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For Your Patients-Stroke Prevention

Aspirin Use Shows No Benefit in Primary Prevention of Heart Attacks and Stroke in Healthy, Older Adults

Borreli, Lizette

doi: 10.1097/01.NT.0000549638.94875.8d
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Three different papers came to the same conclusion: Aspirin did not provide prevention against primary stroke and heart attacks.

The role of aspirin for secondary prevention for recurrent heart attacks and strokes has been well-known for decades; its benefit for primary prevention has been mixed, however. The US Preventative Services Task Force's latest guidelines on aspirin use for the primary prevention of cardiovascular disease in adults aged 70 years or older found “insufficient evidence to assess the balance of benefits and harms” in this population. And now, three separate papers published online on September 16 in the New England Journal of Medicine (NEJM) add further evidence: Aspirin does not improve disability-free survival and cardiovascular disease in healthy, older adults, it reported.

The researchers, led by John J. McNeil, MBBS, PhD, professor in the department of epidemiology and preventive medicine at Monash University in Melbourne, Australia, recruited a healthy, older cohort to estimate whether daily use of 100 mg of enteric-coated aspirin was associated with a prolonged life span for five years.



The Aspirin in Reducing Events in the Elderly (ASPREE), an international, randomized, double-blind, placebo-controlled trial, combined death, dementia, and persistent physical disability as its primary endpoint.

Compared to placebo, aspirin did not provide any benefit in extending disability-free survival and was associated with an increased risk of major hemorrhage and a higher risk of mortality, specifically cancer-related mortality.

The trial was terminated at a median of 4.7 years of follow-up after the researchers determined there would be no benefit with continued aspirin, the researchers wrote, in one of the three papers published online in the NEJM.

There were no significant differences in any of the components of the primary endpoint that suggested a benefit from initiating daily aspirin use.

Dr. McNeil told Neurology Today that although no single study can ever provide a “final word,” it is notable that the ASPREE results are consistent with the results of the two other primary prevention trials, ADVANCE and ASCEND, which were both published in recent weeks.

“The findings of the ASPREE trial were unambiguous,” he said. “They indicated quite clearly that in a ‘typical’ older person, aged over 70 years, and free of clinically manifest cardiovascular or cerebrovascular disease, ongoing therapy with low-dose aspirin neither improved healthy lifespan, nor significantly reduced the incidence of coronary heart disease or stroke.”



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For the study, ASPREE investigators enrolled 19,114 community-dwelling adults who were 70 years of age or older, from Australia and the US between March 2010 through December 2014. At baseline, participants were free from cardiovascular disease, dementia, or physical disability. Of this cohort, 9525 participants were randomly assigned to receive 100 mg of enteric-coated aspirin per day and 9589 to receive placebo. The rate of adherence to treatment was 62.1 percent in the aspirin group and 64.1 percent in the placebo group.

The primary outcome of disability-free survival was a composite measure that included the development of persistent physical disability, dementia, or death. Secondary outcomes included rates of cardiovascular events and bleeding.

In one analysis, the researchers compared the effects of daily low-dose aspirin with placebo on improving participants' odds of disability-free survival within about five years. The researchers found no differences in the rate of the composite death, dementia, or persistent physical disability between those taking low-dose aspirin and placebo (21.5 events per 1000 person-years vs 21.2 per 1000 person-years, [hazard ratio] HR, 1.01; 95% CI, 0.92-1.11; p=.79).

In a separate analysis, the team evaluated the role of aspirin in cardiovascular disease, which included fatal coronary heart disease, non-fatal myocardial infarction (MI), fatal or non-fatal stroke, or hospitalization for heart failure, and bleeding. Following a median of about five years, the rate of cardiovascular disease was lower among the aspirin group, compared to the placebo group (10.7 events per 1000 person-years vs 11.3 events per 1000 person-years, HR, 0.95; 95% CI, 0.83-1.08). However, aspirin use was associated with higher rates of major adverse cardiovascular events, such as major hemorrhage, compared with placebo (8.6 events per 1000 person-years vs 6.2 events per 1000 person-years, HR, 1.38; 95% CI, 1.18-1.62; p<.001). No differences were found in rates among individual cardiovascular events, such as MI and ischemic stroke.

In a third analysis, the researchers examined all-cause mortality outcomes in participants randomized to aspirin, compared to placebo. A total of 1,052 mortality cases occurred during follow-up. In the aspirin group, the risk of an all-cause mortality was 12.7 events per 1000 person-years, and 11.1 events per 1000 person-years in the placebo group (HR, 1.14; 95% CI, 1.01 - 1.29). Cancer-related deaths was the major contributor to higher mortality in the aspirin group, accounting for 6.7 events per 1000 person-years, and 5.1 events per 1000 person-years, with placebo (HR, 1.31; 95% CI, 1.10-1.56).

Overall, aspirin use was associated with an excess of 1.6 deaths per 1000 person-years.

“Low-dose aspirin is unlikely to produce any significant health benefit within five years of its commencement in older people,” said Dr. McNeil. “There was no overall benefit on stroke incidence with any small trend to benefit with ischemic stroke countered by an increased risk on intracranial bleeding.”

The study had several limitations, including the lack of diversity in the population; 56.4 percent were women and 91.3 percent were white. “There were not sufficient minorities included to determine whether the results were applicable to them,” said Dr. McNeil.



The trial was funded by grants from the National Institute on Aging and the National Cancer Institute at the NIH, the National Health and Medical Research Council of Australia, Monash University, and the Victorian Cancer Agency.

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Phillip B. Gorelick, MD, MPH, FACP, FAHA, FANA, FAAN, neurologist and chief medical officer at Thorek Memorial Hospital in Chicago, said while aspirin has been shown to be beneficial for secondary prevention of cardiovascular disease, the current study does not support the beneficial use of aspirin in primary prevention of cardiovascular events.



“The ASPREE trials were generally consistent with existent knowledge about aspirin's role in primary prevention in cardiovascular disease and bleeding risks and will add to the systematic data base and meta-analytic studies,” he told Neurology Today.

Despite a slightly lower rate of cardiovascular disease among participants randomized to aspirin in the study, Dr. Gorelick said older age has been a general risk for bleeding when aspirin is administered.

“Several key consequences of major hemorrhage associated with older age include reduced quality of life, and if there is brain hemorrhage, there may also be resultant neurological disability and heightened risk of cognitive impairment and dementia,” he said.

Nicole Chiota-McCollum, MD, MEd, a neurologist in Charlottesville, VA, affiliated with the University of Virginia Medical Center, shared Dr. Gorelick's concerns about the risk of major hemorrhage associated with aspirin use for primary prevention. “The increased rates of hemorrhage among patients taking aspirin is consistent with previous trials and clinical experience,” she told Neurology Today.

Commenting on the rates of major hemorrhage in the study, Dr. Chiota-McCollum noted that gastrointestinal bleeding was the most common cause of major hemorrhage among all participants. Approximately 4 percent of patients assigned to the aspirin group experienced a bleeding complication, compared to 3 percent in the placebo group. Since no benefit to aspirin was seen in the trial, “these data suggest that the risk of aspirin outweighs the benefit in healthy, low-risk older adults, even if the bleeding risk remains very small,” she said.

Given that aspirin did not improve disability-free survival in healthy, older patients, Patrick D. Lyden, MD, FANA, FAHA, FAAN, professor of neurology and The Carmen and Louis Warschaw Chair in neurology in Cedars-Sinai Medical Center, has advised these patients to absolutely stop taking aspirin.

“The data are unequivocal in my opinion,” he said. “Don't take medicines you don't need if you have no indications.”

Dr. Lyden also advised neurologists to tell their patients to not take aspirin in the absence of vascular risk factors. “Be proactive about asking your patients that you see who might be taking aspirin; ask them why they're taking it, who told them to, and advise them to stop if they don't have an indication.”



Echoing Dr. Lyden's sentiment on aspirin use for primary prevention, S. Claiborne Johnston, MD, PhD, the dean of Dell School of Medicine at The University of Texas at Austin, said aspirin does not appear to produce any real benefit and it increases the risk of hemorrhage. “I think we can lay this question to rest: no aspirin for those without real cardiovascular risk.”

The results of the ASPREE trial should not be applied to all use of low-dose aspirin in older people, especially those with a medical indication, Dr. Chiota-McCollum said. Currently, there is evidence in support of aspirin's use in secondary prevention. But she does advise doctors to exercise caution when prescribing aspirin to patients.

“Primary care physicians, and others conducting primary coordination of care, should carefully consider an older patient's individual risk/benefit balance before reflexively prescribing aspirin for primary prevention.”

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Drs. McNeil, Chiota-McCollum, and Lyden had no disclosures. Dr. Gorelick serves on the Bayer-sponsored ARRIVE trial Steering Committee.

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•. McNeil JJ, Woods RL, Nelson MR, et al Effect of aspirin on disability-free survival in the healthy elderly New Engl J Med 2018; Epub 2018 Sept 16.
    •. McNeil JJ, Wolfe R, Woods RL, et al Effect of aspirin on cardiovascular events and bleeding in the healthy elderly New Engl J Med 2018; Epub 2018 Sept 16.
      •. McNeil JJ, Nelson MR, Woods RL, et al Effect of aspirin on all-cause mortality in the healthy elderly New Engl J Med 2018; Epub 2018 Sept 16.
        © 2018 American Academy of Neurology