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abstract & commentary
Synopsis: The pooled results demonstrate a statistically significant reduction in total stroke and nonfatal stroke attributable to pravastatin administration.
Source: Byington RP, et al. Circulation. 2001;103:387-392.
Strokes, which are the second leading cause of death in the Americas and Europe, occur in 600,000 patients each year and are the leading cause of disability and increased health care costs in the United States resulting in 160,000 deaths.1 Whereas numerous studies have demonstrated that the risk of coronary heart disease events is reduced by lipid-lowering therapy,2-6 the effects of lipid-lowering on stroke events have not been well established even though studies with older lipid-lowering agents have suggested that modest reduction in cholesterol did not reduce stroke.7,8 More recently, the proven efficacy of the HMG-CoA reductase inhibitors (or statin drugs) on the ravages of coronary artery disease have heightened the expectation that these agents might also have a beneficial effect on the prevention of stroke.
The Prospective Pravastatin Pooling (PPP) Project was initiated in 1992 before 3 large, placebo-controlled, randomized trials, which included 19,768 patients with 102,559 person-years of follow-up, had been completed. The effect of pravastatin given in a dosage of 40 mg/d on stroke events was investigated, and a prospectively defined pooled analysis of these 3 large trials4-6,9-11 was performed.12 When the 13,173 patients from the 2 secondary prevention trials7,8 were combined, there was a 22% reduction in total strokes and a 25% reduction in nonfatal stroke. The beneficial effect of pravastatin on total stroke incidence was observed across a wide range of patient characteristics. Pravastatin was associated with a 23% reduction in nonhemorrhagic stroke in the secondary prevention group. The West of Scotland Coronary Prevention Study, which was a primary prevention trial in hypercholesterolemic men, exhibited a similar, although somewhat smaller, reduction in total stroke incidence.
Comment by Harold L. Karpman, MD, FACC, FACP
The data presented by Byington and colleagues in the Prospective Pravastatin Pooling Project represent a carefully performed systematic overview of 3 extremely large lipid-lowering trials. The pooled results demonstrate a statistically significant reduction in total stroke and nonfatal stroke attributable to pravastatin administration. The analyses also clearly demonstrated that pravastatin was more effective than the older, nonstatin lipid-lowering therapies in reducing stroke rates. The consistent reduction in stroke rate across the trials and subgroups were particularly striking, and the drug appeared to have similar beneficial effects on patients taking aspirin and whether they were taking blood pressure-lowering medications.
It is important to recognize that stroke has many causes; therefore, in evaluating specific forms of drug therapy used for prevention, one must separate thrombotic from hemorrhagic strokes. Pravastatin appears to have strong beneficial effects in preventing atherothrombic strokes and has no effect on the prevention of hemorrhagic stroke. Since numerous papers suggest that plaque rupture is the primary pathogenic mechanism in acute thrombotic events in coronary and cerebral arteries, plaque stabilization appears to be an important process by which statins are effective in reducing the frequency of thrombotic events in these areas. Therefore, the nonlipid effects of statin drugs may be more important in the prevention of cerebrovascular disease than are the lipid-lowering actions of the drug. Also, statins have been shown to have an anti-inflammatory effect independent of their LDL-lowering actions by virtue of their ability to reduce inflammatory markers such as C-reactive protein, and this effect may result in improved endothelial function thereby decreasing the incidence of acute coronary events.
From a clinical point of view, the PPP Project results provide strong evidence supporting the view that patients with a prior history of myocardial infarction should be treated with statin drugs—not only to prevent recurrent myocardial infarctions but also possibly to reduce the incidence of stroke event rates. Since stroke is a devastating event in the lives of patients and their families, clinicians should be able to use the results of the PPP Project to generate greater patient acceptance of prolonged statin therapy. Although the principle use of these drugs will largely remain in the prevention of coronary artery heart disease, the evidence of stroke benefit with the use of statin drugs demonstrated by the PPP Project is an important contribution for both clinicians and patients. As we enter an era in which we may be using statin therapy to treat and prevent all cerebrovascular and peripheral arterial thrombotic events and, in fact, even for the treatment of occult atherosclerosis in all arterial systems, we thereby will be reducing the incidence of acute coronary and cerebrovascular events.
1. American Heart Association. 2000 Heart and Stroke Statistical Update. Dallas, Tex: American Heart Association; 1999.
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3. Scandinavian Simvastatin Survival Study Group. Lancet. 1994;344:1383-1389.
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7. Atkins D, et al. Ann Intern Med. 1993;119:136-143.
8. Hebert PR, et al. Arch Intern Med. 1993;155:50-53.
9. PPP Project Investigators. Am J Cardiol. 1995;76:
10. Simes J, et al. Circulation. 1999;100(suppl 1):1-825. Abstract.
11. Sacks FM, et al, for the Prospective Pravastatin Pooling Project Investigators Group. Circulation. 2000;102:1893-1900.
12. Ridker PM, et al. Circulation. 1999;100:230-235.