Imaging vs. no Testing in Asymptomatic High-risk Diabetic Patients

Study Overview
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Brief Summary
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The aim of our study was to evaluate 1- and 3-year outcome of alternative imaging strategies in asymptomatic high-risk diabetic patients: functional stress echocardiography combined with coronary flow reserve (CFR) and strain imaging, or computed tomography (CT) angiography with direct visualization of coronary arteries, and no testing at all.

Detailed Description
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A meta-analysis of >100 prospective studies, showed that diabetes mellitus (DM) in general carries a two-fold excess risk of vascular outcomes (coronary artery disease, ischemic stroke, and vascular deaths), independent of other risk factors (1). Although type 2 diabetes mellitus (DM) is far more common than type 1 DM, these results confirm adverse prognosis in both populations, which is particularly severe in the young in general and young onset female individuals with type 1 DM, emphasizing the need for intensive risk-factor management in these groups. According to new 2019 European Society of Cardiology (ESC) / European Association for the study of diabetes (EASD) guidelines for diabetes, pre-diabetes and cardiovascular diseases (2) individuals with DM and cardiovascular diseases (CVD), or DM with target organ damage, such as proteinuria or renal failure (estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m2), are at very high risk (10-year risk of CVD death >10%). Patients with DM with three or more major risk factors, or with a DM duration of >20 years, are also at very high risk. Type 1 DM at the age of 40 years with early onset (i.e. 1-10 years of age) and particularly female are associated with very high CV risk (2). Most others with DM are high risk, 10 year risk of cardiovascular diseases death (CVD) 5-10%, with the exception of young patients (aged <35 years) with type 1 DM of short duration (<10 years), and patients with type 2 DM aged <50 years with a DM duration of <10 years and without major risk factors, who are at moderate risk. Screening for asymptomatic CAD in patients with DM remains controversial. According to current guidelines only resting ECG is recommended in patients with suspected CVD, whereas computed tomography (CT) angiography or functional imaging (radionuclide myocardial perfusion imaging, magnetic resonance imaging, or physical or pharmacological stress echocardiography) may be considered (class IIb) in asymptomatic patients with DM for screening of coronary artery disease (CAD) (2). With CT, non-invasive estimation of the atherosclerotic burden (based on the coronary artery calcium score) and identification of atherosclerotic plaques causing significant coronary stenosis (CT angiography) can be performed. Patients with DM have a higher prevalence of coronary artery calcification compared with age- and sex-matched subjects without DM (3). While a coronary artery calcium (CAC) score of 0 is associated with favorable prognosis in asymptomatic subjects with DM, each increment in CAC score (from 1 - 99 to 100 - 399 and ≥400) is associated with a 25 - 33% higher relative risk of mortality (3). Importantly, CAC is not always associated with ischemia. Therefore, coronary artery calcium score may be considered as risk modifier in CV assessment in asymptomatic patients with moderate risk (2). Stress testing with myocardial perfusion imaging or stress echocardiography allows the detection of myocardial ischemia, particularly silent form which is more prevalent in patients with DM as demonstrated by observational studies (22%) (4-6). Randomized trials evaluating the impact of routine screening for CAD in asymptomatic DM and no history of CAD have shown no differences in cardiac death and unstable angina at follow-up in those who underwent stress testing, or CT angiography (4,6,7). A meta-analysis of five randomized studies with 3299 asymptomatic subjects with DM showed that non-invasive imaging for CAD did not significantly reduce event rates of non-fatal myocardial infarction (MI) (relative risk 0.65; P=0.062) and hospitalization for heart failure (HF) (relative risk 0.61;P=0.1) (8).Observed low event rates in these studies and the disparities in patient population and the management of screening results (different imaging techniques, invasive coronary angiography and revascularization were not performed systematically) may explain the lack of benefit of the screening strategy. Accordingly, routine screening of CAD in asymptomatic DM is not recommended (2, 8) However, stress testing or CT angiography may be indicated in very high-risk asymptomatic individuals (with peripheral arterial disease (PAD), a high CAC score, proteinuria, or renal failure) (9). The addition of circulating biomarkers for CV risk assessment has limited clinical value (10). In patients with DM without known CVD, measurement of C-reactive protein or fibrinogen (inflammatory markers) provides minor incremental value to current risk assessment. The addition of hs troponin (Tn) T to conventional risk factors has not shown incremental discriminative power in this group (11). In individuals with type 1 DM, elevated high sensitive troponin T (hsTnT) was an independent predictor of renal decline and CV events (12). The prognostic value of N-terminal pro-B-type natriuretic peptide (NT-pro BNP) in an unselected cohort of people with DM (including known CVD) showed that patients with low levels of NT-pro BNP (<125 pg/mL) have an excellent short-term prognosis (13). With emerging role of CT angiography in diagnosis of CAD according to the last 2019 ESC guidelines on Chronic coronary syndrome (14), as well as advanced functional imaging techniques, there is an obvious gap in evidence on prognostic value of both functional and angiographic advanced imaging techniques in patients with diabetes, particularly high risk subgroup. The investigators hypothesized that a strategy using either functional evaluation with advanced stress echocardiography using wall motion abnormalities, coronary flow reserve and strain, or CT angiography visualization will lead to better outcome than no testing at all in asymptomatic high risk diabetic patients.

Official Title
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Functional and Anatomic Imaging Versus No Testing in Asymptomatic High-risk Diabetic Patients

Conditions
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Asymptomatic, High Risk, Diabetes

Intervention / Treatment
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* Diagnostic Test: Echocardiography
* Diagnostic Test: CT angiography


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Asymptomatic patients (>30 years) with duration of diabetes ≥10 years without target organ damage plus any other additional risk factor including age, hypertension, dyslipidemia, smoking, and obesity. Exclusion Criteria: Patient categorized as very high or moderate risk for CV diseases Any symptoms suggestive of angina or heart failure Patients with baseline ECG or echo abnormalities Patients with known CV disease, or previous myocardial revascularization Patients with target organ damage defined as proteinuria, renal impairment defined as eGFR <30 mL/min/1.73 m2, left ventricular hypertrophy, or retinopathy

Ages Eligible for Study
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Minimum Age: 30 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Diagnostic
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: multi-center prospective, randomized, open label, parallel group comparison of 2 diagnostic strategies
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Imaging<br>Echocardiography combined with coronary flow reserve (CFR) and strain imaging, or computed tomography (CT) angiography with direct visualization of coronary arteries. | Diagnostic Test: Echocardiography<br>* Functional assessment of coronary artery disease<br>* Other names: Strain;Diagnostic Test: CT angiography<br>* Anatomical assessment of coronary artery disease<br>|
| No Intervention: Observation<br>No imaging for the estimation of coronary artery disease | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Major adverse cardiovascular events (MACE) | Number of participants with all-cause mortality, non-fatal MI and unstable angina | 1 to 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Individual MACE | Number of participants with all-cause mortality, cardiovascular mortality, non-fatal MI, revascularization (PCI or CABG), acute coronary syndrome, appearance and/or hospitalization for angina, and stroke | 1 to 3 years | 
| Testing-driven invasive angiography and revascularization | Number of participants undergoing invasive coronary angiography (ICA) and revascularization and rate of MACE due to invasive angiogaphy and revascularization | 1 to 3 years | 
| Prognostic role of iFR/FFR imaging in patients referred to angiography | Number of participants with MACE and rate of MACE in patients undergoing instantaneous wave-free ratio (iFR) and fractional flow reserve in (FFR) | 1 to 3 years | 
| Safety and outcome of revascularization in testing arms | Number of participants with MACE and rate of MACE due to revascularization | 1 to 3 years | 
| The role of biomarkers in high risk DM patients on their outcome (MACE) | Value of C-reactive protein (CRP), NT-pro BNP, and hsTnT in all participants | 1 to 3 years | 
| The impact of antidiabetic therapy and sugar control in high risk DM patients on their outcome | Number of participants with MACE and rate of MACE in high risk DM participants regarding antidiabetic therapy | 1 to 3 years | 
| Differences in the outcome between functional and angiographic imaging in imaging arm | Number of participants with MACE and rate of MACE regarding the initial imaging modality | 1 to 3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Imaging, MACE, High risk, Diabetes mellitus