Chronic coronary syndromes: pre-test likelihood, the CCTA pathway and treatment

Overview and definitions

The 2019 ESC guidelines introduced the term chronic coronary syndromes (CCS) to describe the clinical presentations of coronary artery disease (CAD) during stable periods, particularly those preceding or following an acute coronary syndrome (ACS).^[1] In that framework, CAD was defined as the pathological process characterised by atherosclerotic plaque accumulation in the epicardial arteries, whether obstructive or non-obstructive.^[1]

• The 2023 AHA/ACC multisociety guideline uses the term chronic coronary disease (CCD) and gives a patient-centred approach to its management, incorporating shared decision-making, social determinants of health and team-based care.^[2]
• Its recommendations pertain to the chronic outpatient care of patients with CCD; clinicians are referred to the relevant guidelines when evaluating patients with acute chest pain, ACS, or both.^[2]
• For people with stable chest pain and no known CAD, the AHA/ACC pathway sits in the 2021 AHA/ACC chest pain guideline, which describes stable chest pain as a symptom of myocardial ischaemia characterised by chest pain provoked with stress (physical or emotional).^[3]

Classification: clinical presentations of CCS

ESC 2024 lists the following, not entirely exclusive, CCS patients who seek outpatient medical attention.^[1]

1. The symptomatic patient with reproducible stress-induced angina or ischaemia with epicardial obstructive CAD.^[1]
2. The patient with angina or ischaemia caused by epicardial vasomotor abnormalities or functional/structural microvascular alterations in the absence of epicardial obstructive CAD (ANOCA/INOCA).^[1]
3. The non-acute patient post-ACS or after a revascularisation.^[1]
4. The non-acute patient with heart failure (HF) of ischaemic or cardiometabolic origin.^[1]
5. A further growing category: asymptomatic individuals in whom epicardial CAD is detected during an imaging test for refining cardiovascular risk assessment, screening for personal or professional purposes, or as an incidental finding for another indication.^[1]

Patients may experience a variable and unpredictable course, transitioning between different types of CCS and ACS presentations throughout their lifetime.^[1] Symptoms of dysfunctional microvascular angina (MVA) may overlap with those of vasospastic or even obstructive large–medium artery angina.^[1]

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Epidemiology and risk factors

ESC 2024 attributes a decline in the age-standardised prevalence of obstructive epicardial coronary atherosclerosis in patients with suspected CCS to contemporary primary prevention, including lifestyle changes and guideline-directed medical therapy (GDMT).^[1] As a consequence, the diagnostic and prognostic risk prediction models applied in the past to identify obstructive epicardial CAD in patients with suspected angina pectoris have required updating and refinement.^[1]

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ANOCA/INOCA is more frequent among women (approximately 50% to 70%) than men (30% to 50%) referred for ICA (ESC 2024).^[1] ESC 2024 names diabetes, chronic obstructive pulmonary disease, kidney disease, and peripheral and cerebral vascular disease as particularly relevant comorbidities because of their high prevalence in CCS patients.^[1] The RF-CL model counts five risk factors for CAD: family history, smoking, dyslipidaemia, hypertension and diabetes.^[1]

Smoking, age, diabetes, hypertension and dyslipidaemia are associated with coronary microvascular dysfunction (CMD) (ESC 2024).^[1]

Pathophysiology

ESC 2024 says understanding of the pathophysiology of CCS is transitioning from a simple to a more complex and dynamic model.^[1] Current concepts have broadened to embrace structural and functional abnormalities in both the macro- and microvascular compartments of the coronary tree that may lead to transient myocardial ischaemia.^[1]

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• The risk factors that predispose to epicardial coronary atherosclerosis also promote endothelial dysfunction and abnormal vasomotion in the entire coronary tree, including the arterioles that regulate coronary flow and resistance, and adversely affect myocardial capillaries, leading to their rarefaction.^[1]

• ESC 2024 lists potential consequences as a lack of flow-mediated vasodilation in the epicardial conductive arteries and macro- and microcirculatory vasoconstriction, and notes that different mechanisms of ischaemia may act concomitantly.^[1]

• Why stenosis percentage alone misleads: obstructive stenoses have typically been defined by visual thresholds of either 50% or 70% diameter reduction, but not all anatomical stenoses above such thresholds, especially those of moderate (50%–69%) severity, are haemodynamically or functionally significant or induce myocardial ischaemia.^[1]

• Haemodynamic relevance, defined as fractional flow reserve (FFR) of 0.80 or less or instantaneous wave-free ratio (iFR) of 0.89 or less, correlates poorly with diameter stenosis by visual assessment.^[1]

• In the PRIME-FFR and FAME studies, 31% of the 40%–49% stenoses were haemodynamically significant, only 35% of the 50%–70% stenoses were haemodynamically relevant, and 20% of the 71%–90% stenoses were not; only an estimated diameter stenosis of more than 90% predicted haemodynamic relevance with high accuracy (96% correct classification).^[1]

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Clinical presentation

• Careful and detailed history taking is the initial step in diagnostic management for all clinical scenarios within the spectrum of CCS (ESC 2024).^[1]
• Chest pain or discomfort is the most cardinal symptom of CCS, but many patients do not present with characteristic anginal symptoms, and symptomatology may vary with age, sex, race, socioeconomic class and geographical location.^[1]
• In individuals reporting symptoms of suspected myocardial ischaemic origin, ESC 2024 recommends a detailed assessment of cardiovascular risk factors, medical history and symptom characteristics, including onset, duration, type, location, triggers, relieving factors and time of day (Class I, Level C).^[1]

Describing the symptom: from typicality to a symptom score

• Anginal pain has traditionally been classified as typical, atypical, or non-anginal/non-cardiac on the basis of location and of precipitating and relieving factors (ESC 2024).^[1]
• Angina that meets all three characteristics — retrosternal chest discomfort provoked by exertion or emotional stress and relieved by rest or nitroglycerine — is highly suggestive of ischaemia caused by obstructive CAD, but these characteristics are rarely all present when ischaemia is caused by microvascular dysfunction and vasospasm.^[1]
• Patients with typical vs. atypical angina in the PRECISE study had similar 1-year outcomes, which ESC 2024 uses to highlight the limited prognostic value of classifying symptoms by typicality in obstructive CAD prediction models.^[1]
• ESC 2024 therefore says this terminology no longer aligns with current concepts of CCS and should be replaced by a detailed description of symptoms.^[1]
• AHA/ACC 2021 separately recommends that chest pain should not be described as atypical, because it is not helpful in determining the cause and can be misinterpreted as benign; it should be described as cardiac, possibly cardiac or noncardiac (COR 1, LOE C-LD).^[3]

Symptom score (0–3 points): the main symptom is either chest pain (0–3 points) or dyspnoea (2 points)

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• The ESC 2024 Figure 4 legend explains that the symptom score replaces the previous, potentially misleading terminology: three chest pain characteristics (once called typical angina) score 3 points, two of three (once called atypical angina) score 2 points, and none or one (once called non-cardiac/non-anginal) score 0–1 point.^[1]

Angina equivalents, sex and age

• ESC 2024 says symptoms such as chest pain triggered by emotional stress; dyspnoea or dizziness on exertion; pain in the arms, jaw, neck or upper back; or fatigue should be considered as potential angina equivalents (Class IIa, Level B).^[1]
• Recent data show anginal chest pain to be equally prevalent in men and women, albeit with slightly different characteristics.^[1]
• Sex-stratified analyses indicate that women with suspected angina are usually older and have a heavier cardiovascular risk factor burden, more frequent comorbidities, non-anginal symptoms such as dyspnoea and fatigue, and greater prevalence of MVA than men.^[1]
• The absence of anginal symptoms does not preclude CCS: angina may be absent in patients with diabetes with autonomic neuropathy or in elderly patients with a very sedentary lifestyle despite very severe obstructive CAD.^[1]

Grading effort angina

ESC 2024 notes that the Canadian Cardiovascular Society (CCS) classification is still widely used to grade effort-induced angina, quantifying the threshold at which symptoms occur with physical activities.^[1]

ESC 2024 Table 5: grading of effort angina severity according to the Canadian Cardiovascular Society

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• Severity of symptoms is not well associated with the severity of obstructive CAD and appears to differ by sex: women have more frequent angina, independent of less extensive epicardial CAD, and less severe myocardial ischaemia than men.^[1]
• Angina at rest is not always indicative of severe, fixed obstructive CAD, because it may also occur with transient epicardial or microvascular coronary vasospasm.^[1]

Management — urgent: when the presentation is not stable

Differential diagnosis

Chest pain is not always angina (that is, of ischaemic origin): it can be related to non-coronary conditions such as pericarditis, or to non-cardiovascular conditions (ESC 2024).^[1] ESC 2024 asks for thorough evaluation, including objective exclusion of myocardial ischaemia caused by obstructive CAD, microvascular disease and/or coronary vasospasm, before chest pain is classified as non-cardiac.^[1]

Differentials named in the held sources

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Clinical and bedside assessment

• ESC 2024 asks for a thorough physical examination that includes BP measurement and body mass index (BMI) calculation, and an assessment for anaemia, hypertension, valvular heart disease, left ventricular (LV) hypertrophy or arrhythmias.^[1]
• It also recommends searching for evidence of non-coronary vascular disease, which may be asymptomatic (palpation of peripheral pulses; auscultation of carotid and femoral arteries), and for signs of other comorbid conditions such as thyroid disease, renal disease or diabetes.^[1]
• Findings such as cough or stinging pain make CCS less likely; try to reproduce the symptoms by palpation and test the effect of sublingual nitroglycerine to classify them.^[1]
• Document coronary risk factors during history taking: they may be modifiable and are used for the pre-test likelihood estimation of obstructive CAD.^[1]

Investigations

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Step 1: ECG, bloods and other basic tests

• Basic testing in suspected CCS includes a 12-lead ECG, standard laboratory tests, resting echocardiography and, in selected patients, a chest X-ray and a pulmonary function test if dyspnoea is the main symptom; these tests can be done on an outpatient basis (ESC 2024).^[1]
• A normal resting ECG is frequently recorded after an anginal attack, but even without repolarisation abnormalities the resting ECG may suggest CCS indirectly through signs of previous MI (pathological Q or R waves) or conduction abnormalities (mainly left bundle branch block and impaired atrioventricular conduction).^[1]

Step 1 tests (selected rows)

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Step 2: resting echocardiography

• ESC 2024 recommends a resting transthoracic echocardiogram to measure LVEF, volumes and diastolic function; identify regional wall motion abnormalities; identify non-coronary cardiac disease (e.g. hypertrophy, cardiomyopathy, valve disease, pericardial effusion); and assess right ventricular function and estimate systolic pulmonary artery pressure — to refine risk stratification and guide treatment (Class I, Level B).^[1]
• In the initial diagnostic management of individuals with suspected CCS, CMR, if available, may be considered as an alternative imaging test in individuals with inconclusive echocardiographic evaluation (ESC 2024 Class IIb, Level C).^[1]
• The strongest predictor of long-term survival is systolic LV function, so its assessment is useful for risk stratification in all symptomatic individuals with suspected CCS; mortality increases as LVEF declines.^[1]

Step 2: estimating the clinical likelihood of obstructive CAD

• The diagnosis of CCS rests on interpreting the individual’s symptoms, balancing the impact of age, sex, risk factors and comorbidities on the likelihood that CCS is present, and choosing the most appropriate diagnostic test to confirm the clinically suspected diagnosis (ESC 2024).^[1]
• The tables used to estimate the likelihood of obstructive CAD as confirmed by ICA were initially based on the Diamond–Forrester approach (sex, age and angina symptoms) and have had to be updated several times because the prevalence of obstructive CAD at invasive angiography has declined in contemporary Western cohorts.^[1]
• The RF-CL model includes sex, age, angina symptoms and number of risk factors, without losing diagnostic accuracy compared with more advanced models requiring computed calculation.^[1]
• It increases three-fold the number of people categorised at very low (5% or less) likelihood compared with the ESC pre-test probability model (38% vs. 12%), while predicting annualised MI and death rates of 0.5%, 1.1% and 2.1% for very low, low and moderate likelihood, respectively.^[1]

RF-CL, women: clinical likelihood (%) of obstructive CAD for 0–1, 2–3 and 4–5 risk factors (ESC 2024 Figure 4)

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RF-CL, men: clinical likelihood (%) of obstructive CAD for 0–1, 2–3 and 4–5 risk factors (ESC 2024 Figure 4)

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• In each cell the three values are for 0–1, 2–3 and 4–5 risk factors, in that order. Risk factors are family history of CAD (one or more first-degree relatives with early signs of CAD: men younger than 55 and women younger than 65 years), smoking (current or past), and dyslipidaemia, hypertension and diabetes present at the time of diagnosis.^[1]

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Likelihood categories and what ESC 2024 does with them

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Adjusting and reclassifying the estimate

Recommendations for estimating, adjusting and reclassifying the likelihood of obstructive atherosclerotic CAD in suspected CCS

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• The ESC 2024 Figure 5 adjustment step (Class I) lists abnormal clinical findings to adjust for: 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.^[1]

• Individual adjustment may also be needed for severe single risk factors or comorbidities associated with more obstructive CAD that the RF-CL model does not reflect, e.g. familial hypercholesterolaemia, severe kidney dysfunction, rheumatic/inflammatory diseases and peripheral artery disease (PAD).^[1]

• ESC 2024 says individual adjustment of the clinical likelihood should always be considered based on the clinical CCS scenario including ECG and echocardiography findings; the 2025 correction added the cross-reference to Figure 5, section 2.^[1][13]

• Beyond the CACS-weighted clinical likelihood (CACS-CL), no methods are validated to give accurate adjusted values to the RF-CL, so adjusted values rest on clinical judgement.^[1]

• Coronary artery calcium (CAC) is measured as the CACS from an ECG-gated non-contrast-enhanced CT scan; alternatively, its presence can be assessed qualitatively on a previous non-cardiac chest CT, if available.^[1]

• The absence of CAC (CACS = 0) has a very high negative predictive value (more than 95%) for obstructive CAD.^[1]

• Caveat: in younger patients obstructive CAD is rare, but when present a higher percentage have a CACS of 0 (58% of those younger than 40 years) than older patients with obstructive CAD (9% among those aged 60 to 69 years).^[1]

• With the CACS-CL model, substantially more individuals (54%) than with the RF-CL model (38%) were categorised as having a very low clinical likelihood of obstructive CAD in the external validation cohorts, and the CACS-CL model was superior to other clinical prediction models in predicting MI and death during follow-up.^[1]

• Conversely, if CACS is high and clinical findings indicate that the RF-CL model may be underestimating the likelihood, further testing should be selected on the adjusted clinical likelihood and coronary calcium burden.^[1]

Step 3: choosing the first diagnostic test

Recommendations for selection of initial diagnostic tests in individuals with suspected CCS

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• Why CCTA for the low–moderate group: given the low prevalence of CAD in this group and its high negative predictive value, ESC 2024 calls CCTA the most effective diagnostic method to rule out obstructive CAD.^[1]
• CCTA also visualises non-obstructive CAD directly, which may trigger intensification of preventive measures, and its first-line use is supported by large randomised trials showing equivalence in health outcomes with functional testing and even superiority compared with usual care using exercise ECG.^[1]
• Why functional imaging for the moderate–high group: tests for detecting ischaemia have better rule-in power than CCTA, so ESC 2024 says they should be selected if there is a moderate–high (more than 15% to 85%) likelihood of obstructive CAD.^[1]
• Functional imaging also overcomes the limitations of CCTA in certain groups (older patients with more extensive coronary calcification, AF and other irregular or fast heart rates, renal insufficiency, or iodinated contrast allergy) and avoids ionising radiation in young individuals and in those suspected of ANOCA/INOCA.^[1]

Coronary CT angiography

• Through intravenous injection of contrast agent, CCTA gives direct anatomical visualisation of the coronary artery lumen and wall (ESC 2024).^[1]
• A slow and regular heart rate and compliance with breath-holding instructions are generally necessary for good image quality, including suitability for pre-medication (typically oral or intravenous beta-blockers) when needed; kidney function and allergy to contrast agents should be assessed before referral.^[1]
• Temporal and spatial resolution remain technical limitations that can hinder precision in adjudicating stenosis severity; this is most problematic in older patients with heavily calcified coronary arteries, in whom functional testing may be more appropriate than CCTA.^[1]
• Contemporary CT technology (64-slice or above) and a well-trained imaging team must be considered a pre-requisite for CCTA.^[1]

Recommendations for CCTA in the initial diagnostic management of suspected CCS, if available and supported by local expertise

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• CT-derived fractional flow reserve (FFR-CT) can complement CCTA by providing model-based computational FFR values along the coronary tree; it has shown good agreement with invasive FFR and reduces unnecessary ICA procedures, but has less impact on management in patients with severe disease at CCTA (ESC 2024).^[1]
• FFR-CT does not require pharmacological stress, additional contrast or radiation exposure, but it is not ubiquitous and depends on image quality.^[1]
• AHA/ACC 2023 notes that the diagnostic sensitivity of FFR-CT compared with invasive FFR is high.^[2]

Stress imaging

Recommendations for stress echocardiography (Recommendation Table 9) and stress SPECT/PET and CMR (Recommendation Table 10) in the initial diagnostic management of suspected CCS, if available and supported by local expertise

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Exercise ECG

• ESC 2024: exercise ECG testing has lower diagnostic performance for obstructive CAD than modern functional imaging and CCTA, which should therefore be preferred as first-line tests in suspected CCS.^[1]
• Because of its low sensitivity (58%) and specificity (62%), exercise ECG has low diagnostic performance for obstructive CAD and should mainly be used for risk stratification.^[1]
• It is of no diagnostic value when resting ECG abnormalities prevent interpretation of ST changes during stress (LBBB, paced rhythm, Wolff–Parkinson–White syndrome, ST-segment depression of 0.1 mV or more on resting ECG, or treatment with digitalis).^[1]
• It remains clinically useful for reproducing anginal symptoms, which have prognostic value.^[1]

Recommendations for exercise ECG in the initial diagnostic management of suspected CCS

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Sequential testing and post-test likelihood

• Pre-test likelihood combined with a test’s positive and negative likelihood ratios gives the post-test probability of obstructive CAD, which is why pre-test estimation guides the non-invasive testing strategy (ESC 2024).^[1]
• Except for older men with all three CCS symptom characteristics, individuals in the moderate likelihood group will have a likelihood of obstructive CAD around 20%; in them, anatomical and functional testing each give an intermediate positive predictive value with eventually many false positives, especially as CCTA easily overestimates stenosis severity.^[1]
• Sequential testing (functional testing after CCTA, or vice versa) will therefore be needed in many individuals to establish an accurate diagnosis of obstructive, ischaemia-inducing CAD.^[1]

Invasive coronary angiography and pressure-wire assessment

• ICA now also determines the functional consequences of obstructions on coronary blood flow (FFR and iFR) by direct measurement of coronary pressure or by calculating the pressure drop across a stenosis from two or more angiographic projections; new technologies allow measurement of coronary flow reserve (CFR) and microvascular resistance, and protocols have been introduced for testing for coronary vasospasm (ESC 2024).^[1]
• Given the frequent mismatch between angiographic and haemodynamic severity of stenoses, coronary pressure assessment should be readily available to complement ICA for clinical decision-making.^[1]
• Femoral diagnostic catheterisation has been associated with a 0.5%–2.0% composite rate of major complications, mainly bleeding requiring transfusion, so radial access is now the standard access when possible; with radial access the composite rate of death, MI or stroke is of the order of 0.1%–0.2%.^[1]
• The decision to perform ICA should balance benefits and risks and potential therapeutic consequences, as part of shared clinical decision-making, with patients adequately informed beforehand.^[1]

Recommendations for ICA in the diagnostic management of suspected CCS

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Recommendations for functional assessment of epicardial stenosis severity during ICA to guide revascularisation

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• The 0.80 FFR and 0.89 iFR thresholds are crucial in decision-making, particularly for deferring revascularisation when FFR/iFR exceeds the ischaemic threshold, but ESC 2024 says they must be considered alongside other parameters, including a careful assessment of the patient’s symptoms and the results of non-invasive stress testing, to determine the need for revascularisation.^[1]
• In multivessel CAD, intracoronary pressure measurement should only be performed on intermediate lesions, because RIPCORD2 and FUTURE showed no clinical outcome improvement from systematic FFR of all epicardial vessels compared with angiography alone.^[1]
• Meta-analyses of 5-year outcomes from DEFINE-FLAIR and iFR-SWEDEHEART reported a 2% absolute increase in all-cause mortality with iFR, not associated with more unplanned revascularisation or non-fatal MI; ESC 2024 also notes that iFR-based deferral is as safe as FFR-based deferral up to 5 years.^[1]

Adverse-event risk stratification

ESC 2024 says all patients with newly diagnosed obstructive CAD or myocardial ischaemia should undergo an adverse-event risk assessment to identify those at high risk who could benefit from revascularisation beyond symptom relief.^[1] High event risk has been defined as cardiac mortality of more than 3% per year, intermediate as 1% to 3% per year, and low as less than 1% per year.^[1] A patient with an LVEF below 50% is already at high risk for all-cause and cardiovascular death.^[1]

Recommendations for definition of high risk of adverse events: use of one or more of these test results is recommended to identify individuals at high risk

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• ESC 2024 also recommends an initial stratification of risk based on basic clinical assessment (e.g. age, ECG, anginal threshold, diabetes, CKD, LVEF) (Class I, Level B).^[1]
• In individuals at high risk of adverse events, regardless of symptoms, ICA — complemented by invasive coronary pressure (FFR/iFR) when appropriate — is recommended, with the aim of refining risk stratification and improving symptoms and cardiovascular outcomes by revascularisation (ESC 2024 Class I, Level A).^[1]
• ESC 2024 asks for an integrative approach to event risk: risk factors, comorbidities, LV dysfunction, the severity of myocardial ischaemia, the number of functionally significantly stenotic coronary arteries, and coronary plaque burden and characteristics.^[1]

AHA/ACC 2021: stable chest pain with no known CAD

• AHA/ACC 2021 Figure 11 shows pretest probabilities for patients with anginal symptoms; patients with lower-risk symptoms would be expected to have lower pretest probability.^[3]
• In that figure the groups in which noninvasive testing is most beneficial have a pretest probability above 15%, while testing for diagnosis may be considered on clinical judgement in groups with a pretest probability of CAD of 15% or less.^[3]
• Alternatively, low-risk patients may be those younger than 40 years or with symptoms that have a low likelihood of representing ischaemia.^[3]

AHA/ACC 2021: low-risk and intermediate-high risk patients with stable chest pain and no known CAD

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• AHA/ACC 2021 describes intermediate-high risk patients as having modest rates of obstructive CAD (about 10%–20%) and risk of clinical events (about 1%–2% per year).^[3]
• For intermediate-high risk patients with stable chest pain and no known CAD, AHA/ACC 2021 says the diagnostic evaluation should be guided by the ability to achieve high-quality imaging as well as local availability and expertise; CCTA is preferable in those younger than 65 years and not on optimal preventive therapies, while stress testing may be advantageous in those 65 years or older because they have a higher likelihood of ischaemia and obstructive CAD.^[3]
• A CAC score of zero can be useful to identify patients with stable chest pain who are low risk, have a low likelihood of obstructive CAD and a low risk of future cardiovascular events.^[3]
• In its decision pathway, high-risk CAD means left main stenosis of 50% or more or anatomically significant 3-vessel disease (70% or more stenosis).^[3]

AHA/ACC 2023: known chronic coronary disease with a change in symptoms

• In patients with CCD, AHA/ACC 2023 says that, if there is an opportunity to do so, clinicians should first intensify GDMT and defer testing; imaging should be considered in those with new-onset or persistent stable chest pain.^[2]

AHA/ACC 2023 chronic coronary disease guideline: diagnostic evaluation and risk stratification

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The source marks several of these rows as modified from the 2021 AHA/ACC multisociety chest pain guideline.^[2]

Management — definitive and stepwise

After diagnosis is confirmed with the first line of testing, ESC 2024 says all patients should receive lifestyle and risk-factor modification recommendations, and disease-modifying and antianginal therapy should be prescribed.^[1] Event-prevention drugs (antithrombotic, lipid-lowering and others) are taught in the secondary prevention topic; this section covers symptom control and revascularisation.

Antianginal therapy: ESC 2024

• Antianginal therapy aims to control symptoms while ensuring acceptable tolerability and patient adherence.^[1]
• ESC 2024 notes there is no robust evidence from direct comparisons that some antianginal drugs are more effective than others for improving symptoms, and no evidence that any antianginal medication improves long-term cardiovascular outcomes, except beta-blockers if administered within 1 year after an acute MI.^[1]
• Many patients need a combination of anti-ischaemic drugs to control symptoms adequately.^[1]
• ESC 2024 describes the current empirical paradigm as a hierarchical, stepwise approach with first-line (beta-blockers, CCBs) and second-line drugs (long-acting nitrates, nicorandil, ranolazine, ivabradine, trimetazidine); the 2024 task force reinforces the concept that therapy for symptom control should be tailored to each patient’s haemodynamic profile (BP, heart rate), comorbidities (particularly HF), interacting medications, preferences, the pathophysiological basis of ischaemia and local drug availability.^[1]

Recommendations for antianginal drugs in patients with CCS

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• Footnote c: these drugs may require caution or may be contraindicated in certain patients with low BP (beta-blockers and DHP-CCB), diabetes mellitus (beta-blockers), atrioventricular conduction disorders (beta-blockers and non-DHP-CCB), and chronic obstructive pulmonary disease (non-cardioselective beta-blockers).^[1]

• Footnote d: consideration for initial therapy — ivabradine, nicorandil, long-acting nitrates, ranolazine or trimetazidine for patients with intolerance or contraindications to beta-blockers and/or CCBs; ranolazine and trimetazidine for patients with microvascular angina; nicorandil or nitrates for patients with coronary artery spasm (drugs listed in alphabetical order).^[1]

• Practical points from ESC 2024 section 4.2: if beta-blockers are used for angina, the aim should be to lower resting heart rate to 55–60 beats per minute.^[1]

• Starting with monotherapy and escalating to a combination when relief is inadequate is a reasonable approach; the empirical approach of starting with a beta-blocker can be recommended in many patients with CCS, unless there are contraindications or other drugs are more suitable (e.g. patients with low heart rate and/or BP).^[1]

• The combination of a beta-blocker with a dihydropyridine CCB is appropriate for most patients, whereas the addition of other antianginal drugs (long-acting nitrates, ranolazine, nicorandil, trimetazidine, or ivabradine in patients with LV systolic dysfunction) can be considered when a beta-blocker and/or CCB is contraindicated or poorly tolerated, or when angina is inadequately controlled.^[1]

• Response to initial therapy should be reassessed and treatment adapted if angina control is inadequate or the initial treatment is poorly tolerated.^[1]

ESC 2024 refers readers to its Supplementary data for a review of the antianginal agents used in CCS.^[1] Routine antianginal doses are not taught in this topic: prescribe per local formulary and specialist guidance.

Antianginal therapy: AHA/ACC 2023

AHA/ACC 2023: antianginal therapy (rows marked in the source as modified from the 2012 SIHD guideline)

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For refractory angina with no other treatment options, AHA/ACC 2023 (section 4.3.7) says enhanced external counterpulsation may be considered for relief of symptoms (COR 2b, LOE B-R).^[2]

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Revascularisation: what it does and does not do

• Both CABG and PCI increase coronary flow capacity and prevent myocardial ischaemia during exercise or emotional stress, but they do not heal coronary atherosclerosis (ESC 2024).^[1]

• Revascularisation by both modalities improves angina-related health status.^[1]

• Randomised and meta-analytical evidence supports a survival benefit above medical therapy for CABG in left main disease and three-vessel disease, particularly with LV dysfunction, although most of this evidence was obtained before the introduction of disease-modifying therapies such as ACE inhibitors/ARBs and statins; in general, among surgically eligible patients with multivessel disease, CABG is superior to PCI and to medical therapy, particularly with diabetes and higher coronary complexity.^[1]

• ESC 2024 reports that ISCHEMIA, in CAD patients with moderate or severe inducible ischaemia but no left main disease nor LVEF below 35%, did not show significant benefit of an initial invasive strategy over an initial conservative strategy, up to 5 years, for the primary endpoint, which ESC 2024 describes as ischaemic cardiovascular events or death from any cause (the trial’s primary composite was cardiovascular death, MI, or hospitalisation for unstable angina, heart failure or resuscitated cardiac arrest).^[1][4]

• ESC 2024 reads this as suggesting that most such patients should initially be treated conservatively with optimised GDMT.^[1]

• Patients randomised to the invasive strategy did have significantly lower rates of spontaneous MI and greater improvement in angina-related health status.^[1]

• So, although initial conservative management is generally preferred, symptom improvement by revascularisation should not be neglected if patients remain symptomatic despite antianginal treatment.^[1]

• For patients with obstructive CAD and refractory symptoms despite optimised GDMT, ESC 2024 says a referral for ICA may be considered to improve symptoms through revascularisation; optimisation of medical therapy by combining two or more antianginal drugs can safely be obtained over 6 weeks in almost all patients and should be awaited before such a referral.^[1]

• Patients can be referred for ICA if CCTA detects a stenosis of 50% or more of the left main stem, or three-vessel or two-vessel disease including the proximal LAD with 70% or more stenosis, or if functional imaging shows moderate or severe ischaemia encompassing an extensive perfusion territory.^[1]

Recommendations for revascularisation in patients with CCS

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• Newer guidance for patients with heart failure: the 2026 ESC heart failure guideline (Recommendation Table 16, revascularisation in chronic coronary syndrome in patients with heart failure; revascularisation for outcome improvement in HFrEF) says that if revascularisation is planned after assessment by a Heart Team, CABG should be considered as the preferred revascularisation strategy in patients with LVEF 35% or less and multivessel CAD suitable for surgery, to improve long-term survival (ESC 2026 HF Class IIa, Level B1).^[15]
• The 2026 ESC HF Task Force recognises an apparent discrepancy between this recommendation (Class IIa, Level B1) and other recommendations in this context across other guidelines, e.g. the 2024 ESC CCS guideline (Class I, Level B); it notes that the patient populations considered are slightly different (often patients with chronic coronary syndrome presenting with reduced LVEF in the CCS guidelines, and often patients with HFrEF presenting with CAD in the HF guidelines) and that, under the ESC’s most recent level-of-evidence grading, it considered STICHES, with all its limitations (mean age 60 years, limited number of events at 10 years, limited use of modern foundational medical therapy), the only possible study available to support the recommendation.^[15][1]
• The same 2026 ESC HF table recommends coronary revascularisation in patients with HF, obstructive CAD and persistent angina, despite foundational medical therapy (FMT) for HF and antianginal drugs, to relieve symptoms (ESC 2026 HF Class I, Level C).^[15]
• Its text adds that patients with HF and chronic coronary syndrome due to obstructive CAD must receive FMT before revascularisation, and that a multidisciplinary Heart Team discussion including an HF specialist is recommended to decide whether conservative treatment or an invasive treatment strategy should be adopted; its Figure 19 legend notes that PCI or continued medical therapy are alternative treatments if the patient is not eligible for CABG.^[15]

Recommendations for mode of revascularisation in patients with CCS

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Revascularisation: AHA/ACC 2023

AHA/ACC 2023: revascularisation (several rows marked in the source as modified from the 2021 ACC/AHA/SCAI revascularisation guideline)

^[2]

Specific subtypes and scenarios

ANOCA/INOCA: microvascular and vasospastic angina

• ESC 2024 lists the endotypes that invasive functional coronary testing with acetylcholine (Ach) and adenosine can separate in people with suspected CCS and non-obstructive coronary arteries: endothelial dysfunction; impaired vasodilation (low CFR and/or high microvascular resistance); epicardial vasospastic angina; microvascular vasospastic angina; endotype combinations; and equivocal response (angina without fulfilling any endotype criteria).^[1]

• Microvascular angina is the clinical manifestation of myocardial ischaemia caused by structural or functional changes in the coronary microvasculature and/or abnormal vasoconstriction of coronary arterioles; vasospastic angina is myocardial ischaemia caused by abnormal vasoconstriction of one or more epicardial coronary arteries leading to dynamic coronary obstruction.^[1]

• Microvascular angina and epicardial VSA can co-exist, which is associated with a worse prognosis.^[1]

• ANOCA occurs in up to 70% of patients undergoing ICA, of whom 25% have documented ischaemia (INOCA); among patients tested with Ach, 80% show endothelial dysfunction, 60% have MVA/VSA, and 50% have impaired CFR and/or high microvascular resistance.^[1]

• ESC 2024 uses these figures to argue for testing not only patients with INOCA but all patients with ANOCA to determine the final endotype so that appropriate treatment can be started.^[1]

• The diagnosis of ANOCA/INOCA is based exclusively on invasive functional evaluation of the coronary microcirculation, because no technique visualises the coronary microcirculation directly in vivo in humans.^[1]

• Non-invasive tests (stress echocardiography, PET, perfusion CCTA and CMR) can diagnose ANOCA/INOCA by measuring CFR; they 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]

• Only hybrid techniques, such as CCTA with perfusion and PET-CT, offer combined imaging of the epicardial coronary arteries and functional testing of the coronary microcirculation in a single test.^[1]

Invasive coronary functional testing thresholds

^[1]

ESC 2024 notes that the threshold for CMD varies between studies and techniques (PET, CMR, thermodilution or Doppler), with a CFR threshold of below 2.0–2.5.^[1]

Recommendations for diagnosis and management of ANOCA/INOCA

^[1]

• In patients with either epicardial or microvascular spasm after Ach testing, ESC 2024 says calcium antagonists should be considered as first-line therapy.^[1]

• In severe VSA it may be necessary to give unusually high doses of calcium antagonist (diltiazem 2 × 200 mg daily or higher, up to 960 mg daily) or even a combination of a non-dihydropyridine (such as diltiazem) with a dihydropyridine calcium blocker (such as amlodipine).^[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]

• 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]

• The source notes that nonobstructive CAD is present in more than 50% of patients undergoing elective coronary angiography and is associated with an increased risk of all-cause death and MI.^[2]

^{[11] [1]}

Heart failure and reduced LVEF

Recommendations for management of CCS patients with chronic heart failure

^{[1] [15]}

2026 ESC heart failure guideline: specialised diagnostic investigations in patients with established heart failure to detect reversible/treatable causes of heart failure (newer guideline, shown beside ESC 2024 CCS Recommendation Table 24)

^{[15] [1]}

• In the 2026 ESC HF guideline, HFrEF is characterised by LVEF below 50% and symptoms and/or signs of HF.^[15]
• For CABG in LVEF 35% or less with multivessel CAD, the 2026 ESC HF class (IIa, B1) and its Task Force note on an apparent discrepancy with other guidelines’ recommendations, e.g. ESC 2024 CCS (I, B), are given under Revascularisation above.^[15][1]

^{[10] [1]}

ESC 2024 adds that STICH failed its primary endpoint of all-cause mortality at a median of 4 years (HR with CABG 0.86; 95% CI 0.72–1.04; P = .12) before the 9.8-year benefit emerged.^[1]

^{[9] [1]}

Complications and pitfalls

• Ruling out with an exercise ECG when imaging is available. With low or moderate (more than 5% to 50%) pre-test likelihood, ESC 2024 does not recommend exercise ECG to rule out CAD if CCTA or functional imaging tests are available (Class III, Level C).^[1]
• Using ST depression during SVT as proof of CAD. ST-segment depression during supraventricular tachyarrhythmias is not a strong predictor of obstructive CAD.^[1]
• Equating angiographic severity with ischaemia. Diameter stenosis by visual assessment correlates poorly with FFR/iFR, so ESC 2024 wants coronary pressure assessment readily available alongside ICA.^[1]
• CCTA in the wrong patient. In the initial diagnostic management of individuals with suspected CCS, ESC 2024 does not recommend CCTA in severe renal failure (eGFR below 30 mL/min/1.73 m2), decompensated HF, extensive coronary calcification, fast irregular heart rate, severe obesity, inability to cooperate with breath-hold commands, or any other condition that can make good image quality unlikely (Class III, Level C; Recommendation Table 8 is scoped to CCTA if available and supported by local expertise).^[1]
• Stopping at normal epicardial arteries. The likelihood models do not include ANOCA/INOCA, which always needs to be considered if symptoms persist after testing excludes obstructive CAD.^[1]
• Nitrates with phosphodiesterase inhibitors or in hypertrophic cardiomyopathy are not recommended (ESC 2024 Class III, Level B).^[1]
• Ivabradine with verapamil or diltiazem, or with other strong CYP3A4 inhibitors, is not recommended (ESC 2024 Class III, Level B).^[1]
• Procedural complications of ICA. Femoral diagnostic catheterisation carries a 0.5%–2.0% composite rate of major complications, mainly bleeding requiring transfusion.^[1]
• Routine pressure-wire assessment of every vessel is not recommended (ESC 2024 Class III, Level A).^[1]

Prognosis and disposition

^[1]

• ESC 2024 summarises ISCHEMIA and the Coronary Artery Surgery Study as showing that the prognosis of obstructive CAD-related CCS is mainly determined by the number of obstructed coronary arteries (more than 70%) or by a left main stenosis (more than 50% diameter stenosis on coronary angiography).^[1]
• Post hoc analyses of the SCOT-HEART trial and other CCTA-based registries show plaque burden and adverse plaque characteristics, especially low-attenuation plaque, as the strongest predictors of fatal and non-fatal MI above classical risk factors, including stenosis severity.^[1]
• Exercise ECG markers of high cardiac mortality risk are ST-segment depression at a low workload combined with exertional symptoms (angina or dyspnoea), low exercise capacity, complex ventricular ectopy or other arrhythmias, and an abnormal BP response.^[1]
• 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 readmissions and repeat coronary angiograms; vasospastic angina is associated with major adverse events, including sudden cardiac death, acute MI and syncope.^[1]

Special populations

• Older adults (75 years or older): ESC 2024 recommends particular attention to drug side effects, intolerance, drug–drug interactions, overdosing and procedural complications (Class I, Level C), and diagnostic and revascularisation decisions based on symptoms, extent of ischaemia, frailty, life expectancy, comorbidities and patient preferences, in older as in younger individuals (Class I, Level C).^[1]
• Women: usually older at presentation, with a heavier risk-factor burden, more comorbidities, more non-anginal symptoms such as dyspnoea and fatigue, and a greater prevalence of MVA than men; similar guideline-directed cardiovascular preventive therapy is recommended in women and men (ESC 2024 Class I, Level C).^[1]
• Diabetes with autonomic neuropathy, or very sedentary older people: angina may be absent despite very severe obstructive CAD.^[1]
• Younger patients: obstructive CAD is rare, but when present a CACS of 0 is more common (58% of those younger than 40 years) than in older patients (9% at 60 to 69 years).^[1]
• Older patients with heavily calcified arteries: functional testing may be more appropriate than CCTA.^[1]
• Severe comorbidity, severe frailty or very low quality of life with limited life expectancy, where revascularisation is judged futile: the diagnosis of CCS can be made clinically and managed with medical therapy and lifestyle changes alone.^[1]

Evidence, guidelines and regional differences

Landmark trials

^{[5] [1]}

• ESC 2024 suggests test reporting and patient management variability could in part help explain the improved outcomes in the CCTA arm of SCOT-HEART, where CCTA findings, including non-obstructive atherosclerosis, emphasised the need to start or intensify medical treatment.^[1]

^{[6] [1] [7] [1] [4] [1]}

• ESC 2024 adds that extended follow-up to 7 years (ISCHEMIA-EXTEND) showed a significant 2.2% absolute decrease in cardiovascular mortality with the initial invasive strategy (adjusted HR 0.78; 95% CI 0.63–0.96), offset by a significant 1.2% absolute increase in non-cardiac mortality, without a significant difference in all-cause mortality.^[1]

^{[8] [1]}

• ESC 2024 reads ORBITA-2 as showing that patients with stable angina receiving minimal or no antianginal medication with objective evidence of ischaemia had a lower angina symptom score after PCI than after a placebo procedure.^[1]
• In a separate passage, ESC 2024 notes that in the ORBITA trial (Objective Randomised Blinded Investigation with optimal medical Therapy of Angioplasty in stable angina), PCI did not provide short-term advantages compared with GDMT in terms of reducing anginal frequency or physical limitations.^[1]

ESC 2024 versus AHA/ACC: the two pathways side by side (selected rows)

^{[1] [3]}

What is new in ESC 2024 (selected)

• Table 3 of ESC 2024 lists among its new major recommendations: it is recommended to estimate the pre-test likelihood of obstructive epicardial CAD using the RF-CL model (Class I, Level B).^[1]

• In individuals with a low (more than 5% to 15%) pre-test likelihood of obstructive CAD, CACS should be considered to reclassify subjects and to identify more individuals with very low (5% or less) CACS-weighted clinical likelihood (Class IIa, Level B).^[1]

• In individuals with suspected CCS and low or moderate (more than 5% to 50%) pre-test likelihood of obstructive CAD, CCTA is recommended to diagnose obstructive CAD and to estimate the risk of MACE (Class I, Level A; Recommendation Table 8 is scoped to CCTA if available and supported by local expertise).^[1]

• In individuals with suspected CCS and moderate or high (more than 15% to 85%) pre-test likelihood of obstructive CAD, stress echocardiography is recommended to diagnose myocardial ischaemia and to estimate the risk of MACE (Class I, Level B; Recommendation Table 9 is scoped to stress echocardiography if available and supported by local expertise).^[1]

• Symptoms like chest pain triggered by emotional stress; dyspnoea or dizziness on exertion; pain in the arms, jaw, neck or upper back; or fatigue should be considered as potential angina equivalents (Class IIa, Level B).^[1]

• The guideline was corrected in 2025; the changes include: the sentence on individual adjustment of the clinical likelihood now refers to Figure 5, section 2; in Figure 5 the 2-point symptom-score cell for men aged 60–69 (value 12) was re-coloured from yellow to green; and Figure 6 was retitled from ‘Risk factor-weighted clinical likelihood of obstructive CAD’ to ‘Clinical likelihood of obstructive CAD’, with a new footnote saying that the clinical likelihood of obstructive CAD should be estimated with the RF-CL model (Figure 4), that individual adjustment of the RF-CL values is in some cases needed based on an abnormal clinical finding (Figure 5) or highly suspicious symptoms, and that beyond the CACS-CL no methods are validated to give accurate adjusted values to the RF-CL, so adjusted values are based on clinical judgement. This topic quotes the corrected version.^[13][1]

Australia and New Zealand

Exam pearls

• Name the model: ESC 2024 recommends the Risk Factor-weighted Clinical Likelihood (sex, age, angina symptoms and number of risk factors, 0–5); the tables originally based on the Diamond–Forrester approach have had to be updated several times.^[1]
• Know the bands: very low 5% or less, low more than 5% to 15%, moderate more than 15% to 50%, high more than 50% to 85%, very high more than 85%.^[1]
• In individuals with suspected CCS and a low or moderate (more than 5% to 50%) pre-test likelihood of obstructive CAD, CCTA is recommended as the preferred diagnostic modality to rule out obstructive CAD (ESC 2024 Class I, Level B); ESC 2024 notes that tests for detecting ischaemia have better rule-in power compared with CCTA and should be selected at a moderate–high (more than 15% to 85%) likelihood of obstructive CAD; and in individuals with suspected CCS, ICA is recommended to diagnose obstructive CAD in those with a very high (more than 85%) clinical likelihood of disease, severe symptoms refractory to guideline-directed medical therapy, angina at a low level of exercise and/or high event risk (ESC 2024 Class I, Level C).^[1]
• During ICA, selective assessment of the functional severity of intermediate diameter stenoses (typically around 40%–90% for non-left main stem or 40%–70% for left main stem by visual estimate) is recommended to guide the decision to revascularise, using FFR/iFR (significant at 0.8 or less or 0.89 or less, respectively) (ESC 2024 Class I, Level A); systematic and routine wire-based coronary pressure assessment of all coronary vessels is not recommended (ESC 2024 Class III, Level A).^[1]
• ISCHEMIA: in stable coronary disease with moderate or severe ischaemia, the investigators found no evidence that an initial invasive strategy reduced ischaemic cardiovascular events or death from any cause compared with an initial conservative strategy over a median 3.2 years; they note that the trial findings were sensitive to the definition of MI used.^[4]
• Persistent angina or anginal equivalent despite GDMT with functionally significant obstructive CAD: revascularisation is recommended to improve symptoms (ESC 2024 Class I, Level A).^[1]
• Symptoms persisting after testing that excludes obstructive CAD: ANOCA/INOCA always needs to be considered; in persistently symptomatic patients despite medical treatment with suspected ANOCA/INOCA (normal coronary arteries or non-obstructive lesions at non-invasive imaging, or intermediate stenoses with normal FFR/iFR) and poor quality of life, invasive coronary functional testing is recommended to identify potentially treatable endotypes and to improve symptoms and quality of life, considering patient choices and preferences (ESC 2024 Class I, Level B).^[1]

References15ShowHide

1. [1]Vrints C, et al. 2024 ESC Guidelines for the management of chronic coronary syndromes. Eur Heart J, 2024.PMID 39210710
2. [2]Virani SS, et al. 2023 AHA/ACC/ACCP/ASPC/NLA/PCNA Guideline for the Management of Patients With Chronic Coronary Disease: A Report of the American Heart Association/American College of Cardiology Joint Committee on Clinical Practice Guidelines. J Am Coll Cardiol, 2023.PMID 37480922
3. [3]Gulati M, et al. 2021 AHA/ACC/ASE/CHEST/SAEM/SCCT/SCMR Guideline for the Evaluation and Diagnosis of Chest Pain: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. J Am Coll Cardiol, 2021.PMID 34756653
4. [4]Maron DJ, et al. Initial Invasive or Conservative Strategy for Stable Coronary Disease. N Engl J Med, 2020.PMID 32227755
5. [5]Newby DE, et al. Coronary CT Angiography and 5-Year Risk of Myocardial Infarction. N Engl J Med, 2018.PMID 30145934
6. [6]Douglas PS, et al. Outcomes of anatomical versus functional testing for coronary artery disease. N Engl J Med, 2015.PMID 25773919
7. [7]Maurovich-Horvat P, et al. CT or Invasive Coronary Angiography in Stable Chest Pain. N Engl J Med, 2022.PMID 35240010
8. [8]Rajkumar CA, et al. A Placebo-Controlled Trial of Percutaneous Coronary Intervention for Stable Angina. N Engl J Med, 2023.PMID 38015442
9. [9]Perera D, et al. Percutaneous Revascularization for Ischemic Left Ventricular Dysfunction. N Engl J Med, 2022.PMID 36027563
10. [10]Velazquez EJ, et al. Coronary-Artery Bypass Surgery in Patients with Ischemic Cardiomyopathy. N Engl J Med, 2016.PMID 27040723
11. [11]Ford TJ, et al. Stratified Medical Therapy Using Invasive Coronary Function Testing in Angina: The CorMicA Trial. J Am Coll Cardiol, 2018.PMID 30266608
12. [12]Liew G, et al. Cardiac Society of Australia and New Zealand Position Statement: Coronary Artery Calcium Scoring. Heart Lung Circ, 2017.PMID 28690020
13. [13][No authors listed] Correction to: 2024 ESC Guidelines for the management of chronic coronary syndromes: Developed by the task force for the management of chronic coronary syndromes of the European Society of Cardiology (ESC) Endorsed by the European Association for Cardio-Thoracic Surgery (EACTS). Eur Heart J, 2025.PMID 39982387
14. [14]Liew GY, et al. Noninvasive coronary artery imaging: current clinical applications: Cardiac Society of Australia and New Zealand guidelines. Heart Lung Circ, 2011.PMID 21530393
15. [15]Køber L, et al. 2026 ESC Guidelines for the management of heart failure. Eur Heart J, 2026.PMID 42661420