Focus On: Thrombolytic Therapy in Acute Ischemic Stroke

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ACEP News
April 2008

By Brace H. Curry, MD, and Alan Kumar, MD

Learning Objectives

After reading this article, the physician should be able to:

  • Understand the inclusion/exclusion criteria for thrombolytic use in acute stroke patients.
  • Describe the complications of TPA use.
  • Review the major trials discussing the benefits/risks of thrombolysis in stroke patients.

Ischemic stroke is the third leading cause of death in the United States.1 Initial management of the stroke patient in the emergency department requires prompt evaluation and stabilization.

In this time frame, the emergency physician must ensure stability, rapidly recognize and address conditions that may mimic stroke, and do a thorough evaluation to determine a patient's eligibility for intervention. Prompt restoration of cerebral blood flow is the best way to preserve brain tissue that has not yet infarcted.

The American College of Emergency Physicians' policy statement on the use of thrombolytics in the acute stroke setting emphasizes that there must be an institutional commitment from the multiple hospital departments involved (neurology, neurosurgery, radiology, and laboratory services) to ensure that the inclusion/exclusion criteria established by the National Institute of Neurological Disorders and Stroke (NINDS) guidelines for TPA use in acute stroke are followed, and that the systems necessary for the safe use of fibrinolytic agents are in place.

The use of intravenous alteplase (recombinant tissue-type plasminogen activator, or TPA) has been a class I recommendation of the American Heart Association/American Stroke Association (AHA/ASA) guidelines since 2000.1 The AHA's current guidelines also stress the need for institutional commitment.

This article will address the evaluation of patients presenting with acute stroke symptoms for the possibility of thrombolytic therapy.

Inclusion and Exclusion Criteria

According to the "AHA/ASA 2007 Guidelines for Early Management of Adults With Ischemic Stroke," the criteria listed in the sidebar below are characteristics that could be included or excluded from treatment with TPA.1

Although written consent is not required for the use of TPA in the setting of acute stroke (as it is an FDA-approved medication for this indication), it is important to discuss the risks and benefits with the patient or the patient's family prior to the initiation of therapy.1 That discussion should be of an informed consent nature and should be documented in the medical record.

While not an exclusion criterion, caution should be exercised in treating those patients with severe impairment (National Institutes of Health Stroke Scale [NIHSS] score > 22). This subset of patients has a poor prognosis with TPA. While trials have shown some functional improvement with administration, the risk of hemorrhage is considerable in patients with severe deficits.1

Factors in Beneficial vs. Adverse Outcomes

In the Standard Treatment with Alteplase to Reverse Stroke (STARS) trial, a multivariate analysis found predictors of favorable outcome after the administration of TPA. Factors associated with favorable outcome include younger age (< 85 years), less severe stroke symptoms at presentation (NIHSS < 10), absence of specific findings on initial noncontrast CT brain (effacement or hypodensity > 33% of the middle cerebral artery distribution and a hyperdense middle cerebral artery), and a lower mean arterial blood pressure at baseline.2

Additional factors believed to play a role in long-term functional outcomes after thrombolysis include time to treatment, hyperglycemia (serum glucose > 140 mg/dL) at the time of reperfusion, and 24-hour improvement. Several studies have considered the role of gender in outcomes after TPA administration, showing conflicting results.1

NIH Stroke Scale

The National Institutes of Health Stroke Scale is a standardized evaluation of stroke severity. The NIHSS has been shown to be easy to use by nonneurology health care providers (in hospital and prehospital). As a standardized scale, it allows for rapid assessment of important neurologic exam findings and the clear communication of these findings to other health care professionals.

The stroke scale (see table below) provides a score from 0 to 42 based on the level of consciousness, best gaze, visual fields, facial palsy, motor, limb ataxia, sensory, best language, dysarthria, and extinction/neglect.

In addition to initial evaluation of symptom severity, the NIHSS has prognostic and diagnostic significance. The greater the NIHSS, the worse the prognosis, with or without intravenous TPA administration.

In many centers, the initial NIHSS is used to determine eligibility for specific interventions and the risk of complications. In addition to the actual number, the distribution of points on the NIHSS is very helpful in diagnosing the location of the afflicting lesion.1

Why 3 Hours?

The NINDS trial looked at the use of alteplase in acute ischemic stroke.3 All patients receiving TPA were treated within 3 hours of onset of symptoms--half of those received treatment within 90 minutes of onset.

The first arm of this study looked at improved neurological outcome at 24 hours defined as complete resolution (NIHSS 0 or 1, or NIHSS improvement of more than 4 points).

The second arm looked at favorable outcome at 3 months defined as near or complete recovery. One-year follow-up of the patients in the NINDS study was evaluated in a later publication.

Part one showed no significant difference between the group given TPA and the group given placebo at 24 hours.

At 3 months, a significant long-term clinical benefit was seen in patients given TPA. Compared with those receiving placebo, the treatment group was at least 30% more likely to have minimal or no disability at 3 months. Despite a 10-fold increase in symptomatic intracerebral hemorrhage in the treatment group (6.4% vs. 0.6 % in placebo), the 3-month mortality was not significantly different between the groups (17% vs. 21%).3 The 1-year mortality also showed no significant difference (24% vs. 28%).4

A pooled analysis of the four large, multicenter, placebo-controlled trials using alteplase confirmed the time constraints used in the NINDS trial. Subsequent trials have shown similar results as the NINDS study, using the same strict inclusion criteria.5

Trials at 3-6 Hours

Several trials have looked at the administration of thrombolytics in the 3- to 6-hour window after symptom onset.

The European Cooperative Acute Stroke Study (ECASS and ECASS II) studied the use of alteplase in patients within the first 6 hours of symptoms. The results showed the treatment arm to be no more effective than placebo at 3 months. There was no significant difference in 3-month mortality between treatment and placebo groups.6,7

The Alteplase ThromboLysis for Acute Non-interventional Therapy in Ischemic Stroke (ATLANTIS) trial also investigated the use of alteplase in the first 6 hours of symptoms. The study was halted early because of the lack of significant improvement between the placebo and treatment arms in those patients treated after 3 hours. Analysis of the 61 enrolled patients who received thrombolytic therapy within 3 hours of onset showed results consistent with the NINDS findings.8 Currently, intravenous thrombolytics are indicated only in the first 3 hours of symptoms.

Intra-Arterial Lysis

The AHA/ASA recommendations on intra-arterial thrombolytics are based on the results of the PROACT-II study, a prospective, randomized, placebo-controlled trial.

In this study, intra-arterial pro-urokinase was used for MCA occlusion within 6 hours of symptom onset. Recanalization was achieved in 66% of patients (vs. 18% in placebo). Intracranial hemorrhage was seen in 10% (vs. 2% in placebo), but there was no significant difference in mortality. While pro-urokinase has not been FDA approved, extrapolation of these data has been applied to TPA.9

While great clinical benefit has been shown in intra-arterial thrombolysis, this clinical benefit has been shown to be outweighed by the delay to treatment and the necessity of skilled operators. Availability of intra-arterial thrombolysis should not preclude the use of intravenous TPA in eligible candidates.1

Many centers have begun using intra-arterial thrombolysis as an option in patients who are poor candidates for intravenous thrombolysis. This practice may be beneficial for patients who are in the 3- to 6-hour window, have more severe symptoms (NIHSS = 10), have had recent surgery, or have a major vessel occlusion. There are limited data for its use in these situations.

Several studies have considered the use of combination therapies (intravenous and intra-arterial thrombolysis), taking advantage of the speed and ease of intravenous administration and the improved recanalization rates of intra-arterial administration. Initial results showed no improvement in efficacy over that of intravenous administration alone. While this approach still remains controversial, the potential benefit exists for those patients who do not respond adequately to intravenous administration alone.1

For appropriate candidates, alteplase should be given through a dedicated intravenous line. The dose is based on actual body weight at 0.9 mg/kg to a maximum of 90 mg. An initial bolus of 10% of the total dose should be given over 1 minute, with the remaining 90% infused over 1 hour.

All patients receiving TPA should be admitted to an intensive care or dedicated stroke unit. Vital signs and neurologic status should be monitored every 15 minutes for the first 2 hours, then every 30 minutes for 6 hours, then every 60 minutes for the first 24 hours after treatment. Blood pressure should be maintained below 180/105 mm Hg using aggressive measures as needed.

Other antithrombotic agents should be held for at least 24 hours after TPA infusion is complete. A noncontrast head CT should be performed at 24 hours, if initiation of antithrombotic agents such as aspirin or heparin is being considered.

Patients receiving TPA should have another large-bore intravenous line (in addition to their dedicated TPA line). For 24 hours after infusion, venipuncture, arterial lines, and insertion of nasogastric tubes should be avoided because of the increased risk of bleeding.1

Other Thrombolytic and Defibrinogenating Agents

At this time, the only agent that is FDA approved for use is alteplase (TPA). Clinical trials using streptokinase have been stopped early because of the high rates of intracerebral hemorrhage, and this agent should not be used in the setting of acute stroke. Thrombolytic agents urokinase, reteplase, anistreplase, and staphylokinase have not been sufficiently tested and, therefore, should not be used. Ongoing trials using tenecteplase and desmoteplase appear promising for decreased risk of ICH, but additional studies are required before they are used in clinical practice.

Ancrod, an enzyme from snake venom, breaks down fibrinogen in humans. While it is not available in the United States, it has been used in Europe and Canada for the treatment of deep venous thrombosis and peripheral arterial disease. Ancrod has mild thrombolytic and antithrombotic effects.

Several studies have looked at its use in the setting of acute stroke. While this is not currently an accepted practice, the few completed trials show favorable risk/benefit profiles, making it an interesting potential future treatment.

Management of Complications

circle_arrowIntracerebral hemorrhage. The most feared complication of thrombolysis is symptomatic intracerebral hemorrhage. Prevention is an important part of management. Good patient selection, appropriate nursing care, and tight blood pressure control can reduce rates of symptomatic intracerebral hemorrhage.

Suspect intracranial hemorrhage in any patient who has received TPA with the onset of any of the following: neurological decline, decrease in level of consciousness, sudden headache, nausea/vomiting, or sudden increase in blood pressure.

If intracerebral hemorrhage is suspected, the emergency physician should stop infusion immediately. Prompt noncontrast CT brain or MRI is needed for confirmation and management. Type and cross-match, PTT/INR, platelets, and serum fibrinogen levels should be sent immediately.

Symptomatic intracerebral hemorrhage has a 45% mortality rate in patients who have received thrombolytics. Once the diagnosis has been confirmed, the patient should receive cryoglobulin (to increase circulating fibrinogen and factor 8), platelets, and protamine (in any patient who has received heparin). While these measures are the recommendation of the AHA/ASA guidelines on intracerebral hemorrhage after TPA, there is no proven benefit in this setting.10

Neurosurgical consultation is advisable, but intervention in this particular instance is controversial. Surgical evacuation is more complicated in the presence of circulating thrombolytic. While there are no data in the setting of acute stroke, treatment of intracerebral hemorrhage after thrombolytics given for acute myocardial infarction was considered in the GUSTO-I trial. In this study, patients showed significant improvement in 30-day mortality and 30-day functional outcome after surgical evacuation.11

circle_arrowSystemic bleeding. Minor bleeding is common after thrombolytic administration. Oozing at intravenous sites, ecchymosis (particularly under blood pressure cuffs), and bleeding gums are frequently seen. In the case of minor bleeding, there is no need to stop the infusion, but simply monitor for further or more extensive bleeding.

Major systemic bleeding, such as gastrointestinal or urinary bleeding, may require that the infusion be stopped. If hypotension develops after infusion of TPA, consider tamponade physiology and a stat echocardiogram.

circle_arrowAngioedema. Mild orolingual angioedema is seen in 1%-5% of patients receiving intravenous TPA. Typically, it is mild and transient, and affects the contralateral side from the hemisphere of ischemic injury.

Severe angioedema after TPA is a rare occurrence. If the patient becomes stridorous, immediately stop the infusion. Appropriate airway management and antihistamines/corticosteroids should be given.

Summary

Patients presenting with stroke symptoms within 3 hours of onset are a challenging population for the emergency physician because of the time-intensive nature of the evaluation and treatment of these patients.

Thrombolytics are a new treatment modality for these patients, but they carry considerable risks. The decision to use TPA in this patient population should be made at an institutional level prior to implementing its use on an individual basis, so the appropriate resources can be mobilized for the benefit of the patient.

Criteria for TPA Treatment

Inclusion Criteria

  • Clinical diagnosis of ischemic stroke causing measurable neurological deficit.
  • Administration of TPA can be initiated within 3 hours of onset of symptoms (or within 3 hours from the time patient was last seen normal).
  • Age 18 years or older.
  • A patient or family members who understand the potential risks and benefits.

Exclusion Criteria

  • Stroke or head trauma in past 3 months.
  • Symptoms suggestive of subarachnoid hemorrhage (even in the presence of a normal noncontrast CT brain).
  • Any prior history of intracranial hemorrhage.
  • Major surgery in past 14 days.
  • Gastrointestinal or urinary tract hemorrhage in past 21 days.
  • Myocardial infarction in past 3 months.
  • Arterial puncture at a noncompressible site in past 7 days.
  • Rapid improvement of stroke symptoms.
  • Minor or isolated neurological signs.
  • Seizure (if residual impairments are thought possibly to be the result of the post-ictal state).
  • Presentation consistent with acute myocardial infarction or post-myocardial infarction pericarditis.
  • Persistent hypertension (SBP>185 or DBP>110) or requiring aggressive therapy to control blood pressure.
  • Pregnancy.
  • Active bleeding or acute trauma.
  • Platelet count < 100,000.
  • Glucose < 50 or > 400.
  • If patient is taking anticoagulation medications, INR > 1.7 or a PTT > normal range.
  • CT evidence of hemorrhage.

References

  1. Adams H.P. Jr., del Zoppo G., Alberts M.J., 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. Stroke 2007;38:1655-711.
  2. Albers G.W., Bates V.E., Clark W.M., et al. Intravenous tissue-type plasminogen activator for treatment of acute stroke: the Standard Treatment with Alteplase to Reverse Stroke (STARS) study. JAMA 2000;283:1189-91.
  3. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. N. Engl. J. Med. 1995;333:1581-7.
  4. Kwiatkowski T.G., Libman R.B., Frankel M., et al. Effects of tissue plasminogen activator for acute ischemic stroke at one year. N. Engl. J. Med. 1999;340:1781.
  5. Hacke W., Donnan G., Fieschi C., et al. Association of outcome with early stroke treatment: pooled analysis of ATLANTIS, ECASS, and NINDS rt-PA stroke trials. Lancet 2004;363:768.
  6. Hacke W., Kaste M., Fieschi C., et al. Intravenous thrombolysis with recombinant tissue plasminogen activator for acute hemispheric stroke: the European Cooperative Acute Stroke Study (ECASS). JAMA 1995;274:1017-25.
  7. Hacke W., Kaste M., Fieschi C., et al. Randomised double-blind placebo-controlled trial of thrombolytic therapy with intravenous alteplase in acute ischemic stroke (ECASS II). Lancet 1998;352:1245.
  8. Clark W.M., Wissman S., Albers G.W., et al. 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 Non-interventional Therapy in Ischemic Stroke. JAMA 1999;282:2019.
  9. Furlan A., Higashida R., Wechsler L., et al. Intra-arterial prourokinase for acute ischemic stroke. The PROACT II study: a randomized controlled trial. Prolyse in Acute Cerebral Thromboembolism. JAMA 1999;282:2003.
  10. Broderick J., Connolly S., Feldmann E., et al. Guidelines for the management of spontaneous intra-cerebral hemorrhage in adults: 2007 update: a guideline from the American Heart Association/American Stroke Association Stroke Council, High Blood Pressure Research Council, and the Quality of Care and Outcomes in Research Interdisciplinary Working Group. Stroke 2007;38:2001.
  11. Mahaffey K.W., Granger C.B., Sloan M.A., et al. Neurosurgical evacuation of intracranial hemorrhage after thrombolytic therapy for acute myocardial infarction: experience from the GUSTO-I trial. Global Utilization of Streptokinase and tissue-plasminogen activator (TPA) for Occluded Coronary Arteries. Am. Heart J. 1999;138:493.

Contributors

Dr. Curry is a senior resident at the University of Chicago Medical Center.

Dr. Kumar is an attending physician at Lutheran General Hospital in Park Ridge, Ill., and a clinical instructor with the University of Chicago Emergency Medicine Residency Program.

Medical Editor Dr. Robert C. Solomon is an attending emergency physician at Trinity Health System in Steubenville, Ohio, and clinical assistant professor of emergency medicine at the West Virginia School of Osteopathic Medicine.

Disclosures

In accordance with the Accreditation Council for Continuing Medical Education (ACCME) Standards and American College of Emergency Physicians policy, contributors and editors must disclose to the program audience the existence of significant financial interests in or relationships with manufacturers of commercial products that might have a direct interest in the subject matter.

Dr. Curry, Dr. Kumar, and Dr. Solomon have disclosed that they have no significant relationships with or financial interests in any commercial companies that pertain to this educational activity.

"Focus On: Thrombolytic Therapy in Acute Ischemic Stroke" has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Education (ACCME).

ACEP is accredited by the ACCME to provide continuing medical education for physicians. ACEP designates this educational activity for a maximum of one Category 1 credit toward the AMA Physician's Recognition Award. Each physician should claim only those credits that he or she actually spent in the educational activity.

"Focus On: Thrombolytic Therapy in Acute Ischemic Stroke" is approved by ACEP for one ACEP Category 1 credit.

Disclaimer

ACEP makes every effort to ensure that contributors to College-sponsored programs are knowledgeable authorities in their fields. Participants are nevertheless advised that the statements and opinions expressed in this article are provided as guidelines and should not be construed as College policy.

The material contained herein is not intended to establish policy, procedure, or a standard of care. The views expressed in this article are those of the contributors and not necessarily the opinion or recommendation of ACEP. The College disclaims any liability or responsibility for the consequences of any actions taken in reliance on those statements or opinions.

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National Institutes of Health Stroke Scale

Tested Item Title Responses and Scores
1A Level of consciousness 0-alert
1-drowsy
2-obtunded
3-coma/ unresponsive
1B Orientation questions (2) 0-answers both correctly
1-answers one correctly
2-answers neither correctly
1C Response to commands (2) 0-performs both tasks correctly
1-performs one task correctly
2-performs neither correctly
2 Gaze 0-normal horizontal movements
1-partial gaze palsy
2-complete gaze palsy
3 Visual fields 0-no visual field defect
1-partial hemianopia
2-complete hemianopia
3-bilateral hemianopia
4 Facial movement 0-normal
1-minor facial weakness
2-partial facial weakness
3-complete unilateral palsy
5 Motor function (arm)
a. Left
b. Right
0-no drift
1-drift before 5 seconds
2-falls before 10 seconds
3-no effort against gravity
4-no movement
6 Motor function (leg)
a. Left
b. Right
0-no drift
1-drift before 5 seconds
2-falls before 10 seconds
3-no effort against gravity
4-no movement
7 Limb ataxia 0-no ataxia
1-ataxia in 1 limb
2-ataxia in 2 limbs
8 Sensory 0-no sensory loss
1-mild sensory loss
2-severe sensory loss
9 Language 0-normal
1-mild aphasia
2-severe aphasia
3-mute or global aphasia
10 Articulation 0-normal
1-mild dysarthria
2-severe dysarthria
11 Extinction or inattention 0-absent
1-mild (loss of 1 sensory modality)
2-severe (loss of 2 sensory modalities)
  Source: National Institutes of Health

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