PDF: AbESTT-II
(2008)Objective
To determine whether early intravenous administration of abciximab within 5 hours of acute ischemic stroke onset would improve functional outcomes at 3 months, and to evaluate its safety in terms of intracranial hemorrhage.
Study Summary
• Abciximab significantly increased symptomatic or fatal intracranial hemorrhage within 5 days in the primary cohort: 5.5% vs 0.5% (P=0.002); companion and wake-up cohorts trended higher but did not reach significance (P=0.309 and P=0.347)
• Wake-up stroke patients treated with abciximab had hemorrhage rates of 13.6% vs 5.0% for placebo (small subgroup)
• Trial terminated early after 808 of 1800 planned patients due to unfavorable benefit-risk profile; no efficacy benefit demonstrated in any cohort
Intervention
Intravenous abciximab (0.25 mg/kg bolus followed by 12-hour infusion at 0.125 μg/kg per minute) vs identically appearing placebo. Primary cohort: administered within 5 hours of stroke onset. Companion cohort: treated 5 to 6 hours after stroke onset, or within 3 hours of stroke present on awakening (wake-up subgroup).
Inclusion Criteria
Age >18 years; acute ischemic stroke with baseline NIHSS 4–22; treatable within 5 hours of onset (primary cohort) or 5–6 hours after onset / within 3 hours of awakening with stroke signs (companion cohort)
Study Design
Arms: Abciximab 0.25 mg/kg bolus + 0.125 μg/kg/min 12-hr infusion vs identically appearing placebo. Analyzed by cohort — Primary: abciximab n=221, placebo n=218; Companion 5–6 h: abciximab n=160, placebo n=159; Wake-up: abciximab n=22, placebo n=21. Total analyzable: abciximab n=403, placebo n=398 (801 analyzed of 808 randomized).
Patients per Arm: Primary: abciximab 221 / placebo 218. Companion 5–6 h: abciximab 160 / placebo 159. Wake-up: abciximab 22 / placebo 21. Total analyzable: abciximab 403 / placebo 398 (801 analyzed of 808 randomized).
Outcome
• Primary safety: symptomatic or fatal ICH within 5 days 5.5% (12/217) abciximab vs 0.5% (1/217) placebo (P=0.002) — significantly higher with abciximab
• Companion 5–6 h cohort ICH 1.9% vs 0.6% (P=0.309); wake-up cohort ICH 13.6% vs 5.0% (P=0.347) — neither reached significance in isolation
• No efficacy benefit in any cohort; trial halted early by independent safety monitoring board for unfavorable benefit-risk profile
Bottom Line
Abciximab should not be used for acute ischemic stroke treatment. It confers no functional benefit in any cohort studied and significantly increases symptomatic or fatal intracranial hemorrhage in the primary (within-5-hour) cohort (P=0.002). Companion 5–6 hour and wake-up cohorts showed numerically higher hemorrhage without reaching significance in isolation, but combined with the absence of benefit the overall risk-benefit is unfavorable.
Major Points
- Trial terminated prematurely after 808 of 1800 planned patients were enrolled due to an unfavorable benefit-risk profile identified by the independent safety and efficacy monitoring committee
- No improvement in favorable 3-month outcomes in the primary cohort: 32% (71/221) abciximab vs 33% (72/218) placebo (P=0.944); mRS distributions were similar between groups
- Abciximab significantly increased symptomatic or fatal intracranial hemorrhage within 5 days in the primary cohort: 5.5% (12/217) vs 0.5% (1/217) for placebo (P=0.002); fatal ICH 3.7% vs 0% (P=0.004)
- No efficacy benefit demonstrated in the companion cohort (5–6 hours after onset) or wake-up stroke cohort
- Wake-up stroke patients treated with abciximab had a numerically high hemorrhage rate (13.6% vs 5.0% placebo, P=0.347) although the cohort was small (n=43)
- Abciximab cannot be recommended for acute ischemic stroke treatment regardless of time window or clinical subgroup
Study Design
- Study Type
- Randomized, double-blind, placebo-controlled phase 3 trial
- Randomization
- Yes
- Blinding
- Double-blind; identically appearing placebo; central CT core laboratory with blinded independent neuroradiologists; blinded Clinical Endpoint Committee
- Sample Size
- 808
- Follow-up
- 3 months (90–120 days); adverse events collected through 3 months; deaths recorded through 120 days
- Centers
- 112
- Countries
- Argentina, Australia, Austria, Belgium, Brazil, Canada, Finland, France, Germany, Italy, Netherlands, Poland, Portugal, South Africa, Spain, Switzerland, United Kingdom, United States
Primary Outcome
Definition: Proportion of modified Rankin Scale (mRS) responders at 3 months, dichotomized based on baseline NIHSS severity: mRS 0 for NIHSS 4–7; mRS 0–1 for NIHSS 8–14; mRS 0–2 for NIHSS 15–22
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| 33% (72/218) | 32% (71/221) | - | 0.944 |
Limitations & Criticisms
- Trial terminated prematurely after enrolling only 45% of the planned 1800 patients (808 enrolled), substantially limiting statistical power for secondary and subgroup analyses
- The companion and wake-up cohorts were small, rendering conclusions about those populations preliminary; the 13.6% hemorrhage rate in the wake-up cohort is based on few patients (n=22)
- Only the primary-cohort 5-day symptomatic/fatal ICH endpoint reached statistical significance for harm; companion and wake-up cohort ICH signals did not reach significance in isolation, so 'across-cohort' harm claims are supported by pattern rather than by per-cohort significance
- Sponsors (Eli Lilly and Centocor) participated in trial design and conduct, though blinding of the Executive Committee was maintained and an independent monitoring committee oversaw safety decisions
Citation
Adams HP Jr, et al. Stroke. 2008;39:87-99.