Effect of Aspirin on All-Cause Mortality in the Healthy Elderly

Abstract

Background: In the primary analysis of the Aspirin in Reducing Events in the Elderly (ASPREE) trial, now published in the Journal, we report that the daily use of aspirin did not provide a benefit with regard to the primary end point of disability-free survival among older adults. A numerically higher rate of the secondary end point of death from any cause was observed with aspirin than with placebo.

Methods: From 2010 through 2014, we enrolled community-dwelling persons in Australia and the United States who were 70 years of age or older (or ≥65 years of age among blacks and Hispanics in the United States) and did not have cardiovascular disease, dementia, or disability. Participants were randomly assigned to receive 100 mg of enteric-coated aspirin or placebo. Deaths were classified according to the underlying cause by adjudicators who were unaware of trial-group assignments. Hazard ratios were calculated to compare mortality between the aspirin group and the placebo group, and post hoc exploratory analyses of specific causes of death were performed.

Results: Of the 19,114 persons who were enrolled, 9525 were assigned to receive aspirin and 9589 to receive placebo. A total of 1052 deaths occurred during a median of 4.7 years of follow-up. 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). Cancer was the major contributor to the higher mortality in the aspirin group, accounting for 1.6 excess deaths per 1000 person-years. Cancer-related death occurred in 3.1% of the participants in the aspirin group and in 2.3% of those in the placebo group (hazard ratio, 1.31; 95% CI, 1.10 to 1.56).

Conclusions: Higher all-cause mortality was observed among apparently healthy older adults who received daily aspirin than among those who received placebo and was attributed primarily to cancer-related death. In the context of previous studies, this result was unexpected and should be interpreted with caution. (Funded by the National Institute on Aging and others; ASPREE ClinicalTrials.gov number, NCT01038583 .).

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.

Figure 2 (facing page).. 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. 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.