Long-Term Results from the MAJESTIC Trial of the Eluvia Paclitaxel-Eluting Stent for Femoropopliteal Treatment: 3-Year Follow-up

  • Stefan Müller-Hülsbeck
  • Koen Keirse
  • Thomas Zeller
  • Herman Schroë
  • Juan Diaz-Cartelle
Clinical Investigation

Abstract

Purpose

To report the 3-year results of the MAJESTIC first-in-human study of the Eluvia Drug-Eluting Vascular Stent System for treating femoropopliteal artery lesions.

Methods

The prospective, single-arm, multicenter clinical trial enrolled 57 patients with symptomatic lower limb ischemia (Rutherford category 2, 3, or 4) and lesions in the superficial femoral artery or proximal popliteal artery. Mean lesion length was 70.8 ± 28.1 mm, and 46% of lesions were occluded. Efficacy measures at 2 years included primary patency, defined as duplex ultrasound peak systolic velocity ratio of ≤2.5 and the absence of target lesion revascularization (TLR) or bypass. Safety monitoring through 3 years included adverse events and TLR.

Results

Primary patency was estimated as 83.5% (Kaplan–Meier analysis) at 24 months, and 90.6% (48/53) of patients maintained an improvement in Rutherford class. At 36 months, the Kaplan–Meier estimate of freedom from TLR was 85.3%. No stent fractures were identified, and no major target limb amputations occurred.

Conclusion

MAJESTIC results demonstrated long-term treatment durability among patients whose femoropopliteal arteries were treated with the paclitaxel-eluting Eluvia stent.

Level of Evidence

Level 2b, cohort study

Keywords

Claudication Drug-eluting stent Paclitaxel Peripheral artery disease Popliteal artery Superficial femoral artery 

Introduction

Femoropopliteal artery disease treatment with polymer-coated drug-eluting stents was previously investigated in the SIROCCO [1] and STRIDES [2] studies of sirolimus- and everolimus-eluting stents, respectively. The prolonged elution profile enabled by a polymer coating theoretically allows the drug to protect against continued initiation of restenotic pathways caused by persistent mechanical forces on the vessel wall [3] and to inhibit downstream effectors activated weeks to months after stent implantation [4, 5]. Longer-term drug activity may be of particular importance in peripheral arteries, as restenosis follows a longer timecourse than is observed following coronary interventions [6]. Results of these initial clinical studies of “-limus” eluting stents in the femoropopliteal segment were disappointing, however, as 1- and 2-year restenosis rates were similar to those of bare metal stents [1, 2]. More recently, antirestenotic potential of the alternative agent paclitaxel, applied with drug-coated balloons [7, 8, 9, 10] or a polymer-free stent [11, 12], was confirmed in the peripheral vasculature.

The Eluvia Drug-Eluting Vascular Stent System (Boston Scientific, Marlborough, MA) combines paclitaxel with a biocompatible fluoropolymer coating on a stent scaffold and was designed to provide sustained drug release over time [13]. The first-in-human MAJESTIC clinical study was designed to evaluate its performance for treating femoropopliteal artery lesions. At one year, study patients maintained a high patency rate, low reintervention rate, and good clinical improvement [14]. Clinical results through 3 years of follow-up are reported here.

Methods

Study Design and Patient Population

Methodology used in the MAJESTIC study has been described previously [14]. Briefly, 57 patients with chronic, symptomatic lower limb ischemia (Rutherford category 2, 3, or 4) [15] and stenotic or occlusive lesion(s) ≥30 mm and ≤110 mm in length located in the superficial femoral artery (SFA) or proximal popliteal artery were treated with the Eluvia Drug-Eluting Vascular Stent System in this prospective, single-arm, multicenter clinical study. Characteristics of enrolled patients are given in Table 1. Twenty patients (35.1%) had diabetes. Mean lesion length was 70.8 ± 28.1 mm, the proximal reference vessel diameter was 5.2 ± 0.8 mm (range 3.8–7.4 mm), and the minimum lumen diameter was 0.7 ± 0.8 mm as assessed by the angiographic core laboratory (Beth Israel Deaconess Medical Center, Boston, MA). Nearly half (46%) of the lesions were occluded, and 64.9% had severe calcification at baseline [14]. Severe calcification was defined as radio-opacities noted on both sides of the arterial wall and extending more than 1 cm of length prior to contrast injection or digital subtraction.
Table 1

MAJESTIC patients and lesion characteristics

Patients characteristics (n = 57)

 

Age, years

69.3 ± 9.3

Men

47/57 (82)

Race/ethnicity

 Caucasian

54 (95)

 Asian

1 (2)

 Other

2 (3)

Medical history

 Current diabetes mellitus

20 (35)

 Hyperlipidemia requiring medication

36 (63)

 Hypertension requiring medication

42 (74)

 Chronic obstructive pulmonary disease

6 (10)

 Coronary artery disease

22 (39)

 Myocardial infarction

9 (16)

 Congestive heart failure

3 (5)

 History of smoking

50 (88)

Lesionsa (n = 57)

SFA segment

 Proximal

1 (2)

 Mid

34 (60)

 Distal

44 (77)

 PPA involvement

5 (9)

 Length, mm

70.8 ± 28.1

 Diameter stenosis,  %

86.3 ± 16.2

 Reference vessel diameter, mm

5.2 ± 0.8

TASC II classificationb

 A

25 (44)

 B

26 (46)

 C

6 (10)

 D

0 (0)

Calcificationc

 None/mild

12 (21)

 Moderate

8 (14)

 Severe

37 (65)

 Total occlusion

26 (46)

 Ulcerated lesiond

4 (7)

Vessels patent to foot

 0

3 (5)

 1

16 (28)

 2

18 (32)

 3

13 (23)

Modified from [14]; originally published by SAGE

Continuous data are presented as mean ± standard deviation; categorical data are shown as counts (percentages)

PPA proximal popliteal artery, SFA superficial femoral artery, TASC TransAtlantic Inter-Society Consensus

aValues as determined by the angiographic core laboratory, unless otherwise indicated

bSite assessment

cCalcification categorized as none/mild: no radio-opacities noted; moderate: radio-opacities noted on one side of the arterial wall or less than 1 cm of length prior to contrast injection or digital subtraction; or severe: radio-opacities noted on both sides of the arterial wall and extending more than 1 cm of length prior to contrast injection or digital subtraction

dLesions had an appearance of ulceration on angiography

Eluvia is a self-expanding nitinol stent based on the Innova stent platform [16] and is designed with closed cells on the ends and open cells in the middle. The polymer coating is the same as that used on the Promus Element coronary stent but includes paclitaxel at a dose density of 0.167 µg/mm2 [13].

Follow-up

Following 60 days of initial dual antiplatelet therapy, acetylsalicylic acid (ASA) use was recommended to continue at least throughout the 3-year follow-up period.

Duplex ultrasound (DUS), ankle–brachial index (ABI), and Rutherford classification assessments were completed at the 24-month (±30 days) clinical visit. Follow-up at 36 months (±30 days) could be completed by telephone or clinical visit and included adverse event and antiplatelet medication assessments. Primary patency was defined as DUS peak systolic velocity ratio (PSVR) ≤2.5 (as adjudicated by the DUS core laboratory; VasCore, Boston, MA) in the absence of TLR, bypass of the target lesion, or major amputation of the target limb. Assisted primary patency included patients without TLR and those with TLR not for complete occlusion or bypass who were free of restenosis at 24 months. Radiographs taken at the 24-month visit were sent to the X-ray core laboratory (VasCore, Boston, MA), and potential fractures were subject to verification by the angiographic core laboratory by comparison with procedural angiograms.

Statistical Analysis

Patient characteristics and clinical outcome measures are summarized with descriptive statistics. Continuous variables are presented as mean ± standard deviation. Categorical variables are expressed as frequencies and percentages. Kaplan–Meier estimates were determined for primary patency through 24 months and the rate of freedom from TLR through 36 months. Standard errors were calculated using the Society for Vascular Surgery Standard [15], and 95% confidence intervals (CI) were calculated using standard errors by the Greenwood formula. All statistical analyses were performed with the Statistical Analysis System (SAS) for Windows version 9.3 or higher (SAS Institute Inc., Cary, North Carolina).

Results

Patient Disposition

Two patients died and one withdrew consent prior to 2-year follow-up. The 24-month clinic visit was completed by 53 patients; 52 had DUS evaluable by the core laboratory, and 48 had radiographs taken for stent fracture analysis. One patient missed the 2-year visit but returned at 3 years; thus, 36-month follow-up was completed by 54 patients.

Efficacy and Safety

The Kaplan–Meier estimate of primary patency through 2 years was 83.5% (95% CI 73.6, 93.3%; Fig. 1), and for assisted primary patency, it was 88.9%.
Fig. 1

Kaplan–Meier estimate of primary patency through 25 months. Subjects event-free at 25 months or later are censored at greater than 25 months. SE standard error

A total of eight patients had TLRs performed during the study period, and the Kaplan–Meier estimate of freedom from TLR at 36 months was 85.3% (95% CI 75.9, 94.7%; Fig. 2). No target limb amputations (major or minor) occurred during the study period.
Fig. 2

Kaplan–Meier estimate of freedom from TLR through 37 months. Subjects event-free at 37 months or later are censored at greater than 37 months. SE standard error

At least one of the characteristics of diabetes, severe calcification, or total occlusion was present in all but five patients at baseline, and 27 patients (47%) had two or more of these risk factors. As shown in Fig. 3, the Kaplan–Meier estimate of primary patency at 24 months was 76.5% (95% CI 56.3, 96.6%) for patients with diabetes (n = 20; regardless of severe calcification and occlusion status), 85.5% (95% CI 73.8, 97.3%) for patients with severe calcification (n = 37), and 80.3% (95% CI 64.8, 95.8%) for patients with occlusions (n = 26). As shown in Fig. 4, the Kaplan–Meier estimate of freedom from TLR at 36 months was 82.4% (95% CI 64.2, 100%) for patients with diabetes, 85.5% (95% CI 73.8, 97.3%) for patients with severe calcification, and 84.3% (95% CI 70.1, 98.4%) for patients with occlusions.
Fig. 3

Kaplan–Meier estimate of primary patency through 25 months for subgroups of patients with diabetes (DM), severe calcification (Sev Calc), or total occlusion (Occl). The subgroups are not mutually exclusive. Subjects event-free at 25 months or later are censored at greater than 25 months. SE standard error

Fig. 4

Kaplan–Meier estimate of freedom from TLR through 37 months for subgroups of patients with diabetes (DM), severe calcification (Sev Calc), or total occlusion (Occl). The subgroups are not mutually exclusive. Subjects event-free at 37 months or later are censored at greater than 37 months. SE standard error

All but one patient reported the use of at least one antiplatelet medication at 24 and 36 months. Specifically, 90.7% (49/54) of patients reported ASA use, 20.4% (11/54) were on clopidogrel, 1.9% (1/54) were on warfarin, 1.9% (1/54) used prasugrel, and 9.3% (5/54) were prescribed “other” antiplatelet therapy at 36 months.

No stent fractures were identified via X-ray evaluation and angiographic verification through 24 months nor reported in relation to adverse events after that time (per protocol, systematic X-ray fracture evaluation was not completed at 3 years).

Clinical Outcomes

Both symptomatic and hemodynamic improvements were sustained through the last study assessments at 24 months. At 2 years, 90.6% (48/53) of patients had improved by one or more Rutherford categories as compared with the preprocedure level without the need for TLR (when those with TLR were included, 96.2% sustained improvement); only one patient exhibited a worsening in level. As shown in Fig. 4, 66.0% (35/53) of patients exhibited no symptoms (category 0) and 24.5% (13/53) had mild claudication (category 1) at the 24-month visit (Fig. 5).
Fig. 5

Rutherford classification through 24 months

Mean ABI improved from 0.73 ± 0.22 at baseline to 1.02 ± 0.20 at 12 months [14] and 0.93 ± 0.26 at 24 months. At 24 months, 79.2% (38/48) of patients had an ABI increase of at least 0.1 compared with baseline or had reached an ABI of at least 0.9.

Discussion

Long-term results from the MAJESTIC study of the Eluvia stent system continue to demonstrate good technical and clinical outcomes (assessed through 2 years) and a low reintervention rate (through 3 years). Two-year patency remained high, and the assisted patency rate suggests that most patients who did have TLRs were treated for restenotic disease, not occlusions, while the subgroup analysis suggests that the low TLR rate was representative of outcomes for patients with risk factors such as diabetes, severe calcification, and occlusion.

Safety of the polymer system coating of the Eluvia stent has been demonstrated clinically in the coronary vascular bed [17, 18], and fluoropolymer-based paclitaxel delivery was shown to inhibit neointimal proliferation and preserve lumen area gains without hindering healing in a porcine model of femoral artery restenosis [19]. The safety profile observed in MAJESTIC further supports biocompatibility of the polymer coating. Sustained drug release, enabled by the polymer, may help to overcome reduced bioavailability due to lesion calcification, as suggested by the encouraging patency and freedom from TLR rate achieved in MAJESTIC despite the presence of a high proportion of severely calcified lesions.

Achieving and maintaining clinical improvement is of utmost importance from a patient’s perspective. In the MAJESTIC study, symptom improvement (Rutherford category) compared with baseline was observed in more than 96% of patients at 2 years, while only about 7% of patients had undergone a reintervention by that time. The high rate of freedom from TLR was sustained at 36 months, suggesting that patients may be able to compensate (with collaterals) for later loss of vessel patency and therefore remain symptom-free. The longer the restenosis is delayed, the better the patient can clinically adapt. Such compensation may allow walking ability to keep pace with demand, as capacity slowly decreases due to comorbidities and increasing age.

The 24-month primary patency rate of 83.5% observed in MAJESTIC compares well with the 74.8% Kaplan–Meier estimate reported for a randomized trial of the paclitaxel-coated polymer-free Zilver PTX stent [12] and with binary restenosis and freedom from TLR rates reported at 2 years in the SIROCCO study (although those rates did not significantly differ from bare metal in the study) [1]. Contemporary trials of drug-eluting balloon treatment in the femoropopliteal segment have also shown 2-year patency rates close to 80% [9, 20], but the lesions in balloon studies tend to have less severe calcium and fewer occlusions than have been included in the drug-eluting stent studies. At 3 years, the freedom from clinically driven TLR in the Zilver PTX randomized study was reported as 83.6% [11], similar to the 85.3% found in MAJESTIC. Differences in study design and patient characteristics limit comparisons between studies, but MAJESTIC results add to the evidence supporting long-term durability and safety of paclitaxel-eluting stents.

Limitations

The longer-term follow-up presented here supports the durability of treatment through 3 years, but limitations, including the relatively small sample size and single-arm design, must be considered when interpreting results from the first-in-human MAJESTIC study. Although the mean lesion length was comparable to those treated in other trials of drug-eluting stents in the femoropopliteal segment [12], it is not representative of the longer lesions typically observed in practice. Due to the MAJESTIC sample size, exploratory subgroup analyses were limited to descriptive statistics. The large randomized IMPERIAL study of the Eluvia stent was designed to overcome these limitations, and we await results of this ongoing study.

Conclusion

The MAJESTIC clinical study demonstrated long-term treatment durability among patients whose femoropopliteal arteries were treated with the Eluvia stent.

Notes

Acknowledgements

The authors thank the following Boston Scientific employees for their assistance: Lieve Cornelis, Lisa Melchior, and Teri Takle-Flach for clinical program management, H. Terry Liao, PhD, for statistical analysis, and Elizabeth J. Davis, PhD, for medical writing. This study was funded by Boston Scientific Corporation (Marlborough, MA).

Compliance with Ethical Standards

Conflict of interest

Stefan Müller-Hülsbeck serves as a consultant for Boston Scientific and has received consulting fees, speaker honorarium, and support for accommodation and traveling when presenting BSC-related data. Thomas Zeller serves as a consultant for Boston Scientific, Cook, Medtronic, W. L. Gore, Veryan, Spectranetics, Trireme, and Terumo and has received consulting fees, speaker honoraria, and support for accommodation and traveling from the same companies. Herman Schroë serves as a consultant for Boston Scientific and has received consulting fees, speaker honorarium, and support for accommodation and traveling when presenting BSC-related data. Juan Diaz-Cartelle is an employee of and owns stock in Boston Scientific Corporation. Koen Keirse declares no conflicts of interest.

Ethical Approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Informed Consent

Informed consent was obtained from all individual participants included in the study.

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Copyright information

© Springer Science+Business Media, LLC and the Cardiovascular and Interventional Radiological Society of Europe (CIRSE) 2017

Authors and Affiliations

  • Stefan Müller-Hülsbeck
    • 1
  • Koen Keirse
    • 2
  • Thomas Zeller
    • 3
  • Herman Schroë
    • 4
  • Juan Diaz-Cartelle
    • 5
  1. 1.Department of Diagnostic and Interventional Radiology/NeuroradiologyEv. Luth. Diakonissenanstalt FlensburgFlensburgGermany
  2. 2.Regional Hospital Heilig Hart TienenTienenBelgium
  3. 3.Universitäts-Herzzentrum Freiburg - Bad KrozingenBad KrozingenGermany
  4. 4.Ziekenhuis Oost-LimburgGenkBelgium
  5. 5.Boston Scientific CorporationMarlboroughUSA

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