Coronary Calcium Scans May ID Patients Who Benefit From Aspirin

Coronary artery calcium (CAC) screening can help identify patients without atherosclerotic cardiovascular disease (ASCVD) who may benefit from aspirin, provided they are at low risk for bleeding and are considered at least intermediate risk for future cardiovascular events, according to a new analysis from the Dallas Heart Study.

Among primary-prevention patients with a low risk for bleeding and a CAC score of 100 or greater, the benefit of aspirin exceeded the potential harms among those with a 5% to 20% risk of ASCVD in the next 10 years, but not in those with a low 10-year risk of ASCVD (< 5%), Ezimamaka Ajufo, BM (University of Texas Southwestern Medical Center, Dallas, TX), and colleagues report online October 28, 2020, in JAMA Cardiology. In patients at higher risk of bleeding, aspirin was considered harmful regardless of CAC scores across the range of ASCVD-risk levels, they add.

Three randomized trials—ASPREE, ASCEND, and ARRIVE—published in the last couple years have thrown cold water on the widespread use of aspirin for primary prevention. In ASPREE, aspirin for primary prevention in elderly adults was associated with an increased risk of bleeding and mortality, while ARRIVE showed that aspirin failed to reduce cardiovascular events in healthy individuals at moderate risk of ASCVD. The ASCEND trial also showed the cost of aspirin was too high in terms of major bleeding in diabetic patients without ASCVD.

As a result, the American College of Cardiology and American Heart Association (ACC/AHA) downgraded aspirin to a weak class IIb recommendation for primary prevention in 2019. Amit Khera, MD (University of Texas Southwestern Medical Center), senior researcher on the current paper and member of the ACC/AHA task force that drafted the guidelines, said aspirin is not recommended for “most people” but that the door is open for use in selected patients.

“If you could identify those at higher cardiovascular disease and lower bleeding risk, then it could be considered, but we didn’t really provide a lot of guidance for how to find that sweet spot, for how to pick out those people in whom there still might be net benefit,” Khera told TCTMD. “That was the purpose here. The reason we chose calcium is that its one of the best tests we have currently for assessing cardiovascular risk.”  

John McEvoy, MD (National University of Ireland, Galway), who led the review of aspirin for 2019 ACC/AHA primary prevention guidelines but wasn’t involved in the present study, agreed that CAC can serve as a possible gatekeeper for identifying primary-prevention patients who would most likely benefit from statin therapy and even aspirin.

“We know that aspirin can reduce nonfatal CVD in primary prevention, but the number-needed-to-treat for this is about 250 patients, so most primary-prevention adults taking aspirin don’t stand to benefit,” he told TCTMD. “Also, the number needed to harm [NNT] is also about 200 to 250 patients, mostly from bleeding. Elevated CAC is one way to identify adults where the NNT is more favorable than the average of 250 and where the benefit ratio for a given primary-prevention adult justifies consideration of aspirin and a discussion with the patient.”

High CAC, Intermediate ASCVD Risk

Using data from the Dallas Heart Study, the researchers identified 2,191 adults without ASCVD (mean age 44.4 years; 57% women), of whom 49% had a CAC score of zero and 7% had a score of 100 or greater. Overall, bleeding and ASCVD events increased in a graded manner with higher CAC scores. Compared to those who had no coronary calcification, those with a CAC score > 100 had higher cumulative incidence of bleeding (HR 2.6; 95% CI 1.15-4.3) and of ASCVD events (HR 5.3; 95% CI 3.6-7.9). After adjusting for clinical risk factors, the association between CAC and bleeding was attenuated and no longer statistically significant, whereas the relationship between CAC and ASCVD remained.

It really helps us, because we’re all trying to see if there is still a place for aspirin. Amit Khera

Based on a 10% reduction in ASCVD events and a 39% increased risk bleeding with aspirin—which was modelled from a meta-analysis of aspirin studies conducted after 2000—the bleeding risk exceeded the reduction in ASCVD in the overall cohort at all CAC scores. Overall, aspirin use was associated with a 0.5% reduction in ASCVD but a 1.2% increase risk of bleeding. The excess harm was consistent in those at low and intermediate risk for ASCVD. In contrast, among patients at high 10-year ASCVD risk (> 20%), the reduction in ASCVD events with aspirin exceeded the bleeding risks across all CAC scores.

In an analysis that focused only on study participants at low bleeding risk, aspirin reduced ASCVD events in participants with a CAC score ≥ 100, resulting in a net clinical benefit. In those with a lower CAC score, however, the risk of bleeding outweighed the reduction in events. When patients at low risk for bleeding were further stratified by their 10-year risk of ASCVD, aspirin only resulted in a net clinical benefit among those with CAC score ≥ 100 if they were at intermediate risk or higher (10-year ASCVD risk > 5%). In the lower-risk patients, aspirin was harmful regardless of CAC score.

“In patients with a higher bleeding risk, such as people who had a prior bleeding event, or who are on certain drugs, like NSAIDs, it’s never favorable to use aspirin,” said Khera. “That confirms what we say in the guidelines. One thing we did figure out is that there is a bit of a sweet spot. In those who are not at high bleeding risk and whose calcium score was above 100, they did seem to get a net benefit from aspirin. Essentially, it really helps us because we’re all trying to see if there is still a place for aspirin.”

CAC as a Gatekeeper for Aspirin

The idea, according to McEvoy, would be to identify patients at moderate-to-high risk for ASCVD based on risk equations and then use CAC to further individualize decision-making around primary-prevention aspirin. “Remember also that risk equations predict CVD risk but they track with bleeding risk, too, mostly due to age, so CAC appears to be a better way of finding those who are at high CVD risk but whose bleeding risk might be sufficiently low to be favorable for aspirin,” he said.

For the moderate-to-high-risk patient with evidence of elevated CAC, aspirin would be worth considering provided their risk of bleeding is low, which is typically not the case in patients 70 years and older. “Those with zero CAC don’t need aspirin,” said McEvoy. He added that he might even consider aspirin in low-risk patients who had a high burden of CAC. These patients wouldn’t typically be sent for CAC scans, but the information might be available for some other reason, such as in cases where a chest CT is done.

In his own practice, Khera said the discussion on primary prevention often starts with statin therapy, and patients may then end up going for a CAC scan to help decide if lipid-lowering treatment is warranted. When the results come back, if CAC is elevated, and the patient is at a low risk for bleeding, the aspirin can also be considered. “Prior to this work, we’d have said there was no place for aspirin for most people,” he said.

In an editorial, Miguel Cainzos-Achirica, MD, PhD (Houston Methodist DeBakey Heart & Vascular Center, TX), and Philip Greenland, MD (Northwestern University Feinberg School of Medicine, Chicago, IL), also agree that the new study adds more evidence suggesting the CAC score might serve as a gatekeeper for aspirin prescribing in primary prevention. For example, two analyses from the Multiethnic Study of Atherosclerosis (MESA) and one from the CAC Consortium have yielded similar results, although there are some discrepancies in the findings. For example, in the MESA analysis, CAC scores “remained informative” even in patients with low ASCVD risk.

However, taking a broader view, the editorialists say that randomized trials are needed to prove the ability of CAC score to “guide a safe, most efficacious allocation of aspirin in primary prevention.” That might prove challenging, they add, given the widespread use of statins and other available medications that have been shown to improve cardiovascular outcomes, particularly in subgroups like people with diabetes.

McEvoy, who previously led a study showing that CAC can serve as a gatekeeper for intensifying antihypertensive treatment, said there is now observational data suggesting CAC is helpful for allocating statins, aspirin, and antihypertensive medication for primary prevention. “The caveat is that none of these studies are randomized controlled trials, though things like risk scores have not been subjected to randomized outcome trials either,” he said.