ECASS II

Major Points

• ECASS II was the largest European thrombolysis trial of its era (800 patients, 108 centers, 16 countries) — it failed to show benefit with the CORRECT tPA dose (0.9 mg/kg) within 6 hours, unlike the successful NINDS trial (within 3 hours) and the failed ECASS I (which used 1.1 mg/kg).
• Primary outcome (mRS 0–1 at 90 days) NOT significant: 40.3% alteplase vs 36.6% placebo (p=0.277). This was the predefined primary endpoint — ECASS II was a technically negative trial.
• Post hoc analysis (mRS 0–2 at 90 days) WAS significant: 54.3% vs 46.0% (p=0.024) — suggesting a real but modest benefit that the more stringent primary endpoint missed. This post hoc result helped motivate ECASS III.
• sICH significantly higher: 8.8% alteplase vs 3.4% placebo — double the hemorrhage rate. PH2 (large parenchymal hemorrhage, the clinically relevant type): 8.1% vs 0.8%. This highlighted the bleeding cost of extending treatment beyond 3 hours.
• Mortality identical: 10.5% vs 10.3% (p=0.816) — the excess sICH was offset by fewer large infarcts, creating a 'mortality wash' similar to NINDS. The net mortality balance suggested treatment was not futile despite the primary endpoint failure.
• Critical historical context: ECASS I (1995) had failed partly because the 1.1 mg/kg dose caused excessive hemorrhage. ECASS II corrected this to 0.9 mg/kg (the NINDS dose) but extended the window to 6 hours — the results showed that the dose correction worked but the time extension diluted efficacy.
• Used the more stringent mRS 0–1 as primary endpoint — unlike NINDS which used mRS 0–1 as one of multiple co-primary endpoints and also showed benefit on the Barthel Index and NIHSS. The choice of a single strict endpoint reduced power to detect benefit.
• NIHSS improvement at day 30 was statistically better with alteplase (p=0.035) — showing a consistent signal of neurological improvement across multiple outcome measures, even when the primary endpoint was missed.
• Together with NINDS (positive, 0–3h), ECASS I (negative, wrong dose), and ATLANTIS (negative, 3–5h), ECASS II defined the thrombolysis evidence landscape that led to the 3-hour treatment window as the initial standard of care.
• Directly motivated ECASS III (2008), which successfully demonstrated alteplase benefit in the 3–4.5 hour window using lessons learned from ECASS II — ultimately expanding the treatment window by 90 minutes and saving thousands of lives annually.