ehae177 (1)
ehae177 (1)
ehae177 (1)
https://doi.org/10.1093/eurheartj/ehae177
* Corresponding authors: Christiaan Vrints, Department of Cardiology, Antwerp University Hospital, Edegem, Belgium, and Research Group Cardiovascular Diseases, GENCOR, University
of Antwerp, Antwerp, Belgium. Tel: +32 3 8213571, E-mail: christiaan.vrints@uantwerpen.be; and Felicita Andreotti, Cardiovascular Science Department, Fondazione Policlinico Universitario
Gemelli IRCCS, Rome, Italy, and Cardio-Thoracic Department, Catholic University Medical School, Rome, Italy. Tel: +39-06-30154187, E-mail: felicita.andreotti@unicatt.it.
†
The two Chairpersons contributed equally to the document and are joint first authors.
‡
The two Task Force Co-ordinators contributed equally to the document.
Author/Task Force Member affiliations are listed in author information.
1
Representing the Association European Association for Cardio-Thoracic Surgery (EACTS).
ESC Clinical Practice Guidelines (CPG) Committee: listed in the Appendix.
ESC subspecialty communities having participated in the development of this document:
Associations: Association of Cardiovascular Nursing & Allied Professions (ACNAP), Association for Acute CardioVascular Care (ACVC), European Association of Cardiovascular Imaging
(EACVI), European Association of Preventive Cardiology (EAPC), European Association of Percutaneous Cardiovascular Interventions (EAPCI), Heart Failure Association (HFA).
Councils: Council for Cardiology Practice.
Working Groups: Cardiovascular Pharmacotherapy, Cardiovascular Surgery, Coronary Pathophysiology and Microcirculation, Thrombosis.
Patient Forum
© The European Society of Cardiology 2024. All rights reserved. For permissions, please email: journals.permissions@oup.com.
3416 ESC Guidelines
Document Reviewers: Michael Borger, (CPG Review Co-ordinator) (Germany), Ingibjörg J. Gudmundsdóttir,
(CPG Review Co-ordinator) (Iceland), Juhani Knuuti, (CPG Review Co-ordinator) (Finland), Ingo Ahrens
(Germany), Michael Böhm (Germany), Sergio Buccheri (Italy), Davide Capodanno (Italy), Evald Høj Christiansen
(Denmark), Jean-Philippe Collet¶ (France), Kenneth Dickstein (Norway), Christian Eek (Norway), Volkmar Falk
(Germany), Peter A. Henriksen (United Kingdom), Borja Ibanez (Spain), Stefan James (Sweden), Sasko Kedev
(Macedonia), Lars Køber (Denmark), Martha Kyriakou (Cyprus), Emma F. Magavern (United Kingdom),
Angelia McInerny (Ireland), Caius Ovidiu Mersha (Romania), Borislava Mihaylova (United Kingdom),
Richard Mindham (United Kingdom), Lis Neubeck (United Kingdom), Franz-Josef Neumann (Germany), Jens
Cosedis Nielsen (Denmark), Pasquale Paolisso (Italy), Valeria Paradies (Netherlands), Agnes A. Pasquet (Belgium),
Massimo Piepoli (Italy), Eva Prescott (Denmark), Amina Rakisheva (Kazakhstan), Bianca Rocca (Italy), Marc Ruel
(Canada), Sigrid Sandner (Austria), Antti Saraste (Finland), Karolina Szummer (Sweden), Ilonca Vaartjes
(Netherlands), William Wijns (Ireland), Stephan Windecker (Switzerland), Adam Witkowsky (Poland),
¶ Professor Jean-Philippe Collet sadly passed away during the development of these guidelines. Professor Collet’s
contribution to these guidelines was, as always, highly valued.
All experts involved in the development of these guidelines have submitted declarations of interest, which are
reported in a supplementary document to the guidelines. See the European Heart Journal online or https://www.
escardio.org/Guidelines for supplementary documents as well as evidence tables.
Disclaimer. The ESC Guidelines represent the views of the ESC and were produced after careful consideration of the scientific and
medical knowledge and the evidence available at the time of their publication. The ESC is not responsible in the event of any contradiction,
discrepancy and/or ambiguity between the ESC Guidelines and any other official recommendations or guidelines issued by the relevant
public health authorities, in particular in relation to good use of healthcare or therapeutic strategies. Health professionals are encouraged
to take the ESC Guidelines fully into account when exercising their clinical judgment, as well as in the determination and the
implementation of preventive, diagnostic or therapeutic medical strategies; however, the ESC Guidelines do not override, in any way
whatsoever, the individual responsibility of health professionals to make appropriate and accurate decisions in consideration of each
patient’s health condition and in consultation with that patient and, where appropriate and/or necessary, the patient’s caregiver. Nor do
the ESC Guidelines exempt health professionals from taking into full and careful consideration the relevant official updated
recommendations or guidelines issued by the competent public health authorities, in order to manage each patient’s case in light of the
scientifically accepted data pursuant to their respective ethical and professional obligations. It is also the health professional’s
responsibility to verify the applicable rules and regulations relating to drugs and medical devices at the time of prescription. The ESC
warns readers that the technical language may be misinterpreted and declines any responsibility in this respect.
Permissions. The content of these European Society of Cardiology (ESC) Guidelines has been published for personal and educational
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-Keywords
-----------------------------------------------------------------------------------------------------------------------------------------------------------
Guidelines • Antianginal therapy • Antithrombotic therapy • Atherosclerosis • Clinical likelihood • Chronic
coronary syndromes • Coronary artery disease • Diagnostic testing/algorithm • Heart team • Lipid-lowering therapy
• Microvascular disease • Myocardial ischaemia • Myocardial revascularization • Outcomes • PROMS/PREMS •
Shared decision-making • Stable angina • Vasospasm
ESC Guidelines 3417
4.4.6. Patient–physician shared decision-making to perform and 6.5. Recurrent or refractory angina/ischaemia ................................... 3496
select revascularization modality .......................................................... 3475 6.6. Treatment of disease complications .............................................. 3497
4.4.7. Institutional protocols, clinical pathways, and quality of 7. Key messages ..................................................................................................... 3497
care .................................................................................................................... 3475 8. Gaps in evidence .............................................................................................. 3498
5. Optimal assessment and treatment of specific groups ................... 3478 9. ‘What to do’ and ‘What not to do’ messages from the guidelines 3499
5.1. Coronary artery disease and heart failure .................................. 3478 10. Evidence tables ............................................................................................... 3505
5.2. Angina/ischaemia with non-obstructive coronary arteries ... 3479 11. Data availability statement ......................................................................... 3505
5.2.1. Definition ........................................................................................... 3479 12. Author information ...................................................................................... 3505
5.2.2. Angina/ischaemia with non-obstructive coronary arteries 13. Appendix ........................................................................................................... 3506
endotypes ....................................................................................................... 3479 14. References ........................................................................................................ 3507
5.2.2.1. Microvascular angina ............................................................. 3480
5.2.2.2. Epicardial vasospastic angina ............................................. 3481
coronary angiography to guide revascularization (see also Evidence Table 3 New major recommendations in 2024 ...................................... 3426
Table 12) ................................................................................................................... 3447 Table 4 Revised recommendations ............................................................... 3430
Recommendation Table 13 — Recommendations for selection of Table 5 Grading of effort angina severity according to the Canadian
initial diagnostic tests in individuals with suspected chronic coronary Cardiovascular Society ........................................................................................ 3436
syndrome (see also Evidence Table 13) ...................................................... 3453 Table 6 Overview of non-invasive tests used for first-line testing in
Recommendation Table 14 — Recommendations for definition of individuals with suspected chronic coronary syndrome ...................... 3451
high risk of adverse events (see also Evidence Table 14) .................... 3454 Table 7 Practical advice on lifestyle counselling and interventions . 3455
Recommendation Table 15 — Recommendations for cardiovascular Table 8 Options for extended intensified antithrombotic therapy 3464
risk reduction, lifestyle changes, and exercise interventions in Table 9 Summary of trial-based evidence for the comparison of
patients with established chronic coronary syndrome (see also percutaneous coronary intervention and coronary artery bypass
Evidence Table 15) ............................................................................................... 3457 grafting in patients with left main coronary artery disease ................ 3473
Recommendation Table 16 — Recommendations for antianginal Table 10 ‘What to do’ and ‘What not to do’ .......................................... 3499
ARC-HBR Academic Research Consortium for High dPR Diastolic pressure ratio
Bleeding Risk DSE Dobutamine stress echocardiography
ARNI Angiotensin receptor neprilysin inhibitor EACTS European Association for Cardio-Thoracic Surgery
ART Antiretroviral therapy EACVI European Association of Cardiovascular Imaging
ASCVD Atherosclerotic cardiovascular disease ECG Electrocardiogram
ASE American Society of Echocardiography EF Ejection fraction
AUGUSTUS Open-Label, 2 × 2 Factorial, Randomized eGFR Estimated glomerular filtration rate
Controlled, Clinical Trial to Evaluate the Safety of EMA European Medicines Agency
Apixaban versus Vitamin K Antagonist and ESC European Society of Cardiology
Aspirin versus Aspirin Placebo in Patients with EXCEL Evaluation of XIENCE versus Coronary Artery
Atrial Fibrillation and Acute Coronary Syndrome Bypass Surgery for Effectiveness of Left Main
or Percutaneous Coronary Intervention Revascularization
TWILIGHT Ticagrelor with Aspirin or Alone in High-Risk 2019 and partly replace the myocardial revascularization guidelines
Patients after Coronary Intervention from 2018.
vFFR Vessel fractional flow reserve The Members of this task force were selected by the ESC to include
VKA Vitamin K antagonist professionals involved in the medical care of patients with this path
VSA Vasospastic angina ology, as well as patient representatives and methodologists. The selec
VTE Venous thrombo-embolism tion procedure included an open call for authors and aimed to include
WARRIOR Women’s IschemiA Trial to Reduce Events members from across the whole of the ESC region and from relevant
in Non-ObstRuctIve CORonary Artery Disease ESC Subspecialty Communities. Consideration was given to diversity
WOMEN What is the Optimal Method for Ischemia and inclusion, notably with respect to gender and country of origin.
Evaluation of Women The task force performed a critical review and evaluation of the pub
X-ECG Exercise ECG testing lished literature on diagnostic and therapeutic approaches including as
sessment of the risk–benefit ratio. The strength of every
may be harmful.
ESC Guidelines 3423
©ESC 2024
© ESC 2024
for the approval process. In addition to review by the CPG Committee,
ESC Guidelines undergo multiple rounds of double-blind peer review
2. Introduction
by external experts, including members from across the whole of the The 2019 ESC (European Society of Cardiology) Guidelines for the
ESC region, all National Cardiac Societies of the ESC and from relevant diagnosis and management of chronic coronary syndromes introduced
ESC Subspecialty Communities. After appropriate revisions, the the term chronic coronary syndromes (CCS)1 to describe the clinical
guidelines are signed off by all the experts in the task force. The finalized presentations of coronary artery disease (CAD) during stable periods,
document is signed off by the CPG Committee for publication in the particularly those preceding or following an acute coronary syndrome
European Heart Journal. (ACS). CAD was defined as the pathological process characterized by
ESC Guidelines are based on analyses of published evidence, chiefly atherosclerotic plaque accumulation in the epicardial arteries, whether
on clinical trials and meta-analyses of trials, but potentially including obstructive or non-obstructive. Based on expanded pathophysiological
other types of studies. Evidence tables summarizing key information concepts, a new, more comprehensive definition of CCS is introduced:
from relevant studies are generated early in the guideline development ‘CCS are a range of clinical presentations or syndromes that
process to facilitate the formulation of recommendations, to enhance arise due to structural and/or functional alterations related to
comprehension of recommendations after publication, and reinforce chronic diseases of the coronary arteries and/or microcircula
transparency in the guideline development process. The tables are pub tion. These alterations can lead to transient, reversible, myocar
lished in their own section of the ESC Guidelines and are specifically dial demand vs. blood supply mismatch resulting in
related to the recommendation tables. hypoperfusion (ischaemia), usually (but not always) provoked
Off-label use of medication may be presented in these guidelines if a by exertion, emotion or other stress, and may manifest as angina,
sufficient level of evidence shows that it can be considered medically ap other chest discomfort, or dyspnoea, or be asymptomatic.
propriate for a given condition. However, the final decisions concerning Although stable for long periods, chronic coronary diseases
an individual patient must be made by the responsible health profes are frequently progressive and may destabilize at any moment
sional giving special consideration to: with the development of an ACS.’
• The specific situation of the patient. Unless otherwise provided for Of note, ‘disease’ refers to the underlying coronary pathology, and ‘syn
by national regulations, off-label use of medication should be limited drome’ refers to the clinical presentation.
to situations where it is in the patient’s interest with regard to the
quality, safety, and efficacy of care, and only after the patient has
been informed and has provided consent. 2.1. Evolving pathophysiological concepts
• Country-specific health regulations, indications by governmental of chronic coronary syndromes
drug regulatory agencies and the ethical rules to which health profes Our understanding of the pathophysiology of CCS is transitioning from
sionals are subject, where applicable. a simple to a more complex and dynamic model. Older concepts
3424 ESC Guidelines
considered a fixed, focal, flow-limiting atherosclerotic stenosis of a large dysfunctional microvascular angina (MVA) may overlap with those of
or medium coronary artery as a sine qua non for inducible myocardial vasospastic or even obstructive large–medium artery angina.
ischaemia and ischaemic chest pain (angina pectoris). Current concepts Furthermore, it is important to note that CCS doesn’t always present
have broadened to embrace structural and functional abnormalities in as classical angina pectoris and symptoms may vary depending on age
both the macro- and microvascular compartments of the coronary tree and sex. Sex-stratified analyses indicate that women with suspected
that may lead to transient myocardial ischaemia. At the macrovascular angina are usually older and have a heavier cardiovascular risk
level, not only fixed, flow-limiting stenoses but also diffuse atheroscler factor burden, more frequent comorbidities, non-anginal symptoms
otic lesions without identifiable luminal narrowing may cause ischaemia such as dyspnoea and fatigue, and greater prevalence of MVA than
under stress;2,3 structural abnormalities such as myocardial bridging4 men.18–21
and congenital arterial anomalies5 or dynamic epicardial vasospasm
may be responsible for transient ischaemia. At the microvascular level, 2.3. Changing epidemiology and
coronary microvascular dysfunction (CMD) is increasingly acknowl
management strategies
Epicardial Microvascular
Inward arteriolar
Atherosclerosis Epicardial Impaired
remodelling
(focal or diffuse) vasospasm vasodilation
Capillary rarefaction
Stabilized
intramural Endothelial Intravascular plugging Endothelial
haematoma dysfunction and/or dysfunction and/or
VSMC hyperreactivity Perivascular fibrosis VSMC hyperreactivity
Myocardial or infiltration
Autonomic Autonomic
bridge dysregulation dysregulation
Extramural compression
(myocardial hypertrophy,
Coronary increased LVEDP)
aneurysm Increased
vasoconstriction
Figure 1 (Central Illustration) Clinical presentations of chronic coronary syndrome and mechanisms of myocardial ischaemia. ACS, acute coronary
syndrome; ANOCA, angina with non-obstructive coronary arteries; CABG, coronary artery bypass grafting; CAD, coronary artery disease; CCS,
chronic coronary syndrome; INOCA, ischaemia with non-obstructive coronary arteries; LV, left ventricular; LVEDP, left ventricular end-diastolic pres
sure; PCI, percutaneous coronary intervention; VSMC, vascular smooth muscle cell.
3426 ESC Guidelines
History taking and risk factor assessment and resting electrocardiogram in individuals with suspected chronic coronary syndrome—
Section 3
In individuals reporting symptoms of suspected myocardial ischaemic origin, a detailed assessment of cardiovascular risk factors, medical
I C
history, and symptom characteristics (including onset, duration, type, location, triggers, relieving factors, time of day) is recommended.
Symptoms like chest pain triggered by emotional stress; dyspnoea or dizziness on exertion; pain in the arms, jaw, neck, or upper back; or
IIa B
fatigue should be considered as potential angina equivalents.
Indications for invasive coronary angiography in individuals with suspected obstructive coronary artery disease—Section 3
When ICA is indicated, radial artery access is recommended as the preferred access site. I A
When ICA is indicated, it is recommended to have coronary pressure assessment available and to use it to evaluate the functional severity of
I A
intermediate non-left main stem stenoses prior to revascularization.
In individuals with de novo symptoms highly suggestive of obstructive CAD that occur at a low level of exercise, ICA with a view towards
I C
revascularization is recommended as first diagnostic test after clinical assessment by a cardiologist.
Functional assessment of epicardial artery stenosis severity during invasive coronary angiography—Section 3
During ICA, selective assessment of functional severity of intermediate diameter stenoses is recommended to guide the decision to revascularize, using the
following techniques:
• FFR/iFR (significant ≤0.8 or ≤0.89, respectively); I A
• QFR (significant ≤0.8). I B
Ivabradine is not recommended as add-on therapy in patients with CCS, LVEF >40%, and no clinical heart failure. III B
Combination of ivabradine with non-DHP-CCB or other strong CYP3A4 inhibitors is not recommended. III B
Antithrombotic therapy in patients with chronic coronary syndrome—Section 4
Long-term antithrombotic therapy in patients with chronic coronary syndrome and no clear indication for oral anticoagulation
In CCS patients with a prior MI or PCI, clopidogrel 75 mg daily is recommended as a safe and effective alternative to aspirin monotherapy. I A
After CABG, aspirin 75–100 mg daily is recommended lifelong. I A
In CCS patients without prior MI or revascularization but with evidence of significant obstructive CAD, aspirin 75–100 mg daily is
I B
recommended lifelong.
Lipid-lowering drugs in patients with chronic coronary syndrome—Section 4
Lipid-lowering treatment with an LDL-C goal of <1.4 mmol/L (55 mg/dL) and a ≥50% reduction in LDL-C vs. baseline is recommended. I A
ACE-I, angiotensin-converting enzyme inhibitor; ANOCA, angina with non-obstructive coronary arteries; ARB, angiotensin receptor blocker; ARC-HBR, Academic Research Consortium for High
Bleeding Risk; BMI, body mass index; CABG, coronary artery bypass grafting; CACS, coronary artery calcium score; CAD, coronary artery disease; CCB, calcium channel blocker; CCS, chronic
coronary syndrome; CCTA, coronary computed tomography angiography; CFC, coronary flow capacity; CFR, coronary flow reserve; CKD, chronic kidney disease; CMR, cardiac magnetic
resonance; CT, computed tomography; CV, cardiovascular; CVD, cardiovascular disease; CYP3A4, cytochrome P450 3A4; DHP, dihydropyridine; dPR, diastolic pressure ratio; ECG,
electrocardiogram; FFR, fractional flow reserve; FFR-CT, coronary computed tomography angiography-derived fractional flow reserve; GLP-1, glucagon-like peptide-1; HbA1c, glycated
haemoglobin; HF, heart failure; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; HIV, human immunodeficiency virus; HSR, hyperaemic
stenosis resistance; ICA, invasive coronary angiography; iFR, instantaneous wave-free ratio; INOCA, ischaemia with non-obstructive coronary arteries; IVUS, intravascular ultrasound; LAD, left
anterior descending; LDL-C, low-density lipoprotein cholesterol; LV, left ventricular; LVEF, left ventricular ejection fraction; MACE, major adverse cardiovascular events; MCS, mechanical
circulatory support; MI, myocardial infarction; OCT, optical coherence tomography; PCI, percutaneous coronary intervention; Pd/Pa, distal coronary pressure to aortic pressure ratio; PET,
positron emission tomography; PRECISE-DAPT, PREdicting bleeding Complications In patients undergoing Stent implantation and subsEquent Dual AntiPlatelet Therapy; QFR, quantitative
flow ratio; RFR, relative flow reserve; SGLT2, sodium–glucose cotransporter 2; SPECT, single-photon emission computed tomography; T2DM, type 2 diabetes mellitus.
a
Class of recommendation.
b
Level of evidence.
3430 ESC Guidelines
Recommendations in 2019 version Classa Levelb Recommendations in 2024 version Classa Levelb
Long-term antithrombotic therapy in patients with chronic coronary syndrome and an indication for oral anticoagulation—Section 4
When oral anticoagulation is initiated in a patient with In CCS patients with a long-term indication for OAC, an
AF who is eligible for a NOAC, a NOAC is I A AF-therapeutic-dose of VKA alone or, preferably, of
recommended in preference to a VKA. DOAC alone (unless contraindicated) is recommended
Long-term OAC therapy (NOAC or VKA with time in lifelong.
therapeutic range >70%) is recommended in patients
I A
with AF and a CHA2DS2-VASc score ≥2 in males and
≥3 in females.
Long-term OAC therapy (NOAC or VKA with time in
I B
therapeutic range >70%) should be considered in
IIa B
patients with AF and a CHA2DS2-VASc score of 1 in
© ESC 2024
IIb C and with insufficient response to guideline-directed IIb C
medical therapy, not amenable to revascularization by
PCI, CABG may be considered to improve symptoms.
3. Stepwise approach to the initial chest pain or discomfort (Figure 3) is the most cardinal symptom of
CCS, it must be emphasized that many patients do not present with
management of individuals with characteristic anginal symptoms and that the symptomatology may
suspected chronic coronary vary with age, sex, race, socioeconomic class, and geographical location.
In contemporary studies, only 10% to 25% of patients with suspected
syndrome CCS present with angina with classic aggravating and relieving factors,
Managing individuals with suspected CCS involves four steps (Figure 2): while 57% to 78% have symptoms less characteristic of angina and
10% to 15% have dyspnoea on exertion.33,57
STEP 1. The first step is a general clinical evaluation that focuses on as While older studies suggested that women were more likely to ex
sessing symptoms and signs of CCS, differentiating non-cardiac perience less characteristic chest pain symptoms,58 recent data show
causes of chest pain and ruling out ACS. This initial clinical evaluation that anginal chest pain is equally prevalent in both men and women, al
requires recording a 12-lead resting electrocardiogram (ECG), basic beit with slightly different characteristics.59 Symptoms were classified as
blood tests, and in selected individuals, chest X-ray imaging and pul non-characteristic angina in over two-thirds of the patients of both
monary function testing. This evaluation can be done by the general sexes.21,60 Of note, the absence of anginal symptoms does not preclude
practitioner. CCS, as it may be absent in patients with diabetes with autonomic neur
STEP 2. The second step is a further cardiac examination, including opathy or in elderly patients with a very sedentary lifestyle despite very
echocardiography at rest to rule out left ventricular (LV) dysfunc severe obstructive CAD. Of course, chest pain is not always angina (i.e.
tion and valvular heart disease. After that, it is recommended to es of ischaemic origin), since it can be related to non-coronary (e.g. peri
timate the clinical likelihood of obstructive CAD to guide deferral or carditis) or non-cardiovascular conditions.61,62
referral to further non-invasive and invasive testing. Anginal pain symptoms have been traditionally classified as “typical,
STEP 3. The third step involves diagnostic testing to establish the diag atypical, or non-anginal/non-cardiac” based on the location of the
nosis of CCS and determine the patient’s risk of future events. pain, as well as precipitating and relieving factors. Although angina
STEP 4. The final step includes lifestyle and risk-factor modification that meets all three characteristics, with retrosternal chest discomfort
combined with disease-modifying medications. A combination of provoked by exertion or emotional stress and relieved by rest or nitro
antianginal medications is frequently needed, and coronary revascu glycerine, is highly suggestive of ischaemia caused by obstructive CAD,
larization is considered if symptoms are refractory to medical treat these characteristics are rarely all present when ischaemia is caused by
ment or if high-risk CAD is present. If symptoms persist after microvascular dysfunction and vasospasm. Furthermore, patients with
obstructive CAD is ruled out, coronary microvascular disease and “typical” vs. “atypical” angina included in the PRECISE study had similar
vasospasm should be considered. 1-year outcomes,57 highlighting the limited prognostic value of symp
tom classification on typicality of angina used in obstructive CAD pre
diction models. Because this terminology to describe anginal symptoms
3.1. STEP 1: General clinical examination no longer aligns with current concepts of CCS, it should be replaced
3.1.1. History, differential diagnosis, and physical by a detailed description of symptoms (Figure 3). It is important to
examination thoroughly evaluate chest pain, including an objective exclusion of myo
Careful and detailed history taking is the initial step in diagnostic man cardial ischaemia caused by obstructive CAD, microvascular disease,
agement for all clinical scenarios within the spectrum of CCS. Although and/or coronary vasospasm, before classifying it as non-cardiac.
3434 ESC Guidelines
Assess
clinical likelihood
Very low clinical likelihood of of obstructive CAD Severe comorbidities or low quality
obstructive CAD (≤5%): of life: consider no further testing and
consider deferring further testingb Echocardiography at rest treat medically
Exercise ECGa
Selective second-line
imaging to increase
CCTA: obstructive CAD? post-test likelihood Functional imaging: myocardial ischaemia?
In individuals with low and moderate (>5–50%) In individuals with moderate and high (>15–85%)
clinical likelihood clinical likelihood
Step 4 Treatment
Figure 2 Stepwise approach to the initial management of individuals with suspected chronic coronary syndrome. ANOCA, angina with non-
obstructive coronary arteries; CAD, coronary artery disease; CCS, chronic coronary syndrome; CCTA, coronary computed tomography angiography;
ECG, electrocardiogram; ED, emergency department; GDMT, guideline-directed medical therapy; INOCA, ischaemia with non-obstructive coronary
arteries. aIn selected patients. bConsider also coronary spasm or microvascular dysfunction.
ESC Guidelines 3435
Symptom characteristics
Burning Strangling
Sharp Constricting
Quality Tearing - Ripping Squeezing
Pleuritic Pressure
Aching Heaviness
Difficulty to exhale
Quality Difficulty catching breath
With wheezing
Dyspnoea
Slowly subsiding at rest or after Rapidly subsiding after effort
Relief
inhalation of bronchodilators discontinuation
Figure 3 Main CCS symptoms: angina and exertional dyspnoea. CCS, chronic coronary syndrome.
The Canadian Cardiovascular Society classification is still widely used estimation of obstructive CAD. Smoking cessation counselling starts
as a grading system for effort-induced angina to quantify the threshold with a quantitative assessment of prior and current tobacco use to
at which symptoms occur with physical activities (Table 5). Importantly, make the risk factor more evident to the patient. In addition, detailed
the severity of symptoms is not well associated with the severity of ob family history looking for premature cardiovascular disease (CVD) or
structive CAD and appears to differ by sex. Women have more fre sudden cardiac death should always be obtained. If available, cholesterol
quent angina, independent of less extensive epicardial CAD, and less levels help define familial hypercholesterolaemia.64 It is also essential
severe myocardial ischaemia than men.63 Angina at rest is not always to assess the presence of comorbidities that affect the likelihood of
indicative of severe, fixed obstructive CAD, as it may also occur in pa CAD and overall survival. Because of their high prevalence in CCS
tients with transient epicardial or microvascular coronary vasospasm. patients, diabetes, chronic obstructive pulmonary disease, kidney dis
It is essential to document coronary risk factors during history taking, ease, and peripheral and cerebral vascular disease are particularly
as they may be modifiable and will be used for the pre-test likelihood relevant.
3436 ESC Guidelines
Table 5 Grading of effort angina severity according to branch block (LBBB) and impaired atrioventricular conduction]. Atrial
the Canadian Cardiovascular Society fibrillation (AF) is not rarely associated with CCS.68 ST-segment de
pression during supraventricular tachyarrhythmias, however, is not a
Grade Description of angina severity66 strong predictor of obstructive CAD.69–72
I Angina only with Presence of angina during strenuous, The ECG can be crucial for diagnosing transient myocardial ischae
strenuous exertion rapid, or prolonged ordinary activity mia by recording dynamic ST-segment changes during ongoing angina.
(walking or climbing the stairs)
Vasospastic angina (VSA) should be suspected when observing typical
transient ST-segment elevations or depressions with U-wave changes
II Angina with Slight limitation of ordinary activities
during an angina attack at rest.73
moderate exertion when they are performed rapidly, after
Long-term ambulatory ECG monitoring can be considered in se
meals, in the cold, in the wind, under
lected patients to detect ischaemia during anginal episodes unrelated
emotional stress, or during the first
to physical activities. ECG changes suggesting ischaemia on ambulatory
few hours after waking up, but also
© ESC 2024
a normal pace and conditions
IV Angina at rest No exertion is needed to trigger angina Recommendation Table 1 — Recommendations for his
tory taking, risk factor assessment, and resting electro
cardiogram in individuals with suspected chronic
coronary syndrome (see also Evidence Table 1)
Recent-onset anginal symptoms with changing frequency or intensity
Recommendations Classa Levelb
should raise the suspicion that a coronary atherosclerotic plaque may
be destabilizing. In these patients, the diagnostic algorithm recom History taking and risk factor assessment
mended by the 2023 ESC Guidelines for the management of patients In individuals reporting symptoms of suspected
with acute coronary syndromes should be used to rule out an acute myocardial ischaemic origin, a detailed assessment of
event.65
cardiovascular risk factors, medical history, and
When investigating suspected CCS, it is important to perform a I C
symptom characteristics (including onset, duration,
thorough physical examination that includes BP measurement and
type, location, triggers, relieving factors, time of day)
body mass index (BMI) calculation, to assess the presence of anaemia,
is recommended.
hypertension, valvular heart disease, LV hypertrophy, or arrhythmias. It
is also recommended to search for evidence of non-coronary vascular Symptoms like chest pain triggered by emotional
disease, which may be asymptomatic (palpation of peripheral pulses; stress; dyspnoea or dizziness on exertion; pain in the
auscultation of carotid and femoral arteries), and signs of other co arms, jaw, neck, or upper back; or fatigue should be IIa B
morbid conditions, such as thyroid disease, renal disease, or diabetes. considered as potential angina
This should be used in the context of other clinical information, such equivalents.18,33,57,59,77
as the presence of cough or stinging pain, making CCS less likely. Resting ECG
One should also try to reproduce the symptoms by palpation and If clinical or ECG assessment suggests ACS rather
test the effect of sublingual nitroglycerine to classify the symptoms.
than CCS, immediate referral to the emergency
department and/or repeated measurement of blood
I B
3.1.2. Basic testing: 12-lead electrocardiogram and troponin, preferably using high-sensitivity or
biochemistry ultrasensitive assays, to rule out acute myocardial
Basic testing in individuals with suspected CCS includes a 12-lead ECG, injury, is recommended.78,79
standard laboratory tests, resting echocardiography, and, in selected A resting 12-lead ECG is recommended in all
patients, a chest X-ray, and a pulmonary function test if dyspnoea is individuals reporting chest pain (unless an obvious
the main symptom. Such tests can be done on an outpatient basis. non-cardiac cause is identified), particularly during, or I C
immediately after, an episode suggestive of
3.1.2.1. Electrocardiogram myocardial ischaemia.
The paradigm of diagnosing myocardial ischaemia has, for almost a cen Using ST-segment deviations during supraventricular
tury, been based on detecting repolarization abnormalities, mainly in tachyarrhythmias, particularly during re-entrant
© ESC 2024
the form of ST-segment depressions or T wave abnormalities. Thus, atrioventricular tachycardias, per se, as reliable III B
the resting 12-lead ECG remains an indispensable component of the ini evidence of obstructive CAD, is not
tial evaluation of a patient with chest pain.67 recommended.80–84
A normal resting ECG is frequently recorded after an anginal attack.
ACS, acute coronary syndrome; CAD, coronary artery disease; CCS, chronic coronary
However, even in the absence of repolarization abnormalities, the ECG
syndrome; ECG, electrocardiogram.
at rest may suggest CCS indirectly, through signs of previous MI (patho a
Class of recommendation.
logical Q or R waves) or conduction abnormalities [mainly left bundle b
Level of evidence.
ESC Guidelines 3437
© ESC 2024
cular outcomes trials.89–91 Given that circulating lipoprotein(a) levels are to assess thyroid function at least once.137,138
genetically determined and do not fluctuate substantially over a life Additionally, hs-CRP and/or fibrinogen plasma levels
IIa B
time,89,91 a single measure is sufficient in persons with suspected CCS.92 should be considered.109–118,121,125
Renal dysfunction increases the likelihood of CAD and has a negative CCS, chronic coronary syndrome; HbA1c, glycated haemoglobin; hs-CRP, high-sensitivity
impact on prognosis.93–95 Glomerular filtration rate (GFR) also impacts C-reactive protein; LDL-C, low-density lipoprotein cholesterol.
a
renally cleared drugs. It is reasonable to also measure uric acid levels, as Class of recommendation.
b
Level of evidence.
hyperuricaemia is frequent, and may affect renal function.
If there is a clinical suspicion of CAD instability, biochemical markers
of myocardial injury—such as troponin T or troponin I—should be
measured, preferably using high-sensitivity assays, and management 3.2. STEP 2: Further evaluation
should follow the 2023 ESC Guidelines for the management of patients 3.2.1. Pre-test clinical likelihood of obstructive
with acute coronary syndromes.65 If high-sensitivity assays are em atherosclerotic coronary artery disease
ployed, low troponin levels can be detected in many patients with stable The diagnosis of CCS is based on interpreting the individual’s symp
angina. Increased troponin levels are associated with adverse out toms, balancing the impact of age, sex, risk factors, and comorbidities
comes,96–100 and small studies have indicated a possible incremental va on the likelihood that CCS is present, and choosing the most appropri
lue in diagnosing obstructive CAD,101–104 but larger trials are needed to ate diagnostic test to confirm the clinically suspected diagnosis. To aid
verify the utility of systematic assessment in individuals suspected of diagnosis, prediction tables for obstructive CAD can be used that inte
CCS. While multiple biomarkers may be useful for prognostication, grate these clinical factors and provide guidance on selecting diagnostic
they do not yet have a role in diagnosing obstructive CAD, but some tests based on their capacities to rule in and rule out obstructive
promising results have been published.105–108 Measuring NT-proBNP atherosclerotic CAD. Importantly, these models do not include the prob
helps confirm or exclude suspected HF. ability of ANOCA/INOCA, which always needs to be considered if
Markers of inflammation such as C-reactive protein109–113 and symptoms persist after deferral of further testing or diagnostic testing
fibrinogen114–118 are predictors of an individual’s risk of CAD and can that excludes obstructive CAD.
predict cardiovascular event risk in CCS patients,99,111 but their value The tables used to estimate the likelihood of obstructive CAD as
is limited beyond traditional risk factors.111 However, in patients taking confirmed by ICA were initially based on the Diamond–Forrester ap
contemporary statins, high-sensitivity C-reactive protein (hs-CRP) was proach, which considered sex, age, and angina symptoms.25
a stronger predictor for future cardiovascular events and death than However, these tables have had to be updated several times owing
LDL-C.119,120 These patients may benefit from additional LDL-C reduc to the declining prevalence of obstructive CAD at invasive angiography
tion through adjunctive lipid-lowering therapies, such as ezetimibe, in contemporary Western cohorts.26,29 The overestimation of ob
proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition,121 structive CAD prevalence has limited the utility of these tables in clinical
inclisiran, and bempedoic acid.122–124 Elevated hs-CRP levels in patients routine and in accurately estimating the post-test likelihood of ob
taking statins and PCSK9 inhibitors may indicate residual inflammatory structive CAD by diagnostic imaging methods.1,29,30
risk that could be further reduced through inflammation modula The 2019 ESC Guidelines for the diagnosis and management of CCS
tion.119,125,126 Experimental inhibition of interleukin-6, a pivotal factor introduced the concept of clinical likelihood as a more comprehensive
in atherothrombosis, resulted in a marked parallel reduction of and individualized assessment of the probability of obstructive CAD.1
C-reactive protein and fibrinogen in patients with chronic kidney dis Compared with a basic pre-test probability model, incorporation of
ease (CKD) and high cardiovascular risk.127 risk factors in the basic pre-test likelihood model (based on age, sex, and
3438 ESC Guidelines
symptoms) leads to improved prediction of obstructive CAD, down- Detection of atherosclerotic disease in non-coronary arteries with
classifies more individuals to very low and low likelihood of disease, ultrasound or CT scans of, e.g. the aorta, and the carotid or femoral ar
and maintains high calibration.30,139,140 The Risk-Factor-weighted teries, may increase the clinical likelihood of obstructive CAD,155–158
Clinical Likelihood (RF-CL) model includes sex, age, angina symptoms, and the risk for future CVD events.159,160 However, how accurately
and number of risk factors without losing diagnostic accuracy com the detection of non-coronary atherosclerotic disease impacts the like
pared with more advanced models requiring computed calculation lihood estimation of obstructive CAD needs further investigation.
(Figure 4).139,141,142 The RF-CL model increases three-fold the number In general, individuals with a very low (≤5%) likelihood of obstructive
of subjects categorized as at very low (≤5%) likelihood of obstructive CAD do not require further diagnostic testing unless symptoms persist
CAD compared with the ESC pretest probability (ESC-PTP) model and non-cardiac causes have been excluded. In patients with a low
(38% vs. 12%),139 while predicting annualized event rates of MI and (>5%–15%) likelihood of obstructive CAD, the benefit of diagnostic
death of 0.5%, 1.1%, and 2.1% for individuals having very low, low, testing is uncertain but may be performed if symptoms are limiting
and moderate likelihood of obstructive CAD, respectively.143 and require clarification. Patients with moderate (>15%–50%), high
with other clinical prediction models or CACS alone (adjustment of detection of atherosclerotic disease in non-coronary IIb C
the estimation of the clinical likelihood of obstructive CAD).139,154 arteries may be considered to adjust the pre-test
With the CACS-CL model, substantially more individuals (54%) com likelihood estimate.144,166
pared with the RF-CL model (38%) were categorized as having a very
CACS, coronary artery calcium score; CAD, coronary artery disease; ECG,
low clinical likelihood of obstructive CAD in the external validation co electrocardiogram.
horts.139 Finally, the CACS-CL model was superior to other clinical a
Class of recommendation.
prediction models in predicting MI and death during follow-up.143 b
Level of evidence.
ESC Guidelines 3439
Symptom score
0–1 point 2 points 3 points
Figure 4 Estimation of the clinical likelihood of obstructive coronary artery disease. CAD, coronary artery disease; RF-CL, risk factor-weighted clinical
likelihood. Data derived from Winther et al.139 The symptom score replaces the previous, potentially misleading terminology, that defined presence of
three chest pain characteristics as ‘typical’ angina (here = 3 points), two of three characteristics as ‘atypical’ angina (here = 2 points), and no or one
characteristic as ‘non-cardiac/non-anginal’ (here = 0–1 point). Family history of CAD is defined as 1 or more first-degree relatives with early signs
of CAD (men <55 and women <65 years of age); smoking, as current or past smoker; dyslipidaemia, hypertension, and diabetes, as present at the
time of diagnosis. Values in the lower panel are the clinical likelihood estimates expressed as %.
3440 ESC Guidelines
CMR, if available, may be considered as an alternative ECG may be considered in selected patients to complement their clin
imaging test in individuals with inconclusive IIb C ical evaluation for assessing symptoms, ST-segment changes, exercise
echocardiographic evaluation.185,186 tolerance, arrhythmias, BP response, and event risk.
In summary, due to its low sensitivity (58%) and specificity (62%), ex
CMR, cardiac magnetic resonance; LVEF, left ventricular ejection fraction.
a
Class of recommendation. ercise ECG testing has low diagnostic performance for the diagnosis of
b
Level of evidence. obstructive CAD148 and should mainly be used for risk stratification.
ESC Guidelines 3441
© ESC 2024
for the assessment of exercise tolerance, symptoms, I C subjects with chest pain and suspected arrhythmias.
arrhythmias, BP response, and event risk. Ambulatory ECG monitoring should be considered
IIa B
Exercise ECG may be considered as an alternative in subjects with suspected vasospastic angina.192–194
test to rule in and rule out CAD when non-invasive IIb B
ECG, electrocardiogram.
imaging tests are unavailable.148,166,188,190,191 a
Class of recommendation.
invasive FFR. It has shown adequate diagnostic performance in se Recommendation Table 8 — Recommendations for
lected cohorts,205,206 and a potential to reduce the number of un non-invasive anatomical imaging tests in the initial
necessary downstream invasive angiography procedures, when diagnostic management of individuals with suspected
compared with functional tests (mostly symptom-limited exercise chronic coronary syndrome—coronary computed tom
ography angiography, if available, and supported by local
ECG).153 While CT perfusion imaging could complement CCTA dur expertise (see also Evidence Table 8)
ing the same visit, this technique requires the administration of a
pharmacological stressor, contrast agent, and further patient irradi Recommendations Classa Levelb
ation. Imaging techniques and analysis methods are not yet widely
standardized (e.g. static and dynamic imaging techniques, visual and In individuals with suspected CCS and low or
quantitative assessment).207–209 moderate (>5%–50%) pre-test likelihood of
obstructive CAD, CCTA is recommended to I A
diagnose obstructive CAD and to estimate the risk of
3.3.1.2. Prognosis, plaque features, and opportunity to improve
© ESC 2024
CACS.210 Systematically evaluating adverse plaque features by inability to cooperate with breath-hold commands,
CCTA can be challenging due to technical limitations (spatial reso or any other conditions that can make obtaining
lution) and patient characteristics (calcifications). good imaging quality unlikely.
A network meta-analysis of randomized trials suggested that diag
CAD, coronary artery disease; CCS, chronic coronary syndrome; CCTA, coronary
nostic testing with CCTA was associated with clinical outcomes similar computed tomography angiography; eGFR, estimated glomerular filtration rate; MACE,
to those with functional imaging in patients with suspected stable major adverse cardiovascular events.
CAD.197 In another pairwise meta-analysis, CCTA showed a lower
a
Class of recommendation.
b
Level of evidence.
rate of MI compared with functional testing, but the absolute per
cent risk difference was small (0.4%).211
In the available randomized trials comparing CCTA and functional
testing (all testing a diagnostic strategy),33,210,212 test reporting and pa 3.3.2. Functional imaging
tient management variability could in part help explain the improved
3.3.2.1. Stress echocardiography
outcomes observed in the CCTA arm of SCOT-HEART. In this trial,
Stress echocardiography is used to detect myocardial ischaemia by
CCTA findings, including non-obstructive atherosclerosis, emphasized
assessing regional systolic wall-thickening abnormalities (RWTA)
the need to trigger the start or intensification of medical treatment.
during stress. It relies on inducing myocardial ischaemia by increasing
Increased standardization in reporting CCTA to encompass key plaque
myocardial oxygen demand beyond the myocardial blood supply.
features (accepting inherent limitations) will be warranted to systemat
Because ischaemia starts in the subendocardium, which contributes
ically harvest prognostic information and help fine-tune risk manage
to more than 50% of systolic myocardial wall thickening, stress testing
ment strategies.213
will precipitate wall-thickening abnormalities in the perfusion territory
of narrowed coronary arteries. Stress modalities used to increase myo
3.3.1.3. Recognized pre-requisites for coronary computed cardial oxygen demand are exercise (treadmill or bicycle), or i.v. admin
tomography angiography istration of dobutamine, or vasodilators (adenosine, dipyridamole,
Generally, a slow and regular heart rate, and compliance with breath- regadenoson) combined with atropine (to increase heart rate ad
holding instructions are necessary to achieve good image quality. equately—a major determinant of oxygen demand). Stress echocardi
This includes suitability to receive pre-medication (typically oral or ography using demand stress has provided diagnostic accuracy and
i.v. beta-blockers) when needed. Kidney function and allergy to con risk-stratification capabilities similar to those obtained with other con
trast agents should be assessed prior to referral. Temporal and spatial temporary functional imaging testing modalities.148,223 The advantages
resolution remain technical limitations and can hinder precision in of stress echocardiography are that it is widely available, low-cost, can
adjudicating coronary stenosis severity. This is most problematic in be performed and interpreted at the bedside, rapid, free of ionizing ra
older patients with heavily calcified coronary arteries, in whom func diation, and can be repeated without safety concerns.224–227 Although
tional testing may be more appropriate than CCTA. Contemporary stress echocardiography is operator-dependent, which may comprom
CT technology (64-slice technology or above) and a well-trained ise reproducibility, the technique is within reach of every cardiology
imaging team can help mitigate these limitations and must be consid department or office. Compromised image quality, especially in obese
ered a pre-requisite for CCTA. and chronic obstructive pulmonary disease subjects, is a significant
ESC Guidelines 3443
limitation. RWTA may not occur if the myocardial oxygen demand in During stress echocardiography, when two or more
crease is inadequate or if the induced perfusion abnormalities are not contiguous myocardial segments are not visualized, it
large enough (<10% of the myocardium), such as in mild atherosclerot is recommended to use commercially available
ic CAD or single-vessel obstructive CAD.228 As stress echocardiog I B
intravenous ultrasound contrast agents
raphy relies on RWTA as a marker of ischaemia, it may (microbubbles) to improve diagnostic
under-estimate ischaemia in patients with microvascular disease not af accuracy.177,229,236,247,248
fecting the subendocardium as in ANOCA/INOCA.36
During stress echocardiography, myocardial
Ultrasound contrast agents considerably enhance the quality of diag
perfusion using commercially available intravenous
nostic images obtained during stress echocardiography. These micro
ultrasound contrast agents (microbubbles) is
bubbles, consisting of stable gas and shells about the size and I B
recommended to improve diagnostic accuracy and
rheology of red blood cells, can pass through the pulmonary microcir
to refine risk stratification beyond wall
culation and induce a dense opacification of the left heart chambers.
motion.177,230,232,236,249–254
© ESC 2024
in individuals with obesity and chronic obstructive pulmonary disease may be considered to improve risk stratification IIb B
and must be used in all cases if it is evident at baseline that all segments beyond wall motion and to assess microvascular
may not be visible during stress. Passage of ultrasound contrast agents function.177,238,255
through the myocardium allows assessment of myocardial perfusion
CAD, coronary artery disease; CCS, chronic coronary syndrome; MACE, major adverse
simultaneously with regional wall motion, improving the sensitivity of cardiovascular events.
stress echocardiography (better detection of single-vessel and micro a
Class of recommendation.
b
vascular disease) and risk stratification beyond RWTA.231–235 The Level of evidence.
use of ultrasound contrast agents during stress echocardiography for
assessing regional and global LV function is strongly recommended by
the European Association of Cardiovascular Imaging (EACVI) and the 3.3.2.2. Myocardial perfusion scintigraphy—single-photon emission
American Society of Echocardiography (ASE) guidelines—both class I computed tomography
indications. Similarly, myocardial perfusion assessment has received a Myocardial perfusion SPECT imaging relies on the myocardial uptake and
class I recommendation by the EACVI and a class IIa recommendation retention of a radiopharmaceutical. Technetium-99m (99mTc)-based
by the ASE.177,236 Ultrasound contrast agents are generally safe, but tracers are the most commonly used radiopharmaceuticals, whereas
rare cases of anaphylactic reactions have been reported.237 Thallium 201 (201Tl) should be avoided as it is associated with higher ra
Measurement of the coronary flow velocity reserve (CFVR) based diation exposure. Myocardial perfusion SPECT produces images of re
on Doppler flow velocity recordings at rest and during stress in the gional myocardial tracer retention, which reflects relative regional
left anterior descending (LAD) artery, and assessment of lung conges myocardial blood flow (MBF). Myocardial hypoperfusion is characterized
tion through the visualization of B-lines on lung ultrasound, can easily be by relative reduced radionuclide tracer uptake and retention during vaso
added to routine stress echocardiography procedures. In a prospective dilatation or stress, compared with the uptake and retention at rest. The
observational multicentre study, a reduced CFVR was often accompan inherent need for a normally perfused myocardial reference territory al
ied by RWTA, abnormal LV contractile reserve, and pulmonary conges lowing for visualization of the myocardium with relative hypoperfusion
tion during stress, and showed independent value over RWTA in constitutes the main limitation of SPECT (and stress CMR), particularly
predicting an adverse outcome.238 The inclusion of these additional in multivessel CAD. Coronary calcium scoring from non-contrast-
parameters in routine stress echocardiography procedures provides in enhanced CT, acquired for attenuation correction, as well as transient
sights on coronary microcirculatory dysfunction. ischaemic dilatation (TID) and reduced post-stress ejection fraction
Finally, carotid ultrasound may be performed in the same session with (EF) are important non-perfusion predictors of severe obstructive CAD.
stress echocardiography to assess extracoronary atherosclerosis; while Ischaemia can be demonstrated by physical exercise or through the
this does not add value for confirming a CCS diagnosis per se, it provides administration of pharmacological stressors (e.g. dobutamine) or
incremental prognostic value beyond myocardial ischaemia.239,240 vasodilators (e.g. dipyridamole, adenosine, or regadenoson).
Pharmacological agents are indicated in patients who cannot exercise ad
equately or may be used as an alternative or an adjunct to exercise stress.
Recommendation Table 9 — Recommendations for The possibility to use physical exercise and/or different pharmacological
non-invasive tests in the initial diagnostic management stressors in combination with the wide-spread availability of the technique
of individuals with suspected chronic coronary syndrome
—stress echocardiography, if available, and supported by and the lack of absolute contraindications contributes to the high versa
local expertise (see also Evidence Table 9) tility and applicability of myocardial perfusion SPECT in clinical routine.
SPECT myocardial perfusion imaging is associated with good accur
Recommendations Classa Levelb acy for the detection of flow-limiting coronary lesions,148,256–258 and
has been shown to provide prognostic information223,259 and to im
In individuals with suspected CCS and moderate or
prove patient management in a randomized controlled trial (RCT).178
high (>15%–85%) pre-test likelihood of obstructive Newer-generation SPECT cameras based on cadmium–zinc–telluride
CAD, stress echocardiography is recommended to I B (CZT) semiconductor detector technology enable a substantial reduction
diagnose myocardial ischaemia and to estimate the in radiation dose exposure and acquisition time, as well as an increased
risk of MACE.33,241–246 diagnostic accuracy260 and absolute quantification of MBF. Hence, its diag
Continued nostic performance for multivessel CAD has improved substantially.261
3444 ESC Guidelines
However, non-obstructive coronary atherosclerosis not linked with is which relies on the first-pass myocardial perfusion of gadolinium-based
chaemia remains undetected by functional testing in general. contrast agents.
If available, assessment of myocardial perfusion using SPECT is recom Recently, CMR methods using various parameters for quantitative MBF
mended in patients with suspected CCS with moderate or high pre-test assessment have been introduced. However, the diagnostic performance
likelihood of obstructive CAD (15%–85%) or known CCS. Importantly, if of these parameters varies extensively among studies, and standardized
non-contrast-enhanced CT for attenuation correction is acquired, this al protocols and software are lacking.272 Therefore, visual assessment of
lows for additional CAC scoring, providing important information for risk perfusion defects is currently used in clinical practice. Myocardial
stratification even in the absence of flow-limiting coronary lesions. perfusion imaging by stress CMR combines high spatial resolution with
the absence of ionizing radiation. This has been shown to provide high
3.3.2.3. Positron emission tomography-computed tomography diagnostic accuracy in detecting flow-limiting coronary lesions,148,257,258
Similarly to myocardial perfusion SPECT imaging, PET also relies on prognostic value,223,273–275 and improving patient management.178,276
radiopharmaceuticals. Contrary to SPECT, however, the radionuclides Pharmacological vasodilators (e.g. adenosine or regadenoson) or stres
In patients selected for PET or SPECT myocardial Recently, quantitative CMR has been proposed as an emerging tech
perfusion imaging, it is recommended to measure nique for the assessment of microvascular dysfunction through MBF
CACS from unenhanced chest CT imaging (used for I B quantification but is currently limited to experienced centres.275
attenuation correction) to improve detection of Quantitative myocardial perfusion can also be achieved by myocardial
both non-obstructive and obstructive CAD.289–293 contrast echocardiography (MCE) through destruction–reperfusion
imaging and analysis of the time–intensity curves from different regions
In individuals with suspected CCS and moderate
of interest in the myocardium.231,233–235 Of note, MCE assesses capil
or high (>15%–85%) pre-test likelihood of
lary blood flow, and capillaries comprise 90% of the microvasculature.
obstructive CAD, stress CMR perfusion imaging is
I B Measuring MBF at rest and during hyperaemia allows calculation of MBF
© ESC 2024
recommended to diagnose and quantify myocardial
reserve, which is associated with severity of coronary stenoses in pa
ischaemia and/or scar and estimate the risk of
tients with stable angina. In a meta-analysis, MBF reserve had high accur
MACE.148,273,276,278,294–297
acy for predicting flow-limiting CAD.231 However, in the absence of
In patients with suspected ANOCA/INOCA and an ICA/coronary 3.3.3.2. Functional assessment of epicardial stenosis severity to
pressure assessment disclosing no significant epicardial CAD, additional guide coronary revascularization
invasive investigations including index of microcirculatory resistance When non-invasive stress tests are inconclusive or not performed, identi
(IMR), CFR and, if necessary, invasive vasoreactivity testing using Ach fying the artery responsible for ischaemia during ICA can be challenging,
(or ergonovine)36 as part of a complete ‘invasive coronary functional especially in cases with multivessel CAD or coronary stenoses of inter
testing’ (ICFT) can be performed. mediate severity (typically around 40%–90% for non-left main stem sten
Performing ICA is not exempt from potential complications. Given oses or 40%–70% for left main stem stenoses by visual estimate). In such
that femoral diagnostic catheterization has been associated with a cases, recording wire-based intracoronary pressure during maximal hyper
0.5%–2.0% composite rate of major complications, mainly bleeding re aemia to calculate FFR or at rest to measure iFR is recommended to im
quiring blood transfusions,327 radial access is now the standard access prove risk assessment and clinical decision-making and to reduce clinical
when possible. Radial access has been associated with reduced mortal events.318–320 This has been confirmed by large clinical outcome studies
ity and reduced major bleeding while allowing rapid ambulation.327 Still, such as FAME 1,308 FAME 2,49 DEFINE-FLAIR (Functional Lesion
When ICA is indicated, IVUS should be considered to SWEDEHEART studies have reported a 2% absolute increase in all-cause
evaluate the severity of intermediate stenoses of left IIa B mortality in those managed with iFR.343,344 This was not associated with
main stemc prior to revascularization.336,337 any unplanned revascularization or non-fatal MI rate increase.343,344
CAD, coronary artery disease; FFR, fractional flow reserve; ICA, invasive coronary
Although it was initially hypothesized that this mortality excess could be
angiography; iFR, instantaneous wave-free ratio; IVUS, intravascular ultrasound. related to a higher proportion of ‘inappropriate’ revascularization deferral
a
Class of recommendation. with iFR compared with FFR (50% vs. 45%),343 it is reassuring that
b
Level of evidence.
c iFR-based deferral is as safe as FFR-based deferral up to 5 years.345
Typically 40%–90% for non–left main stem stenoses and 40%–70% for left main stem
stenoses by visual estimate. For ICA in the diagnostic management of individuals with In patients with multivessel CAD, systematic FFR measurement of all
suspected ANOCA/INOCA, see Section 5.3. (Specific groups). epicardial vessels has been proposed to select appropriate therapy, but
ESC Guidelines 3447
recent studies (RIPCORD2 and FUTURE) did not demonstrate any clinical Recommendation Table 12 — Recommendations for
outcome improvement compared with angiography alone.346,347 functional assessment of epicardial artery stenosis
Therefore, intracoronary pressure measurement in patients with multi severity during invasive coronary angiography to guide
vessel CAD should only be performed on intermediate lesions. revascularization (see also Evidence Table 12)
Several recent studies using either FFR or iFR suggest that the pattern
Recommendations Classa Levelb
of pressure drop along the coronary artery (focal vs. progressive) re
corded during a pullback is important to select patients who will benefit During ICA, selective assessment of functional severity of intermediatec
more from PCI.2,348–352 Longitudinal functional vessel interrogation can diameter stenoses is recommended to guide the decision to revascularize,
therefore be helpful in patients with serial lesions or diffuse CAD. using the following techniques:
New 3D angiographically derived wireless coronary pressure para • FFR/iFR (significant ≤0.8 or ≤0.89,
meters, such as quantitative flow ratio (QFR) or vessel fractional flow I A
respectively);49,308,310,311,313,321–323,332,373
reserve (vFFR), are at different stages of clinical investigation325,353,354
• QFR (significant ≤0.8).325,355,374,375 I B
© ESC 2024
indexes against FFR alone to demonstrate their clinical value, and it is Systematic and routine wire-based coronary
important to also show benefit in a direct comparative trial vs. angiog pressure assessment of all coronary vessels is not III A
raphy. In that context, the results of the FAVOR III China study355 are recommended.346,347
important, demonstrating an improved clinical outcome in the
CFC, coronary flow capacity; CFR, coronary flow reserve; dPR, diastolic pressure ratio;
QFR-guided group compared with the angiography-guided group,
FFR, fractional flow reserve; HSR, hyperaemic stenosis resistance; ICA, invasive coronary
driven by fewer MIs and ischaemia-driven revascularizations. angiography; iFR, instantaneous wave-free ratio; Pd/Pa, distal coronary pressure to aortic
The combined measurements of pressure and flow (measured by pressure ratio; QFR, quantitative flow ratio; RFR, relative flow reserve.
a
Doppler or thermodilution) may further reduce the number of inter Class of recommendation.
b
Level of evidence.
ventions. Patients with lesions and concordant normal FFR and CFR c
Typically around 40%–90% for non-left main stem or 40%–70% for left main stem by visual
have an excellent prognosis. Patients with lesions and discordant results estimate.
between FFR and CFR have a similar prognosis to that of patients with
lesions and concordant abnormal FFR and CFR, treated with PCI.
Lesions with an abnormal FFR but normal CFR pertain to a good clinical 3.3.3.3. Assessment of microvascular dysfunction
outcome up to 5 years of follow-up if left untreated.356–358 Moreover, Detailed discussion of microvascular dysfunction by invasive coronary
hyperaemic stenosis resistance (HSR), by measuring the pressure gra functional testing is provided in Section 5.2.5.2. After nitroglycerine, ad
dient across a lesion divided by flow, is an excellent index for both enosine is administered to assess endothelium-independent vasodila
diagnostic and prognostic purposes.359,360 The recently introduced tion [CFR, IMR, and hyperaemic myocardial velocity resistance
continuous thermodilution technique for measuring absolute coronary (HMR)]. Coronary flow reserve can be calculated using bolus thermo
flow presents an alternative method for determining CFR. Additionally, dilution (as baseline transit time divided by hyperaemic transit time) or
this method allows for evaluation of the microvascular resistance continuous thermodilution (as the ratio of hyperaemic and resting abso
reserve (MRR), a novel index for assessing coronary microvascular lute coronary flow), or Doppler flow velocity (hyperaemic flow velocity
function.361–364 divided by baseline flow velocity).307,378,379 The IMR is calculated as the
Coronary flow capacity (CFC) integrates hyperaemic flow and CFR product of distal coronary pressure at maximal hyperaemia multiplied
and is useful for both diagnostic purposes as well as the evaluation of by the hyperaemic mean transit time. Increased IMR (≥25 U) indicates
the result after PCI.365–368 microvascular dysfunction.380,381 It is important to note that continuous
Intravascular imaging techniques [e.g. intravascular ultrasound (IVUS) thermodilution-derived measurements have shown higher reproducibil
or optical coherence tomography (OCT)] have demonstrated good ity than similar measurements derived from bolus thermodilution.382
diagnostic accuracy in predicting FFR, especially in stenoses located in Angiography-derived index of coronary microcirculatory resistance
the left main stem.369,370 They are reasonable options to assess left (angio-IMR) allows microcirculation assessment without using intracor
main stenosis severity and prognosis; increasing left main plaque burden onary wires.383
was associated with long-term all-cause and cardiac mortality in pa
tients not undergoing revascularization.371
While coronary pressure thresholds, specifically 0.80 for FFR and 3.3.3.4. Testing for coronary vasospasm
0.89 for iFR, are crucial in aiding clinical decision-making, particularly Vasoreactivity testing explores endothelium-dependent mechanisms of
in the case of deferring revascularization when FFR/iFR exceeds the is CMD and epicardial and microvascular vasomotor tone disorders.36,73,384
chaemic threshold,310,372 they must be considered alongside other The most established approach for coronary vasoreactivity testing
parameters. These include a careful assessment of the patient’s symp is by intracoronary infusion of Ach, although other substances like
toms and the results of non-invasive stress testing to determine the ergonovine have been proposed.384,385 The methodology is described
need for revascularization. in detail in Section 5.2.5.2.2.
3448 ESC Guidelines
3.3.4. Diagnostic algorithm and selection of revascularization is judged to be futile, the diagnosis of CCS can be
appropriate tests made clinically, and managed with medical therapy and lifestyle changes
After estimation of the pre-test likelihood of obstructive epicardial alone. If CCS diagnosis is uncertain in such patients, establishing a
CAD based on the RF-CL model (Figure 4 and Figure 5),139 further diag diagnosis using non-invasive functional imaging for myocardial ischaemia
nostic testing is dependent on the clinical scenario, general condition, before treatment is reasonable.
QoL, presence of comorbidities, local availability and expertise for dif Individual adjustment of the clinical likelihood should always be con
ferent diagnostic techniques, and importantly patient expectations and sidered based on the clinical CCS scenario including ECG and echocar
preferences (Figure 6; Table 6). diography findings. Further diagnostic testing can be deferred in patients
In patients with severe comorbidities or severe frailty or very low with a very low (≤5%) likelihood of obstructive CAD. Based on the
QoL that all contribute to a limited life expectancy, in whom CACS-CL model, in patients with a low (>5%–15%) likelihood of
Symptom score
0–1 point 2 points 3 points
100
85 CACS �1000
70 CACS 400–999
50
CACS 100–399
30
Coronary artery calcium 20 CACS 10–99
15 CACS 1–9
score (CACS)-weighted clinical 10 CACS 0
likelihood of obstructive CAD (%)
5
0
0 10 20 30 40 50 60 70 80
Risk Factor-Weighted Clinical Likelihood of obstructive CAD (%)
Figure 5 Adjustment and reclassification of the estimated clinical likelihood of obstructive coronary artery disease. CACS, coronary artery calcium
score; CACS-CL, coronary artery calcium score + RF-CL model; CAD, coronary artery disease; CT, computed tomography; ECG, electrocardiogram;
LV, left ventricular; RF-CL, risk factor-weighted clinical likelihood.
ESC Guidelines 3449
Functional imaging
Very low
Defer further testing
�5%
Figure 6 Appropriate first-line testing in symptomatic individuals with suspected chronic coronary syndrome. CAD, coronary artery disease; CCS,
chronic coronary syndrome; CCTA, coronary computed tomography angiography; CMR, cardiac magnetic resonance; ECHO, echocardiography;
PET, positron emission tomography; SPECT, single-photon emission computed tomography.
obstructive CAD, CACS can be considered to re-estimate the likeli first-line test in the group with a low or moderate (15%–50%) likeli
hood of obstructive CAD.139,165,141,154 Further diagnostic testing can hood.27,31,32,139,386 Given the low prevalence of CAD in this group of
also be deferred in patients reclassified based on CACS from a low patients and its high negative predictive value, CCTA is the most effect
to a very low (<5%) likelihood of obstructive CAD (Figure 5).143 ive diagnostic method to rule out obstructive CAD. Moreover, besides
Conversely, if CACS is high and there are clinical findings indicating its strength in ruling out CAD, CCTA offers direct visualization of
that the RF-CL model may be under-estimating the likelihood of ob non-obstructive CAD, which may trigger intensification of preventive
structive CAD, further diagnostic testing should be selected based on measures. The use of CCTA as a first-line test is supported by large,
the adjusted clinical likelihood and coronary calcium burden. It is im randomized trials showing equivalence in health outcomes with func
portant to note that patients with a very low and low (≤15%) likelihood tional testing33 and even superiority compared with usual care using ex
of obstructive CAD constitute approximately 85% of individuals with ercise ECG.34
de novo symptoms suspected of CCS.27,30,139 Most can be treated con In patients with a very high (≥85%) clinical likelihood of obstructive
servatively without the need for further testing as they have no sten CAD, symptoms unresponsive to medical therapy, or angina at a low
oses or non-obstructive CAD with a very low incidence of events level of exercise, and an initial clinical evaluation (including echocardio
during long-term follow-up.27,139,143 gram and, in selected patients, exercise ECG) that indicates a high event
Individuals with a moderate or high (>15%–85%) likelihood of risk, proceeding directly to ICA without further diagnostic testing is a
obstructive CAD should be referred for non-invasive anatomical or reasonable option. Under such circumstances, the indication for revas
functional imaging to establish the diagnosis and assess the risk for cularization of stenoses with a diameter reduction of <90% should be
future cardiac events. There is growing support for using CCTA as a guided by coronary pressure assessment (Figure 6; Table 6).
3450 ESC Guidelines
Selective
High-risk sequential Severe
CADa testing Functional ischaemia
CCTA
imaging
Refractory
Lifestyle and risk factor modification symptoms
Disease-modifying and antianginal treatment
Invasive investigation
Figure 7 Initial management of symptomatic individuals with suspected chronic coronary syndrome. ANOCA, angina with non-obstructive coronary
arteries; CAD, coronary artery disease; CCS, chronic coronary syndrome; CCTA, coronary computed tomography angiography; CMR, cardiac mag
netic resonance; Echo, echocardiography; FFR, fractional flow reserve; ICFT, invasive coronary functional testing; iFR, instantaneous wave-free ratio;
INOCA, ischaemia with non-obstructed coronary arteries; LV, left ventricular; PET, positron emission tomography; SPECT, single-photon emission
computed tomography. Consider local availability and expertise, and individual characteristics when choosing non-invasive testing. Table 6 offers
tips for selecting the first-line test in people with suspected CCS. aHigh–risk CAD: obstructive CAD at high risk of adverse events by CCTA: ≥50%
stenosis of the left main stem; three–vessel disease with severe stenoses (≥70% diameter stenosis); single- or two–vessel disease including the proximal
LAD with severe stenoses. Consider functional imaging or invasive investigation.
Functional imaging should be selected as a first line test if information imaging tests overcome the limitations of CCTA in certain groups (old
on myocardial ischaemia, viability, or microvascular disease is desired. er patients with more extensive coronary calcifications, AF, and other
Tests for detecting ischaemia have better rule-in power compared situations with an irregular or fast heart rate, renal insufficiency, or io
with CCTA and therefore should be selected if there is a moderate- dinated contrast allergy), and avoid exposure to ionizing radiation in
high (>15-85%) likelihood of obstsructive CAD. Moreover, functional young individuals and in those suspected of ANOCA/INOCA (Figure 7).
ESC Guidelines 3451
Table 6 Overview of non-invasive tests used for first-line testing in individuals with suspected chronic coronary
syndrome
Anatomical imaging
CCTA Atherosclerosis (obstructive and Iodinated contrast Severely impaired kidney functiona
non-obstructive) in epicardial Radiation Documented allergy to iodinated contrast
coronary arteries Premedication: Tachyarrhythmia refractory to
• Beta-blockers or ivabradine for heart rate control beta-blockade
• Nitroglycerine for adequate vasodilation Irradiation (especially young women)
© ESC 2024
PET LVEF Vasodilator stress Contraindication to stressor
Ischaemia/blood flow Radioactive tracer (13N-ammonia, 15O-water, 82Rb) Irradiation (especially young women)
Viability
CCS, chronic coronary syndrome; CCTA, coronary computed tomography angiography; CMR, cardiac magnetic resonance; CT, computed tomography; Echo, echocardiography; LVEF, left
ventricular ejection fraction; MI, myocardial infarction; PET, positron emission tomography; SPECT, single-photon emission computed tomography.
a
Preventive measures are recommended for patients with eGFR <30 mL/min/1.73 m2.389
The discussion about which modality to use as a first-line test has Individuals in the moderate likelihood group, except older men with all
been heavily focused on the detection of obstructive epicardial sten three CCS symptom characteristics, will have a likelihood of obstructive
oses, neglecting the relatively high prevalence of non-obstructive cor CAD around 20%. In these, anatomical and functional testing will each re
onary disease and ANOCA/INOCA, especially in female patients. sult in an intermediate positive predictive value with eventually many false
The current rationale behind choosing a first-line test should be to as positives, especially with CCTA easily overestimating stenosis severity.
sess the anatomical severity and functional consequences of coronary Sequential testing (i.e. functional testing after CCTA, or vice versa) will
disease, whether obstructive or not. In this regard, PET-CT should therefore be needed in many individuals to establish an accurate diagnosis
be more frequently considered and its availability increased as it of obstructive, ischaemia-inducing CAD (Figure 8). Sequential or combined
combines calcium scoring with accurate operator-independent anatomical and functional testing is also useful for the non-invasive diagnosis
detection of myocardial ischaemia and CMD with a low irradiation of ANOCA/INOCA.41 Moreover, combined testing, e.g. combining CCTA
dose.45 and PET, may result in improved prognostication of CCS patients.387
3452 ESC Guidelines
CCTA +
80
DSE -
40
B
20
A
CCTA -
0
0 20 40 60 80 100
Pre-test likelihood (%)
Figure 8 Ruling in and ruling out functionally significant obstructive coronary artery disease by sequential anatomical (coronary computed tomog
raphy angiography) and functional (dobutamine stress echocardiography) testing.a CAD, coronary artery disease; CCTA, coronary computed tomog
raphy angiography; DSE; dobutamine stress echocardiography; ECG, electrocardiogram; FFR, fractional flow reserve. The curves display the post-test
likelihood of obstructive CAD for a positive (+) and a negative (−) test result for CCTA and DSE, as the pre-test likelihood of obstructive CAD in
creases. The post-test likelihoods were calculated using the likelihood ratios taken from recent meta-analyses.148,388 aBased on invasive FFR measure
ment or diameter stenosis of ≥70%.
• A 70-year-old woman with four coronary risk factors and exertional dyspnoea has a pre-test likelihood of 16% (A). A normal CCTA almost com
pletely rules out obstructive CAD with a very low negative post-test likelihood (2%).
• A 55-year-old man with two coronary risk factors and all three anginal symptom characteristics has a pre-test likelihood of 27% (B). An abnormal
CCTA brings the post-test likelihood to 40%, insufficient to rule in obstructive CAD. Sequential testing with DSE performed after CCTA brings the
post-test likelihood to 82%. A normal CCTA effectively rules out obstructive CAD.
• A 69-year-old man with four coronary risk factors and all three anginal symptom characteristics has an adjusted pre-test likelihood of 60% (C) (ad
justment based on abnormalities on the resting ECG and on symptoms during exercise). A positive DSE alone has a high post-test likelihood
(± 90%). A negative DSE is associated with a 32% post-test likelihood. Sequential testing by CCTA would allow ruling out obstructive CAD
(<5% post-test likelihood).
ESC Guidelines 3453
Recommendation Table 13 — Recommendations for three-vessel or two-vessel disease including the proximal LAD artery
selection of initial diagnostic tests in individuals with sus with ≥70% stenosis, or if functional imaging shows moderate or severe
pected chronic coronary syndrome (see also Evidence ischaemia encompassing an extensive perfusion territory.
Table 13) For patients with obstructive CAD and refractory symptoms despite
optimized GDMT, a referral for ICA may be considered to improve
Recommendations Classa Levelb
symptoms through revascularization. Optimization of medical therapy
Selection of non-invasive testing by combining two or more antianginal drugs can safely be obtained over
6 weeks in almost all patients and should be awaited before referral to
It is recommended to select the initial non-invasive
ICA.402,403 It is worth noting that in the Objective Randomised Blinded
diagnostic test based on pre-test likelihood of
Investigation with optimal medical Therapy of Angioplasty in stable an
obstructive CAD, other patient characteristics that I C
gina (ORBITA) trial, PCI did not provide short-term advantages com
influence the performance of non-invasive tests,c and
pared with GDMT in terms of reducing anginal frequency or physical
local expertise and availability.29,148
registries showing that plaque burden and presence of adverse plaque angiography.433,434 This allows a less invasive, easier and more accurate
characteristics, especially low-attenuation plaque, are the strongest pre global FFR calculation, provided imaging is of sufficiently good
dictors of fatal and non-fatal MI above the classical risk factors, including quality.369–371
stenosis severity.210,415–417 These findings emphasize a major advantage In summary, when assessing event risk, clinicians should choose an
of anatomical imaging by CCTA as an initial test in selected patients, al integrative approach, considering risk factors, comorbidities, LV dys
lowing the assessment of severity and extent of obstructive CAD as function, the severity of myocardial ischaemia, the number of function
well as coronary plaque characteristics. ally significantly stenotic coronary arteries, and the coronary plaque
Regarding the prognostic impact of inducible myocardial ischaemia burden and characteristics, as all of these are likely interrelated factors
by functional stress imaging, the evidence remains conflicting. While that affect overall prognosis.
there are extensive data from large observational studies315,418–425
Recommendation Table 14 — Recommendations for
consistently demonstrating a robust prognostic value conferred by definition of high risk of adverse events (see also
the extent of inducible ischaemia as detected by functional imaging Evidence Table 14)
min of chest discomfort after sublingual nitroglycerine increases the their individual risks and the potential benefit of prevention treatments
likelihood of CCS. Patients may be advised to refrain from strenuous and then actively engaged in managing their disease. Treatment goals
physical activities before the diagnostic process is completed and are communicated using a patient-centred approach (Table 7).
should be instructed what to do if prolonged anginal chest pain indica
tive of acute MI arises.
Table 7 Practical advice on lifestyle counselling and
Guideline-directed management and therapy are started during or
interventions
after the diagnostic process is concluded. The main goals of treating
CCS are to improve both QoL and life expectancy. This involves vari Topic Recommendation and treatment goals in
ous interventions to reduce the risk of (i) cardiac mortality, (ii) non-fatal patients with established CCS
ischaemic events, (iii) progression of epicardial and/or microvascular
chronic coronary disease, and (iv) symptoms and limitations caused Lifestyle counselling
by CCS. When deciding on treatment options, it is important to con Immunization • Vaccination against influenza, pneumococcal
Reducing CVD risk at the individual level begins with effective informa Physical activity and • 30–60 min moderate activity, >5 days/week
tion on risk and anticipated risk reduction by treatment. Risk algorithms exercise • Reduce sedentary time and engage in at least
are available for use in clinical practice by means of interactive tools on light activity throughout the day
line. The use of the Smart risk score (U-prevent.com) is suggested by
BMI, body mass index; CCS, chronic coronary syndrome; COVID-19, coronavirus disease
the European Association of Preventive Cardiology for risk estimation 2019; HbA1c, glycated haemoglobin; LDL-C, low-density lipoprotein cholesterol; PDE-5,
in patients with previous CVD.446 Ideally, patients are made aware of phosphodiesterase-5; SBP, systolic blood pressure.
3456 ESC Guidelines
4.1.2.1. Smoking and substance abuse Double-Blind, Placebo-Controlled Trial) trial showed a dose-dependent
Smoking cessation in CCS patients improves prognosis, with a reported weight-loss benefit (mean weight change of up to −20.9%; 95% CI,
36% risk reduction of premature death in those who quit compared −21.8% to −19.9%) with tirzepatide, a combined glucose-dependent in
with those who continue to smoke.447 Measures to promote smoking ces sulinotropic polypeptide (GIP) and GLP-1 receptor agonist, compared
sation include brief advice, counselling and behavioural interventions, and with placebo in obese adults without diabetes over 72 weeks,466 a dose
pharmacological therapy.448,449 Patients should also avoid passive smoking. effect that was confirmed in the SURMOUNT-2 trial.467 Bariatric surgery
Drug support to assist in smoking cessation should be considered in in severe obesity appears to be a safe and effective intervention for further
all smokers who are ready to undertake this action. Nicotine- weight loss in CCS patients.468
replacement therapy, bupropion, or varenicline are effective,450,451 Cardiac rehabilitation programmes should include weight-loss inter
and are not linked to an increase in MACE.452 ventions to reach a healthy weight as a specific component. The incre
The use of electronic cigarettes (e-cigarettes), as an alternative to con mental value of telehealth interventions and pharmacological
ventional cigarettes, should be discouraged because they are not harm- interventions need full consideration in secondary prevention.469
inactive adults, light-intensity physical activity, even as little as 15 min a through smartphones may be as effective as traditional centre-based
day, is likely to produce benefits.479 cardiac rehabilitation, showing significant improvements in
health-related QoL.496
Small, single-centre studies on exercise training in patients with
4.1.3. Exercise therapy INOCA show that it is feasible and improves cardiorespiratory function
Exercise training, either alone or in the context of multidisciplinary, and QoL.497 Larger trials are needed to determine the optimal rehabili
exercise-based cardiac rehabilitation, leads to reduction in hospitaliza tation protocols and define its long-term benefits.
tions, adverse cardiovascular events, mortality rates, and improved
CVD risk profile in patients with ASCVD.480–483 Therefore, exercise Recommendation Table 15 — Recommendations for
is a therapy that should be offered to every CCS patient in the setting cardiovascular risk reduction, lifestyle changes, and ex
ercise interventions in patients with established chronic
of secondary disease prevention.16
coronary syndrome (see also Evidence Table 15)
Exercise training should be individually prescribed according to the
© ESC 2024
suggested prescription is one to three sets of 8–12 repetitions, at the patients’ long-term adherence to healthy behaviours, IIa B
intensity of 6%–80% of the individual’s one-repetition maximum, at a and to reduce hospitalizations or cardiac
frequency of at least 2 days per week, using a variety of 8–10 different events.480,493,494
exercises involving each major muscle group.16,484
CVD, cardiovascular disease.
Exercise is contraindicated in patients with refractory/unstable angina a
Class of recommendation.
b
and other high-risk cardiovascular conditions (e.g. high-grade arrhyth Level of evidence.
mias, decompensated HF, severe aortic dilatation, active thrombo-
embolic disease). In non-cardiac unstable conditions (e.g. active infection,
uncontrolled diabetes, end-stage cancer, chronic obstructive pulmonary 4.2. Antianginal/anti-ischaemic medication
disease exacerbation), exercise is contraindicated. Maintenance of the 4.2.1. General strategy
prescribed exercise regimen is crucial. According to a meta-regression In patients with CCS, antianginal medical therapy aims to control symp
analysis, no single exercise component predicts mortality outcomes, toms while ensuring acceptable tolerability and patient adherence.
whereas the largest reductions in total and cardiovascular mortality Several factors should be considered for the selection of antianginal
were seen in post-cardiac rehabilitation patients with the highest adher medical therapy. First, there is no robust evidence from direct compar
ence rate.487 In addition, continuation of the exercise therapy (Phase III isons that some antianginal drugs are more effective than others for im
cardiac rehabilitation) is recommended as it will result in increased/main proving symptoms.504,505 There have been no large randomized trials
tained functional capacity, QoL, and physical activity levels.488 comparing head-to-head the historically first approved antianginal
Sharing decision-making and offering a personalized prescription, medications [i.e. beta-blockers or calcium channel blockers (CCBs)]
based on the patient’s preferences (self-selected training) and abilities vs. newer anti-ischaemic drugs (ivabradine, nicorandil, ranolazine,
(age, concomitant diseases, leisure and working habits, logistical re trimetazidine);504,506 the latter have been tested in smaller trials assessing
straints), is recommended to increase long-term adherence.489 In add non-inferiority compared with beta-blockers507 or CCBs,508 or in a lar
ition, smartphone applications490 and wearable activity trackers491 may ger trial as add-on therapy with a background of beta-blockers and/or
assist in long-term adherence to physical activity goals and exercise CCBs.508,509 Moreover, there is no evidence that any antianginal medi
therapy (see Section 6.2.1.3).492 cation may improve long-term cardiovascular outcomes, except beta-
Home-based cardiac rehabilitation with or without telemonitoring blockers if administered within 1 year after an acute MI.510 Second,
may increase participation and be as effective as centre-based cardiac many patients require a combination of anti-ischaemic drugs to ad
rehabilitation.493 Telehealth interventions are more effective than no equately control symptoms.511 It remains unclear whether upfront
intervention and may also complement conventional cardiac rehabilita combination therapy with two antianginal drugs is preferable to mono
tion.494,495 Also, mobile device-based healthcare (mHealth) delivery therapy, or which combinations of antianginal classes may be better
3458 ESC Guidelines
than others for improving angina symptoms. Third, in any given patient, of a beta-blocker and/or a CCB, or as a part of initial combination ther
myocardial ischaemia and angina symptoms may be caused by various apy in appropriately selected patients (Figure 9).
underlying pathophysiological mechanisms, alone or in combin Regardless of the initial strategy, response to initial antianginal therapy
ation;6,512 these may include obstruction of epicardial coronary arter should be reassessed, and treatment should be adapted if adequate an
ies, vasospasm, and endothelial/microvascular dysfunction. Based on gina control is not achieved or if the initial treatment is poorly tolerated.
their mechanisms of action, different classes of antianginal drugs may A review of the antianginal agents that can be used in the medical
be preferable (as initial therapy or as part of combination therapy) treatment of CCS can be found in the Supplementary data.
for patients with myocardial ischaemia of predominantly obstructive,
vasospastic, or microvascular origin.513 4.2.2. Beta blockers
The current empirical paradigm for the selection of antianginal med Beta-blockers can be used for symptomatic relief of angina, or to im
ical therapy has consisted of a hierarchical, stepwise approach including prove prognosis in some patients with CCS. If used for antianginal pur
first-line (beta-blockers, CCBs) and second-line drugs (long-acting ni poses, the aim should be to lower resting heart rate to 55–60 beats per
HFrEF
HCM
Obstructive CAD
HFrEF
Vasospastic angina
Atrial fibrillation Diltiazem Ivabradine
Verapamil Sick sinus syndrome
Sick sinus syndrome
HFrEF
Trimetazidine Ranolazine
Figure 9 Possible combinations of antianginal drugs. CAD, coronary artery disease; CCB, calcium channel blocker; COPD, chronic obstructive pul
monary disease; HCM, hypertrophic cardiomyopathy; HFrEF, heart failure with reduced ejection fraction. The schematic shows useful combinations
(green lines), combinations that are not recommended (red lines), possible combinations (solid blue lines), and drugs with similar effects (blue dashed
lines), which can be combined in selected indications: HFrEF (ivabradine and beta-blocker), atrial fibrillation (diltiazem/verapamil and beta-blocker),
vasospastic angina (dihydropyridine CCB and nitrates). Modified from Davies et al.555.
ESC Guidelines 3459
observational studies and meta-analyses is conflicting (some suggest an as When long-acting nitrates are prescribed, a
sociation between beta-blockers and better clinical outcomes, whereas nitrate-free or low-nitrate interval should be IIa B
others show a lack of association).521,523–526 There have been only two considered to reduce tolerance. 540
open-label trials testing the efficacy of beta blockers in post-MI patients Ivabradine should be considered as add-on
(NCT03278509 and NCT01155635), though both trials were under antianginal therapy in patients with left ventricular
powered to yield solid conclusions.527 To further elucidate the benefit
systolic dysfunction (LVEF <40%) and inadequate IIa B
of beta-blockers in this clinical scenario, three European pragmatic, pro
control of symptoms, or as part of initial treatment in
spective, large-scale RCTs recruiting post-ACS patients with preserved
properly selected patients.541,542
LVEF to receive beta-blockers or control treatment are currently under
Nicorandil or trimetazidine may be considered as
way.522,528–530
The duration of beta-blocker therapy, in the long run, is a matter of add-on therapy in patients with inadequate control
debate, particularly in patients with prior MI and preserved LVEF.531 of symptoms while on treatment with beta-blockers IIb B
© ESC 2024
hypertrophic cardiomyopathy or in
has shown that the discontinuation of beta-blockers beyond 1 year III B
co-administration with phosphodiesterase
after acute MI was associated with an increased risk of a composite
inhibitors.552,553
of death or readmission for ACS, but not of all-cause mortality.534
The impact of beta-blocker withdrawal 6–12 months after uncompli CCB, calcium channel blocker; CCS, chronic coronary syndrome; CYP3A4, cytochrome
cated ACS in patients with LVEF ≥40% is being tested in two large-scale P450 3A4; DHP, dihydropyridine; DM, diabetes mellitus; LVEF, left ventricular ejection
fraction.
RCTs (NCT03498066, NCT04769362.535 a
Class of recommendation.
b
Level of evidence.
c
Recommendation Table 16 — Recommendations for These drugs may require caution or may be contraindicated in certain patients with low BP
antianginal drugs in patients with chronic coronary syn (beta-blockers and DHP-CCB), DM (beta-blockers), atrioventricular conduction disorders
(beta-blockers and non-DHP-CCB), chronic obstructive pulmonary disease
drome (see also Evidence Table 16)
(non-cardioselective beta-blockers).
d
Consideration for initial therapy: ivabradine, nicorandil, long-acting nitrates, ranolazine, or
Recommendations Classa Levelb trimetazidine for patients with intolerance or contraindications to beta-blockers and/or
CCBs; ranolazine and trimetazidine for patients with microvascular angina; nicorandil or
General strategy nitrates for patients with coronary artery spasm. The drugs are listed in alphabetical order.
It is recommended to tailor the selection of
antianginal drugs to the patient’s characteristics,
comorbidities, concomitant medications, treatment I C
4.2.3. Combination therapy
tolerability, and underlying pathophysiology of angina,
The aim of antianginal medications is to ensure adequate relief of angina
also considering local drug availability and cost.
symptoms in patients with CCS, in part independently of their effect or
Selection of antianginal medication lack of effect on MACE. Initiation of monotherapy, with subsequent es
Short-acting nitrates are recommended for calation to a combination of antianginal drugs in the case of inadequate
I B
immediate relief of angina.536,537 relief of symptoms, is a reasonable approach. In this context, the empir
Initial treatment with beta-blockers and/or CCBs to ical approach of starting with a beta-blocker can be recommended in
control heart rate and symptoms is recommended I B many patients with CCS, unless there are contraindications or other
for most patients with CCS.c 518,538 drugs are more suitable instead of beta-blockers (e.g. patients with
If anginal symptoms are not successfully controlled low heart rate and/or BP). If a combination of antianginal drugs is re
by initial treatment with a beta-blocker or a CCB
quired, the selection of the most appropriate drugs should be individua
IIa B
lized and determined by the haemodynamic profile, comorbidities, and
alone, the combination of a beta-blocker and a
tolerability. The combination of a beta-blocker with a dihydropyridine
DHP-CCB should be considered, unless
CCB is appropriate for most patients, whereas the addition of other
contraindicated.505,538,539
antianginal drugs (long-acting nitrates, ranolazine, nicorandil, trimetazi
Long-acting nitrates or ranolazine should be
dine, or ivabradine in patients with LV systolic dysfunction) can be con
considered as add-on therapy in patients with sidered when treatment with a beta-blocker and/or CCB is
inadequate control of symptoms while on treatment IIa B contraindicated or poorly tolerated, or when angina symptoms are in
with beta-blockers and/or CCBs, or as part of initial adequately controlled.
treatment in properly selected patients.d 513,540 The following points should additionally be kept in mind: (i) beta-
Continued blockers are not indicated in the presence of sick sinus syndrome or
3460 ESC Guidelines
atrioventricular conduction disorders,554 and should be used with 4.3.1.1.2. Oral P2Y12 inhibitor monotherapy.
caution in patients with PAD and chronic obstructive pulmonary dis 4.3.1.1.2.1. Clopidogrel monotherapy. In addition to the
ease; (ii) CCBs require caution in patients with heart failure with re cyclooxygenase-I pathway inhibited by aspirin, the platelet P2Y12 recep
duced ejection fraction (HFrEF);526 (iii) ivabradine should not be tor also plays a pivotal role in arterial thrombus formation and is the
combined with non-dihydropyridine CCBs (verapamil or diltiazem); target for three oral platelet inhibitors: clopidogrel, prasugrel, and
and (iv) ranolazine and trimetazidine are reasonable options as part ticagrelor. The relative efficacy and safety of clopidogrel compared
of antianginal combination therapy in patients with low heart rate with aspirin for secondary prevention in CCS patients has been tested
and/or BP. in multiple randomized trials that, taken together, have involved over
29 000 patient-years.562,563
In an overall population of 19 185 patients with either previous MI
4.3. Medical therapy for event prevention
(within 35 days), stroke (within 6 months), or PAD, followed for a
Prevention of coronary ischaemic events is based on lowering the risk
mean of 1.9 years, the CAPRIE trial (Clopidogrel versus Aspirin in
of coronary artery occlusion and consequent ACS. Medical event-
Plaque rupture or
plaque erosion
TxA2 Aspirin
ADP
Platelet rolling
and adhesion P P
Thromboxane
TF:FVIIa Clopidogrel
receptor
coagulation Prasugrel
Edoxaban
Rivaroxaban Platelet
GP IIb/IIIa aggregation
Fibrinogen
Enoxaparin
UFH
VKA
Dabigatran Fibrinogen
Fibrin
Argatroban Thrombin network
Bivalirudin
Fibrin
Figure 10 Antithrombotic drugs for chronic coronary syndromes: pharmacological targets. ADP, adenosine diphosphate; FVIIa, activated factor VII;
FXa, activated factor X; GP, glycoprotein; PAR, protease-activated receptor; TF, tissue factor; TxA2, thromboxane A2; UFH, unfractionated heparin;
VKA, vitamin K antagonist. Orally administered drugs are shown on a blue background, parenterally administered ones on red. Aspirin prevents TxA2
formation by acetylating platelet cyclooxygenase-1.
ACS), showed reduced ischaemic events, but increased BARC 3 and 5 atherectomy-treated calcified lesions) and uneventfully receiving
major bleeding, during ticagrelor monotherapy compared with aspirin 3 months of ticagrelor-based DAPT after PCI, showed that ticagrelor
monotherapy from 1 to 2 years after PCI.572 monotherapy 90 mg b.i.d. (twice daily) compared with ticagrelor-
The double-blind, non-inferiority TWILIGHT trial, conducted in 7119 based DAPT for an additional 12 months significantly reduced the
patients [35% CCS, 65% NSTE (non-ST-segment elevation)-ACS] primary endpoint of clinically relevant bleeds (BARC 2, 3, and 5, or
undergoing high-risk PCI (defined as multivessel, stenting of >30 mm, BARC 3 and 5), with no significant increase in the composite of any
thrombotic, two-stent bifurcation, left main, proximal LAD, or death, MI, or stroke (3.9% in both groups).573
3462 ESC Guidelines
The above trial data570–573 and meta-analytical data562,563,574 suggest that an abbreviated DAPT of 1–3 months reduced both major bleeding
that ticagrelor monotherapy may be an option for selected CCS or sta and ischaemic events, as well as cardiovascular mortality, compared with
bilized post-ACS patients treated with PCI. However, the overall evi standard DAPT, irrespective of CCS or ACS presentation.591
dence is weaker than for other recommended antithrombotic The overall data indicate that, in CCS patients with HBR, DAPT dis
strategies. Moreover, the optimal timing and duration (longest tested continuation 1–3 months after PCI is recommended, while in patients
duration 23 months) are unclear. Only the 90 mg b.i.d. regimen has without HBR, DAPT duration may be reduced only in the absence of
been tested as monotherapy.573,575 Data on prasugrel monotherapy high ischaemic risk (Figure 11). For patients at high ischaemic risk with
for CCS patients are limited to a single-armed, open-label study with out HBR, see below.
3 months of follow-up.576
In summary, for long-term secondary prevention in CCS patients 4.3.1.1.4. Extended intensified antithrombotic therapy. In patients at
without an indication for oral anticoagulant (OAC), aspirin or, as an al high ischaemic risk without HBR, there are three options for intensifying
ternative, clopidogrel monotherapy are generally recommended. In se antithrombotic therapy to prevent ischaemic events, albeit at the cost of
A C A C A C OR A T A C
6 mo. DAPT 1–3 mo. DAPT OR 1–3 mo. DAPT
1 month (Class I) (Class IIb) A P (Class I)
3 months
A OR C A OR C
(Class I)
(Class I)
6 months
A OR C A C A T
OR OR T
(Class I) A R A P
(Class IIa) (Class IIb)
Long term
Figure 11 Antithrombotic treatment in chronic coronary syndrome patients undergoing percutaneous coronary intervention. ARC-HBR, Academic
Research Consortium for High Bleeding Risk; b.i.d., bis in die (twice daily); CCS, chronic coronary syndrome; CYP2C19, cytochrome P450 2C19; DAPT, dual
antiplatelet therapy; mo., months; OAC, oral anticoagulant; o.d., once daily; PCI, percutaneous coronary intervention; PRECISE-DAPT, PREdicting bleeding
Complications In patients undergoing Stent implantation and subsEquent Dual Anti Platelet Therapy. aIn CCS patients undergoing high-thrombotic risk stent
ing (e.g. complex left main stem, 2-stent bifurcation, suboptimal stenting result, prior stent thrombosis, previously known CYP2C19*2/*3 polymorphisms),
prasugrel or ticagrelor (in addition to aspirin) may be considered instead of clopidogrel for the first month, and up to 3-6 months. bPrasugrel 5 mg o.d. for
patients aged ≥75 years or with a body weight <60 kg. Bleeding risk criteria according to PRECISE-DAPT or ARC-HBR.
4.3.1.1.5. Genotype- and phenotype-guided dual antiplatelet with non-carriers.599,600 In ST-segment elevation myocardial infarction
therapy. There is high laboratory interindividual variability in patients (STEMI) patients, early de-escalation from aspirin plus ticagrelor or as
treated with clopidogrel, with patients who carry a cytochrome pirin plus prasugrel to aspirin plus clopidogrel based on genotyping or
P450 2C19 (CYP2C19) loss-of-function allele having less platelet platelet function testing was non-inferior for net adverse clinical events
inhibition and a higher risk of ischaemic events post-PCI compared (ischaemic endpoints and bleeding combined) compared with routine
3464 ESC Guidelines
© ESC 2024
age ≥75 years)
Ticagrelor (PEGASUS-TIMI 60/90 mg b.i.d. Post-MI in patients who have 84 81
54; vs. placebo) tolerated DAPT for 1 year (TIMI major bleeds)
ACS, acute coronary syndrome; BARC, Bleeding Academic Research Consortium; b.i.d., bis in die (twice daily); CAD, coronary artery disease; DAPT, dual antiplatelet therapy; GUSTO,
Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Arteries; ISTH, International Society on Thrombosis and Haemostasis; MI, myocardial infarction;
NNH, number needed to cause a harmful event; NNT, number needed to treat to prevent an adverse event; o.d., once daily; PAD, peripheral artery disease; PCI, percutaneous
coronary intervention; TIMI, Thrombolysis In Myocardial Infarction. Drugs (in addition to aspirin 75–100 mg/day) for extended DAPT options are listed in alphabetical order. For
definitions of highly/moderately increased ischaemic and bleeding risk see Supplementary data, Tables S2 and S3. NNT refers to the primary ischaemic endpoints and NNH refers to the
key safety endpoints of the respective trials. NNT and NNH from the DAPT trial are pooled numbers for clopidogrel and prasugrel.
treatment with ticagrelor or prasugrel.601,602 In patients with CCS, PCI, with a theoretical indication for both OAC for stroke prevention
current evidence does not support the routine use of genotype or plate (for which DOACs are preferred to VKA) and DAPT for stent throm
let function testing.602–607 However, in patients undergoing high-risk PCI bosis and MI prevention, leading to triple antithrombotic therapy.612,613
who are known carriers of a CYP2C19 loss-of-function allele, replacing The combination of an OAC plus DAPT, however, leads to an in
aspirin plus clopidogrel with aspirin plus ticagrelor or prasugrel is a rea creased bleeding risk, and major bleeding is associated with earlier mor
sonable option.600,607,608 tality and should therefore be avoided when possible.614 In this setting,
the results of five RCTs have shown that double compared with triple
4.3.1.2. Anticoagulant therapy antithrombotic therapy reduced major or clinically relevant non-major
4.3.1.2.1. Monotherapy with oral anticoagulant. Historical rando bleeding, without a significant increase of ischaemic events, leading to
mized data from patients with recent MI not undergoing PCI, followed the recommended use of double antithrombotic therapy (OAC plus
for up to 4 years, showed that OAC monotherapy with a vitamin K P2Y12 receptor inhibitor, mostly clopidogrel) after a 1–4 week
antagonist (VKA) targeted to an international normalized ratio (INR) period of triple antithrombotic therapy in CCS patients with AF under
of about 3.0–4.0 was at least as effective as low-dose aspirin in prevent going PCI.615–620
ing MACE, but with a significant increase in major bleeding.609,610 The AUGUSTUS trial (Open-Label, 2 × 2 Factorial, Randomized
Moreover, given the obsoletely high INR target and the cumbersome Controlled, Clinical Trial to Evaluate the Safety of Apixaban versus
management, VKA has not gained popularity for secondary prevention Vitamin K Antagonist and Aspirin versus Aspirin Placebo in Patients
in patients with CCS. Successful introduction of the direct oral with AF and Acute Coronary Syndrome or Percutaneous Coronary
anticoagulants (DOACs) for stroke prevention in AF and for preven Intervention) additionally demonstrated that the DOAC apixaban re
tion and treatment of venous thrombo-embolism (VTE) has renewed duced major or clinically relevant non-major bleeding compared with
the interest in OAC for patients with CAD. The COMPASS trial in VKA, independently of a double or triple antithrombotic regimen.619
CCS and/or PAD patients at high ischaemic risk, however, reported The AUGUSTUS trial and several meta-analyses demonstrated that as
no significant ischaemic benefit of rivaroxaban monotherapy 5 mg twice pirin compared with placebo reduced stent thrombosis events, which
daily over aspirin alone, with a significantly higher incidence of occurred mainly during the first 30 days after PCI and not thereafter,
modified-ISTH major bleeding, although not of fatal bleeding.594 while increasing bleeding risk.620–622
Thus, in CCS patients without a concomitant long-term indication Thus, based on the combined evidence, double antithrombotic ther
for OAC, OAC monotherapy with either VKA or rivaroxaban (the apy with a DOAC and clopidogrel for up to 12 months should be stand
only DOAC currently tested in this context) is not recommended. ard care for CCS patients with AF undergoing PCI, with additional
OAC may be considered, however, when antiplatelet agents are not aspirin only for a limited initial period (from during PCI up to a max
tolerated, if the risk of bleeding is not high,594,611 or in CCS patients imum of 30 days in patients at high ischaemic risk). In patients with
with a concomitant long-term indication for OAC (see below). the highest bleeding risk, clopidogrel discontinuation at 6 (or even 3)
months post-PCI and continuation of OAC alone may be considered
4.3.1.2.2. Combination of anticoagulant and antiplatelet therapy when ischaemic risk is not high [Class IIb/level of evidence (LOE) C].
after percutaneous coronary intervention in chronic coronary Ticagrelor or prasugrel should generally not be used as part of triple an
syndrome patients with AF or other indication for oral anticoagu tithrombotic therapy, while ticagrelor, and possibly prasugrel (although
lant. Approximately one in five patients with AF need to undergo specific data are not available), may be considered as part of double
ESC Guidelines 3465
antithrombotic therapy when there is a very high risk of stent throm revascularization.635 Therefore, in patients undergoing CABG for CCS,
bosis and a low bleeding risk.619,623,624 DAPT is not routinely indicated; however, it may be considered in se
After a 6- to 12-month period of double antithrombotic therapy, in lected cases at increased risk of graft occlusion who are not at high bleed
most AF-PCI CCS patients, OAC alone is preferred over continuation ing risk (defined in Supplementary data, Tables S2 and S3).
of double antithrombotic therapy.625,626 An open-label randomized trial, Transient new-onset AF is common 2 to 3 days after CABG, occur
conducted in 2236 Japanese AF patients who had undergone PCI (71% of ring in approximately one-third of patients.638 AF after CABG is asso
patients) or CABG (11% of patients) >1 year before or had known CAD ciated with a higher stroke risk,639 which is, however, lower than that
not requiring revascularization, compared rivaroxaban monotherapy (15 with AF unrelated to surgery.640 The impact of early OAC initiation
or 10 mg once daily based on creatinine clearance) with rivaroxaban plus on patient outcomes remains unclear.641,642 In a Danish cohort study,
SAPT (mostly aspirin).627 At a median follow-up of 23 months, the occur early OAC initiation was associated with a lower risk of thrombo-
rence of ISTH major bleeding and of all-cause deaths were each signifi embolic events,641 while in a Swedish cohort study, OAC was asso
cantly lower with rivaroxaban monotherapy, whereas MACE ciated with no reduction of thrombo-embolic complications but an
4.3.1.3. Coronary artery bypass grafting and antithrombotic therapy 4.3.1.4. Proton pump inhibitors
Low-dose aspirin is recommended lifelong in patients undergoing Antithrombotic therapy may provoke GI bleeding, especially in patients at
CABG.629,630 Aspirin should be continued until the day of CABG and increased risk, such as the elderly, those with a history of GI bleeding or
restarted as soon as there is no concern over bleeding, possibly within peptic disease, high alcohol consumption, chronic use of steroids or non-
24 h of CABG.631,632 In general, other antithrombotic drugs should be steroidal anti-inflammatory drugs (NSAIDs), or receiving a combination of
stopped at intervals related to their duration of action (prasugrel antithrombotic drugs.643–645 In patients on various types of antithrombo
stopped ≥7 days before; clopidogrel ≥5 days before; ticagrelor tic therapy, proton pump inhibitors may be effective in reducing the risk of
≥3 days before; and rivaroxaban, apixaban, edoxaban, and dabigatran GI bleeding, in particular from gastroduodenal lesions.646–648 In general,
1–2 days before, depending on drug and renal function).633,634 gastric protection with proton pump inhibitors is recommended in pa
Although not consistent, there is evidence that DAPT with a P2Y12 re tients at increased risk of GI bleeding for as long as any antithrombotic
ceptor inhibitor compared with aspirin monotherapy provides higher therapy is administered.65,86 Because the proton pump inhibitors omepra
graft patency rates after CABG.635,636,637 A meta-analysis of four zole and esomeprazole inhibit CYP2C19, when administered with clopi
RCTs, involving 1316 patients (with 3079 grafts) followed for 3 to 12 dogrel, they reduce exposure to clopidogrel’s active metabolite; while
months after CABG, reported superior vein graft patency with their use is discouraged in combination with clopidogrel, univocal effects
ticagrelor-based DAPT vs. aspirin alone, but with increased rates of of these combinations on the risk of ischaemic events or stent thrombosis
BARC 2–5 (but not BARC 3–5) bleeds, and no significant differences have not been demonstrated (https://www.ema.europa.eu/en/medicines/
in cardiovascular death, or the composite of cardiovascular death, human/EPAR/plavix).643,646 Of note, proton pump inhibitors do not in
MI, and stroke, or the composite of all-cause death, MI, stroke, and crease MACE vs. placebo in patients with CVD.646
Recommendation Table 17 — Recommendations for antithrombotic therapy in patients with chronic coronary syn
drome (see also Evidence Table 17)
Long-term antithrombotic therapy in patients with chronic coronary syndrome and no clear indication for oral anticoagulation
In CCS patients with a prior MI or remote PCI, aspirin 75–100 mg daily is recommended lifelong after an initial period of DAPT.558,559 I A
In CCS patients with a prior MI or remote PCI, clopidogrel 75 mg daily is recommended as a safe and effective alternative to aspirin
I A
monotherapy.562,564–566,649
After CABG, aspirin 75–100 mg daily is recommended lifelong.558,559,629 I A
In patients without prior MI or revascularization but with evidence of significant obstructive CAD, aspirin 75–100 mg daily is recommended
I B
lifelong.557–559
Adding a second antithrombotic agent to aspirin for extended long-term secondary prevention should be considered in patients at enhanced
IIa A
ischaemic riskc and without high bleeding riskd (options and definitions in Table 8 and in the Supplementary data online, Tables S2 and S3).592–594
In CCS or stabilized post-ACS patients who underwent PCI and were initially treated with ticagrelor-based DAPT, who remain at high
ischaemic risk and are not at high bleeding risk, ticagrelor monotherapy 90 mg b.i.d. may be considered as an alternative to dual or other IIb C
single antiplatelet therapy.563,570–573
Continued
3466 ESC Guidelines
Antithrombotic therapy post-percutaneous coronary intervention in patients with chronic coronary syndrome and no indication for
oral anticoagulation
In CCS patients with no indication for oral anticoagulation, DAPT consisting of aspirin 75–100 mg and clopidogrel 75 mg daily for up to 6
I A
months is recommended as the default antithrombotic strategy after PCI-stenting.650–654
In patients at high bleeding riskd but not at high ischaemic risk,c it is recommended to discontinue DAPT 1–3 months after PCI and to
I A
continue with single antiplatelet therapy.587,591
Stopping DAPT after 1–3 months from PCI-stenting may be considered in patients who are not at high bleeding risk nor at high risk of
IIb B
ischaemic events.588,655–657,c,d
In CCS patients undergoing high-thrombotic risk stenting (e.g. complex left main stem, 2-stent bifurcation, suboptimal stenting result, prior
stent thrombosis, previously known CYP2C19 *2/*3 polymorphisms), prasugrel or ticagrelor (in addition to aspirin) may be considered IIb C
instead of clopidogrel, for the first month, and up to 3–6 months.
ACS, acute coronary syndrome; AF, atrial fibrillation; ARC-HBR, Academic Research Consortium for High Bleeding Risk; b.i.d., bis in die (twice daily); CABG, coronary artery bypass grafting;
CAD, coronary artery disease; CCS, chronic coronary syndrome; CKD, chronic kidney disease; CYP2C19, cytochrome P450 2C19; DAPT, dual antiplatelet therapy; DOAC, direct oral
anticoagulant; INR, international normalized ratio; LAD, left anterior descending; MI, myocardial infarction; OAC, oral anticoagulant; PCI, percutaneous coronary intervention;
PRECISE-DAPT, PREdicting bleeding Complications In patients undergoing Stent implantation and subsEquent Dual AntiPlatelet Therapy; VKA, vitamin K antagonist.
a
Class of recommendation.
b
Level of evidence.
c
Enhanced thrombotic/ischaemic risk criteria for extended treatment with a second antithrombotic agent (Supplementary data, Table S3). Thrombotic risk encompasses (i) the risk of
thrombosis occurring, and (ii) the risk of death should a thrombotic event occur, both of which relate to anatomical, procedural, and clinical characteristics. Thrombotic/ischaemic risk
factors for CCS (that may also apply to CABG) patients include stenting of left main stem, proximal LAD, or last remaining patent artery; suboptimal stent deployment; stent length of
>60 mm; diabetes mellitus; CKD; bifurcation with two stents implanted; treatment of chronic total occlusion; and previous stent thrombosis on adequate antithrombotic therapy.
d
Bleeding-risk criteria according to PRECISE-DAPT or ARC-HBR (Supplementary data, Table S2).
e
Anatomical/procedural thrombotic risk characteristics: stenting of left main, proximal LAD, or last remaining patent artery; suboptimal stent deployment; stent length of >60 mm; bifurcation
with two stents implanted; treatment of chronic total occlusions.
f
For example, stentectomy, endarterectomy, poor venous graft quality.
ESC Guidelines 3467
4.3.2. Lipid-lowering drugs periprocedural events.682 Routine pre-treatment or loading (in the
Evidence from genetic, epidemiological, and randomized clinical context of pre-existing statin treatment) with a high-dose statin can
studies has established the key causal role of LDL-C and other be considered in patients with CCS undergoing PCI.
apo-B-containing lipoproteins in the development of atherosclerotic
disease.669 In patients with established ASCVD, lowering of LDL-C le Recommendation Table 18 — Recommendations for
vels reduces the risk of recurrent MACE.128,670,671 Elevated lipid levels lipid-lowering drugs in patients with chronic coronary
should be managed according to the 2019 ESC/EAS Guidelines for the syndrome (see also Evidence Table 18)
management of dyslipidaemias64 and the 2021 ESC Guidelines on car
Recommendations Classa Levelb
diovascular disease prevention in clinical practice.16
Because patients with CCS are considered at very high cardiovascular Lipid-lowering treatment with an LDL-C goal of <1.4
risk, the treatment goal is to lower LDL-C levels to <1.4 mmol/L mmol/L (55 mg/dL) and a ≥50% reduction in LDL-C I A
(<55 mg/dL) and achieve a reduction by at least 50% from baseline. vs. baseline is recommended.64,670,671
© ESC 2024
event) while taking maximally tolerated statin IIb B
monotherapy. This LDL-C reduction translated into a modest reduc
therapy, an LDL-C goal of <1.0 mmol/L (<40 mg/dL)
tion of a composite endpoint involving fatal and non-fatal events
may be considered.675,676
(6.4% RR reduction, 2.0% absolute risk reduction).674 Ezetimibe should
be used as second-line therapy when the treatment goal is not achieved CCS, chronic coronary syndrome; LDL-C, low-density lipoprotein cholesterol; PCSK9,
with maximally tolerated statin therapy, or as first-line therapy in the proprotein convertase subtilisin/kexin type 9.
a
Class of recommendation.
case of intolerance to any statin regimen. Proprotein convertase subti b
Level of evidence.
lisin/kexin type 9 inhibitors (alirocumab or evolocumab), administered
subcutaneously every 2 or 4 weeks, lower LDL-C levels by 60% when
added to statin therapy.675 In cardiovascular outcomes trials, these 4.3.3. Renin–angiotensin–aldosterone blockers/
monoclonal antibodies resulted in significant reduction of non-fatal car angiotensin receptor neprilysin inhibitor
diovascular events, with no impact on cardiovascular mortality.675,676 Modulation of the RAAS and the neprilysin inhibitor sacubitril in com
Their favourable safety profile was recently confirmed for longer bination with a RAS blocker has proved beneficial in patients with HF
follow-up (median 5 years) in open-label extension studies of the out post-MI and in patients with hypertension. In these clinical syndromes,
comes trials.677 The high cost of PCSK9 inhibitors is still a limitation for RAAS inhibition has greatly improved morbidity and mortality.
broader implementation. Angiotensin-converting enzyme inhibitors (ACE-Is) can reduce mortal
Bempedoic acid is an oral cholesterol synthesis inhibitor that lowers ity, MI, stroke, and HF among patients with LV dysfunction,683–685 pre
LDL-C by approximately 18% in monotherapy and 38% when com vious vascular disease,686–688 and high-risk DM.689 These data bring
bined with ezetimibe.678,679 In a recent cardiovascular outcomes trial strong evidence to recommend ACE-Is [or angiotensin receptor block
including statin-intolerant patients, bempedoic acid significantly re ers (ARBs) in cases of intolerance] for the treatment of patients with
duced MACE.680 Inclisiran, a small interfering ribonucleic acid molecule, CCS with co-existing hypertension, LVEF ≤40%, DM, or CKD, unless
is administered subcutaneously every 3–6 months and reduces LDL-C contraindicated (e.g. severe renal impairment, hyperkalaemia, etc.). In
by approximately 50% either in combination with statin or without sta trials that include patients with mildly reduced and preserved LV func
tin therapy.681 A cardiovascular outcomes trials for inclisiran is current tion >40%, the effect of ACE-Is to reduce all-cause death, cardiovascu
ly underway (ClinicalTrials.gov identifier: NCT03705234). lar death, non-fatal MI, stroke, or HF in patients with atherosclerosis is
In patients scheduled to undergo elective PCI, pre-treatment with a not uniform.686,687,690 A meta-analysis, including 24 trials and 61 961
high-dose statin in statin-naïve patients or loading with high-dose statin patients, documented that, in CCS patients without HF, RAAS inhibi
in statin-treated patients has been shown to reduce the risk of tors reduced cardiovascular events and death only when compared
3468 ESC Guidelines
with placebo, but not when compared with active control treat composite of death from cardiovascular causes, non-fatal MI, or non-
ment.691 For this reason ACE-I therapy in CCS patients without HF fatal stroke—was reduced significantly, with an HR of 0.80 (95% CI,
or high cardiovascular risk is not generally recommended, unless re 0.72–0.90; P < .001).465
quired to meet BP targets. However, a new observational study
showed that ACE-I/ARB therapy was associated with significant long- Recommendation Table 19 — Recommendations for
term survival benefit in patients post-PCI for STEMI/non-ST-segment sodium–glucose cotransporter 2 inhibitors and/or
glucagon-like peptide-1 receptor agonists in patients
elevation myocardial infarction (NSTEMI). This survival benefit is appar
with chronic coronary syndrome (see also Evidence
ent in patients with both preserved and reduced LV function. These Table 19)
findings provide contemporary evidence to support the use of these
agents in coronary patients who underwent PCI for STEMI/NSTEMI, ir Recommendations Classa Levelb
respective of their baseline LV function.692
Sacubitril/valsartan contains an ARB and a prodrug of neprilysin CCS patients with type 2 diabetes
© ESC 2024
tor agonists were initially intended as glucose-lowering medications for considered in overweight (BMI >27 kg/m2) or obese
IIa B
patients with type 2 DM; however, a growing body of evidence has es CCS patients without diabetes to reduce CV
tablished that these drugs lower ASCVD risk and confer cardiovascular mortality, MI, or stroke.465
benefits beyond their glucose-lowering potential.688,695–697 Among pa
BMI, body mass index; CCS, chronic coronary syndrome; CV, cardiovascular; GLP-1,
tients with DM, SGLT2 inhibitor use was associated with a reduced risk
glucagon-like peptide-1; HbA1c, glycated haemoglobin; MI, myocardial infarction; SGLT2,
of MACE, especially in patients with established ASCVD.698 The exact sodium–glucose cotransporter 2; T2DM, type 2 diabetes mellitus.
mechanism(s) by which SGLT2 inhibitors improve CVD outcomes re a
Class of recommendation.
b
main largely unknown, but several hypotheses have been pro Level of evidence.
c
Canaglifozin, dapagliflozin, empagliflozin, sotagliflozin (listed in alphabetical order).
posed.695,696,699–702 The benefits of SGLT2 inhibitors may relate d
Dulaglutide, efpeglenatide, liraglutide, semaglutide (listed in alphabetical order).
more to cardiorenal haemodynamic effects than to atherosclerosis16
The cardiovascular benefits of GLP-1 receptor agonists is driven by re
duced risk of ASCVD-related events.703 Overall, the results of cardio 4.3.5. Anti-inflammatory agents for event prevention
vascular outcome trials of SGLT2 inhibitors and GLP-1 receptor Four large double-blind trials have compared the effects of anti-
agonists support their recommendation as first-line treatment for all inflammatory agents vs. placebo in patients with atherothrombotic
patients with type 2 DM and ASCVD including CCS, independently CAD. The Canakinumab Antiinflammatory Thrombosis Outcome
of decisions about glycaemic management (Recommendation Table 19). Study (CANTOS) tested three doses of the anti-interleukin-1-beta
In patients with HF with reduced (HFrEF) or preserved EF (HFpEF), monoclonal antibody canakinumab against placebo in over 10 000 pa
dapagliflozin and empagliflozin lowered the risk of worsening HF or car tients with previous MI and plasma C-reactive protein ≥2 mg/L.712
diovascular death in the presence or absence of type 2 DM.704–707 The highest dose (300 mg every 3 months) reduced plasma
Recent results indicate benefits of SGLT2 inhibitors on hospitalization interleukin-6 and C-reactive protein and the combined endpoint of car
for HF and cardiovascular death in patients at high cardiovascular risk, ir diovascular death, non-fatal MI, and non-fatal stroke over a mean of
respective of HF history.708 Recommendations for the use of SGLT2 in 3.7 years: 3.90 vs. 4.50 events per 100 person-years (HR 0.86; 95%
hibitors in patients with diabetes and patients with HF are detailed in the CI, 0.75–0.99; P = .031). The other doses did not provide favourable re
2023 ESC Guidelines for the management of cardiovascular disease in pa sults. Despite efficacy, the drug was not developed further for this indi
tients with diabetes86 and the 2021 ESC Guidelines for the diagnosis and cation because of the risk of fatal infections and high costs.
treatment of acute and chronic heart failure526 and its 2023 Focused Low-dose methotrexate (target dose 15–20 mg once weekly) did not
Update. 709 Recommendations on the use of these medications in pa reduce the composite of cardiovascular death, non-fatal MI, non-fatal
tients with HF are given in Section 4.3.4 and Recommendation Table 24. stroke, or unstable angina-driven revascularization in 4786 patients
In patients with pre-existing CVD, the SELECT trial assessed the ef with previous MI or multivessel coronary atherosclerosis and additional
fect of weekly subcutaneous administration of the GLP-1 receptor DM or metabolic syndrome.713 The trial was stopped early (median
agonist semaglutide at a dose of 2.4 mg on MACE reduction in over 2.3 year follow-up) for futility.
weight or obese adults without type 2 DM. The trial involved 17 604 The COLCOT (Colchicine Cardiovascular Outcomes Trial) tested
patients with established CVD and a BMI ≥27 kg/m2. Patients lost a low-dose colchicine (0.5 mg daily) vs. placebo in 4745 patients with re
mean of 9.4% of body weight over the first 2 years with semaglutide cent MI (<30 days) regardless of C-reactive protein values.714 During a
vs. 0.88% with placebo. The primary cardiovascular endpoint—a median of 2.3 years, the composite of cardiovascular death, resuscitated
ESC Guidelines 3469
cardiac arrest, non-fatal MI, non-fatal stroke, or unstable angina-driven 4.4. Revascularization for chronic coronary
revascularization occurred in 5.5% on colchicine vs. 7.1% on placebo
(HR 0.77; 95% CI, 0.61–0.96; P = .02). Colchicine had favourable effects
syndromes
Invasive treatment of CAD with either CABG or PCI is historically de
on each outcome component. All-cause mortality did not differ (43 vs. 44
scribed under the term revascularization. Although both procedures in
events). Diarrhoea was reported in 9.7% vs. 8.9% (statistically non-
crease CFC365,366 and prevent myocardial ischaemia during exercise or
significant); pneumonia, although not frequent, was recorded more often
emotional stress, they do not heal coronary atherosclerosis.
with colchicine than placebo (0.9% vs. 0.4%; P = .03).
Revascularization by both modalities improves angina-related health
The LODOCO2 trial (Low-Dose Colchicine 2) randomized 5500
status.50,52,717 Randomized and meta-analytical evidence supports a
patients with atherosclerotic CAD who had been stable for at least
survival benefit above medical therapy for CABG in patients with left
6 months to low-dose colchicine (0.5 mg daily) or placebo for a median
main disease,718–721 as well as three-vessel disease,722 particularly in pa
of 2.4 years.715 The primary endpoint (cardiovascular death, spontan
tients with LV dysfunction.719,723,724 Most of this evidence was obtained
eous MI, ischaemic stroke, or ischaemia-driven revascularization) oc
prior to the introduction of disease-modifying therapies such as ACE-Is/
heart failure.683–685 After publication of the ISCHEMIA trial results, several meta-
ACE-Is should be considered in CCS patients at very analyses have reported similar overall survival and inevitably higher
IIa A
high risk of cardiovascular events.686,687,690,691 rates of procedural MI with routine revascularization, while confirming
consistently greater freedom from spontaneous MI, unstable angina,
ACE-I, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; CCS,
and anginal symptoms after revascularization compared with GDMT
chronic coronary syndrome.
a
Class of recommendation. alone.732–734 Of note, these meta-analyses showed some differences
b
Level of evidence. in methodology, in selected trials, and follow-up duration.
3470 ESC Guidelines
Furthermore, the importance of ‘any myocardial infarction’ as an end no overall reduction in cardiac events.746 However, significant benefits
point is complicated by a debate over the prognostic importance of were observed when adhering to PET recommendations (after exclud
procedural infarctions as well as how various MI definitions affect the ing 25% protocol violations).746 Post hoc analyses and substudies con
prediction of long-term outcomes735,736 A more recent meta-analysis firmed the positive outcomes of a PET-guided strategy.747,748
of RCTs that included the longest available follow-up showed that add The Surgical Treatment for Ischemic Heart Failure (STICH) trial ran
ing revascularization to GDMT reduced cardiac mortality compared domized 1212 patients with CAD without left main diseases eligible
with GDMT alone. The cardiac survival benefit improved with the dur for CABG and LVEF ≤35% to receive either CABG and GDMT, or
ation of follow-up and was linearly related to a lower rate of spontan GDMT alone. The trial failed to achieve its primary endpoint of all-cause
eous MI.55 mortality at a median follow-up of 4 years (HR with CABG, 0.86; 95% CI,
In ISCHEMIA, patients randomized to initial medical therapy alone had 0.72–1.04; P = .12).53 However, at a median follow-up of 9.8 years, both
significantly more spontaneous MIs during the 5-year follow-up, which all-cause and cardiovascular mortality were significantly reduced with
were associated with subsequent cardiovascular death.737 An early inva CABG compared with GDMT alone (from 66.1% to 58.9%; HR 0.84;
regardless of whether PCI was performed, suggesting that viability as with PCI compared with those treated with CABG. The rate ranges
sessment may be useful for risk stratification. from 32% to 56% for PCI and 30% to 37% for CABG.759,762,768
The two main RCTs, STICH and REVIVED-BCIS2, differ in various However, interpreting these data is challenging due to several factors.
aspects. The REVIVED-BCIS2 trial patients were, on average, 10 years Firstly, there is no uniform definition of complete revascularization.769,770
older than those in the STICH trial, had a less frequent history of MI Secondly, although completeness of revascularization with PCI can be
(50% vs. 78%) and were more likely to be angina-free at baseline evaluated immediately after the procedure, many patients require staged
(67% vs. 36%). REVIVED-BCIS2 included fewer patients with three- procedures to achieve complete revascularization. Thirdly, within the
vessel disease (38% vs. 60%). Additionally, patients in REVIVED- first year after CABG, 20% to 40% of patients may experience asymp
BCIS2 received more modern HF therapy and were more commonly tomatic graft failure as determined by CCTA.771–773 Therefore, selecting
treated with an ICD/CRT (cardiac resynchronization therapy) a revascularization modality cannot be based solely on completeness of
(21%/53% vs. 2%/19%). Finally, the duration of follow-up was shorter revascularization but rather should be determined through shared
compared with the STICH trials. All these factors may have contributed decision-making and a risk–benefit assessment.
overestimated 4-year all-cause mortality in the EXCEL trial.788 The up studies). Stroke was not statistically different overall [2.7% vs. 3.1%;
dated version, SYNTAX score II 2020, using the SYNTAX Extended HR 0.84 (95% CI, 0.59–1.21); P = .36; absolute risk difference of
Survival (SYNTAXES) data and external validation in the population −0.4%]. However, in a pre-specified analysis of the first 12 months of
of the FREEDOM, BEST, and PRECOMBAT trials,789 showed modest follow-up, stroke was lower after PCI than after CABG [0.6% vs.
discrimination for predicting 5-year MACE (c-index for PCI and 1.6%; HR 0.37 (95% CI, 0.19–0.69); P = .002; absolute risk difference
CABG of 0.62 and 0.67, respectively) and acceptable discrimination of −1.0%].782 Subgroup analysis based on the SYNTAX score and
for predicting 10-year mortality. Another validation study indicated the number of additionally involved coronary vessels revealed no differ
that the score displayed acceptable discrimination for all-cause mortal ence in all-cause mortality between CABG and PCI for SYNTAX score
ity at 5 years in a Japanese cohort with LMCAD and/or multivessel ≤32 or LMCA stenosis with 0/1 vessel disease. However, a trend for
CAD,787 but external validation in a prospective setting is lacking.783 higher all-cause mortality was noted with PCI for SYNTAX score
The British Cardiovascular Intervention Society myocardial jeopardy >32 (HR 1.30; 95% CI, 0.92–1.84) and/or LMCA stenosis with 2/3 ves
score (BCIS-JS) is an alternative to the SYNTAX score, enabling the as sel disease (HR 1.25; 95% CI, 0.97–1.60).782 Of note, the LMCA sten
Table 9 Summary of trial-based evidence for the comparison of percutaneous coronary intervention and coronary artery bypass grafting in patients with left
main coronary artery disease
PRECOMBAT 600 patients with newly diagnosed LMCAD who All-cause death, MI, stroke, or 2 years 1-year follow-up:
(non-inferiority)814 had stable angina, unstable angina, silent ischaemia, ischaemia-driven target vessel 8.7% and 6.7% primary endpoints for PCI and CABG, respectively,
or non-ST-segment elevation MI revascularization absolute risk difference 2% (95% CI, –1.6% to 5.6%), P = .01 for
non-inferiority
2-year follow-up:
12.2% and 8.1% primary endpoints for PCI and CABG, respectively,
HR 1.50 (95% CI, 0.90–2.52), P = .12
PRECOMBAT 5 years 17.5% and 14.3% primary endpoints for PCI and CABG, respectively,
(extended follow-up)815 HR 1.27 (95% CI, 0.84–1.90), P = .26
PRECOMBAT 11.3 years 29.8% and 24.7% primary endpoints for PCI and CABG, respectively,
(extended follow-up)816 (median) HR 1.25 (95% CI, 0.93–1.69)
SYNTAX817 1800 patients with de novo three-vessel (n = 1095) All-cause death, stroke, MI, and 1 year For the LMCAD group: 15.8% and 13.7% primary endpoints for PCI
and LMCAD (n = 795) repeat revascularization and CABG, respectively; P = .44
818
SYNTAX 3 years For the LMCAD group: 26.8% and 22.3%, primary endpoints for PCI
and CABG, respectively; P = .20
SYNTAX813 5 years For the LMCAD group: 36.9% and 31.0% primary endpoints for PCI
and CABG, respectively, HR 1.25 (95% CI, 0.93–1.69), P = .12
SYNTAX (extended All-cause death 10 years For the LMCAD group: 27% and 28% primary endpoints for PCI and
follow-up)795 CABG, respectively, HR 0.92 (95% CI, 0.69–1.22)
NOBLE (non-inferiority 1201 patients with LMCAD who had stable angina All-cause death, non-procedural MI, 3.1 years 28% and 18% primary endpoints for PCI and CABG, HR 1.51 (95%
hypothesis)819 pectoris, unstable angina pectoris, or any repeat coronary (mean) CI, 1.13–2.00), P = .004 for superiority
non-ST-segment elevation myocardial infarction revascularization, or stroke
NOBLE (extended 4.9 years 28% and 19% primary endpoints for PCI and CABG, HR 1.58 (95%
follow-up)820 (median) CI, 1.24–2.01), P < .001 for superiority
EXCEL (non-inferiority 1905 patients with LMCAD of low or intermediate All-cause death, stroke, or MI 3 years 15.4% and 14.7% primary endpoints for PCI and CABG, absolute risk
hypothesis)821 anatomical complexity (SYNTAX score ≤ 32) (median) difference 0.7% (upper 97.5% confidence limit: 4%), P = .02 for
non-inferiority; HR 1.00 (95% CI, 0.79–1.26), P = .98 for superiority
EXCEL (extended 5 years 22.0% and 19.2% primary endpoints for PCI and CABG, absolute risk
follow-up)822 difference 2.8% (95% CI, −0.9 to 6.5), P = .13; OR 1.19 (95% CI,
0.95–1.50)
© ESC 2024
CABG, coronary artery bypass grafting; CI, confidence interval; HR, hazard ratio; LMCAD, left main coronary artery disease; MI, myocardial infarction; OR, odds ratio; PCI, percutaneous coronary intervention.
3473
4.4.5.3. Patients with multivessel coronary artery disease 2.0%; HR 0.8; 95% CI, 0.4–1.7; P = .56) were not different, while MI
The SYNTAX and SYNTAXES randomized trials, comparing PCI and again occurred more frequently after PCI (7.0% vs. 4.2%; HR 1.7;
CABG for multivessel CAD with or without unprotected LMCAD, re 95% CI, 1.1–2.7; P = .02).827 Repeat revascularization was also more
ported differences in terms of survival and freedom from cardiovascular frequent after PCI (11.1% vs. 5.9%; HR 1.9; 95% CI, 1.3–2.7;
events dependent on SYNTAX score.795,798,823 The recently published P = .001). Of note, after both PCI and CABG, event rates were lower
10-year follow-up results of the SYNTAX trial (SYNTAXES trial) re (about half for mortality) than in the SYNTAX cohort of patients with
ported similar all-cause death rates with both revascularization modal three-vessel CAD. There was a narrower difference for MI rates be
ities,795 while there was significantly higher mortality in patients with tween the two modalities, probably owing to procedural advances
SYNTAX scores ≥33 who were randomized for PCI (HR 1.41; 95% with PCI and CABG and improvements in GDMT. In patients with
CI, 1.05–1.89).795 A significant 5-year mortality gap between PCI and less complex CAD (SYNTAX score ≤22), outcomes were as favour
CABG has been reported among patients with complex multivessel able as after CABG.
CAD in the presence of DM (15.7% after PCI vs. 10.7% after CABG;
chronic total occlusion lesions) focused on ‘anatomically’ complex le meetings involving relatives increase patient trust in the physicians,
sions, ILUMIEN IV made the choice to define ‘complexity’ by the clin with greater adherence to therapeutic decisions. Shared decision-
ical context (DM and STEMI/NSTEMI) and/or by the anatomical making and patient medical education, considering the patient’s charac
characteristics of the lesions. teristics, mental status, cultural beliefs, and educational level, are there
In RENOVATE-COMPLEX PCI, intravascular imaging-guided PCI led fore associated with increased patient knowledge and better QoL and
to a lower risk of a composite of death from a cardiac cause, target with lower levels of anxiety and depression.849–851
vessel-related MI, or clinically driven target-vessel revascularization Using lay language and discussion with patients and relatives of short-
than angiography-guided PCI by 2 years (7.7% vs. 12.3%; HR 0.64; term procedure-related and long-term risks and benefits—such as sur
95% CI, 0.45–0.89; P = .008).840 vival, relief of angina, QoL, the potential need for late reintervention,
In OCTOBER, OCT-guided PCI led to a lower risk of a composite of the need for prevention measures, and uncertainties associated with
death from a cardiac cause, target-lesion MI, or ischaemia-driven different treatment strategies—are of great importance. Although cur
target-lesion revascularization than angiography-guided PCI by 2 years rent recommendations are primarily based on the ability of treatments
Recommendation Table 22 — Recommendations for revascularization in patients with chronic coronary syndrome (see
also Evidence Table 22)
In chronic coronary syndrome patients with left ventricular ejection fraction >35%
In CCS patients with LVEF >35%, myocardial revascularization is recommended, in addition to guideline-directed medical therapy, for
I A
patients with functionally significant left main stem stenosis to improve survival.718,719,859,860
In CCS patients with LVEF >35%, myocardial revascularization is recommended, in addition to guideline-directed medical therapy, for
patients with functionally significant three-vessel disease to improve long-term survival and to reduce long-term cardiovascular mortality I A
and the risk of spontaneous myocardial infarction.55,56,317,732–734
In CCS patients with LVEF >35%, myocardial revascularization is recommended, in addition to guideline-directed medical therapy, for
patients with functionally significant single- or two-vessel disease involving the proximal LAD, to reduce long-term cardiovascular mortality I B
and the risk of spontaneous myocardial infarction.55,56,317,719,732–734
In chronic coronary syndrome patients with left ventricular ejection fraction ≤35%
In CCS patients with LVEF ≤35%, it is recommended to choose between revascularization or medical therapy alone, after careful evaluation,
preferably by the Heart Team, of coronary anatomy, correlation between coronary artery disease and LV dysfunction, comorbidities, life I C
expectancy, individual risk-to-benefit ratio, and patient perspectives.
In surgically eligible CCS patients with multivessel CAD and LVEF ≤35%, myocardial revascularization with CABG is recommended over
I B
medical therapy alone to improve long-term survival.53,54,749,861
In selected CCS patients with functionally significant MVD and LVEF ≤35% who are at high surgical risk or not operable, PCI may be
IIb B
considered as an alternative to CABG.526,729
Revascularization to improve symptoms
In CCS patients with persistent angina or anginal equivalent, despite guideline-directed medical treatment, myocardial revascularization of
I A
functionally significant obstructive CAD is recommended to improve symptoms.50,321,402,732,734,757
Assessment of procedural risks and post-procedural outcomes
In patients with complex CAD in whom revascularization is being considered, it is recommended to assess procedural risks and
I C
post-procedural outcomes to guide shared clinical decision-making.
Calculation of the STS score is recommended to estimate in-hospital morbidity and 30-day mortality after CABG.777,862–864 I B
In patients with multivessel obstructive CAD, calculation of the SYNTAX score is recommended to assess the anatomical complexity of
I B
disease.786,865
Intracoronary imaging guidance by IVUS or OCT is recommended when performing PCI on anatomically complex lesions, in particular left
I A
main stem, true bifurcations, and long lesions.866,337,810,840,841
Intracoronary pressure measurement (FFR or iFR) or computation (QFR) :
• is recommended to guide lesion selection for intervention in patients with multivessel disease; 308,826,866,867 I A
• should be considered at the end of the procedure to identify patients at high risk of persistent angina and subsequent clinical
IIa B
events;828,830,831,868
• may be considered at the end of the procedure to identify lesions potentially amenable to treatment with additional PCI.350,829,831 IIb B
Continued
ESC Guidelines 3477
© ESC 2024
Choice of revascularization modality
It is recommended that physicians select the most appropriate revascularization modality based on patient profile,c coronary anatomy,d
I C
procedural factors,e LVEF, preferences, and outcome expectations.719,725,728,792–795,801,816,820,822,859,869
CABG, coronary artery bypass grafting; CAD, coronary artery disease; CCS, chronic coronary syndrome; FFR, fractional flow reserve; iFR, instantaneous wave-free ratio; IVUS, intravascular
ultrasound; LAD, left anterior descending; LV, left ventricular; LVEF, left ventricular ejection fraction; MVD, multivessel disease; OCT, optical coherence tomography; PCI, percutaneous
coronary intervention; QFR, quantitative flow ratio; STS, Society of Thoracic Surgeons; SYNTAX, SYNergy Between PCI with TAXUS and Cardiac Surgery.
a
Class of recommendation.
b
Level of evidence.
c
Age, frailty, cognitive status, diabetes, and any other comorbidities.
d
Multivessel disease with/out left main stem involvement, high anatomical complexity, and likelihood of revascularization completeness.
e
Local expertise and outcomes, surgical and interventional risk.
Anatomically and clinically based recommendations for revascularization in CCS Classa Levelb
CABG, coronary artery bypass grafting; CCS, chronic coronary syndrome; LAD, left anterior descending; LVEF, left ventricular ejection fraction; PCI, percutaneous coronary intervention;
SYNTAX, SYNergy Between PCI with TAXUS and Cardiac Surgery.
a
Class of recommendation.
b
Level of evidence.
c
For example: absence of previous cardiac surgery, or severe morbidities, or frailty, or immobility precluding CABG.
d
Multivessel disease is defined as the involvement of at least two main coronary arteries.
3478 ESC Guidelines
5. Optimal assessment and The role of myocardial revascularization and viability testing is further
addressed in Section 4.4.2.
treatment of specific groups In HF patients with anginal (or equivalent) symptoms, despite opti
mized GDMT, CCTA or ICA is recommended to confirm the diagnosis
5.1. Coronary artery disease and heart of obstructive CAD and its severity.
failure Over the past three decades, several landmark clinical trials have pro
About half of acute and chronic HF patients have an ischaemic aeti vided robust evidence on the prognostic benefit of pharmacological
ology.880,881 Over the last decades, the proportion of ischaemic therapies in patients with HFrEF. In these patients, four drug classes
HFrEF has decreased while that of HFpEF, defined according to the [ACE-Is or angiotensin receptor neprilysin inhibitors (ARNIs),891 beta-
2021 ESC Guidelines for the diagnosis and treatment of acute and blockers, mineralocorticoid receptor antagonists (MRAs), and SGLT2
chronic heart failure,526 has increased.882 The evaluation of inducible is inhibitors] are recommended for outcome improvement regardless
chaemia is important in patients with HF, given the high prevalence of of HF aetiology and comorbidities, including CAD.526
Recommendation Table 24 — Recommendations for management of chronic coronary syndrome patients with chronic
heart failure (see also Evidence Table 24)
In patients with HFpEF with persistent angina or equivalent symptoms and normal or non-obstructive epicardial coronary arteries, PET
or CMR perfusion or invasive coronary functional testing should be considered to detect or rule out coronary microvascular IIa B
883–885,887–889
dysfunction.
In selected patients with HFrEF undergoing high-risk PCI for complex CAD, the use of a microaxial flow pump may be considered in
IIb C
experienced centres.905–907
Managing heart failure in CCS patients
It is recommended that CCS patients with HF be enrolled in a multidisciplinary HF management programme to reduce the risk of HF
I A
hospitalization and to improve survival.526,909–911
An ACE-I, an MRA, an SGLT2 inhibitor (dapagliflozin or empagliflozin), and, in stable conditions, a beta-blocker are recommended for CCS
I A
patients with HFrEF to reduce the risk of HF hospitalization and death.526,704,705,912,913
An SGLT2 inhibitor (dapagliflozin or empagliflozin) is recommended in patients with Heart Failure with mildly reduced Ejection Fraction
© ESC 2024
an LBBB QRS morphology to improve symptoms and survival and to reduce morbidity.526,921,922
CRT rather than right ventricular pacing is recommended for patients with HFrEF regardless of NYHA class or QRS width who have an
I A
indication for ventricular pacing for high-degree AV block in order to reduce morbidity. This includes patients with AF. 923–925
ACE-I, angiotensin-converting enzyme inhibitor; AF, atrial fibrillation; ARB, angiotensin receptor blocker; ARNI, angiotensin receptor neprilysin inhibitor; AV, atrioventricular; CABG,
coronary artery bypass grafting; CAD, coronary artery disease; CCS, chronic coronary syndrome; CCTA, coronary computed tomography angiography; CMR, cardiac magnetic
resonance; CRT, cardiac resynchronization therapy; FFR, fractional flow reserve; GDMT, guideline-directed medical therapy; HF, heart failure; HFpEF, heart failure with preserved
ejection fraction; HFrEF, heart failure with reduced ejection fraction; ICA, invasive coronary angiography; ICD, implantable cardioverter defibrillator; iFR, instantaneous wave-free ratio;
LBBB, left bundle branch block; LVEF, left ventricular ejection fraction; MI, myocardial infarction; MRA, mineralocorticoid receptor antagonist; NYHA, New York Heart Association; PCI,
percutaneous coronary intervention; PET, positron emission tomography; SGLT2, sodium–glucose cotransporter 2.
a
Class of recommendation.
b
Level of evidence.
Ischaemiaª
50–70%
Obstructive CAD 30–50%
Endothelial
80%
dysfunction
Coronary risk
factors
Figure 12 Prevalence of disease characteristics in patients with ANOCA/INOCA referred for invasive coronary functional testing. Ach, acetylcholine;
ANOCA, angina with non-obstructive coronary arteries; CFR, coronary flow reserve; i.c., intracoronary; INOCA, ischaemia with non-obstructive cor
onary arteries. In the ILIAS (Inclusive Invasive Physiological Assessment in Angina Syndromes) registry,927 ANOCA is present in up to 70% of patients
referred for invasive coronary angiography and functional testing. Endothelial dysfunction is present in 80% and an acetylcholine test is positive in 60% of
these patients. An impaired CFR (≤2.5), measured by i.c. Doppler guidewires, is present in 50%, while ischaemia (INOCA) is documented by non-
invasive functional testing in only 25% of ANOCA patients. The prevalence of coronary vasospasm can vary in different studies depending on dose
of acetylcholine and test protocol. aPrevalence of ischaemia by non-invasive functional testing increases from non-obstructive to obstructive CAD.
5.2.2.1. Microvascular angina CFR of <2.0 has low sensitivity for identifying CMD, but using the
Microvascular angina is the clinical manifestation of myocardial ischaemia same threshold as for Doppler (<2.5) results in reasonable diagnostic
caused by structural or functional changes in the coronary microvascula accuracy.937
ture (leading to impaired CFR and/or reduced microcirculatory conduct Smoking, age, diabetes, hypertension, and dyslipidaemia are associated
ance) and/or abnormal vasoconstriction of coronary arterioles (causing with CMD.934,935,938 Other studies have shown that diabetes was un
dynamic arteriolar obstruction).932,933 Both vascular dysfunction me common among patients with angina and non-obstructive CAD, while
chanisms may co-exist and contribute to MVA. hypertension and dyslipidaemia were relatively more prevalent.939,940
The prevalence of MVA was 26% in a study of patients with Inflammatory conditions such as systemic lupus erythematosus (SLE)
non-obstructive CAD who had a CFVR below 2 when assessed by and rheumatoid arthritis appear to be associated with MVA and are
transthoracic Doppler echocardiography.934 Studies assessing CMD in not infrequently encountered in patients with angina.941 Inflammatory
vasively or by PET with different cut-offs have found that 39% to 54% diseases occur more often in women after menopause than in men,
had CMD.935,936 The threshold for CMD varies between studies and which may contribute to the sex differences in MVA.942–944 Last, but
depending on the techniques used (PET, CMR, thermodilution, or not least, there is increasing evidence that psychosocial stress is involved
Doppler); the threshold is a CFR of <2.0–2.5.36,39 A thermodilution in coronary vasomotor disorders.945,946
ESC Guidelines 3481
Figure 13 Diagnostic algorithm for patients with angina/ischaemia with non-obstructive coronary arteries. Ach, acetylcholine; ANOCA, angina with
non-obstructive coronary arteries; CAD, coronary artery disease; CCS, chronic coronary syndrome; CCTA, coronary computed tomography angiog
raphy; CFR, coronary flow reserve; ECG, electrocardiogram; echo, echocardiography; FFR, fractional flow reserve; GDMT, guideline-directed medical
therapy; HMR, hyperaemic myocardial velocity resistance; i.c., intracoronary; ICA, invasive coronary angiography; iFR, instantaneous-wave free ratio;
IMR, index of microcirculatory resistance; INOCA, ischaemia with non-obstructive coronary arteries; MRI, magnetic resonance imaging; PET, positron
emission tomography; SPECT, single-photon emission computed tomography.
bradycardia effect of Ach can be antagonized by atropine. The effect of accompanied by ischaemic ECG changes and an angiographic ≥90% re
Ach is short in contrast to the prolonged effect of ergonovine, which duction of the coronary lumen. If the lumen reduction is <90%, the diag
was previously used for the provocation of coronary vasospasm.969 nosis of microvascular spasm is made. The vasospastic effect of Ach is
The diagnosis of MVA and VSA due to microvascular or macrovascular rapidly transient and can, if needed, be reversed by intracoronary admin
vasospasm is made according to established criteria.41,73,932 The test is istration of nitroglycerine, which also allows assessment of
considered positive for macrovascular spasm if symptoms occur, endothelium-independent epicardial coronary vasodilation. The safety
ESC Guidelines 3483
Ach testing performed after at least 24 hours of washout from CCB and nitrates
Baseline Final
Repeat angiogram after each dose CFR / MR
angiogram angiogram
Ach 2 µga i.c. Ach 20 µga i.c. Ach 100 µga i.c. Ach 200 µga i.c. NTG Adenosine
over 60 s over 60 s over 60 s over 60 s 200 µg i.c. 200 µg i.c.b
Figure 14 Spasm provocation and functional testing protocol. Ach, acetylcholine; CCB, calcium channel blocker; CFR, coronary flow reserve; ECG,
electrocardiogram; i.c., intracoronary; i.v., intravenous; MR, microvascular resistance; NTG, nitroglycerine. i.c. bolus injections of Ach over 60s to assess:
(i) endothelial-dependent vasodilation using low-dose Ach (2–20 µg), and (ii) endothelial dysfunction and vasoconstriction using high-dose Ach
(100–200 µg). This is followed by i.c. administration of nitroglycerine (200 µg) to revert vasospasm. Endothelial-independent vasodilation is assessed
by i.c. adenosine (200 µg) or i.v. infusion to determine CFR and IMR. Coronary flow can be continuously monitored if i.c. Doppler guidewires are used.
a
The incremental administration of Ach is stopped whenever a coronary vasospasm is induced. bi.v. adenosine can also be used.
of coronary vasospasm provocation testing with increasing intracoronary improve QoL and prognosis. Management of traditional CVD risk fac
Ach boluses of up to a maximum of 200 μg has been repeatedly re tors, hypertension, dyslipidaemia, smoking, and diabetes should be as
ported.37,970,971 In a small study, testing coronary vasospasm using this al per clinical practice guidelines recommendations.
gorithm was also safe in patients with a recent ACS.972 Treatment of anginal symptoms in patients with ANOCA/INOCA is
At the end of the procedure, microcirculatory vasomotor response challenging as the patients represent a heterogeneous group and rando
to i.v. administration of the endothelium-independent vasodilator ad mized trials are lacking. A small study showed that a stratified antianginal
enosine973 is assessed and CFR, IMR, HMR, or MRR are measured. In therapy algorithm based on coronary functional testing resulted in im
patients with contraindications to the use of adenosine, papaverine proved angina symptoms and QoL compared with a control group
can be used974 but precautionary measures need to be taken given treated with standard therapy.978 In patients with MVA and reduced
the risk of inducing polymorphic ventricular tachycardia.975,976 CFR and/or increased IMR (which may reflect arteriolar remodelling),
Different protocols have been applied in clinical practice. Figure 14 beta-blockers, CCBs, ranolazine, and ACE-Is are used.979 In these pa
shows an example of a standardized and stepwise algorithm for ICFT tients, anti-ischaemic therapy with amlodipine or ranolazine resulted
that may be adopted in the cardiac catheterization laboratory for diag in a significant improvement in exercise time.980 In patients with either
nosing vasospasm. Informed consent should be obtained, mentioning epicardial or microvascular spasm following Ach testing, calcium an
unlicensed, parenteral use of Ach, and administration performed by tagonists should be considered as first-line therapy. In patients with se
an experienced interventional cardiologist. vere VSA, it may be necessary to administer unusually high dosages of
calcium antagonist (2 × 200 mg diltiazem daily or higher up to 960 mg
5.2.6. Management of angina/ischaemia with daily) or even a combination of non-dihydropyridine (such as diltiazem)
non-obstructive coronary arteries with dihydropyridine calcium blockers (such as amlodipine). Of note, a
Management should be patient-centred with a patient-oriented multi small study using either oral diltiazem or placebo up to 360 mg/day in
disciplinary care approach.977 Figure 15 provides an algorithm for the CMD for 6 weeks did not substantially improve symptoms or QoL,
therapeutic management of ANOCA/INOCA. In all patients with es but diltiazem therapy did reduce the prevalence of epicardial spasm.981
tablished ANOCA/INOCA due to the frequent presence of coronary Nicorandil, a combinatorial vasodilator agent acting via nitrate- and
atherosclerosis and endothelial dysfunction, tailored counselling on life potassium-channel activation, may be an effective alternative, although
style factors is warranted to address risk factors, reduce symptoms, and side effects are frequent.982 First-line therapy can also be combined
3484 ESC Guidelines
Treatment of ANOCA/INOCA
Weight Smoking
management cessation
Figure 15 Treatment of angina/ischaemia with non-obstructive coronary arteries. ACE-I, angiotensin-converting enzyme inhibitor; ANOCA, angina
with non-obstructive coronary arteries; ARB, angiotensin receptor blocker; CCB, calcium channel blocker; INOCA, ischaemia with non-obstructive
coronary arteries. Treatment of ANOCA/INOCA patients includes lifestyle modification, management of cardiovascular risk factors, and antianginal
treatment according to underlying endotypes. Note: endotypes frequently overlap, requiring combined medical therapy.
with ranolazine, an antianginal agent that improves myocyte relaxation prospective, randomized, blinded outcome evaluation to assess inten
and ventricular compliance by decreasing sodium and calcium over sive statin and ACE-I/ARB therapy (ischaemia-intensive medical ther
load.983 Spinal cord stimulation is an option for patients who remain re apy) vs. usual care on MACE in symptomatic women with ANOCA.
fractory after medical therapy.984 The Precision Medicine with Zibotentan in Microvascular Angina
There are currently several studies evaluating therapies specific to (PRIZE) trial holds future promise (NCT04097314). Zibotentan is an
ANOCA/INOCA. The Women’s IschemiA Trial to Reduce Events in oral, endothelin A receptor antagonist that may provide benefit by
Non-ObstRuctIve CORonary Artery Disease (WARRIOR, opposing the reported vasoconstrictor response of coronary micro
NCT03417388) is currently enrolling subjects in a multicentre, vessels to endothelin.
ESC Guidelines 3485
Recommendation Table 25 — Recommendations for For the treatment of isolated vasospastic angina
diagnosis and management of patients with angina/
ischaemia with non-obstructive coronary arteries (see Calcium channel blockers are recommended to
also Evidence Table 25) control symptoms and to prevent ischaemia and I A
potentially fatal complications.991–996
Recommendations Classa Levelb Nitrates should be considered to prevent recurrent
IIa B
episodes.993,997,998
Diagnosis of ANOCA/INOCA endotypes
For the treatment of overlapping endotypes
In persistently symptomatic patients despite
medical treatment with suspected ANOCA/ In patients with evidence of overlapping endotypes,
© ESC 2024
INOCA (i.e. anginal symptoms with normal combination therapy with nitrates, calcium channel
IIb B
coronary arteries or non-obstructive lesions at blockers, and other vasodilators may be
non-invasive imaging, or intermediate stenoses with considered.999,1000
compared with men could contribute to unfavourable outcomes. There Due to concerns of a possible J-curve relationship between achieved
are also risk factors that are unique to women.1014,1015 Not only prema BP and cardiovascular outcomes in patients with CAD, previous guide
ture menopause,1016 but also hypertensive disorders of pregnancy, lines did not recommend a target BP of <120/70 mmHg. In line with the
pre-term delivery, gestational diabetes, small-for-gestational-age delivery, 2024 ESC Hypertension Guidelines1064, the present guidelines recom
placental abruption, and pregnancy loss are predictors of subsequent mend that treated systolic BP values in most CCS patients be targeted
CVD.1017 Also, the association between low socioeconomic status and to 120–129 mmHg, provided the treatment is well tolerated. In cases
increased cardiovascular risk seems stronger in women.1018 In addition, where on-treatment systolic BP is at or below target (120–129
higher levels of residential segregation are associated with incident mmHg) but diastolic BP is not at target (≥80 mmHg), intensifying
CVD and obesity among black women.1019 BP-lowering treatment to achieve an on-treatment diastolic BP of
Women are less likely to be referred for diagnostic testing and are 70–79 mmHg may be considered to reduce CVD risk.1065 More leni
under-treated for essential secondary prevention therapies.1020 ent targets (e.g. 140/90 mmHg) can be considered in older patients
Compared with men, women have a shorter survival after PCI1021 (≥85 years of age) or patients with pre-treatment symptomatic
5.3.8. Chronic kidney disease relatively recent epidemiological transition of HIV to a chronic disease.
Chronic kidney disease increases the risk of CAD progression and is as Dyslipidaemia is a common condition in patients with HIV, whether trea
sociated with high mortality rates due to cardiovascular causes.1069,1070 ted or untreated with ART.1081 The treatment of dyslipidaemia in patients
Patients with CKD have a higher burden of atherosclerosis and more with HIV includes both non-pharmacological and pharmacological options.
advanced plaque features.1070 Despite the higher prevalence of disease, Special attention to the impact of polypharmacy, drug interactions be
non-invasive diagnostic testing is often less accurate, and guidance re tween ART and lipid-lowering medications, and close monitoring for ad
lated to the use of pharmacological and interventional therapy is limited verse events is critical to successfully managing dyslipidaemia and risk of
due to inconsistent definitions of CKD and underrepresentation of CVD in patients with HIV. Hepatic cytochrome P450 3A4 (CYP3A4) me
CKD patients in clinical trials.1070–1072 tabolizes many statins; many ARTs are also metabolized by CYP3A4 and,
Careful assessment of the risk-to-benefit ratio is needed in patients thus, may have interactions with statins. Simvastatin and lovastatin are con
with CKD before considering ICA, CCTA, or non-invasive tests requir traindicated with protease inhibitors; atorvastatin has less of a CYP3A4
ing nephrotoxic agents.1073 Pre-existing CKD is the primary patient- interaction; pravastatin, fluvastatin, pitavastatin and rosuvastatin are not
Recommendation Table 26 — Recommendations for Subclinical Atherosclerosis), 63% of asymptomatic middle-aged partici
older, female, high bleeding risk, comorbid, and socially/ pants had subclinical atherosclerosis,157 although most of them were
geographically diverse patients (see also Evidence categorized as low-risk individuals by several risk scores.142
Table 26) The risk of adverse events in asymptomatic subjects can be estimated
using the European risk-estimation system [Systematic Coronary Risk
Recommendations Classa Levelb
Estimation 2 (SCORE2)], described in the 2021 ESC Guidelines on car
Older adults diovascular disease prevention in clinical practice.16,1101 Systematic
screening of risk factors cannot be strongly recommended in the general
In older adults (≥75 years), particular attention to
population as it did not affect CVD outcomes.1102 However, when pa
drug side effects, intolerance, drug–drug interactions,
I C tients are seen for other reasons, opportunistic screening is effective at
overdosing, and procedural complications is
increasing detection rates of CVD risk factors, such as high BP or lipids.
recommended.
Hence, opportunistic screening is recommended, although its beneficial
In older, as in younger, individuals, diagnostic and
• to enhance inclusion in future clinical trials of future cardiovascular events using scoring systems,
I C
geographical, social, or other groups that are e.g. SCORE2 and SCORE-OP, is recommended to
currently underrepresented. detect individuals at high risk and guide treatment
ARC-HBR, Academic Research Consortium for High Bleeding Risk; CCS, chronic coronary
decisions.16,1101,1112
syndrome; HIV, human immunodeficiency virus; PRECISE-DAPT, PREdicting bleeding When coronary artery calcification findings are
Complications In patients undergoing Stent implantation and subsEquent Dual available from previous chest CT scans, using these
AntiPlatelet Therapy.
a
Class of recommendation. findings to enhance risk stratification and guide IIa C
b
Level of evidence. treatment of modifiable risk factors should be
considered.17,1108–1110
CACS may be considered to improve risk classification
5.4. Screening for coronary artery disease around treatment decision thresholds.1104–1106
IIb C
in asymptomatic individuals An ultrasound of the carotid arteries may be
Presence of asymptomatic atherosclerotic CAD is common in the gen considered as an alternative when CACS is
eral population.1097–1100 In the Swedish Cardiopulmonary Bioimage
© ESC 2024
6. Long-term follow-up and care Communication should be clear regarding symptoms, even if not car
diac. Patients with CCS experiencing non-cardiac chest pain experience
6.1. Voice of the patient uncertainty about the cause and actions to take. A multidisciplinary ap
A diagnosis of CCS can have an impact on self-identity, lifestyle, employ proach and evaluation of non-cardiac aetiology with an appropriate re
ment, and cause anxiety, depression, and burdensome treatment. ferral are advocated to ensure that appropriate treatment is
Patients are experts in their own conditions, and their voices and pre initiated.1127,1128
ferences are integral to decisions about treatment. Health outcomes
improve with better patient involvement, and shared decision-making 6.1.2. Depression and anxiety
is central to future patient care.1113 Depression is common (15%–20% prevalence) in CVD, and associated
with poor adherence and worse outcomes, including MACE and pre
mature death.1129 Coronary microvascular dysfunction (prevalent in
6.1.1. Communication INOCA) is linked with psychological stress and depression.946
Provide additional
Make access to
Provide correct, psychosocial
Be aware of care
timely and support in Prefer poly-pill
Intensify/increase Implement
Consider graded Improve
Optimize health use of community-based
therapy in communication
literacy mHealth and programs/
multimorbidity skills
e-Health interventions
Shared-decision making
Structured tools (PROMs and clinical processes)
Improved outcomes
Figure 16 Actions on the five dimensions of adherence to therapy. e-Health, healthcare services provided electronically; mHealth, mobile device-
based healthcare; PROMs, patient-reported outcome measures. Adapted from Pedretti et al.1139.
of behaviour. Habits and environmental cues primarily govern beha nurse-led patient-centred interventions for secondary prevention
viours, so education and information alone are seldom enough.1140 found greater adherence to smoking cessation and physical activity,
Factors such as psychological state and low health literacy (associated and better control of total cholesterol (with medication titration),
with depression and worse behavioural risk factors) also impact the but no improvements in dietary habits, BP, blood glucose, or sur
ability to make changes.1141,1142 vival.1143 A systematic review of behavioural counselling found that
medium- to high-contact counselling resulted in 20% lower risk of
CVD events, lower BP, and decreased LDL-C and adiposity in adults
6.2.1.2. How to change behaviour and support healthy lifestyles with CVD risk factors.1144 Incorporating cardiovascular visual images
A multidisciplinary approach and behavioural counselling can improve into risk-factor discussions is effective in reducing subsequent 10-year
adherence. A systematic review and meta-analysis of 12 RCTs of risk assessment and individual risk factors.445
ESC Guidelines 3491
Supporting adherence
E xercise
L eave smoking
Figure 17 Strategies for long-term adherence to a healthy lifestyle. mHealth, mobile device-based healthcare; PROMs, patient-reported outcome
measures.
Lifestyle changes also impact relatives, partners, and friends, so they studies including 5165 patients with CAD or cerebrovascular disease,
should be involved in patient support.1139 Physical activity can be incor text messaging and smartphone apps resulted in a greater ability to
porated flexibly, either daily, or limited to specific days. Activity pat reach BP targets and exercise goals, less anxiety, and increased aware
terns limited to 1–2 sessions per week but meeting recommended ness of diet and exercise compared with control.1146 Nevertheless,
levels of physical activity have been shown to reduce or postpone there was no significant difference in smoking cessation, LDL-C, and
all-cause, CVD, and cancer mortality risk.477 Importantly, maintaining hospital readmissions.1146 Digital interventions mainly stimulate healthy
changed behaviour over time is a challenge. Some trials have shown behavioural factors but are less effective in reducing unhealthy behav
an impact of lifestyle intervention on cardiovascular health and behav ioural factors (smoking, alcohol intake, sedentary behaviour, and un
ioural metrics, which became attenuated in the long term as the inten healthy diet) and clinical outcomes.1146,1147
sity of the intervention declined.1145 The use of wearable devices has significantly increased physical activ
ity and decreased waist circumference, systolic BP, and LDL-C among
individuals with chronic conditions including CVD.491 Younger age
6.2.1.3. Digital and mHealth has been associated with a higher increase in physical activity, and
Behavioural change and habit formation can be facilitated through tech CVD has been associated with a lower increase. Wearable activity
nology such as wearable devices, the internet, and smartphones. In 27 trackers have shown effectiveness, but the effect was greater when
3492 ESC Guidelines
combined with other behaviour-change strategies.491 A systematic re Simplifying medication regimens using fixed-dose polypills has been
view of CCS patients that used activity trackers combined with feed shown to increase adherence.1159–1162 The SECURE trial demon
back by healthcare professionals (most also giving lifestyle education) strated that patients 6 months post-MI randomized to a polypill con
showed a significant increase in peak VO2 in studies using an acceler taining aspirin, ramipril, and atorvastatin had significantly lower MACE
ometer (but not a pedometer) compared with non-users. The overall and were more likely to have high adherence at 6 and 24 months com
effect across studies reduced MACE and improved QoL.1148 Similarly, pared with the usual care group.1163
smartphone and tablet computer apps have been shown to increase
physical activity (minutes per week or steps per day) among people
with CVD (1543 participants, most of them with CCS). This effect 6.2.2.2. mHealth strategies for medication adherence
was largest in small studies focused on physical activity only, partici A review of mobile phone text messaging found promising, if limited,
pants ≥60 years old, and duration of up to 3 months.1149 evidence that such messaging could improve medication adherence
Adherence to the apps was 20% to 85% and tended to wane over up to 12 months after acute coronary events.1164 Similarly, another re
view of 24 studies of text messages and/or apps found robust evidence
© ESC 2024
Multiprofessional and family involvement is
recommended to promote adherence, in addition to I C
6.2.2.1. Strategies to improve medication adherence patient education and involvement.1139
Improving adherence to medications has proved challenging.1153 One a
Class of recommendation.
systematic review and meta-analysis (771 studies to 2015) found that b
Level of evidence.
interventions that were behaviourally focused, e.g. linking medication-
taking to existing habits, were more effective than those that were
cognitively focused.1154 A systematic review of 17 trials of adherence 6.3. Diagnosis of disease progression
for secondary CVD prevention found that a short message service, a Long-term follow-up of patients with CCS who have either established
fixed-dose combination pill, and a community health worker-based CAD (prior acute MI, revascularization, known CAD) or non-
intervention (one trial each) increased adherence compared with obstructive CAD includes surveillance for disease progression.
usual care.1155 Behavioural and mixed behavioural/educational inter However, current literature is sparse regarding mode, frequency, and
ventions improved adherence in older adults with multiple medica duration. Follow-up of patients is based on their clinical condition,
tions (low-quality evidence), with little evidence for educational-only which includes cardiovascular risk factors, residual symptoms, cardiac
interventions.1156 Drug reminder packaging—i.e. incorporating the complications [such as post-infarction LV remodelling and dysfunction,
date and time for the medication to be taken in a package (pre-filled associated mitral regurgitation (mostly functional), known HF, signifi
containers)—can act as a prompt, with some evidence that it in cant arrhythmias], and non-cardiac comorbidities like PAD, stroke,
creases pills taken and improves diastolic BP and HbA1c levels.1157 and renal dysfunction.
Treating depression is important, as depression was associated with The main goal of follow-up is to determine the patient’s risk of
reduced adequate and optimal adherence to recommended medica developing new cardiac events through risk stratification and to
tions 12 months post-PCI in an analysis of 124 443 patients.1158 identify symptoms suggestive of CAD progression. A second goal is
ESC Guidelines 3493
to promptly diagnose and manage extracoronary complications, such as examination methods during long-term follow-up may vary based on
the onset of HF, arrhythmias, and valvular dysfunction. Additionally, the CCS phenotype, coronary atherosclerotic burden, presence of
during long-term follow-up, antianginal and disease-modifying medica CMD, and severity of ischaemic LV dysfunction.
tion should be optimized and adjusted based on the development of co A stepwise approach based on risk assessment can be followed, like
morbidities. The potential benefits vs. bleeding risks of antithrombotic that applied for diagnosing and treating individuals with suspected CCS.
drugs should be considered and evaluated over time. Step 1: This involves an annual clinical evaluation, by a general prac
Although assessing the anginal status is traditionally considered the titioner or a cardiologist, encompassing symptom evaluation, medica
cornerstone of clinical follow-up, it is worth noting that angina resolves tion review, physical examination, a resting 12-lead ECG, and blood
in 40% of CCS patients at 1 year with further annual decreases, most tests for lipid profile, renal function, glycaemic status, and full blood
often without revascularization or adaptation of antianginal therapy.404 count. The ECG should be scrutinized for heart rate, rhythm, evidence
In contrast to patients with resolving symptoms, those with persistent of silent ischaemia/infarction, and evaluation of PR, QRS, and QT inter
or recurrent angina are at higher risk of cardiovascular death or MI.404 vals. Any new symptoms suggestive of ACS, especially with ECG
Recurrent or
new CAD event?
6 1
ECG changes?
3
Consider:
Age and gender 4
Prior ACS, PCI or CABG
Risk factors for CAD
Comorbidities (e.g. CKD, PAD)
Treatment compliance
and lifestyle Extent and severity of known CAD?
Genetic predisposition
Inflammatory markers
Psychosocial factors LV-function? Other heart diseases?
(e.g. AF, valve disease, RV dysfunction)
Figure 18 Approach for the follow-up of patients with established chronic coronary syndrome. ACS, acute coronary syndrome; AF, atrial fibrillation;
CABG, coronary aortic bypass grafting; CAD, coronary artery disease; CCS, chronic coronary syndrome; CKD, chronic kidney disease; ECG, electro
cardiogram; LV, left ventricle; PAD, peripheral artery disease; PCI, percutaneous coronary intervention; RV, right ventricle.
6.3.3. Non-invasive diagnostic testing management plan. For example, symptomatic patients with
All non-invasive diagnostic testing, including CCTA, stress SPECT, moderate-to-severe myocardial ischaemia despite GDMT will usu
or PET myocardial perfusion imaging, stress echocardiography, ally undergo additional revascularization. In patients with known
and stress CMR have been shown to provide prognostic informa ANOCA/INOCA, non-invasive imaging with stress SPECT or PET
tion in patients with established CAD.296,1180,1181 Anatomical im myocardial perfusion imaging, stress CMR, or stress echocardiog
aging with CCTA has the advantage of providing information on raphy remain first-line investigations, although the diagnostic yield
left main disease and graft patency. Stress imaging provides informa may be low;927 however, the current standard remains invasive cor
tion on the degree of ischaemia, which helps guide an appropriate onary functional testing.
ESC Guidelines 3495
CAD, coronary artery disease; CCS, chronic coronary syndrome; CCTA, coronary
computed tomography angiography; FFR, fractional flow reserve; iFR, instantaneous 6.4.2. Managing graft failure after coronary artery
wave-free ratio; LV, left ventricular; QFR, quantitative flow ratio.
a
Class of recommendation. bypass grafting
b
Level of evidence. A variety of reasons have the potential to adversely affect bypass graft
patency.1189 These include technical (quality of graft material, surgical
precision) and pathophysiological aspects (competitive flow, activity
of the coagulation system, disease progression, etc.). Technical aspects
and competitive flow are thought to influence early graft failure, while
6.4. Treatment of myocardial disease progression and graft degeneration affect long-term
revascularization failure patency.1182,1189
One in five revascularized patients needs a repeat revascularization The majority of graft occlusions are clinically silent.1189 If symptoms
within the first 5 years after myocardial revascularization, with higher occur, prompt diagnostic workup (including ECG, assessment of bio
risk after PCI compared with CABG.1182 Revascularization failure can markers, and possibly repeat coronary angiography) is warranted to
manifest either shortly after the initial procedure (within 30 days) or la limit or prevent potential damage from graft occlusion.316 Acute
ter on, and recurring symptoms may result from either restenosis of CABG graft failure (<1 month after surgery) is observed in approxi
the treated coronary segment or the failure of bypass grafts,772 along mately 12% of grafts mostly due to technical problems.1190 Late failure
side the progression of underlying native CAD.1183,1184 Published evi of saphenous vein grafts occurs in up to 50% at 10 years, with vein graft
dence regarding diagnosis and management of myocardial occlusion rates in up to 27% within 1 year after surgery. 771,1191
revascularization failure has been summarized in the 2020 EAPCI The decision for optimal treatment (conservative, CABG revision/
(European Association of Percutaneous Cardiovascular Interventions) redo CABG or PCI of the native vessel or of the failed graft) should
Expert Consensus Paper.1182 be made individually considering haemodynamic stability, technical
3496 ESC Guidelines
reasons for graft failure, and ability to treat native CAD. PCI is the first promising and easily implementable in everyday clinical practice are en
choice over redo CABG for late graft failure, with PCI of the native ves hanced external counterpulsation and the coronary sinus reducer de
sel rather than PCI of the graft. 772,1182,1192,1193 vice,555 after all medical therapy and mechanical revascularization
If re-operation is required, the surgical risk is generally in options have been exhausted (see Sections 4.2 and 4.4). Enhanced ex
creased.1182,1192 If acute re-operation is required, acute ischaemia is ternal counterpulsation has been shown to ameliorate refractory an
generally present, and adhesions and the presence of patent grafts in gina in several trials.1198
crease the complexity of the procedure. It is, therefore, important to The coronary sinus reducer consists of controlled coronary sinus
weigh this risk against the expected benefit. Since a patent left internal narrowing with the implantation of a large stainless-steel device to in
thoracic artery (LITA) to the LAD confers the largest part of CABG crease coronary sinus pressure and improve perfusion in the LAD ter
prognostic potential,1189,1194 redo CABG is primarily recommended ritory.1199 In a recent meta-analysis including eight registries and one
in patients with indications for CABG and occluded LITA or if the RCT, in a total of 846 patients with refractory angina, use of a coronary
LITA was not used during the first operation.772 sinus reducer led to improvement of ≥1 CCS class in 76% (95% CI,
without a patent LIMA graft to the LAD. 842,1192,1196 and includes angiogenetic therapies with vascular endothelial growth
PCI of the bypassed native artery should be factors and fibroblast growth factors, as well as stem cell therapy
IIa B with intramyocardial delivery of CD34+ cells.1202,1203 However, further
considered over PCI of the bypass graft.1197
RCTs are needed to validate the feasibility of such therapeutic
CABG, coronary artery bypass grafting; DES, drug-eluting stent; LAD, left anterior strategies.
descending; LIMA, left internal mammary artery; PCI, percutaneous coronary intervention.
a
Class of recommendation. To date, the main limitations of reported experiences with all novel
b
Level of evidence. therapeutic options regard the small number of treated patients and
the duration of follow-up. Larger sham-controlled RCTs are required
to define the role of each treatment modality for specific subgroups,
6.5. Recurrent or refractory and ultimately to aim at the best possible personalized treatment algo
angina/ischaemia rithm, based on aetiology stratification, and escalation of available thera
An ageing population and an increased survival rate in patients with peutic modalities.
CAD due to improvements in anti-ischaemic medical therapy and cor
onary revascularization have led to a growing number of patients with
Recommendation Table 31 — Recommendations for
severe and diffuse CAD not amenable to further revascularization pro recurrent or refractory angina/ischaemia (see also
cedures. Despite the use of antianginal drugs and/or PCI or CABG, the Evidence Table 31)
proportion of patients with CAD who have daily or weekly angina
ranges from 2% to 24%.555 Recommendations Classa Levelb
Refractory angina is defined as long-lasting symptoms (for >3 months)
In patients with refractory angina leading to poor
due to established reversible ischaemia: (i) in the presence of ob
structive CAD, which cannot be controlled by escalating medical ther quality of life and with documented or suspected
apy with additional antianginal drugs, bypass grafting, or PCI including ANOCA/INOCA, invasive coronary functional
I B
recanalization of chronic total coronary occlusion; or (ii) due to testing is recommended to define ANOCA/INOCA
ANOCA/INOCA. In the case of ANOCA/INOCA, further investiga endotypes and appropriate treatment, considering
tions are required to define the different endotypes (Section 4.4.2) and patient choices and preferences.36,37,298,930,939,985
appropriate treatment (Section 6.3) before diagnosing refractory In patients with debilitating angina and obstructive
angina.36 CAD refractory to optimal medical and
The QoL of patients with refractory angina is poor, with frequent revascularization strategies, a reducer device for
IIb B
hospitalization and a high level of resource utilization.555 Once conven
© ESC 2024
6.6. Treatment of disease complications • CCTA is preferred to rule out obstructive CAD and detect non-
Patients with CCS who develop LV dysfunction may experience ad obstructive CAD.
vanced HF, malignant arrhythmias and secondary valvular heart disease • Functional imaging is preferred to correlate symptoms to myocardial
(i.e. mitral and tricuspid regurgitation). ischaemia, estimate myocardial viability, and guide decisions on cor
Prior MI and ischaemic aetiology are negative prognostic markers in onary revascularization.
patients with advanced HF,1205 as well as in those with secondary mitral • PET is preferred for absolute MBF measurements, but CMR perfu
regurgitation.1206 Specific treatments need to be considered in these sion studies may offer an alternative.
patients regardless of HF aetiology (i.e. ischaemic).526 Advanced HF • Selective second-line cardiac imaging with functional testing in pa
treatments include: high diuretic doses; a combination of diuretics tients with abnormal CCTA and CCTA after abnormal functional
and renal replacement therapy to treat congestion; inotropic and vaso testing may improve patient selection for ICA.
pressor agents to reduce hypoperfusion; and mechanical circulatory • ICA is recommended to diagnose obstructive CAD in individuals
support in selected patients with severe symptoms or exercise intoler with a very high pre- or post-test likelihood of disease, severe symp
• Shared decision-making between patients and healthcare profes • A post hoc analysis of ISCHEMIA detected a graded association
sionals, based on patient-centred care, is paramount in defining the between the severity of obstructive CAD assessed by CCTA
appropriate therapeutic pathway for CCS patients. Patient education and all-cause mortality and acute MI during follow-up.317 There
is key to improve risk-factor control in the long term. is a need for randomized data comparing contemporary medical
• The relatively high prevalence of ANOCA/INOCA and its associated treatment against early revascularization plus medical therapy in
MACE rate warrants improvement in the diagnosis and treatment of subsets of patients with an increased risk for death or MI as de
affected patients. termined by the post hoc analysis. Moreover, because the benefit
• Persistently symptomatic patients with suspected ANOCA/INOCA of an invasive strategy with respect to cardiac mortality was
who do not respond to GDMT should undergo invasive coronary shown in a meta-analysis of chronologically heterogeneous trials,
functional testing to determine underlying endotypes. including several conducted more than two decades ago, the im
• Characterization of endotypes is important to guide appropriate pact of early revascularization plus GDMT vs. contemporary
medical therapy for ANOCA/INOCA patients. GDMT on all-cause and cardiac mortality in patients with CCS
9. ‘What to do’ and ‘What not to do’ messages from the guidelines
Table 10 lists all Class I and Class III recommendations from the text alongside their level of evidence.
Recommendations for history taking, risk factor assessment, and resting electrocardiogram in individuals with suspected chronic
coronary syndrome
In individuals reporting symptoms of suspected myocardial ischaemic origin, a detailed assessment of cardiovascular risk factors, medical
I C
history, and symptom characteristics (including onset, duration, type, location, triggers, relieving factors, time of day) is recommended.
Recommendations for non-invasive anatomical imaging tests in the initial diagnostic management of individuals with suspected chronic
coronary syndrome—coronary computed tomography angiography, if available, and supported by local expertise
In individuals with suspected CCS and low or moderate (>5%–50%) pre-test likelihood of obstructive CAD, CCTA is recommended to
I A
diagnose obstructive CAD and to estimate the risk of MACE.
CCTA is recommended in individuals with low or moderate (>5%–50%) pre-test likelihood to refine diagnosis if another non-invasive test is
I B
non-diagnostic.
CCTA is not recommended in patients with severe renal failure (eGFR <30 mL/min/1.73 m2), decompensated heart failure, extensive
coronary calcification, fast irregular heart rate, severe obesity, inability to cooperate with breath-hold commands, or any other conditions III C
that can make obtaining good imaging quality unlikely.
Recommendations for non-invasive tests in the initial diagnostic management of individuals with suspected chronic coronary syndrome
—stress echocardiography, if available, and supported by local expertise
In individuals with suspected CCS and moderate or high (>15%–85%) pre-test likelihood of obstructive CAD, stress echocardiography is
Functional imaging for myocardial ischaemia is recommended if CCTA has shown CAD of uncertain functional significance or is not
I B
diagnostic.
Invasive coronary angiography with the availability of invasive functional assessments is recommended to confirm or exclude the diagnosis of
I B
obstructive CAD or ANOCA/INOCA in individuals with an uncertain diagnosis on non-invasive testing.
Recommendations for definition of high risk of adverse events
An initial stratification of risk of adverse events is recommended based on basic clinical assessment (e.g. age, ECG, anginal threshold,
I B
diabetes, CKD, LVEF).
The use of one or more of the following test results is recommended to identify individuals at high risk of adverse events:
• Exercise ECG:
⚬ Duke Treadmill Score < −10;
• stress SPECT or PET perfusion imaging:
In patients who are eligible for OAC, DOAC (unless contraindicated) is recommended in preference to VKA. I A
After uncomplicated PCI in CCS patients with concomitant indication for OAC:
• early cessation of aspirin (≤1 week);
• followed by continuation of OAC and clopidogrel:
⚬ up to 6 months in patients not at high ischaemic risk; or I A
⚬ up to 12 months in patients at high ischaemic risk;
• followed by OAC alone;
is recommended.
The use of ticagrelor or prasugrel is generally not recommended as part of triple antithrombotic therapy with aspirin and an OAC. III C
It is recommended to initiate aspirin post-operatively as soon as there is no concern over bleeding. I B
A proton pump inhibitor is recommended in patients at increased risk of gastrointestinal bleeding for the duration of combined
I A
In surgically eligible CCS patients with multivessel CAD and LVEF ≤35%, myocardial revascularization with CABG is recommended over
I B
medical therapy alone to improve long-term survival.
In CCS patients with persistent angina or anginal equivalent, despite guideline-directed medical treatment, myocardial revascularization of
I A
functionally significant obstructive CAD is recommended to improve symptoms.
In patients with complex CAD in whom revascularization is being considered, it is recommended to assess procedural risks and
I C
post-procedural outcomes to guide shared clinical decision-making.
Calculation of the STS score is recommended to estimate in-hospital morbidity and 30-day mortality after CABG. I B
In patients with multivessel obstructive CAD, calculation of the SYNTAX score is recommended to assess the anatomical complexity of
I B
disease.
Intracoronary imaging guidance by IVUS or OCT is recommended when performing PCI on anatomically complex lesions, in particular left
I A
main stem, true bifurcations, and long lesions.
© ESC 2024
In patients with refractory angina leading to poor quality of life and with documented or suspected ANOCA/INOCA, invasive coronary
function testing is recommended to define ANOCA/INOCA endotypes and appropriate treatment, considering patient choices and I B
preferences.
ACE-I, angiotensin-converting enzyme inhibitor; ACS, acute coronary syndrome; AF, atrial fibrillation; ANOCA, angina with non-obstructive coronary arteries; ARB, angiotensin receptor
blocker; ARC-HBR, Academic Research Consortium for High Bleeding; ARNI, angiotensin receptor neprilysin inhibitor; AV, atrioventricular; BP, blood pressure; CABG, coronary artery
bypass grafting; CACS, coronary artery calcium score; CAD, coronary artery disease; CCB, calcium channel blocker; CCS, chronic coronary syndrome; CCTA, coronary computed
tomography angiography; CKD, chronic kidney disease; CMR, cardiac magnetic resonance; CRT, cardiac resynchronization therapy; CT, computed tomography; CV, cardiovascular;
CVD, cardiovascular disease; CYP3A4, cytochrome P450 3A4; DAPT, dual antiplatelet therapy; DES, drug-eluting stent; DHP, dihydropyridine; DOAC, direct oral anticoagulant; ECG,
electrocardiogram; eGFR, estimated glomerular filtration rate; FFR, fractional flow reserve; FFR-CT, coronary computed tomography angiography-derived fractional flow reserve;
GDMT, guideline-directed medical therapy; GLP-1, glucagon-like peptide-1; HbA1c, glycated haemoglobin; HF, heart failure; HFpEF, heart failure with preserved ejection fraction; HFrEF,
heart failure with reduced ejection fraction; HIV, human immunodeficiency virus; ICA, invasive coronary angiography; ICD, implantable cardioverter defibrillator; iFR, instantaneous
wave-free ratio; INOCA, ischaemia with non-obstructive coronary arteries; IVUS, intravascular ultrasound; LAD, left anterior descending; LBBB, left bundle branch block; LDL-C,
low-density lipoprotein cholesterol; LIMA, left internal mammary artery; LV, left ventricular; LVEF, left ventricular ejection fraction; MACE, major adverse cardiovascular events; MI,
myocardial infarction; MRA, mineralocorticoid receptor antagonist; NYHA, New York Heart Association; OAC, oral anticoagulant; OCT, optical coherence tomography; PCI,
percutaneous coronary intervention; PCSK9, proprotein convertase subtilisin/kexin type 9; PET, positron emission tomography; PRECISE-DAPT, PREdicting bleeding Complications In
patients undergoing Stent implantation and subsEquent Dual AntiPlatelet Therapy; QFR, quantitative flow ratio; SCORE2, Systematic Coronary Risk Estimation 2; SCORE-OP,
Systematic Coronary Risk Estimation 2–Older Persons; SGLT2, sodium–glucose cotransporter 2; SPECT, single-photon emission computed tomography; STS, Society of Thoracic
Surgeons; SYNTAX, SYNergy Between PCI with TAXUS and Cardiac Surgery; T2DM, type 2 diabetes mellitus; VKA, vitamin K antagonist.
a
Class of recommendation.
b
Level of evidence.
Center, Institute of Cardiovascular Diseases, Timisoara, Romania; Kingdom); Richard Mindham (United Kingdom); Lis Neubeck (United
Christi Deaton, Public Health and Primary Care, Cambridge Kingdom); Franz-Josef Neumann (Germany); Jens Cosedis Nielsen
University School of Clinical Medicine, Cambridge, United Kingdom; (Denmark); Pasquale Paolisso (Italy); Valeria Paradies (Netherlands);
Torsten Doenst, Department of cardiothoracic surgery, Agnes A. Pasquet (Belgium); Massimo Piepoli (Italy); Eva Prescott
Friedrich-Schiller-University Jena, university hospital, Jena, Germany; (Denmark); Amina Rakisheva (Kazakhstan); Bianca Rocca (Italy); Marc
Hywel W. Jones, ESC Patient Forum, Sophia Antipolis, France; Vijay Ruel (Canada); Sigrid Sandner (Austria); Antti Saraste (Finland);
Kunadian, Translational and Clinical Research Institute, Faculty of Karolina Szummer (Sweden); Ilonca Vaartjes (Netherlands); William
Medical Sciences, Newcastle University and Cardiothoracic Centre, Wijns (Ireland); Stephan Windecker (Switzerland); Adam Witkowsky
Freeman Hospital, Newcastle upon Tyne Hospitals NHS Foundation (Poland); Marija Zdrakovic (Serbia); and Katja Zeppenfeld
Trust, Newcastle upon Tyne, United Kingdom; Julinda Mehilli, (Netherlands).
¶
Medizinische Klinik I, Landshut-Achdorf Hospital, Landshut, Germany, Professor Jean-Philippe Collet sadly passed away during the development
and Klinikum der Universität München Ludwig-Maximilians of these guidelines. Professor Collet’s contribution to these guidelines was, as
Anna Holm; Switzerland: Swiss Society of Cardiology, Raban Jeger; 14. Bajaj Navkaranbir S, Osborne MT, Gupta A, Tavakkoli A, Bravo PE, Vita T, et al.
Coronary microvascular dysfunction and cardiovascular risk in obese patients. J Am
Syrian Arab Republic: Syrian Cardiovascular Association, Mhd
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