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Increase in mortality with daily aspirin attributable to cancer
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Healthy older adults who used aspirin daily had higher mortality rates, primarily driven by cancer-related death, than those who took placebo, according a randomized, placebo-controlled, dual-country trial.
Because other trials have not shown this effect, the results should be interpreted with caution, the researchers wrote.
“The Aspirin in Reducing Events in the Elderly (ASPREE) trial was a primary prevention trial that was established to investigate whether the daily use of 100 mg of enteric-coated aspirin would prolong the healthy life span of older adults,” John J. McNeil, MB, BS, PhD, Sir John Monash distinguished professor and head of the department of epidemiology and preventive medicine at Monash University in Melbourne, Australia, and colleagues wrote. “Overall mortality was higher in the aspirin group than in the placebo group, but not to an extent that reached significance if the P value was corrected for multiple comparisons. Other primary prevention trials of aspirin have not identified similar higher all-cause mortality.”
McNeil and colleagues examined the specific causes of deaths among individuals taking aspirin.
The ASPREE trial included 19,144 people aged 70 years or older from Australia (n = 16,703) and the United States (n = 2,411); the latter group included black and Hispanic participants aged 65 years or older.
All participants were free of cardiovascular disease, dementia and disability and were community-dwelling.
Researchers randomly assigned participants to 100 mg aspirin (n = 9,525) or placebo (n = 9,589).
During a median follow-up of 4.7 years, 1,052 participants (5.5%) died.
Risk for death of any cause appeared slightly higher among participants receiving aspirin (12.7 events per 1,000 person-years) than placebo (11.1 events per 1,000 person-years; HR = 1.14; 95% CI, 1.01-1.29).
Researchers identified cancer as the underlying cause of death for 49.6% of participants. Cardiovascular disease accounted for 19.3% of deaths and major hemorrhage for 5%.
Cancer accounted for 1.6 excess deaths per 1,000 person-years among those assigned aspirin, and therefore appeared to be the major contributor to the higher morality in that group.
Cancer-related death occurred among 3.1% of those receiving aspirin compared with 2.3% of those receiving placebo (HR = 1.31; 95% CI, 1.1-1.56).
“All-cause mortality and cancer-related mortality in the trial population were 32% and 49% of the rates in the general population, respectively,” the researchers wrote. “The lower rates in the trial population probably reflect the healthy nature of the trial volunteers and the exclusion of participants with previous cardiovascular or cerebrovascular disease, cognitive impairment, or a physician-estimated life expectancy of less than 5 years.”
The researchers said the results of the study should be interpreted with caution.
“In conclusion, among healthy adults who did not have an indication for aspirin use and were predominantly 70 years of age or older at enrollment, all-cause mortality was apparently higher among those who received daily low-dose aspirin than among those who received placebo ... [and] cancer was the principal cause of the excess deaths,” they wrote.
have not identified similar results, which suggests that the mortality results reported here should be interpreted with caution.” – by Cassie Homer
Disclosures: McNeil reports nonfinancial support from Bayer. Please see the study for all other authors’ relevant financial disclosures.
Perspective
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The ASPREE results contrast sharply with previous secondary analyses of randomized controlled trials (RCTs) that show cancer mortality benefits among largely younger populations after 5 to 10 years of aspirin initiation. What could explain such a discordant effect of aspirin on cancer mortality among the elderly compared with younger adults? There are several potential possibilities.
First, aspirin’s biological effects may vary according to the timing of exposure. Aspirin may effectively prevent the initial formation of tumors by affecting pathways fundamental to tumor initiation. In contrast, aspirin could accelerate development or spread of an in-situ tumor. This would explain a short-term adverse effect on cancer mortality that would be evident only in a RCT in which aspirin was administered to population with a high prevalence of undiagnosed cancer. For example, the anti-inflammatory effects of aspirin may inhibit tumor initiation, resulting in lower cancer incidence. In contrast, aspirin’s anti-inflammatory effects may blunt already-mobilized antitumor immune responses for undiagnosed established tumors, leading to an increase in cancer mortality.
Second, aspirin’s biological effects may vary according to age or other risk factors for cancer. It is conceivable that cancers that arise in the elderly may be a consequence of pathways specific to aging (eg, epigenetic alterations) or arise from different cells of origin than cancers among younger individuals who respond differently to aspirin.
Third, aspirin treatment within the context of a RCT may have led to unexpected consequences. For example, aspirin assignment in the context of a RCT in which participants may have cancers that are not yet clinically apparent could have led to a higher prevalence of cancer-associated bleeding complications that may have hastened death or influenced tolerance of cancer treatment.
Fourth, the ASPREE results could be due to chance. If the findings are scrutinized according to the most stringent standards of adjustment for multiple testing, the increase in cancer mortality does not strictly achieve statistical significance.
Fifth, the ASPREE results may represent the “true” effect of aspirin. This would imply that prior RCTs of aspirin based on secondary analyses showing the benefit for cancer incidence and mortality were flawed. However, five separate RCTs have each found that aspirin reduces risk for adenomatous polyps, establishing that an antineoplastic effect of aspirin is, indeed, causal.
What are the implications of the early results of ASPREE for cancer prevention?
The lack of effect on disability or dementia-free survival suggest that aspirin should not be initiated for the sole purpose of chronic disease prevention among an otherwise healthy elderly population. However, the results should not influence established U.S. Preventive Services Task Force guidelines supporting the use of aspirin among individuals with a prior history of a vascular event (secondary prevention) or for individuals aged 50 to 59 years with at least a 10% 10-year risk for a CVD event (primary prevention). It remains unanswered as to whether aspirin should be discontinued among elderly individuals who already take aspirin, particularly given the results in ASPREE that mortality was primarily observed among individuals without a prior history of aspirin use. Thus, the decision to discontinue aspirin for primary prevention should remain individualized.
Given the overwhelming evidence of aspirin’s beneficial effects in other RCTs, the already established USPSTF guidelines supporting its use in a large subset of the population, the ongoing conduct of RCTs of aspirin in other settings — including among cancer survivors — as well as the large number of individuals already taking aspirin, it is imperative the reasons for the unexpected early findings in ASPREE are better understood. This will necessitate long-term follow up of the ASPREE cohort, as well as additional clinical review and in-depth characterization of the population through biospecimens collected during the trial.
Longer-term follow-up of ASPREE may identify a benefit in either cancer incidence or mortality that has yet to emerge, as was the case with prior RCTs. In the end, optimal chemoprevention will likely require a more precise, potentially molecularly targeted approach that accounts for timing of intervention and the heterogeneity in the underlying biology of the host.
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