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400 Part IV / Practical Issues and Future Applications
the 30-d period, the incidence of fatal and nonfatal stroke was 3.2%. The 3-yr freedom
from ipsilateral or fatal stroke was 92%. Of note, their minor stroke rate decreased signif-
icantly after their first year of carotid interventions. This large series suggests that carotid
stenting is not only safe but also durable.
The only randomized study to date, the Carotid and Vertebral Artery Transluminal Angio-
plasty Study (CAVATAS), compared carotid angioplasty vs carotid endarterectomy in
504 symptomatic patients (12). This trial demonstrated a similar death or stroke rate at
30 d (10% in the angioplasty group vs 10% in the surgery group). The periprocedural dis-
abling stroke and nondisabling stroke rates were similar between the two groups. More-
over, there was no substantial difference in the rate of ipsilateral stroke at 3 yr between
the two groups [odds ratio (OR) 1.04, 95% confidence interval (CI) 0.63–1.70, p = 0.9].
Local complications were lower for the PTA group than the surgery group. This trial has
been criticized by both carotid interventionalists and surgeons. In this study, only 25%
had stent use and there was no emboli protection used. These devices were not widely
accepted or used during the enrollment time of CAVATAS. Also, the surgical stroke and
death rates were higher than those reported by the NASCET investigators. The stroke and
death rate was 5.8% in that trial compared with 9.9% in CAVATAS (12,13). CAVATAS
II will enroll patients to carotid stent vs endarterectomy using stents and emboli protec-
tion device. As of now, the current indication for carotid stenting is reserved for high-risk
carotid endarterectomy patients. From all these studies, carotid stenting appears safe and
feasible. The next 2 yr will bring much data from many randomized trials currently enroll-
ing patients.
ADJUNCTIVE THERAPY: ASPIRIN AND THIENOPYRIDINES
The role of aspirin and thienopyridines for percutaneous carotid intervention has not
been well studied. Aspirin monotherapy has not been tested in percutaneous carotid inter-
vention. Ticlopidine with aspirin has been tested as adjuvant therapy for carotid angio-
plasty and stenting in patients with contralateral occlusion or post-carotid endarterectomy
restenosis. These types of patients typically have higher complication rates after procedure.
In 31 patients who underwent elective carotid stenting in the presence of contralateral
occlusion, there were no neurologic events during a mean follow-up of 16 mo. Because of
serious hematologic side effects with ticlopidine, clopidogrel has become the preferred
thienopyridine. To date, there has been only one study comparing ticlopidine with clopid-
ogrel in carotid stenting. Bhatt et al. published a single center experience of 162 patients
undergoing carotid stenting. The cumulative rate of 30-d death, stroke, TIA, or myocar-
dial infarction (MI) was 13% in the ticlopidine group compared with 4.3% in the clopid-
ogrel group (p = 0.001) and 5.6% in the overall cohort (13a).
ADJUNCTIVE THERAPY: GPIIb/IIIa INHIBITORS
The role of glycoprotein (GP) IIb/IIIa inhibitors has been established in coronary inter-
ventions. These agents decrease periprocedural ischemic complications in patients under-
going both emergent and elective coronary interventions. However, there have been few
studies using these agents in carotid interventions. In a small study, 22 patients under-
going carotid intervention involving visible thrombus, total occlusion, or acute stroke
were given abciximab (14). The preliminary data from these high-risk patients suggested
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Chapter 19 / Cerebrovascular Interventions 401
higher bleeding complications, with two patients having central nervous system bleeding,
one patient with hemorrhagic transformation of a previously ischemic stroke, and one patient
having subarachnoid hemorrhage from a ruptured aneurysm. Another small study reported
outcomes of 13 internal carotid, 4 vertebral, and two basilar artery angioplasty and stent-
ing procedure using abciximab (15). Two patients experienced transient ischemic attacks
during and immediately after the procedure. Major or minor bleeding was not experienced
in any patient. Schneiderman et al. (16) published a 16-patient study using abciximab in
patients undergoing carotid stenting for recurrent internal carotid artery stenosis. They
found no neurologic ischemic events during and following the procedure and no greater
increase in bleeding rates.
In a much larger study, Kapadia et al. (17) have studied the safety and efficacy of
abciximab in 151 consecutive patients at high surgical risk undergoing carotid stenting.
In this study 128 high surgical risk patients received adjuvant therapy with abciximab
(0.25 mg/kg bolus before the lesion was crossed with guidewire and 0.125 µg/kg/min
infusion for 12 h) with 50 U/kg of heparin at the time of carotid stenting; 23 patients were
used as controls. An activated clotting time was maintained between 250 and 300 s. All
patients received aspirin and thienopyridine. The primary endpoints of stroke (major or
minor), intracranial hemorrhage, and neurologic death within 30 d were more frequent in
the control group (8% vs 1.6%, p = 0.05) (Table 2). At 30-d follow-up, one patient presented
with delayed intracranial hemorrhage in the abciximab group. This study demonstrated
that abciximab appears to be safe, with no increase in the risk of intracranial hemorrhage
and a lowering of the ischemic stroke risk.
GPIIb/IIIa inhibitors may play a role in stroke patients. In an experimental stroke model,
studies have shown that marked sparing of brain infarction and relief of microvascular
obstruction using a platelet GPIIb/IIIa inhibitor (17a,17b). Initial experience with GPIIb/
IIIa inhibitors in acute stroke management appeared to be safe and showed a trend toward
improved outcome in stroke patients treated up to 24 h after symptom onset in a joint US
European clinical trial (17c). This study randomized 74 patients in a 1:3 ratio to placebo
or to one of four doses of abciximab bolus: (1) 0.15 mg/kg or 0.20 mg/kg (2) 0.20 mg/kg
or 0.25 mg/kg followed by 0.125 µg/kg/min infusion for 12 h. The primary safety end-
point was the presence or absence of major intracerebral hemorrhage on d 5 accompanied
by neurologic worsening. No patient had intracranial hemorrhage associated with neuro-
logic worsening. The 3-mo follow-up showed that 10 of 54 abciximab patients had asymp-
tomatic hemorrhagic transformation compared with 1 of 20 placebo patients. Abciximab-
treated patients showed a trend toward improved outcome. Global recovery was measured
by Rankin score, which showed that 35% of abciximab patients had minimal or no deficit
at 3 mo compared with 20% of placebo patients. On the Barthel index of daily activities,
50% of abciximab patients had a score of 95 or higher compared with 40% of placebo
patients. Also, stroke progression occurred in 11% of abciximab patients and 15% of the
placebo group, and the stroke recurrence occurred in 2% of the abciximab patient com-
pared with 5% of the placebo group. A large clinical trial is needed to assess the role of
abciximab further in stroke.
In coronary interventions, periprocedural ischemic complications are easier to quantify,
whereas in carotid interventions small embolic phenomenon may be more difficult to detect.
Embolization detection with transcranial Doppler (TCD) during carotid intervention may
better assess the effectiveness of GPIIb/IIIa inhibitors. However, to date, no study has been
done using TCD and GPIIb/IIIa inhibitors. Although it may be safe to use GPIIb/IIIa
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402 Part IV / Practical Issues and Future Applications
inhibitors in carotid interventions, its role may be less important now that mechanical
strategies for emboli protection have emerged.
EMBOLI PROTECTION DEVICES
A major cause of neurologic complications during carotid endarterectomy and percu-
taneous carotid intervention is microembolization of plaque debris. This leads to release
of platelet and thrombin aggregates into the cerebral circulation. TCD monitoring, a non-
invasive method to detect microemboli, has demonstrated frequent embolization with
both endarterectomy and stenting (18–20). There appears to be some correlation between
the number of emboli and neurologic outcome. Currently, there are several mechanical
devices for emboli protection under investigation. The first approach is the use of distal
occlusion balloon to occlude the outflow temporarily from the distal internal carotid
artery. The PercuSurge Guard Wire has a low crossing profile and flexibility and provides
occlusion of the distal internal carotid artery (Fig. 1). However, because of the complete
occlusion of flow, patients are exposed to a prolonged ischemic time. Although this is well
tolerated by many, it may be risky in patients with contralateral occlusions or an incom-
plete circle of Willis. Also, the inability to perform angiograms is problematic. Finally,
there is a potential for particles to embolize via the patent external carotid artery.
The second method is the filter wire device placed distal to the lesion (AngioGuard or
AccuNet) (Fig. 2). The advantages of this system are preservation of flow, ability to per-
form angiograms during the procedure, and ease of use of the device. However, these filter
wire devices may allow larger particles to pass through than the balloon occlusion devices.
The third type of embolism protection devices occludes the inflow to the brain by using
a proximal occlusion balloon in the common carotid artery (ArteriA PAEC). Unlike the
other two, the proximal occlusion system protects the brain prior to manipulating the
lesion, captures particle of all sizes, can use the guidewire of choice, and allows the oper-
ators to treat tight and tortuous lesions. However, like PercuSurge, they do occlude flow
and require larger puncture sites in the groin. Also, like all the devices, they may cause
spasm and dissection of the artery.
To date there have been several reports of carotid interventions using these emboli pro-
tection devices. Henry et al. (21) have reported 58 carotid stent procedures using a distal
occlusion balloon protection device and compared the results with 212 other patients treated
without emboli protection device. In this study, there were two major strokes with the
Table 2
Procedural Event Rates Using Abciximab
Control Abciximab
Event (%) (n = 23) (n = 128)
Major stroke 4 0
Minor stroke 0 1
Retinal infarct 0 1
Intracerebral hemorrhage 0 0
Death 1 0
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Chapter 19 / Cerebrovascular Interventions 403
Fig. 1. PercuSurge, a balloon occlusion emboli protection device.
Fig. 2. Angioguard, a filter wire emboli protection device.
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404 Part IV / Practical Issues and Future Applications
cerebral protection balloon catheter and one major stroke, one minor stroke, and three TIAs
without its use.
Tubler et al. (22) reported a multicenter, Phase I trial of 54 patients undergoing carotid
stenting using the PercuSurge Guard Wire system. They reported one prolonged revers-
ible ischemic deficit that resolved in less than 48 h, one stroke, and one TIA. They found
particles with areas >10,000 µm
2
in 83% of the patients (Fig. 3).
Al-Mubarak et al. (23) have reported the effect of a distal balloon protection system
on microembolization during carotid stenting. They used TCD studies to demonstrate
microembolization. They found that microembolization was significantly decreased by
the use of a distal balloon protection device (164 ± 108 vs 68 ± 83, p = 0002) in patients
undergoing percutaneous carotid intervention. Also, Reimer et al. (24) have reported on
their feasibility and safety study using three types of filter wire emboli protection devices.
They reported 96.5% procedural success rate in placing the filter device. They were unable
to place the filter in 3.5% of the cases owing to the inability of the filter to cross the lesion.
In 6.9% of the patients, they predilated with 2.0-mm balloons prior to placing the filter
device. They reported a 3.6% rate of vessel spasm requiring nitroglycerin and no case
of dissection. However, in 7.2% of patients, the filter did cause flow impairment owing
to heavy emboli burden. They retrieved macroscopic evidence of emboli in 53% of these
patients. At 30 d, they found one case of minor stroke and two cases of MI.
The largest study to date is the Carotid Artery Intervention Free of Emboli (CAFÉ-
USA), which used a distal balloon protection device in 212 patients undergoing carotid
stenting. The device was successfully deployed in 98.1% of patients, and 92.3% patients
Fig. 3. (A) Aspirated particles from a patient who underwent carotid stenting with the PercuSurge
emboli protection device.
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Chapter 19 / Cerebrovascular Interventions 405
were able to tolerate the complete occlusion. There were 3 deaths, 2 of which were neuro-
logic deaths from hemorrhagic stroke, 12 ipsilateral strokes, 5 TIAs, and no major strokes.
In both hemorrhagic stroke cases, GPIIb/IIIa inhibitors were used. These initial trials
point to the safety and feasibility of using these devices in high-risk patients undergoing
carotid stenting.
There are two important trials currently under way comparing carotid artery stenting
with endarterectomy using emboli protection devices. The Stenting and Angioplasty with
Protection in Patients at High Risk for Endarterectomy (SAPPHIRE) trial will randomize
patients at high surgical risk to carotid endarterectomy or carotid artery stenting using
the Cordis nitinol carotid stent and Cordis Angioguard, a filter-type emboli protection
Fig. 3. (B,C) Microscopic view of a particle retrieved from a PercuSurge emboli protection device.
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406 Part IV / Practical Issues and Future Applications
device. The high-risk patient population is defined as patients with severe cardiac comor-
bidities (severe congestive heart failure, valvular heart disease, or unstable angina), pre-
vious neck radiation or neck dissection, and restenosis after endarterectomy or presence
of contralateral occlusion. Both de novo and restenotic lesions will be treated in sympto-
matic (>70% stenosis) or asymptomatic (>80% stenosis) patients. A total of 720 patients
at 24 sites will be enrolled, and parallel registries for both percutaneous intervention and
surgery will be maintained for randomized patients. The primary endpoint is a 30-d com-
posite of any stroke, death, or MI. The secondary endpoint is the 1-yr ipsilateral stroke and
death rate. The Carotid Revascularization Endarterectomy versus Stent Trial (CREST)
will randomize patients who are at low surgical risk to stenting or surgery. The primary
endpoints for this trial are any stroke, MI, or death within 30 d and ipsilateral stroke after
30 d. This trial is planning to recruit 2500 patients and will use Guidant AccuLink and
Guidant AccuNet, another filter-type emboli protection device.
CONCLUSIONS
Much has been learned about antiplatelet therapy in coronary intervention in the last
two decades. Although the role of aspirin and thienopyridine has been solidified in per-
cutaneous carotid interventions, the role of GPIIb/IIIa inhibitors is uncertain with the
advent of emboli protection devices. Promising preliminary studies have been performed
in acute stroke patients using GPIIb/IIIa inhibitors. Further large, randomized studies are
warranted.
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408 Part IV / Practical Issues and Future Applications
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Chapter 20 / Cerebrovascular Aspects of GPIIb/IIIa Receptor Inhibitors 409
409
From: Contemporary Cardiology: Platelet Glycoprotein IIb/IIIa
Inhibitors in Cardiovascular Disease, 2nd Edition
Edited by: A. M. Lincoff © Humana Press Inc., Totowa, NJ
20 Cerebrovascular Aspects
of Glycoprotein IIb/IIIa
Receptor Inhibitors
CONTENTS
INTRODUCTION
TREATMENTS FOR CARDIAC DISEASE
TREATMENTS FOR CEREBROVASCULAR DISEASE
CONCLUSIONS
REFERENCES
Cathy A. Sila, MD
INTRODUCTION
Ischemic and hemorrhagic subtypes of stroke are important complications of treatments
for cardiac disease, as they impact significantly on patient management and outcome.
Their frequency varies with the characteristics of the patient population under study, the
procedures involved, and the combination and intensity of antiplatelet, antithrombotic,
and fibrinolytic strategies employed. Understanding the mechanisms contributing to the
various stroke subtypes is important, not only to improve the overall outcome for patients
with cardiac disease, but also to translate similar strategies to patients with cerebrovascu-
lar disease, for whom the risk-to-benefit ratio is more acute.
TREATMENTS FOR CARDIAC DISEASE
Ischemic Stroke Complicating Coronary Artery Disease and Treatment
In the prethrombolytic era, stroke occurred in 0.8–5.5% of patients with acute myocar-
dial infarction (AMI) and was largely ischemic in nature (1). Features typical of cerebral
embolism include predominantly middle cerebral artery territory involvement, the rela-
tionship to cardiac rhythm and ventricular function, and declining risk over time. With
the introduction of thrombolysis for AMI, the risk of ischemic stroke declined to 0.1–1.3%
within the first month, with one-third occurring within the first day, one-third within the
first week, and the remaining one-third clustered within the second week (1,2). Risk factors
for stroke include advanced age, higher heart rate, history of prior stroke, diabetes mellitus,
previous angina, hypertension, worse Kilip class, coronary angiography, bypass surgery,
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