PDF: MASH
(2006)Objective
To assess whether acetylsalicylic acid (ASA) reduces the risk of delayed ischemic neurological deficit (DIND) in patients with aneurysmal subarachnoid hemorrhage
Study Summary
• Relative risk reduction for poor outcome was 21% (RR 0.79, 95% CI 0.38-1.6)
• Study stopped early after second interim analysis when 161 of planned 200 patients enrolled
Intervention
100 mg acetylsalicylic acid (ASA) daily via suppository for 14 days starting within 12 hours after aneurysm treatment, versus placebo
Inclusion Criteria
Aneurysmal subarachnoid hemorrhage with aneurysm treatment within 4 days after SAH onset, age ≥18 years
Study Design
Arms: ASA 100 mg daily vs Placebo
Patients per Arm: ASA: 87, Placebo: 74
Outcome
• Poor outcome (mRS ≥4): ASA 14% vs Placebo 18% (RR 0.79, 95% CI 0.38-1.6)
• Excellent outcome (mRS 0): ASA 8% vs Placebo 14% (RR 0.60, 95% CI 0.24-1.5)
Bottom Line
ASA given after aneurysm treatment does not appreciably reduce the occurrence of DIND in patients with aneurysmal SAH. The study was stopped early after the second interim analysis showed negligible chances of positive effect. However, there was a non-significant trend toward better functional outcome.
Major Points
- Randomized, placebo-controlled trial with factorial design (magnesium vs placebo AND ASA vs placebo)
- Study stopped early after second interim analysis: 161 of planned 200 patients enrolled
- ASA did not reduce DIND risk; actually showed non-significant trend toward increased DIND (HR 1.83)
- Despite negative effect on DIND, functional outcome trended toward improvement with ASA (21% relative risk reduction for poor outcome)
- Only patients with aneurysm treated within 4 days after SAH were included in ASA arm
- Primary outcome (DIND) analyzed according to 'on-treatment' principle
- Secondary outcomes (poor outcome, nonexcellent outcome) analyzed by intention-to-treat
- Majority of patients (67%) underwent surgical clipping rather than endovascular treatment
- Study population had relatively low risk for DIND due to selection of patients in good neurological condition for early surgery
- 100 mg ASA dose may have been insufficient to prevent DIND
Study Design
- Study Type
- Randomized, placebo-controlled trial with factorial design (2x2: magnesium vs placebo AND ASA vs placebo)
- Randomization
- Yes
- Blinding
- Double-blind. Blinded allocation using consecutive series of numbered boxes containing either ASA or placebo suppositories
- Sample Size
- 161
- Follow-up
- 3 months
- Centers
- 4
- Countries
- The Netherlands
Primary Outcome
Definition: Delayed ischemic neurological deficit (DIND) within 3 months after SAH onset, defined as new spontaneous hypodense lesion on CT accompanied by new clinical features (gradually developed focal deficits, decreased consciousness, or both)
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| 11 (15%) - On-treatment: 10/70 (14%) | 20 (23%) - On-treatment: 20/83 (24%) | 1.83 (0.85 to 3.9) | Not significant |
Limitations & Criticisms
- Study stopped early after second interim analysis (161 of 200 planned patients) when chances of positive effect were negligible
- Primary outcome showed trend toward harm rather than benefit (HR 1.83 for DIND)
- Wide confidence intervals for all outcomes limit precision of estimates
- Only patients with aneurysm treatment within 4 days after SAH were included in ASA arm, leading to selection of patients in good neurological condition
- 100 mg ASA dose may have been insufficient; unclear if it adequately inhibited endothelial thromboxane
- Timing of drug administration (post-aneurysm treatment) may have been too late; benefit may require pre-SAH or immediate post-SAH administration
- Majority of patients (67%) underwent surgical clipping; results may not be generalizable to modern era with predominant endovascular treatment
- Study population had relatively low risk for DIND due to selection bias (good neurological condition required for early surgery)
- No information on whether endothelial thromboxane was inhibited at this dose
- Factorial design (magnesium AND ASA tested) may complicate interpretation
- Only 161 of 283 patients enrolled in magnesium part could be enrolled in ASA part
- Power calculation based on pilot study data may have been optimistic
- Mechanism of potential benefit on outcome despite lack of effect on DIND is unclear
Citation
Stroke. 2006;37:2326-2330