Safety and efficacy of drug-eluting stents versus heparin-bonded stents in treatment of femoropopliteal peripheral artery disease: study protocol for a multicentre, prospective randomised controlled trial in China (ELITE trial)

Abstract

Introduction

Endovascular therapy has emerged as a prominent strategy for managing femoropopliteal peripheral artery disease, offering acceptable safety and efficacy compared with open surgical bypass. Both paclitaxel-eluting stents and heparin-bonded covered stents have exhibited enhanced clinical outcomes compared with bare metal stents. However, there is currently a lack of level I evidence comparing the safety and efficacy of paclitaxel-eluting stents and heparin-bonded covered stents. Therefore, the primary objective of this study is to systematically evaluate the efficacy and safety outcomes of these two types of stents.

Methods and analysis

The ELITE trial is a prospective, multicentre, parallel, randomised controlled trial. A total of 450 patients will be recruited. The primary endpoints of the study include primary patency at 1 year post-index procedure.

Ethics and dissemination

Ethical approval for this study was obtained from the Ethics Committee of West China Hospital of Sichuan University (approval number: 2023–1186). The results will be submitted to a major clinical journal for peer review and publication.

Trial registration

ELITE trial was registered on 27 September 2023 in the Chinese Clinical Trials Registry (ChiCTR2300076236).

YQ and HZ are joint first authors.

Strengths and limitations of this study

• Patients actively participated in the design of this multicentre, prospective randomised controlled trial.

• This study represents the first direct comparison between drug-eluting stents and heparin-bonded stents.

• This trial will be conducted in China, which may introduce potential bias in terms of the interpretation and generalisability of the results.

• This lack of blinding to surgeons and participants may introduce bias.

Introduction

Peripheral artery disease refers to the manifestation of atherosclerotic vascular disease in the lower extremities, which poses a severe threat to limb safety and human health. Timely and appropriate intervention is crucial in patients with femoropopliteal artery disease. Effective blood flow reconstruction is the foundation for limb salvage and a key factor in reducing mortality and improving the quality of life. For patients with relatively uncomplicated anatomical structures and moderate to high risk of limb threat, endovascular intervention is recommended.¹ The 2017 clinical guidelines of the European Society for Vascular Surgery emphasise that prioritising endovascular intervention is class I evidence for the treatment of occlusive femoropopliteal artery disease.²

Although endovascular interventions are minimally invasive and have a rapid recovery, neointimal hyperplasia following balloon angioplasty and bare metal stent placement is a significant cause of post-procedural restenosis.³ With the rapid development of endovascular techniques, drug-eluting bare metal and covered stents have emerged as powerful tools against neointimal hyperplasia and restenosis.^{4 5} Heparin-bonded covered stents, represented by Viabahn (WL Gore & Associates Inc, Flagstaff, AZ, USA), have demonstrated excellent outcomes in managing complex femoropopliteal lesions by preventing in-stent restenosis caused by neointimal hyperplasia.⁶ Meanwhile, paclitaxel-eluting stents, represented by Eluvia (Boston Scientific, Marlborough, MA, USA), have shown superior primary patency rates at 12 months compared with bare metal stents.⁷ Currently, there are a few retrospective cohort studies comparing these two types of stents, However, the evidence derived from these studies is of low quality, making it challenging to determine the clinical superiority between drug-coated stents and heparin-bonded covered stents.^{8 9} The superiority of drug-eluting stents vs heparin-bonded covered stents remains inconclusive. Therefore, this multicentre, prospective, parallel, non-inferiority, randomised controlled trial aims to investigate the safety and efficacy in the treatment of occlusive femoropopliteal artery disease. The aim is to provide higher-level evidence to guide the selection of first-line stents in endovascular interventions for patients with peripheral arterial disease.

Methods and analysis

Study design

This study is a multicentre, prospective, randomised, single-blind and non-inferiority parallel trial. It is scheduled to be conducted from 1 March 2024 to 1 March 2029, at West China Hospital of Sichuan University, Affiliated Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu First People’s Hospital and Zigong First People’s Hospital. West China Hospital of Sichuan University is the leading research centre, and each research centre competes to enrol patients. Investigators and assistants undergo unified training by the leading centre to ensure consistency. Postoperative follow-ups for patients are conducted separately by each centre. Data for enrolled patients are recorded using a uniform case report form and postoperative follow-up questionnaire. A total of 450 participants will be assigned randomly in a 1:1 ratio to either the drug-eluting stents group or the heparin-bonded covered stents group. Outcomes are primarily based on patient care, and the follow-up method will be determined according to patient preference. The study follows the Recommendations for Interventional Trial (SPIRIT). The SPIRIT flow diagram and the SPIRIT Checklist are shown in figure 1 and in online additional file 1. Table 1 shows the schedule of enrollment, interventions and assessments.

Table 1

The schedule of enrollment, interventions and assessments

Time point	Study period
	Enrollment	Allocation	Post allocation			Close-out
		0	perioperative period	t1 (1 month)	t2 (6 months)	t3 (12 months)
Enrollment:
Eligibility screen	X
Informed consent	X
Demographic details and medical history	X
Allocation		X
Intervention:
Eluvia stent
Viabahn stent
Assessments:
Stent patency			X	X	X	X
Maximum walking distance			X	X	X	X
Free target lesion revascularisation			X	X	X	X
Free major extremity amputation of index limb			X	X	X	X
Major adverse limb event			X	X	X	X
Quality of life			X	X	X	X

Figure 1. The procedure of screening, randomisation and follow-up of patients in the trial.

Recruitment

On obtaining informed consent, participants will be recruited from outpatient departments, emergency departments and through posters or online advertisements to achieve the required sample size.

Inclusion criteria

(1) Male or non-pregnant female subjects aged 18 years or older, with a life expectancy sufficient to complete all study procedures; (2) Diagnosis of femoropopliteal peripheral artery disease using preoperative computed tomography angiography (CTA) (Rutherford classification from 2 to 6); (3) Preoperative CTA indicating more than 70% stenosis in the femoropopliteal artery, with no limitation on lesion length; (4) The target lesions will undergo percutaneous transluminal angioplasty to achieve sufficient luminal preparation. According to the Instruction For Use, the diameter of the covered stent should be enlarged by approximately 5%–20% compared with the proximal and distal healthy vessel diameters adjacent to the lesion site. The covered stent must extend at least 1 cm beyond the proximal and distal edges of the lesion site. When overlapping multiple stents, there should be a minimum overlap region of 1 cm between the stents; (5) Presence of at least one inflow artery or successfully treated inflow artery (iliac artery) and at least one outflow artery or successfully treated outflow below the knee; (6) Informed consent approved by the ethics committee.

Exclusion criteria

(1) History of previous stent placement in the femoropopliteal artery (Previous intervention by plain old balloon angioplasty or arterial embolectomy is not excluded); (2) History of previous drug-coated balloons in the femoropopliteal artery (History of treatment with drug-coated balloons is a significant confounding factor); (3) Known allergy to contrast agent; (4) History of myocardial infarction, thrombolytic therapy or angina pectoris within 2 weeks prior to enrollment; (5) Stroke or transient ischaemic attack within 3 months prior to surgery; (6) Individuals with cancer or with a high risk of bleeding (Patients with cancer have a shorter life expectancy and poorer quality of life, so they are excluded. Patients with a high risk of bleeding are unable to complete postoperative dual antiplatelet therapy, so they are also excluded.)

Criteria for dropout

(1) Poor compliance by subjects, such as being lost to follow-up for more than 12 months post-intervention; (2) Subject withdrawal from the trial for any reason; (3) Death, if the cause of death is known, it must be recorded.

Study termination criteria

(1) Participant safety risks warranting immediate termination; (2) High voluntary withdrawal, poor compliance or repeated non-compliance affecting the study; (3) High number of patients no longer followed up or receiving treatment.

Randomization and allocation

Patients meeting inclusion criteria will be enrolled with informed consent. An allocation sequence was generated by a biostatistician using Statistical Analysis System (SAS, V.9.4). Stratified block randomisation based on lesion length (>15 cm) will be used. Participants will be randomly assigned to either the paclitaxel-eluting stents group or the heparin-bonded covered stents group in a 1:1 ratio. Allocation information will be kept in sealed, opaque, consecutively numbered envelopes, and allocation results will be communicated to surgeons by blinded research assistants before the procedure. The blindfold could not be removed during the trial.

Study intervention

The lead researcher will obtain informed consent from participants and their legal representatives by obtaining signatures on a written version of the informed consent document before the intervention (online additional file 2). Consistent perioperative management will be provided to eligible patients, including blood pressure control and pain relief. Additionally, CTA of the head and neck will be conducted to assess combined carotid stenosis and intracranial vascular disease. Based on these findings, the choice of general or local anaesthesia will be determined by anaesthesiologists.

During the procedure, both common femoral and brachial arteries will be accessible for access, and unfractionated heparin (0.5 mg/kg) will be administered. Throughout the procedure, a guidewire may be advanced intraluminally or subintimally through the target lesions. Angiography will confirm the guidewire and catheter are correctly placed in the true lumen at the distal extent of the lesion. The target lesion can be dilated using balloon angioplasty, followed by the placement of either Eluvia stent or Viabahn stent.

The Eluvia stent, a drug-eluting bare metal stent, is a self-expanding nitinol alloy stent coated with a fluoropolymer and paclitaxel. The dosage density is 0.167 µg/mm² of stent surface area. Available in lengths from 40 to 150 mm, it suits reference vessel diameters of 4–8 mm. The selected stent size is 1 mm larger than the reference vessel diameter, allowing for overlapping stent deployment. The Viabahn stent, a heparin-bonded covered stent, is a self-expanding nitinol alloy stent covered with a polytetrafluoroethylene (PTFE) membrane and a biologically active heparin coating. Available in lengths from 25 to 250 mm, it fits reference vessel diameters of 4–8 mm. The selected stent size is 5%–20% larger than the reference vessel diameter, allowing for overlapping stent deployment.

During the procedure, interventions such as balloon angioplasty, stent placement in the iliac artery or infrapopliteal artery, as well as endarterectomy of the common femoral artery may be performed based on the surgeon’s judgement.

Intervention modifications and adherence

If endovascular therapy fails to yield satisfactory results, or if vessel wall thinning occurs after endarterectomy, consideration will be given to open surgical bypass or artificial vessel graft replacement. Patients undergoing open surgical repair will be recorded and excluded from this trial. Non-substantial amendments will be recorded by the researcher and will not require notification to the monitoring committee or upstream authorities. In order to improve adherence to intervention protocols, the investigators will be urged to follow-up on patients by telephone contacts or WeChat. participants can contact the surgeon through WeChat when needed. Furthermore, a green channel for outpatient visits will be available for follow-up participants.

Follow-up

Subsequent to the initial intervention, both outpatient clinic visits and online follow-ups (via telephone or WeChat) will be available. Questionnaires will be administered at 1-month, 6-month and 12-month post-procedure. Duplex ultrasound will be routinely performed during outpatient clinic follow-ups at 6 months post-index procedure, while CTA will be conducted at 12 months post-procedure. Participants unable to return to the clinic will undergo Duplex ultrasound and CTA at local hospitals, with images and records sent to investigators. Postoperatively, the patient will undergo 3 months dual antiplatelet therapy, consisting of aspirin (100 mg once daily) and clopidogrel (75 mg once daily).

Post-trial care

There is no underlying harm for trial participants when Eluvia or Viabahn stents are placed. After treatment, patients will be provided with guidance on specialised treatment protocols and dressing changes

Outcomes of interest

Primary outcome

Primary patency (clinical-centred outcome, Primary patency is defined as the absence of flow-limiting stenosis (peak systolic velocity ratio >2.5) or occlusion of the treated artery.).

Secondary outcomes

(1) Secondary patency (Secondary patency was defined as a secondary procedure is performed for graft or stent occlusion in an afterwards patent vessel.). (2) Freedom from target lesion revascularisation. (3) Freedom from major extremity amputation of index limb at 1 year post-index procedure. (4) Major adverse limb event (MALE) at 1 year post-index procedure (MALE is defined as the occurrence of one or more of the following conditions within the treated limb subsequent to endovascular therapy: limb necrosis, thrombosis necessitating immediate surgical or endovascular intervention, notable stenosis or occlusion of the target lesions, limb ulceration, ischaemia-related pain or functional impairment. (5) Major adverse cardiovascular events (MACE) (MACE is defined as a composite of death, myocardial infarction, transient ischaemic attack and stroke), pulmonary infection and renal adverse events. (6) Maximum walking distance (patient-centred outcome, maximum walking distance is defined as the greatest linear distance walked on level ground at a typical walking pace before the onset of lower limb pain or lower limb weakness) at 1-year post-index procedure. (7) Quality of life (EQ-5D-5L, Peripheral Artery Questionnaire, Vascular Quality of Life Questionnaire-6).

Sample size calculation

As previously reported, the EMINENT study indicated a 12-month primary patency rate of 83.2% for paclitaxel-eluting stents in femoropopliteal lesions. Recent data from the VIASTAR study demonstrated a 12-month primary patency rate of 70.9% for heparin-coated covered stents in femoropopliteal lesions. In this study, we conducted a non-homogeneity test with a non-inferiority margin of 0.075. The type I error rate is set at 0.05, with a test power of 80%, and a randomisation ratio of 1:1. Accounting for a 10% dropout rate, a total of 450 lesions with 225 lesions per group was calculated as the required sample size. Participant enrollment will be achieved through posters, online advertising, as well as recruitment from outpatient and emergency departments.

Data collection and management

A unified case report form will be used by trained investigators to gather data. Patient demographics, comorbidities, imaging anatomic parameters and laboratory results will be extracted from patient charts, the picture archiving and communication system and the laboratory information system. Data will be cross-checked by two independent investigators to ensure accuracy. Follow-up data will be collected via phone calls and the WeChat platform to ensure participant retention and complete follow-up. Data details can be obtained from the monitoring committee.

Statistical analysis

Statistical analysis will be performed using R software (V.3.1.1) to analyse baseline characteristics, perioperative indicators and long-term outcome measures of the two groups. Normally distributed continuous variables will be presented as mean±SD, and non-normally distributed continuous variables will be presented as median with IQR. Equivalence tests will be employed to compare outcome measures between the groups, followed by superiority tests if equivalence criteria are met. Both modified intention-to-treat (mITT) and per-protocol (PP) analyses will be conducted for primary outcome measures, with mITT as the primary analysis and PP serving as a sensitivity analysis. Comparisons will be conducted through independent t-tests, Mann-Whitney U tests, and analysis of variance or Fisher’s exact test for different data types. Kaplan-Meier curves and log-rank tests will analyse time-event-related data, while Cox proportional hazards regression models will calculate HR and corresponding 95% CIs. Multivariable regression adjustments will be performed for baseline differences. Subgroup analyses will be performed based on the following factors: smoking status, lesions longer than 15 cm, Rutherford classifications and number of runoff vessels. Multiple imputation will address missing data.

Monitoring and protocol amendments

The monitoring committee is composed of biostatisticians, surgeons, investigators and assistant. Substantial amendments such as adjusted sample size or eligibility criteria will be notified to the monitoring committee, while non-substantial amendments will only be recorded by the researcher. Annual monitoring will be conducted and problems will be fed back to investigators by the monitoring committee. The ethics committee and monitoring committee will have access to check the collected data at any time and question the rationality of the study. An independent statistician will also conduct the classical interim analyses. Study modifications or rest with both ethics committee and monitoring committee. The study will be terminated when any of the following situations occur: (a) one treatment group is significantly superior or inferior to the other; (b) serious adverse events occur; and (c) other unintended effects of trial interventions or trial conduct happen.

Declarations

All team members have signed confidentiality agreement with the investigator. Furthermore, team members will treat the reports, meeting discussions and minutes as confidential. Participants’ identity information is encrypted to prevent any data leaks throughout the study.

The investigator is required to maintain adequate records to enable the conduct of the study being fully documented. Documents used in the conduct of the study must be retained by the investigator for a period of 15 years.

Patient and public involvement

Patients were involved in the design of this research (patient-centred outcomes: maximum walking distance and quality of life, as well as the method of postoperative follow-up through WeChat, were all derived from the pre-research questionnaire conducted on previous patients).

Discussion

It is estimated that more than 200 million people worldwide have peripheral arterial disease (PAD).¹⁰ The prevalence of this disease is increasing due to ageing populations and an increasing number of diabetic patients.^{11 12} Although best medical therapy and supervised exercise have been effective in enhancing walking capacity, a randomised study highlighted that a combination therapy of endovascular revascularisation followed by supervised exercise has demonstrated significantly greater improvement in walking distances and health-related quality-of-life scores compared with supervised exercise alone after 1 year of follow-up in patients with intermittent claudication.¹³ More recently, the BASIL-2 trial demonstrated that an endovascular treatment-first strategy was associated with a 35% higher risk of major amputation or death compared with vein bypass first revascularisation strategy in patients with chronic limb-threatening ischaemia requiring infra-popliteal revascularisation.¹⁴

Femoropopliteal artery disease is a primary manifestation of peripheral arterial disease, and recent analysis demonstrated that drug-eluting devices may have better clinical outcomes than traditional devices.¹⁵ However, the specific drug-eluting device that confers optimal benefits for femoropopliteal disease remains elusive.

Paclitaxel has demonstrated the ability to inhibit neointimal hyperplasia. It possesses robust lipophilic properties, exhibits strong protein-binding affinity and effectively permeates arterial tissue where it lingers.^16–18 Recent clinical studies have indicated that using paclitaxel-coated devices has better clinical results than bare metal stent (BMS) in the patients with superficial femoral artery disease.^19–21 The IMPERIAL Study was designed to compare the 12-month clinical outcomes of a paclitaxel-coated polymer-free stent with percutaneous transluminal angioplasty with BMS placement in patients with femoropopliteal PAD. Results demonstrated that the drug-eluting stent (DES) was associated with superior 12-month event-free survival and sustained primary patency. However, the polymer-free Zilver PTX delivers the drug within a short time frame, which may influence the long-term patency. The durable polymer-coated Eluvia DES can control sustained release of drugs. Recently, a prospective, multicentre randomised controlled trial (RCT) (EMINENT Trial) was designed to evaluate the safety and efficacy of the Eluvia DES compared with BMS, and result showed that the primary patency and sustained clinical improvement for DES treatment was significantly greater than BMS in patients with femoropopliteal artery lesions. Moreover, the IMPERIAL study, an RCT comparing Eluvia stent with Zilver PTX stent, exhibited higher primary patency in the Eluvia group, along with reduced major adverse events risk at 12 months post-procedure.

Meanwhile, the expanded polytetrafluoroethylene (ePTFE) covering of stents prevents neointimal tissue in growth. Studies have indicated that immobilised heparin on ePTFE vascular grafts could decrease platelet deposition and neointimal hyperplasia.²² The VIASTAR Trial contrasted the heparin-bonded covered stents vs bare metal stents for femoropopliteal artery lesions, with results favouring the heparin-bonded covered stents in terms of increased ankle-brachial index and improved patency, especially patency benefits in patients with lesions exceeding 15 cm in length.

Nonetheless, no cohort or RCT study has yet compared the efficacy or safety of paclitaxel-eluting bare metal stents vs heparin-bonded covered stents. Our present study aims to primarily assess primary patency and maximum walking distance at 1 year post-index procedure.

In conclusion, this trial was designed to compare the efficacy and safety of the Eluvia stent vs Viabahn stent in femoropopliteal artery disease patients, hoping to provide level 1 evidence for stent selection in femoropopliteal occlusive lesions.

Ethics and dissemination

Ethical approval for this study was obtained from the Ethics Committee of West China Hospital of Sichuan University (approval number: 2023-1186), and the trial was registered in the China Clinical Trial Registry (ChiCTR ChiCTR2300076236). In this study, the ethics committee acknowledges the ethical review conducted by the leading centre. Additionally, participating centres recognise and adopt the ethical approval from the leading centre (Ethics Review Board of West China Hospital). Upon completion of the trial, the main manuscript containing the results will be submitted to a major clinical journal for peer review and publication and presented in academic conferences.

Data availability statement

Data are available upon reasonable request.

Ethics statements

Patient consent for publication

Not applicable.

Footnote

Contributors WTH and WCX: Conception and Design, Critical Revision, Approval of the Manuscript, Agreement to be Accountable, Statistical Analysis;QYH and ZHW: Conception and Design, Writing the Manuscript, Approval of the Manuscript, Agreement to be Accountable, Statistical Analysis;YD, WJR and GJT: Conception and Design, Writing the Manuscript, Approval of the Manuscript, Agreement to be Accountable, Statistical Analysis;ZJC and HB: Conception and Design, Writing the Manuscript, Approval of the Manuscript, Agreement to be Accountable;

Funding This work was granted by the National Natural Science Foundation of China (82302152, 82300542), Sichuan Province Science and Technology Support Program [grant number: 2022YFS0366, 2022YFS0187, 2022YFS0359].

Competing interests None declared.

Patient and public involvement Patients and/or the public were involved in the design, or conduct, or reporting, or dissemination plans of this research. Refer to the Methods section for further details.

Provenance and peer review Not commissioned; externally peer reviewed.

Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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