What is Atherothrombosis?

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.

The development of atherothrombosis a generalized and progressive process

Acute syndrome: coronary cerebrovascular peripheral

Occlusive thrombus

Plaque rupture

Platelet activation and aggregation

Non-occlusive thrombus

Healing and resolution

Plaque growth

Adapted from: Drouet L. Cerebrovasc Dis 2002; 13(suppl 1): 16.

Atherothrombosis Significantly Shortens Life

Atherothrombosis reduces life expectancy by around 8-12 years in patients aged over 60 years1
Average Remaining Life Expectancy at Age 60 (Men)
20 16

-7.4 years

Years

-9.2 years

12 8 4 0 Healthy History of Cardiovascular Disease History of AMI

-12 years

History of Stroke

Analysis of data from the Framingham Heart Study. Peeters A, et al. Eur Heart J. 2002;23:458-466.

Major Clinical Manifestations of Atherothrombosis

TIA, Ischemic stroke Angina, Myocardial infarction Renovascular disease Intermittent claudication Critical leg ischemia

Average Annual Stroke Incidence

Northern Manhattan Stroke Study - NOMAS
Average Annual Age-Adjusted Incidence Rate per 100,000

300 259 250 200 150 100 50 0 Men Women 118 80

232

222
172

White
Black Hispanic

Adapted from Sacco R, et al. Am J Epidemiol 1998;147:259-268.

Prognosis of Ischemic Stroke

German Stroke Data Bank
Follow-up after 90 days

Slight disabilities (mRS 0-2) Moderate disabilities (mRS 3)

18.60%

14.70%

Severe disabilities (mRS 4-5)

Deceased n = 5,017

9.40%
mRS =modified Rankin scale

57.20%
Grau AJ, et al. Stroke 2001;32:2559-2566.

How frequent is intracranial stenosis?

8-10% of CVD in western countries Asian(Korea ,China, Japan), Black more common than Whites, a major problem in Asia

INTRACRANIAL STENOSIS IS COMMON AMONG ASIAN

Feldmann et al: whites had more severe (greater than or equal to 50% stenosis) extracranial lesions, while Chinese had more severe intracranial lesions (Neurology. 1990; 40: 15411545.)
Dae Chul Suh et al: Korean patients with severe atherosclerotic stenosis tend to have more intracranial stenosis (American Journal of Neuroradiology 24:239244, February 2003 ) Suwanwela, N and Chutinetr,A: Among the patients with extracranial stenosis, 98% had associated intracranial disease, whereas none of those with intracranial stenosis had more than 50% of extracranial carotid stenosis (Neuroepidemiology 2003;22:37-40) Wong KS, Huang YN et al: intracranial occlusive disease is the most commonly found vascular lesion in our acute stroke patients.(Neurology. 1998 Mar;50(3):812-3).

Intracranial Arterial Stenosis

May be underestimated: Lacune-like infarction may be caused by intracranial stenosis No prospective study to define the natural history of IAS No proven management strategy to reduce the risk of ischemic stroke

Distribution of vascular lesions

0.8% 13.0% 2.0% ACA MCA PCA BA VA ExCrICA InCrICA CCA

28.3%
15.3% 37.7%

14.6% 7.8% 8.8%

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

What makes stroke subtypes different ?

Different risk factor ? Genetic factors ?

Risk factor differences

Yasaka et al (Stroke, 1993) DM, cholesterol - Internal carotid Artery disease Advanced Hypertension Middle Cerebral Artery disease Uehara et al (Cerebrovas Dis,1998) Internal Carotid Artery disease: age and hyperlipidemia Intracranial Disease: age and hypertension Bogousslavksy et al (Arch Neurol 1996) Large Vessel Infarction vs. Small Vessel Infarction: smoking, TIA, CHD, Family history, claudication

Tentative summary of risk factor differences

DM, Hyperlipidaemia or obesity : Brain Infarct > Intra Cranial Haemorrhage Male, smoking: Large Vessel Infarct > Intra Cranial Haemorrhage or Small Vessel Infarct Inadequate control of Hypertension: Intra Cranial Haemorrhage > Brain Infarct No differences in risk factors between Large Vessel Infarct and Small Vessel Infarct

Are ethnic differences in stroke subtype related to

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

Natural course of intracranial stenosis

Akins et al (Stroke 1998): 45 Intra Cranial stenosis (in 21 pts) at 26.7 months Internal Carotid Artery: 20 % progressive, 14% regressive Ant CA, Middle CA,Post CA: 61% progressive, 28% regressive. 4 TIAs , 1 Intra Cranial Hemorrhage Arenillas et al (Stroke 2001) 40 Middle Cerebral Artery stenosis at 26.6 months 33% progressive; 7.5% regressive, 60% stable 20% developed Middle Cerebral Artery related ischemic events

Annual Risk of stroke in intracranial stenosis

Any territory

Same territory 8% 8%

Carotid bifurcatio MCA

4-12% 10%

VA
BA

4-13%
3-15%

3-8%
2.5-11%

How to treat intracranial stenosis ?

Management of risk factors Medication Surgery: bypass Angioplasty & Stent

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

(Trial of Cilostazol in Symptomatic Intracranial

Stenosis)

Multicenter, double blind, placebo controlled randomized trial

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

Aspirin 100 mg/day + Pletaal100 mg bid

0 month MRA TCD

1 month TCD

6 months MRA 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

0.828 0.915 0.195 0.779 0.262 0.514 0.535 0.626

Pletaal

placebo

total

p-value
0.018

The MRA outcome of symptomatic stenosis

Regression 11 (24.4%) 8 (15.4%) 19 (19.6%)

Stationary

31 (68.9%)

29 (55.8%)

60 (61.9%)

Progression

3 (6.7%)

15 (28.8%)

18 (18.6%)

Kwon et al, TOSS. Stroke, 2005

Pletaal placebo

Total

P-val.
0.004

The TCD outcome of symptomatic stenosis

Regression Stationary 12 (28.6%) 8 (15.7%) 20 (21.5%)

29 (69.0%) 30 (58.8%) 59 (63.4%)

Progression

1(2.4%)

13(25.5%)

14 (15.1%)

Kwon et al, TOSS. Stroke, 2005

Pletaal

placebo

total

P-val.

The MRA outcome of asymptomatic stenosis

Regression 4 (10.3%) 7 (13.7%) 11 (12.2%)

0.465

Stationary

34 (87.2%)

40 (78.4%)

74 (82.2%)

Progression

1 (2.6%)

4 (7.8%)

5 (5.5%)

Kwon et al, TOSS. Stroke, 2005

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