Review of antiplatelet agents in acute ischemic stroke. Including aspirin, clopidogrel, cilostazol, ticagrelor. Also discussed the indication of DAPT(dual antiplatelet therapy)

1. Antiplatelet Agents after
Acute Ischemic Stroke
2018/11
Summarized by Yung-Tsai Chu
Reference:
Leng, X. et al.(2017). Antiplatelet therapy after stroke. Current Opinion in Neurology.
台灣腦中風學會 缺血性腦中風的抗血小板藥物治療指引2016

2. When is Antiplatelet Agent Indicated?
• Non-Cardioembolic Etiology
• If Atrial Fibrillation is known or detected, use anti-coagulant as
secondary prevention
• SPAF trial: Aspirin is also effective to prevent stroke in Afib, but warfarin is
more effective than aspirin.

3. When to Start
• Not using t-PA
• within 24 to 48 hours after onset
• If t-PA is administered
• Delayed after 24 hours

4. Commonly Available Agents
• Aspirin
• Clopidogrel
• Cilostazol
• Ticagrelor
• Aspirin + extended-release Dipyridamole

5. Aspirin
• First-line agent(both in Taiwan and AHA guideline)
• Dose: 75-100mg QD
• Inhibit cyclooxygenase(COX)  Less thromboxane A2(TXA2)
• Side effect:
• ICH (overall benefit still outweigh risk)
• GI bleeding

6. Clopidogrel
• Dose: 75mg QD
• Inhibit ADP receptor
• Compared with Aspirin
• Similar efficacy to prevent ischemic stroke
• Less GI bleeding(according to CAPRIE trial)
• Might prevent more cardiovascular event
• Interaction with PPI(especially omeprazole)
• Inhibit CYP2C19 P-450 cytochrome

7. Cilostazol
• Dose: 100mg BID
• Inhibit phosphodiesterase(PDE)-3
• More cAMP Activate Protein kinase A(PKA)
• Also vasodilatory effect (thus indicated in PAOD)
• May be better for small-vessel disease (lacunar stroke) or high risk of
bleeding (CSPS-2 trial) in Asian population
• PICASSO: prevented more strokes in case of previous ICH or cerebral
microbleed compared with Aspirin
• Contraindication:
• Heart failure
• Other side effect: dizziness, headache, diarrhea

8. Ticagrelor
• Not recommended by 2016 Taiwan guideline yet
• SOCRATES trial (VS. Aspirin)
• extracranial or intracranial atherosclerotic stenosis: better than aspirin
• Asian population: better than aspirin

9. Can 1+1 >2?
When To Use DAPT?

10. Dual Antiplatelet Therapy(DAPT)
• Most common combination: Aspirin + Clopidogrel
• Other options (limited evidence)
• Aspirin + Cilostazol
• Aspirin + Dipyridamole (PRoFESS trial: similar efficacy to clopidogrel), may be
used as long-term prevention
• Why DAPT?
• Most beneficial in large artery atherosclerosis
• Prevent short-term recurrence
• Mostly during first 1-2 weeks

11. When to Use DAPT? (Aspirin + Clopidogrel)
• Minor stroke(NIHSS <4) or High-risk TIA(ABCD2 >=4)
• Intracranial Artery Stenosis (Stenosis 70-99%)
• Unstable angina or NSTEMI
• Before carotid artery stenting

12. Minor stroke or High-risk TIA
• Minor stroke(NIHSS <4) or High-risk TIA(ABCD2 >=4)
• According to CHANCE trial
• Exclusion
• Isolated sensory, visual, or vertiginous symptoms without infarct on MRI
• mRS >2 (ADL dependent)
• History of ICH, GI bleeding, anticoagulant use
• Regimen: Clopidogrel + Aspirin for 21 days, then clopidogrel only
• Bleeding risk: similar to single agent
• Preferably within 24 hours after onset

13. Protocol (CHANCE trial)
Clopidogrel Aspirin
Day 1 300mg STAT 75-300mg QD
Day 2-21 75mg QD 75-300mg QD
Day 22- 75mg QD nil

14. CHANCE Subgroup Analysis
• More benefit if …
• Multiple acute infarcts
• Intracranial arterial stenosis

15. Intracranial Artery Stenosis(ICAS)
• Stenosis 70-99%
• According to SAMMPRIS trial(published in 2011)
• Regimen: Clopidogrel + Aspirin for 90 days, with medical therapy(BP,
lipid, DM)
• SBP <140 mmHg
• LDL<70mg/dL
• Less stroke or death within 30 days compared with stenting
• 11.5% VS. 20.5%

16. Caution for DAPT
• No Long-term Use
• MATCH and CHARISMA trials: no long-term benefit, more bleeding
complication
• History of major bleeding (ICH, GI bleeding)
• Excluded in CHANCE trial
• Less beneficial in lacunar stroke (SPS3 trial)
• Consistent with CHANCE trial subgroup analysis
• Control other risk factors as well
• How about triple???
• TARDIS trial: more bleeding complication, ended prematurely…

17. New stroke when patient is
already taking antiplatelet…

18. High On-Treatment Platelet Reactivity (HTPR)
• So-called “resistance”
• No standardized lab test now
• Check compliance first
• Other risk factor control
• Options (no standard now)
• Change to another agent
• Add another agent at DAPT (short term)

19. Take Home Message
• Antiplatelet agents are indicated in secondary prevention of non-
cardioembolic stroke.
• Common options include aspirin, clopidogrel and cilostazol
• Short-term dual antiplatelet therapy (DAPT) could be used in
intracranial artery stenosis and minor stroke or high-risk TIAs, esp.
when the etiology is large artery atherosclerosis.
• Currently there is no standard way to deal with suspected
‘antiplatelet resistance’ (high on-treatment platelet reactivity).
• Check compliance and other risk factor control first
• May change to other agent or add another agent