J Thromb Thrombolysis (2010) 29:368–377
DOI 10.1007/s11239-010-0439-7
Antithrombotic therapy for ischemic stroke: guidelines translated
for 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 of
ischemic 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
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: John.H.Alexander@duke.edu
L. B. Goldstein
Division of Neurology, Department of Medicine,
Duke University Medical Center, Durham, NC, USA
123
Ischemic stroke is a complex disease with a significant public
health burden in the United States [1, 2]. Optimal prevention
and 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.
 Table 1 Guideline grading system mapping
Description Grade of recommendation Benefits vs. risk and Methodological quality of Implications
burdens supporting evidence
ACCP AHA ESO

Strong recommendation, Grade 1A Class I, A Class I, A RCTs without important

high-quality evidence limitations or overwhelming
evidence from observational
studies Strong recommendation, can apply
Antithrombotic therapy for ischemic stroke

Strong recommendation, Grade 1B Class I, B Class I, B Benefits clearly outweigh RCTs with important to most patients in most
moderate-quality risk and burdens, or vice limitations (inconsistent circumstances without
evidence versa results, methodological flaws, reservation
indirect, or imprecise) or
exceptionally strong evidence
from observational studies
Strong recommendation, Grade 1C Class I, C Class I, C Observational studies or case Strong recommendation but may
low-quality or very low- series change when higher quality
quality evidence evidence becomes available
Weak recommendation, Grade 2A Class IIa, A Class II, A RCTs without important
high-quality evidence limitations or overwhelming
Benefits closely balanced evidence from observational
with risks and burdens studies Weak recommendation, best
Weak recommendation, Grade 2B Class IIb, B Class II, B or RCTs with important action may differ depending on
moderate-quality Class III, A limitations (inconsistent circumstances or patients’ or
evidence results, methodological flaws, societal values
indirect or imprecise) or
exceptionally strong evidence
from observational studies
Weak recommendation, Grade 2C Class III Class III, B or Uncertainty in the estimates Observational studies or case Very weak recommendations;
low-quality or very low- Class III, C of benefits, risks, and series other alternatives may be equally
quality evidence or Class IV, burden; benefits, risks, reasonable
GCP and burden may be
closely balanced
ACCP American College of Chest Physicians, AHA American Heart Association, ESO European Stroke Organization, GCP good clinical practice, RCT randomized clinical trial
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 1–6% 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
[12–15]. The therapeutic window, however, is challengingly
Table 2 Acute ischemic
treatments of choice by time
since stroke onset
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A. Krishnan et al.
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 of
patients 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 3–4.5 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 acute
ischemic 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].
Antithrombotic therapy for ischemic stroke 371

Within 3 h of onset of symptoms artery intracranial occlusion using modern neuro-imaging;

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
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

Table 3 Characteristics of patients who may be eligible for IV
fibrinolytic therapy (0- to 3-h window since stroke onset)
Based on a single prospective, randomized, placebo-con-
Characteristics of patients with stroke who may be eligible for IV tPA trolled trial of rtPA administered between 3 and 4.5 h after
therapy
stroke onset [22], the time window for administering tPA to
Age [ 18 years
patients with acute ischemic stroke has been recently
Diagnosis of ischemic stroke causing clinically apparent neurologic
extended to 4.5 h in an AHA scientific statement (Grade
deficit
1B) [17]. Using the modified Rankin Scale (0 or 1) score at
Onset of symptoms \ 3 h before possible beginning of treatment
90 days after stroke occurrence as the primary endpoint,
No stroke or head trauma during preceding 3 months
the study found a modest statistically significant increase
No major surgery during preceding 14 days
(7%) in the likelihood of being normal or near normal with
No history of or current intracranial hemorrhage (baseline CT
evidence)
treatment (unadjusted OR, 1.34; 95% CI, 1.02–1.76;
Systolic blood pressure \ 185 mmHg
P = 0.04) [22]. The eligibility criteria for treatment in this
time period are largely the same as the earlier time window
Diastolic blood pressure \ 110 mmHg
(Table 3), but with the following additional exclusions: (1)
No rapidly resolving symptoms or only minor symptoms of stroke
patients older than 80 years, (2) patients receiving an oral
No symptoms suggestive of subarachnoid hemorrhage
anticoagulant regardless of their INR, (3) those with a
No gastrointestinal or urinary tract hemorrhage within preceding
3 weeks baseline National Institutes of Health Stroke Scale
No arterial puncture at a noncompressible site or lumbar puncture score [ 25, and (4) those with a history of both stroke and
within preceding 7 days diabetes.
No seizure at the onset of stroke
No clinical presentation suggesting post-MI pericarditis
Not pregnant Within 6 h of onset of symptoms
Prothrombin time \ 15 s or INR \ 1.7, without use of an
anticoagulant Intraarterial fibrinolytic therapy is suggested to be benefi-
Partial thromboplastin time within normal range, if heparin was cial within 6 h of stroke onset for patients with angio-
given in preceding 48 h graphically demonstrated middle cerebral artery occlusion.
Platelet count [ 100,000/mm3 Those with acute basilar artery thrombosis might be con-
Blood glucose concentration between 50–400 mg/dL sidered for treatment for even more extended periods. In
No need for aggressive measures to lower blood pressure to within both cases, the guidelines recommend baseline computed
above-specified limits tomography/magnetic resonance imaging to confirm that
CT computed tomography, INR international normalized ratio, IV there is no major early infarction. There is very little
intravenous, tPA tissue plasminogen activator clinical trial evidence to aid in selecting an optimal dose or

Table 4 Treatment of ischemic stroke with IV tPA

Treatment of ischemic stroke with IV tPA in an intensive care/stroke unit
Determine patient’s 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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372
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 150–325 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 50–100 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 or
dependency 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 risk–benefit ratio remains challenging
[24]. Despite the risk and uncertainty in utilizing antico-
agulation, a certain group of high-risk patients—such as
those with mechanical heart valves, an established intra-
cardiac thrombus, atrial fibrillation with associated valvular
disease, or severe congestive heart failure—may 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 stroke—DVT and
pulmonary embolism (PE) as a consequence of restricted
mobility (Grade 1A) [25–27]. For patients with contrain-
dications to anticoagulants, intermittent pneumatic com-
pression (IPC) devices or elastic stockings are
123
A. Krishnan et al.
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 3–10% in the first month and over 5–14% 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-cardioembolic
stroke 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
(50–100 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
Antithrombotic therapy for ischemic stroke 373

Table 5 Stroke prevention and antithrombotics

A. Non-cardioembolic stroke/TIA Antiplatelet therapy (Grade 1A) antiplatelet agents recommended
(atherothrombotic, lacunar, cryptogenis) over oral anticoagulation (Grade 1A)

General guidelines
Applicable to most patients Aspirin (50–100 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 Clopidogrel and aspirin; 75–100 mg (Grade 1A) (long-term use of the
coronary stent combination discouraged; Grade 1B)
Aspirin allergy Clopidogrel (Grade 1A)
Carotid endarterectomy Aspirin (50–100 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
Prosthetic mechanical valves
Left ventricular thrombus Long-term oral anticoagulation (Grade 1A)
Endocarditis (infective, marantic) Warfarin (target INR 2.5; range 2.0–3.0)
Mitral stenosis
Atrial myxoma
Minor/uncertain risk
Mitral prolapse
Mitral annular calcification
Patent foramen ovale
Antiplatelet therapy (Grade 1A)
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 Oral anticoagulation or antiplatelet therapy (Grade 2C)
arch thrombi
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 2.0–3.0
Arterial dissection Oral anticoagulation or antiplatelet therapy for 3–6 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

scientific statement on extended time frame for intravenous comparison with the ESO guidelines [8]. The AHA/ACCP
tPA use in acute ischemic stroke. We have chosen to group and ESO guidelines are in close agreement on intravenous
the ACCP [3] and AHA [6] guidelines for purposes of thrombolytic therapy over the first 3 h as well as the first

123
374 A. Krishnan et al.

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)’’
3–4.5 h IV tPA (Class I, Level B) IV tPA (Class I, Level A)
‘‘…should be administered to eligible patients who can be ‘‘…although treatment between 3 and 4.5 h is not included in
treated in the time period of 3 to 4.5 h after stroke’’ the European labeling’’
Beyond 4.5 h ‘‘For patients with acute ischemic stroke of [ 3 but \ 4.5 h ‘‘Intravenous rtPA may be of benefit also for acute ischemic
we suggest clinicians do not use IV tPA (Grade 2A). For stroke beyond 3 h after onset (Class I, Level B) but is not
patients with acute stroke onset of [4.5 h, we recommend recommended for routine clinical practice’’
against the use of IV tPA (Grade 1A)’’
Thrombolytic ‘‘For patients with angiographically demonstrated MCA ‘‘Intraarterial treatment of acute MCA occlusion within a
therapy occlusion…who can be treated within 6 h of symptom onset, 6-hour time window is recommended as an option (Class II,
we suggest intraarterial thrombolytic therapy with tPA Level B)’’
(Grade 2C)’’
‘‘For patients with acute basilar artery thrombosis and without ‘‘Intraarterial thrombolysis is recommended for acute basilar
major CT/MRI evidence of infarction, we suggest either occlusion in selected patients (Class III, Level B).
intraarterial or IV thrombolysis with tPA (Grade 2C)’’ Intravenous thrombolysis for basilar occlusion is an
acceptable alternative even after 3 h (Class III, Level B)’’
Antiplatelet ‘‘…we recommend early aspirin therapy (initial dose 150– ‘‘It is recommended that aspirin (160–325 mg loading dose)
therapy 325 mg) (Grade 1A)’’ be given within 48 h after ischaemic stroke (Class I, Level
A)’’
‘‘Following tPA administration, antithrombotic agents, ‘‘It is recommended that if thrombolytic therapy is planned or
including aspirin, should be avoided for 24 h (Grade 1A)’’ given, aspirin or other antithrombotic therapy should not be
initiated within 24 h (Class IV, GCP)’’
Anticoagulant ‘‘…we recommend against full-dose anticoagulation with IV, ‘‘Early administration of UFH, low-molecular-weight heparin
therapy SC, or low-molecular-weight heparins or heparinoids (Grade or heparinoids is not recommended (Class I, Level A)’’
1B)’’
Secondary prevention
Antiplatelet ‘‘Aspirin, the combination of aspirin 25 mg and extended- ‘‘It is recommended that patients receive antithrombotic
therapy release dipyridamole 200 mg twice daily and clopidogrel therapy (Class I, Level A) aspirin (50–1,300 mg/24 h),
75 mg/24 h are all acceptable options for initial therapy clopidogrel, dipyridamole, triflusal, or dipyridamole
(Grade 1A)’’ (200 mg extended-release twice daily) combined with
aspirin (30–300 mg/24 h)’’
‘‘We recommend using the combination of aspirin and ‘‘Where possible, combined aspirin and dipyridamole, or
extended-release dipyridamole (25/200 mg twice daily) over clopidogrel alone, should be given (Class 1, Level A)’’
aspirin (Grade 1A) and suggest clopidogrel over aspirin
(Grade 2B)’’
Anticoagulant ‘‘We recommend antiplatelet agents over oral anticoagulation ‘‘…anticoagulation should not be used after non-cardio-
therapy (Grade 1A)’’ 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

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.

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Antithrombotic therapy for ischemic stroke
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 objective
of 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 randomized
trials that marry translational laboratory research to clinical
reality in stroke treatment [36–40]. The key finding from
current stroke research is that the time window for effective
neuronal salvage by reperfusion or neuroprotection is very
brief [41–44]. 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 system—of achieving the fine balance between risks of
thrombosis and hemorrhage—particularly 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
375
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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