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Original paper
2019NEJMNeurology

EXTEND

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

RCTAcute ischemic stroke

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Overview

In perfusion-selected late or wake-up stroke, alteplase at 4.5 to 9 hours improved excellent 90-day outcomes versus placebo, with more symptomatic hemorrhage.

Clinical takeaway

EXTEND supports alteplase beyond 4.5 hours, or for wake-up stroke, when automated perfusion imaging shows salvageable tissue.

Key result

mRS 0-1 at 90 days occurred in 35.4% with alteplase vs 29.5% with placebo (adjusted RR 1.44; 95% CI 1.01-2.06; p=0.04).

Practice impact

Late or wake-up stroke can be treated with alteplase if perfusion imaging shows hypoperfused but salvageable brain.

Evidence

Study design

Multicenter, randomized, placebo-controlled trial using automated perfusion imaging selection.

Enrollment

225

Follow-up

Modified Rankin scale assessed at 90 days.

Geography

Not listed

Clinical question

Does intravenous alteplase improve excellent 90-day outcome when given 4.5 to 9 hours after stroke, or for wake-up stroke, in patients with salvageable perfusion imaging?

Population

  • Patients with ischemic stroke and hypoperfused but salvageable brain on automated perfusion imaging, treated between 4.5 and 9.0 hours after onset or on awakening (if within 9 hours from the midpoint of sleep).

Intervention

Intravenous alteplase.

Comparator

Placebo.

Primary outcome

Modified Rankin scale score of 0 or 1 at 90 days.

Alteplase increased the chance of no or minor neurologic deficit at 90 days in perfusion-selected late or wake-up stroke.

Adjusted risk ratio / 1.44 / 95% CI 1.01-2.06 / p=0.04

Key results

  • The primary outcome occurred in 35.4% with alteplase vs 29.5% with placebo (adjusted RR 1.44; 95% CI 1.01-2.06; p=0.04).
  • The trial stopped after 225 of a planned 310 patients because of loss of equipoise after another positive trial.
  • A secondary ordinal analysis of 90-day modified Rankin scores did not show a significant between-group difference.

Harms

  • Symptomatic intracerebral hemorrhage occurred in 6.2% with alteplase vs 0.9% with placebo (adjusted RR 7.22; 95% CI 0.97-53.5; p=0.05).

Clinical Use

Practice impact

  • Late or wake-up stroke can be treated with alteplase if perfusion imaging shows hypoperfused but salvageable brain.

Applicability

  • Most applicable to ischemic stroke with automated perfusion mismatch treated between 4.5 and 9 hours, or on awakening within 9 hours from the midpoint of sleep.

Limitations

  • The trial stopped early after 225 of 310 planned patients, so the estimate is less stable.
  • The ordinal modified Rankin analysis did not show a significant functional shift.
  • There were more cases of symptomatic intracerebral hemorrhage with alteplase, but the confidence interval included no difference.

Common misinterpretations

  • This is not a license for late alteplase without perfusion selection.
  • A positive dichotomized mRS 0-1 result does not mean the full disability distribution clearly improved.

Related evidence

ECASS III - Earlier TrialWAKE-UP - Similar QuestionNINDS tPA - Earlier Trial

Citation

Ma H, Campbell BCV, Parsons MW, et al. Thrombolysis Guided by Perfusion Imaging up to 9 Hours after Onset of Stroke. N Engl J Med. 2019;380(19):1795-1803. doi:10.1056/NEJMoa1813046

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.