Early Management of

TIA & Ischemic Stroke:

What’s The Update?
DR. RR. FIKA TIARA WAHYU WIDAYATI SP.S
Stroke Overview
A syndrome characterized by rapidly developing clinical signs of focal (or global) disturbance
lasting 24 hours or longer, or leading to death/disability with no apparent cause other than of
vascular origin

Transient Ischemic Attack (TIA) is defined as a transient episode of neurologic dysfunction

due to the focal brain, spinal cord, or retinal ischemia, without acute infarction or tissue
injury. The symptoms may last from only a few minutes up to 24 hours.
Prevalence Global Stroke

Feigin VL et al. Int J Stroke. 2022 Jan;17(1):18-29

Prevalence stroke in Indonesia
 RISKESDAS & STROKE REGISTRY
• Stroke prevalence increase 56% within
5 years (from 0.7% to 1.09%, 2013-
2018)
• 70% cases are ischemic
• Only 39.4% stroke patient did routine
Ischemic stroke Hemorrhagic stroke
check ups to doctor
67% 33% • 63.7% elderly patients (>60 yo) cannot
SAH 3.3% live
ICH 29.6%
BPJS
• Steady increase of stroke cases and
its treatment cost every year
SAH: Subarachnoid • 54% and 37% average increase,
Haemorrhage
respectively
• Stroke remains in the top 4
catastrophic disease after 5 years of
UHC implementation
1. Venketasubramanian N et al. Cerebrovasc Dis Extra. 2022;12(1):53-57
2. Harris S et al. SAGE Open Med. 2018 Jun 20;6:1-6

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CHARACTERISTICS OF STROKE AND TIA

STROKE TIA
Abrupt onset of focal Yes Yes
neurologic deficit
infarction Yes No
Duration of neurologic sign > 24 hours < 24 Hours
and symptom

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TOAST CLASSIFICATION OF STROKE

Adams HP et al. Stroke 2015;46:e114-117

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NIHSS National Institutes of Health Stroke Scale: SCORE FROM 11 DOMAINS
• Tools for rapid determine the severity of the stroke
• Strongly associated with outcome and help identify those
patient who are likely to benefit from reperfusion
therapies or not.

1. Level of consciousness (A, B, or C)

2. Best gaze
3. Visual
4. Facial palsy
5. Motor arm
6. Motor leg
7. Limb ataxia
8. Sensory
9. Best language
10. Dysarthria
11. Extinction and inattention (formerly
neglect)
Powers WJ, et al. Stroke. 2019;50(12):e344–e418

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NIHSS National Institutes of Health Stroke Scale: SCORE FROM 11 DOMAINS

Powers WJ, et al. Stroke. 2019;50(12):e344–e418

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MODIFIED RANKIN SCALE

Harrison JK, et al. Clin Interv Aging. 2013;8:201–211.

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Transient Ischemic Attack
Typical symptom Atypical symptom
Unilateral weakness : Face, arm and limb Confusion
Unilateral sensation change Syncope
Disphasia Dizziness
Hemianopia General weakness or sensory symptoms
Mononuclear blindness Bilateral visual impairment
Incontinentia uri or/and alvi
Amnesia
ABCD & ABCD2 - SCORES

Risk stratification tool to

identify patients at high risk
of stroke following a TIA

Score / 7days-risk 30days-risk 1yr-risk of

Risk of stroke of stroke stroke
0 – 3 / Low 5.9% 5.9% 16.2%
4/ 6.9% 9.7% 12.6%
Moderate
>4 / High 19.2% 20.7% 31.0%

Fothergill A et al. Stroke.2009;40 (8) 2669-73

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 RISK FACTORS

Modifiable Non-modifiable
Hypertension Age
Smoking Race
Diabetes Gender
Carotid, or other artery, disease Family history
PAD Prior stroke, TIA, or heart attack
Atrial fibrillation
Other heart disease
Sickle cell disease Other
High blood cholesterol Geographical location
Poor diet Socioeconomic
Physical inactivity and obesity Alcohol abuse
Drug abuse

American heart Association. Stroke Risk Factors. Available at

http://www.strokeassociation.org/STROKEORG/AboutStroke/UnderstandingRisk/Understanding
-Stroke-Risk_UCM_308539_SubHomePage.jsp

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Guidelines

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European Stroke Organization Guidelines on the Management of
Transient Ischemic Attack

Fonseca AC et al. European Stroke Journal. 2021;6(2):CLXIII-CLXXXVI.

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2021 AHA/ASA Guidelines for the Prevention of Stroke in Patients with
Stroke & TIA
Recommendations for Antithrombotic Medications in Secondary Prevention

Kleindorfer D. et al. Stroke. 2021;52:e364–e467

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2021 AHA/ASA Guidelines for the Prevention of Stroke in Patients with
Stroke & TIA
Recommendations for Antithrombotic Medications in Secondary
Prevention

Kleindorfer D. et al. Stroke. 2021;52:e364–e467

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2021 AHA/ASA Guidelines for the Prevention of Stroke in Patients with
Stroke & TIA
Recommendations for Antithrombotic Medications in Secondary
Prevention

Kleindorfer D. et al. Stroke. 2021;52:e364–e467

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2021 AHA/ASA Guidelines for the Prevention of Stroke in Patients with
Stroke & TIA
Recommendations for Antithrombotic Medications in Secondary
Prevention

Kleindorfer D. et al. Stroke. 2021;52:e364–e467

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2021 AHA/ASA Guidelines for the Prevention of Stroke in Patients with
Stroke & TIA
Recommendations for Antithrombotic Medications in Secondary
Prevention

Kleindorfer D. et al. Stroke. 2021;52:e364–e467

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2021 AHA/ASA Guidelines for the Prevention of Stroke in Patients with
Stroke & TIA
Recommendations for Antithrombotic Medications in Secondary
Prevention

Kleindorfer D. et al. Stroke. 2021;52:e364–e467

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Stroke Disease Management

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 CONSIDERATIONS FOR MANAGEMENT

v Primary prevention
• Assessment of modifiable factors
v Consider specific cause of minor stroke/TIA and individual patient factors
v Secondary prevention
v Surgical management
• Extracranial carotid artery disease
• Symptomatic carotid stenosis
• Asymptomatic carotid stenosis

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TREATMENT OPTIONS FOR LONG-TERM PREVENTION

v Risk Factor Management

v Surgical Treatment
• Carotid endarectomy (CEA)
• Carotid stenting
v Pharmacologic Management
• Antiplatelets
• Anticoagulants

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Treatment Options for Secondary Prevention After a Transient Ischemic
Attack or Ischemic Stroke

Diener HC, et al. J Am Coll Cardiol. 2020;75(15):1804-18

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 Algorithm For Antiplatelet Therapy For Non-Cardioembolic Stroke and
Transient Ischemic Attack

• Algorithm does not apply to patients who receive

acute thrombolysis
• Early ischemic stroke (IS) : <24 hours from onset
• High -risk TIA : ABCD2 score ≥4
• Low -risk TIA: ABCD2 score <4
• Dual antiplatelet : Acetylsalicylic Acid (ASA) +
Clopidogrel.

Kleindorfer D. et al. Stroke. 2021;52:e364 –e467

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2019 Update in AHA/ASA Guidelines for the Early Management of Patients
with Acute Ischemic Stroke

Powers WJ, et al. Stroke. 2019;50(12):e344–e418.

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Clinical Studies

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 CHANCE

Incidence of primary and secondary outcomes

PATIENTS SAFETY
Patients aged ≥40 years old, diagnosed with 14 Placebo + aspirin Clopidogrel + aspirin Rates of any bleeding were non-
acute minor ischemic stroke or TIA 12 significantly increased with clopidogrel +
aspirin vs aspirin alone (2.3% vs 1.6%;
10 p=0.09)
THERAPIES
All patients, aspirin 75–300 mg on Day 1 8
Clopidogrel 300 mg loading dose/75 mg/day 6
on Days 2–90 + aspirin 75 mg/day on Days
2–21 and placebo aspirin on Days 22–90 4
Aspirin: placebo clopidogrel on Days 1–90 plus
aspirin 75 mg/day on Days 2–90 2
0

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CONCLUSION
In patients with high-risk TIA or minor ischemic stroke treated within 24 hours of symptom onset, clopidogrel plus aspirin was superior to aspirin alone for reducing the risk of stroke over
the first 90 days. Clopidogrel plus aspirin was not associated with an increased incidence of bleeding, although there was a nonsignificant increase in overall and mild bleeding with dual
antiplatelet therapy

Wang et al., N Eng J Med 2013;369(1):11–9

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 POINT STUDY: Platelet-Oriented Inhibition in New TIA and Minor Ischemic
Stroke

PATIENTS Primary Efficacy Outcomes SAFETY

Patients aged ≥18 years old, with high risk TIA Major haemorrhage occurred in
or minor ischemic stroke “clopidogrel + aspirin” group compared to
aspirin group alone (Hazard ratio, 2.22
( 95% CI, 1.05-4.68); P=0.03)
THERAPIES
Clopidogrel or placebo (600mg loading dose on
day 1 followed by 75 mg daily for 2-90 days); all
patients also received open-label aspirin (50-
325 mg/d)

CONCLUSION
The combination of clopidogrel and aspirin in patients with minor ischemic stroke or high-risk TIA reduced the risk of the composite of ischemic stroke, MI, and ischemic vascular death
over 90 days while increasing the risk of major haemorrhage compared to aspirin alone

Johnston SC et al. N Engl J Med. 2018 Jul 19;379(3):215-225

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CHANCE & POINT Meta-analysis
To precise estimates of efficacy and risk of DAPT after minor ischemic stroke
(NIHSS ≤3) or high-risk TIA (age, blood pressure, clinical features, duration of
symptomobtain s, and presence of diabetes[ABCD2] score ≥4)

Study design:
• Pooled analysis (N=10051) of two double-blind, randomized, placebo controlled clinical trails (CHANCE and POINT) that evaluated clopidogrel-
aspirin (n=5016) or aspirin alone (n=5035) as a treatment to prevent stroke after a minor stroke or high-risk TIA
CHANCE trial: October 1st, 2009 to July 30th, 2012
POINT trial: May 28th to December 19th, 2017
Data analysis of this study: November 2018-May 2019
Treatment regimen
• Patients were randomized to clopidogrel-aspirin or aspirin alone within 12 hours (POINT) or 24 hours (CHANCE) and followed up to 90 days
• In CHANCE trial (N=5170), DAPT was administered for 21 days followed by clopidogrel alone from 22 to 90 days in clopidogrel-aspirin arm
• In POINT trial (N=4881), DAPT was administered for 90 days in the clopidogrel-aspirin arm
Primary outcome:
• A new major ischemic event (eg., ischemic stroke, myocardial infarction, or death from ischemic vascular causes) at 90 days
Secondary outcome:
• A composite of primary efficacy outcome and major haemorrhage and stroke (whether ischemic or haemorrhagic)
Primary Safety outcome:
• Major haemorrhage at 90 days
Secondary Safety outcome:
• Haemorrhagic stroke, minor haemorrhage, major or minor haemorrhage, and death from any cause

Pan Y et al., JAMA Neurology 2019. 76(12):1466-1473

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CHANCE & POINT Meta-analysis
Primary Efficacy Results
Major ischemic Event

A major ischemic event occurred in:

• 328 patients (6.5%) receiving clopidogrel-aspirin
and
• 458 patients (9.1%) receiving aspirin alone at 90
days
(adjusted HR, 0.70 [95%CI, 0.61- 0.81]; P < .001

Pan Y et al., JAMA Neurology 2019. 76(12):1466-1473

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CHANCE & POINT Meta-analysis
Secondary Efficacy Results
New Stroke

At 90 days, a new stroke (ischemic or

haemorrhagic) had occurred in:
• 316 patients (6.3%) receiving clopidogrel-
aspirin and
• 450 patients (8.9%) receiving aspirin alone
(adjusted HR, 0.70 [95% CI, 0.61-0.80]; P < .001

Pan Y et al., JAMA Neurology 2019. 76(12):1466-1473

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CHANCE & POINT Meta-analysis
Primary Safety Results
Major Haemorrhage

Major haemorrhage occurred in:

• 30 patients (0.6%) receiving clopidogrel-aspirin
and
• 18 patients (0.4%) receiving aspirin alone
(adjusted HR, 1.59 [95%CI,0.88-2.86];P = .12

Pan Y et al., JAMA Neurology 2019. 76(12):1466-1473

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CHANCE & POINT Meta-analysis
Conclusions

Early, short-term treatment with clopidogrel-

aspirin reduced the risk of major ischemic In this analysis of the POINT and CHANCE
events without increase in the risk of major trials, the main net clinical benefit of dual
haemorrhage at 90 days in patients with antiplatelet therapy occurred within the first 3
minor ischemic stroke or high-risk TIA weeks

Pan Y et al., JAMA Neurology 2019. 76(12):1466-1473

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 CAPRIE Trial Overview
CAPRIE was a randomized, blinded, international trial, designed to assess the relative efficacy of Clopidogrel (75
mg od) and Aspirin (325 mg od) in reducing the risk of a composite outcome cluster of ischemic events,
myocardial infarction, or vascular death

Cumulative event rate for the MI, ischemic stroke or vascular death
PATIENTS (primary endpoint) Aspirin SAFETY
Patients with ischemic stroke, 16 8.7% Both clopidogrel and aspirin

Cumulative event rate (%)

RRR
recent MI, or PAD were well-tolerated over 3
12 Clopidogrel
years of follow-up; rates of
8 gastritis, gastrointestinal ulcer,
THERAPIES p=0.043; and severe gastrointestinal
4 bleeding were lower with
Clopidogrel 75 mg od (n=9,599) or n=19,185
aspirin 325 mg od (n=9,586) for 1–3 clopidogrel (p<0.05)
0
years 0 3 6 9 12 15 18 21 24 27 30 33 36
Months of follow-up

CONCLUSION
In patients with ischemic stroke, recent MI, or PAD, clopidogrel was more effective than aspirin for the reduction of the
combined risk of MI, ischemic stroke, or vascular death
CAPRIE Steering Committee. Lancet. 1996;348:1329–1339
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Prevention Regimen for Effectively Avoiding Second Strokes (PRoFESS) Trial

Double- blind, 2-by-2 factorial trial, with randomly assigned patients receiving either 25 mg of Aspirin plus 200
mg of extended-release Dipyridamole twice daily or to be receiving 75 mg of Clopidogrel daily

20,322 patients were followed for a

mean of 2.5 years

The PRoFESS Trial found no differences in secondary stroke prevention after non cardiometabolic stroke
for Aspirin-Dipyridamole vs. Clopidogrel
Diener HC et al. Expert Rev Neurother. 2007 Sep;7(9):1085-91.
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Benefits & Risks of Clopidogrel Vs Aspirin Monotherapy After Ischemic
Stroke: A Systematic Review & Meta-analysis

❖ OBJECTIVE
To compare the Efficacy & Safety of Clopidogrel Vs Aspirin monotherapy in patients with recent ischemic
stroke

❖ STUDIES
Five Studies meeting eligibility criteria were included in the analysis. A total of 29,357 adult patients who
had recent ischemic stroke received either Clopidogrel (n=14,293) or Aspirin (n=15,064) for secondary
prevention

❖ STUDY POPULATION
• Patients with recent ischemic stroke within the previous year
• Subgroup data for ischemic stroke patients with mixed stroke/TIA populations

Paciaroni M. et al. Cardiovasc Ther. 2019; 2019: 1607-181

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Efficacy Outcome: Forest Plot Showing Pooled Risk Ratio for MACCE

A statistically significantly
lower risk of MACCE was
observed in the Clopidogrel
Group (RR 0.77 {95% CI,
0.63,0.95})

Paciaroni M. et al. Cardiovasc Ther. 2019; 2019: 1607-181

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Efficacy Outcome: Forest Plot Showing Pooled Risk Ratio for Recurrent
Ischemic Stroke

The risk of recurrent

ischemic stroke (RR 0.72
{95% CI, 0.55,0.94}) showed
a statistical reduction with
Clopidogrel

Paciaroni M. et al. Cardiovasc Ther. 2019; 2019: 1607-181

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 Conclusion of the Meta-analysis

As per the systemic literature

The Clinical benefit of single
review & meta-analysis,
antiplatelet therapy with
Clopidogrel monotherapy was Further Longitudinal data and high-
Clopidogrel over Aspirin for
associated with a significantly quality studies are required to
secondary prevention in patients
lower risk of MACCE, recurrent verify the findings of this systemic
with recent ischemic stroke is
stroke & Bleeding events literature review & meta-analysis
supported by the results of this
compared to Aspirin in patients
meta-analysis
with ischemic stroke

MACCE: Major adverse cardiovascular and cerebrovascular events.

Paciaroni M. et al. Cardiovasc Ther. 2019; 2019: 1607-181

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CONCLUSIONS
v Stroke is associated with significant morbidity and mortality, including coronary events
v Patients with TIA or minor IS are at a very high risk for stroke, especially during the first few days after the event.
v Early treatment initiation is crucial in such patients to prevent subsequent stroke
v Risk of atherothrombosis in patients with stroke is high
v National guidelines exist for secondary stroke prevention including initiation of antiplatelet therapy
v There are large ‘gaps’ in implementing secondary risk reduction in stroke patients
v Evidence to date on the efficacy of clopidogrel:
Ø CHANCE study: ‘clopidogrel+aspirin’ was superior to aspirin alone for reducing the risk of stroke over the first 90 days in
high-risk patients with minor IS/TIA
Ø CHANCE POINT meta-analysis: early, short-term treatment with clopidogrel-aspirin reduced the risk of major ischemic events
without increase in the risk of major haemorrhage at 90 days in patients with minor ischemic stroke or high-risk TIA
Ø PACIARONI study: Clopidogrel monotherapy was associated with a significantly lower risk of MACCE, recurrent stroke &
bleeding events compared to Aspirin in patients with ischemic stroke

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