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Clinical Program for
Cerebrovascular Disorders
Mount Sinai Medical Center
Stroke Associated with Intracranial Vascular
Disease and A Discussion of WASID
(The Warfarin-Aspirin Symptomatic Intracranial Disease Trial)
Clinical Case Presentation
Clara Raquel Epstein, MD Fellow
Stroke Associated with Intracranial Vascular
Disease - Pathogenesis
• Occlusion
– Atheromatous/Thrombotic
• Large Vessel Occlusion or Stenosis (ie. Carotid A.)
• Branch Vessel Occlusion or Stenosis (ie. Middle Cerebral
A.)
• Perforating Vessel Occlusions (ie. Lacunar infarction)
– Non-atheromatous Diseases of the Vessel Wall
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Collagen Disease (ie. Rheumatoid arthritis, SLE)
Vasculitis (ie. Polyarteritis Nodosa, Temporal Arteritis)
Granulomatous Vasculitis (ie. Wegener’s granulomatosis
Miscellaneous (ie. Syphilitic vasculitis, fibromuscular
dysplasi, sarcoidosis, trauma)
Stroke Associated with Intracranial Vascular
Disease - Pathogenesis
• Embolization
– Atheromatous plaque in the intracranial or
extracranial or extracranial arteries or from the
aortic arch.
– The heart
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valvular heart disease
arrhythmias
ischemic heart disease
bacterial endocarditis
atrial myxoma
prosthetic valves
patent foramen ovale
– Miscellaneous- fat, air, or tumor emboli
Stroke Associated with Intracranial Vascular
Disease - Vasculitis and Collagen Vascular Diseases
• Collagen Vascular Diseases
– Systemic lupus erythematosus
– Rheumatoid arthritis
• Vasculitis
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Associated with connective tissue disease
Polyarteritis nodosa (PAN)
Takayasu’s arteritis
Isolated angiitis of the central nervous system
Giant cell arteritis/Temporal arteritis
Churg-Strauss angiitis
• Granulomatous vasculitis (ie. Wegener’s
Stroke Associated with Intracranial Vascular
Disease - Pathogenesis
• Coagulopathies
• Venous Thrombosis (ie. Infection and
dehydration)
• Decreased Cerebral Perfusion (ie. Cardiac
dysrythmia, GI blood loss)
• Hemorrhage
Stroke Associated with Intracranial Vascular Disease
Clinical Case Presentation
• A 68 year old right handed Haitian male with a
history of hypertension presented to the Mount
Sinai Medical Center Emergency Department
with complaints of left sided weakness (leg
greater than arm) which had been present on
awakening four days prior to admission. Per
history the patient was previously taking
Vasotec for 15 years but had self discontinued
his medications approximately one year prior to
admission.
Stroke Associated with Intracranial Vascular Disease
Clinical Case Presentation
Hospital Course
On initial examination the patient was found to have a left
facial droop, a mild left upper extremity pronator drift,
decreased rapid arm movement on the left and
proximal left lower extremity weakness of 4/5. Pinprick and proprioceptive sensory deficits were evident
in a stocking glove distribution. The patient
demonstrated a left hemiparetic gait.
Stroke Associated with Intracranial Vascular Disease
Clinical Case Presentation
Hospital Course
The patient was admitted to the Stroke Unit for further
diagnostic evaluation and intervention. A non-contrast
head CT was obtained on admission which revealed
hypodensities in the left internal capsule and in the
right Globus Pallidus compatible with ischemia. It was
suggested that this could represent lacunar strokes.
He was initially started on aspirin, lisinopril, simvistatin
and glyburide. On hospital day #3 the patient was then
started on heparin per protocol and the aspirin was
discontinued. Coumadin was then started on hospital
day #7.
Stroke Associated with Intracranial Vascular Disease
Clinical Case Presentation
Hospital Course
Further evaluation included MRI and MRA with
diffusion and cerebral angiography. The MRI/A
revealed increased signal on flair and diffusion in the
right basis pontis indicating acute infarction. This area
corresponds to the right posterior cerebral artery
narrowing which was visualized on the MRA. There
also appeared to be narrowing of the distal vertebral
artery at its junction with the basilar artery. In
addition, some stenosis of the basilar artery appeared
to be present.
Stroke Associated with Intracranial Vascular Disease
Clinical Case Presentation
Hospital Course
The cerebral angiography showed evidence of atherosclerotic
narrowing of the distal left vertebral intradural segment. The
luminal caliber is less than what would be expected for normal
anatomic tapering. The degree of stenosis is approximately 60%
as compared with the normal intradural vertebral artery
proximally. Mild atherosclerotic narrowing of the distal right
vertebral artery intradural portion. The degree of stenosis is mild
and approximately 40% as compared with the vessel proximally.
A small focal smooth atherosclerotic plaque within the midbasilar
artery at the right lateral wall producing no significant narrowing
of the vessel lumen was also seen. Mild atherosclerotic change
within the bilateral posterior cerebral arteries without significant
focal stenosis was seen. Minimal atherosclerotic change of the right
internal carotid artery origin was also seen.
Adam Davis, MD
Interventional Neuroradiology
CT Head 12/29/99
CT Head 12/29/99
MRI Sagittal T1 12/30/99
MRI Axial Flair 12/30/99
MRI Axial Flair 12/30/99
MRI Axial T2 12/30/99
MRI Axial T2 12/30/99
MRI Diffusion 12/30/99
MRA Posterior Circulation
12/30/99
MRA Right PCA 12/30/99
MRA Posterior Circulation
12/30/99
A Discussion of WASID
(The Warfarin-Aspirin Symptomatic Intracranial Disease Trial)
A Discussion of WASID
(The Warfarin-Aspirin Symptomatic Intracranial Disease Trial
Funding Source: National Institute of
Neurological Disorders and Stroke
Coordinating Center: Emory University
Principal Investigator:
Marc I. Chimowitz, MBChB
Associate Professor of Neurology
Emory University Hospital
A Discussion of WASID
(The Warfarin-Aspirin Symptomatic Intracranial Disease Trial
• The major goal of this 5 year multi-center trial is to determine optimal
antithrombotic for symptomatic atherosclerotic intracranial arterial
stenosis. Atherosclerotic stenosis of the major intracranial arteries
(carotid siphon, middle cerebral artery, vertebral artery, basilar artery)
is an important cause of ischemic stroke, especially in Blacks, Asians,
and Hispanics. In the USA, intracranial stenosis causes approximately
40,000 ischemic strokes annually ie. 10% of ischemic strokes.
Moreover, the risk of recurrent strokes in these patients 4%-15% per
year.
A Discussion of WASID
(The Warfarin-Aspirin Symptomatic Intracranial Disease Trial
• Despite the importance of intracranial stenosis as a cause of ischemic
stroke, the treatment of this disease remains empirical. Antiplatelet
agents (aspirin or ticlopidine) are frequently used in this setting based
on studies that have shown a benefit of these agents for lowering the
risk of stroke in patients with non-cardioembolic TIA or minor stroke.
However, the efficacy of antiplatelet agents has not been established in
patients with symptomatic intracranial large artery disease. In fact, the
high rate of stroke in patients with carotid siphon or middle cerebral
artery stenosis who were treated with aspirin in the medical arm of the
Extracranial-Intracranial (EC_IC) Bypass Study (approximately 10%
per patient year) raises a question about the efficacy of aspirin in this
setting.
A Discussion of WASID
(The Warfarin-Aspirin Symptomatic Intracranial Disease Trial
• Warfarin is also frequently used for the treatment of symptomatic
intracranial large artery disease based on retrospective data that
suggests warfarin may lower the risk of stroke in patients with carotid
or vertebro-basilar TIAs. In a retrospective, nonrandomized, multicenter pilot study performed by our study group, warfarin was
compared with aspirin for prevention of major ischemic vascular
events (stroke, myocardial infarction (MI) or vascular death) in 151
patients with TIA or stroke attributed to stenosis (50-99%) of a major
intracranial artery.
A Discussion of WASID
(The Warfarin-Aspirin Symptomatic Intracranial Disease Trial
•
Overall, the relative risk of a major ischemic event in patients treated with
warfarin was 0.45 compared with patients treated with aspirin. A Kaplan
Meier analysis that included hemorrhagic deaths as a primary end point (ie. In
addition to ischemic stroke, MI or sudden death) showed that a significantly
higher proportion of patients treated with warfarin survived free of these end
points compared with patiens treated with aspirin. Patients with moderate
intracranial stenosis (50%-69%) had a lower risk of stroke in the same
vascular territory than patients with severe intracranial stenosis (70-99%). Of
62 patients with 50-69% intracranial , five patients (8%) had a stroke in the
same territory as the stenotic artery during a median followup of 20 months (4
of 28 (14%) on aspirin, 1 of 34 (3%) on warfarin). In comparison, of 89
patients with 70-99% intracraninal stenosis, nine patients (10%) had a stroke
in the same territory as the stenotic artery during a median followup of 14
months (5 of 35 (14%) on aspirin, 4 of 54(7%) on warfarin).
A Discussion of WASID
(The Warfarin-Aspirin Symptomatic Intracranial Disease Trial
•
Transluminal angioplasty is another therapeutic option for the treatment of
intracranial stenosis. Early experience suggested that intracranial angioplasty
was associated with an unacceptably high risk of stroke or death and the
procedure was largely abandoned. However, recent advances in microcatheter
and balloon technology have led to renewed interest in intracranial angioplasy.
Several recent studies of small series of patients have shown that intracranial
angioplasy is technically feasible and may be performed relatively safely. In
these studies, the risk of stroke during angioplasy was 0%-11.7% and the risk
of stroke during followup was 2%-4% per year. These recent studies suggest
that angioplasy is a promising therapy that is increasingly being used to treat
symptomatic intracranialstenosis
A Discussion of WASID
(The Warfarin-Aspirin Symptomatic Intracranial Disease Trial
• The Primary Specific Aim of this randomized, doubleblind, multi-center clinical trial is to compare the efficacy
and safety of warfarin (INR 2-3) with high dose aspirin
(1300 mg per day) for preventing stroke (ischemic and
hemorrhagic) and vascular death in patients with transient
ischemic attack (TIA) or non-severe stroke caused by
symptomatic stenosis of a major intracranial artery.
A Discussion of WASID
(The Warfarin-Aspirin Symptomatic Intracranial Disease Trial
• The Secondary Specific Aim is to identify patients whose
rate of ischemic stroke in the territory of the stenotic
intracranial artery on best medical therapy is sufficiently
high (ie. >6% per year) to justify a subsequent trial
comparing intracranial angioplasty with best medical
therapy in these patients.
A Discussion of WASID
(The Warfarin-Aspirin Symptomatic Intracranial Disease Trial
• Primary Hypothesis: Warfarin (INR 2-3) reduces the rate
of stroke (ischemic and hemorrhagic) and vascular death
by 33% over three years compared with high dose aspirin
(1300 mg per day) in patients with TIA or non-severe
stroke caused by >50% stenosis of a major intracranial
artery (intracranial carotid artery, MCA, intracranial
vertebral artery, basilar artery).
A Discussion of WASID
(The Warfarin-Aspirin Symptomatic Intracranial Disease Trial
• Secondary Hypothesis: In the best medical therapy group,
the rate of ischemic stroke in the territory of the stenotic
intracranial artery will be 3% per year in patient with 50%69% intracranial stenosis and .6% per year in patients with
70%-99% intracranial stenosis.
A Discussion of WASID
(The Warfarin-Aspirin Symptomatic Intracranial Disease Trial
• Criteria for measuring percent stenosis of the major
intracranial arteries were adapted from the NASCET
method for measuring percent diameter stenosis of the
extracranial internal carotid artery. The diameter of the
extracranial internal carotid artery at the site of stenosis (D
stenosis) is compared with the normal diameter of the
artery just distal to the stenosis (D distal) using the
following formula:
% stenosis = (1-(D stenosis/ D distal)) x 100%