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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_3660_Библиотеки_им_академика_М_И_Перельмана
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CHAPTER 2
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Historical Perspective and
Current Practice of Carotid
Artery Stenting (CAS)
Naoya Kuwayama
57
58 CAROTID TREATMENT: PRINCIPLES AND TECHNIQUES
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HISTORICAL REVIEW AND RECENT EVIDENCE
Carotid artery stenting (CAS) is an alternative treatment to carotid endarterectomy (CEA) and started with the
development of self-expanding stents and then embolic protective devices. There have been several prospective
randomized clinical trials reported comparing the results of CAS to CEA (Table 2.1). The results of these trials
varied, some were less favorable for CAS, while some others reported non-inferiority (equal effectiveness) of
CAS to CEA.
EVA-3S (1–3), SPACE (4, 5), and ICSS (6, 7) were published in 2004, 2006, and 2010, respectively, and showed
less favorable results for CAS compared to CEA. These trials showed neither superiority nor non-inferiority of
CAS to CEA. On the other hand, SAPPHIRE (8), CREST (9) and ACT I (10) were reported in 2004, 2010, and 2016,
respectively, and proved non-inferiority of CAS to CEA.
(1) Less Favorable Studies for CAS
EVA-3S (2006) was conducted at multiple centers in France to compare the results of CAS and CEA in patients
with symptomatic severe carotid stenosis and was terminated prematurely because of high stroke or death rates
in the CAS group. The 30-day incidence rate of any stroke or death was 3.6% after endarterectomy and 9.6%
TABLE 2.1
Randomized Clinical Trials of CEA and CAS
Rate of
Inclusion criteria
(% stenosis)
SAPPHIRE
(2004)
EVA-3S
(2006)
SPACE
(2006)
ICSS
(2010)
CREST
(2010)
ACT I
(2016)
Abbreviations: EPD: embolic protective device, MI: myocardial infarction.
CEA high risk
Symptomatic stenosis ≥50%
Asymptomatic stenosis
≥80%
Symptomatic stenosis ≥60%
Symptomatic stenosis ≥50%
(NASCET), ≥70% (ECST)
Symptomatic stenosis ≥50%
Symptomatic stenosis ≥50%
(DSA), ≥70% (US, CTA,
MRA)
Asymptomatic stenosis
≥60% (DSA), ≥70%(US),
≥80% (CTA, MRA)
Asymptomatic stenosis
70–99%
without contralateral
stenosis
Case number
(CEA/CAS)
334
(167/167)
527
(262/265)
1200
(595/605)
1713
(858/855)
2502
(1262/1240)
1453
(364/1089)
symptomatic
patients (%) Devices used Results
29 Angioguard XP
Precise, Smart
EPD usage rate: 96%
100 Not designated
EPD usage rate: 92%
100 Not designated
EPD usage rate: 27%
100 Not designated
EPD usage rate: 72%
53 RX Accunet
RX Acculink
EPD usage rate: 96%
0 Emboshield
Xact
EPD usage rate: 98%
30-day stroke, death,
MI: CEA-9.6%, CAS-4.8%
1-year stroke, death: CEA-20.1%,
CAS-12.2%
# CAS was not inferior to CEA
30-day stroke, death: CEA-3.9%,
CAS-9.6%
# CAS was inferior to CEA
(discontinued)
30-day stroke, death: CEA-6.3%,
CAS-6.8%
# Non-inferiority of CAS was not
proven (discontinued)
120-day stroke, MI, death:
CEA-5.2%, CAS-8.5%
# CAS was inferior to CEA
4-year stroke MI death: CEA-6.8%,
CAS-7.2%
# CAS was not inferior to CEA
1-year stroke, MI, death:
CEA-3.4%, CAS-3.8%
# CAS was not inferior to CEA
CHAPTER 2: HISTORICAL PERSPECTIVE AND CURRENT PRACTICE OF CAS 59
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after stenting. The distal embolic protective devices (DEPDs) were used in 92% of the patients. It appears that the
treating physicians’ technical level was apparently less experienced in the CAS group than the CEA group, i.e.,
the cerebrovascular surgeons had to have done at least 25 endarterectomies in the year, while the interventional
physicians to have done at least 12 stenting procedures.
SPACE (2006) was conducted at multiple centers in Germany, Austria, and Switzerland to compare the
results of either procedure in patients with symptomatic severe carotid stenosis. SPACE failed to prove noninferiority of stenting to endarterectomy; the 30-day incidence rate of death or ipsilateral ischemic stroke was
6.84% with CAS and 6.34% with CEA. The DEPDs were used in only 27% of the patients treated with CAS. There
was no clear description provided why no protective devices were used.
ICSS (2010) was conducted at multiple centers in Europe, Australia, New Zealand, and Canada to compare
the results of CEA and CAS in patients with symptomatic severe carotid stenosis. The DEPDs were used in 72%
of the patients. ISCC showed a signicantly higher ratio of stroke, death, and procedural myocardial infarction
with CAS (8.5% in CAS and 5.2% in CEA) at 120 days from randomization. The characteristic features of this
study are the enrollment period of 7 years from 2001 to 2008 and the small number of enrolled cases in one center
(4 to 5 cases per center).
All of these trials also reported the long-term results (3, 5, 7) after several years and showed no differences
of the re-stroke ratio in CAS and CEA groups.
(2) More Favorable Studies for CAS
The SAPPHIRE trial (2004) was a prospective randomizedtrialconducted in the United States of high-risk
patients and designed to test the non-inferiority of carotid stenting in terms of death, stroke, and myocardial
infarction rates when compared with CEA over a 3-year period. Both patients with symptomatic and asymptomatic severe carotid stenosis were enrolled. The cumulative incidence of stroke, death, and myocardial infarction
was 12.2% in the CAS group and 20.1% in the CEA group with p = 0.004 for non-inferiority and p = 0.053 for supe-
riority. The primary endpoints included myocardial infarction and cranial nerve injury, which may be disadvantageous features of CEA. Note that the results of this study only reected the treatment results in CEA “high
risk” category patients, in other words, patients with such comorbidities as severe cardiopulmonary diseases,
contralateral carotid occlusion, contralateral laryngeal nerve palsy, previous radical neck surgeries or radiation,
recurrent stenosis after CEA, age >80 years, etc.
Noteworthy in SAPPHIRE is the use of Angioguard® (Cordis), DEPD protective lter, which is an older
type of DEPD. Like many cooperative trials, devices, and techniques change with time, and results should be
interpreted with circumspection as newer and potentially more effective strategies become available.
CREST (2010) was conducted in the United States and Canada to compare the results of CAS and CEA for
patients with both symptomatic and asymptomatic carotid stenosis, in any risk category. The primary endpoint
(any peri-procedural stroke, myocardial infarction, or death or post-procedural ipsilateral stroke) in the periprocedural period was 5.2% in the CAS group and 4.5% in the CEA group (p = 0.38). Four-year rate was 7.2%
in CAS and 6.8% in the CEA group (p = 0.51). The CREST investigators concluded that this study proved noninferiority of CAS, but subgroup analysis showed a higher rate of cerebral infarction in CAS group (4.1% vs.
2.3%, p = 0.01) and conversely a higher rate of myocardial infarction in the CEA group (1.1% vs. 2.3%, p = 0.03).
Particularly the rate of minor ipsilateral stroke was higher in the CAS group (2.9%) than in CEA group (1.4%),
while there were no signicant differences in the rate of major ipsilateral stroke in two groups. A crossover at
an age of approximately 70 years was detected; CAS tended to show greater efcacy at younger ages, and CEA
at olderages.
ACT I (2016) is a randomized clinical trial to compare CAS and CEA in patients 79 years of age or younger
who had asymptomatic severe carotid stenosis and were not considered to be at high risk for surgical complications. The DEPD (EmboshieldTM, Abbott) was used in 98% of the patients. ACT 1 showed that CAS was
non-inferior to CEA with the primary composite endpoint (event rate: 3.8% and 3.4%, respectively; p = 0.01 for
non-inferiority). The cumulative 5-year rate of stroke-free survival was 93.1% in CAS and 94.7% in the CEA
group (p = 0.44). ACT 1 demonstrated equal efcacy of both carotid revascularization methods (CEA and CAS)
for asymptomatic carotid stenosis. However, we recognize that the stroke incidence in patients with asymptomatic stenosis is not high in nature and the results of the best medical treatment (BMT) have recent been
rapidly improving as compared with the era of ACAS (Asymptomatic Carotid Atherosclerosis Study, 1995).
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TABLE 2.2
Meta-Analysis of EVA-3S, SPACE, and ICSS
CEA
(n = 1645) (%)
30-day stroke rate 4.3 7.4 0.0001
Fatal 0.4 0.7 0.16
Disabling 2.1 2.8 0.18
Non-disabling 1.9 3.9 0.0004
CAS
(n = 1679) (%) p value
TABLE 2.3
Meta-Analysis of EVA-3S, SPACE, ICSS, and CREST
CEA
(n = 2361) (%)
Primary endpoint 7.8 11.0 1.45
120-day stroke and death 5.5 8.7 1.61
Annual stroke rate after 120 days 0.60%
CAS
(n = 2393) (%)
0.64 1.06
Hazard ratio
(CAS vs. CEA)
Further three-arm trials are ongoing to compare the results of CAS and CEA with the BMT for the
asymptomatic patients.
(3) Meta-Analysis
Meta-analysis of data from EVA-3S, SPACE and ICSS (11) (Table 2.2) showed that non-disabling stroke hap-
pened more often with CAS than in the CEA group (4.2% vs. 2.1%, respectively; p = 0.0004). The patients’ age
was shown to be an important affecting factor to the treatment results. The stroke event rate was similar in both
groups (5.8% in CAS an 5.7% in CEA) in patients younger than 70 years, while the stroke rate of CAS was signicantly higher than that of CEA group (12.0% vs. 5.9%, respectively) in patients 70 years or older.
Meta-analysis of EVA-3S, SPACE, ICSS, and CREST (12) (Table 2.3) proved the superiority of CEA in peri-
and post-procedural periods, but after the peri-procedural period (120 days), the annual rates of ipsilateral stroke
were similar for the two treatments, suggesting that improvements in the peri-procedural safety of CAS could
provide similar outcomes of the two treatments in the future.
(4) Comparative Study with Medical Treatments
SPACE-2 (13) (Table 2.4) was a randomized three-arm clinical trial that compared CAS, CEA, and the best medi-
cal treatment (BMT) in patients with asymptomatic carotid stenosis. SPACE 2 was abandoned after enrolling
513 patients in 5 years because of slow recruitment rates. The 30-day rate of death/stroke was 1.97% for patients
undergoing CEA, and 2.54% for patients undergoing CAS. Of interest, no strokes or deaths occurred in the rst
30 days after randomization in patients treated with BMT.
TABLE 2.4
SPACE-2
CEA CAS BMT p value
30-day stroke 1.9% 2.54% 0%
30-day stroke, death one year
ipsilateral stroke
One-year any stroke 3.9% 4.1% 0.9% 0.256
One-year any death 2.5% 1.0% 3.0% 0.304
Abbreviations:
BMT: best medical treatment.
3.9% 4.1% 0.9% 0.256
CHAPTER 2: HISTORICAL PERSPECTIVE AND CURRENT PRACTICE OF CAS 61
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TECHNIQUES FOR CAROTID ARTERY STENTING
Techniques to Address Peri-Procedural Risk Management in CAS
Risk management is very important to reduce complications of carotid revascularization. Specically for CAS,
thromboembolic risk, anatomical risk, cardiac risk, plaque risk, and cerebral blood ow (CBF) risk should be
evaluated before treatment.
(1) Antiplatelet Therapy (Thromboembolic Risk)
Dual antiplatelet therapy (DAPT) is a standard treatment to reduce thromboembolic complications during and
after CAS. Usually, trans-oral aspirin (80–325 mg) and clopidogrel (75 mg) are given 1–2 weeks before treatment.
Ideally platelet aggregation function should be monitored before treatment to know the effectiveness of the
antiplatelet agents. VerifyNow (Fig. 2-1) is an easy and rapid monitoring device to check the inhibition rate of
platelet aggregation. Optimal range of P2Y12 response units (PRU) should be ≥80 and ≤230 for clopidogrel (if it’s
less than 80, hemorrhagic complication will more frequently happen andif it’s more than 230, thromboembolic complication
will more frequently happen), and that of aspirin response units (ARU) should be less than 550 for aspirin.
Clopidogrel is a pro-drug that must undergo hepatic biotransformation to convert the active metabolite that
inhibits platelet aggregation. Therefore, the antiplatelet effect of clopidogrel is affected by CYP2C19 phenotypes (14).
Twenty to thirty percent of people are said to be the poor responders to clopidogrel (PRU >230). Dosage increases
(150–300 mg) or a change to other antiplatelet agents such as prasugrel or ticagrelor would be an alternative way to
manage poor responders to clopidogrel. Of course, for an international readership, indications, and availability of
these new antiplatelet agents will depend on the drug regulatory processes and drug availability in each country.
In addition, some subset of the population (10%–20%) can be characterized as patients with a hyper-response
to clopidogrel (PRU <80), and these patients may be at increased risk of bleeding (15). Therefore, also for these
hyper-responders, optimal antiplatelet effect should be maintained by evidence-based dose adjustment of clopidogrel (16) to reduce the hemorrhagic complications.
For patients who need urgent CAS, a loading dose of 300–600 mg of clopidogrel is recommended (17) to
obtain the optimal level of PRU prior to treatment.
After CAS, DAPT should be converted to single antiplatelet therapy 3–6 months later to reduce the hemorrhagic complications caused by long-term and excessive antiplatelet therapy (18).
FIGURE 2-1
VerifyNow®.
62 CAROTID TREATMENT: PRINCIPLES AND TECHNIQUES
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FIGURE 2-2
Abdominal (left, arrow) and thoracic (right, arrow) aortic aneurysm.
(2) 3D-CTA for Evaluation of Access Routes (Anatomical Risk)
The use of pre-procedure 3D-CTA facilitates an evaluation of the access routes from the femoral arteries,
abdominal/thoracic aorta, aortic arch, and common carotid arteries.
Abdominal aortic aneurysms (Fig. 2-2) are not high risk for CAS because the guiding catheters can pass
through the aneurysm safely if the operators recognize it, while aneurysms at the aortic arch, particularly dissecting aneurysms (Fig. 2-2) do confer increased risk because the guiding catheters could injure the vessel wall
and may cause aneurysmal rupture. In these cases, a transbrachial approach or direct carotid puncture would be
an alternative strategy for risk amelioration..
The presence of multiple atheromatous plaques in the aortic wall, a “shaggy aorta” (Fig. 2-3), has the propensity to cause cholesterol crystal embolization by rupture of plaques caused by passage of catheters and guide
wires, which can result in necrosis of the abdominal organs and toes (blue toe syndrome, Fig. 2-3) in the terminal
vessels. In case with the shaggy aorta, again, a transbrachial approach would be a safer access route.
3D-CTA also enables treating physicians to recognize the type (type 1, 2, or 3) of aortic arch before treatment and to predict the difculty of the catheterization of the common carotid arteries (Fig. 2-4). In a type-3
aortic arch, Simmons type inner catheters will be recommended to send a guiding catheter to the carotid artery.
3D-CTA also provides variant images of major aortic arch branches such as a bovine arch and aberrant subclavian arteries (Fig. 2-5). In the latter case, approach to the carotid artery would be extremely difcult if operators
did not recognize it before catheterization.
(3) Assessment of Cardiac Function (Cardiac Risk)
Cardiac function should be assessed before the treatment to rule out cardiac failure, ischemic coronary diseases,
and valvular diseases. Balloon dilatation of the carotid artery frequently induces bradycardia and hypotension,
which will aggravate the pre-existing cardiac failure and coronary ischemia. If the patient has severe aortic valve
stenosis, carotid artery dilatation would cause irreversible cardiac arrest which would not respond to any cardiac
resuscitation. Therefore, severe aortic valve stenosis should be recognized as the contraindication of CAS.
CHAPTER 2: HISTORICAL PERSPECTIVE AND CURRENT PRACTICE OF CAS 63
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FIGURE 2-3
Shaggy aorta (left) and blue toe syndrome (right, arrow indicates a necrotic toe).
FIGURE 2-4
3D-CTA demonstrating a type-3 aortic arch, suggesting the difculty of approach to the carotid arteries.
64 CAROTID TREATMENT: PRINCIPLES AND TECHNIQUES
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FIGURE 2-5
Bovine arch (left) and aberrant subclavian artery (middle: AP view, right: left oblique view).
In patients with carotid stenosis associated with coronary artery disease, the timing and order of treatments
of these co-existing diseases are controversial. It should be planned in case by case according to the severity of
the cardiac condition.
(4) Plaque Images (Plaque Risk)
The standard method to evaluate the carotid plaque is ultrasound. Unstable plaque is usually expressed as a
hypoechoic lesion in the carotid echogram. Recently the plaque tissue composition can be evaluated more accurately with MRI (19, 20). Evaluation using a large variety of MRI sequences is very precise, but sometimes complicated in the clinical settings. In our practice at Toyama, we simplify the ndings and apply the next formulas;
a stable (brous) plaque is expressed as T1-iso and TOF-iso signal intensity, a lipid-rich plaque as T1-high and
TOF-iso signal intensity, and a hemorrhagic plaque as T1-high and TOF-high signal intensity (Fig. 2-6). Plaque
composition and volume are the most signicant factors affecting thromboembolic complications of CAS. A large
vulnerable plaque treated with CAS is at increased risk of embolization to the distal intra-cranial vessels (21, 22).
Severely calcied plaque is also a risk of CAS. In particular, circumferential calcication all around the vessel wall and/or a large concentric calcication are both rare but very resistant lesions for balloon dilatation, and in
such cases the stent will not be expanded in the calcied stenotic part, resulting in catheter entrapment (Fig. 2-7).
(5) Evaluation of Cerebral Blood Flow (CBF) Risk
Pre-operative cerebral hemodynamic compromise or dysautoregulation is one of the important factors to predict post-operative cerebral hyperperfusion syndrome (CHS) (23). The incidence of intra-cranial hemorrhage
from CHS is very low (less than 1%), but once it occurs, the result is catastrophic. Retrospective analysis of 4494
patients treated with CAS or CEA reported that the characteristic features of CHS after CAS differed from those
after CEA (24); when treated with CAS, post-operative hemorrhagic complications caused by CHS included not
FIGURE 2-6
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MRI plaque images, our criteria for plaque diagnosis.
CHAPTER 2: HISTORICAL PERSPECTIVE AND CURRENT PRACTICE OF CAS 65
only intraparenchymal hematomas, but also subarachnoid hemorrhage. It is also reported that CHS characteristically occurred within 12 hours after CAS (unlike after CEA), and that blood pressure control (standard treatment in CEA cases) did not protect against intra-cranial hemorrhages in the CAS group. Staged angioplasty,
thus, has been developed and introduced for the patients with increased risk of CHS. The details of this are
described later.
FIGURE 2-7
A large concentric calcication causing catheter entrapment.
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