Coronary Artery Calcium for Personalized Risk Management—A Second Chance for Aspirin in Primary Prevention?

“Over the last 2 years, use of low-dose aspirin for the primary prevention of atherosclerotic cardiovascular disease (ASCVD) has become one of the most debated topics in cardiology. Initial trials conducted between the 1980s and early 2000s suggested a significant benefit in a primary prevention population at high risk. However, with expanded use of statins and declining ASCVD rates in Western countries in the last 2 decades, the benefit of prophylactic aspirin became progressively less certain among individuals without established ASCVD. Three trials published in 2018 found no benefit or modest benefit with aspirin and raised concerns about the potential for net harm in populations at increased bleeding risk. Still, given some trial and updated meta-analytic evidence of modest reductions in nonfatal ASCVD events, the 2019 American College of Cardiology (ACC)/American Heart Association (AHA) primary prevention guideline acknowledged that aspirin could have a role in helping candidates who are adequately selected: individuals younger than 70 years at low risk of bleeding and highest risk of ASCVD events (class IIb).

[..] Until further studies become available, the overall consistent observations from the DHS [Dallas Heart Study] and the MESA [Multi-Ethnic Study of Atherosclerosis] have important clinical implications. They confirm that the restricted criteria for aspirin consideration recommended in the ACC/AHA guidelines identify populations with low rates of bleeding. Consequently, such criteria should be strictly implemented and frequently reassessed among individuals who use aspirin to maximize safety. Although it has been proposed that clinical risk scores could aid in the identification of optimal candidates for aspirin therapy, CAC scores seem to be a better tool to inform risk management discussions involving aspirin, leading to a safer allocation in candidates who are appropriate and motivated—particularly in middle-aged populations. The study by Ajufo et al adds to a growing body of literature suggesting that plaque burden, rather than clinical risk estimations, should be the main driver in the allocation of preventive interventions expected to benefit patients only at highest risk and with potential for severe adverse effects—such as aspirin.”

Full editorial, Cainzos-Achirica M and Greenland P. JAMA Cardiology, 2020.10.28

[Article about coronary artery calcium risk score and that triggered the editorial]
“In three 2018 primary prevention randomized clinical trials, aspirin, taken with a background of contemporary primary prevention pharmacologic therapies, conferred no or marginal benefit while carrying significant bleeding risk leading to a net neutral or net harmful risk-benefit profile. Based on these studies, aspirin was downgraded to a weak class IIb recommendation for primary prevention in the 2019 American College of Cardiology/American Heart Association (ACC/AHA) Primary Prevention guideline, compared with a more supportive recommendation in the 2016 US Preventive Task Force guidelines.

[..] we examined the association between CAC [coronary artery calcium], bleeding, and ASCVD using observed bleeding and ASCVD events in the Dallas Heart Study (DHS) cohort, including participants at increased risk of bleeding.

[..] The Dallas Heart Study is a multiethnic probability-based population cohort study comprising 6101 Dallas County, Texas, residents aged 18 to 65 years with deliberate oversampling of African American individuals.

[..] After applying exclusion criteria, 2191 participants were included in the main analysis. Of these, 1063 (49%) had a CAC score of 0, and 161 (7%) had a score of at least 100.

[..] After multivariable adjustment for risk factors, the association between CAC and bleeding was attenuated (CAC ≥100 vs CAC 0; HR, 1.5, 95% CI, 0.8-2.6), but the association between CAC and ASCVD remained significant in all of the CAC categories examined.

[..] Applying effect estimates extrapolated from a 2019 primary prevention aspirin meta-analysis16 to observed 10-year bleeding and ASCVD event rates in the overall cohort, aspirin would increase bleeding more than it would reduce ASCVD events for all CAC groups. This excess harm across CAC categories was consistent in those at low (<5%) and intermediate (5%-20%) 10-year ASCVD risk. However, in those at high estimated 10-year ASCVD risk (>20%), aspirin was anticipated to be net beneficial regardless of CAC value. These findings were consistent even when evaluating individuals with CAC ≥300.

[..] In those at lower bleeding risk, bleeding with aspirin exceeded ASCVD reduction in those with CAC of 0 and 1 to 99, but aspirin was net beneficial in those with CAC of at least 100. When stratifying by estimated 10-year ASCVD risk, those with CAC of at least 100 demonstrated potential net benefit from aspirin in the intermediate 10-year ASCVD risk (5%-20%) group but not in the low 10-year ASCVD risk (<5%) group. Similar to the overall cohort, aspirin was anticipated to be net beneficial regardless of CAC value in those at high 10-year ASCVD risk (≥20%), although no bleeding events were observed in this group. In those at higher bleeding risk, aspirin was net harmful regardless of CAC value in all ASCVD risk groups.

[..] we found that at the extremes of ASCVD risk, CAC had no value for identifying individuals who would benefit from primary prevention aspirin therapy. Notably, aspirin would be net harmful in those at low (<5%) ASCVD risk regardless of CAC. Our results align with those from 3 contemporary randomized controlled primary prevention aspirin trials that showed that aspirin therapy conferred no or marginal net benefit in individuals at low observed ASCVD risk (5-year risk <10%). We also show that aspirin would result in net harm, irrespective of CAC and ASCVD risk, in individuals at higher risk of bleeding. Although the greatest risk of net harm was predicted in individuals at the lowest cardiovascular risk, those at the highest cardiovascular risk were also predicted to suffer net harm. These findings provide empirical support for the 2019 ACC/AHA guidelines on the primary prevention of cardiovascular disease, which recommend against the use of primary prevention aspirin in individuals at increased risk of bleeding. It is important to note that there is some subjectivity on factors associated with increased bleeding, and a “nonexhaustive list” was provided by the 2019 ACC/AHA prevention guidelines that differ somewhat from the 2016 US Preventive Services Task Force list. More work is needed to examine primary prevention aspirin use patterns, clearly define individuals at higher risk of bleeding, and discourage the use of aspirin for primary prevention in these individuals. In the high (≥20%) ASCVD risk group, we estimated aspirin to be beneficial in the overall cohort and net harmful in those at higher bleeding risk, regardless of CAC. However, given the small number of participants and bleeding events in this subgroup, we believe these findings require further validation.”

Value of Coronary Artery Calcium Scanning in Association With the Net Benefit of Aspirin in Primary Prevention of Atherosclerotic Cardiovascular Disease, Ajufo E, Ayers CR, Vigen R et al. JAMA Cardiology 2020.10.28