Author + information
- Received March 22, 2018
- Revision received May 8, 2018
- Accepted May 15, 2018
- Published online October 1, 2018.
- Nicolas W. Shammas, MD, MSa,∗ (, )
- Anthony Pucillo, MDb,
- J. Stephen Jenkins, MDc,
- Lawrence A. Garcia, MDd,
- Tom Davis, MDe,
- Herbert D. Aronow, MD, MPHf,
- Ehrin J. Armstrong, MD, MScg,
- Thomas Zeller, MDh,
- Dierk Scheinert, MDi,
- Uri Rosenschein, MDj and
- William Gray, MDk
- aMidwest Cardiovascular Research Foundation, Davenport, Iowa
- bDivision of Cardiology, Columbia Presbyterian, New York, New York
- cDivision of Cardiology, Ochsner Medical Center, New Orleans, Louisiana
- dDivision of Cardiology, St. Elizabeth’s Medical Center, Steward Health Care, Boston, Massachusetts
- eDivision of Cardiology, St. John Hospital and Medical Center, Detroit, Michigan
- fDivision of Cardiology, Lifespan Cardiovascular Institute, Providence, Rhode Island
- gDivision of Cardiology, University of Colorado, Aurora, Colorado
- hDivision of Cardiology, Universitaets-Herzzentrum Freiburg – Bad Krozingen, Bad Krozingen, Germany
- iDivision of Cardiology, Leipzig University Hospital, Leipzig, Germany
- jDivision of Cardiology, Bnai Zion Medical Center, Haifa, Israel
- kDivision of Cardiology, Lankenau Heart Institute, Wynnewood, Pennsylvania
- ↵∗Address for correspondence:
Dr. Nicolas W. Shammas, Midwest Cardiovascular Research Foundation, 1622 East Lombard Street, Davenport, Iowa 52803.
Objectives The WISE LE (WIRION™ EPS in Lower Extremities Arteries) study was designed to assess the clinical performance of the WIRION Embolic Protection System (EPS) in subjects undergoing lower extremity atherectomy for the treatment of peripheral artery disease.
Background Embolization is ubiquitous during endovascular procedures for lower extremity peripheral artery disease.
Methods The WISE LE was a multicenter study, performed in the United States and Germany. The primary endpoint was freedom from major adverse events (MAEs) occurring within 30 days post-procedure and was compared with an objective performance goal derived from historical atherectomy trials. MAE was defined as a serious adverse event that resulted in death, acute myocardial infarction, thrombosis, pseudoaneurysm, dissection (grade C or greater), or clinical perforation at the filter location, clinically relevant distal embolism, unplanned amputation, or clinically driven target vessel revascularization. The study also included a histopathological analysis of debris captured by the filter during the procedures.
Results The study protocol specified enrollment of 153 patients with the primary endpoint successfully met if 18 (12.0%) or fewer MAEs occurred. A pre-specified interim analysis performed after 103 patients revealed only 2 MAEs, and the study was stopped because it had met its pre-determined metric for success. Lesion deemed not accessible by the WIRION EPS occurred in 7 patients. Debris of <1-mm, 1- to 2-mm, and >2-mm diameter were found in 98%, 22%, and 9% of patients, respectively.
Conclusions The WIRION EPS is safe and noninferior to the pre-specified performance goal in capturing debris in the vast majority of patients and with the use of a broad range of atherectomy systems.
- arterial interventions
- distal embolization
- embolic filter
- embolic protection
- lower extremity
- peripheral arterial disease
Distal embolization (DE) is a frequent occurrence during lower extremity arterial interventions, with rates that reach 100% in some series (1–11). The incidence of clinically apparent DE requiring additional treatment with pharmacological and/or mechanical intervention is much lower, occurring in 2% to 3% of patients on average, but can approach 20% to 30% in thrombotic lesions (12–14). DE is associated with longer procedure times, greater contrast use, higher radiation exposure, and longer hospital stays (15–17). DE can result in devastating consequences, including amputation, in patients with compromised distal runoff or in those with acute and critical limb ischemia (13–15).
Embolic protection devices have been used to minimize the impact of DE in patients undergoing lower extremity peripheral arterial endovascular interventions. The only currently approved distal embolic filter for the lower extremity in the United States is the SpiderFX (Medtronic, Minneapolis, Minnesota), which is labeled for use with the SilverHawk/TurboHawk atherectomy system in severely calcified femoropopliteal arterial disease (2). The WIRION EPS filter (Gardia Medical, Hertzliya Pituach, Israel) is already approved in the United States and Australia for carotid interventions and in Europe and Israel for all cardiovascular indications. We report results from the pivotal WISE LE (WIRION™ EPS in Lower Extremities Arteries) trial, a study designed to seek Food and Drug Administration (FDA) clearance of the WIRION EPS filter in femoropopliteal interventions using all FDA-approved atherectomy devices.
The WIRION EPS is a rapid exchange system that can be mounted on any commercially available 0.014-inch guidewire and at any location on the wire, using a proprietary remote locking system. The filter itself is made of a Nylon-12 membrane with an array of 120-μm pores mounted on a nitinol concentric design frame. The filter can be retrieved using a rapid exchange retrieval catheter with a retractable tip. The filter is available in a single size, compatible with all vessels ranging in diameter from 3.5 to 6 mm.
The WISE LE study was a prospective, multicenter (8 United States and 2 outside United States), nonrandomized, open-label, single-arm investigation performed to demonstrate the safety of the WIRION EPS in subjects undergoing atherectomy procedures for lower extremity peripheral artery disease (PAD). The original enrollment target was 153 subjects, and a protocol-specified interim analysis was to occur after the first 100 patients reached 30-day follow-up. The sponsor was blinded to study results until after the independent statistician’s interim analysis, except for mandatory reporting of adverse events (AEs). For the interim analysis, all serious AEs (SAEs) were reviewed and adjudicated by a clinical evaluation committee (CEC), all AEs were reviewed by a central data safety monitoring board (DSMB), and angiographic findings were analyzed by an independent angiographic core laboratory. The CEC, DSMB, and angiographic core laboratory were all located at the Cardiovascular Research Foundation, New York, New York.
All subjects who met eligibility criteria and provided written informed consent were eligible for enrollment. Patients were eligible for inclusion if ≥18 years of age, with Rutherford classification 2 to 4 symptoms, moderate-to-severe femoropopliteal artery calcification on angiography, planned femoropopliteal atherectomy, reference vessel diameter at the site of intended filter deployment ≥3.5 mm to ≤6.0 mm, and had an adequate “landing zone” for placement of the WIRION device at least 30 mm distal to the target lesion. Patients were excluded for any of the following: had a surgical or endovascular intervention planned within 30 days before or after the index procedure, had a target lesion not accessible by the WIRION EPS, was unable to take aspirin or adenosine diphosphate receptor antagonists, had a history of bleeding diathesis or coagulopathy or was unwilling to receive a blood transfusion if deemed necessary, had perforation, dissection, or other injury of the access or target vessel requiring additional stenting or surgical intervention before enrollment, was enrolled in another drug or device study that has not reached its primary endpoint (participating in registry studies was not excluded), had a life expectancy <12 months, or had an estimated glomerular filtration rate <30 ml/min/1.72 m2, or ≤1-vessel tibial runoff. A patient was considered to be enrolled in the study once a guidewire was positioned distal to the target lesion and the WIRION EPS was introduced into the guiding catheter or sheath.
All SAEs were recorded and adjudicated by a CEC. The primary safety endpoint was freedom from major AEs (MAEs), defined as a SAE that resulted in death, acute myocardial infarction, thrombosis, pseudoaneurysm, dissection (grade C or greater) or clinical perforation at the filter location, clinically relevant distal embolism, unplanned amputation, or clinically driven target vessel revascularization (TVR) through 30 days post-procedure. Clinically significant distal embolization was defined as angiographically demonstrated emboli distal to the filter site that caused clinically evident distal ischemia and required additional interventional procedures or surgery for resolution, or caused tissue loss/extended hospitalization.
Device success was defined as successful delivery and deployment of the WIRION EPS distal to the intervention site without complications, and successful EPS retrieval following completion of the stenting procedure without complications. Clinical success was defined as device success and freedom from procedure-related SAEs ascribed to the WIRION device. Technical success was defined as freedom from device malfunctioning resulting in termination of the procedure. Percentage of filters with debris was evaluated visually by the investigator and by histology analysis performed by NAMSA (Lyon, France). Filters were collected following the procedure and kept in formaldehyde. The filter and captured debris were fixed and a 2-mm-wide central transverse segment was collected and embedded in a paraffin block for analysis. The analysis was adapted from the ISO 10993-6 standard. Qualitative and semiquantitative histological evaluation of the debris was performed, assessing the following parameters: polymorphonuclear cells, lymphocytes, plasma cells, monocytes/macrophages, giant cells, red blood cells, foam cells, leukocytes, smooth muscle cells, fibrocytes, fibrous tissue, calcium deposits, cholesterol clefts, fibrin, necrosis, neovessels, and foreign material debris. The approximate number and size (diameter <1 mm, 1 to 2 mm, or >2 mm) of debris were evaluated as well.
This was a single-arm study using a historic performance goal (PG) as a control. The PG was derived from 2 published studies using the SpiderFX EPS: DEFINITIVE CA++ (Study of the SilverHawk™/TurboHawk™ Plaque Excision Systems Used With SpiderFX to Treat Calcified Peripheral Arterial Disease) (2) and DEFINITIVE LE (Study of SilverHawk®/TurboHawk® in Lower Extremity Vessels) (18). Both included patients who underwent directional atherectomy for symptomatic PAD and contained sufficient data on the outcomes, comprising the present study’s primary endpoint. We defined the PG on the basis of the weighted average of MAE rates in these 2 trials, applying a 97.5% 1-sided confidence interval (CI), which yielded a 19.26% MAE goal. The study was designed to test the primary null hypothesis that the incidence of MAE at 30 days using the WIRION EPS in conjunction with atherectomy was ≥ the PG of 19.26%. An interim analysis was planned when 100 patients, 68.5% of the originally planned enrollment, had reached 30-day follow-up. In the interim and final analysis, the null hypothesis was tested using an Exact Binomial Test under the following assumptions: alpha (1-sided) = 0.025; β = 0.20; PE = 10.7%; PG = 19.26%. An estimated 145 evaluable subjects were required for 80% power if the study reached the final analysis. With an anticipated combined loss to follow-up and unsuccessful deployment rate of 5%, 153 patients were to be enrolled in the study. Two potential options were pre-specified for the interim analysis. The study would be stopped for efficacy if the primary null hypothesis was rejected at 1-sided alpha = 0.0068 based on the Lan-DeMets alpha spending function with O’Brien-Fleming boundaries (calculated using EAST software, version 6.3.1; Cytel, Cambridge, Massachusetts) (19). However, if the primary null hypothesis could not be rejected, the trial would continue to a total enrollment of 153 subjects (i.e., 145 evaluable subjects).
All enrolled patients (those deemed suitable for treatment with the WIRION EPS and who had deployment of the device attempted) including technical failures were included in the intent-to-treat (ITT) analysis. An additional per protocol (PP) analysis was performed in patients who had the WIRION device successfully deployed and who met all inclusion/exclusion criteria.
Patient flow for the ITT population is detailed in Figure 1. Of 175 patients screened, 103 (58.9%) were enrolled and comprised the ITT population. The main reasons for patients' exclusion were as follows:
1. Not meeting the inclusion criteria of “Planned atherectomy of the native femoropopliteal and/or tibial arteries” in 11 patients;
2. Meeting the exclusion criteria of “≤1 vessel tibial run-off status” in 9 patients;
3. Meeting the exclusion criteria of “Lesion deemed not accessible by the WIRION EPS” in 7 patients.
Enrollment was stopped after 103 patients reached 30-day follow-up, and they comprise the ITT population. Eleven enrolled patients did not meet eligibility criteria, and the remaining 92 patients comprised the PP population.
In the ITT population, mean age was 68.2 ± 9.1 years, and 68.9% were men. Diabetes was present in 46.6%, hypertension in 93.2%, hyperlipidemia in 92.2%, and history of smoking in 79.7%. Table 1 displays the demographics and clinical characteristics of enrolled patients. The mean lesion length was 16.1 ± 10.8 cm according to operator assessment and 11.3 ± 7.9 cm according to the core lab. Angiographic and procedural data appear in Table 2. Procedural equipment is detailed in Table 3: Jetstream (Boston Scientific, Marlborough, Massachusetts), Hawk (HawkOne, TurboHawk or SilverHawk) (Medtronic), and Diamondback Orbital Atherectomy System (CSI, St. Paul, Minnesota) were the dominant atherectomy devices used. Stents were used in approximately 25% of patients. Table 4 displays the demographic and lesion characteristics of the WISE LE patients when compared with the DEFINITIVE Ca++ and DEFINITIVE LE trials in the PG. The baseline characteristics are similar with the exception of lesion length in the WISE LE study that was longer than the comparator.
Primary safety outcome
Table 5 summarizes the primary composite endpoint and its individual components at 30-days post-procedure in the ITT population, and contrasts these findings with those from the DEFINTIVE Ca++ (2) and DEFINITIVE LE (18) studies. Two MAEs occurred in the ITT population: TVR (n = 1) and pseudoaneurysm (n = 1); neither were device- or procedure-related. The composite primary endpoint of MAE at 30 days post-procedure, occurred in 1.9% (95% CI: 0.2% to 0.7%) of the ITT population, which was lower than the 19.26% PG (exact p value <0.0001) despite longer lesions and similar degree of calcification in the WISE LE population. Consequently, the study was stopped for efficacy at its interim analysis, because the primary null hypothesis was rejected. In the PP population, 2 MAEs occurred, yielding an MAE rate in the PP patients of 2.2% (95% CI: 0.3% to 7.7%) (p < 0.0001 when compared with the PG). Accordingly, the primary endpoint was also met in PP patients. Of the 103 patients included, 1 patient had follow-up after 12 days due to travel, and the second patient did not return for the 30-day follow-up but was evaluated later. None of these patients had any AEs. All other 101 patients had 30-day follow-up as specified by the protocol.
Device success was achieved in 98 patients, representing 95.1% of the ITT and 94.6% of the PP populations, respectively. Of the 5 device failures, another WIRION device was used successfully in 3 cases and the Emboshield (Abbott Vascular, Santa Clara, California) in 1 case. In 2 cases, device failure was due to a kink in the guidewire that occurred during the atherectomy procedure and required retrieval of the guidewire with the locked filter and exchange for another guidewire. These cases were not related to the WIRION device failure. No AEs occurred in any of the 5 cases. There were 3 patients with SAEs considered related or possibly related to the procedure/device. In conjunction with the 5 device failures, the clinical success was 95 of 103 (92.2%). Three events were considered technical failures, yielding a technical success rate of 97.1% for the ITT population and 96.7% for the PP population. The ankle-brachial index (ABI) was 0.7 ± 0.2 (n = 99) pre-procedure, 0.9 ± 0.2 (n = 90) before discharge, and 0.9 ± 0.2 (n = 94) at 30 days. Both the pre-discharge and 1-month follow-up ABIs were significantly improved (p < 0.0001 and p < 0.0001, respectively) compared with baseline ABIs.
Serious adverse events
A total of 8 patients had 9 SAEs that occurred during the 30-day follow-up period: 3 patients during the index procedure and 5 patients during the 30-day follow-up period. Five of the 9 SAEs were graded as moderate, 1 as mild, and 3 as severe. All SAEs were adjudicated by the CEC and DSMB. Five SAEs were not related to the study procedure or device, 3 were possibly related, and 1 was related. All SAEs were anticipated, and all patients recovered. SAEs are summarized below:
1. Hypotension following catheterization procedure. Patient was given intravenous fluids; hemoglobin dropped from 11.3 to 6.2 mg/dl post-procedure, and patient was transfused with 2 U of packed red blood cells (considered 2 SAEs; hypotension and transfusion);
2. Leg pain that was found on ultrasound to have an occlusion of the superficial artery stent;
4. Thrombus formation during index procedure in 2 patients;
5. Coronary intervention due to dyspnea;
6. Access site complication requiring transfusion;
7. Distal embolism requiring additional treatment.
Filter debris analysis
Histopathological analysis demonstrated debris in all WIRION filters. An example of filter content is depicted in Figure 2. Thrombi of <1 mm, 1 to 2 mm, and >2 mm were captured in 98%, 22%, and 9% of filters, respectively (Figure 3). In general, the debris captured exhibited fibrous tissue fragments, red cells, leukocytes, and fibrin-platelet aggregates. The fibrous debris were typical of fibrous caps seen on atherosclerotic plaques. Cholesterol clefts, located within the thrombi, were detected in 8% of explants. Of the filters analyzed, 64% showed signs of debris microcalcification representative of fibrocalcific plaque.
This prospective, multicenter, open label, single-arm investigation demonstrating the safety of the WIRION EPS in subjects undergoing atherectomy procedures for lower extremity PAD, with the primary composite outcome of 30-day MAE was not inferior to the pre-specified PG. The rate of MAEs at 30 days, including SAEs resulting in death, acute myocardial infarction, thrombosis, pseudoaneurysm, grade C or greater dissection or clinical perforation at the filter location, clinically relevant distal embolism, unplanned amputation, or clinically driven TVR was 1.9%, comparing favorably with the 10.6% weighted mean rate of this composite in 2 prior trials of the SpiderFx, the only FDA-approved EPS for lower extremity endovascular procedures. The WIRION EPS was also highly effective in capturing debris, which was noted in 100% of analyzed filters. WIRION EPS is the first filter to be prospectively tested with all commercially available atherectomy devices and with any 0.014-inch operator-selected guidewire.
The WISE LE study population was comparable to that enrolled in the DEFINITIVE-LE and DEFINITIVE CA++ studies that comprised its control population. Patient characteristics including average age, sex composition, and proportion of patients with diabetes, hypertension, hyperlipidemia, history of smoking, and prior peripheral intervention were similar. Although the degree of lesion calcification was similar across studies, lesion length in the WISE LE study was much greater than in either of the 2 DEFINITIVE studies. Despite the higher angiographic risk profile, there were significantly fewer MAEs in the WISE LE study.
Distal embolization occurs frequently during lower extremity atherectomy procedures, ranging from ∼60% to 100% in certain series (1,2,4,5,10,11). The relative frequency of distal embolization in patients undergoing angioplasty, stenting, and SilverHawk atherectomy was evaluated in the PROTECT (Preventing Lower Extremity Distal Embolization Using Embolic Filter Protection) registry (1), where SilverHawk atherectomy was associated with a 31 times greater odds of distal embolization with angioplasty and/or stenting (p < 0.003). Predictors of distal embolization were chronic total occlusions, in-stent restenosis, and thrombotic, calcific, or long lesions (11). The WISE LE findings were consistent with prior studies in that embolization was observed in conjunction with all atherectomy devices, including directional, rotational, orbital, and laser, and occurred in 100% of cases, suggesting that the WIRION filter use may be of benefit during all lower extremity atherectomy procedures. Importantly, the WIRION filter captured both micro and macro debris and was associated with very low AE rates. Clinically important distal embolization requiring more than simple aspiration did not occur in any of the enrolled subjects.
Because the WISE LE study was not randomized and because patient-level data were not available from previous embolic protection trials of lower extremity atherectomy, we were not able to account for inherent bias and confounding. Further, there are no randomized data assessing the cost effectiveness of embolic filter protection in patients undergoing endovascular treatment for infrainguinal PAD. Large randomized trials and/or prospective registries are needed to determine the added value of embolic filter protection to peripheral arterial endovascular procedures. The WISE LE study does not address the long-term impact of the WIRION filter on patients’ outcomes.
The WIRION filter captured debris in all procedures and was associated with a high device, clinical and technical success, thereby demonstrating the safety and noninferiority to the PG of the WIRION EPS when used in the lower extremities simultaneously with all commercially available atherectomy devices.
WHAT IS KNOWN? Distal embolization is a frequent occurrence during peripheral arterial interventions particularly with the use of atherectomy. Clinically significant distal embolization occurs in 2% to 3% of cases treated. Currently there are 3 embolic protection devices approved in the United States for peripheral arterial interventions. These include the Spider Filter (Medtronic), the Proteus embolic protection balloon (Angioslide, Netanya, Israel) and recently the WIRION filter (Gardia Medical) based on the data of the current pivotal WISE LE trial that showed that it is noninferior to the pre-specified performance goal.
WHAT IS NEW? The WIRION filter offers the following distinct advantages over currently approved filters: 1) it can be used with any atherectomy device; and 2) it is mounted on any 0.014-inch wire. The WISE LE trial does not address the long-term outcomes with the use of the WIRION filter.
WHAT IS NEXT? Larger clinical trials are needed to demonstrate the cost-effectiveness of embolic filter protection use in lower extremity arterial interventions.
The authors thank the following for their contributions: DSMB members: Chairman John Ambrose, MD, Chief of Cardiology and Professor of Medicine, UCSF, Fresno, California, Harold L. Dauerman, MD, Professor of Medicine and Surgery, University of Vermont, Medical Biostatistician Tim Collier, MScn, London School of Hygiene and Tropical Medicine, London, and Independent Biostatistician Melek Ozgu Ozan; CEC members: Steven Marx, MD, Associate Professor of Medicine and Surgeons, Columbia Presbyterian Hospital, Shing Chiu Wong, MD, Director, Cardiac Catheterization Laboratory, New York Presbyterian Hospital Cornell, Mark Connolly, MD, Chairman of Surgery, St. Joseph's Regional Medical Center, and Monica Embacher, MD, Clinical Endpoint Adjudication and Data Monitoring, Cardiovascular Research Foundation, New York.
This study was sponsored by Gardia Medical. Dr. Shammas has received research and educational grants from Boston Scientific and Bard; and has served on Speaker Bureau for Novartis, Boehringer Ingelheim, and Janssen. Dr. Jenkins has served on the Speakers Bureau of Abbott Vascular; and has proctored for Endologix and St. Jude Medical. Dr. Garcia has equity interest with Scion CV; has received research funding from Abbott and Medtronic; has served as an advisor to Medtronic, Abbott, and Boston Scientific; has equity in Syntervention, Essential Medical, CV Ingenuity, Spirox, Tissue Gen, Primacea, and Arsenal; and is founder of Innovation Vascular Partners Consulting. Dr. Davis is a stockholder in Avinger; and has served on scientific advisory boards for Volcano, Boston Scientific, Medtronic, Avinger, and Roxwood Medical. Dr. Armstrong has been a consultant to Abbott Vascular, Boston Scientific, Cardiovascular Systems, Medtronic, and Philips. Dr. Zeller has received honoraria from Abbott Vascular, Veryan, Biotronik, Boston Scientific, Cook Medical, Gore & Associates, Medtronic, Philips-Spectranetics, TriReme, Veryan, Shockwave, Bayer, B. Braun, and Vesper Medical; has consulted for Boston Scientific, Cook Medical, Gore & Associates, Medtronic, Spectranetics, Veryan, B. Braun, Shockwave, Bayer, Vesper Medical, and Intact Vascular; and holds common stock in Veryan Medical and QT Medical. Prof. Scheinert has served on advisory boards and/or as a consultant for Abbott, Bayer, Boston Scientific, Cook Medical, Cardionovum, CR Bard, Gardia Medical/Allium, Medtronic, Philips, and Upstream Peripheral Technologies. Dr. Rosenschein is the inventor of the WIRION EPS device; and has been a consultant to Abbott, Bayer, Boston Scientific, Cook Medical, Cardionovum, CR Bard, Gardia Medical/Allium, Medtronic, Philips, and Upstream Medical Technologies. Dr. Gray has equity in Allium Medical; and has been a consultant to Gardia Medical. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- ankle-brachial index
- adverse event(s)
- Clinical Evaluation Committee
- confidence interval
- distal embolization
- Data Safety Monitoring Board
- embolic protection system
- Food and Drug Administration
- intention to treat
- major adverse event(s)
- peripheral arterial disease
- performance goal
- per protocol
- serious adverse event(s)
- target vessel revascularization
- Received March 22, 2018.
- Revision received May 8, 2018.
- Accepted May 15, 2018.
- 2018 American College of Cardiology Foundation
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