Differences in Intravascular Ultrasound Measurement Values Between Treatment Modalities for Restenosis in Femoropopliteal Lesions

Abstract

Background: The risk of restenosis after intervention is higher in femoropopliteal than in aortoiliac lesions. However, the appropriate endovascular therapy (EVT) for preventing restenosis after intervention for femoropopliteal lesions remains unknown. This study aimed to elucidate the relationship between lesion characteristics and patency after EVT using intravascular ultrasound (IVUS) measurement and to determine the predictors of restenosis on IVUS.

Methods and Results: This prospective observational study was performed at 18 Japanese centers. We evaluated the lesion characteristics before and after EVT for femoropopliteal lesion using IVUS. Angiographic or duplex ultrasound follow-up was performed at 1 year after EVT. A total of 263 lesions underwent EVT between December 2016 and December 2017. In total, 20 lesions (8 cases of isolated common femoral artery lesion and 12 cases of restenosis lesion) were excluded, and 243 lesions were enrolled in this study. A total of 181 lesions were treated with stent placement, and 62 lesions were treated only with balloon angioplasty. In the case of stent use, a larger distal plaque burden was associated with restenosis, while a lower calcification angle was associated with higher patency in the case of balloon angioplasty alone.

Conclusions: The factors related to patency differed depending on the treating modality. The findings suggest that IVUS is a useful tool for predicting patency because it can provide a more accurate evaluation after EVT for femoropopliteal lesions.

The patency rate of endovascular therapy (EVT) is lower for femoropopliteal artery lesions than for aortoiliac artery lesions, especially C or D type in the Inter-Society Consensus for the Management of Peripheral Arterial Disease guidelines (TASC II).^1–5 Some clinical studies have been conducted to predict restenosis, and methods for predicting patency rates based on patient background and lesion characteristics have been published.⁶

Several clinical studies have assessed lesion characteristics using quantitative vascular analysis (QVA) and intravascular ultrasound (IVUS).¹ IVUS is more accurate than QVA; it has been in use for approximately 30 years, and its efficacy in percutaneous coronary interventions (PCI) is well established.⁷ However, the usage rate of IVUS in EVT is lower and more limited than in PCI.^8,9

Although the utility of IVUS in EVT has been reported, analyses of the IVUS prognostic factors are mostly from retrospective or single-center trials, with substantial bias.^10,11 Furthermore, a few reports have shown a relationship between IVUS measurement and balloon angioplasty without stent deployment.¹² The aim of this study was to evaluate the relationship between lesion characteristics and patency at 1 year after EVT for femoropopliteal lesions, using IVUS for each treatment device; it also aimed to determine the predictors of restenosis on IVUS.

Methods

Data Source

We pooled the data from patients enrolled in the AngiograPHy follow up and intravascular imAging modaLity indiCate Optimal eNdovascular direction in femoropopliteal artery disease (PHALCON) registry, a multicenter registry in Japan that enrolls consecutive patients. The study was performed in accordance with the Declaration of Helsinki, and was registered with the University Hospital Medical Information Network–Clinical Trials Registry (UMIN-CTR), a registry accepted by the International Committee of Medical Journal Editors (no. UMIN000025204). Written informed consent was given by all patients, and data collection for this study was approved by the ethics review boards of all participating institutions.

Study Population

This was a multicenter prospective analysis of 240 patients (263 lesions) who underwent EVT for femoropopliteal lesions between December 2016 and December 2017. Among them, 20 were excluded because the target lesions included either isolated common femoral artery (8 lesions) or restenosis lesions (12 lesions). Finally, 220 patients (243 lesions) who underwent EVT for de novo femoropopliteal lesions were analyzed with regard to endpoints. The mean follow-up interval was 358±166 days.

Study Protocol

EVT was performed using standard techniques with the strategy of provisional stenting. A 6Fr sheath was inserted via a contralateral or ipsilateral approach. After infusing 5,000 U heparin, a 0.014-, 0.018-, or 0.035-inch (0.036, 0.046, and 0.089 cm, respectively) guidewire was advanced across the lesion. The strategy of provisional stenting was not to deploy the stent from the beginning, but to deploy it if bailout stent implantation was needed after predilation. Although we recommended considering conversion to a stent EVT in the case of flow-limiting dissection after predilation, the decision to deploy the stent and the type of stent were left to the operator’s discretion. The stents used were as follows: SMART stent (Cordis Endovascular, Warren, NJ, USA), LifeStent (Bard Peripheral Vascular, Tempe, AZ, USA), INNOVA stent (Boston Scientific, Maple Grove, MN, USA), Zilver PTX stent (Cook Medical, Bloomington, IN, USA), and VIABAHN (W.L. Gore & Associates, Flagstaff, AZ, USA).

Angiographic success was defined as a final residual stenosis <50% by visual estimates, with a TIMI flow grade of 3. In the current study, IVUS was used to record the data before predilation and at the end of the procedure. In case of chronic total occlusion, IVUS was used after predilation with a 2–3-mm balloon. IVUS was performed with a commercially available IVUS console and mechanical scan 30-MHz IVUS catheter (Opticross 18; Boston Scientific, Marlborough, MA, USA). A slow pullback was performed manually at a constant speed of 10 mm/s between the distal and proximal reference segments. All patients underwent clinical follow-up after 3, 6, 9, and 12 months. At each follow-up, ischemic symptoms and duplex ultrasonography (DUS) were routinely evaluated to assess vessel patency. At 12 months after EVT, patients who had not received any reintervention or major amputation underwent follow-up angiography for the treated lesions when possible.

Quantitative Analysis of Vascular Angiography

Quantitative analysis of the angiographic data was initially assessed by a single experienced investigator, using the CAAS7 software (Pie Medical Imaging, Maastricht, The Netherlands). The following parameters were analyzed: reference vessel diameter (RVD), minimal lumen diameter (MLD), percent diameter stenosis (difference between RVD and MLD divided by RVD), lesion length, and National Heart, Lung, and Blood Institute classification of dissection. Measurements included the whole segment treated and 10 mm proximally and distally. Binary restenosis was defined as stenosis of at least 50% of the luminal diameter at angiographic follow-up. Vessel calcification was also evaluated using the Peripheral Arterial Calcium Scoring System (PACCS).¹³

Quantitative Analysis of IVUS

IVUS images were reviewed off-line at a single institute, and quantitative IVUS analysis was performed using computerized planimetry (EchoPlaque; Indec Systems, Santa Clara, CA, USA) by 2 independent experienced investigators. The external elastic membrane cross-sectional area (EEM-CSA) was measured at the medial–adventitial interface (approximating the EEM) as the vessel size at the proximal and distal reference sites. Reference measures were taken at the proximal and distal sites adjacent to the lesion, which correlated with the angiographically normal-appearing reference segments. The minimum lumen and stent areas were measured before predilation and at the end of the procedure. The maximum calcification angle before predilation, the lumen or stent symmetry, proximal and distal plaque burden (plaque burden = [(EEM-CSA) − (Lumen-CSA) / (EEM-CSA) × 100]) (Supplementary Figure), and stent edge dissection and stent expansion ratio (for those with stent placement; stent group) or maximum dissection angle (for those without stent placement; percutaneous transluminal angioplasty [PTA] group) at the end of the procedure were also measured and calculated.¹⁴

Definitions

Hypertension was defined as systolic blood pressure ≥140 mmHg and/or diastolic blood pressure ≥90 mmHg or ongoing therapy for hypertension. Hyperlipidemia was defined as low-density lipoprotein cholesterol ≥140 mg/dL or ongoing therapy for hyperlipidemia. Diabetes mellitus was defined as HbA1c >6.5%, casual plasma glucose >200 mg/dL, or treatment with oral hypoglycemic agents or insulin injection. Coronary artery disease (CAD) was defined as stable angina with documented CAD, including any history of PCI or coronary artery bypass graft surgery, with or without previous myocardial infarction.

Study Endpoints

The primary endpoint was 12-month primary patency, as assessed by follow-up angiography or DUS. Primary patency was defined as a treated vessel that remained patent without restenosis or revascularization. Restenosis was defined as a peak systolic velocity ratio >2.4 on DUS or >50% stenosis on angiography. A restenosis was determined to have developed if the findings of DUS and angiography differed.

Statistical Analysis

Continuous variables are expressed as mean±standard deviation, and categorical variables are presented as percentages. Comparisons of continuous variables between groups were performed using Student’s t-test, and categorical variables were compared between groups using the chi-squared test. Univariate and multivariate logistic regression analyses were performed to determine predictors of primary patency rates. Factors of IVUS measurement that were identified on univariate analysis (P<0.05) were tested using multivariate logistic regression analysis.

The Kaplan-Meier method and log-rank test were used to compare vessel patency rates. P<0.05 was considered to indicate a statistically significant difference. All statistical analyses were performed with JMP version 14.2.0 for Windows (SAS Institute, Cary, NC, USA).

Results

Among 243 lesions, 181 underwent EVT with stent placement (stent group) and 62 underwent EVT without stent placement (PTA group). At 1 year after EVT, the primary patency rates were 67% and 74% in the stent and PTA groups, respectively, and restenosis rates were 33% and 26% in the stent and PTA groups, respectively (Figure 1). The rate of follow-up angiography was 50%.

Figure 1.

Study flowchart. PTA, percutaneous transluminal angioplasty; TLR, target lesion revascularization.

The baseline clinical characteristics of the study participants are presented in Table 1; there was no significant difference between the 2 groups. Regarding lesion character, the stent group had a higher proportion of chronic total occlusion, longer lesion length, and larger vessel size than the PTA group. According to the PACCS grade and IVUS evaluation, the PTA group had a higher proportion of more severe calcification than the stent group (Table 1).

Table 1. Baseline Characteristics of Patients Undergoing Endovascular Therapy for Femoropopliteal Lesions

	Stent (n=181)	PTA (n=62)	P value
Age (years)	75±8	73±11	0.116
Sex (male, %)	122 (67)	42 (68)	0.961
BMI (kg/m2)	22.5±4.1	22.4±7.2	0.872
Hypertension	162 (90)	54 (87)	0.608
Dyslipidemia	110 (61)	39 (63)	0.766
Diabetes mellitus	96 (53)	34 (55)	0.810
Smoker	116 (64)	35 (56)	0.287
Dialysis	42 (23)	22 (35)	0.063
History of CAD	103 (57)	37 (60)	0.703
Baseline ABI
Right	0.79±0.20	0.81±0.22	0.494
Left	0.81±0.20	0.81±0.26	0.986
Rutherford class
II/III/IV/VI	7/136/17/21	3/41/6/12	0.471
Claudicant	143 (79)	44 (71)	0.202
Medications
Aspirin	149 (82)	43 (69)	0.036
Thienopyridine	161 (89)	45 (73)	0.003
Cilostazol	58 (32)	25 (40)	0.239
Ethyl icosapentate	22 (12)	6 (10)	0.592
Warfarin	15 (8)	1 (2)	0.038
Direct oral anticoagulant	14 (8)	5 (8)	0.934
Statin	29 (47)	96 (53)	0.394
Lesion
CTO	77 (43)	9 (15)	<0.001
Involving popliteal lesion	36 (20)	7 (11)	0.112
PACCS grade 0/1/2/3/4	53/44/10/44/30	16/6/2/21/17	0.033
PACCS 1–2	54 (30)	8 (13)	0.006
PACCS 3–4	74 (41)	38 (61)	0.005
Reference vessel diameter (mm)	6.0±1.1	5.4±1.3	<0.001
Lesion vessel diameter (mm)	0.8±0.9	1.3±0.8	<0.001
Percent diameter stenosis (%)	85.3±15.7	76.2±15.0	<0.001
Lesion length (cm)	16.1±9.0	9.2±6.0	<0.001
Procedural data
Predilatation
Balloon size (mm)	5.1±0.9	5.0±0.8	0.670
Inflation pressure (atm)	12.0±4.6	13.1±6.5	0.121
Stent usage
No. of stents	1.1±0.8
Stent size (mm)	6.4±1.2
Total stent length (cm)	16.3±9.7
Bare nitinol stent	204 (78)
DES	20 (8)
Stent graft	36 (14)

Continuous data are presented as mean±standard deviation, categorical data are given as count (percentage). ABI, ankle-brachial index; BMI, body mass index; CAD, coronary artery disease; CTO, chronic total occlusion; DES, drug-eluting stent; PACCS, peripheral arterial calcium scoring system.

In the PTA group, there was significant difference in body mass index and in dialysis, claudicant, and thienopyridine use among the baseline characteristics between the restenosis and nonrestenosis group. The calcification angle was significantly larger and the PACCS grade was significantly higher in the restenosis group (Table 2). Univariate analysis performed on the PTA group showed that the calcification angle of IVUS was the only significant factor (Table 3). According to receiver-operating characteristics (ROC) analysis (area under curve (AUC)=0.769), the cutoff value for the calcification angle was 180° (sensitivity, 81%; specificity, 54%). When Kaplan-Meier analysis was performed for 2 groups with a calcification angle of 180°, the rate of restenosis was significantly higher in the group with >180° calcification (Figure 2).

Table 2. Baseline Characteristics and Lesion Measurements in the PTA Group

	Nonrestenosis (n=46)	Restenosis (n=16)	P value
Age (years)	72±11	76±11	0.192
Sex (male, %)	30 (65)	12 (75)	0.464
BMI (kg/m2)	21.5±4.2	24.8±3.2	0.007
Hypertension	41 (89)	13 (81)	0.434
Dyslipidemia	31 (67)	8 (50)	0.220
Diabetes mellitus	26 (57)	8 (50)	0.652
Smoker	24 (52)	11 (69)	0.244
Dialysis	13 (28)	9 (56)	0.047
History of CAD	28 (61)	9 (56)	0.746
ABI
Right	0.83±0.22	0.75±0.20	0.185
Left	0.82±0.26	0.76±0.25	0.473
Rutherford class
II/III/IV/VI	3/33/2/8	0/8/4/4	0.060
Claudicant	36 (78)	8 (50)	0.037
Medications
Aspirin	32 (70)	11 (69)	0.952
Thienopyridine	30 (65)	15 (94)	0.015
Cilostazol	20 (43)	5 (31)	0.385
Ethyl icosapentate	6 (13)	0 (0)	0.051
Warfarin	1 (2)	0 (0)	0.438
Direct oral anticoagulant	5 (11)	0 (0)	0.077
Statin	23 (50)	6 (38)	0.386
PTA
Balloon size (mm)	5.1±0.8	4.9±0.8	0.419
Inflation pressure (atm)	13.3±7.1	12.8±4.6	0.781
IVUS before PTA
Proximal EEM-CSA (mm2)	34.1±9.2	36.1±8.6	0.543
Minimal lumen EEM-CSA (mm2)	31.5±10.9	40.4±12.5	0.172
Minimal lumen area (mm2)	4.3±2.3	3.9±2.2	0.567
Distal EEM-CSA (mm2)	31.4±9.5	34.8±9.9	0.333
Calcification angle (°)	150±117	267±126	0.001
IVUS after PTA
Minimal lumen area (mm2)	12.0±4.7	11.5±4.3	0.741
Dissection (%)	33 (72)	13 (81)	0.443
Dissection angle (°)	52±49	60±42	0.618
QVA
CTO	7 (15)	2 (13)	0.788
Involving popliteal lesion	4 (9)	3 (19)	0.300
PACCS grade 0/1/2/3/4	16/5/1/14/10	0/1/1/7/7	0.012
PACCS 1–2	6 (13)	2 (13)	0.955
PACCS 3–4	24 (52)	14 (88)	0.008
Reference vessel diameter (mm)	5.4±1.2	5.3±1.4	0.709
Lesion vessel diameter (mm)	1.4±0.8	1.0±1.0	0.166
Percent diameter stenosis (%)	74±14	81±16	0.107
Lesion length (cm)	93±61	90±56	0.868
Dissection (%)	30 (65)	10 (63)	0.845
Dissection A/B/C/D	12/10/5/4	2/5/3/0	0.341

Continuous data are presented as mean±standard deviation, categorical data are given as count (percentage). CSA, cross-sectional area; EEM, external elastic membrane; IVUS, intravascular ultrasound; PTA, percutaneous transluminal angioplasty; QVA, quantitative vascular analysis. Other abbreviations as in Table 1.

Table 3. Univariate Analysis for Primary Patency in the PTA Group

Variables	Univariate analysis (95% CI)
IVUS before PTA
Proximal EEM-CSA (mm2)	1.02 (0.95–1.12), P=0.534
Minimal lumen EEM-CSA (mm2)	1.08 (0.97–1.23), P=0.153
Minimal lumen area (mm2)	0.91 (0.63–1.22), P=0.545
Distal EEM-CSA (mm2)	1.04 (0.96–1.13), P=0.321
Calcification angle (°)	1.01 (1.00–1.02), P=0.001
IVUS after PTA
Minimal lumen area (mm2)	0.98 (0.85–1.11), P=0.735
Dissection	1.71 (0.46–8.33), P=0.443
Dissection angle (°)	1.00 (0.99–1.02), P=0.613

Continuous data are presented as mean±standard deviation, categorical data are given as count (percentage). CI, confidence interval. Other abbreviations as in Table 2.

Figure 2.

Primary patency rate of lesions with a calcification angle <180° or >180° by Kaplan-Meier analysis in the PTA group. The log-rank test showed that the primary patency rate of lesions with a calcification angle >180° was significantly lower than for lesions with a calcification angle <180°. EVT, endovascular therapy; PTA, percutaneous transluminal angioplasty; SE, standard error.

In the stent group, the restenosis group had a significantly higher percentage of dyslipidemia and claudicant use, but there were no other significant differences. Regarding lesion morphology, the restenosis group had higher proportions of distal plaque burden and stent edge dissection. According to the QVA, in the restenosis group, lesions were longer and the minimum stent diameter was significantly smaller. The higher rate of diameter stenosis in the restenosis group may be due to more occlusive lesions (Table 4). Univariate analysis of IVUS parameters showed that distal plaque burden and stent edge dissection were significantly associated with restenosis. From the multivariate analysis, distal plaque burden was calculated as an independent factor (Table 5). According to ROC analysis (AUC=0.637), the cutoff value for the distal plaque burden was 40% (sensitivity, 80%; specificity, 42%). Kaplan-Meier analysis was performed for the 2 groups using 40% of distal plaque burden as the cutoff. The group with a distal plaque burden >40% had a significantly higher restenosis rate (Figure 3).

Table 4. Baseline Characteristics and Lesion Measurements in the Stent Group

	Nonrestenosis (n=122)	Restenosis (n=59)	P value
Age (years)	76±9	74±7	0.139
Sex (male, %)	80 (66)	42 (71)	0.448
BMI (kg/m2)	22.5±4.6	22.6±2.9	0.845
Hypertension	108 (89)	54 (92)	0.530
Dyslipidemia	67 (55)	43 (73)	0.019
Diabetes mellitus	61 (50)	35 (59)	0.239
Smoker	78 (64)	38 (64)	0.951
Dialysis	30 (25)	12 (20)	0.522
History of CAD	67 (55)	36 (61)	0.436
ABI
Right	0.79±0.19	0.79±0.20	0.875
Left	0.83±0.19	0.76±0.21	0.051
Rutherford class
II/III/IV/VI	4/87/12/19	3/49/5/2	0.061
Claudicant	91 (75)	52 (88)	0.029
Medications
Aspirin	99 (81)	50 (85)	0.548
Thienopyridine	107 (88)	54 (92)	0.433
Cilostazol	45 (37)	13 (22)	0.041
Ethyl icosapentate	14 (11)	8 (14)	0.690
Warfarin	14 (11)	1 (2)	0.012
Direct oral anticoagulant	6 (5)	8 (14)	0.049
Statin	63 (52)	33 (56)	0.587
Predilation
Balloon size (mm)	5.1±0.9	5.0±0.8	0.347
Inflation pressure atm)	12.1±4.6	11.7±4.8	0.649
Stent usage
No. of stents	1.4±0.5	1.5±0.6	0.715
Stent size (mm)	6.5±1.0	6.2±1.6	0.090
Bare nitinol stent	96 (79)	51 (86)	0.201
DES	11 (9)	4 (7)	0.603
Stent graft	15 (12)	4 (11)	0.240
IVUS before PTA
Proximal EEM-CSA (mm2)	41.6±13.6	37.6±10.8	0.197
Minimal lumen EEM-CSA (mm2)	32.7±10.2	30.3±10.2	0.464
Minimal lumen area (mm2)	4.6±2.5	3.9±2.5	0.319
Distal EEM-CSA (mm2)	32.8±11.8	32.3±8.6	0.865
Calcification angle (°)	150±128	141±119	0.651
IVUS after stenting
Minimal stent area (mm2)	18.8±4.8	18.8±5.6	0.926
Proximal plaque burden (%)	46.5±12.2	47.6±12.1	0.593
Distal plaque burden (%)	43.4±10.5	47.4±8.7	0.014
Stent expansion ratio (%)	86.2±30.7	89.5±35.0	0.525
Radial symmetry index	0.29±0.14	0.29±0.14	0.936
Axial symmetry index	0.33±0.17	0.33±0.16	0.968
Stent edge dissection	23 (19)	21 (36)	0.016
QVA
Chronic total occlusion	53 (43)	24 (41)	0.724
Involving popliteal lesion	20 (16)	16 (27)	0.100
PACCS grade 0/1/2/3/4	37/30/6/29/20	16/14/4/15/10	0.979
PACCS 1–2	36 (30)	18 (31)	0.891
PACCS 3–4	49 (40)	25 (42)	0.777
Reference vessel diameter (mm)	6.0±1.1	6.0±1.1	0.841
Lesion vessel diameter (mm)	0.9±0.9	0.7±0.8	0.233
Percent diameter stenosis (%)	84.1±16.3	87.8±13.9	0.142
Lesion length (cm)	15.4±8.8	17.4±9.3	0.155
Stent edge dissection (%)	4 (3)	2 (3)	0.969
Minimal stent diameter (mm)	4.5±0.8	4.2±0.9	0.033

Continuous data are presented as mean±standard deviation, categorical data are given as count (percentage). Abbreviations as in Tables 1,2.

Table 5. Univariate and Multivariate Analyses for Primary Patency in the Stent Group

Variables	Univariate analysis (95% CI)	Multivariate analysis (95% CI)
IVUS before PTA
Proximal EEM-CSA (mm2)	0.97 (0.93–1.01), P=0.149
Minimal lumen EEM-CSA (mm2)	0.97 (0.90–1.04), P=0.400
Minimal lumen area (mm2)	0.89 (0.68–1.11), P=0.303
Distal EEM-CSA (mm2)	0.99 (0.94–1.04), P=0.706
Calcification angle (°)	1.00 (1.00–1.00), P=0.655
IVUS after stenting
Minimal stent area (mm2)	1.00 (0.94–1.07), P=0.951
Proximal plaque burden (%)	1.00 (0.98–1.03), P=0.755
Distal plaque burden (%)	1.04 (1.01–1.08), P=0.013	1.04 (1.00–1.07), P=0.041
Stent expansion ratio (%)	1.00 (0.99–1.01), P=0.407
Radial symmetry index	1.06 (0.11–10.06), P=0.961
Axial symmetry index	1.04 (0.15–6.86), P=0.970
Stent edge dissection	2.25 (1.11–4.56), P=0.025	1.91 (0.91–3.99), P=0.089

Continuous data are presented as mean±standard deviation, categorical data are given as count (percentage). Abbreviations as in Tables 2,3.

Figure 3.

Primary patency rate of lesions with distal plaque burden <40% or >40% by Kaplan-Meier analysis in the stent group. The log-rank test showed that the primary patency rate of lesions with distal plaque burden >40% was significantly lower than for lesions with distal plaque burden <40%. EVT, endovascular therapy; SE, standard error.

Discussion

To our knowledge, this is the first prospective, multicenter study that quantitatively analyzed the IVUS images and angiographic data of patients who underwent EVT with and without stent placement. Although most of the previous studies showed a relationship between stenting and IVUS with the strategy of primary stent, this study was characterized by the strategy of provisional stent. Our results confirmed that a larger calcification angle is associated with poor patency after PTA, and a larger stent distal plaque burden is associated with high frequency of in-stent restenosis after stent placement, using IVUS assessment.

Although the treatment success rate for femoropopliteal lesions is acceptable, the durability is not. The outcome of EVT depends on clinical and anatomic factors. According to previous reports on femoropopliteal lesion, the durability of EVT diminishes according to clinical factors such as diabetes mellitus, chronic kidney disease, renal failure (including hemodialysis), smoking, and critical limb ischemia. The anatomic factors that affect the patency rate are greater lesion length, occluded lesion (rather than stenosis), presence of multiple and diffuse lesions, and poor runoff.^6,15,16 Although QVA is very reliable with angiography, the true vessel diameter, actual area stenosis, plaque concentricity, and calcification angle are impossible to evaluate without IVUS.^11,17

To date, there have been several reports of the association between IVUS and patency. Iida et al reported in a retrospective multicenter analysis that IVUS use in femoropopliteal stenting for TASC II A–C lesions appeared to be associated with a higher primary patency rate.⁶ According to previous reports, small vessels, stent edge dissection, and insufficient expansion of the stent were associated with poor patency in femoropopliteal lesions treated using bare nitinol stents.^18–20 In an IVUS evaluation of drug-eluting stents (Zilver PTX; Cook Medical), longer lesion length, smaller EEM area, smaller distal lumen-CSA, and insufficient and more asymmetric expansion of the stent were reported as independent predictors for restenosis.^21,22 In the current study, not all of these factors were significantly associated with outcome. The main reason for the discrepancy is that, aside from the use of different treatment devices, the treatment method was determined by the operator and the lesion backgrounds were not the same.

A few reports have shown a relationship between IVUS assessment and outcome after PTA. The patency rate of drug-coated balloon (DCB) is reduced in advanced calcified lesions.^23,24 Although DCB was not used in this study, severe calcification also decreased the patency rate in the PTA group, suggesting that scaffold or atherectomy are required for advanced calcified lesions. The burden of calcified plaque, but not soft or fibrocalcific plaque, is reported to be related to restenosis.^22,25 It has been also reported that the higher the PACCS grade, the lower the patency rate, even if a drug-eluting stent is used, especially in the case of bilateral PACCS 3–4 calcification.^26,27 Fujihara et al²⁸ reported that the restenosis rate for lesions with calcification ≥180° was significantly higher than that for lesions with less severe calcification despite the lack of a relationship between PACCS grade and patency. And there was no significant relationship between dissection and restenosis after PTA in the present study. Although IVUS can evaluate dissection more accurately than angiography, the presence of dissection and its angle, as assessed by IVUS, were not significant predictors of restenosis.

In the current study, the distal plaque burden was a predictor for restenosis in the stent group. A higher distal plaque burden may be a surrogate marker of diffuse lesions, which generally have low patency. Conversely, proximal plaque burden was not a predictor for restenosis. During stenting, a stent that is relatively large compared with the diameter of the distal vessel is often placed to prevent incomplete stent apposition in the proximal portion. A stronger radial force will be therefore applied to the distal part of the stent, resulting in more stress in the distal vessel wall. Because regions of high vessel stress are most susceptible to an adverse biological response, the distal plaque burden may have more effect on restenosis than the proximal plaque burden.²⁹

As observed from the results of this study, in the case of PTA for a femoropopliteal lesion, it is important to perform predilation with a balloon large enough for the target vessel diameter and it is not appropriate to use a downsized balloon to avoid dissection. In cases where acute gain cannot be obtained because of advanced calcification, alternatives to PTA (scaffold and/or atherectomy) should be considered. During stent deployment, IVUS should be used to find the site with a plaque burden of ≤40% on the distal side of the lesion, and stent placement should be performed from there.

At present, the results of EVT for femoropopliteal lesions are not satisfactory, and it is important to understand the vessel morphology before and after angioplasty and to avoid the factors of restenosis as much as possible in order to improve the performance. To identify more universal factors for patency in femoropopliteal lesions, a large-scale prospective multicenter study is required to confirm these findings.

Study Limitations

The limitations of the present study include a relatively small sample size and the nonrandomized study design. This was not a blinded study and thus has the potential for observation bias. The stent group included more patients with severe lesions than the PTA group. When treatment strategies were selected, other conditions had to be taken into account, including the operator’s skill and the type of medical treatment and follow-up provided in the various regions in which the studies were conducted. In observational studies, the outcome may reflect a lack of comparability between the treatment groups rather than the effects of treatment. Despite these limitations, factors related to patency differed depending on the treating modality. Further investigation is needed to determine whether comparable results can be achieved with other drug-eluting stents and DCBs.

Conclusions

In femoropopliteal lesions, a larger calcification angle is associated with poor patency after PTA, and a larger stent distal plaque burden is associated with a high frequency of in-stent restenosis after stent placement, using IVUS assessment. Our results suggest that IVUS assessment can be useful for predicting vessel patency after EVT with and without stents for femoropopliteal lesions.

Acknowledgments

We thank Tomofumi Tanaka, MD, Department of Cardiology, Sakakibara Heart Institute, Tokyo Japan, Shinya Kogure, MD, Department of Cardiology, Maebashi Red Cross Hospital, Gunma, Japan, Shinya Hata, MD, Department of Cardiology, IMS Miyoshi General Hospital, Saitama, Japan, and Kodama Takahide MD, Department of Cardiology, Toranomon Hospital, Tokyo, Japan.

This work was supported by TOkyo taMA peripheral vascular intervention research COmraDE (TOMA-CODE) study group.

Data Availability

The de-identified participant data will not be shared.

Disclosures

None of the authors have any real or perceived conflicts of interest regarding the work described in this manuscript.

IRB Information

The present study was approved by the Tokyo Medical University Ibaraki Medical Center Institutional Review Board (16-25).

Supplementary Files

Please find supplementary file(s);

http://dx.doi.org/10.1253/circj.CJ-20-0218

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