Persistent angina with non-obstructive coronary arteries — case discussion

Presentation

Practice case (not a real patient). A 63-year-old woman has had six months of constricting retrosternal discomfort brought on by walking uphill and by emotional stress, settling with rest within 5 minutes. She has hypertension, dyslipidaemia and type 2 diabetes and is a current smoker; no first-degree relative has had early CAD. Examination, resting ECG and resting echocardiogram (LVEF 62%, no regional wall motion abnormality, no valve disease) are normal; she has no known peripheral artery disease, has had no exercise ECG or previous chest CT, and no ventricular arrhythmia has been documented.^[1]

Step 1 — How likely is obstructive CAD?

Discussion:

• In the initial diagnostic management of individuals with suspected CCS, ESC 2024 recommends estimating the pre-test likelihood of obstructive epicardial CAD with the Risk Factor-weighted Clinical Likelihood (RF-CL) model (Class I, Level B).^[1]
• Her chest pain scores 3 points: 1 for constricting retrosternal discomfort, 1 for aggravation by physical or emotional stress, and 1 for relief by rest within 5 min.^[1]
• She has 4 of the 5 counted risk factors (family history, smoking, dyslipidaemia, hypertension and diabetes); ESC 2024 counts smoking as current or past smoking, and family history as 1 or more first-degree relatives with early signs of CAD (men below 55 and women below 65 years).^[1]
• In ESC 2024 Figure 4, a woman aged 60–69 with a symptom score of 3 and 4–5 risk factors has an RF-CL of 19%: a moderate likelihood (more than 15% to 50%).^[1]
• In individuals with suspected CCS, ESC 2024 recommends using additional clinical data (e.g. examination of peripheral arteries, resting ECG, resting echocardiography, vascular calcification on previous imaging) to adjust the RF-CL estimate (Class I, Level C).^[1]
• ESC 2024 Figure 5 lists the abnormal clinical findings on which the clinical likelihood is adjusted: resting ECG changes (Q-wave or ST-segment/T-wave changes), exercise ECG with abnormal findings, LV dysfunction (severe or segmental), ventricular arrhythmia, peripheral artery disease and coronary calcification on pre-existing chest CT; none is known or documented in this scenario (she has had no exercise ECG or previous chest CT), so there is no adjustment on those grounds.^[1]
• ESC 2024 adds that individual adjustment of the RF-CL values is in some cases needed based on abnormal clinical findings or highly suspicious symptoms, and that beyond the CACS-CL no methods are validated to give accurate adjusted RF-CL values, so adjusted values are based on clinical judgement; in this scenario her clinician does not adjust the estimate.^[1]

Step 2 — First test and its result

Discussion:

• In individuals with suspected CCS, to rule out obstructive CAD at low or moderate (more than 5% to 50%) pre-test likelihood, ESC 2024 recommends CCTA as the preferred diagnostic modality (Class I, Level B).^[1]
• Kidney function and allergy to contrast agents should be assessed before referral, and a slow and regular heart rate and compliance with breath-holding instructions are generally necessary for good image quality.^[1]
• Her CCTA shows mild plaque in the LAD and right coronary artery, with no stenosis of 50% or more.
• ESC 2024 notes that obstructive stenoses have typically been defined by visual thresholds of either 50% or 70% diameter reduction, so by either threshold her CAD is non-obstructive.^[1]
• Besides ruling out obstructive CAD, CCTA visualises non-obstructive CAD directly, which may trigger intensification of preventive measures.^[1]
• Event-prevention drugs are covered in the secondary-prevention topic and are not repeated here.

Step 3 — Symptoms persist

Discussion:

• Scenario: she starts a beta-blocker and a DHP-CCB is added; three months later exertional angina still limits her walking and she rates her quality of life as poor.
• The likelihood models do not include ANOCA/INOCA, which ESC 2024 says always needs to be considered if symptoms persist after diagnostic testing that excludes obstructive CAD.^[1]
• ANOCA/INOCA is more frequent among women (approximately 50% to 70%) than men (30% to 50%) referred for ICA.^[1]
• Smoking, age, diabetes, hypertension and dyslipidaemia are associated with coronary microvascular dysfunction.^[1]
• In persistently symptomatic patients despite medical treatment with suspected ANOCA/INOCA (anginal symptoms with normal coronary arteries or non-obstructive lesions at non-invasive imaging, or intermediate stenoses with normal FFR/iFR at coronary arteriography) and poor quality of life, ESC 2024 recommends invasive coronary functional testing to identify potentially treatable endotypes and to improve symptoms and quality of life, considering patient choices and preferences (Class I, Level B).^[1]
• Transthoracic Doppler of the LAD, stress echocardiography, CMR and PET may be considered for non-invasive assessment of coronary/myocardial flow reserve in persistently symptomatic patients with documented or suspected ANOCA/INOCA (ESC 2024 Class IIb, Level B).^[1]
• Non-invasive tests that measure CFR (stress echocardiography, PET, perfusion CCTA and CMR) have an excellent negative predictive value, but positive predictive value is an issue for most, as obstructive CAD needs to be ruled out before CMD can be diagnosed.^[1]
• She chooses invasive testing.

Step 4 — Invasive coronary functional testing

Discussion:

• When ICA/coronary pressure assessment shows no significant epicardial CAD in suspected ANOCA/INOCA, ESC 2024 describes additional invasive investigations, including IMR, CFR and, if necessary, vasoreactivity testing with acetylcholine (or ergonovine), as part of complete invasive coronary functional testing.^[1]
• Scenario results: no significant epicardial stenosis, LAD FFR 0.88, thermodilution-derived CFR 1.9 and IMR 31; the low-dose acetylcholine response is reported as normal, and the higher dose provokes neither symptoms nor ischaemic ECG changes.
• An FFR of 0.88 is above the 0.8 significance threshold for FFR.^[1]
• A Doppler-derived CFR below 2.5 in non-obstructive CAD indicates an abnormal microcirculatory response, corresponding to a thermodilution-derived CFR below 2.5; ESC 2024 notes that the CMD threshold varies between studies and techniques, at a CFR below 2.0–2.5.^[1]
• An increased IMR (25 or more) indicates microvascular dysfunction.^[1]
• The acetylcholine test is positive for macrovascular spasm if symptoms occur with ischaemic ECG changes and an angiographic lumen reduction of 90% or more; with symptoms and ischaemic ECG changes but a lumen reduction below 90%, microvascular spasm is diagnosed.^[1]
• Of the ESC 2024 endotypes (endothelial dysfunction; impaired vasodilation, meaning low coronary flow reserve and/or high microvascular resistance; epicardial vasospastic angina; microvascular vasospastic angina; endotype combinations; and equivocal response), her results fit impaired vasodilation.^[1]
• Clinically this is microvascular angina: myocardial ischaemia caused by structural or functional changes in the coronary microvasculature (leading to impaired CFR and/or reduced microcirculatory conductance) and/or abnormal vasoconstriction of coronary arterioles.^[1]

Step 5 — Treatment

Discussion:

• In symptomatic patients with ANOCA/INOCA, ESC 2024 says medical therapy based on coronary functional test results should be considered to improve symptoms and quality of life (Class IIa, Level A).^[1]
• In patients with ANOCA/INOCA, for microvascular angina associated with reduced coronary/myocardial blood flow reserve, antianginal medications aiming at preventing demand myocardial ischaemia should be considered for symptom control (ESC 2024 Class IIa, Level B).^[1]
• In patients with MVA and reduced CFR and/or increased IMR (which may reflect arteriolar remodelling), beta-blockers, CCBs, ranolazine and ACE inhibitors are used.^[1]
• A footnote to ESC 2024 Recommendation Table 16 lists ranolazine and trimetazidine for patients with microvascular angina among its considerations for initial therapy.^[1]
• In all patients with established ANOCA/INOCA, because coronary atherosclerosis and endothelial dysfunction are frequently present, ESC 2024 says tailored counselling on lifestyle factors is warranted, including to address risk factors and reduce symptoms.^[1]
• CorMicA, a randomised, controlled, blinded trial, enrolled 391 patients with angina undergoing invasive coronary angiography; coronary angiography revealed obstructive disease in 206 (53.7%), and 151 (39%) patients without angiographically obstructive CAD were randomised 1:1 to stratified medical therapy guided by an interventional diagnostic procedure (guidewire-based CFR, IMR and FFR, then acetylcholine vasoreactivity testing; n = 76) or to standard care with a sham procedure (n = 75).^[11]
• Its primary endpoint, the mean difference in angina severity at 6 months on the Seattle Angina Questionnaire summary score, improved by 11.7 units with the intervention (95% CI 5.0 to 18.4; p = 0.001), with no difference in major adverse cardiac events at 6 months (2.6% in both groups; p = 1.00).^[11]
• AHA/ACC 2023: in symptomatic patients with nonobstructive CAD, a strategy of stratified medical therapy guided by invasive coronary physiologic testing can be useful for improving angina severity and quality of life (COR 2a, LOE B-R).^[2]

Step 6 — What to tell her

Discussion:

• ANOCA/INOCA is associated with poor quality of life, higher risk of disability and a higher incidence of adverse events, including mortality, morbidity, healthcare costs, recurrent hospital readmissions and repeat coronary angiograms.^[1]
• ESC 2024 notes that these conditions are rarely correctly diagnosed, so no tailored therapy is prescribed, and patients continue to have recurrent angina with poor quality of life, repeated hospitalisations, unnecessary repeat coronary angiography and adverse cardiovascular outcomes in the short and long term.^[1]