AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Background

Thrombolytic therapy is of proven benefit for selected patients with ischemic stroke. Completion of 9 large phase III trials of intravenous thrombolytic therapy, which employed various agents, doses, and time windows, has provided a substantial database to guide clinical practice.

The pivotal National Institutes of Neurological Disorders and Stroke (NINDS) tissue plasminogen activator (tPA) trials were completed in 1995 and randomized 624 subjects within 3 hours of stroke onset to receive 0.9 mg/kg of intravenous tPA or placebo. These 2 trials found that patients treated with tPA within 3 hours of onset had a substantially better chance of functional independence with minimal or no disability 3 months after treatment. The proportion of patients with minimal or no disability increased from 38% with placebo to 50% with tPA, a 12% absolute improvement. The number needed to treat for 1 more patient to have a normal or near normal outcome was 8, and the number needed to treat for 1 more patient to have an improved outcome was 3.1.

An independent reanalysis of the trials demonstrated a robust treatment effect in favor of tPA. The use of tPA for acute ischemic stroke was approved by the US Food and Drug Administration (FDA) in 1996 and subsequently by regulatory agencies in Canada, Europe, South America, and Asia.

The favorable results of the NINDS tPA trials have generally been duplicated in phase IV studies examining the use of intravenous tPA in routine clinical practice. These studies have documented that rates of favorable outcome and symptomatic hemorrhage (see Complications) similar to those of the original NINDS tPA trials can be achieved in medical centers that have made institutional commitments to providing acute stroke therapy. The largest study of actual clinical practice evaluated 6843 patients treated at 285 centers in 14 countries and found the rate of complications and favorable outcomes similar to those of the NINDS tPA trials. These findings show that tPA is just as effective in clinical practice as in clinical trials when inclusion and exclusion guidelines are followed.

The European Cooperative Acute Stroke Study (ECASS) I was completed in 1995 and randomized 620 subjects within 6 hours of stroke onset to receive 1.1 mg/kg of intravenous tPA or placebo. This study failed to find a benefit for the use of tPA within 6 hours of stroke onset. However, in a subgroup analysis that excluded subjects with protocol violations, most of whose CT scans exhibited early signs of major infarction, the functional outcome 90 days after stroke was better in subjects treated with tPA than in those who received placebo.

ECASS II was conducted to build on the results of ECASS I and further define the parameters for use of intravenous tPA. ECASS II was completed in 1998 and randomized 800 subjects within 6 hours of stroke onset to receive 0.9 mg/kg of intravenous tPA or placebo. This study found no significant difference between the tPA and placebo groups in the prespecified, primary endpoint of excellent functional outcome 90 days after stroke. However, for another clinically relevant endpoint, avoidance of death or dependency 90 days after stroke, the outcome in the tPA group was significantly better than in the placebo arm.

In a parallel attempt to extend the therapeutic window beyond 3 hours, the Alteplase ThromboLysis for Acute Noninterventional Therapy in Ischemic Stroke (ATLANTIS) trials were undertaken. The larger ATLANTIS B trial was completed in 1999 and randomized 613 subjects 3-5 hours after stroke onset to receive 0.9 mg/kg of intravenous tPA or placebo.¹ This study found no significant difference in functional outcome 90 days after stroke between the tPA and placebo groups, while the risk of symptomatic intracerebral hemorrhage (ICH) was increased with tPA treatment.

A pooled analysis of all 2775 patients enrolled in the 6 intravenous tPA trials provides clear and convincing evidence of a time-dependent benefit of thrombolytic therapy. Treatment within the first 90 minutes of onset increased the odds of a favorable outcome by 2.8-fold, in the 91-180 minute window by 1.6-fold, and in the 181-270 minute window by 1.4 fold, while treatment in the 271-360 minute window did not improve outcome in a statistically significant manner. The sooner tPA is given to patients, the greater the benefit.

Three randomized placebo-controlled trials of intravenous streptokinase were conducted in the mid-1990s. The Multicentre Acute Stroke Trial - Italy (MAST-I)² and the Multicentre Acute Stroke Trial - Europe (MAST-E) allowed treatment in a 6-hour time window and randomized subjects to receive 1.5 million units of intravenous streptokinase or placebo. The Australian Streptokinase (ASK)³ Trial used the same dose of streptokinase but shortened the time window to 4 hours. The MAST-E and ASK trials were terminated because of a disproportionate number of deaths and symptomatic ICH in patients who received streptokinase. Similarly, the MAST-I trial was halted because of an increased 10-day fatality rate in patients treated with streptokinase. These negative results with late-administered, high-dose intravenous streptokinase have discouraged further investigational studies of this agent.

The collective results from the intravenous thrombolytic trials show a clear and consistent pattern. Patients treated with moderate-dose intravenous thrombolysis within 3 hours after onset of stroke symptoms benefit substantially from therapy, despite a modest increase in the rate of symptomatic hemorrhage. In contrast, patients treated 3-6 hours after stroke onset show a less substantial benefit from therapy. Current consensus guidelines accordingly recommend intravenous thrombolysis only when treatment can be initiated within 3 hours from stroke onset.

Several phase 2 trials have used multimodal CT or MR imaging to identify select 3- to 9-hour postonset patients who still harbor substantial salvageable tissue and are likely to benefit from late intravenous treatment.⁴ This strategy appears highly promising, but is not yet validated by a positive phase 3 trial.

Intra-arterial thrombolysis has also been investigated as a treatment for acute ischemic stroke. The phase III Prolyse in Acute Cerebral Thromboembolism II (PROACT II) study, reported in 1999, randomized 180 subjects within 6 hours of stroke onset to receive 9 mg of intra-arterial pro-urokinase (pro-UK) and heparin or intravenous heparin alone.⁵ All subjects had documented middle cerebral artery occlusion. The recanalization rate was significantly greater for the pro-UK group than for the control group. In addition, subjects treated with pro-UK had a significantly improved functional outcome 90 days after stroke on the prespecified primary trial endpoint.

Although the rate of symptomatic ICH was greater in the pro-UK group, overall mortality rates were equal in the 2 treatment arms. This single positive phase 3 trial was not sufficient evidence to gain FDA approval, and pro-UK is not available for therapy in the United States. However, reports of large case series suggest that outcomes of IA therapy employing other fibrinolytic agents (eg, tPA, urokinase, reteplase) generally approximates that achieved with pro-UK in the PROACT II trial. Most recently, the Middle Cerebral Artery Embolism Local Fibrinolytic Intervention Trial (MELT) investigated intra-arterial urokinase up to 6 hours after onset in 114 subjects.⁶ Favorable trends were noted in good functional outcome and substantial benefits observed in the rate of excellent functional outcome. As a result, intra-arterial fibrinolytic therapy is commonly administered as an off-label therapy for stroke at tertiary centers, within 6 hours of onset in the anterior circulation and up to 12-24 hours after onset in the posterior circulation.

Pathophysiology

Ischemic strokes are caused by occlusions of cervicocerebral blood vessels. Focal brain infarction results. Cerebral angiography performed shortly after the onset of ischemic stroke reveals clots in large cerebral vessels in up to 80% of cases. Thrombolytic agents convert plasminogen to plasmin. Plasmin cleaves fibrin strands in intravascular thrombi, resulting in clot lysis and restoration of blood flow.

Frequency

United States

Stroke is the third leading cause of death and the leading cause of adult disability in the United States, with an incidence of 256-411 per 100,000 individuals per year. Approximately 730,000 strokes occur yearly in the United States, of which 80-85% are ischemic and the remainder are primary hemorrhages. Various US centers have reported treating 1-11% of ischemic stroke patients with intravenous tPA in clinical practice.

International

Worldwide, stroke is the second leading cause of death, responsible for 4.4 million (9%) of the total 50.5 million deaths each year. Globally, stroke death rates vary widely; the highest rates are in Portugal, China, Korea, and most of Eastern Europe, and the lowest rates are in Switzerland, Canada, and the United States. ICH is more common and ischemic stroke less common in Asian countries than in the United States.

Mortality/Morbidity

The 3-month mortality rate from ischemic stroke is approximately 12%. However, patients who are candidates for thrombolytic stroke therapy tend to have more severe strokes than the average patient with ischemic stroke. The 3-month mortality rate in these more severe patients is approximately 21% when they do not receive thrombolytic therapy. This death rate is not increased by the use of thrombolytic treatment.

Common acute complications of stroke include pneumonia, urinary tract infection, and pulmonary embolism. Long-term morbidity in survivors of stroke is common, with ambulation difficulty in 20%, need for assistance in activities of daily living in 30%, and vocational disability in 50-70% of patients.

Race

Comparison of stroke rates among races is confounded by socioeconomic, environmental, and nutritional factors. The age-adjusted incidence rate for black men is 1.5 times higher than that for white men; that for black women is 2.3 times higher than that for white women. The age-adjusted mortality rate for blacks is 1.98 times that for whites.

Sex

The male-to-female ratio for stroke is about 1.35:1.

Age

The incidence of stroke doubles in every decade after the age of 45 years, rising from 104 per 100,000 per year for adults aged 45-54 years to 1113 per 100,000 per year for adults aged 75-84 years. Two thirds of strokes occur in persons older than 65 years. No absolute age limits apply to the use of thrombolytic therapy.

CLINICAL

Section 3 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

History

• Determination of the time of onset of symptoms is critical in deciding eligibility for thrombolytic therapy. Treatment must be initiated within 3 hours of onset of symptoms.
• Sometimes the precise onset time cannot be determined with certainty; for example, when a patient awakens with a deficit after a night's sleep or after a nap or is found stricken and unable to communicate the onset time.
• In these instances, the onset time is taken as the last time the patient was known to be well.
• Caution should be exercised in patients with neglect syndromes who may not have observed their onset time reliably.
• History exclusion criteria
• • Seizure at stroke onset
  • Symptoms suggestive of subarachnoid hemorrhage
  • Stroke or serious head trauma within 3 months
  • Major surgery or serious bodily trauma within 2 weeks
  • History of a prior ICH
  • Intracranial neoplasm
  • Arteriovenous malformation or aneurysm
  • GI or urinary tract hemorrhage within 21 days
  • Arterial puncture at a noncompressible site or lumbar puncture within 1 week
  • Concomitant oral anticoagulant (INR>1.7)

Physical

To be considered for thrombolytic therapy, a patient must have more than a minimal neurological deficit (eg, greater than minimal weakness, isolated ataxia, isolated sensory deficit, isolated dysarthria).

• The National Institutes of Health Stroke Scale (NIHSS), a standardized rating scale, is helpful in characterizing the severity of a patient's neurologic deficit. For a copy of the scale, go to NIH Stroke Scale.
• • NIHSS is a reproducible 13-item scale that quantifies the neurologic examination, ascertaining level of alertness and orientation, gaze difficulty, visual field defects, facial weakness, limb weakness, sensory loss, speech and language defects, and neglect.
  • Scores range from 0 to 42, with 0 denoting no neurologic deficit.
  • The FDA approved a package insert for tPA listing as a warning an NIHSS score greater than 22, indicating a severe neurologic deficit.
  • Patients with NIHSS scores greater than 22 are at increased risk of symptomatic hemorrhagic transformation if they receive tPA.
  • However, patients with NIHSS scores greater than 22 still tend to benefit from treatment.
• Physical exam exclusion criteria
• • Rapidly improving neurological signs
  • Systolic blood pressure (SBP) greater than 185 mm Hg or diastolic blood pressure (DBP) greater than 110 mm Hg or aggressive (continuous intravenous) treatment required to lower BP to this range
  • Suspected acute pericarditis

Causes

• Risk factors for ischemic stroke
• • Age
  • Hypertension
  • Diabetes
  • Smoking
  • Atrial fibrillation
  • Hypercholesterolemia
  • Coronary artery disease
• Mechanisms of ischemic stroke
• • In situ atherothrombosis
  • Artery to artery embolism
  • Cardioembolism
  • Lipohyalinosis
  • Hypercoagulable state

DIFFERENTIALS

Section 4 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Other Problems to be Considered

Hypoglycemia
Somatization disorder
Vertigo
Carotid disease and stroke

WORKUP

Section 5 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Lab Studies

• Laboratory exclusion criteria
• • Platelet count <100 x 10⁹/L
  • Prothrombin time (PT) >15 (INR >1.7)
  • Activated partial thromboplastin time (aPTT) elevated beyond reference range
  • Glucose <50 mg/dL or >400 mg/dL
  • Positive pregnancy test (in woman of childbearing age)
• Blood should be sent for type and screen in case transfusions are required.

Imaging Studies

• Noncontrast head CT scanning
• • Immediate head CT scanning is imperative. Any ICH is an absolute contraindication to thrombolysis.
  • Early signs of major infarction on initial CT scan (eg, mass effect, edema, hypodensity involving more than one third of the middle cerebral artery territory) are a reason for caution in the use of thrombolytic therapy, because the risk of hemorrhage is increased.
• MRI: At centers capable of performing MRI emergently, an immediate MRI may be obtained in lieu of a CT scan. Imaging acquisitions should include a susceptibility-weighted sequence to detect acute ICH.

Other Tests

• An ECG is useful in diagnosing pericarditis and stroke etiologies, including myocardial infarction and atrial fibrillation. An ECG is not required before administering tPA.

TREATMENT

Section 6 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical Care

• Prehospital care
• • Stabilize airway, breathing, circulation, and acute life-threatening conditions.
  • Identify time of and witnesses to stroke onset.
  • Establish emergent radio/telephone communication with receiving hospital to prepare the stroke team and CT or MRI unit before patient's arrival.
  • Administer oxygen by nasal canula as needed.
  • Place intravenous line en route, if possible.
• Emergency department (ED) care
• • Arrange for emergent head CT or MRI scanning and laboratory studies.
  • Monitor BP at least every 15 minutes before tPA. If SBP greater than 185 mm Hg or DBP greater than 110 mm Hg on 2 successive readings, treat with intravenous labetalol bolus (or other suitable agent).
  • BP must be under these parameters to administer tPA.
  • Establish intravenous access for hydration and thrombolytic therapy.
  • Mix tPA as soon as the patient is deemed to be a potential candidate for treatment (the manufacturer will restock unused vials at no charge).
  • Monitor for improvement of neurological deficits.
  • Place a Foley indwelling catheter and nasogastric tube, if necessary, prior to starting tPA.
  • During and after tPA infusion, monitor BP at least every 15 minutes for 2 hours.
  • Aim for a "door-to-needle time" (interval from patient arrival at ED to start of thrombolytic therapy) of 60 minutes.

Consultations

A neurologist should be consulted to assist in the decision-making process.

Diet

Nothing by mouth

Activity

Patient should be confined to bed rest.

MEDICATION

Section 7 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Streptokinase, urokinase, tPA, and additional fibrinolytic agents have been investigated for the treatment of acute stroke. Variations in the outcome of trials of these agents were most likely due to variations in the properties of the individual agents, dosing, time to treatment, and BP control. Currently, tPA is the only medication that has been approved by the FDA for treatment of acute ischemic stroke.

Inclusion criteria for intravenous tPA use in acute stroke include the following:

• More than minimal neurologic deficit (greater than minimal weakness, isolated ataxia, isolated sensory deficits, or isolated dysarthria)
• Time of onset <3 hours
• No CT or MRI evidence of acute ICH

Drug Category: Thrombolytics

The goal of thrombolytic therapy is to restore blood flow to ischemic neurons. This is accomplished by clot lysis that results in reperfusion of stunned but not yet infarcted tissue. The greatest risk of thrombolytic therapy is symptomatic ICH. Although the risk of hemorrhage is increased with thrombolytic therapy, the risk is outweighed by improved functional outcome at 3 months after stroke onset.

Drug Category: Antihypertensives

BP elevations are treated more aggressively in patients identified for tPA administration than in other patients with ischemic stroke to minimize risk of ICH. Close regulation of BP is critical in the first 24 h after administration of thrombolytic therapy. When appropriate, a modified version of the regimen employed in NINDS tPA trials is recommended for regular practice. This regimen requires BP checks at least every 15 min for the first 2 h after start of therapy; then at least every 30 min for the next 6 h and at least hourly for the next 16 h. If SBP is 180-230 mm Hg or DBP is 105-120 mm Hg on 2 readings 5-10 min apart, or if SBP >230 mm Hg or DBP is 121-140 mm Hg on a single reading, IV labetalol boluses are employed. When DBP >140 mm Hg, continuous IV nitroprusside or nicardipine is employed.

Drug Name	Nitroprusside sodium (Nitropress)
Description	Vasodilates and increases inotropic activity of heart. At higher dosages, may exacerbate myocardial ischemia by increasing heart rate. Onset of action within 1 min, with peak effect at 1-2 min.
Adult Dose	0.5-10 mg/kg/min IV continuous infusion prn
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; active hepatic disease such as acute hepatitis or active cirrhosis; vitamin B-12 deficiency; hereditary optic atrophy; increased intracranial pressure; hypotension
Interactions	May increase hypotensive effects when combined with other antihypertensives
Pregnancy	C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions	Use caution in patients with increased intracranial pressure, hepatic failure, severe renal impairment, hypothyroidism; in renal or hepatic insufficiency, nitroprusside levels may increase and can cause cyanide toxicity Used only in patients with mean arterial pressures >70 mm Hg

Drug Name	Nicardipine (Cardene)
Description	Inhibits influx of calcium into cardiac and smooth muscles resulting in vasodilation and decrease in blood pressure. Onset of action within minutes and reaches 50% of its maximum effect within 45 min.
Adult Dose	5 mg/h IV continuous infusion prn
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; advanced aortic stenosis; lower doses should be used in patients with hepatic disease
Interactions	May increase hypotensive effects when combined with other antihypertensives
Pregnancy	C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions	Caution in patients with impaired hepatic and renal function

FOLLOW-UP

Section 8 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Further Inpatient Care

• After thrombolytic therapy is initiated, transfer the patient to an intensive care unit, stroke unit, or other unit capable of close observation.
• No antiplatelet or anticoagulant therapy should be administered for 24 hours following tPA.
• Obtain a repeat head CT scan or MRI 24 hours after tPA to rule out asymptomatic hemorrhagic transformation prior to initiating antithrombotic therapy.
• BP should be monitored closely and controlled.
• Physical, occupational, and speech therapy can be initiated after the first 24 hours of bedrest.

Transfer

• Transfer should be initiated if CT or MRI is not available. However, remember that the time to transfer a patient may exceed the 3-hour time-window for treatment.

Complications

• Intracerebral hemorrhage
• • In the NINDS trials, the rate of symptomatic ICH (ie, clinical worsening temporally coincident with new ICH) 24-36 hours after treatment was 6.4% with tPA versus 0.6% without tPA.
  • ICH may be signaled by acute hypertension, headache, neurological deterioration, and nausea or vomiting.
  • If ICH is suspected, obtain an emergent head CT scan and obtain PT, aPTT, platelet count, and fibrinogen.
  • If ICH is present on CT scan, evaluate lab studies and administer, if needed, 6-8 units of cryoprecipitate containing fibrinogen and factor VIII, 6-8 units of platelets, and/or fresh frozen plasma. Use of recombinant factor VII may also be considered but carries a risk of inducing thrombotic events.
  • Obtain neurosurgery consultation.
  • Obtain hematology consultation.
• Oozing from intravenous line and venous puncture sites (up to 30% of cases)
• Angioedema (rare)

Prognosis

• Neurological deficits: Three months following tPA therapy, approximately 30% of patients are neurologically normal or near normal; 30% have mild to moderate neurological deficits; 20% have moderate to severe neurological deficits; and 20% have died.
• Functional disability: Three months following tPA therapy, approximately 50% of patients are completely or almost completely independent in activities of daily living; 15% are moderately dependent on others; 15% are completely dependent on others; and 20% have died.

Patient Education

• Education regarding the availability of thrombolytic therapy for stroke is important for patients with risk factors for stroke and those who have experienced a transient ischemic attack or prior stroke.
• Emphasizing the importance of arriving at the hospital as early as possible for treatment is imperative.
• The 4 main warning signs of an acute ischemic stroke are the following:
• • Sudden weakness or numbness on one side of the body
  • Sudden loss or change of vision
  • Sudden speech difficulty or language comprehension difficulty
  • Sudden dizziness or gait difficulty
• Patients should be instructed that if they experience any of these symptoms and the symptoms last for 10 minutes, they should call 911 immediately or be driven to the nearest emergency department (American Heart Association guidelines).
• For excellent patient education resources, visit eMedicine's Stroke Center. Also, see eMedicine's patient education article Stroke.

MISCELLANEOUS

Section 9 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical/Legal Pitfalls

• Identifying the onset time as the time when the symptoms were first observed rather than the last time the patient was known to be well
• Not following the FDA-approved inclusion/exclusion criteria for thrombolytic therapy with tPA in stroke
• Failing to discuss with the patient and family the benefits and risks of thrombolytic therapy, including potential for ICH, worsening of neurological deficits, coma, and death
• Failing to proceed with thrombolytic therapy when it is consistent with best clinical practice and judgment because the patient is unable to authorize treatment and a legally authorized representative is not available
• Administering anticoagulants or antiplatelet agents during first 24 hours after intravenous tPA
• Failing to notify the local EMS system of the hospital's readiness to provide thrombolytic therapy, and continuing to accept direct ambulance routing of stroke patients when the facility is not treatment-capable.
• Failing to offer or administer tPA therapy to patients who are candidates probably the most common cause of tPA-related malpractice litigation

MULTIMEDIA

Section 10 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Media file 1:  The bar graphs show the percent of patients with different outcomes on the modified Rankin Scale of global disability 3 months following treatment with TPA or placebo in the NINDS-TPA Trials 1 and 2. Rankin 0 = no symptoms; 1 = No significant disability, despite symptoms; able to perform all usual duties and activities; 2 = Slight disability; unable to perform all previous activities but able to look after own affairs without assistance; 3 = Moderate disability; requires some help, but able to walk without assistance; 4 = Moderately severe disability; unable to walk without assistance and unable to attend to own bodily needs without assistance; 5 = Severe disability; bedridden, incontinent, and requires constant nursing care and attention; 6 = Dead. Image courtesy of UCLA Stroke Center.
	View Full Size Image
Media type:  Image

REFERENCES

Section 11 of 11

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

1. Clark WM, Wissman S, Albers GW, Jhamandas JH, Madden KP, Hamilton S. Recombinant tissue-type plasminogen activator (Alteplase) for ischemic stroke 3 to 5 hours after symptom onset. The ATLANTIS Study: a randomized controlled trial. Alteplase Thrombolysis for Acute Noninterventional Therapy in Ischemic Stroke. JAMA. Dec 1 1999;282(21):2019-26. [Medline].
2. MAST-I group. Randomised controlled trial of streptokinase, aspirin, and combination of both in treatment of acute ischaemic stroke. Multicentre Acute Stroke Trial--Italy (MAST-I) Group. Lancet. Dec 9 1995;346(8989):1509-14. [Medline].
3. Donnan GA, Davis SM, Chambers BR, Gates PC, Hankey GJ, McNeil JJ, et al. Streptokinase for acute ischemic stroke with relationship to time of administration: Australian Streptokinase (ASK) Trial Study Group. JAMA. Sep 25 1996;276(12):961-6. [Medline].
4. Furlan AJ, Eyding D, Albers GW, Al-Rawi Y, Lees KR, Rowley HA, et al. Dose Escalation of Desmoteplase for Acute Ischemic Stroke (DEDAS): evidence of safety and efficacy 3 to 9 hours after stroke onset. Stroke. May 2006;37(5):1227-31. [Medline].
5. Furlan A, Higashida R, Wechsler L, Gent M, Rowley H, Kase C, et al. Intra-arterial prourokinase for acute ischemic stroke. The PROACT II study: a randomized controlled trial. Prolyse in Acute Cerebral Thromboembolism. JAMA. Dec 1 1999;282(21):2003-11. [Medline].
6. Ogawa A, Mori E, Minematsu K, Taki W, Takahashi A, Nemoto S, et al. Randomized Trial of Intraarterial Infusion of Urokinase Within 6 Hours of Middle Cerebral Artery Stroke. The Middle Cerebral Artery Embolism Local Fibrinolytic Intervention Trial (MELT) Japan. Stroke. Aug 16 2007;[Medline].
7. Adams HP Jr, Brott TG, Furlan AJ, Gomez CR, Grotta J, Helgason CM, et al. Guidelines for Thrombolytic Therapy for Acute Stroke: a Supplement to the Guidelines for the Management of Patients with Acute Ischemic Stroke. A statement for healthcare professionals from a Special Writing Group of the Stroke Council, American Heart Association. Stroke. Sep 1996;27(9):1711-8. [Medline].
8. Adams HP Jr, del Zoppo G, Alberts MJ, Bhatt DL, Brass L, Furlan A, et al. Guidelines for the early management of adults with ischemic stroke: a guideline from the American Heart Association/American Stroke Association Stroke Council, Clinical Cardiology Council, Cardiovascular Radiology and Intervention Council, and the Atherosclerotic Peripheral Vascular Disease and Quality of Care Outcomes in Research Interdisciplinary Working Groups: the American Academy of Neurology affirms the value of this guideline as an educational tool for neurologists. Stroke. May 2007;38(5):1655-711. [Medline].
9. Albers GW, Bates VE, Clark WM, Bell R, Verro P, Hamilton SA. Intravenous tissue-type plasminogen activator for treatment of acute stroke: the Standard Treatment with Alteplase to Reverse Stroke (STARS) study. JAMA. Mar 1 2000;283(9):1145-50. [Medline].
10. Albers GW, Thijs VN, Wechsler L, Kemp S, Schlaug G, Skalabrin E, et al. Magnetic resonance imaging profiles predict clinical response to early reperfusion: the diffusion and perfusion imaging evaluation for understanding stroke evolution (DEFUSE) study. Ann Neurol. Nov 2006;60(5):508-17. [Medline].
11. Alberts MJ, Hademenos G, Latchaw RE, Jagoda A, Marler JR, Mayberg MR, et al. Recommendations for the establishment of primary stroke centers. Brain Attack Coalition. JAMA. Jun 21 2000;283(23):3102-9. [Medline].
12. American College of Emergency Physicians. Use of intravenous tPA for the management of acute stroke in the emergency department. Policy Resource and Education Paper; Feb 2002.
13. Ezaki Y, Tsutsumi K, Onizuka M, Kawakubo J, Yagi N, Shibayama A, et al. Retrospective analysis of neurological outcome after intra-arterial thrombolysis in basilar artery occlusion. Surg Neurol. Nov 2003;60(5):423-9; discussion 429-30. [Medline].
14. Fiebach JB, Schellinger PD, Gass A, Kucinski T, Siebler M, Villringer A, et al. Stroke magnetic resonance imaging is accurate in hyperacute intracerebral hemorrhage: a multicenter study on the validity of stroke imaging. Stroke. Feb 2004;35(2):502-6. [Medline].
15. Graham GD. Tissue plasminogen activator for acute ischemic stroke in clinical practice: a meta-analysis of safety data. Stroke. Dec 2003;34(12):2847-50. [Medline].
16. Hacke W, Donnan G, Fieschi C, Kaste M, von Kummer R, Broderick JP, et al. Association of outcome with early stroke treatment: pooled analysis of ATLANTIS, ECASS, and NINDS rt-PA stroke trials. Lancet. Mar 6 2004;363(9411):768-74. [Medline].
17. Hacke W, Kaste M, Fieschi C, Toni D, Lesaffre E, von Kummer R, et al. Intravenous thrombolysis with recombinant tissue plasminogen activator for acute hemispheric stroke. The European Cooperative Acute Stroke Study (ECASS). JAMA. Oct 4 1995;274(13):1017-25. [Medline].
18. Hacke W, Kaste M, Fieschi C, von Kummer R, Davalos A, Meier D, et al. Randomised double-blind placebo-controlled trial of thrombolytic therapy with intravenous alteplase in acute ischaemic stroke (ECASS II). Second European-Australasian Acute Stroke Study Investigators. Lancet. Oct 17 1998;352(9136):1245-51. [Medline].
19. Heuschmann PU, Berger K, Misselwitz B, Hermanek P, Leffmann C, Adelmann M, et al. Frequency of thrombolytic therapy in patients with acute ischemic stroke and the risk of in-hospital mortality: the German Stroke Registers Study Group. Stroke. May 2003;34(5):1106-13. [Medline].
20. Hill MD, Buchan AM. Thrombolysis for acute ischemic stroke: results of the Canadian Alteplase for Stroke Effectiveness Study. CMAJ. May 10 2005;172(10):1307-12. [Medline].
21. Ingall TJ, O'Fallon WM, Asplund K, Goldfrank LR, Hertzberg VS, Louis TA, et al. Findings from the reanalysis of the NINDS tissue plasminogen activator for acute ischemic stroke treatment trial. Stroke. Oct 2004;35(10):2418-24. [Medline].
22. Kalafut MA, Saver JL. The acute stroke patient: the first six hours. In: Cohen SN, ed. Management of Ischemic Stroke. 2000:17-52.
23. Katzan IL, Hammer MD, Furlan AJ, Hixson ED, Nadzam DM,. Quality improvement and tissue-type plasminogen activator for acute ischemic stroke: a Cleveland update. Stroke. Mar 2003;34(3):799-800. [Medline].
24. Levy EI, Firlik AD, Wisniewski S, Rubin G, Jungreis CA, Wechsler LR, et al. Factors affecting survival rates for acute vertebrobasilar artery occlusions treated with intra-arterial thrombolytic therapy: a meta-analytical approach. Neurosurgery. Sep 1999;45(3):539-45; discussion 545-8. [Medline].
25. National Stroke Association. Stroke: the first hours. In: Guidelines for Acute Treatment. Consensus Statement. 2000:1-13.
26. Saver JL. Hemorrhage after thrombolytic therapy for stroke: the clinically relevant number needed to harm. Stroke. Aug 2007;38(8):2279-83. [Medline].
27. Saver JL. Number needed to treat estimates incorporating effects over the entire range of clinical outcomes: novel derivation method and application to thrombolytic therapy for acute stroke. Arch Neurol. Jul 2004;61(7):1066-70. [Medline].
28. Saver JL, Kidwell CS, Starkman S. Commentary: Thrombolysis in stroke: it works!. Br Med J. 2002;324:727-729.
29. The Multicenter Acute Stroke Trial--Europe Study Group. Thrombolytic therapy with streptokinase in acute ischemic stroke. N Engl J Med. Jul 18 1996;335(3):145-50. [Medline].
30. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. Generalized efficacy of tPA for acute stroke. Stroke. 1997;28:2119-25.
31. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. N Engl J Med. Dec 14 1995;333(24):1581-7. [Medline].
32. Wahlgren N, Ahmed N, Davalos A, Ford GA, Grond M, Hacke W, et al. Thrombolysis with alteplase for acute ischaemic stroke in the Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST): an observational study. Lancet. Jan 27 2007;369(9558):275-82. [Medline].
33. Wolf PA, D'Agostino RB. Epidemiology of stroke. In: Barnett, HJM et al, eds. Stroke: Pathophysiology, Diagnosis, and Management. 1998:3-28.
34. Zweifler RM. Management of acute stroke. South Med J. Apr 2003;96:380-5. [Medline].

Article Last Updated: Nov 30, 2007