Primary Prevention of Stroke: Fish and Aspirin Work, Vitamin E Doesn’t
Abstracts & Commentary
Sources: Iso H, et al. Intake of fish and omega-3 fatty acids and risk of stroke in women. JAMA 2001;285:304-312. Collaborative Group of the Primary Prevention Project (PPP). Low-dose aspirin and vitamin E in people at cardiovascular risk: A randomized trial in general practice. Lancet 2001; 357:89-95.
These two studies addressed the question of primary prevention of stroke and heart disease. In the first, a prospective cohort study of women in the Nurses’ Health Study, almost 80,000 women aged 34-59 years in 1980 were followed up for 14 years. Women in the study were free of diagnosed heart disease, cancer, diabetes, and hypercholesterolemia, and completed a food frequency questionnaire.
Women in the study experienced 574 documented strokes, including 119 subarachnoid hemorrhages, and 62 intraparencymal bleeds. There were 303 ischemic strokes of which 264 were thrombotic (90 large-artery occlusive infarctions and 142 lacunes); 39 were embolic, and 90 were of undetermined type.
The risk of thrombotic stroke was significantly reduced by 48% among women who ate fish two to four times a week. There was no excess risk of hemorrhagic stroke with fish intake.
An inverse relationship appeared between intake of omega-3 fatty acids (fish oil) and risk of all types of stroke. Risk reduction was of borderline statistical significance for thrombotic stroke and statistically significant for lacunar infarction. Women with a high intake of omega-3 fatty acids (e.g., 15g/d of eicoapentanenoic acid) who did not use aspirin had a significant 49% reduction in risk of thrombotic stroke. The mechanism of protection may have been the action of high doses of omega-3 fatty acids to reduce blood pressure and to reduce the formation of thromboxane A2 in platelets but not the synthesis of prostaglandin I2 in vascular endothelium.
The Primary Prevention Project was a randomized, open-label clinical trial designed to test whether chronic treatment with low-dose aspirin (100 mg/d) and vitamin E (300 mg/d) reduces the frequency of major cardiovascular and cerebrovascular events. There were more than 4000 participants (57% women) aged 50 years or older (mean age 64 years) with at least one major risk factor for vascular disease. After 3.6 years the trial was stopped on the basis of evidence of an aspirin benefit in primary prevention of cardiovascular disease reported by two large trials (MRC General Practice Research Framework. Lancet 1998; 351:233-241. Hansson L, et al. Lancet 1998;351: 1755-1762). Aspirin significantly lowered the risk both for cardiovascular death by 44% and for any cardiovascular event (myocardial infarction, stroke, TIA, angina pectoris, peripheral artery disease, and revascularization procedure) by 23%. There was no major difference in type or severity of stroke between the two groups. For example, two of 16 strokes in the aspirin group and three of 24 strokes in the no aspirin group were hemorrhagic.
Bleeding complications were significantly higher in the aspirin group (1.1% vs 0.3%) but three of the four deaths caused by hemorrhage occurred in the no aspirin group.
Vitamin E showed no effect on any end point.
Commentary
The Nurses’ Health Study data indicate that higher consumption of fish and omega-3 polyunsaturated fatty acids reduced the risk for thrombotic stroke primarily among women not taking aspirin regularly. However, it did not increase the risk for hemorrhagic stroke. The PPD study showed that low-dose enteric coated aspirin had a protective effect in subjects with one or more cardiovascular risk factors. The fact that more than half of the patients in this series were women makes the results even more noteworthy. The higher bleeding complications in the aspirin group highlights the dangers of even low-dose coated aspirin taken chronically. This study like a recent randomized clinical trial (The Heath Outcomes Prevention Evaluation Study Investigators. N Engl J Med 2000;342:154-160) failed to find any beneficial effect of vitamin E.
These results enable physicians to make evidence-based recommendations to their patients with regard to diet modification and aspirin therapy for the primary prevention of cardiovascular events. —John J. Caronna
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