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Thrombolysis Guided by Perfusion Imaging After Stroke Onset
Study Questions:
Is treatment of acute ischemic stroke patients with intravenous (IV) tissue-type plasminogen activator (tPA) beneficial in an extended (4.5- to 9-hour) window when perfusion imaging shows a small core of infarction and a large area of hypoperfusion?
Methods:
This is a multicenter, 1:1 randomized, placebo-controlled trial of acute ischemic stroke patients. Eligible patients had a favorable cerebral perfusion imaging profile (imaging showing a hypoperfusion/core mismatch ratio >1.2, a difference between volume of hypoperfusion and volume of core >10 ml, and a core volume <70 ml). Patients were treated with IV tPA versus placebo between 4.5 and 9 hours after stroke onset or after awakening with stroke symptoms. Exclusion criteria included National Institutes of Health Stroke Scale score (NIHSS) <4, NIHSS >26, and/or plans for mechanical thrombectomy. The primary outcome was a favorable modified Rankin scale score (0 or 1) at 90 days. Safety outcomes were death within 90 days and symptomatic intracranial hemorrhage.
Results:
A favorable modified Rankin scale score of 0 or 1 occurred in 40 of 113 patients (35.4%) in the IV tPA group and in 33 of 112 patients (29.5%) in the placebo group (risk ratio [RR] adjusted for baseline NIHSS and age, 1.44; 95% confidence interval [CI], 1.01-2.06). There was no difference in mortality at 90 days between the two groups (11.5% tPA vs. 8.9% placebo, p = 0.67). Symptomatic intracranial hemorrhage occurred in 7 of 113 patients (6.2%) in the IV tPA group and in 1 of 112 patients (0.9%) in the placebo group (adjusted RR, 7.22; 95% CI, 0.97-53.54). An ordinal analysis of the distribution of scores on the modified Rankin scale in each trial group (i.e., shift analysis) did not show a significant between-group difference at 90 days (common odds ratio, 1.55; 95% CI, 0.96-2.49).
Conclusions:
When compared to placebo, the use of IV tPA between 4.5 and 9 hours after ischemic stroke onset in patients with a favorable perfusion imaging profile results in a higher likelihood of no or minor neurologic deficits at 90 days. There was a higher risk of symptomatic cerebral hemorrhage in the IV tPA group than in the placebo group.
Perspective:
For over a decade, acute ischemic stroke treatment with IV tPA has been limited to use within 4.5 hours of last known normal. This short treatment window precludes many otherwise eligible patients from receiving IV tPA because they either wake up with their deficits or arrive to the emergency room too late. The EXTEND trial builds on the results of the WAKE-UP trial (N Engl J Med 2018;379:611-22) and suggests a role for extended-window thrombolysis based on a tissue-based rather than a time-based strategy. The results of this trial are likely to have a major impact on acute stroke systems of care by doubling the potential thrombolysis treatment window. Careful patient selection will be key. The rates of hemorrhage in extended-window thrombolysis should continue to be monitored.
Clinical Topics: Cardiac Surgery, Dyslipidemia, Invasive Cardiovascular Angiography and Intervention, Noninvasive Imaging, Prevention, Cardiac Surgery and Arrhythmias, Lipid Metabolism, Interventions and Imaging, Nuclear Imaging
Keywords: Brain Ischemia, Cerebral Hemorrhage, Emergency Service, Hospital, Infarction, Intracranial Hemorrhages, Perfusion Imaging, Risk Factors, Secondary Prevention, Stroke, Thrombectomy, Thrombolytic Therapy, Tissue Plasminogen Activator, Vascular Diseases
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