Scholarly article on topic 'Zilver PTX Post-Market Surveillance Study of Paclitaxel-Eluting Stents for Treating Femoropopliteal Artery Disease in Japan'

Zilver PTX Post-Market Surveillance Study of Paclitaxel-Eluting Stents for Treating Femoropopliteal Artery Disease in Japan Academic research paper on "Clinical medicine"

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JACC: Cardiovascular Interventions
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{"drug-eluting stent(s)" / "paclitaxel-eluting stent(s)" / "peripheral artery disease" / "peripheral vascular disease" / "popliteal artery" / "superficial femoral artery"}

Abstract of research paper on Clinical medicine, author of scientific article — Hiroyoshi Yokoi, Takao Ohki, Kimihiko Kichikawa, Masato Nakamura, Kimihiro Komori, et al.

Abstract Objectives This multicenter, prospective, post-market surveillance study in Japan evaluates the paclitaxel-coated Zilver PTX stent in real-world patients with complex lesions. Background The Zilver PTX stent is the first drug-eluting stent (DES) approved for the superficial femoral artery. Previously, results from a large randomized study and a complementary, large single-arm study supported the safety and effectiveness of the DES. Methods There were no exclusion criteria, and consecutive patients with symptomatic peripheral artery disease (PAD) treated with the DES were enrolled in the study. Clinically driven target lesion revascularization (TLR) was defined as reintervention performed for ≥50% diameter stenosis after recurrent clinical symptoms of PAD. Clinical benefit was defined as freedom from persistent or worsening symptoms of ischemia. Patency was evaluated by duplex ultrasound where physicians considered this standard of care. Results In this study, 907 patients were enrolled at 95 institutions in Japan. There were numerous comorbidities including high incidences of diabetes (58.8%), chronic kidney disease (43.8%), and critical limb ischemia (21.5%). Lesions were also complex, with an average length of 14.7 cm, 41.6% total occlusions, and 18.6% in-stent restenosis. In total, 1,861 DES were placed in 1,075 lesions. Twelve-month follow-up was obtained for >95% of eligible patients. Freedom from TLR was 91.0%, and clinical benefit was 87.7% through 12 months. The 12-month primary patency rate was 86.4%. Conclusions Despite more challenging lesions, results from the current study are similar to outcomes from the previous Zilver PTX studies, confirming the benefit of the Zilver PTX DES in a real-world patient population. (Zilver PTX Post-Market Study in Japan; NCT02254837)

Academic research paper on topic "Zilver PTX Post-Market Surveillance Study of Paclitaxel-Eluting Stents for Treating Femoropopliteal Artery Disease in Japan"

© 2016 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION PUBLISHED BY ELSEVIER

VOL. 9, NO. 3, 2016 ISSN 1936-8798/$36.00 http://dx.doi. org/10.101 6/j. j c i n. 2015.09. 035

Zilver PTX Post-Market Surveillance Study

CrossMark

of Paclitaxel-Eluting Stents for Treating Femoropopliteal Artery Disease in Japan

12-Month Results

Hiroyoshi Yokoi, MD,a Takao Ohki, MD, PHD,b Kimihiko Kichikawa, MD,c Masato Nakamura, MD, PHD,d Kimihiro Komori, MD, PHD,e Shinsuke Nanto, MD, PHD,f Erin E. O'Leary, PHD,g Aaron E. Lottes, PHD,g Scott A. Snyder, PHD,g Michael D. Dake, MDh

ABSTRACT

OBJECTIVES This multicenter, prospective, post-market surveillance study in Japan evaluates the paclitaxel-coated Zilver PTX stent in real-world patients with complex lesions.

BACKGROUND The Zilver PTX stent is the first drug-eluting stent (DES) approved for the superficial femoral artery. Previously, results from a large randomized study and a complementary, large single-arm study supported the safety and effectiveness of the DES.

METHODS There were no exclusion criteria, and consecutive patients with symptomatic peripheral artery disease (PAD) treated with the DES were enrolled in the study. Clinically driven target lesion revascularization (TLR) was defined as reintervention performed for $50% diameter stenosis after recurrent clinical symptoms of PAD. Clinical benefit was defined as freedom from persistent or worsening symptoms of ischemia. Patency was evaluated by duplex ultrasound where physicians considered this standard of care.

RESULTS In this study, 907 patients were enrolled at 95 institutions in Japan. There were numerous comorbidities including high incidences of diabetes (58.8%), chronic kidney disease (43.8%), and critical limb ischemia (21.5%). Lesions were also complex, with an average length of 14.7 cm, 41.6% total occlusions, and 18.6% in-stent restenosis. In total, 1,861 DES were placed in 1,075 lesions. Twelve-month follow-up was obtained for >95% of eligible patients. Freedom from TLR was 91.0%, and clinical benefit was 87.7% through 12 months. The 12-month primary patency rate was 86.4%.

CONCLUSIONS Despite more challenging lesions, results from the current study are similar to outcomes from the previous Zilver PTX studies, confirming the benefit of the Zilver PTX DES in a real-world patient population. (Zilver PTX Post-Market Study in Japan; NCT02254837) (J Am Coll Cardiol Intv 2016;9:271-7) © 2016 by the American College of Cardiology Foundation.

From the department of Cardiovascular Medicine, Fukuoka Sanno Hospital, Fukuoka, Japan; bDepartment of Surgery, Jikei University Hospital, Tokyo, Japan; cDepartment of Radiology, Nara Medical University, Kashihara, Japan; dDivision of Cardiovascular Medicine, Toho University, Ohashi Medical Center, Tokyo, Japan; eDivision of Vascular Surgery, Division of Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan; fNishinomiya Hospital Affairs, Nishinomiya Municipal Central Hospital, Nishinomiya, Japan; gCook Research Incorporated, West Lafayette, Indiana; and the hDepartment of Cardiothoracic Surgery, Stanford University Medical Center, Stanford, California. This study was sponsored by Cook Medical. Dr. Ohki is a paid consultant for Terumo, Gore, and Cordis; and has received research funding from Cook Medical. Dr. Nakamura has received consulting fees for this post-market study (Cook Japan) and Terumo; and has received speaking fees for Cook Japan, Terumo, Cordis Japan, and Medico. Drs. O'Leary, Lottes, and Snyder are paid employees of Cook Research Incorporated, a contract research organization and Cook Group Company. Dr. Dake is a member of the scientific advisory board for Abbott Vascular and W.L. Gore and Associates; and has received consulting fees from Medtronic, Intact Vascular, and Cook Medical. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Manuscript received July 13, 2015; revised manuscript received August 27, 2015, accepted September 24, 2015.

FEBRUARY 8, 2016:271 - 7

ABBREVIATIONS AND ACRONYMS

ABI = ankle brachial index

BMS = bare-metal stent(s)

CLI = critical limb ischemia

DCB = drug-coated balloon(s)

DES = drug-eluting stent(s)

ISR = in-stent restenosis

PAD = peripheral artery disease

PTA = percutaneous transluminal angioplasty

SFA = superficial femoral artery

TLR = target lesion revascularization

Endovascular treatment of symptomatic peripheral artery disease (PAD) is the preferred revascularization strategy when feasible. Percutaneous trans-luminal angioplasty (PTA) has historically been the most common endovascular treatment option; however, restenosis rates following PTA are high, resulting in frequent revascularization procedures. In an effort to reduce restenosis rates, a number of other endovascular treatment options have been developed, including atherectomy, bare-metal stents (BMS), drug-coated balloons (DCB), and drug-eluting stents (DES). Among these, a paclitaxel-coated DES has successfully reduced restenosis and reintervention rates for patients suffering from superficial femoral artery (SFA) disease (1,2).

SEE PAGE 278

A large randomized study in the United States, Germany, and Japan demonstrated the safety and effectiveness of the paclitaxel-coated DES for treating SFA disease in patients with moderate lesions (mean lesion length 6.5 cm) (1,2). A complementary singlearm study in Europe, Korea, and Canada, further supported the performance of the DES in a broader patient population with more complex lesions (mean lesion length 10.0 cm) (3). The current study evaluates the safety and effectiveness of the paclitaxel-coated DES in a large, real-world patient population with long, complex lesions in Japan.

METHODS

This multicenter, prospective, post-market surveillance study planned to enroll the first 900 consecutive patients with symptomatic PAD involving the above-the-knee femoropopliteal arteries who were treated with the Zilver PTX Drug-Eluting Peripheral Stent (Cook Medical, Bloomington, Indiana) in Japan. This DES is a self-expanding nitinol stent with a polymerfree paclitaxel coating (3 mg/mm2 dose density). This post-market surveillance study was required and regulated by the Japanese Ministry of Health, Labour, and Welfare, and was therefore required to be conducted in accordance with Japanese Good Postmarket Surveillance Practice Regulations, which dictate that informed consent processes be determined by each institution's ethical committee policy to specify whether informed consent was necessary or outcome data could be abstracted while protecting patient's rights without requiring individual patient consent.

BASELINE ASSESSMENT, INTERVENTIONS, AND MEDICATIONS. Rutherford classification and ankle brachial index (ABI) were assessed pre-procedure. The device instructions for use recommends that stents be oversized by 1 to 2 mm with respect to the reference vessel, and placed at least 1 cm below the SFA origin and above the medial femoral epi-condyle. Treatment of lesions in both legs was permitted. Pre- and post-dilation and treatment of inflow and outflow disease were at the physician's discretion.

The same antiplatelet regimen used in previous studies was recommended for all patients: clopidog-rel or ticlopidine starting at least 24 h before the procedure, or a procedural loading dose; continued clopidogrel or ticlopidine therapy for at least 60 days post-procedure; and aspirin indefinitely.

FOLLOW-UP ASSESSMENT. ABI and Rutherford classification were assessed before discharge and at the 12-month clinical visit. Clinically driven target lesion revascularization (TLR) was defined as reintervention performed for $50% diameter stenosis within ±5 mm of the target lesion after recurrent clinical symptoms of PAD. Thrombosis was site-reported as total occlusion of suspected thrombotic origin. Stent integrity was assessed by radiography at 12 months, with site-reported fractures reviewed by a radiographic core laboratory for classification of fracture type. Clinical benefit was defined as freedom from persistent or worsening symptoms of ischemia (i.e., claudication, rest pain, ulcer, or tissue loss) after the initial study treatment. Patency was evaluated by duplex ultrasonography at 12 months where physicians considered this standard of care, with loss of patency corresponding to a peak systolic velocity ratio $2.4. Deaths were adjudicated by an independent clinical events committee.

STATISTICAL ANALYSIS. The sample size of 900 was selected to provide 95% confidence for determination of events at rates as low as 1% to 2%. The data were analyzed using SAS 9.3 (SAS Institute, Cary, North Carolina). Continuous variables were summarized with means and SD, with p values calculated using the standard t test. Dichotomous and polytomous variables were reported as counts and percentages, with p values calculated using the Fisher exact test. As appropriate, the number of observations represented the number of patients, the number of treated lesions, or the number of treated limbs. Kaplan-Meier analyses were performed to assess freedom from TLR, freedom from thrombosis, clinical benefit, and patency over time.

RESULTS

Between May 2012 and February 2013, 907 patients were enrolled at 95 institutions in Japan. In total, 1,075 lesions were treated with 1,861 DES in these patients. A mean of 1.7 stents per lesion, and a mean of 2.1 stents per patient, were implanted. The stents used were 6 to 8 mm in diameter and 40 to 120 mm in length. Demographics, comorbidities, and baseline lesion characteristics reported by the investigative sites are shown in Table 1. There was a 58.8% incidence of diabetes, a 43.8% incidence of chronic kidney disease, and a 21.5% incidence of critical limb ischemia (CLI) in these patients. The lesions were complex with an average lesion length of 14.7 ± 9.7 cm (range 0.5 to 40 cm), 41.6% total occlusions, and 18.6% in-stent restenosis (ISR).

SAFETY. Twelve-month follow-up was obtained for 787 patients, representing >95% of those eligible. The DES was safe in Japanese patients. All-cause

TABLE 1 Demographics and Lesion Characteristics

Patient characteristics

Patients, N 907

Mean age, yrs 73.5 ± 8.5 (907)

Men 70.3 (638)

Diabetes 58.8 (533)

Hypertension 85.3 (774)

Hypercholesterolemia 60.9 (552)

Chronic kidney disease 43.8 (397)

eGFR <60 ml/min/1.73 m2 and/or dialysis 35.5 (322)

Pulmonary disease 8.0 (73)

Lesion characteristics

Lesions 1,075

Lesion length, cm 14.7 ± 9.7 (1,074)

Lesions >15 cm 42.0 (451)

Lesions >20 cm 29.7 (319)

Lesion location*

Proximal SFA 61.1 (657)

Distal SFA 64.5 (693)

Popliteal 9.4 (101)

Total occlusion 41.6 (447)

In-stent restenosis 18.6 (200)

Percent diameter stenosis 91.9 ± 10.7(1,075)

Reference vessel diameter, mm 5.7 ± 0.9 (1,075)

Critical limb ischemia (Rutherford classes 4-6)t 21.5 (218)

Number of patent runoff vessels^

0 6.6 (71)

1 31.8 (340)

2 32.4 (347)

$3 29.2 (312)

Values are mean ± SD (n) or % (n). *Of the 1,075 lesions in this study, 376 lesions span more than 1 segment. fRutherford classification data not available for 60 lesions. iData not available for 5 lesions. eGFR = estimated glomerular filtration rate; SFA = superficial femoral artery.

mortality was 5.1% through 12 months. There were no device- or procedure-related deaths. No paclitaxel-related adverse events were reported. Seven patients in the study had an amputation for a 12-month rate of 0.8%. At the time of enrollment, 6 of the 7 patients had CLI with tissue loss (Rutherford class 5). The 12-month Kaplan-Meier estimate of freedom from TLR was 91.0% (Figure 1). The 12-month Kaplan-Meier estimate of freedom from thrombosis was 97.0%, with 6 cases reported within 30 days, 12 cases between 30 days and 6 months, and 13 cases between 6 and 12 months of the study procedure.

STENT INTEGRITY. At 12 months, 1,118 of 1,135 DES (98.5%) were free from fracture, yielding a 12-month fracture rate of 1.5% (17 of 1,135). The core laboratory classified the fractures as 5 Type I, 2 Type II, 1 Type III, and 9 Type IV (4).

CLINICAL OUTCOMES. Clinical assessment at 12 months revealed significant improvement in Rutherford classification (p < 0.01) (Table 2). Clinical improvement of at least 1 Rutherford class was

FIGURE 1 12-Month Freedom From TLR

1 1 1 0 6 1 Months 1 12 1 1 18

Kaplan-Meier Estimates for Freedom from TLR, Values Represent Patients

Months Postprocedure Freedom from TLR Cumulative Cumulative Number

± Standard Error Failed Censored Remaining

0 100.0% ±0.0% 0 0 907

6 97.2% ±0.6% 25 43 839

12 91.0% ±1.0% 77 81 749

The Kaplan-Meier curve shows 91.0% freedom from TLR through 12 months for patients treated with the DES. The life table is included. DES = drug-eluting stent(s); TLR = target lesion revascularization.

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TABLE 2 Clinical Outcomes

Pre-Procedure Post-Procedure* 12 Months*

ABI 0.63 ± 0.18 (974) 0.90 ± 0.16 (691) 0.86 ± 0.17 (824)

Rutherford class-]

0 0.9 (9) 48.6 (352) 54.2 (427)

1 7.3 (74) 25.3 (183) 23.9 (188)

2 26.9 (273) 11.0 (80) 10.9 (86)

3 43.4 (441) 5.7 (41) 5.3 (42)

4 10.3 (105) 1.2 (9) 2.8 (22)

5 9.8 (99) 6.8 (49) 2.4 (19)

6 1.4 (14) 1.4 (10) 0.5 (4)

Values are mean ± SD (n) or % (n). ^Statistically significant compared to pre-procedure, p < 0.01. fPre-procedure Rutherford class was obtained for 1,015 lesions, post-procedure Rutherford class was obtained for 725 lesions, and 12-month Rutherford class was obtained for 788 lesions.

ABI = ankle brachial index.

achieved in 638 of 757 patients (84.3%), ~80% of patients were classified as Rutherford class 0 or 1 at 12 months, and the median Rutherford classification improved from class 3 to class 0 (Table 2). Similarly, the mean ABI also significantly improved at 12 months from 0.63 to 0.86. Post-treatment clinical benefit, defined as freedom from persistent or

FIGURE 2 12-Month Clinical Benefit

0 6 12 18

Months

Kaplan-Meier Estimates for Clinical Benefit, Values Represent Patients

Months Postprocedure Clinical Benefit ± Standard Error Cumulative Failed Cumulative Censored Number Remaining

0 100.0% ± 0.0% 0 0 907

6 95.2% ± 0.7% 43 43 821

12 87.7% ± 1.1% 106 77 724

The Kaplan-Meier curve shows 87.7% clinical benefit through 12 months for patients treated with the DES. The life table is included. DES = drug-eluting stent(s).

worsening symptoms of ischemia (i.e., claudication, rest pain, ulcer, or tissue loss), was 87.7% at 12 months (Figure 2).

PATENCY. Duplex ultrasound was performed for approximately 65% of patients. The DES was effective in treating SFA lesions in Japanese patients. Based on Kaplan-Meier estimates, the 12-month primary patency rate was 86.4% (Figure 3). To evaluate whether the ultrasound subset was representative of the entire patient population, the demographics, comorbidities, lesion characteristics, 12-month freedom from TLR rates, and 12-month freedom from thrombosis rates for patients who underwent ultrasound were compared with those for patients who did not undergo ultrasound, and no significant differences were found.

DISCUSSION

The 1-year results of the present study demonstrate the safety and effectiveness of the paclitaxel-coated DES for the treatment of femoropopliteal PAD in a large, real-world Japanese patient population with numerous risk factors including high incidences of diabetes, chronic kidney disease, and CLI. The lesions were also complex, including approximately 40% of lesions >15 cm and 30% >20 cm in length, and a high rate of total occlusions and ISR. The low frequencies of stent fracture and thrombotic occlusion after DES placement reported in the present study are comparable to the published rates for nitinol BMS and to previous reports with the DES (1,2,5-10). The freedom from TLR, clinical benefit, and patency results from the present study are similar to previous clinical studies that evaluated the DES in patients with femoropopliteal PAD. The previous studies included the Zilver PTX Randomized Clinical Trial, which demonstrated the benefit of the DES compared with PTA or provisional BMS through

2 years (1,2). The results with the DES in the Japanese subgroup from the randomized trial also showed no major differences in safety and effectiveness compared with the non-Japanese patient group (10). Additionally, a complementary singlearm study supported the performance of the DES in a broader patient population than the randomized trial (3). The results from the present study are similar to the previously published results and confirm the benefit of the DES despite the inclusion of patients with increased risk factors and more complex lesions.

Results with this DES were also recently reported from the ZEPHYR (Zilver PTX for the Femoral Artery

and Proximal Popliteal Artery-Prospective Multicenter Registry) study, which was designed to examine the possible predictors of restenosis after DES implantation (11). The ZEPHYR study involved an even more challenging Japanese patient population that included a larger percentage of diabetic patients (69% vs. 59%) and critical limb ischemia patients (32% vs. 22%), as well as a somewhat longer average lesion length (17 cm vs. 15 cm), compared with the current study. Furthermore, there are important differences in the definitions, methodologies, and reporting practices for the ZEPHYR study compared with the current study and also compared with many previous peripheral endovascular device studies, which reinforce the difficulties in comparing results across studies.

Other than the Zilver PTX randomized study (1,2), there are currently no results available from randomized controlled studies directly comparing this DES to other endovascular therapies, and caution must be taken when comparing outcomes between different studies. Although not a randomized comparison, results from the current study of the DES, such as the 12-month patency rate, compare favorably to the limited available results with BMS in populations including complex lesions, which report patency rates ranging from 49% to 65% (9,12-14). Differences such as patient demographics and lesion characteristics can make comparisons between studies difficult, and in this regard, randomized studies usually provide more meaningful comparisons. The previously published randomized study showed significant benefit with the DES over BMS (1,2). Despite the inclusion of more complex lesions, the results with the DES in the current study are also consistent with the DES results in the randomized study.

Similarly, results from the current DES study, such as the 12-month patency rate of 86.4%, compare favorably to results for DCB, which range from 73.5% to 89.5% (15-18). However, lesions in the DES study were more challenging than those in the DCB studies. For instance, the lesions in the DES study were approximately twice as long, with approximately twice as many total occlusions, and included ISR. Successful pre-dilation was also typically required before DCB treatment. Because of such differences, comparisons between these studies should be interpreted with caution. Previously published results also show that the benefit of the DES is sustained over time (2); whereas, the long-term outcomes with the DCB are limited to a small number of patients (19). The 12-month patency rate from the current study also compares favorably to the patency

FIGURE 3 12-Month Primary Patency

The Kaplan-Meier curve shows 86.4% primary patency through 12 months for lesions treated with the DES. The life table is included. DES = drug-eluting stent(s).

rates, ranging from 51.1% to 78.0%, reported for atherectomy (20,21).

STUDY LIMITATIONS. Stent thrombosis in the SFA can be difficult to distinguish from total occlusion caused by restenosis because there is no standardized classification for SFA stent thrombosis unlike the ARC classification for coronary stent thrombosis (22). Additionally, risk factors beyond the stented lesion, for example, untreated residual inflow or outflow stenosis or poor runoff, may contribute to the potential for thrombosis within the infrainguinal arteries. Due to these risk factors and the possible inclusion of total occlusions that are of restenotic rather than thrombotic origin, the site-reported rate may overestimate the DES thrombosis rate in this study. At longer times since the study procedure, the likelihood that the occlusions were of restenotic rather than thrombotic origin increases. Accordingly, the cases reported within 30 days of the study procedure may be considered probable thromboses, those cases reported between 30 days and 6 months may be considered possible thromboses, and those

FEBRUARY 8, 2016:271 - 7

cases reported between 6 and 12 months may be considered probable restenoses. Despite this possibility for overestimation, the thrombosis rate through 12 months in this study was low and comparable to the published rates for nitinol BMS as well as previous reports with the DES, and demonstrates no increased risk of stent thrombosis due to the paclitaxel drug coating on the DES (1,2,5-10).

In this study, duplex ultrasonography was performed by the investigative sites where physicians considered this standard of care. As a result, patency through 12 months was evaluated for a subset of approximately 65% (702 1,075) of lesions. Additional analyses indicated that the demographics, comor-bidities, lesion characteristics, 12-month freedom from TLR rates, and 12-month freedom from thrombosis rates for the ultrasound subset were not significantly different from those for patients who did not undergo ultrasound. Therefore, the ultrasound subset adequately represents the overall study population, supporting the validity of the patency results.

Although this was a post-market, single-arm study without an internal control group, the study enrolled a large number of patients with symptomatic SFA disease representing a real-world patient population. The outcomes with the DES also remained similar to those from the previously published randomized study and similar to those from the complementary single-arm study (1-3).

CONCLUSIONS

Despite more challenging lesions, the results from this real-world, post-market study are similar to

outcomes from the previous Zilver PTX studies, confirming the benefit of the Zilver PTX DES.

ACKNOWLEDGMENTS The authors thank Anthony O. Ragheb, Alan T. Saunders, and Bret Teany of Cook Research Incorporated (a contract research organization and Cook Group Company) for assistance with data analysis, figure preparation, and critical review of the manuscript.

REPRINT REQUESTS AND CORRESPONDENCE: Dr.

Hiroyoshi Yokoi, Department of Cardiovascular Medicine, Cardiovascular Center, Fukuoka Sanno Hospital, 3-6-45, Momochihama, Sawara-ku, Fukuoka 814-0001, Japan. E-mail: hiroyokoi@circus.ocn.ne.jp.

PERSPECTIVES

WHAT IS KNOWN? Experience with the Zilver PTX drug-eluting stent in previous studies has shown long-term benefits, including a randomized controlled trial that demonstrated superiority to standard care (balloon angioplasty with provisional bare-metal stent placement) and to bare-metal stents.

WHAT IS NEW? This large, all-comer, post-market study confirms the benefits with this drug-eluting stent and extends the results to more complex patients, lesions, and risk factors.

WHAT IS NEXT? Further understanding of the results with drug-eluting stents compared with other new therapies, such as drug-coated balloons and resorbable stents, especially in long-term outcomes, would provide valuable insights.

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KEYWORDS drug-eluting stent(s), paclitaxel-eluting stent(s), peripheral artery disease, peripheral vascular disease, popliteal artery, superficial femoral artery