The NINDS rt-PA trial (1995) established intravenous thrombolysis as the first effective treatment for acute ischaemic stroke, but within a strict 3-hour time window. Patients treated with alteplase were 30% more likely to have minimal or no disability at 3 months. This 3-hour window became dogma — and meant most stroke patients arrived too late for treatment.

NINDS rt-PA1995Landmark

Favourable outcome (mRS 0-1) at 3 months: OR 1.7; 30% more likely to have minimal disability

NEJMRCTN=624

Proof

Landmark RCTs and pivotal trials that established the evidence base

ECASS III (2008) extended the thrombolysis window to 4.5 hours, showing benefit with OR 1.34 for favourable outcome. Then mechanical thrombectomy transformed the field. MR CLEAN (2015) proved endovascular treatment effective for large vessel occlusion. DAWN (2018) and DEFUSE 3 (2018) dramatically extended the thrombectomy window to 16-24 hours using perfusion imaging to select patients with salvageable brain tissue, fundamentally changing stroke care from time-based to tissue-based selection.

ECASS III2008Landmark

mRS 0-1 at 90 days: OR 1.34 (95% CI 1.02–1.76), p=0.04

NEJMRCTN=821

MR CLEAN2015Landmark

mRS shift: adjusted OR 1.67 (95% CI 1.21–2.30) favouring thrombectomy

NEJMRCTN=500

DAWN2018Landmark

Weighted utility score: 2.0 vs −0.2 favouring thrombectomy (posterior probability >0.999)

NEJMRCTN=206

DEFUSE 32018Landmark

mRS 0-2 at 90 days: 45% vs 17% (RR 2.67, p<0.001)

NEJMRCTN=182

Guidelines

Integration into clinical practice guidelines and recommendations

AHA/ASA 2019 guidelines incorporated thrombectomy within 24 hours for selected patients with large vessel occlusion and favourable perfusion imaging. This transformed stroke systems of care, requiring CT angiography and perfusion imaging capability, and driving the expansion of comprehensive stroke centres and telestroke networks.

AHA/ASA 2019 Stroke Guidelines

Thrombectomy recommended up to 24 hours with perfusion mismatch (Class I, Level A)

Now

Current standard of care and ongoing research directions

The stroke treatment paradigm has shifted from rigid time windows to tissue-based patient selection. Thrombectomy within 24 hours for selected large vessel occlusions is standard of care. Current research explores extending thrombolysis windows with tenecteplase (faster, single-bolus), thrombectomy for medium vessel occlusions, and mobile stroke units with CT capability to bring treatment to the patient.

Landmark Trials in This Story

NINDS rt-PA1995Landmark

Tissue plasminogen activator for acute ischemic stroke

Favourable outcome (mRS 0-1) at 3 months: OR 1.7; 30% more likely to have minimal disability

NEJMRCTN=624

ECASS III2008Landmark

Thrombolysis 3 to 4.5 hours after acute ischemic stroke

mRS 0-1 at 90 days: OR 1.34 (95% CI 1.02–1.76), p=0.04

NEJMRCTN=821

MR CLEAN2015Landmark

A randomized trial of intraarterial treatment for acute ischemic stroke

mRS shift: adjusted OR 1.67 (95% CI 1.21–2.30) favouring thrombectomy

NEJMRCTN=500

DAWN2018Landmark

Thrombectomy 6 to 24 Hours after Stroke with a Mismatch between Deficit and Infarct

Weighted utility score: 2.0 vs −0.2 favouring thrombectomy (posterior probability >0.999)

NEJMRCTN=206

DEFUSE 32018Landmark

Thrombectomy for Stroke at 6 to 16 Hours with Selection by Perfusion Imaging

mRS 0-2 at 90 days: 45% vs 17% (RR 2.67, p<0.001)

NEJMRCTN=182

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Frequently Asked Questions

How long after a stroke can treatment be given?+

IV thrombolysis can be given up to 4.5 hours (ECASS III, 2008). Mechanical thrombectomy can be performed up to 24 hours after stroke onset in patients with large vessel occlusions and favourable perfusion imaging (DAWN, DEFUSE 3, 2018). This extended window dramatically increased the number of patients eligible for treatment.

What changed stroke treatment from time-based to tissue-based?+

DAWN and DEFUSE 3 (2018) showed that perfusion CT or MRI could identify patients with salvageable brain tissue ('penumbra') up to 24 hours after stroke onset. Patients selected by imaging mismatch benefited from thrombectomy regardless of the time elapsed, shifting the paradigm from 'time is brain' to 'physiology is brain.'