Macrovascular Residual Risk Studies

COMMENT

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.