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SPARCL

High-Dose Atorvastatin after Stroke or Transient Ischemic Attack

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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.

Link: https://www.nejm.org/doi/full/10.1056/NEJMoa061902

PDF: https://www.nejm.org/doi/pdf/10.1056/NEJMoa061894

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.

Content summarized and formatted by NeuroTrials.ai.

SPARCL

(2006)

Objective

To assess whether high-dose atorvastatin reduces the risk of stroke in patients with a recent stroke or TIA and no known coronary heart disease.

Study Summary

• High-dose atorvastatin reduced the risk of stroke in patients with recent stroke or TIA and no known coronary heart disease; • Atorvastatin reduced ischemic stroke and major CV events but increased hemorrhagic stroke.

Intervention

Atorvastatin 80 mg daily vs. placebo.

Inclusion Criteria

Patients ≥18 years with ischemic stroke or TIA in the past 1–6 months, LDL 100–190 mg/dL, no known coronary heart disease.

Study Design

Arms: Atorvastatin vs. Placebo

Patients per Arm: Atorvastatin: ~2365, Placebo: ~2366

Outcome

• Stroke: 11.2% atorvastatin vs 13.1% placebo (HR 0.84; 95% CI, 0.71–0.99; P=0.03). <br>• Ischemic stroke reduced; hemorrhagic stroke increased (55 vs. 33). <br>• Major CV events also reduced (HR 0.80; P=0.002)..

Bottom Line

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.

Study Design

Study Type: Randomized, double-blind, placebo-controlled trial.
Randomization: Yes
Blinding: Double-blind.
Sample Size: 4731
Follow-up: Median of 4.9 years.
Centers: 205
Countries: International, multiple countries

Primary Outcome

Definition: First nonfatal or fatal stroke.

Control	Intervention	HR/OR	P-value
13.1% (311 patients)	11.2% (265 patients)	0.84 (0.71 to 0.99)	0.03

Limitations & 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.

Citation

N Engl J Med 2006;355:549-59.

View Original Publication →

SPARCL

High-Dose Atorvastatin after Stroke or Transient Ischemic Attack

Clinical Question

Bottom Line

Major Points

Design

Inclusion Criteria

Exclusion Criteria

Baseline Characteristics

Arms

Outcomes

Subgroup Analysis

Criticisms

Funding

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