Introduction

In part one, we explored the use of the coronary artery calcium (CAC) score to risk stratify asymptomatic patients with diabetes. Here, we review the use of cardiac computed tomography angiography (CCTA) in symptomatic patients with diabetes with both stable and acute chest pain, deriving insights from the SCOT-HEART, PROMISE, ISCHEMIA, and ROMICAT-II trials. We build upon a recent review led by select authors of this piece.¹

CCTA in Patients with Diabetes and Stable Chest Pain

CCTA for Diagnosis of CAD: Impact on Outcomes

In SCOT-HEART (Scottish Computed Tomography of the Heart), 4,146 patients with stable chest pain (11% with diabetes) were randomized to standard care alone (including stress testing) or standard care with CCTA.² At 5-year follow-up, use of CCTA was associated with a significant reduction in the composite outcome of death from coronary artery disease (CAD) or nonfatal myocardial infarction (MI) in those with and without diabetes. The absolute risk reduction was over three-fold higher in those with diabetes compared to those without (4.6% vs. 1.3%, respectively). 

As rates of revascularization did not differ between groups, the visualization of plaque and its effect on medical therapy likely drove outcomes, supported by more frequent initiation of preventive therapies and optimized lifestyle habits in the CCTA group (Table 1). CCTA enables detection of non-obstructive plaque which can prompt initiation or intensification of therapies that may have been foregone by the lower sensitivity of non-anatomic alternatives.

Table 1

In an observational analysis of PROMISE (Prospective Multicenter Imaging Study for Evaluation of Chest Pain) examining the diabetes subset (n =1,908) of the trial population, those with diabetes and stable chest pain randomized to CCTA had a significant reduction in cardiovascular death and MI compared to those undergoing stress testing (HR 0.38).³ Although the overall PROMISE trial yielded null findings, the results of this higher-risk subgroup are consistent with those from SCOT-HEART.

From Diagnosis to Management

ISCHEMIA (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches) demonstrated medical management to be non-inferior to revascularization in patients with stable chest pain (42% with diabetes) and moderate to severe ischemia.⁴ CCTA was used to exclude those with significant left main disease (detecting 5% of enrolled) and those with non-obstructive CAD (detecting 14% of enrolled). Beyond its management implications, ISCHEMIA set a new precedent by extending the use of CCTA beyond the low to intermediate risk population.

While referral for CCTA for revascularization may not be warranted in stable coronary disease given medical management is non-inferior, it has utility in ruling out left main disease given the evidence favoring revascularization in this population.⁵ CCTA can identify these patients non-invasively and minimize angiography-related complications.

This point was highlighted in ISCHEMIA-CKD, where those randomized to revascularization experienced a higher rate of stroke and composite outcome of death and initiation of dialysis.⁶ Given the frequent co-prevalence of chronic kidney disease (CKD) and diabetes, minimally invasive diagnostics and optimal medical therapy should be emphasized in this population.

CCTA in Patients with Diabetes and Acute Chest Pain

In the ROMICAT II trial (Rule out Myocardial Ischemia/Infarction by Computer Assisted Tomography), use of CCTA versus standard care in a subset of patients with diabetes (n=173) presenting to the emergency department (ED) with low-risk chest pain (absent ECG changes and negative initial biomarkers) led to higher rates of direct discharge (40% vs. 14%).⁷ Safety endpoints demonstrated no missed acute coronary syndrome (ACS) events nor difference in major adverse cardiovascular events (MACE) at 28 days with use of CCTA compared to standard testing.⁸ CCTA proved more sensitive than standard care in diagnosing CAD (68% vs. 17%). Earlier diagnosis of CAD in the ED with CCTA can increase initiation of preventive therapies,⁹ with potential implications for outcomes as demonstrated in stable chest pain patients.

Future Research

CCTA can detect low-attenuation plaque which has been associated with higher risk for future MI.¹⁰ The PARADIGM trial (Progression of Atherosclerotic Plaque Determined by Computed Tomographic Angiography Imaging) demonstrated a greater prevalence of low-attenuation plaque among those with diabetes.¹¹ In the future, this may motivate intensification of preventive therapies and use of novel agents in these individuals.

In a small cohort of patients with diabetes (n=142) with low-attenuation plaque by CCTA already on intensive statin therapy, addition of a PCSK9 inhibitor led to a significant improvement in plaque attenuation, with a three-fold increase in Hounsfield units.¹² Whether change in plaque attenuation leads to clinically meaningful event reduction requires further investigation yet highlights another application of CCTA in guiding more advanced preventive therapies in diabetes.

Additionally, there is growing interest in using CCTA to assess not only coronary macrovascular disease, but also microvascular disease. Diabetes has both macro- and microvascular complications, and a better understanding of microvascular coronary disease and resulting microvascular angina (MVA) is important because approximately 30-40% of patients referred to angiography for chest pain do not have obstructive CAD, and 50-65% of these patients are diagnosed with MVA.¹³

Patients with MVA typically have more atherosclerotic cardiovascular disease (ASCVD) risk factors, particularly diabetes. Software to diagnose MVA using data from CCTA and CT perfusion is currently being developed.¹⁴ CCTA can go beyond diagnosis of stenosis and attain comprehensive coronary assessment, which includes microvascular disease.¹⁵

Conclusion

In symptomatic patients with diabetes and stable chest pain, compared to stress testing, a diagnostic workup including CCTA improves outcomes through visualization of non-obstructive plaque and subsequent optimization of preventive pharmacotherapies. Medical therapy is non-inferior to revascularization in this patient population; however, CCTA appears as a key non-invasive tool to rule out left main stenosis. CCTA has emerged as a promising modality for the assessment and management of patients with diabetes, and future research will help further define its use in clinical practice.

References

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11. Kim U, Leipsic JA, Sellers SL, et al. Natural history of diabetic coronary atherosclerosis by quantitative measurement of serial coronary computed tomographic angiography: results of the PARADIGM study. JACC Cardiovasc Imaging 2018;11:1461-71.
12. Hirai A, Fujimura K, Hirai K, et al. 457-P: One-year administration of anti-PCSK9 antibody is enough to stabilize vulnerable coronary plaques in diabetic patients, which are resistant to intensive statin therapy. Diabetes 2019;68:(Supplement 1).
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Clinical Topics: Acute Coronary Syndromes, Diabetes and Cardiometabolic Disease, Dyslipidemia, Stable Ischemic Heart Disease, Atherosclerotic Disease (CAD/PAD), Lipid Metabolism, Nonstatins, Novel Agents, Statins, Chronic Angina

Keywords: Dyslipidemias, Coronary Artery Disease, Plaque, Atherosclerotic, PCSK9 protein, human, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Proprotein Convertase 9, Acute Coronary Syndrome, Microvascular Angina, Risk Factors, Patient Discharge, Constriction, Pathologic, Prospective Studies, Numbers Needed To Treat

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