PDF: HDS-SAH
(2015)Objective
To determine whether high-dose simvastatin (80 mg daily) for treatment of aneurysmal SAH is superior to lower-dose simvastatin (40 mg daily) in terms of clinical outcomes and cost-effectiveness
Study Summary
• No difference in favorable outcomes (mRS 0-2) at 3 months (73% vs 72%, OR 1.1, p=0.770)
• High-dose simvastatin should not be prescribed routinely for aneurysmal SAH
Intervention
Simvastatin 80 mg daily (high dose) vs simvastatin 40 mg daily (lower dose) orally or via nasogastric tube for 21 days, started within 96 hours of ictus
Inclusion Criteria
Age 18-70 years, radiological diagnosis of SAH, intracranial aneurysm as cause of SAH, randomized within 96 hours of SAH onset, nonchildbearing potential or negative pregnancy test
Study Design
Arms: High-dose simvastatin 80 mg daily vs Lower-dose simvastatin 40 mg daily
Patients per Arm: High-dose: 124, Lower-dose: 131
Outcome
• Favorable outcome (mRS 0-2): High-dose 73% vs Lower-dose 72% (OR 1.1, 95% CI 0.6-1.9, p=0.770)
• Clinical vasospasm: High-dose 15% vs Lower-dose 12% (OR 1.2, p=0.589)
Bottom Line
High-dose simvastatin (80 mg daily) was not superior to lower-dose simvastatin (40 mg daily) for treatment of aneurysmal SAH. No differences were observed in delayed ischemic deficits, clinical vasospasm, delayed cerebral infarction, or functional outcomes. High-dose simvastatin should not be prescribed routinely for aneurysmal SAH.
Major Points
- Multicenter randomized controlled double-blind trial comparing 80 mg vs 40 mg simvastatin daily
- 255 patients randomized from 6 centers in Hong Kong and China (September 2010 to September 2013)
- No difference in primary outcome of delayed ischemic deficit (27% vs 24%, OR 1.2, p=0.586)
- No difference in favorable outcome at 3 months (73% vs 72%, OR 1.1, p=0.770)
- No difference in clinical vasospasm (15% vs 12%) or delayed cerebral infarction (16% vs 17%)
- Treatment started within 96 hours of ictus and continued for 21 days
- Study extended from 24 to 30 months due to recruitment challenges after FDA warnings about 80 mg simvastatin
- Only 5 patients (2%) had adverse events requiring treatment cessation (all reversible)
- Nearly half of patients had poor WFNS grade on admission
- Recruited patients more likely to be smokers and less likely to have acute hydrocephalus requiring EVD compared to non-recruited
- No cost-effectiveness analysis performed due to lack of efficacy difference
Study Design
- Study Type
- Investigator-initiated, multicenter, randomized controlled trial with blinded outcome assessment
- Randomization
- Yes
- Blinding
- Double-blind. Both assessors and patients blinded to study drug allocation. Permuted-block randomization using computer system with allocation list generated by statistician. Study drug assignments kept in sealed envelopes opened by site investigators not involved in clinical management. Identical tablets used
- Sample Size
- 255
- Follow-up
- 3 months
- Centers
- 6
- Countries
- Hong Kong, China (Guangxi and Sichuan provinces)
Primary Outcome
Definition: Delayed ischemic deficit (DID) defined as: (1) clinical vasospasm with fall of ≥2 points on modified Glasgow Coma Scale or new focal neurological deficit lasting >2 hours when compared to best neurological status after admission, or (2) delayed cerebral infarction unrelated to surgery/intervention, rebleed, hydrocephalus, infection, electrolyte, or metabolic disturbance
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| 32/131 (24%) | 34/124 (27%) | - (0.7 to 2.0) | 0.586 |
Limitations & Criticisms
- Study recruitment extended from 24 to 30 months due to FDA warnings about 80 mg simvastatin and muscle injury risk (June 2011)
- No pill counts performed to confirm compliance with study medication
- No measurement of serum simvastatin concentrations to correlate with outcomes
- Could not rule out potential benefit against early brain injury in first 24-48 hours
- No specific data on timing of first dose of study treatment
- Event rate of DID lower than expected (24-27% vs 35% predicted), though no trend suggested increasing sample size would show difference
- No generic or disease-specific quality of life assessments included
- No central adjudication of radiological data due to funding restraints
- All patients were Chinese, limiting generalizability to other ethnicities
- Angiographic studies not mandated for patients with DID or delayed cerebral infarction
- Sealed envelope randomization less secure than remote phone/internet system
- No cognitive function assessments despite their importance in SAH outcomes
- Study design precluded assessment of whether higher dose statins (e.g., rosuvastatin) might be effective
- Lower than expected recruitment rate (255 of 428 eligible patients, 60%)
- Recruited patients differed from non-recruited (more smokers, less acute hydrocephalus)
Citation
Stroke. 2015;46:382-388