Methods

In this report, we present a meta-analysis of 9 primary prevention trials with aspirin, including the AAAT, POPADAD, and JPAD trials, added to the 6 trials included in the previous meta-analyses (the Antithrombotic Trialists’ Collaboration [ATTC] and Bartolucci and Howard ). Features of the studies included in the 9 trial meta-analysis are listed in Table 1 .

The United States Preventive Services Task Force described the data collection and analysis from the first 5 primary prevention trials—the British Doctors’ Trial (BMD), the Physicians’ Health Study (PHS), the Thrombosis Prevention Trial (TPT), the Hypertension Optimal Treatment (HOT) study, the Primary Prevention Project (PPP)—and the addition of the new data from the Women’s Health Study (WHS) was described by Bartolucci and Howard. The new sources of data are from the AAAT, POPADAD, and JPAD trials.

Because aspirin may have a differential effect on different aspects of cardiovascular (CV) disease, outcomes were classified as follows: (1) total coronary heart disease (CHD) as nonfatal and fatal myocardial infarction (MI) and death due to CHD; (2) nonfatal MI as confirmed MI that did not result in death; (3) total CV events as a composite of CV death, MI, or stroke; (4) stroke as ischemic or hemorrhagic stroke that may or may not have resulted in death; (5) CV mortality as death related to CHD or stroke; and (6) all-cause mortality as death related to any cause. Where applicable (data available), we performed a meta-analysis and summary overview for each of these end points for the 9 study data sets. All 9 studies were screened for these outcomes.

Data from the United States Preventive Services Task Force for each patient trial and data from the WHS, AAAT, JPAD, and POPADAD were combined for analysis. For each previously described end point, a meta-analysis was performed for the comparison of aspirin with placebo or control. A summary odds ratio with 95% confidence interval was calculated. The odds ratio is the appropriate effect size statistic for our 5 risk ratio outcomes noted in the previous paragraph. The odds ratio is the ratio of the odds of an event occurring in 1 group to the odds of it occurring in another group. The term is also used to refer to sample-based estimates of this ratio. Obviously, an odds ratio of 1 would indicate even odds or no difference between the 2 groups of aspirin and control with respect to the odds of an event such as MI. Calculation of the overall effect combining the 9 studies used the Mantel-Haenszel chi-square statistic with 1 degree of freedom. This test does not assume that patients in 1 study can be directly compared with those in another study, and it does not assume that any treatment effects are similar in different studies. It does not assume homogeneity but does take into account heterogeneity. Heterogeneity was calculated using the chi-square test with n − 1 degrees of freedom, where n represents the number of studies contributing to the meta-analysis. Forest plots were used to assess if there was significant heterogeneity (defined as p <0.01) and allowed assessment by considering the direction of the results. A weighting factor was also used that depended in part on the size of the study, which in turn affected the inverse variance formula that the Mantel-Haenszel procedure uses to calculate heterogeneity. The random-effects model also helps further account for the heterogeneity across the studies, between-study variation, and within-study variation or patient selection. However, given the summary data, within-study variation is not easily assessed. The standard procedure for the assessment of small study effects (i.e., a trend for relatively smaller studies to show larger treatment effects) has been the use of funnel plots using Egger’s test. There has been considerable discussion regarding the properties of this test. The technique of Macaskill et al was used to adjust for this shortcoming (also see Harbord et al ).

Results

Among the 9 trials in the analysis, 50,868 subjects were treated with aspirin and 49,170 received placebo or control. Table 2 lists each study and indicates if statistical significance of aspirin versus placebo was reached when using the odds ratio for any of the end points or groups of end points. The combined effects of aspirin on these end points are listed in Table 3 . In subjects treated with aspirin, there was significantly decreased risk for nonfatal MI (p = 0.042) and total CV events (p = 0.001). There was significant heterogeneity (p ≤0.01) for several of the end points listed in Table 3 (e.g., for total CHD events and nonfatal MI). The data for nonfatal MI and total CV events are shown in Figures 1 and 2 , respectively.

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