Practical Cardiovascular Medicine. Elias B. Hanna

on the resting ECG imply a higher probability of CAD and a higher-risk CAD, even out- side unstable angina.¹³

      Only 50% of women with classic angina have CAD (as opposed to ~90% of men). The WISE registry shows that ~40% of women undergoing coronary angiography for suspected myocardial ischemia have CAD; the remaining patients likely have macrovascular spasm or microvascular dysfunction without obstructive CAD. While fewer women have obstructive CAD than men, women without obstructive CAD who continue to have chest pain have a worrisome ~9% risk of death/MI at 4 years.¹⁴

      C. Pre-test probability of high-risk CAD (multivessel, extensive CAD)

      Hubbard et al. identified five clinical parameters that predict severe (three-vessel or left main) CAD, beside age: male sex, typical angina, diabetes, insulin dependency, prior MI by history or ECG.¹⁵ A 40-year-old patient with four or more of these parameters, or a 60-year-old patient with three or more of these parameters, has a probability of severe CAD of over 40% (e.g., a 60-year-old diabetic man with typical angina). Such symptomatic patients are appropriately referred directly to coronary angiography or CTA without stress testing, as it is highly unlikely that the latter will be normal and, if normal, it may represent a false negative test.¹⁶

      Other clinical features are predictive of severe CAD and may justify direct referral to angiography (class I for severe angina):^13,17,18

       High-probability angina that is severe or frequent (e.g., ≥daily). A severe angina is likely to require revascularization for symptom control regardless of stress test results or extent of CAD, as standalone medical therapy is less effective than PCI for symptom control of class III or IV angina.

       HF that is likely ischemic (HF with angina, flash pulmonary edema, or older age/combination of risk factors).

       Q waves or primary ST-T abnormalities on the baseline ECG, or regional wall motion abnormalities on echo.

      D. Testing modalities (diagnostic and prognostic purposes):

       High pre-test probability:Coronary angiography is directly performed if typical exertional angina is severe and requires revascularization.CTA is preferred if typical angina is not severe. It excludes left main disease and allows conservative CAD management, as per ISCHEMIA trial.¹⁹As an alternative to CTA in typical angina that is not severe, stress testing may be performed, especially in CKD. Here, stress testing is less useful for diagnostic purposes, as the likelihood of CAD remains high even with a negative test. It is, however, useful for risk stratification: a low-risk result allows conservative management.²⁰

       Intermediate pre-test probability: stress testing or CTA is performed for diagnosis and prognosis. CTA is also indicated after a high- or intermediate-risk stress test or a negative stress test yet persistent symptoms. SCOT-Heart trial showed that routine CTA on top of functional testing reduces the 5-year MI risk in patients with chest pain, typical or atypical, compared to functional testing alone, not via more revascularizations but via assessing plaque burden and dictating aggressive risk factor control.²¹

       Low pre-test probability (young patient with atypical angina): stress testing may not need to be performed. Even if the stress test is positive, the probability of CAD increases from <10% up to 20%, i.e., the stress test is likely falsely positive. However, if judged necessary, ECG or echo stress testing may be performed (class IIa). Avoid nuclear stress testing in low-probability patients, as it has a high false-positive rate in this population and a radiation hazard.

Table 3.1 Indications for stress imaging, as opposed to plain treadmill stress ECG.

Treadmill stress imaging (nuclear or echo) >Treadmill stress ECGBaseline ST depression >1 mmaHigh pre-test probability of CADPrior coronary revascularization (stress imaging allows localization of ischemia and has a higher sensitivity in detecting single-vessel ischemia)Prior stress ECG with intermediate result Pharmacological stress imaging (nuclear or echo)Unable to walkAble to walk but baseline ECG has LBBB or ventricular paced rhythm (classically, pharmacological nuclear imaging is performed)b

      ^a LVH without ST depression is appropriately tested with stress ECG.

      ^b Exercise and dobutamine may exaggerate the septal motion abnormality and septal defect present in LBBB, falsely suggesting ischemia, but have shown an appropriate yield when the apical motion or perfusion is analyzed, rather than the septum.²⁵

Table 3.2 Risk stratification with stress testing.

High risk: yearly cardiac mortality >3%, yearly cardiac events >5%DTS ≤–11aReversible, large or severe perfusion defect (summed stress score >+8, corresponding to ischemia involving >10% of the myocardium)Fixed, large or severe perfusion defect with LV dilatation/low EFRest- or stress-induced LV dysfunction with EF ≤35%, even if the defect is mild or moderateOn stress echo: ischemia of ≥3 segments (out of 17), or >one coronary distribution, especially if it occurs at a low rate <120 bpm or a low dose of dobutamine (≤10 mcg/kg/min) Intermediate risk: yearly cardiac mortality 1–3%, cardiac events 1–5%DTS –10 to +4Summed stress score 4–8 Low risk: yearly cardiac mortality and cardiac events <1% (~0.5% with stress imaging)DTS ≥+5 (≥ +8 is very low risk)No perfusion defect or small perfusion defect with a summed stress score <4

      ^a Duke Treadmill Score (DTS) = prognostic score for treadmill stress testing

      = Exercise time on Bruce protocol – 5 × (the deepest ST depression on ECG) – 4 × (angina score) (Angina score: 0 = no angina, 1 = non-limiting angina, 2 = exercise-limiting angina)

      E. Risk stratification with stress testing

Treadmill stress ECG, more specifically the Duke Treadmill Score (DTS), is a powerful risk stratifier. A high-risk DTS implies an increased cardiac mortality and a 75% probability of left main or three-vessel CAD, regardless of imaging results. A low-risk DTS often implies a low mortality; however, ~10% of patients with a low-risk DTS have severe three-vessel or left main disease with a high mortality, and another 10% have two-vessel or proximal LAD disease, and thus, 20% of symptomatic patients with normal stress ECG have significant, high-risk CAD (particularly men).²² These patients are likely to be picked up by stress imaging.^23,24 In fact, a high-risk result on nuclear or echo stress imaging overrules a low- or intermediate-risk result on stress ECG.^23,24 Thus, stress imaging is preferred to stress ECG in patients with a high probability of CAD or with prior coronary revascularization even if ECG is interpretable, while stress ECG is preferred in patients with an intermediate or low CAD probability who are able to walk and have an interpretable baseline ECG (Table 3.1).¹⁸

A high-risk DTS, on the other hand, implies a high risk regardless of imaging results, with a 75% probability of left main or three-vessel CAD and >90% probability of any significant CAD.²² Because of balanced ischemia, some patients with extensive disease have normal or mildly abnormal perfusion imaging but are picked up by ECG variables, DTS, severe angina during testing, and post-stress LV dysfunction. Table 3.2 stratifies the risk according to stress testing.

      In patients who have undergone PCI: (i) chest pain relief followed by recurrence months later is typical of in-stent restenosis, or progression of moderate disease outside the stented area (especially in patients who initially presented with ACS); (ii) a persistent chest pain without a pattern of relief