Background: Diabetes increases a person's risk of developing cardiovascular events two-to fourfold. Daily aspirin therapy is an effective secondary prevention strategy, especially in persons at high risk. Several clinical guidelines extend this recommendation to primary prevention, despite limited evidence of effectiveness. Although large trials of aspirin for primary prevention of cardiovascular events have examined diabetes in subgroups, these analyses have been underpowered, and have not shown marked effects on cardiovascular outcomes. Ogawa and colleagues designed the Japanese Primary Prevention of Atherosclerosis With Aspirin for Diabetes (JPAD) trial to study primary prevention in patients with type 2 diabetes mellitus.

The Study: JPAD, a prospective, randomized, open-label, controlled trial enrolled patients at 163 medical sites throughout Japan between December 2002 and May 2005, with follow-up through April 2008. Persons between 30 and 85 years of age with type 2 diabetes were eligible. Exclusion criteria included known coronary vascular disease; history of stroke, cerebral hemorrhage, or transient ischemic attacks; electrocardiographic changes consistent with ischemia or previous infarct; atrial fibrillation; peripheral vascular disease requiring treatment; current anticoagulant or antiplatelet therapy; and contraindications to aspirin use.

Participants were randomly assigned to the aspirin group or the nonaspirin group. Patients in the aspirin group received 81 or 100 mg of aspirin daily, and were evaluated for cardiovascular events at follow-up visits every two weeks in the clinic or every four weeks in the hospital. The primary end point was a composite of any atherosclerotic event, including fatal or nonfatal cardiac or cerebrovascular disease; or symptomatic peripheral vascular disease. The secondary end points included each primary end point alone and combined with all-cause mortality. Monitored adverse events included gastrointestinal events and any hemorrhagic complication other than hemorrhagic stroke. Analysis was performed according to the intention-to-treat principle. Participants in each group were allowed to take concurrent therapy, including antithrombotic therapy when needed.

Results: Of the 2,567 patients screened, only 28 were excluded. Both groups had a follow-up rate of 92 percent through the end of the study. Baseline characteristics were similar between the two groups. Blood pressure and diabetes were well-controlled in both groups, with an average blood pressure of 135/76 mm Hg and A1C levels of 7.1 percent in the aspirin group and 7.0 percent in the nonaspirin group. Ten percent of patients in the aspirin group discontinued the study medication, and 0.7 percent of those in the nonaspirin group had taken aspirin or other antiplatelet medication. There were no notable differences between groups in the primary or secondary end points, except for a decrease in fatal coronary events plus fatal cerebrovascular events for the aspirin group. Although four persons in the aspirin group experienced bleeding that required transfusion, the composite of hemorrhagic stroke and severe gastrointestinal bleeding was similar between groups.

Conclusion: The authors concluded that low-dose aspirin is not effective for the primary prevention of cardiovascular events.

editor's note: Several large studies, such as the JPAD trial and a similar study released about the same time (see Secondary Prevention of Cardiovascular Events in Diabetes, page 1000), fail to show a benefit of aspirin for the primary prevention of cardiovascular events, especially in high-risk populations such as those with diabetes. Despite these cumulative data, several groups, including the American Diabetes Association, recommend that patients at high risk of cardiovascular disease (e.g., patients with diabetes; patients older than 40 years; patients with hypertension, hyperlipidemia, or a family history of these conditions) take aspirin to prevent a first cardiovascular event. These clinical guidelines stem from extrapolated data from secondary prevention trials and subgroup analysis that demonstrated positive results.

The JPAD and POPADAD studies focus on patients with diabetes. Because they had lower-than-expected rates of events in the study populations, it is unclear whether the results may be generalized to populations with a higher prevalence of cardiovascular disease. In both studies, complications from aspirin use were low but trended toward increased rates of gastrointestinal bleeding and the need for transfusion. In editorials accompanying both articles, Nicolucci¹ and Hiatt² concur that current data do not support the use of aspirin for primary prevention of cardiovascular events, although the need for larger studies remains.—a.c.f.