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Managing Acute Ischemic Stroke
The author updates key clinical issues surrounding patients with signs and symptoms of acute ischemic stroke, including the therapeutic implications of onset time and imaging results, intravenous versus intraarterial thrombolysis, and the risks, contraindications, and precautions associated with recombinant tissue plasminogen activator as a thrombolytic agent.
By Mel L. Anderson III, MD
Each year in the United States approximately 700,000 people suffer a new or recurrent stroke. This translates into an average of one acute stroke every 45 seconds. Stroke remains the third leading cause of mortality in this country and a significant cause of direct and indirect morbidity and health care expenditures.
The concept of using thrombolytic therapy for acute ischemic stroke is not new. It was first reported in the literature nearly 50 years ago. However, it was not until June 1996 that the FDA approved the use of intravenous (IV) recombinant tissue plasminogen activator (rt-PA) for the treatment of acute ischemic stroke, administered within three hours of the onset of symptoms, based primarily on the results of a landmark trial sponsored by the National Institute of Neurological Disorders and Stroke (NINDS). Despite the availability of this and other forms of thrombolytic therapy, less than 5% of patients in the United States receive one of these agents for acute ischemic stroke.
This article will review the diagnosis and management of acute ischemic stroke, focusing on the indications and contraindications for the use of thrombolytics.
CONFIRMING THE PRESENCE OF STROKE
Evaluation of the patient with suspected acute stroke should focus on two overriding priorities: ruling out other conditions that mimic acute stroke and determining the onset of symptoms and whether the patient might be a candidate for thrombolysis.
The first step is to establish with certainty that the patient has indeed had an acute stroke. The history and physical examination should confirm the presence of focal neurologic signs and symptoms. The National Institutes of Health Stroke Scale (NIH-SS) or another standardized assessment tool should be used for all patients with acute stroke to objectively assess for the presence of stroke and its severity (see http://www.stroke center.org/trials/scales/nihss.html). Three criteria on this scale provide the highest positive predictive value for the presence of acute stroke: acute facial paresis, arm drift, and abnormal speech. Measurable deficits on NIHSS scores were used as inclusion criteria in clinical trials; high scores (above 20) predicted poorer clinical outcomes and higher rates of intracranial bleeding.
Several conditions can mimic acute stroke—brain tumors, subdural hematomas, unrecognized seizures, and toxic and metabolic confusional states, especially hypoglycemia. These conditions are typically readily detected with routine laboratory testing (see box below). In one series of 336 patients presenting with suspected acute stroke, 31% were found to have stroke mimics. The presence of cognitive impairment and abnormal signs in a nonneurologic system suggested a stroke mimic. Several factors, on the other hand, suggested the presence of acute stroke: an exact time of symptom onset, focal neurologic symptoms or signs, the ability to lateralize the patient’s symptoms to the left or right side of the brain, the ability to subclassify the type of stroke, and the presence of abnormal vascular findings on brain imaging.
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In this same series, the reliability of stroke history and physical examination findings between paired observers was studied. It was found that while most factors had moderate-to-good interobserver reliability, there was only 45% agreement for the hour and minute of symptom onset. Knowledge of these data should inform clinicians about the potential fallibility of their exams, the importance of considering multiple aspects of the history and physical exam in arriving at a correct diagnosis, and even the importance of further neurologic training for physicians treating acute stroke patients.
DETERMINING TIME OF ONSET
The second crucial step is to determine the exact time of onset of stroke symptoms in order to decide whether thrombolytic therapy is indicated. The last time at which neurologic function was clearly normal is the time from which onset is measured. If a patient awakens from sleep with new neurologic symptoms, the last time of normal neurologic function prior to sleep must be used to calculate the duration of symptoms.
Thrombolytics are most beneficial when administered within three hours of the onset of symptoms; an even greater benefit is seen in patients treated within 90 minutes of symptom onset. As in the case of acute myocardial infarction, time is of the essence. During each minute of ischemic stroke, approximately 1.9 million neurons (7.5 miles of myelinated fibers) are destroyed. An acutely ischemic brain ages 3.6 years for every hour without treatment, compared to normal age-related neuronal loss.
Patients presenting more than three hours from the onset of symptoms might still benefit from treatment with thrombolytics, although the margin of benefit will be
smaller. A pooled analysis of three large trials involving rt-PA showed that the lower limit of the 95% confidence interval crossed unity at 4.5 hours from the onset of symptoms. Trials to test the effects of therapy between 3 and 4.5 hours from the onset of symptoms are ongoing. Nevertheless, the most current guidelines suggest that the three-hour window should not be altered.
IMAGING STUDIES
A critical step in the initial evaluation of the suspected stroke patient is emergent brain imaging, usually with noncontrast computed tomography (CT). The CT scan should be reviewed for evidence of intracranial hemorrhage, signs of alternate diagnoses (such as neoplasm), and the extent of involvement. Imaging can exclude stroke mimics and can be instrumental in determining whether the patient is a candidate for IV thrombolytic therapy.
Historically, CT scanning has been promoted as a more sensitive technology than magnetic resonance imaging (MRI) for the detection of intracranial bleeding, but the findings of a recent study suggest otherwise. In comparison with CT, MRI detected intracranial hemorrhage with 100% sensitivity and 100% diagnostic accuracy, according to the interpretations of three experienced radiologists. The investigators in this study also found that three medical students were able to evaluate MRI scans for signs of hemorrhage with 95% sensitivity. It is not known whether MRI test characteristics are similar in routine clinical practice.
Because MRI is not universally available, patient care should not be delayed if a CT scan is more readily available. The scan should be interpreted by a clinician skilled in CT assessment and formally evaluated for the presence of early infarct signs. These signs include a hyperdense middle cerebral artery (MCA) indicative of acute thrombus or embolism in the first portion of the artery, loss of the gray-white matter junction along the cortical ribbon of the lateral insular cortex in the setting of an MCA stroke, and loss of the gray-white matter junction within the lentiform nucleus and general sulcal effacement (see image below). Patients with a normal CT scan generally have the best outcomes with thrombolytic therapy. Early infarct signs are associated with higher complication rates, especially intracranial hemorrhage, although patients may still benefit compared to those who receive no treatment.
 Early infarct sign. A hyperdense left middle cerebral artery (arrow) is one of the key things to look for in a CT scan as an early sign of an infarct.
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Intravenous thrombolytic trials for acute ischemic stroke have excluded patients with intracranial hemorrhage. The ATLANTIS (Alteplase Thrombolysis for Acute Noninterventional Therapy in Ischemic Stroke) study also excluded patients with CT involvement of more than one-third of the MCA territory, loss of gray-white matter distinction or sulcal effacement, and evidence of a mass induced midline shift. The NINDS study excluded only those patients with evidence of hemorrhage. The ECASS (European Cooperative Acute Stroke Study) I and II studies excluded patients with hemorrhage or involvement of more than one-third of the MCA territory, as evidenced by either hypodensity or swelling. Trials of intra-arterial (IA) thrombolytics and combined IV and IA thrombolytics have in large measure used the ECASS criteria for exclusion.
Newer trials have used MRI to select patients who may benefit from thrombolytic therapy up to six or even nine hours from the onset of symptoms. However, until the MRI imaging techniques used in these trials have been further validated, the three-hour time window is still the most universal recommendation.
BENEFITS OF THROMBOLYTIC THERAPY
Pooled analysis of the major rt-PA trials (NINDS, ATLANTIS, and ECASS II) showed an improvement in three-month favorable outcome, defined as being alive with minimal disability. Improvements in formal stroke scale scores provided the primary measure of thrombolytic effect. Because the ECASS II trial included treatment out to six hours, the pooled results in this analysis are reported from 0 to 360 minutes from the onset of symptoms. Looking only at patients treated within 180 minutes across these three trials, mortality rates at 90 days were the same between treatment
and placebo groups. However, there was an overall
increase in favorable outcome at three months from
12.7% with placebo to 18% with rt-PA. Intracranial hemorrhage
occurred in 0.65% of placebo-treated patients
and 4.75% of treatment patients. More than half of the
patients suffering significant intracranial hemorrhage
died. In short, the current evidence shows that IV thrombolysis
with rt-PA significantly improves level of function
at three months but does not decrease mortality.
Intra-arterial thrombolysis for acute ischemic stroke
has also been studied. The PROACT II (Prourokinase in Acute Cerebral Thromboembolism) study randomized
180 patients with angiographically proven occlusion of
the MCA without hemorrhage or major early infarct
signs on CT to receive IA prourokinase (r-proUK) plus
IV heparin versus heparin alone in patients presenting
within six hours of symptom onset. The heparin was
administered in a low dose for four hours around the
time of angiography. The primary endpoint of minimal
disability at 90 days, defined as alive and with a modified
Rankin score of <2 (see http://www.strokecenter.org/trials/scales/rankin.html), occurred in 40% of treatment
patients versus 25% of controls, a 15% absolute risk reduction. Mortality rates were the same. Significant intracranial hemorrhage occurred in 10% of treatment patients versus 2% of controls. There were no significant benefits for any of the study’s prespecified secondary endpoints.
No direct comparisons between IV and IA thrombolytic therapy for acute ischemic stroke have been conducted. Prourokinase has not been approved by the FDA for IA treatment of stroke. Accordingly, the American Heart Association 2005 Guidelines for stroke care recommend offering IA therapy “preferably in the setting of randomized clinical trials.”
RISKS OF THROMBOLYTIC THERAPY
Intracranial hemorrhage is the primary risk with thrombolytic therapy. The risk of treatment-related intracranial hemorrhage correlates with the presence of significant hypertension, the extent of infarction on CT, the degree of neurologic impairment as measured by the NIH-SS score, and the type of thrombolytic agent used
and route of administration. Randomized, placebo-controlled trials in the early 1990s using streptokinase showed harm well in excess of benefit and were stopped prematurely. Streptokinase should not be used in the treatment of acute ischemic stroke.
While the FDA approved the use of rt-PA for acute ischemic stroke in 1996, its use was not approved in Canada until 1999, in Germany until 2000, and in member states of the European Agency for the Evaluation of Medicinal Products (EMEA) until 2002. The EMEA stipulates that rt-PA treatment is limited to patients who are treated within three hours of the onset of symptoms, are under 80 years old, have no history of stroke or diabetes or signs of extensive infarction on CT, and have an NIHSS score below 25. Written informed consent must be documented and the presenting data and outcomes entered into a safety registry, the Safe Implementation of Thrombolysis in Stroke: A Multinational, Multicenter Monitoring Study of Safety and Efficacy of Thrombolysis in Stroke (SITS-MOST).
These constraints illustrate the caution that must be used with thrombolytics. Early data from the Cleveland area showed that the use of rt-PA for acute stroke in community hospitals did not show the same benefits as seen in the NINDS, ATLANTIS, AND ECASS trials, with higher rates of hemorrhage likely attributable to a nearly 50% rate of deviation from stroke treatment protocols in one study. Subsequent institution of a stroke quality improvement program in this region reduced the rates of protocol deviation to 19.1% and reduced the rates of intracranial hemorrhage. Stroke registries in the United States and Canada have subsequently shown that trial-quality outcomes are attainable in clinical practice. Proper patient selection and adherence to stroke protocols are requisite aspects of safe treatment.
KEYS TO DECISION-MAKING
Rapid but thoughtful assessment of the risks and benefits of thrombolytic therapy is essential. Intravenous thrombolytic therapy is indicated for acute ischemic stroke when treatment can be initiated within three hours of the onset of symptoms and the patient has a measurable deficit on an objective stroke scale and symptoms that are not spontaneously clearing. Dosing for rt-PA in acute ischemic stroke is 0.9 mg/kg (up to a maximum of 90 mg), with 10% given as an initial bolus over one minute and the remainder as a continuous infusion over 60 minutes (see box below). Intravenous rt-PA should be used with caution in patients with a suppressed level of consciousness and a high score on the NIH-SS scale (above 20). Old age has been associated with an increased risk of in-hospital death, especially in patients who are 75 years of age or older. Clinical trials have excluded patients over age 80, with the exception of the NINDS trial, where 42 of the 624 patients were over that age.
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Thrombolytics should not be used in patients with marked hypertension (systolic pressure 185 mm Hg or higher, diastolic pressure 110 mm Hg or higher), hypoglycemia (blood glucose below 50 mg/dl), hyperglycemia (blood glucose above 400 mg/dl), or other standard contraindications (see first box below). Hypertension should be treated cautiously and according to a defined protocol established by Adams and colleagues. Intracranial hemorrhage must be ruled out with CT or MRI. The presence of extensive infarction or multiple early infarct signs should caution against the use of thrombolytics, since the risk of hemorrhagic transformation is greater. Intravenous rt-PA should be administered only after clinical, radiographic, and laboratory assessments have been completed (see second box below). Patients taking oral anticoagulants and those with liver disease can be treated if their INR is 1.7 or lower. It is acceptable to begin thrombolytic therapy prior to getting the results of coagulation testing in patients who are not taking an anticoagulant and in whom there is no clinical suspicion of coagulopathy.
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CAUTIONS WITH THROMBOLYTIC THERAPY
Because of the substantial risk of intracranial hemorrhage, clinicians should keep a low threshold for repeat CT imaging should there be a change in the patient’s clinical status. Aspirin use prior to presentation is not a contraindication to thrombolytic treatment. However, neither aspirin nor any other anticoagulant, including unfractionated or a low-molecular-weight heparin, should be administered within the first 24 hours. Based on the results of two trials, the American Heart Association recommends beginning (or restarting) aspirin therapy within 24 to 48 hours of stroke onset in most patients.
Orolingual angioedema is a recognized side effect of rt-PA administration, more common among patients with concomitant use of an angiotensin-converting enzyme inhibitor. Should angioedema occur, the rt-PA infusion should be stopped and 0.5 to 1 ml of 1:1000 epinephrine administered subcutaneously or intramuscularly, along with 200 mg of IV hydrocortisone and 10 mg of IV chlorpheniramine.
Elevated blood glucose levels are associated with poorer outcomes in stroke patients. A recent retrospective study of 960 patients discharged with a diagnosis of ischemic stroke compared outcomes among patients presenting with hyperglycemia (blood glucose level 130 mg/dl or higher), those with persistent hyperglycemia, and those demonstrating glycemic control within 48 hours of admission.
Patients with hyperglycemia had a higher mortality than nonhyperglycemic patients; those with persistent hyperglycemia had an even greater mortality. However, those who achieved glycemic control within 48 hours of admission had a 4.6-fold decrease in mortality compared to patients with persistent hyperglycemia. While this was not a prospective randomized trial, the results suggest that tight glycemic control in acute ischemic stroke is beneficial.
Elevated blood pressure in acute stroke is not uncommon and is associated with a greater risk of death or disability. Optimal treatment of hypertension in this setting is controversial. Persistent hypertension may increase the risk of hemorrhage, cause further brain damage, and worsen brain edema. On the other hand, lowering blood pressure may cause cerebral hypoperfusion and extend the area of infarction. Consensus guidelines suggest cautious treatment of hypertension if the systolic blood pressure is above 220 mm Hg or diastolic blood pressure is more than 120 mm Hg.
Patients given rt-PA should be admitted to an intensive care unit or stroke unit for careful monitoring of their blood pressure, as well as monitoring for evidence of hemorrhage and serial performance of neurologic examinations.
CLINICAL VIGNETTE
Consider the case of a 64-year-old woman who presents to the emergency department one hour after developing acute dysarthria and right-sided weakness. How should she be evaluated and treated?
Because this patient presents within three hours of the onset of symptoms, she is a candidate for IV rt-PA therapy provided there are no contraindications. After stroke mimics are ruled out, an NIHSS score should be determined. Also, her blood pressure should be measured and a noncontrast CT of the brain performed. If her systolic pressure is less than 185 mm Hg and her diastolic pressure is below 110 mm Hg, her CT scan is negative for intracranial hemorrhage, and no other contraindications are present, then rt-PA should be administered. Evidence on CT of involvement of more than one-third of the MCA territory or evidence of a mass effect or multiple early infarct signs would increase her risk of hemorrhage. She should not initially receive aspirin or heparin if a thrombolytic is being administered, and she should be admitted to an intensive care unit for careful monitoring.
Based on current data, the use of rt-PA in this setting does not offer a mortality benefit but does significantly decrease stroke morbidity at 90 days. It is also important to note that thrombolytics are most safely administered for acute ischemic stroke when a local written protocol is followed to ensure that inclusion and exclusion criteria are met.
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Suggested Reading
Wardlaw JM, et al.: Thrombolysis for acute ischaemic stroke.
Cochrane Database Syst Rev (3):CD000213, 2003.
Goldstein LB and Simel DL: Is this patient having a stroke? JAMA 293(19):2391, 2005.
Hacke W, et al.: Association of outcome with early stroke treatment: pooled analysis of ATLANTIS, ECASS, and NINDS rt-PA stroke trials. Lancet 363(9411):768, 2004.
Adams H, et al.: Guidelines for the early management of patients with ischemic stroke: a scientific statement from the Stroke Council of the American Stroke Association. Stroke 34(4):1056, 2003.
Adams H, et al.: Guidelines for the early management of patients with ischemic stroke: 2005 Guidelines Update: a scientific statement from the Stroke Council of the American Heart Association/American Stroke Association. Stroke 36(4):916, 2005.
Thomalla G, et al.: Outcome and symptomatic bleeding complications of intravenous thrombolysis within 6 hours in MRI-selected stroke patients. Stroke 37(3):852, 2006.
Gentile NT, et al.: Decreased mortality by normalizing blood glucose after acute ischemic stroke. Acad Emerg Med 13(2):174, 2006.
Willmot M, et al.: High blood pressure in acute stroke and subsequent outcomes: a systematic review. Hypertension 43(1):18, 2004.
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