Alongside developments in anatomical, functional and biomarker assessment, the evaluation of stable chest pain has evolved rapidly in recent years. Accurate assessment becomes particularly relevant in higher-risk patient subgroups such as individuals with type 2 diabetes mellitus (T2DM), a population which is growing rapidly in the U.S. and elsewhere.^1,2 The recent International Study of Comparative Health Effectiveness with Medical and Invasive Approaches (ISCHEMIA) trial has updated our understanding about the value not only of invasive versus noninvasive management of stable coronary artery disease (CAD), but also about the comparative utility of different non-invasive testing strategies.³ In this piece, we discuss current trends in stable chest pain evaluation in patients with diabetes, how recent studies may alter clinicians' approach, and implications for future guidelines.

Burden of T2DM and Importance of CAD

The burden of diabetes in the US and globally is immense, with the International Diabetes Foundation estimating 451 million patients with diabetes worldwide in 2017, and over 5 million deaths attributable to diabetes every year.² The global economic burden of T2DM in 2015 was $1.3 trillion, with nearly 35% due to indirect costs.⁴ Atherosclerotic cardiovascular disease (ASCVD) is a key morbidity and main cause of death in patients with diabetes, with recent European Society of Cardiology (ESC) guidelines estimating roughly half of deaths in persons with diabetes being attributed to macrovascular causes.¹ As a result, most clinical practice guidelines recommend aggressive risk factor evaluation and management in patients with diabetes, as well as ASCVD risk estimation to guide tailored risk management on top of moderate intensity statin therapy.^5-7

Further, recent developments in our understanding of the relationship between ASCVD and T2DM are rapidly changing treatment considerations for practitioners. From advancements in medications such as sodium-glucose cotransporter-2 (SGLT-2) inhibitors and glucose-like peptide-1 receptor (GLP-1) agonist to additional data on glycemic control, a restructuring of recommendations in these patient populations has led significant therapeutic developments. Undoubtedly further developments in this area are forthcoming, as guidelines work to adjust to novel treatment paradigms.

New Trial Data in New-Onset Stable Chest Pain Evaluation

Evaluating and intervening upon chest pain has evolved dramatically in recent years, with perhaps the key action point being anatomic versus functional testing. Until recently, functional imaging, such as stress electrocardiogram (ECG), stress echocardiography, or exercise/pharmacologic nuclear imaging, remained in many areas the primary modalities for further evaluation in patients with chest pain of suspected coronary origin.⁸ This was driven in many cases by a lack of availability of alternative, anatomic imaging modalities such as coronary computed tomography angiography (CCTA). Novel work, however, has challenged this paradigm.

In 2015, the Prospective Multicenter Imaging Study for Evaluation of Chest Pain (PROMISE) trial exhibited noninferiority of CCTA to functional imaging in the initial evaluation of stable chest pain.⁹ Although this study was initially interpreted as null, given the often greater financial burden, radiation exposure, and other concerns surrounding functional imaging, in the least it suggested greater flexibility in chest pain evaluation for clinicians was appropriate. Of note, 90% participants in PROMISE had atypical or nonanginal symptoms, which might explain the overall null findings.⁹

Also in 2015,¹⁰ and subsequently in 2018, the Scottish Computed Tomography of the Heart (SCOT-HEART) trial showed a significant improvement in a composite primary endpoint combining death from coronary heart disease or nonfatal myocardial infarction with CCTA-guided management added on top of standard care, which typically included functional testing, compared to standard care alone.¹¹ This improvement was largely believed to be secondary to greater use of ASCVD preventative medications such as statins —rather than revascularizations, which were almost identical in both study arms— in the CCTA treatment arm, suggesting that CCTA can guide medical treatment in a positive manner.

Following these results together with additional economic evaluations, UK's National Institute for Health and Care Excellence (NICE) guidelines recommended in 2016 using CCTA as a first-line test for the evaluation of stable chest pain secondary to suspected ASCVD, particularly to rule out CAD in patients with low to intermediate pre-test risk.¹² In the 2019 ESC guidelines, CCTA and stress testing were both recommended as class I approaches for the assessment of chest pain, with CCTA being favored in low and intermediate pre-test risk scenarios while functional testing was favored in higher pre-test risk patients.¹³

New-Onset Stable Chest Pain Evaluation in Patients with Diabetes

Patients with diabetes are broadly considered at high pre-test risk of CAD. Therefore, does CCTA retain a role in this group? Chest pain assessment in men and women with diabetes is often complicated by atypical or masking characteristics that may otherwise lead clinicians to alternative etiologies than cardiac for the source of the pain. Given frequent diabetic neuropathy, a coronary cause is often suspected in the presence of atypical non-anginal clinical presentations such as shortness of breath, abdominal discomfort, or syncope, all of which may result in a lower pre-test risk than that of patients with more typical anginal symptoms. In this setting, CCTA may be a relevant test to rule-out CAD.

Moreover, going back to SCOT-HEART, in a subgroup analysis in 444 participants with diabetes at baseline, the association between the CCTA strategy and a reduced risk of the primary endpoint was even stronger than in the overall study population: hazard ratio (HR) in the overall study population was 0.59, 95% confidence interval (CI) 0.41–0.84; in participants with diabetes, HR 0.36, 95% CI 0.15–0.87.¹¹ Although there was marked overlap between the CIs, these results confirm that overall SCOT-HEART findings also apply to patients with diabetes.

Secondary analyses of PROMISE found that clinical presentation of patients with T2DM versus those without was not significantly different, with typical chest pain being the most common complaint.¹⁴ Patients with T2DM were more likely to be referred for noninvasive testing than their counterparts in the cohort, more likely to be referred for nuclear stress testing, and more likely to have positive results in non-invasive anatomical (CCTA) and functional tests.¹³ Subsequent analyses showed that in participants with diabetes, CCTA imaging versus functional imaging of stable chest pain led to significantly fewer adverse cardiovascular outcomes (1.1% versus 2.6%, HR 0.38, 95% CI 0.18–0.79), a finding not seen in non-diabetic participants.¹⁵ In both groups, use of pharmacotherapies —e.g., statin use— was higher in the CCTA group as opposed to functional imaging group.¹¹

This sub-analysis of PROMISE had considerable methodological limitations, including an analytic approach closer to that of an observational study. However, combined with prior and subsequent studies, these results further emphasize the value that CCTA may have in the assessment of chest pain also in the diabetic population. It has been argued that optimal medical therapy (OMT; e.g., use of statins) in patients with diabetes should occur regardless of plaque burden demonstrated in a CCTA, and that this would make the test less informative should the benefit occur through OMT. Nevertheless, even in such best case scenario, the anatomical characterization of the presence and burden of CAD has additional benefits, including initiation of additional medical therapies such as aspirin,^10,11,15 which are recommended in international clinical practice guidelines in highest risk patients,⁷ titration of pharmacotherapies to higher doses tailored to the burden of plaque and severity of the stenosis, or enhanced patient motivation to adhere to therapy after visualization of plaque,^15,16 among other advantages.

The ISCHEMIA Trial: Insights Relevant to Functional and Anatomical Testing

The ISCHEMIA study has been one of the landmark trials in cardiovascular medicine in recent months.¹⁷ The investigators evaluated, in patients with stable CAD and moderate-to-severe ischemia on stress testing, whether there would be a benefit to early revascularization added to OMT versus OMT alone. A total of 5179 patients with moderate-to-severe ischemia, determined by a number of stress imaging modalities as selected by the provider, went on to CCTA, were included via inclusion criteria consisting of obstructive disease in major epicardial vessels. Patients with ≥50% left main disease were excluded. Remaining patients were subsequently randomized to revascularization plus OMT versus OMT alone. The authors found that revascularization provided no benefit compared to OMT alone over a median follow-up time of 3.3 years in the primary outcome of myocardial infarction, death from cardiovascular cause, or hospitalization for unstable angina, heart failure or cardiac arrest.³ A significant benefit was found in terms of angina-related health status, particularly among participants with angina at baseline. Nonetheless, lack of blinding and of sham invasive procedures in the control group represent important limitations.¹⁸

Although ISCHEMIA was designed to evaluate management rather than assessment strategies, the results of this landmark trial also have important implications for testing approaches in patients with stable CAD—including patients with CAD-related stable chest pain. On the one hand, the fact that the invasive management approach did not yield benefit in terms of the primary study endpoint calls into question the utility of systematic stress testing, which is typically used to identify optimal candidates for revascularization and guide the procedure. On the other hand, because CCTA was used per the study protocol prior to randomization to rule out left main CAD, ISCHEMIA further reinforces the value that anatomical evaluation of the coronary vasculature can have in the routine management of patients with stable chest pain, adding strength to ongoing recommendations for CCTA as first-line imaging approach and extending such recommendation to moderate-to-high risk patients.

But, how does ISCHEMIA affect decision-making for practitioners in patients with diabetes? Importantly, 41% of ISCHEMIA participants had diabetes. In a pre-specified subgroup analysis by baseline diabetes status, results in patients with diabetes were consistent with those from the main analysis, suggesting that a systematic invasive management and therefore the systematic use of stress testing may have limited value also in this higher-risk subgroup. Nonetheless, longer follow-up is needed to further confirm these findings.¹⁷

Implications for Guidelines

Undoubtedly, recent data on the cardiovascular benefits of treatment options in T2DM and the recent release of ISCHEMIA will have a major impact on upcoming guidelines. NICE guidelines recommended CCTA as first-line imaging in stable ASCVD even before the recent data, while 2020 US guidelines remain pending at this time. It is notable that the 2019 ESC guidelines were released immediately prior to ISCHEMIA, and therefore largely do not yet reflect this data in their analysis. While CCTA and stress imaging were given similarly strong recommendations by the ESC, given recent further evidence particularly ISCHEMIA, it is likely that this recommendation will need to be re-evaluated in the future.

Conclusion

CCTA as a first-line imaging modality in patients with stable chest pain, already prominent following PROMISE and particularly SCOT-HEART, will likely become even more so following ISCHEMIA. Conversely, the role of functional testing may be restricted to specific patient subgroups, such as those excluded from ISCHEMIA, or those in which CCTA may provide limited information. Importantly, pre-specified subgroup analyses in diabetic participants from SCOT-HEART and ISCHEMIA were consistent with those of the overall study, signaling their applicability to this important patient population. Undoubtedly updated guidelines will follow from ISCHEMIA's results, but in the interim, there are immediate implications for the care of the diabetes patient with chest pain.

References

1. Cosentino F, Grant PJ, Aboyans V, et al. 2019 ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD. Eur Heart J 2020;41:255–323.
2. Cho NH, Shaw JE, Karuranga S, et al. IDF diabetes atlas: global estimates of diabetes prevalence for 2017 and projections for 2045. Diabetes Res Clin Pract 2018;138:271–81.
3. Maron DJ, Hochman JS, Reynolds HR, et al. Initial invasive or conservative strategy for stable coronary disease. N Engl J Med 2020;382:1395-1407.
4. Bommer C, Heesemann E, Sagalova V, et al. The global economic burden of diabetes in adults aged 20-79 years: a cost-of-illness study. Lancet Diabetes Endocrinol 2017;5:423–30.
5. American Diabetes Association. 10. Cardiovascular disease and risk management: standards of medical care in diabetes-2020. Diabetes Care 2020;43:S111–S134.
6. Mitchell S, Malanda B, Damasceno A, et al. A roadmap on the prevention of cardiovascular disease among people living with diabetes. Glob Heart 2019;14:215–40.
7. Arnett DK, Blumenthal RS, Albert MA, et al. 2019 ACC/AHA guideline on the primary prevention of cardiovascular disease: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol 2019;74:1376–1414.
8. Siontis GC, Mavridis D, Greenwood JP, et al. Outcomes of non-invasive diagnostic modalities for the detection of coronary artery disease: network meta-analysis of diagnostic randomized controlled trials. BMJ 2018;360:k504.
9. Douglas PS, Hoffmann U, Patel MR, et al. Outcomes of anatomical versus functional testing for coronary artery disease. N Engl J Med 2015;372:1291–1300.
10. SCOT-HEART investigators. CT coronary angiography in patients with suspected angina due to coronary heart disease (SCOT-HEART): an open-label, parallel-group, multicentre trial. Lancet 2015;385:2383–91.
11. SCOT-HEART Investigators, Newby DE, Adamson PD, et al. Coronary CT angiography and 5-year risk of myocardial infarction. N Engl J Med 2018;379:924–33.
12. Moss AJ, Williams MC, Newby DE, Nicol ED. The updated NICE guidelines: cardiac CT as the first-line test for coronary artery disease. Curr Cardiovasc Imaging Rep 2017;10:15.
13. Knuuti J, Wijns W, Saraste A, et al. 2019 ESC Guidelines for the diagnosis and management of chronic coronary syndromes. Eur Heart J 2020;41:407–77.
14. Sharma A, Sekaran NK, Coles A, et al. Impact of diabetes mellitus on the evaluation of stable chest pain patients: insights from the PROMISE (Prospective Multicenter Imaging Study for Evaluation of Chest Pain) trial. J Am Heart Assoc 2017;6:e007019.
15. Sharma A, Coles A, Sekaran NK, et al. Stress testing versus CT angiography in patients with diabetes and suspected coronary artery disease. J Am Coll Cardiol 2019;73:893–902.
16. Orakzai RH, Nasir K, Orakzai SH, et al. Effect of patient visualization of coronary calcium by electron beam computed tomography on changes in beneficial lifestyle behaviors. Am J Cardiol 2008;101:999–1002.
17. Antman EM, Braunwald E. Managing stable ischemic heart disease. N Engl J Med 2020;382:1468-70.
18. Spertus JA, Jones PG, Maron DJ, et al. Health-status outcomes with invasive or conservative care in coronary disease. N Engl J Med 2020;382:1408-19.

Clinical Topics: Diabetes and Cardiometabolic Disease, Dyslipidemia, Invasive Cardiovascular Angiography and Intervention, Noninvasive Imaging, Atherosclerotic Disease (CAD/PAD), Nonstatins, Novel Agents, Statins, Interventions and Coronary Artery Disease, Interventions and Imaging, Angiography, Echocardiography/Ultrasound, Nuclear Imaging

Keywords: Diabetes Mellitus, Echocardiography, Stress, Coronary Artery Disease, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Diabetes Mellitus, Type 2, Coronary Angiography, Cost-Benefit Analysis, Prospective Studies, Cardiovascular Diseases, Cost of Illness, Pain Measurement, Diabetic Neuropathies, Confidence Intervals, Constriction, Pathologic, Follow-Up Studies, Motivation, Random Allocation, Angina Pectoris, Myocardial Infarction, Angina, Unstable, Chest Pain, Control Groups, Cause of Death, Aspirin, Risk Factors, Glucose, Metabolic Syndrome

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