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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

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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.

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Strong recommendation, can apply to most patients in most circumstances without reservation

Very weak recommendations; other alternatives may be equally reasonable

Weak recommendation, best action may differ depending on circumstances or patients’ or societal values

Strong recommendation but may change when higher quality evidence becomes available

ACCP American College of Chest Physicians, AHA American Heart Association, ESO European Stroke Organization, GCP good clinical practice, RCT randomized clinical trial

Implications

RCTs with important limitations (inconsistent results, methodological flaws, indirect, or imprecise) or exceptionally strong evidence

RCTs with important limitations (inconsistent results, methodological flaws, indirect or imprecise) or exceptionally strong evidence

RCTs without important limitations or overwhelming evidence from observational studies

RCTs without important limitations or overwhelming evidence from observational studies

Observational studies or case

Observational studies or case

from observational studies

from observational studies

Methodological quality of supporting evidence

series

series

Uncertainty in the estimates of benefits, risks, and burden; benefits, risks, and burden may be closely balanced

Benefits clearly outweigh risk and burdens, or vice versa

Benefits closely balanced with risks and burdens

Benefits vs. risk and burdens

Class III, B or Class III, C or Class IV, GCP

Class II, B or Class III, A

Class II, A

Class I, A

Class I, C

Class I, B

ESO

Class IIa, A

Class IIb, B

Grade of recommendation

Class I, A

Class I, C

Class I, B

Class III

AHA

Table 1 Guideline grading system mapping

Grade 1A

Grade 2A

Grade 1C

Grade 2C

Grade 1B

Grade 2B

ACCP

Strong recommendation, low-quality or very low- quality evidence

Weak recommendation, low-quality or very low- quality evidence

Strong recommendation, high-quality evidence

Strong recommendation, moderate-quality evidence

Weak recommendation, high-quality evidence

Weak recommendation, moderate-quality evidence

Description

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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 [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 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].

Table 2 Acute ischemic treatments of choice by time since stroke onset

from early anticoagulation [ 20 , 21 ]. Table 2 Acute ischemic treatments of choice by

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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

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 days

No 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/mm 3

Blood glucose concentration between 50–400 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

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 with treatment (unadjusted OR, 1.34; 95% CI, 1.02–1.76; 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

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

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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 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) [2527]. For patients with contrain- dications to anticoagulants, intermittent pneumatic com- pression (IPC) devices or elastic stockings are

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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

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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

Specific guidelines

Acute MI, coronary syndrome, recent coronary stent

Aspirin allergy

Carotid endarterectomy

Aortic atherosclerotic lesions

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)

Clopidogrel and aspirin; 75–100 mg (Grade 1A) (long-term use of the combination discouraged; Grade 1B)

Clopidogrel (Grade 1A)

Aspirin (50–100 mg/day); recommended prior to and following procedure (Grade 1A)

Antiplatelet therapy recommended over no therapy (Grade 1A)

B. Cardioembolic stroke/TIA

Major risk

Atrial fibrillation

Prosthetic mechanical valves

Left ventricular thrombus

Endocarditis (infective, marantic)

Mitral stenosis

Atrial myxoma

Minor/uncertain risk

Mitral prolapse

Mitral annular calcification

Patent foramen ovale

Atrioseptal aneurysm

Calcific aortic stenosis

Mitral valve strands

Long-term oral anticoagulation (Grade 1A) Warfarin (target INR 2.5; range 2.0–3.0)

Antiplatelet therapy (Grade 1A)

C. Other specific conditions for anticoagulation

Pregnancy

Cryptogenic stroke with mobile aortic arch thrombi

Cerebral venous sinus thrombosis

Arterial dissection

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)

Oral anticoagulation or antiplatelet therapy (Grade 2C)

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

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 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

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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 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

‘‘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, we suggest intraarterial thrombolytic therapy with tPA (Grade 2C)’’

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

‘‘ 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, 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

‘‘ 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 75 mg/24 h are all acceptable options for initial therapy (Grade 1A)’’

therapy (Class I, Level A) aspirin (50–1,300 mg/24 h), clopidogrel, dipyridamole, triflusal, or dipyridamole (200 mg extended-release twice daily) combined with aspirin (30–300 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

‘‘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

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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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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 [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 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

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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