Participants

From March 2010 through December 2014, a total of 19,114 persons (16,703 from Australia and 2411 from the United States) were enrolled in the trial, of whom 9525 were randomly assigned to receive aspirin and 9589 to receive placebo. Details regarding the characteristics of the participants have been published previously.17 Blacks and Hispanics constituted 52.7% of the 2411 trial participants from the United States. At the end of the trial, the total number of years during which participants were at risk for death (person-years) was 44,007 in the aspirin group and 44,382 in the placebo group.

All-Cause Mortality

Table 1. Table 1. Mortality According to the Underlying Cause of Death.

A total of 1052 participants (5.5%) died during the trial. The analysis of the secondary end point of death from any cause included the 141 deaths that occurred after another primary end-point event (i.e., a diagnosis of dementia or permanent physical disability). The risk of death from any cause was 12.7 events per 1000 person-years in the aspirin group and 11.1 events per 1000 person-years in the placebo group (hazard ratio, 1.14; 95% confidence interval [CI], 1.01 to 1.29), with 1.6 excess deaths per 1000 person-years in the aspirin group. Table 1 shows the risk of death according to the major underlying causes (cancer, cardiovascular disease, and major hemorrhage), as well as the risk of death related to other causes, such as sepsis, chronic lung disease, dementia, or heart failure.

Cancer was the underlying cause in 49.6% of the deaths, cardiovascular disease (including ischemic stroke) in 19.3%, and major hemorrhage (including hemorrhagic stroke) in 5.0% (Table 1). In only 12 cases of death (4 in the aspirin group and 8 in the placebo group), insufficient information was available to allow an underlying cause to be determined. A total of 97.6% of the deaths were detected during the trial, with 2.4% (25 deaths) identified during the final search of the National Death Index.

Cancer-Related Mortality

Figure 1. Figure 1. Cumulative Incidence of Death According to the Underlying Cause. Shown is the cumulative incidence of death according to major underlying causes (cancer, cardiovascular disease, and major hemorrhage) and of death related to other causes. For each cause of death, the cumulative incidence was based on a competing-risks model, which was stratified according to trial group, with the remaining causes of death as competing events. Data are not shown for 12 deaths for which insufficient information was available to adjudicate an underlying cause, even after linkage with the National Death Index. The insets show the same data on an enlarged y axis.

Among participants who received aspirin, the major contributor to the higher all-cause mortality was the higher risk of death for which the underlying cause was adjudicated to be cancer. The risk of cancer-related death was 6.7 events per 1000 person-years in the aspirin group and 5.1 events per 1000 person-years in the placebo group (hazard ratio, 1.31; 95% CI, 1.10 to 1.56) (Table S3 in the Supplementary Appendix). In a separate analysis that was based on a tabulation of the number of deaths in which cancer was recorded as a contributing cause on the death certificate, a similar pattern was observed, with 272 deaths (6.2 events per 1000 person-years) in the aspirin group and 206 deaths (4.6 events per 1000 person-years) in the placebo group. In curves showing the cumulative incidence of death according to each major cause, there is a progressive divergence beginning in the third year after randomization in the curves for death from any cause1 and for death related to cancer, as compared with the curves for death related to other major causes (Figure 1).

Table 2. Table 2. Cancer-Related Mortality According to Type of Cancer.

Table 2 shows cancer-related mortality according to the type of cancer. Despite the small number of deaths associated with each type of cancer, it is apparent that the higher cancer-related mortality in the aspirin group was not confined to specific tumor locations or pathologic types. A higher rate of death from gastrointestinal cancer (including colorectal cancer) in the aspirin group than in the placebo group contributed substantially to the overall excess mortality associated with aspirin. The excess cancer-related mortality among participants who received aspirin was seen both among those who entered the trial with a personal history of cancer (with cancer-related death occurring in 94 such participants in the aspirin group and in 88 in the placebo group) and among those in whom cancer was first diagnosed after randomization (with cancer-related death occurring in 198 and 138, respectively) (Table S3 in the Supplementary Appendix).

The higher cancer-related mortality among those who received aspirin was accompanied by a higher incidence of cancer among those who received aspirin, although to a lesser degree: cancer (excluding nonmelanoma skin cancer) was diagnosed in 981 participants in the aspirin group, as compared with 952 in the placebo group. Among the 66% of deaths for which information regarding the terminal phase of the illness was available, there were no apparent differences between the two trial groups in the rate of each proximal cause of death, including bleeding (Tables S4 and S5 in the Supplementary Appendix).

Subgroup Analyses

Figure 2. Figure 2. Subgroup Analyses of All-Cause Mortality. Race and ethnic group were reported by the participants. Other race or ethnic group was defined as any category with less than 200 participants overall, which included Aboriginal or Torres Strait Islander (12 participants), Native American (6), multiple races or ethnic groups (64), Native Hawaiian or Pacific Islander (11), and those who indicated that they were not Hispanic but did not state another race or ethnic group (18). The arrows indicate that the 95% confidence intervals were beyond the scale. The presence of diabetes was based on participants’ report of diabetes mellitus or a fasting glucose level of at least 126 mg per deciliter (≥7 mmol per liter) or receipt of treatment for diabetes. Hypertension was defined as treatment for high blood pressure or a blood pressure of more than 140/90 mm Hg at trial entry. Previous regular aspirin use was defined according to participant-reported regular use of aspirin immediately before the first baseline visit, with a 1-month washout period before randomization. Frailty was categorized on the basis of the adapted Fried frailty criteria, which included body weight, strength, exhaustion, walking speed, and physical activity.15 The category of prefrail included participants who met one or two criteria, and the category of frail included those who met three or more criteria. Dyslipidemia was defined as the receipt of cholesterol-lowering medication or as a serum cholesterol level of at least 212 mg per deciliter (≥5.5 mmol per liter) in Australia and at least 240 mg per deciliter (≥6.2 mmol per liter) in the United States or as a low-density lipoprotein level of more than 160 mg per deciliter (>4.1 mmol per liter). Body-mass index is the weight in kilograms divided by the square of the height in meters.

The effect of aspirin on all-cause mortality appeared to be consistent across a series of prespecified and nonprespecified subgroups (Figure 2, and Fig. S1 and Table S6 in the Supplementary Appendix). The only significant interaction term was country of origin (P=0.02); the effect of aspirin on mortality appeared to be limited to Australian participants. Interpretation of this interaction is limited because P values were not adjusted for multiple comparisons and is complicated by differences between participants from the two countries in age and race (and possibly other factors).

Figure S2 and Table S3 in the Supplementary Appendix show the difference between the aspirin group and the placebo group in cancer-related mortality according to a variety of prespecified and nonprespecified subgroups. There was no evidence of a modification in the effect of aspirin on cancer-related mortality among the examined subgroups.

In addition, Figure S3 in the Supplementary Appendix shows the hazard ratios for all-cause mortality for aspirin as compared with placebo that were reported in other major primary prevention trials involving this agent. The higher mortality in the aspirin group in this trial was an unexpected result in the context of previous trials.

Mortality in the Trial Population as Compared with the General Population

As a frame of reference, we examined all-cause mortality and cancer-related mortality in a simulated cohort of the general population that was matched to the trial population in age, sex, country of origin, and race or ethnic group (with data for the final characteristic available only for the U.S. participants). All-cause mortality was 34.9 events per 1000 person-years in the matched population, as compared with 11.1 events per 1000 person-years in the trial population. Cancer-related mortality was 10.5 events per 1000 person-years in the matched population, as compared with 5.1 events per 1000 person-years in the trial population.