Aspirin as Primary Prevention Curbs CV Events but Ups Major Bleeding, Too: Meta-analysis

When used as primary prevention, aspirin reduces the risk that patients will experience a cardiovascular event, a new meta-analysis confirms. But that benefit is largely canceled out by an increased risk of major bleeding.

Late in 2018, no fewer than three randomized trials showed lackluster results for prophylactic aspirin in various patient populations: ASPREE in elderly patients, ARRIVE in those at moderate risk for disease, and ASCEND in patients with diabetes.

These results came on the backdrop of existing uncertainty and conflicting advice. European guidelines released in 2016 do not recommend aspirin for primary prevention. That same year the US Preventive Services Task Force tightened its earlier guidelines, which had recommended low-dose aspirin more broadly, to encourage preventive aspirin only in high-risk patients.

Adding the latest studies into the mix with the existing literature “provides a contemporary overview of the evidence supporting the cardiovascular effectiveness and the bleeding risk of aspirin in primary prevention. This is particularly relevant given that many of the previous studies were conducted in the 70s to 90s,” Sean L. Zheng, BM, BCh (King’s College Hospital NHS Foundation Trust, London, England), told TCTMD via email.

In the end, decisions on whether to take aspirin or not require dialogue between patients and their physicians, and an understanding of the risks of aspirin. Sean L. Zheng

Zheng and his coauthor Alistair J. Roddick, BSc (King’s College London), outline their findings in a paper published in the January 22, 2019, issue of JAMA.

ARRIVE investigator J. Michael Gaziano, MD (Brigham and Women’s Hospital, Boston, MA), writing in an accompanying editorial, praises the meta-analysis as well conducted and expresses no surprise at its findings.

“The best estimates for the effects of aspirin on CVD events and bleeding have not materially changed after the results of the 2018 trials,” he says. But, he adds, “these recent trials provide important data for older individuals, patients with diabetes, and patients with multiple risk factors, and may contribute meaningfully to the effect of aspirin use on cancer after longer follow-up.”

Gaziano and the study authors agree that, for now, the best approach is for clinicians to help patients understand their risks and make an informed choice.

‘The Totality of Evidence’

To take a big-picture look at prophylactic aspirin use, Zheng and Roddick combined data from 13 randomized trials, ASCEND, ARRIVE, and ASPREE among them. The data set included 164,225 patients (median age 62 years; 47% men) and over a million participant-years of follow-up. One in five individuals had diabetes, and the 10-year estimated cardiovascular event risk was 9.2%.

Compared with no aspirin, aspirin was linked to a 0.38% absolute risk reduction in the primary cardiovascular outcome (CV mortality, nonfatal MI, and nonfatal stroke), with a number needed to treat of 265. Major bleeding, however, was increased by 0.47% with aspirin use, with a number needed to harm of 210. The same patterns were seen whether patients had diabetes or were at low or high CV risk. Additionally, the researchers found no difference in cancer incidence or in cancer mortality based on aspirin use.

Events per 10,000 Participant-Years

“The current study demonstrates that when considering the totality of evidence, cardiovascular benefits associated with aspirin are modest and equally balanced by major bleeding events,” the researchers say, adding, “This information may inform discussions with patients about aspirin for primary prevention of cardiovascular events and [the risk of] bleeding.”

Exactly how to tailor care, though, is still unclear, Zheng commented. “It is not known from current data which patients would be expected to have the greatest absolute benefit with aspirin. Our study certainly shows that although the absolute cardiovascular benefit of aspirin is greater in higher-risk patients or in those with diabetes, it is these same groups which also have the highest absolute bleeding risks with aspirin.

“Therefore, it is not straightforward to use cardiovascular risk alone to guide these decisions. In the end, decisions on whether to take aspirin or not require dialogue between patients and their physicians, and an understanding of the risks of aspirin,” he advised.

In his editorial, Gaziano points out that weighing aspirin’s benefits versus its risks is a complex endeavor. “A personalized approach toward aspirin use for patients above a certain threshold of CVD risk is predicated on the ability to accurately estimate the risk of future events. CVD risk calculators tend to overestimate risk for populations in which CV risk is declining, such as in the United States and Europe,” he observes. “Further, risk is not static.”

Gaziano also argues for a personalized approach to decision-making that includes open discussion.

“When applying these results to an individual patient, clinicians must consider other interventions in addition to aspirin, such as smoking cessation and control of blood pressure and lipid levels, to lower risk. In places of the world in which CVD risk is rising or where other preventive strategies, such as statins, are less available, aspirin as a low-cost intervention may have a more important role,” he suggests.

Zheng said aspirin as a means of primary prevention appears to be on the decline in the United Kingdom, where he practices. “Nevertheless, there are still many patients who may have been started on aspirin many years ago and who simply continue it, or a group who take aspirin over the counter with the expectation that it is safe and effective,” he added.

Moving forward, the biggest question involves identifying subgroups in whom the benefit outweighs the risk, he said. “It will also be interesting to see if drugs which protect the stomach, for example proton pump inhibitors, can reduce bleeding complications with aspirin and therefore push the balance in favor of aspirin. Such trials are not currently planned.”