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Cerebral Protection Systems for Distal Emboli During Carotid Artery
Interventions
WALTER A. TAN, M.D., M.S., MARK C. BATES, M.D.,* and MARK H. WHOLEY, M.D.

From the Departments of Radiology and Cardiology, Pittsburgh Vascular Institute, University of Pittsburgh Medical Center, Pittsburgh,
Pennsylvania and *Departmentof Surgery, West Virginia University Charleston Division, Charleston, South Carolina

Carotid angioplasty and stenting is associated with liberation of cerebral emboli that can cause periprocedural
stroke. There are currently three classes of emboli protection devices (EPDs) that are undergoing feasibility
studies and one randomized clinical trial. Preliminary data from a small series appear to be promising, and there
appears to be attenuation of embolic signals on a cerebral Doppler exam with EPD use. However, rare strokes
and patient intolerance due to imposed ischemia have been observed. The advantages and disadvantages of each
EPD class and the issues involving clinical trials and surrogate end points in this area of study are discussed. (J
Interven Cardiol2001;14:465-474)

Introduction
Periprocedural athero- and thromboembolic events
have long been observed spontaneously or during surgical or endovascular procedures for peripheral arterial occlusive diseases.'-5 In carotid endarterectomy (CEA),
embolism is still the most common cause (up to 54%) of
all cerebrovascular complications, followed by hyperperfusion (29%) and hypoperfusion (17%) in a series of
500 CEA patients that had a neurological complication
rate of 4.8%.6 Gross samples of atheromatous and
thrombotic debris have been collected in humans downstream from the site of percutaneous revascularization of
native coronary, carotid, and renal arteries7 This type of
phenomenon was described even during the early experience with percutaneous transluminal coronary angioplasty (PTCA) of a vein graft by Aueron and Gruentzig.'
The proclivity of degenerated saphenous vein coronary
bypass grafts (SVGs) for procedurally related embolic



sequelae has since been well documented and may be
paradigmatic for other similarly diseased vascular temtories?." Microvascular occlusion and vasospasm result
in impaired blood flow or "no-reflow" to the distal vascular bed, culminating in end organ ischemia and infarction."-I3 These events have been shown to translate into
unfavorable clinical outcomes for these patients, including higher short- and long-term mortality.'4-'6
Preliminary data indicate that percutaneous carotid
revascularization is a promising alternative to CEA for
the treatment of atherosclerotic carotid artery stenosis.
However, procedural strokes continue to be a problem,
and are observed in approximately < 6%of cases depending on the case mix, which is highly variable from
center to center. Not only stroke, but also subtle neurological outcomes like cognitive decline and delirium
after ischemic or embolic insults during cardiovascular operative procedures have been shown to contribute significantly to mortality and the necessity for
prolonged care.I7 Embolic signals (ESs) or high intensity transient signals (HITSs) on transcranial Doppler
(TCD) is perhaps the best surrogate currently available
for cerebral emboli from the perspective of cost, convenience, and invasiveness.'' In a study of 119 patients with anterior circulation strokes of different etiologies, spontaneous ES on serial 1-hour TCD monitoring were found to be more common in patients with

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Mark H. Wholey is a shareholder in AngioGuard, Cordis, Warren,
NJ and Embolic Protection, Inc., Campbell, CA.
Mark C. Bates is on the Scientific Board of ARTERIA.

Address for reprints: Walter A. Tan, M.D., Staff Interventionalist,
Depts. of Radiology and Cardiology, Director of Clinical Research,
Pittsburgh Vascular Institute, University of Pittsburgh Medical Center- Shadyside, 5230 Centre Ave., Pittsburgh, PA 15232. Fax: (412)
623-1761 ; e-mail: tanwa@msx.upmc.edu

Vol. 14, No. 4, 2001


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TAN, ET AL.

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carotid artery stenosis (50%) as opposed to those classified as having cardioembolic (4.5%) or lacunar
strokes (O%).19 The same group of investigators found
that ES was more common in patients with symptomatic, as opposed to asymptomatic, carotid stenosis
(34 vs 3.6%, P = 0.003), and serves as an independent
predictor of future stroke in symptomatic and asymptomatic patients.20921
Crawley and coworkers22quantified ES in 28 patients randomized between CEA with
a shunt and carotid percutaneous transluminal angioplasty (PTA). While CEA patients had longer mean
cerebral ischemic times compared to PTA (165 vs 17
min; P = 0.001), there were more ES indicative of particulate emboli in the PTA group (202 ? 119) as opposed to the CEA group (52 t 64). In a retrospective
study of TCD during carotid angioplasty and stenting
(CAS) and CEA, the former was associated with a
higher proportion of patients with detectable emboli,
and a higher mean emboli count (59 vs 8.3).2 It is unclear if attempts were made to distinguish between
aeroemboli commonly associated with contrast injection, from particulate or atheroemboli. Each may carry
different degrees of significance. Nonetheless, the accumulated evidence suggests strongly that distal cerebral embolization is more prevalent during carotid endovascular procedures than CEA.

Table 1. Classification of Emboli Protection Devices

I. Distal Occlusion Devices
A. Balloon Occluder

1. Theron Triple Coaxial Catheter System"
2. PercuSurge Guardwire (Sunnyvale, CA, USA)
3. Endeavor nondetachable silicon balloon catheter
(Target Therapeutics, Fremont, CA)*'
B. Filter
1. AngioGuard (Cordis, Warren, NJ, USA)
2. AccuNet (Advanced Cardiovascular Systems, Inc.,
Santa Clara, CA, USA)
3. MedNova (Abbott, Abbott Park, IL, USA)
4. E-Trap Filter (Metamorphic Surgical Devices Inc.,
Pittsburgh, PA)35
5 . Filterwire EX (Boston Scientific, Maple Grove, MN,
USA)'
6. TRAP Vascular Filtration System (Microvena C o p ,
White Bear Lake, MN, USA)82
7. Scion CV (Miami, FL)
11. Circulatory Control Devices
Parodi Anti-Embolization Catheter (PAEC) (ArteriA, Inc.
San Francisco, CA, USA)37

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Types of Emboli Protection Device
As early as 1979, Parodi conceptualized a technique
of carotid artery flow reversal by means of a gradient
created by a guide catheter in the context of proximal
balloon occlusion. Theron et al.23were the first to publish, in 1987, on the technique of distal balloon occlusion for cerebral protection in the context of carotid

angioplasty. In 1988, Wholey et al.24were issued the
first patent on the design of a collapsible basket filter
for distal embolic protection positioned between the
dilating balloon and the distal end of the catheter.
Currently, there are three basic classes of emboli
protection devices (EPDs) that are currently undergoing clinical evaluation: balloon occluders, filters, and a
circulatory control system (Table 1). Filters and soft
occlusive balloon catheters are advanced past the lesion to prevent downstream particle escape, whereas
the circulatory control system sits proximal to the lesion (Figs. 1 4 ) . Catheter aspiration of embolic debris
is done prior to deflation of the balloon occluder, as

466

opposed to filters, which are retracted like an umbrella
that closes around the captured debris.25
Balloon Occluders. From a clinical perspective, the
best studied EPD is the PercuSurge GuardWire balloon occluder (PercuSurge Inc., Sunnyvale, CA, USA)
(Fig. l).26-32
The largest patient series (164 carotid arteries in 148 patients) was published by Henry et
al.26333who noted 1.8% periprocedural complications:
one major stroke, one transient ischemic attack (TIA),
and one intracerebral hemorrhage. This compares favorably to their historical death or stroke rate of 4.6%
prior to their use of E P D s . ~Similar
~
encouraging preliminary results have been observed in the Carotid Angioplasty Free of Emboli (CAFE) Registries in Europe
and the United States.2933o
Evidence supporting the
success of EPDs in mitigating cerebral embolization
comes in a study of 24 patients in whom TCD of the
middle cerebral artery was performed during CAS.

Embolic signal counts were significantly lower in the
group where PercuSurge was used compared to patients without distal balloon occlusion (Table 2).3' It is
unclear why ES counts favored the balloon occlusion
group during the stage of wiring across the lesion,
since the EPD would not yet have been deployed at
that juncture.
Filters. The filter class of EPDs are typically systems that use a 0.014" steerable guidewire that incorporates a porous filter membrane in a basket or umbrella configuration that is scaffolded open by a wire
loop structure. The current generation of filters have

Journal of Interventional Cardiology

Vol. 14, No. 4, 2001


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EMBOLI PROTECTION DEVICES FOR CAS

a

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b

Note: Investigational device. Not currently for sale in the US

Figure 1. PercuSurge Guardwire. (a) The balloon is advanced distal to the target lesion. (b) The balloon is inflated for the

duration of the procedure. After the final manipulation at the target lesion (stenting or postdilation), an aspiration catheter is
advanced over the wire to suction the column of blood along with debris that is caught behind the emboli protection device
balloon (not shown). (c) Angiographic depiction of the inflated PercuSurge device at the top, followed by the longer balloon
that is inflated across the lesion just past the tip of the guide catheter.

pore sizes that are 100-150 pm. Loop diameters must
be chosen carefully to guarantee apposition of the hem
of the filter to the carotid vessel wall for optimal particle capture. This should not be too oversized as to create device pleating or redundancy, and yet has to ac-

Figure 2. Hoop-type filter. Bottom: predeployment with filter
constrained within the delivery catheter. Top: opened configuration.

Vol. 14, No. 4, 2001

count for the possibility of slight vessel expansion during the post-CAS hyperemic phase. The guidewire and
EPD delivery sheath is passed across the target lesion
in standard fashion and deployed distally prior to any
manipulation of the lesion. CAS is then performed
with the filter capturing particulate material while allowing blood to flow unimpeded. After the final procedural step (stenting or postdilation), the filter is collapsed and recaptured (Fig. 2).
Some clinical data is already available for the AngioGuard distal protective device (Cordis, Warren, NJ,
USA). Yadav and G r ~ b e ’have
~ reported the use of
this device in 32 patients, mostly in coronary arteries
and SVGs, but also in six carotid arteries. One patient
had a procedure related event deemed not to be related
to the EPD with retarded distal flow observed prior to
retrieval of the collection basket. The composition of
the captured embolic material included acute (in 3/6
carotid procedures) and chronic (4/6) thrombus, neutrophils (4/6), foam cells (1/6), plaque (1/6), and calcium (1/6). The EPI Filterwire (Embolic Protection,
Inc.? Campbe11,

USA) is a 3*7Frdevice that had a
particle capture efficiency of 95% under experimental

Journal of Interventional Cardiology

CAy

461


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TAN, ET AL.

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-30C C / S ~

)

+

~cc/sec

Figure 4. Retrograde flow.
Figure 3. Flow pattern with occuded common carotid.

testing. This has been applied successfully to 80 patients in Europe, about half of whom were for carotid

artery interventions, and in the United States, a
prospective feasibility study in SVGs is now in
progress.’ Other filter devices have had uncomplicated
use in small numbers of human subjects as
Circulatory Control. The Parodi Anti-Embolization System (PAES) creates temporary passive or active blood flow reversal from the carotid artery into a
9Fr catheter that also allows simultaneous passage of
balloons and ~ t e n t s The
. ~ ~ catheter tip is positioned
proximal to the carotid artery target lesion. When the
balloon cuff around the tip of this catheter is inflated,
blood flow is occluded at the level of the common
carotid artery. A “steal” physiology is then created in
which blood flows retrogradely from the external
carotid or superior thyroid arteries resulting in persistent low velocity antegrade flow in the internal carotid
artery (Fig. 3).
Of the common and external
carotid arteries will create cessation of any antegrade

468

blood flow in the ipsilateral carotid territory (Fig. 4).
An exit port in the proximal portion of the catheter is
then connected to a filtered conduit that is attached to
a venous sheath. The low pressure in the venous system creates a gradient that allows continuous passive
retrograde flow in the internal carotid during all phases
of the procedure. Active suction is applied to the system by syringe withdrawal of 10 cc from the exit port
following the interventional steps that yield the highest burden of embolic material. This debris is captured
Table 2. Microemboli During Various Stages of CAS With
and Without EPD”


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Stage of
Procedure

No EPD
(n = 13)

EPD
(n = 11)

P value

Sheath
Wire
Predilation
Stent
Postdilation

11 f 1 1
2.5 ? 23
41 ? 40
68 ? 41
21 2 2s

1 4 f 12
11 ? 9

5f6
4?4
0.8 ? 0.9

0.3
0.03
0.004
0.002
0.003

CAS = carotid angioplasty and stenting; EPD = emboli protec.

tion device.

Journal of Interventional Cardiology

Vol. 14, No. 4,2001


EMBOLI PROTECTION DEVICES FOR CAS

in a filter in the blood return system attached to the venous sheath outside the body. Published clinical experience with the PAES consists of an international
prospective series of 60 patients, 45% of whom had
angiographic evidence of carotid artery stenosis with
thrombus or ulceration. Deployment of the PAES was
successful in all patients, and none had any periprocedural stroke or TIA. It is interesting to note that a third
of the patients did not require external carotid artery
occlusion to achieve complete flow reversal.37

a study of nine patients with carotid artery stenosis of

75%-90% (median 80%), guidewire passage alone
produced a statistically significant diminution in middle cerebral artery blood flow (48 vs 72 c d s e c at baseline) and jugular venous oxygen saturation (68 vs
70%):’
Bulkiness has also resulted in occasional failure to pass these devices across tight lesions or past
tortuous anatomy, making these useless for the patient
subsets that stand to gain the most benefit from cerebral protection. Vasospasm is also a common occurrence with some filters. To and fro excursions of filters, particularly during wire exchanges, may conCurrent Limitations
tribute to vasospasm, and they may produce
microscopic furrows in the carotid artery intima. Fibrin deposition or clot formation on the distal surface of
Device Pitfalls. There are important pitfalls to the
the device is possible, especially in circumstances
first-generation devices that are currently under inveswhere there is increased procedural time or cessation
tigation. Seizures, changes in sensorium, or TIAs and
of distal flow. Vessel dissection can theoretically ocstroke resulting from transient cerebral ischemia have
been documented for all three classes of EPDs. ~ ~ , ~ ’, cur.
Particle capture efficiency is not perfect, as up to a
In the largest EPD single center series, the Perfifth of total embolic debris were missed or liberated
cuSurge device was applied to 148 patients, 5.4% of
during filter passage in the Ohki
Retinal
whom had an occluded contralateral carotid artery. Insymptoms could result from debris of only 20 km in
tolerance to balloon occlusion of cerebral flow was obsize, and dilatations in terminal arterioles of as small as
served in 4.9% of patients.33This was in the context of
10-50 pm are considered pathological evidence of
a mean occlusion time of 422 seconds (range 2.1-24.6
embolic event^.^' One clinical study indicated that as
minutes), although neurological events have been obfew as 11 TCD particulate emboli can be associated
served well within 3 minutes of imposed ischemia. In
the series using the PAES, 5% of patients were intolwith a measurable deterioration of cognitive function
in patients undergoing CEA, but aggregate particulate
erant to flow reversal without ~ e q u e l a e Specific

.~~
size and time density (quantity per unit time) are probmechanisms of cerebral flow attenuation vary among
ably important determinants of adverse ~ e q u e l a eIn
.~
devices. This can be seen during balloon occlusion
with the PercuSurge device. The PAES has the addithe First Clinical Experience with the PercuSurge
GuardWire System study (n = 100 patients), emboli
tional component of imposing carotid flow reversal.
were recovered from every case with an average of 77
Filters, however, occasionally accumulate enough parparticles per patient (range 7-27 1).27Embolic particle
ticulate or thrombotic material to plug up the pores and
size ranged from 16 to 6,206 pm, and more imporimpede blood flow. Patients who are at particular risk
tantly, 54% of particles were 5 100 pm in size. The
for intolerance to EPD are those with contralateral
carotid artery occlusion, or in patients with only modprocess of laser cutting allows ease of manufacturing
filters of much smaller pore sizes, but this may come
erate degrees of ~ t e n o s i s . ~ ~
The
. ~ ’latter phenomenon
at the cost of accelerating plugging of filter pores with
may be due to a lack of hemodynamically significant
consequent cessation of distal flow. Spillage or overstenosis to provoke adequate development of intracraflow of particulate debris can also occur with filters.
nial collateral blood flow.
Neither is complete occlusion with distal balloons a
Another drawback is that EPDs are not mass free.
perfect solution, since visual deficits have been docuThese add additional bulk to the guidewire, and remented after flushing towards the external carotid
quire manipulations and traversal of proximal great
artery while the balloon was inflated, and in another
vessels and the target lesion just like any other decase after withdrawal of the balloon o c c l ~ d e rThere
.~~

vice.3s Ohki et al.39have shown in an ex vivo model
can be residual debris after the aspiration of blood
that passage of a 0.014” guidewire-based filter was asproximal to the balloon occluder, either in the “gutter”
sociated with dotterization of embolic material that
along the balloon-vessel interface, or particulates that
constituted up to 12% of the total embolic burden.39In

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TAN. ET AL.

16

n


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times more MES during preangioplasty catheter manipulation than during the balloon angioplasty itself.22
None of these devices offer protection from embolic
phenomena that occur during the procedural steps that
precede deployment of the EPD. The current generation of EPDs also add blood loss, procedural time, and
complexity to a technique where minimum manipulation is the guiding principle. The potential advantages
and disadvantages of each class of EPDs are tabulated
in Table 3.
Clinical Trial Methodology. There are no Food
and Drug Administration (FDA) approved devices for
cerebral protection at this time. However, numerous
EPDs are entering the phase of human feasibility trials.
There are several industry-sponsored studies, one randomized clinical trial comparing CEA to CAS with
EPD, and three feasibility trials. The completed series
on PAES and PercuSurge have been discussed. The
Stenting and Angioplasty with Protection in Patients at
High-Risk for Endarterectomy (SAPPHIRE) trial is
under way and plans to randomize 600-900 patients
with high risk features that are medically (e.g., severe
cardiac or pulmonary disease) or anatomically challenging (e.g., high cervical or intrathoracic lesions,
prior CEA or neck radiation). Patients deemed by the
surgeon or interventionalist to be nonrandomizable by
objective or subjective criteria are entered into the
CEA or CAS registries. The Prospective, Non-randomized, Multi-center Feasibility Study to Assess the
Safety of the ACCUNET Embolic Protection System
with the Acculink Carotid Stent System in the Treatment of Patients with Lesions in the ICA (ACCUNET)
has recently completed enrollment of their target 50

patients in 12 sites. This carefully structured and administered study includes high risk patients and moderate risk subsets such as age 2 80 years, serum creatinine > 1.5 mg/dL, or presence of any nonrevascularized coronary artery disease. Five issues remain: (1)
Different patient subpopulations with a very heteroge-

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.

100

.

2W

.

300

.

.

400

SO0


.

600

.

.

700

1100

.

900

.

1000

1100

P.tthb SlU (mlcm".)

Figure 5. Size distribution of embolic particles retrieved after using
the PercuSurge device in conjunction with carotid angioplasty and
stenting (CAS) in two human subjects. Note the expected normal
distribution but with left truncation at 50-wm threshold, raising the
possibility of noncapture of particles smaller than those depicted in
this graph.


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remain suspended in solution (Fig. 5). Technology is
potentially available to assist in elucidating this problem, as the resolution of TCD for embolic particle
sizes can be as small as 24 km.43
Clinical studies have shown that strokes occur with
diagnostic catheterization alone in the order of
0.8%-2%.44-47 A majority of these events are attributable to arch atheroma and diffuse atherosclerotic
involvement of the carotid
The prevalence of
moderate-to-severe atherosclerosis of the ascending
aorta as determined by epiaortic echocardiography
during open heart surgery goes from 9% in the 50-59
year age group, to 33% in people 2 80 years of age,
and even higher in patients with a history of
stroke.53954
To compound the problem, routine noninvasive studies or even arteriography do not consistently identify high risk lesion characteristics like
atherosclerotic aortic arch or ulcerated carotid artery
These diseased vessel segments must be
traversed by catheters and devices to get to the target
l e s i ~ n . One
~ * ~study
~ ~ revealed that there were three

Table 3. Embolic Protection Devices (EPDs): Potential Advantages and Disadvantages

EPD Type

Fi 1ter *
Occlusion balloon
Circulatory control

Need to
Cross Lesion

yes
yes
no

-

Impedes
Cerebral Flow

Trauma to
Vessel Intima

rare
routinely"
routinely

some?
Some?
Some?b

Vasospasm
occasional
rare

none?

Particle Escape
yes
minimal
none?

*Filter designs may var significantly and may have intraclass differences in performance characteristics. "Mean flow occlusion time
Y '
= 542 5 243 seconds;'- bSince proximal occlusive balloon is required. .

470

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EMBOLI PROTECTION DEVICES FOR CAS

nous risk status will make the general conclusion less
meaningful for individual subsets. For example, patients who are enrolled because of a need for coronary
revascularization will be subjected to the cumulative
risk of sequential high risk procedures (CEA or CAS
followed by coronary artery bypass grafting (CABG),
or simultaneous CEA + CABG in some centers).
Their risk profile is very different from the patient who
just has a restenotic carotid artery post-CEA and perhaps should be analyzed separately. (2) A related concern is differential risk depending on strategy. Patients

who present with Class IV angina or heart failure, or
contralateral ICA occlusion will probably have less
morbidity with the percutaneous approach, whereas
the results in restenotic patients will more likely be
competitive for both CEA and CAS arms. It is unclear
that subanalyses will be possible since SAPPHIRE is
only powered for the global primary end points. (3)
Multiple competing studies and involvement of centers that do not have experience with complex randomized clinical trial designs may introduce enrollment biases. (4) Different levels of experience and
credentialing criteria for study surgeons and interventionalist may introduce operator or center effects that
make interpretation of outcomes more difficult. (5)
There are no studies comparing the strategies of CAS
without “cerebral protection” versus CAS with EPD.
This assumes that EPDs are uniformly protective,
which may not be the case. Not all stents or EPDs are
created equal, and the fixed coupling of stent-EPD in
current industry-sponsored trials will make it difficult
to separate out the individual impact of CAS as opposed to EPD, especially if event rates turn out to be
unexpectedly high.60
Furthermore, the selection and measurement of end
points for the investigation of the true impact of EPDs
is an incompletely resolved issue. The primary end
points of most of the current studies are death or any
stroke or myocardial infarction (MI) periprocedurally
or within 30 days. However, in the final analysis,
preservation of brain function is the goal of all neurointerventional procedures, and cognitive function
encompasses much more than what is conveniently
measured by clinical neurological examination or
imaging modalities. EPDs might have a salutary impact on subtle decrements in cognitive and intellectual
function due to ischemic insults that can only be detected with detailed and laborious neuropsychometric
tests6‘-@ While ESs on TCD remain the most readily

available proxy for documenting cerebral embolic

phenomena, to date there is no direct evidence that
causally links embolic signatures to neurological
events.38364Whether the emboli is composed of air,
thrombus, or particulate matter (cholesterol or atheromatous debris) may have important implications, but
there is no foolproof and objective method of distinguishing the nature of emboli because of significant
signal overlap amongst these element^.^"^^ It is notable that in spite of consensus definitions of MES to
optimize the trade-off between sensitivity and specificity, there remain nonstandardized protocols, confounding with nonparticulate signals, and significant
variability from center-to-center.68.69

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Vol. 14, No. 4, 2001

Future Challenges
Some studies do not show consistent capture of debris in every patient, thereby raising the possibility that
some lesions (e.g., restenotic lesions due to intimal hyperplasia) may carry an inherently low risk for embolic phenomena. As more studies refining risk stratification become available, it will ultimately be possible to apply EPDs selectively to patients identified to
be at high risk for particulate e m b o l i ~ a t i o n . ~This
~~~’
will allow for further optimization of the risk-to-benefit ratio of CAS. Other strategies for the reduction of
embolic phenomena and their sequelae include refinement of operator technique, further miniaturization
and customization of interventional equipment, and
evolution of EPD designs.72s73Optimal antithrombotic
treatment should be further elucidated, as acute and
chronic thrombus have been histologically documented from captured specimens in at least half of patients in a small pilot study. Epiphenomena from embolic debris like inflammation or oxidative cellular
damage might become apparent in future investigations, presenting new therapeutic targets for adjunctive
pharmacological therapy.7437s
Persistent particulate embolization during the recovery phase of procedures have been documented for
CEA and CAS, and delayed neurological events have

been described by a number of investigator^?,^^.^^^"
This problem might be addressed by improvements in
procedural technique or application of maintenance antiplatelet or anticoagulant therapy.4,’2,7h277Embolic
events can also originate from nonstented vascular segments, arguing for the importance of general preventive measures to decrease the global atherosclerotic
burden to secure better overall long-term outcomes.

Journal of lnterventional Cardiology

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TAN, ET AL.

Summary
Emboli Protection Devices are key innovations that
hold the promise of enhancing the safety of CAS.
However, there remain important limitations with the
current generation of EPDs. Each type of EPD has specific strengths and weaknesses, and may ultimately
have niche applications for unique patient subsets.

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