Judicious use of coronary computed tomography angiography reduces major procedure-related complications in patients aged <65 years with stable chest pain

Coronary computed tomography angiography (CCTA) is a widely used non-invasive modality in the clinical assessment of the degree of coronary stenosis in patients with suspected coronary artery disease (CAD) (1-6). CCTA is a well-established diagnostic tool with high diagnostic performance in excluding obstructive CAD with favourable outcomes achieved when it is used to guide patient management, according to multicentre studies (7-10). Two large randomized controlled trials, the PROMISE, and SCOT-HEART trials confirmed that CCTA is a valuable diagnostic test in patients with suspected chest pain due to CAD and use of CCTA leads to greater clarity, more focused appropriate treatments with significant reductions in fatal and nonfatal myocardial infarctions when compared to standard care or use of functional tests (9,10). While invasive coronary angiography (ICA) remains the preferred method for confirming the extent of coronary stenosis, its invasiveness and cost need careful consideration in clinical settings to determine if its utilization results in enhanced clinical outcomes.

The CONSERVE (Coronary Computed Tomography Angiography for Selective Cardiac Catheterization) trial directly compared CCTA vs. ICA as a direct referral strategy in stable patients with suspected CAD who were referred for non-emergent ICA examinations (11). Of 1,503 patients, 784 were allocated to undergo CCTA as a selective referral strategy (CCTA as the initial diagnostic approach with ICA determined by the local physician according to CCTA findings) and 719 to undergo ICA examinations as a direct referral strategy. The median follow-up was 12.3 months with similar major adverse cardiovascular events (MACEs) observed in both groups (4.6% vs. 4.6%, P=0.99). The selective referral group was associated with a significantly lower rate of follow-up ICA than that of the direct referral group (23% vs. 100%), and a lower rate of percutaneous coronary intervention in the selective referral group than that in the direct referral group (11% vs. 15%, P<0.001). Further, the rate of normal ICA (no obstructive CAD) was 25% in the selective referral group while this was 62% in the direct referral group (P<0.001). The use of CCTA as a selective diagnostic approach resulted in 77% of patients avoiding ICA and diagnostic costs were reduced by 57%. This trial provides evidence to support the clinical value of CCTA in guiding decision-making of ICA performance.

The DISCHARGE (Diagnostic Imaging Strategies for Patients with Stable Chest Pain and Intermediate Risk of Coronary Artery Disease) trial is a recent multicentre study providing further evidence on the effectiveness of CCTA in comparison with the management of patients with stable chest pain (intermediate 10–60% pretest probability of obstructive CAD) (12). This randomized controlled trial involved 3,561 patients from 26 European centres with patients randomly assigned in a 1:1 ratio to undergo CCTA (n=1,808) and ICA (n=1,753) for diagnosis of obstructive CAD and patient management. The trial centres followed the European guidelines to manage patients with stable CAD with decisions regarding treatment made by the local cardiac teams and referring physicians based on the findings of CCTA and ICA. Clinical outcomes included the primary outcome of MACEs and secondary outcomes referring to major procedure-related complications such as nonfatal myocardial infarction, nonfatal stroke, cardiac arrhythmia, complications prolonged hospitalization, aortic or coronary artery dissection, cardiac arrest or cardiac tamponade. The median follow-up was 3.5 years with 98.9% of patients having complete follow-up for the primary outcome. The incidence of the primary outcome of MACE was similar in both groups (2.1% and 3.0% in the CCTA and ICA groups, respectively; P=0.10). However, the CCTA group was associated with significantly lower major procedure-related complications than the ICA group (7 vs. 30 in the CCTA and ICA groups, respectively). The frequency of coronary revascularization procedures was also lower in the CCTA group than in the ICA group (14.2% vs. 18.0%, hazard ratio, 0.76). This trial further confirms the safety of using CCTA as a first-line strategy in diagnosing patients with stable chest pain.

The DISCHARGE trial group did a further analysis of the age’s impact on CCTA and ICA’s clinical outcomes in patients with stable chest pain (13). The rationale for conducting this analysis is due to the limited diagnostic value of CCTA in assessing calcified coronary plaques which are more commonly observed in patients older than 75 years (14,15). Blooming and beam hardening artifacts associated with calcified plaques significantly compromise the diagnostic performance of CCTA resulting in high false positive rates (16-19). According to the American Heart Association/American College of Cardiology guideline, CCTA is recommended as the first-line test in patients younger than 65 years while a functional test is preferred in older patients (20). In the secondary analysis of the DISCHARGE trial, researchers categorized patients into three subgroups, <65 years (n=2,360), 65–75 years (n=982), and >75 years (n=219) as defined in the study protocol (13). Primary and secondary outcomes of MACE were compared between these three groups to determine the association of age with outcomes. Their analysis did not show a significant interaction between age and the randomization group in terms of individual MACE (P=0.15–0.99). When age was analyzed as a categorical variable their analysis revealed that major procedure-related complications were significantly lower in the CCTA group in patients younger than 65 years (0.2% vs. 1.6%, P=0.006). There were no procedure-related myocardial infarction and stroke events (secondary outcomes) in the CCTA group in patients younger than 65 years, while there were 7 events (6 procedure-related myocardial infarction and 1 procedure-related stroke) noticed in the direct-to-ICA group. In patients aged between 65 and 75 years, a possible reduction in major procedure-related complications was noticed in the CCTA group although this did not reach statistical significance (0.8% vs. 2.5%, P=0.13). In contrast, the rate of these complications was similar in the CCTA and ICA groups in patients older than 75 years (2.6% vs. 1.9% vs. P=0.99).

This secondary analysis of the DISCHARGE clinical trial further validates that CCTA is preferred in patients younger than 65 years due to its lower risk of major procedure-related complications, while in patients older than 65 years, the use of ICA as a direct strategy could be justified. Although age did not show a significant impact on the primary outcome of major adverse cardiovascular events (hazard ratio 0.63, 95% CI: 0.35–1.14), the findings of this study have significant clinical value and impact as CCTA is a widely used modality in the current practice to diagnose and exclude obstructive CAD. There is a lack of clear evidence of the relationship between patient’s age and adverse effects associated with the use of CCTA and ICA in the condition of stable chest pain in the current literature. This analysis provides further clarification of justifying the selection of CCTA in younger patient group which could lead to a reduction of unnecessary invasive procedures such as ICA, in addition to the reduction of secondary adverse cardiovascular events. Various approaches including the use of image post-processing algorithms, high-resolution CT, dual-energy CT approach and even some recent reports of using artificial intelligence tools have been attempted to suppress the blooming artifacts associated with calcified coronary plaques with improvements in specificity and positive predictive value (21-25) (Figure 1). Although there have been advancements in diagnostic accuracy for identifying the severity of coronary stenosis caused by extensive calcification, it is important to underscore that CCTA retains only a limited to moderate diagnostic efficacy in evaluating calcified plaques, commonly seen in older individuals. The findings from the DISCHARGE trial analysis offer valuable insights for healthcare providers in selecting between CCTA and ICA based on the patient’s age, ultimately leading to optimal outcomes, particularly in younger patients where referral for ICA procedures may not be necessary.

Figure 1 Multiple calcified plaques at the LAD in a 72-year-old female. Coronary stenoses were measured at 80%, 78%, 72%, and 70% corresponding to the original CCTA, Real-ESRGAN-HR, Real-ESRGAN-Average and Real-ESRGAN-Median images [short arrows in (A)], respectively. ICA [short arrow in (B)] confirms 75% stenosis. The distal stenoses at LAD due to calcified plaques were measured at 70%, 50%, and 51% stenosis on original CCTA, Real-ESRGAN-HR, and Real-ESRGAN-Average images but measured at 45% on Real-ESRGAN-Median images [long arrows in (A)]. ICA confirmed the only 37% stenosis [long arrow in (B)]. Reprinted with permission under open access from Sun and Ng (24). LAD, left anterior descending artery; CCTA, coronary computed tomography angiography; ESRGAN, enhanced super-resolution generative adversarial network; HR, high resolution; ICA, invasive coronary angiography; Real-ESRGAN, real-enhanced super-resolution generative adversarial network.

In summary, this secondary analysis of the DISCHARGE trial presents findings of no impact of patient’s age on the primary outcomes of major adverse cardiovascular events, but with a significant association of age with the rate of major procedure-related complications in different age groups who were randomly assigned to undergo CCTA vs. ICA examinations. In patients younger than 65 years, CCTA is a preferred option as an initial diagnostic strategy, thus physicians should consider using it to manage patients effectively with stable chest pain.

Acknowledgments

Funding: None.

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