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Antithrombotic therapy for ischemic stroke: guidelines translatedfor the clinician

Anandi Krishnan Renato D. Lopes

John H. Alexander Richard C. Becker

Larry B. Goldstein

Published online: 2 February 2010

Springer Science+Business Media, LLC 2010

Abstract Acute ischemic stroke is the result of abrupt

interruption of focal cerebral blood flow. The majority ofischemic strokes are caused by embolic or thrombotic

arterial occlusions. Acute stroke management is complex,

in part because of the varying etiologies of stroke and the

very brief window of time for reperfusion therapy. Efforts

to optimize stroke care have also encountered barriers

including low public awareness of stroke symptoms. As

initiatives move forward to improve stroke care worldwide,

health care providers and institutions are being called onto

deliver the most current evidence-based care. Updated

versions of three major guidelines were published in 2008

by the American College of Chest Physicians, the Ameri-

can Heart Association, and the European Stroke Organi-

zation. This article presents a concise overview of current

recommendations for the use of fibrinolytic therapy for

acute ischemic stroke and antithrombotic therapy for sec-

ondary prevention. Future directions are also reviewed,

with particular emphasis on improving therapeutic options

early after stroke onset.

Keywords Antithrombotic therapy Ischemic stroke

Guidelines

Ischemic stroke is a complex disease with a significant public

health burden in the United States [1, 2]. Optimal preventionand treatment is largely based on identifying the underlying

cause and the specific risk factors [3, 4]. Yet, despite a rea-

sonably thorough evaluation, nearly 30% of ischemic strokes

remain cryptogenic, eluding the identification of a specific

pathophysiological mechanism [5]. The complexity and

economic impact of stroke has prompted the development

of guidelines for its prevention and treatment [3, 4, 6, 7].

Implementation of the various evidence-based recommen-

dations can be challenging [7]. We aim to provide a digest of

the most recent guidelines for antithrombotic and fibrinolytic

therapy for ischemic stroke. Throughout the review, we also

compare and consolidate recommendations from the

American College of Chest Physicians (ACCP) [3], the

American Heart Association (AHA) [6], and the European

Stroke Organization (ESO) [8] guidelines.

The ACCP [9] provides a grading scheme for recom-

mended therapies and is adopted herein. Grade 1 recom-

mendations are strong and indicate that the benefits clearly

do or do not outweigh the associated risks, burden, and

costs. Grade 2 indicates recommendations for which the

relation between the benefits and risks of a given strategy is

not as strong. Additionally, all recommendations are tiered

on the basis of the quality/strength of supporting evidence,

with Level A being the strongest (e.g., multiple, well-

designed, randomized, controlled trials with concordant

results), B being intermediate (e.g., 1 randomized, con-

trolled trial or multiple trials without concordant results),

and C being the weakest (e.g., small, observational study

with significant potential for selection or reporting bias).

The underlying theme of the guideline grading systems is

similar across the three organizations, but there are distinct

differences (Table 1). Recommendations in the present

review are drawn from each of the above three guidelines.

A. Krishnan R. D. Lopes J. H. Alexander (&) R. C. Becker

Duke Clinical Research Institute, Duke University Medical

Center, Box 3850, 27710 Durham, NC, USA

e-mail: [email protected]

L. B. Goldstein

Division of Neurology, Department of Medicine,

Duke University Medical Center, Durham, NC, USA

123

J Thromb Thrombolysis (2010) 29:368377

DOI 10.1007/s11239-010-0439-7


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Table1

Guidelinegradingsystem

mapping

Description

Gradeofrecommendation

Benefitsvs.riskand

burdens

Methodologicalqualityof

supportingevidence

Implications

ACCP

AHA

ESO

Strongrecommendation,

high-qualityevidence

Grade1A

ClassI,A

ClassI,A

Benefitsclearlyoutweigh

riskandburdens,orvice

versa

RC

Tswithoutimportant

limitationsoroverwhelming

e

videncefromobservational

s

tudies

Strongre

commendation,canapply

tomostpatientsinmost

circumstanceswithout

reservation


moderate-quality

evidence

Grade1B

ClassI,B

ClassI,B

RC

Tswithimportant

limitations(inconsistent

results,methodologicalflaws,

indirect,orimprecise)or

e

xceptionallystrongevidence

fromobservationalstudies


low-qualityorverylow-

qualityevidence

Grade1C

ClassI,C

ClassI,C

Ob

servationalstudiesorcase

s

eries

Strongre

commendationbutmay

change

whenhigherquality

evidenc

ebecomesavailable

Weakrecommendation,

high-qualityevidence

Grade2A

ClassIIa,A

ClassII,

A

Benefitscloselybalanced

withrisksandburdens

RC

Tswithoutimportant

limitationsoroverwhelming

e

videncefromobservational

s

tudies

Weakrecommendation,

best

actionmaydifferdependingon

circumstancesorpatientsor

societalvalues

Weakrecommendation,

moderate-quality

evidence

Grade2B

ClassIIb,

B

ClassII,

Bor

ClassIII,A

RC

Tswithimportant

limitations(inconsistent

results,methodologicalflaws,

indirectorimprecise)or

e

xceptionallystrongevidence

fromobservationalstudies

Weakrecommendation,

low-qualityorverylow-

qualityevidence

Grade2C

ClassIII

ClassIII,Bor

ClassIII,C

orClassIV,

GCP

Uncertaintyintheestimates

ofbenefits,risks,and

burden;benefits,risks,

andburdenmaybe

closelybalanced

Ob

servationalstudiesorcase

s

eries

Veryweakrecommendations;

otheralternativesmaybeequally

reasona

ble

ACCPAmericanCollegeofChest

Physicians,AHAAmericanHeartAssociation,

ESO

EuropeanStrokeOrganization,G

CPgoodclinicalpractice,RCTrandomize

dclinicaltrial

Antithrombotic therapy for ischemic stroke 369

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Unless otherwise indicated, the recommendations are

similar between the systems.

Recommendations for stroke treatment are based on the

net difference between the potential benefits and risks of

the intervention. For fibrinolytic and antithrombotic ther-

apy, the balance is generally between the potential benefits

of reperfusion and thrombus prevention and the risks of

bleeding [10, 11]. The first-line treatment for acute ische-mic stroke is intravenous fibrinolytic therapy, strongly

recommended to be initiated as soon as possible after

symptom onset. Antithrombotic therapy is expected to

follow as subacute treatment to help prevent ischemic

stroke recurrence. However, only 16% of stroke patients

seen in the emergency department are eligible for fibrino-

lytic therapy, often due to the challengingly brief treatment

window (until recently, within the first 3 h after symptom

onset) [3, 10]. A recent scientific statement from the AHA

extends the fibrinolytic treatment window to 4.5 h after

symptom onset for a subgroup of patients. Regardless of

the use of fibrinolytic therapy, most patients are subse-quently treated with an antithrombotic agent, most com-

monly with aspirin. Our guideline review emphasizes

identifying the various indications for the use or avoidance

of antiplatelet and anticoagulant therapy for the broad

group of patients ineligible for fibrinolytic therapy and for

specific stroke subtypes. Overall, our objective is to high-

light important recommendations that influence day-to-day

clinical management with specific focus on therapeutic

systems that target specific stroke mechanisms.

Treatment of acute ischemic stroke

Shorter time-to-treatment has a strong and consistent effect

on improving favorable clinical outcomes after stroke

[1215]. The therapeutic window, however, is challengingly

brief. The only U.S. Food and Drug Administration-

approved treatment for acute ischemic stroke is intravenous

tissue plasminogen activator (tPA) which, based on current

labeling, must be given within 3 h of symptom onset. Since

quicker treatment with tPA greatly improves the odds of a

favorable outcome, treatment without delay is paramount.

Thus, an acute stroke intervention team can be critical to

increasing the speed and quality of the assessment ofpatients with a suspected acute stroke [3, 4, 16].

Table 2 categorizes treatment of acute ischemic stroke

on the basis of time since stroke onset. Within the first 3 h

of symptom onset, intravenous tPA is strongly recom-

mended (Grade 1A) for selected patients. Intravenous tPA

may also be considered for a subset of patents who can be

treated within 34.5 h after stroke onset [17]. Endovascular

treatment, including the use of intraarterial tPA, may also

be considered for a select group of patients with certain

contraindications to treatment with intravenous tPA.

Antithrombotic therapy is generally not administered

within the first 24 h after intravenous tPA. For acuteischemic stroke patients ineligible for intravenous fibrino-

lytic therapy, antithrombotic agents can be started imme-

diately. However, antithrombotic therapy is complicated,

not only by the need to balance the benefits of preventing

recurrent thromboembolism versus the risk of cerebral and

systemic bleeding but also because of the various stroke

etiologic subtypes, each with distinct pathophysiologic

mechanisms. Antiplatelet therapy with aspirin is the only

antithrombotic agent recommended for patients with acute

ischemic stroke who have not received thrombolytic ther-

apy [18, 19]. Early anticoagulation is not recommended for

this group of patients due to the at best uncertain benefit

combined with an unacceptably high risk of bleeding [19].

However, certain subgroups of patients such as those with

ischemic stroke caused by cardiogenic embolism may

benefit from early anticoagulation [20, 21].

Table 2 Acute ischemic

treatments of choice by time

since stroke onset

370 A. Krishnan et al.

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Within 3 h of onset of symptoms

Intravenous tPA 0.9 mg/kg (maximum dose of 90 mg),

with 10% of the total dose given as an initial bolus and the

remainder infused over 60 min is recommended for eligi-

ble ischemic stroke patients (Grade 1A) (Tables 3, 4). Prior

to tPA administration, some experts recommend that, if

possible, efforts should be made to demonstrate a large

artery intracranial occlusion using modern neuro-imaging;

but the ACCP guidelines discourage undue delays to

treatment to complete vascular imaging. Following tPA

administration, close monitoring of blood pressure is rec-

ommended (goal blood pressure\ 180/105 mmHg) and

antithrombotic agents including aspirin should be avoided

for 24 h.

Between 3 and 4.5 h of onset of symptoms

Based on a single prospective, randomized, placebo-con-

trolled trial of rtPA administered between 3 and 4.5 h after

stroke onset [22], the time window for administering tPA to

patients with acute ischemic stroke has been recently

extended to 4.5 h in an AHA scientific statement (Grade

1B) [17]. Using the modified Rankin Scale (0 or 1) score at

90 days after stroke occurrence as the primary endpoint,

the study found a modest statistically significant increase

(7%) in the likelihood of being normal or near normal withtreatment (unadjusted OR, 1.34; 95% CI, 1.021.76;

P = 0.04) [22]. The eligibility criteria for treatment in this

time period are largely the same as the earlier time window

(Table 3), but with the following additional exclusions: (1)

patients older than 80 years, (2) patients receiving an oral

anticoagulant regardless of their INR, (3) those with a

baseline National Institutes of Health Stroke Scale

score[ 25, and (4) those with a history of both stroke and

diabetes.

Within 6 h of onset of symptoms

Intraarterial fibrinolytic therapy is suggested to be benefi-

cial within 6 h of stroke onset for patients with angio-

graphically demonstrated middle cerebral artery occlusion.

Those with acute basilar artery thrombosis might be con-

sidered for treatment for even more extended periods. In

both cases, the guidelines recommend baseline computed

tomography/magnetic resonance imaging to confirm that

there is no major early infarction. There is very little

clinical trial evidence to aid in selecting an optimal dose or

Table 3 Characteristics of patients who may be eligible for IV

fibrinolytic therapy (0- to 3-h window since stroke onset)

Characteristics of patients with stroke who may be eligible for IV tPA

therapy

Age[ 18 years

Diagnosis of ischemic stroke causing clinically apparent neurologic

deficit

Onset of symptoms\ 3 h before possible beginning of treatment

No stroke or head trauma during preceding 3 months

No major surgery during preceding 14 daysNo history of or current intracranial hemorrhage (baseline CT

evidence)

Systolic blood pressure\ 185 mmHg

Diastolic blood pressure\110 mmHg

No rapidly resolving symptoms or only minor symptoms of stroke

No symptoms suggestive of subarachnoid hemorrhage

No gastrointestinal or urinary tract hemorrhage within preceding

3 weeks

No arterial puncture at a noncompressible site or lumbar puncture

within preceding 7 days

No seizure at the onset of stroke

No clinical presentation suggesting post-MI pericarditis

Not pregnant

Prothrombin time\ 15 s or INR\ 1.7, without use of an

anticoagulant

Partial thromboplastin time within normal range, if heparin was

given in preceding 48 h

Platelet count[100,000/mm3

Blood glucose concentration between 50400 mg/dL

No need for aggressive measures to lower blood pressure to within

above-specified limits

CT computed tomography, INR international normalized ratio, IV

intravenous, tPA tissue plasminogen activator

Table 4 Treatment of ischemic stroke with IV tPA

Treatment of ischemic stroke with IV tPA in an intensive care/stroke unit

Determine patients eligibility for treatment (Table 3)

Infuse tPA at 0.9 mg/kg (maximum 90 mg) over a 60-min period with first 10% given as bolus over a 1-min period

Perform neurologic assessments every 15 min during infusion of tPA, every 30 min for next 6 h, and every 60 min for next 16 h

If severe headache, acute hypertension, or nausea and vomiting occur, discontinue infusion and obtain emergency CT scan

Measure BP every 15 min for 2 h, every 30 min for 6 h, and every 60 min for 16 h; repeat measurements more frequently if systolic BP is

[180 mmHg or diastolic BP is[105 mmHg, and administer antihypertensive drugs as needed to maintain BP at or below these levels

BP blood pressure, CT computed tomography, IV intravenous, tPA tissue plasminogen activator


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mode of delivery [3]. Intraarterial tPA has not been tested

in a randomized trial, and the efficacy of this approach as

compared with intravenous tPA has not been directly

evaluated.

Acute ischemic stroke patients not eligible

for thrombolysis

Aspirin is the only antiplatelet agent shown to be helpful in

patients with acute ischemic stroke [18, 19]. Early aspirin

therapy (initial dose of 150325 mg per day started within

48 h of stroke onset) is recommended for patients with

acute ischemic stroke who did not receive fibrinolytic

therapy (Grade 1A). Reducing the dose to 50100 mg per

day is thought to help reduce bleeding complications.

Aspirin may be used safely in combination with low doses

of subcutaneous heparin for deep vein thrombosis (DVT)

prophylaxis. There are small yet significant absolute ben-

efits of aspirin in reducing the outcomes of death ordependency at 6 months after stroke [23]. The low cost of

aspirin also provides a significant public health benefit

[3, 4].

Very early anticoagulation is not recommended for

patients with acute ischemic stroke (Grade 1B). No ade-

quately powered trials have evaluated the efficacy of

anticoagulation within 12 h of stroke onset in any stroke

population. Even though some experts have recommended

the use of heparin in specific stroke subtypes such as car-

dioembolic and large artery atherosclerotic stroke, evalu-

ating the associated riskbenefit ratio remains challenging

[24]. Despite the risk and uncertainty in utilizing antico-

agulation, a certain group of high-risk patientssuch as

those with mechanical heart valves, an established intra-

cardiac thrombus, atrial fibrillation with associated valvular

disease, or severe congestive heart failuremay benefit

from early anticoagulation [3, 4]. Brain imaging is always

recommended prior to anticoagulant therapy to help esti-

mate infarct size as well as to exclude brain hemorrhage.

Anticoagulant therapy is especially hazardous for patients

with large infarctions, uncontrolled hypertension, or other

bleeding disorders.

DVT and PE in acute ischemic stroke

The only instance of a strong recommendation for antico-

agulant therapy in acute ischemic stroke is for the pre-

vention of two frequent complications in strokeDVT and

pulmonary embolism (PE) as a consequence of restricted

mobility (Grade 1A) [2527]. For patients with contrain-

dications to anticoagulants, intermittent pneumatic com-

pression (IPC) devices or elastic stockings are

recommended (Grade 1B). IPC devices are also recom-

mended for the initial treatment of DVT/PE prophylaxis in

patients with intracerebral hemorrhage (Grade 1B), to be

followed by low-dose subcutaneous heparin as soon as the

second day after the onset of hemorrhage (Grade 2C).

Secondary stroke prevention

The probability of a recurrent stroke following the first

stroke is over 310% in the first month and over 514% in

the first year [28, 29]. A recurrent stroke can be devastating,

with twice the probability of death and increased cardio-

vascular complications as compared with a first stroke [30].

There are well-defined modifiable risk factors and effective

secondary prevention measures [30, 31]. Antithrombotic

therapies for secondary stroke prevention include both

antiplatelet agents and anticoagulants. Respective treat-

ments are based on the mechanism of the cerebral ischemic

event, with antiplatelet drugs used for non-cardioembolicstroke and anticoagulants for high-risk cardioembolic cau-

ses. Table 5 summarizes specific recommendations for

antiplatelet or anticoagulant treatment. Choices for anti-

platelet therapy in current guidelines include aspirin

monotherapy, the combination of aspirin and extended-

release dipyridamole, or clopidogrel monotherapy. This is

broadly applicable for patients who have experienced an

atherothrombotic, lacunar or cryptogenic stroke and

have no contraindications for antiplatelet therapy. Aspirin

(50100 mg daily), the combination of aspirin and exten-

ded-release dipyridamole (25/200 mg twice daily), and

clopidogrel (75 mg daily) are each appropriate for initial

therapy. The combination of aspirin and extended-release

dipyridamole is recommended over aspirin alone (Grade

1A), and clopidogrel is suggested over aspirin (Grade 2B).

The combination of aspirin and clopidogrel is not advised

(Grade 1B) due to the increased risk of life-threatening

bleeding with no significant reduction in ischemic events.

See Table 5 for specific exceptions. Oral anticoagulation is

beneficial for recurrent stroke prevention in specific sub-

groups of patients, primarily those with high-risk cardiac

sources of embolism (Table 5b, c). The clinical data, how-

ever, are minimal; therefore, antiplatelet therapy is gener-

ally recommended over anticoagulation especially if the

cardioembolic sources of stroke are minor or uncertain.

ACCP, AHA, and ESO

Table 6 compares salient recommendations between the

ACCP, AHA, and the ESO guidelines for treatment of

ischemic stroke. The 2008 ACCP and AHA guidelines are

virtually identical with the exception of the recent AHA


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scientific statement on extended time frame for intravenous

tPA use in acute ischemic stroke. We have chosen to group

the ACCP [3] and AHA [6] guidelines for purposes of

comparison with the ESO guidelines [8]. The AHA/ACCP

and ESO guidelines are in close agreement on intravenous

thrombolytic therapy over the first 3 h as well as the first

Table 5 Stroke prevention and antithrombotics

A. Non-cardioembolic stroke/TIA

(atherothrombotic, lacunar, cryptogenis)

Antiplatelet therapy (Grade 1A) antiplatelet agents recommended

over oral anticoagulation (Grade 1A)

General guidelines

Applicable to most patients Aspirin (50100 mg/day)

Aspirin (25 mg) and ER-dipyridamole (200 mg twice daily)

(recommended over aspirin; Grade 1A)Clopidogrel (75 daily) (recommended over aspirin; Grade 2B)

Specific guidelines

Acute MI, coronary syndrome, recent

coronary stent

Clopidogrel and aspirin; 75100 mg (Grade 1A) (long-term use of the

combination discouraged; Grade 1B)

Aspirin allergy Clopidogrel (Grade 1A)

Carotid endarterectomy Aspirin (50100 mg/day); recommended prior to and following

procedure (Grade 1A)

Aortic atherosclerotic lesions Antiplatelet therapy recommended over no therapy (Grade 1A)

B. Cardioembolic stroke/TIA

Major risk

Atrial fibrillation

Long-term oral anticoagulation (Grade 1A)

Warfarin (target INR 2.5; range 2.03.0)

Prosthetic mechanical valves

Left ventricular thrombus

Endocarditis (infective, marantic)

Mitral stenosis

Atrial myxoma

Minor/uncertain risk

Mitral prolapse

Antiplatelet therapy (Grade 1A)

Mitral annular calcification

Patent foramen ovale

Atrioseptal aneurysm

Calcific aortic stenosis

Mitral valve strands

C. Other specific conditions for anticoagulation

Pregnancy Adjusted-dose UFH or LMWH with factor Xa monitoring throughout

pregnancy,

UFH or LMWH until week 13 followed by

warfarin until mid-third trimester and then UFH/LMWH reinstituted

until delivery (Grade 2C)

Cryptogenic stroke with mobile aortic

arch thrombi

Oral anticoagulation or antiplatelet therapy (Grade 2C)

Cerebral venous sinus thrombosis UFH or LMWH over no anticoagulant therapy (Grade 1B) continued

use of vitamin K

antagonist therapy for up to 12 months

recommended (Grade 1B); target INR 2.5; range 2.03.0

Arterial dissection Oral anticoagulation or antiplatelet therapy for 36 months (Grade

2B); followed

by antiplatelet therapy (Grade 2C)

TIA transient ischemic attack, INR international normalized ratio, TIA transient ischemic attack, LMWH low-molecular-weight heparin, UFH

unfractionated heparin


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4.5 h after stroke onset. The differences, if any, are in the

strength of recommendation for the recently expanded 4.5-

h window of tPA treatment (AHA Class IB vs. ESO Class

IA) and in that the ESO guidelines do not strongly dis-

courage exclusion of certain groups of patients such as

those with seizures at stroke onset or those under 18 and

over 80 years of age. The two guidelines are similar

regarding eligibility and use of intraarterial thrombolytic

therapy within a 6-h time frame. The guidelines are similar

for secondary stroke prevention as well with the main

difference being a stronger recommendation by the ESO

for clopidogrel.

Table 6 Comparison of American and European guidelines

Stroke treatment American (ACCP and AHA) guidelines European (ESO) guidelines

Acute care

Within 3 h IV tPA (Grade 1A) IV tPA (Class I, Level A)

Inclusion criteria for IV tPA: age[18 years Recommended that IV rtPA may also be administered in

selected patients\18 years and[80 years (Class III, Level

C)Exclusion criteria for IV tPA: seizure at stroke onset Recommended that IV rtPA may be used in patients with

seizures at stroke onset, if the neurological deficit is related

to acute cerebral ischaemia (Class IV, GCP)

34.5 h IV tPA (Class I, Level B) IV tPA (Class I, Level A)

should be administered to eligible patients who can be

treated in the time period of 3 to 4.5 h after stroke

although treatment between 3 and 4.5 h is not included in

the European labeling

Beyond 4.5 h For patients with acute ischemic stroke of[ 3 but\ 4.5 h

we suggest clinicians do not use IV tPA (Grade 2A). For

patients with acute stroke onset of[4.5 h, we recommend

against the use of IV tPA (Grade 1A)

Intravenous rtPA may be of benefit also for acute ischemic

stroke beyond 3 h after onset (Class I, Level B) but is not

recommended for routine clinical practice

Thrombolytic

therapy

For patients with angiographically demonstrated MCA

occlusionwho can be treated within 6 h of symptom onset,

we suggest intraarterial thrombolytic therapy with tPA

(Grade 2C)

Intraarterial treatment of acute MCA occlusion within a

6-hour time window is recommended as an option (Class II,

Level B)

For patients with acute basilar artery thrombosis and without

major CT/MRI evidence of infarction, we suggest either

intraarterial or IV thrombolysis with tPA (Grade 2C)

Intraarterial thrombolysis is recommended for acute basilar

occlusion in selected patients (Class III, Level B).

Intravenous thrombolysis for basilar occlusion is an

acceptable alternative even after 3 h (Class III, Level B)

Antiplatelet

therapy

we recommend early aspirin therapy (initial dose 150

325 mg) (Grade 1A)

It is recommended that aspirin (160325 mg loading dose)

be given within 48 h after ischaemic stroke (Class I, Level

A)

Following tPA administration, antithrombotic agents,

including aspirin, should be avoided for 24 h (Grade 1A)

It is recommended that if thrombolytic therapy is planned or

given, aspirin or other antithrombotic therapy should not be

initiated within 24 h (Class IV, GCP)

Anticoagulant

therapy

we recommend against full-dose anticoagulation with IV,

SC, or low-molecular-weight heparins or heparinoids (Grade

1B)

Early administration of UFH, low-molecular-weight heparin

or heparinoids is not recommended (Class I, Level A)

Secondary prevention

Antiplatelet

therapy

Aspirin, the combination of aspirin 25 mg and extended-

release dipyridamole 200 mg twice daily and clopidogrel

75 mg/24 h are all acceptable options for initial therapy

(Grade 1A)

It is recommended that patients receive antithrombotic

therapy (Class I, Level A) aspirin (501,300 mg/24 h),

clopidogrel, dipyridamole, triflusal, or dipyridamole

(200 mg extended-release twice daily) combined with

aspirin (30300 mg/24 h)

We recommend using the combination of aspirin and

extended-release dipyridamole (25/200 mg twice daily) over

aspirin (Grade 1A) and suggest clopidogrel over aspirin

(Grade 2B)

Where possible, combined aspirin and dipyridamole, or

clopidogrel alone, should be given (Class 1, Level A)

Anticoagulant

therapy

We recommend antiplatelet agents over oral anticoagulation

(Grade 1A)

anticoagulation should not be used after non-cardio-

embolic ischaemic stroke, except in some specific situations

(Class IV, GCP)

ACCP American College of Chest Physicians,AHA American Heart Association, CT computed tomography, ESO European Stroke Organization,GCP good clinical practice, IV intravenous, MCA middle cerebral artery, MRI magnetic resonance imaging, SC subcutaneous, tPA tissue

plasminogen activator, UFH unfractionated heparin


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The primary challenge in reducing the risk of recurrent

stroke is not necessarily due to lack of access to guidelines

but rather due to underutilization of evidence-based rec-

ommendations and suboptimal patient adherence to the

prescribed treatment regimen [7, 32, 33]. Challenges in

effective transitioning between care settings may also

contribute to the lack of adherence in preventive and

therapeutic interventions [30]. With the primary objectiveof improving adherence to evidence-based guidelines, the

American Stroke Association initiated the Get With The

Guidelines-Stroke quality improvement program [34, 35].

To date, this program has demonstrated significant

improvements in both acute antithrombotic and thrombo-

lytic therapy utilization as well as in the implementation

and adherence to secondary prevention measures.

Future directions

There is an acknowledged need for large scale randomizedtrials that marry translational laboratory research to clinical

reality in stroke treatment [3640]. The key finding from

current stroke research is that the time window for effective

neuronal salvage by reperfusion or neuroprotection is very

brief [4144]. Effective urgent stroke therapy cannot be

achieved without augmenting current thrombolysis, possi-

bly with better thrombolytic agents, intraarterial drug

delivery, mechanical clot disruption, or through adding

anticoagulants, newer antiplatelet agents, and neuropro-

tective drugs [36, 42]. Landmark clinical trials have

investigated the aforementioned avenues of treatment, such

as with novel thrombolytic agents (desmoteplase into an

extended treatment window) [45], adjunctive drug treat-

ments (combination of eptifibatide, aspirin or low-molec-

ular-weight heparin with intraarterial or intravenous tPA)

[46, 47], and novel applications of known neuroprotective

agents (minocycline and enoxaparin) [48]. Yet despite

early positive results and significant promise, several of the

above investigations have ended as negative studies; hence,

the potential for a useful stroke therapy in clinical practice

remains elusive.

This does, however, help bring the focus back to the

basics of stroke therapy with drugs affecting the coagula-

tion systemof achieving the fine balance between risks of

thrombosis and hemorrhageparticularly through regu-

latable [49, 50] antithrombotics. Antithrombotic therapy is

critical in short-term as well as long-term treatment of

stroke [51]. Antithrombotic agents that are more effica-

cious than aspirin and that are safer and easier to use than

heparin/adjusted-dose warfarin represent a substantial

unmet need in stroke treatment.

The key to meeting this need lies in a generalizable

strategy that helps regulate the effects of antithrombotic

agents [52], the first step in reaching the balance between

thrombotic and hemorrhagic risks. Reversibility certainly

affords an important option in patients with a hemorrhagic

complication [53, 54]. Recent studies have demonstrated

effective control of both anticoagulation [55, 56] and

antiplatelet [57] mechanisms through a rationally designed

drug-antidote pair for antithrombotic therapy. Essentially,

the activity of target coagulation proteins (for anticoagu-lation) or plasma glycomeric proteins (for antiplatelet

mechanisms) are modulated using properties inherent to

nucleic acid ligands [55, 57]. Aptamers, as reversible

anticoagulants, are currently undergoing in-human studies

[58, 59].

It is our view that the focus of future studies should be a

paradigm shift from isolated drug/device interventions to a

more comprehensive approach, especially considering the

heterogeneity of acute ischemic stroke. The time frame in

which a promising drug is administered is a key factor in

the study and development of novel therapies.

Summary

Several guidelines have been published regarding different

aspects of stroke care [3, 4, 6, 7]. Yet, the clinical appli-

cation of the guidelines remains challenging. In an effort to

facilitate ease of use for the practitioner, this article pre-

sents a condensed formulation of the recent ACCP guide-

lines on antithrombotic and thrombolytic therapy for

ischemic stroke. Our review identifies relevant guidelines

not only for the majority of stroke patients but also for the

instances in which recommendations differ.

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