Aspirin Falters Yet Again in Primary Prevention: ASPREE

Another large-scale clinical trial tackling the use of aspirin for the primary prevention of cardiovascular events has come up empty, this time in healthy, elderly adults.

Moreover, the study suggested use of aspirin might be harmful, with investigators reporting that 100 mg of daily enteric-coated aspirin was associated with an increased risk of major bleeding and an increased risk of mortality, specifically cancer-related mortality, in the Aspirin in Reducing Events in the Elderly (ASPREE) trial.

The full ASPREE results make up three papers published in the New England Journal of Medicine over the weekend. According to the ASPREE investigators, use of aspirin over a median follow-up of 4.7 years did not reduce the risk of fatal coronary heart disease, nonfatal MI, fatal or nonfatal stroke, or hospitalization for heart failure. When compared with placebo, however, aspirin was associated with a relative 38% increased risk of major hemorrhage and 14% increased risk of all-cause mortality.

Lead ASPREE investigator John McNeil, MD (Monash University, Melbourne, Australia), told TCTMD that at least in the healthy elderly population studied in this trial, “if you don’t need it, aspirin isn’t going to do you any good and it might possibly cause side effects.”

The ASPREE trial comes on the heels two other studies showing aspirin failed to lower the risk of cardiovascular events in different patient populations. In ARRIVE, which included patients at moderate risk for cardiovascular disease, a 100-mg daily dose of aspirin failed to reduce the risk of cardiovascular events and was associated with an increased risk of gastrointestinal bleeding. In ASCEND, which tested aspirin for primary prevention in patients with diabetes, there was a reduction in major vascular events among aspirin-treated patients, but the benefit was offset by a significantly increased risk of major bleeding.

To TCTMD, McNeil said there are a large number of individuals on aspirin, some for valid medical reasons, but many are recommended the antiplatelet agent based on data from older primary prevention studies and data extrapolated from the secondary prevention setting. While use might seem reasonable, data from ASPREE, as well as ARRIVE and ASCEND, clearly refute the benefits in primary prevention.

“If you put these together with our study, which showed no benefit in older people, I think we have, as people say, a beautiful theory slain by cynical facts,” said McNeil.

John Cleland, MD (Imperial College London, England), who has previously criticized the use of aspirin for primary prevention, said the results of ASPREE, which was stopped for futility, didn’t surprise him.

“There has been so much bias in the reporting of aspirin data that when we start to do proper trials, we find that they’re essentially neutral,” Cleland told TCTMD. “There is a widespread belief that anybody who is perceived to be at increased risk, with any sort of family history, or even just those who are getting older and are worried about their health, should be started on aspirin. People thought that it was harmless, and while I don’t think there is evidence of a great deal of harm, there is some harm, and there really is no evidence of benefit.”

Healthy Adults Without Evidence of CVD

The ASPREE trial, which was conducted in Australia and the United States, randomized 19,114 individuals 70 years or older (or older than 65 years if black or Hispanic in the US) without cardiovascular disease, dementia, or disability to treatment with aspirin or placebo. At the time of randomization, one-third of the participants reported use of statins and 14% were taking a nonsteroidal anti-inflammatory drug.

Regarding cardiovascular disease events, there was no difference in risk among those treated with aspirin or placebo (HR 0.95; 95% CI 0.83-1.08). The rate of major hemorrhage (per 1,000 person-years) was 8.6 events in the aspirin group and 6.2 events among those treated with placebo (HR 1.38; 95% CI 1.18-1.62). There was a progressive increase in the cumulative incidence of major hemorrhage over the study period. Overall, use of aspirin was associated with a significant 87% increased risk of upper gastrointestinal bleeding and a 50% increased risk of intracranial bleeding.

Additionally, there 12.7 deaths from any cause per 1,000 person-years in the aspirin arm and 11.1 deaths in the placebo arm, a statistically significant difference (HR 1.14; 95% CI 1.01-1.29). Cancer was the leading contributor to the higher mortality risk in the aspirin arm, with cancer-related mortality occurring in 3.1% of aspirin-treated patients and 2.3% of those treated with placebo (HR 1.31; 95% CI 1.10-1.56).

In analyzing disability-free survival, a unique endpoint that includes mortality, dementia, or persistent physical disability, aspirin was not associated with any benefit compared with placebo.

“The focus of preventive medicine is starting to swing away from how to prevent a heart attack in middle age to how do we keep older people alive, healthy, independent, and out of institutional care, which is a massive drain on the community [resources],” said McNeil, explaining their rationale for the endpoint. “The purpose of prescribing a preventive drug in the elderly really is to extend disability-free life. If it’s not going to do that, what’s the purpose of taking it?” 

Joseph Meyer, MD (Johns Hopkins Hospital, Baltimore, MD), who was not involved in the study, said ASPREE was one of the first trials to truly question the role of aspirin in an elderly population.

“Based on this study, there really isn’t a role for aspirin in primary prevention in elderly patients given that they have a higher risk of bleeding events and despite having a higher inherent risk of atherosclerotic cardiovascular disease,” he told TCTMD. Moreover, when bleeding does occur, these events are more damaging to a 75-year-old patient than a 55-year-old given other age-related morbidities.

Meyer said the observed event rates in all the recent aspirin trials were very low, “which suggests we’re making good progress in preventing cardiovascular disease in the populations we’re studying.” In ASPREE and ARRIVE, the cardiovascular event rates were approximately half what had been expected, and this reflects better efforts at smoking cessation, diabetes and hypertension control, weight management, and so on.

Risk of Cancer, Risk of Hemorrhage

To TCTMD, Cleland highlighted the increased cancer risk with aspirin, noting there was a substantial increase in gastrointestinal and hepatobiliary cancers, which is unexplained. The trend toward an increased risk of cancer was also observed in the ASCEND trial. Given these risks, along with the risk of hemorrhage observed in all of the trials, as well as the increased risk of all-cause mortality in ASPREE, Cleland does not believe aspirin for primary prevention is warranted for any patient, even those at higher risk.

“You’d be insane to say there was a positive story with aspirin,” said Cleland. “We should stop using it for primary prevention.”  

You’d be insane to say there was a positive story with aspirin,” said Cleland. “We should stop using it for primary prevention. John Cleland

Cleland pointed out that another potential harm is the “false sense of security” people might feel when taking aspirin, especially if they’re not willing to do other things that have been proven useful for the prevention of cardiovascular disease. For example, patients might be unwilling to take a statin, he said, a drug class much maligned in the media, because they feel protected with aspirin.

Meyer noted that the first trial testing the prophylactic use of aspirin for primary cardiovascular disease prevention goes back to 1988 in a study of British male doctors. Although it didn’t show a benefit, other trials, including the US Physicians’ Health Study, the Thrombosis Prevention Trial, and the Hypertension Optimal Treatment studies all suggested aspirin reduced the risk of cardiovascular events in primary prevention.  

By the mid-2000s, there were broad indications for aspirin in primary prevention, but a series of inconclusive trials followed, said Meyer. Prior to ASPREE, ARRIVE, and ASCEND, the United States Preventive Services Task Force (USPSTF) had already pared back their recommendations, stating low-dose aspirin for primary prevention should be used in adults ages 50 to 59 with a 10-year risk ≥ 10% (grade B). For elderly patients, aspirin use should be personalized for those ages 60 to 69 with a 10-year risk ≥ 10% (grade C), but the USPSTF said there is insufficient evidence to recommend use in those 70 years and older.

To TCTMD, Meyer said there remains some uncertainty about aspirin in primary prevention given that the per-protocol analysis from the ARRIVE trial—a study which included patients whose 10-year risk of a first acute cardiovascular event fell into the “moderate” range of 10% to 20%—showed aspirin reduced the risk of MI. As reported by TCTMD, the per-protocol analysis conflicts with the intention-to-treat analysis, mainly because compliance was around 60% and there was significant crossover.

“We think there might be an effect there with aspirin, but it’s really not that strong in a broad population in the modern era,” said Meyer. At their hospital, the general practice in light of the recent trials is to recommend aspirin only if primary prevention patients have a 10-year risk of atherosclerotic cardiovascular disease exceeding 20%.