Coronary artery calcium imaging (CAC) is a powerful tool for risk stratification of individuals with low-to-intermediate risk of atherosclerotic cardiovascular disease and has recently been integrated to multi-society guidelines as a decision-making aid for primary prevention in asymptomatic patients. The role of CAC in stable, symptomatic patients remains controversial.

To further explore this hot topic, Parham Eshtehardi, MD, asked four experts to share their opinions.

CAC is a low cost, readily available and low radiation test. Do you think there is enough evidence to use CAC as the front-line test and the gatekeeper for coronary CT angiography (CCTA) in low-to-intermediate risk symptomatic patients with de novo chest pain?

Shaw: Yes, you should review the two CRESCENT trials (CRESCENT Trial and CRESCENT-II Trial). They provide strong evidence along with numerous observational registry findings. The most compelling finding was from the PROMISE Trial. This report noted that about 80 percent of major coronary artery disease (CAD) events occurred in symptomatic patients with detectable CAC (CAC score greater than zero). If you want to detect risk, know a patient's CAC score. This evidence supports that in lower risk, symptomatic patients, CAC can be effective at identifying patients at risk for major CAD events.

Chinnaiyan: As mentioned by Shaw, we have some data that CAC is a safe test in the emergency department for low-to-intermediate risk patients with acute chest pain. CRESCENT Trials specifically demonstrated the safety of CAC in a tiered approach, where CCTA was utilized only in low-to-intermediate risk patients with a CAC greater than zero.

This approach was also associated with fewer invasive coronary angiograms without Class I indication for revascularization. One meta-analysis by Kongkiat Chaikriangkrai, MD, et al., also demonstrated the safety of CAC in acute chest pain. These data are encouraging, especially as a gatekeeper for CCTA.

However, more studies using CAC, especially vs. CCTA, would be interesting and useful to accept it as the front-line test.

Nasir: In an era where it is obvious that the majority of advanced imaging tests are normal (including stress studies and CCTA), we have now accumulated extensive evidence that absence of CAC has favorable diagnostic and prognostic profile that can allow us to incorporate it as an efficient gatekeeper.

To summarize the extensive data so far, among low-intermediate risk patients with CAC zero:

• negative predictive value of obstructive disease is 97 – 99 percent;
• excellent short-to-long term favorable prognosis, with one study showing no coronary death in an extended follow-up of 13 years;
• multiple studies in the UK have validated the prior NICE algorithm of doing no further testing with CAC zero;
• negligible risk of ischemia with CAC zero (exclusively mild) and no events in follow-up up to 5 years;
• in CRESCENT Trial, no patients with CAC zero and a low pretest probability of CAD had obstructive disease and events during follow up; and
• negative predictive value of more than 99 percent in ruling out acute coronary syndromes (ACS) among low-risk patients presenting with acute chest pain in multiple studies.

What are your concerns about using CAC for clinical decision-making in this population?

Shaw: You want to be sure that the patient is at lower risk. You may be concerned in higher-risk, symptomatic patients that a burden of noncalcified plaque would exist. For higher-risk patients with a CAC zero, you may be concerned that they have totally noncalcified plaque with significant stenosis. However, in the lower-risk patients, this concern is far less. For example, in an acute chest pain cohort, of those at lower risk with a CAC zero, the likelihood of ACS was less than 1 percent.

Chinnaiyan: The most obvious concern is about missing noncalcified plaques, especially high-risk plaques. In acute chest pain, CCTA's ability to delineate high-risk plaque is superior, which can (and does) influence management. The other concern is missing noncalcified non-obstructive disease that would be amenable to aggressive preventive therapy. While some might argue that prevention is not a concern in the emergency room, it can be an opportunity for implementing these measures.

Nasir: My major concern is the wide spread implicit bias and distinctive standards in general discussions/guidelines/social media for evaluating diagnostic and prognostic value for CAC testing as compared to other established standard of care diagnostic imaging.

Furthermore, it is important to note studies in the literature has suggested a much lower risk of missing out obstructive CAD and possibly a short-term risk of ACS with CAC zero (among low-risk patients) than a normal stress perfusion imaging or stress echocardiography.

For example, in acute chest pain settings, while about 8 – 16 percent of those with obstructive disease can have a normal stress echo or stress myocardial perfusion imaging, we are very reassured in discharging them from emergency department with a normal stress test.

However, with multiple studies including a large meta-analysis showing that a CAC zero is associated with more than 99 percent negative predictive value for ruling out ACS, as well as a prior large study highlighting four-fold lower seven-month MACE in patients with CAC zero vs. normal stress myocardial perfusion imaging, the continuous opposition to acknowledge this is baffling.

I am hopeful that the upcoming chest pain guidelines update will undergo proper due diligence of published data, and if fairly looked upon, I cannot see any reason why CAC testing should not be afforded a level IIA recommendation, especially for consideration in low-risk patients with chest pain.

Do you see a future for using CAC in symptomatic patients and what would be needed to make it happen?

Chinnaiyan: There may be a future for using CAC in symptomatic patients if more evidence comparable to those of CCTA is generated. While contrast and radiation dose has traditionally been a concern for CCTA, the evolution of scanner technology has resulted in a significant reduction of both.

The strength of CCTA lies in its ability to detect calcified and noncalcified obstructive and non-obstructive disease, which have tremendous implications for not just immediate therapy but also long-term preventive measures, clinical outcomes and resource utilization.

While there are extensive data on CAC in asymptomatic individuals with regard to clinical decision-making, clinical outcomes and resource utilization, such data are lacking in symptomatic patients.

Blankstein: I see a role for CAC testing in low-risk symptomatic patients, especially in health care settings that will strive to minimize cost and enhance resource allocation. However, adoption of CAC testing will also require better access and reimbursement for this test.

With respect to future studies, it would be useful to have a prospective randomized trial in low-risk symptomatic patients where CAC will serve as a gatekeeper for further testing. In such a trial, only patients who are found to have CAC greater than zero will require further testing.

Another potential option will be to combine CAC testing with exercise treadmill testing as the combination of the two, when negative, may provide even further reassurance.

Nasir: I definitely see CAC testing being adopted in the management pathway of triaging low-risk symptomatic patients. We are right now at a critical juncture where there is significant emphasis on value-based management, finding ability of doing more with less without lowering our quality of care and jeopardizing outcomes.

With the extensive data, I strongly feel that incorporation of upstream CAC testing in low-risk chest pain patients can reduce associated cost with advanced imaging including stress imaging and/or CCTA, as well as increase their yield considering majority of them are negative otherwise.

I think we now have enough data from observational studies for clinical equipoise as well a real world needs to test in a controlled setting the upstream role of CAC as a gatekeeper at a larger scale than done in CRESCENT Trial.

Furthermore, I implore the leadership of imaging societies, such as the Society of Cardiovascular Computed Tomography, to develop a white paper that can systematically assess existing literature to provide if this is a worthy cause to explore, where the gaps are, if do we have enough data to incorporate CAC testing as a gatekeeper for low-risk patients, and if not, what evidence is needed to achieve that.

I can assure you that if we are able to systematically navigate this issue with much needed consensus, the role of #PowerOfZero will no longer be one of the biggest debates among the imaging community.

Eshtehardi: There is consensus among experts that there is favorable data on using CAC in low-risk, symptomatic patients, mainly stemming from three trials and a meta-analysis. Some believe that these data are sufficient to support using CAC as a clinical decision-making tool in this population while others believe that we need more data.

Nevertheless, all experts agree that we need to address current clinical concerns before introducing CAC as a gatekeeper for advanced imaging in this population. Appropriate risk stratification of symptomatic patients and identification of low-risk patients who would benefit from CAC remains challenging. More importantly, experts are concerned about a relatively small chance of missing significant noncalcified plaques on CAC imaging, preventing further testing and/or preventive medical therapy such as statins.

While CAC imaging has become a very attractive tool because it is cheap, widely available, easy to perform and measure, and has low radiation, experts are hopeful that professional societies consider systemic evaluation of the current evidence and address this issue in their practice guidelines in the near future.