ECASS III Trial: IV tPA for Acute Ischemic Stroke (3–4.5 Hours)
In patients with acute ischemic stroke 3 to 4.5 hours after symptom onset, does IV alteplase 0.9 mg/kg improve functional outcome (mRS 0–1) at 90 days compared with placebo?
Hacke et al. (NEJM 2008) · doi:10.1056/NEJMoa0804656 · 821 patients
Population
Included
- Age 18 to 80 years
- Acute ischemic stroke, symptom onset 3–4.5 hours before IV alteplase
- Symptoms ≥30 minutes without significant improvement before treatment
- Measurable neurological deficit (NIHSS)
- Female or male inpatients
- Age: 18 - 80 years
- Clinical diagnosis of ischemic stroke causing a measurable neurological deficit defined as impairment of language, motor function, cognition and/or gaze, vision or neglect. Ischemic stroke is defined as an event characterized by the sudden onset of an acute focal neurologic deficit presumed to be due to cerebral ischemia after CT scan excludes hemorrhage
- Onset of symptoms between 3 and 4 hours prior to initiation of administration of study drug
- Stroke symptoms are to be present for at least 30 minutes and have not significantly improved before treatment. Symptoms must be distinguishable from an episode of generalized ischemia (i.e. syncope), seizure, or migraine disorder
- Patient is willing to participate voluntarily and to sign a written patient informed consent (informed consent obtained from the patient, legally authorized representative or relatives, or deferred where applicable, per the regulatory and legal requirements of the participating country)
- Patients who are unable to sign but who are able to understand the meaning of participation in the study may give an oral witnessed informed consent
- Willingness and ability to comply with the protocol
Excluded
- Intracranial hemorrhage on imaging
- Symptom onset unknown (e.g., wake-up stroke)
- NIHSS >25 or imaging-defined severe stroke (>1/3 MCA territory)
- Oral anticoagulant use (regardless of INR)
- Combination of prior stroke AND diabetes mellitus
- SBP >185 or DBP >110 mmHg
- Platelets <100,000/mm³; glucose <50 or >400 mg/dL
- Evidence of intracranial hemorrhage (ICH) on the CT-scan
- Symptoms of ischaemic attack began more than 4 hours and 30 minutes prior to infusion start or when time of symptom onset is unknown
- Minor neurological deficit or symptoms rapidly improving before start of infusion
- Severe stroke as assessed clinically (e.g. NIHSS >25) and/or by appropriate imaging techniques
- Epileptic seizure at onset of stroke
- Symptoms suggestive of subarachnoid haemorrhage, even if the CT-scan is normal
- Administration of heparin within the previous 48 hours and a thromboplastin time exceeding the upper limit of normal for laboratory
- History of prior stroke and concomitant diabetes
- Prior stroke within the last 3 months
- Platelet below 100,000/mm³
- Systolic blood pressure >185 mmHg or diastolic blood pressure >110 mmHg, or aggressive management (IV medication) necessary to reduce BP to these limits
- Blood glucose <50 or >400 mg/dl (<2.77 or >22.15 mmol/l)
- Known haemorrhagic diathesis
- Patients receiving oral anticoagulants
- Manifest or recent severe or dangerous bleeding
- Known history of or suspected intracranial haemorrhage
- Suspected subarachnoid haemorrhage or condition after subarachnoid haemorrhage from aneurysm
- History of central nervous system damage (i.e. neoplasm, aneurysm, intracranial or spinal surgery)
- Haemorrhagic retinopathy, e.g. in diabetes (vision disturbances may indicate haemorrhagic retinopathy)
- Recent (less than 10 days) traumatic external heart massage, obstetrical delivery, recent puncture of a non-compressible blood-vessel (e.g. subclavian or jugular vein puncture)
- Bacterial endocarditis, pericarditis
- Acute pancreatitis
- Documented ulcerative gastrointestinal disease during the last 3 months, oesophageal varices, arterial aneurysm, arterial/venous malformation
- Neoplasm with increased bleeding risk
Source: ClinicalTrials.gov NCT00153036· Retrieved 2026-06-08
Primary Outcome
mRS 0–1 at 90 Days
Study Arms
- Agent
- Alteplase (Actilyse, Boehringer Ingelheim), rt-PA
- Dose
- 0.9 mg/kg (upper limit 90 mg)
- Route
- IV
- Frequency
- 10% of the total dose as an IV bolus, then the remainder as a continuous IV infusion
- Duration
- 60-minute infusion (remainder after bolus)
- Co-interventions
- Best medical care. For the first 24 h after study-drug completion, IV heparin, oral anticoagulants, aspirin, and volume expanders (hetastarch/dextrans) were prohibited; subcutaneous heparin ≤10,000 IU (or equivalent LMWH) was permitted for DVT prophylaxis.
Dose/administration from Hacke NEJM 2008 p.1318–1319; concomitant-therapy rules from p.1320 (Concomitant Therapies). Block-of-four randomization via interactive voice system. Time window extended 3–4 h to 3–4.5 h by a May-2005 protocol amendment.
- Agent
- Matched placebo
- Dose
- Volume-matched to alteplase
- Route
- IV
- Frequency
- Identical bolus-then-infusion schedule
- Duration
- 60-minute infusion
- Co-interventions
- Best medical care; same 24-hour prohibition (IV heparin, oral anticoagulants, aspirin, volume expanders) with the same SC-heparin DVT-prophylaxis exception
Double-blind, parallel-group, 1:1. Source: Hacke NEJM 2008 p.1318–1320; CT.gov NCT00153036.
Safety
Symptomatic ICH (ECASS III definition)
2.4%
0.2%
10/418 alteplase vs 1/403 placebo (OR 9.85, 95% CI 1.26–77.32; P=0.008). ECASS III definition: ICH on follow-up imaging with NIHSS ≥4 deterioration or death.
90-day mortality
7.7%
8.4%
32/418 alteplase vs 34/403 placebo (OR 0.90, 95% CI 0.54–1.49; P=0.68). No mortality penalty from extended-window thrombolysis.
Trial Design
Type
- Multicenter randomized controlled trial
- Double-blind, placebo-controlled
- 1:1 allocation (Alteplase vs. Placebo)
Timeline
Enrolled 2003-2007
N
821
Enrollment
821 patients (418 alteplase / 403 placebo, ITT) at 130 sites across 19 European countries. Enrolled July 2003 – November 2007. Published NEJM 2008.
ClinicalTrials.gov
NCT00153036Bedside Pearl
For eligible patients within 3–4.5 hours of symptom onset, IV alteplase improves the chance of mRS 0–1 at 90 days (NNT 14). The benefit is smaller than the 0–3 hour window (NINDS), so start treatment as soon as you confirm eligibility.