Intensive statin therapy after stroke or transient ischemic attack: a SPARCLing success?

Anyone aware of the conflicting data regarding the importance of circulating cholesterol in stroke will welcome the results of the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial.1 Unlike with coronary heart disease, epidemiological studies often failed to demonstrate an association between elevated cholesterol levels and stroke incidence.2 However, many studies did not take into account the distinct underlying pathophysiological mechanisms of stroke and instead examined conflated end points such as a combination of ischemic and hemorrhagic stroke, or total ischemic stroke without subtyping, and others did not evaluate cholesterol subfractions. In contrast, epidemiological studies that carefully distinguished ischemic and hemorrhagic strokes generally found both a modest association of elevated cholesterol with increased risk of ischemic events and of low cholesterol with an increased risk of intracerebral hemorrhage.3 HMG-CoA reductase inhibitors or “statins,” which inhibit the synthesis of cholesterol that contributes to atheroma development and progression, have been shown to reduce the risk of first stroke in patients with established coronary heart disease, diabetes, or multiple cardiovascular risk factors.4 Indeed, as our cardiology colleagues kept finding the benefit of lower and lower cholesterol targets for reducing the risk of coronary heart disease events,5 the jury remained out as to what role, if any, that statins played in stroke patients without established coronary heart disease. Subset analyses of prior clinical trials had suggested, but not definitely proved, a benefit of statin therapy in patients with prior strokes. A retrospective subset analysis of 3280 subjects with a remote (mean 4.3 years) history of symptomatic ischemic cerebrovascular disease enrolled in the Heart Protection Study (HPS) showed that simvastatin therapy yield a 20% reduction in major vascular events (0.80, 0.71 to 0.92).6 This benefit was driven by a reduction in myocardial infarction and vascular death end points. For the end point of recurrent strokes, the statin exerted no net benefit (0.98, 0.79 to 1.22), being associated with both a nonsignificant 19% reduction in ischemic stroke and a nonsignificant doubling of hemorrhagic stroke (1.3% simvastatin, 0.7% placebo; relative risk 1.91, 0.92 to 3.96). Because avoiding death and heart attack are outcomes highly desired by stroke patients, the benefit observed in HPS was deemed by most to be clinically worthwhile. In the wake of HPS, the FDA approved simvastatin as indicated for patients with evidence of cerebrovascular disease and the AHA/ASA National practice guidelines recommended statin therapy for patients with ischemic stroke or transient ischemic attack presumed attributable to atherosclerosis.7 Appropriately, for symptomatic cerebrovascular disease patients without coexisting coronary artery disease, the guidelines rated the evidence supporting this recommendation as level B, reflecting an evidence base of post hoc, subgroup analyses that were not definitive. SPARCL was designed to prospectively examine whether statin treatment prevents secondary stroke among individuals with recent symptomatic cerebrovascular disease.1 In the trial, 4731 individuals with nonseverely disabling (modified Rankin scale score 3) strokes or transient ischemic attacks, LDL cholesterol levels between 100 to 190 mg/dL, and no known history of coronary artery disease, were randomized between 1 to 6 months after the index event to atorvastatin 80 mg daily versus placebo. Approximately 67% of entry events were ischemic strokes, 2% primary hemorrhages, and 31% transient ischemic attacks. During the trial, LDL cholesterol levels dropped by 45% in the atorvastatin group (132.7 to 72.9 mg/dL) and only 4% in the placebo group (133.7 to 128.5 mg/dL). During a median follow-up of 4.9 years, the incidence of fatal or nonfatal stroke was lower in the atorvastatin arm than in the placebo group (11.2% versus 13.1%, adjusted hazard ratio 0.84, 0.71 to 0.99; P 0.03, unadjusted P 0.05). There was also a significant reduction in major coronary events in favor of atorvastatin (3.4% versus