What actions should the hospital staff take to determine whether the patient is a candidate for fibrinolytic therapy?

In 1994 a panel of the American Heart Association Stroke Council wrote guidelines on the management of patients with acute ischemic stroke.1 The panel predicted that its recommendations would change as the results of ongoing clinical trials became available. At that time the panel recommended that thrombolytic drugs should not be given to persons with acute ischemic stroke outside the clinical trial setting. Since publication of the guidelines, the results of five clinical trials of intravenously administered thrombolytic drugs have been reported.23456 The use of intra-arterial thrombolytic drugs continues to be reported. In light of these data, the Stroke Council reviewed the status of thrombolytic therapy and prepared this supplement, which includes recommendations for the use of thrombolytic drugs in clinical practice. In preparing this report, panel members used the rules of evidence for treatments used during the writing of the previous report17 (Table 1). The target audience for this statement includes neurologists, emergency physicians, primary care physicians, neurosurgeons, and vascular surgeons who care for persons seen within the first few hours after stroke.

Thrombolytic Therapy

Measures to expedite clot lysis and restore circulation may limit the extent of brain injury and improve outcome after stroke. Unfortunately, intracranial bleeding was frequent among persons enrolled in studies performed in the late 1960s and 1970s, and the therapy was abandoned8910 (Level of Evidence II). More recently, interest in thrombolytic therapy revived because of development of new drugs and their successful use in the care of persons with myocardial ischemia.11 In addition, a meta-analysis combining data from several pilot studies in stroke suggested that thrombolytic therapy might be useful.12 Available thrombolytic drugs are recombinant tissue plasminogen activator (r-TPA), streptokinase, p-anisoylated lys-plasminogen-streptokinase activator complex, urokinase, and prourokinase. A number of pilot studies evaluated the potential safety and efficacy of early administration of thrombolytic drugs using both intravenous and intra-arterial approaches131415161718192021222324252627282930313233343536373839 (Levels of Evidence III through V). Investigators reported generally positive results and an acceptable degree of safety. Recanalization after treatment was reported in 21% to 93% of cases.172122283233

Recent Studies of Intra-arterial Thrombolysis

Several groups have described the results of regional or local intra-arterial administration of a thrombolytic drug273031333437 (Levels of Evidence III through V). A potential limitation to the use of intra-arterial treatment is the time required to mobilize a team to perform angiography. In response, the EMS Bridging Trial evaluated the safety of emergent intravenous administration of r-TPA or placebo followed by intra-arterial drug.40 The goal was to start treatment while the resources needed to give the intra-arterial drug were being assembled. Detailed results of this trial are pending (Level of Evidence II). The Prolyse in Acute Cerebral Thromboembolism Trial (PROACT) was a randomized, controlled, double-blind trial38 (Level of Evidence II). It tested the rate of recanalization, safety, and clinical efficacy of 6 mg local intra-arterial recombinant prourokinase (r-proUK) or placebo given within 6 hours of stroke secondary to occlusion of the middle cerebral artery. Patients also received either low or high doses of heparin. Recanalization of the middle cerebral artery was found in 58% of persons given r-proUK and in 14% given placebo (P=.017). The frequency of brain hemorrhage with clinical deterioration was no different in the r-proUK (15%) and placebo (14%) groups.

Supplementary techniques, including mechanical clot disruption, pulse spray delivery, distal clot delivery, modifications in catheter design, and concomitant administration of heparin or lys-plasminogen, may improve the likelihood of recanalization.39 No technique has been shown to be better than others. The North American Cerebral Local Intra-arterial Registry is gathering data about the safety and potential efficacy of technical refinements in the local intra-arterial use of thrombolytic drugs41 (Level of Evidence V). A clinical trial of r-proUK (PROACT2) has begun.42

1. Intra-arterial thrombolysis can reopen arterial occlusions (Levels of Evidence II through V). Rates of recanalization are lower for occlusions of the internal carotid artery or basilar artery than for occlusions of branches of the middle cerebral artery.

2. There is no evidence that intra-arterial thrombolysis is superior or inferior to intravenous thrombolysis. There is no evidence that one thrombolytic drug is superior to others in terms of rates of recanalization or safety when used for local or intra-arterial thrombolysis.

3. The usefulness of supplementary techniques to speed recanalization with intra-arterial administration of thrombolytic drugs is not determined. Concomitant administration of heparin may influence the efficacy of intra-arterial thrombolysis38 (Level of Evidence II).

4. One small study reported that the risk of hemorrhage was less with intra-arterial thrombolysis than with intravenous administration34 (Level of Evidence III). The risk of bleeding may be increased with concomitant use of heparin38 (Level of Evidence II).

Available data favor further testing of intra-arterial thrombolysis. It should be considered investigational and only used in the clinical trial setting. Intra-arterial thrombolysis should be performed only by physicians who are experienced in neurointerventional techniques and in centers with neurological expertise (Grade B recommendation).

Recent Trials of Intravenous Thrombolysis in Management of Acute Ischemic Stroke

The results of recent clinical trials of intravenous thrombolytic therapy are conflicting. Results of two clinical trials are published in brief letters, and data are limited.23 Three trials of streptokinase were stopped by safety committees because of high rates of acute mortality and intracranial bleeding.235 One trial of r-TPA provides inconclusive data and the other trial is positive.46 The differences in results may be explained by the drug administered, the dosage, the severity of stroke or neurological signs, varying sites of occlusion, ancillary treatment including the use of aspirin after treatment, and, most important, the interval from stroke until treatment.

The safety committee of MAST-E recommended that recruitment be stopped after data from 270 persons were available.2 This trial recruited persons with acute severe stroke and randomly assigned them to treatment with intravenous placebo or 1.5 million U of streptokinase given over 1 hour. The rate of symptomatic hemorrhages and deaths was significantly higher in persons treated with streptokinase, and any benefit from treatment was likely to be marginal (Level of Evidence I) (Table 2).

The Australian Streptokinase Trial was a randomized, double-blind, placebo-controlled trial of intravenous streptokinase (1.5 million U) given within 4 hours of stroke.3 On the basis of an interim analysis of 300 persons (72 treated less than 3 hours after stroke), the trial's safety committee recommended that recruitment of persons seen more than 3 hours after stroke onset be halted because of a significant increase in adverse experiences among those given streptokinase. Subsequently the entire trial was stopped. Among persons treated 3 to 4 hours after stroke, unfavorable outcomes (death or death/severe disability) were significantly more frequent among persons treated with streptokinase (Level of Evidence I) (Table 2).

MAST-I was a controlled, randomized, unblinded trial that compared outcomes among persons enrolled in one of four treatment groups.5 Within 6 hours of stroke they were assigned to treatment with 1.5 million U of intravenous streptokinase given over 1 hour, 300 mg aspirin daily for 10 days, the combination, or control. The safety committee stopped the trial after 622 persons were enrolled. A nonsignificant reduction in the likelihood of death or disability at 6 months after treatment was shown with streptokinase (Table 2) (Level of Evidence I). However, mortality within 10 days and symptomatic intracranial hemorrhage were significantly higher among persons treated with streptokinase. The risk of early death or bleeding was particularly high when streptokinase was combined with aspirin.

The European Cooperative Acute Stroke Study (ECASS) enrolled persons within 6 hours of stroke in a randomized, double-blind, placebo-controlled trial.4 Most persons were treated more than 3 hours after stroke. Persons assigned to active treatment received r-TPA in a dose of 1.1 mg/kg up to a total of 100 mg. A bolus of 10% of the total dose was given over 1 to 2 minutes, and the remainder was administered during the next hour. Persons with evidence on computed tomography (CT) of a major infarction including diffuse swelling of the hemisphere, parenchymal hypodensity, or effacement of the cerebral sulci in more than 33% of the territory of the middle cerebral artery were excluded from the trial. Also excluded were persons with signs of an infarction involving the entire territory of the middle cerebral artery. Besides an intention-to-treat analysis that included data from all randomly selected persons, a target population analysis excluded results in 109 patients. The most common reason for exclusion was enrollment of a person with CT findings that contraindicated treatment. No significant difference in the Barthel Index was found between the two treatment groups using either the intention-to-treat or target population analyses. The median Rankin Scale score in the target population was 3 in the cohort receiving placebo and 2 in the group receiving r-TPA (P=.035). Other predefined end points, including neurological outcome, speed of recovery, and duration of in-hospital stay, favored patients treated with r-TPA. Parenchymal hematomas were significantly more common among persons receiving r-TPA (Level of Evidence I) (Table 3).

The NINDS Study was a randomized, double-blind, placebo-controlled trial consisting of two parts.6 In part I, 291 persons were enrolled in a project that assessed early response to treatment, although data about long-term outcome were also collected. In part II, 333 persons were recruited into a study to examine the effects of treatment at 3 months. Because the results of part I were not known before part II was completed, combined data were reported. Persons with ischemic stroke in either the carotid or vertebrobasilar circulation and a wide range of severity of signs were treated within 3 hours of onset. Patients with isolated neurological deficits such as ataxia alone, sensory loss alone, dysarthria alone, or minimal weakness that could not be assessed by the NIH Stroke Scale were not enrolled. Persons with rapidly resolving neurological symptoms were also excluded. The trial's design required very early entry of a large proportion of persons; as a result, 302 persons were treated within 90 minutes of onset of stroke. Persons assigned to active treatment received r-TPA in a dose of 0.9 mg/kg up to a maximum of 90 mg; 10% of the dose was given in a bolus, and the remainder was infused over 60 minutes. Blood pressure was managed closely, and no anticoagulants or antiplatelet aggregating drugs were given within 24 hours of treatment. No significant differences in mortality were noted acutely or at 3 months (Table 3) (Level of Evidence I). A significant increase in improvement at 24 hours and favorable outcomes at 3 months were noted among persons treated with r-TPA (Level of Evidence I). Symptomatic intracranial hemorrhage was significantly increased with treatment, although the overall rate (6.4%) was lower than that reported in other studies (Level of Evidence I). Despite the hemorrhages, the rate of death or severe disability was less in the actively treated groups.

The findings of the NINDS Study show that intravenous r-TPA (given in a dose of 0.9 mg/kg up to a maximum of 90 mg—10% of the dose in a bolus and the remainder infused over 1 hour) improves outcome after stroke when given very early and within 3 hours of onset of stroke in carefully selected persons. The benefit persists over the long term (3 months).

If the 3-hour time window of treatment can be met, the indications for intravenous therapy supported by the NINDS Study are broad.6 Treatment can be beneficial irrespective of the patient's age, gender, ethnicity, or presumed cause of stroke. Treatment can be beneficial for persons with a wide spectrum of neurological deficits. Patients with extensive neurological deficits and occlusion of the proximal middle cerebral artery may be less likely to benefit from intravenous thrombolysis.43 The exclusions used in the NINDS Study should be considered contraindications for noninvestigational use of r-TPA in persons with acute ischemic stroke. Not only has benefit in excluded persons not been established, but the risk of complications, particularly brain hemorrhage, may be unacceptably high.

The administration of thrombolytic drugs to persons with acute ischemic stroke can be complicated by bleeding even if the drug is given within 3 hours. Use of these drugs increases the risk of intracranial hemorrhage, which can be severe or fatal (Level of Evidence I). The risk of intracranial hemorrhage in persons with acute ischemic stroke is much greater than the risk of bleeding in persons who receive thrombolytic drugs for management of myocardial ischemia23456114445 (Level of Evidence I).

The relation between elevated blood pressure and intracranial bleeding after the use of thrombolytic drugs in treatment of acute ischemic stroke is not well defined. Uncontrolled arterial hypertension is considered a contraindication for the emergent use of thrombolytic drugs for treatment of acute myocardial ischemia464748 (Level of Evidence I). According to current guidelines for the early management of acute myocardial infarction developed by the American College of Cardiology and the American Heart Association, a recorded blood pressure greater than 200/120 mm Hg is a contraindication to the use of thrombolytic drugs.49 In a retrospective review of the results of two pilot studies of r-TPA,2425 Levy et al50 correlated an increased risk of intracranial bleeding when the diastolic pressure was greater than 100 mm Hg.

1. Intravenous r-TPA (0.9 mg/kg, maximum 90 mg) with 10% of the dose given as a bolus followed by an infusion lasting 60 minutes is recommended treatment within 3 hours of onset of ischemic stroke (Grade A recommendation). The benefit of intravenous r-TPA for acute ischemic stroke beyond 3 hours from onset of symptoms is not established. At this time intravenous administration of r-TPA for a person who has had a stroke more than 3 hours earlier cannot be recommended outside the clinical investigation setting. Intravenous r-TPA is not recommended when the time of onset of stroke cannot be ascertained reliably, including strokes recognized upon awakening.

2. Intravenous administration of streptokinase outside the clinical investigation setting is not indicated for management of ischemic stroke (Grade A recommendation). Data on the efficacy or safety of any other intravenously administered thrombolytic drug are not available to provide a recommendation.

3. Thrombolytic therapy is not recommended unless the diagnosis is established by a physician with expertise in diagnosis of stroke and CT of the brain is assessed by physicians with expertise in reading this imaging study. If CT demonstrates early changes of a recent major infarction such as sulcal effacement, mass effect, edema, or possible hemorrhage, thrombolytic therapy should be avoided (Grade A recommendation).

4. Thrombolytic therapy cannot be recommended for persons excluded from the NINDS Study6 for one of the following reasons: (1) current use of oral anticoagulants or a prothrombin time greater than 15 seconds (International Normalized Ratio [INR] greater than 1.7); (2) use of heparin in the previous 48 hours and a prolonged partial thromboplastin time; (3) a platelet count less than 100 000/mm3; (4) another stroke or a serious head injury in the previous 3 months; (5) major surgery within the preceding 14 days; (6) pretreatment systolic blood pressure greater than 185 mm Hg or diastolic blood pressure greater than 110 mm Hg; (7) rapidly improving neurological signs; (8) isolated, mild neurological deficits, such as ataxia alone, sensory loss alone, dysarthria alone, or minimal weakness; (9) prior intracranial hemorrhage; (10) blood glucose less than 50 mg/dL or greater than 400 mg/dL; (11) seizure at the onset of stroke; (12) gastrointestinal or urinary bleeding within the preceding 21 days; or (13) recent myocardial infarction.

5. Thrombolytic therapy should not be given unless the emergent ancillary care (below) and the facilities to handle bleeding complications are readily available.

6. Caution is advised before giving r-TPA to persons with severe stroke (NIH Stroke Scale Score greater than 22).

7. Because the use of thrombolytic drugs carries the real risk of major bleeding, whenever possible the risks of potential benefits of r-TPA should be discussed with the patient and his or her family before treatment is initiated.

Use of Thrombolytic Therapy in Management of Stroke in Children and Infants

There are no data concerning the use of r-TPA for the treatment of acute ischemic stroke in neonates, infants, or children. Persons younger than 18 years were not enrolled in the recent trials.46 Thrombolytic drugs have been given to children with other thromboembolic diseases, including arterial thrombosis, right atrial and caval thrombosis, pulmonary embolism, thrombosis of a Blalock-Taussig shunt, thrombosed dialysis shunts, and cerebral venous thrombosis. One study suggests that a dose of 0.5 mg/kg should be used in children.51

The safety and efficacy of the use of r-TPA in neonates, infants, and children with acute ischemic stroke requires further study. The risk of bleeding may be particularly high in neonates because plasminogen concentrations are often low, hemostatic and fibrinolytic mechanisms are not fully developed, and the cerebral vasculature is still changing.

If, recognizing that risk benefit has not been established, r-TPA is to be given to a pediatric patient, the same guidelines as in adults should be followed (Grade C recommendation). This medication should be administered only with caution in a highly individualized manner to pediatric patients with acute ischemic stroke. Because of the potential high risk of hemorrhage, neonates and infants should be treated only in very exceptional circumstances.

Emergent Ancillary Care

The investigators in the NINDS study paid considerable attention to ancillary care during administration of r-TPA and the ensuing 24 hours. Accordingly, the following ancillary care used by this group is advised:

1. Admission to a skilled care facility (intensive care unit or acute stroke care unit) that permits close observation, frequent neurological assessments, and cardiovascular monitoring.

2. Careful management of arterial blood pressure is critical during administration of r-TPA and the ensuing 24 hours (Table 4). An excessively high blood pressure might predispose the patient to bleeding, while excessive lowering of blood pressure may worsen ischemic symptoms.

3. Central venous access and arterial punctures are restricted during the first 24 hours. (See note, Table 4.)

4. Placement of an indwelling bladder catheter should be avoided during drug infusion and for at least 30 minutes after infusion ends.

5. Insertion of a nasogastric tube should be avoided, if possible, during the first 24 hours after treatment.

Management of Bleeding Complications

Bleeding is the most feared complication. Hemorrhagic events generally are divided into those that directly affect the central nervous system and those that involve other organs. The treatment of thrombolysis-related bleeding is guided by (1) the location and size of the hematoma, (2) the likelihood that the bleeding can be controlled mechanically, (3) the risk of neurological worsening or death, (4) the interval between administration of the drug and the onset of hemorrhage, and (5) the thrombolytic drug used. Information is scarce to guide recommendations about treatment of hemorrhagic complications of thrombolytic therapy (Levels of Evidence III through V).

If bleeding is suspected, blood should be drawn to measure the patient's hematocrit, hemoglobin, partial thromboplastin time, prothrombin time/INR, platelet count, and fibrinogen. Blood should be typed and cross-matched if transfusions are needed (at least 4 U of packed red blood cells, 4 to 6 U of cryoprecipitate or fresh frozen plasma, and 1 U of single donor platelets). These therapies should be made available for urgent administration.

In some instances active bleeding can be controlled mechanically. For example, arterial or venous puncture sites can be compressed. Depending on the severity of bleeding and the success of mechanical compression, it may be necessary to discontinue ongoing infusion of the thrombolytic drug. For all potentially life-threatening hemorrhages, including suspected intracranial bleeding, ongoing infusion of a thrombolytic drug should be stopped immediately. Although most persons with acute intracranial hemorrhage have elevated blood pressure, those with gastrointestinal or retroperitoneal bleeding are more likely to develop hypotension or hypovolemic shock, sometimes refractory to massive fluid resuscitation. Emergent CT of the brain is needed if an intracranial hemorrhage is suspected; if bleeding is demonstrated, neurosurgical consultation should be obtained in the event surgical treatment is needed. Surgery is delayed until the fibrinolytic state is corrected. For patients with severe non-neurological hemorrhage, emergency imaging studies should be performed before prescribing any surgical or medical therapy. Surgical interventions usually are delayed until the fibrinolytic state is corrected.

1. Thrombolytic therapy should not be used unless facilities to handle bleeding complications are readily available.

2. Bleeding should be considered as the likely cause of neurological worsening after use of a thrombolytic drug until CT is available. The study should be obtained on an emergent basis whenever neurological worsening follows administration of r-TPA.

3. Any life-threatening hemorrhagic complication, including intracranial bleeding, should be followed by these sequential steps:

(1) Discontinue ongoing infusion of thrombolytic drug

(2) Obtain blood samples for coagulation tests (see above)

(3) Obtain surgical consultation, as necessary

(4) Consider other interventions that may be useful, such as transfusion, cryoprecipitate, and platelets

Antithrombotic and Antiplatelet Aggregating Drugs and Use of Thrombolytic Drugs

The usual adjunctive therapy for thrombolysis in the setting of acute myocardial infarction is aspirin and heparin.52 The use of adjunctive therapy with thrombolysis is distinguished from treatment during the chronic phase for prevention of recurrence. The successful treatment of acute ischemic stroke with thrombolysis does not replace the diagnostic challenge of defining the potential cause for recurrence.53 Risk factors, pathogenesis, and mechanisms of stroke must be assiduously sought in the patient who has had a stroke so that appropriate treatment for the subacute and chronic phases is chosen. In most cases, long-term treatment will involve antiplatelet aggregating or antithrombotic drugs such as aspirin, ticlopidine, or warfarin.54

Prior use of either antiplatelet or antithrombotic drugs may influence the patient's eligibility for or success of thrombolysis in the setting of acute ischemic stroke. Many persons with acute stroke were taking aspirin, ticlopidine, or warfarin at the time of their stroke. Although the NINDS trial excluded persons who were taking warfarin or who had a prolonged prothrombin time, persons taking aspirin constituted a sizable proportion of patients.6 Limited information is available about the influence of prior aspirin use on the risk of bleeding after administration of r-TPA or other thrombolytic drugs. Aspirin use and hemorrhage were checked in the NINDS r-TPA pilot study, but the study lacked the power to test aspirin as a risk factor for thrombolysis-related bleeding.50 No data are available about the influence of ticlopidine on the response to thrombolysis.

Aspirin (100 mg/d) was an adjunctive therapy in persons enrolled in the Australian trial of streptokinase.3 Although the investigators did not attribute bleeding events to the aspirin, the trial was stopped prematurely because of the very high rate of serious hemorrhage. In MAST-I, aspirin (325 mg/d) was added to streptokinase in one quarter of the study participants.5 This group had significantly higher rates of bleeding than those noted among persons who received either agent alone. Subcutaneous heparin was allowed in ECASS, but aspirin, warfarin, and intravenous heparin were not permitted.4 It is unclear if subcutaneous heparin had an influence on outcomes. Heparin was an adjunctive treatment for persons entered in the pilot study of intra-arterial administration of prourokinase; although heparin increased the likelihood of recanalization, it was also associated with an increased risk of clinically significant bleeding.38 Higher doses of heparin were associated with more bleeding. The NINDS study prohibited the use of any antithrombotic drugs for the first 24 hours after treatment.6 This trial reports the lowest rate of symptomatic hemorrhage among treated persons.

Many patients who might be eligible for thrombolytic therapy have been taking antithrombotic and antiplatelet aggregating drugs before ischemic stroke. Persons who had been taking antiplatelet agents have been treated successfully, but persons with a prolonged prothrombin time (secondary to warfarin) or a prolonged partial thromboplastin time (secondary to heparin) were excluded because of the concern about brain hemorrhage. In the NINDS Study, patients taking oral anticoagulants were excluded. In addition, the use of antithrombotic or antiplatelet drugs was forbidden for 24 hours after treatment. This is the only trial with positive results on improving outcome.6 Pending the results of additional studies of thrombolytic therapy, the same prohibition should be applied to the clinical setting.

1. Persons who have taken aspirin are eligible for treatment with r-TPA if they meet all other criteria for therapy (Grade A recommendation). The lack of information about the safety of r-TPA in management of acute ischemic stroke in persons who have taken ticlopidine or other antiplatelet agents does not permit any recommendation.

2. Persons who are taking warfarin or heparin or who have prolongation of baseline clotting factors should not be given r-TPA for treatment of acute ischemic stroke (Grade A recommendation).

3. Persons given intravenous r-TPA should not receive aspirin, heparin, warfarin, ticlopidine, or other antithrombotic or antiplatelet aggregating drugs within 24 hours of treatment (Grade A recommendation). Additional research on the usefulness of such adjunctive therapies is needed because they may affect time to lysis, degree of reperfusion, occurrence of reocclusion, and/or clinical outcome.

Requests for reprints should be sent to the Office of Scientific Affairs, American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231-4596.

This statement is also being published in the September issue of Stroke.

Figure 1. Risk ratios for long-term mortality and death and disability among persons given streptokinase for treatment of acute ischemic stroke in the Multicentre Acute Stroke Trial–Europe (MAST-E), Australian Streptokinase Trial (ASK), and the Multicentre Acute Stroke Trial–Italy (MAST-I). Included are 95% confidence intervals. A risk ratio of less than 1.0 favors treatment with streptokinase.

Figure 2. Risk ratios for 30-day mortality and death and disability among persons given intravenous tissue plasminogen activator (r-TPA) for treatment of acute ischemic stroke in the European Cooperative Acute Stroke Study (ECASS) and the National Institute of Neurological Disorders and Stroke study of r-TPA (NINDS). The ECASS study includes data collected from all randomized patients (all) and the desired treatment group (target). Included are 95% confidence intervals. A risk ratio of less than 1.0 favors treatment with r-TPA.

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