From Wiki Journal Club
Jump to: navigation, search
Amarenco P, et al. "High-dose atorvastatin after stroke or transient ischemic attack". The New England Journal of Medicine. 2006. 355(6):549-559.
PubMedFull textPDF

Clinical Question

In patients with prior stroke or TIA, does high-dose atorvastatin reduce the risk of recurrent stroke?

Bottom Line

In patients with prior stroke/TIA, atorvastatin reduces risk of recurrent ischemic stroke, but may increase risk of hemorrhagic stroke.

Major Points

Stroke and TIA are well established complications of CV disease, and prior studies such as the CARE, LIPID, and 4S trials helped establish the role of statins in primary prevention of stroke and TIA among patients at high risk of cerebrovascular disease. However, prior to SPARCL, the role of statins in secondary prevention of stroke and TIA was not well established.

The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial randomized 4,700 patients with prior stroke or TIA to either high-dose statin therapy with atorvastatin 80mg daily, or matching placebo, and followed patients for a mean of 5 years. Atorvastatin reduced the composite primary outcome of fatal or non-fatal stroke by 16% and the secondary outcome of fatal stroke by 43% at 5 years, when compared to placebo. There was no significant mortality difference, although the trial was not adequately powered to detect such a difference. Interestingly, a post hoc analysis suggested that atorvastatin was associated with an increased risk of hemorrhagic stroke, which led some to criticize the trial for enrolling patients with prior hemorrhagic stroke.[1]

SPARCL was criticized for receiving industry funding[2] and for demonstrating only a modest benefit, although the latter is typical of prevention trials. Kaplan-Meier analysis indicated a 2.2% absolute risk reduction of fatal or non-fatal stroke, suggesting that the NNT to prevent one stroke at 5 years is 45, and at one year is 258.


AHA/ASA Prevention of stroke in patients with stroke or TIA (2011, adapted):[3]

  • Intensive lipid-lowering statin if evidence of atherosclerosis, LDL-cholesterol ≥100 mg/dL, and without CAD (class I level B)
  • In above patients, an LDL-cholesterol reduction of ≥50% or target <70 mg/dL is reasonable (class IIa, level B)
  • If hyperlipidemia and CAD, patients should also be treated per the NCEP III guidelines (class I level A)
  • If low HDL-C, may opt to treat with gemfibrozil or niacin (class IIb, level B)

Canadian Stroke Strategy Canadian Best Practice Recommendations for Stroke Care (2012, adapted):[4]

  • For primary prevention of CV events, including stroke:
    • Prescribe statins if high global CV risk (evidence level A)
    • Consider prescribing statins if intermediate global CV risk (level B)
  • Prescribe statins for secondary prevention in ischemic stroke/TIA for most patients with a target LDL ≤2.0 mmol/L, or 50% reduction in LDL from baseline (level B)
  • Adults with diabetes and ischemic stroke are at high risk of further vascular events and should also be treated with a statin to achieve a LDL ≤2.0 mmol/L (level A)
  • Statins have not been well-studied in certain subpopulations (eg >80 years of age, cardioembolic stroke, or arterial dissection) and appropriateness of the therapy should be based upon health status, comorbidities, and presence of systemic vascular disease (level C)


  • Multicenter, double blind, parallel-group, randomized, placebo-controlled trial
  • N=4,731 patients with prior stroke/TIA
    • Atorvastatin (n=2,365)
    • Placebo (n=2,366)
  • Setting: 205 centers
  • Enrollment: 1998-2001
  • Analysis: Intention-to-treat
  • Mean follow-up: 4.9 years
  • Primary outcome: fatal or non-fatal stroke


Inclusion Criteria

  • Age ≥18 years
  • Ischemic stroke, hemorrhagic stroke, or TIA in the 1-6 months before randomization
    • TIAs diagnosed by a neurologist within 30 days of the primary event
    • Those with hemorrhagic stroke thought to be at risk for ischemic stroke or CAD by the investigator
  • Modified Rankin score ≤3
  • LDL 100-190 mg/dL (2.59-4.92 mmol/L)

Exclusion Criteria

  • Non-ambulatory
  • Atrial fibrillation
  • Cardiac sources of embolism
  • Subarachnoid hemorrhage
  • While not a strict exclusion criterion, patients with LDL >160 mg/dL (4.14 mmol/L) were excluded in 15 of 205 centers

Baseline Characteristics

Values provided are for the atorvastatin arm.

  • Age: 63 years
  • Male: 60%
  • BMI: 27.5
  • SBP: 139 mmHg
  • DBP: 82 mmHg
  • Smoker: 19.1%
  • Former smoker: 40.7%
  • HTN: 62.4%
  • DM: 16.7%
  • LDL: 132.7 mg/dL (3.44 mmol/L)
  • HDL: 50 mg/dL (1.3 mmol/L)
  • Total cholesterol: 211.4 mg/dL (5.48 mmol/L)
  • Stroke: 70%
    • Ischemic: 67.4%
    • Hemorrhagic: 1.9%
    • Other: 0.6%
  • TIA: 29.9%
  • Mean time since event: 87.1 days

Baseline Medications

  • Antiplatelet (including ASA), not heparin: 87.4%
  • ACE-I: 28.9%
  • ß-blocker: 17.5%
  • Dihydropyridine (calcium channel blockers): 14.8%
  • Vit K antagonist (including warfarin): 5.9%
  • ARB: 4.7%
  • Previous statin use: 2.4%


  • Cessation of any lipid-lowering medications 30 days before screening
  • Randomization to atorvastatin 80mg PO daily or placebo
  • Counseling on the National Cholesterol Education Program Step 1 or similar diets throughout the study
  • Visits on months 1, 3, and 6 months and every 6 months subsequently
  • Labs and EKGs at screening, at regular intervals during study, and at completion of the study


All comparisons are atorvastatin vs. placebo. Statistics given are calculated per the prespecified adjusted model.

Primary Outcomes

Fatal or non-fatal stroke
11.2% vs. 13.1% (HR 0.84; 95% CI 0.71-0.99; P=0.03)
Fatal stroke
1.0% vs. 1.7% (HR 0.57; 95% CI 0.35-0.95; P=0.03)
Non-fatal stroke
10.4 % vs. 11.8% (HR 0.87; 95% CI 0.73-1.03; P=0.11)

Secondary Outcomes

Stroke or TIA
15.9% vs. 20.1% (HR 0.77; 95% CI 0.67-0.88; P<0.001)
6.5% vs. 8.8% (HR 0.74; 95% CI 0.60-0.91; P<0.004)
Major coronary event (defined as death from cardiac causes, nonfatal MI, or resuscitation after cardiac arrest)
3.4% vs. 5.1% (HR 0.65; 95% CI 0.49-0.87; P=0.003)
Death from cardiac causes
3.4% vs. 5.1% (HR 1.00; 95% CI 0.64-1.56; P=1.00)
Non-fatal MI
1.8% vs. 3.5% (HR 0.51; 95% CI 0.35-0.74; P<0.001)
Resuscitation after cardiac event
one in each group, no analysis
Major CV event
14.1% vs. 17.2% (HR 0.80; 95% CI 0.69-0.92; P=0.002)
Acute coronary event
4.3% vs. 6.4% (HR 0.65; 95% CI 0.50-0.84; P=0.001)
Any coronary event (defined as ACS plus revascularization procedure, unstable angina, or angina or ischemia requiring hospitalization)
5.2% vs. 8.6% (HR 0.58; 95% CI 0.46-0.73; P<0.001)
Revascularization (including coronary, carotid, or peripheral)
4.0% vs. 6.9% (HR 0.55; 95% CI 0.43-0.72; P<0.001)
Any cardiovascular event (all above plus "clinically significant" PVD)
22.4% vs. 29.0% (HR 0.74; 95% CI 0.66-0.83; P<0.001)
9.1% vs. 8.9% (HR 1.00; 95% CI 0.82-1.21; P=0.98)
Death from CV disease
3.3% vs. 4.1% (HR 0.78; 95% CI 0.58-1.06; P=0.11)
Death from cancer
2.4 vs. 2.2 (HR 1.05; 95% CI 0.72-1.53; P=0.80)

Adverse Events

There were no differences between the groups for any adverse events (including rhabdomyolysis and liver failure) except listed below.

ALT or AST above 3x the ULN in two consecutive draws
2.2% vs. 0.5% (P<0.001)

Post hoc analysis of reduction in stroke risk, by stroke subtype:

HR 0.78; 95% CI 0.66-0.94
2.3% vs. 1.4% (HR 1.66; 95% CI 1.08-2.55)
HR 0.55; 95% CI 0.21-1.40


  • Not powered to assess the effect on mortality
  • Lack of run-in period makes it difficult to compare tolerability of high-dose atorvastatin in SPARCL to the tolerability of statins in other statin trials, many of which did use a run-in period


Funding from Pfizer, maker of atorvastatin (Lipitor). Authors with multiple financial disclosures.

Further Reading

  1. Stroke — An Equal Opportunity for the Initiation of Statin Therapy
  2. Statin Therapy after Stroke or Transient Ischemic Attack
  3. Furie KL, et al. "Guidelines for the prevention of stroke in patients with stroke or transient ischemic attack." Stroke. 2011;42:227-276.
  4. Lindsay MP et al. "Canadian Best Practice Recommendations for Stroke Care." 4th ed. 2012. Accessed 2014-07-23.