Antiplatelet Therapy for Acute Stroke

Related Summaries

● Stroke (acute management)

● Anticoagulation therapy for acute stroke

● Antiplatelet Therapy for Secondary Prevention of Stroke or Transient Ischemic Attack

● Transient ischemic attack (TIA)

Overview

● aspirin 160-300 mg/day should be started 24-48 hours after an ischemic stroke in most patients to
reduce the risk of death, dependency, and recurrent stroke
⚬ start immediately if no thrombolytic therapy, or after 24 hours among patients receiving
thrombolytic therapy, unless major contraindications are present
⚬ consider clopidogrel as alternate antiplatelet monotherapy in patients with allergy to aspirin
⚬ if there is minor stroke, consider combination aspirin plus clopidogrel for up to 21 days for early
secondary prevention of stroke
– clopidogrel loading dose 300-600 mg on rst day and then 75 mg/day after that
– aspirin loading dose 75-300 mg on rst day and 75 mg/day after that, or aspirin 50-325 mg/day
(no loading dose)

● antiplatelets other than aspirin or clopidogrel are generally not recommended

Recommendations from Professional Organizations

American Heart Association/American Stroke Association (AHA/ASA) - Early

Management of Acute Ischemic Stroke

● start aspirin therapy 160-300 mg/day within 24-48 hours of stroke onset (AHA/ASA Class I, Level A) 1

⚬ use rectal or nasogastric administration if oral administration is di cult or not safe

⚬ consider alternate antiplatelets if contraindications to aspirin

● for patients treated with IV alteplase, delay starting aspirin for 24 hours after alteplase treatment, but
consider starting earlier if patients has concomitant conditions for which aspirin given in absence of
alteplase is known to provide substantial bene t or withholding aspirin is known to cause substantial
risk (AHA/ASA Class I, Level A) 1

● for patients with minor (NIHSS score ≤ 3 points) noncardioembolic ischemic stroke who did not have
IV alteplase, start dual antiplatelet therapy with aspirin and clopidogrel within 24 hours of symptom
onset and continue for 21 days to reduce risk of recurrent stroke (AHA/ASA Class I, Level A), with
suggested regimens of 1
⚬ clopidogrel loading dose 300-600 mg on rst day and then 75 mg/day after that
⚬ aspirin loading dose 75-300 mg on rst day and 75 mg/day after that, or aspirin 50-325 mg/day (no
loading dose)
● other antiplatelets are generally not recommended 1

⚬ e cacy not well-established for IV tiro ban or epti batide (glycoprotein IIb/IIIa inhibitors)
(AHA/ASA Class IIb, Level B-R)
⚬ do not give ticagrelor instead of aspirin for minor stroke (AHA/ASA Class III No bene t, Level B-R)
⚬ do not give IV abciximab (glycoprotein IIb/IIIa inhibitor) (AHA/ASA Class III Harm, Level B-R)

● do not give aspirin as a substitute treatment to IV alteplase or mechanical thrombectomy in eligible

patients (AHA/ASA Class III Harm, Level B-R) 1

● urgent anticoagulant therapy is generally not recommended for acute ischemic stroke 1

⚬ do not give urgent anticoagulation in order to prevent early recurrent stroke, halt neurological
worsening, or improve outcomes (AHA/ASA Class III No bene t, Level A)
⚬ unclear utility for urgent anticoagulation in patients with severe stenosis of internal carotid artery
ipsilateral to ischemic stroke (AHA/ASA Class IIb, Level B-NR)
⚬ unclear safety and usefulness for short-term anticoagulation in patients with acute ischemic stroke
and nonocclusive, extracranial intraluminal thrombus (AHA/ASA Class IIb, Level C-LD)
⚬ unclear usefulness for argatroban, dabigatran, or other thrombin inhibitors (AHA/ASA Class IIb,
Level B-NR)
⚬ unclear safety and usefulness for oral factor Xa inhibitors (AHA/ASA Class IIb, Level C-LD)
⚬ anticoagulants may be considered for secondary prevention of stroke in some patients (such as if
atrial brillation or arterial dissection); see Secondary Prevention of Stroke or Transient Ischemic
Attack for details

Canadian Stroke Best Practice Recommendations (CSBPR) - Acute Stroke

Management

● for patients not already on antiplatelets, who did not have IV alteplase, for whom intracranial

hemorrhage and dysphagia have been excluded 2

⚬ give aspirin ≥ 160 mg once (as initial loading dose) (CSBPR Level A)
⚬ continue with aspirin 81-325 mg/day inde nitely or until starting another antithrombotic regimen
(CSBPR Level A)

● if treated with IV alteplase, delay starting antiplatelet therapy until after the patient has had 24-hour

postthrombolysis brain imaging and intracranial hemorrhage has been excluded (CSBPR Level B) 2

● if dysphagia, consider combination clopidogrel 75 mg/day and aspirin 80 mg/day by enteral tube or

aspirin 325 mg/day by rectal suppository (CSBPR Level A) 2

● for patients with very high-risk transient ischemic attack or minor noncardioembolic stroke
(presenting within 48 hours of event with additional symptoms associated with recurrent stroke
[transient, uctuating, or persistent unilateral weakness or language/speech disturbance and/or other
uctuating or persistent symptoms such as hemibody sensory symptoms, monocular vision loss,
hemi eld vision loss, binocular diplopia, dysarthria, dysphagia, and ataxia]) 2
⚬ give dual antiplatelet therapy with clopidogrel and aspirin for 21-30 days followed by antiplatelet
monotherapy (such as aspirin or clopidogrel alone) (CSBPR Level A)
⚬ start with initial loading doses of clopidogrel 300-600 mg and aspirin 160 mg (CSBPR Level A)
⚬ start as soon as possible after brain imaging, within 24 hours of symptom onset (ideally within 12
hours), and before discharge from emergency department
 ⚬ counsel patients that dual antiplatelet therapy with clopidogrel and aspirin should continue for
only 21-30 days, and that they should then resume monotherapy and continue inde nitely
⚬ if cerebrovascular event cause by high-grade carotid stenosis and patient is candidate for urgent
carotid endarterectomy or carotid stenting, review patient with interventionalist or surgeon to
determine appropriate timing and selection of antiplatelet agent(s); aspirin monotherapy may be
preferred over dual antiplatelet therapy if urgent carotid endarterectomy is planned

● for pediatric patients (CSBPR Level B) 2

⚬ consider initial therapy with heparin or aspirin at established age-appropriate doses and continue
until cervical artery dissection and intracardiac thrombus is excluded
⚬ if no cervical artery dissection or intracardiac thrombus, switch to acute aspirin therapy at 1-5
mg/kg

● consider gastrointestinal protection if high risk of gastrointestinal bleeding 2

National Institute for Health and Care Excellence (NICE) - Stroke and Transient
Ischaemic Attack in Over 16s

● for most patients with acute ischemic stroke 3

⚬ if intracerebral hemorrhage (ICH) ruled out with imaging, give aspirin 300 mg (or alternative
antiplatelet if allergic to aspirin) as soon as possible and ≤ 24 hours after stroke onset
– if dysphagia, administer rectally or by enteral tube; if no dysphagia, administer orally
– if dyspepsia associated with aspirin, o er proton pump inhibitor
– continue aspirin 300 mg/day until hospital discharge or up to 2 weeks, then start de nitive long-
term antithrombotic treatment
⚬ do not routinely give anticoagulation for acute ischemic stroke

● for patients with acute ischemic stroke with characteristics or comorbidities that may require

anticoagulation 3
⚬ if cerebral venous sinus thrombosis give full-dose anticoagulation treatment (initially full-dose
heparin and then warfarin [INR 2-3]; even if patient has secondary cerebral hemorrhage) unless
there are comorbidities that preclude its use
⚬ if stroke secondary to acute arterial dissection, give either anticoagulant or antiplatelet agent
therapy
⚬ if antiphospholipid syndrome, manage as with patients with acute ischemic stroke not associated
with antiphospholipid syndrome
⚬ if disabling ischemic stroke and atrial brillation, give aspirin 300 mg/day for 2 weeks before
considering anticoagulation
⚬ if prosthetic valves, disabling cerebral infarction, and signi cant risk of hemorrhagic
transformation, replace anticoagulation therapy with aspirin 300 mg/day for 1 week
⚬ if symptomatic proximal deep vein thrombosis or pulmonary embolism, give anticoagulation
treatment in preference to aspirin unless there are contraindications to anticoagulation

Aspirin

● professional organizations generally recommend

⚬ starting aspirin therapy 160-300 mg/day within 24-48 hours of stroke onset (see related evidence
summary for additional information)
 ⚬ delaying aspirin therapy for 24 hours in patients who had thrombolytic therapy, but consider
starting earlier if comorbid conditions for which aspirin may be bene cial (see related evidence
summary for additional information)
⚬ see Recommendations from Professional Organizations section for organization-speci c
recommendations

STUDY
● SUMMARY
daily aspirin started within 48 hours of onset of presumed ischemic stroke reduces mortality
and recurrent stroke but increases risk of major extracranial hemorrhage DynaMed Level 1

Cochrane Database Syst Rev 2014 Mar 26;(3):CD000029

Details
⚬ based on Cochrane review
⚬ systematic review of 8 randomized trials comparing oral antiplatelet therapy vs. placebo or no
treatment starting at ≤ 14 days of stroke onset in 41,483 patients with de nite or presumed
ischemic stroke
⚬ 2 trials evaluating aspirin 160-300 mg once daily (started ≤ 48 hours of onset of stroke) provided
98% of the data, maximum follow-up was 6 months
⚬ comparing aspirin to placebo or no treatment, aspirin associated with

– decreased all-cause mortality during follow-up in analysis of 4 trials with 41,291 patients

● odds ratio (OR) 0.92 (95% CI 0.87-0.98)

● NNT 108 (95% CI 66-436)

– reduced death or dependency at end of follow-up in analysis of 4 trials with 41,291 patients

● OR 0.95 (95% CI 0.91-0.99)

● NNT 79 (95% CI 43-400)

– reduced recurrent ischemic or unknown stroke during treatment in analysis of 3 trials with
40,850 patients
● OR 0.77 (95% CI 0.69-0.87)
● NNT 140 (95% CI 104-248)

– reduced pulmonary embolism during treatment in analysis of 3 trials with 40,850 patients

● OR 0.71 (95% CI 0.53-0.97)

● NNT 693 (95% CI 427-6,700)

– increased major extracranial hemorrhage during treatment in analysis of 3 trials with 40,850
patients
● OR 1.69 (95% CI 1.35-2.11)
● NNH 245 (95% CI 153-481)

– nonsigni cant increase in symptomatic intracranial hemorrhage during treatment (OR 1.22, 95%
CI 1-1.5) in analysis of 3 trials with 40,850 patients
⚬ Reference - Cochrane Database Syst Rev 2014 Mar 26;(3):CD000029
⚬ aspirin within 48 hours reduces 4-week mortality and risk for recurrent ischemic stroke
DynaMed Level 1

– based on randomized trial

– 21,106 patients within 48 hours of onset of acute ischemic stroke were randomized to aspirin
160 mg vs. placebo orally once daily for 4 weeks
– comparing aspirin vs. placebo
 ● death or dependence at hospital discharge 30.5% vs. 31.6% (p = 0.08)
● 4-week mortality 3.3% vs. 3.9% (p = 0.04, NNT 167)
● recurrent ischemic strokes in 1.6% vs. 2.1% (p = 0.01, NNT 200)
● hemorrhagic strokes in 1.1% vs. 0.9% (not signi cant)

– Reference - Chinese Acute Stroke Trial (CAST) (Lancet 1997 Jun 7;349(9066):1641 )
⚬ aspirin within 48 hours associated with reduced death and dependency at 6 months
DynaMed Level 2

– based on randomized trial without blinding

– 19,5435 stroke patients randomized within 48 hours to aspirin 300 mg orally once daily vs. no
aspirin, and also randomized to heparin (5,000 or 12,500 units subcutaneously twice daily) vs.
no heparin, for up to 14 days
– comparing aspirin vs. no aspirin at 14 days

● 14-day mortality 9% vs. 9.4% (not signi cant)

● recurrent ischemic stroke within 14 days in 2.8% vs. 3.9% (p < 0.001, NNT 91)
● hemorrhagic stroke in 0.9% vs. 0.8% (not signi cant)
● death or recurrent stroke in 11.3% vs. 12.4% (p = 0.02, NNT 84)
● transfused or fatal extracranial bleeds in 1.1% vs. 0.6% (p = 0.0004, NNH 200), but not
signi cant in absence of concurrent heparin administration
– at 6 months, aspirin use associated with

● nonsigni cant reduction in death and dependency (62.2% vs. 63.5%, p = 0.07)
● but statistically signi cant after adjustment for baseline prognosis (p = 0.03, NNT 72)

– Reference - IST trial (Lancet 1997 May 31;349(9065):1569 )

STUDY
● SUMMARY
aspirin within 90 minutes of alteplase treatment may increase risk of symptomatic intracranial
hemorrhage in patients with acute ischemic stroke and may not improve functional outcome
DynaMed Level 2

RANDOMIZED TRIAL: Lancet 2012 Aug 25;380(9843):731

Details
⚬ based on randomized trial without blinding
⚬ 642 patients (mean age 67 years) with acute ischemic stroke randomized ≤ 90 minutes after start of
alteplase to aspirin 300 mg IV vs. no aspirin
⚬ all patients received alteplase 0.9 mg/kg IV within 4.5 hours of symptom onset followed by oral
antiplatelet therapy 24 hours later
⚬ trial terminated early due to signi cant increase in symptomatic intracranial hemorrhage in aspirin
group with no evidence of bene t
⚬ comparing aspirin vs. no aspirin

– good functional outcome (modi ed Rankin score of 0-2) at 3 months in 54% vs. 57.2% (not
signi cant)
– symptomatic intracranial hemorrhage in 4.3% vs. 1.6% (p = 0.04, NNH 37)

⚬ Reference - ARTIS trial (Lancet 2012 Aug 25;380(9843):731 ), editorial can be found in Lancet 2012
Aug 25;380(9843):706

Clopidogrel Monotherapy or with Aspirin

● professional organizations generally recommend considering dual antiplatelet therapy with
clopidogrel and aspirin
⚬ clopidogrel as alternate antiplatelet monotherapy in patients with allergy to aspirin
⚬ starting dual antiplatelet therapy if noncardioembolic ischemic stroke and no thrombolytic therapy
⚬ see Recommendations from Professional Organizations section for organization-speci c
recommendations

● see Antiplatelet Therapy for Secondary Prevention of Stroke or Transient Ischemic Attack for
additional information

Other Antiplatelets

● professional organizations generally do not recommend antiplatelets other than aspirin or

clopidogrel; see Recommendations from Professional Organizations section for organization-speci c
recommendations

STUDY
● SUMMARY
IV abciximab increases risk of intracranial hemorrhage in patients with acute ischemic stroke
DynaMed Level 1 and may not reduce risk of death or dependency DynaMed Level 2

COCHRANE REVIEW: Cochrane Database Syst Rev 2014 Mar 8;(3):CD005208

Details
⚬ based on Cochrane review with wide con dence intervals
⚬ systematic review of 4 randomized trials evaluating IV glycoprotein IIb/IIIa inhibitors in 1,365
patients with acute ischemic stroke
⚬ comparing IV abciximab to placebo in analyses of 3 trials with 1,215 patients

– IV abciximab associated with

● increased symptomatic intracranial hemorrhage

⚬ odds ratio (OR) 4.6 (95% CI 2.01-10.54)

⚬ NNH 9-84 with symptomatic intracranial hemorrhage in 1.2% of placebo group

● nonsigni cantly increased risk of major extracranial hemorrhage (OR 1.81, 95% CI 0.96-3.41)

– no signi cant di erence in death or dependency (OR 0.97, 95% CI 0.77-1.22), but con dence
interval cannot exclude clinically relevant di erences
⚬ comparing tiro ban vs. aspirin, no signi cant di erences in death or dependency, symptomatic
intracranial hemorrhage, and major extracranial hemorrhage in 1 trial with 150 patients
⚬ Reference - Cochrane Database Syst Rev 2014 Mar 8;(3):CD005208
⚬ IV abciximab for acute stroke increases rate of intracranial hemorrhage
DynaMed Level 1

without apparent bene t

DynaMed Level 2

– based on randomized trial with early termination

– 801 patients > 18 years old with acute ischemic stroke randomized to IV abciximab (0.25 mg/kg
bolus then 0.125 mcg/kg/minute [maximum 10 mcg/minute] for 12 hours) vs. placebo
– patients strati ed to 3 cohorts by stroke onset

● primary cohort included 439 patients who could be treated < 5 hours after stroke onset
● second cohort included 319 patients treated 5-6 hours after onset
 ● third cohort included 43 patients treated within 3 hours of stroke present on awakening

– trial terminated early for unfavorable bene t-risk pro le

– primary outcome was favorable response de ned as modi ed Rankin score (mRS) 0 if baseline
National Institutes of Health Stroke Scale (NIHSS) score 4-7, mRS 0-1 if baseline NIHSS score 8-14
or mRS 0-2 if baseline NIHSS score 15-22
– comparing abciximab vs. placebo in primary cohort

● favorable response rate at 3 months 32% vs. 33% (not signi cant)
● neurologic recovery at 3 months in 43.4% vs. 42.2% (not signi cant)
● mRS score 0-1 at 3 months in 44.5% vs. 42.5% (not signi cant)
● symptomatic or fatal intracranial hemorrhage within 5 days in 5.5% vs. 0.5% (p = 0.002, NNH
20)
● symptomatic or fatal intracranial hemorrhage within 3 months in 13.6% vs. 5% (p < 0.001,
NNH 11)
– other cohorts showed no signi cant di erences in e cacy or safety outcomes
– Reference - AbESTT-II trial (Stroke 2008 Jan;39(1):87 full-text )

Quality Improvement

Quality and Outcomes Framework Indicators

● STIA7. Percentage of patients with stroke shown to be nonhemorrhagic, or history of transient

ischemic attack (TIA), who have a record in preceding 12 months that antiplatelet agent or
anticoagulant is being taken

● see Quality and Outcomes Framework Indicators for additional information

Guidelines and Resources

Guidelines

United States Guidelines

● American Heart Association/American Stroke Association (AHA/ASA)

⚬ AHA/ASA 2019 update to the 2018 guidelines for the early management of acute ischemic stroke
can be found in Stroke 2019 Dec;50(12):e344 , correction can be found in Stroke 2019
Dec;50(12):e440
⚬ AHA/ASA scienti c statement on management of stroke in neonates and children can be found in
Stroke 2019 Mar;50(3):e51
⚬ AHA/ASA guidelines for the prevention of stroke in patients with stroke and transient ischemic
attack can be found in Stroke 2014 Jul;45(7):2160 , correction can be found in Stroke 2015
Feb;46(2):e54

● Institute for Clinical Systems Improvement (ICSI) guideline on diagnosis and initial treatment of
ischemic stroke can be found at ICSI 2016 Dec PDF

● American College of Chest Physicians (ACCP) evidence-based clinical practice guideline (ninth edition)
on antithrombotic and thrombolytic therapy for ischemic stroke can be found in Chest 2012 Feb;141(2
Suppl):e601S full-text
● American Geriatrics Society (AGS) 2019 Beers Criteria for potentially inappropriate medication use in
older adults can be found in J Am Geriatr Soc 2019 Apr;67(4):674 , commentary can be found in J
Urol 2019 Sep;202(3):438

Canadian Guidelines

● Canadian Stroke Best Practice Recommendations (CSBPR) for Acute Stroke Management: Prehospital,
Emergency Department, and Acute Inpatient Stroke Care can be found in Int J Stroke 2018
Dec;13(9):949

United Kingdom Guidelines

● National Institute for Health and Care Excellence (NICE) guideline on diagnosis and initial
management of acute stroke and transient ischemic attack (TIA) can be found at NICE 2019
May:NG128

● Royal College of Physicians (RCP) national clinical guideline on stroke can be found at RCP 2016 Oct 3
PDF

● Scottish Intercollegiate Guidelines Network (SIGN) national clinical guideline on management of

patients with stroke or transient ischemic attack (TIA) (assessment, investigation, immediate
management, and secondary prevention) can be found at SIGN 2008 Dec PDF

Asian Guidelines

● Japan Stroke Society (JSS) guideline on management of stroke can be found at JSS 2019 PDF
[Japanese 日本語]

References

General references used

1. Powers WJ, Rabinstein AA, Ackerson T, et al. Guidelines for the Early Management of Patients With
Acute Ischemic Stroke: 2019 Update to the 2018 Guidelines for the Early Management of Acute
Ischemic Stroke: A Guideline for Healthcare Professionals From the American Heart
Association/American Stroke Association. Stroke. 2019 Dec;50(12):e344-e418 , correction can be
found in Stroke 2019 Dec;50(12):e440

2. Boulanger JM, Lindsay MP, Gubitz G, et al.. Canadian Stroke Best Practice Recommendations (CSBPR)
for Acute Stroke Management: Prehospital, Emergency Department, and Acute Inpatient Stroke Care,
6th Edition, Update 2018. Int J Stroke. 2018 Dec;13(9):949-984

3. National Institute for Health and Care Excellence (NICE). Stroke and transient ischaemic attack in over
16s: diagnosis and initial management. NICE 2019 May:NG128 PDF

Recommendation grading systems used

● American Heart Association/American Stroke Society (AHA/ASA) 2019 grading system for
recommendations
⚬ classes of recommendations

– Class I (Strong) - should be performed or administered; indicated/useful/e ective/bene cial

– Class IIa (Moderate) - reasonable to perform or administer; can be useful/e ective/bene cial
 – Class IIb (Weak) - may be considered; usefulness/e ectiveness is unknown/unclear/uncertain or
not well established
– Class III: No Bene t (Moderate) - should not be performed or administered; not
indicated/useful/e ective/bene cial
– Class III: Harm (Strong) - should not be performed or administered; potentially harmful, causes
harm, or associated with excess morbidity/mortality
⚬ levels of evidence

– Level A - high-quality evidence from > 1 randomized controlled trial (RCT), meta-analyses of
high-quality RCTs, or ≥ 1 RCTs corroborated by high-quality registry studies
– Level B-R - moderate-quality evidence from ≥ 1 RCTs or meta-analysis of moderate-quality RCTs
– Level B-NR - moderate-quality evidence from ≥ 1 well-designed, well-executed nonrandomized
studies, observational studies, or registry studies, or meta-analysis of such studies
– Level C-LD - randomized or nonrandomized observational or registry studies with limitations of
design or execution, meta-analyses of such studies, or physiological or mechanistic studies in
human subjects
– Level C-EO - consensus of expert opinion based on clinical experience

⚬ Reference - AHA/ASA guideline on early management of patients with acute ischemic stroke (Stroke
2019 Dec;50(12):e344 )

● Canadian Stroke Best Practice Recommendations (CSBPR) levels of evidence

⚬ Evidence Level A

– meta-analysis of randomized controlled trials or consistent ndings from ≥ 2 randomized trials

– desirable e ects clearly outweigh undesirable e ects or vice versa

⚬ Evidence Level B

– single randomized controlled trial or consistent ndings from ≥ 2 well-designed nonrandomized

and/or uncontrolled trials, and large observational studies
– desirable e ects outweigh or are closely balanced with undesirable e ects or vice versa

⚬ Evidence Level C

– writing group consensus and/or supported by limited research evidence

– desirable e ects outweigh or are closely balanced with undesirable e ects or vice versa

⚬ Clinical Consideration

– reasonable practical advice provided by consensus of writing group on speci c clinical issues
that are common and/or controversial and lack research evidence to guide practice
⚬ Reference - CSBPR Overview and Methodology (CSBPR 2018 PDF )

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