vs. LD-DCB) |
4.29 |
1.21–15.22 |
0.024 |
3.08 |
1.02–9.34 |
0.048 |
Values are presented as mean±SD or n (%). CI, confidence interval; HR, hazard ratio; PACSS, Peripheral Arterial Calcification Scoring System. Other abbreviations as in Table 1.
Discussion
The main findings of this study were that in EVT of FP CTO lesions, (1) both primary patency and freedom from TLR were superior in the HD-DCB group compared with the LD-DCB group, and (2) larger MLA and use of a HD-DCB were favorable predictors of primary patency at 1 year in a multivariate analysis, while small vessel diameter (≤4.5 mm) was an unfavorable predictor. This is the first report to compare the clinical outcomes of HD-DCB and LD-DCB for FP CTO lesions.
FP CTO lesions are among the most difficult to treat with EVT.16,17 Intraluminal guidewire crossing is challenging in almost all of these lesions, and the plaque burden and CTO lesion calcification can cause severe dissection and elastic recoil after balloon dilation.18,19 Stent implantation can resolve the mechanical issues related to balloon dilation for CTO lesions, but can lead to stent-related complications such as in-stent restenosis, in-stent occlusion, stent thrombosis, and stent fracture in the chronic phase.3–5,20
A previous report showed the efficacy of DCB for FP CTO lesions, but the incidence of provisional stenting remained high.16 Because provisional stenting after using DCBs for FP lesions is not covered by insurance in Japan, a variety of techniques have been developed to avoid severe vessel dissection when using DCBs for FP lesions, including the use of chocolate balloons, scoring balloons, and long balloons.21–23 Moreover, IVUS has played a significant role in improving clinical outcomes for FP lesions treated with DCBs,24,25 because it can determine the external elastic membrane (EEM) diameter, which is valuable when utilized in DCB therapy.25,26 In this study, long balloons, chocolate balloons, or scoring balloons were used in almost all lesions, and IVUS was utilized for all lesions across both patient groups. As a result, approximately 80% of the lesions achieved procedural success. A Japanese clinical study reported the effectiveness of DCBs for treating FP CTO lesions without provisional stenting in most cases, and identified renal failure on hemodialysis, chronic limb-threatening ischemia (CLTI), and pre-existing restenosis as independent predictors of restenosis.27 It should be noted that the present study included only de novo lesions, and relatively few patients developed renal failure on hemodialysis or CLTI. Therefore, the FP CTO lesions in this study were considered suitable candidates for DCB treatment.
Currently, 3 types of DCBs for FP lesions are available in Japan (IN.PACT Admiral, Lutonix, and Ranger) and broadly classified as HD-DCB or LD-DCB on the basis of the paclitaxel concentration used. We defined the IN.PACT Admiral as a HD-DCB, and the Lutonix and Ranger as LD-DCBs. Several studies have compared the efficacy of HD-DCBs and LD-DCBs; while some found no difference between them,9–11 one study showed that HD-DCBs were more effective than LD-DCBs.12 However, those trials included both simple and complex lesions, and the efficacy of DCBs in complex lesions was unknown. Furthermore, the COMPARE study showed that the clinical outcomes of HD-DCBs and LD-DCBs were comparable,9 but that study included provisional stenting for approximately 30% of the patients, preparation failure cases. Because the present study included approximately 20% of preparation failure cases without provisional stenting, the results of this study may suggest an additional effect of HD-DCBs.15
When treating CTO lesions by EVT using DCBs, crossing the intraluminal lumen, which describes the wire navigating through the interior of the plaque, can improve clinical outcomes.28 In this study, the lesion length and CTO lesion length were greater than in previous studies. As a result, even if IVUS was used in all FP lesions, it would be difficult to pass the intraluminal lumen in all of them. Consequently, when a balloon for preparation is dilated, grade C or higher dissection or residual stenosis ≥50% is likely to occur.18 A previous study has reported that HD-DCBs are effective in such situations.15 Our results support those of previous studies and suggest that the clinical outcome of FP CTO lesions treated by EVT with HD-DCBs is superior to that with LD-DCBs.
This study demonstrated that a small vessel diameter (≤4.5 mm) was an unfavorable predictor of primary patency at 1 year. Several clinical trials involving DCB angioplasty have shown that small vessels are positive predictors of restenosis,17 possibly due to an inadequate lumen area after balloon dilation. By contrast, getting larger postprocedural MLA and the use of HD-DCBs were favorable predictors of patency in this study. Several clinical trials have shown that obtaining an adequate lumen area before DCB treatment improves clinical performance.29
Study Limitations
First, this was a retrospective, observational, single-center study with a small number of participants. As such, the selection of balloon type and DCB was made by each operator, and selection bias and unmeasured confounding might have occurred. Second, the sample size may be insufficient to adequately evaluate clinical outcomes for each type of DCB. Future prospective studies with larger numbers of patients are needed to confirm these findings. Finally, anticoagulant therapy was not well implemented.
Conclusions
The clinical outcome with HD-DCBs was superior to that with LD-DCBs for de novo FP CTO lesions.
Acknowledgment
The authors are grateful to the staff of the Miyazaki Medical Association Hospital.
Disclosures
K.T. is Editor-in-Chief of Circulation Journal. The other authors have no conflicts of interest to declare.
IRB Information
This study was approved by Miyazaki Medical Association Hospital (Reference no.2024-30).
Data Availability
The deidentified participant data will not be shared.
Supplementary Files
Please find supplementary file(s);
https://doi.org/10.1253/circj.CJ-24-0813
References
- 1.
Jaff MR, Klein AJ, Parikh SA, Prasad A, Rosenfield K, Shishehbor MH, et al. SCAI consensus guidelines for device selection in femoral-popliteal arterial interventions. Catheter Cardiovasc Interv 2018; 92: 124–140.
- 2.
Aboyans V, Ricco JB, Bartelink MEL, Björck M, Brodmann M, Cohnert T, et al. 2017 ESC Guidelines on the diagnosis and treatment of peripheral arterial diseases, in collaboration with the european society for vascular surgery (ESVS): Document covering atherosclerotic disease of extracranial carotid and vertebral, mesenteric, renal, upper and lower extremity arteries. Endorsed by The European Stroke Organization (ESO)The Task Force for the Diagnosis and Treatment of Peripheral Arterial Diseases of the European Society of Cardiology (ESC) and of the European Society for Vascular Surgery (ESVS). Eur Heart J 2018; 39: 763–816.
- 3.
Tosaka A, Soga Y, Iida O, Ishihara T, Hirano K, Suzuki K, et al. Classification and clinical impact of restenosis after femoropopliteal stenting. J Am Coll Cardiol 2012; 59: 16–23.
- 4.
Nagita H, Wang C, Saigusa H, Hoshina K, Suhara M, Oshima M. Deformed popliteal artery due to highly flexed knee position can cause kinks, creating an unfavorable hemodynamic state. Circ J 2024; 88: 351–358.
- 5.
Ogata K, Nishihira K, Asano Y, Honda Y, Yamamoto K, Emori H, et al. Clinical comparison of drug-coated balloon and drug-eluting stent for femoropopliteal lesions in chronic limb-threatening ischemia with wounds. Circ J 2024; 88: 1647–1655.
- 6.
Rosenfield K, Jaff MR, White CJ, Rocha-Singh K, Mena-Hurtado C, Metzger DC, et al. Trial of a paclitaxel-coated balloon for femoropopliteal artery disease. N Engl J Med 2015; 373: 145–153.
- 7.
Tepe G, Laird J, Schneider P, Brodmann M, Krishnan P, Micari A, et al. Drug-coated balloon versus standard percutaneous transluminal angioplasty for the treatment of superficial femoral and popliteal peripheral artery disease: 12-month results from the IN.PACT SFA randomized trial. Circulation 2015; 131: 495–502.
- 8.
Steiner S, Willfort-Ehringer A, Sievert H, Geist V, Lichtenberg M, Del Giudice C, et al. 12-month results from the first-in-human randomized study of the Ranger paclitaxel-coated balloon for femoropopliteal treatment. JACC Cardiovasc Interv 2018; 11: 934–941.
- 9.
Steiner S, Schmidt A, Zeller T, Tepe G, Thieme M, Maiwald L, et al. COMPARE: Prospective, randomized, non-inferiority trial of high- vs. low-dose paclitaxel drug-coated balloons for femoropopliteal interventions. Eur Heart J 2020; 41: 2541–2552.
- 10.
Mori S, Yamauchi Y, Doijiri T, Tobita K, Hishikari K, Honda Y, et al. Comparison between clinical outcomes of low- and high-dose paclitaxel drug-coated balloon in endovascular therapy for femoropopliteal lesion. Cardiovasc Intervent Radiol 2023; 46: 590–597.
- 11.
Nakama T, Takahara M, Iwata Y, Suzuki K, Tobita K, Hayakawa N, et al. Low-dose vs high-dose drug-coated balloon for symptomatic femoropopliteal artery disease: The PROSPECT MONSTER study outcomes. JACC Cardiovasc Interv 2023; 16: 2655–2665.
- 12.
Fujihara M, Takahara M, Soga Y, Iida O, Kawasaki D, Tomoi Y, et al. Application of first-generation high- and low-dose drug-coated balloons to the femoropopliteal artery disease: A sub-analysis of the POPCORN registry. CVIR Endovasc 2023; 6: 41.
- 13.
Okuno S, Iida O, Shiraki T, Fujita M, Masuda M, Okamoto S, et al. Impact of calcification on clinical outcomes after endovascular therapy for superficial femoral artery disease: Assessment using the peripheral artery calcification scoring system. J Endovasc Ther 2016; 23: 731–737.
- 14.
Rogers JH, Lasala JM. Coronary artery dissection and perforation complicating percutaneous coronary intervention. J Invasive Cardiol 2004; 16: 493–499.
- 15.
Tomoi Y, Soga Y, Imada K, Sakai N, Katsuki T, Ando K. Impact of a less than 50% residual stenosis following vessel preparation in femoropopliteal drug-coated balloon angioplasty. J Endovasc Ther 2024; 9: 15266028231223086.
- 16.
Tepe G, Micari A, Keirse K, Zeller T, Scheinert D, Li P, et al. Drug-coated balloon treatment for femoropopliteal artery disease: The Chronic Total Occlusion Cohort in the IN.PACT Global Study. JACC Cardiovasc Interv 2019; 12: 484–493.
- 17.
Soga Y, Takahara M, Iida O, Tomoi Y, Kawasaki D, Tanaka A, et al. Vessel patency and associated factors of drug-coated balloon for femoropopliteal lesion. J Am Heart Assoc 2023; 12: e025677.
- 18.
Fujihara M, Takahara M, Sasaki S, Nanto K, Utsunomiya M, Iida O, et al. Angiographic dissection patterns and patency outcomes after balloon angioplasty for superficial femoral artery disease. J Endovasc Ther 2017; 24: 367–375.
- 19.
Conte MS, Bradbury AW, Kolh P, White JV, Dick F, Fitridge R, et al. Global vascular guidelines on the management of chronic limb-threatening ischemia. J Vasc Surg 2019; 69: 3S–125S.e40.
- 20.
Tsujimura T, Iida O, Ishihara T, Asai M, Masuda M, Okamoto S, et al. Angioscopic evaluation of vascular response after fluoropolymer-based drug-eluting stent implantation for femoropopliteal artery lesions. Circ J 2023; 87: 432–429.
- 21.
Tan M, Urasawa K, Koshida R, Haraguchi T, Kitani S, Igarashi Y, et al. Comparison of angiographic dissection patterns caused by long vs short balloons during balloon angioplasty of chronic femoropopliteal occlusions. J Endovasc Ther 2018; 25: 192–200.
- 22.
Horie K, Tanaka A, Taguri M, Inoue N. Impact of scoring balloons on percutaneous transluminal angioplasty outcomes in femoropopliteal lesions. J Endovasc Ther 2020; 27: 481–491.
- 23.
Shirai S, Mori S, Yamaguchi K, Mizusawa M, Chishiki T, Makino K, et al. Impact of Chocolate percutaneous transluminal angioplasty balloon on vessel preparation in drug-coated balloon angioplasty for femoropopliteal lesion. CVIR Endovasc 2022; 5: 46.
- 24.
Allan RB, Puckridge PJ, Spark JI, Delaney CL. The impact of intravascular ultrasound on femoropopliteal artery endovascular interventions: A randomized controlled trial. JACC Cardiovasc Interv 2022; 15: 536–546.
- 25.
Kurata N, Iida O, Takahara M, Asai M, Masuda M, Okamoto S, et al. Clinical impact of the size of drug-coated balloon therapy on restenosis rate in femoropopliteal lesions. J Endovasc Ther 2023; 30: 269–280.
- 26.
Kurata N, Iida O, Asai M, Okamoto S, Ishihara T, Nanto K, et al. Factors in sufficient endovascular vessel preparation for severely calcified femoropopliteal lesions. Circ J 2023; 87: 424–431.
- 27.
Hayakawa N, Takahara M, Nakama T, Horie K, Takanashi K, Kanagami T, et al. Clinical outcome of drug-coated balloons in patients with femoropopliteal chronic total occlusive lesions: Results from the multicenter EAGLE study. CVIR Endovasc 2022; 5: 51.
- 28.
Toyoshima T, Takahara M, Iida O, Tomoi Y, Kawasaki D, Tanaka A, et al. Intraluminal vs subintimal drug-coated balloon angioplasty for the treatment of femoropopliteal chronic total occlusions. JACC Cardiovasc Interv 2024; 17: 608–618.
- 29.
Horie K, Takahara M, Nakama T, Tanaka A, Tobita K, Hayakawa N, et al. Impact of postoperative lumen gain on the reduction of restenosis risk after endovascular treatment using drug-coated balloon for femoropopliteal lesions assessed by intravascular ultrasound. J Atheroscler Thromb 2023; 30: 1142–1151.
