Am Fam Physician. 2001;64(4):661-665
Low-dose aspirin and vitamin E have been advocated as preventive therapy in patients with risk factors for cardiovascular disease. The value of these interventions remains uncertain because their efficacy has not been conclusively demonstrated in communitybased studies. The Primary Prevention Project was designed to assess the effectiveness of aspirin and vitamin E in preventing cardiovascular events in adults with one or more risk factors for cardiovascular disease.
Participants 50 years and older were recruited through primary care practices in Italy. Patients were eligible for the study if they had at least one significant cardiovascular risk factor, such as age of 65 years or older; systolic blood pressure of 160 mm Hg or greater or diastolic blood pressure of 95 mm Hg or greater on at least three occasions; hypercholesterolemia; diabetes mellitus; obesity; or family history of myocardial infarction before the age of 55 in at least one parent or sibling. Patients with a poor short-term prognosis, those with contraindications to aspirin and those taking anticoagulants or anti-inflammatory agents were excluded from the study. Participants were randomly allocated to receive placebo, 100-mg entericcoated aspirin or 300-mg synthetic vitamin E daily. Patients were reviewed every four months for compliance and to assess symptoms, evidence of cardiovascular conditions or development of new risk factors.
About 4,500 patients and 15 hospital hypertension units were recruited for the study by 315 participating general practitioners. The mean age of the 2,583 women and 1,912 men was 64.4 years. In each group, about 30 percent of patients had one risk factor, and 40 percent had two risk factors for cardiovascular disease. The remaining patients had three or more risk factors. The most common risk factor was hypertension, which affected 68 percent of patients. With the exception of elevated cholesterol levels, the rate of which was slightly higher in patients treated with aspirin, the occurrence of hypertension and other risk factors was balanced across the treatment groups.
By the end of the study, 19 percent of patients assigned to aspirin and 13 percent of patients assigned to vitamin E had discontinued treatment. Side effects were cited as the principal reason for discontinuation by about 8 percent of the aspirin group and 1 percent of the vitamin E group. Follow-up of 3.6 years was achieved in 4,150 patients (92 percent). One percent of the aspirin group and 0.3 percent of the other patients developed bleeding complications, but three of the four deaths attributed to hemorrhage occurred in patients who were not treated with aspirin.
The accompanying table provides a profile of the effects of aspirin and vitamin E on the efficacy end points of the study. Aspirin therapy consistently lowered adverse cardiovascular outcomes, and the study was discontinued because of the strength of evidence supporting patient benefit from aspirin therapy. The reduction in all end points was most significant for that of cardiovascular death, the rate of which decreased from 1.4 to 0.8 percent, and for total cardiovascular events, the rate of which decreased from 8.2 to 6.3 percent. Patients taking vitamin E showed no advantage over those taking placebo with the exception of a 46 percent reduction in peripheral artery disease. Noncardiovascular events occurred equally in all groups.
| End points | Aspirin n = 2,226 (%) | No aspirin n = 2,269 (%) | Vitamin E n = 2,231 (%) | No vitamin E n = 2,264 (%) | |
|---|---|---|---|---|---|
| Main combined end point (cardiovascular death, nonfatal myocardial infarction and nonfatal stroke) | 45 (2.0) | 64 (2.8) | 56 (2.5) | 53 (2.3) | |
| Total cardiovascular events or diseases* | 141 (6.3) | 187 (8.2) | 158 (7.1)` | 170 (7.5) | |
| All deaths | 62 (2.8) | 78 (3.4) | 72 (3.2) | 68 (3.0) | |
| Cardiovascular | 17 (0.8) | 31 (1.4) | 22 (1.0) | 26 (1.1) | |
| Noncardiovascular | 45 (2.0) | 47 (2.0) | 50 (2.2) | 42 (1.9) | |
| All myocardial infarction | 19 (0.8) | 28 (1.2) | 22 (1.0) | 25 (1.1) | |
| Nonfatal myocardial infarction | 15 (0.7) | 22 (1.0) | 19 (0.8) | 18 (0.8) | |
| All stroke | 16 (0.7) | 24 (1.1) | 22 (1.0) | 18 (0.8) | |
| Nonfatal stroke | 15 (0.7) | 18 (0.8) | 20 (0.9) | 13 (0.6) | |
| Angina pectoris | 54 (2.4) | 67 (3.0) | 66 (3.0) | 55 (2.4) | |
| Transient ischemic attack | 28 (1.3) | 40 (1.8) | 33 (1.5) | 35 (1.5) | |
| Peripheral-artery disease | 17 (0.8) | 29 (1.3) | 16 (0.7) | 30 (1.3) | |
| Revascularization procedure | 20 (0.9) | 29 (1.3) | 27 (1.2) | 22 (1.0) | |
The authors conclude that low-dose aspirin conferred significant benefit in patients at risk of cardiovascular events. In about 8,000 person-years of aspirin treatment, there was no excess risk of hemorrhagic cerebrovascular events. In contrast, patients taking vitamin E had no benefit and, in some end points, had worse results than patients taking placebo. The authors urge primary care physicians and public policy makers to promote the use of low-dose aspirin in patients with risk factors for cardiovascular disease.