Aspirin’s benefit in primary CVD prevention countered by bleeding risks

Aspirin offers modest protection against cardiovascular events in primary prevention, but that benefit is at least partially offset by an increase in major bleeding events, according to a meta-analysis published Jan. 22 in JAMA.

London-based researchers Sean L. Zheng, BM BCh, MA, and Alistair J. Roddick, BSc, evaluated the rates of cardiovascular events—defined as cardiovascular death, stroke or MI—and major bleeding in 164,225 participants from 13 clinical trials. All included studies enrolled at least 1,000 participants with no known cardiovascular disease at baseline, compared aspirin use to either a placebo treatment or no treatment and had follow-up periods of at least one year. The ASCEND, ASPREE and ARRIVE trials from 2018 were included.

Aspirin use was associated with an 11 percent reduction in the composite cardiovascular outcome, with 57.1 events per 10,000 patient-years in aspirin users and 61.4 events per 10,000 patient-years in nonusers. The number needed to treat to prevent one event was calculated at 265.

On the other hand, major bleeding rates were 43 percent higher among aspirin users, with a number needed to harm (or cause one event) of 210. Nearly seven more major bleeding events per 10,000 patient years were estimated to occur in those taking aspirin (23.1 versus 16.4). Intracranial hemorrhage and major gastrointestinal bleeding were 34 percent and 56 percent more common, respectively, in aspirin users versus nonusers.

“The current study demonstrates that when considering the totality of evidence, cardiovascular benefits associated with aspirin were modest and equally balanced by major bleeding events,” Zheng and Roddick wrote.

The authors said the role of aspirin for secondary prevention following stroke or MI is well-established but guidelines provide conflicting recommendations for the antiplatelet therapy in primary prevention. Varying results regarding aspirin’s ability to prevent cardiovascular events in patients without CVD are at the heart of this uncertainty, along with higher rates of clinically significant bleeding.

Zheng and Roddick’s meta-analysis suggests those concerns are justified, as even participants deemed to have a greater than 10 percent risk of suffering a CVD event within 10 years had offsetting risks and benefits with statin therapy. Aspirin use in these higher-risk people was associated with an absolute risk decrease of 0.51 percent for stroke, MI or cardiovascular death, but also an absolute risk increase of 0.64 percent for major bleeding.

When applying these results to clinical practice, it’s important to remember that not all events are created equal. Zheng and Roddick suggested clinicians use their results to guide patient discussions while weighing the severity of each outcome.

For instance, although their meta-analysis revealed a lower hazard of a composite of cardiovascular outcomes with aspirin, only reductions in MI (15 percent) and ischemic stroke (19 percent) were determined to be statistically significant. Total strokes and cardiovascular deaths weren’t significantly reduced.

“Aspirin use was not associated with a reduction in cardiovascular mortality, and deaths due to bleeding were rare,” the researchers wrote. “Consequently, the decision to use aspirin for primary prevention may need to be made on an individual basis, accounting for the patient’s risk of bleeding and their views on the balance of risk vs benefit.”

J. Michael Gaziano, MD, MPH, who authored an accompanying editorial in JAMA, agreed with that patient-specific approach. He said decisions may ultimately rely on the predicted risk of each patient, but current CVD risk calculators often overestimate the likelihood of events in areas of the world where disease incidence is declining. Also, estimates can change over time as individuals have better or worse control of modifiable risk factors.

“Perhaps new genetic markers and risk estimators derived from artificial intelligence approaches will help refine risk assessment,” wrote Gaziano, with Brigham and Women’s Hospital and Harvard Medical School in Boston. “Because weighing the risks and benefits of aspirin in primary prevention is complicated, it should involve a shared decision-making discussion between the patient and the clinician.”

Gaziano said aspirin, given its low cost and availability, could be more useful as a primary prevention tool in populations where other preventive strategies are less available.

“Aspirin remains an important medication for acute management of vascular events; for use after certain procedures; for secondary prevention; and, after careful selection of the right patients, for primary prevention,” Gaziano wrote.

Zheng and Roddick acknowledged their meta-analysis was subject to the limitations of the included studies. Endpoint definitions, follow-up periods and aspirin doses also differed between the studies, although most trials used daily doses from 75 mg to 100 mg.