Angioscopic Evaluation of Vascular Response After Fluoropolymer-Based Drug-Eluting Stent Implantation for Femoropopliteal Artery Lesions

Abstract

Background: Although favorable clinical outcomes have been demonstrated for fluoropolymer-based paclitaxel-eluting stents (FP-DES) in the treatment of femoropopliteal lesions, the vascular response after implantation has not been systematically studied through intravascular imaging.

Methods and Results: We angioscopically compared FP-DES: 24 in the early phase (mean [±SD] 3±1 months), 26 in the middle phase (12±3 months), and 20 in the late phase (≥18 months) after implantation. The dominant neointimal coverage grade, heterogeneity of neointimal coverage grade, and thrombus adhesion in the stent segment were evaluated. Neointimal coverage was graded as follows: Grade 0, stent struts exposed; Grade 1, struts bulging into the lumen, although covered; Grade 2, struts embedded in the neointima, but visible; Grade 3, struts fully embedded and invisible. Dominant neointimal coverage and heterogeneity grades were significantly higher in the middle and late phases than in the early phase (all P<0.05), but did not differ significantly between the middle and late phases. The incidence of thrombus adhesion was recorded for all stents in each of the 3 different phases.

Conclusions: The middle and late phases after FP-DES implantation were associated with significantly higher dominant neointimal coverage and heterogeneity grades than the early phase. However, thrombus adhesion was observed in all phases after FP-DES implantation. Arterial healing may not be completed even in the late phase after FP-DES implantation.

With the development of antirestenotic devices, endovascular therapy (EVT) has been established as an option for the treatment of femoropopliteal lesions in patients with symptomatic lower extremity arterial disease.^1–3 IMPERIAL (A randomIzed trial coMParing the ELUVIA dRug-elutIng stent versus Zilver PTX stent for treatment of superficiAL femoral and/or proximal popliteal arteries) compared a fluoropolymer-based drug-eluting stent (FP-DES; Eluvia^TM; Boston Scientific, Marlborough, MA, USA) with a polymer-free drug-coated stent (PF-DCS; Zilver PTX^TM; Cook Corporation, Bloomington, IN, USA) for the treatment of trial-based femoropopliteal lesions, and found that the rate of 1-year primary patency and 2-year freedom from clinically driven target lesion revascularization was significantly higher in patients with FP-DES than PF-DCS.^4,5 The CAPSICUM (Contemporary outcomes After Paclitaxel-eluting peripheral Stent implantation for symptomatic lower limb IsChemia with sUperficial feMoral or proximal popliteal lesion) study was an investigator-initiated clinical study that examined the clinical outcomes of FP-DES for real-world femoropopliteal lesions and found an acceptable and consistent 1-year primary patency.⁶ However, with regard to the morphology of restenosis after FP-DES implantation, the frequency of totally occlusive restenosis (including acute stent thrombosis) was remarkably high at 71.1%. Another study evaluating 2-year clinical outcomes after FP-DES implantation found a gradual reduction in primary patency and an increased frequency of vessel wall degeneration from 1 to 2 years of follow-up.⁷ Based on these clinical scenarios, it is clinically important to determine the intravascular status after FP-DES implantation and whether the artery is optimally healed. Therefore, the aim of this study was to angioscopically investigate the time course of changes in the intravascular status after FP-DES implantation for femoropopliteal lesions.

Methods

Patients

This was a single-center retrospective observational study. We extracted angioscopic data from the Kansai Rosai Hospital database (January 2017–February 2022) regarding the evaluation of FP-DES in the early phase (mean [±SD] 3±1 months after implantation; 24 stents in 12 lesions from 12 patients), middle phase (12±3 months after implantation; 26 stents in 13 lesions from 13 patients), or late phase (>18 months after implantation; 20 stents in 10 lesions from 9 patients). Subsequently, we compared the angioscopic findings between the 3 phases.

All FP-DESs were implanted in de novo lesions located in native femoropopliteal arteries. We excluded patients who exhibited any event of earlier stent failure, such as in-stent restenosis, or who could not undergo successful angioscopic evaluation. Although angioscopic evaluation was recommended for all patients with staged or required EVT for other lesions, it was not performed when informed consent could not be obtained or when a specialist for angioscopic evaluation was not available. In principle, the elective patients received clopidogrel (75 mg/day) or prasugrel (3.75 mg/day) in addition to aspirin (100 mg/day) at least 1 week before EVT with FP-DES implantation. Furthermore, patients continued to receive dual antiplatelet therapy (DAPT) for at least 3 months. Based on the instruction for use of FP-DES, DAPT was switched to single antiplatelet therapy 3 months after FP-DES implantation at the discretion of the attending physician. In addition, DAPT was switched to single antiplatelet therapy after EVT in some patients treated with anticoagulants to decrease the bleeding risk at the discretion of the attending physician.

This study was approved by the Medical Ethics Committee of Kansai Rosai Hospital, and all patients provided written informed consent. This study was performed in accordance with the Declaration of Helsinki and the ethical standards of the responsible committee on human experimentation.

Angiographic and Angioscopic Follow-up

Unfractionated heparin (5,000 IU) was administered into the femoral artery via the inserted sheath. Angioscopy was subsequently performed between January 2017 and March 2017 using a Vecmova NEO^TM angioscopic catheter (FiberTech, Tokyo, Japan), as described previously.^8,9 Briefly, the optical fiber was placed at the proximal segment of the peripheral artery and manually pushed from the proximal to the distal edge of the stent. Next, it was pulled back to the original position under careful angioscopic and angiographic guidance. Angioscopic images consisted of 3,000 pixels with full color.

The use of Vecmova NEO^TM was discontinued in April 2017. Since then, we have been using a smart-i^TM angioscopic catheter (i Heart Medical, Tokyo, Japan), which can project images with 6,000 pixels with full color, and a Zemporshe^TM angioscopic catheter (OVALIS, Osaka, Japan), which can project images with 480,000 pixels with full color. With these catheters, an optical fiber is placed at the distal segment of the femoropopliteal artery slightly protruding from the guiding sheath. Thereafter, it is manually withdrawn from the distal to proximal edge of the stent under careful angioscopic and angiographic guidance. Simultaneously, blood flow is blocked by flushing with low-molecular weight dextran.

All angioscopic images were digitally stored for off-line analysis.

Angioscopic Analysis and Outcome Measures

Angioscopic images were analyzed for each stent to determine: (1) the dominant degree of neointimal coverage over the stent; (2) the heterogeneity of neointimal coverage; (3) the yellow color grade of the stented segment; and (4) thrombus adhesion in the stented segment. Neointimal coverage over the stent was classified into 4 grades, as described previously:¹⁰ Grade 0, stent struts fully visible, similar to the status observed immediately after implantation; Grade 1, stent struts bulging into the lumen, although covered, still visible; Grade 2, stent struts embedded in the neointima, but visible; and Grade 3, stent struts fully embedded and invisible on angioscopy.

Heterogeneity of neointimal coverage has been previously defined.¹⁰ Briefly, neointimal coverage was evaluated throughout the entire stented segments, and was judged as heterogeneous when differences in the neointimal coverage grade became apparent. Struts located in the overlapped segment were excluded from grading, as were stent edges.

The yellow color of the stented segment was graded as follows: Grade 0, white; Grade 1, light yellow; Grade 2, yellow; Grade 3, intense yellow.¹⁰ Finally, thrombus adhesion was defined on the basis of the criteria adopted by the European Working Group on Coronary Angioscopy.¹⁰

Statistical Analysis

There were no previous data available on the angioscopic evaluation of FP-DESs in the middle and late phases to inform our choice of sample size. However, we set 20 FP-DESs as the target sample for each phase; this number seemed reasonable for an initial investigation based on previous angioscopic studies in the femoropopliteal artery.^9,11,12

All results are presented as the mean±SD, unless stated otherwise. Continuous variables with and without homogeneity of variance were analyzed by one-way analysis of variance and the Kruskal-Wallis test, respectively. For more than 2×2 comparisons, nominal variables and ordinal variables were analyzed with the Chi-squared and Mann-Whitney tests, respectively. Two-side P<0.05 denoted statistically significant difference.

All analyses were performed using IBM SPSS Statistics Package version 24 (IBM Corp., Armonk, NY, USA).

Results

Baseline Characteristics

Patient characteristics are presented in Table 1. There were no significant differences in patient characteristics between the 3 phases. Lesions characteristics are presented in Table 2. There were no significant differences among the 3 groups in chronic limb-threatening ischemia, lesion length, chronic total occlusion, involving popliteal lesion, peripheral artery calcification scoring system grade, or Trans-Atlantic Inter-Society Consensus II classification. The distal reference vessel diameter was significantly shorter in the early phase than in the middle and late phases.

Table 1. Patient Characteristics According to Time After Implantation of a Fluoropolymer-Based Drug-Eluting Stent

	Early phase (n=12)	Middle phase (n=13)	Late phase (n=9)	P value
Age (years)	74±10	74±11	77±7	0.70
Male sex	7 (58)	9 (69)	4 (44)	0.51
Hypertension	10 (83)	10 (77)	6 (67)	0.67
Dyslipidemia	9 (75)	9 (69)	3 (33)	0.12
Diabetes	8 (67)	7 (54)	5 (56)	0.79
Current smoker	1 (8)	1 (8)	0 (0)	0.68
Hemodialysis	8 (67)	6 (46)	4 (44)	0.49
Cerebrovascular disease	2 (17)	2 (15)	2 (22)	0.91
Coronary artery disease	9 (75)	9 (69)	7 (78)	0.90
Medications at follow-up
Aspirin	10 (83)	9 (69)	5 (56)	0.38
P2Y12 inhibitor	11 (92)	13 (100)	8 (89)	0.50
Clopidogrel	9 (75)	12 (92)	5 (56)	0.13
Prasugrel	2 (17)	1 (8)	3 (33)	0.30
Cilostazol	1 (8)	0 (0)	1 (11)	0.50
Anticoagulant drug	4 (33)	3 (23)	4 (44)	0.57
SAPT	0 (0)	1 (8)	1 (11)	0.53
DAPT	8 (67)	9 (69)	3 (33)	0.19
SAPT plus anticoagulant drug	3 (25)	3 (23)	2 (22)	0.99
DAPT plus anticoagulant drug	1 (8)	0 (0)	2 (22)	0.20
Statin	8 (67)	7 (54)	4 (44)	0.59

Numbers represents the number of patients. Data are presented as mean±SD or number (%). DAPT, dual antiplatelet therapy; SAPT, single antiplatelet therapy.

Table 2. Lesion Characteristics According to Time After Implantation of a Fluoropolymer-Based Drug-Eluting Stent

	Early phase (n=12)	Middle phase (n=13)	Late phase (n=10)	P value
CLTI	9 (75)	6 (46)	5 (50)	0.30
Lesion length (cm)	21.0±10.4	17.9±11.4	18.7±6.8	0.73
Distal reference vessel diameter (mm)	4.8±0.9	5.4±0.6	5.6±0.4	0.037
Chronic total occlusion	3 (25)	4 (31)	3 (30)	0.94
Including in the popliteal lesion	4 (33)	2 (15)	0 (0)	0.12
PACCS grade				0.87
Grade 0	1 (8)	1 (8)	0 (0)
Grade 1	3 (25)	5 (39)	3 (30)
Grade 2	1 (8)	2 (15)	0 (0)
Grade 3	4 (33)	3 (23)	4 (40)
Grade 4	3 (25)	2 (15)	3 (30)
TASC II classification				0.49
A	1 (8)	2 (15)	1 (10)
B	1 (8)	3 (23)	3 (30)
C	1 (8)	2 (15)	3 (30)
D	9 (75)	6 (46)	3 (30)

Numbers represents the number of lesions. Data are presented as mean±SD or number (%). CLTI, chronic limb-threatening ischemia; PACCS, peripheral artery calcification scoring system; TASC, Trans-Atlantic Inter-Society Consensus.

Procedural characteristics are presented in Table 3. There were no significant differences in procedural characteristics among the 3 groups.

Table 3. Procedural Characteristics According to Time After Implantation of a Fluoropolymer-Based Drug-Eluting Stent

	Early phase (n=24)	Middle phase (n=26)	Late phase (n=20)	P value
IVUS use (n)	24	26	20	NS
Predilatation	24 (100)	24 (92)	20 (100)	0.18
Maximum predilatation balloon diameter (mm)	5.6±1.0	5.5±1.4	6.5±0.6	0.007
Mean stent length (cm)	10.5±2.8	9.9±3.4	10.2±2.9	0.75
Mean stent diameter (mm)	6.8±0.4	6.7±0.5	6.9±0.3	0.37
Post-dilatation	24 (100)	26 (100)	20 (100)	NS
Maximum post-dilatation balloon diameter (mm)	6.0±0.4	6.3±0.7	6.5±0.6	0.012

Numbers represents the number of stents. Data are presented as mean±SD or number (%). IVUS, intravascular ultrasound.

Angioscopic Findings

The mean duration of the follow-up for the early, middle, and late phase groups was 92±17, 347±39, and 808±327 days, respectively (P<0.001). The inter- and intra-observer κ coefficient for evaluating angioscopic findings was determined for 30 randomly selected stents. The estimated respective inter- and intra-observer κ coefficients were 0.81 and 0.87 for the dominant degree of neointimal coverage over the stent; 0.77 and 0.77 for heterogeneity of neointimal coverage; 0.65 and 0.71 for yellow color grade of the stented segment; and 1.00 and 1.00 for the presence of intrastent thrombus. The grade of dominant neointimal coverage was significantly higher in the middle and late phases than in the early phase (P=0.021 and P<0.001, respectively). However, there was no significant difference between the middle and late phases (P=0.11; Figure 1). Although the difference in the heterogeneity of neointimal coverage between the middle and late phases was not statistically significant (P=0.13), heterogeneity was greater in the middle and late phases than in the early phase (P=0.003 and P<0.001, respectively; Figure 2). The maximum yellow color grade was not significantly different among the 3 groups (Figure 3). Moreover, the incidence of thrombus adhesion was recorded for all stents in the 3 groups (Figure 4).

Figure 1.

Grade of dominant neointimal coverage after implantation of a fluoropolymer-based drug-eluting stent. The grade of dominant neointimal coverage was significantly higher in the middle and late phase than in the early phase (P=0.021 and P<0.001, respectively); however, the grade was similar in the middle and late phases (P=0.11).

Figure 2.

Heterogeneity of neointimal coverage after implantation of a fluoropolymer-based drug-eluting stent. Although the heterogeneity of neointimal coverage was similar in the middle and late phases (P=0.13), it was greater in these 2 groups than in the early phase (P=0.003 and P<0.001, respectively).

Figure 3.

Maximum yellow color grade after implantation of a fluoropolymer-based drug-eluting stent. The maximum yellow color grade did not differ significantly among the 3 groups.

Figure 4.

Incidence of thrombus adhesion after implantation of a fluoropolymer-based drug-eluting stent. Thrombus adhesion was observed in all stents and groups.

Discussion

There are 4 main findings of the present study. First, the grade of dominant neointimal coverage after FP-DES implantation was significantly higher in the middle and late phases than in the early phase, with was no statistically significant difference between the middle and late phases. Second, the heterogeneity of neointimal coverage was similar in the middle and late phases, and was greater in these groups than in the early phase. Third, the maximum yellow color grade did not differ significantly among the 3 groups. Finally, the incidence of thrombus adhesion did not differ significantly between the 3 groups.

The grade of dominant neointimal coverage was significantly higher in the middle phase than in the early phase. The dominant neointimal coverage grade in the middle phase was Grade 1, which accounted for approximately 60% of cases in this group. This result differs from the findings of a previous angioscopy report evaluating intravascular status 12 months after PF-DCS implantation.¹³ In that study, the grade of dominant neointimal coverage 12 months after PF-DCS implantation was mostly Grade 3.¹³ This difference could be explained by differences in the duration of paclitaxel elution. PF-DCS does not contain a polymer, and the elution period of paclitaxel is approximately 2 months.¹⁴ In contrast, FP-DES contains a polymer that can elute paclitaxel over approximately 12 months.⁴ Therefore, the inhibition of neointimal proliferation by paclitaxel could be maintained in the middle phase after FP-DES implantation, resulting in a lower grade of dominant neointimal coverage. Notably, the grade of dominant neointimal coverage was not significantly different between the middle and late phases in the present study. This suggests that neointimal proliferation was not advanced beyond 12 months after FP-DES implantation, when the elution of paclitaxel is already completed.

Vascular inflammation caused by paclitaxel may be associated with delayed arterial healing. Farb et al showed a dose-dependent increase in fibrin deposition and medial necrosis after deployment of paclitaxel-eluting stents in rabbit iliac arteries, suggesting that paclitaxel was responsible for these effects.¹⁵ It has been reported that the presence of polymer could also increase vessel inflammation, which is occasionally severe and may lead to medial disruption and the development of an aneurysm.^16–18 A previous pathological study investigating vascular responses to PF-DCS vs. FP-DES showed higher inflammatory reactions around struts in FP-DES 12 months after implantation.¹⁹ Therefore, although the amount of paclitaxel is lower in FP-DES than in PF-DCS,⁴ prolonged exposure to paclitaxel or the presence of a durable polymer coating may affect vascular inflammation. Consequently, this results in delayed vascular healing after FP-DES implantation, even in the late phase.

In the present study, greater heterogeneity of neointimal coverage was observed in the middle and late phases compared with the early phase. The mechanism underlying this greater heterogeneity is unclear. We speculated that lesion characteristics may have contributed to the variability in the effect of paclitaxel and the degree of vascular inflammation, possibly leading to a greater degree of heterogeneity of neointimal coverage after FP-DES implantation. However, further investigations are needed.

In general, it is considered that angioscopically detected yellow plaque represents arteriosclerotic changes. Previous angioscopic studies reported that yellow plaque was less frequently observed 12 months after implantation of a bare nitinol stent in femoropopliteal lesions than at 3 months.^11,13 However, in the present study, the maximum yellow color grade was not significantly different among the 3 groups after FP-DES implantation. This may be attributed to the inhibition of the growth of white neointima by paclitaxel. Therefore, the underlying yellow plaque before FP-DES implantation was not completely covered, even in the late phase. In addition, vascular inflammation caused by paclitaxel and the polymer contained in the FP-DES may have promoted neoatherosclerosis, leading to the formation of yellow plaques.

At the beginning of arterial healing, thrombi are attached to the stented segment. Hence, thrombus adhesion can be considered an initial phase of arterial healing.²⁰ Conversely, when arterial healing is sufficient and mature re-endothelialization is established, the vessel exerts its own anti-thrombotic effect via mature endothelial cells. Therefore, the presence of a thrombus within the stent (detected by angioscopy) is thought to be a sign of delayed arterial healing in the chronic phase after stent implantation.²¹ In the present study we observed thrombus adhesion in all FP-DESs and in all phases. Although thrombus adhesion in the early phase may simply reflect the initial phase of arterial healing, it is reasonable to assume that delayed arterial healing is associated with thrombus adhesion in the middle and late phases. However, approximately half the peripheral artery disease patients in the present study had concomitant chronic kidney disease and were on hemodialysis. In general, patients on hemodialysis are more likely to have multiple risk factors for atherosclerosis and advanced atherosclerosis with severe calcification. A previous pathological study reported that severe calcification, especially surface calcified area, is an independent predictor of uncovered struts and delayed arterial healing after stent implantation.²² In addition, hemodialysis results in platelet dysfunction and may activate plasma coagulation factors that can cause in-stent thrombosis.^23–25 The high proportion of patients on hemodialysis in the present study may have contributed to the delayed arterial healing and high frequency of thrombus adhesion. Although an advantage of angioscopy compared with other intravascular imaging modalities is its ability to directly visualize the presence of a thrombus, there are limits to quantitative assessments with angioscopy. Therefore, it was difficult to assess differences in the degree of the thrombus burden among the 3 groups in the present study. Further investigations are needed.

The angioscopic findings of this study revealed that neointimal proliferation was relatively suppressed, suggesting that FP-DES prevents in-stent restenosis due to neointimal proliferation. Of note, thrombogenicity at the site of FP-DES implantation was relatively high due to delayed vascular healing, even in the late phase. Although the present study did not investigate the relationship between angioscopic findings of FP-DES and clinical outcomes because of the limited number of participants, delayed vascular healing may contribute to the risk of a thrombotic adverse event after FP-DES implantation. Further long-term data after FP-DES implantation are needed.

The present study has several limitations. First, this was a single-center observational investigation. Second, the sample size was relatively small. However, the sample size of this study was comparable to that of previous angioscopic studies. Third, the data for the early, middle, and late phases were not serial data for the same patients. Fourth, although lesion characteristics may have affected the angioscopic findings at follow-up, we could not elucidate their relationships in the population included in this study. Fifth, cytochrome P450 family 2 subfamily C member 19 (CYP2C19) gene polymorphisms were not evaluated in this study. Because CYP2C19 gene polymorphisms affect the effect of P2Y12 inhibitor,^26,27 it may affect the angioscopic findings, especially with regard to thrombus adhesion in this study. Sixth, angioscopy was not always able to evaluate the entire stented segment because of a limited angioscopic visual field, especially in tortuous lesions. Finally, we excluded patients who exhibited any event of earlier stent failure. In addition, we did not investigate the relationship between angioscopic findings of FP-DES and clinical outcomes, and the optimal medical therapy after FP-DES implantation remains unclear. Further investigation of the relationship between angioscopic findings and clinical outcomes is warranted.

Conclusions

The middle and late phases after FP-DES implantation for femoropopliteal lesions were linked to significantly higher grades of dominant neointimal coverage and heterogeneity compared with the early phase. In addition, thrombus adhesion was observed in all stents and in all phases. Arterial healing may not be sufficient, even in late phase after FP-DES implantation for femoropopliteal lesions.

Acknowledgments

The authors thank Naoya Kurata, Takashi Sumikawa, Hiroki Oyama, Yusuke Katagiri, Kohei Nanri, and Haruna Miyaguchi for their expertise in performing the angioscopic examinations and Saori Sinohara for her expertise in data collection.

Sources of Funding

This study did not receive any specific funding.

Disclosures

O.I. has received remuneration from Medtronic Japan and Boston Scientific Japan. T.M. has received research funding from Abbott Vascular Japan. The remaining authors have no conflicts of interest to disclose.

IRB Information

This study was approved by the Medical Ethics Committee of Kansai Rosai Hospital (Reference no. 22D032g).

Data Availability

The deidentified participant data will not be shared.

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