Thrombolytic Therapy in Stroke

Introduction

Background

Thrombolytic therapy is of proven and substantial benefit for select patients with acute cerebral ischemia. The evidence base for thrombolysis 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:

1. 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.
2. 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.
3. 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.
4. 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 onset is directly supported by the 2 phase 3 National Institutes 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 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 NINDS tPA trials have generally been duplicated in phase IV 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 6843 patients treated at 285 centers in 14 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 2775 patients enrolled in the first 6 intravenous tPA trials provided clear and convincing evidence of a time-dependent benefit of thrombolytic therapy.⁷ Treatment within the first 90 minutes of onset increased the odds of a favorable outcome by 2.8-fold, in the 91- to 180-minute window by 1.6-fold, and in the 181- to 270-minute window by 1.4 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.

The European Cooperative Acute Stroke Study 3 (ECASS 3) trial was performed to confirm or disconfirm the finding from the pooled analysis of 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 European prospective registry identified 664 patients treated in the 3- to 4.5-hour window in regular practice at 2-3 centers from 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.¹³

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 tPA¹⁴ , 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 time frame.^15,16

Several phase 2 and 1 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.^17,18 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.¹⁹

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.²⁰

Additional promising thrombolytic strategies investigated in pilot trials include 1) combined intravenous and intra-arterial thrombolysis, bringing together the speed of initiation of IV and the higher recanalization rates of IA²¹ and 2) 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)²² .

Pathophysiology

Ischemic strokes are caused by occlusions of cervicocerebral blood vessels. Focal brain infarction results. Cerebral angiography performed shortly after the onset of ischemic stroke reveals clots in large cerebral vessels in up to 80% of cases. Thrombolytic agents convert plasminogen to plasmin. Plasmin cleaves fibrin strands in intravascular thrombi, resulting in clot lysis and restoration of blood flow.

Frequency

United States

Stroke is the third leading cause of death and the leading cause of adult disability in the United States, with an incidence of 256-411 per 100,000 individuals per year. Approximately 730,000 strokes occur yearly in the United States, of which 80-85% are ischemic and the remainder are primary hemorrhages. Various US centers have reported treating 1-11% of ischemic stroke patients with intravenous tPA in clinical practice.

International

Worldwide, stroke is the second leading cause of death, responsible for 4.4 million (9%) of the total 50.5 million deaths each year. Globally, stroke death rates vary widely; the highest rates are in Portugal, China, Korea, and most of Eastern Europe, and the lowest rates are in Switzerland, Canada, and the United States. ICH is more common and ischemic stroke less common in Asian countries than in the United States.

Mortality/Morbidity

The 3-month mortality rate from ischemic stroke is approximately 12%. However, patients who are candidates for thrombolytic stroke therapy tend to have more severe strokes than the average patient with ischemic stroke. The 3-month mortality rate in these more severe patients is approximately 21% when they do not receive thrombolytic therapy. This death rate is not increased by the use of thrombolytic treatment.

Common acute complications of stroke include pneumonia, urinary tract infection, and pulmonary embolism. Long-term morbidity in survivors of stroke is common, with ambulation difficulty in 20%, need for assistance in activities of daily living in 30%, and vocational disability in 50-70% of patients.

Race

Comparison of stroke rates among races is confounded by socioeconomic, environmental, and nutritional factors. The age-adjusted incidence rate for black men is 1.5 times higher than that for white men; that for black women is 2.3 times higher than that for white women. The age-adjusted mortality rate for blacks is 1.98 times that for whites.

Sex

The male-to-female ratio for stroke is about 1.35:1.

Age

The incidence of stroke doubles in every decade after the age of 45 years, rising from 104 per 100,000 per year for adults aged 45-54 years to 1113 per 100,000 per year for adults aged 75-84 years. Two thirds of strokes occur in persons older than 65 years. No absolute age limits apply to the use of thrombolytic therapy.

Clinical

History

• Determination of the time of onset of symptoms is critical in deciding eligibility for thrombolytic therapy. On-label treatment must be initiated within 3 hours of onset of symptoms.
• Sometimes the precise onset time cannot be determined with certainty; for example, when a patient awakens with a deficit after a night's sleep or after a nap or is found stricken and unable to communicate the onset time. In these instances, the onset time is taken as the last time the patient was known to be well.
• Caution should be exercised in patients with neglect syndromes who may not have observed their onset time reliably.
• History exclusion criteria
  • Seizure at stroke onset
  • Symptoms suggestive of subarachnoid hemorrhage
  • Stroke or serious head trauma within 3 months
  • Major surgery or serious bodily trauma within 2 weeks
  • History of a prior ICH
  • Intracranial neoplasm
  • Arteriovenous malformation or aneurysm
  • GI or urinary tract hemorrhage within 21 days
  • Arterial puncture at a noncompressible site or lumbar puncture within 1 week
  • Concomitant oral anticoagulant (INR>1.7)

Physical

To be considered for thrombolytic therapy, a patient must have more than a minimal neurological deficit. Patients with only minimal weakness, isolated ataxia, isolated sensory deficit, or isolated dysarthria are generally not lytic candidates.

• The National Institutes of Health Stroke Scale (NIHSS), a standardized rating scale, is helpful in characterizing the severity of a patient's neurologic deficit. For a copy of the scale, go to NIH Stroke Scale.
  • NIHSS is a reproducible 13-item scale that quantifies the neurologic examination, ascertaining level of alertness and orientation, gaze difficulty, visual field defects, facial weakness, limb weakness, sensory loss, speech and language defects, and neglect.
  • Scores range from 0 to 42, with 0 denoting no neurologic deficit.
  • The FDA-approved package insert for tPA lists as a warning an NIHSS score greater than 22, indicating a severe neurologic deficit.
  • Patients with NIHSS scores greater than 22 are at increased risk of symptomatic hemorrhagic transformation if they receive tPA.
  • However, patients with NIHSS scores greater than 22 still tend to benefit from treatment.
• Physical exam exclusion criteria
  • Rapidly improving neurological signs
  • Systolic blood pressure (SBP) greater than 185 mm Hg or diastolic blood pressure (DBP) greater than 110 mm Hg or aggressive (continuous intravenous) treatment required to lower BP to this range
  • Suspected acute pericarditis

Causes

• Risk factors for ischemic stroke
  • Age
  • Hypertension
  • Diabetes
  • Smoking
  • Atrial fibrillation
  • Hypercholesterolemia
  • Coronary artery disease
• Mechanisms of ischemic stroke
  • In situ atherothrombosis
  • Artery to artery embolism
  • Cardioembolism
  • Lipohyalinosis
  • Hypercoagulable state

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