Thrombolytic Therapy in Stroke 

Thrombolytics restore cerebral blood flow in some patients with acute ischemic stroke and may lead to improvement or resolution of neurologic deficits.

Thrombolytic therapy is of proven and substantial benefit for select patients with acute cerebral ischemia. The evidence base for thrombolysis in stroke includes 21 completed randomized controlled clinical trials enrolling 7152 patients, using various agents, doses, time windows, and intravenous or intra-arterial modes of administration .^{[1, 2]} Data from these trials are congruent in supporting the following conclusions:

• Intravenous fibrinolytic therapy at the cerebral circulation dose within the first 3 hours of ischemic stroke onset offers substantial net benefits for virtually all patients with potentially disabling deficits.
• Intravenous fibrinolytic therapy at the cerebral circulation dose within 3-4.5 hours offers moderate net benefits when applied to all patients with potentially disabling deficits.
• MRI of the extent of the infarct core (already irreversibly injured tissue) and the penumbra (tissue at risk but still salvageable) can likely increase the therapeutic yield of lytic therapy, especially in the 3- to 9-hour window.
• Intra-arterial fibrinolytic therapy in the 3- to 6-hour window offers moderate net benefits when applied to all patients with potentially disabling deficits and large artery cerebral thrombotic occlusions.

Intravenous thrombolytic therapy in the first 3 hours after stroke onset was first demonstrated beneficial in the 2-phase 3 National Institute of Neurological Disorders and Stroke (NINDS) tissue plasminogen activator (tPA) trials, completed in 1995 and reported together.^[3]

NINDS Trial 1 and NINDS Trial 2 together randomized 624 subjects within 3 hours of stroke onset to receive 0.9 mg/kg of intravenous tPA or placebo and 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 .^[4] Brain hemorrhages related to tPA caused severe worsened final outcome in 1% of patients.^[5] Overall, for every 100 patients treated within the first 3 hours, 32 had a better outcome as a result and 3 had a worse outcome.

An independent reanalysis of the NINDS trials demonstrated a robust treatment effect in favor of tPA.^[6] Four other phase 3 IV tPA trials, ECASS 1, ECASS 2, ATLANTIS A, and ATLANTIS B, have enrolled small subsets of patients in the under 3-hour time window. The degree of benefit of lytic therapy in the under 3-hour period observed in these trials was concordant with that found in the 2 NINDS trials.^{[7, 8]} 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 randomized clinical trials have generally been duplicated in phase 4 studies examining the use of intravenous tPA in routine clinical practice.^{[9, 10, 11]} 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 23,942 patients treated at 650 centers in more than 25 countries and found the rate of complications and favorable outcomes similar to those of the NINDS tPA trials.^[11] These findings show that tPA is just as effective in clinical practice as in clinical trials when inclusion and exclusion guidelines are followed.

Time lost is brain lost in acute cerebral ischemia. In a typical middle cerebral artery ischemic stroke, 2 million nerve cells are lost each minute in which reperfusion has not been achieved.^[12] A pooled analysis of all 3670 patients enrolled in the first 8 intravenous tPA trials provided clear and convincing evidence of a time-dependent benefit of thrombolytic therapy.^{[7, 13]} Treatment within the first 90 minutes of onset increased the odds of an excellent outcome by 2.6-fold, in the 91- to 180-minute window by 1.6-fold, and in the 181- to 270-minute window by 1.3 fold, while treatment in the 271- to 360-minute window did not improve outcome in a statistically significant manner. The sooner tPA is given to patients, the greater the benefit. Every 10 minutes in which therapy is delayed, one fewer of each hundred treated patients benefits.^[14]

The European Cooperative Acute Stroke Study 3 (ECASS 3) trial was performed to confirm or disconfirm the findings from initial trials suggesting benefit of IV tPA therapy in the 3- to 4.5-hour window. In ECASS 3, 821 patients were randomized to IV tPA or placebo. Major symptomatic hemorrhages occurred in 2.4% of the tPA group versus 0.2% of the placebo group, with no increase in mortality. Patients treated with tPA 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 45% with placebo to 52% with tPA, a 7% absolute improvement. The number needed to treat for 1 more patient to have a normal or near normal outcome was 14, and the number needed to treat for 1 more patient to have an improved outcome was 8. Overall, for every 100 patients treated within the 3- to 4.5-hour window, 16 had a better outcome as a result and 3 had a worse outcome. ^[2]

The favorable results of the pooled and ECASS 3 trials in the 3- to 4.5-hour window have been duplicated in a large phase 4 study examining the use of intravenous tPA in routine clinical practice. The international Safe Implementation of Treatment in Stroke (SITS) prospective registry identified 2376 patients treated in the 3- to 4.5-hour window in regular practice at 650 centers from more than 25 countries. The rates of complications and of favorable outcomes were similar to those in ECASS 3. These findings confirm tPA as effective in clinical practice as it is efficacious in clinical trials in the 3- to 4.5-hour window when inclusion and exclusion guidelines are followed.^[15]

In May 2009, the American Heart Association/American Stroke Association (AHA/ASA) guidelines for the administration of recombinant tPA (rtPA) following acute stroke were revised to expand the window of treatment from 3 hours to 4.5 hours to provide more patients with an opportunity to receive benefit from this effective therapy.^[16] {{15}^{[17, 18]} This has not yet been FDA approved.

Patients who are eligible for treatment with rtPA within 3 hours of onset of stroke should be treated as recommended in the 2007 guidelines.^[19] Although a longer time window for treatment with rtPA has been tested formally, delays in evaluation and initiation of therapy should be avoided because the opportunity for improvement is greater with earlier treatment. rtPA should be administered to eligible patients who can be treated in the time period of 3 to 4.5 hours after stroke (Class I Recommendation, level of Evidence B). Eligibility criteria for treatment in the 3 to 4.5 hours after acute stroke are similar to those for treatment at earlier time periods, with any one of the following additional exclusion criteria:

• Patients older than 80 years
• All patients taking oral anticoagulants are excluded regardless of international normalized ratio (INR)
• Patients with baseline National Institutes of Health Stroke Scale score ³25
• Patients with a history of both prior stroke and diabetes

Intravenous trials of other fibrinolytic agents in clinically selected patients are consistent with the tPA trial results, but have not yet identified another proven agent. Three trials of streptokinase predominantly enrolled patients in the 4.5- to 6-hour window, a time period in which tPA is not beneficial, and tested a high dose of lytic agent. These trials found no net benefit of high dose, late IV lytic therapy. A pilot trial of tenecteplase in the under 3-hour time window suggested potential safety and benefit ratio greater than or equal to that of tPA^[20] , a potential efficacy signal now being explored in a larger study.

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 the onset of stroke symptoms benefit substantially from therapy, despite a modest increase in the rate of symptomatic hemorrhage. Patients treated in the 3- to 4.5-hour window show a modest, but still clinically worthwhile, therapeutic yield. Beyond 4.5 hours after onset, no net benefit of therapy has been demonstrated. Current US and international consensus guidelines accordingly recommend intravenous thrombolysis when treatment can be initiated within 3 hours from stroke onset, the most well-established treatment timeframe.^{[19, 21]}

Several phase 2 and one phase 3 trial have used multimodal CT or MRI to identify select 3- to 9-hour postonset patients who still harbor substantial salvageable tissue and are likely to benefit from late intravenous treatment.^[22] {Ref22}This strategy appears highly promising but is not yet validated by an unambiguously positive phase 3 trial.

Intra-arterial (IA) thrombolysis has also been investigated as a treatment for acute ischemic stroke. Compared with intravenous therapy, IA therapy offers several advantages, including a higher concentration of lytic agent delivered to the clot target, a lower systemic exposure to drug, and higher recanalization rates. Disadvantages include additional time required to initiate therapy, availability only at specialized centers, and mechanical manipulation within potentially injured vessels.

The phase 3 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. 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.^[23]

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 using 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. 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.^[24]

Additional promising thrombolytic strategies investigated in pilot trials include the following:

• Combined intravenous and intra-arterial thrombolysis, bringing together the speed of initiation of IV and the higher recanalization rates of IA^[25]
• Combined IV and/or IA thrombolysis with endovascular mechanical clot retrieval or aspiration, joining the ability of mechanical devices to dispose of large proximal clot burdens with the ability of lytics to initiate therapy early (IV lysis) or clean up smaller occlusions in distal arteries not accessible to mechanical attack (IA lysis)^[26]
• Ultrasonography-enhanced thrombolysis, using high-frequency ultrasonography to accelerate enyzymatic fibrinolysis by increasing penetration of drug molecules into the clot^[27]

The American Heart Association/American Stroke Association (AHA/ASA) inclusion guidelines for the administration of rt-PA in under 3 hours are as follows^[7] :

• Diagnosis of ischemic stroke causing measurable neurologic deficit
• Neurologic signs not clearing spontaneously
• Neurologic signs not minor and isolated
• Symptoms not suggestive of subarachnoid hemorrhage
• Onset of symptoms less than 3 hours hours before beginning treatment
• No head trauma or prior stroke in past 3 months
• No MI in prior 3 months
• No GI/GU hemorrhage in previous 21 days
• No arterial puncture in noncompressible site during prior 7 days
• No major surgery in prior 14 days
• No history of prior intracranial bleed
• Systolic blood pressure under 185 mm Hg, diastolic blood pressure under 110 mm Hg
• No evidence of acute trauma or bleeding
• Not taking an oral anticoagulant, or if so, INR under 1.7
• If taking heparin within 48 hours, a normal activated prothrombin time (aPT)
• Platelet count of more than 100,000/μL
• Blood glucose greater than 50 mg/dL (2.7 mmol)
• No seizure with residual postictal impairments
• CT scan does not show evidence of multilobar infarction (hypodensity over one-third hemisphere)
• The patient and family understand the potential risks and benefits of therapy

In May 2009, the AHA/ASA guidelines for the administration of rt-PA following acute stroke were revised to expand the window of treatment from 3 hours to 4.5 hours to provide more patients with an opportunity to receive benefit from this effective therapy.^{[4, 8, 9]}

Eligibility criteria for treatment in the 3 to 4.5 hours after acute stroke are similar to those for treatment at earlier time periods, with any 1 of the following additional exclusion criteria:

• Patients older than 80 years
• All patients taking oral anticoagulants are excluded regardless of the international normalized ratio (INR)
• Patients with baseline NIHSS score > 25
• Patients with a history of stroke and diabetes

The chief benefit of thrombolysis is improved final functional outcome through reperfusion salvage of threatened tissue. The chief risk is intracerebral hemorrhage.

With intravenous thrombolysis, about 6% of patients have intracerebral hemorrhage associated with early worsening,^{[3, 11]} and half of these patients have their final outcome altered as a result.^[5] With intra-arterial thrombolysis, about 10% of patients have major early hemorrhage, but again many of these occur in already infarcted fields and do not clearly alter final outcome. Other less frequent complications of thrombolytics include systemic hemorrhage, angioedema, and allergic reactions.^[7]

Figure 1 is a visual decision aid that depicts the benefits and risks of intravenous thrombolytic therapy provided to patients within 3 hours of stroke onset. Overall, of every 100 patients treated, 32 will have a better and 3 will have a worse final global disability outcome as a result of therapy.

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. Blood pressure should be monitored closely and controlled. Physical, occupational, and speech therapy can be initiated after the first 24 hours of bedrest.

Obtain neurosurgery and hematology consultation.

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 combined minor and major symptomatic ICH (ie, any clinical worsening temporally coincident with any 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.

Other complications may include oozing from intravenous line and venous puncture sites (up to 30% of cases) and angioedema, although this is rare.

Prognosis

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.

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 5 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.

• 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.^[13]