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May - 2019

   

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Thrombolysis Guided by Perfusion Imaging up to 9 Hours after Onset of Stroke

H Ma, B Campbell, M Parsons, for the EXTEND Investigators New Eng J Med, 2019, 380:1795-1803

Comment

Current guidelines for use of intravenous thrombolysis for acute stroke generally recommend initiation within 4.5 hours of symptom onset. This multicenter, placebo controlled RCT;

  • Enrolled adults with excellent functional status prior to enrolment, had stroke with NIHSS 4-26, hypoperfused but salvageable regions of brain detected on automated perfusion imaging. Consideration of endovascular thrombectomy at time of enrolment. 
  • Randomised patients 1:1 to alteplase (0.9 mg / kg body weight, max 90 mg), IV as a 10% bolus and 90% infusion over 1 hour) or matching placebo
  • Trial stopped at 225 of planned 310 patients due to lack of equipoise
  • Primary outcome was 90-d modified Rankin scale score of 0-1 - 35.4% alteplase group vs 29.5% placebo (adj RR, 1.44; 95% CI, 1.01 to 2.06; P=0.04). S
  • Symptomatic intracerebral hemorrhage 6.2% alteplase vs 0.9% placebo group (adj RR, 7.22; 95% CI, 0.97 to 53.5; P=0.05). 
  • Proporption of patients who died was 11.5% alteplase vs 8.9% placebo, adj RR 1.17, 95% CI 0.57,2.4, p=0.67
  • Secondary ordinal analysis of the distribution of scores on the modified Rankin scale did not show a significant between-group difference in functional improvement at 90 days. 

Overall patients with ischaemic stroke and salvageable brain tissue who received alteplase between 4.5 and 9.0 hours after stroke onset or at the time the patient awoke with stroke symptoms, had higher percentage of patients with no or minor neurologic deficits than patients who received placebo. There were more cases of symptomatic cerebral hemorrhage in the alteplase group. Because of the limited power of our conclusions as a result of premature termination, and the lack of a significant between-group difference in the secondary outcome of functional improvement, further trials of thrombolysis in this time window are required.

 

Abstract

BACKGROUND

The time to initiate intravenous thrombolysis for acute ischemic stroke is generally limited to within 4.5 hours after the onset of symptoms. Some trials have suggested that the treatment window may be extended in patients who are shown to have ischemic but not yet infarcted brain tissue on imaging.

METHODS

We conducted a multicenter, randomized, placebo-controlled trial involving patients with ischemic stroke who had hypoperfused but salvageable regions of brain detected on automated perfusion imaging. The patients were randomly assigned to receive intravenous alteplase or placebo between 4.5 and 9.0 hours after the onset of stroke or on awakening with stroke (if within 9 hours from the midpoint of sleep). The primary outcome was a score of 0 or 1 on the modified Rankin scale, on which scores range from 0 (no symptoms) to 6 (death), at 90 days. The risk ratio for the primary outcome was adjusted for age and clinical severity at baseline.

RESULTS

After 225 of the planned 310 patients had been enrolled, the trial was terminated because of a loss of equipoise after the publication of positive results from a previous trial. A total of 113 patients were randomly assigned to the alteplase group and 112 to the placebo group. The primary outcome occurred in 40 patients (35.4%) in the alteplase group and in 33 patients (29.5%) in the placebo group (adjusted risk ratio, 1.44; 95% confidence interval [CI], 1.01 to 2.06; P=0.04). Symptomatic intracerebral hemorrhage occurred in 7 patients (6.2%) in the alteplase group and in 1 patient (0.9%) in the placebo group (adjusted risk ratio, 7.22; 95% CI, 0.97 to 53.5; P=0.05). A secondary ordinal analysis of the distribution of scores on the modified Rankin scale did not show a significant between-group difference in functional improvement at 90 days.

CONCLUSIONS

Among the patients in this trial who had ischemic stroke and salvageable brain tissue, the use of alteplase between 4.5 and 9.0 hours after stroke onset or at the time the patient awoke with stroke symptoms resulted in a higher percentage of patients with no or minor neurologic deficits than the use of placebo. There were more cases of symptomatic cerebral hemorrhage in the alteplase group than in the placebo group.

May


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