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Atherothrombosis is characterized by a sudden (unpredictable) atherosclerotic plaque disruption (rupture or erosion) leading to platelet activation and thrombus formation
Plaque rupture1
Plaque erosion2
Atherothrombosis is the underlying condition that results in events leading to myocardial infarction, ischemic stroke, and vascular death
1. Falk E et al. Circulation 1995; 92: 65771. 2. Arbustini E et al. Heart 1999; 82: 26972.
Occlusive thrombus
Plaque rupture
Non-occlusive thrombus
Plaque growth
-7.4 years
Years
-9.2 years
-12 years
History of Stroke
Analysis of data from the Framingham Heart Study. Peeters A, et al. Eur Heart J. 2002;23:458-466.
232
222
172
White
Black Hispanic
18.60%
14.70%
9.40%
mRS =modified Rankin scale
57.20%
Grau AJ, et al. Stroke 2001;32:2559-2566.
28.3%
15.3% 37.7%
ACA=anterior cerebral artery ;MCA = middle cerebral artery ; PCA = posterior cerebral artery ; BA basilary artery VA = vertebra artery ExCr ICA= extra cranial internal carotid artery InCr ICA=intra cranial internal carotid artery CCA = communicant carotid artery
Location of Atherosclerosis
Taiwan (Liu et al, 1996) Among 108 carotid Large Vessel Infarct , 26% Extra Cranial Carotid Artery : 28% Intra cranial CA Hong Kong (Wong et al, 1998) Among 66 patients (TCD assessed) 6 % extracranial vs. 33 % intracranial diseases Japan (Uehara et al, 1998) Among 156 stroke free people, Internal Carotid Artery 4.2 %, Middle CA 5.5 %, Basilar Artery 2.6 % In White people : 42% Ext cranial CA : 13% Intra cranial CA
Genetic differences ?
Sacco et al. Stroke (1997) Risk factors for ICA plaque thickness
Mast et al. Stroke (1998) Smoking vs. ICA stenosis in Northern Manhattan Stroke Study
Same territory 8% 8%
4-12% 10%
VA
BA
4-13%
3-15%
3-8%
2.5-11%
Medications
Antiplatelet is better than anticoagulation
Arenillas (Stroke 2001) a factor (p<0.05) for reduced MCA stenosis progression WASID (Neurology 1995) 151 pt (88 warfarin, 63 aspirin) In warfarin group: less major events (RR 0.46), but with more bleeding WASID (Lancet 2005) not superior to aspirin in prospective study higher bleeding risk
Which antiplatelet ?
Aspirin alone ? 7.7%-9.5%/pt-yr among patients with Intra Cranial Stenosis (EC/IC bypass trial. NEJM, 1985) Ticlopidine ? may be more effective in blacks (TASS, Neurology, 1993) Clopidogrel ? not more effective than aspirin in stroke arm (CAPRIE, Lancet 1996) Combination ? Aspirin, ticlopidine, clopidogrel, dipyridamol,pletaal
Stenosis)
Inclusion criteria
35 to 80 years old ischemic stroke within 2 weeks from onset with symptomatic M1 segment of middle cerebral artery (MCA) or basilar artery (BA)
Exclusion criteria
potential sources of cardiac embolism > 50% stenosis of arteries proximal to the index artery recent major bleeding history, anemia, thrombocytopenia concurrent malignancy or other severe medical condition non-atherosclerotic vasculopathy inadequate TCD evaluation due to poor temporal window concurrent antiplatelets or anticoagulants user severe stroke (NIHSS 16)
Study Design
Aspirin 100 mg/day + placebo
1 month TCD
End points
Primary end points The progression rate of symptomatic ICS on MRA Secondary end points The progression rate of symptomatic stenosis on TCD asymptomatic stenosis on MRA The rate of major cardiovascular events
Pletaal
number
Age (yr) male Hypertension Diabetes mellitus Hyerlipidemia Mean Cholesterol Cigarette smoking NIH stroke scale
Placebo
68
62.59.0 41 (60.3%) 43 (63.2%) 28 (41.2%) 12 (16.2%) 20143 29 (42.6%) 3.73.7
p-value
67
62.210.4 41 (61.2%) 37 (55.2%) 26 (38.8%) 5 (7.5%) 19639 31 (46.3%) 3.43.1
Pletaal
placebo
total
p-value
0.018
Stationary
31 (68.9%)
29 (55.8%)
60 (61.9%)
Progression
3 (6.7%)
15 (28.8%)
18 (18.6%)
Pletaal placebo
Total
P-val.
0.004
Progression
1(2.4%)
13(25.5%)
14 (15.1%)
Pletaal
placebo
total
P-val.
0.465
Stationary
34 (87.2%)
40 (78.4%)
74 (82.2%)
Progression
1 (2.6%)
4 (7.8%)
5 (5.5%)
Conclusions (I)
Intra Cranial Stenosis, a major stroke subtype in Asia Risk factors specific for Intra Cranial Stenosis remain unclear Intra Cranial Stenosis, a dynamic process with relatively frequent progression leading to ischemic events Efficacy of and indication for bypass surgery or angioplasty/stent yet unclear No definitive advantage of anticoagulation over antiplatelets
Conclusions (II)
Aspirin alone appears to be insufficient in preventing the progression of Intra Cranial Stenosis Combination therapy may have to be assessed appropriately Different mechanism Multiple mechanism Less bleeding Tolerable