Statins for Stroke Prevention
By Paul J. Grant, MD
Amarenco P, Bogousslavsky J, Callahan A III, et al. Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) Investigators. High-dose atorvastatin after stroke or transient ischemic attack. N Engl J Med. 2006 Aug 22;355:549-559.
Despite recent advances, the physician’s armamentarium for secondary stroke prevention is limited. The literature regarding optimal blood pressure management for stroke prevention is sparse, and the data addressing the best antiplatelet regimen remain controversial. This is troubling, given the fact that cerebrovascular disease remains the third leading cause of death in the United States.
Although extensive data exists for the benefits of using 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) for the prevention and treatment of cardiovascular disease, little is known about their role in decreasing the risk of stroke. The highly anticipated Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial sought to determine if statin therapy would decrease the risk of recurrent stroke in patients with no known coronary heart disease.
This prospective, randomized, double-blind, placebo-controlled trial included 4,731 men and women with no history of coronary heart disease. Eligible patients had a history of stroke (ischemic or hemorrhagic) or a transient ischemic attack (TIA) within a one- to six-month period before randomization as diagnosed by a neurologist. All patients required a low-density lipoprotein (LDL) cholesterol level between 100 and 190 mg/dL, while exclusion criteria included atrial fibrillation. Patients were randomized either to a dosage of 80 mg of atorvastatin daily or to a placebo and were followed for a median duration of 4.9 years. The primary endpoint was fatal or nonfatal stroke.
The average patient age in this trial was 63; approximately 60% of the patients were male. A total of 265 patients reached the primary endpoint in the atorvastatin group, versus 311 patients in the placebo group. This translates to an adjusted relative risk reduction of 16% in the primary endpoint for patients receiving atorvastatin (hazard ratio 0.84; 95% confidence interval 0.71 to 0.99; p=0.03). Although there was no difference in overall mortality between the two groups, the incidence of cardiovascular events was significantly lower in those receiving atorvastatin. Interestingly, more hemorrhagic strokes were noted in the atorvastatin group. With respect to safety, no significant differences in serious adverse events were noted. The atorvastatin group did, however, encounter significantly more cases of persistently elevated aspartate aminotransferase (AST) or alanine aminotransferase (ALT), at 2.2% versus 0.5% in the placebo group.
The findings by the SPARCL investigators provide strong evidence that atorvastatin reduces the incidence of stroke recurrence. The mechanism for risk reduction with statin exposure is most likely due to the dramatic lowering of LDL cholesterol. This effect has been shown in numerous trials resulting in the reduction of cardiovascular events. The present trial observed a 53% decrease in LDL cholesterol in the atorvastatin group compared with no change in the placebo arm. In addition to their powerful lipid-lowering role, statins also appear to prevent plaque rupture, optimize endothelial function, and provide anti-inflammatory effects. These are the so-called “pleiotropic effects” of statins and may be another factor contributing to the benefits observed.
Although some physicians are already prescribing statins for stroke patients, the literature supporting this practice has been sparse. The latest guidelines for prevention of stroke in patients with ischemic stroke or TIA were published in February 2006 by the American Heart Association/American Stroke Association Council on Stroke. These guidelines state that patients with a history of ischemic stroke or TIA are “reasonable candidates” for statin therapy. One could argue that these guidelines should now be revised to include a strong recommendation for statin therapy in secondary stroke prevention.