Clinical impact of fluoropolymer-based drug-eluting stent thrombosis in femoropopliteal artery occlusive lesions

Abstract

Background

Endovascular treatment (EVT) is recommended for superficial femoral artery (SFA) lesions, and good results have been reported after implantation of drug-eluting stents (DES) for SFA. However, the major concern after implantation is acute thrombosis during the follow-up period, resulting in major amputation and major adverse limb events. In this study, we examined the incidence and outcome of acute thrombosis after DES implantation in the SFA.

Objectives and Methods

DES implantation for a femoropopliteal lesion was performed in 288 patients at multiple centers in Japan from 2019 to 2021. A total of 25 patients (8.6%) with DES acute occlusion were analyzed retrospectively. The primary endpoint was amputation-free survival (AFS) after acute occlusion.

Results

The median patient age was 77 years, with 48% having diabetes, 40% undergoing maintenance dialysis, and 66% having chronic limb-threatening ischemia (CLTI). The mean time from initial DES implantation to acute occlusion was 153.5 ± 177.6 days, with a median of 104 days. EVT was performed in 18 patients (72%), surgical revascularization in 3 (12%), and conservative treatment in 4 (16%). Two deaths within 30 days were both due to sepsis. No major amputation or major adverse cardiovascular events occurred within 30 days. The 1-year rates of patency and freedom from target lesion revascularization after DES thrombosis were 22.9% and 48.8%, respectively. AFS at 1 year was 55.1%.

Conclusion

Acute DES occlusion is relatively frequent, and the outcome is poor. Therefore, the indication of DES implantation for a complex SFA lesion may require careful consideration. Further investigation may be needed in DES implantation for a complex SFA lesion.

Keywords

Endovascular treatment drug-eluting stent femoropopliteal artery acute thrombosis acute limb ischemia

Introduction

Society for Vascular Surgery (SVS) guidelines recommend endovascular treatment (EVT) for superficial femoral artery (SFA) lesions up to 15 cm, exclusive of the bifurcation.¹ European Society of Cardiology (ESC) guidelines in collaboration with the European Society for Vascular Surgery (ESVS) recommend EVT as the first choice for lesions shorter than 25 cm.² Revascularization of SFA lesions may lead to improvement of symptoms, physical function, and walking distance in patients with peripheral artery disease.^3–5

Positive outcomes have been obtained following implantation of drug-eluting stents (DES) for treatment of SFA lesions.^6–11 However, the major concern after implantation of a SFA device is acute thrombosis during the follow-up period; when the SFA device is acutely occluded, the probability of major amputation and major adverse limb events is higher.^12,13 Some studies have reported a lower stent thrombosis rate after DES,^4,5,9,11 but real-world outcomes have not been fully explored. Therefore, the purpose of this study is to evaluate the incidence of acute occlusion after DES implantation for SFA lesions and to investigate clinical outcomes after DES acute occlusion.¹⁴

Patients and methods

Of 288 patients who underwent DES implantation for femoropopliteal occlusive lesions from January 2019 to December 2021 in multiple centers in Japan, 25 (8.6%) with acute DES occlusion were reviewed retrospectively. These patients included cases with a DES implanted for symptomatic (Rutherford classification ≥2) chronic femoropopliteal occlusive lesions, intra-stent stenosis (ISR), and intra-stent occlusion (ISO). Patients who underwent initial DES implantation for acute occlusion or DES implantation that covered the common femoral artery were excluded. Patient characteristics, procedural details, hospital outcomes, and short-term outcomes were collected from medical records.

Study endpoints

The primary endpoint was amputation-free survival (AFS) after acute DES occlusion. The secondary endpoints were survival, limb salvage, patency after acute DES occlusion, and freedom from re-target lesion revascularization (re-TLR) after acute occlusion.

Definition

Limb salvage was defined as a major amputation-free case, with major amputation defined as above-ankle amputation. Patency after DES thrombosis was defined as a condition in which the treated artery or bypass graft had no restenosis and needed no further treatment. Cases with conservative treatment were defined as having loss of patency. Re-TLR was defined as an intervention in the treated artery or bypass graft including the anastomotic site, and freedom from re-TLR was considered only in patients undergoing revascularization after acute occlusion. DES thrombosis was defined as a case with acute limb ischemia and DES occlusion diagnosed by duplex ultrasound (DUS), computed tomography (CT), or angiography. Cases with recurrent intermittent claudication in which angiography revealed thrombosis or thrombosis was detected on intraprocedural findings (thrombolysis and thrombectomy) also included in DES thrombosis. Technical success of the EVT procedure was defined as no more than 30% residual stenosis in the treated area on completion angiography.

Medication and follow-up

Dual antiplatelet therapy (DAPT) or single antiplatelet therapy (SAPT) plus anticoagulant therapy (warfarin or direct oral anticoagulants) was used after initial DES implantation and continued for at least 6 months after implantation. Follow-up was performed every 3 months, and the ankle-brachial index (ABI) was measured at each follow-up. If the symptom was recurrent or ABI decreased by ≥ 0.15, further DUS or angiography and/or additional treatment was performed. Follow-up after acute DES occlusion was also performed as above.

Ethics

This study was conducted within the principles of the Declaration of Helsinki. The study was approved by the ethics committee of JA Hiroshima General Hospital (Hiroshima, Japan; approval number: 22-6) on an opt-out basis due to the non-invasive and retrospective design.

Statistical analysis

Continuous variables are expressed as medians (25^th–75^th percentiles) or mean ± standard deviation (SD), and categorical variables as absolute values (percentages). Patency after DES thrombosis, freedom from re-TLR, limb salvage, AFS, and survival were calculated by the Kaplan–Meier method. JMP (ver. 16) was used for statistical analysis.

Results

The background of the patients at the time of DES acute occlusion is shown in Table 1. The median age was 77 (70–82) years, 48% had diabetes, and 40% had chronic kidney disease (CKD) that required dialysis. Chronic limb-threatening ischemia (CLTI) was present in 66% of patients. The mean time from initial DES implantation to acute occlusion was 153.5 ± 177.6 days, and the median time was 104 (33.5–203.5) days.

Table 1.

Baseline characteristics of study population at onset of drug-eluting stent thrombosis (n = 25).

Variables	N	(%)
Time between stent graft implantation and thrombosis, months	3.5 (1.1–6.8)
Age	77 (70–82)
Male	10	(40)
Hypertension	20	(80)
Dyslipidemia	11	(44)
Congestive heart failure	6	(24)
Coronary artery disease	9	(36)
Cerebrovascular disease	4	(16)
Atrial fibrillation	4	(16)
Smoking
Current	7	(28)
Past	8	(32)
Never	9	(36)
Missing	1	(4)
Diabetes mellitus	12	(48)
Renal function
eGFR ≥ 60 mL/min/1.73 m²	7	(28)
eGFR < 60 mL/min/1.73 m²	8	(32)
Hemodialysis	10	(40)
Medication
Aspirin	14	(56)
P2Y12	17	(68)
Cilostazol	5	(20)
Warfarin	3	(12)
Direct oral anticoagulants	3	(12)
Statin	12	(48)
Range of thrombosis
Limited to stent	11	(44)
Stent with proximal extension	2	(8)
Stent with distal extension	5	(20)
Stent with bidirectional extension	6	(24)
Symptom
Mild-same compared to before the first treatment	11	(44)
Severe compared to before the first treatment	7	(28)
ALI	7	(28)
Halo phenomenon	1	(4)

Data are presented as n (%) or median (interquartile range).

N, number; eGFR estimated glomerular filtration rates; ALI, Acute Limb Ischemia.

The lesion background at the time of initial DES implantation is shown in Table 2. The median target vessel diameter was 5.0 (4.3–5.5) mm, and the median lesion length was 230 (190–300) mm. The median below-the-knee runoff vessel was 2 (0.5–3) and the peripheral artery calcium scoring system (PACCS) classification of the lesions was Grade 0 in 9 (36%) limbs, Grade 1 in 4 (16%), Grade 2 in 2 (8%), Grade 3 in 4 (16%), and Grade 4 in 6 (16%). A total of 19 patients (76%) underwent EVT for a SFA chronic total occlusion (CTO) lesion. The site of occlusion at the time of acute occlusion was in-stent only in 44%, proximal extension in 8%, distal extension in 20%, and bilateral extension in 24% (Figure 1(A) and (B)). The symptoms after acute DES occlusion compared to those before the first treatment were mild to similar in 11 patients (44%) and severe in 7 (28%), and acute limb ischemia was present in 7 patients (28%).

Table 2.

Baseline characteristics of study population at the time of drug-eluting stent implantation (n = 25).

Variables	N	(%)
Rutherford classification
Category2	4	(16)
Category3	6	(24)
Category4	4	(16)
Category5	10	(40)
Category6	1	(4)
Prior EVT
Iliac artery	12	(48)
Femoro-popliteal artery	13	(52)
TASC Ⅱ classification
B	6	(24)
C	9	(36)
D	10	(40)
Chronic total occlusion	19	(76)
Peripheral arterial calcium scoring system classification
Grade 0	9	(36)
Grade 1	4	(16)
Grade 2	2	(8)
Grade 3	4	(16)
Grade 4	6	(24)
ISO or ISR	5	(20)
Reference vessel diameter, mm	5.0 (4.3–5.5)
Lesion length, mm	225 (175–300)
Treatment length, mm	302.5 (215–352.5)
Proximal stent diameter, mm	6 (6-6)
Distal stent diameter, mm	6 (6-6)
Distal site of stent implantation
SFA	9	(36)
P1	5	(20)
P2	8	(32)
P3	3	(12)
Below-the-knee runoff
No vessel runoff	6	(24)
One vessel runoff	6	(24)
Two vessel runoff	9	(36)
Three vessel runoff	4	(16)
Combined device
Drug-coated balloon	2	(8)
Bare-nitinol stent	1	(4)
Interwoven nitinol stent	2	(8)
Combined procedure
EVT for infrapopliteal lesion	6	(24)
Popliteal to distal bypass	2	(8)
Common femoral endarterectomy	2	(8)
IVUS Use	12	(48)

Data are presented as n (%) or median (interquartile range).

N. number; EVT, endovascular treatment; TASC, Trans-Atlantic Inter-Society Consensus; ISO, intra-stent occlusion; ISR, intra-stent restenosis; SFA, superficial femoral artery; IVUS, intravascular ultrasound.

Procedural details and hospital outcomes are shown in Table 3. EVT was performed in 18 patients (72%), including for thrombolysis (n = 7, 39%), DES (n = 4, 25%), stent graft (n = 3, 17%), drug-coated balloon (n = 3, 17%), bare-nitinol stent (n = 1, 6%), and interwoven nitinol stent (n = 1, 6%). The technical success of EVT was 78%. Surgical revascularization was performed in 3 patients (12%), including thrombectomy (n = 1) and femoropopliteal bypass (n = 2). Four patients were treated conservatively due to mild symptoms (n = 2) and declined revascularization in patients (n = 2) with severe septic shock at readmission. There were two hospital deaths within 30 days, due to sepsis from acute lower extremity occlusion in the two declined cases. No major amputation was required within 30 days. No major adverse cardiovascular events occurred, and 16 patients (64%) were discharged as ambulatory.

Table 3.

Treatment strategy and peri-operative complications in patients undergoing reintervention for drug-eluting stent thrombosis (n = 25).

Variables	N	(%)
Time between thrombosis and reintervention, days	104 (33.5–203.5)
Treatment strategy
EVT	18	(72)
Thrombolysis	7	(39)
Stent graft	3	(17)
Drug-eluting stent	4	(25)
Bare-nitinol stent	1	(6)
Interwoven nitinol stent	1	(6)
Drug-coated balloon	3	(17)
Surgical revascularization	4	(16)
Thrombectomy	1	(25)
Bypass	3	(75)
Conservative treatment	4	(16)
Technical success of EVT	14	(78)
Hospital death within 30 days	2	(8)
Major amputation within 30 days	0	(0)
MACE within 30 days	0	(0)
Ambulatory at discharge	16	(64)

Data are presented as n (%) or median (interquartile range).

N, number; EVT, endovascular treatment; MACE, major adverse cardiovascular events.

The follow-up rate was 100%, with a mean follow-up period of 320 ± 267.9 days. During follow-up, restenosis of the treated lesion was observed in 12 patients (48%), of whom 8 required re-TLR. The 1-year patency after DES thrombosis was 22.9% (Figure 2(A)) and the 1-year freedom from re-TLR was 48.8% (Figure 2(B)). Major amputation was required in 4 patients and the 1-year limb salvage rate was 79.3% (Figure 3(A)). During follow-up, 9 patients died due to infection (n = 4), cardiovascular events (n = 3) and unknown causes (n = 2), and 1-year overall survival was 63.7% (Figure 3(B)). The 1-year AFS was 55.1% (Figure 4).

Discussion

This study had two main findings. First, acute occlusion after DES implantation occurred in 8.6% of patients. Second, 1-year patency after acute DES thrombosis, 1-year limb salvage, and 1-year AFS were 22.9%, 79.3%, and 55.1% respectively, all of which were unfavorable.

In a series of 430 DES implantation cases, Müller-Hülsbeck et al. found rates of clinically driven TLR and stent thrombosis of 13.5% and 3.1% at 24 months after fluoropolymer-based DES implantation.⁸ Iida et al. reported a series of 84 DES implantations in which the 2-year primary patency of a fluoropolymer-based DES was 88.5% and stent thrombosis occurred in 1.9% of fluoropolymer-based DES cases in 24 months follow-up.⁹ Compared to other SFA devices, a fluoropolymer-based DES is associated with a higher patency and a lower frequency of acute occlusion (1.9%–4.4%).^8,9,11,13 In the current study, the rate of acute thrombo-occlusion was 8.6%, which is higher than in previous reports. The reason is unclear, but in a series of 1204 fluoropolymer-based DES, Iida et al. reported dialysis, CLTI, a smaller reference vessel diameter, and CTO as risk factors for DES restenosis.¹¹ In the current study, 40% of the patients had CKD requiring dialysis, 66% had CLTI, and 76% had CTO, and the median reference diameter in the cohort was 5.0 (4.3–5.5) mm. These results suggest that our cohort might have been at high risk for DES stenosis and occlusion. In patients with these risk factors, the indication for fluoropolymer-based DES implantation should be carefully considered, and if implantation is performed, strict follow-up is required.

A possible reason for acute occlusion is retention of paclitaxel in the fluoropolymer-based DES, which is reported to be longer than that in a polymer-free DES. Sustained drug release from a fluoropolymer-based DES gives better results for patency and freedom from TLR¹⁰ and continuous release of paclitaxel reduces intimal hyperplasia. However, intima might not cover the stent wall in the SFA as for a stent graft compared with a BMS, which might affect fluoropolymer-based DES acute occlusion in the long term. In this study, the average time to acute occlusion was 150 days (maximum 691 days), indicating that most acute occlusions occurred in the long term. Thus, long-term follow-up is important after fluoropolymer-based DES implantation.

As far as we are aware, this is the first report to assess the outcomes of acute occlusion after fluoropolymer-based DES implantation. Outcomes after acute occlusion of SFA devices are generally unfavorable. Ichihashi et al. found that 13% (159/1215) of patients had acute occlusion of a stent graft for SFA lesions, and both EVT and surgical revascularization for acute occlusion had poor outcomes, with 1-year overall patency of 54%.¹⁵ In our cohort, the 1-year overall patency was 21% and the 1-year freedom from re-TLR was 55%. These poor outcomes may be due to thrombosis extending proximal and distal to the DES during device occlusion, resulting in a greater volume of thrombosis and occlusion of collateral arteries. In their stent graft series, Ichihashi et al. reported that 65% of patients had proximal and/or distal extension of acute thrombosis.¹⁵ In the current study, this rate was 56%. The poor prognosis after thrombotic occlusion of a DES suggests that careful consideration may be given to the initial indication for DES implantation in patients with dialysis, CLTI, CTO, or small reference vessel diameter, and strict follow-up including ABI measurement and DUS may be needed if implanted.

This study has several limitations, including the retrospective design, the relative rarity of DES acute occlusion, and the consequent small sample size. Thus, further investigation may be needed in the validation of DES implantation for complex SFA lesion. The multicenter design also prevented comparison of the results with those for patients who did not have acute occlusion. And we could not assess the risk factors for DES acute occlusion. Comparison was not made in outcomes (patency, TLR, limb salvage, and AFS) between a DES and other device thrombosis. Selection of devices to treat the occluded DES was at each interventionist’s discretion, which might affect the outcomes. Various revascularization techniques are used for DES acute occlusion, but the small sample size prevented examination of the results by technique. The lower usage of intravascular ultrasounds (IVUS) in initial endovascular treatment might affect the higher acute occlusion rate. Finally, the subjects were limited to Japanese patients. However, despite these limitations, this study is clinically significant because no previous detailed study of acute DES occlusion has been conducted.

Conclusion

Acute occlusion of a fluoropolymer-based DES is relatively frequent (8.6%) in the real world and the outcomes are poor. These findings suggest that the indication for DES implantation in patients with dialysis, CLTI, CTO, or small vessel diameter may be considered carefully. Further investigation may be needed in DES implantation for a complex SFA lesion.

Footnotes

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

Ethical statement

ORCID iDs

Haruna Shimizu

Taira Kobayashi

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