Zero CAC Questionable for Ruling Out Obstructive CAD in Young Adults

A new study is challenging the idea that the absence of coronary artery calcium (CAC) on computed tomography can safely rule out obstructive coronary artery disease in stable patients with chest pain, especially younger adults.   

In a large cohort of patients from the Western Denmark Heart Registry, investigators found that one in seven patients with a CAC score of zero had evidence of obstructive CAD on coronary CT angiography (CCTA) and that this percentage increased in younger patients. For example, 58% of those younger than 40 years old had evidence of obstructive CAD despite having a CAC score of zero.

“We know from clinical experience—we do a lot of these scans in Denmark, where CCTA has been the number one imaging modality for ruling in and ruling out obstructive disease—that we see young patients with obstructive disease despite having no calcium,” said lead investigator Martin Bødtker Mortensen, MD, PhD (Aarhus University Hospital, Denmark).

Several studies have emerged in recent years emphasizing that patients with a CAC score of zero—the so-called power of zero—have a favorable prognosis in terms of future risk of CVD events. It’s also been shown that CAC testing can improve the pretest probability of obstructive disease and one recent study even suggested that a CAC score of zero in chest pain patients could rule out CAD and the need for revascularization in the vast majority of patients.    

To TCTMD, Mortensen said it can take decades for atherosclerotic lesions to progress to calcified plaque, which may lead to younger patients with significant CAD being overlooked. For this reason, if a stable patient with a CAC score of zero continues to have symptoms, physicians should be aware there might be a risk of obstructive disease, he said. In another recent study, Mortensen and colleagues found any amount of coronary calcium in young adults with symptomatic chest pain was associated with a higher risk of coronary heart disease events. That study suggested different CAC thresholds might be necessary when evaluating young adults as opposed to middle-aged patients.    

Ron Blankstein, MD (Brigham and Women’s Hospital, Boston, MA), who wasn’t involved in the current study, said there are numerous advantages for using CAC testing as a potential gatekeeper in stable, low-risk patients. In fact, in the new American Heart Association/American College of Cardiology (AHA/ACC) chest pain guidelines, CAC testing is a recommended option (class 2, level of evidence A) in low-risk patients with stable chest pain. Blankstein, one of the co-authors of the AHA/ACC guidelines, said that CAC scoring can help defer further testing, act as a catalyst for aggressive preventive therapy, or to guide decisions for the best next test (depending on the extent of calcification). 

“While there are advantages to CAC testing as a gatekeeper, such as low cost and that it’s easy to do, like most other tests that we use for evaluating patients with suspected CAD, it is not perfect and we need to use it on the right population,” he said.

Regarding age, Blankstein said that most patients younger than 40 years are going to be at low risk for CAD and likely wouldn’t require any testing. Moreover, the present analysis identified very few young patients with obstructive CAD. “To imply that everybody with symptoms under the age of 40 requires coronary CT angiography is not exactly right because some of these patients don’t need any testing at all,” he said. “I still think that CAC was effective in identifying a large proportion of patients who did not have disease.”

Western Denmark Heart Registry

Speaking with TCTMD, Mortensen stressed that it’s important to distinguish between the diagnostic and prognostic capabilities of CAC. As a prognostic tool, there is a large amount of research showing that CAC is reliable for predicting the future risk of cardiovascular events in symptomatic and asymptomatic patients with stable CAD. As a diagnostic tool used in the workup of patients with symptoms suggestive of CAD, however, there is less clinical support. 

The study, published October 27, 2021, in JAMA Cardiology, included 23,759 stable patients (55% women; median age 58 years) with symptoms suggestive of CAD who underwent CCTA between 2008 and 2017. Of these, 54% had a CAC score of zero. Overall, the rate of obstructive CAD was low among symptomatic patients with no evidence of coronary calcification, with just 6% having a luminal stenosis ≥ 50%. In fact, the prevalence of obstructive CAD was low across all age groups in those with a CAC of zero, from as low as 3% in those younger than 40 years to 8% in those aged 70 years and older.

In total, 14% of patients with obstructive CAD had a CAC score of zero, but this rate was significantly higher in younger adults. Among those 40 years and younger, 58% of patients with obstructive CAD had a CAC score of zero compared with 34% of those aged 40 to 49 years, 18% of those aged 50 to 59 years, 9% of those aged 60 to 69 years, and 5% of those 70 years and older. Similar trends were observed in men and women, although women with obstructive CAD were more likely than men to have a CAC score of zero.

After 4.3 years of follow-up, 31% of all-cause deaths or new MIs occurred in individuals with a CAC score of zero. In multivariate analysis of all patients with a CAC score of zero, the presence of obstructive CAD was associated with a trend toward a higher risk of MI/all-cause mortality when compared with those with no CAD/nonobstructive CAD. In those younger than 60 years with a CAC score of zero, the presence of obstructive CAD was associated with a significant 80% higher risk of clinical events compared with those without CAD or nonobstructive CAD.

Among those with a CAC score of zero, the annualized risk of MI/all-cause mortality was very low at less than 1% regardless of whether patients had obstructive disease or not. Mortensen said this finding suggests that CAC may still a good prognostic marker in patients who have stable chest pain, even if they have obstructive CAD. Blankstein added that while physicians don’t want to miss patients with obstructive disease, the study shows that the presence of obstructive disease did not help inform risk prediction in the overall population, a finding attributable to their low overall risk of events.

“There is no question that if you perform coronary CT angiography, you’ll find more disease because of the small proportion of patients that will have disease that is exclusively noncalcified,” said Blankstein. “There’s no debate here. CCTA does identify more disease. In fact, if CCTA could be done as cheap as a calcium score and without resulting in unnecessary downstream testing, then we should just do a CT angiogram in everyone. The reality is that those assumptions don’t hold.”

In healthcare systems where cost is an issue, or there are limitations with CCTA availability, calcium scoring in “the right patient” still provides useful information about the risk of obstructive CAD, said Blankstein. The use of CAC testing as a potential gatekeeper is most useful in patients with a low risk of CAD, he added, noting that the Western Denmark Heart Registry included an “all-comers” patient population with stable chest pain.

For that reason, the new study does not imply that one test—CAC versus CCTA—is better than the other, said Blankstein.

In an editorial accompanying the study, Sadiya Khan, MD (Northwestern University Feinberg School of Medicine, Chicago, IL), Ann Marie Navar, MD, PhD (UT Southwestern Medical Center, Dallas), note that CAC testing is recommended in select patients aged 40 to 75 years with a borderline- or intermediate-risk of atherosclerotic cardiovascular disease and can help guide preventive strategies. The new study is a reminder to doctors that the absence of CAC is not the absence of atherosclerosis, particularly in younger adults and women, and that physicians should not solely rely on it to guide treatment decisions.

“Coronary artery calcium scoring is an excellent tool for identifying adults at a high risk for CVD, but caution should be exercised when translating the absence of CAC into delaying primary preventive interventions in younger adults and women,” they write. “The goal of primary prevention should be to prevent the atherosclerotic lesions that lead to CAC, not to wait for CAC to develop before initiating risk-lowering therapy.”