SPARCL
High-Dose Atorvastatin after Stroke or Transient Ischemic Attack
Year of Publication: 2006
Authors: The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) Investigators
Journal: The New England Journal of Medicine
Citation: N Engl J Med 2006;355:549-59.
PDF: Clinical Question
In patients with a recent stroke or TIA but without known coronary heart disease, does treatment with high-dose atorvastatin (80 mg) reduce the risk of a subsequent fatal or nonfatal stroke?
Bottom Line
In patients with a recent stroke or TIA and no known coronary heart disease, treatment with 80 mg of atorvastatin per day significantly reduced the risk of recurrent stroke and other major cardiovascular events. This benefit came with a small but significant increase in the incidence of hemorrhagic stroke.
Major Points
- Landmark statin trial for secondary stroke prevention — only RCT specifically designed to test statins after stroke/TIA. 4,731 patients randomized across 205 international centers, median follow-up 4.9 years.
- Entry event: ~69% ischemic stroke, ~31% TIA, ~2% hemorrhagic stroke. Qualifying event 1–6 months before enrollment. No known coronary heart disease at baseline.
- Primary endpoint (fatal or nonfatal stroke): 11.2% vs 13.1% (adjusted HR 0.84, 95% CI 0.71–0.99, P=0.03). ARR = 1.9%, NNT = 46 over 4.9 years.
- Major cardiovascular events reduced by 20% (HR 0.80, 95% CI 0.69–0.92, P=0.002). Major coronary events reduced by 35% (HR 0.65, P=0.003).
- Hemorrhagic stroke: 55 events (atorvastatin) vs 33 events (placebo) — HR 1.66 (95% CI 1.08–2.55). This finding raised concern about high-dose statins in ICH patients, though net stroke benefit was positive.
- Mean LDL reduction: from 133 mg/dL to 73 mg/dL in atorvastatin group vs 129 mg/dL in placebo. 25% of placebo patients started open-label statins during the trial.
- Ischemic stroke reduction was more pronounced: HR 0.78 (95% CI 0.66–0.94), partially offset by increased hemorrhagic stroke.
- SPARCL established high-dose statin therapy as standard of care for secondary stroke prevention. Later post hoc analyses showed patients achieving LDL <70 mg/dL had the largest stroke reduction.
Design
Study Type: Randomized, double-blind, placebo-controlled trial.
Randomization: 1
Blinding: Double-blind.
Enrollment Period: September 1998 to March 2001.
Follow-up Duration: Median of 4.9 years.
Centers: 205
Countries: International, multiple countries
Sample Size: 4731
Analysis: Intention-to-treat.
Inclusion Criteria
- Age >18 years.
- Ischemic or hemorrhagic stroke or a TIA within the previous 1 to 6 months.
- Ambulatory (modified Rankin score of ≤3).
- Low-density lipoprotein (LDL) cholesterol level of 100 to 190 mg per deciliter.
- No known coronary heart disease.
Exclusion Criteria
- Atrial fibrillation or other high-risk cardioembolic source (mechanical valve, intracardiac thrombus, mitral stenosis).
- Known coronary heart disease (prior MI, angina, coronary revascularization).
- Subarachnoid hemorrhage as the qualifying event.
- Need for statin therapy for another indication (per treating physician).
- LDL cholesterol <100 mg/dL or >190 mg/dL.
- Triglycerides >500 mg/dL.
- Severe disability from qualifying stroke (mRS >3).
- Active liver disease or unexplained persistent ALT/AST elevations >2× ULN.
- Creatine kinase >3× ULN.
- Pregnancy, lactation, or women of childbearing potential not using contraception.
- Known hypersensitivity to atorvastatin or any component.
Baseline Characteristics
| Characteristic | Control | Active |
|---|---|---|
| Age-yr | 62.5±0.2 | 63.0±0.2 |
| Male sex no. (%) | 1396 (59.0) | 1427 (60.3) |
| Entry event (Stroke)-no. (%) | 1613 (68.2) | 1655 (70.0) |
| Entry event (TIA)-no. (%) | 752 (31.8) | 708 (29.9) |
| Systemic hypertension-no. (%) | 1452 (61.4) | 1476 (62.4) |
| History of diabetes mellitus-no. (%) | 399 (16.9) | 395 (16.7) |
| Current smoker-no. (%) | 456 (19.3) | 452 (19.1) |
| LDL cholesterol-mg/dl | 133.7±0.7 | 132.7±0.5 |
| HDL cholesterol-mg/dl | 50.0±0.3 | 50.0±0.3 |
| Triglycerides-mg/dl | 143.2±1.4 | 144.2±1.9 |
Arms
| Field | Control | Atorvastatin |
|---|---|---|
| Intervention | Matching daily placebo tablet. Risk factor management per local guidelines (antihypertensives, antiplatelets, lifestyle modifications). Open-label statin use was not prohibited but discouraged — approximately 25% of placebo patients initiated statins during the trial, which may have attenuated the treatment effect. | Atorvastatin 80 mg once daily (highest approved dose). No dose titration — started at full dose. Mean achieved LDL was 73 mg/dL (from baseline 133 mg/dL). Liver function tests monitored per protocol. Same risk factor management as placebo group. |
| Duration | Median of 4.9 years | Median of 4.9 years |
Outcomes
| Outcome | Type | Control | Intervention | HR / OR / RR | P-value |
|---|---|---|---|---|---|
| First nonfatal or fatal stroke. | Primary | 13.1% (311 patients) | 11.2% (265 patients) | 0.84 | 0.03 |
| Major cardiovascular event (stroke plus any major coronary event) | Secondary | 17.2% (407 patients) | 14.1% (334 patients) | HR 0.80 (95% CI, 0.69-0.92) | 0.002 |
| Major coronary event | Secondary | 5.1% (120 patients) | 3.4% (81 patients) | HR 0.65 (95% CI, 0.49-0.87) | 0.003 |
| Any cardiovascular event | Secondary | 29.0% (687 patients) | 22.4% (530 patients) | HR 0.74 (95% CI, 0.66-0.83) | <0.001 |
| Hemorrhagic stroke | Adverse | 33 events | 55 events | HR 1.66 (95% CI, 1.08 to 2.55) | |
| Elevated liver enzymes (ALT or AST >3x ULN at 2 consecutive measurements) | Adverse | 0.5% (11 patients) | 2.2% (51 patients) | <0.001 | |
| Any serious adverse event | Adverse | 41.2% | 41.8% |
Subgroup Analysis
Prespecified subgroup analyses showed consistent benefit across age (<65 vs ≥65), sex, entry event (stroke vs TIA), baseline LDL (<130 vs ≥130), diabetes, hypertension, and smoking status. Post hoc analyses: (1) ischemic stroke was significantly reduced (HR 0.78, P=0.008) while hemorrhagic stroke was increased (HR 1.66, P=0.02) — significant interaction P=0.01; (2) patients achieving LDL <70 mg/dL had greater stroke reduction than those with LDL 70–100; (3) patients with carotid stenosis had larger benefit; (4) hemorrhagic stroke increase was concentrated in patients with prior hemorrhagic stroke at entry, raising concern about high-dose statins after ICH (later addressed by the ongoing SATURN trial).
Criticisms
- Modest absolute benefit (NNT=46) — reflects relatively low baseline stroke recurrence rate and long follow-up needed.
- Hemorrhagic stroke increase (HR 1.66) raised significant clinical concern — debate continues about statins after ICH. SATURN trial (ongoing) aims to address this.
- 25% of placebo patients received open-label statins — likely attenuated the observed treatment effect (true benefit may be larger).
- Only tested atorvastatin 80 mg — no dose-response data from the trial. Lower doses or other statins may have different risk/benefit profiles.
- Excluded patients with known CAD — these patients were already receiving statins. Cannot assess incremental benefit of high-dose in dual-indication patients.
- Industry-funded (Pfizer — atorvastatin manufacturer).
- Entry criteria allowed patients 1–6 months post-event — does not address acute-phase statin initiation.
- LDL entry range 100–190 mg/dL — does not inform treatment of patients already at LDL <100.
Funding
Pfizer
Based on: SPARCL (The New England Journal of Medicine, 2006)
Authors: The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) Investigators
Citation: N Engl J Med 2006;355:549-59.
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