What is the efficacy of thrombolytic therapy following a stroke?

Updated: Jan 24, 2018
  • Author: Jeffrey L Saver, MD, FAHA, FAAN; Chief Editor: Helmi L Lutsep, MD  more...
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Answer

Intravenous thrombolytic therapy in the first 3 hours after stroke onset was first demonstrated to be 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, and again in March 2013, 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, 19] This has not yet been FDA approved.

A study by Kim et al looked at the pace of decline in intravenous tPA therapy benefit as onset-to-treatment time grew for patients with acute ischemic stroke. Between 20 and 270 minutes after onset, the pace of decline for discharge to home was mildly nonlinear, although the odds of discharge, independent ambulation at discharge, and freedom from disability at discharge were best for patients treated within the first 60 minutes. Independent ambulation and inhospital mortality both had a linear pace of decline. [20]

Patients who are eligible for treatment with rtPA within 3 hours of onset of stroke should be treated as recommended in the 2007 guidelines. [21] 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 > 25

  • Patients with a history of both prior stroke and diabetes

A 2014 meta-analysis presented at the American Stroke Association (ASA) International Stroke Conference (ISC) found that regardless of patient age or stroke severity, thrombolytic treatment of ischemic stroke significantly improves outcomes. [22]

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. [23]

A phase 3 study by Logallo et al that included 1100 patients with ischemic stroke who were randomly assigned tenecteplase, 0.4 mg/kg bolus, or alteplase, 0.9 mg/kg infusion within 4.5 hours of onset of symptoms. The study found that 354 (64%) patients in the tenecteplase group and 345 (63%) patients in the alteplase group achieved excellent functional outcome (a modified Rankin Scale score 0-1 at 3 months). The study concluded that tenecteplase was not superior to alteplase and showed a similar safety profile and that further studies are necessary to establish the effectiveness in patients with severe stroke. [24]

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. [21, 25]

A study aimed to assess the safety and efficacy of the thrombolytic agent desmoteplase, a fibrin-dependent plasminogen activator, given between  3 h and 9 h after symptom onset in patients with occlusion or high-grade stenosis in major cerebral arteries. The study concluded that treatment with desmoteplase did not cause safety concerns and did not improve functional outcome when given to patients who had ischemic stroke and major cerebral artery occlusion beyond 3 h of symptom onset. [26, 27]

A large study of more than 23,000 tPA-treated patients in the US national registry confirmed that there is no increased bleeding risk associated with treating patients on warfarin whose INR levels are subtherapeutic (< 1.8). [28]

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. [29, 23] This strategy appears highly promising but is not yet validated by an unambiguously positive phase 3 trial.

A study presented at the XXIII European Stroke Conference (ESC) found that using computed tomography (CT) to view the amount of dead tissue in the brain can also be a predictor of who will benefit most from thrombolysis. Further studies are necessary to evaluate whether CT is a stronger predictor than calculations based on time when making treatment decisions. [30, 31]

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. [32]

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. [33]


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