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ECASS III

Thrombolysis with Alteplase 3 to 4.5 Hours after Acute Ischemic Stroke

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Year of Publication: 2008

Authors: Werner Hacke, Markku Kaste, Erich Bluhmki, ..., for the ECASS Investigators

Journal: New England Journal of Medicine

Citation: N Engl J Med 2008;359:1317-1329

Link: https://www.nejm.org/doi/full/10.1056/NEJMoa0804656

PDF: https://www.nejm.org/doi/pdf/10.1056/NEJMoa0804656

Clinical Question

Does intravenous alteplase administered 3 to 4.5 hours after symptom onset improve outcomes in acute ischemic stroke compared to placebo?

Bottom Line

Alteplase given between 3–4.5 hours after stroke significantly improved functional outcomes but increased the risk of symptomatic intracranial hemorrhage, with no difference in mortality.

        Major Points
        Landmark randomized, double-blind, placebo-controlled trial that extended the IV alteplase treatment window from 3 to 4.5 hours after stroke onset.
821 patients randomized 1:1 across 130 centers in 19 European countries. Median onset-to-treatment time: 3 hours 59 minutes.
Primary outcome (mRS 0–1 at 90 days): 52.4% vs 45.2% (OR 1.34, 95% CI 1.02–1.76, P=0.04, NNT 14).
Global outcome (composite mRS, BI, NIHSS, GOS): OR 1.28 (95% CI 1.00–1.65, P=0.05) — borderline significant.
Symptomatic ICH (per ECASS definition): 2.4% vs 0.2% (P=0.008). Any ICH: 27.0% vs 17.6% (P=0.001).
90-day mortality: 7.7% vs 8.4% (P=0.68) — no difference despite higher ICH rate.
Alteplase dose: 0.9 mg/kg (max 90 mg), 10% bolus + 90% over 60 minutes — same NINDS protocol.
Notable exclusion: patients with combination of prior stroke AND diabetes were excluded (concern for higher ICH risk), limiting generalizability to this common subgroup.
Led to AHA/ASA guideline update recommending IV alteplase up to 4.5 hours (Class I, Level B). FDA never formally approved the extended window, but 3–4.5h became standard of care.

      

Design

Study Type: Randomized, double-blind, placebo-controlled trial

Randomization: 1

Blinding: Double-blind

Enrollment Period: July 2003 – November 2007

Follow-up Duration: 90 days

Centers: 130

Countries: Austria, Belgium, Czech Republic, Denmark, Finland, France, Germany, Greece, Hungary, Italy, Netherlands, Norway, Poland, Portugal, Slovakia, Spain, Sweden, Switzerland, United Kingdom

Sample Size: 821

Analysis: Intention-to-treat and per-protocol; logistic regression; global odds ratio; adjusted for NIHSS, time to treatment, hypertension, smoking, prior stroke

Inclusion Criteria

Age 18–80 years (upper age limit 80, unlike NINDS which had no upper limit).
Acute ischemic stroke with clearly defined symptom onset 3.0–4.5 hours before planned treatment start.
Persistent neurological deficit lasting ≥30 minutes with no significant improvement before treatment.
NIHSS score between 1 and 25 (excluded very severe strokes NIHSS >25).
Non-contrast CT or MRI excluding hemorrhage, tumor, and large established infarction (>1/3 MCA territory).

Exclusion Criteria

ICH on imaging
Unknown onset time
Rapidly improving or minor symptoms
NIHSS >25
Seizure at onset
Stroke or head trauma in past 3 months
Combined stroke and diabetes history
Recent heparin or abnormal aPTT
Platelets <100,000/mm³
SBP >185 or DBP >110
Blood glucose <50 or >400 mg/dL
Oral anticoagulants
Recent major surgery or trauma
High bleeding risk

Baseline Characteristics

Characteristic	Comorbidities	Qualifying Event
Hypertension	62.4
Diabetes	14.8
Prior Stroke	7.7
Smoker	30.6

Arms

Field	Alteplase	Control
Intervention	Intravenous alteplase 0.9 mg/kg (maximum 90 mg): 10% administered as IV bolus over 1–2 minutes, remaining 90% infused over 60 minutes. Treatment initiated 3.0–4.5 hours after symptom onset. No anticoagulants, antiplatelet agents, or heparin for 24 hours after infusion. BP maintained <185/110 mmHg before and during infusion and <180/105 mmHg for 24 hours post-treatment. Follow-up CT at 22–36 hours before starting antithrombotics.	Matched IV placebo (identical appearance and volume to alteplase), administered with the same bolus + infusion protocol. Same BP management and 24-hour anticoagulant restriction as the alteplase group.
Duration	Single infusion in the 3–4.5 hour window	Single infusion

Outcomes

Outcome	Type	Control	Intervention	HR / OR / RR	P-value
mRS 0–1 at 90 days	Primary	45.2%	52.4%	14	0.04
Global outcome composite (mRS, BI, NIHSS, GOS) \| 95% CI: 1.00–1.65	Secondary	Not quantified	Global OR 1.28		0.05
Barthel Index ≥95 \| 95% CI: 0.93–1.62	Secondary	58.6%	63.4%		0.16
NIHSS 0–1 at 90 days \| 95% CI: 1.01–1.75	Secondary	43.2%	50.2%		0.04
Symptomatic ICH (ECASS III definition)	Adverse	0.2%	2.4%		0.008
Any ICH	Adverse	17.6%	27.0%		0.001
Death (90 days)	Adverse	8.4%	7.7%		0.68
Symptomatic Edema	Adverse	7.2%	6.9%		0.89

Subgroup Analysis

Prespecified subgroup analyses showed no significant heterogeneity by age (<65 vs ≥65), sex, baseline NIHSS (<10 vs 10–19 vs ≥20), time to treatment (3–3.5h vs 3.5–4h vs 4–4.5h), hypertension, smoking status, prior stroke, or diabetes. The magnitude of benefit was numerically larger in patients treated earlier (3–3.5h: OR ~1.5) compared to later (4–4.5h: OR ~1.2), consistent with the time-dependent nature of thrombolysis. Notable: patients with prior stroke + diabetes were excluded, so no data for this subgroup. Stroke subtype was not a significant effect modifier.

Criticisms

Modest absolute benefit (NNT=14) compared to NINDS (NNT=8) — reflects diminishing returns of later treatment.
Upper age limit of 80 years — excluded elderly patients who represent a large proportion of real-world stroke patients (later addressed by IST-3).
NIHSS cap at 25 — excluded very severe strokes.
Exclusion of patients with combined prior stroke AND diabetes is clinically limiting — this is a common combination in stroke populations.
Global outcome composite was only borderline significant (P=0.05) — raises questions about robustness.
Higher sICH rate (2.4% vs 0.2%) — although not offset by mortality increase, still a concern.
Industry-funded (Boehringer Ingelheim) — alteplase manufacturer.
FDA never approved the 3–4.5h window despite guideline adoption — regulatory gap persists.
No vascular imaging required — vessel occlusion status unknown, no ability to assess for LVO vs small vessel.

Funding

Boehringer Ingelheim

Based on: ECASS III (New England Journal of Medicine, 2008)