Trials show risks of aspirin use may outweigh benefits for CVD

Pharmacists can expect questions from patients

Aspirin may have struck out as a tool for primary prevention of cardiovascular events. This year alone, results from three major trials have shown that the risks offset and may outweigh the benefits of taking aspirin every day in an effort to prevent heart attack and stroke: the Aspirin in Reducing Events in the Elderly (ASPREE) trial, A Study of Cardiovascular Events iN Diabetes (ASCEND), and A Study to Assess the Efficacy and Safety of Enteric-Coated Acetylsalicylic Acid in Patients at Moderate Risk of Cardiovascular Disease (ARRIVE).

In the October 18, 2018, New England Journal of Medicine, researchers in the ASPREE trial published three papers about the benefits and risks of daily aspirin use in adults aged 70 years or older, or at least 65 years old if they were black or Hispanic, who did not have cardiovascular disease, dementia, or physical disability. The 19,114 participants were randomized to 100 mg daily of enteric-coated aspirin or placebo, with a mean follow-up of 4.7 years.

In their first paper, the researchers reported on the primary endpoint, disability-free survival, which was measured via a composite endpoint of death, dementia, or persistent (>6 mo) physical disability. There were 21.5 events per 1,000 person-years in the aspirin group compared with 21.2 events per 1,000 person-years in the placebo group, leading the researchers to conclude that aspirin use did not prolong healthy lifespan in their study population.

In their second paper, the researchers looked at the effect of aspirin on the prespecified secondary endpoints of cardiovascular events and bleeding. Over the 4.7 years of follow-up, the rate of cardiovascular events was 10.7 events per 1,000 person-years in the aspirin group compared with 11.3 events per 1,000 person-years in the placebo group. The rate of major hemorrhage was significantly higher in the aspirin group, 8.6 events per 1,000 person-years, compared with 6.2 events per 1,000 person-years in the placebo group.

Death was the most common event contributing to the primary endpoint, so in their third paper, the researchers looked at all-cause mortality in further detail. They found that the risk of death from any cause was 12.7 events per 1,000 person-years in the aspirin group and 11.1 events per 1,000 person-years in the placebo group. They noted that the higher rate of deaths in the aspirin group was attributable mainly to cancer, with cancer-related death occurring in 3.1% of participants in the aspirin group compared with 2.3% in the placebo group.

Michael E. Ernst, PharmD, FCCP, BCGP, BCPS, clinical professor in the department of pharmacy practice and science at the University of Iowa College of Pharmacy in Iowa City and coauthor of the ASPREE papers, said that the trial’s results could be a practice-changer.

“If you are an otherwise healthy person, it doesn’t make any sense to take a preventive medication if it doesn’t help you live longer and remain healthy. I don’t see any reason to recommend initiating aspirin for primary prevention in healthy people age 70 and older,” Ernst said.

“Then when you look at the secondary endpoint of rates of cardiovascular events, the rates were essentially no different between aspirin and placebo. Instead, it raised the risk of bleeding, which is not surprising because that has been shown in other trials,” Ernst added.

Ernst noted that some patients had a history of cancer before enrolling in the trial, and he repeated what he and his colleagues wrote in their conclusion to the paper about all-cause mortality: because the higher death rate with aspirin has not previously been reported, the results should be interpreted with caution.

“Cancer is more common among older people, and [in our results] death from cancer wasn’t really clustered around any particular type,” Ernst said. “It’s not that aspirin causes cancer, but that aspirin may do things differently in people with cancer. That’s something we need to look into more.”

One of the other trials to show an increased risk of bleeding is ASCEND. In the same issue of the New England Journal of Medicine in which Ernst and his colleagues reported their findings, the ASCEND Study Collaborative Group published research comparing 100 mg aspirin daily with placebo in 15,480 adults at least 40 years old who had diabetes and no signs of cardiovascular disease when they entered the study.

They reported that over a mean follow-up of 7.4 years, 8.5% of those in the aspirin group had major adverse cardiovascular events—vascular death, myocardial infarction, or stroke or transient ischemic attack—compared with 9.6% of the placebo group. However, 4.1% of the aspirin group experienced major bleeding, such as intracranial hemorrhage, gastrointestinal (GI) hemorrhage, or sight-threatening eye bleeding, compared with 3.2% of the placebo group, leading the researchers to conclude that although aspirin use prevented serious vascular events in people with diabetes, the benefits were “largely counterbalanced” by the risk of bleeding.

Tiffany Vogeler, PharmD, BCACP, clinical pharmacy specialist in ambulatory care at Community Heart and Vascular Care in Indianapolis, who was not involved in ASCEND, reflected on the increased risk of cardiovascular disease inherent in diabetes and the implications of the trial’s results.

“Some studies have shown a trend toward a benefit  [of aspirin use for people with diabetes], and when you look at cumulative CVD risk, it is expected that with a higher baseline risk there would be a greater benefit with aspirin, but in ASCEND, the benefit was outweighed by bleeding. You’ll have to look at total CVD risk on an individual patient basis in these patients,” Vogeler said.

Both ASPREE and ASCEND align with ARRIVE, which compared the effects of 100 mg enteric-coated aspirin per day with placebo for preventing a first cardiovascular event among men aged 55 and older and women aged 60 and older. In a paper published in the September 22 Lancet, J. Michael Gaziano, MD, FACC, and his colleagues reported that cardiovascular events occurred in 4.3% of the aspirin group compared with 4.5% of the placebo group over a mean follow-up of 5 years. However, GI bleeding, though rare in both groups, occurred at a higher rate in the aspirin group.

Because the three trials made national headlines, you can expect questions from your patients.

“This is a big issue for pharmacists because aspirin is over-the-counter, and they will find themselves being asked whether patients should or shouldn’t start, or should stop, taking aspirin,” said Ernst.

 “The first thing I would say is that these studies are about primary prevention. If you have a patient who already has existing cardiovascular disease or stroke, then these results don’t apply. We know aspirin is beneficial for secondary prevention in those patients,” Ernst said. “But if someone comes in who would have met ASPREE criteria—primary prevention, age 70 or older, taking aspirin—find out whether they decided to do it on their own or under the instruction of a physician. If they take it on their own, you’re in a good position to let them know about the recent evidence.”

Ernst added that if a physician advised the patient to take it, there needs to be a broader conversation.

For the full article, please visit www.pharmacytoday.org for the December 2018 issue of Pharmacy Today.