Early Experimental and Clinical Experience With a Focal Implant for Lower Extremity Post-Angioplasty Dissection

JACC: CARDIOVASCULAR INTERVENTIONS

VOL. 8, NO. 2, 2015

ª 2015 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION PUBLISHED BY ELSEVIER INC.

ISSN 1936-8798/$36.00 http://dx.doi.org/10.1016/j.jcin.2014.07.032

PERIPHERAL

Early Experimental and Clinical Experience With a Focal Implant for Lower Extremity Post-Angioplasty Dissection Peter A. Schneider, MD,* Robert Giasolli, MS,y Adrian Ebner, MD,z Renu Virmani, MD,x Juan F. Granada, MDk

ABSTRACT OBJECTIVES This study provides preliminary data on the safety and feasibility of the use of a novel focal implant for managing post–percutaneous transluminal balloon angioplasty (post-PTA) dissection. BACKGROUND Post-PTA dissection of the lower extremity arteries is managed with stent placement. This provides an acceptable post-intervention result but has long-term disadvantages, such as in-stent restenosis. Focal treatment of postPTA dissection and avoidance of stents are the objectives of the Tack-It (Intact Vascular, Inc., Wayne, Pennsylvania) device. METHODS A preclinical study and first-in-human data are presented. Seven swine underwent superficial femoral artery device placement, with a self-expanding nitinol stent on 1 side and a series of 4 Tack-It devices on the other side. Specimens were harvested at 28 days. The clinical study included 15 limbs that underwent revascularization for critical limb ischemia (n ¼ 9) or claudication (n ¼ 6). Twenty-five lesions were treated in the superficial femoral (n ¼ 8), popliteal (n ¼ 7), and tibial (n ¼ 10) arteries. RESULTS The preclinical study demonstrated a reduction in stenosis with the Tack-It (16.8  2.6%) compared with stents (46.4  9.8%). Neointimal thickness and injury score decreased with the Tack-It. Clinically, Tack-It placement resulted in acute technical success with resolution of the post-PTA dissection in 100% of lesions. There were no devicerelated complications or major amputations. Eighteen of the 25 lesions were available for angiographic follow-up at 1-year, and patency was 83.3%. CONCLUSIONS Preclinical data suggest that the Tack-It device causes minimal vessel injury. Clinical use of the Tack-It to manage post-PTA dissection was safe and feasible in this early study and resulted in apposition of dissection flaps without stent placement. (J Am Coll Cardiol Intv 2015;8:347–54) © 2015 by the American College of Cardiology Foundation.

T

he existing paradigm for managing lower ex-

causes excessive acute vascular injury (1–4). Post-

tremity occlusive lesions is severely limited

PTA results are often suboptimal, and stents are

by currently available tools. Balloon angio-

the only practical solution available to manage

plasty (percutaneous transluminal balloon angio-

this problem. Challenging morphologies such as

plasty [PTA]) functions by inducing dissection and

longer lesions and occlusions are more likely to

From the *Kaiser Foundation Hospital, Honolulu, Hawaii; yIntact Vascular, Inc., Wayne, Pennsylvania; zThe Italian Hospital, Asuncion, Paraguay; xCV Path, Gaithersburg, Maryland; and the kSkirball Research Center, Cardiovascular Research Foundation, Orangeburg, New York. Both the pre-clinical and clinical studies were supported by Intact Vascular, Inc. Work on this project was contracted to and performed by both CV Path and Cardiovascular Research Foundation. Mr. Giasolli is a cofounder of Intact Vascular. Dr. Virmani has financial relationships with Abbott Vascular, Atrium 3, Biosensors International, Biotronik, Boston Scientific, CeloNova, Cordis J&J, GlaxoSmithKline, Kona Medical, Medtronic, MicroPort Medical, Mitralign, OrbusNeich, ReCor Medical, SINO Medical, Terumo, 480 Biomedical, and W.L. Gore. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Manuscript received July 8, 2014; accepted July 31, 2014.

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Focal Implant for Post-Angioplasty Dissection

stent

thickness of 17 to 70 m m using Exakt Linear Grinding

induce

technology (EXAKT Technologies, Inc., Oklahoma

chronic injury and underlying inflamma-

City, Oklahoma). All sections were examined by light

tion, leading to intimal hyperplasia forma-

microscopy

tion and in-stent restenosis (5–7). Stent

thrombus, neointimal formation, and vessel wall

angioplasty

fracture is the consequence of implanting

injury. Histologic sections were analyzed using digital

SFA = superficial femoral

relatively rigid metal scaffolds in areas

planimetry with a calibrated microscope system (IP

artery

exposed to complex biomechanical forces,

Lab Software, Rockville, Maryland). Cross-sectional

leading to the continuous and unrelenting deforma-

areas of the vessel, stent, and lumen were analyzed

tion of the stent within the vessel (8,9).

using conventional and previously published for-

ABBREVIATIONS

require

AND ACRONYMS

placement.

MAE = major adverse event PTA = percutaneous transluminal balloon

mechanical

support

Unfortunately,

with

stents

for

the

presence

of

inflammation,

These untoward clinical outcomes have motivated

mulas. In addition, vessel healing was analyzed by

investigators to seek alternative solutions that pro-

quantifying strut apposition, fibrin deposition, gran-

vide the benefits of scaffolding but aim to induce low

uloma and giant cell reactions, hemorrhage around the

levels of inflammation and neointimal hyperplasia. It

device struts, and total number of uncovered struts.

has been proposed that treatment with a minimal implant aimed at providing focal tissue apposition and fixation of dissection flaps would provide a smooth arterial flow surface without the long-term disadvantages imposed by a stent. The Tack-It device (Intact Vascular, Inc., Wayne, Pennsylvania) provides focal mechanical support only where needed after PTA. This is an opportunity to achieve an acute stentlike angiographic result without a stent. The technology functions on the basis of less metal, less outward force, minimal scaffolding, spot treatment, and an opportunity for more natural remodeling of the treated lesion while maintaining arterial flexibility.

PATIENT

POPULATION

AND

STUDY

DESIGN. The

clinical study was a prospective, nonrandomized, first-in-human safety and feasibility study with 1-year follow-up, registered at ClinicalTrials.gov (NCT02044003). Patients were treated at 2 sites in Asunción, Paraguay (Santa Clara Hospital and The Italian Hospital). Eleven patients were enrolled (15 lower extremities treated). Seven patients underwent treatment of 1 lower extremity, and 4 patients underwent treatment in both legs. The protocol was approved by the Human Subjects and Ethics Committee of each hospital. Major adverse events (MAEs) were reviewed by an independent clinical events committee. The subjects’ written informed consent was ob-

METHODS

tained. Baseline clinical data were collected on case EXPERIMENTAL PROTOCOL. A total of 7 healthy

report forms by a clinical research coordinator at the

swine received bilateral superficial femoral artery

study sites. A database of patients and dissections was

(SFA) implants and were kept alive for 28 days. At the

maintained. Data management was performed by

time of the implantation, 1 SFA underwent deploy-

Northwest Clinical Research Group, Inc. (Woodinville,

ment of a series of 4 (each 6 mm in length) nitinol self-

Washington). The database was built on Microsoft

expanding Tack-It devices. The contralateral artery

Excel, and the data were audited by Databent (Seattle,

received a self-expanding nitinol stent (40 mm long

Washington). The safety endpoint was the MAE rate,

SMART stent [Cordis Corporation, Fremont, Califor-

defined as the composite of death, device emboliza-

nia) as a control. Fourteen vessels were explanted at 28

tion, the occurrence of surgery related to the device,

days and submitted for light microscopy and mor-

device-related occlusion of the artery, or major un-

phometric analysis. Animal investigation included

planned amputation of the ipsilateral lower extremity

animal care and use by qualified individuals, super-

at 30 days. The feasibility endpoint was the ability to

vised by veterinarians, and facilities and transpor-

secure vascular dissection flaps with the device at

tation

and

the time of implantation. The technical success

guidelines; anesthesia was used for all interventions,

endpoint was defined as acute luminal patency at

and animal facilities met the standards of the American

the conclusion of the revascularization procedure,

Association for Accreditation of Laboratory Animal

with angiography demonstrating that the lumen of

Care.

the artery at the location of implant remains patent.

complying

with

legal

requirements

LIGHT MICROSCOPY PROTOCOL. Explanted vessels

were dehydrated in a graded series of ethanol solutions and embedded in methyl methacrylate plastic. After polymerization, each Tack-It device was sawed at 3

Patients were followed at 1 month, 6 months, and 12 months

with clinical

examination.

One-year

angiographic follow-up was obtained. Restenosis was defined as $50% by angiography.

levels, and each stent was sawed at 4 levels. All seg-

TACK-IT DEVICE AND PLACEMENT PROCEDURE.

ments were glued onto plastic slides and ground to a

Each patient underwent angiography to assess lower

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Focal Implant for Post-Angioplasty Dissection

extremity lesions. Heparin was administered, and

over range of diameters of several millimeters. The

transfemoral sheath placement was performed, using

unconstrained diameter of the device is 7.3 mm. It

either up-and-over or antegrade approach using a 6-

is indicated for vessels with a reference diameter

French access sheath. Heavily calcified lesions were

ranging from 2.5 to 5.5 mm. This permits serial im-

excluded from the study (defined as circumferential

plantation of the devices into a tapering artery

calcification or contiguous calcification of $4 cm

without significant change in the mechanism and

along the length of the lesion). The lesion was crossed

function of the device and without exerting increased

using a standard guidewire technique. Each patient

outward force. The outward force exerted by the tack

underwent balloon angioplasty with the balloon

is lower than that observed in commercially available

inflated to nominal pressure to match the reference

lower extremity stents. After deployment across the

vessel diameter. Post-PTA angiograms were obtained

dissected segment, post-placement balloon angio-

in multiple views. Any significant residual stenosis

plasty is performed to secure the device and the

($30%) was treated with repeat PTA. Post-PTA

anchor fixation barbs. Follow-up catheter-based

dissection flaps were identified. The Tack-It delivery

angiography was performed in all available patients

catheter was loaded onto the same guidewire and

after 12 months or sooner if repeat revascularization

advanced to the site of the post-PTA dissection. The

was required.

tacks were deployed separately at intervals of $6 mm from each other across the lesion. Each tack has an

RESULTS

axial length of 6 mm (Figure 1) (10). The Tack-It is a self-expanding nitinol device that is specifically

EXPERIMENTAL STUDY. All implanted animals sur-

designed for tissue apposition and focal pressure

vived the entire in-life duration. Both devices

application. Tack-It device features include low out-

matched vessel anatomy with good apposition (<5%

ward force, paired anchor fixation barbs in the center

malapposed struts in both groups). The percent

of the implants, and variable pressure application,

of diameter stenosis was reduced (16.82  2.64%) in

with more pressure exerted by the middle section of

the Tack-It group compared with the stent group

the device than by the wings. The device has a rela-

(46.37  9.75%). Neointimal growth consisted of

tively flat outward force curve, so there is minimal

organizing smooth muscle cells in a proteoglycan

change in outward force when implanted in vessels

matrix, and it was higher in the stent group (Figure 2).

F I G U R E 1 The Tack-It Device Is Indicated for the Focal Treatment of Post-PTA Dissection

The Tack-It device is a self-expanding nitinol design that is 6 mm in length and is able to treat arteries over a 3-mm range of diameters, from 2.5 mm to 5.5 mm. The device is secured by 6 pairs of anchor fixation features that are located in the center of the Tack-It, each with a radiopaque (RO) marker for radiographic visualization of the device.

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F I G U R E 2 Histology Specimens Were Obtained From the Proximal, Mid-, and Distal Segments of the Implants

The Tack-It device has lower outward force and stimulated less neointimal response. The stent is able to create a larger lumen with higher outward force but stimulates significant neointimal hyperplasia.

Peristrut fibrin deposits were minimal in the Tack-It

25 treated lesions of the SFA (n ¼ 8), popliteal artery

group and occurred in 11.01  11.10% of the struts,

(n ¼ 7), and tibial artery (n ¼ 10). Six of the 25 lesions

whereas they were greater and more frequently seen

(24%) were occlusions, and 19 were stenoses. Among

(48.14  14.61%) in the stent group. The Tack-It group

the 6 occlusions, 5 were crossed using a looped sub-

demonstrated lower injury scores, less inflammation,

intimal wire, and 1 was crossed transluminally. The

and more endothelialization than the stent group.

mean lesion length was 5.6  4.2 cm. Acute technical

Histological parameters are summarized in Table 1.

success was achieved with Tack-It placement and tissue apposition/flap management in 25 of 25 treated

EARLY HUMAN CLINICAL STUDY. The mean age of

arteries (100%), as determined by completion angi-

the 11 enrolled patients was 66 years (range 47 to 85

ography (Figure 3). In each case, the area of dissection

years). Five of the 11 (45%) were male. All patients

was successfully tacked down, and no dissection flaps

had a history of hypertension (11 of 11), hyperlipid-

persisted. The safety, feasibility, and technical end-

emia was present in 72.7% (8 of 11), and coronary

points are summarized in Table 2. The number of

artery disease was present in 72.7% (8 of 11). The

Tack-It devices placed per patient ranged from 1 to 12

indication for revascularization in the 15 limbs ac-

(mean 3.4). Forty-eight of 50 devices were placed

cording to the Rutherford classification was gangrene

accurately (96%). In 1 case, 2 Tack-It devices were

(stage 5) in 5 patients, rest pain (stage 4) in 4, and

placed imprecisely near, but not at, the intended

claudication (stage 3) in 6. Of the 15 limbs, there were

target (reference vessel diameter, 5.2 mm). Additional

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Focal Implant for Post-Angioplasty Dissection

T A B L E 1 Comparison of Self-Expanding Nitinol Stent and

Tack-It Device

lesion revascularization rate of 4%. The 1-year patency rate for the femoral and popliteal artery lesions was 87.5%. Recurrent stenosis developed in 2 patients with

Tack-It Implant Group (n ¼ 28)*

Implant Group Stent (n ¼ 7)

Implant Group p Value

tibial artery lesions, for a 1-year tibial artery patency rate of 80%. One lesion recurred after treatment of an

EEL area, mm2

11.85  1.38

19.63  1.63

<0.0001

occluded tibioperoneal trunk, and 1 occurred after

IEL area, mm2

9.91  1.29

17.27  1.29

<0.0001

treatment of a stenosis. Both patients initially had

Lumen area, mm2

8.22  1.11

8.85  1.87

0.269

Medial area, mm2

1.94  0.34

2.35  0.79

healed ischemic foot ulcers that healed and neither

0.0232

Strut malapposition, %

4.14  8.68

4.17  7.22

0.994

Struts with fibrin, %

11.01  11.10

Struts with giant cells, %

0.33  0.89

48.14  14.61 <0.0001 0.10  0.27

for tibial artery lesions was 80%.

0.497

Struts with RBCs, %

10.29  7.06

44.38  9.21

<0.0001

Endothelialization, %

99.28  2.50

96.79  3.01

0.0355 0.209

Uncovered struts, %

1.56  7.14

5.48  6.21

Mean injury score

0.12  0.069

0.44  0.24 <0.0001

Mean fibrin score

0.25  0.31

1.25  0.20 <0.0001

Neointimal inflammation score

0.11  0.20

0.57  0.28 <0.0001

Adventitial inflammation score

0.00  0.00

0.14  0.20

required repeat intervention. The 1-year patency rate

0.0004

Values are mean  SD. *Animal 16-106D (CV29819) RSFA Tack 1 mid-section excluded from analysis due to processing artifacts, and a section was unavailable from the proximal region of animal 16-117D (CV29821) RSFA Tack 4. EEL ¼ external elastic lamina; IEL ¼ internal elastic lamina; RBCs ¼ red blood cells.

DISCUSSION These preliminary results suggest that use of the TackIt device is safe and that this alternative nonstent method of securing post-PTA dissection flaps is feasible. The experimental evaluation of the Tack-It device at 28 days demonstrated less neointimal formation, degree of injury, inflammation, and stenosis than an SFA-approved self-expanding nitinol stent. In addition, overall vascular healing was superior with the Tack-It device as reflected by the lower amounts of peristrut fibrin and red blood cell deposits. The anchor fixation segment of the Tack-It device did not induce additional degrees of inflammation. The first-in-human study demonstrated the feasi-

Tack-It devices were implanted, and there were no

bility and safety of focal treatment of post-PTA

untoward consequences. Of the 15 lesions of the su-

dissection in the lower extremity using a novel

perficial femoral and popliteal arteries, there were 5

implant designed to achieve tissue apposition but

occlusions (33%), and of the 10 lesions of the tibial

maintaining the natural configuration and qualities

arteries, there was 1 occlusion (10%). The number of

of the artery. Multiple post-PTA dissections were

Tack-It devices implanted in the femoral-popliteal

managed in a range of arteries and lesion morphol-

lesions ranged from 1 to 5, and in the tibial lesions,

ogies without bailout stent placement. The 1-year

it ranged from 1 to 3. The mean procedure time was 51

angiographic patency was acceptable in this small

min (range 10 to 128 min). The mean fluoroscopy time

preliminary study comprising all-comers: lesions of

was 13 min (range 5 to 30 min).

the superficial femoral, popliteal, and tibial arteries

One patient had an intraprocedure puncture site

and in limbs with gangrene, rest pain, or claudication.

thrombosis (contralateral femoral area using up-and-

The principles used in the construction of the Tack-It

over approach) that required thrombus aspiration.

device (less outward force, less metal, and spot treat-

One patient died of a myocardial infarction in the

ment) are specifically intended to address areas in

perioperative period. The MAE rate was 9.1% (1/11) due

which currently available devices have failed (Table 3).

to the death in the perioperative period. Two patients

A much larger study is required to understand the

were lost to follow-up before 1 year. There was no

overall patency implications of this approach.

occurrence of device embolization, surgery related to

Balloon angioplasty plays a major role in lower

the device, device-related occlusion of the artery, or

extremity revascularization and will likely be an

major amputation. Eighteen of the 25 lesions were

essential technique in the foreseeable future. Drug-

available for follow-up at 1 year, and angiographic

coated balloons have shown promise and will prompt

patency was 83.3%. There was recurrent stenosis

renewed interest in the angioplasty mechanism and

($50%) in 3 of 18 (16.7%). One patient with a popliteal

how it may be optimized (11–13). In arteries that are

artery occlusion and toe gangrene underwent recana-

obstructed by atherosclerotic plaque, balloon angio-

lization, balloon angioplasty, and Tack-It placement

plasty increases the vessel lumen diameter by causing

but returned with a recurrent stenosis as seen on

dissection. Post-PTA dissections are uncontrolled

duplex ultrasonography at 3 months and required

arterial injuries that are usually manifested by longi-

repeat angioplasty and Tack-It placement for a target

tudinal tears creating tissue flaps of varying degrees of

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F I G U R E 3 A 65-Year-Old Man With Short-Distance Right Leg Claudication

(A) Angiogram of right superficial femoral artery before treatment. (B) Post-angioplasty dissection (arrows). (C) Three Tack-It devices (arrows) deployed in right superficial femoral artery to treat post-angioplasty dissection. (D) Completion angiogram after Tack-It device placement. (E) Angiogram performed in follow-up at 1 year.

severity that are visible angiographically. When post-

occlusions) are even more likely to require mechanical

PTA dissection produces a suboptimal result in cur-

support, and a stent is often deployed to achieve an

rent practice, the only reasonable option available is

acceptable result (16–18). One major unsolved chal-

stent placement to secure the dissection flap and

lenge is that it remains unclear which dissections

ensure the integrity of the lumen. Contemporary SFA

require treatment and which do not.

stent trials conducted primarily in TASC A and B le-

Almost every important aspect of stent design and

sions have a stent bailout rate of 35% to 50% in patients

construction is associated in some way with stent

randomized to balloon angioplasty (14,15). The more

failure. For example, the stent material, degree of

challenging lesions (TASC C and D, longer lesions,

outward force, wall pattern, rigidity, stent length, and

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Focal Implant for Post-Angioplasty Dissection

T A B L E 2 Perioperative and Long-Term Results of the

T A B L E 3 Principles of Design of the Tack-It Device

Tack-It Device Minimal Implant

Technical success

100

Feasibility (ability to secure dissection flaps)

100

Safety (rate of MAE)

9.1

Accuracy (ability to place Tack-It at the desired location)

96

12-month angiographic patency

83.3

12-month target lesion revascularization

4.0

Low Outward Force

Focal Treatment

Minimizes metal to artery interface

Low outward force with minimal inflammatory response

Treat multiple lesions/ dissections with 1 device

Maintain arterial flexibility minimizing device stress

Same outward force over a range of diameters

Mechanically tacks down dissection flap to create

Allow artery to remodel in more natural manner

Pressure exerted by device at focal points

Smooth vessel wall surface Tissue apposition Stable deployment

Values are %. MAE ¼ major adverse event.

the conformational quality of the artery. When instent restenosis occurs, there is no durable treatstrut thickness are all associated with in-stent reste-

ment (27,28). When the continuum of care is assessed

nosis (16,19–24). It is apparent that the longer the

over the patient’s life span, the patient may be better

lesion is, the lower the long-term patency. This is

off without a stent in the lower extremity. When a

typically attributed to lesion length; however, it may

stent is placed, a bridge is burned along that care

also be due to stent length, which becomes corre-

continuum. Perhaps a stentlike acute angiographic

spondingly longer with lesion length. It is generally

result could be achieved without the late complica-

agreed that a “full metal jacket” is not a durable or

tions of a stent. In addition, the availability of an

desirable solution (25). This suggests that when me-

accurate method of spot treatment returns control of

chanical support is required at the treatment site, one

the procedure to the operator. This increases preci-

consideration may be to minimize the implant.

sion, provides only as much mechanical support as is

The current treatment paradigm with balloon angioplasty and stenting is somewhat inflexible and

needed, and is more akin to a dose-response approach to optimizing balloon angioplasty.

indicates stent placement even when much less me-

Use of the Tack-It is a highly versatile solution to a

chanical support and less metal may actually be

complex problem. This approach provides the ability

required. A stent is generally able to provide a smooth

to treat a broad range of artery diameters with a single

post-intervention surface but may also provide too

device and to treat multiple locations with a single

much scaffolding, causing increased stiffening of a

catheter. Use of the Tack-It Endovascular Stapler to

highly mobile and flexible artery. Stents may also

manage post-PTA dissection is safe and feasible. It

cover too much surface area with metal, apply too

resulted in less injury, inflammation, and stenosis

much chronic outward force against the artery wall,

than standard control SFA stents in the pre-clinical

and allow too much friction between the metal

study and permanent securement of dissection flaps

implant and the artery wall. In the interest of man-

without stent placement and with reasonable angio-

aging post-PTA dissection, the function of a stent in

graphic patency at 1 year in this first-in-human study.

the current treatment paradigm is to force the artery

This device provides focal treatment of post-PTA

into a configuration that it would not otherwise

dissections, allowing the artery to maintain its natu-

naturally assume. Newer stents of various configura-

ral configuration, avoid overscaffolding with stents,

tions or that exert varying forces or are coated with

and potentially avoid the long-term failure modes of

medication have been introduced, with each design

in-stent restenosis and stent fracture.

intended to minimize the impact of the implant on the recipient artery (26). However, it is possible that

REPRINT REQUESTS AND CORRESPONDENCE: Dr.

these constructs cause injury that exceeds the

Peter A. Schneider, Division of Vascular Therapy,

acceptable threshold that might avoid the previously

Kaiser Foundation Hospital, 3288 Moanalua Road,

mentioned stent-related failure modes. Substantial

Honolulu, Hawaii 96819. E-mail: peterschneidermd@

arterial scaffolding with a stent permanently alters

aol.com.

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KEY WORDS angioplasty, dissection, tack