Clinical Challenges: Aspirin’s Role in Subclinical Atherosclerosis

While guidelines have frowned upon aspirin for primary prevention of atherosclerotic cardiovascular disease (ASCVD), questions linger about whether it can still be used in people with early-stage narrowing of the arteries.

Aspirin is well established for secondary prevention patients with cardiovascular disease (CVD), for whom the antiplatelet’s reduction in ischemic events are judged to outweigh the risk of bleeding.

Professional societies like the American Heart Association (AHA) and American College of Cardiology (ACC) warn against extending aspirin use to routine primary prevention, however, for lack of a proven net benefit in this setting.

This was driven by three major studies reported in 2018 — ARRIVE, ASCEND, and ASPREE — that all found aspirin to be modestly helpful in preventing cardiovascular mortality, myocardial infarction, and stroke among people with low-to-moderate cardiovascular risk but at the cost of an increased risk of gastrointestinal bleeding and other hemorrhagic events.

However, people with subclinical atherosclerosis, whose CVD is detectable on imaging but has not translated into a major cardiovascular event, fall somewhere between primary and secondary prevention.

“Subclinical atherosclerosis can be a bit of a gray zone. Many of our practice guidelines will look at patients who have clinically overt atherosclerosis,” said Marc Sabatine, MD, MPH, cardiologist and cardiac ICU specialist at Brigham and Women’s Hospital and Harvard Medical School in Boston. “People with atherosclerosis on imaging only, who haven’t had a heart attack or stroke, that is a group that is less well studied.”

This means there are a lot of people for whom the optimal treatment is unclear.

Among middle-age individuals in the PESA study, ultrasound and CT coronary artery calcification (CAC) analysis found subclinical atherosclerosis — spread among the iliofemoral, carotid, and abdominal aortic territories — to be present in 63% of people.

Separately, in a random sample of the general population in Sweden, there was a 42.1% prevalence of coronary CT angiography-detected atherosclerosis in people who had no history of established coronary heart disease. Although the prevalence of significant stenosis (≥50%) was 5.2% overall — and just 0.4% in people with CAC scores of zero — this figure reached a whopping 45.7% in those with CAC scores exceeding 400, the SCAPIS investigators reported.

Nevertheless, the guidelines would give the thumbs down to routine aspirin for these patients.

Recent draft recommendations from the U.S. Preventive Services Task Force do not recommend aspirin for primary CVD prevention — and this covers people with subclinical CAD, according to general cardiologist Rita Redberg, MD, MS, of UCSF Health.

Yet to be finalized, USPSTF provisionally gives a Grade C recommendation to individualize the decision for adults ages 40-59 years with 10-year ASCVD risk ≥10% who are not at increased bleeding risk and a Grade D recommendation against initiating aspirin for those age 60 and older.

Similarly, the 2019 ACC/AHA guideline on primary prevention gives aspirin a class IIb recommendation only for people ages 40-70 who have high risk of ASCVD but not bleeding. A class III indication of harm is listed for anybody older or at increased risk of bleeding.

People likely to experience major bleeding include those with a history of GI bleeding or peptic ulcer disease, thrombocytopenia, coagulopathy, chronic kidney disease, and users of anticoagulants.

It’s more complicated for older people: While older age does increase bleeding risk, it’s also linked to increased risk of ischemic events.

Aspirin treatment of subclinical atherosclerosis runs into the issue of trying to find subgroups of patients for whom benefits would outweigh the risk, Sabatine said in an interview.

“Antithrombotic therapy gets a bit trickier, because unlike statins … there is a risk for bleeding. It’s a more complicated issue. You have to look at the patient and have a sense for what their risk is for ischemic events versus their risk for bleeding,” he said.

For all the recommendations to individualize aspirin therapy to the patient, balancing aspirin’s benefits and harms remains a challenge for patients without established ASCVD. More answers are needed for clinicians and patients trying to make informed decisions regarding treatment for subclinical atherosclerosis.

For instance, these discussions could be assisted by a validated risk calculator weighing bleeding and ischemic risks, although such a tool is currently lacking in subclinical ASCVD.

For now, the CAC score may help identify those most likely to benefit from aspirin, though it is unclear which CAC threshold would be appropriate when even a score of 1 is associated with increased risk. In contrast, CAC scoring is currently established in decision-making for statin therapy, with CAC scores above 1 favoring statins in people with high LDL cholesterol and intermediate cardiovascular risk.

More research is needed to better understand the benefits and risks of CAC-guided aspirin or another antithrombotic in subclinical atherosclerosis.

A clinical trial is underway to determine whether CAC-guided primary prevention, with aspirin suggested if CAC exceeds 100, might help people with diabetes in Taiwan.