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Macrovascular Residual Risk Studies

10 January 2009
The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial
Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) Investigators. High-dose atorvastatin after stroke or transient ischemic attack. N Engl J Med 2006;355:549-59.
Amarenco P, Bogousslavsky J, Callahan A 3rd, Goldstein LB, Hennerici M, Rudolph AE, Sillesen H, Simunovic L, Szarek M, Welch KM, Zivin JA
Objective and study population: To determine whether a daily dose of 80 mg of atorvastatin would reduce the risk of stroke in 4,731 patients aged 63 years on average, with no known coronary heart disease and with low-density lipoprotein (LDL) cholesterol levels of 100 to 190 mg per deciliter (2.6 to 4.9 mmol per liter), who suffered a stroke or a transient ischemic attack (TIA) within the previous six months.
Exclusion criteria:
  • Atrial fibrillation
  • Other cardiac sources of embolism
  • Subarachnoid hemorrhage
  • Patients randomized to 80 mg of atorvastatin per day or placebo
  • Aspirin or other antiplatelet agents in all patients
  • Vitamin K antagonists and antihypertensive agents as appropriate
  • Diet (National Cholesterol Education Program Step 1) counseled to all patients throughout the study.
Primary outcomes:
  • Time from randomization to first nonfatal or fatal stroke
Scondary outcomes: Main secondary outcomes included stroke or TIA, major coronary event (death from cardiac causes, nonfatal myocardial infarction, or resuscitation after cardiac arrest), major cardiovascular event (stroke plus any major coronary event), and death from any cause.
Study design:
  • Double-blind, prospective outcome study
  • All analyses were performed on an intention-to-treat basis
  • A pre-specified per-protocol analysis of the primary outcome was also performed
Main results:
  • Mean follow-up: 4.9 years.
  • Mean LDL cholesterol level during the trial: 73 mg/dL (1.9 mmol/L ) and 129 mg/dL (3.3 mmol/L) in the atorvastatin and placebo group, respectively
  • High-dose atorvastatin treatment significantly reduced 
    • nonfatal and fatal strokes: absolute risk reduction: 2.2% ; relative risk reduction: 16% (hazard ratio, 0·84; 95CI, 0·71–0·99; P=0·03)
    • fatal strokes considered separately reduced by 43% (HR, 0.57; 95CI, 0.35-0.95; P=0.03)
    • major cardiovascular events: absolute risk reduction: 3.5% ; relative risk reduction: 20% (hazard ratio, 0·80; 95CI, 0·69–0·92; P=0·002).
  • The incidence of hemorrhagic stroke was slightly increased in the atorvastatin group (55 vs. 33 cases in the atorvastatin and placebo group, respectively).
  • The rate of death from any cause was similar in both groups (216 and 211 deaths, respectively; P=0·098).
  • Elevated liver enzyme values were more common in patients taking atorvastatin but the incidence of serious adverse events was similar in both groups.
Author's conclusion: Initiated soon after a stroke or TIA in patients without known coronary heart disease, treatment with atorvastatin 80 mg per day reduced the overall incidence of stroke and of cardiovascular events, despite a small increase in the incidence of hemorrhagic stroke.


Post-hoc analyses of primary cardiovascular prevention studies (ALLHAT-LLT, WOSCOPS, ASCOT-LLA and CARDS) have suggested that statin therapy is effective in the primary prevention of stroke. Stroke was also effectively prevented in secondary cardiovascular prevention studies assessing the efficacy of statins in patients with coronary heart disease (4S, GREACE, CARE, HPS, LIPID and MIRACL). A meta-analysis of 27 statin trials, showed that every 1 mmol/L (39 mg/dL) decrease in LDL cholesterol was associated with a reduction in relative risk for stroke of 21.1%, 1 but this was only a secondary endpoint in most of these trials. In addition, even in the secondary cardiovascular prevention studies, only the reduction of first stroke events by statins was evaluated. Thus, none of these studies had evaluated the use of statins for secondary prevention of stroke.

SPARCL was the first prospective clinical trial in which reduction of recurrent stroke in patients who already had a stroke or TIA was the primary endpoint. Another major difference with previous trials was that SPARCL was conducted in patients with no history of coronary events (approximately 80% of stroke patients had no known coronary heart disease history).

In view of the significant 16% relative reduction of fatal and nonfatal stroke in patients treated with high-dose atorvastatin demonstrated by SPARCL, guidelines were modified to include statin therapy in the armamentarium used for secondary prevention of stroke, which already comprised antiplatelet agents or oral anticoagulants, plus antihypertensive agents to control blood pressure.

Post-hoc analyses revealed a small increase in hemorrhagic strokes in the atorvastatin group but the small number of such events (55 and 33 in the atorvastatin and placebo group, respectively) precluded any firm conclusion.

The SPARCL investigators explained that the study was not powered to assess the effect of treatment on the risk of death from any cause or on fatal or nonfatal stroke separately. Nevertheless, the risk of fatal stroke was significantly reduced by 43% (P=0.03).

Results of SPARCL contrast with those of the Heart Protection Study (HPS) in which statin therapy did not reduce the risk of stroke in patients with prior cerebrovascular disease.2 However, the HPS participants were included 4.3 years after the index event, whereas the risk of recurrence is highest 1 year after stroke.

SPARCL from a residual risk perspective

SPARCL was acclaimed by the neurology community as it represented a real breakthrough in the prevention of recurrent stroke. There is however still room for improvement: atorvastatin did not prevent recurrent stroke in 11.2% of patients of the active treatment group; in terms of relative risk, 84% of recurrent strokes that were not prevented by routine measures recommended until 1996 were still not prevented by the addition of the statin. Since the publication of their princeps study, the SPARCL investigators have been working to identify modifiable risk factors that may contribute to this marked residual risk and the appropriate interventions that will lead to further progress in the prevention of recurrent stroke.


1. Amarenco P, Labreuche J. Lipid management in the prevention of stroke: review and updated meta-analysis of statins for stroke prevention. Lancet Neurol 2009;8:453-63.

2. Collins R, Armitage J, Parish S, Sleight P, Peto R; Heart Protection Study Collaborative Group. Effects of cholesterol-lowering with simvastatin on stroke and other major vascular events in 20536 people with cerebrovascular disease or other high-risk conditions. Lancet 2004;363:757-67.
Key words Transient ischemic attack – Stroke – Statin therapy – Secondary prevention