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European Heart Journal (2024) 45, 3415–3537 ESC GUIDELINES

https://doi.org/10.1093/eurheartj/ehae177

2024 ESC Guidelines for the management


of chronic coronary syndromes
Developed by the task force for the management of chronic
coronary syndromes of the European Society of Cardiology (ESC)

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Endorsed by the European Association for Cardio-Thoracic Surgery (EACTS)

Authors/Task Force Members: Christiaan Vrints *†, (Chairperson) (Belgium),


Felicita Andreotti *†, (Chairperson) (Italy), Konstantinos C. Koskinas‡,
(Task Force Co-ordinator) (Switzerland), Xavier Rossello ‡, (Task Force
Co-ordinator) (Spain), Marianna Adamo (Italy), James Ainslie (United Kingdom),
Adrian Paul Banning (United Kingdom), Andrzej Budaj (Poland),
Ronny R. Buechel (Switzerland), Giovanni Alfonso Chiariello (Italy),
Alaide Chieffo (Italy), Ruxandra Maria Christodorescu (Romania),
1
Christi Deaton (United Kingdom), Torsten Doenst (Germany),
Hywel W. Jones (United Kingdom), Vijay Kunadian (United Kingdom),
1
Julinda Mehilli (Germany), Milan Milojevic (Serbia), Jan J. Piek
(Netherlands), Francesca Pugliese (United Kingdom), Andrea Rubboli (Italy),
Anne Grete Semb (Norway), Roxy Senior (United Kingdom),
Jurrien M. ten Berg (Netherlands), Eric Van Belle (France),
Emeline M. Van Craenenbroeck (Belgium), Rafael Vidal-Perez (Spain),
Simon Winther (Denmark), and ESC Scientific Document Group

* 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),

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Marija Zdrakovic (Serbia), and Katja Zeppenfeld (Netherlands)

¶ 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
use only. No commercial use is authorized. No part of the ESC Guidelines may be translated or reproduced in any form without written
permission from the ESC. Permissions can be obtained upon submission of a written request to Oxford University Press, the publisher of
the European Heart Journal and the party authorized to handle such permissions on behalf of the ESC (journals.permissions@oup.com).

-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

Table of contents 4.1.2.4. Mental health ........................................................................... 3456


4.1.2.5. Physical activity and sedentary behaviour .................... 3456
1. Preamble .............................................................................................................. 3422 4.1.3. Exercise therapy .............................................................................. 3457
2. Introduction ....................................................................................................... 3423 4.2. Antianginal/anti-ischaemic medication ........................................... 3457
2.1. Evolving pathophysiological concepts of chronic coronary 4.2.1. General strategy .............................................................................. 3457
syndromes .......................................................................................................... 3423 4.2.2. Beta blockers .................................................................................... 3458
2.2. Chronic coronary syndromes: clinical presentations 4.2.3. Combination therapy .................................................................... 3459
(Figure 1) ............................................................................................................. 3424 4.3. Medical therapy for event prevention ........................................... 3460
2.3. Changing epidemiology and management strategies .............. 3424 4.3.1. Antithrombotic drugs ................................................................... 3460
2.4. What is new ............................................................................................. 3426 4.3.1.1. Antiplatelet drugs ................................................................... 3460
3. Stepwise approach to the initial management of individuals with 4.3.1.1.1. Aspirin monotherapy ................................................... 3460
suspected chronic coronary syndrome ....................................................... 3433 4.3.1.1.2. Oral P2Y12 inhibitor monotherapy ....................... 3460

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3.1. STEP 1: General clinical examination ............................................. 3433 4.3.1.1.2.1. Clopidogrel monotherapy ................................. 3460
3.1.1. History, differential diagnosis, and physical examination 3433 4.3.1.1.2.2. Ticagrelor monotherapy .................................... 3460
3.1.2. Basic testing: 12-lead electrocardiogram and 4.3.1.1.3. Dual antiplatelet therapy post-percutaneous
biochemistry .................................................................................................. 3436 coronary intervention ..................................................................... 3462
3.1.2.1. Electrocardiogram ................................................................. 3436 4.3.1.1.4. Extended intensified antithrombotic therapy ... 3462
3.1.2.2. Biochemical tests .................................................................... 3437 4.3.1.1.5. Genotype- and phenotype-guided dual
3.2. STEP 2: Further evaluation ................................................................. 3437 antiplatelet therapy .......................................................................... 3463
3.2.1. Pre-test clinical likelihood of obstructive atherosclerotic 4.3.1.2. Anticoagulant therapy .......................................................... 3464
coronary artery disease ............................................................................ 3437 4.3.1.2.1. Monotherapy with oral anticoagulant .................. 3464
3.2.2. Transthoracic echocardiography and cardiac magnetic 4.3.1.2.2. Combination of anticoagulant and antiplatelet
resonance at rest ........................................................................................ 3440 therapy after percutaneous coronary intervention in
3.2.3. Exercise electrocardiogram testing ......................................... 3440 chronic coronary syndrome patients with AF or other
3.2.4. Chest X-ray ....................................................................................... 3441 indication for oral anticoagulant ................................................. 3464
3.2.5. Ambulatory electrocardiogram monitoring ........................ 3441 4.3.1.3. Coronary artery bypass grafting and antithrombotic
3.3. STEP 3: Confirming the diagnosis ................................................... 3441 therapy ........................................................................................................ 3465
3.3.1. Anatomical imaging: coronary computed tomography 4.3.1.4. Proton pump inhibitors ....................................................... 3465
angiography .................................................................................................... 3441 4.3.2. Lipid-lowering drugs ...................................................................... 3467
3.3.1.1. Computed tomography perfusion imaging ................. 3441 4.3.3. Renin–angiotensin–aldosterone blockers/angiotensin
3.3.1.2. Prognosis, plaque features, and opportunity to receptor neprilysin inhibitor .................................................................. 3467
improve outcomes ................................................................................ 3442 4.3.4. Sodium–glucose cotransporter 2 inhibitors and glucagon-
3.3.1.3. Recognized pre-requisites for coronary computed like peptide-1 receptor agonists ........................................................... 3468
tomography angiography .................................................................... 3442 4.3.5. Anti-inflammatory agents for event prevention ................ 3468
3.3.2. Functional imaging .......................................................................... 3442 4.4. Revascularization for chronic coronary syndromes ................ 3469
3.3.2.1. Stress echocardiography ..................................................... 3442 4.4.1. Appropriate indication for myocardial revascularization 3469
3.3.2.2. Myocardial perfusion scintigraphy—single-photon 4.4.2. Additional considerations on reduced systolic left
emission computed tomography .................................................... 3443 ventricular function: myocardial viability, revascularization, and
3.3.2.3. Positron emission tomography-computed its modality .................................................................................................... 3470
tomography .............................................................................................. 3444 4.4.3. Additional considerations—complete vs. partial
3.3.2.4. Cardiac magnetic resonance imaging ............................. 3444 revascularization .......................................................................................... 3471
3.3.2.5. Non-invasive testing for microvascular dysfunction 3445 4.4.4. Assessment of clinical risk and anatomical complexity .. 3471
3.3.3. Invasive tests ..................................................................................... 3445 4.4.5. Choice of myocardial revascularization modality ............. 3472
3.3.3.1. Invasive coronary angiography ......................................... 3445 4.4.5.1. Patients with single- or two-vessel coronary artery
3.3.3.2. Functional assessment of epicardial stenosis severity disease ......................................................................................................... 3472
to guide coronary revascularization ............................................... 3446 4.4.5.2. Patients with unprotected left main coronary artery
3.3.3.3. Assessment of microvascular dysfunction ................... 3447 disease ......................................................................................................... 3472
3.3.3.4. Testing for coronary vasospasm ..................................... 3447 4.4.5.3. Patients with multivessel coronary artery disease ... 3474
3.3.4. Diagnostic algorithm and selection of appropriate tests 3448 4.4.5.4. Impact of coronary pressure guidance on multivessel
3.3.5. Adverse-event risk assessment ................................................. 3453 coronary artery disease patients undergoing percutaneous
3.4. STEP 4: Initial therapy .......................................................................... 3454 coronary intervention .......................................................................... 3474
4. Guideline-directed therapy .......................................................................... 3455 4.4.5.5. Virtual percutaneous coronary intervention:
4.1. Patient education, lifestyle optimization for risk-factor combination of coronary pressure mapping with coronary
control, and exercise therapy .................................................................... 3455 anatomy for percutaneous coronary intervention planning 3474
4.1.1. Patient education ............................................................................ 3455 4.4.5.6. Impact of intracoronary imaging guidance on
4.1.2. Key lifestyle interventions for risk-factor control ............ 3455 multivessel coronary artery disease patients undergoing
4.1.2.1. Smoking and substance abuse .......................................... 3456 percutaneous coronary intervention ............................................. 3474
4.1.2.2. Weight management ............................................................ 3456 4.4.5.7. Hybrid revascularization in multivessel coronary
4.1.2.3. Diet and alcohol ..................................................................... 3456 artery disease patients ......................................................................... 3475
3418 ESC Guidelines

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

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5.2.3. Clinical presentations .................................................................... 3481 Tables of Recommendations
5.2.4. Short- and long-term prognosis ............................................... 3481 Recommendation Table 1 — Recommendations for history taking,
5.2.5. Diagnosis ............................................................................................ 3481 risk factor assessment, and resting electrocardiogram in individuals
5.2.5.1. Non-invasive diagnosis ......................................................... 3481 with suspected chronic coronary syndrome (see also Evidence
5.2.5.2. Invasive coronary functional testing ............................... 3481 Table 1) ............................................................................................................................... 3436
5.2.5.2.1. Basic coronary functional testing ............................ 3481 Recommendation Table 2 — Recommendations for basic
5.2.5.2.2. Coronary vasomotor testing .................................... 3481 biochemistry in the initial diagnostic management of individuals
5.2.6. Management of angina/ischaemia with non-obstructive with suspected chronic coronary syndrome (see also Evidence
coronary arteries ........................................................................................ 3483 Table 2) ............................................................................................................................... 3437
5.3. Other specific patient groups ........................................................... 3485 Recommendation Table 3 — Recommendations for estimating,
5.3.1. Older adults ...................................................................................... 3485 adjusting and reclassifying the likelihood of obstructive
5.3.2. Sex differences in chronic coronary syndromes ............... 3485 atherosclerotic coronary artery disease in the initial diagnostic
5.3.3. High bleeding-risk patients ......................................................... 3486 management of individuals with suspected chronic coronary
5.3.4. Inflammatory rheumatic diseases ............................................. 3486 syndrome (see also Evidence Table 3) ......................................................... 3438
5.3.5. Hypertension .................................................................................... 3486 Recommendation Table 4 — Recommendations for resting
transthoracic ultrasound and cardiac magnetic resonance imaging in
5.3.6. Atrial fibrillation ............................................................................... 3486
the initial diagnostic management of individuals with suspected
5.3.7. Valvular heart disease ................................................................... 3486
chronic coronary syndrome (see also Evidence Table 4) ................... 3440
5.3.8. Chronic kidney disease ................................................................. 3487
Recommendation Table 5 — Recommendations for exercise ECG
5.3.9. Cancer ................................................................................................. 3487
in the initial diagnostic management of individuals with suspected
5.3.10. Optimal treatment of patients with human
chronic coronary syndrome (see also Evidence Table 5) ................... 3441
immunodeficiency virus ............................................................................ 3487
Recommendation Table 6 — Recommendations for chest X-ray in
5.3.11. Socially and geographically diverse groups ........................ 3487 the initial diagnostic management of individuals with suspected
5.4. Screening for coronary artery disease in asymptomatic chronic coronary syndrome (see also Evidence Table 6) ................... 3441
individuals ........................................................................................................... 3488 Recommendation Table 7 — Recommendations for ambulatory ECG
6. Long-term follow-up and care ................................................................... 3489 monitoring in the initial diagnostic management of individuals with
6.1. Voice of the patient .............................................................................. 3489 suspected chronic coronary syndrome (see also Evidence Table 7) . 3441
6.1.1. Communication ............................................................................... 3489 Recommendation Table 8 — Recommendations for non-invasive
6.1.2. Depression and anxiety ............................................................... 3489 anatomical imaging tests in the initial diagnostic management of
6.2. Adherence and persistence ............................................................... 3489 individuals with suspected chronic coronary syndrome—coronary
6.2.1. Adherence to healthy lifestyle behaviours ........................... 3489 computed tomography angiography, if available, and supported by
6.2.1.1. Why behavioural changes are difficult .......................... 3489 local expertise (see also Evidence Table 8) ............................................... 3442
6.2.1.2. How to change behaviour and support healthy Recommendation Table 9 — Recommendations for non-invasive
lifestyles ...................................................................................................... 3490 tests in the initial diagnostic management of individuals with suspected
6.2.1.3. Digital and mHealth .............................................................. 3491 chronic coronary syndrome—stress echocardiography, if available,
6.2.1.4. How to assess adherence .................................................. 3492 and supported by local expertise (see also Evidence Table 9) .............. 3443
6.2.2. Adherence to medical therapy ................................................. 3492 Recommendation Table 10 — Recommendations for non-invasive
6.2.2.1. Strategies to improve medication adherence ............ 3492 functional myocardial imaging tests in the initial diagnostic
6.2.2.2. mHealth strategies for medication adherence .......... 3492 management of individuals with suspected chronic coronary
syndrome—resting and stress single-photon emission computed
6.3. Diagnosis of disease progression ..................................................... 3492
tomography/positron emission tomography—cardiac magnetic
6.3.1. Risk factors for recurrent coronary artery disease
resonance imaging, if available, and supported by local expertise (see
events ............................................................................................................... 3493
also Evidence Table 10) ...................................................................................... 3444
6.3.2. Organization of long-term follow-up ..................................... 3493
Recommendation Table 11 — Recommendations for invasive
6.3.3. Non-invasive diagnostic testing ................................................. 3494
coronary angiography in the diagnostic management of individuals
6.4. Treatment of myocardial revascularization failure ................... 3495
with suspected chronic coronary syndrome (see also Evidence
6.4.1. Percutaneous coronary intervention failure ....................... 3495 Table 11) ................................................................................................................... 3446
6.4.2. Managing graft failure after coronary artery bypass Recommendation Table 12 — Recommendations for functional
grafting ............................................................................................................. 3495 assessment of epicardial artery stenosis severity during invasive
ESC Guidelines 3419

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

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drugs in patients with chronic coronary syndrome (see also Evidence
Table 16) ................................................................................................................... 3459
List of figures
Recommendation Table 17 — Recommendations for Figure 1 (Central Illustration) Clinical presentations of chronic
antithrombotic therapy in patients with chronic coronary syndrome coronary syndrome and mechanisms of myocardial ischaemia ........ 3425
(see also Evidence Table 17) ............................................................................ 3465 Figure 2 Stepwise approach to the initial management of individuals
Recommendation Table 18 — Recommendations for lipid-lowering with suspected chronic coronary syndrome ............................................ 3434
drugs in patients with chronic coronary syndrome (see also Evidence Figure 3 Main CCS symptoms: angina and exertional dyspnoea ..... 3435
Table 18) ................................................................................................................... 3467 Figure 4 Estimation of the clinical likelihood of obstructive coronary
Recommendation Table 19 — Recommendations for sodium– artery disease .......................................................................................................... 3439
glucose cotransporter 2 inhibitors and/or glucagon-like peptide-1 Figure 5 Adjustment and reclassification of the estimated clinical
receptor agonists in patients with chronic coronary syndrome (see likelihood of obstructive coronary artery disease .................................. 3448
also Evidence Table 19) ...................................................................................... 3468 Figure 6 Appropriate first-line testing in symptomatic individuals
Recommendation Table 20 — Recommendations for with suspected chronic coronary syndrome ............................................ 3449
anti-inflammatory drugs in patients with chronic coronary syndrome Figure 7 Initial management of symptomatic individuals with
(see also Evidence Table 20) ............................................................................ 3469 suspected chronic coronary syndrome ....................................................... 3450
Recommendation Table 21 — Recommendations for Figure 8 Ruling in and ruling out functionally significant obstructive
angiotensin-converting enzyme inhibitors in patients with chronic coronary artery disease by sequential anatomical (coronary
coronary syndrome (see also Evidence Table 21) ................................. 3469 computed tomography angiography) and functional (dobutamine
Recommendation Table 22 — Recommendations for stress echocardiography) testing.a ................................................................. 3452
revascularization in patients with chronic coronary syndrome (see Figure 9 Possible combinations of antianginal drugs .............................. 3458
also Evidence Table 22) ...................................................................................... 3476 Figure 10 Antithrombotic drugs for chronic coronary syndromes:
Recommendation Table 23 — Recommendations for mode of pharmacological targets ...................................................................................... 3461
revascularization in patients with chronic coronary syndrome (see Figure 11 Antithrombotic treatment in chronic coronary syndrome
also Evidence Table 23) ...................................................................................... 3477 patients undergoing percutaneous coronary intervention ................. 3463
Recommendation Table 24 — Recommendations for management Figure 12 Prevalence of disease characteristics in patients with
of chronic coronary syndrome patients with chronic heart failure ANOCA/INOCA referred for invasive coronary functional testing 3480
(see also Evidence Table 24) ............................................................................ 3478 Figure 13 Diagnostic algorithm for patients with angina/ischaemia
Recommendation Table 25 — Recommendations for diagnosis and with non-obstructive coronary arteries ...................................................... 3482
management of patients with angina/ischaemia with non-obstructive Figure 14 Spasm provocation and functional testing protocol ......... 3483
coronary arteries (see also Evidence Table 25) ........................................ 3485 Figure 15 Treatment of angina/ischaemia with non-obstructive
Recommendation Table 26 — Recommendations for older, female, coronary arteries .................................................................................................. 3484
high bleeding risk, comorbid, and socially/geographically diverse Figure 16 Actions on the five dimensions of adherence to therapy 3490
patients (see also Evidence Table 26) ........................................................... 3488 Figure 17 Strategies for long-term adherence to a healthy lifestyle 3491
Recommendation Table 27 — Recommendations for screening for Figure 18 Approach for the follow-up of patients with established
coronary artery disease in asymptomatic individuals (see also chronic coronary syndrome ............................................................................. 3494
Evidence Table 27) ............................................................................................... 3488
Recommendation Table 28 — Recommendations for adherence to
medical therapy and lifestyle changes (see also Evidence Table 28) 3492
Abbreviations and acronyms
Recommendation Table 29 — Recommendations for diagnosis of 99mTc Technetium-99m
disease progression in patients with established chronic coronary ACE-I Angiotensin-converting enzyme inhibitor
syndrome (see also Evidence Table 29) ...................................................... 3495 Ach Acetylcholine
Recommendation Table 30 — Recommendations for treatment of ACS Acute coronary syndrome(s)
revascularization failure (see also Evidence Table 30) .......................... 3496 AF Atrial fibrillation
Recommendation Table 31 — Recommendations for recurrent or AKI Acute kidney injury
refractory angina/ischaemia (see also Evidence Table 31) .................. 3496 ALPHEUS Assessment of Loading with the P2Y12 Inhibitor
Ticagrelor or Clopidogrel to Halt Ischemic
Events in Patients Undergoing Elective Coronary
List of tables Stenting
Table 1 Classes of recommendations .......................................................... 3422 ANOCA Angina with non-obstructive coronary arteries
Table 2 Levels of evidence ................................................................................ 3423 ARB Angiotensin receptor blocker
3420 ESC Guidelines

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

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BARC Bleeding Academic Research Consortium FAME Fractional Flow Reserve versus Angiography for
b.i.d. bis in die (twice daily) Multivessel Evaluation
BMI Body mass index FFR Fractional flow reserve
BP Blood pressure FFR-CT Coronary computed tomography
b.p.m. Beats per minute angiography-derived fractional flow reserve
CABG Coronary artery bypass grafting FREEDOM Strategies for Multivessel Revascularization in
CAC Coronary artery calcification Patients with Diabetes
CACS Coronary artery calcium score GDMT Guideline-directed medical therapy
CACS-CL CACS + risk-factor-weighted clinical likelihood GI Gastrointestinal
(RF-CL) model GIP Glucose-dependent insulinotropic polypeptide
CAD Coronary artery disease GLOBAL Ticagrelor plus aspirin for 1 month, followed by
CANTOS Canakinumab Antiinflammatory Thrombosis LEADERS ticagrelor monotherapy for 23 months vs. aspirin
Outcome Study plus clopidogrel or ticagrelor for 12 months,
CAPRIE Clopidogrel versus Aspirin in Patients at Risk of followed by aspirin monotherapy for 12 months
Ischaemic Events after implantation of a drug-eluting stent (DES):
CCB Calcium channel blocker a multicentre, open-label, randomized
CCS Chronic coronary syndrome(s) superiority trial
CCTA Coronary computed tomography angiography GLP-1 Glucagon-like peptide-1
CFC Coronary flow capacity GUSTO Global Utilization of Streptokinase and Tissue
CFR Coronary flow reserve Plasminogen Activator for Occluded Arteries
CFVR Coronary flow velocity reserve HbA1c Glycated haemoglobin
CHA2DS2-VASc Congestive heart failure or left ventricular HBR High bleeding risk
dysfunction, hypertension, age ≥75 (doubled), HDL-C High-density lipoprotein cholesterol
diabetes, stroke (doubled), vascular disease, age HF Heart failure
65–74, sex category (female) HFmrEF Heart failure with mildly reduced ejection fraction
CI Confidence interval HFpEF Heart failure with preserved ejection fraction
CKD Chronic kidney disease HFrEF Heart failure with reduced ejection fraction
CMD Coronary microvascular dysfunction HIV Human immunodeficiency virus
CMR Cardiac magnetic resonance HMR Hyperaemic myocardial velocity resistance
COLCOT Colchicine Cardiovascular Outcomes Trial HOST-EXAM Harmonizing Optimal Strategy for Treatment of
COMPASS Cardiovascular Outcomes for People Using Coronary Artery Stenosis-EXtended
Anticoagulation Strategies Antiplatelet Monotherapy
COURAGE Clinical Outcomes Utilizing Revascularization HR Hazard ratio
and Aggressive Drug Evaluation hs-CRP High-sensitivity C-reactive protein
CRT Cardiac resynchronization therapy HSR Hyperaemic stenosis resistance
CT Computed tomography i.c. Intracoronary
CVD Cardiovascular disease i.v. Intravenous
CYP2C19 Cytochrome P450 2C19 ICA Invasive coronary angiography
CYP3A4 Cytochrome P450 3A4 ICD Implantable cardioverter defibrillator
CZT Cadmium–zinc–telluride ICFT Invasive coronary functional testing
DAPT Dual antiplatelet therapy iFR Instantaneous wave-free ratio
DEFINE GPS Distal Evaluation of Functional Performance with iFR- Instantaneous Wave-free Ratio versus Fractional
Intravascular Sensors to Assess the Narrowing SWEDEHEART Flow Reserve in Patients with Stable Angina
Effect: Guided Physiologic Stenting Pectoris or Acute Coronary Syndrome
DES Drug-eluting stent ILIAS Inclusive Invasive Physiological Assessment in
DEFINE-FLAIR Functional Lesion Assessment of Intermediate Angina Syndromes
Stenosis to Guide Revascularisation IMR Index of microcirculatory resistance
DHP Dihydropyridine INOCA Ischaemia with non-obstructive coronary arteries
DM Diabetes mellitus INR International normalized ratio
DOAC Direct oral anticoagulant IQR Interquartile range
ESC Guidelines 3421

ISCHEMIA Initial Invasive or Conservative Strategy for PDE-5 Phosphodiesterase-5


Stable Coronary Disease (trial) PEGASUS-TIMI Prevention of Cardiovascular Events in Patients
ISR In-stent restenosis 54 with Prior Heart Attack Using Ticagrelor
ISTH International Society on Thrombosis and Compared to Placebo on a Background of
Haemostasis Aspirin Thrombolysis In Myocardial Infarction
IVUS Intravascular ultrasound PESA Progression of Early Subclinical Atherosclerosis
LAD Left anterior descending PET Positron emission tomography
LBBB Left bundle branch block PRECISE-DAPT PREdicting bleeding Complications In
LDL-C Low-density lipoprotein cholesterol patients undergoing Stent implantation
LGE Late gadolinium enhancement and subsEquent Dual AntiPlatelet Therapy
LIMA Left internal mammary artery PRECOMBAT Randomized Trial of Stents versus Bypass
LITA Left internal thoracic artery Surgery for Left Main Coronary Artery Disease

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LMCA Left main coronary artery (trial)
LMCAD Left main coronary artery disease PRIZE Precision Medicine with Zibotentan in
LODOCO2 LOw-DOse COlchicine 2 Microvascular Angina
LOE Level of evidence PROM Patient-reported outcome measure
LV Left ventricular PROMISE Prospective Multicenter Imaging Study for
LVEF Left ventricular ejection fraction Evaluation of Chest Pain
MACCE Major adverse cardiac or cerebrovascular events PTP Pre-test probability
MACE Major adverse cardiovascular events QFR Quantitative flow ratio
MASTER-DAPT Management of High Bleeding Risk Patients Post QoL Quality of life
Bioresorbable Polymer Coated Stent Implantation R3F French FFR Registry
with an Abbreviated versus Standard DAPT Regimen RAAS Renin–angiotensin–aldosterone system
MBF Myocardial blood flow RCT Randomized controlled trial
MCE Myocardial contrast echocardiography REVIVED-BCIS2 Percutaneous Revascularization for Ischemic Left
MCS Mechanical circulatory support Ventricular Dysfunction
MFR Myocardial flow reserve RF-CL Risk-factor-weighted clinical likelihood
mHealth Mobile device-based healthcare RFR Relative flow reserve
MI Myocardial infarction RIPCORD Routine Pressure Wire Assessment Influence
MIDCAB Minimally invasive direct coronary artery bypass Management Strategy at Coronary Angiography
MRA Mineralocorticoid receptor antagonist for Diagnosis of Chest Pain trial
MRI Magnetic resonance imaging RR Relative risk
MRR Microvascular resistance reserve RWTA Regional systolic wall-thickening abnormalities
MVA Microvascular angina SAPT Single antiplatelet therapy
MVD Multivessel disease SCORE2 Systematic Coronary Risk Estimation 2
NNH Number needed to harm SCORE2-OP Systematic Coronary Risk Estimation 2–Older
NNT Number needed to treat to prevent an adverse event Persons
NOBLE Nordic–Baltic–British Left Main SCOT-HEART Scottish Computed Tomography of the Heart
Revascularisation Study SELECT Semaglutide Effects on Cardiovascular
NSTEMI Non-ST-segment elevation myocardial infarction Outcomes in People With Overweight or
NTG Nitroglycerine Obesity
NYHA New York Heart Association SGLT2 Sodium–glucose cotransporter 2
OAC Oral anticoagulant SLE Systemic lupus erythematosus
OCT Optical coherence tomography SPECT Single-photon emission computed
OR Odds ratio tomography
ORBITA Objective Randomised Blinded Investigation with STEMI ST-segment elevation myocardial infarction
optimal medical Therapy of Angioplasty in stable STICH Surgical Treatment for Ischemic Heart Failure
angina STS-PROM Society of Thoracic Surgeons Predicted Risk of
ORBITA-COSMIC Coronary Sinus Reducer Objective Impact on Mortality
Symptoms, MRI Ischaemia and Microvascular SURMOUNT Efficacy and Safety of Tirzepatide Once Weekly
Resistance in Participants Without Type 2 Diabetes Who
PAD Peripheral artery disease Have Obesity or Are Overweight With Weight-
PAR Protease-activated receptor Related Comorbidities: A Randomized, Double-
PARR-2 F-18-Fluorodeoxyglucose Positron Emission Blind, Placebo-Controlled Trial
Tomography Imaging-Assisted Management of SYNTAX SYNergy between PCI with TAXUS and Cardiac
Patients with Severe Left Ventricular Surgery
Dysfunction and Suspected Coronary Disease: a THEMIS The Effect of Ticagrelor on Health Outcomes
Randomized, Controlled Trial in diabEtes Mellitus patients Intervention Study
PCI Percutaneous coronary intervention TID Transient ischaemic dilatation
PCSK9 Proprotein convertase subtilisin/kexin type 9 TIMI Thrombolysis In Myocardial Infarction
Pd/Pa Distal coronary pressure to aortic pressure ratio Tx Thromboxane
3422 ESC Guidelines

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

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recommendation and the level of evidence supporting them were
weighed and scored according to predefined scales as outlined in
1. Preamble Tables 1 and 2 below. Patient-reported outcome measures (PROMs)
Guidelines evaluate and summarize available evidence with the aim of as­ and patient-reported experience measures (PREMs) were also evalu­
sisting health professionals in proposing the best diagnostic or therapeut­ ated as the basis for recommendations and/or discussion in these guide­
ic approach for an individual patient with a given condition. Guidelines are lines. The task force followed ESC voting procedures and all approved
intended for use by health professionals, and the European Society of recommendations were subject to a vote and achieved at least 75%
Cardiology (ESC) makes its guidelines freely available. agreement among voting members. Members of the task force with de­
ESC Guidelines do not override the individual responsibility of health clared interests on specific topics were asked to abstain from voting on
professionals to make appropriate and accurate decisions in consider­ related recommendations.
ation of each patient’s health condition and in consultation with that pa­ The experts of the writing and reviewing panels provided declaration
tient or the patient’s caregiver where appropriate and/or necessary. It is of interest forms for all relationships that might be perceived as real or
also the health professional’s responsibility to verify the rules and reg­ potential sources of conflicts of interest. Their declarations of interest
ulations applicable in each country to drugs and devices at the time of were reviewed according to the ESC declaration of interest rules,
prescription and to respect the ethical rules of their profession. which can be found on the ESC website (http://www.escardio.org/
ESC Guidelines represent the official position of the ESC on a given guidelines) and have been compiled in a report published in a supple­
topic and are regularly updated when warranted by new evidence. ESC mentary document with the guidelines. Funding for the development
Policies and Procedures for formulating and issuing ESC Guidelines can of ESC Guidelines is derived entirely from the ESC with no involvement
be found on the ESC website (https://www.escardio.org/Guidelines/ of the healthcare industry.
Clinical-Practice-Guidelines/Guidelines-development/Writing-ESC-Gui The ESC Clinical Practice Guidelines (CPG) Committee supervises
delines). These guidelines update and replace the previous version from and co-ordinates the preparation of new guidelines and is responsible

Table 1 Classes of recommendations

Definition Wording to use


Classes of recommendations

Class I Evidence and/or general agreement Is recommended or is indicated


that a given treatment or procedure is
beneficial, useful, effective.

Class II Conflicting evidence and/or a divergence of opinion about the usefulness/


efficacy of the given treatment or procedure.

Class IIa Weight of evidence/opinion is in Should be considered


favour of usefulness/efficacy.

Class IIb Usefulness/efficacy is less well May be considered


established by evidence/opinion.

Class III Evidence or general agreement that the Is not recommended


given treatment or procedure is not
©ESC 2024

useful/effective, and in some cases


© ESC 2024

may be harmful.
ESC Guidelines 3423

Table 2 Levels of evidence

Level of Data derived from multiple randomized clinical trials


evidence A or meta-analyses.

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Level of Data derived from a single randomized clinical trial
evidence B or large non-randomized studies.

Level of Consensus of opinion of the experts and/or small studies,


evidence C retrospective studies, registries.

©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

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edged as a prevalent factor characterizing the entire spectrum of
CCS;6 functional and structural microcirculatory abnormalities may Contemporary primary prevention,16 including lifestyle changes and
cause angina and ischaemia even in patients with non-obstructive guideline-directed medical therapy (GDMT), has led to a decline of
disease of the large or medium coronary arteries [angina with the age-standardized prevalence22,23 of obstructive epicardial coronary
non-obstructive coronary arteries (ANOCA); ischaemia with non- atherosclerosis in patients with suspected CCS.24–28 As a consequence,
obstructive coronary arteries (INOCA)].6 Finally, systemic or extracor­ the diagnostic and prognostic risk prediction models applied in the past
onary conditions, such as anaemia, tachycardia, blood pressure (BP) to identify obstructive epicardial CAD in patients with suspected angina
changes, myocardial hypertrophy, and fibrosis, may contribute to the pectoris have required updating and refinement.27,29,30 Initial use of
complex pathophysiology of non-acute myocardial ischaemia.7 coronary computed tomography angiography (CCTA)31,32 for detect­
The risk factors that predispose to the development of epicardial ing and assessing epicardial coronary atherosclerosis is increasingly
coronary atherosclerosis also promote endothelial dysfunction and ab­ being adopted since it has shown similar performance to non-invasive
normal vasomotion in the entire coronary tree, including the arterioles stress testing for detecting segmental myocardial ischaemia.33–35
that regulate coronary flow and resistance,8–10 and adversely affect Invasive coronary angiography (ICA), classically used to detect anatom­
myocardial capillaries,6,11–14 leading to their rarefaction. Potential con­ ically significant stenoses, has expanded to become a functional test36
sequences include a lack of flow-mediated vasodilation in the epicardial that includes refined haemodynamic assessment of epicardial stenoses,
conductive arteries9 and macro- and microcirculatory vasoconstric­ provocative testing for the detection of epicardial or microvascular
tion.15 Of note, different mechanisms of ischaemia may act spasm,37–40 and a functional assessment of CMD.41–43 Moreover, there
concomitantly. is a growing interest in non-invasive imaging methods such as stress
positron emission tomography (PET)44,45 or stress magnetic resonance
imaging (MRI),46 which allow accurate assessment of the coronary
2.2. Chronic coronary syndromes: clinical microcirculation in a quantitative manner.
presentations (Figure 1) Medical therapy for CCS patients, including antithrombotic strat­
In clinical practice, the following, not entirely exclusive, CCS patients egies, anti-inflammatory drugs, statins and new lipid-lowering, meta­
seek outpatient medical attention: (i) the symptomatic patient with re­ bolic, and anti-obesity agents, has significantly improved survival
producible stress-induced angina or ischaemia with epicardial obstruct­ after conservative treatment, making it harder to demonstrate the
ive CAD; (ii) the patient with angina or ischaemia caused by epicardial benefits of early invasive therapy.47 However, revascularization can
vasomotor abnormalities or functional/structural microvascular altera­ still benefit patients with obstructive CAD at high risk of adverse
tions in the absence of epicardial obstructive CAD (ANOCA/INOCA); events, not only for symptom relief48–52 but also to prevent spontan­
(iii) the non-acute patient post-ACS or after a revascularization; eous myocardial infarction (MI) and cardiac death and, in some
(iv) the non-acute patient with heart failure (HF) of ischaemic or groups, to improve overall survival53–56 during long-term follow-up.
cardiometabolic origin. A further growing category (v) are the Recently, revascularization through percutaneous coronary interven­
asymptomatic individuals in whom epicardial CAD is detected during tion (PCI) was shown to provide more angina relief than a placebo
an imaging test for refining cardiovascular risk assessment,16 screening procedure in patients with stable angina and evidence of ischaemia,
for personal or professional purposes, or as an incidental finding for an­ on minimal or no antianginal therapy, confirming the beneficial effects
other indication.17 Patients may experience a variable and unpredict­ of revascularization.52
able course, transitioning between different types of CCS and ACS The present guidelines deal with the assessment and diagnostic algo­
presentations throughout their lifetime. rithm in patients with symptoms suspected of CCS (Section 3) and their
The clinical presentations of CCS are not always specific for the treatment (Section 4), special subgroups of CCS patients (Section 5) and
mechanism causing myocardial ischaemia; thus, symptoms of finally, long-term follow-up and care (Section 6).
ESC Guidelines 3425

A Stress-induced angina, or equivalent,


with obstructive CAD

Angina or equivalent Stabilized phase


with no obstructive CAD after ACS, PCI, or CABG
(ANOCA/INOCA)

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Clinical spectrum
of suspected, or
confirmed,
chronic coronary
syndromes

Asymptomatic with abnormal LV dysfunction or heart


coronary anatomical failure of ischaemic origin
or functional test

B Main mechanisms of myocardial ischaemia


in chronic coronary syndromes

Epicardial Microvascular

Structural Functional Structural Functional

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

2.4. What is new


The 2024 Guidelines contain a number of new and revised recommendations, which are summarized in Tables 3 and 4, respectively.
Table 3 New major recommendations in 2024

Recommendations Classa Levelb

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.

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Basic biochemistry in the initial diagnostic management of individuals with suspected chronic coronary syndrome—Section 3
• Additionally, high-sensitivity C-reactive protein and/or fibrinogen plasma levels should be considered. IIa B
Likelihood of obstructive atherosclerotic coronary artery disease in the initial diagnostic management of individuals with suspected
chronic coronary syndrome—Section 3
It is recommended to estimate the pre-test likelihood of obstructive epicardial CAD using the Risk Factor-weighted Clinical Likelihood
I B
model.
It is recommended to use additional clinical data (e.g. examination of peripheral arteries, resting ECG, resting echocardiography, presence of
vascular calcifications on previously performed imaging tests) to adjust the estimate yielded by the Risk Factor-weighted Clinical Likelihood I C
model.
In individuals with a very low (≤5%) pre-test likelihood of obstructive CAD, deferral of further diagnostic tests should be considered. IIa B
In individuals with a low (>5%–15%) pre-test likelihood of obstructive CAD, CACS should be considered to reclassify subjects and to
IIa B
identify more individuals with very low (≤5%) CACS-weighted clinical likelihood.
In individuals with an initially low (>5%–15%) likelihood of obstructive CAD, exercise ECG and detection of atherosclerotic disease in
IIb C
non-coronary arteries may be considered to adjust the pre-test likelihood estimate.
Ambulatory electrocardiogram in the initial diagnostic management of individuals with suspected chronic coronary syndrome—Section 3
Ambulatory ECG monitoring should be considered in subjects with suspected vasospastic angina. IIa B
Non-invasive anatomical imaging tests in the initial diagnostic management of individuals with suspected obstructive coronary artery
disease—coronary computed tomography angiography, if available and supported by local expertise—Section 3
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.
Non-invasive tests in the initial diagnostic management of individuals with suspected chronic coronary syndrome—stress
echocardiography, if available and supported by local expertise—Section 3
In individuals with suspected CCS and moderate or high (>15%–85%) pre-test likelihood of obstructive CAD, stress echocardiography is
I B
recommended to diagnose myocardial ischaemia and to estimate the risk of MACE.
During stress echocardiography, when two or more contiguous myocardial segments are not visualized, it is recommended to use
I B
commercially available intravenous ultrasound contrast agents (microbubbles) to improve diagnostic accuracy.
During stress echocardiography, myocardial perfusion using commercially available intravenous ultrasound contrast agents (microbubbles)
I B
is recommended to improve diagnostic accuracy and to refine risk stratification beyond wall motion.
During stress echocardiography, Doppler left anterior descending coronary artery flow reserve may be considered to improve risk
IIb B
stratification beyond wall motion and to assess microvascular function.
Non-invasive functional myocardial imaging tests in the initial diagnostic management of individuals with suspected chronic coronary
syndrome—resting and stress single-photon emission computed tomography/positron emission tomography—cardiac magnetic
resonance imaging, if available and supported by local expertise—Section 3
In individuals with suspected CCS and moderate or high (>15%–85%) pre-test likelihood of obstructive CAD, SPECT or, preferably, PET
myocardial perfusion imaging is recommended to:
• diagnose and quantify myocardial ischaemia and/or scar; I B
• estimate the risk of MACE;
• quantify myocardial blood flow (PET).
In patients selected for PET or SPECT myocardial perfusion imaging, it is recommended to measure CACS from unenhanced chest CT
I B
imaging (used for attenuation correction) to improve detection of both non-obstructive and obstructive CAD.
In individuals with suspected CCS and moderate or high (>15%–85%) pre-test likelihood of obstructive CAD, CMR perfusion imaging is
I B
recommended to diagnose and quantify myocardial ischaemia and/or scar and estimate the risk of MACE.
Continued
ESC Guidelines 3427

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

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In addition:
• CFR/HSR/CFC should be considered as a complementary investigation; IIa B
• resting invasive measurement of Pd/Pa, dPR, RFR, or angiography-derived vessel FFR may be considered as alternative parameters. IIb C
Systematic and routine wire-based coronary pressure assessment of all coronary vessels is not recommended. III A
Selection of individual diagnostic tests in individuals with suspected chronic coronary syndrome—Section 3
To rule out obstructive CAD in individuals with low or moderate (>5%–50%) pre-test likelihood, CCTA is recommended as the preferred
I B
diagnostic modality.
CCTA is recommended in individuals with low or moderate (>5%–50%) pre-test likelihood of obstructive CAD if functional imaging for
I B
myocardial ischaemia is not 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.
In patients with a known intermediate coronary artery stenosis in a proximal or mid coronary segment on CCTA, CT-based FFR may be
IIb B
considered.
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:
⚬ area of ischaemia ≥10% of the LV myocardium;
• stress echocardiography:
⚬ ≥3 of 16 segments with stress-induced hypokinesia or akinesia;
• stress CMR: I B
⚬ ≥2 of 16 segments with stress perfusion defects or
⚬ ≥3 dobutamine-induced dysfunctional segments;
• CCTA:
⚬ left main disease with ≥50% stenosis,
⚬ three-vessel disease with ≥70 stenosis, or
⚬ two-vessel disease with ≥70% stenosis, including the proximal LAD or
⚬ one-vessel disease of the proximal LAD with ≥70% stenosis and FFR-CT ≤0.8
Cardiovascular risk, lifestyle changes, and exercise interventions in patients with established chronic coronary syndrome—Section 4
An informed discussion on CVD risk and treatment benefits tailored to individual patient needs is recommended. I C
Multidisciplinary behavioural approaches to help patients achieve healthy lifestyles, in addition to appropriate pharmacological management,
I A
are recommended.
Aerobic physical activity of at least 150–300 min per week of moderate intensity or 75–150 min per week of vigorous intensity and
I B
reduction in sedentary time are recommended.
Home-based cardiac rehabilitation and mobile health interventions should be considered to increase patients’ long-term adherence to
IIa B
healthy behaviours, and to reduce hospitalizations or cardiac events.
Antianginal drugs in patients with chronic coronary syndrome—Section 4
It is recommended to tailor the selection of antianginal drugs to the patient’s characteristics, comorbidities, concomitant medications,
I C
treatment tolerability, and underlying pathophysiology of angina, also considering local drug availability and cost.
Ivabradine should be considered as add-on antianginal therapy in patients with left ventricular systolic dysfunction (LVEF <40%) and
IIa B
inadequate control of symptoms, or as part of initial treatment in properly selected patients.
Continued
3428 ESC Guidelines

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

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For patients who are statin intolerant and do not achieve their goal on ezetimibe, combination with bempedoic acid is recommended. I B
For patients who do not achieve their goal on a maximum tolerated dose of statin and ezetimibe, combination with bempedoic acid should
IIa C
be considered.
Sodium–glucose cotransporter 2 inhibitors and/or glucagon-like peptide-1 receptor agonists in patients with chronic coronary
syndrome—Section 4
SGLT2 inhibitors with proven CV benefit are recommended in patients with T2DM and CCS to reduce CV events, independent of baseline
I A
or target HbA1c and independent of concomitant glucose-lowering medication.
The GLP-1 receptor agonist semaglutide should be considered in CCS patients without diabetes, but with overweight or obesity
IIa B
(BMI >27 kg/m2), to reduce CV mortality, MI, or stroke.
Anti-inflammatory drugs in patients with chronic coronary syndrome—Section 4
In CCS patients with atherosclerotic CAD, low-dose colchicine (0.5 mg daily) should be considered to reduce myocardial infarction, stroke,
IIa A
and need for revascularization.
Revascularization in patients with chronic coronary syndrome—Section 4
Informed and shared decisions
For complex clinical cases, to define the optimal treatment strategy, in particular when CABG and PCI hold the same level of
recommendation, a Heart Team discussion is recommended, including representatives from interventional cardiology, cardiac surgery,
I C
non-interventional cardiology, and other specialties if indicated, aimed at selecting the most appropriate treatment to improve patient
outcomes and quality of life.
It is recommended that the decision for revascularization and its modality be patient-centred, considering when possible patient
I C
preferences, health literacy, cultural circumstances, and social support.
Revascularization to improve outcomes
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.
Assessment of procedural risks and post-procedural outcomes
Intracoronary imaging guidance by IVUS or OCT is recommended for performing PCI on anatomically complex lesions, in particular left
I A
main stem, true bifurcations and long lesions.
Intracoronary pressure measurement (FFR or iFR) or computation (QFR):
• is recommended to guide lesion selection for intervention in patients with multivessel disease; I A
• should be considered at the end of the procedure to identify patients at high risk of persistent angina and subsequent clinical events; IIa B
• may be considered at the end of the procedure to identify lesions potentially amenable to treatment with additional PCI. IIb B
Choice of revascularization modality
It is recommended that physicians select the most appropriate revascularization modality based on patient profile, coronary anatomy,
I C
procedural factors, LVEF, patient preferences and outcome expectations.
Mode of revascularization in patients with chronic coronary syndrome
Left main disease
In CCS patients at low surgical risk with significant left main coronary stenosis, CABG:
• is recommended over medical therapy alone to improve survival; I A
• is recommended as the overall preferred revascularization mode over PCI, given the lower risk of spontaneous myocardial infarction and
I A
repeat revascularization.
In CCS patients with significant left main coronary stenosis of low complexity (SYNTAX score ≤22), in whom PCI can provide equivalent
completeness of revascularization to that of CABG, PCI is recommended as an alternative to CABG, given its lower invasiveness and non- I A
inferior survival.
Continued
ESC Guidelines 3429

Management of chronic coronary syndrome patients with chronic heart failure—Section 5


In HF patients with LVEF ≤35% in whom obstructive CAD is suspected, ICA is recommended with a view towards improving prognosis by
I B
CABG, taking into account the risk-to-benefit ratio of the procedures.
In HF patients with LVEF >35% and suspected CCS with low or moderate (>5%–50%) pre-test likelihood of obstructive CAD, CCTA or
I C
functional imaging is recommended.
In patients with HFpEF with angina or equivalent symptoms and normal or non-obstructive epicardial coronary arteries, PET or CMR
IIa B
perfusion or invasive functional coronary testing should be considered to detect or rule out coronary microvascular 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.
It is recommended that CCS patients with heart failure be enrolled in a multidisciplinary heart failure management programme to reduce
I A
the risk of heart failure hospitalization and to improve survival.

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Sacubitril/valsartan is recommended as a replacement for an ACE-I or ARB in CCS patients with HFrEF to reduce the risk of heart failure
I B
hospitalization and death.
Diagnosis and management of patients with angina/ischaemia with non-obstructive coronary arteries—Section 5
Management of ANOCA/INOCA
In symptomatic patients with ANOCA/INOCA, medical therapy based on coronary functional test results should be considered to improve
IIa A
symptoms and quality of life.
For the management of endothelial dysfunction, ACE-I should be considered for symptom control. IIa B
For the management of microvascular angina associated with reduced coronary/myocardial blood flow reserve, beta-blockers should be
IIa B
considered for symptom control.
For the treatment of isolated vasospastic angina:
I A
• calcium channel blockers are recommended to control symptoms and to prevent ischaemia and potentially fatal complications;
• nitrates should be considered to prevent recurrent episodes. IIa B
In patients with evidence of overlapping endotypes, combination therapy with nitrates, calcium channel blockers, and other vasodilators may
IIb B
be considered.
Older, female, high bleeding risk, comorbid, and socially/geographically diverse patients—Section 5
Similar guideline-directed cardiovascular preventive therapy is recommended in women and men. I C
Bleeding risk assessment is recommended using the PRECISE-DAPT score, the qualitative ARC-HBR tool or other, validated methods. I B
Attention to interaction between antiretroviral treatment and statins is recommended in patients with HIV. I B
Socioeconomic, geographical, and under-investigated groups
Continued targeted efforts are recommended:
• to increase delivery of safe and effective cardiac care to all CCS patients, especially those of lower socioeconomic classes, and I C
• to enhance inclusion in future clinical trials of geographical, social, or other groups that are currently underrepresented.
Screening for coronary artery disease in asymptomatic individuals—Section 5
When coronary artery calcification findings are available from previous chest CT scans, using these findings to enhance risk stratification and
IIa C
guide treatment of modifiable risk factors should be considered.
Coronary artery calcium scoring (CACS) may be considered to improve risk classification around treatment decision thresholds. IIb C
Adherence to medical therapy and lifestyle changes—Section 6
Mobile health interventions (e.g. using text messages, apps, wearable devices) are recommended to improve patient adherence to healthy
I A
lifestyles and medical therapy.
Behavioural interventions are recommended to improve adherence. I B
Simplifying medication regimens (e.g. using fixed-dose drug combinations) is recommended to increase patient adherence to medications. I B
Multiprofessional and family involvement is recommended to promote adherence, in addition to patient education and involvement. I C
© ESC 2024

Recurrent or refractory angina/ischaemia


In patients with refractory angina leading to poor quality of life and with documented or suspected ANOCA/INOCA, invasive coronary functional
I B
testing is recommended to define ANOCA/INOCA endotypes and appropriate treatment, considering patient choices and preferences.

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

Table 4 Revised recommendations

Recommendations in 2019 version Classa Levelb Recommendations in 2024 version Classa Levelb

Recommendations for antianginal drugs in patients with chronic coronary syndrome—Section 4


Nicorandil, ranolazine, ivabradine, or trimetazidine Long-acting nitrates or ranolazine should be considered
should be considered as a second-line treatment to as add-on therapy in patients with inadequate control of
reduce angina frequency and improve exercise symptoms while on treatment with beta-blockers and/
tolerance in subjects who cannot tolerate, have IIa B or CCBs, or as part of initial treatment in properly IIa B
contraindications to, or whose symptoms are not selected patients.
adequately controlled by beta-blockers, CCBs, and
long-acting nitrates.

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In selected patients, the combination of a beta-blocker Nicorandil or trimetazidine may be considered as
or a CCB with second-line drugs (ranolazine, nicorandil, add-on therapy in patients with inadequate control of
ivabradine, and trimetazidine) may be considered for IIb B symptoms while on treatment with beta-blockers and/ IIb B
first-line treatment according to heart rate, blood or CCBs, or as part of initial treatment in properly
pressure, and tolerance. selected patients.
Antithrombotic therapy in patients with chronic coronary syndrome—Section 4
Aspirin 75–100 mg daily is recommended in patients In CCS patients with a prior MI or remote PCI, aspirin
with a previous MI or revascularization. I A 75–100 mg daily is recommended lifelong after an initial I A
period of DAPT.
Clopidogrel 75 mg daily is recommended as an In CCS patients with a prior MI or remote PCI,
I B
alternative to aspirin in patients with aspirin intolerance. clopidogrel 75 mg daily is recommended as a safe and
Clopidogrel 75 mg daily may be considered in effective alternative to aspirin monotherapy.
I A
preference to aspirin in symptomatic and asymptomatic
IIb B
patients with either PAD or a history of ischaemic
stroke or transient ischaemic attack.
Aspirin 75–100 mg daily may be considered in patients In patients without prior MI or revascularization but with
without a history of MI or revascularization, but with IIb C evidence of significant obstructive CAD, aspirin 75–100 I B
definitive evidence of CAD on imaging. mg daily is recommended lifelong.
Antithrombotic therapy post-percutaneous coronary intervention in patients with chronic coronary syndrome and no indication for
oral anticoagulation—Section 4
Aspirin 75–100 mg daily is recommended following In CCS patients with no indication for oral
I A
stenting. anticoagulation, DAPT consisting of aspirin 75–100 mg
Clopidogrel 75 mg daily following appropriate loading and clopidogrel 75 mg daily for up to 6 months is
(e.g. 600 mg or >5 days of maintenance therapy) is recommended as the default antithrombotic strategy
I A
recommended, in addition to aspirin, for 6 months after PCI-stenting.
I A
following coronary stenting, irrespective of stent type,
unless a shorter durations (1–3 months) is indicated due
to risk of occurrence of life-threatening bleeding.
Clopidogrel 75 mg daily following appropriate loading In patients at high bleeding risk but not at high ischaemic
(e.g. 600 mg or >5 days of maintenance therapy) may be risk, it is recommended to discontinue DAPT 1–3
IIb C I A
considered for 1 month in patients with very high risk of months after PCI and continue single antiplatelet
life-threatening bleeding. therapy.
Clopidogrel 75 mg daily following appropriate loading Stopping DAPT after 1–3 months from PCI-stenting
(e.g. 600 mg or >5 days of maintenance therapy) should may be considered in patients who are not at high
IIa A IIb B
be considered for 3 months in patients with a higher risk bleeding risk nor at high risk of ischaemic events.
of life-threatening bleeding.
Continued
ESC Guidelines 3431

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

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males and 2 in females.
Aspirin 75–100 mg daily (or clopidogrel 75 mg daily)
may be considered in addition to long-term OAC
therapy in patients with AF, history of MI, and at high IIb B
risk of recurrent ischaemic events who do not have a
high bleeding risk.
Antithrombotic therapy post-percutaneous coronary intervention in chronic coronary syndrome patients and an indication for oral
anticoagulation—Section 4
After uncomplicated PCI, early cessation (≤1 week) of After uncomplicated PCI in CCS patients with
aspirin and continuation of dual therapy with an OAC concomitant indication for OAC:
and clopidogrel should be considered if the risk of stent • early cessation of aspirin (≤1 week);
thrombosis is low, or if concerns about bleeding risk • followed by continuation of OAC and clopidogrel:
IIa B I A
prevail over concerns about the risk of stent ⚬ up to 6 months in patients not at high ischaemic
thrombosis, irrespective of the type of stent used. risk or
⚬ up to 12 months in patients at high ischaemic risk;
• followed by OAC alone; is recommended.
Triple therapy with aspirin, clopidogrel, and an OAC for Continuation of aspirin up to 1 month after PCI, in
≥1 month should be considered when the risk of stent addition to OAC and clopidogrel, should be considered
thrombosis outweighs the bleeding risk, with the total IIa C in patients at high thrombotic risk or with anatomical/ IIa B
duration (≤6 months) decided according to assessment procedural characteristics judged to outweigh the
of these risks and clearly specified at hospital discharge. bleeding risk.
Recommendations for lipid-lowering drugs in patients with chronic coronary syndrome—Section 4
Statins are recommended in all patients with CCS. A high-intensity statin up to the highest tolerated dose
I A to reach the LDL-C goals is recommended for all I A
patients with CCS.
Diagnosis and management of patients with angina/ischaemia with non-obstructive coronary arteries—Section 5
Guidewire-based CFR and/or microcirculatory In persistently symptomatic patients despite medical
resistance measurements should be considered in treatment with suspected ANOCA/INOCA (i.e. anginal
patients with persistent symptoms, but coronary IIa B symptoms with normal coronary arteries or
arteries that are either angiographically normal or have non-obstructive lesions at non-invasive imaging, or
moderate stenoses with preserved iwFR/FFR. intermediate stenoses with normal FFR/iFR at coronary
I B
Intracoronary acetylcholine with ECG monitoring may arteriography) and poor quality of life, invasive coronary
be considered during angiography, if coronary arteries functional testing is recommended to identify
are either angiographically normal or have moderate IIb B potentially treatable endotypes and to improve
stenoses with preserved iwFR/FFR, to assess symptoms and quality of life, considering patient choices
microvascular vasospasm. and preferences.
Diagnostic tests for vasospastic angina—Section 5
Ambulatory ST-segment monitoring should be In individuals with suspected vasospastic angina and
considered to identify ST-segment deviation in the frequent symptoms, ambulatory ST-segment
IIa C IIa B
absence of increased heart rate. monitoring should be considered to identify
ST-segment deviation during angina.
Continued
3432 ESC Guidelines

Screening for coronary artery disease in asymptomatic individuals—Section 5


Total risk estimation using a risk-estimation system such Opportunistic screening of healthy individuals for
as SCORE is recommended for asymptomatic adults cardiovascular risk factors and to estimate risk of future
>40 years of age without evidence of CVD, diabetes, I C cardiovascular events using scoring systems, e.g. I C
CKD, or familial hypercholesterolaemia. SCORE2 and SCORE2-OP, is recommended to detect
individuals at high risk and guide treatment decisions.
Diagnosis of disease progression in patients with established chronic coronary syndrome—Section 6
Risk stratification is recommended in patients with new Risk stratification is recommended in patients with new
or worsening symptom levels, preferably using stress I B or worsening symptoms, preferably using stress I C
imaging or, alternatively, exercise stress ECG. imaging.
2018 ESC/EACTS Guidelines on myocardial Classa Levelb Recommendations in 2024 version Classa Levelb

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revascularization
Recommendations for revascularization in patients with chronic coronary syndrome—Section 4
Revascularization to improve outcomes
In CCS patients with LV ejection fraction ≤35%
In patients with one- or two-vessel disease, PCI should In selected CCS patients with functionally significant
be considered as an alternative to CABG when IIa C MVD and LVEF ≤35% who are at high surgical risk or
complete revascularization can be achieved. not operable, PCI may be considered as an alternative
In patients with three-vessel disease, PCI should be to CABG.
IIb B
considered based on the evaluation by the Heart Team
of the patient’s coronary anatomy, the expected IIa C
completeness of revascularization, diabetes status, and
comorbidities.
Anatomically and clinically based recommendations for revascularization in chronic coronary syndrome—Section 4
Left main disease
Left main disease with low SYNTAX score (0–22), PCI. In CCS patients with significant left main coronary
stenosis of low complexity (SYNTAX score ≤22), in
whom PCI can provide equivalent completeness of
I A I A
revascularization to that of CABG, PCI is recommended
as an alternative to CABG, given its lower invasiveness
and non-inferior survival.
Left main disease with intermediate SYNTAX score In CCS patients with significant left main coronary
(23–32), PCI. stenosis of intermediate complexity (SYNTAX score
23–32), in whom PCI can provide equivalent
IIa A IIa A
completeness of revascularization to that of CABG, PCI
should be considered, given its lower invasiveness and
non-inferior survival.
Left main with multivessel disease
For left main disease with high SYNTAX score (≥33), In CCS patients at high surgical risk, PCI may be
III B IIb B
PCI. considered over medical therapy alone.
Multivessel disease and diabetes
For CCS patients with diabetes and three-vessel disease In CCS patients at very high surgical risk, PCI should be
IIb A
with low SYNTAX score 0–22, PCI. considered over medical therapy alone to reduce
IIa B
For CCS patients with diabetes and three-vessel disease symptoms and adverse outcomes.
III A
with intermediate or high SYNTAX score (>22), PCI.
Single- or double-vessel disease involving the proximal LAD
For one or two-vessel disease with proximal LAD In CCS patients with significant single- or double-vessel
stenosis, CABG, or PCI are recommended. disease involving the proximal LAD and insufficient
response to guideline-directed medical therapy, CABG I A
or PCI is recommended over medical therapy alone to
improve symptoms and outcomes.
I A In CCS patients with complex significant single- or
double-vessel disease involving the proximal LAD, less
amenable to PCI, and insufficient response to
I B
guideline-directed medical therapy, CABG is
recommended over PCI to improve symptoms and
reduce revascularization rates.
Continued
ESC Guidelines 3433

Single- or double-vessel disease not involving the proximal LAD


For one or two-vessel disease without proximal LAD In symptomatic CCS patients with single- or
stenosis PCI is recommended. double-vessel disease not involving the proximal LAD
I C and with insufficient response to guideline-directed I B
medical therapy, PCI is recommended to improve
symptoms.
For one or two-vessel disease without proximal LAD In symptomatic CCS patients with single- or
stenosis, CABG may be considered. double-vessel disease not involving the proximal LAD

© 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.

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AF, atrial fibrillation; ANOCA, angina with non-obstructive coronary arteries; CABG, coronary artery bypass grafting; CAD, coronary artery disease; CCB, calcium channel blocker; CCS,
chronic coronary syndrome; CFR, coronary flow reserve; CHA2DS2-VASc, congestive heart failure or left ventricular dysfunction, hypertension, age ≥75 (doubled), diabetes, stroke
(doubled), vascular disease, age 65–74, sex category (female); CKD, chronic kidney disease; CVD, cardiovascular disease; DAPT, dual antiplatelet therapy; DOAC, direct oral
anticoagulant; EACTS, European Association for Cardio-Thoracic Surgery; ECG, electrocardiogram; ESC, European Society of Cardiology; FFR, fractional flow reserve; iFR(iwFR),
instantaneous wave-free ratio; INOCA, ischaemia with non-obstructive coronary arteries; LAD, left anterior descending; LDL-C, low-density lipoprotein cholesterol; LV, left ventricular;
LVEF, left ventricular ejection fraction; MI, myocardial infarction; MVD, multivessel disease; NOAC, non-vitamin K antagonist oral anticoagulant; OAC, oral anticoagulant; PAD,
peripheral artery disease; PCI, percutaneous coronary intervention; SCORE2, Systematic Coronary Risk Estimation 2; SCORE-OP, Systematic Coronary Risk Estimation 2–Older
Persons; SYNTAX, SYNergy Between PCI with TAXUS and Cardiac Surgery; VKA, vitamin K antagonist.
a
Class of recommendation.
b
Level of evidence.

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

Step 1 Initial evaluation


History,
symptoms,
physical examination
Non-cardiac reason for Unstable cardiac symptoms with angina,
symptoms identified: Resting ECG. Biochemistry heart failure or arrhythmia:
treat underlying cause acute assessment by the ED
Pulmonary function testa
Chest X-raya

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Step 2 Further evaluation

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

Step 3 Confirming diagnosis and


estimating event-risk
Further non-invasive
testing recommended Invasive angiography if:
based on clinical likelihood, Very high clinical likelihood (>85%)
availability, Suspicion of high-risk obstructive CAD
local expertise, patient Severe myocardial ischaemia
Consider ANOCA/INOCA characteristics and
preferenceb

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

Lifestyle and risk factor Revascularization


modification Revascularization if: To reduce symptoms
To improve prognosis To improve prognosis in patients
high risk of adverse events with obstructive CAD who are at
GDMT fails to relieve high risk of adverse events
Disease-modifying medical symptoms
treatment
Antianginal medical treatment
To improve prognosis To reduce symptoms

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

Decreasing likelihood of CCS Increasing likelihood of CCS

Burning Strangling
Sharp Constricting
Quality Tearing - Ripping Squeezing
Pleuritic Pressure
Aching Heaviness

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Retrosternal
Right
Location Extending to left arm, or to jugular
Shifting
and size Large area or fine spot
or intrascapular region
“Fist”-size

Short: up to 5–10 min if triggered by


Duration Lasting
physical exertion or emotion

Chest At rest On effort


discomfort On deep inspiration or when More frequent in cold weather, strong winds
Trigger coughing or after a heavy meal
When pressing on ribs or sternum Emotional distress (anxiety, anger,
excitation or nightmare)

Subsiding within 1–5 min after


effort discontinuation
Relief By antacids, drinking milk
Relief accelerated by sublingual
nitroglycerin

Difficulty to exhale
Quality Difficulty catching breath
With wheezing

Both at rest and on effort


Trigger On effort
While coughing

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

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ECG monitoring are frequent in women but do not correlate with find­
walking uphill, climbing more than one ings during stress testing.74 Ambulatory ECG monitoring may also re­
flight of ordinary stairs at a normal veal ‘silent’ ischaemia in patients with CCS, but therapeutic strategies
pace, and in normal conditions targeting it have not demonstrated clear survival benefits.75,76
III Angina with mild Having difficulties walking one or two
exertion blocks or climbing one flight of stairs at

© 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

3.1.2.2. Biochemical tests Recommendation Table 2 — Recommendations for ba­


Laboratory blood tests identify potential causes of ischaemia (e.g. se­ sic biochemistry in the initial diagnostic management of in­
dividuals with suspected chronic coronary syndrome (see
vere anaemia, hyperthyroidism), cardiovascular risk factors (e.g. lipids,
also Evidence Table 2)
fasting glucose), and yield prognostic information (e.g. renal disease, in­
flammation). When fasting plasma glucose and glycated haemoglobin Recommendations Classa Levelb
(HbA1c) are both inconclusive, an additional oral glucose tolerance
test is useful.85,86 The following blood tests are recommended in all
A lipid profile, including total cholesterol, high-density lipoprotein individuals to refine risk stratification, diagnose
cholesterol (HDL-C), and triglycerides, allowing calculation of low- comorbidities, and guide treatment:
density lipoprotein cholesterol (LDL-C), is necessary in every person • lipid profile including LDL-C;64,128 I A
with suspected CCS to refine his/her risk profile and guide treat­ • full blood count (including haemoglobin);129–133 I B
ment.16,64 Fasting values are needed to characterize severe dyslipidae­ • creatinine with estimation of renal function;134 I B

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mia or follow-up hypertriglyceridaemia,64 but not in other
• glycaemic status with HbA1c and/or fasting plasma
situations.87 Elevated lipoprotein(a) is a marker of cardiovascular risk, I B
glucose.16,86,135,136
particularly early-onset atherosclerotic disease;88 lipoprotein(a)-
In patients with suspected CCS, it is recommended
lowering strategies are currently being investigated in phase 3 cardiovas­ I B

© 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

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Individual adjustment of the likelihood may be necessary for indivi­ (>50%–85%), and very high (>85%) likelihood of obstructive CAD
duals with severe single risk factors or comorbidities associated with are encouraged to undergo further diagnostic testing.
an increased prevalence of obstructive CAD, which are not reflected By using pre-test likelihood estimates and diagnostic imaging-test
in the RF-CL model, e.g. familial hypercholesterolaemia, severe kidney positive and negative likelihood ratios, it is possible to calculate the
dysfunction, rheumatic/inflammatory diseases, and peripheral artery post-test probability of obstructive CAD. Hence, pre-test likelihood es­
disease (PAD). timation is useful to guide non-invasive diagnostic test strategies for de­
Exercise ECG testing may modify the likelihood of obstructive CAD tecting obstructive CAD (Section 3.3.4).
and can be used in patients with low (>5%–15%) clinical likelihood, in
whom a negative test allows reclassification to the very low (≤5%) clin­
ical likelihood group with a favourable prognosis.144 However, CCTA
as a first-line diagnostic test can give more accurate information and Recommendation Table 3 — Recommendations for
has been associated with fewer angina symptoms during follow-up estimating, adjusting and reclassifying the likelihood of
than a strategy with exercise ECG as the first investigation.145–148 In obstructive atherosclerotic coronary artery disease in
addition, more adverse events were observed in randomized trials the initial diagnostic management of individuals with sus­
pected chronic coronary syndrome (see also Evidence
with an exercise ECG than with a CCTA-based diagnostic strat­
Table 3)
egy.34,146 However, exercise ECG remains clinically useful for reprodu­
cing anginal symptoms, which have a prognostic value.149,150 Recommendations Classa Levelb
In contrast to exercise ECG, visualization of calcified atherosclerotic
plaque in the coronary artery significantly impacts the clinical likelihood It is recommended to estimate the pre-test
of atherosclerotic obstructive CAD. Coronary artery calcification likelihood of obstructive epicardial CAD using the
I B
(CAC) can be measured using the coronary artery calcium score Risk Factor-weighted Clinical Likelihood
(CACS), which is derived from an ECG-gated non-contrast-enhanced model.139,140,142,143,161,162
computed tomography (CT) scan. Alternatively, the presence of It is recommended to use additional clinical data (e.g.
CAC can be evaluated qualitatively by visually inspecting the coronary examination of peripheral arteries, resting ECG,
arteries on a previous non-cardiac chest CT scan, if available. The ab­ resting echocardiography, presence of vascular
I C
sence of CAC (CACS = 0) has a very high negative predictive value calcifications on previously performed imaging tests)
(>95%) for obstructive CAD.151 Of note, in younger patients, obstruct­ to adjust the estimate yielded by the Risk
ive CAD is rare, but when present, a higher percentage (58% of those Factor-weighted Clinical Likelihood model.163
younger than 40 years) have a CACS of 0 compared with older patients
In individuals with a very low (≤5%) pre-test likelihood
with obstructive CAD (9% among those aged 60 to 69 years).152
of obstructive CAD, deferral of further diagnostic IIa B
Small, randomized studies have shown that further testing can safely
tests should be considered.139,164
be deferred in patients without CAC, without increased event rates
In individuals with a low (>5%–15%) pre-test
during follow-up.146,153 Finally, in a larger prospective observational
study, absence of CAC alone was sufficient to define a low-risk likelihood of obstructive CAD, CACS should be
group with no need for further testing with improved accuracy com­ considered to reclassify subjects and to identify more IIa B
pared with basic clinical prediction models.154 The combination of individuals with very low (≤5%) CACS-weighted
CACS with the RF-CL model [CACS + RF-CL (the Coronary Artery clinical likelihood.139,143,165
Calcium Score-Weighted Clinical Likelihood—CACS-CL)] showed In individuals with an initially low (>5%–15%)
the strongest potential to effectively defer cardiac testing compared likelihood of obstructive CAD, exercise ECG and
© ESC 2024

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

1 Symptom score (0–3 points)

Chest pain characteristics Symptom score


Constricting discomfort located retrosternally
Type and location Main symptom either:
or in neck, jaw, shoulder or arm (I point)
Chest pain
Aggravated by Physical or emotional stress (1 point)
(0–3 points)
Relieved by Rest or nitrates within 5 min (1 point)

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or
Dyspnoea characteristics Dyspnoea
Shortness of breath and/or trouble catching breath (2 points)
aggravated by physical exertion (2 points)

Number of risk factors for CAD (0–5):


2 Family history, smoking, dyslipidaemia, hypertension and diabetes

Estimate the Risk Factor-weighted Clinical Likelihood (RF-CL)


3 of obstructive CAD

Symptom score
0–1 point 2 points 3 points

Women Men Women Men Women Men


Number of
0–1 2–3 4–5 0–1 2–3 4–5 0–1 2–3 4–5 0–1 2–3 4–5 0–1 2–3 4–5 0–1 2–3 4–5
risk factors
Age 30–39 0 1 2 1 2 5 0 1 3 2 4 8 2 5 10 9 14 22
Age 40–49 1 1 3 2 4 8 1 2 5 3 6 12 4 7 12 14 20 27
Age 50–59 1 2 5 4 7 12 2 3 7 6 11 17 6 10 15 21 27 33
Age 60–69 2 4 7 8 12 17 3 6 11 12 17 25 10 14 19 32 35 39
Age 70–80 4 7 11 15 19 24 6 10 16 22 27 34 16 19 23 44 44 45

Clinical likelihood: Very low Low Moderate

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

3.2.2. Transthoracic echocardiography and cardiac 3.2.3. Exercise electrocardiogram testing


magnetic resonance at rest Exercise ECG testing is low cost, does not use ionizing radiation, is
An echocardiographic study will provide important information about car­ widely accessible, and remains an alternative for diagnostic testing de­
diac function and anatomy. Patients with CCS have often preserved left pending on local resources and individual characteristics.
ventricular ejection fraction (LVEF).167 A decreased LV function and/or The classical exercise ECG, involving graded exercise until the occur­
regional wall motion abnormalities may increase the suspicion of ischaemic rence of fatigue, limiting chest pain or discomfort, significant ischaemic
myocardial damage,167 and a pattern of LV dysfunction following the ECG changes, arrhythmias, excessive hypertension, a BP drop or after
anatomical perfusion territory of the coronary arteries is typical in patients reaching 85% of the maximal predicted heart rate, has been the main­
who have already had an MI.168,169 The detection of regional wall motion stay of the examination techniques used in clinical cardiology for asses­
abnormalities can be challenging by visual assessment, and detection of sing individuals with suspected CCS. Exercise ECG testing has a lower
early systolic lengthening, decreased systolic shortening, or post-systolic diagnostic performance of obstructive CAD compared with modern
shortening by strain imaging techniques,170–172 or new parameters such functional imaging and CCTA,148 which, therefore, should be preferred

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as global myocardial work,173 may be helpful in individuals with apparently as a first-line test in subjects with suspected CCS. Several clinical trials
normal LV function but with clinical suspicion of CCS. Diastolic LV dysfunc­ have confirmed that a strategy based on anatomical34,146,187,188 or func­
tion has been reported to be an early sign of ischaemic myocardial dysfunc­ tional imaging189 simplifies the diagnosis, enables the targeting of pre­
tion and may also be indicative of microvascular dysfunction.174,175 ventive therapies and interventions, and potentially reduces the risk
Echocardiography can help in detecting alternative causes of chest of MI compared with usual care based on exercise ECG. In addition,
pain (e.g. pericarditis) and in diagnosing valvular heart diseases, ischae­ two randomized trials showed that patients reported fewer anginal
mic HF, and most cardiomyopathies,176 though these diseases may co- complaints during follow-up when randomized to CCTA as an index
exist with obstructive CAD. The use of an echocardiographic contrast investigation for stable chest pain compared with exercise ECG.145,146
agent can be helpful in patients with poor acoustic windows.177 Although the Scottish Computed Tomography of the Heart
Cardiac magnetic resonance (CMR) is an alternative in patients with (SCOT-HEART) trial favoured CCTA as first-line test in CCS, a post
suspected CAD when the echocardiogram (having used ultrasound hoc analysis suggested that abnormal results of exercise ECG remain
contrast agent) is inconclusive.178 Cardiac magnetic resonance can as­ a specific indicator of obstructive CAD, and are associated with future
sess global and regional function,179 and the use of late gadolinium en­ coronary revascularization and risk of MI.188 Exercise ECG testing with
hancement (LGE) CMR can reveal a typical pattern of scarred clearly abnormal results was most predictive for these outcomes; how­
myocardium in patients who have already experienced an MI.180 ever, in a large proportion of individuals who underwent exercise ECG,
Moreover, CMR provides information on myocardial ischaemia particularly those with normal or inconclusive results, there was still a
through the evaluation of stress-induced perfusion defects.181 significant amount of unrecognized non-obstructive and obstructive
The strongest predictor of long-term survival is systolic LV function. CAD, which can be detected by additional CCTA imaging.188 In the
Hence, risk stratification through the assessment of systolic LV function WOMEN trial (What is the Optimal Method for Ischemia Evaluation
is useful in all symptomatic individuals with suspected CCS. Mortality of Women), including low-risk symptomatic women, exercise ECG
increases as LVEF declines.182 Management of patients with either an­
was equally effective compared with exercise myocardial perfusion
gina or HF symptoms, with reduced LVEF ≤40% or mildly reduced
scintigraphy, with a similar 2-year incidence of major adverse cardiovas­
LVEF 41%–49%, is described in Section 4.
cular events (MACE), defined as CAD death, or hospitalization for an
Recommendation Table 4 — Recommendations for ACS or HF, while providing significant diagnostic cost savings.190
resting transthoracic ultrasound and cardiac magnetic
Individuals exercising >10 metabolic equivalents with a negative exer­
resonance imaging in the initial diagnostic management
of individuals with suspected chronic coronary syn­ cise ECG and a low-risk Duke Treadmill Score have a good prognosis
drome (see also Evidence Table 4) with limited need for downstream testing and revascularization.166,191
Patients with marked ischaemia at a low workload and a high-risk
Recommendations Classa Levelb Duke Treadmill Score may benefit from further anatomical or function­
al testing. In regions with limited access to functional imaging or CCTA,
A resting transthoracic echocardiogram is
or in individuals with a low (>5%–15%) pre-test likelihood of obstruct­
recommended:
ive CAD,144 exercise ECG remains, therefore, useful for risk stratifica­
to measure LVEF, volumes and diastolic function;
tion and prognostication.144 Particularly, in subjects with a low (>5%–
• identify regional wall motion abnormalities;
15%) likelihood of obstructive CAD, a negative exercise ECG may help
• identify non-coronary cardiac disease (e.g.
to down-classify patients into the very low likelihood (<5%) class, in
hypertrophy, cardiomyopathy, valve disease, I B
whom further testing can be deferred.144
pericardial effusion); An exercise ECG is of no diagnostic value in patients with ECG ab­
• assess right ventricular function and estimate normalities at rest that prevent interpretation of the ST-segment
systolic pulmonary artery pressure; changes during stress (i.e. LBBB, paced rhythm, Wolff−Parkinson
to refine risk stratification and guide −White syndrome, ≥0.1 mV ST-segment depression on resting ECG,
treatment.167,183,184 or treatment with digitalis). In patients with known CAD, exercise
© ESC 2024

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

Recommendation Table 5 — Recommendations for Recommendation Table 7 — Recommendations for am­


exercise ECG in the initial diagnostic management of in­ bulatory ECG monitoring in the initial diagnostic manage­
dividuals with suspected chronic coronary syndrome ment of individuals with suspected chronic coronary
(see also Evidence Table 5) syndrome (see also Evidence Table 7)

Recommendations Classa Levelb Recommendations Classa Levelb

Exercise ECG is recommended in selected patientsc Ambulatory ECG monitoring is recommended in


I C

© 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.

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b
An exercise ECG may be considered to refine risk Level of evidence.
IIb B
stratification and treatment.188
In individuals with a low (>5%–15%) pre-test
likelihood of obstructive CAD, an exercise ECG may
IIb C
be considered to identify patients in whom further
144
3.3. STEP 3: Confirming the diagnosis
testing can be deferred.
3.3.1. Anatomical imaging: coronary computed
Exercise ECG is not recommended for diagnostic
tomography angiography
purposes in patients with ≥0.1 mV ST-segment
III C Through the intravenous (i.v.) injection of contrast agent, CCTA allows
depression on resting ECG, left bundle branch block
direct anatomical visualization of the coronary artery lumen and wall.
or who are being treated with digitalis.
CCTA offers a practical, non-invasive test, with proven diagnostic per­
In individuals with a low or moderate (>5%–50%) formance in detecting obstructive coronary artery stenoses when com­
© ESC 2024

pre-test likelihood of obstructive CAD, an exercise pared with ICA.32,148


III C
ECG is not recommended to rule out CAD if CCTA Obstructive coronary stenoses have typically been defined using
or functional imaging tests are available.148 visual thresholds of either 50% or 70% diameter reduction. It is
BP, blood pressure; CAD, coronary artery disease; CCTA, coronary computed accepted that not all anatomical stenoses above such thresholds, es­
tomography angiography; ECG, electrocardiogram. pecially those of moderate (50%–69%) stenosis severity, are haemo­
dynamically or functionally significant195 or induce myocardial
a
Class of recommendation.
b
Level of evidence.
c ischaemia.196 Depending on the clinical context, it may be necessary
When this information will have an impact on diagnostic strategy or management.
to complement CCTA with functional data either from non-invasive
3.2.4. Chest X-ray imaging techniques or from invasive angiography with fractional
Chest X-ray is commonly utilized in the evaluation of patients experi­ flow reserve (FFR) (see Section 3.3.3.2), when the haemodynamic con­
encing chest pain. However, in the context of CCS, it does not yield sequence of a stenosis is deemed questionable for management
specific information for accurate diagnosis or risk stratification. The options.
test may provide assistance in assessing patients with suspected HF. While several earlier trials (publication date during or before 2016)
Additionally, chest X-ray may prove beneficial in diagnosing pulmonary reported a higher rate of downstream ICA in patients receiving CCTA
conditions that often co-exist with CAD, or in ruling out other poten­ compared with functional imaging,197 this was no longer observed in
tial causes of chest pain. more recent trials (publication date after 2016). Moreover, increased
downstream use of invasive procedures was linked to non-adherence
3.2.5. Ambulatory electrocardiogram monitoring to guideline recommendations as these procedures were used signifi­
cantly less when the guidelines were adopted.198
Ambulatory ECG monitoring can assist in evaluating patients with chest
Coronary computed tomography angiography-derived fractional
pain and palpitations. It can also help in detecting and evaluating silent
flow reserve (FFR-CT) can complement CCTA by providing values
myocardial ischaemia, as well as suspected VSA.192–194
of model-based computational FFR along the coronary tree.
Recommendation Table 6 — Recommendations for FFR-CT has shown good agreement with invasive FFR,199 and has clin­
chest X-ray in the initial diagnostic management of indi­ ical utility by reducing the number of unnecessary ICA procedures.200
viduals with suspected chronic coronary syndrome (see However, in patients with severe disease at CCTA, FFR-CT has less
also Evidence Table 6) impact on patient management.201 FFR-CT does not require pharma­
cological stress, additional contrast agent injection, or radiation ex­
Recommendations Classa Levelb
posure. FFR-CT, however, is not ubiquitous and depends on image
A chest X-ray should be considered for individuals with: quality. Nevertheless, the rejection rate is reported to be quite low
• signs and symptoms suggestive of heart failure; in real-world data with newest-generation scanners.202–204
© ESC 2024

• suspected acute pulmonary disease; IIa C


• suspected aortic, non-coronary cardiac, or other
3.3.1.1. Computed tomography perfusion imaging
thoracic causes of chest pain.
Computed tomography perfusion imaging, performed under pharma­
a
Class of recommendation. cological stress, has been validated against several reference stan­
b
Level of evidence. dards, including single-photon computed tomography (SPECT) and
3442 ESC Guidelines

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

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MACE.33,34,145,212,214–221
outcomes
CCTA is recommended in individuals with low or
The SCOT-HEART trial demonstrated a small but significant decrease
moderate (>5%–50%) pre-test likelihood of
of the combined endpoint of cardiovascular death or non-fatal MI I B
obstructive CAD to refine diagnosis if another
(from 3.9% to 2.3% during 5-year follow-up) in patients in whom
non-invasive test is non-diagnostic.222
CCTA was performed in addition to routine testing (exercise
ECG).34 In a post hoc analysis of this trial, CCTA features (low- CCTA is not recommended in patients with severe
attenuation plaque, positive remodelling, spotty calcifications, and renal failure (eGFR <30 mL/min/1.73 m2),
napkin-ring sign) conferred an increased risk of death or non-fatal decompensated heart failure, extensive coronary
MI, although these plaque features were not independent of calcification, fast irregular heart rate, severe obesity, III C

© 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

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The enhanced image quality and endocardial border definition by using
ultrasound contrast agents markedly improve the accuracy of stress During stress echocardiography, Doppler left
echocardiography.229,230 Ultrasound contrast agents may be required anterior descending coronary artery flow reserve

© 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

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commonly used (i.e. 13N-ammonia, 15O-water, and 82Rubidium) are sors (e.g. dobutamine) are commonly applied, as physical exercise is chal­
short-lived, with half-lives in the range of minutes, requiring production lenging to perform. In conjunction with a dobutamine infusion, wall
of these radionuclides ad hoc for every investigation. As attenuation motion abnormalities induced by ischaemia can also be detected.277 Of
correction is mandatory, PET is routinely performed in combination note, and as for all non-invasive imaging modalities used for assessing myo­
with non-contrast-enhanced CT. Scans are performed during both cardial perfusion, incorporating all available imaging and non-imaging in­
rest and infusion of pharmacological stressors (e.g. dobutamine) or va­ formation as part of an integrative approach is mandatory. For CMR, a
sodilators (e.g. dipyridamole, adenosine, or regadenoson). multiparametric protocol, including LV function and assessment of LGE
While myocardial perfusion PET-CT produces retention images de­ along with myocardial perfusion, increases the ability to rule in or rule
picting relative differences in regional MBF similar to those from SPECT out obstructive CAD in suspected CCS.278
—albeit with superior image quality and at much lower radiation dose Coronary magnetic resonance angiography allows non-invasive visu­
exposure—the unique strength of PET-CT imaging is its ability to pro­ alization of the coronary arteries.279 However, CMR angiography re­
vide robust absolute quantitative measures of MBF. Measuring MBF mains primarily a research tool due to limitations arising from long
with cardiac PET does not increase radiation or imaging time. Several imaging times, low spatial resolution, and operator dependency.
measurements of MBF can be routinely obtained, including MBF during General limitations of CMR for myocardial perfusion arise from its lim­
hyperaemia, MBF at rest, the MBF reserve, and the relative MBF reserve, ited availability, the claustrophobia experienced by patients, duration of
and confer added diagnostic and prognostic value beyond relative per­ image acquisition,280 and possible contraindications to CMR [e.g. non-
fusion assessment.262,263 conditional pacemakers and implantable cardioverter defibrillators
Quantitative measures of MBF offer the ability to assess individuals (ICDs)] or to gadolinium-based contrast agents (e.g. renal failure due
with known or suspected diffusely impaired MBF, e.g. with multivessel to the potential risk of nephrogenic systemic fibrosis). Finally, and con­
CAD, or microvascular dysfunction.45,264 In general, PET-CT myocar­ trary to SPECT/CT or PET-CT, stress CMR does not currently provide
dial perfusion imaging is associated with high accuracy for detecting information on presence or absence of coronary calcifications.
flow-limiting coronary lesions,148,258,265 and has been shown to provide If available, and if no contraindications are met, stress CMR is recom­
prognostic information.223,262,263 In several head-to-head comparisons, mended as an option in patients with suspected CCS with moderate or
PET-CT myocardial perfusion imaging outperformed other functional high (>15%–85%) pre-test likelihood of obstructive CAD or known
imaging modalities.257,266–269 However, whether the superiority in diag­ CCS, particularly if additional information on cardiac function and tissue
nostic accuracy leads to improved clinical effectiveness and post-test characterization is warranted.
management remains to be elucidated.270 In a large retrospective study,
a low MBF reserve measured by PET independently predicted mortality
and helped identify patients with a survival benefit from early revascu­ Recommendation Table 10 — Recommendations for
larization with PCI or coronary artery bypass grafting (CABG) beyond non-invasive functional myocardial imaging tests in the
the extent of myocardial ischaemia.271 initial diagnostic management of individuals with
suspected chronic coronary syndrome—resting and
Limitations of PET-CT arise from its limited availability compared with
stress single-photon emission computed tomography/
other imaging modalities. Furthermore, methodological heterogeneity positron emission tomography—cardiac magnetic
exists, particularly regarding thresholds for abnormality of quantitative resonance imaging, if available, and supported by local
measurements. Finally, physical exercise is challenging to perform. expertise (see also Evidence Table 10)
If available, assessment of myocardial perfusion using PET-CT is par­
ticularly recommended in obese patients (due to the high photon en­ Recommendations Classa Levelb
ergy), in young patients (due to the low radiation dose exposure),
In individuals with suspected CCS and moderate or
and in those with known or suspected diffusely impaired MBF, e.g. those
high (>15%–85%) pre-test likelihood of obstructive
with multivessel CAD or microvascular dysfunction.264 Notably, the
CAD, stress SPECT or, preferably, PET myocardial
mandatory non-contrast-enhanced CT for attenuation correction al­
perfusion imaging is recommended to:
lows for additional CAC scoring, providing essential information for
• diagnose and quantify myocardial ischaemia and/or I B
risk stratification even in the absence of flow-limiting coronary lesions.
scar;
3.3.2.4. Cardiac magnetic resonance imaging • estimate the risk of MACE;
Aside from providing highly accurate and reproducible assessments of • quantify myocardial blood flow
overall cardiac anatomy, cardiac volumes, function, and tissue charac­ (PET).33,44,223,257,263,268,270,271,281–288
terization, CMR also offers the ability to assess myocardial perfusion, Continued
ESC Guidelines 3445

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

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CACS, coronary artery calcium score; CAD, coronary artery disease; CCS, chronic obstructive CAD, reduced MBF reserve by MCE depicts microcircula­
coronary syndrome; CMR, cardiac magnetic resonance; CT, computed tomography; tory abnormalities. Transthoracic Doppler evaluation of the LAD ar­
MACE, major adverse cardiovascular events; PET, positron emission tomography;
tery is also used to assess coronary flow reserve (CFR) during stress
SPECT, single-photon emission computed tomography.
a
Class of recommendation. hyperaemia and has prognostic value.238,255,305,306
b
Level of evidence. In contrast, the diagnosis of VSA ideally relies on the results of provo­
cation tests in the catheterization laboratory through selective intracor­
onary acetylcholine (Ach) infusion (see Section 5.2.5.2).
It is important to note that there is only a modest correlation be­
tween the values of MBF reserve measured by different techniques
3.3.2.5. Non-invasive testing for microvascular dysfunction and modalities.269,305,307
Angina/ischaemia with non-obstructive coronary arteries (ANOCA/
INOCA) may be caused by transient and/or sustained impairments in 3.3.3. Invasive tests
the supply–demand of myocardial perfusion. Functional disorders leading Invasive coronary angiography has undergone significant advancements
to ANOCA/INOCA (e.g. MVA and VSA) are more common in women over time. It is no longer just an angiographic technique that provides ana­
than in men.298,299 A recent meta-analysis reported an overall prevalence tomical information about the presence of coronary atherosclerosis and
of MVA of 41% and VSA of 40% in selected patients without obstructive luminal obstructions of the epicardial coronary arteries. It can also deter­
CAD.299 However, the true prevalence in unselected patient populations mine the functional consequences of these obstructions on coronary
with suspected CCS remains unclear. Patients with ANOCA/INOCA blood flow [FFR and instantaneous wave-free ratio (iFR)] by direct meas­
have increased morbility/mortality,300,301 impaired quality of life (QoL), urement of the coronary BP49,308–311 or by calculating the coronary
and weigh on health resource utilization. Early, accurate, and preferably pressure drop across a stenosis based on two or more angiographic
non-invasive diagnosis is, therefore, of importance. projections.312 Furthermore, new technologies allow measurement of
The possibility of a microcirculatory origin of angina should be con­ CFR and microvascular resistance, and protocols have been introduced
sidered in individuals with symptoms suggestive of myocardial ischaemia for testing the presence of coronary vasospasm.36,39
and coronary arteries that are either normal or with non-obstructive
lesions on CCTA or ICA. Several measurements that rely on quantify­ 3.3.3.1. Invasive coronary angiography
ing blood flow through the coronary circulation are used to describe Invasive coronary angiography with available coronary pressure
the function of the microvasculature to identify cases of MVA. assessment49,308–311,313 is indicated in patients with a very high
Among the non-invasive imaging modalities, transthoracic Doppler (>85%) clinical likelihood of obstructive CAD,1 in particular those
echocardiography has been used as a non-invasive means to measure with severe symptoms refractory to antianginal treatment, or charac­
coronary blood flow but is limited to the assessment of the LAD artery teristic angina or dyspnoea at a low level of exercise1,47 or left ventricle
and is affected by high inter- and intra-operator variability.302,303 dysfunction suggesting extensive obstructive CAD.47,182,314,315
Furthermore, this modality cannot distinguish between impairment of Invasive coronary angiography/coronary pressure assessment is also
coronary flow caused by epicardial CAD or coronary microcirculatory indicated if non-invasive assessment suggests high event risk—e.g.
dysfunction. CCTA shows ≥50% left main stenosis, or ≥70% proximal LAD stenosis
A more direct and accurate microvascular function assessment is with single or two-vessel CAD, or ≥70% proximal three-vessel
based on MBF measurement. This is commonly achieved by PET-CT CAD56,182,316,317—or when any stress test shows moderate to severe
myocardial perfusion imaging.299 PET allows for the quantification of inducible ischaemia316 or when symptoms are highly suggestive for ob­
MBF (expressed as millilitres per minute per gram of myocardium) structive CAD. In all the above situations, ICA/coronary pressure as­
and myocardial flow reserve (MFR). The latter reflects the magnitude sessment is performed for additional risk stratification318–320 and to
of the increase in MBF that can be achieved by maximal coronary vaso­ determine a potential revascularization approach (see Section
dilation conferred by vasodilators, such as adenosine or regadenoson. 4.4).49,308,309,313
Since the microvasculature primarily determines vascular resistance, Invasive coronary angiography/coronary pressure assessment may
MFR measures the ability of the microvasculature to respond to a also be indicated to confirm or exclude the diagnosis of obstructive
stimulus and therefore represents small vessel function. An MFR of CAD in patients with uncertain results on non-invasive testing.316
less than 2.0 (2.5 for non-obstructive CAD) is often considered abnor­ Given the frequent mismatch between the angiographic and haemo­
mal for PET.304 Of note, however, no definitive references are available dynamic severities of coronary stenoses, coronary pressure assessment
across imaging modalities due to the moderate correlation among dif­ should be readily available to complement ICA investigation for clinical
ferent MBF estimates.264 decision-making.321–326
3446 ESC Guidelines

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

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the composite ICA rate of death, MI, or stroke through radial access is Assessment of Intermediate Stenosis to Guide Revascularisation),310
of the order of 0.1%–0.2%.327 The decision to perform ICA should bal­ iFR-SWEDEHEART (Instantaneous Wave-free Ratio versus Fractional
ance benefits and risks, as well as potential therapeutic consequences, Flow Reserve in Patients with Stable Angina Pectoris or Acute Coronary
of the investigation that should be part of the process of shared clinical Syndrome),311 R3F (French FFR Registry),313 and RIPCORD (Routine
decision-making. Patients should be adequately informed of these as­ Pressure Wire Assessment Influence Management Strategy at Coronary
pects ahead of the procedure. Angiography for Diagnosis of Chest Pain trial).309 Haemodynamic rele­
vance, as defined by FFR of ≤0.80, or iFR of ≤0.89, correlates poorly
with diameter stenosis by visual assessment. In the PRIME-FFR [Insights
From the POST-IT (Portuguese Study on the Evaluation of FFR-Guided
Recommendation Table 11 — Recommendations for Treatment of Coronary Disease) and R3F Integrated Multicenter
invasive coronary angiography in the diagnostic manage­ Registries—Implementation of FFR (Fractional Flow Reserve) in Routine
ment of individuals with suspected chronic coronary Practice]322 and FAME (Fractional Flow Reserve versus Angiography for
syndrome (see also Evidence Table 11) Multivessel Evaluation) study,195 31% of the 40%–49% stenoses were
haemodynamically significant while only 35% of the 50%–70% stenoses
Recommendations Classa Levelb were haemodynamically relevant, and of the 71%–90% stenoses, 20%
When ICA is indicated, radial artery access is
were not. Only an estimated diameter stenosis of >90% predicted haemo­
I A dynamic relevance with high accuracy (96% correct classification). The
recommended as the preferred access site.327–330
discordance between angiographical and functional assessment of cor­
When ICA is indicated, it is recommended to have
onary stenosis severity varies with age, presence of CMD and lesion-
coronary pressure assessment available and to use it
specific factors.338,339 Lesions in the left main or proximal LAD are
to evaluate the functional severity of intermediate I A
more likely to result in a significant FFR, as they supply a larger myocar­
non-left main stem stenosesc prior to dial mass than those in smaller arteries. As a result, the optimal angio­
revascularization.49,195,308,313,321,322,325,331–333 graphic cut-off value for functionally non-significant stenosis is 43% for
Invasive coronary angiography is recommended to the left main and 55% for small vessels.339 This implies that the thresh­
diagnose obstructive CAD in individuals with a very old for functional assessment for larger arteries should be set at 40%
high (>85%) clinical likelihood of disease, severe diameter stenosis.
I C
symptoms refractory to guideline-directed medical Large management studies showed that integration of FFR to ICA is
therapy, angina at a low level of exercise, and/or high associated with treatment reclassification in 30%–50% of cases in the
event risk. R3F, POST-IT, RIPCORD, and DEFINE-REAL studies.309,313,340,341
In individuals with de novo symptoms highly Subsequently, many other non-hyperaemic pressure parameters
suggestive of obstructive CAD that occur at a low were introduced [distal coronary pressure to aortic pressure ratio
level of exercise, ICA with a view towards I C (Pd/Pa), diastolic pressure ratio (dPR), relative flow reserve (RFR)],
revascularization is recommended as first diagnostic with good correlation with FFR or iFR, but without available clinical out­
test after clinical assessment by a cardiologist.
come data. It is interesting to note that both separate and pooled ana­
lyses of the patients included in those studies reveal that ‘FFR/iFR-based
When ICA is indicated, measurement of FFR/iFR
reclassification’ does not have any significant effect on the number of
should be considered to evaluate the functional
IIa A patients recommended for revascularization.342
severity of intermediate left main stem stenosesc
Meta-analyses of the 5-year outcome of patients managed with iFR
prior to revascularization.331,334,335
and FFR as part of the randomized DEFINE-FLAIR and DEFINE-
© ESC 2024

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

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(NCT03729739) and have important features that may help to increase
In addition:
the use of coronary pressure measurement during ICA significantly.
These technologies have indeed the unique advantage of providing • CFR/HSR/CFC should be considered as a
IIa B
both distal coronary pressure measures and a coronary pressure complementary investigation;359,360,366–368,376
map along the coronary vessel without requiring the use of any pres­ • resting invasive measurement of Pd/Pa, dPR, RFR,
sure wire. The lack of benefits shown in some recent FFR trials demon­ or angiography-derived vessel FFR may be IIb C
strates that it is not sufficient to validate such new coronary pressure considered as alternative parameters.353,377

© 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

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1 Risk Factor-weighted Clinical Likelihood (RF-CL) (Class I)

Symptom score
0–1 point 2 points 3 points

Women Men Women Men Women Men


Number of
0–1 2–3 4–5 0–1 2–3 4–5 0–1 2–3 4–5 0–1 2–3 4–5 0–1 2–3 4–5 0–1 2–3 4–5
risk factors
Age 30–39 0 1 2 1 2 5 0 1 3 2 4 8 2 5 10 9 14 22
Age 40–49 1 1 3 2 4 8 1 2 5 3 6 12 4 7 12 14 20 27
Age 50–59 1 2 5 4 7 12 2 3 7 6 11 17 6 10 15 21 27 33
Age 60–69 2 4 7 8 12 17 3 6 11 12 17 25 10 14 19 32 35 39
Age 70–80 4 7 11 15 19 24 6 10 16 22 27 34 16 19 23 44 44 45

Clinical likelihood: Very low Low Moderate

2 Adjust clinical likelihood based on abnormal clinical findings (Class I)

Resting ECG changes (Q-wave or ST-segment/T-wave changes)


Exercise ECG with abnormal findings
LV dysfunction (severe or segmental)
Ventricular arrhythmia
Peripheral artery disease
Coronary calcification on pre-existing chest CT

Consider reclassification of low RF-CL (>5–15%) using


3 CACS to identify very low (�5%) CACS-CL
(Class IIa)

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

Risk factor-weighted clinical likelihood Appropriate first-line test for


of obstructive CAD suspected CCS
Invasive coronary angiography
Very
high
>85%

Functional imaging

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High
>50–85%
PET/SPECT CMR Stress ECHO

CCTA Functional imaging


Moderate OR
>15–50%
PET/SPECT CMR Stress ECHO

Adjust the clinical likelihood CCTA


Low
>5–15% OR

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

Individual with suspected CCS: pre-test likelihood of obstructive CAD?

Invasive coronary angiography


with FFR/iFR preferable if:
Very high pre-test likelihood
Anatomical imaging by CCTA Functional imaging by stress echo, of obstructive CAD
preferable if: SPECT, PET or CMR preferable if: Low-threshold angina or
Low or moderate pre-test likelihood of equivalent

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obstructive CAD Moderate or high pre-test likelihood Findings suggestive of poor
Information on CAD (also of obstructive CAD prognosis: e.g. severe
non-obstructive) desired Information on myocardial ischaemia, LV dysfunction, ventricular
Individual characteristics suggest high viability or microvascular disease arrhythmia, or hypotension
image quality desired during exercise

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

Obstructive epicardial CAD No obstructive CAD


Consider revascularization Consider ICFT: ANOCA/INOCA?

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

Main imaging target(s) in Requirements Limitations


CCS

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)

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SPECT/CT Atherosclerosis coronary artery Radiation Irradiation (especially young women)
PET/CT calcium score
Functional imaging
Stress Echo LVEF and volumes Poor Echo windows
Wall motion abnormalities Performed with exercise, dobutamine and vasodilators Poor Echo windows
Myocardial perfusion Echo contrast to improve image quality and assess Contraindications to stressor
Coronary velocity flow reserve perfusion
CMR LVEF and volumes Non-CMR-compatible metal devices
Severe claustrophobia
MI (scar) Paramagnetic contrast Non-CMR-compatible metal devices
Severe claustrophobia
Haemodialysis
Ischaemia/blood flow Vasodilator stress + paramagnetic contrast Non-CMR-compatible metal devices
Severe claustrophobia
Contraindications to stressor
Haemodialysis
Wall motion abnormalities Inotropic stress (dobutamine) Non-CMR-compatible metal devices
Severe claustrophobia
Contraindication to stressor
SPECT LVEF and volumes Vasodilator or exercise stress Contraindication to stressor
Ischaemia/viability Radioactive tracer 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

Post-test likelihood (%)


100
DSE +

CCTA +

80

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C
60

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

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limitations.402 In the CLARIFY registry, anginal symptoms resolved in
In symptomatic patients in whom the pre-test many CCS patients over time without requiring revascularization or
likelihood of obstructive CAD by clinical assessment changes in antianginal therapy.404
is >5%, CCTA or non-invasive functional imaging for I B Combined anatomical and functional imaging before ICA facilitates
myocardial ischaemia is recommended as the initial its planning by orientating the invasive cardiologist to perform, in the
diagnostic test.33,148,178,187,189,211,212,219,222,390 same session, haemodynamic assessment of coronary stenoses and
To rule out obstructive CAD in individuals with low ICFT to detect microvascular disease or vasospasm in individuals sus­
or moderate (>5%–50%) pre-test likelihood, CCTA pected of ANOCA/INOCA, performing these tests in a single session
I B
is recommended as the preferred diagnostic rather than in staged procedures.
modality.29,148
CCTA is recommended in individuals with low or
3.3.5. Adverse-event risk assessment
moderate (>5%–50%) pre-test likelihood of
I B Chronic coronary syndromes can be complicated by cardiovascular
obstructive CAD if functional imaging for myocardial
death, ischaemic and haemorrhagic events, HF, arrhythmic events, the
ischaemia is not diagnostic.391
development of valvular heart disease, and other comorbidities, which
Functional imaging for myocardial ischaemia is
are further discussed in the Supplementary data, available at European
recommended if CCTA has shown CAD of
I B Heart Journal online. It is recommended that all patients with newly diag­
uncertain functional significance or is not
nosed obstructive CAD or myocardial ischaemia undergo an adverse-
diagnostic.392–394 risk event assessment to identify those at high risk of adverse outcomes
In patients with a known intermediate coronary who could benefit from revascularization beyond symptom relief. Based
artery stenosisd in a proximal or mid coronary on large registries and historical RCTs, a high event risk has been defined
IIb B
segment on CCTA, CT-based FFR may be as a cardiac mortality rate of >3% per year, intermediate event risk as
considered.395–401 between ≥1% and ≤3% per year, and low event risk as <1% per year.405
Subsequent invasive testing Adverse-event risk stratification is usually based on the same clinical,
non-invasive and invasive investigations used to diagnose obstructive
Invasive coronary angiography with the availability of
CAD (see Table 14).
invasive functional assessments is recommended to
Clinical history, physical examination, 12-lead ECG and laboratory
© ESC 2024

confirm or exclude the diagnosis of obstructive CAD I B


tests can provide important prognostic information. Assessment of
or ANOCA/INOCA in individuals with an uncertain
risk factors such as advanced age, diabetes mellitus (DM), or renal fail­
diagnosis on non-invasive testing.36,49,308,384
ure allows the identification of patients at high risk of events.406–408 Left
ANOCA, angina with non-obstructive coronary arteries; CAD, coronary artery disease; ventricular function is the strongest predictor of long-term survival; a
CCTA, coronary computed tomography angiography; CT, computed tomography; FFR, patient with an LVEF of <50% is already at high risk for all-cause and
fractional flow reserve; INOCA, ischaemia with non-obstructive coronary arteries.
a cardiovascular death.409,410
Class of recommendation.
b
Level of evidence. Although the diagnostic value of an exercise ECG is limited, the oc­
c
Characteristics determining ability to exercise, likelihood of good image quality, expected currence of ST-segment depression at a low workload combined with
radiation exposure, and risks or contraindications. exertional symptoms (angina or dyspnoea), low exercise capacity, com­
d
Typically around 40%–90% by visual estimate.
plex ventricular ectopy, or other arrhythmias and abnormal BP re­
sponse are markers of a high risk of cardiac mortality.411–414
After confirmation of diagnosis with the first line of testing, all patients High plaque burden and coronary stenoses are well-known prognostic
should receive lifestyle and risk-factor modification recommendations, markers. The ISCHEMIA trial using a cut-off of 70% stenosis on CCTA317
and disease-modifying and antianginal therapy should be prescribed. confirms the very old observations of the Coronary Artery Surgery
The ISCHEMIA trial (Initial Invasive or Conservative Strategy for Stable Study182 that the prognosis of obstructive CAD-related CCS is mainly
Coronary Disease)47 showed that an early revascularization strategy determined by the number of >70% obstructed coronary arteries or
did not yield a short-term survival benefit in patients without left main by the presence of a left main stenosis (using for the latter a cut-off of
disease nor reduced LVEF and with moderate-severe ischaemia at >50% diameter stenosis on coronary angiography).317 More recently,
non-invasive testing, suggesting that most such patients should initially the classical paradigm that the severity of stenoses and the number of dis­
be treated conservatively with optimized GDMT. Patients can be re­ eased vessels are the main determinants of prognosis has been challenged
ferred for ICA if CCTA detects a ≥50% stenosis of the left main stem, by post hoc analyses of the SCOT-HEART trial and other CCTA-based
3454 ESC Guidelines

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)

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(e.g. ≥3/16 abnormal segments at stress echocardiography, ≥10% LV
ischaemia at nuclear or magnetic resonance perfusion imaging, or de­ Recommendations Classa Levelb
creased hyperaemic flow or flow reserve at quantitative PET imaging),
An initial stratification of risk of adverse events is
post hoc analyses of the randomized COURAGE426,427 and
ISCHEMIA317 trials showed that only CAD severity, but not ischaemia recommended based on basic clinical assessment
I B
severity, was independently predictive of long-term mortality and MI (e.g. age, ECG, anginal threshold, diabetes, CKD,
406–408
risk. These discrepancies may be explained by selection and entry biases LVEF).
between registries and RCTs.428 Registries typically report on all- The use of one or more of the following test results is
comer populations with suspected CCS referred for diagnostic testing recommended to identify individuals at high risk of
and/or revascularization, representing the real-life scenario. RCTs usu­ adverse events:405
ally include only a very selected group of patients, and the external ap­ • exercise ECG:
plicability of their findings is always open for debate. As COURAGE and ⚬ Duke Treadmill Score < −10;191
ISCHEMIA selectively included only patients with functionally moderate • stress SPECT or PET perfusion imaging:
or severe myocardial ischaemia but without any information on CAD ⚬ area of ischaemia ≥10% of the LV
anatomical severity, it becomes harder to demonstrate a prognostic ef­ myocardium;287,315,422,423,435
fect of myocardial ischaemia, and the anatomical burden becomes the • stress echocardiography:
prominent prognostic factor. The PROMISE (Prospective Multicenter ⚬ ≥3 of 16 segments with stress-induced
Imaging Study for Evaluation of Chest Pain) trial, which included pa­ hypokinesia or akinesia;435 I B
tients more representative of an all-comer population, demonstrated • stress CMR:
that CCTA, mainly by detecting non-obstructive CAD, outperformed
⚬ ≥2 of 16 segments with stress perfusion defects
functional testing in predicting outcomes, emphasizing the prognostic
or ≥3 dobutamine-induced dysfunctional
significance of imaging coronary atherosclerosis beyond myocardial is­
segments;435
chaemia.208 However, adding the Framingham Risk Score to the func­
• CCTA:
tional test result improved its prognostic value, making the difference
⚬ left main disease with ≥50% stenosis, three-vessel
with anatomical testing insignificant. Both modalities are thus equivalent
disease with ≥70 stenosis, or two-vessel disease
for detecting CCS symptoms and predicting outcomes when consider­
ing risk factors. with ≥70% stenosis, including the proximal LAD
Besides imaging coronary atherosclerosis, the additional benefit of ICA or317 one-vessel disease of the proximal LAD with
is the ability to perform intracoronary pressure measurements. While ≥70% stenosis and FFR-CT ≤0.8.
FFR of ≤0.8 and iFR of ≤0.89 have been associated with a higher risk of In individuals at high risk of adverse events (regardless
vessel-related cardiovascular events, it is important to remember that a of symptoms), ICA—complemented by invasive
lower FFR/iFR reflects more profound ischaemia in the vessel territory coronary pressure (FFR/iFR) when appropriate—is
I A
© ESC 2024
and is associated with a progressive and proportional increase in recommended, with the aim of refining risk
risk.318,319 A similar observation has been made with FFR-CT.401 It has stratification and improving symptoms and
also been shown that for any given FFR value, a more proximal lesion is cardiovascular outcomes by revascularization.318,319
associated with more extensive ischaemia and an increased risk of a clinical
CCTA, coronary computed tomography angiography; CKD, chronic kidney disease; CMR,
event.429 In addition, global FFR, summing the coronary pressure collected cardiac magnetic resonance; CT, computed tomography; ECG, electrocardiogram; FFR,
in each of the three main coronary vessel territories as a single patient- fractional flow reserve; FFR-CT, CCTA-derived FFR; ICA, invasive coronary angiography;
related index (normal value of global FFR = 1 + 1 + 1 = 3), can appreciate iFR, instantaneous wave-free ratio; LAD, left anterior descending; LV, left ventricular;
overall cardiovascular risk; patients with a borderline FFR but with a global LVEF, left ventricular ejection fraction; PET, positron emission tomography; SPECT,
single-photon emission computed tomography.
FFR of <2.72 showed a significantly increased risk compared with higher a
Class of recommendation.
global-FFR patients.430,431 One of the main limitations of such a global in­ b
Level of evidence.
tegrative approach based on invasive coronary pressure is that it requires
advancing a pressure wire in each of the three coronary arteries, which is
not often performed341 and is not recommended as a routine, based on 3.4. STEP 4: Initial therapy
the RIPCORD2347 and FUTURE results.346 Recent methods using 3-di­ Initial therapy frequently starts during the diagnostic process. In indivi­
mensional image reconstruction and computational fluid dynamics enable duals with a high suspicion of CCS, sublingual nitroglycerine is frequent­
FFR estimation with CCTA432 or with ’wire-less’ invasive coronary ly prescribed to treat anginal pain symptoms. Rapid relief within 1 or 2
ESC Guidelines 3455

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

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sider patient preferences, possible complications of procedures or disease and other widespread infections, e.g.
medications, and healthcare costs. In shared decision-making with pa­ COVID-19
tients, clinicians should clearly explain that certain treatments can alle­ Sleep quality • Treat sleep-related breathing disorders
viate symptoms, while others can reduce the likelihood of ischaemic Sexual activity • Males and females: low risk for stable patients
events.
who are not symptomatic at low-to-moderate
activity levels
4. Guideline-directed therapy • Males: PDE-5 inhibitors are generally safe, not
to be taken in combination with nitrate
4.1. Patient education, lifestyle medications because of risk of severe
optimization for risk-factor control, hypotension
Psychosocial aspects • Avoid psychosocial stress
and exercise therapy
• Treat depression and anxiety by psychological
4.1.1. Patient education
or pharmacological interventions
In CCS patients, education on risk factors and symptom management is
Environment/pollution • Avoid passive smoking
associated with improvements in knowledge, self-care, and patient
• Reduce environmental noise
empowerment, and may improve health-related QoL.436 In addition,
• Avoid exposure to air pollution
education can facilitate long-term adherence to lifestyle interven­
tions.437,438 Educational programmes—either alone or as a core compo­ Lifestyle interventions for risk-factor control
nent of multidisciplinary care management programmes—promote Smoking and • Use pharmacological and behavioural
patients’ awareness of their condition and the rationale for lifestyle inter­ substance abuse strategies to assist in smoking cessation
ventions. However, awareness of CVD risk factors through education • Avoid e-cigarettes
alone might be insufficient for adoption of healthy behaviour.439 • Abstain from substance abuse
Therefore, self-care programmes are needed to enable patients to have Obesity and being • Obtain and maintain a healthy weight (BMI
a major role in coping with their condition and accepting their prescribed overweight 18.5–25 kg/m2)
treatment.440,441 Elements in patient education include (modifiable) risk • Reduce weight through recommended energy
factors in relation to individual cardiovascular risk, since risk perception intake and increased physical activity and
is an integral part of many major health behaviour theories, ultimately through pharmacological/surgical
leading to modification of human habits.441,442 interventions in selected patients
Information on benefits of risk-factor control on recurrence risk, dis­
Hyperlipidaemia • Ultimate LDL-C goal of <1.4 mmol/L (55 mg/
ease progression, complications, and overall survival should be dis­
dL) and a ≥50% reduction in LDL-C vs.
cussed. The format, time horizon, and outcome used for risk
baseline is recommended
estimation influence patient perceptions and should be considered
when designing risk communication tools.443–445 Diabetes • HbA1c < 7.0% (53 mmol/mol)
Lifelong education for patient-centred information and problem- Arterial hypertension • SBP 120–129 mmHg, provided the
based learning is superior to home-sent information in improving risk- antihypertensive treatment is well tolerated
factor control in the long term.438,444 Refer to Section 6.2.1 for further Diet and alcohol • Limit alcohol consumption to <100 g/week
guidance on patient education. consumption • Diet high in vegetables, fruit, and wholegrains
(Mediterranean diet)
4.1.2. Key lifestyle interventions for risk-factor • Limit saturated fat to <10% of total calorie
control intake
© ESC 2024

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

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free.453 Newer devices deliver higher nicotine contents, and e-cigarettes
emit other constituents, such as carbonyls, and fine and ultrafine particu­ 4.1.2.3. Diet and alcohol
lates.454 Evidence from several studies indicates that acute inhalation of Dietary habits influence cardiovascular risk, mainly through risk factors
e-cigarettes leads to negative changes in vascular endothelial func­ such as lipids, BP, body weight, and DM. It is recommended to adopt a
tion.453,454 E-cigarettes should only be considered to aid tobacco cessa­ Mediterranean or similar diet to lower the risk of CVD, as described in
tion alongside a formal tobacco cessation programme.453,455,456 the 2021 ESC Guidelines on cardiovascular disease prevention in clinical
Various substances, including cocaine, opioids, and marihuana can practice.16 If alcohol is consumed, it should be limited to <100 g/week
have adverse effects on the cardiovascular system and have a potential or 15 g/day, since alcohol intake of >100 g/week is associated with higher
for drug–drug interactions with cardiovascular medication.457–459 all-cause and other CVD mortality in large individual-data meta-analyses.470
Single-question screening for unhealthy drug use has been validated A recent genetic analysis showed that the causal association between
in primary care and can identify individuals requiring counselling on ad­ light-to-moderate levels of alcohol intake and lower cardiovascular risk is
verse cardiovascular effects.460 possibly mediated by confounding lifestyle factors, therefore questioning
the previously observed cardioprotective role of light alcohol use.471

4.1.2.2. Weight management


4.1.2.4. Mental health
In a population-based study, lifetime risk of incident CVD, and cardiovas­
Psychosocial stress, depression, and anxiety are associated with worse
cular morbidity and mortality, were higher in those who were overweight
cardiovascular outcomes, and make it difficult for patients to make posi­
or obese compared with those with a normal BMI (18.5–24.9 kg/m2).461
tive changes to their lifestyles or adhere to a therapeutic regimen.
Compared with normal BMI, among middle-aged men and women,
Therefore, assessment for psychosocial risk factors is recommended
competing hazard ratios (HR) for incident CVD were 1.21 [95%
in secondary prevention.16 Clinical trials have shown that psychological
confidence interval (CI), 1.14–1.28] and 1.32 (95% CI, 1.24–1.40), respect­
(e.g. counselling and/or cognitive behavioural therapy) and pharmaco­
ively, for overweight (BMI of 25.0–29.9 kg/m2), 1.67 (95% CI, 1.55–1.79)
logical interventions have a beneficial effect on depression, anxiety,
and 1.85 (95% CI, 1.72–1.99) for obesity (BMI of 30.0–39.9 kg/m2),
and stress, with some evidence of a reduction in cardiac mortality
and 3.14 (95% CI, 2.48–3.97) and 2.53 (95% CI, 2.20–2.91) for mor­
and events compared with placebo (see Section 6.1.2).472
bid obesity (BMI of ≥40.0 kg/m2). Obesity was associated with a
shorter overall lifespan, and being overweight was associated with
developing CVD at an earlier age.461 In subjects with CAD, intention­ 4.1.2.5. Physical activity and sedentary behaviour
al weight loss is associated with a significantly lower risk of adverse Physical activity reduces the risk of many adverse health outcomes and risk
clinical outcomes,462 and has beneficial effects on risk-factor control factors in all ages and both sexes. There is an inverse relationship between
and QoL.463 Healthy diets with energy intake limited to the amount moderate-to-vigorous physical activity and all-cause mortality, cardiovascu­
needed to obtain and maintain a healthy weight (BMI of 18.5–25 kg/m2), lar mortality, and atherosclerotic cardiovascular disease (ASCVD).473 The
and combined with increasing physical activity, are recommended for reduction in risk continues across the full range of physical activity volumes,
weight management.16 If weight targets are not reached, pharmaco­ and the slope of risk decline is steepest for the least active individuals.474
logical treatment with glucagon-like peptide-1 (GLP-1) receptor ago­ Adults are recommended to perform at least 150–300 min per week of
nists may be considered for further weight reduction (Section 4.3.4). moderate-intensity physical activity, or 75–150 min of vigorous-intensity
In patients without diabetes, the STEP8 trial showed a significant reduc­ physical activity, or an equivalent combination of both, spread throughout
tion in weight after 68 weeks with either semaglutide (mean weight the week.473 Additional benefits are gained with even more physical activ­
change of −15.8%; 95% CI, −17.6% to −13.9%) or liraglutide (mean ity.475 Practising physical activity should still be encouraged in individuals un­
weight change of −6.4%; 95% CI, −8.2% to −4.6%) compared with pla­ able to meet the minimum. In sedentary individuals, a gradual increase in
cebo (−1.9%; 95% CI, −4.0% to 0.2%).464 The double-blind, placebo- activity level is recommended.476 Physical activity can be incorporated flex­
controlled Semaglutide Effects on Cardiovascular Outcomes in ibly, either daily or limited to specific days. Activity patterns limited to 1–2
People with Overweight or Obesity (SELECT) trial showed a significant sessions per week but meeting recommended levels of physical activity
reduction in the incidence of cardiovascular death, MI, or stroke (HR have been shown to reduce all-cause mortality (HR 0.66; 95% CI, 0.62–
0.80; 95% CI, 0.72–0.90) in patients with pre-existing CVD who 0.72), CVD mortality (HR 0.60; 95% CI, 0.52–0.69), and cancer mortality
were overweight or obese, but without diabetes, treated with weekly (HR 0.83; 95% CI, 0.73–0.94) when compared with inactive partici­
subcutaneous semaglutide.465 pants.477 Physical activity accumulated in bouts of even <10 min is asso­
The SURMOUNT-1 (Efficacy and Safety of Tirzepatide Once Weekly ciated with favourable outcomes, including mortality.478
in Participants Without Type 2 Diabetes Who Have Obesity or Are High levels of time spent sedentary is associated with an increased
Overweight With Weight- Related Comorbidities: A Randomized, risk for several major chronic diseases and mortality.479 For physically
ESC Guidelines 3457

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

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FITT (frequency, intensity, time, type) model for aerobic and resistance Recommendations Classa Levelb
training.484
For aerobic training (walking, jogging, cycling, swimming, etc.), an ex­ An informed discussion on CVD risk and treatment
ercise frequency of at least 3 days/week, preferably 6–7 days/week, at benefits tailored to individual patient needs is I C
moderate or moderate-to-high intensity is recommended. Relative in­ recommended.16
tensity is determined based on an individual’s maximum (peak) effort, Multidisciplinary behavioural approaches to help
e.g. percentage of cardiorespiratory fitness (%VO2 max), percentage patients achieve healthy lifestyles, in addition to
I A
of maximum (peak) heart rate (%HRmax) or ventilatory thresholds appropriate pharmacological management, are
(VT1 and VT2).485 To date, there is insufficient evidence to promote recommended.484,498–503
high-intensity interval training over moderate-intensity continuous A multidisciplinary exercise-based programme to
training; nevertheless, optimizing total energy expenditure (either by improve cardiovascular risk profile and reduce I A
increasing intensity or total exercise volume) is related to greater cardiovascular mortality is recommended.480–482
favourable changes in cardiovascular risk and physical fitness.486
Aerobic physical activity of at least 150–300 min per
Moderate-intensity continuous training is the most feasible and cost-
week of moderate intensity or 75–150 min per week
effective aerobic training modality for patients with CCS. I B
of vigorous intensity and reduction in sedentary time
High-intensity interval training can be prescribed in selected patients
are recommended.16,473,478,479
for specific targets of intervention (e.g. to increase VO2 peak).485
Resistance exercise in addition to aerobic training is associated with Home-based cardiac rehabilitation and mobile health
lower risks of total cardiovascular events and all-cause mortality.16 The interventions should be considered to increase

© 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

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trates, nicorandil, ranolazine, ivabradine, trimetazidine).1,514 This task minute (b.p.m.).517,518
force reinforces the concept that medical therapy for symptom control Beyond improving symptoms, the clinical benefit of beta-blockers in
in CCS should be tailored to each patient’s haemodynamic profile (BP, patients with CAD without prior MI and with normal LVEF is largely un­
heart rate), comorbidities (particularly presence of HF), concomitant known in the absence of evidence from RCTs. The main findings of
medications with potential drug interactions, and preferences, also tak­ some observational studies addressing this issue are summarized in
ing into account the pathophysiological basis of myocardial ischaemia in the Supplementary data.
each patient, as well as local availability of different drugs.515,516 For The clinical benefit of beta-blockers in post-ACS patients with reduced
many patients with CCS, initial drug therapy should include a beta- LVEF is supported by solid evidence.519–521 However, there are no large
blocker and/or a CCB. Other antianginal drugs (long-acting nitrates, RCTs supporting the prescription of beta-blockers after uncomplicated
ivabradine, nicorandil, ranolazine, trimetazidine) can be added on top ACS in patients with LVEF >40%.522 The evidence provided by

Obstructive CAD COPD


Microvascular dysfunction Peripheral arterial disease
Arterial hypertension Type I diabetes mellitus
Atrial fibrillation
HFrEF Sick sinus syndrome

Beta-blockers Obstructive CAD


Obstructive CAD Vasospastic angina
Vasospastic angina Dihydropyridine- Nitrates
Arterial hypertension CCB Nicorandil HFrEF

HFrEF
HCM

Obstructive CAD
HFrEF
Vasospastic angina
Atrial fibrillation Diltiazem Ivabradine
Verapamil Sick sinus syndrome
Sick sinus syndrome
HFrEF
Trimetazidine Ranolazine

Obstructive CAD Obstructive CAD


Microvascular dysfunction Microvascular dysfunction

Indicated unless there are May be indicated in


Contraindicated
specific contraindications specific situations

Useful combinations Possible combinations


Not recommended Drugs with similar effects

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

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Evidence from RCTs assessing beta-blockers rarely goes beyond a and/or CCBs, or as part of initial treatment in
few years of follow-up, but patients are often given continuous treat­ properly selected patients.543–550
ment up to old age.531 Observational data are also conflicting in this re­ Ivabradine is not recommended as add-on therapy in
gard. One study has suggested that the clinical benefit of beta-blockers patients with CCS, LVEF >40%, and no clinical heart III B
might be restricted to the first year after the index event, showing that failure.509
their discontinuation at 1 year was not associated with higher 5-year Combination of ivabradine with non-DHP-CCB or
mortality.532 In contrast, a Swedish study starting the follow-up 1 other strong CYP3A4 inhibitors is not III B
year after the ACS episode has shown a lack of association between recommended.551
the use of beta-blockers and a composite of all-cause mortality, MI, un­ Nitrates are not recommended in patients with
scheduled revascularization, or hospitalization for HF.533 Another study

© 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-

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Patients at Risk of Ischaemic Events) demonstrated a small benefit in is­
preventing therapies include antithrombotic, lipid-lowering,
chaemic events (RR reduction of 8.7%) with clopidogrel 75 mg/day vs.
anti-RAAS (renin–angiotensin–aldosterone system), anti-inflammatory,
aspirin 325 mg/day.564
and metabolic-acting agents.
In the recent, open-label, South Korean, non-inferiority HOST-EXAM
(Harmonizing Optimal Strategy for Treatment of Coronary Artery
4.3.1. Antithrombotic drugs Stenosis-EXtended Antiplatelet Monotherapy) trial, clopidogrel was
The standard antithrombotic treatment of patients with epicardial ath­ compared with low-dose aspirin in 5530 patients after 6–18 months of
erosclerotic CAD is single antiplatelet therapy (SAPT), typically with as­ uneventful DAPT post-PCI (72% initial ACS, 28% initial CCS).565
pirin. In patients with ACS or post-PCI, standard treatment is dual Relative to aspirin, clopidogrel reduced the composite of all-cause death,
antiplatelet therapy (DAPT) with aspirin and an oral P2Y12 inhibitor, non-fatal MI, readmission attributable to ACS, stroke, and BARC
for a duration of 12 months after ACS (with or without PCI)65 or (Bleeding Academic Research Consortium) ≥3 bleeding from 7.7% to
6 months after CCS-PCI.1,556 Thus, in ACS or CCS-PCI patients, 5.7% at the end of the 2-year follow-up; the results were maintained
DAPT is usually replaced by SAPT at some point. Several recent trials at 5.8 years, in a post hoc, per-protocol, post-trial analysis.566
have investigated shortened DAPT durations and P2Y12 inhibitor A very recent individual patient-level meta-analysis examined seven
monotherapy post-PCI to reduce the risk of bleeding. On the other trials involving 24 325 patients (including recent ACS, post-CABG, or
hand, in CCS patients with persistently high ischaemic risk and low initial CCS patients) randomized to either aspirin monotherapy
bleeding risk, extended intensified antithrombotic therapy should be (12 147 patients) or P2Y12 inhibitor monotherapy [clopidogrel in 7545
considered. Ultimately, the choice and duration of antithrombotic regi­ (62.0%), ticagrelor in 4633 (38.0%)] and followed for 6–36 months.562
mens largely depend on the delicate balance between each individual’s P2Y12 inhibitors reduced the combined ischaemic outcome of cardio­
ischaemic and bleeding risks. vascular death, MI, and stroke compared with aspirin (in doses of 100
The mechanisms of action of the most commonly used antithrombo­ or 325 mg daily), mainly through reduction of infarction. The risk of ma­
tic drugs in CCS patients are depicted in Figure 10. jor bleeding was similar, whereas GI bleeding and haemorrhagic stroke
occurred less frequently with a P2Y12 inhibitor. The treatment effect
was consistent across pre-specified subgroups (ACS or CCS) and
4.3.1.1. Antiplatelet drugs
type of P2Y12 inhibitor.562
For details on antiplatelet drugs, please see Supplementary data, The above overall evidence supports clopidogrel monotherapy as an
Table S1. effective and safe alternative to aspirin monotherapy for long-term sec­
ondary prevention in patients with CCS.
4.3.1.1.1. Aspirin monotherapy. Low-dose aspirin (75–100 mg once
daily) is the traditional drug of choice in patients with CCS, with or 4.3.1.1.2.2. Ticagrelor monotherapy. Since ticagrelor compared with
without prior MI.557,558 In an individual-patient data meta-analysis of clopidogrel is more effective and displays less variable platelet inhib­
secondary prevention trials (43 000 patient-years), aspirin vs. no aspirin ition,567,568 although with greater bleeding potential,569 ticagrelor
significantly reduced the combined risk of non-fatal MI, non-fatal ischae­ monotherapy has been compared with aspirin monotherapy for sec­
mic stroke, or death from vascular causes [from 8.2% to 6.7% per year ondary prevention in CCS patients treated with PCI.
(P < .0001), with relative risk (RR) reductions of 31%, 22%, and 9%, re­ The RCT GLOBAL LEADERS trial [Ticagrelor plus aspirin for
spectively], translating into 15 fewer fatal and non-fatal serious vascular 1 month, followed by ticagrelor monotherapy for 23 months vs. as­
events for every 1000 patients treated for 1 year.558 Aspirin allocation pirin plus clopidogrel or ticagrelor for 12 months, followed by aspirin
increased major gastrointestinal (GI) and extracranial bleeds, from monotherapy for 12 months after implantation of a drug-eluting stent
0.07% to 0.10% per year (P < .0001), with a non-significant increase (DES): a multicentre, open-label, randomized superiority trial]570 of
in haemorrhagic stroke but reductions of about a fifth in total stroke 15 968 patients (53% with initial CCS) did not show superiority of
(from 2.54% to 2.08% per year, P = .002) and in coronary events ticagrelor monotherapy vs. standard of care in terms of survival or
(from 5.3% to 4.3% per year, P < .0001). new Q-wave MI.570 A pre-specified GLOBAL LEADERS ancillary ana­
Thus, for secondary prevention, the reduction of ischaemic events lysis of independently adjudicated outcomes in 7585 patients reported
with aspirin outweighs serious bleeding events.557,558 There is no evi­ non-inferiority for ischaemic events and no difference in BARC major
dence of different aspirin effects in women and men.558,559 Daily aspirin bleeding between the two strategies.571 A post hoc landmark analysis
doses of 75–100 mg seem to be as effective as higher doses for long- of the GLOBAL LEADERS trial, conducted in 11 121 uneventful patients
term treatments.558–561 at 1 year (53% CCS from trial onset, 47% transitioning to CCS from
ESC Guidelines 3461

Plaque rupture or
plaque erosion

TxA2 Aspirin

ADP

Platelet rolling
and adhesion P P

Thromboxane
TF:FVIIa Clopidogrel
receptor
coagulation Prasugrel

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Thrombin Ticagrelor
P2Y12 receptor Cangrelor
Vorapaxar PAR I
PAR 4
Eptifibatide
Platelet
Apixaban activation Tirofiban

Edoxaban
Rivaroxaban Platelet
GP IIb/IIIa aggregation

Fibrinogen

Fondaparinux FXa GP IIb/IIIa Platelet fibrin


thrombus

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

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lected patients at high ischaemic risk without high bleeding risk (HBR), increased bleeding: (i) continue DAPT, consisting of aspirin and clopido­
ticagrelor monotherapy may be considered [at the time of writing grel or of aspirin and prasugrel after PCI, based on the results of the
not contemplated by the European Medicines Agency (EMA) (https:// DAPT Study;592 (ii) add ticagrelor to aspirin in post-MI patients, based
www.ema.europa.eu/en/medicines/human/EPAR/brilique)] with a low­ on the PEGASUS-TIMI (Prevention of Cardiovascular Events in
er level of evidence than for aspirin or clopidogrel (Figure 11). Details Patients with Prior Heart Attack Using Ticagrelor Compared to
on the pharmacology of antiplatelet drugs567,577–582 and on the rando­ Placebo on a Background of Aspirin - Thrombolysis In Myocardial
mized evidence (including trial limitations) can be found in the Infarction) 54 trial;593 or (iii) add very low-dose rivaroxaban to aspirin
Supplementary data, Table S1 and in the evidence tables. in CCS patients, based on the COMPASS trial (Cardiovascular
Outcomes for People Using Anticoagulant Strategies).594
4.3.1.1.3. Dual antiplatelet therapy post-percutaneous coronary The randomized DAPT Study demonstrated, in patients at 1-year
intervention. After PCI for CCS, DAPT consisting of aspirin and clopido­ post-PCI, that an additional 18 months of DAPT reduced ischaemic
grel is recommended to reduce the risk of stent thrombosis and MI com­ events compared with aspirin alone, but moderate and severe GUSTO
pared with aspirin alone.556 With few exceptions, there is no reason to (Global Utilization of Streptokinase and Tissue Plasminogen Activator
replace clopidogrel with ticagrelor, based on the ALPHEUS for Occluded Arteries) or BARC bleeding rates were higher, and all-
(Assessment of Loading with the P2Y12 Inhibitor Ticagrelor or cause death tended to be increased.592 Of note, in the DAPT Study, first-
Clopidogrel to Halt Ischemic Events in Patients Undergoing Elective generation DES were used with an increased risk of stent thrombosis.
Coronary Stenting) trial results demonstrating, in 1883 patients followed The PEGASUS-TIMI 54 trial showed that in aspirin-treated patients
for 30 days, that ticagrelor did not significantly reduce PCI-related MI or with a history of MI 1–3 years previously and at least one high-risk char­
major myocardial injury, while minor bleeding was significantly increased acteristic (i.e. aged >65 years, DM, second MI, multivessel CAD, or
compared with clopidogrel.583 CKD), ticagrelor (90 or 60 mg b.i.d.) vs. placebo reduced ischaemic
In the THEMIS trial (The Effect of Ticagrelor on Health Outcomes in events at 3 years, while it increased TIMI (Thrombolysis In Myocardial
diabEtes Mellitus patients Intervention Study) of 19 220 CCS patients aged Infarction) major, but not fatal, bleeding.593 The 60 mg dose was safer
≥50 years, with type 2 DM and no previous MI or stroke (58% with prior and better tolerated than the 90 mg dose584,593 and therefore approved.
PCI), ticagrelor plus low-dose aspirin marginally reduced ischaemic events The subgroups of patients with (compared with those without) DM,
compared with placebo plus aspirin at a median follow-up of 40 months, multivessel CAD, and PAD benefited more from ticagrelor.595–597
but increased major bleeding, including intracranial haemorrhage.584 The COMPASS trial demonstrated that the combination of aspirin
A default DAPT duration of 6 months is recommended for CCS pa­ plus rivaroxaban 2.5 mg b.i.d., but not rivaroxaban 5.0 mg b.i.d. mono­
tients undergoing PCI.556 However, multiple RCTs have investigated therapy, reduced ischaemic events, but increased modified-ISTH
shorter DAPT durations (1 or 3 months) to decrease the risk of (International Society on Thrombosis and Haemostasis) major bleeding,
bleeding.570,573,585–588 The combined evidence indeed shows a decrease compared with aspirin alone in patients with stable atherosclerotic
in—mostly minor—bleeding, without an increase in ischaemic events, in­ disease (mostly CAD, with additional risk conditions if younger than
dicating that a shorter duration of DAPT of 1–3 months post-PCI may 65 years).594 There was no significant difference in intracranial or fatal
benefit CCS patients who are not at high ischaemic risk or who are at HBR. bleeding between the two treatment arms, and death rates were lower
This concept was tested in the MASTER-DAPT trial (Management of in the aspirin plus rivaroxaban 2.5 mg b.i.d. group. Subgroups of patients
High Bleeding Risk Patients Post Bioresorbable Polymer Coated Stent with (compared with those without) DM, PAD, mild CKD, and active
Implantation with an Abbreviated versus Standard DAPT Regimen), smoking habit benefited more from aspirin plus rivaroxaban.594,598
randomizing 4579 PCI patients (∼50% CCS) with HBR, after 1-month Patient eligibility for extended intensified antithrombotic therapy
uneventful DAPT, to immediate DAPT discontinuation or to DAPT must be defined taking into account individual patient characteristics
continuation for at least 2 additional months.587 After 335 days, the trial (see Supplementary data, Table S2), as well as study inclusion and exclu­
demonstrated that discontinuation was non-inferior for ischaemic sion criteria. The different options are described in Table 8.
events compared with standard duration of DAPT, but major and clin­ In summary, in high ischaemic risk CCS patients without HBR, either
ically relevant non-major bleeding was reduced.587 aspirin plus ticagrelor 60 mg b.i.d. or aspirin plus rivaroxaban 2.5 mg
A meta-analysis, including 11 RCTs and 9006 patients (42% CCS) at b.i.d. should be considered, based on patient characteristics
HBR [defined by a PREdicting bleeding Complications In patients (Figure 11). DAPT prolongation with clopidogrel or prasugrel may
undergoing Stent implantation and subsEquent Dual AntiPlatelet also be an option, although the evidence for this choice suffers limita­
Therapy (PRECISE-DAPT) score of >25 or by Academic Research tions. In patients with extended intensified antithrombotic therapy, re-
Consortium for High Bleeding Risk (ARC-HBR) criteria, listed in evaluation of bleeding and ischaemic risk at regular intervals is essential.
Supplementary data, Table S2]589–591 showed at 12 months of follow-up Randomized evidence beyond study follow-up times is unavailable.
ESC Guidelines 3463

Patients with CCS without indication for OAC undergoing PCI

Assess bleeding risk

Non-high bleeding risk High bleeding risk

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Non-high
Default High ischaemic risk Default
ischaemic risk

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)

6 mo. DAPT 1–6 mo. DAPTa


(Class I) (Class IIb)

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

A Aspirin 100 mg o.d. R Rivaroxaban 2.5 mg b.i.d.

C Clopidogrel 75 mg o.d. T Ticagrelor 60 mg b.i.d.

P Prasugrel 10 mg o.d.b T Ticagrelor 90 mg b.i.d.

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

Table 8 Options for extended intensified antithrombotic therapy

Drug Dose Clinical setting NNT (ischaemic NNH (bleeding outcomes)


outcomes)

Co-administered with aspirin 100 mg o.d.


Rivaroxaban (COMPASS 2.5 mg b.i.d. Patients with CAD or symptomatic 77 84
trial; vs. placebo) PAD at high risk of ischaemic events (modified-ISTH major bleeding)
Co-administered with low-dose aspirin 75–162 mg o.d.
Clopidogrel, (6505/9961 of 75 mg/day Post MI in patients who have 63 105
DAPT trial; vs. placebo) tolerated DAPT for 1 year (25% ACS, (moderate and severe GUSTO
22% previous MI) bleeds, or BARC 2, 3, and 5

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bleeds)
Prasugrel, (3456/9961 of 10 mg/day (5 mg/day if Post PCI for MI in patients who have 63 105
DAPT trial; vs. placebo) body weight <60 kg or tolerated DAPT for 1 year (as above)

© 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

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occurrence did not differ significantly in the two treatment arms.627 increased risk of major bleeding.642
Whether the above considerations remain valid when the indication Decisions on OAC should consider thrombo-embolic and bleeding
for OAC is other than AF, e.g. mechanical heart valves (where risks, timing, and duration of post-operative AF. Longer AF durations
DOACs are not indicated) or VTE, is uncertain given limited available evi­ and delayed-onset post-CABG have higher risks. We refer to the
dence. In the absence of data regarding the efficacy for MACE prevention 2024 ESC Guidelines for the management of AF regarding recommen­
of rivaroxaban 10 mg once daily and apixaban 2.5 mg twice daily, which dations for OAC in this context. It is unknown whether, in such pa­
should be used for extended OAC after the first 6 months of therapeutic tients, the combination of aspirin and OAC may be more effective
anticoagulation in patients with VTE,628 it is recommended to resume full compared with OAC alone in preventing ischaemic events post-CABG.
doses of these anticoagulants in case of concomitant CCS.

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)

Recommendations Classa Levelb

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.

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Long-term antithrombotic therapy in patients with chronic coronary syndrome and an indication for oral anticoagulation
In CCS patients with a long-term indication for OAC, an AF therapeutic dose of VKA alone or, preferably, of DOAC alone (unless
I B
contraindicated) is recommended lifelong.609,627
Antithrombotic therapy post-percutaneous coronary intervention in chronic coronary syndrome patients with an indication for oral
anticoagulation
In patients with an indication for OAC who undergo PCI, initial low-dose aspirin once daily is recommended (loading dose when not on
I C
maintenance dose) in addition to OAC and clopidogrel.
In patients who are eligible for OAC, DOAC (unless contraindicated) is recommended in preference to VKA.619,658 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;c or I A
⚬ up to 12 months in patients at high ischaemic risk;c
• followed by OAC alone;
is recommended.616–619,622,627,659
Continuation of aspirin up to 1 month after PCI, in addition to OAC and clopidogrel, should be considered in patients at high ischaemic riskc
IIa B
or with anatomical/procedural characteristics judged to outweigh the bleeding risk.620–622,e
When concerns about high bleeding risk prevail over concerns about stent thrombosis or ischaemic stroke:
IIa B
rivaroxaban 15 mg daily should be considered in preference to rivaroxaban 20 mg daily for the duration of concomitant antiplatelet therapy;616
dabigatran 110 mg twice daily should be considered in preference to dabigatran 150 mg twice daily for the duration of concomitant
IIa B
antiplatelet therapy.617
In patients with an indication for VKA in combination with single or dual antiplatelet therapy, targeting VKA intensity to an INR in the lower
IIa B
part of the recommended range and to a time in therapeutic range >70% should be considered.615,660–663
The use of ticagrelor or prasugrel is generally not recommended as part of triple antithrombotic therapy with aspirin and an OAC. III C
Antithrombotic therapy post-coronary artery bypass grafting
It is recommended to initiate aspirin post-operatively as soon as there is no concern over bleeding.629,630 I B
DAPT may be considered after CABG in selected patients at greater risk of graft occlusionf and at low risk of bleeding.635 IIb B
Use of proton pump inhibitors
A proton pump inhibitor is recommended in patients at increased risk of gastrointestinal bleeding for the duration of combined
I A
© ESC 2024

antithrombotic therapy (antiplatelet therapy and/or OAC).646–648,664


A proton pump inhibitor should be considered when a single antithrombotic (antiplatelet or anticoagulant) drug is used, considering the
IIa A
gastrointestinal bleeding risk of the individual patient.646,665–668

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

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For patients who experience a second vascular event within 2 years A high-intensity statin up to the highest tolerated
while taking maximum tolerated statin-based therapy, an even lower dose to reach the LDL-C goals is recommended for I A
LDL-C goal of <1.0 mmol/L (40 mg/dL) may be considered. all patients with CCS.670,671
In addition to exercise, diet, and weight control, which favourably af­
If a patient’s goal is not achieved with the maximum
fect blood lipid levels and are recommended for all patients with CCS
tolerated dose of statin, combination with ezetimibe I B
(see Section 5.1), pharmacological treatment with a maximally tolerated
is recommended.674
dose of a potent statin is the first-line therapy recommended for all
CCS patients.128,670,671 In a landmark meta-analysis involving patients For patients who are statin intolerant and do not
with and without ASCVD, statin treatment was shown to reduce the achieve their goal on ezetimibe, combination with I B
680
risk of major vascular events by 22%, all-cause mortality by 10%, and bempedoic acid is recommended.
mortality due to coronary heart disease by 20% per 1.0 mmol/L of For patients who do not achieve their goal on a
achieved reduction in LDL-C levels.670 High-intensity statin treatment maximum tolerated dose of statin and ezetimibe,
I A
(i.e. atorvastatin ≥40 mg or rosuvastatin ≥20 mg daily) reduces combination with a PCSK9 inhibitor is
LDL-C levels by 45%–50% on average, although interindividual variabil­ recommended.675,676
ity exists.672 Statins should not be given when pregnancy is planned, For patients who do not achieve their goal on a
during pregnancy, or during the breastfeeding period.64 maximum tolerated dose of statin and ezetimibe,
In many patients with CCS, statin therapy alone will not suffice to IIa C
combination with bempedoic acid should be
achieve the recommended LDL-C goals;673 hence, a combination of considered.
lipid-lowering drug therapy is required. In a trial of patients with recent
For patients with a recurrent atherothrombotic
ACS, the combination of statin with ezetimibe resulted in additional re­
event (not necessarily of the same type as the first
duction of LDL-C levels by 20%–25% compared with simvastatin

© 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

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inhibitor, which inhibits the degradation of endogenous natriuretic pep­ SGLT2 inhibitors with proven CV benefitc are
tides. In patients with LVEF ≤35% (of ischaemic aetiology in 60%), recommended in patients with T2DM and CCS to
sacubitril/valsartan proved to reduce HF hospitalization and cardiovas­ reduce CV events, independent of baseline or target I A
cular death compared with ACE-I.693 Moreover, sacubitril/valsartan HbA1c and independent of concomitant
may decrease myocardial ischaemia because of its effect in reducing glucose-lowering medication.86,688,695,697,700
LV wall stress and improving coronary circulation. The risk of coronary GLP-1 receptor agonists with proven CV benefitd
events using sacubitril/valsartan compared with ACE-I was also signifi­
are recommended in patients with T2DM and CCS
cantly reduced on post-hoc analyses.694
to reduce CV events, independent of baseline or I A
target HbA1c and independent of concomitant
4.3.4. Sodium–glucose cotransporter 2 inhibitors and glucose-lowering medication.710,711
glucagon-like peptide-1 receptor agonists CCS patients without type 2 diabetes
Sodium–glucose cotransporter 2 (SGLT2) inhibitors and GLP-1 recep­ The GLP-1 receptor agonist semaglutide should be

© 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/

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curred in 6.8% on colchicine vs. 9.6% on placebo (HR 0.69; 95% CI,
ARBs and statins. Meta-analytical evidence suggests a potential benefit
0.57–0.83; P < .001). The main secondary endpoint (cardiovascular
of PCI on cardiovascular survival,55,725,726 which, similarly to CABG, ap­
death, non-fatal MI, or non-fatal stroke) was reduced by 28% (4.2%
pears to be related to the prevention of MI.55,727 In general, among sur­
on colchicine vs. 5.7% on placebo; HR 0.72; 95% CI, 0.57–0.92;
gically eligible patients with multivessel disease, CABG is superior to
P = .007). There were no significant differences in rates of pneumonia
PCI and to medical therapy, particularly in those with diabetes and high­
or GI disorders. The incidence of non-cardiovascular death was nomin­
er coronary complexity.727,728 Recent evidence has generated contro­
ally higher, but not statistically significant (0.7 vs. 0.5 events per 100
versy on (i) the value of routine early revascularization compared with
person-years; HR 1.51; 95% CI, 0.99–2.31).
optimal medical therapy alone,47,56,314,729 (ii) the value of PCI vs. CABG
A recent meta-analysis including over 12 000 patients with athero­
for complex CAD,326,730 and (iii) the value of ischaemia testing for
thrombotic CAD716 has estimated the treatment effects of colchicine
decision-making in revascularization.315,317,726 At the same time, ad­
vs. placebo for individual outcome components. Significantly lower risks
vances in interventional technologies and medications have expanded
were found for MI (RR, 0.76; 95% CI, 0.61–0.96), stroke (RR, 0.48; 95%
the application of PCI to more complex forms of CAD.731
CI, 0.30–0.77) and unstable angina-driven revascularization (RR, 0.61;
95% CI, 0.42–0.89), with no significant difference for cardiovascular
death (RR, 0.73; 95% CI, 0.45–1.21), all-cause death (RR, 1.01; 95% 4.4.1. Appropriate indication for myocardial
CI, 0.71–1.43), or GI events (provided colchicine daily dose did not ex­ revascularization
ceed 0.5 mg; RR, 1.02; 95% CI, 0.92–1.14). In CAD patients with moderate or severe inducible ischaemia but no
left main disease nor LVEF of <35%, the largest-to-date ISCHEMIA trial,
Recommendation Table 20 — Recommendations for up to 5 years, did not show significant benefit of an initial invasive strat­
anti-inflammatory drugs in patients with chronic coron­ egy over an initial conservative strategy for the primary endpoint of is­
ary syndrome (see also Evidence Table 20) chaemic cardiovascular events or death from any cause,47 triggering
discussion about the role of initial angiography followed by revascular­
Recommendation Classa Levelb ization when feasible, in this type of CCS patients, once optimal medical
In CCS patients with atherosclerotic CAD, low-dose
therapy has been established. The CLARIFY registry found that many
CCS patients with angina experience a resolution of symptoms over
© ESC 2024

colchicine (0.5 mg daily) should be considered to


IIa A time, often without changes in treatment or revascularization, and ex­
reduce myocardial infarction, stroke, and need for
perience good outcomes.404 While these findings suggest that this type
revascularization.714–716
of CCS patients should initially receive conservative medical manage­
CAD, coronary artery disease; CCS, chronic coronary syndrome. ment, it is worth noting that patients who were randomly assigned
a
Class of recommendation. to the invasive strategy in the ISCHEMIA trial experienced significantly
b
Level of evidence.
lower rates of spontaneous MI and greater improvement in
angina-related health status compared with those assigned to the con­
Recommendation Table 21 — Recommendations for servative strategy.47,50 Furthermore, the ORBITA 2 trial demonstrated
angiotensin-converting enzyme inhibitors in patients that patients with stable angina, who were receiving minimal or no anti­
with chronic coronary syndrome (see also Evidence
anginal medication and had objective evidence of ischaemia, experi­
Table 21)
enced a lower angina symptom score following PCI treatment
Recommendations Classa Levelb compared with a placebo procedure, indicating a better health status
with respect to angina.52 Although initial conservative medical manage­
In CCS patients, ACE-Is (or ARBs) are ment of CCS patients is generally preferred, symptom improvement by
recommended in the presence of specific revascularization should therefore not be neglected if patients remain
I A
comorbidities, such as hypertension, diabetes, or symptomatic despite antianginal treatment.
© ESC 2024

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;

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sive strategy was associated with lower long-term risks of cardiovascular 95% CI, 0.73–0.97; P = .02; and from 49.3% to 40.5%; HR 0.79; 95%
events, mainly spontaneous MIs, compared with a conservative strategy, CI, 0.66–0.93; P = .006, respectively).54 The reduction of cardiovascular
at the cost of a higher risk of procedural MIs.738 mortality by CABG was greater in patients with three-vessel disease54
Extended follow-up of the ISCHEMIA trial population up to 7 years and the reduction of all-cause mortality was greater in younger patients,
(ISCHEMIA-EXTEND) revealed a significant 2.2% absolute decrease in in whom cardiovascular deaths accounted for a larger proportion of
cardiovascular mortality (adjusted HR 0.78; 95% CI, 0.63–0.96) favour­ deaths vs. older patients (P = .004 for interaction).749 Viability was as­
ing the initial invasive strategy.56 The benefit was most marked in pa­ sessed by SPECT, dobutamine echocardiography, or both in 50% of
tients with multivessel CAD (≥70% diameter stenosis on CCTA; STICH patients (298 randomized to CABG and 303 randomized to
adjusted HR 0.68; 95% CI, 0.48–0.97) but was offset by a significant GDMT alone).750 There were no significant interactions between pres­
1.2% absolute increase in non-cardiac mortality, without a significant ence or absence of myocardial viability and improved LV function or
difference (absolute decrease of −0.7%) in all-cause mortality.56 In a re­ long-term survival benefit for CABG above GDMT.747,748,750
cent meta-analysis of 18 trials, on the other hand, non-cardiac mortality There have been no RCTs directly comparing CABG and PCI in pa­
did not differ significantly by initial invasive or conservative strategy in tients with ischaemic HF. A meta-analysis of 21 studies, mostly obser­
CCS patients with preserved or slightly impaired LVEF.739 In a post vational except three including STICH, published between 1983 and
hoc analysis of the ISCHEMIA trial, CAD severity was associated with 2016, supported CABG and PCI on a background of GDMT in appro­
a higher risk of all-cause death, MI, and the primary endpoint of the priate patients with multivessel disease and LV systolic dysfunction; re­
trial.317 This effect appeared to be most noticeable in patients with mul­ vascularization with either CABG or PCI improved long-term survival
tivessel disease and/or proximal LAD stenosis (≥70% diameter stenosis compared with GDMT, but compared with PCI, CABG provided a sur­
on CCTA). vival benefit and a lower risk of MI or repeat revascularization, with a
slightly higher incidence of stroke.751
PCI is increasingly used over CABG for treating patients with ischaemic
4.4.2. Additional considerations on reduced systolic HF and multivessel disease, as shown by two large registries.752,753 While
left ventricular function: myocardial viability, these registries suggest that CABG is associated with a lower risk of long-
revascularization, and its modality term all-cause and cardiovascular mortality and lower MACE compared
Ischaemic cardiomyopathy is the leading cause of HFrEF, and new ischae­ with PCI in patients with CAD and LVEF ≤35%,752,753 it is important to
mic events are the main drivers of worsening LV function, strongly im­ interpret these observational studies with great caution, given significant
pacting long-term survival.740 Ischaemic HFrEF is characterized by differences in baseline characteristics, including age, history of previous MI,
irreversibly damaged and scarred myocardium alternating with ‘viable’ severity of CAD, and completeness of revascularization.754 For the com­
myocardium that may be dysfunctional owing to repetitive ischaemic epi­ parison of CABG with PCI in managing ischaemic HF with severely im­
sodes (stunning) or chronic hypoperfusion (hibernation).741 According paired LV dysfunction and multivessel CAD, the results of ongoing trials
to classical concepts, revascularization combined with GDMT synergis­ (NCT05427370 and NCT05329285) are awaited.
tically improves systolic LV function and overall prognosis in patients The Percutaneous Revascularization for Ischemic Left Ventricular
with ischaemic HFrEF by restoring sufficient perfusion to dysfunctional Dysfunction (REVIVED-BCIS2) trial randomized 700 patients with im­
yet viable myocardial segments and preventing new ischaemic events.742 paired LV function (EF ≤ 35%), extensive CAD amenable to PCI, and
However, it carries increased periprocedural risk, especially in patients evidence of myocardial viability in at least four dysfunctional myocardial
with severe LV dysfunction (LVEF ≤ 35%). A meta-analysis of 26 obser­ segments to a strategy of PCI plus GDMT or GDMT alone.729 After a
vational studies, including 4119 patients, showed that CABG can be per­ 3.4-year follow-up, PCI showed no significant reduction in the compos­
formed with acceptable operative mortality (5.4%; 95% CI, 4.5%–6.4%) ite primary endpoint of all-cause death or HF rehospitalization (HR
and 5-year actuarial survival (75%) in patients with severe LV dysfunction 0.99; 95% CI, 0.78–1.27; P = .96). Patients treated by PCI showed slight
(mean pre-operative EF of 24.7%).743 and temporary improvements in their symptoms and no incremental
In the 1990s, observational studies reported improved survival after improvement of overall LV function compared with GDMT.
revascularization in patients with severe CAD, significant LV dysfunc­ A pre-specified secondary analysis of REVIVED-BCIS2, conducted in
tion, and evidence of myocardial viability on imaging tests.744 The 87% of patients, failed to establish significant correlations between via­
PARR-2 trial (PET and Recovery Following Revascularization) rando­ bility extent (assessed by CMR or dobutamine stress echocardiog­
mized 430 patients with suspected ischaemic cardiomyopathy to an raphy) and outcomes, thereby challenging the traditional concept of
F-18-fluorodeoxyglucose PET-assisted strategy or standard care. myocardial hibernation, which can be reversed by revascularization.755
While there was a non-significant trend towards lower risk of cardiac However, the analysis did find that larger amounts of non-viable myo­
events at 1 year with PET assistance,745 the 5-year follow-up showed cardium were linked to an increased risk of the primary outcome,
ESC Guidelines 3471

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.

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to the absence of any PCI effect on survival.
In conclusion, the heterogeneous designs of the above studies, the
statistical underpower of subgroup analyses, the heterogeneous meth­ 4.4.4. Assessment of clinical risk and anatomical
ods of viability assessments (e.g. based on metabolism, contractile re­ complexity
serve, or scar extent) and variable quantification (dichotomous vs. While both CABG and PCI have shown continuous technical improve­
continuous) leave many open questions on how viability should be de­ ments and better clinical outcomes over time,774,775 the potential benefit
fined,756 and when and why it should be assessed in ischaemic HFrEF of revascularization must be carefully evaluated against the procedural
patients. For instance, the classical binary definition of myocardial viabil­ risk. The Society of Thoracic Surgeons Predicted Risk of Mortality
ity may benefit from more contemporary paradigms and from greater (STS-PROM) risk model has proved to be more effective than the
focus on anatomic alignment between viable myocardial regions and EuroSCORE II risk model in predicting peri-operative mortality and com­
feasible revascularization of corresponding perfusing arteries.741 plications in CABG patients due to its continuous calibration.776 It has
Moreover, therapeutic aims should go beyond enhancing local and also shown satisfactory discrimination for all-cause death at 30 days in pa­
overall LV function to include safeguarding against new ischaemic tients undergoing CABG, allowing differentiation of high (>8%) and inter­
events727 and their ensuing possibly lethal arrhythmias. Therefore, an mediate (4% to 8%) from low (<4%) surgical mortality risk. Although
integrative approach, including highly specialized imaging, HF, arrhyth­ primarily designed for surgical risk assessment, the STS-PROM score
mia, and revascularization specialists, is needed for optimal patient man­ can also be used to evaluate the risk of revascularization through PCI
agement and improved outcomes. in patients with multivessel disease, as recent studies326 have shown simi­
lar mortality rates between PCI and CABG. However, in patients with
left main coronary artery disease (LMCAD) participating in the EXCEL
4.4.3. Additional considerations—complete vs. partial trial (Evaluation of XIENCE versus Coronary Artery Bypass Surgery
revascularization for Effectiveness of Left Main Revascularization), the STS risk models
Complete revascularization treating all vessels and lesions causing is­ were effective in predicting outcomes for CABG but not for PCI regard­
chaemia is preferable to incomplete revascularization.757 However, ing peri-operative mortality and renal failure.777 Interestingly, the STS
various factors may influence the implementation of complete revascu­ stroke risk model was more successful in predicting outcomes for PCI
larization, including clinical setting, comorbidities, anatomical and pro­ compared with CABG. More accurate risk prediction tools are needed
cedural features, advanced age, or frailty.758,759 Furthermore, to precisely estimate adverse events following LMCAD revascularization
whether the focus of complete revascularization should be anatomical through both CABG and PCI. Other clinical factors, such as frailty or liver
or functional is still unclear. In the PCI group of the SYNTAX (SYNergy cirrhosis,778,779 have been found to increase post-operative mortality and
Between PCI with TAXUS and Cardiac Surgery) trial, a higher residual should be taken into consideration during the decision-making
SYNTAX score, indicating incomplete anatomical revascularization, process.780
was associated with a higher mortality rate.760 However, the outcomes The SYNTAX score was prospectively developed as an angiographic
of anatomically incomplete but functionally complete revascularization stratification tool to quantify the complexity of coronary lesions in pa­
by PCI were superior to those of anatomically complete revasculariza­ tients with left main coronary artery (LMCA) or multivessel CAD and
tion.49,308,761 Of note, recent studies suggest that significant levels of re­ aid clinicians in deciding the most appropriate revascularization proced­
sidual ischaemia can persist despite good angiographic results after ure during Heart Team discussions.781 However, there are limitations
complex coronary stenting. to the SYNTAX score. Firstly, it is a time-consuming score requiring
Individual reports suggest that incomplete revascularization is asso­ a detailed angiographic evaluation of each lesion. Secondly, there is con­
ciated with increased mortality compared with complete revasculariza­ siderable inter-observer variability in its calculation, with a poor correl­
tion.762 In addition, unintended incomplete revascularization appears to ation between core lab and operator-calculated SYNTAX score being
be a surrogate marker of anatomic complexity and comorbidities, pre­ reported.779 Thirdly, it is an anatomical score that quantifies obstruc­
disposing to more rapid native CAD progression.760,763 An important tion but not plaque burden. Fourthly, it does not take physiological
predictor of anatomical incomplete revascularization by PCI is the pres­ and clinical variables into account.782 Machine learning may streamline
ence of chronic total occlusion. Randomized trials have shown im­ this process, generating prognostic information that is superior to clin­
provements of angina and QoL with PCI for chronic total occlusion ical risk scores783 and relevant to clinical decision-making.
lesions,764,765 but failed to show any reduction of mortality risk and The SYNTAX II score was developed by combining clinical and ana­
MI rates.764–767 tomic features to better guide decision-making between CABG and PCI
Among patients with high-risk multivessel CAD, incomplete anatom­ than the anatomical SYNTAX score.784,785 Although the usefulness of
ical revascularization is reported more frequently among those treated the SYNTAX II score was demonstrated in several studies,785–787 it
3472 ESC Guidelines

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

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sessment of the severity and extent of CAD. It has been proven effect­ osis involved distal bifurcation in 75% of the patients, and the absence of
ive in predicting mortality after PCI and assessing the completeness of a bifurcation lesion had no impact on mortality.730 True bifurcation left
revascularization,790 but it is not as commonly used as the SYNTAX main lesions (defined as Medina type 1,1,1 or 0,1,1 both main vessel and
score. side vessel >50% narrowed with reference diameters ≥2.75 mm),805
which frequently require 2-stent techniques, have worse clinical out­
4.4.5. Choice of myocardial revascularization comes than non-bifurcation lesions.806–808 Despite excellent results
modality after LMCA bifurcation stenting on angiography, 13% of patients still
Both myocardial revascularization modalities—PCI and CABG—can experience residual ischaemia in turn associated with higher long-
achieve excellent outcomes, although through different mechanisms, term cardiovascular mortality.809 Using intracoronary imaging guidance
in appropriately selected patients when GDMT alone fails. to optimize stent expansion and prevent side-branch jailing may im­
prove outcomes after PCI of bifurcation LMCA lesions.810
Operator experience may significantly affect the outcomes after
4.4.5.1. Patients with single- or two-vessel coronary artery disease
interventional procedures. A single-centre study from China found
Randomized evidence and subgroup analyses of trials enrolling a broad­ that operators with a higher volume of procedures performed
er spectrum of CAD patients showed similar performance of PCI and (>15 per year) had better outcomes for unprotected LMCA PCI.811
CABG in patients with one- or two-vessel CAD, with or without the An analysis of the outcome data from the British Cardiovascular
involvement of the proximal LAD in terms of death, stroke, or Intervention Society’s national PCI database on 6724 patients who under­
MI.791–797 In patients with complex LAD lesions, the need for late re­ went PCI for unprotected LMCA between 2012 and 2014 revealed that
peat revascularization is higher after PCI than CABG,797 but CABG is the volume of procedures performed by the operator plays a significant
a more invasive procedure with inherent risks, longer hospital stay role in determining the outcome after PCI of unprotected LMCA.812
and healing.758 Although high-volume operators undertook PCIs on patients with greater
comorbid burden and CAD complexity compared with low-volume op­
4.4.5.2. Patients with unprotected left main coronary artery disease erators, 12-month survival was lower in high-volume operators [odds
Over the past two decades, several trials have compared PCI and ratio (OR) 0.54; 95% CI, 0.39–0.73]. A close association between oper­
CABG in patients with multivessel CAD, with or without unprotected ator volume and superior 12-month survival was observed (P < .001).
LMCAD326,728,730,798–801 (Table 9). The patients who were included in A 2022 Joint ESC/EACTS (European Association for Cardio-
these trials had to meet the eligibility criteria for both CABG or PCI at Thoracic Surgery) task force recently reviewed the 2018 guideline
an acceptable risk level, and their coronary anatomy had to allow com­ recommendations on the revascularization of LMCAD in low-risk
plete revascularization through both procedures. However, due to the surgical patients with suitable anatomy for PCI or CABG.782 The
strict inclusion criteria, only a small percentage of eligible patients (ran­ review was mainly based on the recent individual-patient data
ging from 6% to 40%) were enrolled in these trials.798,801 The strict in­ meta-analysis730 of the long-term outcomes after CABG or PCI for
clusion criteria resulted in enrolling a relatively young population with a LMCAD from four randomized clinical trials that included 4394 pa­
lower burden of comorbidities (mean age <66 years).728,730,798,801 tients between March 2005 and January 2015. The review confirmed
Meta-analyses of RCTs have shown that the risk of death is similar for that for stable CCS patients with left main stem disease requiring re­
both CABG and PCI for LMCAD, even for patients with a high vascularization, both treatment options are clinically reasonable based
SYNTAX score, up to 5–10 years after the intervention. However, on patient preference, expertise availability, and local operator vo­
the risk of stroke is higher with CABG, while the risk of spontaneous lumes. It was proposed that revascularization with CABG be the re­
MI is higher with PCI.728,730,800,802–804 In the individual-patient data commended option, with suggested class I and LOE A, while PCI be
meta-analysis of four randomized trials,730 mortality over 5 years was overall recommended with a suggested class IIa and LOE A. The pre­
not statistically different between patients treated with PCI or with sent guidelines confirm that, among patients suitable for both revascu­
CABG [11.2% vs. 10.2%; HR 1.10 (95% CI, 0.91–1.32); P = .33; absolute larization modalities, CABG is recommended as the overall preferred
risk difference of 0.9%]. A similar treatment effect was observed for revascularization mode over PCI, given the lower risk of spontaneous
10-year mortality [22.4% vs. 20.4%; HR 1.10 (95% CI, 0.93–1.29); MI and repeat revascularization.730,782 The present guidelines also ac­
P = .25; absolute risk difference 2.0%]. Spontaneous MI was lower in knowledge that in patients with significant LMCA stenosis of low com­
the CABG arm [6.2% vs. 2.6%; HR 2.35 (95% CI, 1.71–3.23); plexity (SYNTAX score ≤22), in whom PCI can provide equivalent
P < .0001; absolute risk difference 3.5%], while the results of periproce­ completeness of revascularization to that of CABG, PCI is recom­
dural MI differed according to whether the analysis used the protocol mended as an alternative to CABG, given its lower invasiveness and
definition or the universal definition of MI (available for only two non-inferior survival.718,728,730,802,813
ESC Guidelines

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

Study Study population Primary endpoint Follow-up Findings

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

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3474 ESC Guidelines

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;

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HR 1.44; 95% CI, 1.20–1.77; P = .0001).728 4.4.5.5. Virtual percutaneous coronary intervention: combination of
In the FREEDOM trial (Strategies for Multivessel Revascularization in coronary pressure mapping with coronary anatomy for percutaneous
Patients with Diabetes), 1900 patients with diabetes and multivessel coronary intervention planning
disease without LMCAD were randomized to CABG vs. PCI (using There is increasing evidence on the impact of post-PCI FFR/iFR/QFR on
first-generation DES). Long-term results at a median follow-up dur­ outcomes after PCI.828–833 A quarter of these patients have residual is­
ation of 3.8 years [interquartile range (IQR) 2.5–4.9 years] showed chaemia (FFR < 0.80 or iFR ≤ 0.89) after angiographically successful
higher all-cause mortality in the PCI group vs. CABG group (24.3% PCI, with circa 80% of cases attributable to focal lesions not identified
vs. 18.3%; P = .01).801 Out of all the centres that participated in the by angiography alone.830 One randomized trial reported that post-PCI
study, only 25 agreed to participate in the FREEDOM extended follow- iFR/FFR can be improved by additional intracoronary intervention, in­
up, and therefore, only 49.6% of patients in the study were followed up cluding post-dilatation or additional stent implantation, but remains
for up to 8 years thus limiting statistical power. The all-cause mortality ≤0.80 in 18% of cases.829 Preliminary results demonstrate that the
rate among the FREEDOM follow-up patients was not significantly dif­ combination of invasive coronary pressure mapping by iFR pullback
ferent between those who underwent PCI and CABG procedures or QFR mapping superimposed on the anatomical information of
(23.7% vs. 18.7%; HR 1.32; 95% CI, 0.97–1.79; P = .076). In multivariable ICA accurately predict the post-PCI coronary pressure for any combin­
analysis, a significant interaction emerged between patient age and long- ation of stent location and stent length, as part of a ‘virtual PCI’ ap­
term survival benefit of CABG surgery. Patients younger than the proach,348,834 and allows modification of the procedural planning in
median age at study entry (63.3 years) preferentially derived benefit about 30% of cases.835 The AQVA (Angio-based Quantitative Flow
from CABG; mortality among patients ≤63.3 years old was 20.7% Ratio Virtual PCI Versus Conventional Angio-guided PCI in the
(PCI) vs. 10.2% (CABG); mortality among patients >63.3 years old Achievement of an Optimal Post-PCI QFR) trial (n = 300) demonstrated
was 26.3% vs. 27.6% (P = .01 for interaction).824 that a strategy of QFR/ICA-based virtual PCI was associated with a higher
rate of post-PCI QFR ≥0.90 compared with angiography-based PCI
4.4.5.4. Impact of coronary pressure guidance on multivessel coronary (93.4% vs. 84.9%, P = .009).836 The DEFINE GPS trial (NCT04451044)
artery disease patients undergoing percutaneous coronary intervention is currently investigating the clinical benefit of pre-procedural coronary
pressure mapping with iFR pullback and ‘virtual PCI’ to clarify this issue
Consistently higher rates of repeat revascularizations following PCI
further and improve post-PCI clinical outcomes.
compared with CABG have been shown in clinical trials involving multi­
Virtual PCI can be conducted by combining anatomical information
vessel CAD patients, with significant impacts on outcomes.825 With the
from CCTA with that of FFR-CT. FFR-CT/CCTA-based virtual PCI has
use of modern DESs, the rate of repeat revascularization after PCI has
two theoretical advantages over ICA-based virtual PCI: (i) it does not re­
declined.725,795,802,820 FFR guidance during PCI leads to lower revascu­
quire invasive investigation, and (ii) it provides information on vessel wall/
larization rates compared with angiography-guided PCI, with fewer
plaque composition.837 FFR-CT/CCTA-based virtual PCI has been
stents placed in the FFR group.826
shown to accurately predict post-PCI FFR838 and to modify PCI proced­
In the FAME 3 trial, 1500 patients with three-vessel CAD not involv­
ural planning in 31% of lesions and 45% of patients.839 The Precise
ing the LMCA were randomly assigned to PCI with second-generation
Procedural and PCI Plan (P4) trial (NCT05253677) is currently investi­
DESs (durable polymer zotarolimus-eluting stents) guided by FFR, or to
gating the clinical benefit of iFR-based virtual PCI to clarify this issue fur­
CABG.326 At 1-year follow-up, the incidence of the composite primary
ther and improve post-PCI clinical outcomes.
endpoint, MACCE [major adverse cardiac (death from any cause, MI,
stroke, or repeat revascularization) or cerebrovascular events], was
10.6% among patients assigned to FFR-guided PCI and 6.9% among 4.4.5.6. Impact of intracoronary imaging guidance on multivessel
patients assigned to CABG surgery (HR 1.5; 95% CI, 1.1–2.2), findings coronary artery disease patients undergoing percutaneous coronary
that were not consistent with non-inferiority (P = .35 for non- intervention
inferiority).326 At 3-year follow-up, there still was a significantly higher Three large randomized trials have recently investigated the clinical
rate of MACCE for PCI than for CABG (18.6% vs. 12.5%; HR 1.5; 95% benefit of intracoronary imaging during ‘complex’ PCI. One trial,
CI, 1.2–2.0; P = .002), consistent with the 1-year follow-up results. RENOVATE-COMPLEX PCI,840 mainly investigated the benefit of
However, there was no difference in the incidence of the composite IVUS (74% IVUS, 26% OCT), while the two others, OCTOBER810
of death, MI, or stroke after FFR-guided PCI compared with CABG and ILUMIEN IV,841 investigated the benefit of OCT. Importantly,
(12.0% vs. 9.2%; HR 1.3; 95% CI, 0.98–1.83; P = .07). The rates of death while OCTOBER (true bifurcation lesions) and RENOVATE-
(4.1% vs. 3.9%; HR 1.0; 95% CI, 0.6–1.7; P = .88) and stroke (1.6% vs. COMPLEX PCI (including true bifurcation lesions, long lesions,
ESC Guidelines 3475

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

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(10.1% vs. 14.1%; HR 0.70; 95% CI, 0.50–0.98; P = .035).810 In ILUMIEN to reduce adverse events, including improved survival, there is growing
IV, OCT-guided PCI failed to decrease the rate of the primary efficacy interest in PROMs.852 Patients are not only interested in knowing how
endpoint of target-vessel failure, defined as death from cardiac causes, recommended treatment impacts prognosis but also their QoL in the
target-vessel MI, or ischaemia-driven target-vessel revascularization way they perceive it.853 The patient’s right to decline the treatment op­
(7.4% vs. 8.2%; HR 0.90; 95% CI, 0.67–1.19; P = .45), while the incidence tion recommended by the Heart Team must be respected. Patient re­
of definite/probable stent thrombosis was significantly reduced by OCT fusal of a recommended treatment should be acknowledged in a
guidance vs. angiography guidance (0.5% vs. 1.4%; HR 0.36; 95% CI, written document after the patient has received the necessary informa­
0.14–0.91; P = .02).841 tion. In this case, the Heart Team may offer the patient an alternative
treatment option.
4.4.5.7. Hybrid revascularization in multivessel coronary artery The multidisciplinary Heart Team, on site or with partner institutions
disease patients (Hub-Spoke institutions)—comprising clinical or non-invasive cardiolo­
gists, cardiac surgeons and interventional cardiologists, as well as anaes­
Arterial grafting with left internal mammary artery (LIMA) to the LAD
thetists or other specialists and healthcare professionals, if deemed
system and multiple arterial grafting reduces the risk of graft occlusion,
necessary—should provide a balanced multidisciplinary decision-
thus increasing the longevity of revascularization efficacy after
making process.
CABG.842,843 Hybrid revascularization of multivessel CAD with minim­
Transparency in informed consent is critical, particularly when treat­
ally invasive direct coronary artery bypass (MIDCAB)-LAD plus PCI of
ment options are debated. Complex cases, such as patients with CAD
the remaining arteries may represent an alternative option. Hybrid off-
of high anatomic complexity and significant non-cardiac comorbidities,
pump revascularization seems a suitable option for patients at moder­
should be discussed in the Heart Team, taking into consideration other
ate-to-high risk for surgery by avoiding the use of cardiopulmonary by­
characteristics not always included in traditional databases, such as
pass. Despite this attractive concept, the frequency of hybrid
frailty. Heart Team/guideline discordance is common in complex
revascularizations remains extremely modest, with about 0.1% of sur­
CAD patients undergoing revascularization, especially in elderly pa­
gical revascularizations.844 Few data are available comparing hybrid re­
tients, those with complex coronary disease, and those treated at cen­
vascularization vs. conventional CABG or PCI. Large registry data
tres without cardiac surgery service. These patients have a higher risk of
report higher rates of bleeding, renal failure, MI, and HF with hybrid re­
mid-term mortality.854
vascularization compared with PCI alone,844 while a very small rando­
In all cases, it is necessary to allow sufficient time to assess all available
mized trial reported similar clinical outcomes at long-term
information and clearly explain and discuss the findings with each patient.
follow-up.845 It seems challenging to perform larger RCTs to investigate
The rationale for a decision and consensus on the optimal revasculariza­
this question. The recent National Heart, Lung, and Blood
tion treatment should be documented on the patient’s chart. While the
Institute-funded Hybrid Trial (Hybrid Coronary Revascularization
Heart Team decision is mainly driven by long-term survival benefits with
Trial; NCT03089398) was prematurely discontinued due to slow en­
a certain modality of revascularization, patient’s preferences must be
rolment, with only 200 patients in 5 years.
respected.853,855,856

4.4.6. Patient–physician shared decision-making to


perform and select revascularization modality 4.4.7. Institutional protocols, clinical pathways, and
Shared decision-making between patients and healthcare professionals, quality of care
based on patient-centred care, is considered a paramount process in Institutional protocols, developed by the Heart Team and aligned with
defining the appropriate therapeutic pathway. Essential aspects of the current guidelines, should delineate specific anatomical and func­
shared decision-making are: a complete and accurate explanation of tional criteria of disease complexity and specific clinical subsets of pa­
the disease; presentation and description of therapeutic options; dis­ tient’ risk for cardiac surgery or intervention that may or may not be
cussion of potential risks, benefits, and impact on QoL for each proced­ treated ad hoc. These protocols should be incorporated into clinical
ure; considering patient preferences and goals; and carefully explaining pathways, with regular meetings to assess the applied indications for
each step of the post-procedural course and follow-up. Poor shared myocardial revascularization and monitor the safety and effectiveness
decision-making is associated with worse physical and mental out­ of the procedures, ensuring the quality of delivered patient care.
comes, lower adherence to therapy, and an increased number of emer­ Collaborative protocols are necessary when cardiac surgery isn’t avail­
gency department visits.846–848 Shared decision-making and family able on site, and remote Heart Team meetings should be established.
3476 ESC Guidelines

Recommendation Table 22 — Recommendations for revascularization in patients with chronic coronary syndrome (see
also Evidence Table 22)

Recommendations Classa Levelb

Informed and shared decisions


It is recommended that patients scheduled for percutaneous or surgical revascularization receive complete information about the benefits,
I C
risks, therapeutic consequences, and alternatives to revascularization, as part of shared clinical decision-making.847,848,857
For complex clinical cases, to define the optimal treatment strategy, in particular when CABG and PCI hold the same level of
recommendation, a Heart Team discussion is recommended, including representatives from interventional cardiology, cardiac surgery,
I C
non-interventional cardiology, and other specialties if indicated, aimed at selecting the most appropriate treatment to improve patient
outcomes and quality of life.

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It is recommended to communicate the proposal of the Heart Team in a balanced way using language that the patient can understand. I C
It is recommended that the decision for revascularization and its modality be patient-centred, considering patient preferences, health
I C
literacy, cultural circumstances, and social support.849–851
It is recommended that the Heart Team (on site or with a partner institution) develop institutional protocols to implement the appropriate
I C
revascularization strategy in accordance with current guidelines.855,856,858
Revascularization to improve outcomes

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.

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Recommendation Table 23 — Recommendations for mode of revascularization in patients with chronic coronary syn­
drome (see also Evidence Table 23)

Anatomically and clinically based recommendations for revascularization in CCS Classa Levelb

Left main disease


In CCS patients at low surgical riskc with significant left main coronary stenosis, CABG:
• is recommended over medical therapy alone to improve survival;719 I A
• is recommended as the overall preferred revascularization mode over PCI, given the lower risk of spontaneous myocardial infarction and
I A
repeat revascularization.728,730,782
In CCS patients with significant left main coronary stenosis of low complexity (SYNTAX score ≤22), in whom PCI can provide equivalent
completeness of revascularization to that of CABG, PCI is recommended as an alternative to CABG, given its lower invasiveness and I A
non-inferior survival. 718,728,730,802,813
In CCS patients with significant left main coronary stenosis of intermediate complexity (SYNTAX score 23–32), in whom PCI can provide
equivalent completeness of revascularization to that of CABG, PCI should be considered, given its lower invasiveness and non-inferior IIa A
survival.718,728,730,802,805,809,813,820,822
Left main with multivessel diseased
In CCS patients at low surgical risk with suitable anatomy, CABG is recommended over medical therapy alone to improve survival.718,719,870 I A
In CCS patients at high surgical risk, PCI may be considered over medical therapy alone.728,813 IIb B
Multivessel diseased and diabetes
In CCS patients with significant multivessel disease and diabetes, with insufficient response to guideline-directed medical therapy, CABG is
I A
recommended over medical therapy alone and over PCI to improve symptoms and outcomes.801,824,871–874
In CCS patients at very high surgical risk, PCI should be considered over medical therapy alone to reduce symptoms and adverse
IIa B
outcomes.55,874
Three-vessel disease, without diabetes
In CCS patients with significant three-vessel disease, preserved LVEF, no diabetes, and insufficient response to guideline-directed medical
I A
therapy, CABG is recommended over medical therapy alone to improve symptoms, survival, and other outcomes.719,722,875
In CCS patients with preserved LVEF, no diabetes, insufficient response to guideline-directed medical therapy, and significant three-vessel
disease of low-to-intermediate anatomic complexity in whom PCI can provide similar completeness of revascularization to that of CABG, I A
PCI is recommended, given its lower invasiveness, and generally non-inferior survival.326,728,795,798,876
Single- or double-vessel disease involving the proximal LAD
In CCS patients with significant single- or double-vessel disease involving the proximal LAD and insufficient response to guideline-directed
I A
medical therapy, CABG or PCI is recommended over medical therapy alone to improve symptoms and outcomes.52,321,719,791,792
In CCS patients with complex significant single- or double-vessel disease involving the proximal LAD, less amenable to PCI, and insufficient
I B
response to guideline-directed medical therapy, CABG is recommended to improve symptoms and reduce revascularization rates.877–879
Single- or double-vessel disease not involving the proximal LAD
In symptomatic CCS patients with significant single- or double-vessel disease not involving the proximal LAD and with insufficient response
I B
© ESC 2024

to guideline-directed medical therapy, PCI is recommended to improve symptoms.50,321,732


In symptomatic CCS patients with significant single- or double-vessel disease not involving the proximal LAD and with insufficient response
IIb C
to guideline-directed medical therapy, not amenable to revascularization by PCI, CABG may be considered to improve symptoms.

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

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CAD.883–885 Moreover, patients with HFpEF may present MVA due to In patients with HFrEF, an ARB is recommended in patients who do
CMD.886 Indeed, CMD was observed in up to 75% of patients with not tolerate ACE-Is or ARNIs. Also, ivabradine should be considered in
HFpEF and was associated with worse diastolic relaxation velocities, addition to the four pillars. It can be used as an alternative to beta-
as well as higher filling pressures, and an increased risk of adverse blockers, when contraindicated or not tolerated, or as additional
events.883–885,887–890 Clinical assessment alone may under-estimate antianginal therapy in patients with sinus rhythm and heart rate of
the proportion of patients with obstructive or non-obstructive CAD, >70 b.p.m.899 Other antianginal drugs (e.g. amlodipine, felodipine, ni­
which can be found in up to 81% of HFpEF patients.887 corandil, trimetazidine, ranolazine, and nitrates) are effective for im­
Under-estimation of obstructive CAD leads to failure in identifying proving symptoms in patients with HFrEF.546,900–902 Diltiazem and
those patients who may benefit from revascularization. Conversely, verapamil increase HF-related events in patients with HFrEF and are
in ANOCA patients with preserved LV function, a CFR of <2 was in­ contraindicated.526 In patients with LVEF ≤35% of ischaemic aetiology,
dependently associated with diastolic dysfunction and future MACE, es­ an ICD is strongly recommended for primary prevention; in those with
pecially HFpEF events.891 This suggests that CMD and myocardial LVEF ≤35% and QRS >130 ms, CRT needs to be considered.526
stiffness may contribute to HFpEF pathophysiology.892 In HFpEF pa­ Further details regarding the management of patients with HFrEF are
tients, functional imaging should, therefore, be considered to detect reported in the 2021 ESC Guidelines for the diagnosis and treatment
CMD and epicardial CAD. of acute and chronic heart failure.526
Exercise or pharmacological stress echocardiography can be used In patients with HFpEF, in addition to diuretics for treating conges­
for the assessment of inducible ischaemia and can also help in the dif­ tion, SGLT2 inhibitors are now recommended for outcome improve­
ferential diagnosis of HFpEF.893,894 Stress SPECT or PET can also be ment.709 Additionally, beta-blockers, long-acting nitrates, CCBs,
used for the detection of inducible ischaemia. Non-invasive stress ivabradine, ranolazine, trimetazidine, nicorandil, and their combinations
testing can be difficult in patients with HF because of possible exer­ should be considered in patients with HFpEF and CAD for angina relief,
cise intolerance. CCTA is recommended in patients with HF with a but without foreseen benefits on HF and coronary endpoints.
low-to-intermediate pre-test likelihood of obstructive CAD and Low-dose rivaroxaban may be considered in patients with CAD and
those with equivocal non-invasive stress tests, provided there is no HF, LVEF of >40%, and sinus rhythm when at high risk of stroke and
contraindication to contrast administration.894–898 In HFpEF pa­ with low haemorrhagic risk.526,903,904
tients, perfusion PET should be considered for the detection of Evidence and recommendations for myocardial revascularization in
CMD.891 In patients with HFrEF and moderate-to-severe inducible patients with HF are reported in Section 4.4.2. Notably, patients with
myocardial ischaemia, surgical revascularization improved long-term advanced HF may be candidates for LV assistance devices and/or heart
survival.54,315 The results of the REVIVED-BCIS2 trial seem to transplantation.526
contradict these findings, as PCI did not reduce mortality or HF hos­ During of high-risk PCI for complex CAD905 in patients with HFrEF,
pitalization in patients with severe LV systolic dysfunction (LVEF ≤ mechanical cardiac support, such as the microaxial flow pump, may min­
35%) receiving optimal medical therapy.729 The same trial also re­ imize the risk of severe complications and provide haemodynamic stabil­
vealed that viability testing did not offer any prognostic benefit.755 ity, facilitating the achievement of complete revascularization.906,907

Recommendation Table 24 — Recommendations for management of chronic coronary syndrome patients with chronic
heart failure (see also Evidence Table 24)

Recommendations Classa Levelb

Managing CCS in heart failure patients


In HF patients with LVEF ≤35% in whom obstructive CAD is suspected, ICA is recommended with a view towards improving prognosis by
I B
CABG, taking into account the risk-to-benefit ratio of the procedures.54,729,749,908
In HF patients with LVEF >35% and suspected CCS with low or moderate (>5%–50%) pre-test likelihood of obstructive CAD, CCTA or
I C
functional imaging is recommended.887
In HF patients with LVEF >35% and suspected CCS with very high (>85%) pre-test likelihood of obstructive CAD, ICA (with FFR, iFR, or
I C
QFR when needed) is recommended.887
Continued
ESC Guidelines 3479

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

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I A
(HFmrEF) or HFpEF to reduce the risk of HF hospitalization or cardiovascular death.706,707
An ARB is recommended in symptomatic patients with CCS and HFrEF unable to tolerate an ACE-I or ARNI to reduce the risk of HF
I B
hospitalization and cardiovascular death.914
Sacubitril/valsartan is recommended as a replacement for an ACE-I or ARB in CCS patients with HFrEF to reduce the risk of HF
I B
hospitalization and of cardiovascular and all-cause death.693
Diuretics are recommended in CCS patients with HF and signs and/or symptoms of congestion to alleviate symptoms, improve exercise
I B
capacity, and reduce HF hospitalizations.915
An ICD is recommended to reduce the risk of sudden death and all-cause mortality in patients with symptomatic HF (NYHA class II–III) of
ischaemic aetiology (unless they have had an MI in the prior 40 days), and an LVEF ≤35% despite ≥3 months of optimized medical treatment, I A
provided they are expected to survive substantially longer than 1 year with good functional status.526,916
An ICD is recommended to reduce the risk of sudden death and all-cause mortality in patients who have recovered from a ventricular
arrhythmia causing haemodynamic instability, and who are expected to survive for >1 year with good functional status, in the absence of I A
reversible causes or unless the ventricular arrhythmia has occurred <48 h after an MI. 917–920
CRT is recommended for CCS patients with symptomatic HF, sinus rhythm, LVEF ≤35% despite GDMT, and a QRS duration ≥150 ms with
I A

© 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.

5.2. Angina/ischaemia with 5.2.2. Angina/ischaemia with non-obstructive


non-obstructive coronary arteries coronary arteries endotypes
Invasive functional coronary testing using Ach and adenosine in indivi­
5.2.1. Definition
duals suspected of CCS and with non-obstructive coronary arteries en­
A large proportion of patients undergoing coronary angiography be­
ables the differentiation of the following endotypes: (i) endothelial
cause of angina do not have obstructive epicardial coronary arteries
dysfunction; (ii) impaired vasodilation (low coronary flow reserve and/
(ANOCA). In these patients, the prevalence of demonstrable ischaemia
(INOCA) varies, depending on the stress test performed, between 10% or high microvascular resistance); (iii) epicardial vasospastic angina;
and 30% (Figure 12).926–928 Angina/ischaemia with non-obstructive cor­ (iv) microvascular vasospastic angina; (v) endotype combinations; (vi)
onary arteries is more frequent among women (approximately 50% to equivocal response, i.e. angina without fulfilling any endotype criteria.37,38
70%) than in men (30% to 50%) referred for ICA.7,929 The mismatch The prevalence of ANOCA and INOCA in relation to the presence of
between blood supply and myocardial oxygen demands leading to an­ the endotypes is shown in Figure 12. Angina with non-obstructive cor­
gina and ischaemia in ANOCA/INOCA may be caused by CMD and/ onary arteries occurs in up to 70% of the patients undergoing ICA, of
or epicardial coronary artery spasm.36 However, these conditions are whom 25% have documented ischaemia (INOCA). Among the patients
rarely correctly diagnosed, and, therefore, no tailored therapy is pre­ who are tested with Ach, 80% show endothelial dysfunction, 60% have
scribed for these patients. As a consequence, these patients continue MVA/VSA, and 50% have an impaired CFR and/or high microvascular
to experience recurrent angina with poor QoL, leading to repeated resistance.38,927,930,931 This emphasizes the importance of testing not
hospitalizations, unnecessary repeat coronary angiography, and adverse only patients with INOCA but also all patients with ANOCA to deter­
cardiovascular outcomes in the short and long term.36 mine the final endotype so that appropriate treatment can be initiated.
3480 ESC Guidelines

Ischaemiaª

50–70%
Obstructive CAD 30–50%

Detectable demand INOCA


25%
30–50%

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ischaemia
50–70%
Abnormal vasodilation 50%
Non-obstructive or (CFR <2.5)
ANOCA
no apparent CAD
Vasospasm on Ach 60%

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

5.2.2.2. Epicardial vasospastic angina 5.2.5.1. Non-invasive diagnosis


Vasospastic angina is the clinical manifestation of myocardial ischaemia Non-invasive tests (stress echocardiography, PET, perfusion CCTA, and
caused by abnormal vasoconstriction of one or more epicardial coron­ CMR) allow diagnosing ANOCA/INOCA by measuring the CFR.41
ary arteries leading to a dynamic coronary obstruction. Standardized These techniques have an excellent negative predictive value, but the
diagnostic criteria for VSA have been defined.73 Microvascular angina positive predictive value is an issue for most, as obstructive CAD needs
and epicardial VSA can co-exist, which is associated with a worse prog­ to be ruled out before the diagnosis of CMD can be made. Only hybrid
nosis.947 Concomitant endothelial dysfunction is prevalent in most pa­ techniques such as CCTA with perfusion and PET-CT offer combined
tients with INOCA with inducible coronary artery spasm and/or imaging of the epicardial coronary arteries and functional testing of the
impaired adenosine-mediated vasodilation.38,948 coronary microcirculation in a single test.6,964
The Japanese population has a higher prevalence of coronary vaso­
spasm than Western populations. In addition, the frequencies of mul­ 5.2.5.2. Invasive coronary functional testing
tiple coronary spasms (≥2 spastic arteries) by provocative testing in Invasive coronary functional testing consists of a comprehensive

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Japanese (24.3%) and Taiwanese populations (19.3%) are markedly evaluation of the coronary circulation in a single procedure by combin­
higher than those in Caucasians (7.5%).949–951 ing angiography, direct invasive assessment of the coronary haemo­
dynamics by intracoronary pressure and flow measurement either by
5.2.3. Clinical presentations thermodilution (bolus/continuous) or Doppler techniques, and
pharmacological vasomotor testing. Recently, a standardized protocol
Angina/ischaemia with non-obstructive coronary arteries is associated
has been proposed.36
with a wide variation in its clinical presentation, and symptom burden
may vary over time. Failure to diagnose epicardial obstructive CAD in
5.2.5.2.1. Basic coronary functional testing. Intracoronary pressure
a patient with documented ischaemia should stimulate a subsequent
and flow measurements allow assessment of the haemodynamic signifi­
search pathway to elucidate ANOCA/INOCA endotypes.
cance of focal or diffuse coronary lesions by measuring FFR or iFR (see
Section 3.3.3.2) and of microcirculatory function by measuring CFR and
5.2.4. Short- and long-term prognosis IMR, HMR, or MRR361,961 (see Section 3.3.3.3). Coronary microvascular
Symptoms of angina/ischaemia with non-obstructive coronary arteries dysfunction is characterized by decreased CFR and increased microvascu­
are associated with adverse physical, mental, and social health.952 lar vascular resistance (IMR, HMR, MRR). Decreased CFR can be due to
Angina/ischaemia with non-obstructive coronary arteries is associated structural or functional microvascular dysfunction.926,966 Functional CMD
with poor QoL, higher risk of disability, and a higher incidence of ad­ is characterized by increased resting flow linked to enhanced nitric oxide
verse events, including mortality, morbidity, healthcare costs, recurrent synthase (NOS) activity, whereas patients with structural CMD have
hospital readmissions and repeat coronary angiograms.300,953–958 The endothelial dysfunction, leading to a reduced increase of coronary blood
incidence of all-cause death and non-fatal MI in patients with non- flow during exercise.926,966
obstructive atherosclerosis was higher than in those with angiographi­ A Doppler-derived CFR of <2.5 in non-obstructive CAD indicates
cally normal epicardial vessels.298,959–961 Proven myocardial ischaemia an abnormal microcirculatory response corresponding to a
by stress echocardiography or nuclear imaging was associated with a thermodilution-derived CFR of <2.5.361,926,937,961 Of note, in assessing
higher incidence of events compared with ischaemia detected by exer­ coronary microvascular function, continuous thermodilution showed
cise electrocardiographic stress testing.958 There is a two- to four-fold significantly less variability than bolus thermodilution on repeated mea­
higher risk of adverse cardiovascular outcomes in patients with MVA surements.382 An increased IMR (≥25) indicates microvascular dysfunc­
diagnosed by PET or transthoracic echocardiography and a two-fold tion.380,381 For the Doppler-derived HMR, a value of >2.5 mmHg/cm/s
higher risk in patients with epicardial endothelial-dependent dysfunc­ indicates augmented microvascular resistance.42 Recently, MRR has
tion.300,962 Microvascular angina due to impaired CFR was associated been considered abnormal for values <2.7.364,967 Doppler flow analysis
with increased major adverse cardiac events and target-vessel failure allows assessment of the flow-recovery time after Ach administration
rates over a 5-year follow-up period.931 Vasospastic angina is associated as a sign of myocardial ischaemia, which is helpful in the diagnosis of pa­
with major adverse events, including sudden cardiac death, acute MI, tients with equivocal test results.968
and syncope.963 In a group of ANOCA/INOCA patients, abnormal
non-invasive testing did not allow the identification of patients with a 5.2.5.2.2. Coronary vasomotor testing. Epicardial and microvascular
higher risk of long-term cardiovascular events. However, adding intra­ endothelium-dependent vasodilation and vasospasm are tested by in­
coronary physiological assessment to non-invasive information allowed tracoronary bolus administration or graded infusion of Ach, first at a
the identification of patient subgroups with up to a four-fold difference low dose/grade to assess endothelial dysfunction at the microvascular
in long-term cardiovascular events.357 or epicardial level, and after that at a higher dose/grade to eventually in­
duce microvascular or/and epicardial coronary vasospasm. The LAD ar­
tery is usually preferred as the pre-specified target vessel reflecting its
5.2.5. Diagnosis subtended myocardial mass and coronary dominance. The left circum­
The presence of myocardial ischaemia on functional imaging without flex coronary artery is also tested if Ach is administered in the LMCA.
obstructive CAD on CCTA or ICA should always raise the clinical sus­ Additional studies in the right coronary artery may be appropriate if the
picion of ANOCA/INOCA. The diagnosis of ANOCA/INOCA is exclu­ initial tests are negative and clinical suspicion is high. As Ach exerts a
sively based on invasive functional evaluation of the coronary cholinergic effect on the atrioventricular node, significant bradycardia
microcirculation, given that no technique allows direct visualization of may ensue if infused especially in the right coronary artery or a domin­
the coronary microcirculation in vivo in humans. Several non-invasive ant left circumflex coronary artery. Bradycardia can be prevented by se­
and invasive tests have been established to assess the coronary micro­ lective infusion in the LAD, prophylactic ventricular pacing, or reduction
vascular function (Figure 13).6,41,964,965 of the concentration infused or of the injected dose. If necessary, the
3482 ESC Guidelines

Initial clinical evaluation

History including risk factors


Exclude non-cardiac symptoms CCS likely
Physical exam
ECG

Further cardiac evaluation

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Sequential testing (in any order):
Coronary microvascular
Functional imaging
dysfunction and/or
(PET, MRI, stress echo, SPECT)
Myocardial ischaemia
and
No apparent or
Anatomical imaging (CCTA)
non-obstructive CAD

[Obstructive CAD GDMT ± ICA] ANOCA/INOCA

Treat for ANOCA-INOCA and evaluate symptoms

Invasive coronary functional testing if persisting symptoms

FFR, iFR: distal pressure drop ~ focal or diffuse epicardial atherosclerosis?

Abnormal vasodilation? Abnormal vasoconstriction?


Endothelium- Endothelium-
Epicardial Microvascular
independent dependent
Adenosine
Ach Ach Ach
CFR <2.5
Low dose High dose High dose
IMR >25
2–20 µg i.c. 100–200 µg i.c. 100–200 µg i.c.
HMR >2.5

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- and adenosine-based vasoreactivity protocol

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

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Continuous Doppler flow monitoring,12-lead ECG and symptom monitoring

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

1 Lifestyle Nutrition Exercise


Coping with
stress

Weight Smoking
management cessation

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2 Risk
factors
Hypertension Dyslipidaemia
Diabetes
mellitus

3 Medical treatment based on


pathophysiological endotypes Endothelial dysfunction and
co-existing atherosclerosis

Consider statins and ACEi

Abnormal vasodilation Abnormal vasoconstriction

Microvascular Microvascular Epicardial


Beta-blocker CCB CCB
CCB 2nd CCB Nitrates
Ranolazine Nitrates Nicorandil
Trimetazidine
Ivabradine

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

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normal FFR/iFR at coronary arteriography) and I B ACE-I, angiotensin-converting enzyme inhibitor; ANOCA, angina with non-obstructive
poor quality of life, invasive coronary functional coronary arteries; CMR, cardiac magnetic resonance; ECG, electrocardiogram; FFR,
testing is recommended to identify potentially fractional flow reserve; iFR, instantaneous wave-free ratio; INOCA, ischaemia with
non-obstructive coronary arteries; LAD, left anterior descending; PET, positron emission
treatable endotypes and to improve symptoms and tomography.
a
quality of life, considering patient choices and Class of recommendation.
b
preferences.36,37,298,930,939,985 Level of evidence.

In persistently symptomatic patients with


documented or suspected ANOCA/INOCA,
transthoracic Doppler of the LAD, stress
5.3. Other specific patient groups
echocardiography, CMR, and PET may be IIb B
5.3.1. Older adults
considered for the non-invasive assessment
of coronary/myocardial flow reserve.44,231,233–
Between 2015 and 2050, the proportion of the world’s population
235,300,986,987 aged >60 years is set to nearly double to 22%. Ageing predisposes
patients to a high incidence and prevalence of CAD, in both men
Diagnostic tests for vasospastic angina and women. Typically, in the context of CVD, older patients are de­
In individuals with suspected vasospastic angina, a fined as those ≥75 years of age;1 it should be noted, however, that
resting 12-lead ECG recording during angina is I C such age cut-offs are relatively arbitrary, and biological age influences
recommended. this threshold in clinical practice. Clinical characteristics of the older
In patients with suspected vasospastic angina and adult population are heterogeneous, with frailty, comorbidity, cogni­
repetitive episodes of rest angina associated with tive function, and health-related QoL playing important roles in guid­
ST-segment changes that resolve with nitrates and/or ing clinical care and as predictors of adverse outcomes.1001–1005
calcium antagonists, invasive coronary functional I C Older patients often present with symptoms other than angina,
testing is recommended to confirm the diagnosis and which may delay the diagnosis of CCS.1004
to determine the severity of underlying
Ageing is often accompanied by both comorbidities and frailty, and
consequently leads to potentially excessive polypharmacy.531 In mak­
atherosclerotic disease.
ing treatment decisions, clinicians should take into account the lim­
In individuals with suspected vasospastic angina and
ited external validity of RCTs for older adults.36 Older people are
frequent symptoms, ambulatory ST-segment
IIa B often underrepresented in RCTs as a consequence of exclusion cri­
monitoring should be considered to identify
teria and under-recruitment,531,1006,1007 though they have been
ST-segment deviation during angina.192–194 shown to have a higher underlying risk for cardiovascular out­
Management of ANOCA/INOCA comes.1008 The treatment of CCS in older adults is complicated by
In symptomatic patients with ANOCA/INOCA, a higher vulnerability to complications for both conservative and in­
medical therapy based on coronary functional test vasive strategies, such as bleeding, renal failure, and neurological im­
IIa A pairments, all of which require special attention. The use of DES,
results should be considered to improve symptoms
and quality of life.298,977 compared with bare-metal stents, in combination with a short dur­
ation of DAPT, is associated with significant safety and efficacy ben­
For the management of endothelial dysfunction,
efits in older adults.1009 Frailty is of utmost importance in the clinical
ACE-I should be considered for symptom IIa B
decision-making.1010
control.988
For the management of microvascular angina
5.3.2. Sex differences in chronic coronary syndromes
associated with reduced coronary/myocardial blood
Ischaemic heart disease is the leading cause of mortality for women, yet
flow reserve, antianginal medications aiming at IIa B
they have been historically underrepresented in RCTs.1011–1013
preventing demand myocardial ischaemia should be
Differences in symptom presentation, in the accuracy of diagnostic tests
considered for symptom control.989,990
for obstructive CAD, and other factors that lead to differential triage,
Continued evaluation, or early treatment of women with myocardial ischaemia
3486 ESC Guidelines

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

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and CABG.1022 In a large-scale, individual-patient data pooled analysis orthostatic hypotension. In hypertensive patients with a history of
of contemporary PCI trials with early and new-generation DES, women MI, beta-blockers and RAS blockers are first-line treatments. In
had a higher risk of MACE and ischaemia-driven target-lesion revascu­ patients with symptomatic angina, beta-blockers and/or CCBs can
larization compared with men at 5 years following PCI.1021 However, be useful.1065
the excess risk after PCI among women can be primarily explained
by a greater burden of cardiovascular risk factors and comorbid condi­
tions.1023 Nevertheless, in a population undergoing contemporary PCI, 5.3.6. Atrial fibrillation
women and men had similar risks of death or new Q-wave MI at 2 years, Diagnostic assessment of CAD (CCTA and non-invasive tests) may be
but women faced a higher risk of bleeding and haemorrhagic stroke difficult in AF with a high ventricular rate. In patients with CAD and AF,
compared with men.1024 rhythm or rate control strategies may help improve symptoms of myo­
Women with signs and symptoms suggestive of cardiac ischaemia cardial ischaemia. Amiodarone or dronedarone are drugs of choice for
should be investigated carefully. The same guideline-recommended car­ rhythm control, as an alternative to catheter ablation, in patients with
diovascular preventive therapy should be provided to women and CAD and AF. Sotalol may also be considered. Beta-blockers, diltiazem,
men.1025 Hormone replacement therapy in post-menopausal women verapamil, or digoxin can be used for rate control depending on the
does not reduce the risk of ischaemic myocardial disease1015 and it LVEF.613 After PCI, combined anticoagulant and antiplatelet therapies
may come at the cost of other health risks,1026 which should be dis­ are needed. Recommendations on post-PCI antithrombotic therapy
cussed with the patient. in patients with AF and indication for OAC are detailed in Section
4.3.1.2.2 and Recommendation Table 17.613,621,659 Surgical ablation of
5.3.3. High bleeding-risk patients AF during isolated CABG seems to be safe and effective in improving
An HBR is increasingly present in many CCS patients referred for cor­ long-term outcomes.1066 Concomitant surgical closure of the left atrial
onary revascularization. The ARC-HBR consortium provided a consist­ appendage is recommended as an adjunct to oral anticoagulation in
ent definition of HBR for patients undergoing PCI. Patients are patients with AF undergoing cardiac surgery (e.g. CABG) to prevent is­
considered at HBR if at least one major or two minor criteria are chaemic stroke and thrombo-embolism (see the ESC 2024 Guidelines
met.590 In the context of PCI in HBR patients, short duration of for the management of Atrial Fibrillation).1067
DAPT (1–3 months) and PCI with a DES was beneficial in many recent
studies.1009,1027–1032
5.3.7. Valvular heart disease
In patients with valvular heart disease with a risk for associated CAD
5.3.4. Inflammatory rheumatic diseases
who require surgery or in whom a decision of a percutaneous or sur­
Patients with inflammatory rheumatic diseases have an increased risk of gical approach is still pending, ICA or CCTA is recommended to deter­
CVD compared with the general population.1033,1034 Accumulating evi­ mine the need for coronary revascularization.1068 Evidence of CAD in
dence has shown elevated cardiovascular morbidity and mortality in patients with valvular heart disease can drive to a surgical instead of a
other rheumatic and musculoskeletal diseases, including gout, vasculitis, percutaneous treatment of valvular heart disease. Invasive coronary
systemic sclerosis, myositis, mixed connective tissue disease, Sjögren angiography is recommended in patients with secondary mitral regur­
syndrome, SLE, and the antiphospholipid syndrome.1035–1044 gitation as this condition is frequently due to ischaemic LV dysfunc­
Some of these patient categories have two- to three-fold higher pre­ tion.1068 Routine stress testing to detect CAD associated with severe
valences of asymptomatic ASCVD compared with the general popula­ symptomatic valvular heart disease is not recommended because of
tion,1045–1051 which is linked to ASCVD outcomes.1049,1052–1054 Thus, low diagnostic value and potential risk. The usefulness of FFR or iFR
identification of ASCVD such as carotid artery plaque(s) may be consid­ in patients with valvular heart disease is not well established, and cau­
ered in ASCVD and CAD risk evaluation.1050,1055–1057 tion is warranted in interpreting these measurements, especially in
In patients with inflammatory rheumatic diseases and CCS, CVD the presence of aortic stenosis.1068 Beta-blockers need to be used
preventive medications such as lipid-lowering medications and antihy­ with caution in patients with aortic valve disease. Coronary artery by­
pertensive treatment should be used as in the general popula­ pass grafting is recommended in patients with a primary indication for
tion.1058–1062 aortic/mitral/tricuspid valve surgery and significant coronary stenosis.
Percutaneous coronary intervention should be considered in patients
5.3.5. Hypertension with a primary indication of transcatheter aortic valve implantation
Blood pressure lowering has been associated with favourable cardio­ or transcatheter mitral valve intervention and coronary artery diameter
vascular outcomes in patients regardless of the presence of CAD.1063 stenosis of >70% in proximal segments.1068
ESC Guidelines 3487

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

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related risk factor for the development of acute kidney injury (AKI), or minimally metabolized through CYP3A4.1082,1083 Ezetimibe has no in­
whereas DM increases the susceptibility to develop AKI. The most im­ teractions with CYP3A4 or ART.1081
portant measures to prevent AKI are using the lowest necessary total A clinical trial investigating the impact of PCSK9 inhibitor therapy on
dose of low-osmolality or iso-osmolality contrast medium and suffi­ lipids, inflammatory markers, and subclinical ASCVD (including non-
cient pre- and post-hydration.1073 calcified plaque and arterial inflammation) in HIV is currently being con­
CKD raises the risks associated with both CABG and PCI.316 The ducted [EPIC-HIV study (Effect of PCSK9 Inhibition on Cardiovascular
ISCHEMIA-CKD trial included patients with advanced CKD [estimated Risk in Treated HIV Infection), NCT03207945]. Future studies are
glomerular filtration rate (eGFR) of <30 mL/min/1.73 m2 or dialysis] needed to evaluate the impact of PCSK9 inhibition on clinical events
and CCS with moderate or severe myocardial ischaemia detected by in HIV.
stress test. An invasive strategy of ICA and PCI was not superior to con­
servative management in reducing the primary endpoint of death or 5.3.11. Socially and geographically diverse groups
non-fatal MI.1074
A lower socioeconomic status has implications of increased CVD mor­
In a propensity score-matched analysis involving 5920 CKD patients
tality1084 and poorer CVD risk factor profiles.1085 A multicohort study
(2960 pairs), PCI utilizing second-generation DES displayed a reduced
of 1.7 million adults followed up for any cause of death for an average of
risk of death, stroke, and repeat revascularization at 30 days when com­
13 years found that low socioeconomic status was associated with a
pared with CABG.1075 However, PCI was associated with a higher risk
2.1-year reduction in life expectancy between the ages 40 and 85
of repeat revascularization over the long term. Conversely, among pa­
years.1086 Education level, occupation, household income, health, dis­
tients on dialysis, the findings favoured CABG over PCI. Additionally, a
ability, and living conditions also contribute to socioeconomic status.
meta-analysis of 11 registries revealed lower rates of death, MI, and re­
There were different rates of decline in mortality from CVD in
peat revascularization with CABG in contrast to PCI among patients
Europe between the most and the least deprived.1087 It has been pro­
with eGFR of <60 mL/min/1.73 m².1076 Nevertheless, there is a notable
posed that on this basis, CVD could become a disease prevalently of the
absence of large RCTs comparing revascularization modalities among
lower socioeconomic groups by the mid-2020s.1088
CKD patients.
Black patients with diabetes have a higher hospitalization burden
with a concomitant disparity in comorbid presentation and outcome
5.3.9. Cancer compared with other patients with diabetes.1089 South Asian ethnicity,
Several cancer treatments are associated with an increased risk of CCS. even after adjustment for traditional risk factors, is associated with an
Spontaneous bleeding in ACS and CCS patients has been associated increased risk of coronary heart disease outcomes. This risk was great­
with subsequent cancer diagnosis.1077 A prompt evaluation of bleeding er than other studied racial/ethnic groups and second only to diabetes
may be useful to enable an early detection of cancer. The management in coronary heart disease risk prediction.1090
of CCS is similar in patients with and without cancer. However, deci­ Within a large prospective study, South Asian individuals had a
sions regarding coronary revascularization should be undertaken by a substantially higher risk of ASCVD than individuals of European
multidisciplinary team. The approach should be individualized and based ancestry.1091 South Asians have a more diffuse pattern with multives­
on life expectancy, additional comorbidities such as thrombocyto­ sel involvement. However, less is known about other morphological
paenia, increased thrombosis, or bleeding risk, and potential interac­ characteristics, such as atherosclerotic plaque composition and
tions between drugs used in CCS management and anticancer coronary diameter in South Asian populations. Despite a similar cor­
therapy.1078,1079 onary calcification burden, higher non-calcified plaque contribution,
elevated thrombosis, and inflammatory markers likely contribute to
the disease pattern. Although the current evidence on the role of cor­
5.3.10. Optimal treatment of patients with human onary vessel size remains inconsistent, smaller diameters in South
immunodeficiency virus Asians could play a potential role in the higher disease prevalence.1092
Patients with human immunodeficiency virus (HIV) have longer life expect­ Individuals of South Asian descent have a high prevalence of CYP2C19
ancy than before due to effective antiretroviral therapy (ART), but are loss-of-function alleles (poor metabolizers: 13% vs. 2.4% in European
twice as likely to develop CVD compared with the general population.1080 populations),1093 which are associated with reduced efficacy of
The long-term CVD outcomes in patients with HIV may change, given the clopidogrel.
3488 ESC Guidelines

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

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effect on clinical outcomes remains uncertain.1103
revascularization decisions based on symptoms, Information on CAC can be used to guide risk-factor management, and
extent of ischaemia, frailty, life expectancy, I C initiate lipid-lowering and antithrombotic treatment in patients with esti­
comorbidities, and patient preferences are mated future risk around treatment decision thresholds.1104 To date, two
recommended. randomized screening studies have indicated that statin therapy impacts
Sex outcomes when guided by CACS in younger patients with high
Similar guideline-directed cardiovascular preventive
CACS.1105,1106 Coronary artery calcium score could potentially guide
I C not only risk-factor management but also primary prophylaxis with as­
therapy is recommended in women and men.
pirin, but randomized studies are lacking.1107 Importantly, opportunistic
Systemic post-menopausal hormone therapy is not
screening of the burden of calcified atherosclerotic CAD can be accurate­
recommended in women with CCS, given the lack of
III A ly accessed with non-ECG-gated chest CT performed for other rea­
cardiovascular benefit and an increased risk of
1026,1094,1095
sons.17,1108 Reporting the visual interpretation of the coronary plaque
thrombo-embolic complications. burden according to a simple score with four categories (none, mild,
High bleeding risk moderate, severe) is recommended.1108–1110 However, there is no
Bleeding risk assessment is recommended using the current evidence to support further diagnostic imaging in asymptomatic
PRECISE-DAPT score, the qualitative ARC-HBR tool I B individuals on the basis of presence of calcified plaque alone.
or other, validated methods.589,590 Carotid ultrasound,1111 aortic pulse wave velocity, arterial augmen­
tation index, and ankle–brachial index are other modalities to improve
HIV
the prediction of future CVD events. However, evidence is less exten­
Attention to interaction between antiretroviral sive for these modalities compared with CACS.
treatment and statins is recommended in patients I B
Recommendation Table 27 — Recommendations for
with HIV.1096
screening for coronary artery disease in asymptomatic
Socioeconomic, geographical, and under-investigated groups individuals (see also Evidence Table 27)
Continued targeted efforts are recommended:
Recommendations Classa Levelb
• to increase delivery of safe and effective cardiac
care to all CCS patients, especially those of lower Opportunistic screening of healthy individuals for
socioeconomic classes; and I C cardiovascular risk factors and to estimate the risk of
© ESC 2024

• 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

unavailable or not feasible to detect atherosclerotic IIb B


Study, CCTA was performed in randomly selected individuals from disease and to improve risk classification around
the general population.1097 In the 25 182 individuals without known
treatment decision thresholds.1111
CAD, atherosclerotic plaque was present in 42% of participants.
Plaque was more common in older individuals and in males (males CACS, coronary artery calcium scoring; CT, computed tomography; SCORE2, Systematic
Coronary Risk Estimation 2; SCORE-OP, Systematic Coronary Risk Estimation 2–Older
50–54 vs. 60–64 years old: 41% vs. 69%, and females 50–54 vs.
Persons.
60–64 years old: 19% vs. 40%). Obstructive coronary stenosis was pre­ a
Class of recommendation.
sent in 5% of participants. In the PESA study (Progression of Early b
Level of evidence.
ESC Guidelines 3489

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

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Communication is essential to support patients’ understanding, adher­ Unfortunately, depression and psychological stress are often unrecog­
ence, and engagement in decision-making.1114 Good communication nized due to a lack of systematic screening using validated tools.1129 For
requires providing information at an appropriate level, active listening, anxiety, a recent meta-analysis involving 16 studies reported a preva­
assessing patient understanding, and determining patient perspectives lence in post-MI between 5.5% and 58%, and a 27% greater risk of
and priorities. A meta-analysis summarizing a total of 127 studies of poor clinical outcomes in anxious patients compared with those with­
communication training concluded that patients were 19% more likely out anxiety.1130 In contrast, in a 15-year follow-up of 1109 patients with
to be non-adherent when physicians had poor communication, and CCS moderate anxiety did not increase the risk of cardiovascular
12% more likely to be non-adherent when their physicians had not events compared with low anxiety levels. Patients on a high but de­
received communication training.1115 Communication and shared creasing anxiety trajectory had an HR of 1.72 (95% CI, 1.11–2.68) for
decision-making can be particularly challenging when patients have co­ cardiovascular events.1131 Treatment of psychosocial factors, depres­
morbidities, low health literacy, language differences, cognitive impair­ sion, and anxiety with pharmacotherapy, psychotherapy, and/or exer­
ment, depression, or anxiety, and when evidence for treatment is less cise can improve symptoms and QoL in some patients, and there is
robust. some evidence for improvement in cardiac outcomes.472,1132–1134
Patient reported outcome measures can be useful to improve as­ Stepped care (initial therapy based on patient preferences) and a com­
sessment and communication of symptoms, function, and QoL, and bination of therapies may be more efficacious.1129,1135 First-line treat­
can highlight problems that may not have been previously discussed. ment with selective serotonin reuptake inhibitors (recommended in
Under- and overestimation of symptoms can lead to a lack of or in­ CCS) or non-pharmacological interventions and a multidisciplinary col­
appropriate treatment.1116,1117 The routine use of PROMs in clinical laborative approach are recommended.1129
practice is hampered by the challenge of interpretation of scores and
their integration into routine clinical processes.1116 6.2. Adherence and persistence
Although quality of communication can be improved through train­
Earlier analyses reported that adherence to long-term therapies in
ing, meta-analyses have not found evidence of significant impact on out­
chronic conditions in Western countries averaged 50% and was lower
comes such as physical or mental health, satisfaction, QoL, or specific
in developing countries.1136 Pooled prevalence of non-adherence from
risk factors in patients with cancer, diabetes, and hyperten­
a recent meta-analysis of eight studies (n = 3904 patients with multimor­
sion.1115,1118,1119 Structured tools and a flexible range of resources (in­
bidity) was 42.63% (95% CI, 34%–51%).1137 Data from the ESC-EORP
cluding videos, workbooks, and health-literacy materials) that provide
EUROASPIRE V registry indicate that many CCS patients still have un­
individualized information and decision aids can be adjuncts to better
healthy lifestyles in terms of smoking, diet, and sedentary behaviour.1138
communication and shared decision-making.443 A systematic review
Poor adherence and persistence (duration of time in which medications
of 17 RCTs of tools to support decision-making in severe illness con­
and healthy behaviours are continued) have a profound effect on effect­
cluded that they improved patient knowledge and readiness to make
ive management, patient safety, and outcomes. The World Health
decisions.1120
Organization (WHO) advocates training in adherence for healthcare
Communicating the risk of future CVD events and how risk can be
professionals, a multidisciplinary approach, support rather than blame,
lowered through lifestyle and medications is best presented using visual
tailored interventions based on illness-related demands for each patient,
or imaging approaches, natural frequencies rather than percentages,
and viewing adherence as a dynamic process.1136
and positive framing (focusing on risk-reduction benefits).1121–1125
The five dimensions of adherence are patient, disease, provider, ther­
Relative risk reduction is more persuasive than either absolute risk re­
apy, and healthcare system (Figure 16).1139 Therefore, identifying pa­
duction or the number needed to treat.1122 The use of risk prediction
tients at risk of non-adherence, addressing all five dimensions,
estimates may have an impact on individuals’ health when their informa­
developing a multidisciplinary pathway to support sustained adherence,
tion (i.e. predicted risk stratification) changes individuals’ behaviour,
and a follow-up strategy are essential steps.1139
self-management decisions, and even treatment decisions.446 This en­
ables patients to gain insights into their cardiovascular prognosis and
to empower them to take part in the decision-making process.1126 6.2.1. Adherence to healthy lifestyle behaviours
This approach may increase self-motivation for therapy adherence Different strategies may help improve long-term adherence to a
and lifestyle changes, including changes in nutrition, physical activity, healthy lifestyle (Figure 17).
relaxation training, weight management, and participation in smoking
cessation programmes for resistant smokers.446 Previous unsuccessful 6.2.1.1. Why behavioural changes are difficult
attempts to change to a healthy lifestyle or take guideline- Making changes to unhealthy lifestyles and controlling risk factors can
recommended treatment can be addressed to set realistic goals.446 be a daunting task as these are usually longstanding habits and patterns
3490 ESC Guidelines

Actions on the five dimensions of adherence to therapy

Health care Healthcare


Disease Patient Therapy
provider system

Provide additional
Make access to
Provide correct, psychosocial
Be aware of care
timely and support in Prefer poly-pill

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low adherence easy, rapid,
sufficient distress, treatment
predictors efficient and
information depression and
affordable
anxiety

Intensify/increase Implement
Consider graded Improve
Optimize health use of community-based
therapy in communication
literacy mHealth and programs/
multimorbidity skills
e-Health interventions

Empower the Encourage social


Optimize the Consider
Prevent frequent patient. media coverage
patient’s complexity and
change in therapy Increase the to assist
perception workload for
(especially in patient's therapeutic
of risk patient
multimorbidity) self-efficacy adherence

Prevent Involve informal


clinical inertia caregivers

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

Good communication, Multidisciplinary


structured tools and behavioural
visual images Cardiovascular risk reduction interventions

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H ealthy diet

E xercise

A chieve normal weight

L eave smoking

T ake control of cholesterol and


blood pressure
H andle alcohol consumption

Y ield to stress management

mHealth Fixed dose


and telehealth combination pills
and simplified
medication regimens

PROMs and feedback

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

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time. Of note, the implementation of digital and mHealth should
not be at odds with a less digital-oriented care for those unfamiliar for adherence to pharmacological therapy.1146 A pilot trial of 135
with new technologies (e.g. elderly people). non-adherent patients with hypertension and/or diabetes randomized
patients to a highly tailored digital intervention (text messages and
interactive voice response) or usual care for 12 weeks. Medication
6.2.1.4. How to assess adherence
adherence was significantly improved in the intervention group, along
Addressing lifestyle behaviour and medication adherence in a non- with improvements in systolic BP and HbA1c, compared with the con­
judgemental way at clinical encounters is important to identify barriers trol group.1165
and offer tailored solutions to promote healthier actions. The encoun­
ter can be useful to review patient self-monitoring records (digital or
written), accelerometer data, and diaries, or validated questionnaires Recommendation Table 28 — Recommendations for
on physical activity. adherence to medical therapy and lifestyle changes
(see also Evidence Table 28)

6.2.2. Adherence to medical therapy Recommendations Classa Levelb


Guideline-directed medications are key to the effective management of
Mobile health interventions (e.g. using text messages,
CCS and prevention of subsequent cardiovascular events, but depend­
ent on patient adherence and persistence with treatment. Despite ro­ apps, wearable devices) are recommended to
I A
bust evidence of benefits in terms of mortality and morbidity,1150 improve patient adherence to healthy lifestyles and
adherence remains suboptimal.1151 Although adherence is usually high­ medical therapy.491,1148,1149,1154,1156,1164
er in RCTs, approximately 28% of CCS patients in the ISCHEMIA trial Behavioural interventions are recommended to
I B
were non-adherent to prescribed medications at baseline.1152 improve adherence.491,1140,1144
Non-adherence was associated with significantly worse health status Simplifying medication regimens (e.g. using
regardless of randomization to the conservative or invasive strat­ fixed-dose drug combinations) is recommended to
I B
egy.1152 Medication adherence can be intentional or unintentional, increase patient adherence to
and can be adversely affected by polypharmacy, complex drug regi­ medications.1139,1163,1166
mens, high cost, and side effects.

© 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

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The worse prognosis of persisting angina, however, was only observed changes, warrant adherence to the 2023 ESC Guidelines for the man­
in patients with a previous MI.408 agement of patients with acute coronary syndromes. 65 Current med­
ical therapy and lifestyle measures for risk-factor control can be
6.3.1. Risk factors for recurrent coronary artery maintained or optimized for asymptomatic patients.
Step 2: If CCS patients develop new or worsening angina or HF
disease events
symptoms, arrhythmias or ECG changes, further cardiac evaluation is
Patients with established ASCVD are at high risk of recurrent events
crucial, especially if symptoms persist despite optimized GDMT.
and different risk factors have been identified. The REACH registry de­
Recurrent CAD event risk should be assessed based on symptoms,
monstrated that, in addition to the traditional risk factors, the burden of
progression of risk factors, and resting ECG changes.
disease, lack of treatment, and geographical location are all related to an
Echocardiography may be performed to assess LV function, cardiac di­
increased risk of cardiovascular morbidity and mortality in CCS patients
mensions, and valvular abnormalities. Exercise ECG testing may be con­
and validated a risk score that allows estimation of the risk for
sidered to confirm symptoms and evaluate functional capacity if it alters
MACE.1167 Using data from stabilized CCS patients from 27
patient management. However, routine functional testing is not recom­
European countries included in the EUROASPIRE IV and V surveys, a
mended for asymptomatic post-PCI patients, as it has not been shown
new risk model with an online risk calculator to predict recurrent
to improve outcomes compared with standard care after 2 years.1173
CVD events in patients under the age of 75 years was developed and
Step 3: CCS patients with persistent symptoms at low exercise levels
externally validated in the SWEDEHEART registry.1168,1169 This model
despite optimized GDMT or unexpectedly reduced LV function, espe­
indicated that the risk of recurrent MACE is mainly driven by comorbid­
cially with regional contraction abnormalities, need further cardiac test­
ities including diabetes, renal insufficiency, and dyslipidaemia, but also
ing to detect the progression of CAD and assess the event risk.
symptoms of depression and anxiety. A study of patients with estab­
For patients with known non-obstructive CAD, CCTA can help
lished CAD from the UK Biobank confirmed the value of classical risk
detect new obstructive stenoses, evaluate atherosclerotic disease pro­
factors, lifestyle, and sociodemographic factors in predicting recurrent
gression, and identify high-risk plaque features, while functional imaging
MACE.1170 In addition, it was found that high genetic predisposition to
is reasonable for detecting myocardial ischaemia and guiding further
CAD, low HDL-C, and younger age at first ACS event most strongly
management. In patients with ANOCA/INOCA and stratified medical
predicted the recurrence risk. A polygenic risk score, when added to
therapy, CCTA can be useful to detect new or progressing CAD.
the Framingham score, improved predictions of events in a large popu­
For patients with obstructive CAD or previous cardiac events, non-
lation in the USA.1171 Although the prediction of recurrent MACE has
invasive functional imaging is the preferred method to detect and quan­
been refined, it must be emphasized that the predictive power of the
tify myocardial ischaemia and/or scar. However, in patients with severe­
different risk factors is weak and that a significant part of recurrent
ly limiting angina and known severe ischaemia on functional testing or
MACE in CCS patients remains unexplained. Furthermore, the models
high-risk CAD on CCTA, direct referral to ICA for revascularization
do not incorporate information on LV function, HF, concomitant valvu­
is preferred due to the very high risk of recurrent CAD events.
lar disease, atherosclerotic disease burden in other vascular beds, or the
Although CCTA can detect CABG graft patency and exclude in-stent
severity of existing CAD.1172 While risk factors for recurrent cardiac
restenosis (ISR) in broad lumen arteries, functional imaging is preferred
events have been established, no clinical studies have tested predefined
for assessing patients with prior revascularization because of the high
clinical pathways for long-term follow-up of various types of CCS pa­
frequency of extensive CAD in these patients.1174–1176
tients. As a result, the long-term clinical follow-up of CCS patients is
Step 4: In all patients with recurrent or worsening anginal symptoms,
primarily empirical, based on good clinical judgement, and on the
lifestyle modifications, risk-factor management, and GDMT should be
same criteria used in the initial diagnostic process to define high risk
intensified before considering further interventions. For patients with
of adverse events (Section 3.3.5 and Figure 18).
significant inducible myocardial ischaemia or high-risk CAD, and persist­
ent anginal symptoms despite lifestyle modifications and intensified
6.3.2. Organization of long-term follow-up GDMT, repeat coronary revascularization may be necessary to alleviate
When scheduling long-term follow-up for CCS patients with recurring symptoms and improve prognosis. For patients with prior CABG ex­
or worsening angina, it is important to consider factors such as patient periencing stable symptoms, it’s important to optimize GDMT when­
type, the presence of risk factors, availability of diagnostic techniques, ever possible. If frequent angina persists despite GDMT optimization,
and cost-effectiveness following regional or national healthcare policies. ICA or CCTA can assist in guiding treatment decisions.1177–1179
Different CCS phenotypes may develop or recur during long-term When symptoms are uncertain, functional testing may help clarify the
follow-up, altering the follow-up needed over time. The intervals and presence and extent of myocardial ischaemia.
3494 ESC Guidelines

Recurrent or
new CAD event?

6 1

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More frequent follow-up or Symptom severity and frequency?
new diagnostic or
therapeutic action needed?
2

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

Recommendation Table 29 — Recommendations for 6.4.1. Percutaneous coronary intervention failure


diagnosis of disease progression in patients with estab­ Stent thrombosis and ISR are the most frequent reasons for PCI failure.
lished chronic coronary syndrome (see also Evidence
Stent thrombosis occurs infrequently and is multifactorial. Anatomical
Table 29)
and mechanical factors, as well as lack of adherence or hyporesponsive­
Recommendations Classa Levelb ness to antiplatelet treatment, are frequently the reasons behind
this.1182,1185 The majority of patients with stent thrombosis present
Asymptomatic patients with established chronic coronary with ACS and should be treated according to the 2023 ESC
syndromes Guidelines for the management of patients with acute coronary syn­
Regardless of symptoms, periodic visits (e.g. annual) dromes.65 Urgent ICA to confirm diagnosis and treatment is indicated.
to a general practitioner or cardiovascular healthcare After restoration of coronary flow, intracoronary imaging to identify
professional are recommended to evaluate
mechanical failure should be performed. Repeated DES implantation
is indicated in case of stent fracture or collapse and residual edge dissec­
cardiovascular risk factor control and to assess I C

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tions, while high-pressure non-compliant balloon dilation is indicated in
changes in risk status, disease status, and
case of stent under-expansion or malapposition.
comorbidities that may require lifestyle, medical, or
In-stent restenosis results as a response to vessel wall injury
procedural interventions.
(neointimal hyperplasia) or neoatherosclerosis in the stented segment
Symptomatic patients with established chronic coronary of the coronary artery. Although significantly less frequent than after
syndromes bare-metal stent implantation, the incidence of clinical in-DES restenosis
Reassessment of CAD status is recommended in is up to 10% within the first 10 years after DES implantation1182 and re­
patients with deteriorating LV systolic function that mains the most frequent cause of PCI failure. The clinical presentation
I C of ISR is mostly CCS, with 20% ACS, and the remaining asymptomatic.
cannot be attributed to a reversible cause (e.g.
longstanding tachycardia or myocarditis). The indication to treat ISR is like that for native CAD. Radiological stent
Risk stratification is recommended in patients with
enhancement and intracoronary imaging are encouraged to determine
the ISR mechanism. PCI treatment of ISR should be focused on the
new or worsening symptoms, preferably using stress I C
stenotic segment. Lesion preparation (ultra-high pressure balloon dila­
imaging.
tion, intravascular lithotripsy, rotation atherectomy) and correction of
In patients with symptoms refractory to medical
mechanical issues are required.1182 Thereafter, drug-coated balloon
treatment or at high risk of adverse events, invasive
angioplasty or DES implantation is necessary.1186,1187 Drug-eluting bal­
coronary angiography (with FFR/iFR when necessary) loon angioplasty and repeat stenting with DES were equally effective
I C
is recommended for risk stratification and for and safe in treating bare-metal ISR, but drug-coated balloon angioplasty
possible revascularization aimed at improving was less effective than repeat paclitaxel DES implantation in treating
symptoms and prognosis. DES ISR.1186 However, at 10-year follow-up there was no difference
In CCS patients with symptoms refractory to medical in clinical endpoints between drug-coated balloon angioplasty and
treatment, and who have had previous coronary DES implantation, whereas both were more effective than balloon
© ESC 2024

revascularization, CCTA should be considered to IIa B angioplasty in preventing target-lesion revascularization.1187


evaluate bypass graft or stent patency (for stents ≥3 Everolimus DES was associated with better long-term outcomes than
mm).1174–1176 drug-coated balloons.1188

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,

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73%–80%) of patients and an improvement of ≥2 CCS class in 40%
(95% CI, 35%–46%) of patients.1200 The Coronary Sinus Reducer
Recommendation Table 30 — Recommendations for
treatment of revascularization failure (see also Objective Impact on Symptoms, MRI Ischaemia and Microvascular
Evidence Table 30) Resistance (ORBITA-COSMIC) trial, a small proof-of-concept RCT,
found no evidence that implantation of a coronary sinus reducer im­
Recommendations Classa Levelb proved transmural myocardial perfusion, but it was associated with im­
proved angina symptoms compared with placebo. 1201
DES is recommended over drug-coated balloons for
I A There are several ongoing RCTs evaluating the use of coronary
treatment of in-DES restenosis.1186–1188 sinus reducer in ANOCA/INOCA, such as COronary SInus Reducer
LIMA is indicated as the conduit of choice for redo for the Treatment of Refractory Microvascular Angina (COSIMA;
CABG in patients in whom the LIMA was not used I B NCT04606459), and the Efficacy of the COronary SInus Reducer in
previously.1195 Patients with Refractory Angina II (COSIRA-II; NCT05102019).
Redo CABG should be considered for patients A variety of new pharmacological approaches is becoming available
IIa B
© ESC 2024

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

coronary sinus constriction may be considered to


tional anti-ischaemic targets have been exhausted, novel therapies can improve symptoms, in experienced centres.1199–
be ranked by mechanism of action, promotion of collateral growth, 1201,1204

transmural redistribution of blood flow, and neuromodulation of the


ANOCA, angina with non-obstructive coronary arteries; CAD, coronary artery disease;
cardiac pain syndrome.
INOCA, ischaemia with non-obstructive coronary arteries.
Considering the chronic nature of the disease and according to risk– a
Class of recommendation.
benefit assessments, among the currently available options, the most b
Level of evidence.
ESC Guidelines 3497

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

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ance, despite optimal medical therapies, and without right ventricular toms refractory to GDMT, angina at a low level of exercise, and/or
dysfunction. Heart transplantation is recommended for patients with high event risk.
advanced HF, refractory to medical/device therapy, and who do not • When ICA is indicated, it is recommended to evaluate the functional
have absolute contraindications. Early evaluation for mechanical circu­ severity of ‘intermediate’ stenoses by invasive functional testing (FFR,
latory supports or heart transplantation is currently suggested also in iFR) before revascularization.
patients with mild symptoms [i.e. New York Heart Association • Computed FFR based on the 3D reconstruction of ICA is emerging as
(NYHA) class II] and high-risk profile (i.e. LVEF of <20%, recurrent a valuable alternative to wire-based coronary pressure to evaluate
HF events, hypotension, intolerance to medical therapy, worsening or­ the functional severity of ‘intermediate’ stenoses.
gan failure, ventricular arrhythmias/ICD shock).526 • The use of imaging guidance is now recommended when performing
An ICD is recommended in patients with ischaemic cardiomyopathy complex PCI.
and LVEF of <35% or who have recovered from ventricular arrhyth­ • A single antiplatelet agent, aspirin or clopidogrel, is generally recom­
mias.526 Frequent, symptomatic ventricular arrhythmias in ICD recipi­ mended long term in CCS patients with obstructive atherosclerotic
ents should be treated medically with either beta-blockers or CAD.
amiodarone. In patients with CCS who develop ventricular fibrillation • For high thrombotic-risk CCS patients, long-term therapy with two
or polymorphic ventricular tachycardia, assessment for myocardial is­ antithrombotic agents is reasonable, as long as bleeding risk is not
chaemia should be performed without delay. In patients with CAD in high.
whom sustained monomorphic ventricular tachycardia recurs while • For CCS patients with sinus rhythm, DAPT is recommended at the
on amiodarone treatment, catheter ablation is recommended over time of PCI and for 1 to 6 month(s), according to high or low bleeding
the escalation of antiarrhythmic drugs.1207 Percutaneous treatment risk, respectively.
of secondary mitral regurgitation in patients with advanced HF may • For CCS patients requiring OAC and undergoing PCI, OAC and
be considered to improve symptoms.526 Treatment of secondary tri­ DAPT (aspirin and clopidogrel) for 1 to 4 weeks, followed by
cuspid regurgitation in advanced stages of disease was, until recently, OAC and clopidogrel for up to 6 months in patients not at high is­
supported by limited evidence.1208 Percutaneous tricuspid transcath­ chaemic risk and up to 12 months in patients at high ischaemic risk,
eter edge-to-edge repair was found to reduce significantly severe tri­ followed by OAC alone should be considered.
cuspid regurgitation and was associated with improvements in QoL • In CCS patients with functionally significant multivessel CAD, current
at 1 year.1209 evidence indicates benefit of myocardial revascularization over
GDMT alone for symptom improvement, prevention of spontaneous
MI, and reduction of cardiovascular mortality at long follow-up.
• Among CCS patients with normal LV function and no significant left
7. Key messages main or proximal LAD lesions, current evidence indicates that myo­
cardial revascularization over GDMT alone does not prolong overall
• Symptoms of myocardial ischaemia due to obstructive atherosclerot­ survival.
ic CAD overlap with those of CMD or vasospasm. • Among CCS patients with reduced LV function and ischaemic cardio­
• Similar guideline-directed cardiovascular preventive therapy is re­ myopathy, current evidence indicates that surgical revascularization
commended in women and men in spite of the sex differences in compared with GDMT alone prolongs overall survival at very long
the clinical presentation. follow-up.
• Inclusion of risk factors to classic pre-test likelihood models of ob­ • Among patients with complex multivessel CAD without LMCAD,
structive atherosclerotic CAD improves the identification of patients particularly in the presence of diabetes, who are clinically and ana­
with very low (≤5%) pre-test likelihood of obstructive CAD in whom tomically suitable for both revascularization modalities, current evi­
deferral of diagnostic testing should be considered. dence indicates longer overall survival after CABG than PCI.
• CACS is a reliable ‘simple’ test to modify the pre-test likelihood of • Among patients who are clinically and anatomically suitable for both
atherosclerotic obstructive CAD. revascularization modalities, a greater need for repeat revasculariza­
• First-line diagnostic testing of suspected CCS should be done by non- tion after PCI than surgery, independently of multivessel CAD ana­
invasive anatomic or functional imaging. tomical severity, has been consistently reported with current
• Selection of the initial non-invasive diagnostic test should be based on surgical and stent technology.
the pre-test likelihood of obstructive CAD, other patient character­ • Lifestyle and risk-factor modification combined with disease-
istics that influence the performance of non-invasive tests, and local modifying and antianginal medications are cornerstones in the man­
expertise and availability. agement of CCS.
3498 ESC Guidelines

• 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

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• Research on effective methods to support specific healthy lifestyle should ideally be tested in a well-designed, adequately powered
behaviours, and sustain medication and healthy lifestyle adherence randomized trial.
over time, is needed. • Some meta-analyses have reported a reduction in cardiac mortality
• More research is needed on improving the implementation of health- without a reduction in all-cause mortality. There is a need to clarify
promoting policies and practices in the workplace setting. the impact of revascularization in CCS patients on cardiovascular
and non-cardiovascular mortality.
• Complete revascularization of multivessel CAD by PCI can be
8. Gaps in evidence achieved as a single procedure (index PCI) or as staged PCI. In the
setting of CCS, the value of staged PCI and the optimal interval be­
• It remains unclear if screening for subclinical obstructive CAD in the tween interventions needs to be evaluated.
general population is useful.1106,1210 Further large-scale studies are • Whether CABG surgery and PCI are comparable among patients
needed to investigate the prognostic benefit of screening and treating with ischaemic cardiomyopathy and HFrEF in the modern era of
asymptomatic CCS in the general population, preferably involving dif­ HF treatment needs to be evaluated.
ferent geographical regions. Optimal screening options remain to be • Various imaging techniques, such as low-dose DSE, CMR, and PET/
determined for specific groups at high risk (e.g. asymptomatic indivi­ CT, can identify hibernating myocardium with the potential for func­
duals with diagnosed diabetes for longer than 10 years). tional recovery after revascularization.1211 Further randomized trials
• Most studies assessing diagnostic strategies in individuals with symp­ with contemporary, well-defined modalities and strict adherence to
toms suspected of CCS were performed in populations with a mod­ protocol are needed to clarify the clinical benefits (if any) of viability
erate (>15%–50%) pre-test clinical likelihood of obstructive CAD. testing.
Further studies are needed to determine the optimal and most cost- • Residual ischaemia post-PCI, as determined by FFR/iFR, reflects re­
effective diagnostic strategy in individuals with a low (>5%–15%) pre- maining atherosclerotic lesions and/or suboptimal PCI results, but
test clinical likelihood of obstructive CAD. also persistent or worsening microvascular dysfunction. Whether
• The current diagnosis of ANOCA/INOCA and its different endo­ post-PCI FFR/iFR is a ‘modifiable’ risk factor remains to be proved.
types is mainly determined by invasive coronary functional testing.36 • Among patients suitable for off-pump CABG with complex multives­
Further research is needed to refine and assess non-invasive diagnos­ sel CAD but no LMCAD, the impact of hybrid revascularization on
tic imaging modalities for CMD. Currently available and new outcomes, including peri-operative complications other than
non-invasive imaging modalities should be calibrated against invasive MACE, needs more extensive investigation. Data on the optimal
testing, allowing the use of their measurements interchangeably. time interval between MIDCAB-LIMA and PCI are lacking.
• The role of antithrombotic therapy in CCS patients with ANOCA/ • Whether the decision process based on a multidisciplinary Heart
INOCA remains to be established. Team leads to better outcomes than standard institutional practice
• Because of how evidence has accrued over time, there is no clear evi­ remains to be investigated.
dence about the existence of first- and second-line antianginal ther­ • The medical therapy of ANOCA/INOCA is largely empirical.
apy. It is unclear whether long-acting nitrates, ranolazine, nicorandil, Therefore, prospective randomized clinical trials are needed to de­
ivabradine, trimetazidine, or any of their combinations improve an­ termine the efficacy of antianginal treatments in improving symptoms
ginal symptoms more than beta-blockers or CCBs. and outcomes for the different endotypes.
• The optimal type and duration of DAPT is still uncertain in some sub­ • Research on effective methods to support healthy lifestyle beha­
sets of patients (e.g. patients with prior revascularization who might viours, and sustain medication and healthy lifestyle adherence over
benefit from shorter or longer DAPT strategies). time, is needed. In addition, more research is needed on improving
• The long-term benefit of beta-blocker therapy in post-MI patients the implementation of health-promoting policies and practices in
without reduced EF remains to be elucidated. the workplace setting.
• In view of the reported positive impact of low-dose colchicine in pa­ • There is a need for further evidence on the effectiveness of neuro­
tients with CCS in reducing MI, stroke, and revascularization, future modulation, spinal cord stimulation, therapeutic angiogenesis, and
studies should identify whether certain patient subgroups (e.g. those coronary sinus occlusion in patients who suffer from refractory
with elevated biomarker levels) might derive even greater clinical angina, despite guideline-directed medical treatment and
benefit from this treatment. revascularization.
ESC Guidelines 3499

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.

Table 10 ‘What to do’ and ‘What not to do’

Recommendations Classa Levelb

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.

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If clinical or ECG assessment suggests ACS rather than CCS, immediate referral to the emergency department and/or repeated
measurement of blood troponin, preferably using high-sensitivity or ultrasensitive assays, to rule out acute myocardial injury is I B
recommended.
A resting 12-lead ECG is recommended in all individuals reporting chest pain (unless an obvious non-cardiac cause is identified), particularly
I C
during, or immediately after, an episode suggestive of myocardial ischaemia.
Using ST-segment deviations during supraventricular tachyarrhythmias, particularly during re-entrant atrioventricular tachycardias, per se,
III B
as reliable evidence of obstructive CAD, is not recommended.
Recommendations for basic biochemistry in the initial diagnostic management of individuals with suspected chronic coronary syndrome
The following blood tests are recommended in all individuals to refine risk stratification, diagnose comorbidities, and guide treatment:
• lipid profile including LDL-C; I A
• full blood count (including haemoglobin); I B
• creatinine with estimation of renal function; I B
• glycaemic status with HbA1c and/or fasting plasma glucose. I B
In patients with suspected CCS, it is recommended to assess thyroid function at least once. I B
Recommendations for estimating, adjusting and reclassifying the likelihood of obstructive atherosclerotic coronary artery disease in the
initial diagnostic management of individuals with suspected chronic coronary syndrome
It is recommended to estimate the pre-test likelihood of obstructive epicardial CAD using the Risk Factor-weighted Clinical Likelihood
I B
model.
It is recommended to use additional clinical data (e.g. examination of peripheral arteries, resting ECG, resting echocardiography, presence of
vascular calcifications on previously performed imaging tests) to adjust the estimate yielded by the Risk Factor-weighted Clinical Likelihood I C
model.
Recommendations for resting transthoracic ultrasound and cardiac magnetic resonance imaging in the initial diagnostic management of
individuals with suspected chronic coronary syndrome
A resting transthoracic echocardiogram is recommended:
• to measure LVEF, volumes and diastolic function;
• identify regional wall motion abnormalities;
I B
• identify non-coronary cardiac disease (e.g. hypertrophy, cardiomyopathy, valve disease, pericardial effusion);
• assess right ventricular function and estimate systolic pulmonary artery pressure;
to refine risk stratification and guide treatment.
Recommendations for the use of exercise ECG in the initial diagnostic management of individuals with suspected chronic coronary
syndrome
Exercise ECG is recommended in selected patients for the assessment of exercise tolerance, symptoms, arrhythmias, BP response, and
I C
event risk.
Exercise ECG is not recommended for diagnostic purposes in patients with ≥0.1 mV ST-segment depression on resting ECG, left bundle
III C
branch block or who are being treated with digitalis.
In individuals with a low or moderate (>5–50%) pre-test likelihood of obstructive CAD, an exercise ECG is not recommended to rule out
III C
CAD if CCTA or functional imaging tests are available.
Recommendations for ambulatory ECG monitoring in the initial diagnostic management of individuals with suspected chronic coronary
syndrome
Ambulatory ECG monitoring is recommended in subjects with chest pain and suspected arrhythmias. I C
Continued
3500 ESC Guidelines

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

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I B
recommended to diagnose myocardial ischaemia and to estimate the risk of MACE.
During stress echocardiography, when two or more contiguous myocardial segments are not visualized, it is recommended to use
I B
commercially available intravenous ultrasound contrast agents (microbubbles) to improve diagnostic accuracy.
During stress echocardiography, myocardial perfusion using commercially available intravenous ultrasound contrast agents (microbubbles)
I B
is recommended to improve diagnostic accuracy and to refine risk stratification beyond wall motion.
Recommendations for non-invasive functional myocardial imaging tests in the initial diagnostic management of individuals with
suspected chronic coronary syndrome—resting and stress single-photon emission computed tomography/positron emission
tomography—cardiac magnetic resonance imaging, 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 SPECT or, preferably,
PET myocardial perfusion imaging is recommended to:
• diagnose and quantify myocardial ischaemia and/or scar; I B
• estimate the risk of MACE;
• quantify myocardial blood flow (PET).
In patients selected for PET or SPECT myocardial perfusion imaging, it is recommended to measure CACS from unenhanced chest CT
I B
imaging (used for attenuation correction) to improve detection of both non-obstructive and obstructive CAD.
In individuals with suspected CCS and moderate or high (>15%–85%) pre-test likelihood of obstructive CAD, CMR perfusion imaging is
I B
recommended to diagnose and quantify myocardial ischaemia and/or scar and estimate the risk of MACE.
Recommendations for invasive coronary angiography in individuals with suspected obstructive coronary artery disease
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.
Invasive coronary angiography is recommended to diagnose CAD in individuals with a very high (>85%) clinical likelihood of disease, severe
I C
symptoms refractory to guideline-directed medical therapy, angina at a low level of exercise, and/or high event risk.
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.
Recommendations for functional assessment of epicardial artery stenosis severity during invasive coronary angiography to guide
revascularization
During ICA, selective assessment of functional severity of intermediate diameter stenoses is recommended to guide the decision to
revascularize, using the following tools:
• FFR/iFR (significant ≤0.8 or ≤0.89, respectively); I A
• QFR (significant ≤0.8). I B
Systematic and routine wire-based coronary pressure assessment of all coronary vessels is not recommended. III A
Recommendations for selection of initial diagnostic tests in individuals with suspected chronic coronary syndrome
It is recommended to select the initial non-invasive diagnostic test based on pre-test likelihood of obstructive CAD, other patient
I C
characteristics that influence the performance of non-invasive tests, and local expertise and availability.
In symptomatic patients in whom the pre-test likelihood of obstructive CAD by clinical assessment is >5%, CCTA or non-invasive functional
I B
imaging for myocardial ischaemia is recommended as the initial diagnostic test.
To rule out obstructive CAD in individuals with low or moderate (>5%–50%) pre-test likelihood, CCTA is recommended as the preferred
I B
diagnostic modality.
CCTA is recommended in individuals with low or moderate (>5%–50%) pre-test likelihood if functional imaging for myocardial ischaemia is
I B
not diagnostic.
Continued
ESC Guidelines 3501

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:

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⚬ Area of ischaemia ≥10% of the LV myocardium;
• Stress echocardiography:
I B
⚬ ≥3 of 16 segments with stress-induced hypokinesia or akinesia;
• stress CMR:
⚬ ≥2 of 16 segments with stress perfusion defects or ≥3 dobutamine-induced dysfunctional segments;
• CCTA:
⚬ left main disease with ≥50% stenosis, three-vessel disease with ≥70 stenosis, or two-vessel disease with ≥70% stenosis, including the
proximal LAD or one-vessel disease of the proximal LAD with ≥70% stenosis and FFR-CT ≤0.8.
In individuals at high risk of adverse events (regardless of symptoms), ICA—complemented by invasive functional measures (FFR/iFR) when
appropriate—is recommended, with the aim of refining risk stratification and improving symptoms and cardiovascular outcomes by I A
revascularization.
Recommendations for cardiovascular risk reduction, lifestyle changes, and exercise interventions in patients with established chronic
coronary syndrome
An informed discussion on CVD risk and treatment benefits tailored to individual patient needs is recommended. I C
Multidisciplinary behavioural approaches to help patients achieve healthy lifestyles, in addition to appropriate pharmacological management,
I A
are recommended.
A multidisciplinary exercise-based programme to improve cardiovascular risk profile and reduce cardiovascular mortality is recommended. I A
Aerobic physical activity of at least 150–300 min per week of moderate intensity or 75–150 min per week of vigorous intensity and
I B
reduction in sedentary time are recommended.
Recommendations for antianginal drugs in patients with chronic coronary syndrome
It is recommended to tailor the selection of antianginal drugs to the patient’s characteristics, comorbidities, concomitant medications,
I C
treatment tolerability, and underlying pathophysiology of angina, also considering local drug availability and cost.
Short-acting nitrates are recommended for immediate relief of angina. I B
Initial treatment with beta-blockers and/or CCBs to control heart rate and symptoms is recommended for most patients with CCS. 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
Nitrates are not recommended in patients with hypertrophic cardiomyopathy or in co-administration with phosphodiesterase inhibitors. III B
Recommendations for antithrombotic therapy in patients with chronic coronary syndrome
In CCS patients with a prior MI or remote PCI, aspirin 75–100 mg daily is recommended lifelong after an initial period of DAPT. 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.
After CABG, aspirin 75–100 mg daily is recommended lifelong. 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.
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.
In patients at high bleeding risk, but not at high ischaemic risk, it is recommended to discontinue DAPT 1–3 months after PCI and to
I A
continue with single antiplatelet therapy.
In CCS patients with a long-term indication for OAC, an AF therapeutic dose of VKA alone or, preferably, of DOAC alone (unless
I B
contraindicated) is recommended lifelong.
In patients with an indication for OAC who undergo PCI, initial low-dose aspirin once daily is recommended (loading dose when not on
I C
maintenance dose) in addition to OAC and clopidogrel.
Continued
3502 ESC Guidelines

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

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antithrombotic therapy (antiplatelet therapy and/or OAC).
Recommendations for lipid-lowering drugs in patients with chronic coronary syndrome
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
A high-intensity statin up to the highest tolerated dose to reach the LDL-C goals is recommended for all patients with CCS. I A
If a patient’s goal is not achieved with the maximum tolerated dose of statin, combination with ezetimibe is recommended. I B
For patients who are statin intolerant and do not achieve their goal on ezetimibe, combination with bempedoic acid is recommended. I B
For patients who do not achieve their goal on a maximum tolerated dose of statin and ezetimibe, combination with a PCSK9 inhibitor is
I A
recommended.
Recommendations for sodium–glucose cotransporter 2 inhibitors and/or glucagon-like peptide-1 receptor agonists in patients with
chronic coronary syndrome
CCS patients with type 2 diabetes
SGLT2 inhibitors with proven CV benefit are recommended in patients with T2DM and CCS to reduce CV events, independent of baseline
I A
or target HbA1c and independent of concomitant glucose-lowering medication.
GLP-1 receptor agonists with proven CV benefit are recommended in patients with T2DM and CCS to reduce CV events, independent of
I A
baseline or target HbA1c and independent of concomitant glucose-lowering medication.
Recommendations for angiotensin-converting enzyme inhibitors in patients with chronic coronary syndrome
In CCS patients, ACE-Is (or ARBs) are recommended in the presence of specific comorbidities, such as hypertension, diabetes, or heart
I A
failure.
Recommendations for revascularization in patients with chronic coronary syndrome
It is recommended that patients scheduled for percutaneous or surgical revascularization receive complete information about the benefits,
I C
risks, therapeutic consequences, and alternatives to revascularization, as part of shared clinical decision-making.
For complex clinical cases, to define the optimal treatment strategy, in particular when CABG and PCI hold the same level of
recommendation, a Heart Team discussion is recommended, including representatives from interventional cardiology, cardiac surgery,
I C
non-interventional cardiology, and other specialties if indicated, aimed at selecting the most appropriate treatment to improve patient
outcomes and quality of life.
It is recommended to communicate the proposal of the Heart Team in a very balanced way and in a language that the patient can
I C
understand.
It is recommended that the decision for revascularization and its modality be patient-centred, considering patient preferences, health
I C
literacy, cultural circumstances, and social support.
It is recommended that the Heart Team (on site or with a partner institution) develop institutional protocols to implement the appropriate
I C
revascularization strategy in accordance with current guidelines.
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.
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.
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.
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.
Continued
ESC Guidelines 3503

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.

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Intracoronary pressure measurement (FFR or iFR) or computation (QFR) is recommended to guide lesion selection for intervention in
I A
patients with multivessel disease.
It is recommended that physicians select the most appropriate revascularization modality based on patient profile, coronary anatomy,
I C
procedural factors, LVEF, preferences, and outcome expectations.
Recommendations for mode of revascularization in patients with chronic coronary syndrome
Left main disease
In CCS patients at low surgical risk with significant left main coronary stenosis, CABG:
I A
• is recommended over medical therapy alone to improve survival
• is recommended as the overall preferred revascularization mode over PCI, given the lower risk of spontaneous myocardial infarction and
I A
repeat revascularization
In CCS patients with significant left main coronary stenosis of low complexity (SYNTAX score ≤22), in whom PCI can provide equivalent
completeness of revascularization to that of CABG, PCI is recommended as an alternative to CABG, given its lower invasiveness and I A
non-inferior survival.
Left main with multivessel disease
In CCS patients at low surgical risk with suitable anatomy, CABG is recommended over medical therapy alone to improve survival. I A
Multivessel disease and diabetes
In CCS patients with significant multivessel disease and diabetes, with insufficient response to guideline-directed medical therapy, CABG is
I A
recommended over medical therapy alone and over PCI to improve symptoms and outcomes.
Three-vessel disease, without diabetes
In CCS patients with significant three-vessel disease, preserved LVEF, no diabetes, and insufficient response to guideline-directed medical
I A
therapy, CABG is recommended over medical therapy alone to improve symptoms, survival, and other outcomes.
In CCS patients with preserved LVEF, no diabetes, insufficient response to guideline-directed medical therapy, and significant three-vessel
disease of low-to-intermediate anatomic complexity in whom PCI can provide similar completeness of revascularization to that of CABG, I A
PCI is recommended, given its lower invasiveness, and generally non-inferior survival.
Single- or double-vessel disease involving the proximal LAD
In CCS patients with significant single- or double-vessel disease involving the proximal LAD and insufficient response to guideline-directed
I A
medical therapy, CABG or PCI is recommended over medical therapy alone to improve symptoms and outcomes.
In CCS patients with complex significant single- or double-vessel disease involving the proximal LAD, less amenable to PCI, and insufficient
I B
response to guideline-directed medical therapy, CABG is recommended over PCI to improve symptoms and reduce revascularization rates.
Single- or double-vessel disease not involving the proximal LAD
In symptomatic CCS patients with single- or double-vessel disease not involving the proximal LAD and with insufficient response to
I B
guideline-directed medical therapy, PCI is recommended to improve symptoms.
Recommendations for management of chronic coronary syndrome patients with chronic heart failure
Managing CCS in heart failure patients
In HF patients with LVEF ≤35% in whom obstructive CAD is suspected, ICA is recommended with a view towards improving prognosis by
I B
CABG, taking into account the risk-to-benefit ratio of the procedures.
In HF patients with LVEF >35% and suspected CCS with low or moderate (>5%–50%) pre-test likelihood of obstructive CAD, CCTA or
I C
functional imaging is recommended.
In HF patients with LVEF >35% and suspected CCS with very high (>85%) pre-test likelihood of obstructive CAD, ICA (with FFR, iFR, or
I C
QFR when needed) is recommended.
Continued
3504 ESC Guidelines

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.
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.
An SGLT2 inhibitor (dapagliflozin or empagliflozin) is recommended in patients with HF with mildly reduced ejection fraction (HFmrEF) or
I A
HFpEF to reduce the risk of HF hospitalization or cardiovascular death.
An ARB is recommended in symptomatic patients with CCS and HFrEF unable to tolerate an ACE-I or ARNI to reduce the risk of HF
I B
hospitalization and cardiovascular death.
Sacubitril/valsartan is recommended as a replacement for an ACE-I or ARB in CCS patients with HFrEF to reduce the risk of HF
I B
hospitalization and death.

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Diuretics are recommended in CCS patients with HF and signs and/or symptoms of congestion to alleviate symptoms, improve exercise
I B
capacity, and reduce HF hospitalizations.
An ICD is recommended to reduce the risk of sudden death and all-cause mortality in patients with symptomatic HF (NYHA class II–III) of
ischaemic aetiology (unless they have had an MI in the prior 40 days), and an LVEF ≤35% despite ≥3 months of optimized GDMT, provided I A
they are expected to survive substantially longer than 1 year with good functional status.
An ICD is recommended to reduce the risk of sudden death and all-cause mortality in patients who have recovered from a ventricular
arrhythmia causing haemodynamic instability, and who are expected to survive for >1 year with good functional status, in the absence of I A
reversible causes or unless the ventricular arrhythmia has occurred <48 h after an MI.
CRT is recommended for CCS patients with symptomatic HF, sinus rhythm, LVEF ≤35% despite GDMT, and a QRS duration ≥150 ms with
I A
an LBBB QRS morphology to improve symptoms and survival and to reduce morbidity.
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.
Recommendations for diagnosis and management of patients with angina with non-obstructive coronary arteries/ischaemia with
non-obstructive coronary arteries
In persistently symptomatic patients despite medical treatment with suspected ANOCA/INOCA (i.e. anginal symptoms with normal
coronary arteries or non-obstructive lesions at non-invasive imaging, or intermediate stenoses with normal FFR/iFR at coronary
I B
arteriography) and poor quality of life, invasive coronary functional testing is recommended to identify potentially treatable endotypes and
to improve symptoms and quality of life, considering patient choices and preferences.
In individuals with suspected vasospastic angina, a resting 12-lead ECG recording during angina is recommended. I C
In patients with suspected vasospastic angina and repetitive episodes of rest angina associated with ST-segment changes that resolve with
nitrates and/or calcium antagonists, invasive functional angiography is recommended to confirm the diagnosis and to determine the severity I C
of underlying atherosclerotic disease.
For the treatment of isolated vasospastic angina:
I A
• calcium channel blockers are recommended to control symptoms and to prevent ischaemia and potentially fatal complications.
Recommendations for older, female, high bleeding risk, comorbid, and socially/geographically diverse patients
In older adults (≥75 years), particular attention to drug side effects, intolerance, drug–drug interactions, overdosing, and procedural
I C
complications is recommended.
In older, as in younger, individuals, diagnostic and revascularization decisions based on symptoms, extent of ischaemia, frailty, life expectancy,
I C
comorbidities, and patient preferences are recommended.
Similar guideline-directed cardiovascular preventive therapy is recommended in women and men. I C
Systemic post-menopausal hormone therapy is not recommended in women with CCS, given the lack of cardiovascular benefit and an
III A
increased risk of thrombo-embolic complications.
Bleeding risk assessment is recommended using the PRECISE-DAPT score, the qualitative ARC-HBR tool or other, validated method. I B
Attention to interaction between antiretroviral treatment and statins is recommended in patients with HIV. I B
Continued targeted efforts are recommended:
• to increase delivery of safe and effective cardiac care to all CCS patients, especially those of lower socioeconomic classes; and I C
• to enhance inclusion in future clinical trials of geographical, social, or other groups that are currently underrepresented.
Recommendations for screening for coronary artery disease in asymptomatic individuals
Opportunistic screening of healthy individuals for cardiovascular risk factors and to estimate the risk of future cardiovascular events using
I C
scoring systems, e.g. SCORE2 and SCORE-OP, is recommended to detect individuals at high risk and guide treatment decisions.
Continued
ESC Guidelines 3505

Recommendations for adherence to medical therapy and lifestyle changes


Mobile health interventions (e.g. using text messages, apps, wearable devices) are recommended to improve patient adherence to healthy
I A
lifestyles and medical therapy.
Behavioural interventions are recommended to improve adherence. I B
Simplifying medication regimens (e.g. using fixed-dose drug combinations) is recommended to increase patient adherence to medications. I B
Multiprofessional and family involvement is recommended to promote adherence, in addition to patient education and involvement. I C
Recommendations for diagnosis of disease progression in patients with established chronic coronary syndrome
Regardless of symptoms, periodic visits (e.g. annual) to a general practitioner or cardiovascular healthcare professional are recommended to
evaluate cardiovascular risk factor control and to assess changes in risk status, disease status, and comorbidities that may require lifestyle, I C
medical, or procedural interventions.
Reassessment of CAD status is recommended in patients with deteriorating LV systolic function that cannot be attributed to a reversible

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I C
cause (e.g. longstanding tachycardia or myocarditis).
Risk stratification is recommended in patients with new or worsening symptoms, preferably using stress imaging. I C
In patients with symptoms refractory to medical treatment or at high risk of adverse events, invasive coronary angiography (with FFR/iFR
I C
when necessary) is recommended for risk stratification and for possible revascularization aimed at improving symptoms and prognosis.
Recommendations for treatment of revascularization failure
DES is recommended over drug-coated balloons for treatment of in-DES restenosis. I A
LIMA is indicated as the conduit of choice for redo CABG in patients in whom the LIMA was not used previously. I B
Recommendations for recurrent or refractory angina/ischaemia

© 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.

10. Evidence tables de Investigaciones Cardiovasculares (CNIC), Madrid, Spain;


Marianna Adamo, Department of Medical and Surgical Specialties,
Evidence tables are available at European Heart Journal online. Radiological Sciences and Public Health, Institute of Cardiology, ASST
Spedali Civili di Brescia and University of Brescia, Brescia, Italy;
James Ainslie, ESC Patient Forum, Sophia Antipolis, France;
11. Data availability statement Adrian Paul Banning, Oxford Heart Centre, Oxford University
Hospitals, Oxford, United Kingdom; Andrzej Budaj, Department
No new data were generated or analysed in support of this research.
of Cardiology, Centre of Postgraduate Medical Education, Warsaw,
Poland; Ronny R. Buechel, Department of Nuclear Medicine,
Cardiac Imaging, University and University Hospital Zurich, Zurich,
12. Author information Switzerland; Giovanni Alfonso Chiariello, Department of
Author/task force Member Affiliations: Konstantinos Cardiovascular Sciences, Fondazione Policlinico Universitario
C. Koskinas, Department of Cardiology, Bern University Hospital— Agostino Gemelli IRCCS, Rome, Italy, and Università Cattolica del
INSELSPITAL, University of Bern, Bern, Switzerland; Xavier Sacro Cuore, Rome, Italy; Alaide Chieffo, Vita Salute San Raffaele
Rossello, Cardiology Department Hospital Universitari Son Espases, University, Milan, Italy, and Interventional Cardiology Unit, IRCCS San
Palma de Mallorca, Spain, Health Research Institute of the Balearic Raffaele Scientific Institute, Milan, Italy; Ruxandra Maria
Islands (IdISBa), Universitat de les Illes Balears (UIB), Palma de Christodorescu, Department V Internal Medicine, University of
Mallorca, Spain, and Clinical Research Department, Centro Nacional Medicine and Pharmacy V Babes, Timisoara, Romania, and Research
3506 ESC Guidelines

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

Downloaded from https://academic.oup.com/eurheartj/article/45/36/3415/7743115 by guest on 24 December 2024


University, Munich, Germany; Milan Milojevic, Department of always, highly valued.
Cardiac Surgery and Cardiovascular Research, Dedinje ESC National Cardiac Societies actively involved in the review
Cardiovascular Institute, Belgrade, Serbia; Jan J. Piek, Heart Center, process of the 2024 ESC Guidelines on the management of chronic
Department of Clinical and Experimental Cardiology, Amsterdam coronary syndromes:
Cardiovascular Sciences, Amsterdam UMC, University of Albania: Albanian Society of Cardiology, Naltin Shuka; Algeria:
Amsterdam, Amsterdam, Netherlands; Francesca Pugliese, Algerian Society of Cardiology, Mohamed Abed Bouraghda;
Centre for Advanced Cardiovascular Imaging, The William Harvey Armenia: Armenian Cardiologists Association, Hamlet
Research Institute, Queen Mary University of London, London, G. Hayrapetyan; Austria: Austrian Society of Cardiology, Sebastian
United Kingdom, Barts Health NHS Trust, London, United Kingdom, J. Reinstadler; Azerbaijan: Azerbaijan Society of Cardiology, Ogtay
and Heart Vascular and Thoracic Institute, Cleveland Clinic London, Musayev; Belgium: Belgian Society of Cardiology, Michel De Pauw;
London, United Kingdom; Andrea Rubboli, Department of Bosnia and Herzegovina: Association of Cardiologists of Bosnia
Emergency, Internal Medicine, and Cardiology, Division of Cardiology, and Herzegovina, Zumreta Kušljugić; Bulgaria: Bulgarian Society of
S. Maria delle Croci Hospital, Ravenna, Italy; Anne Grete Semb, Cardiology, Valeri Gelev; Croatia: Croatian Cardiac Society, Bosko
Preventive cardio-rheuma clinic, Diakonhjemmet Hospital, Oslo, Skoric; Cyprus: Cyprus Society of Cardiology, Maria Karakyriou;
Norway, and REMEDY Centre Diakonhjemmet Hospital, Oslo, Czechia: Czech Society of Cardiology, Tomas Kovarnik; Denmark:
Norway; Roxy Senior, Cardiology Royal Brompton Hospital and Danish Society of Cardiology, Lene H. Nielsen; Egypt: Egyptian
Imperial College London, London, United Kingdom, and Cardiology, Society of Cardiology, Islam Sh. Abdel-Aziz; Estonia: Estonian
Northwick Park Hospital, Harrow, United Kingdom; Jurrien M. ten Society of Cardiology, Tiia Ainla; Finland: Finnish Cardiac Society,
Berg, Cardiology, St Antonius Hospital, Nieuwegein, Netherlands, Pekka Porela; France: French Society of Cardiology, Hakim
and Cardiology, Maastricht University Medical Centre, Maastricht, Benamer; Georgia: Georgian Society of Cardiology, Kakha Nadaraia;
Netherlands; Eric van Belle, Cardiology, Institut Cour Poumon— Germany: German Cardiac Society, Gert Richardt; Greece:
CHU de Lille, Lille, France, and Equipe 2, INSERM U 1011, Lille, Hellenic Society of Cardiology, Michail I. Papafaklis; Hungary:
France; Emeline M. Van Craenenbroeck, Cardiology department, Hungarian Society of Cardiology, Dávid Becker; Iceland: Icelandic
Antwerp University Hospital, Edegem, Belgium, and GENCOR, Society of Cardiology, Ingibjörg J. Gudmundsdóttir; Israel: Israel
University of Antwerp, Antwerp, Belgium; Rafael Vidal-Perez, Heart Society, Arik Wolak; Italy: Italian Federation of Cardiology,
Cardiology, Cardiac Imaging Unit, Complexo Hospitalario Carmine Riccio; Kazakhstan: Association of Cardiologists of
Universitario de A Coruña (CHUAC), A Coruña, Spain, and Centro Kazakhstan, Bekbolat Kulzhanovich Zholdin; Kosovo (Republic
de Investigación Biomédica en Red de Enfermedades of): Kosovo Society of Cardiology, Shpend Elezi; Kyrgyzstan:
Cardiovasculares (CIBERCV), Madrid, Spain; and Simon Winther, Kyrgyz Society of Cardiology, Saamay Abilova; Latvia: Latvian
Department of cardiology, Gødstrup hospital, Herning, Denmark, Society of Cardiology, Iveta Mintale; Lebanon: Lebanese Society of
and Institute of clinical medicine, Aarhus university, Aarhus, Denmark. Cardiology, Bachir Allam; Lithuania: Lithuanian Society of
Cardiology, Jolita Badarienė; Luxembourg: Luxembourg Society
of Cardiology, Bruno Pereira; Malta: Maltese Cardiac Society, Philip
Dingli; Moldova (Republic of): Moldavian Society of Cardiology,
13. Appendix Valeriu Revenco; Montenegro: Montenegro Society of Cardiology,
ESC Scientific Document Group Nebojsa Bulatovic; Morocco: Moroccan Society of Cardiology, El
Includes Document Reviewers and ESC National Cardiac Societies. Ghali Mohamed Benouna; Netherlands: Netherlands Society of
Document Reviewers: Michael Borger (CPG Review Cardiology, Admir Dedic; North Macedonia: National Society of
Co-ordinator) (Germany); Ingibjörg J. Gudmundsdóttir (CPG Review Cardiology of North Macedonia, Irena Mitevska; Norway:
Co-ordinator) (Iceland); Juhani Knuuti (CPG Review Co-ordinator) Norwegian Society of Cardiology, Kristin Angel; Poland: Polish
(Finland); Ingo Ahrens (Germany); Michael Böhm (Germany); Davide Cardiac Society, Krzysztof Bryniarski; Portugal: Portuguese Society
Capodanno (Italy); Evald Høj Christiansen (Denmark); Jean-Philippe of Cardiology, André Miguel Coimbra Luz; Romania: Romanian
Collet¶ (France); Kenneth Dickstein (Norway); Christian Eek Society of Cardiology, Bogdan Alexandru Popescu; San Marino: San
(Norway); Volkmar Falk (Germany); Peter A. Henriksen (United Marino Society of Cardiology, Luca Bertelli; Serbia: Cardiology
Kingdom); Borja Ibanez (Spain); Stefan James (Sweden); Sasko Kedev Society of Serbia, Branko Dušan Beleslin; Slovakia: Slovak Society of
(Macedonia); Lars Køber (Denmark); Martha Kyriakou (Cyprus); Cardiology, Martin Hudec; Slovenia: Slovenian Society of
Emma F. Magavern (United Kingdom); Angelia McInerny (Ireland); Cardiology, Zlatko Fras; Spain: Spanish Society of Cardiology,
Caius Ovidiu Mersha (Romania); Borislava Mihaylova (United Román Freixa-Pamias; Sweden: Swedish Society of Cardiology,
ESC Guidelines 3507

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