MI Risk in Subclinical CAD? Both Extent and Stenosis Severity Matter

New population-based CCTA findings pave the way for grouping asymptomatic patients according to their underlying risk.

MI Risk in Subclinical CAD? Both Extent and Stenosis Severity Matter

For middle-aged, asymptomatic adults, the risk of MI is eight times higher over 3 years in those with subclinical, obstructive coronary atherosclerosis as identified by coronary computed tomography angiography (CCTA) than in those without atherosclerosis, according to new Danish population data.

The results with regard to the identification of clinically silent obstructive and nonobstructive disease are in line with previous estimations in both the SCAPIS and FACTOR-64 studies—in this case, roughly two-thirds of the asymptomatic population had nonobstructive disease and 10% had obstructive disease (≥ 50% luminal stenosis), with most of the affected patients having nonextensive disease (less than one-third of the coronary tree).

But while the new data highlight the advantages of using CT technology to screen an otherwise healthy population, they also raise questions about the relative importance of obstructive versus nonobstructive diffuse subclinical disease.

“In people who are already undergoing CT for other clinical indications, [if] you see these high-risk features of the coronary atherosclerosis, I think it would be fair to say that that should somehow lead to referral to primary prevention clinics that can assist in understanding whether these people would benefit from having statins or at least [lifestyle] counseling,” senior author Klaus Fuglsang Kofoed, MD, PhD, DMSc (Copenhagen University Hospital-Rigshospitalet, Denmark), told TCTMD.

However, the data are not yet enough to support routine CT screening of the general population, he added.

The value of this study, according to Brendan M. Everett, MD (Brigham and Women's Hospital, Boston, MA), who was not involved in the research, is that it shows that the risk of subclinical atherosclerosis is related to “a combination not just of having obstructive lesions, but also [to] the extent of that coronary disease in the tree.” He told TCTMD that “whether or not it is ready to be used as a broadscale population screening [tool] remains to be seen, but what this tells us as cardiologists about the prevalence of this highly morbid and mortal disease is really fascinating and intriguing.”

Biggest Risk With Obstructive Disease

For the study, published online today in the Annals of Internal Medicine, Kofoed, lead author Andreas Fuchs, MD, PhD (Copenhagen University Hospital-Rigshospitalet), and colleagues included 9,533 asymptomatic adults (mean age 60.2 years; 57.1% women) from the Copenhagen General Population Study without known ischemic heart disease. After undergoing CCTA between February 2010 and December 2018, 36% were found to have nonobstructive coronary atherosclerosis while 10% had obstructive disease, including 2% with multivessel disease or left main stenosis. Notably, subclinical atherosclerosis was found more frequently in men (61%) than in women (36%).

Over a median follow-up of 3.5 years, 193 participants died and MI was reported in 71. MI risk over time increased with both obstructive (adjusted RR 9.19; 95% CI 4.49-18.11) and extensive disease (adjusted RR 7.65; 95% CI 3.53-16.57). However, the highest risks were noted in those with both obstructive and extensive (adjusted RR 12.48; 95% CI 5.5-28.12) as well as obstructive and nonextensive coronary atherosclerosis (adjusted RR 8.28; 95% CI 3.75-18.32).

What this tells us as cardiologists about the prevalence of this highly morbid and mortal disease is really fascinating and intriguing. Brendan M. Everett

The composite secondary endpoint of death and MI increased with extensive disease, both nonobstructive (adjusted RR 2.70; 95% CI 1.72-4.25) and obstructive (adjusted RR 3.15; 95% CI 2.05-4.83).

While obstructive disease has been the focus of CVD research for more than half a century, nonobstructive, diffuse disease has more recently been identified as a key driver of morbidity and mortality in patients with subclinical atherosclerosis. As such, Kofoed said, “it was a little surprising” that obstructive disease ended up being associated with the highest risk of MI in this study. “Having said that, it just tells you that [there are] two different schools of thought saying obstructive disease is the only interesting thing [or] nonobstructive is the only is true information you need. Both these schools of thought, I would say, were correct in that [each] contributes to the risk of having a heart attack. . . To some extent, both of these features of the disease are very important,” he explained.

That extensive disease led to a higher risk of events is “not surprising as much as it is illustrative,” according to Everett. “That has probably been suggested by a lot of the data that we have seen from CAC studies where the extent of the calcium score gives you a sense of how high risk somebody is. The higher the calcium score, the higher risk they are. That probably is a proxy really just for the extent of disease and the distribution of the disease throughout the coronary tree,” he said.

It’s notable that CAC tests “haven't gained as much traction” as CCTA for identifying extensive disease, said Everett, suggesting that if primary prevention trials ultimately show a benefit of population-wide screening, CAC might be a better way to stratify patients. “It seems to me that that actually would be an intermediate step where the study requires less radiation, there is not an intravenous contrast dye load that is required,” he continued, adding that he would like to see future study of newer CCTA techniques in conjunction with CAC scanning to see if the predictive power of the two together would be better than standard risk scoring.

Implications for DANE-HEART

According to Kofoed, results from this study will be applied to the recently initiated DANE-HEART trial, which will randomize 6,000 primary prevention patients to treatment guided by CCTA or Danish clinical guidelines then track CV outcomes over 5 years. “The people that are entering the intervention arm will have the same type of CT or even more advanced CT than we did in this study,” he said. Those with low-risk findings will be notified of them, while patients with “intermediate findings, meaning that you have some coronary atherosclerosis, maybe not so extensive and obviously not obstructive,” will receive video counseling with nurses to discuss lifestyle improvements and statin therapy, he said.

Those at high risk—with obstructive or extensive disease—will be seen in person to have a “very thorough examination of exercise capacity, potential ischemia, echocardiography, and all of the usual things that you would do for a patient that has symptoms. They will be followed very closely and to the extent that they have any current guideline indication for revascularization, they will have that,” Kofoed specified.

These three groups, as defined by the current study, will provide standards going forward, he added.

In an accompanying editorial, Michael McDermott, MBChB, and David E. Newby, DM, PhD (both University of Edinburgh, Scotland), appear to agree. “This exceptional and important study now provides a benchmark against which to observe the contemporary natural history of coronary artery disease. It also provides invaluable data about event rates and prevalence of asymptomatic coronary artery disease that will inform public health prevention strategies and ongoing clinical trials of targeting preventative therapies in persons screened for occult coronary artery disease.”

Specifically, they said, it’s notable that obstructive disease seemed to be the most predictive of MI in these asymptomatic patients. “This contrasts with symptomatic populations where nonobstructive disease accounts for most future myocardial infarctions, presumably from plaque rupture,” the editorialists write. “This suggests that in asymptomatic patients, obstructive disease may be more closely linked to myocardial infarction perhaps because the provocation of more severe ischemia is left unchecked in the absence of limiting symptoms. This needs further exploration in future studies.”

Still, plaque burden and characteristics also had important clinical implications and predictive value, McDermott and Newby write.

Different Subpopulations

A major limitation of the study was that the population was primarily white, the authors acknowledge. However, Kofoed said, “mostly healthy people” tend to participate in trials like this. That they were able to identify very clear, high-risk groups “even under these conditions” means that “I would expect that the findings would be even more pronounced in other groups [with different] types of ethnic backgrounds,” he speculated.

Kofoed said another avenue of future research would be to further look at the differences between men and women. “We can see that women have a lower frequency of subclinical coronary atherosclerosis, but it is still one of the big mysteries why women still have quite a high risk of having heart attacks, although we find a lower frequency of subclinical coronary atherosclerosis,” he said.

“We know that risk factors differ across different populations,” Everett added. “They differ by sex, they differ by race, and so understanding how those factors might contribute to the development of cardiovascular disease and at what age and whether or not these approaches of screening that they proposed will be effective it is important, I think, to test that in the broadest group of people possible.”

  • Fuchs A, Kühl JT, Sigvardsen PE, et al. Subclinical coronary atherosclerosis and risk for myocardial infarction in a Danish cohort: a prospective observational cohort study. Ann Intern Med. 2023;Epub ahead of print.

  • McDermott M, Newby DE. Contemporary natural history of coronary artery disease. Ann Intern Med. 2023;Epub ahead of print.

  • The study was funded by AP Møller og hustru Chastine McKinney Møllers Fond.
  • Kofoed reports receiving institutional funding from The Danish Agency for Science, Technology and Innovation by The Danish Council for Strategic Research, Foundation of Sygeforsikringen Danmark – Health Insurances, Novo Nordic Foundation, Canon Medical Corporation, and GE Health Care; serving on the speakers bureau for Canon Medical Corporation; and holding stock in Novo Nordic A/S.
  • Fuchs and Everett report no relevant conflicts of interest.
  • Newby reports receiving grants and funding from the British Heart Foundation.
  • McDermott reports receiving funding from the British Heart Foundation to support research.