What are the recommended approaches for provocative testing in patients with suspected Coronary Artery Disease (CAD)?

Provocative Testing for Coronary Artery Disease

Direct Recommendation

For patients with suspected CAD and pre-test probability >5%, coronary CT angiography (CCTA) is the preferred initial test for low-to-moderate risk (>5%-50% pre-test likelihood), while functional imaging (stress echocardiography, SPECT, PET, or stress CMR) is recommended for moderate-to-high risk patients (>15%-85% pre-test likelihood). 1

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Risk-Stratified Testing Algorithm

Pre-test Probability <5%

• No routine diagnostic testing is recommended 1
• Testing should only be performed for compelling clinical reasons beyond typical age, sex, and symptom presentation 1
• Annual risk of cardiovascular death or MI is <1% in this population 1

Pre-test Probability 5-15%

• CCTA or functional imaging may be considered, though false-positive rates are higher 1
• Patient preference, symptom severity, and local expertise should guide decision-making 1
• Exercise ECG or coronary artery calcium scoring can further risk-stratify to determine need for advanced testing 2

Pre-test Probability >5%-50% (Low-to-Moderate Risk)

• CCTA is the preferred diagnostic modality (Class I, Level A recommendation) 1
• CCTA effectively rules out obstructive CAD and provides prognostic information 1, 3
• If CCTA is non-diagnostic or shows CAD of uncertain functional significance, proceed to functional imaging 1

Pre-test Probability >15%-85% (Moderate-to-High Risk)

Functional imaging is recommended as the initial test 1:

• Stress SPECT or preferably PET myocardial perfusion imaging to diagnose and quantify ischemia/scar, estimate MACE risk, and quantify myocardial blood flow 1
• Stress echocardiography to diagnose ischemia and estimate MACE risk; use microbubble contrast agents when ≥2 contiguous segments are not visualized 1
• Stress CMR perfusion imaging to diagnose and quantify ischemia/scar and estimate MACE risk 1
• When performing PET/SPECT, measure coronary artery calcium score from attenuation correction CT to improve detection of non-obstructive and obstructive CAD 1

Pre-test Probability >85% (Very High Risk)

• Invasive coronary angiography (ICA) is recommended, particularly in patients with severe refractory symptoms, angina at low exercise levels, or high event risk 1
• Radial artery access is the preferred approach 1
• Coronary pressure assessment (FFR/iFR) must be available to evaluate intermediate stenoses before revascularization 1

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Test Selection Considerations

When to Choose CCTA

CCTA is preferred when 3:

• Ruling out disease is the primary goal 3
• Patient is younger (<65 years) and not on optimal preventive therapy 3
• Plaque burden assessment is needed for risk stratification and preventive therapy guidance 3
• Another functional test was equivocal or non-diagnostic 1, 3

When to Choose Functional Imaging

Functional imaging is preferred when 3:

• Direct assessment of hemodynamic significance is needed 3
• Quantification of ischemia burden is required for risk stratification (≥10% LV ischemia on SPECT/PET identifies high-risk patients) 1, 3
• CCTA contraindications exist (see below) 1

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Critical Contraindications and Pitfalls

CCTA Should NOT Be Used When 1:

• Extensive coronary calcification is present 1
• Fast irregular heart rate or atrial fibrillation 1
• Severe obesity 1
• Inability to cooperate with breath-hold commands 1
• Severe renal failure (eGFR <30 mL/min/1.73 m²) 1
• Decompensated heart failure 1

Exercise ECG Should NOT Be Used for Diagnosis When 1:

• ≥0.1 mV ST-segment depression on resting ECG 1
• Left bundle branch block 1
• Patient is taking digitalis 1
• CCTA or functional imaging is available in low-to-moderate risk patients 1

Common Pitfall

Testing low pre-test probability patients (<5%) leads to false-positive results and unnecessary invasive procedures 1, 4. A retrospective study demonstrated that low-probability patients had significantly lower likelihood of positive coronary imaging after stress testing (RR=0.061, P=0.001), putting them at risk for unnecessary invasive confirmatory testing 4.

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High-Risk Features Requiring Aggressive Evaluation

The following findings identify patients at high risk of adverse events requiring ICA 1:

• Duke Treadmill Score <−10 1
• Area of ischemia ≥10% of LV myocardium on SPECT/PET 1
• ≥3 of 16 segments with stress-induced hypokinesia/akinesia on stress echo 1
• ≥2 of 16 segments with stress perfusion defects or ≥3 dobutamine-induced dysfunctional segments on stress CMR 1
• Left main disease ≥50% stenosis, three-vessel disease ≥70% stenosis, or two-vessel disease ≥70% stenosis including proximal LAD on CCTA 1

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Sequential Testing Strategy

If initial testing is inconclusive 1, 3:

• If CCTA shows CAD of uncertain functional significance → proceed to functional imaging (Class I recommendation) 1
• If functional imaging is negative but symptoms persist → consider CCTA to detect obstructive CAD and atherosclerotic plaque 3
• FFR-CT can be added to CCTA for stenoses 40-90% to assess functional significance and avoid unnecessary invasive procedures 3
• If non-invasive testing remains uncertain → ICA with invasive functional assessment (FFR/iFR) is recommended 1

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Prognostic Benefits

CCTA demonstrates mortality and morbidity benefits through enhanced preventive therapy, with the SCOT-HEART trial showing long-term reduction in death and nonfatal MI 3. Knowledge of plaque presence motivates lifestyle changes and treatment adherence 3. Nuclear stress testing provides ischemia quantification critical for risk stratification and identifying patients requiring invasive evaluation 3.