PDF: ECASS I Post Hoc
(1998)Objective
To evaluate whether applying a global end-point analysis to ECASS I intention-to-treat data would show benefit of rtPA administered within 6 hours for acute ischemic stroke.
Study Summary
Intervention
Retrospective application of NINDS statistical methods (global end-point analysis) to ECASS I data; original trial used 1.1 mg/kg IV rtPA within 6 hours of stroke onset.
Inclusion Criteria
Patients with acute ischemic stroke randomized and treated within 6 hours of symptom onset; intention-to-treat population (N=615).
Study Design
Arms: rtPA treatment arm vs. placebo control arm.
Patients per Arm: rtPA: 310, Placebo: 305
Outcome
Bottom Line
Post hoc reanalysis of ECASS I ITT data (615 patients) using NINDS global endpoint methodology converted the 'negative' trial to 'positive': global OR 1.5 (95% CI 1.1-2.0; P=0.008). Individual outcomes: mRS 0-1 36% vs 28% (OR 1.4; P=0.044); NIHSS 0-1 36% vs 22% (OR 1.9; P=0.001); Barthel ≥95 44% vs 38% (OR 1.3; P=0.102, NS). Suggests benefit of IV rtPA (1.1 mg/kg) extends to 6 hours, but is a post hoc non-prespecified analysis.
Major Points
- ECASS I ITT data reanalyzed with NINDS global endpoint method: global OR 1.5 (95% CI 1.1-2.0; P=0.008).
- NIHSS 0-1: 36% vs 22% (OR 1.9; P=0.001) — largest individual effect.
- mRS 0-1: 36% vs 28% (OR 1.4; P=0.044).
- Barthel ≥95: 44% vs 38% (OR 1.3; P=0.102, NS).
- Effect sizes smaller than NINDS for mRS (+8% vs +13%) and BI (+6% vs +12%), consistent with diminishing benefit at longer time-to-treatment.
- rtPA dose was 1.1 mg/kg (higher than NINDS 0.9 mg/kg) within a 6-hour window.
- Demonstrates critical importance of pre-specifying endpoints — same data yields opposite conclusions depending on analysis method.
- Post hoc, non-prespecified analysis — cannot override the original negative ECASS I result.
- Provided methodological justification for ECASS II and ECASS III design.
- 615 patients, 6-hour window. Funded by Boehringer Ingelheim.
Study Design
- Study Type
- Post hoc reanalysis of a randomized controlled trial
- Randomization
- Yes
- Blinding
- Not specified for reanalysis
- Sample Size
- 615
- Follow-up
- 90 days
- Countries
- Europe
Primary Outcome
Definition: Global outcome based on 3 dichotomized endpoints: mRS 0–1, BI 95–100, NIHSS 0–1
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| 28% (mRS), 38% (BI), 22% (NIHSS) | 36% (mRS), 44% (BI), 36% (NIHSS) | - (Global OR 1.5 (1.1–2.0)) | 0.008 |
Limitations & Criticisms
- Post hoc analysis not predefined in original trial design
- Global end-point strategy may inflate positive findings via redundant measures
- BI did not reach statistical significance individually (P=0.102)
- Increased mortality in rtPA group vs. placebo (likely due to CT protocol violations)
- No formal adjustment for multiplicity
Citation
Stroke. 1998;29:2073–2075