The Evidence

Early intravenous administration of recombinant tissue-type plasminogen activator (rtPA, alteplase) has been proven to improve functional outcome after acute ischemic stroke.2 The pivotal trial leading to the international approval of intravenous rtPA for the treatment of cerebral ischemia was the National Institute of Neurological Disorders and Stroke (NINDS) rtPA Stroke Study.3 In this trial, 624 patients were randomized to receive intravenous rtPA (0.9 mg/kg, maximum 90 mg) or a placebo within 3 hours of stroke symptom onset. Treatment with intravenous rtPA was associated with at least a 30% increase in the chances of achieving functional independence with complete or nearly complete neurologic recovery at 3 months.3 The main risk of treatment was symptomatic intracerebral hemorrhage, which occurred in 6.4% of patients treated with rtPA versus 0.6% of patients who received placebo, but it did not result in an increase in mortality among rtPA-treated patients. Efficacy was greatest for patients treated within 90 minutes of symptom onset. For patients treated within 90 minutes, the odds ratio for complete recovery was 2.11 compared with an odds ratio of 1.69 for patients treated within 91 to 180 minutes.4 A graphic illustration of the benefit that patients can expect when given intravenous rtPA within 3 hours of stroke symptom onset is presented in Fig. 3.2 . Functional benefit was sustained at 1 year.5 Subgroup analyses confirmed that the efficacy of intravenous rtPA extended to all patients meeting the trial inclusion and exclusion criteria, including older patients with severe strokes at presentation.3

Shortly after publication of the NINDS trial, rtPA was approved for intravenous use in patients with acute ischemic stroke in the United States, mostly following the patient selection criteria of the NINDS study. An additional radiologic exclusion criterion was added based on the finding that the presence of large early ischemic changes on a baseline computed tomography (CT) scan was associated with a higher risk of symptomatic intracranial hemorrhage, and results from earlier European studies that suggested poorer outcomes in patients with multilobar low-attenuation changes,6 which had led to the exclusion of these patients from subsequent European trials. Since then, treatment with intravenous rtPA has gained acceptance worldwide, and its effectiveness has been confirmed in multiple observational studies.

The largest of these observational studies has been the Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST),7 which enrolled nearly 6500 patients from 14 European countries. Intravenous fibrinolysis with rtPA was at least as safe and effective in routine clinical practice as it had been in the randomized trials.7 ^, 8 Over three quarters of treated patients had moderate to severe strokes at baseline, and 55% were independent at 3 months despite only 10.6% being treated within 90 minutes (versus half of the rtPA group in the NINDS trial). Even centers with limited experience on the administration of fibrinolysis for acute stroke achieved good results when adhering to the accepted indications and contraindications. The risk of intracranial hemorrhage, defined using various criteria, was acceptably low. Substantial neurologic decline from brain hemorrhage only occurred in 1.7% of patients.

Although intravenous fibrinolysis has become the standard of care for emergency treatment of patients with acute ischemic stroke, only a small minority of these patients receive the therapy. The main reason for the limited application of this effective intervention in clinical practice is that patients often arrive at the emergency department too late. As a consequence, there has been a lot of interest in extending the therapeutic window for acute reperfusion therapies, including intravenous rtPA.

A pooled analysis of six major trials evaluating the effectiveness of intravenous rtPA for acute ischemic stroke within 6 hours of symptom onset suggested that fibrinolysis could produce clinical benefit when administered beyond 3 hours.9 In fact, this analysis showed that the benefit was much greater within the first 90 minutes of symptom onset, but much more similar when the time to treatment was 91 to 180 minutes and 181 to 270 minutes. These findings provided the rationale for the design of the European Cooperative Stroke Study (ECASS III) trial, a multicenter, randomized trial conducted in Europe to evaluate intravenous rtPA versus placebo administered between 3 and 4.5 hours after the onset of ischemic stroke symptoms.10 A total of 821 patients were enrolled, nearly one-third more than in the NINDS trial. Treatment with rtPA was associated with a significant improvement in the rate of favorable functional outcome using various scales. Overall, the chances of regaining full independence were 28% higher among patients treated with rtPA, and 14 patients had to be treated for one additional patient to achieve a favorable outcome. Mortality was not significantly different between the groups, but was slightly higher in the placebo arm. The rate of symptomatic intracranial hemorrhage as defined by the NINDS criteria was 7.9% in the rtPA group (versus 6.4% in the NINDS trial), but only 2.4% of patients were considered to have worsened because of the bleeding. Intravenous fibrinolysis with rtPA within 3 and 4.5 hours was also shown to be safe in a large European observational study (Safe Implementation of Thrombolysis in Stroke-International Thrombolysis Registry (SITS-ISTR), which included over 650 patients treated in that time window.11 Therefore, intravenous rtPA should be considered for selected patients with symptom duration of between 3 and 4.5 hours.

Patient Evaluation and Selection

Acute stroke patients must be evaluated emergently for consideration of reperfusion treatments. Hospitals need to implement a stroke code process to streamline immediate patient assessment, brain imaging, and drug administration. Development of critical care pathways (ideally starting from assessment in the field by paramedics or other first responders), easily accessible written protocols, and order sets are highly useful to ensure rapid and effective evaluation and treatment (Fig. 3.3). Hospitals should monitor their performance to recognize areas for improvement and to ensure consistent compliance with the recommended time metrics (Table 3.1).

Strict adherence to the prescribed criteria for patient selection is crucial to avoid complications and optimize the likelihood of benefit from intravenous fibrinolysis. Table 3.2 presents the indications and contraindications for treatment with intravenous rtPA. Note that some additional contraindications should be considered when contemplating the use of rtPA between 3 and 4.5 hours.

The importance of the careful determination of time of symptom onset cannot be overemphasized. Current guidelines on rtPA administration are based on the definition of symptom onset as the last time that the patient was symptom-free or at his/her previous baseline.2 For patients who wake up with symptoms, the time of onset is considered the last time the patient was awake and without the symptoms. A recent transient ischemic attack similar to the current symptoms is generally not considered a contraindication for fibrinolysis; the clock can be reset to the time of onset of the new symptoms as long as there is clear knowledge that the previous symptoms resolved fully.

Some factors initially listed among the exclusion criteria for intravenous fibrinolysis in the seminal trials are no longer considered to be contraindications in practice. For instance, the report of a seizure at the onset of deficits should not preclude fibrinolysis as long as the treating physician is convinced that the persistent deficits are secondary to a stroke and not merely a postictal phenomenon.2 Similar reasoning might be applied to hypoglycemic patients who fail to improve after administration of dextrose. One should also be careful when deciding not to treat a stroke patient with fibrinolysis because of mild or rapidly improving symptoms. All too often, these patients subsequently suffer permanent disability from these strokes.12

Interpretation of brain imaging in the emergency setting has the primary objective of excluding intracranial hemorrhage. Noncontrast CT scan of the head is sufficient for this objective, and emergency treatment should not be delayed to obtain more advanced imaging modalities (such as multimodality magnetic resonance imaging [MRI] and multimodality CT).2 Apart from hemorrhage, only the presence of multilobar hypodensity (involving more than one third of the cerebral hemisphere) should be considered a radiologic contraindication for fibrinolysis (Fig. 3.4). Other CT findings may have prognostic value, but they do not negate the benefit of fibrinolysis and should not preclude its use (Fig. 3.5). For instance, the presence of a hyperdense middle cerebral artery sign is associated with worse prognosis13 and higher risk of hemorrhage after fibrinolysis,14 but intravenous rtPA can still be useful for these patients.13 Other early signs of brain ischemia can often be seen when the CT scan is assessed in detail, such as loss of insular ribbon, obscuration of the lenticular nucleus, loss of gray-white matter differentiation, and sulcal effacement. However, these signs do not have the same implication as areas of definite hypodensity because they probably indicate focal tissue edema rather than established infarction.15 Interpretation of brain imaging should be performed by a physician with expertise reading brain scans, but formal training in neuroradiology is not required.

Adequate control of blood pressure before, during, and after administration of intravenous fibrinolysis must be achieved to reduce the risk of intracranial bleeding. Table 3.3 summarizes the recommendations for blood pressure control. Most stroke specialists deem administration of fibrinolysis unsafe for patients who require sodium nitroprusside infusion to lower the blood pressure below 185/110 mm Hg in the emergency department.